50 Big Debates in Gynecologic Oncology (2023) - Dennis S. Chi

50 Big Debates
in Gynecologic Oncology
Published online by Cambridge University Press

50 Big Debates
in Gynecologic
Oncology
Edited by
Dennis S. Chi
Memorial Sloan-Kettering Cancer Center, New York, NY
Nisha Lakhi
Richmond University Medical Center, Staten Island, NY
Nicoletta Colombo
University of Milan-Bicocca

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Contents
List of Contributors xiii
Section I: Perioperative Oophorectomy for Ovarian Cancer

Risk Reduction? No 13
Management Steven A. Narod
1A. Should Routine Mechanical Bowel 4A. Can High-risk HPV Testing be Used
Preparation be Performed before Alone as the Primary Screening
Primary Debulking Surgery? Yes 1 Modality for Cervical Cancer?
Lea A. Moukarzel and Oliver Yes 16
Zivanovic Thomas C. Wright
1B. Should Routine Mechanical Bowel 4B. Can High-risk HPV Testing be Used
Preparation be Performed before Alone as the Primary Screening
Primary Debulking Surgery? No 4 Modality for Cervical Cancer?
Shannon D. Armbruster and Fidel No 20
A. Valea Ibraheem O. Awowole and Olusegun
2A. Should Preoperative Carbohydrate O. Badejoko
Loading be Routine prior
to Debulking Surgery? Yes 6 Section III: Ovarian Cancer
Arwa Mohammad, Deepa Maheswari
Narasimhulu, and Sean C. Dowdy 5A. Should CA-125 Surveillance be
Performed after Completion of
2B. Should Preoperative Carbohydrate Primary Treatment for Ovarian
Loading be Routine prior Cancer Patients in Remission?
to Debulking Surgery? No 9 Yes 23
Kathryn Miller, Dib Sassine, and Eseohi Ehimiaghe and Edward
Yukio Sonoda Tanner
5B. Should CA-125 Surveillance be
Section II: Screening, Performed after Completion of
Prevention, and Early Diagnosis Primary Treatment for Ovarian
Cancer Patients in Remission?
3A. Should Women with BRCA No 26
Mutations be Offered Bilateral Gordon J. S. Rustin
Salpingectomy with Delayed
Oophorectomy for Ovarian Cancer 6A. In Patients with BRCA-negative
Risk Reduction? Yes 11 and HRD-negative Epithelial
Thomas Boerner and Kara Long Roche Ovarian Cancer, Should Molecular
Profiling be Routinely Done to
3B. Should Women with BRCA Guide Adjuvant Therapy?
Mutations be Offered Bilateral Yes 29
Salpingectomy with Delayed Ilaria Betella and Matteo Repetto
v

vi Contents
6B. In Patients with BRCA-negative 10A. Patients with Advanced Ovarian

and HRD-negative Epithelial Cancer who are 75 Years Old
Ovarian Cancer, Should and Above Should Routinely
Molecular Profiling be Routinely be Treated with Neoadjuvant
Done to Guide Adjuvant Chemotherapy? Yes 52
Therapy? No 32 Michelle Davis and Ursula Matulonis
Raanan Alter and Ernst Lengyel
10B. Patients with Advanced Ovarian
7A. Is MEK Inhibitor Therapy the Best Cancer who are 75 Years Old and
Treatment Recommendation for Above Should Routinely be
Low-Grade Serous Ovarian Cancer Treated with Neoadjuvant
Patients at First Relapse? Yes 35 Chemotherapy? No 55
Rachel N. Grisham Olga T. Filippova and William P. Tew
7B. Is MEK Inhibitor Therapy the Best 11A. Should an Attempt at Aggressive
Treatment Recommendation for Cytoreduction be Made for all
Low-Grade Serous Ovarian Cancer Surgical Candidates with Advanced
Patients at First Relapse? No 38 Ovarian Cancer prior to Treatment
David M. Gershenson with Adjuvant Chemotherapy?
Yes 58
8A. Should Stage IC Mucinous Ovarian
Sven Mahner, Anca Chelariu-Raicu,
Carcinoma be Managed by
and Fabian Trillsch
Observation or Adjuvant
Chemotherapy? Observation 41 11B. Should an Attempt at Aggressive
Jason D. Wright Cytoreduction be Made for all
Surgical Candidates with Advanced
8B. Should Stage IC Mucinous Ovarian Ovarian Cancer prior to Treatment
Carcinoma be Managed by with Adjuvant Chemotherapy?
Observation or Adjuvant No 61
Chemotherapy? Adjuvant
Sean Kehoe and Jason Yap
Chemotherapy 44
Yien Ning Sophia Wong and 12A. Should Minimally Invasive
Jonathan A. Ledermann Modalities be Routinely/Uniformly
Utilized for Assessment
9A. How Many Cycles of Adjuvant of Resectability prior to Attempted
Chemotherapy Should Primary Debulking in Patients with
be Administered to Patients Advanced Ovarian Cancer? Yes 64
with High-risk Stage I Epithelial
Juliet E. Wolford and Robert
Ovarian Cancer? Three Cycles 47
E. Bristow
Annalisa Garbi, Eleonora Zaccarelli,
and Federica Tomao 12B. Should Laparoscopic Modalities be
Routinely Utilized for Assessment
9B. How Many Cycles of Adjuvant of Resectability prior to Attempted
Chemotherapy Should Primary Debulking in Patients with
be Administered to Patients Advanced Ovarian Cancer? No 67
with High-risk Stage I
Beverly Long and William A. Cliby
Epithelial Ovarian Cancer? Six
Cycles 49 13A. Should Enlarged
John K. Chan and Daniel S. Kapp Supradiaphragmatic Lymph Nodes

Contents vii
be Routinely Removed during 16B. What is the Best Front-line

Debulking Surgery Procedures Maintenance Therapy for
for Patients with Advanced HRD-positive Ovarian Cancer?
Ovarian Cancer? Yes 70 Bevacizumab plus PARP
Annalisa Garbi and Vanna inhibitor 91
Zanagnolo Hélène Vanacker, Olivia Le Saux,
and Isabelle Ray-Coquard
13B. Should Enlarged
Supradiaphragmatic Lymph Nodes 17A. When is the Best Time to Use PARP
be Routinely Removed during Inhibitors for Maintenance?
Debulking Surgery Procedures Front-line 95
for Patients with Advanced Duaa H. Al-Rawi, Karen Cadoo,
Ovarian Cancer? No 73 and Roisin O’Cearbhaill
Javier F. Magrina, Kristina Butler,
17B. When is the Best Time to Use PARP
and Paul Magtibay
Inhibitors for Maintenance? First
14A. Is there a Role for Hyperthermic Recurrence 98
Intraperitoneal Chemotherapy in Alvin Jun Xing Lee and
Front-line Therapy for Ovarian Jonathan A. Ledermann
Cancer? Yes 76
S. Lot Aronson, Gabe S. Sonke, 18A. What is the best front-line
and Willemien J. van Driel maintenance therapy for optimally
debulked HRD-negative advanced
14B. Is there a Role for Hyperthermic epithelial ovarian cancer?
Intraperitoneal Chemotherapy Bevacizumab 101
in Front-line Therapy for Ovarian Krishnansu S. Tewari
Cancer? No 79
Richard Schwameis, Luis M. Chiva, 18B. What is the best front-line
and Philipp Harter maintenance therapy for
optimally debulked
15A. Is there a Role for Intraperitoneal
HRD-negative advanced
Chemotherapy after Optimal
epithelial ovarian cancer? PARP
Cytoreduction of Ovarian Cancer?
inhibitor 104
Yes 82
Francisco Grau, Lorena Fariñas-
Molly Morton, Tiffany Y. Sia, Laura
Madrid, and Ana Oaknin
M. Chambers, Roberto Vargas,
and Robert Debernardo 19A. What is the Optimal Therapeutic
15B. Is there a Role for Intraperitoneal Option for Platinum-resistant
Chemotherapy after Optimal Recurrent Ovarian Cancer?
Cytoreduction of Ovarian Cancer? Single-agent Chemotherapy 106
No 85 David F. Cantú de León, Daniel Flores
Angeles Alvarez Secord and Laura Alatriste, and Milagros Pérez
J. Havrilesky Quintanilla
16A. What is the Best Front-line 19B. What is the Optimal Therapeutic
Maintenance Therapy Option for Platinum-resistant
for HRD-positive Ovarian Cancer? Recurrent Ovarian Cancer?
Single-agent PARP Inhibitor 88 Other 109
Antonio González-Martín Olivia Lara and Bhavana Pothuri

viii Contents
20A. Should Patients 24A. What is the Optimal

with Platinum-sensitive Recurrent Chemotherapy Regimen
Ovarian Cancer Undergo for Ovarian Germ-cell Tumors?
Secondary Cytoreduction prior Bleomycin, Etoposide and
to Receiving Platinum-containing Cisplatinum (BEP) 139
Second-line Chemotherapy? Michael J. Seckl
Yes 113
24B. What is the Optimal Chemotherapy
Sarah Ehmann, Andreas du Bois,
Regimen for Ovarian Germ-cell
and Mareike Bommert
Tumors? Other 142
20B. Should All Patients with Michael L. Friedlander
Platinum-sensitive Recurrent
Ovarian Cancer be Considered 25A. What is the Optimal Adjuvant
for Secondary Cytoreduction prior Chemotherapy Regimen for
to Receiving Second-line Platinum Primary Granulosa Cell Tumor?
Chemotherapy? No 116 Bleomycin, Etoposide, and
Cisplatinum (BEP) 145
Anca Chelariu-Raicu and Robert
L. Coleman Olivia Le Saux, Hélène Vanacker,
and Isabelle Ray-Coquard
21A. Should Tertiary Debulking
for Patients with Recurrent Ovarian 25B. What is the Optimal Adjuvant
Cancer be Performed? Yes 120 Chemotherapy Regimen
for Primary Granulosa Cell Tumor?
Karin K. Shih
Carboplatin/Paclitaxel 149
21B. Should Tertiary Debulking be Dib Sassine and Chrissy Liu
Performed for Patients with
Recurrent Ovarian Cancer? 26A. What is the Best Management
No 123 Strategy for a Recurrent Granulosa
Cell Tumor? Surgery 152
Antonio González-Martín
Alice Bergamini, Luca Bocciolone,
22A. Is there a Role for Immunotherapy and Gioriga Mangili
in Ovarian Cancer? Yes 126
26B. What is the Best Management
Claire F. Friedman
Strategy for Recurrent Granulosa
22B. Is there a Role for Immunotherapy Cell Tumor? Chemotherapy 155
in Ovarian Cancer? Not Yet 130 Amanika Kumar and Simrit Warring
Tiffany Y. Sia and Dmitriy Zamarin
27A. Is progression-free survival a
23A. What is the Best Management rational surrogate endpoint in
Option for Malignant Bowel front-line ovarian cancer clinical
Obstruction? Surgery 133 trials? Yes 158
Joanie M. Hope and Jill S. Whyte Daniel Margul and Thomas J. Herzog
23B. What is the Best Management 27B. Is progression-free survival a
Option for Malignant Bowel rational surrogate endpoint in
Obstruction? Percutaneous front-line ovarian cancer clinical
Endoscopic Gastrostomy 136 trials? No 161
Claire V. Hoppenot and S. Diane Eric Pujade-Lauraine, Benoit You,
Yamada and Jean Sebastien Frenel

Contents ix
Section IV: Endometrial Cancer Chemotherapy and Radiation

Therapy 189
28A. Fertility-sparing Surgery in Stephanie M. de Boer and Catheryn
Early-stage Endometrial Cancer is M. Yashar
Safe and Does not Compromise
Oncological Outcome: Yes 165 32A. How Should Stage IA Serous
Enes Taylan and Kutluk Oktay Papillary Endometrial Cancer
Confined to a Polyp or
28B. Fertility-sparing Treatment for the Endometrial Lining be
Early-stage Endometrial Cancer is Managed? Observation 192
Safe and Does Not Compromise Ryan M. Kahn and Ginger J. Gardner
Oncological Outcome: No 168
Jessica E. Parker and David S. Miller 32B. How Should Stage IA Serous
Papillary Endometrial Cancer
29A. Sentinel Lymph Node Mapping Confined to a Polyp or the
Should be the Standard for Endometrial Lining be Managed?
Staging Patients with High-grade Adjuvant Chemotherapy 195
Endometrial Cancers: Yes 171 Alessia Aloisi, Federica Tomao, and
Patricia Rivera, Andrea Mariani, Eleonora Zaccarelli
and Brooke A. Schlappe
33A. What is the Optimal Sequence
29B. Sentinel Lymph Node Mapping of Therapy for Patients with Stage
Should be the Standard IIIC Endometrial Carcinoma
for Staging Patients with High-grade Treated with Multimodal Therapy?
Endometrial Cancers: No 174 Sandwich Therapy 198
Camilla Yu, Payam Katebi Kashi, Lauren Thomaier Bollinger and
and Amanda N. Fader Melissa A. Geller
30A. Molecular Profiling Should be 33B. What is the Optimal Sequence
Done to Guide the Management of Therapy for Patients with Stage
of Endometrial Cancer? Yes 179 IIIC Endometrial Carcinoma
Karen Cadoo Treated with Multimodal Therapy?
Sequential 202
30B. Molecular Profiling Should be
Nasuh Utku Dogan and Selen Dogan
Done to Guide the Management
of Endometrial Cancer? No 182 34A. Should an Attempt at Debulking
Michael Wilkinson, Paul Downey, Grossly Metastatic Endometrial
and Donal J. Brennan Cancer be Undertaken?
Yes 205
31A. What is the Best Adjuvant Therapy
Brooke M. Lamparello and Joyce
for Management of Stage III
N. Barlin
Endometrial Cancer?
Chemotherapy Alone 186 34B. Should an Attempt at Debulking
Daniela Matei Grossly Metastatic Endometrial
Cancer be Undertaken? No 208
31B. What is the Best Adjuvant Therapy
Frederick M. Howard and Gini
for Management of Stage III
F. Fleming
Endometrial Cancer? Combined

x Contents
35A. Should Secondary Cytoreduction Uterine Leiomyomas?

be Performed for Recurrent Oophorectomy 234
Endometrial Cancer? Anastasios Tranoulis, Kavita Singh,
Sometimes 210 and Janos Balega
Lea A. Moukarzel, Kevin Espino,
39B. What is the Best Management
and Chris Awtrey
for Premenopausal Women with
35B. Should Secondary Cytoreduction Early-stage Uterine
be Performed for Recurrent Leiomyosarcoma Status Post
Endometrial Cancer? Never 213 Hysterectomy for Presumed
Marcela G. del Carmen Uterine Leiomyomas? Ovarian
Preservation 237
36A. Is Hormonal Therapy the Best
Melissa K. Frey and Ryan M. Kahn
Therapy for Chemo-resistant
Endometrial Cancer? Yes 216 40A. Should Primary Debulking Surgery
Roni Nitecki and Pamela T. Soliman be Performed for Metastatic
Leiomyosarcoma? Yes 240
36B. Is Hormonal Therapy the Best
Sumer K. Wallace and Jamie
Therapy for Chemo-resistant
N. Bakkum-Gamez
Endometrial Cancer? No 219
Julianne Lima and Susana Banerjee 40B. Should Primary Debulking Surgery
be Performed for Metastatic
37A. Is there a Role for Using Leiomyosarcoma? No 243
Immunotherapy in Endometrial
Beatrice Seddon
Cancer? Yes 223
Ana Oaknin, Lorena Farinas-Madrid, 41A. Should Secondary Cytoreductive
and J. Francisco Grau Surgery be Offered to all Patients
that are Surgical Candidates
37B. Is there a Role for Using with Optimally Resectable
Immunotherapy in Endometrial Recurrent Uterine
Cancer? No 226 Leiomyosarcoma? Yes 245
William A. Zammarrelli III and Vicky Giovanni Aletti
Makker
41B. Should Secondary Cytoreductive
38A. What is the Best Chemotherapy Surgery be Offered to all Patients
Regimen for Uterine that are Surgical Candidates
Carcinosarcoma? Carboplatin/ with Optimally Resectable
Paclitaxel 229 Recurrent Uterine
Domenica Lorusso Leiomyosarcoma? No 250
38B. What is the Best Chemotherapy Félix Blanc-Durand, Amandine
Regimen for Uterine Maulard, and Patricia Pautier
Carcinosarcoma? The Case
for “Other” Regimens 232 Section V: Cervical Cancer
Sara Bouberhan, Whitfield
B. Growdon, and Richard T. Penson 42A. Is there a Role for Minimally
Invasive Radical Hysterectomy for
39A. What is the Best Management Management of Cervical Cancer?
for Premenopausal Women Yes 253
with Early-stage Uterine Vanna Zanagnolo, Francesco
Leiomyosarcoma Status Post Multinu, and Stefano Bogliolo
Hysterectomy for Presumed

Contents xi
42B. Is there a Role for Minimally 46A. What is the Best Initial Treatment
Invasive Radical Hysterectomy for Stage IB3 to IIB Cervical
for Management of Cervical Cancer? Neoadjuvant
Cancer? No 256 Chemotherapy Followed
Pedro T. Ramirez by Radical Hysterectomy 278
Jolien Haesen, Rawand Salihi, and
43A. Is Radical Surgery or
Ignace B. Vergote
Parametrectomy Needed
for Early-stage FIGO IA2 and 46B. What is the Best Initial Treatment
Microscopic IB1 Cervical Cancer? for Stage IB3 to IIB Cervical
Yes 259 Cancer? Primary
Joo-Hyun Nam and Jeong-Yeol Park Chemoradiation 280
Sudeep Gupta, Amita Maheshwari,
43B. Is Radical Surgery
and Supriya Chopra
or Parametrectomy Needed
for Early-stage FIGO IA2 47A. Is there a Role for Immunotherapy
and Microscopic IB1 Cervical in Treatment of Cervical Cancer?
Cancer? No 262 Yes 285
Zibi Marchocki and Allan Covens Chrisann Kyi and Dmitriy Zamarin
44A. What is the Best Management 47B. Is there a Role for Immunotherapy
Option for Young Women with in Treatment of Cervical Cancer?
Stage IB2 Cervical Cancer Who No 288
Wish to Preserve Fertility? Fernando Cotait Maluf, Daniele
Abdominal Radical Xavier Assad, and Angelica Nogueira-
Trachelectomy 265 Rodrigues
Michael Frumovitz
44B. What is the Best Management Section VI: Vaginal and Vulvar
Option for Young Women with
Stage IB2 Cervical Cancer Who Wish
Cancer
to Preserve Fertility? Neo-adjuvant 48A. Should the Subsequent
Chemotherapy Followed by Management of Patients with
Fertility-sparing Surgery 268 Vulvar Cancer and a Positive
Marie Plante Sentinel Lymph Node be Complete
Groin Lymph Node Dissection
45A. Should Adjuvant Hysterectomy or Radiation Therapy?
be Performed for Patients with Dissection 291
Locally Advanced Cervical Cancer
Lilian T. Gien
Treated with Concurrent
Chemoradiotherapy? Yes 272 48B. Should the Subsequent
Dib Sassine, Alexandra Diggs, and Management of Patients
Yukio Sonoda with Vulvar Cancer and a
Positive Sentinel Lymph Node be
45B. Should Adjuvant Hysterectomy Complete Groin Lymph Node
be Performed for Patients with Dissection or Radiation Therapy?
Locally Advanced Cervical Cancer Radiation Therapy 294
Ryan M. Kahn and Wui-Jin Koh
Chemoradiotherapy? No 275
Philippe Morice, Sebastien Gouy, and 49A. What is the Best Treatment for Stage
Cyrus Chargari I Vulvar Squamous Cell Carcinoma

xii Contents
with either a Close or Positive with Single Node Positive Vulvar

Surgical Margin? Re-excision 297 Cancer? No 304
Sabrina M. Bedell and Britt Aaron M. Praiss and Kaled
K. Erickson M. Alektiar
49B. What is the Best Treatment 51A. Is Pelvic Exenteration an Option
for Stage I Vulvar Squamous Cell for a Pelvic Recurrence of a Vulvar/
Carcinoma with either Vaginal Melanoma after Previous
a Close or Positive Surgical Radiation Therapy? Yes 307
Margin? Adjuvant John P. Geisler and Kelly J. Manahan
Radiation 300
51B. Is Pelvic Exenteration an Option
Rachel C. Sisodia
for a Pelvic Recurrence of a Vulvar/
50A. Should Adjuvant Radiation Vaginal Melanoma after Previous
be Given to Women with Single Radiation Therapy? No 310
Node Positive Vulvar Cancer? Mario M. Leitao, Jr.
Yes 302
Rachel C. Sisodia
50B. Should Adjuvant Radiation
Therapy be Given to Patients Index 313

Contributors
Giovanni Damiano Aletti Jamie N. Bakkum-Gamez

Division of Gynecologic Oncology, IEO, Division of Gynecologic Oncology Surgery,
European Institute of Oncology IRCCS, Mayo Clinic, Rochester, MN, USA
Milan, Italy – Department of Oncology and
Hemato-Oncology, University of Milan, Janos Balega
Milan, Italy Pan-Birmingham Gynaecological Cancer
Centre, Birmingham, UK
Alessia Aloisi
Division of Gynecologic Oncology, IEO, Susana Banerjee
European Institute of Oncology IRCCS, The Royal Marsden NHS Foundation Trust
Milan, Italy and Institute of Cancer Research,
London, UK
Duaa H. Al-Rawi
Department of Medicine, MemorialSloan Joyce N. Barlin
Kettering Cancer Center, New York, Women’s Cancer Care Associates, Albany,
NY, USA NY and Albany Medical Center, Albany,
NY, USA
Shannon D. Armbruster
Division of Gynecologic Oncology, Sabrina Marie Bedell
Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology,
Virginia Tech Carilion School of Medicine, Cleveland Clinic, Cleveland, OH, USA
VA, USA
Alice Bergamini
S. Lot Aronson Department of Obstetrics and Gynecology,
Department of Gynecologic Oncology., IRCCS San Raffaele and Vita-Salute San
Netherlands Cancer Institute, Amsterdam Raffaele University, Milan, Italy
Daniele Xavier Assad Ilaria Betella

Hospital Sírio-Libanês, Brasília-DF, Brazil Division of Gynecologic Oncology, IEO,
European Institute of Oncology IRCCS,
Ibraheem O. Awowole Milan, Italy
Department of Obstetrics, Gynaecology
and Perinatology, Obafemi Awolowo Félix Blanc-Durand
University, Osun State, Nigeria. Medical Department, Gustave-Roussy
Cancer Center, Villejuif, France
Chris Awtrey
Intermountain Health Peaks Region Luca Bocciolone
Medical Group, Denver, CO, USA Department of Obstetrics and Gynecology,
IRCCS San Raffaele and Vita-Salute San
Olusegun O. Badejoko Raffaele University, Milan, Italy
Department of Obstetrics, Gynaecology
and Perinatology, Obafemi Awolowo Thomas Boerner
University, Osun State, Nigeria Gynecology Service, Department of
xiii

xiv List of Contributors
Surgery, Memorial Sloan Kettering Cancer Laura M. Chambers

Center, New York, NY, USA Division of Gynecologic Oncology;
Obstetrics, Gynecology and Women’s
Stefano Bogliolo Health Institute, Cleveland Clinic,
Department of Gynecology Oncology, Cleveland, OH, USA
European Institute of Oncology-Milan, Italy
John K. Chan
Stephanie M. de Boer Director of Gynecologic Oncology,
Department of Radiation Oncology, Leiden California Pacific; Palo Alto Medical
University Medical Center, Leiden, Foundation; and Sutter Research Institute,
Netherlands San Francisco, CA, USA
Mareike Bommert Cyrus Chargari
Department of Gynecology and Gynecologic Unit INSERM 10–30, and Department of
Oncology; Evangelische Kliniken Radiation Therapy, Gustave Roussy Cancer
Essen-Mitte, Evangelische Huyssens-Stiftung Campus, Villejuif, France
Essen-Huttrop, Germany
Anca Chelariu-Raicu
Sara Bouberhan Department of Obstetrics and Gynecology,
Department of Hematology/Medical University Hospital, LMU Munich,
Oncology, Massachusetts General Hospital, Germany
Boston, MA, USA
Dennis Chi
Donal J. Brennan Gynecology Service, Department of
UCD Gynaecological Oncology Group, UCD Surgery, Memorial Sloan Kettering Cancer
School of Medicine, Catherine McAuley Center, New York, NY, USA and Weill
Research Centre, Mater Misericordiae Cornell Medical College, New York,
University Hospital, Dublin, NY, USA
Ireland
Luis Chiva
Robert E Bristow Director of Department of Obstetrics
Department of Obstetrics & and Gynecology, Clinica Universidad de
Gynecology, University of California, Navarra. Spain
Irvine, CA, USA
Supriya Chopra
Kristina Butler Advanced Centre for Treatment, Research
Department of Medical and Surgical and Education in Cancer, Tata Memorial
Gynecology, Mayo Clinic, Phoenix, Centre and Homi Bhabha National
Arizona, USA Institute, Mumbai, India
Karen Cadoo William A. Cliby
St James’s Hospital, Trinity College Dublin, Professor Obstetrics and Gynecology,
Trinity St. James’s Cancer Institute Dublin, Virgil S. Counseller M.D. Professor of
Ireland Surgery, Mayo Clinic, Rochester,
MN, USA
David F. Cantú de León
Ginecología Oncológica, Dirección de Robert L. Coleman
Investigación, Instituto Nacional de Sarah Cannon Research Institute (SCRI),
Cancerología, Mexico Nashville, TN, USA

List of Contributors xv
Nicoletta Colombo Paul Downey

IRCCS European Institute of Oncology Department of Pathology, National
(IEO), University of Milan-Bicocca, 20126 Maternity Hospital, Dublin
Milan, Italy.
Willemien J. van Driel
Fernando Cotait Maluf Department of Gynecologic Oncology.,
Hospital Israelita Albert Einstein, São Netherlands Cancer Institute, Amsterdam
Paulo, Brazil and Beneficência Portuguesa
de São Paulo, Brazil Andreas du Bois
Department of Gynecology and Gynecologic
Allan Covens Oncology, Evangelische Kliniken
Division of Gynecologic Oncology, Odette Essen-Mitte, Evangelische Huyssens-
Cancer Centre, Sunnybrook, Health Stiftung Essen-Huttrop, Germany
Sciences Centre, Toronto, Ontario,
Canada Eseohi Ehimiaghe
Northwestern University, Evanston, IL,
Michelle Davis USA
Dana Farber Cancer Institute and Brigham
and Women’s Hospital, Division of Sarah Ehmann
Gynecologic Oncology, Boston, MA, Department of Gynecology and
USA Gynecologic Oncology; Evangelische
Kliniken Essen-Mitte, Evangelische
Robert Debernardo Huyssens-Stiftung Essen-Huttrop,
Division of Gynecologic Oncology; Germany and Gynecology Service,
Obstetrics, Gynecology and Women’s Department of Surgery, Memorial
Health Institute, Cleveland Clinic, Sloan-Kettering Cancer Center,
Cleveland, OH, USA NY, USA
Marcela G. del Carmen Britt K Erickson

Division of Gynecologic Oncology, Division of Gynecologic Oncology,
Massachusetts General Hospital, Harvard Department of Obstetrics, Gynecology and
Medical School, Boston, MA, USA Women’s Health, University of Minnesota,
Minneapolis, MN USA
Alexandra Diggs
Department of Obstetrics and Gynecology, Kevin Espino
College of Physicians and Surgeons, New York University Langone Health,
Columbia University, NY, USA Department of Obstetrics and Gynecology,
Division of Gynecologic Oncology, New
Nasuh Utku Dogan York, NY, United States
Akdeniz University Faculty of Medicine,
Department of Gynecology, Antalya, Turkey Amanda N. Fader
The Kelly Gynecologic Oncology Service,
Selen Dogan Department of Gynecology and Obstetrics,
Akdeniz University Faculty of Medicine, Johns Hopkins University School of
Department of Gynecology, Antalya, Turkey Medicine, Baltimore, MD, USA
Sean C. Dowdy Lorena Fariñas-Madrid
Division of Gynecologic Oncology, Mayo Gynaecologic Cancer Programme. Vall
Clinic, Rochester, MN, USA d’Hebron Institute of Oncology (VHIO),

xvi List of Contributors
Hospital Universitari Vall d’Hebron, Vall Ginger J. Gardner

d’Hebron Barcelona Hospital Campus, Memorial Sloan Kettering Cancer Center,
Barcelona, Spain NY, USA
Olga T. Filippova John P. Geisler

Gynecology Service, Department of Specialty Cancer Care, MG Wellness,
Surgery, Memorial Sloan Kettering Cancer Columbus, GA, USA
Center, NY, USA
Melissa A. Geller
Gini F. Fleming University of Minnesota, Division of
University of Chicago Medical Center, Gynecologic Oncology, Department of
Chicago, IL, USA Obstetrics Gynecology and Women’s
Health, Minneapolis, MN. USA
Daniel Flores Alatriste
Servicio de Oncología Ginecológica. David M. Gershenson
Hospital Militar de Especialidades de la Department of Gynecologic Oncology and
Mujer y Neonatología. Ciudad de México. Reproductive Medicine, The University of
Texas MD Anderson Cancer Center,
Jean Sebastien Frenel Houston, TX, USA
ICO Saint-Herblain, Boulevard Jacques
Monod, 44805 Saint-Herblain, Lilian T. Gien
France Division of Gynecologic Oncology, Odette
Cancer Centre, Sunnybrook Health
Michael L. Friedlander Sciences Centre, Toronto, Ontario, Canada
School of Clinical Medicine, University of
New South Wales and Gynaecologic Cancer Antonio González-Martín
Centre, Royal Hospital for Women, Department of Medical Oncology and
Sydney, Australia Program in Solid Tumors (Cima), Cancer
Center Clínica Universidad de Navarra
Claire Friedman (CCUN), Madrid and Pamplona, Spain.
Memorial Sloan Kettering Cancer Center
and Weill Cornell Medical College, New Sebastien Gouy
York, NY, USA Department of Gynecologic Surgery, Gustave
Roussy Cancer Campus, Villejuif, France
Melissa K. Frey
Division of Gynecologic Oncology, Francisco Grau
Department of Obstetrics and Gynecology, Gynaecologic Cancer Programme.Vall
Weill Cornell Medicine, NY NY d’Hebron Institute of Oncology (VHIO),
USA Hospital Universitari Vall d’Hebron, Vall
d’Hebron Barcelona Hospital Campus,
Michael Frumovitz Barcelona, Spain
Department of Gynecologic Oncology and
Reproductive Medicine, MD Anderson Rachel N. Grisham
Cancer Center, Houston, TX, Department of Medicine, Memorial Sloan
USA Kettering Cancer Center and Weill Cornell
Medical College, New York, NY, USA
Annalisa Garbi
Division of Gynecologic Oncology, IEO, Whitfield B. Growdon
European Institute of Oncology IRCCS, Massachusetts General Hospital, Boston,
Milan, Italy MA, USA

List of Contributors xvii
Dr. Sudeep Gupta Payam Katebi Kashi

Advanced Centre for Treatment, Research The Kelly Gynecologic Oncology
and Education in Cancer; Tata Memorial Service, Department of Gynecology and
Centre and Homi Bhabha National Obstetrics, Johns Hopkins University
Institute, Mumbai, India School of Medicine, Baltimore,
MD, USA
Philipp Harter
Department of Gynecology & Gynecologic Sean Kehoe
Oncology, Ev. Kliniken Essen-Mitte, Essen, Oxford Gynaecological Cancer Centre,
Germany Churchill Hospital, Oxford, UK
Laura J. Havrilesky Wui-Jin Koh

Division of Gynecology Oncology, National Comprehensive Cancer Network,
Department of Obstetrics and Gynecology, Plymouth Meeting, PA, USA
Duke Cancer Institute, Duke University
Medical Center, Durham, NC, USA Amanika Kumar
Department of Obstetrics and Gynecology,
Thomas J. Herzog Division of Gynecologic Surgery, Mayo
University of Cincinnati Division of Clinic, Rochester, MN, USA.
Gynecology Oncology and University of
Cincinnati Cancer Center, Cincinnati, Chrisann Kyi
OH, USA Department of Medicine, Memorial Sloan
Kettering Cancer Center, New York, NY and
Claire V. Hoppenot Department of Medicine, Weill-Cornell
Department of Obstetrics and Gynecology, Medical College, New York, NY,
Section of Gynecologic Oncology, Baylor USA
College of Medicine, Houston, TX, USA
Nisha Lakhi
Frederick M. Howard Department of Obstetrics and Gynecology,
University of Chicago Medical Center, New York Medical College School of
Chicago, IL, USA Medicine, Valhalla, NY, USA and
Department of Gynecologic Oncology,
Haesen Jolien Richmond Univesrity Medical Center,
Division of Gynecologic Oncology, Staten Island, NY, USA
Department of Gynaecology and
Obstetrics, Leuven Cancer Institute, Brooke M. Lamparello
University Hospitals Leuven, Leuven, Albany Medical Center, Albany,
Belgium NY, USA
Ryan M. Kahn Olivia Lara

Memorial Sloan Kettering Cancer Center, Division of Gynecologic Oncology,
Department of Surgery, New York, University of North Carolina, Chapel Hill,
USA NC, USA
Daniel S. Kapp Olivia Le Saux

Department of Radiation Oncology, Medical Oncology Department, Centre
Stanford University School of Medicine, Léon Bérard, University Claude Bernard,
Stanford, CA, USA Lyon, France

xviii List of Contributors
Jonathan A. Ledermann Gynecology, Mayo Clinic, Phoenix,

Department of Oncology, UCL Cancer AZ, USA
Institute, University College
London, UK Javier F. Magrina
The Department of Medical and Surgical
Alvin Jun Xing Lee Gynecology, Mayo Clinic, Phoenix,
Department of Oncology, UCL Cancer AZ, USA
Institute, University College London, UK
Amita Maheshwari
Mario M. Leitao, Jr Tata Memorial Centre and Homi Bhabha
Gynecology Service, Department of National Institute, Mumbai, India
Surgery, Memorial Sloan Kettering Cancer
Center and Department of Obstetrics and Sven Mahner
Gynecology, Weill Cornell Medical College, Department of Obstetrics and Gynecology,
New York, NY, USA University Hospital, LMU Munich,
Munich, Germany
Ernst Lengyel
Department of Obstetrics and Gynecology/ Vicky Makker
Section of Gynecologic Oncology, The Gynecologic Medical Oncology Service,
University of Chicago, Chicago, IL, USA Memorial Sloan Kettering Cancer Center,
New York, NY, USA and Department of
Julianne Lima Medicine, Weill Cornell Medical College,
The Royal Marsden NHS Foundation New York, NY, USA
Trust, London, UK
Kelly J. Manahan
Chrissy Liu Specialty Cancer Care, MG Wellness,
SUNY Downstate Health Sciences Columbus, GA, USA
University, NY, US
Gioriga Mangili
Beverly Long Department of Obstetrics and Gynecology,
Division of Gynecologic Oncology, IRCCS San Raffaele and Vita-Salute San
Sarasota Memorial Healthcare System, Raffaele University, Milan, Italy
Sarasota, FL
Zibi Marchocki
Kara Long Roche Department of Obstetrics and
Gynecology Service, Department of Gynaecology, Division of Gynaecologic
Surgery, Memorial Sloan Kettering Cancer Oncology, University College Cork, Cork,
Center and Department of Obstetrics & Ireland
Gynecology, Weill Cornell Medical Center,
NY, USA Daniel Margul
University of Cincinnati Department of
Domenica Lorusso Obstetrics and Gynecology and University
Catholic University of Sacred Heart and of Cincinnati Cancer Center, Cincinnati,
Fondazione Policlinico Gemelli IRCCS, OH, USA
Rome, Italy
Andrea Mariani
Paul Magtibay Division of Gynecologic Surgery, Mayo
The Department of Medical and Surgical Clinic, Rochester, MN, USA

List of Contributors xix
Daniela Matei Lea A. Moukarzel

Diana Princess of Wales Professor in Gynecology Service, Department of
Cancer Research, Division of Gynecology Surgery, Memorial Sloan Kettering Cancer
Oncology, Department of Obstetrics and Center, New York, New York, USA.
Gynecology, Northwestern University
Feinberg School of Medicine, Chicago, Il Francesco Multinu
Department of Gynecology Oncology,
Ursula Matulonis European Institute of Oncology, Milan, Italy
Dana Farber Cancer Institute, Boston,
MA, USA Joo-Hyun Nam
Amandine Maulard University of Ulsan College of Medicine,
Surgical Department, Gustave-Roussy Asan Medical Center, Seoul, Republic of
Cancer Center, Villejuif, France Korea
Joanie Mayer Hope Deepa Maheswari Narasimhulu

Founding Partner, Alaska Women’s Cancer Department of Obstetrics and Gynecology,
Care and Director of Gynecologic Division of Gynecologic Oncology, Mayo
Oncology, Alaska Native Medical Center & Clinic, Rochester, MN, USA
Providence Alaska Cancer Center, AK,
USA Steven A. Narod
Women’s College Research Institute,
David S. Miller Women’s College Hospital and Dalla
Division of Gynecologic Oncology, Lana School of Public Health,
Department of Obstetrics & Gynecology, University of Toronto, Toronto,
University of Texas Southwestern ON, Canada
Medical Center, Dallas, Texas,
U.S.A. Roni Nitecki
Gynecologic Oncology and Reproductive
Kathryn Miller Medicine, MD Anderson Cancer Center,
Gynecology Service, Department of Houston, TX, US
Center, NY, USA Angelica Nogueira-Rodrigues
Federal University of Minas Gerais, Belo
Arwa Mohammad Horizonte, Brazil
Division of Gynecologic Oncology, Mayo
Clinic, Rochester, MN, Roisin O’Cearbhaill
USA Gynecologic Medical Oncology Service,
Department of Medicine, Memorial Sloan
Philippe Morice Kettering Cancer Center and Department
Department of Gynecologic Surgery, of Medicine, Weill Cornell Medical College,
Gustave Roussy Cancer Campus, Villejuif, NY, USA
France; University Paris Sud, Bures-sur-
Yvette, France Ana Oaknin
Gynaecologic Cancer Programme, Vall
Molly Morton d’Hebron Institute of Oncology (VHIO),
Obstetrics, Gynecology and Women’s Hospital Universitari Vall d’Hebron, Vall
Health Institute, Cleveland Clinic, d’Hebron Barcelona Hospital Campus,
Cleveland, OH, USA Barcelona, Spain

xx List of Contributors
Kutluk Oktay Pedro T. Ramirez

Department of Obstetrics, Gynecology and Department of Obstetrics & Gynecology,
Reproductive Sciences, Yale University The Houston Methodist Hospital,
School of Medicine, New Haven, CT, USA Houston, TX, USA
and Innovation Institute for Fertility
Preservation and IVF, New York, NY, USA Salihi Rawand
Division of Gynecologic Oncology,
Jeong-Yeol Park Department of Gynaecology and Obstetrics,
Department of Obstetrics and Gynecology, Leuven Cancer Institute, University
University of Ulsan College of Medicine, Hospitals Leuven, Leuven, Belgium
Asan Medical Center, Seoul, Republic of
Korea Isabelle Ray-Coquard
Medical Oncology Department, Centre Léon
Jessica E. Parker Bérard, University Claude Bernard, Lyon,
Division of Gynecologic France
Oncology, Department of Obstetrics and
Gynecology, Indiana University, Patricia Rivera
Indianapolis, IN, USA Department of Obstetrics and Gynecology,
Ascension Health, Racine, WI, USA
Patricia Pautier
Medical Department, Gustave-Roussy Matteo Repetto
Cancer Center, Villejuif, France Division of Early Drug Development for
Innovative Therapies, IEO, European
Richard T. Penson Institute of Oncology IRCCS, Milan,
Massachusetts General Hospital, Boston, Italy
MA, USA
Gordon J. S. Rustin
Milagros Pérez Quintanilla Mount Vernon Cancer Centre, Northwood,
Ginecología Oncológica, Instituto Nacional Middlesex, UK
de Cancerología, Mexico
Dib Sassine
Marie Plante Gynecology Service, Department of
Division of Gynecologic Oncology, Surgery, Memorial Sloan Kettering Cancer
Department of Obstetrics and Center, NY, USA
Gynaecology, Laval University, Quebec
City, Canada Brooke A. Schlappe
Department of Gynecologic Oncology,
Bhavana Pothuri Advocate Aurora Health, Milwaukee,
Department of Obstetrics and Gynecology, WI, USA
Perlmutter Cancer Center, NYU Langone
Health, NY, USA Michael J. Seckl
Department of Medical Oncology, Charing
Aaron M. Praiss Cross Hospital Campus of Imperial College
Gynecology Service, Department of London, London, UK
Center, NY, USA Angeles Alvarez Secord
Division of Gynecology Oncology,
Eric Pujade-Lauraine Department of Obstetrics and
Medical Director, ARCAGY Paris, France Gynecology, Duke Cancer Institute, Duke

List of Contributors xxi
University Medical Center, Durham, Hospital NHS Foundation Trust,

NC, USA London, UK
Karin K. Shih Kavita Singh

Division of Gynecologic Oncology, Pan-Birmingham Gynaecological Cancer
Department of Obstetrics and Gynecology, Centre, Birmingham, UK
Zucker School of Medicine at Hofstra
University/Northwell Health, New Hyde Pamela T. Soliman
Park, NY Department of Gynecologic Oncology and
Reproductive Medicine, MD Anderson
Rachel C. Sisodia Cancer Center, Houston, TX, USA
Harvard Medical School, Massachusetts
General Hospital, MA, USA Krishnansu S. Tewari
Department of Obstetrics & Gynecology,
Gabe S. Sonke University of California, Irvine, CA, USA
Department of Medical Oncology,
Netherlands Cancer Institute, Amsterdam Lauren Thomaier Bollinger
Division of Gynecologic Oncology, University
Yukio Sonoda of Minnesota, Minneapolis, MN, USA
Gynecology Service, Department of
Surgery, Memorial Sloan Kettering Cancer Federica Tomao
Center and Department of Obstetrics & IEO, European Institute of Oncology
Gynecology, Weill Cornell Medical Center, IRCCS, Milan, Italy
NY, USA
Tiffany Y. Sia
Richard Schwameis Gynecology Service, Department of
Department of Gynecology & Gynecologic Surgery, Memorial Sloan Kettering Cancer
Oncology, Ev. Kliniken Essen-Mitte, Essen, Center, USA
Germany and Department of General
Federica Tomao
Gynecology and Gynecologic Oncology,
Department of Gynecology Oncology,
Gynecologic Cancer Unit, Comprehensive
European Institute of Oncology-Milan,
Cancer Center, Medical University of
Italy
Vienna, 1080 Vienna, Austria.
Yien Ning Sophia Wong
Edward Tanner
Department of Oncology, UCL Cancer
Institute, University College London, UK
Northwestern University, Chicago, IL, USA
William P. Tew
Enes Taylan
Gynecologic Medical Oncology Service,
Department of Obstetrics and
Department of Medicine, Memorial
Gynecology, Wayne State University
Sloan Kettering Cancer Center,
School of Medicine, Detroit, MI, USA and
NY, USA
Department of Obstetrics, Gynecology
and Reproductive Sciences, Yale Anastasios Tranoulis
University School of Medicine, New Pan-Birmingham Gynaecological Cancer
Haven, CT, USA Centre, Birmingham, UK
Beatrice Seddon Fabian Trillsch
Department of Oncology,University College Department of Obstetrics and Gynecology,

xxii List of Contributors
University Hospital, LMU Munich, Center; and New York

Munich, Germany Presbyterian Hospital, NY, USA
Hélène Vanacker Thomas C. Wright

Medical Oncology Department, Centre Columbia University, NY,
Léon Bérard, University Claude Bernard, USA
Lyon, France
Sumer K. Wallace
Fidel A. Valea Division of Gynecologic Oncology,
Department of Obstetrics and University of Wisconsin School of
Gynecology Virginia Tech Carilion School Medicine and Public Health, Madison,
of Medicine, VA, USA WI, USA
Ignace B. Vergote Juliet E. Wolford

Division of Gynecologic Oncology, University of Cincinnati Department of
Department of Gynaecology and Obstetrics, Obstetrics and Gynecology and University
Leuven Cancer Institute, University of Cincinnati Cancer Center, Cincinnati,
Hospitals Leuven, Leuven, Belgium OH, USA
Roberto Vargas S. Diane Yamada

Division of Gynecologic Oncology; Department of Obstetrics and
Obstetrics, Gynecology and Women’s Gynecology/Section of Gynecologic
Health Institute, Cleveland Clinic, Oncology, The University of Chicago,
Cleveland, OH, USA Chicago, IL, USA
Simrit Warring Jason Yap

Department of Obstetrics and University of Birmingham and
Gynecology, Division of Gynecologic Pan-Birmingham Gynaecological Cancer
Surgery, Mayo Clinic, Rochester, Center, Birmingham, UK
MN, USA
Catheryn M. Yashar
Jill S. Whyte Department of Radiation Oncology,
Division of Gynecologic Oncology, University of California San Diego, San
Department of Obstetrics and Gynecology, Diego, CA, USA
Zucker School of Medicine at Hofstra
University/Northwell Health, New Hyde Benoit You
Park, NY Université Lyon, Université Claude
Bernard Lyon 1, Faculté de Médecine Lyon-
Michael Wilkinson Sud, EA3738 CICLY; Medical Oncology,
UCD Gynaecological Oncology Group, Institut de Cancérologie des Hospices
UCD School of Medicine, Catherine Civils de Lyon (IC-HCL), CITOHL,
McAuley Research Centre, Mater EPSILYON, Lyon, France and GINECO,
Misericordiae University Hospital, Dublin, Paris France
Ireland
Camilla Yu
Jason D. Wright The Kelly Gynecologic Oncology
Columbia University College of Service, Department of Gynecology and
Physicians and Surgeons; Obstetrics, Johns Hopkins University
Herbert Irving Comprehensive Cancer School of Medicine, Baltimore,
MD, USA

List of Contributors xxiii
Eleonora Zaccarelli Vanna Zanagnolo

Department of Gynecology Oncology, Department of Gynecology Oncology,
European Institute of Oncology, Milan, Italy European Institute of Oncology, Milan,
Italy
Dmitriy Zamarin
Department of Medicine, Memorial Sloan Oliver Zivanovic
Kettering Cancer Center, New York, NY Gynecology Service, Department of
and Department of Medicine, Weill- Surgery, Memorial Sloan Kettering Cancer
Cornell Medical College, NY, USA Center, New York, NY, USA and Weill
Cornell Medical College, New York,
William A. Zammarrelli III NY, USA
Gynecology Service, Department of Surgery,
Memorial Sloan Kettering Cancer Center, Chrissy Liu
New York, NY, USA and Weill Cornell SUNY Downstate Health Sciences
Medical College, New York, NY, USA University

Section I Perioperative Management
Debate
Should Routine Mechanical Bowel
1A Preparation be Performed before

Primary Debulking Surgery?
Yes
Lea A. Moukarzel and Oliver Zivanovic
Debate
Maximal reduction of postoperative residual disease is a well-established prognostic factor
in advanced or recurrent ovarian and uterine cancer. Intestinal surgery is often required in
order to achieve complete gross resection of malignant disease. Given the anatomical
location of these primary tumors in the pelvis, a significant portion of these intestinal
surgeries encompass rectosigmoid and ileocecal resections. One key perioperative interven-
tion that has been employed for many years to optimize these procedures is mechanical
bowel preparations (MBPs).
There are several reasons as to why mechanical bowel preparations have been used in
surgeries requiring colonic or rectal resections. A clean colon can facilitate bowel manipu-
lation, passage and firing of surgical staplers, and significantly improves visualization
during intraoperative proctoscopy or colonoscopy. Additionally, MBP has also shown
potential reduction in postoperative complications including surgical site infections (SSIs)
and anastomotic leaks. This effect is most pronounced when used in combination with oral
antibiotic bowel preparations (OABPs).
Mechanical Bowel Preparation is a Commonly Used and Safe

Intervention
Regarding the safety of MBP, studies have repeatedly shown it to be a safe and feasible
intervention. Some might speculate that the rate of clostridium difficile colitis might increase
among patients undergoing bowel preparation. However, in line with multiple other
studies, Kim et al. found that C. difficile colitis was actually less likely among those with
who received bowel preparation with combination oral antibiotics and MBP as compared to
those who received no bowel preparation (0.5% vs. 1.8%; p=0.01) [1].
Mechanical Bowel Preparation Decreases Postoperative Complications,

Specifically Surgical Site Infection
The impact of MBP on reducing surgical morbidity, primarily surgical site infections, remains
the most debated aspect of bowel preparation. Colon and rectal surgery are among the most
significant surgeries associated with SSIs and therefore any intervention that could decrease
this morbidity rate is of critical value. Based on a recent review of the literature, the American
Society of Colon and Rectal Surgeons recently released recommendations supporting the use
1

Section I Perioperative Management
Debate
1A Preparation be Performed before

Yes
Lea A. Moukarzel and Oliver Zivanovic
Debate
Maximal reduction of postoperative residual disease is a well-established prognostic factor
in advanced or recurrent ovarian and uterine cancer. Intestinal surgery is often required in
order to achieve complete gross resection of malignant disease. Given the anatomical
location of these primary tumors in the pelvis, a significant portion of these intestinal
surgeries encompass rectosigmoid and ileocecal resections. One key perioperative interven-
tion that has been employed for many years to optimize these procedures is mechanical
bowel preparations (MBPs).
There are several reasons as to why mechanical bowel preparations have been used in
surgeries requiring colonic or rectal resections. A clean colon can facilitate bowel manipu-
lation, passage and firing of surgical staplers, and significantly improves visualization
during intraoperative proctoscopy or colonoscopy. Additionally, MBP has also shown
potential reduction in postoperative complications including surgical site infections (SSIs)
and anastomotic leaks. This effect is most pronounced when used in combination with oral
antibiotic bowel preparations (OABPs).
Mechanical Bowel Preparation is a Commonly Used and Safe

Intervention
Regarding the safety of MBP, studies have repeatedly shown it to be a safe and feasible
intervention. Some might speculate that the rate of clostridium difficile colitis might increase
among patients undergoing bowel preparation. However, in line with multiple other
studies, Kim et al. found that C. difficile colitis was actually less likely among those with
who received bowel preparation with combination oral antibiotics and MBP as compared to
those who received no bowel preparation (0.5% vs. 1.8%; p=0.01) [1].
Mechanical Bowel Preparation Decreases Postoperative Complications,

Specifically Surgical Site Infection
The impact of MBP on reducing surgical morbidity, primarily surgical site infections, remains
the most debated aspect of bowel preparation. Colon and rectal surgery are among the most
significant surgeries associated with SSIs and therefore any intervention that could decrease
this morbidity rate is of critical value. Based on a recent review of the literature, the American
Society of Colon and Rectal Surgeons recently released recommendations supporting the use
1
https://doi.org/10.1017/9781108935579.001 Published online by Cambridge University Press

2 Lea A. Moukarzel and Oliver Zivanovic
of combined MBP with OABP in elective colorectal resections [2]. This recommendation was
assigned a level 1B grade as a strong recommendation that can apply to most patients in most
circumstances without reservation based on moderate-quality evidence.
Two randomized control trials formed the foundation for this recommendation where
the use of combined MBP and oral antibiotics was associated with a significant decrease in
SSI rates [3,4]. This includes the study by Nichols et al., which reported a marked reduction
in SSI with the combination of MBP with OABP as compared to MBP alone. Clark et al.
performed a similar study where the combination therapy demonstrated a reduction in
postoperative complications including not only SSI, but also anastomotic leaks. Multiple
studies have subsequently reproduced these findings.
More recently, Morris et al. performed propensity matching on 8,415 patients having
undergone colorectal surgery through the National Surgical Quality Improvement Program
(NSQIP) database [5]. They found on multivariate analysis that the use of OABP was
protective against SSI (OR=0.46, 95% CI: 0.63–0.58) as compared to no bowel preparation.
Importantly, among these patients, 92% had also received a MBP. A protective effect against
SSI was also present with the use of MBP alone (OR=0.85, 95% CI: 0.72–0.99). In addition to
the reduction in SSI, both OABP and MBP alone were associated with a decrease in
readmission as compared to no preparation. Importantly, there was also a significant
reduction in frequency of anastomotic leaks, postoperative ileus, return to the operating
room, acute renal injury, and sepsis among patients that received MBP with or without
OABP as compared to those that did not receive any form of bowel preparation.
These findings led to several studies in the colorectal literature that have demonstrated
a reduction in SSIs after introduction of SSI bundles that included MBP along with OABP.
More recently, there has been similar studies performed in the gynecologic oncology
literature with comparable results. This includes a study by Schiavone et al. which reported
a significant decrease in the incidence of SSI from 37% to 12% (p<0.001) after the imple-
mentation of a SSI reduction bundle that included the use of preoperative OABP with
almost routine use of MBP [6].
Mechanical Bowel Preparation Improves Visualization during

Intraoperative Proctoscopy or Colonoscopy
Surgical interventions are continuously advancing in order to improve postoperative mor-
bidity and mortality from debulking surgery. One such morbidity is anastomotic leaks after
colorectal resection. Proctoscopy is increasingly being used to visualize the anastomosis and
aid in assessing its integrity. More recently data has suggested that the addition of near-
infrared (NIR) angiography via proctoscopy might reduce anatomic leak rates and is associ-
ated with fewer postoperative abscesses and diverting ostomies after rectosigmoid resection
performed during surgeries for gynecologic malignancies [7]. In order to use proctoscopy
with or without NIR angiography, optimization of visual assessment is paramount. The use of
MBPs would assist in insuring adequate visualization of the anastomosis via proctoscopy.
Conclusions
Based on the emergence of data supporting the use of combination bowel prep, four large
societies currently recommend the use of combination bowel preparation. These include the
American Society of Colon and Rectal Surgeons, the Society of American Gastrointestinal

Mechanical Bowel Preparation before Primary Surgery? Yes 3
and Endoscopic Surgeons, the American Society for Enhanced Recovery, and the
Perioperative Quality Initiative. In addition, the American Society of Colon and Rectal
Surgeons specifically states that OABP alone, without mechanical preparation, is generally
not recommended. This is largely based on the lack of any randomized trials evaluating the
use of oral antibiotics without concurrent MBP. These recommendations in combination
with the literature support the standard use of OABP with MBP among patients at risk of
requiring colonic resection, such as in the setting of primary debulking surgery for gyneco-
logic malignancy. The benefit of MBP appears to be synergistic with the use of OABP and
therefore we recommend it always be used in combination, while the use of MBP alone
should fall out of practice.
References
1. Kim EK, et al. A statewide colectomy complications following colon surgery. Ann
experience: the role of full bowel preparation Surg 1973;178(4):453–462.
in preventing surgical site infection. Ann 5. Morris MS, et al. Oral antibiotic bowel
Surg 2014;259(2):310–314. preparation significantly reduces surgical
2. Migaly J, et al. The American Society of site infection rates and readmission rates in
Colon and Rectal Surgeons Clinical Practice elective colorectal surgery. Ann Surg
Guidelines for the Use of Bowel Preparation 2015;261(6):1034–1040.
in Elective Colon and Rectal Surgery. DC&R 6. Schiavone MB, et al. Surgical site infection
2019;62(1):3–8. reduction bundle in patients with
3. Clarke JS, et al. Preoperative oral gynecologic cancer undergoing colon
antibiotics reduce septic complications surgery. Gynecol Oncol 2017;147
of colon operations: results of (1):115–119.
prospective, randomized, double-blind 7. Moukarzel LA, et al. The impact of
clinical study. Ann Surg 1977;186 near-infrared angiography and proctoscopy
(3):251–259. after rectosigmoid resection and
4. Nichols RL, et al. Effect of preoperative anastomosis performed during surgeries for
neomycin-erythromycin intestinal gynecologic malignancies. Gynecol Oncol
preparation on the incidence of infectious 2020;158(2):397–401.

Debate
1B Preparation be Performed before

No
Shannon D. Armbruster and Fidel A. Valea
Debate
Since the early 1970s, surgeons have debated the value of preoperative mechanical bowel
preparation (MBP) for patients undergoing bowel surgery. Proponents claim that MBP
decreases rates of surgical site infections and anastomotic leaks; however, current literature
does not support these assertions. In fact, negative impacts of MBP including patient discom-
fort, dehydration, and electrolyte abnormalities have been reported. For gynecologic oncolo-
gists, this debate rages on, as gynecologic oncology-based evidence is limited. Nevertheless, the
debate can be settled upon review of the colorectal literature, as suggested by the Enhanced
Recovery After Surgery (ERAS) Society Gynecologic Oncology guidelines published in 2019 [1].
The most recent Cochrane Review, published in 2011, included 4595 patients who
underwent elective colorectal surgery with (n=2305) and without (n=2290) preoperative
MBP. When comparing those patients receiving MBP to those who did not, no differences
were observed in rates of anastomotic leak for low anterior resections (8.8% vs. 10.3%,
OR=0.88, 95% CI: 0.55, 1.4), anastomotic leak for colon surgery (3.0% vs. 3.5%, OR=0.85,
95%CI: 0.58, 1.26), and overall anastomotic leakage (4.4% vs. 4.5%, OR=0.99, 95% CI: 0.74,
1.31). Furthermore, no differences were seen in the secondary outcomes of mortality (1.6%
vs. 1.8%, OR=0.93, 95% CI: 0.58, 1.47), peritonitis (2.2% vs. 3.0%, OR=0.74, 95% CI: 0.5,
1.08), wound infection (9.6% vs. 8.5%, OR=1.16, 95% CI: 0.95, 1.42), reoperation (6.1% vs.
5.8%, OR=1.06, 95% CI: 0.83, 1.37), infectious extra-abdominal complication (11.4% vs.
11.1%, OR=1.05, 95% CI: 0.85, 1.3), or non-infectious extra-abdominal complications (6.4%
vs. 6.6%, OR=0.98, 95% CI: 0.71, 1.36) [2]. These data were confirmed in a National Surgery
Quality Improvement Program (NSQIP) database review including patients undergoing
elective colorectal surgery with (n=11,836) and without (n=8640) MBP. No differences were
observed in rates of any surgical site infection (OR= 0.92, 95% CI: 0.84, 1.02), anastomotic
leak (OR=0.91, 95% CI 0.77, 1.08), return to the operating room (OR=1.03, 95% CI: 0.88,
1.21), readmission (OR=0.98, 95% CI: 0.89, 1.08), or death (OR=0.77, 95% CI: 0.57, 1.05).
Furthermore, patient organ-related outcomes were similar, including cardiac complications
(OR=0.83, 95% CI: 0.59, 1.18), renal complications (OR=0.92; 95% CI: 0.65, 1.31), or
postoperative ileus (OR=1.04, 95% CI: 0.95, 1.18) [3]. Given these findings, the American
Society of Colon and Rectal Surgery does not recommend MBP alone for patients undergo-
ing elective colorectal surgery, a recommendation supported by strong evidence [4].
Colorectal surgery results and national guidelines influence gynecology and gynecologic
oncology-specific MBP recommendations. In 2018, a surgical technical evidence review by

Mechanical Bowel Preparation before Primary Surgery? No 5
the Agency for Healthcare Research and Quality Safety Program for Improving Surgical
Care and Recovery noted a paucity of gynecology-driven data, and thus the need to examine
data from the colorectal surgery population. In this review, Kalogera et al. included results
from four meta-analyses demonstrating that patients receiving MBPs derived no benefit in
overall mortality, surgical site infection, incidence of anastomotic leak, or reoperation
compared to those not undergoing MBP. They concluded with the moderate-strength
recommendation that MBP alone is discouraged, unless combined with oral antibiotics
[5]. In accord, the Enhanced Recovery After Surgery (ERAS) Society guidelines for gyneco-
logic oncology were updated in 2019 and recommended that MBP alone should not be used
to decrease postoperative morbidity in laparotomy cases, and should not be used at all for
minimally invasive gynecologic surgery cases [1].
Conclusion
In conclusion, the 50-year debate can be laid to rest. Strong data from the colorectal
literature has led to national and international recommendations to avoid MBP alone for
patients undergoing bowel surgery. The value of oral antibiotic bowel preparation versus no
MBP was observed in a retrospective study, while the addition of an MBP did not add
further benefit [5]. Therefore, MBP should only be considered when combined with oral
antibiotic preparations.
References
1. Nelson G, et al. Guidelines for 2018;267(4):734–742. https://doi.org/10
perioperative care in gynecologic/ .1097/SLA.0000000000002159
oncology: Enhanced Recovery After 4. Migaly J, et al. The American Society of
Surgery (ERAS) Society Colon and Rectal Surgeons Clinical Practice
recommendations – 2019 update. Guidelines for the Use of Bowel Preparation
Int J Gynecol Cancer 2019;29(4):651–668. in Elective Colon and Rectal Surgery. Dis
https://doi.org/10.1136/ijgc-2019-000356 Colon Rectum 2019;62(1):3–8. https://doi
2. Güenaga KF, et al. Mechanical bowel .org/10.1097/dcr.0000000000001238
preparation for elective colorectal surgery. 5. Kalogera E, et al. Surgical technical evidence
Cochrane Database Syst Rev 2011;9: review for gynecologic surgery conducted
CD001544. https://doi.org/10.1002/1465185 for the Agency for Healthcare Research and
8.CD001544.pub4 Quality Safety Program for Improving
3. Koller SE, et al. Comparative effectiveness Surgical Care and Recovery. Am J Obstet
and risks of bowel preparation before Gynecol 2018;219(6):563.e561–563.e519. htt
elective colorectal surgery. Ann Surg ps://doi.org/10.1016/j.ajog.2018.07.014

Debate
Should Preoperative
2A Carbohydrate Loading be Routine

prior to Debulking Surgery?
Yes
Arwa Mohammad, Deepa Maheswari Narasimhulu, and
Sean C. Dowdy
Debate
Preoperative fasting was the surgical dogma for over 100 years, but has been chal-
lenged and modified within the last few decades. An abundance of evidence supports
the safety of reducing preoperative fasting to six hours for solids and two hours for
clear liquids. This practice does not increase the risk of pulmonary aspiration and is
supported by the American Society of Anesthesiology [1]. In fact, rather than with-
holding nutrition, preoperative carbohydrate loading (typically a beverage containing
50 grams of carbohydrates) has been shown to mitigate metabolic derangements
related to surgical stress by converting the fasted catabolic state to a fed, anabolic
state [1]. The concept of carbohydrate loading was first studied in performance
athletes and was found to increase muscle glycogen stores and improve performance
during endurance exercise.
The endocrine and immunologic systems demonstrate the most pronounced response
to surgical stress. The magnitude of this response is proportional to surgical complexity,
and is mediated by the release of catecholamines, cortisol, glucagon, growth hormone and
cytokines, causing immunosuppression and insulin resistance [2]. The result is a catabolic
state characterized by hyperglycemia, impaired protein metabolism, and lipolysis which
may lead to muscle weakness and delayed wound healing. This catabolic state is exacer-
bated by preoperative fasting [1].
Carbohydrate loading improves insulin resistance and patient comfort measures such
as hunger, thirst, anxiety, and nausea, with no delay in gastric emptying or change in
gastric pH [1,2]. While a direct cause-and-effect relationship between carbohydrate
loading and improvements in clinically significant endpoints has not been proven,
reduced insulin resistance has been associated with improved bowel function and
decreases in infectious morbidity [1,3]. A National Institute for Health and Care
Excellence (NICE) guideline evidence review showed that compared to fasting, preopera-
tive carbohydrate loading decreased length of stay for major abdominal surgery and
orthopedic surgery, but not for minor and intermediate abdominal surgery. No differ-
ences were found for other types of surgery compared to placebo [2].
Although the quality of evidence supporting carbohydrate loading is low to moderate,
there are no clear risks. Some have raised theoretical concerns about the risk of pulmonary
aspiration and hyperglycemia. Gastric emptying time for a preoperative carbohydrate
6

Preoperative Carbohydrate Loading prior to Surgery? Yes 7
solution is only 90 to 120 minutes. No significant increase in preoperative gastric volumes

or risk of pulmonary aspiration has been shown with carbohydrate loading [1]. However,
beverages containing fat or those with high osmolality may slow gastric emptying and
should not be used. Although hyperglycemia is a common event after major abdominal
surgery even in nondiabetic patients, carbohydrate loading minimizes the risk of peri-
operative hyperglycemia by improving insulin resistance.
Most trials investigating carbohydrate loading have excluded diabetics due to concerns
of delayed gastric emptying and hyperglycemia. One small trial with 35 patients demon-
strated no difference in gastric emptying times [4]. The improvement in perioperative
insulin sensitivity seen with carbohydrate loading should theoretically benefit noninsulin-
dependent diabetic patients, but not those who are insulin dependent. A study of type 2
diabetics undergoing colorectal surgery found no relationship between preoperative
carbohydrate loading and postoperative glycemic control, however, preoperative glucose
levels were higher [4]. More studies are awaited to guide optimal care in diabetics, but
together with concerns about delays in gastric emptying, water may be substituted for
a carbohydrate drink in diabetic patients. Patients with known delayed gastric emptying
may be at higher risk of aspiration with oral preoperative carbohydrate loading.
Intravenous preoperative carbohydrate loading has been studied and may be an option
for nondiabetics.
Apart from calories, protein is crucial for postoperative recovery as it promotes
anabolism, slows muscle catabolism, and shortens the postsurgical inflammatory
phase. Many practices have added nutritional supplements containing protein in the
postoperative period as an element of their Enhanced Recovery After Surgery (ERAS)
protocol. There has been recent interest in studying the value of adding whey protein to
the preoperative carbohydrate drink. Yi et al. randomized 118 patients undergoing
elective surgery for gynecological cancer to preoperative carbohydrate-only loading
versus whey protein-infused carbohydrate loading. The whey protein-infused carbohy-
drate loading group had shorter hospital stay, lower readmission rates, less weight loss,
lower C-reactive protein–albumin ratio, preserved muscle mass, and better handgrip
strength when compared to the preoperative carbohydrate-only loading group. No
significant differences were noted in mid-upper arm circumference and serum albumin
level upon discharge [5].
Conclusion
Proven reductions in insulin resistance provide the physiologic rationale for the use of oral
carbohydrate loading before surgery to attenuate surgical stress and improve healing. While
evidence of clinical benefit is of low to moderate quality, preoperative carbohydrate loading
is neither costly nor labor intensive, improves patient satisfaction and well-being, and
should be incorporated into Enhanced Recovery After Surgery protocols given the very
low risk of harm. Recognizing the high surgical complexity of cytoreductive surgery in
patients with ovarian cancer and the high incidence of mild to moderate nutritional
compromise, these patients may have comparatively more to gain from carbohydrate
loading. ERAS Society guidelines for gynecologic surgery provide a strong recommenda-
®
tion grade for ingesting a 50-gram preoperative carbohydrate drink up until two hours prior
to induction of anesthesia, with the exception of patients with risk factors for delayed gastric
emptying [3].

8 Arwa Mohammad et al.
References
1. Pillinger NL, et al. Nutritional recommendations – 2019 update.
prehabilitation: physiological basis and Int J Gynecol Cancer 2019;29(4):651–668.
clinical evidence. Anaesth Intensive Care 4. Cua S, et al. The effect of an enhanced
2018;46(5):453–462. recovery protocol on colorectal surgery
2. National Institute for Health and Care patients with diabetes. J Surg Res
Excellence. Perioperative care in adults. [H] 2021;257:153–160.
Evidence review for pre-operative fasting. 5. Yi HC, et al. Impact of enhanced recovery
NICE guideline NG180 Perioperative care. after surgery with preoperative whey
Available at: www.nice.org.uk/guidance/n protein-infused carbohydrate loading
g180/documents/evidence-review-7 [last and postoperative early oral feeding
accessed October 17, 2022]. among surgical gynecologic
3. Nelson G, et al. Guidelines for perioperative cancer patients: an open-labelled
care in gynecologic/oncology: Enhanced randomized controlled trial. Nutrients
Recovery After Surgery (ERAS) Society 2020;12(1):264.

Debate
Should Preoperative
2B Carbohydrate Loading be Routine

prior to Debulking Surgery?
No
Kathryn Miller, Dib Sassine, and Yukio Sonoda
Debate
In patients undergoing surgery, nutritional status is a key component in the body’s ability to
mount an appropriate metabolic response to postoperative inflammation and stress. The
negative effects of long-term protein and caloric deficits on outcomes for surgical patients
have been well-established in the literature and are associated with higher risk of poor
wound healing, sepsis, and mortality. Frequently, the patients at highest risk of poor
preoperative nutritional status are those for whom surgery cannot be avoided: oncology,
geriatrics, or critical care patients.
To correct nutritional deficits for patients at high metabolic risk, studies have shown that
10–14 days of enteral or parenteral nutritional support confers some benefit. Even with
these interventions, measurable change may not be induced in body composition or serum
albumin concentration. Prehabilitation, a comprehensive program which combines pre-
operative nutritional support and exercise has been shown to decrease rates of complica-
tions in patients undergoing abdominal surgery and those with cancer, but meaningful
changes may take up to four to six weeks to occur.
Of course, delaying surgery in the cancer patient to fully optimize preoperative
nutritional status may not be feasible, for numerous reasons. To address nutritional
status in the short term, preoperative nutritional support has been added as an element
of fast-track recovery or Enhanced Recovery After Surgery (ERAS) programs now in
widespread use across surgical disciplines. ERAS preoperative nutrition guidelines gen-
erally advise against prolonged periods of fasting and include recommendations for
carbohydrate-rich beverages prior to surgery [1]. Typical guidelines are to consume
a beverage containing roughly 100 grams of carbohydrates the night before surgery
and 50 grams on the day of surgery.
The goal of preoperative carbohydrate-loading is prevention and mitigation of insulin
resistance, which has been associated with immune suppression, poor wound healing, and
longer hospital stays. However, the impact of its use on outcomes has not been clearly
supported throughout various surgical subspecialties, and many studies have demonstrated
no benefit. In cohorts of colorectal patients, carbohydrate loading decreased rates of insulin
resistance but did not affect complication rates. A large randomized trial of 142 patients
undergoing open colorectal or liver surgery did not demonstrate differences in early plasma
glucose sensitivity or insulin resistance compared with the control group, and showed no
differences in outcomes. Trials in cardiothoracic surgery similarly did not demonstrate

10 Kathryn Miller et al.
differences in insulin resistance, with one study demonstrating increased postoperative

nausea and vomiting in the carbohydrate-loading group.
Several recent meta-analyses and a Cochrane Database systematic review have been
performed to summarize these studies and determine the benefit of carbohydrate treatment
in the preoperative setting [2–5]. One meta-analysis found that carbohydrate loading
conferred a slightly shorter length of stay (LOS) compared with fasting, but showed no
benefit over water or placebo [2]. The systematic review demonstrated a small reduction in
LOS (between 0.04 to 0.56 days) in the carbohydrate treatment group compared with the
fasting or placebo groups, but showed no effect on complication rates [4]. All meta-analyses
and the systematic review concluded that the evidence from published trials is of low quality
and fraught with inconsistencies, and that very few studies have demonstrated meaningful
differences in clinical outcomes based on carbohydrate loading alone.
Conclusion
While it is obvious that improvement in nutritional status prior to surgery is ideal, it has
been shown that weeks of nutritional support and prehabilitation are needed to truly make
a difference in a patient’s nutritional profile. Unfortunately, many cancer patients do not
have the luxury of delaying necessary surgical interventions. For these patients, one night of
carbohydrate loading is insufficient to induce meaningful metabolic change, and may be
considered “too little, too late.” While many components of ERAS have proven beneficial in
improving patient outcomes, preoperative carbohydrate loading is unsupported by the
evidence. Its use does not appear to improve outcomes in patients undergoing debulking
surgery.
References
1. Nelson G, et al. Guidelines for perioperative review and meta-analysis. Surg Today
care in gynecologic/oncology: Enhanced 2012;42(7):613–624.
Recovery After Surgery (ERAS) Society 4. Smith MD, et al. Preoperative carbohydrate
recommendations – 2019 update. treatment for enhancing recovery after
Int J Gynecol Cancer 2019;29(4):651–668. elective surgery. Cochrane Database Syst Rev
2. Amer MA, et al. Network meta-analysis of 2014;8:CD009161. https://doi.org/10.1002/1
the effect of preoperative carbohydrate 4651858.CD009161.pub2
loading on recovery after elective surgery. 5. Bilku DK, et al. Role of preoperative
Br J Surg 2017;104(3):187–197. carbohydrate loading: a systematic
3. Li L, et al. Preoperative carbohydrate review. Ann R Coll Surg Engl 2014;96
loading for elective surgery: a systematic (1):15–22.

Section II Screening, Prevention, and Early Diagnosis
Debate
Should Women with BRCA
3A Mutations be Offered Bilateral

Oophorectomy for Ovarian Cancer
Risk Reduction?
Yes
Thomas Boerner and Kara Long Roche
Debate
Hereditary ovarian cancer syndromes are associated with increased risk of developing pelvic
high grade serous carcinomas (HGSC), with lifetime risks ranging from 10% to 58%
depending on the identified mutation [1]. As the genetic landscape of ovarian cancer
broadens beyond BRCA1 and BRCA2 with the discovery and inclusion of additional
moderate penetrance genetic mutations (for example: RAD51C, RAD51D, BRIP1, PALB2),
patients are significantly more likely to be identified as carrying a pathologic variant than in
decades past. Patients are appropriately seeking, and being referred, for genetic assessment
at earlier ages, and thus there is an increasing need for improved, patient center risk-
reduction strategies.
There is no effective screening test for ovarian cancer. Risk-reducing bilateral salpingec-
tomy (RRSO) is the current gold standard procedure for decreasing the risk of HGSC in
patients at elevated genetic risk [1]. RRSO results in robust protection with a decrease in the
risk of developing HGSC of up to 96% [2]. However, infertility and abrupt surgical
menopause are inevitable sequelae of this procedure, resulting in significant and detrimen-
tal impacts on overall health and quality of life. Cardiovascular disease, osteoporosis,
dyslipidemia, sexual dysfunction, and cognitive decline have all been shown to be associated
with premature menopause. Additionally, quality of life is impacted with the onset of hot
flashes, insomnia, and dyspareunia. Some of these toxicities, notably the decline in sexual
function, persist despite the use of hormone replacement therapy. Recently published
prospective data from GOG-199 support the validity of these concerns, as seen in the
significant decline in sexual function in women who underwent RRSO [3]. These side
effects are unacceptable to many and undoubtedly, there is a need to improve options for
high-risk patients.
There is overwhelming evidence that the fimbriated end of the fallopian tube plays an
important role in the pathogenesis of pelvic HGSC. The identification of serous tubal
intraepithelial carcinomas (STIC lesions), believed to be the precursor to HGSC, as well
as molecular markers and gene expression profiles support a tubal origin for the majority of
HGSC. As the data continues to amass implicating the fallopian tube in this process, the
11

Section II Screening, Prevention, and Early Diagnosis
Debate
3A Mutations be Offered Bilateral

Risk Reduction?
Yes
Thomas Boerner and Kara Long Roche
Debate
Hereditary ovarian cancer syndromes are associated with increased risk of developing pelvic
high grade serous carcinomas (HGSC), with lifetime risks ranging from 10% to 58%
depending on the identified mutation [1]. As the genetic landscape of ovarian cancer
broadens beyond BRCA1 and BRCA2 with the discovery and inclusion of additional
moderate penetrance genetic mutations (for example: RAD51C, RAD51D, BRIP1, PALB2),
patients are significantly more likely to be identified as carrying a pathologic variant than in
decades past. Patients are appropriately seeking, and being referred, for genetic assessment
at earlier ages, and thus there is an increasing need for improved, patient center risk-
reduction strategies.
There is no effective screening test for ovarian cancer. Risk-reducing bilateral salpingec-
tomy (RRSO) is the current gold standard procedure for decreasing the risk of HGSC in
patients at elevated genetic risk [1]. RRSO results in robust protection with a decrease in the
risk of developing HGSC of up to 96% [2]. However, infertility and abrupt surgical
menopause are inevitable sequelae of this procedure, resulting in significant and detrimen-
tal impacts on overall health and quality of life. Cardiovascular disease, osteoporosis,
dyslipidemia, sexual dysfunction, and cognitive decline have all been shown to be associated
with premature menopause. Additionally, quality of life is impacted with the onset of hot
flashes, insomnia, and dyspareunia. Some of these toxicities, notably the decline in sexual
function, persist despite the use of hormone replacement therapy. Recently published
prospective data from GOG-199 support the validity of these concerns, as seen in the
significant decline in sexual function in women who underwent RRSO [3]. These side
effects are unacceptable to many and undoubtedly, there is a need to improve options for
high-risk patients.
There is overwhelming evidence that the fimbriated end of the fallopian tube plays an
important role in the pathogenesis of pelvic HGSC. The identification of serous tubal
intraepithelial carcinomas (STIC lesions), believed to be the precursor to HGSC, as well
as molecular markers and gene expression profiles support a tubal origin for the majority of
HGSC. As the data continues to amass implicating the fallopian tube in this process, the
11

12 Section II: Screening, Prevention, and Early Diagnosis
concept of salpingectomy as a risk-reducing strategy has emerged. Similar to RRSO,

salpingectomy can be performed via an outpatient, minimally invasive procedure and
should incorporate a comprehensive evaluation of the peritoneal cavity (e.g., inspection
and peritoneal washings for cytology) and a pathological assessment of the fallopian tube via
Sectioning and Extensively Examining the Fimbriated End (SEE-FIM protocol).
Salpingectomy performed early, with oophorectomy delayed until the guideline-based
recommended age (or possibly beyond) has been proposed as an additional option for
patients seeking risk-reduction and is currently under investigation. This approach allows
for the preservation of endogenous hormone production and fertility potential, the oppor-
tunity for identification of early precursor lesions such as STIC lesions, and has been
hypothesized to result in an increased degree of risk-reduction.
The majority of high-risk patients welcome a salpingectomy option. In a study by Gaba et al.,
RRESDO in a trial setting was acceptable to approximately 70% of premenopausal patients.
Currently, there are four major ongoing prospective trials looking at RRESDO as compared to
standard RRSO in the high-risk population. Enrolment in these trials has been steady, however
the oncologic data regarding salpingectomy alone as a risk-reduction strategy is unlikely to be
available for many years. Therefore, the most appropriate use of salpingectomy remains within
the context of a RRESDO strategy. Patients motivated to pursue risk-reduction earlier than
guideline age, who have completed childbearing or who have elected to utilize assisted repro-
ductive techniques to allow for preimplantation genetic diagnosis, may be ideal candidates for
RRESDO. Additionally, many patients who are not eligible for hormone replacement therapy
due to a personal history of breast cancer, may opt for RRESDO as a way to delay oophorectomy
to the latter end of guideline-based recommendations, or possibly beyond. RRESDO may also
provide a more palatable option for patients who would otherwise decline RRSO due to
concerns about health and quality of life. While concerns have been raised about the feasibility
of this approach, and specifically the need for patients to undergo two separate surgical
procedures, overall data supports its safety. Ovarian function does not appear to be comprom-
ised and moreover, the approach is cost effective when quality of life is considered [4].
Conclusion
In summary, the incorporation of RRESDO represents a valuable and compelling option for
patients with an elevated risk of ovarian cancer. Shared decision making incorporating
specific genetic mutation profiles, family history, desires for childbearing, eligibility for
hormone replacement therapy, surgical risk, and individual preferences should guide
planning for high-risk patients.
References
1. National Comprehensive Care Network. 3. Mai PL, et al. Prospective follow-up of quality
Genetic/familial high-risk assessment: of life for participants undergoing
breast, ovarian, and pancreatic. risk-reducing salpingo-oophorectomy or
Version 2. 2021. Available from: www ovarian cancer screening in GOG-0199: and
.nccn.org NRG Oncology/GOG Study. Gynecol Oncol
2. Rebbeck TR, et al. Prophylactic 2020;156(1):131–139.
oophorectomy in carriers of BRCA1 or 4. Long Roche KC, et al. Risk-reducing
BRCA2 mutations. N Engl J Med 2002;346 salpingectomy: let us be opportunistic.
(21):1616–1622 Cancer 2017;123(10):1714–1720.

Chapter
3B Mutations be Offered Bilateral

Risk Reduction?
No
Steven A. Narod
Debate
The hope that we can prevent ovarian cancer in women at high risk by removing their
fallopian tubes while leaving their ovaries intact is based on the belief that many, if not most,
high-grade serous ovarian cancers originate in the tubes. The current recommendation for
surgical prevention is bilateral salpingo-oophorectomy (BSO). Salpingectomy alone is not
yet the standard of care for women with a BRCA1 of BRCA2 mutation, but is being proposed
widely and is offered in many centers.
Ovarian tumors have long been thought to arise from the ovarian surface epithelium or
from ovarian surface inclusion cysts. Emerging data support an alternate model whereby the
fallopian tubes are the site of origin for a large proportion of high-grade serous cancers [1].
Studies of occult cancers diagnosed at oophorectomy in asymptomatic mutation carriers
often report finding lesions in both the tubes and the ovaries – and sometimes in the tubes
alone – but rarely on one ovary alone. If the tumour is symptomatic, it is usually widespread
in the pelvis. It may be that the fallopian tube is the origin and nascent cancer cells migrate
outwards and are manifest later in the ovary or on the peritoneum. Pathologists have
described a tubal lesion Serous Tubal Intraepithelial Carcinoma (STIC) and have proposed
this to be a precursor to high-grade serous ovarian cancer. Sequencing studies of p53 and
other genes have shown genetic identity between STICs and accompanying high-grade
serous tumors, consistent with a shared lineage.
The lifetime risk of ovarian cancer is estimated at 45% for BRCA1 mutation carriers and
20% for BRCA2 mutation carriers. The majority of ovarian cancers which arise in BRCA
mutation carriers are of the serous histology and are diagnosed at an advanced stage. The
best preventive strategy is surgery. At present, we cannot offer chemoprevention, lifestyle
change, or screening as a rational alternative. Both oral contraceptives and breastfeeding
have been associated with a reduced risk of ovarian cancer in BRCA1 and BRCA2 carriers.
We recently reported that, compared to women who never breastfed, breastfeeding for
seven or more months was associated with a 32% reduction in risk [2]. The combination of
breastfeeding and oral contraceptive use was strongly protective (OR=0.47). A good
recommendation, but not strong enough to forego surgery.
13

14 Steven A. Narod
With regards to screening, the evidence from large clinical trials does not support
a reduction in mortality associated with annual cancer antigen 125 (CA-125) or ultrasound
imaging among women in the general population. In Poland, we screened BRCA1 mutation
carriers with annual ultrasound [3]. Among the 1,196 women who had one or more
ultrasound examinations and no oophorectomy, there were 73 incident cancers detected
and 27 deaths from ovarian/fallopian cancer. The ten-year cumulative risk of death was
2.0%. Among the 659 women who had a preventive oophorectomy there were 12 incident
cancers and two deaths from ovarian cancer. The ten-year cumulative risk of death
was 0.5%.
Based on the age distribution of occult cancers identified at surgery, salpingo-
oophorectomy is recommended at age 35 to 40 for BRCA1 mutation carriers and at age
45 for BRCA2 mutation carriers. However, potential negative consequences associated with
early surgical menopause are manifold and include infertility, vasomotor symptoms,
a decline in sexual functioning and a diminishment in quality of life. If salpingectomy
alone were equally effective as salpingo-oophorectomy, both fertility and quality of life
could be maintained.
Oophorectomy (or salpingo-oophorectomy) has been shown to be effective in prevent-
ing cancer incidence and cancer mortality in BRCA1 and BRCA2 carriers. In an early study,
we estimated the hazard ratio for incident ovarian, fallopian, or peritoneal cancer associated
with bilateral oophorectomy to be 0.20 (95% CI: 0.13–0.30; P<.001) [4]. Among women who
had no history of cancer at baseline, the hazard ratio for all-cause mortality to age 70 years
associated with an oophorectomy was 0.23 (95% CI: 0.13–0.39; P<.001). The benefit of
salpingo-oophorectomy extends beyond preventing ovarian and fallopian cancer.
Surprisingly, several studies have also shown that oophorectomy prevents death from breast
cancer [4–6]. This includes deaths from breast cancer in women who had the oophorectomy
before getting breast cancer as well as in women who had the oophorectomy after getting
breast cancer. For example, Metcalfe and colleagues reported that oophorectomy confers
a significant reduction in breast cancer mortality among BRCA mutation carriers
with a personal history of breast cancer (HR=0.46; 95% CI: 0.27–0.79) [5]. Recently we
describe a 55% decline in breast cancer mortality among women with breast cancer and
a BRCA2 mutation who had an oophorectomy after diagnosis [6]. The ten-year breast
cancer survival for women who had a bilateral oophorectomy was 89% and for women who
did not have an oophorectomy was 59% (adjusted HR=0.45; 95% CI: 0.28–0.72; p=0.001)
It is not clear why oophorectomy prevents death from breast cancer. Surprisingly, it was
effective for both ER-positive pre- and post-menopausal women, and in BRCA1 and BRCA2
carriers [5,6]. It worked for oophorectomies done before a diagnosis of breast cancer and for
oophorectomies done after diagnosis [4]. It is not clear why the effect is not restricted to
premenopausal oophorectomies in women with ER-positive breast cancers and the possi-
bility of bias in study design cannot be excluded. Based on these results, the author is
reluctant to recommend an unproven alternative (salpingectomy) when the gold standard
(salpingo-oophorectomy) has been shown to have a profound impact on cancer incidence
and mortality. In any case, the author would be more comfortable if offering salpingectomy
to women who had a bilateral preventive mastectomy.
There is little empirical evidence that salpingectomy is effective and the recommenda-
tion is based on theoretical grounds and surveys of patient satisfaction. It is less contentious
to offer salpingectomy to women without a BRCA mutation because for these women, the
risk of ovarian cancer is not high enough to warrant preventive oophorectomy.

Bilateral Salpingectomy for Risk Reduction? No 15
There are no long-term research studies comparing cancer incidence and mortality
according to the two surgical approaches. Chi and colleagues reported a woman with
a BRCA1 mutation who underwent prophylactic mastectomy and bilateral salpingectomy
with ovarian retention before the age of 40 years. She later developed stage IV high-grade
serous ovarian cancer – four years after her initial surgery [7]. But to be fair, there are also
many cases of women developing primary peritoneal cancer after undergoing oophorectomy.
Large-scale prospective studies that describe the impact of salpingectomy on cancer
incidence and mortality, as well as menopausal symptoms or quality of life, are warranted.
Trials currently recruiting BRCA mutation carriers have the more limited goal of evaluating
the impact of salpingectomy (with delayed oophorectomy) on non-cancer endpoints,
including safety, acceptability, menopausal symptoms, and quality of life. It remains to be
seen whether women who are at a substantially elevated risk of developing serous cancer
return for ovarian removal.
Conclusion
Salpingectomy alone should not be offered to high-risk women as a prevention strategy
outside of research studies until prospective data on risk and mortality are available. To
reach this goal it is important that gynecologists who perform the operation enrol the
patients in appropriate research studies with this goal in mind.
References
1. Bowtell DD, et al. Rethinking ovarian cancer 4. Finch AP, et al. Impact of oophorectomy on
II: reducing mortality from high-grade cancer incidence and mortality in women
serous ovarian cancer. Nat Rev Cancer with a BRCA1 or BRCA2 mutation. J Clin
2015;15(11):668–679. Oncol 2014;32(15):1547–1553.
2. Kotsopoulos J, et al. Hereditary Ovarian 5. Metcalfe K, et al. Effect of oophorectomy on
Cancer Clinical Study Group. Breastfeeding survival after breast cancer in BRCA1 and
and the risk of epithelial ovarian cancer BRCA2 mutation carriers. JAMA Oncol
among women with a BRCA1 or BRCA2 2015;1(3):306–313.
mutation. Gynecol Oncol 2020;2020:S0090– 6. Evans DG, et al. Survival from breast cancer
8258. in women with a BRCA2 mutation by
3. Gronwald J, et al. A comparison of treatment. Br J Cancer 2021;124
ovarian cancer mortality in women with (9):1524–1532.
BRCA1 mutations undergoing annual 7. Lugo Santiago N, et al. Ovarian cancer after
ultrasound screening or preventive prophylactic salpingectomy in a patient with
oophorectomy. Gynecol Oncol 2019;155 germline BRCA1 mutation. Obstet Gynecol
(2):270–274. https://doi.org/10.1016/j 2020;135(6):1270–1274. https://doi.org/10
.ygyno.2019.08.034 .1097/AOG.0000000000003864

Debate
Can High-risk HPV Testing be Used
4A Alone as the Primary Screening

Modality for Cervical Cancer?
Yes
Thomas C. Wright
Debate
Cervical cytology reduced cervical cancer incidence by approximately 70% in countries with
widespread screening. Despite cytology’s success, there is interest in improving screening by
incorporating sensitive molecular testing for high-risk HPV genotypes that cause most
cervical cancer. This is because cytology is now recognized to have a sensitivity of only 50–
75% for high-grade cervical neoplasia (CIN3+). Low sensitivity means cytology needs to be
repeated frequently to obtain high levels of protection.
HPV testing can be incorporated into screening in two ways. One is to replace cytology
with HPV testing (i.e., primary HPV screening). The other is to combine HPV testing with
cytology (i.e., co-testing). Nonrandomized studies and seven randomized screening trials
have evaluated the safety and effectiveness of these two approaches [1]. These studies clearly
demonstrate that HPV testing increases the detection of CIN3+ at the initial round of
screening compared to cytology alone and reduces CIN3+ found at subsequent screening
rounds. A meta-analysis of long-term follow-up data from several randomized trials found
a 40% lower incidence of invasive cervical cancer in women screened with HPV compared
to cytology. Therefore, some countries have adopted HPV primary screening for their
national screening programs. These include Australia, United Kingdom, Netherlands,
Denmark, Sweden, Turkey, and regions of Italy. In contrast, United States policy makers
initially adopted co-testing, which was cleared by the United States Food and Drug
Administration (US FDA) for use in women >30 years in 2003 and classified as the preferred
screening approach for women >30 years by the American Cancer Society in 2012.
The reasons why co-testing was initially preferred in the United States include that
clinicians want to reduce cervical cancer risk to a minimum and believed two tests would
provide the greatest protection. This is not the case. The National Cancer Institute (NCI)
analyzed over one million women co-tested at Kaiser Permanente and found that risk of
CIN3+ was similar among HPV-negative and co-test-negative women [2]. After three years,
the cumulative risk of CIN3+ was 0.07% in HPV-negative women compared to 0.05% for
co-test-negative women. The risk in women with a negative cytology was 0.19%.
Three US FDA registration trials of HPV primary screening with up to three years of
follow-up have been completed (Table 4A.1). The first is the ATHENA study that evaluated
the Roche cobas 4800 HPV test. In ATHENA, all women received HPV testing and cytology
and HPV-positive and/or cytology-positive women received colposcopy, as did a random
subset of women negative on both tests. This allowed verification bias adjustment. In
ATHENA, women without CIN2+ who underwent colposcopy were followed for three
16

HPV Testing Alone as Primary Screening Modality? Yes 17
Table 4A.1 Verification bias adjusted comparative performance of HPV primary screening and co-testing
algorithms for detection of CIN3+ in women >25 years
ATHENA1 BD Onclarity2 IMPACT3
Number of subjects 40,901 29,633 34,807

HPV (+) rate 10.5% 12.7% 15.1%
>ASCUS 6.4% 8.4% 9.8%
HPV primary screening
Sensitivity (%) 76.1 64.2 79.9
Specificity (%) 93.5 94.4 92.9
Positive predictive value (%) 12.9 9.0 9.0
Negative predictive value (%) 99.7 99.7 99.8
Colposcopy referral (%) 9.2 6.1 7.7
Co-testing
Sensitivity (%) 61.7 57.7 77.6
Specificity (%) 94.6 94.2 92.5
Cytology alone
Sensitivity (%) 47.8 49.2 66.1
Specificity (%) 97.1 92.0 90.7
1
Algorithm performance was assessed after three years of follow-up and is verification bias adjusted. Co-testing
algorithm performance does not include HPV testing (i.e., uses cytology only) for women 25–29 years of age.
2
Algorithm performance was assessed at baseline and is verification bias adjusted.
3
Algorithm performance was assessed at baseline and is verification bias adjusted. Co-testing algorithm
performance does not include HPV testing (i.e., uses cytology only) for women 25–29 years of age.
years. This allowed evaluation of the performance of different screening algorithms over
a three-year screening cycle [3]. The HPV primary screening algorithm that was evaluated is
shown in Figure 4A.1, as is the co-testing algorithm. The HPV primary screening algorithm
incorporates HPV 16/18 genotyping and HPV 16-/18-positive women receive colposcopy.
The performance characteristics of the HPV primary screening and co-testing algorithms
for CIN3+ in women >30 years are shown in Table 4A.1. HPV primary screening detected
more cases of CIN3+ over the three-year period than did co-testing. It is important to
recognize that the sensitivity and specificities shown in Table 4A.1 are those of the screening
algorithms, not simply the screening test, and have been adjusted for verification bias. The
sensitivity of HPV testing, as opposed to the algorithm, for CIN3+ without verification bias
adjustment is typically higher, about 90%.
The two other US FDA registration trials are the Onclarity HPV study and the IMPACT
study [4,5]. Both trials had similar study designs to that of ATHENA and evaluated HPV
primary screening and co-testing algorithms that were similar to ATHENA’s. Table 4A.1

18 Thomas C. Wright
HPV Primary Screening
Routine
Negative
Screening
Repeat LBC/
Negative
HPV 1 yr
12 other
HPV LBC
HPV
≥ASC-US Colposcopy
16/18
Colposcopy
Positive
Cotesting (Used only for women >30 yrs. Women 25–29 yrs received cytology only)
Negative Routine
Both Screening
Negative LBC/ Repeat LBC/

Positive HPV HPV 1 yr
LBC/HPV
HPV Routine
Negative Screening
ASC-US
HPV
Colposcopy
Positive
>ASC-US Colposcopy
LBC, liquid-based cytology
Figure 4A.1 Screening algorithms evaluated in ATHENA.

HPV Testing Alone as Primary Screening Modality? Yes 19
shows the comparative performance characteristics of HPV primary screening and co-
testing. Both the BD Onclarity HPV assay (Becton, Dickinson, and Company) and the
Roche cobas 6800 HPV assay are now FDA cleared for HPV primary screening in women
>25 years using the algorithm incorporating HPV 16/18 genotyping and cytology triage of
women with 12 “other” HPV genotypes.
Conclusion
Data from the European randomized clinical trials, the large NCI-Kaiser Permanente real-
world follow-up study, and the three US FDA registration trials clearly demonstrate that
HPV primary screening is safe and effective. Moreover, co-testing which combines both
HPV testing and cytology offers minimal, if any, benefit compared to HPV primary testing.
Co-testing increases costs, requires follow-up of HPV-negative women with ASCUS and
LSIL that can lead to unnecessary colposcopies/biopsies, and retains the medico-legal risk of
false-negative cytology results. It is also expected that as HPV vaccination reduces the
prevalence of CIN3+, the performance of cytology will decrease more than the performance
of HPV testing. HPV primary screening is now classified as the preferred screening
approach for women >25 years by the 2020 American Cancer Society guidelines.
References
1. US Preventive Services Task Force, et al. of study results from the ATHENA study
Screening for cervical cancer: US Preventive using HPV as the first-line screening test.
Services Task Force Recommendation Gynecol Oncol 2015;136:189–197.
Statement. JAMA 2018;320:674–686. 4. Food and Drug Administration. FDA
2. Gage JC, et al. Reassurance against future Summary of Safety and Effectiveness Data;
risk of precancer and cancer conferred by cobas HPV for use on the cobas 6800/8800
a negative human papillomavirus test. J Natl System. 2020.
Cancer Inst 2014;56(5):106. 5. Food and Drug Administration. FDA
3. Wright TC, et al. Primary cervical cancer Summary of Safety and Effectiveness Data;
screening with human papillomavirus: end BD Onclarity HPV Assay. 2018.

Debate
Can High-risk HPV Testing be Used
4B Alone as the Primary Screening

Modality for Cervical Cancer?
No
Ibraheem O. Awowole and Olusegun O. Badejoko
Debate: High-risk HPV is Insufficient as a Stand-alone Primary

Screening Modality for Cervical Cancer
Cervical cancer, with its global incidence of 570,000, and annual mortality of 311,000 (which
represents 7.5% of all female cancer deaths), is the second most common cancer in women
living in developing countries [1]. In the United States, cervical cancer used to be the leading
cause of cancer death among women, but this narrative has changed significantly over the last
four decades. The statistics are similar in other developed countries, due to the impact of the
established screening program, which is estimated to prevent up to 80% of cervical cancers [1].
The reduction in the incidence of cervical cancer and associated mortality in developed
countries was hinged on conventional and liquid-based cytology screening. The discourse
however continues to evolve, concerning what the best modality of screening should be, with
some countries gradually transitioning towards high-risk HPV-based primary screening.
HPV is a group of about 200 related viruses, 14 of which have been identified as high-risk
HPV (Hr-HPV). These 14 Hr-HPV are reportedly found in 99% of cervical cancer specimens,
with HPV 16 and 18 alone accounting for at least 70% of all cervical cancers. This knowledge
has been utilized extensively in the primary (vaccination) and secondary (screening) preven-
tion of cervical cancer [1]. A meta-analysis involving 140,000 women concluded that primary
screening with Hr-HPV was more sensitive than liquid-based cytology (LBC) for CIN2+, with
a pooled sensitivity estimate of 89.9% vs. 72.9% (Relative Sensitivity=1.18). Pooled specificity
estimate of Hr-HPV is however slightly lower, with a Relative Specificity Estimate of 0.96 (95%
CI: 0.95–0.97). Hr-HPV-based screening may also lead to the detection of more CIN2+
lesions [2].
Despite these benefits however, Hr-HPV alone is insufficient as a screening test for cervical
cancer. Almost all sexually active women below the age of 30 years will screen positive for
HPV at some point, with about 50% being the Hr-HPV serotypes [1,3]. These infections are
however transient and more than 90% are cleared by the host immunity within two years,
thereby preventing progression to CIN or invasive cancers, which is only seen in persistent
cases. Cervical cancer is therefore a low-probability event compared with the total number of
HPV-infected women in this age group, making screening with Hr-HPV less effective. This
was confirmed by Koliopoulos et al. [2] in their systematic review, which concluded that
screening with Hr-HPV may be less likely to miss cases of CIN2+, but will lead to more
unnecessary referrals. WHO also recommended that screening with Hr-HPV should not start
20

HPV Testing Alone as Primary Screening Modality? No 21
until the age of 30 years [1], while the U.S. Preventative Task Force (USPTF) and the
American College of Obstetricians and Gynecologists (ACOG) currently recommend that
LBC, not Hr-HPV should be used for screening women aged 21–29 years [3].
NHS England and the American Cancer Society [4,5] adopted a middle ground, recom-
mending transitioning to Hr-HPV-based screening from 25 years as the preferred option,
with LBC or LBC/Hr-HPV co-testing as alternatives. This option may reduce the unnecessary
follow-up testing for women <25 years, but it is not without its limitation. Between 2011 and
2015, some 108 new cervical cancers were reported annually among women <25 years in the
American Cancer Registry [3]. This was despite over a decade of HPV vaccination, with many
of those that were vaccinated now in the 20–24 years group. Suspending screening in that
group may leave them vulnerable, especially in settings where vaccination is yet to be
established. Screening women <29 years with LBC, and not Hr-HPV therefore appears to
be the pragmatic option.
Women that are aged 30–65 years with negative Hr-HPV can be reasonably assured of
being at very low risk for cervical cancer. The utility of Hr-HPV is however limited to the
negative predictive value. The test is inadequate among women with positive Hr-HPV, as
a substantial proportion of these infections will only be transient as well. Cytological triage
is therefore essential to design a plan of care, for evaluation of the cytopathic effects of HPV
which are only seen in persistent infections. Screening with Hr-HPV alone, without
recourse to cytology for women with positive Hr-HPV will therefore be associated with
unnecessary referrals to colposcopy and treatment. Furthermore, there is a subset of high
grade squamous intraepithelial lesion (HGSIL) cytology and cervical carcinomas that are
Hr-HPV negative. The American Society for Clinical Pathology (ASCP) expressed concerns
that 9–10% of invasive cancers and that 8.3–14% of HGSIL cases may test negative with
commercially available Hr-HPV kits, leading to delayed diagnosis that may result in higher
stage tumors, especially in the setting of a longer screening interval of five years. To avoid
this, the ASCP advised that Hr-HPV alone may be insufficient, and women should have
cytological examination at some point during their screening.
Lastly, concerns have been expressed that some women may test positive to Hr-HPV due
to a reactivation of an old, supposedly cleared infection, akin to the phenomenon in chicken-
pox. LBC co-testing remains the best plan of care for such patients, while research continues
on the subject.
Conclusion
Hr-HPV is insufficient as a stand-alone primary screening test for cervical cancer. As
countries transition to Hr-HPV for cervical cancer screening, it is important to acknow-
ledge the limitations of the test and refine its utilization across different populations.
References
1. World Health Organization. Human general population. Cochrane Database Syst
papillomavirus (HPV) and cervical cancer. Rev 2017;8(8):CD008587.
Geneva: WHO, 2018. Available at: www 3. United States Preventive Service Task
.who.int/en/news-room/fact-sheets/detail/h Force. Cervical Cancer: Screening. 2018.
uman-papillomavirus-(hpv)-and-cervical- Available at: www.uspreventiveservices
cancer [last accessed October 18, 2022]. taskforce.org/uspstf/recommendation/
2. Koliopoulos G, et al. Cytology versus HPV cervical-cancer-screening [last accessed
testing for cervical cancer screening in the October 18, 2022].

22 Ibraheem O. Awowole and Olusegun O. Badejoko
4. Public Health England with NHS England 5. Fontham ETH, et al. Cervical cancer
and NHS Improvement Public Health screening for individuals at average risk:
Commissioning. NHS public health 2020 Guideline Update from the American
functions agreement 2019–2020 Service Cancer Society. CA Cancer J Clin 2020;70
specification No.25; Cervical Screening (5):321–346.
Programme. PHE England, 2020.

Section III Ovarian Cancer
Debate
Should CA-125 Surveillance
5A be Performed after Completion

of Primary Treatment
for Ovarian Cancer Patients
in Remission?
Yes
Eseohi Ehimiaghe and Edward Tanner
Debate
Serum CA-125 levels have been widely used to assess disease status in patients with
advanced epithelial ovarian cancer. Although CA-125 is only elevated in half of patients
with early-stage disease, the majority of patients with advanced stage disease will have an
elevation at diagnosis. The rate of CA-125 decline following cytoreductive surgery and
chemotherapy predicts treatment response and recurrence risk [1,2]. Increases in serum
CA-125 levels generally herald disease recurrence, with CA-125 levels rising at recurrence in
at least 70% of patients with an elevated level at baseline [3]. Even small increases in CA-125
levels have a strong association with recurrence risk. For example, Piatek et al. found
a seven-fold increased risk of recurrence when serum CA-125 levels increased by as little
as 5 U/ml from baseline [4].
Conventional wisdom suggests that early detection of recurrent disease would lead
to superior post-recurrence survival – much like the diagnosis of early-stage disease
results in superior survival versus advanced stage disease [5]. Surprisingly, this correl-
ation is not as strong as one may assume. A large European Organisation for Research
and Treatment of Cancer (EORTC) trial, which randomized patients with advanced
ovarian cancer in first remission to CA-125 surveillance as a mechanism to detect
disease recurrence versus identification based on symptoms [6], showed early initiation
of salvage chemotherapy based on increased CA-125 levels led to earlier initiation of
chemotherapy but did not improve survival. While it is difficult to disagree with the
results of a well conducted randomized trial, the results were limited by the fact that
only 19% of patients underwent secondary surgery. Two recently completed random-
ized trials demonstrate a mixed benefit of secondary surgery [7,8], so we must consider
the value CA-125 has in subsets of patients. Most surgeons agree that healthy women
with a long progression-free interval and high likelihood of complete secondary cytor-
eduction benefit from surgery and multiple retrospective studies have found that
women who have a recurrence identified by CA-125 elevation without symptoms
have a higher chance of complete secondary cytoreduction [3,9]. Given these findings,
and the small proportion of patients who underwent secondary surgery in the EORTC
23

Section III Ovarian Cancer
Debate
5A be Performed after Completion

of Primary Treatment
for Ovarian Cancer Patients
in Remission?
Yes
Eseohi Ehimiaghe and Edward Tanner
Debate
Serum CA-125 levels have been widely used to assess disease status in patients with
advanced epithelial ovarian cancer. Although CA-125 is only elevated in half of patients
with early-stage disease, the majority of patients with advanced stage disease will have an
elevation at diagnosis. The rate of CA-125 decline following cytoreductive surgery and
chemotherapy predicts treatment response and recurrence risk [1,2]. Increases in serum
CA-125 levels generally herald disease recurrence, with CA-125 levels rising at recurrence in
at least 70% of patients with an elevated level at baseline [3]. Even small increases in CA-125
levels have a strong association with recurrence risk. For example, Piatek et al. found
a seven-fold increased risk of recurrence when serum CA-125 levels increased by as little
as 5 U/ml from baseline [4].
Conventional wisdom suggests that early detection of recurrent disease would lead
to superior post-recurrence survival – much like the diagnosis of early-stage disease
results in superior survival versus advanced stage disease [5]. Surprisingly, this correl-
ation is not as strong as one may assume. A large European Organisation for Research
and Treatment of Cancer (EORTC) trial, which randomized patients with advanced
ovarian cancer in first remission to CA-125 surveillance as a mechanism to detect
disease recurrence versus identification based on symptoms [6], showed early initiation
of salvage chemotherapy based on increased CA-125 levels led to earlier initiation of
chemotherapy but did not improve survival. While it is difficult to disagree with the
results of a well conducted randomized trial, the results were limited by the fact that
only 19% of patients underwent secondary surgery. Two recently completed random-
ized trials demonstrate a mixed benefit of secondary surgery [7,8], so we must consider
the value CA-125 has in subsets of patients. Most surgeons agree that healthy women
with a long progression-free interval and high likelihood of complete secondary cytor-
eduction benefit from surgery and multiple retrospective studies have found that
women who have a recurrence identified by CA-125 elevation without symptoms
have a higher chance of complete secondary cytoreduction [3,9]. Given these findings,
and the small proportion of patients who underwent secondary surgery in the EORTC
23

24 Eseohi Ehimiaghe and Edward Tanner
trial, as oncologists, we could consider CA-125 surveillance as part of the follow-up

plan for patients who are good candidates for secondary cytoreduction.
Conclusion
Even if CA-125 surveillance does not provide an objective survival advantage for most
patients with ovarian cancer, there may still be a patient-centered benefit to CA-125
surveillance. Many patients recognize loss of control as a leading cause of anxiety after
a cancer diagnosis. While some patients feel that earlier identification of recurrence without
survival advantage would lead to unnecessary anxiety during a time when they are otherwise
well, others feel that knowing their disease status adds a level of control and life planning
that is beneficial to their health and well-being [10]. While our focus as gynecology
oncologists is often on quantifiable improvement in clinical outcomes and mortality,
patients might consider the heralding impact of CA-125 changes as important information
to guide life decisions [11,12]. We must be willing to discuss the benefits and harms of CA-
125 surveillance with our patients, so that we provide them with options that empower
decision making.
References
1. Rodriguez N, et al. Changes in serum CA-125 during follow-up. Ann Oncol Off
CA-125 can predict optimal cytoreduction J Eur Soc Med Oncol 2011;22(Suppl. 8):
to no gross residual disease in patients with viii40–viii44. https://doi.org/10.1093/anno
advanced stage ovarian cancer treated with nc/mdr470
neoadjuvant chemotherapy. Gynecol Oncol 6. Rustin GJS, et al. Early versus delayed
2012;125:362–366. https://doi.org/10.1016 treatment of relapsed ovarian cancer (MRC
/j.ygyno.2012.02.006 OV05/EORTC 55955): a randomised trial.,
2. Rustin GJS, et al. Definitions for response Lancet 2010;376:1155–1163. https://doi.org
and progression in ovarian cancer clinical /10.1016/S0140-6736(10)61268-8
trials incorporating Response Evaluation 7. Coleman RL, et al. Secondary surgical
Criteria In Solid Tumors (RECIST) 1.1 and cytoreduction for recurrent ovarian cancer.
CA-125 agreed by the gynecological cancer N Engl J Med 2019;381:1929–1939. https://
intergroup (GCIG). Int J Gynecol Cancer doi.org/10.1056/NEJMoa1902626
2011;21:419–423. https://doi.org/10.1097/I
GC.0b013e3182070f17 8. Du Bois A, et al. Randomized phase III
study to evaluate the impact of secondary
3. Fleming ND, et al. CA-125 surveillance cytoreductive surgery in recurrent ovarian
increases optimal resectability at secondary cancer: final analysis of AGO DESKTOP
cytoreductive surgery for recurrent III/ENGOT-ov20. J Clin Oncol
epithelial ovarian cancer. Gynecol Oncol 2020;38:6000. https://doi.org/10.1200/JCO
2011;121:249–252. https://doi.org/10.1016 .2020.38.15_suppl.6000
/j.ygyno.2011.01.014
9. Tanner EJ, et al. Surveillance for the
4. Piatek S, et al. Rising serum CA-125 levels detection of recurrent ovarian cancer:
within the normal range is strongly survival impact or lead-time bias? Gynecol
associated recurrence risk and survival Oncol 2010;2010:117. https://doi.org/10
of ovarian cancer. J Ovarian Res .1016/j.ygyno.2010.01.014
2020;13:102. https://doi.org/10.1186/
s13048-020-00681-0 10. Jordens CFC, et al. Cancergazing? CA-125
and post-treatment surveillance in
5. Pignata S, et al. Follow-up with CA-125 advanced ovarian cancer. Soc Sci Med
after primary therapy of advanced ovarian 2010;71:1548–1556. https://doi.org/10
cancer: in favor of continuing to prescribe .1016/j.socscimed.2010.07.033

Should CA-125 Surveillance be Performed? Yes 25
11. Tsai L-Y, et al. Life experiences and disease 12. Jolicoeur LJA, et al. Women’s decision-
trajectories in women coexisting with making needs related to treatment for
ovarian cancer. Taiwan J Obstet Gynecol recurrent ovarian cancer: a pilot study. Can
2020;59:115–119. https://doi.org/10.1016/j Oncol Nurs J 2009;19:117–121. https://doi
.tjog.2019.11.032 .org/10.5737/1181912x193117121

Debate
5B be Performed after Completion

of Primary Treatment for Ovarian
Cancer Patients in Remission?
No
Gordon J. S. Rustin
Debate
Relapse diagnosed by CA-125 is detected about six months earlier than relapse diagnosed
through development of symptoms. If earlier treatment of relapse improves survival and/or
quality of life, patients should be advised to have CA-125 surveillance. However, if earlier
diagnosis of relapse and earlier treatment do not improve survival and lead to a worse
quality of life, patients should be advised against having CA-125 surveillance.
The only randomized trial that investigated the role of CA-125 surveillance found that
routine CA-125 measurements did not benefit patients. The MRC OV05/ EORTC 55955
trial enrolled 1442 patients with a CA-125 level within the normal range following
platinum-based chemotherapy for epithelial ovarian cancer [1]. If CA-125 levels rose to
more than twice the upper limit of normal, patients were randomized to immediate or
delayed chemotherapy. Those randomized in the early arm started chemotherapy
a median of 4.8 months earlier than those on the delayed arm. There was no difference
in survival between the early and delayed arms, with worse quality of life of patients in the
early arm.
This led to a change in practice in some centers with 80% of patients in a retrospective
audit choosing not to have routine CA-125 follow-up [2]. However, an audit of six United
States cancer centres showed that routine use of CA-125 did not change and there was no
lengthening of time from CA-125 doubling to re-treatment [3]. Why do some patients opt
for CA-125 surveillance and some do not?
A major reason why patients want CA-125 surveillance is the belief that earlier detection
of relapsed disease will lead to longer survival. The OVO5 trial clearly showed that earlier
starting of chemotherapy does not help, but too few patients had second surgery in that trial
to determine whether surgery improves survival. Retrospective studies have suggested that
asymptomatic patients whose relapse was detected by surveillance are more likely to receive
optimal surgery and have longer survival following surgery than those who relapsed with
symptoms. Lead time bias could explain some of this difference as could selection of patients
for surgery.
The results of two trials randomizing patients to secondary surgery followed by chemo-
therapy or chemotherapy alone, have unfortunately not resolved this dilemma. The
GOG213 trial failed to show any survival benefit from surgery, but the DESKTOP 3 trial
26

Should CA-125 Surveillance be Performed? No 27
showed a significantly longer survival in the surgery arm [4,5]. The GOG trial was per-
formed in a country where most patients had frequent CA-125 measurements during
follow-up. The DESKTOP 3 trial was performed in countries where patients were recom-
mended not to have routine CA-125 surveillance. One can envisage that asymptomatic
relapse just detected by CA-125 is more likely to be associated with peritoneal thickening or
just ascites, that is not helped by surgery, whilst those with symptomatic relapse might be
more likely to have resectable disease. As most surgeons would not consider secondary
surgery before patients are treatment-free for at least 12 months, there is no point in
measuring CA-125 during the first year of follow-up.
Patient decision making as to what surveillance policy to adopt is likely to be influenced
by the local culture and the opinions of their oncologist. If the culture supports maximal
intervention regardless of cost (both financial and impact on quality of life) patients will
expect intense surveillance and the oncologist might go along with it to appear to be fighting
hard for their patient. Those doctors who are happy that their patients erroneously believe
that cure of relapsed ovarian cancer is still possible, are likely to be in favor of routine CA-
125 measurements. If the culture is to be guided by experts who accurately inform patients
of the scientific evidence, patients entering remission should be offered the following
options:
1. Not to have routine CA-125 measurements if they are well and have no symptoms
suggesting relapse.
2. To continue having CA-125 measurements but not be told the results. This option is
particularly useful if they are in a clinical trial.
3. To have routine CA-125 measurements so that they have more warning as to when
they might require relapse chemotherapy.
Further requirements to enable safe follow-up of ovarian cancer patients who opt for no
routine CA-125 measurements are: (1) A leaflet about follow-up which includes a list of
likely symptoms that should prompt an early clinic appointment (see http://links.lww.com
/IGC/A456); (2) Facilities for patients to make urgent appointments; (3) Availability of
a support nurse for telephone advice.
Conclusion
After completion of primary treatment for ovarian cancer, some patients are started on
maintenance therapy with bevacizumab or a PARP inhibitor. These patients need moni-
toring by CA-125 and scans. Most patients are not on maintenance therapy and risk
having their remission shortened and hope of cure destroyed by being told their CA-125 is
rising. Worrying about CA-125 results increases anxiety before clinic appointments. Once
patients are aware of a rising CA-125 level it becomes difficult to delay starting relapse
therapy. Patients need to be told before embarking on CA-125 surveillance that it could
lead to a worse quality of life with more chemotherapy than needed, for no survival
benefit.
References
1. Rustin GJ, et al. Early versus delayed 2. Krell D, et al. Audit of CA-125
treatment of relapsed ovarian cancer follow-up after first-line therapy for
(MRCOV05/EORTC 55955): a randomised ovarian cancer. Int J Gynecol Cancer
trial. Lancet 2010;376:1155–1163. 2017;27:1118–1122.

28 Gordon J. S. Rustin
3. Esselen KM, et al. Use of CA-125 tests and 5. Du Bois A, et al. Randomized phase III study
CT scans for surveillance in ovarian cancer. to evaluate the impact of secondary
JAMA Oncol 2016;2(11):1427–1433. cytoreductive surgery in recurrent ovarian
4. Coleman RL, et al. Secondary surgical cancer: final analysis of AGO DESKTOP III/
cytoreduction for recurrent ovarian cancer. ENGOT-ov20. J Clin Oncol 2020;38(Suppl.
N Engl J Med 2019;381(20):1929–1939. 15):6000.

Chapter
In Patients with BRCA-negative
6A and HRD-negative Epithelial

Ovarian Cancer, Should Molecular
Profiling be Routinely Done
to Guide Adjuvant Therapy?
Yes
Ilaria Betella and Matteo Repetto
Debate
Undoubtedly, gynecological oncologists have witnessed a dramatic change in the landscape
of epithelial ovarian cancer (EOC) management since the introduction of poly ADP-ribose
polymerase inhibitors (PARPi) into adjuvant standard-of-care therapy in 2018. In this
relatively short period, not only geneticists and molecular biologists, but all healthcare
providers involved in EOC treatment had to expand their knowledge of cancer genetics and
molecular profiling in order to acquire expertise to integrate the new clinical available tools
in the appropriate management strategy. Since the advent of PARPi, which target cells with
homologous recombination repair deficiency (HRD), including BRCA mutated cells, dif-
ferent HRD panels and assays have been investigated for predicting the response to PARPi.
To date, there are two commercially available tests to assess HRD: Myriad myChoice CDx
and Foundation Medicine’s Foundation Focus CDx. Beside sequencing and evaluating ®
®
large rearrangement of BRCA1/2 genes, both these assays only analyze the phenotypic
consequence on DNA of genomic instability, without identifying the specific causative
gene alterations. Thus, further molecular profiling in BRCA-negative and HRD-negative
EOCs is still worthy to guide adjuvant therapy [1].
Molecular profiling is not a new concept, if immunohistochemistry (IHC), Fluorescence
In Situ Hybridization (FISH), Sanger sequencing or Quantitative Polymerase Chain
Reaction (qPCR) are taken in consideration. However, all these techniques permit the
identification of few specific alterations at a time. The advent of the Next-Generation
Sequencing (NGS), which allows us to simultaneously examine millions of gene fragments
and more broadly detect DNA mutations, copy number variations and gene fusions across
the genome in only a few days and at affordable cost, represents a major breakthrough,
allowing the routine use of comprehensive molecular profiling in clinical decision mak-
ing [2].
The cornerstone in extensive genomic analysis in EOC was settled in 2011, with the
publication of The Cancer Genome Atlas (TCGA). Methylation, messenger RNA (mRNA)
and microRNA (miRNA) expression, and DNA copy number variations were tested as
prognostic predictors in advanced high-grade serous (HGS) EOC, enabling the identification
29

30 Ilaria Betella and Matteo Repetto
of four subtypes, namely differentiated, immunoreactive, mesenchymal, and proliferative.

Moreover, the DNA exome sequencing and the pathway analysis not only identified that 50%
of HGS-EOC harbor homologous recombination repair (HRR) defects and may benefit from
PARPi, but also pinpointed other commonly deregulated pathways, including RB, RAS/PI3 K,
FOXM1, and NOTCH, which are potential targets for therapeutic treatment. Furthermore,
comparison with literature allowed identification of different mutation spectrums across
distinct EOC histological subtypes: while HGS-EOCs harbor TP53 and BRCA mutations in
96% and 22% of specimens respectively, clear-cell ovarian cancers show recurrent ARID1A
and PIK3CA mutations and endometrioid ovarian tumors frequently have CTNNB1,
ARID1A, and PIK3CA mutations [3].
Despite the obvious benefit of gaining a deeper understanding of tumor biology, the
huge amount of data obtained from NGS panels may quickly overwhelm gynecological
oncologists, increasing the risk of missing clinically valuable information. To overcome the
complexity of interpreting the NGS data and providing timely results according to the
clinical need, a number of precision medicine platforms have been developed to assist
Molecular Tumor Boards (MTB) and oncologists. An example is OncoKb, a comprehensive
and curated precision oncology knowledge base, which classifies the clinical actionability of
mutations in levels ranging from 1, that identifies a biomarker for a Food and Drug
Administration (FDA-) approved drug for that same indication, to 4, indicating
a biomarker potentially predictive of response based on compelling biological evidence
[4]. Specifically for EOC, as of October 2020, the OncoKb database identified 15 actionable
genes (NTRK1-2–3, AKT1, BRAF, CDK12, CDKN2A, FGFR1-2–3, KRAS, MET, MTOR, NF1
and PTEN) and two actionable signatures, named Tumor Mutational Burden (TMB) and
MicroSatellite Instability (MSI), in addition to BRCA1 and BRCA2 mutations. Among these
17 actionable alterations, MSI-high, TMB-high, and NTRK1-2–3 fusions are targets for
FDA-approved therapies in EOC. Specifically, MSI-high, occurring in roughly 3% of HGS-
EOC, is a genomic signature characterized by abundant nonsynonymous mutations and
neoantigens, causing a high tumor mutational burden (TMB), conditions that predict
sensibility to immunotherapy. NTRK1-2–3 fusions predict sensitivity to specific small-
molecule inhibitors named Larotrectinib and Entrectinib [4]. As these alterations are
relatively rare when considered singularly, routine use of an alteration-specific test might
not be a viable strategy. Instead, NGS multiplexing allows us to simultaneously investigate
several genes, cumulatively increasing the probability of finding at least one rare actionable
mutation. Considering that the list of actionable alterations is progressively growing,
routinely performing NGS in EOC can help in expanding therapeutic options for strategic
management of patients.
Additionally, NGS panels represent clinically valuable prognostic tools. As a number of
alterations have been linked to worse response to platinum salts and PARPi, for example
EMSY and CCNE1 amplifications [5], their early identification might predict drug resistance
and avoid unnecessary costs and drug-associated morbidity. Indeed, in some countries,
patients with cancer are required to pay a variable proportion of their medical bills leading
sometimes even to bankruptcy, while in other countries public health resources are limited,
requiring a cautious evaluation of the balance between advantages and risks of a specific
therapy. Moreover, adjuvant therapy is responsible for a range of adverse events which, in
drug-resistant disease, may worsen the patient’s quality of life without improvement in
prognosis. As such, extended NGS-derived information represents an additional instrument
that can be adopted in oncological counseling to help patients making an aware choice.

Molecular Profiling to Guide Adjuvant Therapy? Yes 31
Furthermore, tumor molecular profiling can favor patient enrollment in basket or

umbrella clinical trials for testing the efficacy of new drugs against specific molecular targets.
This achieves two purposes: on the one hand, it allows patients to access innovative tailored
treatment with potential benefit; on the other hand, it helps fast-track evaluation and
approval of tailored adjuvant therapies with improved efficacy and a more favorable toxicity
profile [2].
Conclusion
In conclusion, molecular profiling should be routinely done in BRCA-negative HRD-
negative EOC. Even though EOC guidelines do not recommend systematical NGS analysis
at diagnosis yet, it effectively helps fulfill several purposes. Indeed, the use of extended
molecular panels not only leads to greater understanding of tumor biology, but it also
identifies alternative actionable alterations, predicts prognosis and/or drug resistance, and
allows access to alteration-directed clinical trials with potential benefit for the patients.
References
1. Mirza MR, et al. The forefront of ovarian carcinoma. Nature 2011;474(7353):609–15.
cancer therapy: update on PARP inhibitors. https://doi.org/10.1038/nature10166.
Ann Oncol 2020;31(9):1148–1159. https://d Erratum in: Nature 2012;490(7419):298.
oi.org/10.1016/j.annonc.2020.06.004 4. www.oncokb.org/ [last accessed October 18,
2. Berger MF, et al. The emerging clinical 2022].
relevance of genomics in cancer medicine. 5. Konstantinopoulos PA, et al. Homologous
Nat Rev Clin Oncol 2018;15:353–365. http recombination deficiency: exploiting
s://doi.org/10.1038/s41571-018-0002-6 the fundamental vulnerability of
3. Cancer Genome Atlas Research Network. ovarian cancer. Cancer Discov
Integrated genomic analyses of ovarian 2015;5:1137–1154.

Debate
In Patients with BRCA-negative
6B and HRD-negative Epithelial

Ovarian Cancer, Should Molecular
Profiling be Routinely Done
to Guide Adjuvant Therapy?
No
Raanan Alter and Ernst Lengyel
Debate
In the era of targeted medicine, the use of poly (ADP-ribose) polymerase (PARP) inhibitors
in homologous recombination deficient (HRD) tumors has represented the first clinically
actionable mutation in gynecologic malignancies. The dramatic results seen across multiple
clinical trials completely changed the landscape of epithelial ovarian cancer (EOC) treat-
ments in both primary and recurrent settings. For many, it has spawned hope that add-
itional biomarkers would soon be discovered that could find similarly spectacular results in
different patient populations. However, molecular profiling’s efficacy in selecting targeted
therapies and its economic practicality are difficult to justify.
Multigene panel testing using Next Generation Sequencing (NGS) for both germline
and somatic mutations are now offered by dozens of companies and often tests for over
1000 different genetic mutations, insertions/deletions, copy number variations, and
fusion/translocations. While these represent significant advances in molecular profiling
technology and contribute to the overall understanding of ovarian cancer biology, their
clinical utility is controversial. Up to 50% of patients will have HRD tumors and thus
have the ability to be treated with a PARP inhibitor; however, the clinical relevance of
NGS for treating the other half has not been at all established. As it turns out, the rate
of matching an “actionable” mutation to a targeted therapy is quite low. In a 2020
National Cancer Institute (NCI) match trial analysis, only 75 out of 530 (14.2%)
patients with EOC were paired with a targeted therapy [1]. In a 2019 study, Jae Lee
et al. found that out of 84 EOC patients, 57 (67.9%) were determined to have an
actionable mutation; out of which only seven patients were matched to a targeted
therapy [2]. Even those patients who had been matched to a therapy exhibited low
response rates. In the MOSCATO-1 trial, 199 out of 1035 patients were paired to
a targeted therapy, although only 22 (11% of the paired patients or 2.1% of the total
patient population) achieved an objective response. In the published literature, clinically
meaningful response rates for common targetable non-HRD mutations (HER2/NEU,
PI3 K) range from 10–17%, which is similar to standard of care cytotoxic chemothe-
rapies in the platinum-resistant setting.
32

Molecular Profiling to Guide Adjuvant Therapy? No 33
Additionally, there is also data that suggests a significant discordance between commer-
cial tests. In a 2017 study, Kuderer et al. compared two commercial NGS platforms on
specimens from the same patients. They found a 22% concordance between the specimens
and only nine of 36 targeted drugs were suggested by both tests [3]. While this discordance
was thought to be attributed to tumor heterogeneity from different biopsy specimens or
anatomic locations, this would question the overall utility of NGS from a single sample
given that tumor heterogeneity can heavily influence results.
One must acknowledge the dramatic costs associated with these panels. The cost to
patients for multigene panels ranges anywhere from $4000–$6500 [4]. While most
insurances will provide coverage for these panels, that does not diminish the large
cost incurred by our healthcare system for such a relatively low-yield product paired
with aggressive direct-to-consumer advertising by companies. Furthermore, the muta-
tions found in NGS may lead to the prescribing of off-label targeted therapy which can
be extremely costly (>$100,000 per year of therapy) and has not been shown to provide
improvements in response rates, progression-free survival or overall survival over
traditional cytotoxic chemotherapy regimens. In a recent cost utility model,
Wallbillich et al. found that treatments with targeted therapies were projected to have
a mean cost of $90,271 with 0.71 quality-adjusted life years (QALY), compared with
standard of care therapies which would cost $74,926 and 0.68 QALYs resulting in an
incremental cost-effectiveness ratio (ICER) of over $470,000 per QALY [5]. In fact, in
a sensitivity analysis, the genomic strategy never became cost effective even when the
genomic testing was free, as the driver of cost-effectiveness lay in the high price per
cycle of targeted therapies.
Conclusion
In summary, while the remarkable technological advances and the results seen in the
treatment of HRD tumors with PARP inhibitors are impressive, we do not recommend
the routine molecular profiling of EOC patients. The concordance between NGS platforms
is disappointingly low, the actionability of mutations is low, and the subsequent response
rates remain unchanged.
Ordering molecular testing can also generate a false sense of hope among our patients
that a novel or targeted therapy may be an option, when for almost all of these patients, such
options are not available. To this end, in an European Society for Medical Oncology
(ESMO) Precision Medicine Working Group analysis in 2020, the writing group felt that
the use of multigene NGS is justified, but cautions against larger panels on the basis that the
overall cost of the strategy must be considered. We would argue that beyond testing for
BRCA and HRD, molecular profiling for epithelial ovarian cancer should only be performed
in the clinical trial setting or for research purposes.
References
1. Flaherty KT, et al. Molecular landscape 2. Lee YJ, et al. Integrating a next generation
and actionable alterations in sequencing panel into clinical practice in
a genomically guided cancer clinical trial: ovarian cancer. Yonsei Med J 2019;60
National Cancer Institute Molecular (10):914–923.
Analysis for Therapy Choice 3. Kuderer NM, et al. Comparison of 2
(NCI-MATCH). J Clin Oncol 2020;38 commercially available next-generation
(33):3883–3894.

34 Raanan Alter and Ernst Lengyel
sequencing platforms in oncology. JAMA 5. Wallbillich JJ, et al. A personalized

Oncol 2017;3(7):996–998. paradigm in the treatment of
4. Haunschild CE, et al. The current landscape platinum-resistant ovarian cancer: a cost
of molecular profiling in the treatment of utility analysis of genomic-based versus
epithelial ovarian cancer. Gynecol Oncol cytotoxic therapy. Gynecol Oncol 2016;142
2020;160(1):333–345. (1):144–149.

Debate
Is MEK Inhibitor Therapy the Best
7A Treatment Recommendation
for Low-Grade Serous Ovarian
Cancer Patients at First Relapse?
Yes
Rachel N. Grisham
Debate
Patients with recurrent low-grade serous ovarian cancer have multiple options for treat-
ment: chemotherapy with or without bevacizumab, bevacizumab alone, or endocrine
therapy with Lupron, tamoxifen, or aromatase inhibitors. While all of these are viable and
appropriate options, recently reported data regarding the activity of MEK inhibitors in
recurrent low-grade serous ovarian cancer has shown that MEK inhibitors are a key
treatment option that should be considered at time of first recurrence in all patients with
low-grade serous ovarian cancer.
There has been considerable interest in the use of MEK inhibitors for the treatment of
low-grade serous ovarian cancer for over a decade, since the molecular profile of low-grade
serous ovarian cancer was first characterized as most commonly displaying alterations
affecting the Mitogen Activated Pathway Kinase (MAPK) pathway. Approximately a third
of patients with recurrent low-grade serous ovarian cancer harbor KRAS mutations, while
additional patients display fewer common alterations affecting components of the MAPK
pathway, such as in the BRAF, NF1, and MAPK1 genes [1,2].
The first prospective clinical trial examining the use of single agent MEK inhibitor in
recurrent low-grade serous ovarian cancer (GOG 0239), treated women with recurrent
measurable disease with single agent selumetinib (AZD6244) until progression of disease or
intolerable toxicity. Patients had a median of three prior lines of chemotherapy. The study
showed a promising objective response rate of 15%. No correlation was found between
presence of KRAS or BRAF mutation and response to therapy; however, sufficient DNA was
available for analysis in only 34/52 (65%) of evaluable patients [3].
Subsequently, two randomized phase III studies were performed comparing use of
single-agent MEK inhibitor to standard of care, in patients with recurrent measurable low-
grade serous ovarian cancer [4,5]. The GOG 0281 phase II/III study of the MEK inhibitor
trametinib versus physician’s choice of chemotherapy or endocrine therapy in patients with
recurrent disease and unlimited prior lines of chemotherapy found a significant difference
in median progression-free survival (PFS) with trametinib (13 months) versus physician’s
choice of chemotherapy (7.2 months; HR=0.48; p<0.001). The overall response rate (ORR)
was 26% and 6.2% for trametinib and physician’s choice, respectively (p < 0.0001) [4]. The
MILO/ENGOT-ov11 study was a phase III study of the MEK inhibitor binimetinib versus
physician’s choice of chemotherapy in patients with recurrent low-grade serous ovarian
35

36 Rachel N. Grisham
cancer and up to three prior lines of chemotherapy. Although the study was discontinued
early based on an interim analysis revealing that the PFS hazard ratio crossed the predefined
futility boundary, an updated analysis indicated a median PFS of 10.4 months for binimetinib
versus 11.5 months for physician’s choice (HR=1.15; p=0.748), and an ORR of 24% in both
arms of the study. Notably, for patients treated with binimetinib, the ORR and median PFS in
the KRAS mutant group (ORR=44%; median PFS=17.7 months) were significantly better than
in the KRAS wild-type group (ORR=19%; median PFS=10.8 months) (p=.006) [5] indicating
that patients with KRAS mutation may be most likely to respond to MEK inhibitor treatment.
Based on the above results, trametinib is now National Comprehensive Cancer
Network (NCCN) compendium listed for the treatment of recurrent low-grade serous
ovarian cancer, and combination studies seeking to further enhance efficacy both for MEK
inhibitor-naïve patients, and for patients following progression on MEK inhibition, are
ongoing. While MEK inhibitors have shown clear efficacy in the treatment of recurrent
low-grade serous ovarian cancer, these agents also cause considerable toxicity, with rash,
diarrhea, edema, and ocular toxicity all commonly observed. In many cases, these toxi-
cities are most pronounced within the first three months of starting treatment and can be
more significant than the toxicities most frequently seen with chemotherapy, bevacizu-
mab, or endocrine therapies. These associated toxicities can lead to dose interruptions and
dose reductions, causing decreased dose intensity that translates into a missed opportun-
ity for optimal response and control of disease. MEK inhibitors are therefore best
administered early in the disease course, at time of first relapse, when patients generally
have the best performance status and are most likely to be able to tolerate continuous
therapy without dose reduction.
A particular concern in patients with recurrent low-grade serous ovarian cancer is the
risk of small bowel or large bowel obstruction, as this is frequently a consequence of
progressive disease. All of the currently Food and Drug Administration (FDA)-approved
MEK inhibitors (trametinib, binimetinib, and cobimetinib) are oral drugs which require
gastrointestinal absorption. Unfortunately, patients with progressive disease and bowel
obstruction are not candidates for oral MEK inhibitors but can benefit from infusional
chemotherapy and certain endocrine therapies such as fulvestrant. It is therefore important
to give patients the opportunity to receive a MEK inhibitor earlier in their disease course
before progressive symptoms may eliminate this option.
In making treatment decisions for patients, it is essential to perform somatic mutation
testing at time of first recurrence or earlier, as the third of patients with KRAS mutations
may derive the greatest benefit from treatment with MEK inhibitors, and should preferen-
tially be treated with MEK inhibitors early in their disease course.
Conclusion
MEK inhibitors offer the best chance of response in the recurrent setting and should be
considered for all patients with low-grade serous ovarian cancer at time of first recurrence.
MEK inhibitors are associated with significant toxicity, which may result in dose reductions
or early discontinuation of treatment in patients with multiple prior lines of therapy and
more symptomatic disease. In addition, the need for oral administration may limit the
ability to receive this important treatment in later line settings where patients are more
likely to develop obstructive complications. Therefore, it is imperative to evaluate patients
for potential treatment with MEK inhibitors at time of their first recurrence.

MEK Inhibitor Therapy: Yes 37
References
1. Grisham RN, et al. Extreme outlier single-arm, phase 2 study. Lancet Oncol
analysis identifies occult 2013;14(2):134–140.
mitogen-activated protein kinase pathway 4. Gershenson DM, et al. A randomized phase
mutations in patients with low-grade II/III study to assess the efficacy of
serous ovarian cancer. J Clin Oncol trametinib in patients with recurrent or
2015;33(34):4099–4105. progressive low-grade serous ovarian or
2. Grisham RN, et al. BRAF mutation is peritoneal cancer. Ann Oncol 2019;30(Suppl.
associated with early stage disease and 5):v851–v934.
improved outcome in patients with low- 5. Monk BJ, et al. MILO/ENGOT-ov11:
grade serous ovarian cancer. Cancer binimetinib versus physician’s choice
2012;119(3):548–554. chemotherapy in recurrent or persistent
3. Farley J, et al. Selumetinib in women with low-grade serous carcinomas of the ovary,
recurrent low-grade serous carcinoma of the fallopian tube, or primary peritoneum.
ovary or peritoneum: an open-label, J Clin Oncol 2020;2020:JCO2001164.

Debate
Is MEK Inhibitor Therapy the Best
7B Treatment Recommendation for

Low-Grade Serous Ovarian Cancer
Patients at First Relapse?
No
David M. Gershenson
Debate
Low-grade serous carcinoma of the ovary/peritoneum (LGSOC) is a rare ovarian cancer
characterized by younger age at diagnosis, relative chemoresistance, and prolonged overall
survival compared to high-grade serous carcinoma. Like high-grade serous carcinoma,
however, it is most frequently diagnosed in advanced stages, and over 70% of women
relapse. The mitogen-activated protein kinase (MAPK) pathway plays a major role in the
pathogenesis of LGSOC, with frequent mutations of KRAS, NRAS, and BRAF.
Early studies consistently indicated that LGSOC is relatively chemoresistant in the
adjuvant, neoadjuvant, and recurrent settings – clearly signaling the need for novel therap-
ies [1]. Once MEK inhibitors – orally bioavailable, non-ATP competitive, small molecule
inhibitors of MEK 1/2 – were developed, it was natural to study them in LGSOC based on its
biology. To date, three clinical trials of MEK inhibitors for recurrent LGSOC have been
completed – two fully published and the third published only in abstract form thus far. In
a phase II trial of selumetinib in recurrent LGSOC, the response rate was 15%; another 65%
of patients had stable disease [2]. The median progression-free survival (PFS) was 11.0
months. However, there was no correlation between presence of KRAS or BRAF mutation in
tumor tissue and objective response. The MEK inhibitor in low-grade serous ovarian cancer
(MILO)/ENGOT-ov11 trial was a randomized trial of binimetinib versus physician’s choice
of chemotherapy (pegylated liposomal doxorubicin (PLD), weekly paclitaxel, or topotecan)
in 341 patients [3]. Although the study was closed early based on interim analysis that
revealed the PFS hazard ratio had crossed the predefined futility boundary, the updated
response rate was 24% in both arms of the study, and the median PFS was 10.4 months for
binimetinib versus 11.5 months for the chemotherapy arm (HR=1.15; p=0.748).
Additionally, the response rate and median PFS in the KRAS mutant group were signifi-
cantly better than in the KRAS wild-type group (response rate=44% vs. 19%; median
PFS=17.7 months vs. 10.8 months). GOG 0281 was a phase II/III randomized trial of
trametinib versus standard of care (physician’s choice of one of five drugs – pegylated
liposomal doxorubicin (PLD), weekly paclitaxel, topotecan, letrozole, and tamoxifen) in 260
women [4]. This trial was successful in meeting its primary end point, with a median PFS of
13.0 months versus 7.2 months for trametinib and standard of care, respectively (HR=0.48;
p<0.001) as well as a better response rate for trametinib – 26% versus 6.2% (p<0.0001).
38

MEK Inhibitor Therapy: No 39
Mutational analysis associated with this trial is pending. The difference in the outcomes of
the two latter trials is likely due in part to an unexpected higher response rate in the
chemotherapy arm of MILO related to the lower number of prior regimens compared to
the GOG 0281 trial.
Thus, MEK inhibitors clearly have demonstrated promising activity against recurrent
LGSOC. However, they can be somewhat difficult to manage, especially for the neophyte,
related to potential side effects. The most common side effects are skin rash, fatigue,
gastrointestinal side effects, anemia, and hypertension. Rarer but potentially serious side
effects include pneumonitis, retinal vein occlusion, and decreased ejection fraction or left
ventricular dysfunction. In fact, in the MILO trial, 31% of women had adverse effects serious
enough to lead to permanent discontinuation of binimetinib. In GOG 0281, the permanent
discontinuation rate was 35%.
Since the majority of women with stage II–IV LGSOC will require salvage therapy at
some point in their clinical course, comprehensive counseling regarding various treatments
is essential. The good news is that there are several options. However, there is no standard of
care related to precise sequencing of therapeutics in the recurrent setting. Options for
treatment at first relapse include clinical trials, endocrine therapies (aromatase inhibitors,
tamoxifen, fulvestrant, and leuprolide acetate), chemotherapy (platinum-based, pegylated
liposomal doxorubicin, gemcitabine/cisplatin, weekly paclitaxel, topotecan, etc.), bevacizu-
mab, and targeted agents (usually either MEK inhibitors or BRAF inhibitors).
Conclusion
The choice of therapy for first relapse of LGSOC – the focus of this debate – is based on
several key factors, including type of primary therapy, efficacy and side effects of standard
regimens, availability of clinical trials, and patient preferences. If a clinical trial is available,
that is this author’s preference. Off protocol, while a MEK inhibitor is an attractive option
and should be included in discussion with the patient, it is not necessarily the first choice.
This opinion is based on its therapeutic index relative to other options. First, not all women
with relapse of LGSOC have received endocrine therapy – either monotherapy or mainten-
ance therapy following chemotherapy – as part of their primary treatment. In such a case,
the author’s priority recommendation is an aromatase inhibitor. If aromatase inhibitor
therapy has been included in a patient’s primary therapy, then the author generally priori-
tizes initial options for first relapse, in no particular order, to platinum-based chemotherapy
(especially if they have either never received it or if they are still platinum-sensitive),
pegylated liposomal doxorubicin (PLD), bevacizumab-containing regimens (e.g., PLD/
bevacizumab), or trametinib. For instance, the author will often recommend PLD at first
relapse and consider trametinib at the time of second relapse. In the MILO trial, in which
42% of patients had received only one prior systemic regimen, the updated response rates
for binimetinib and chemotherapy were both 24%. And, as noted, the permanent discon-
tinuation rate of binimetinib was 31%. GOG 0281 included patients who were significantly
more heavily pre-treated, with only 23% of patients receiving one prior line of systemic
therapy. As noted, the response rate to trametinib and the median PFS were significantly
better compared to the control arm. Is trametinib simply a more potent MEK inhibitor than
binimetinib or does it really matter when in the course of treating recurrent LGSOC a MEK
inhibitor is employed? There may be one caveat in choosing a regimen for first LGSOC
relapse, and that is related to genomic profiling results. If a patient has a mutation in the

40 David M. Gershenson
MAPK pathway, especially if a KRAS mutation, based on the preliminary findings of the
MILO trial, should a MEK inhibitor be more seriously considered as the drug of choice for
first relapse? The author believes that further study is required to answer this question.
References
1. Slomovitz B, et al. Low-grade serous ovarian chemotherapy in recurrent or persistent
cancer: state of the science. Gynecol Oncol low-grade serous carcinomas of the ovary,
2020;156:715–725. fallopian tube, or primary peritoneum.
2. Farley J, et al. Selumetinib in women with J Clin Oncol 2020;38(32):3753–3762.
recurrent low-grade serous carcinoma of the 4. Gershenson DM, et al. A randomized phase
ovary or peritoneum: an open-label II/III study to assess the efficacy of
single-arm, phase 2 study. Lancet Oncol trametinib in patients with recurrent or
2013;14:134–140. progressive low-grade serous ovarian or
3. Monk BJ, et al. MILO/ENGOT-ov11: peritoneal cancer. Ann Oncol
binimetinib versus physician’s choice 2019;30(Suppl. 5):v851–v934.

Debate
Should Stage IC Mucinous Ovarian
8A Carcinoma be Managed by
Chemotherapy?
Observation
Jason D. Wright1
Debate
Mucinous carcinomas of the ovary are a rare histologic subtype that account for approxi-
mately 3% of all newly diagnosed epithelial ovarian carcinomas [1]. Compared to serous
carcinomas, mucinous tumors are more commonly diagnosed in younger women and are
much more likely to present as early-stage tumors that are confined to the ovary.
Survival rates for stage I mucinous carcinomas are similar to high-grade serous carcin-
omas. In a population-based dataset, five-year survival was 81.5% for stage I mucinous
tumors compared to 80.8% for high-grade serous carcinomas. Ten-year survival for women
with stage I mucinous tumors is 67.9%. In contrast, advanced stage mucinous tumors are
associated with inferior survival compared to serous carcinomas. Among women with stage
III–IV tumors, five-year survival is 18.4% for mucinous carcinomas compared to 24.0% for
high-grade serous carcinomas [2]. Interestingly, the percentage of women with mucinous
ovarian carcinomas diagnosed at an early-stage appears to be increasing. From 2000 to 2016,
there was a 1.5-fold increase in the percentage of women with mucinous carcinomas
identified with stage I tumors, increasing from 50.5% to 75.6% during the time period [2].
Historically, early-stage mucinous carcinomas of the ovary have been treated in a similar
manner to other histologic subtypes of epithelial ovarian cancer. For women with stage IC
tumors, treatment would typically include surgical resection followed by adjuvant plat-
inum- and taxane-based chemotherapy. However, there is growing recognition that indi-
vidualized management of mucinous carcinomas may be warranted. In particular, evidence
suggests that observation may be appropriate for stage IC mucinous ovarian carcinomas.
First, the biologic underpinnings of mucinous carcinomas differ significantly from serous
carcinomas and other epithelial ovarian tumors. Unlike serous tumors, mucinous tumors
frequently harbor KRAS mutations which are identified in 40–65% of these neoplasms [1].
This mutational profile is similar to colorectal cancers. Second, mucinous carcinomas are
poorly responsive to chemotherapy. Reviews of reports of women with ovarian cancer
treated with first-line, platinum-based chemotherapy have consistently shown that response
rates in women with mucinous tumors are much lower than in women with serous
carcinomas, with response rates of 13–60% versus 64–87%, respectively [1]. The poor
1
Dr. Wright has served as a consultant for Clovis Oncology and received research support from
Merck.
41

42 Jason D. Wright
response rates to platinum-based chemotherapy and biologic similarity of mucinous ovar-

ian carcinomas to colorectal tumors has led many to advocate for treatment with 5-fluor-
ouracil and gastrointestinal chemotherapy regimens when chemotherapy is utilized. Finally,
data from large cohort studies and subgroup analyses from prospective trials have suggested
that chemotherapy is not associated with improved survival for women with stage
I mucinous ovarian carcinomas [3,4].
Prospective trials examining the value of adjuvant chemotherapy for women with stage
IC mucinous carcinomas are largely lacking. A combined analysis of the International
Collaborative Ovarian Neoplasm Trial 1 (ICON1) and Adjuvant ChemoTherapy in
Ovarian Neoplasm Trial (ACTION) which randomized women with apparent early-stage
ovarian cancer to either platinum-based adjuvant chemotherapy or observation included
180 women with mucinous ovarian carcinomas. Although this cohort included women with
a wide variety of stages, it found no statistically significant association with use of adjuvant
chemotherapy and overall survival [5].
Observational data and data from population-based tumor registries have also failed to
demonstrate a benefit for chemotherapy for women with stage I mucinous ovarian carcinoma
[3,4]. In an analysis of 4811 women with stage I mucinous ovarian carcinoma recorded in the
National Cancer Data Base, adjuvant chemotherapy was utilized in 20.2% of women with stage
IA/IB tumors and in 60.2% of those with stage IC neoplasms. Use of chemotherapy was relatively
stable over time. Within this cohort there was no association between chemotherapy use and
survival for any patients with stage I neoplasms. For women with stage IA and IB tumors, five-
year overall survival was 90.5% for women who did not receive chemotherapy compared to
88.1% for those who received chemotherapy. Similarly, for patients with stage IC carcinomas,
five-year overall survival was 85.1% for women who had observation compared to 85.6% in those
treated with adjuvant chemotherapy. These results were unchanged when stratified by tumor
grade. In a sensitivity analysis including only patients who underwent lymphadenectomy (at
least ten nodes removed) to exclude women with occult stage III disease the investigators also
noted no beneficial effect of chemotherapy. In the cohort of women with stage IC tumors who
underwent lymphadenectomy, five-year overall survival was 89.4% in patients who did not
receive chemotherapy compared to 88.8% in those treated with chemotherapy [4].
Matsuo and colleagues performed a similar analysis using the National Cancer Data
Base of women with stage IC mucinous carcinomas. The overall findings were similar, with
no benefit in survival for chemotherapy. The investigators performed a rigorous series of
sub-group analyses and confirmed that there was a lack of survival benefit for adjuvant
chemotherapy regardless of age, tumor grade, stage IC sub-stage, or performance of
lymphadenectomy. These investigators also performed a confirmatory analysis using popu-
lation-based data from the National Cancer Institute’s Surveillance, Epidemiology, and End
Results database. Again, there was no association between adjuvant chemotherapy use and
survival. In the validation cohort, adjuvant chemotherapy had no impact on seven-year
cancer-specific survival (84.6% for chemotherapy vs. 88.3% for observation) or seven-year
overall survival (77.1% for chemotherapy vs. 77.1% for observation) [3].
Conclusion
Improved understanding of the biology and natural history of mucinous ovarian carcin-
omas has led to changes in treatment recommendations for women with early-stage
mucinous tumors. The National Comprehensive Cancer Network (NCCN) now considers

Ovarian Carcinoma Management? Observation 43
either observation or systemic chemotherapy as appropriate for women with stage IC

mucinous ovarian carcinomas [6]. Further, for those women treated with systemic therapy,
either a platinum and taxane-based therapy or a gastrointestinal regimen including 5-fluor-
ouracil/leucovorin and oxaliplatin or capecitabine/oxaliplatin are considered appropriate
[6]. In sum, given the lack of data supporting chemotherapy for women with stage IC
mucinous ovarian carcinomas, observation appears to be warranted in the majority of
women.
References
1. Morice P, et al. Mucinous ovarian carcinoma. Gynecol Oncol
carcinoma. N Engl J Med 2019;154:302–307.
2019;380:1256–1266. 5. Trimbos JB, et al. International
2. Matsuo K, et al. Evolving population-based Collaborative Ovarian Neoplasm trial 1 and
statistics for rare epithelial ovarian cancers. Adjuvant ChemoTherapy In Ovarian
Gynecol Oncol 2020;157:3–11. Neoplasm trial: two parallel randomized
3. Matsuo K, et al. Effectiveness of phase III trials of adjuvant chemotherapy in
postoperative chemotherapy for stage IC patients with early-stage ovarian carcinoma.
mucinous ovarian cancer. Gynecol Oncol J Natl Cancer Inst 2003;95:105–112.
2019;154:505–515. 6. National Comprehensive Cancer Network.
4. Nasioudis D, et al. Adjuvant chemotherapy Ovarian Cancer Including Fallopian Tube
is not associated with a survival benefit for and Primary Peritoneal Cancer. Version
patients with early-stage mucinous ovarian 2.2021. Available from: www.nccn.org/pro
fessionals/physician_gls/pdf/ovarian.pdf

Debate
Should Stage IC Mucinous Ovarian
8B Carcinoma be Managed by
Chemotherapy?
Adjuvant Chemotherapy
Yien Ning Sophia Wong and Jonathan A. Ledermann
Debate
Mucinous ovarian carcinomas (MOCs) are a rare subtype of epithelial ovarian cancer
accounting for less than 10% of all epithelial ovarian cancers. Improvements in diagnosis
have suggested that the incidence has been overestimated and the true incidence is less than
5% [1]. Adjuvant chemotherapy studies have included mucinous tumors and other less
common types of epithelial ovarian cancers together with high-grade serous tumors, the
most common subtype.
Sixty-five to eighty percent of mucinous ovarian cancers are diagnosed at an early stage
and have an excellent prognosis compared to early-stage serous cancers. The standard
treatment approach for stage I MOC is surgery and based upon the surgical and patho-
logical staging, further adjuvant treatment may be needed. The International Federation
of Gynecology and Obstetrics (FIGO) staging classification, last updated in 2018, defined
substages of stage I ovarian cancers that are confined to the ovaries. In particular, tumor
rupture – intraoperative (IC1) or preoperative (IC2), surface involvement by tumor cells
or presence of malignant cells in the ascites or peritoneal washings (IC3) are the sub-
categories of stage IC [1]. Tumor rupture, whether intraoperative or preoperative, may
become a risk factor for recurrence, regardless of the presence or absence of surface
invasion, because it has the possibility of seeding recurrence in the peritoneal cavity. In
the case of a large cystic mucinous tumor, preoperative or intraoperative rupture is a real
possibility and contributes to the decision regarding the role of adjuvant chemotherapy to
eliminate microscopic cells and prevent their further growth leading to recurrence of the
disease.
There are few prospective large-scale randomized controlled trials (RCTs) comparing
chemotherapy to observation in stage I ovarian cancers. The International Collaborative
Ovarian Neoplasm 1 (ICON1) and EORTC-Adjuvant ChemoTherapy In Ovarian
Neoplasm (ACTION) trials, together recruited over 900 patients who had surgery for early-
stage ovarian cancer. Patients were randomly assigned to receive platinum-based adjuvant
chemotherapy or observation until chemotherapy was indicated. This demonstrated that
patients who received chemotherapy had an improved five-year overall survival (OS) with
a hazard ratio (HR) of 0.67 (95% CI: 0.50–0.90; p=0.008), as well as an improved five-year
recurrence-free survival with a HR of 0.64 (95% CI: 0.50–0.82; p=.001) [2]. It is worth noting
44

Ovarian Carcinoma Management? Adjuvant Chemotherapy 45
that nearly 20% of patients (n=180) had a mucinous tumor. Although confidence intervals
were wide for all subgroups, the HR in favor of chemotherapy for mucinous tumors was no
less favorable than any of the other subgroups, including the serous subtype [2].
Currently, several guidelines worldwide recommend all patients with high-risk
early-stage epithelial ovarian cancer should receive adjuvant chemotherapy, regardless
of histology. However, it is worth noting that only a fraction of patients with MOCs
were included in these large clinical trials. For example, only 7% of patients had MOCs
in ICON3, which assessed the addition of paclitaxel to carboplatin-based chemother-
apy; while only 2–6% of patients had MOCs in recent studies such as ICON7 and
GOG 218, which assessed the addition of bevacizumab to standard carboplatin and
paclitaxel chemotherapy [1]. Therefore, whilst robust RCTs are lacking to guide the
management of MOCs, this “one-size-fits-all” approach is obsolete and is not evidence
based.
Given that MOCs are distinctly different biologically and clinically compared to the
other epithelial histological subtypes, it is crucial to evaluate MOCs as a separate entity.
Several studies have shown that advanced MOCs respond poorly to platinum and taxane
chemotherapy and have a worse prognosis to other histologies, in part due to inherent
platinum resistance [1]. Large RCTs have used platinum-based chemotherapy as the
backbone treatment in epithelial ovarian cancer, making it more difficult to ascertain the
true benefit of chemotherapy in patients with early-stage MOCs. Interestingly, MOCs share
many similarities with gastrointestinal (GI) adenocarcinomas and there is preclinical
evidence to support a GI-based approach in the management of this unique group, with
platinum-resistant in vitro and in vivo models exhibiting responses to 5-FU and oxalipla-
tin [1].
In one of the largest retrospective studies, Richardson and colleagues [3] looked at over
2000 patients from the National Cancer Database from 2004 to 2014 with stage I MOCs,
including 1362 (67%) with stage IA/IB disease, 598 (29%) with stage IC disease, and 81
(4%) with stage I disease not otherwise specified. A total of 737 patients (36%) received
adjuvant chemotherapy in this cohort. A nomogram was used to stratify between low- and
high-risk groups which included age, stage, presence of lympho-vascular invasion, malig-
nant ascites and grade. Patients with a score of higher than 93 were put into a high-risk
group. Whilst there was no difference in survival in the low-risk group with or without
adjuvant chemotherapy, the authors found that in the high-risk patients (n=405), chemo-
therapy was associated with an improvement in ten-year OS of 23% (74% vs. 51%).
Patients in the high-risk group not treated with adjuvant chemotherapy had a 58%
increased risk of death (HR=1.58, 95% CI: 1.05–2.38, p=0.03) and worse survival relative
to those treated with adjuvant chemotherapy. The likelihood ratio test showed an inter-
action between higher patient risk score and increasing survival benefit from chemother-
apy (p=0.02).
In contrast, another large database study from the United States that included patients
with stage I mucinous ovarian cancer did not show a survival benefit associated with
chemotherapy, regardless of the substage of disease [4,5]. However, when compared to
Richardson et al.’s study, these analyses only reported five-year rather than ten-year
survival data, and did not consider any prognostic index that might guide clinicians in
deciding who may benefit from chemotherapy. The type of chemotherapy may impact on
survival and none of these large database studies reported which chemotherapy regimens
were used.

46 Yien Ning Sophia Wong and Jonathan A. Ledermann
Conclusion
Taken together, there is evidence for the use of adjuvant chemotherapy in stage IC MOCs,
particularly in those in a high-risk group. Continued national and international collabora-
tive efforts are needed to collect high-quality data and to conduct meaningful clinical trials
to find better treatments that will help guide clinicians to improve the outcome of this
unique subset of patients.
References
1. Crane EK, et al. Early stage mucinous cancer – A clinical calculator predictive of
ovarian cancer: a review. Gynecol Oncol chemotherapy benefit. Gynecol Oncol
2018;149(3):598–604. 2020;159(1):118–128.
2. Trimbos JB, et al. International 4. Nasioudis D, et al. Adjuvant chemotherapy
Collaborative Ovarian Neoplasm trial 1 and is not associated with a survival benefit for
Adjuvant ChemoTherapy In Ovarian patients with early stage mucinous ovarian
Neoplasm trial: two parallel randomized carcinoma. Gynecol Oncol 2019;154
phase III trials of adjuvant chemotherapy in (2):302–307.
patients with early-stage ovarian carcinoma. 5. Matsuo K, et al. Effectiveness of
J Natl Cancer Inst 2003;95(2):105–112. postoperative chemotherapy for stage IC
3. Richardson MT, et al. Long-term survival mucinous ovarian cancer. Gynecol Oncol
outcomes of stage I mucinous ovarian 2019;154(3):505–515.

Debate
How Many Cycles of Adjuvant
9A Chemotherapy Should be
Administered to Patients
Ovarian Cancer?
Three Cycles
Annalisa Garbi, Eleonora Zaccarelli, and Federica Tomao
Debate
High-risk stage I ovarian cancer (OC) encompass clear cell and grade 3 tumors according to
European Society of Medical Oncology-European Society of Gynaecological Oncology
(ESMO–ESGO) consensus conference recommendations [1]. Carboplatin in monotherapy
for six cycles or the combination of carboplatin and paclitaxel for a minimum of three cycles
are available options for adjuvant treatment adhering to ESMO–ESGO guidelines [1].
A Cochrane systematic review evaluated the role of adjuvant chemotherapy for early-
stage tumors, demonstrating that platinum-based chemotherapy after an optimal staging
surgery is effective in significantly prolonging long-term overall survival (OS) and progres-
sion-free survival (PFS) [2].
Particularly, a long-term survival update from the two most important randomized
clinical trials (ICON1 and ACTION) included in the meta-analysis described a benefit in
terms of OS (HR=0.67, 95% CI: 0.50–0.90; p=.008) and in terms of recurrence-free survival
(RFS) (HR=0.64, 95% CI: 0.50–0.82; p=.001) for women considered at high-risk of recur-
rence (stage IA grade 3, IB, or IC, grade 2 or 3, any clear cell tumors and un-optimally staged
tumours) who received chemotherapy. The chemotherapy administered in the ICON1 and
ACTION trials consisted of a variety of platinum-based regimens with heterogynous
number of cycles, thus being inconclusive to establish the optimal duration of treatment.
Scientific evidence comparing three versus six cycles are limited to retrospective analysis
and few data are available from prospective studies about the comparison of monotherapy
versus combination regimen and shorter versus longer treatment.
GOG-157 clinical trial randomized patients with early-stage tumors to receive three
versus six cycles of adjuvant chemotherapy with carboplatin and paclitaxel administered
every three weeks [3]. This study found that longer treatment was not associated with
a significant reduction in recurrence risk (HR for PFS adjusted for stage and grade: 0.76,
95% CI: 0.512–1.13, p=0.19; HR for OS: 1.02, 95% CI: 0.662–1.57, p=0.9), but resulted in
significant increased toxicity (neurotoxicity, granulocytopenia, and anemia). A post-hoc
analysis of the same trial (GOG 157) [4] revealed that longer adjuvant therapy was associ-
ated with a significant reduction in recurrence risk for serous tumors, but not for nonserous
47

48 Annalisa Garbi, Eleonora Zaccarelli, and Federica Tomao
tumors, suggesting that three cycles of chemotherapy could be considered to treat nonser-
ous tumors.
Prendergast et al. retrospectively compared six versus three cycles of adjuvant platinum-
based chemotherapy with or without taxane in early-stage ovarian clear cell carcinoma with
90% receiving combination therapy. The longer treatment was not associated to survival
benefit. Subgroup analysis of surgically staged patients also showed no difference in survival
between three versus six cycles of chemotherapy [5].
Conclusion
In conclusion, on the basis of these data, three cycles of carboplatin plus paclitaxel repre-
sents an effective strategy to reduce the probability of recurrence in high-risk early-stage OC
patients, especially in nonserous tumors. Notably, three cycles compared with six cycles of
carboplatin and paclitaxel do not significantly alter the recurrence rate in high-risk OC, but
six cycles are associated with more toxicity.
Nevertheless, further studies are needed to better define the duration of treatment.
Moreover, in the era of personalized medicine, molecular characteristics of tumors could
help in the therapeutic decision-making process. Finally, the advent of genomic character-
ization is continuously changing our knowledge about peculiarities and differences among
single histotype that might influence the response to standard medical treatment. This
would make adjuvant treatment personalized in terms of duration and schedule, according
to molecular characteristics.
References
1. Colombo N, et al. ESMO-ESGO Ovarian epithelial ovarian carcinoma: a Gynecologic
Cancer Consensus Conference Working Oncology Group study. Gynecol Oncol
Group. ESMO-ESGO consensus conference 2006;102:432–439.
recommendations on ovarian cancer: 4. Chan JK, et al. The potential benefit of 6
pathology and molecular biology, early and vs. 3 cycles of chemotherapy in subsets of
advanced stages, borderline tumours and women with early-stage high-risk
recurrent disease. Ann Oncol 2019;30 epithelial ovarian cancer: an exploratory
(5):672–705. analysis of a Gynecologic Oncology
2. Lawrie TA, et al. Adjuvant (post-surgery) Group study. Gynecol Oncol
chemotherapy for early stage epithelial 2010;116:301–306.
ovarian cancer. Cochrane Database Syst Rev 5. Prendergast H, et al, Three versus six cycles
2015;12:CD004706. of adjuvant platinum-based chemotherapy
3. Bell J, et al. Randomized phase III trial of in early stage clear cell ovarian carcinoma –
three versus six cycles of adjuvant A multi-institutional cohort. Gynecol Oncol
carboplatin and paclitaxel in early stage 2017;144:274–278.

Debate
How Many Cycles of Adjuvant
9B Chemotherapy Should be
Administered to Patients
Ovarian Cancer?
Six Cycles
John K. Chan and Daniel S. Kapp
Debate
Early-stage Ovarian Cancer Treatment Indications and Controversies
Based on a systematic review of clinical trials, chemotherapy is currently recommended in
all early stages of disease after surgical staging except those with stage IA–B, grade 2 disease
[1]. However, the number of cycles of adjuvant chemotherapy remains controversial.
Prospective Randomized Trial: Interpretations and Statistical

Considerations
The Gynecologic Oncology Group conducted a randomized phase III trial of three versus
six cycles of adjuvant carboplatin and paclitaxel in early-stage epithelial ovarian carcinoma.
Of 427 patients with surgically staged IA grade 3, IB grade 3, clear cell, IC and completely
resected stage II disease, it was reported that “the recurrence rate for 6 cycles was 24% lower
(hazard ratio [HR]: 0.761; 95% confidence interval [CI]: 0.51–1.13, p=0.18), and the esti-
mated probability of recurrence within 5 years was 20.1% (6 cycles) versus 25.4% (3 cycles)”
[2]. It was concluded that “compared to 3 cycles, 6 cycles of [chemotherapy] do not
significantly alter the recurrence rate.” The statistical design of GOG-157 aimed to achieve
an 85% chance of finding that the additional three cycles regimen as active if it decreased the
recurrence rate by 50%. It is likely that the power analysis in this trial design may have been
overly optimistic [3].
Exploratory Analysis Results

An exploratory analysis was performed to identify any subgroups of patients within the
GOG-157 trial who might have benefited from six cycles of treatment [4]. The results
demonstrated that those with serous tumors had a significantly higher recurrence-free
survival after six versus three cycles (82.7% vs. 60.4%). However, no significant improve-
ments in recurrence-free survival (RFS) were noted in those with nonserous cancers.
Statisticians caution clinical researchers on the perils of subset analyses to guide treatment;
49

50 John K. Chan and Daniel S. Kapp
in particular they warn of dangers in reporting on a lack of benefit in subgroups in a clinical

trial showing an overall benefit. On the other hand, it is unclear if there is more validity in
subset analysis demonstrating a benefit in a subgroup of patients in an overall negative
clinical trial as shown in this current exploratory analysis. Obviously, the results of this
current study are based on an exploratory analysis, and only a randomized clinical trial
comparing three versus six cycles of chemotherapy in serous ovarian cancer patients can
definitively confirm these preliminary findings. However, with the knowledge that it is not
feasible to conduct a randomized trial on uncommon diseases such as that in early-stage
epithelial ovarian cancer, clinicians are compelled to make decisions based on limited
scientific evidence. It is then important to carefully consider these options for each individ-
ual patient, weighing the potential risk of toxicities and consequence of recurrence.
Consequences of Recurrent Early-stage Cancer

It is important to avoid under treatment of women with early-stage high-risk ovarian cancer
who have a high likelihood of cure. In fact, the survival after recurrence of early-stage
disease is poor and comparable to those with recurrent advanced-stage disease; both with
a median survival of only 24 months [5]. Thus, as oncologists, we have an important role in
helping patients to make sound decisions and to ensure that they feel comfortable that they
made the best possible choice to avoid future decisional regret or remorse.
Toxicity of Six Cycles Compared to Three Cycles?

It was clear that compared to three cycles, those who had six cycles of chemotherapy had
significantly higher grade 3 and 4 neurotoxicity (2% vs. 11%) and grade 4 granulocytopenia
(52% vs. 66%). Nevertheless, the additional treatment did not result in any worsening of
thrombocytopenia, gastrointestinal, renal, alopecia, ototoxicity, infection, fever, allergy, or
myalgia. Although there were no formal studies on the patient-reported outcome, it is
unlikely that the additional three cycles of chemotherapy significantly affected their overall
quality of life.
Consensus Guidelines and Adoption of Early-stage Disease in Ovarian

Cancer Trials
Based on the results seen in advanced disease, platinum-based chemotherapy has been
adopted for use in early-stage disease. Accepted practice in the UK NICE 2011 clinical
guideline on ovarian cancer states that adjuvant chemotherapy with six cycles of adjuvant
chemotherapy should be offered to women with stage IC disease or more. Other countries
including Canada (Alberta consensus) and the United States (NCCN guidelines) have also
recommended a minimum of three cycles and up to six cycles, particularly in those with
serous histology.
Clinical Evidence of Advantages of Six Cycles of Treatment and Beyond

in Advanced Disease
Over the last few years, a number of clinical trials in advanced ovarian cancer have
demonstrated a significant advantage of extended treatment with maintenance therapy
using anti-vascular or Poly (ADP-ribose) polymerase inhibition for up to three years.

How Many Adjuvant Chemotherapy Cycles? Six 51
Clearly, it is not our intent to adopt maintenance strategies in early-stage disease, but it is
important to highlight the trends in treatment and maintenance of advanced cancer and the
potential implications toward more cycles or maintenance strategies, possibly in stage II
high-risk disease.
Adoption of Cycles in Real World and Future Clinical Trials

Since early-stage ovarian cancer trials may not feasible due to low accrual and lack statistical
power in design, most cooperative groups have included high-risk early ovarian cancer
patients in the phase III randomized trials in advanced ovarian cancer. For example, clinical
trial researchers have incorporated these high-risk early-stage ovarian cancer patients into
advanced-stage cancer trials with regimens that contain six cycles of chemotherapy. This
strategy has been adopted by the U.S. NRG Gynecologic Oncology Group (GOG-261 – stage
I–IV carcinosarcoma of uterus or ovary) and in Europe, Gynaecological Cancer Intergroup
(GCIG) trial, Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) OVAR-9, and the
GCIG-EORTC trials.
Conclusion
Recognizing that it is important to individualize treatment based on risk factors and the
tolerance of therapy, we advise administration of paclitaxel plus carboplatin for six cycles
for all early-stage ovarian cancer patients.
References
1. Lawrie TA, et al. Adjuvant (post-surgery) Oncol 2003;15(6):452–455. https://doi.org/1
chemotherapy for early stage epithelial 0.1097/00001622-200311000-00008
ovarian cancer. Cochrane Database Syst Rev 4. Chan JK, et al. The potential benefit of 6 vs. 3
2015;;2015(12):CD004706. https://doi.org/1 cycles of chemotherapy in subsets of women
0.1002/14651858.CD004706.pub5 with early-stage high-risk epithelial ovarian
2. Bell J, et al. Gynecologic Oncology Group. cancer: an exploratory analysis of
Randomized phase III trial of three versus a Gynecologic Oncology Group study.
six cycles of adjuvant carboplatin and Gynecol Oncol 2010;116(3):301–306. https://
paclitaxel in early stage epithelial ovarian doi.org/10.1016/j.ygyno.2009.10.073
carcinoma: a Gynecologic Oncology Group 5. Chan JK, et al. Survival after recurrence in
study. Gynecol Oncol 2006;102(3):432–439. early-stage high-risk epithelial ovarian
https://doi.org/10.1016/j.ygyno.2006.06.013 cancer: a Gynecologic Oncology Group
3. Vergote I, et al. Treatment of patients with study. Gynecol Oncol 2010;116(3):307–311.
early epithelial ovarian cancer. Curr Opin https://doi.org/10.1016/j.ygyno.2009.10.074

Debate
Patients with Advanced
10A Ovarian Cancer who are 75

Years Old and Above Should
Routinely be Treated with
Neoadjuvant Chemotherapy?
Yes
Michelle Davis and Ursula Matulonis
Debate
A combination of surgical cytoreduction and chemotherapy has been the foundation of
treatment for newly diagnosed advanced-stage ovarian cancer since the 1930s. However,
elderly patients remain at risk for undertreatment of advanced ovarian cancer. United
States national registry studies have demonstrated that elderly women with ovarian cancer
are less likely to complete combination therapy because of their inability to tolerate therapy or
medical complications of receiving that therapy. Approximately 20% of patients with ovarian
cancer are above 75 years of age. The probability of dying from ovarian cancer increases with
increasing age; however, some studies suggest that when elderly women receive optimal
therapy, outcomes are equivalent to younger counterparts. The question remains, how to
ensure optimal therapy and best manage women with ovarian cancer over the age of 75?
While it is agreed upon that complete cytoreduction to no visible disease (i.e., R0) as well
as six cycles of platinum- and taxane-based chemotherapy is the preferred treatment for newly
diagnosed advanced-stage ovarian cancer, the optimal sequencing of treatment has been
debated. To date, there have been three multi-center international randomized controlled
trials (RCTs) (EORTC-GCG, CHORUS, JCOG 0602) and two international single institution
RCTs (the Scorpion trial and Chekman et al.) comparing primary cytoreductive surgery (PCS)
followed by platinum-based chemotherapy to neoadjuvant chemotherapy (NACT) with
interval cytoreductive surgery. All these studies showed equivalency of PCS versus NACT.
The TRUST trial which included only surgical centers with high rates (>50%) of complete
cytoreduction is awaiting results. In a Cochrane review which evaluated 1952 articles, a meta-
analysis was performed with the five above RCTs. In a pooled analysis of 1713 patients, there
was no difference in progression-free survival (PFS) (HR=1.02, 95% CI: 0.92–1.13) or overall
survival (OS) (HR=1.06; 95% CI: 0.94–1.19) between NACT and PCS [1]. Surgical morbidity
and quality-of-life outcomes were reported inconsistently; however, pooled data from
available studies show a significant reduction in serious advance events (SAE) grade 3+
with NACT, most prominently, infection. Perhaps most importantly, there was a reduction
in 30-day mortality in all five RCTs reported at 0.4% (NACT) versus 3.1% in PCS (RR=0.18;
52

Older Patients with Cancer Treated with NACT? Yes 53
95% CI: 0.06–0.54) [1]. This equates to 31 deaths per 1000 patients with PCS compared to six
per 1000 patients following interval cytoreduction surgery. While some observational studies
have favored PCS, these data remain limited by selection bias. The highest level of evidence to
date suggests equivalent oncologic outcomes with PCS and NACT with a reduction in
perioperative morbidity and mortality with NACT.
There are no randomized trials that address the role for NACT versus PCS specifically in
an elderly patient population. Of the available RCTs, only two include patients above75
years of age, and the SCORPION trial specifically excluded patients over 75 years. In
a subgroup analysis by age, there was no difference in OS for patients 70 years or above
(20% with PCS vs. 18% for NACT) with similar rate of receipt of both surgery and
chemotherapy [1]. In a study by Melamed et al., comparing regions with high adoption of
NACT to low adoption regions as controls, adoption of NACT led to a reduction in
mortality at three years over time compared to no change in mortality among low-
adopter regions [2]. In regions where NACT increased, there was a reduction in 30- and 90-
day mortality as well as a higher rate of receipt of both surgery and chemotherapy [2]. In
another paper by the same group, older age was a significant factor associated with increased
utilization of NACT. This suggests that triaging higher risk, elderly patients to NACT can
reduce morbidity and improve rates of optimal therapy which may explain the benefit of
NACT in these data, more reflective of true practice.
For an elderly patient population, consideration of co-morbidities and treatment-related
SAEs is critical to minimize harm. Thrall et al. evaluated 30-day postoperative mortality from
the Surveillance Epidemiology, End Results (SEER) database in ovarian cancer patients over
the age of 65 (just under half of patients were above 75 years of age) [3]. Each increasing year
of age was associated with a 7.5% increased risk of 30-day mortality (95% CI: 1.06–1.10).
Patients who received NACT had a 70% lower 30-day postoperative mortality compared to
PCS (1.8% vs. 6.1%, p<0.001) and in the adjusted model this remained significant (RR=0.37,
95% CI: 0.17–0.83) [3]. They concluded that all women age 75+ with stage IV disease and
women age 75+ with Stage III disease and a Charleson Comorbidity Index score of 1+
comprised the highest risk group with a 12.7% average 30-day mortality. Several tools have
sought to predict treatment morbidity in the elderly; however, no clear superior tool has
emerged [4]. Neither the Preoperative Assessment of Cancer in the Elderly (PACE) study
evaluating patients with solid tumors nor NRG CC-002 evaluating patients above70 years of
age with ovarian cancer found an association between preoperative assessment tools and
major postoperative complications. However, a single institution retrospective study utilizing
the frailty index (FI) did demonstrate an association between frailty and postoperative
morbidity and mortality [5]. It is unclear in this study the percentage of patients above 75
years of age that were considered frail, but there is a statistically significant increase in age
(mean 67.8 years) among frail patients and age remains an independent predictor of mortality
[5]. While frailty is an important area of ongoing investigation, increasing age, consistently
across studies, is predictive of increased morbidity and mortality with treatment.
Conclusion
Based on these data, all patients over the age of 75 with a single medical co-morbidity are at
high risk for treatment morbidity and the highest risk for postoperative death. Treatment
with NACT can minimize these risks without compromising oncologic outcomes based on
randomized clinical trial data. In the treatment of women above 75 years of age with ovarian

54 Michelle Davis and Ursula Matulonis
cancer, the goal should be to maximize receipt of optimal therapy while minimizing SAEs,
to which they are more susceptible. Patients with advanced ovarian cancer who are 75 years
old and older should routinely be treated with NACT.
References
1. Coleridge SL, et al. Chemotherapy versus 3. Thrall MM, et al. Thirty-day mortality after
surgery for initial treatment in advanced primary cytoreductive surgery for advanced
ovarian epithelial cancer. Cochrane ovarian cancer in the elderly. Obstet Gynecol
Database Syst Rev 2019;10:CD005343. 2011;118(3):537–547. https://doi.org/10
https://doi.org/10.1002/14651858 .1097/AOG.0b013e31822a6d56
.CD005343.pub4 4. Tew W. Ovarian cancer in the older woman.
2. Melamed A, et al. Effect of adoption of J Geriatr Oncol 2016;7(5):354–361.
neoadjuvant chemotherapy for advanced 5. Kumar A, et al. Functional not chronologic
ovarian cancer on all-cause mortality: age: frailty index predicts outcomes in
quasi-experimental study. Br Med J advanced ovarian cancer. Gynecol Oncol
2018;360:5463. 2017;147(1):104–109.

Debate
Patients with Advanced
10B Ovarian Cancer who are 75

Years Old and Above Should
Routinely be Treated with
Neoadjuvant Chemotherapy?
No
Olga T. Filippova and William P. Tew
Debate
When choosing between primary debulking surgery (PDS) or neoadjuvant chemotherapy
(NACT) for upfront treatment of women with advanced-stage ovarian cancer, we must
balance two opposing approaches. On one hand is the “optimize survival” approach, with all
four large randomized studies – CHORUS, EORTC 55971, SCORPION, and JGOG 0602 –
showing the longest survival in women treated with PDS in whom complete gross resection
was achieved [1,2]. On the other hand is the “do minimal harm” view, as it is well known
that NACT followed by interval debulking surgery systematically leads to fewer postopera-
tive complications [1,2]. Therefore, the real question that should be posed is how do we
safely maximize the number of women above 75 years of age who are treated with PDS, thus
allowing them the survival benefit, without undue morbidity. Instead of an “all or nothing”
approach, we propose the following ways to select appropriate PDS candidates, and reserve
NACT for those not meeting these criteria.
First and foremost, we must stop using chronological age alone for selection of
upfront treatment, and instead must transition to evaluating a patient’s functional age.
Not only is ageism a source of significant bias, many studies have shown that age alone is
a poor predictor of a patient’s physiologic reserve. Several reliable, objective, and easy-to-
use tools for accessing function have been introduced, and should be used for all women,
not just patients ≥75 years of age. Frailty is defined as a decrease in physiologic reserve
beyond that expected with aging alone. While the geriatric assessment continues to be
the most comprehensive evaluation of frailty and the gold standard supported by
international societies, several frailty indices are available with similar predictive value
and can be easily incorporated into daily clinical practice [3]. With the use of these tools,
we propose that all women identified as vulnerable, regardless of age, should routinely be
treated with NACT.
We must also not forget that older women, especially vulnerable women, are com-
monly not included in randomized trials, making it difficult to extrapolate the findings of
these studies to the older cohort. While both CHORUS and EORTC 55971 did not have
age restrictions and included octogenarians, they are a minority of the cohort and their
55

56 Olga T. Filippova and William P. Tew
outcomes were not reported separately [1]. Additionally, it is not possible to judge the
functional status of older, or any, women included in these two studies. On the other
hand, the two most recent trials, SCORPION and JGOG 0602, had an upper age cut-off at
75 years [1,2]. Since JGOG 0602 was the first trial that was not able to demonstrate the
noninferiority of NACT [2], we do not know if the lack of this noninferiority holds in the
older population. We must not take the lack of data as evidence of a lack of benefit. All
eyes are now on the International Trial on Radical Upfront Surgery in Advanced Ovarian
Cancer (TRUST), which not only includes all women 18 and older, but focuses on
surgical quality. We must also acknowledge that the optimal chemotherapy regimen
for older women is yet to be determined. EWOC-1, a trial investigating single-agent
carboplatin, and carboplatin with either weekly or every three-week paclitaxel in women
70 or older, was closed early, as the survival of the carboplatin-only arm was found to be
significantly worse [4]. GOG 273 aimed at evaluating chemotherapy tolerance based on
pre-treatment instrumental activities of daily living, and showed that performance status
was not as good a predictor as functional status [5]. These two studies are a step in the
right direction toward evaluating our “standard” treatments in the vulnerable and frail
population.
The question of PDS versus NACT must be discussed in the setting of the latest
developments for the treatment of ovarian cancer. Novel therapeutics, such as vascular
endothelial growth factor (VEGF) and poly (ADP-ribose) polymerase (PARP) inhibitors,
have been developed for use in the postoperative or maintenance phase of treatment. While
the use of bevacizumab is common in the NACT setting in Europe, it is not approved for this
indication in the United States. All novel therapies must be studied in the older population
to determine benefit, and more importantly, tolerance.
Conclusion
In summary, we believe that it is time to stop framing the question as “PDS vs. NACT” and
instead start focusing on how to identify and safely maximize the number of women
treated with PDS during which optimal or complete resection is achieved, resulting in the
longest survival, as well as how to identify women in whom the morbidity of PDS is too
high and thus NACT is the better upfront approach. NACT should only be the approach
in those unfit for PDS or those with truly unresectable disease, not just older women. Just
because a treatment is not inferior does not mean it is superior. An “all or nothing”
approach is never the best answer, especially in the older, commonly more vulnerable,
population.
References
1. Long Roche K, et al. Practical guidelines for phase III randomized trial. Eur J Cancer
trial to neoadjuvant chemotherapy in 2020;130:114–125.
advanced ovarian cancer: big risk, big 3. Wright AA, et al. Neoadjuvant
reward . . . or too much risk? Gynecol Oncol chemotherapy for newly diagnosed,
2020;157:561–562. advanced ovarian cancer: Society of
2. Onda T, et al. Comparison or survival Gynecologic Oncology and American
between primary debulking surgery and Society of Clinical Oncology Clinical
neoadjuvant chemotherapy for stage III/IV Practice Guideline. Gynecol Oncol
ovarian, tubal and peritoneal cancers in 2016;143:3–15.

Older Patients with Cancer Treated with NACT? No 57
4. Falandry C, et al. EWOC-1: a randomized 5. von Gruenigen VE, et al. Chemotherapy

trial to evaluate the feasibility of three completion in elderly women with ovarian,
different first-line chemotherapy regimens primary peritoneal or fallopian tube
for vulnerable elderly with ovarian cancer cancer – an NRG oncology/Gynecologic
(OC): a GCIG-ENGOT-GINECO study. Oncology Group study. Gynecol Oncol
J Clin Oncol 2019;37S:ASCO #5508. 2017;144(3):459–467.

Debate
Should an Attempt
11A at Aggressive Cytoreduction

be Made for all Surgical
Candidates with Advanced
Ovarian Cancer prior
to Treatment with Adjuvant
Chemotherapy?
Yes
Sven Mahner, Anca Chelariu-Raicu,
and Fabian Trillsch
Debate
The extent of residual disease following upfront cytoreductive surgery for stage III–IV
ovarian cancer is one of the strongest prognostic factors for progression-free and overall
survival. Currently, there are two approaches proposed in order to achieve minimal residual
disease: primary debulking surgery (PDS) and neoadjuvant chemotherapy (NACT) fol-
lowed by interval debulking surgery. In the last decade, the field has developed a greater
understanding of both approaches and more importantly, several prospective randomized
trials were designed to address the question of which patients are most or least likely to
benefit from primary debulking surgery versus neoadjuvant chemotherapy.
In this context, two randomized controlled trials showed that neoadjuvant chemother-
apy followed by interval cytoreductive surgery can be a suitable therapeutic approach in
patients with comorbidities and high tumor burden, especially when full cytoreductive
surgery is not feasible. While there is general consensus regarding the group of patients who
will be triaged directly for palliative chemotherapy, there is still debate over the remaining
surgical candidates, including the patients with whom complete gross resection can be
achieved and patients who will be left with residual tumor. Our objective here is to state the
rationale for PDS as the primary treatment in this heterogeneous group of surgical candi-
dates with advanced ovarian cancer. To demonstrate our perspective, we will discuss topics
such as the surgical management, systemic therapy, and the biology of ovarian cancer.
It is widely accepted that the maximal surgical effort towards complete gross resection
yields the best clinical outcome [1]. In specialized gynecologic cancer centers, the rate of
macroscopic complete resection ranges from 50% to 70% [2]. Contrarily, some studies have
reported a rate of less than 20% [3], with factors such as patient selection or lack of surgical
qualification or infrastructure potentially contributing to the low resection rate. In this
context, intraoperative findings preventing complete resection in some cancer centers,
58

Cytoreduction for all prior to Treatment? Yes 59
including diffuse carcinomatosis, tumor involvement of the pancreas or the truncus celia-
cus, or central or multisegmental liver metastasis, are not reliably diagnosed before surgery.
Therefore, complete resection in these patients could be impaired by a lack of expertise in
more sophisticated surgical techniques such as diaphragmatic stripping, splenectomy, distal
pancreatectomy, resection of porta hepatis, or partial liver resection.
Clear evidence is available demonstrating that ovarian cancer is a disease with distinct
molecular abnormalities, including TP53, BRCA1/2, and mutations in homologous
recombination [4]. Furthermore, others have observed that recurring tumors have sub-
stantial heterogeneity due to multiple spontaneous genetic and epigenetic events. This
dynamic tumor phenotype results in emerging drug resistance in almost every patient,
even though some of these patients initially responded to the platinum-based chemother-
apy. One explanation might be that the initial response of ovarian cancer to chemotherapy
initiates clonal selection of resistant cells to platinum or other therapies. These cellular
events might result in the reduced overall survival of 45.2% in patients with residual
tumors greater than 10 mm in diameter compared to 65.8% in patients who underwent
complete resection or a debulking surgery with a residual tumor of less than 10 mm in
diameter [1].
In contrast to other solid tumors being treated with NACT, ovarian cancer still remains
a disease best treated by upfront surgery, especially since patients receiving NACT rarely
respond completely. Furthermore, previous studies clearly show a benefit in patients after
treatment with PDS followed by chemotherapy. One large retrospective meta-analysis
suggested that early initiation of first-line chemotherapy following surgical resection
might improve overall survival [5]. Given the purpose of removing as much tumor as
possible in order to augment the effectiveness of subsequent chemotherapy and mainten-
ance, changing the treatment sequence by introducing NACT before surgery for patients
with advanced ovarian cancer calls previous studies into question [1, 5]. Furthermore,
a subgroup of patients diagnosed with advanced-stage ovarian cancer are usually symptom-
atic with very large masses, and may have a partial bowel obstruction. Therefore, these
patients require immediate attention, so that front-line NACT would be not appropriate
due to the required interval for the chemotherapy to be effective.
Conclusion
In summary, several aspects favor upfront cytoreduction. First, the complexity of cytor-
eductive surgery performed for ovarian cancer plays an important role in achieving com-
plete resection. Since patients receiving NACT rarely respond completely and the molecular
heterogeneity of ovarian cancer might play a role in drug resistance, systemic therapy is
likely to be more effective in surgically debulked, chemotherapy-naïve patients. Therefore,
the treatment sequence including primary cytoreductive surgery followed by early induc-
tion of chemotherapy might augment the effectiveness of chemotherapy. In the scenario of
interval debulking surgery, given the fact that patients rarely attain pathologic complete
response after NACT, its effectiveness might potentially be affected by the high tumor
burden, since most patients are primarily diagnosed with advanced-stage ovarian cancer.
Taken together, there is a strong rationale to support primary debulking for all surgical
patients with advanced ovarian cancer. Nevertheless, the group of women triaged to be
suitable for surgery is sometimes overestimated and the procedure is then abandoned due to
intraoperative complications or technical issues preventing resection. Despite advanced

60 Sven Mahner et al.
radiologic images, it is still not possible to reliably preoperatively predict which patients will
fall into this class.
To address these observations, an international collaboration of expert surgical centers
for ovarian cancer initiated the prospectively randomized TRUST trial (NCT02828618),
designed to evaluate the caliber of PDS as well as its relative benefit versus NACT [6]. In
contrast with previous trials, the TRUST trial includes rigorous criteria in selecting patients
with operable disease and on the other hand focuses on high volume centers with proven
high complete resection rates at upfront debulking surgery for patient recruitment. In
addition, this study will perform a systematic collection of biomaterials for translational
research, to potentially identify markers to select patients for either PDS or NACT. The trial
completed recruitment in 2019, is expected to report results in 2024, and may define the
standard of care in regards to the optimal timing of primary debulking surgery in ovarian
cancer.
References
1. du Bois A, et al. Role of surgical outcome as individual patient data from the EORTC
prognostic factor in advanced epithelial 55971 and CHORUS trials. Lancet Oncol
ovarian cancer: a combined exploratory 2018;19(12):1680–1687.
analysis of 3 prospectively randomized 4. Cancer Genome Atlas Research.
phase 3 multicenter trials: by the Integrated genomic analyses of ovarian
Arbeitsgemeinschaft Gynaekologische carcinoma. Nature 2011;474
Onkologie Studiengruppe Ovarialkarzinom (7353):609–615.
(AGO-OVAR) and the Groupe
d’Investigateurs Nationaux Pour les Etudes 5. Mahner S, et al. Prognostic impact of the
des Cancers de l’Ovaire (GINECO). Cancer time interval between surgery and
2009;115(6):1234–1244. chemotherapy in advanced ovarian
cancer: analysis of prospective
2. Woelber L, et al. Perioperative morbidity randomised phase III trials. Eur J Cancer
and outcome of secondary cytoreduction 2013;49(1):142–149.
for recurrent epithelial ovarian
cancer. Eur J Surg Oncol 2010;36 6. Reuss A, et al. TRUST: Trial of Radical
(6):583–588. Upfront Surgical Therapy in
advanced ovarian cancer (ENGOT
3. Vergote I, et al. Neoadjuvant chemotherapy ov33/AGO-OVAR OP7). Int J Gynecol
versus debulking surgery in advanced Cancer 2019;29(8):1327–1331.
tubo-ovarian cancers: pooled analysis of

Debate
Should an Attempt
11B at Aggressive Cytoreduction

be Made for all Surgical
Candidates with Advanced
Ovarian Cancer prior
to Treatment with Adjuvant
Chemotherapy?
No
Sean Kehoe and Jason Yap
Debate
Primary cytoreductive surgery [PCS] in ovarian cancer is an important therapeutic strategy.
In early-stage disease, excision of all disease is relatively uncomplicated and affords cure for
many patients, which is further increased in selected patients by the addition of adjuvant
chemotherapy. However, in advanced disease, particularly in FIGO stage IIIC and IV, the
surgical goal of PCS remains excision of all visible disease, but may require more extensive
surgical procedures, such as splenectomy; bowel and liver resection; and diaphragmatic
stripping. The average age at diagnosis of women with ovarian cancer is 65 years, and at least
a quarter of those are over 75-year-olds. Naturally, underlying medical co-morbidities
increase with age; rendering many patients unsuitable for extensive surgery and even
those selected may experience a protected period of postoperative recovery, delaying
commencement of chemotherapy with potential impact on outcome [1]. Recently, one
center which achieves high rates of macroscopic clearance at primary surgery, reported
that 17% of the patients initially deemed suitable for primary surgery were in fact operated
on after Neo-Adjuvant ChemoTherapy (NACT) [2]. Hence, despite with the best of inten-
tions, stating “attempt at aggressive cytoreduction should be made for all surgical candi-
dates with advanced ovarian cancer prior to treatment with adjuvant chemotherapy,” the
reality is different.
The role of PCS and NACT in advanced ovarian cancer has generated widespread
discussion and predictably divided opinion. Focusing on the two pivotal randomized
controlled trials (RCTs), the findings were that both PCS and NACT had similar survival
outcomes, but morbidities significantly reduced in NACT [3,4]. However, advocates of
PCS were quick to unpick the potential bias in these RCTs, namely that the studies
recruited a bias study population; there was a lack of standardization in surgical skills;
61

62 Sean Kehoe and Jason Yap
and that NACT is associated with more “resistant disease,” rendering surgery more
difficult. The “bias study population” is interesting. Arguably, patients who agree to
become involved in trials are to some extent subjected to “self- selection bias.” Taken to
its logical conclusion, trials are “inherently biased” as patients in trials rarely reflect all
patients treated in the health service, and, thus, let’s abandon trials altogether! A more
recent example of rebuttal of a trial that challenged “standard care” is the Laparoscopic
Approach to Cervical Cancer (LACC) study for early cervical cancer where rebuttals
occurred even before peer-reviewed publication [5]. Nevertheless, when the outcomes
of the clinical trials befit the practice already deemed “standard of care,” these studies
often go unchallenged.
A major issue with debates on PCS versus NACT is the inability to “fight fire with fire.” If
an RCT is the evidence base, then ideally this should be refuted or challenged by evidence
from another RCT. But such studies are unavailable, so there is an element of imbalance in
the debate. However, finally the first attempt at a prospective RCT has commenced explor-
ing the value of PCS in advanced ovarian cancer, the TRUST trial, which aims to standardize
the surgical component of the study, and the results are keenly awaited. But remember in the
TRUST trial – it is likely not all those recruited will totally reflect the entire population of
women with advanced ovarian cancer.
We now recognize the complexities of the disease called “ovarian cancer” or maybe
it is more accurate to say: what we believed in the past as correct is now proven wrong.
It is now accepted that most, if not all, high-grade serous carcinomas arise from the
distal end of the fallopian tubes, which has major implications for screening and
detecting earlier stage disease. Mucinous tumors, once deemed common, have been
shown to be mainly metastatic from the gastro-intestinal tract. We categorize diseases
into type 1 and 2, the latter more chemo-sensitive, more mutational aberrations, and
more aggressive in nature. Equally, evidence continues to accumulate on the mutational
heterogeneity of high-grade serous cancers, depending where the biopsy is taken. These
evolutionary advances in knowledge are welcomed and permit exploration of potential
novel therapeutic strategies. But the important point is that in advanced disease,
a single approach as suggested in the title seems somewhat simplistic when dealing
with such a complex disease.
Conclusion
So where are we now? It is time to consider cessation of the debate and focus on other
matters. Irrespective of the outcomes in the TRUST trial, we need systems to identify the
preferable primary therapy for each patient – which could be either PCS or NACT or some
novel approaches for others, rather than “a one size fits all” approach. We should endeavor
to avoid “open and close” operations and identify those where, following long extensive
surgery and chemotherapy, relapse early after completion of treatment – and develop
alternative therapeutic strategies. Do we need to reconsider our chemotherapeutic
approach – do all patients require six cycles of chemotherapy – should it be less or
more? Should treatment strategies be switched after three cycles in those patients with
limited response? Or should the circulating cells or tumor mutational profiles guide
treatment? Research in this and other areas is required, as the reality remains that few
patients with advanced disease achieve a “cure,” as defined by surviving ten years from
diagnosis.

Cytoreduction for all prior to Treatment? No 63
A final thought, what would have happened if by some statistical quirk the two trials had
shown that PCS was preferable to NACT? Could it be possible that the studies would have
been hailed as excellent, unbiased, well-constructed and with the appropriate patient group?
A thought for reflection?
References
1. Gemma Searle, et al. Prolonged interruption Cancer-Gynaecological Cancer Group;
of chemotherapy in patients undergoing NCIC Clinical Trials Group. Neoadjuvant
delayed debulking surgery for advanced chemotherapy or primary surgery in stage
high-grade serous ovarian cancer is IIIC or IV ovarian cancer. N Engl J Med
associated with a worse prognosis. Gynecol 2010;363(10):943–953.
Oncol 2020;158(1):54–58. https://doi.org/10 4. Kehoe S, et al. Primary chemotherapy versus
.1016/j.ygyno.2020.04.048 primary surgery for newly diagnosed
2. Straubhar AM, et al. A multimodality triage advanced ovarian cancer (CHORUS): an
algorithm to improve cytoreductive open-label, randomized, controlled,
outcomes in patients undergoing primary non-inferiority trial. Lancet 2015;386
debulking surgery for advanced ovarian (9990):249–257.
cancer: a Memorial Sloan Kettering Cancer 5. Ramirez PT, et al. Minimally invasive versus
Center team ovary initiative. Gynecol Oncol abdominal radical hysterectomy for cervical
2020;158(3):608–613. cancer. N Engl J Med 2018;379
3. Vergote I, et al. European Organization for (20):1895–1904. https://doi.org/10.1056
Research and Treatment of /NEJMoa1806395

Debate
Should Minimally Invasive
12A Modalities be Routinely/

Uniformly Utilized
for Assessment of Resectability
prior to Attempted Primary
Debulking in Patients with
Advanced Ovarian Cancer?
Yes
Juliet E. Wolford and Robert E. Bristow
Debate
Ovarian cancer, though not the most common gynecologic malignancy, remains the
deadliest. The lethality attributed to its aggressive nature, nondescript symptomatology,
and absence of effective screening, has resulted in 85% of the population diagnosed at an
advanced stage with widespread disease at time of presentation. Standard treatment for
advanced ovarian cancer is a complete or a “so-called” optimal cytoreductive surgery (no
gross versus <1 cm of residual disease) followed by a platinum-based chemotherapy doublet,
except in those patients where it is thought that a primary cytoreductive surgery would not
be possible. In these patients there is determined to be a high risk of perioperative morbidity
and mortality based on functional status, preexisting medical co-morbidities, and/or the
amount or location of disease burden limiting the ability to achieve a complete cytoreduc-
tive surgery. Those patients are given neoadjuvant chemotherapy with a plan to then
proceed with an interval debulking surgery if there is a satisfactory response to chemother-
apy. Often, the widespread extent of the disease is not known until the time of surgery,
despite standard axial imaging. There have been numerous previous studies done to
determine if standard CT imaging can predict feasibility of a primary optimal cytoreductive
surgery but thus far, results have been inconsistent and as of yet there is no accurate
standard in place for determining potential resectability. As a result, many gynecologic
oncologists have adopted the use of diagnostic laparoscopy prior to deciding to proceed
with an exploratory laparotomy in order to determine feasibility of cytoreduction. In newly
diagnosed ovarian cancer patients where axial imaging is inconclusive for determining
resectability potential, as it often is, we routinely perform diagnostic laparoscopy for several
reasons. Although it adds time to the start of the case, it can spare patients from an invasive
open procedure if they are deemed to not be able to undergo an optimal cytoreductive
64

Minimal Invasive Modalities before Debulking? Yes 65
procedure. Thus, avoiding recovery from a procedure associated with more pain, a higher
risk of infection, costlier hospital stays, and a potential cause of delay in starting chemo-
therapy which could have a significant impact on their overall survival.
In 2019, there was a Cochrane review analyzing the data to determine the accuracy of
this exact question. At the time, there were 18 studies, evaluating a total of 1563 women
who underwent laparoscopy to identify the feasibility of optimal cytoreductive surgery.
They found across the included trials that 16–73% of patients on laparoscopic assessment
were considered to have extensive disease excluding the attempt of an exploratory
laparotomy. While the remaining patients who had been deemed as resectable by lapar-
oscopy, 54–96% ultimately had a complete cytoreductive surgery to no gross residual
disease and 69–100% had an optimal cytoreductive surgery with <1 cm of residual cancer
at the conclusion of the case. Unfortunately, only two of the studies included laparotomy
despite findings on laparoscopy (thus a reference standard) to provide data that could be
analyzed for sensitivity or specificity, indicating verification bias of the other included
studies. Importantly though, there were no false positives identified, in other words: there
were no patients that were deemed unresectable by laparoscopic criteria and then were
able to be completely or optimally debulked [1]. Accordingly, the authors suggested that
diagnostic laparoscopy offers benefit to determining the extent of disease at the time of
surgery.
The Cochrane analysis was unable to complete a meta-analysis as there was marked
heterogeneity across trials. The two studies that included the reference standard were by
Fagotti et al., which led to a laparoscopic scoring system in order to provide standardization
[2,3]. The Fagotti system calculates a predictive index value (PIV) to estimate the achiev-
ability of optimal cytoreduction. The variables in this system include the presence of the
following at the time of laparoscopy: peritoneal carcinomatosis, diaphragmatic carcinoma-
tosis, mesenteric retraction, omental caking, gastric and/or bowel infiltration, and liver
metastases. In a pilot study, it was found that a high score (greater than 8) was associated
with prediction of a suboptimal cytoreductive procedure with a positive predictive value of
100% and a negative predicative value of 70% [4]. To validate the findings and to prove the
reproducibility of the findings at other institutions, the Olympia-MITO13 trial was imple-
mented to assess the applicability of the laparoscopic scoring algorithm across multiple
institutions. The most difficult assessment to achieve on laparoscopy was mesenteric root
retraction, but overall the study did find an accuracy rate of 80% or greater across the sites
included for determining disease extent [5].
Conclusion
Laparoscopy has known limitations. It adds operative time; also, the surgeon is unable to
completely visualize all areas of concern, which could limit ability to perform a complete or
optimal cytoreductive surgery. Thus, there will still be patients that will have a laparotomy
that may not be able to have a complete or optimal cytoreductive surgery once completely
assessed open. However, we have concluded that with a step-wise, multimodal approach, the
benefits outweigh the drawbacks of proceeding with laparoscopy. Patients should be
assessed carefully for concerning symptomatology and functional status. Images should
be reviewed thoroughly to assess if there are any clear indicators of an unsuccessful
cytoreductive procedure, such as liver parenchymal disease, lung metastases, or obvious
large tumor implants seen at the celiac axis or porta hepatis.

66 Juliet E. Wolford and Robert E. Bristow
Once it is confirmed that the patient can proceed with an operative assessment, the
procedure starts with a laparoscopic approach to determine disease extent. If the patient is
deemed appropriate for laparotomy, at that time we proceed will a small (10 cm) incision to
assess the abdomen and pelvis with palpation before proceeding with a full incision from
xiphoid to pubis. Laparoscopy has minimal associated complications as compared to open
laparotomy, with complications related to the initial access into the peritoneal cavity as
being less than 1% [6].
In addition, there are many other known advantages to MIS approach versus laparot-
omy, such as decreases in hospital stay length, postoperative pain, wound infection rates,
and healing time. Furthermore, at the time of laparoscopy, directed biopsies of tumor tissue
can be obtained for a more definitive diagnosis and further somatic tumor testing. The time
added with laparoscopy is minimal, often only 15–20 minutes. When you consider the
addition of laparoscopy can spare patients from an open procedure with associated
increased costs secondary to unnecessary hospital stays, as well as increased morbidity
that could potentially delay the initiation of their neoadjuvant chemotherapy, we feel that
the added time and potential need for further exploration are small disadvantages when
considerable benefit is acheived.
References
1. Vrie Rvan de et al. Laparoscopy for 4. Fagotti A, et al. A laparoscopy-based
diagnosing resectability of disease in women score to predict surgical outcome in
with advanced ovarian cancer. Cochrane patients with advanced ovarian
Database Syst Rev 2019;3: CD009786. http carcinoma: a pilot study. Ann Surg Oncol
s://doi.org/10.1002/14651858 2006;13(8):1156–1161. https://doi.org/10
.CD009786.pub3 .1245/ASO.2006.08.021
2. Fagotti A, et al. Role of laparoscopy to assess 5. Fagotti A, et al. A multicentric trial
the chance of optimal cytoreductive surgery (Olympia–MITO 13) on the accuracy of
in advanced ovarian cancer: a pilot study. laparoscopy to assess peritoneal spread in
Gynecol Oncol 2005;96(3):729–735. https:// ovarian cancer. Am J Obstet Gynecol
doi.org/10.1016/j.ygyno.2004.11.031 2013;209(5):462.e1–462.e11. https://doi.org
3. Fagotti A, et al. Prospective validation of /10.1016/j.ajog.2013.07.016
a laparoscopic predictive model for optimal 6. Jansen FW, et al. Complications of
cytoreduction in advanced ovarian laparoscopy: an inquiry about closed- versus
carcinoma. Am J Obstet Gynecol 2008;199 open-entry technique. Am J Obstet Gynecol
(6):642.e1–642.e6. https://doi.org/10.1016/j 2004;190(3):634–638. https://doi.org/10
.ajog.2008.06.052 .1016/j.ajog.2003.09.035

Debate
Should Laparoscopic Modalities
12B be Routinely Utilized

for Assessment of Resectability
prior to Attempted Primary
Debulking in Patients with
No
Beverly Long and William A. Cliby
Debate
Routine laparoscopy is increasingly being used to assess resectability of ovarian cancer prior
to laparotomy for primary debulking. Laparoscopic scoring algorithms are designed to
triage patients to primary debulking surgery or neoadjuvant chemotherapy and reduce the
number of unsuccessful primary debulking attempts. However, we do not recommend
routine laparoscopy prior to debulking surgery for the following reasons: additional opera-
tive time and risk associated with laparoscopy, inaccuracy of laparoscopy compared to
palpation, lack of validated or reproducible laparoscopic scoring algorithms, limited
improvement compared to CT scan alone to predict suboptimal debulking, and excellent
outcomes with the use of small laparotomy [1], CT scan, and careful patient selection.
Laparoscopy can immediately precede a planned laparotomy or be performed as
a separate procedure. A separate procedure does provide final histologic results prior to
laparotomy and may allow for more precise operating room planning. However, it also adds
an additional anesthetic risk, a small but definite surgical risk, and a high risk of port-site
implantation when done separately. When performed immediately prior to laparotomy,
laparoscopy adds additional equipment and time to an already complex procedure. In
a single institution study of one laparoscopic algorithm, laparoscopic assessment required
a median of 37 minutes and was associated with a 2% risk of gastrointestinal trocar injury in
addition to a lengthy debulking operation [2].
Notwithstanding, laparoscopy could be justified if laparoscopic assessment consistently
prevented laparotomy in patients destined for suboptimal debulking. Laparoscopy is excel-
lent for detection of miliary disease but is relatively fruitless for the common barriers to
successful debulking. Lesser sac disease, upper abdominal lymphadenopathy, mesenteric
involvement, and porta hepatis disease is not well characterized by laparoscopy and is better
assessed by preoperative CT scan and intraoperative palpation. The findings of mesenteric
retraction or bowel immobility are subjective and impossible to evaluate adequately in the
67

68 Beverly Long and William A. Cliby
setting of a large omental cake. In the prospective, multi-center Olympia-MITO 13 trial,

mesenteric retraction was not evaluable in over 25% of cases [3]. Multiple studies also report
adhesions and extensive disease as barriers to accurate laparoscopic assessment. In our
experience, a small laparotomy is superior to laparoscopy, as it allows palpation of areas that
may be difficult or impossible to access laparoscopically, such as the root of the mesentery,
celiac axis, porta hepatis, lesser sac, pelvis, and spleen with lower risk of viscus injury or port
site metastases
Scoring algorithms have been developed to standardize laparoscopic assessment. The
scoring system published by Fagotti et al. is the most widely used [3]. However, by using
scoring systems that are additive rather than exclusionary, most laparoscopic algorithms
inappropriately equate “surgical resectability” with “surgical complexity.” For instance,
mesenteric retraction (disease at the root of the mesentery or extensive mesenteric disease)
typically precludes optimal cytoreduction even in the absence of other scoring criteria. Still,
in the Fagotti algorithm this factor is given equal weight to other findings, including liver
surface implants, stomach infiltration, diaphragmatic carcinomatosis, and omental cake,
which while adding operative time and requiring specialized expertise, are not barriers to
successful debulking. While a high score correlates with increased surgical complexity, it
should not preclude primary debulking surgery in a fit surgical candidate. With appropriate
patient selection, aggressive debulking procedures can be safely performed and are associ-
ated with higher rates of optimal cytoreduction and ovarian cancer survival. Because
laparoscopic scoring algorithms do not account for patient factors, they may not be valid
for fit patients who would tolerate complex surgery and may not be useful for frail patients
who would benefit from neoadjuvant chemotherapy and a less complex procedure.
Laparoscopic scoring algorithms cannot account for varying levels of surgical experience
and resources among gynecologic oncologists. Data from the Mayo Clinic demonstrated
higher disease-specific survival in patients whose surgeons more frequently performed
radical procedures. Chi et al. reported higher rates of optimal debulking when extensive
upper abdominal procedures were systematically incorporated into their department’s
surgical approach. Because thresholds for resectability vary by surgeon, institution, and
time period, laparoscopic algorithms are impossible to widely validate or standardize. While
one could argue laparoscopy could be used to triage patients to centers of excellence, there
does not appear to be enthusiasm for that.
Most importantly, laparoscopic assessment may not improve sensitivity for sub-optimal
debulking compared to a preoperative CT scan. Laparoscopy cannot replace preoperative
imaging, since parenchymal liver metastases, pleural metastases, and upper abdominal
lymphadenopathy cannot be assessed laparoscopically and may significantly alter the
treatment approach. Some CT findings may rule out optimal debulking without the need
for surgery. Multiple CT-based algorithms have been developed to predict suboptimal or
incomplete cytoreduction preoperatively. Many of these models compare favorably to the
Fagotti score, predicting incomplete cytoreduction with an accuracy of 65–75%. A CT-
based model proposed by the group at Memorial Sloan Kettering to predict gross residual
disease was recently validated by the Mayo clinic and further reduces the value of laparos-
copy [4].
Despite advances in preoperative imaging, surgical exploration will always play a role in
assessment of resectability. Intraoperative palpation through a small laparotomy incision
overcomes most of the challenges associated with laparoscopic scoring. In a European
study, resectability assessment via mini-laparotomy demonstrated improved positive

Laparoscopic Modalities before Debulking? No 69
predictive value (89% vs. 60%) and equivalent negative predictive value (both 100%)
compared to a Fagotti score cut-off ≥8. Median time from incision to complete assessment
was only 10 minutes [1], and this method carries a lower risk of aborted debulking and port
site implants. This approach, combined with a novel, evidence-based triage algorithm,
produced excellent surgical and long-term outcomes in a recent study from the Mayo
Clinic. This suggests that a multi-modality approach, incorporating patient performance
status, nutrition status, CT findings, and intraoperative assessment, can predict optimal
cytoreduction without undue surgical morbidity [5]. The fact that routine laparoscopy was
not performed in this cohort demonstrates that superior outcomes can be achieved without
the use of laparoscopy.
Conclusion
In summary, patient selection for ovarian cancer surgery is complex and requires consider-
ation of multiple patient, surgeon, and disease-related factors. In our experience, routine
laparoscopy is not the optimal method to assess resectability of ovarian cancer due to the
need for additional operating room time and equipment, inability to assess common
barriers to optimal debulking, poor sensitivity and reproducibility, and little to no improve-
ment over CT scan alone. A multi-modality approach can appropriately triage patients
without the need for routine laparoscopy.
References
1. Sircar S, et al. Mini-laparotomy in advanced 4. Kumar A, et al. Models to predict outcomes
ovarian cancer. Gynecol Surg after primary debulking surgery:
2011;9:179–183. independent validation of models to
2. Fleming N, et al. Laparoscopic algorithm to predict suboptimal cytoreduction and gross
triage the timing of tumor reductive surgery residual disease. Gynecol Oncol 2019;154
in advanced ovarian cancer. Obstet Gynecol (1):72–76.
2018;132(3):545–554. 5. Narasimhulu DM, et al. Using an
3. Fagotti A, et al. A multicentric trial evidence-based triage algorithm to
(Olympia-MITO 13) on the accuracy of reduce 90-day mortality after primary
laparoscopy to assess peritoneal spread in debulking surgery for advanced epithelial
ovarian cancer. Am J Obstet Gynecol ovarian cancer. Gynecol Oncol 2019;155
2013;209(5):462.e1–462.e11.90 (1):58–62.

Debate
Should Enlarged
13A Supradiaphragmatic Lymph

Nodes be Routinely Removed
during Debulking Surgery
Procedures for Patients with
Yes
Annalisa Garbi and Vanna Zanagnolo
Debate
The goal of advanced ovarian cancer treatment is the achievement of a complete cytoreduc-
tion. Although the ideal timing of debulking surgery (primary vs. interval) is still under
discussion, its primary aim is to remove all the macroscopically visible disease, since
a complete cytoreduction is significantly associated with a better prognosis. According to
the European Society of Gynaecological Oncology (ESGO) and to the American Society of
Clinical Oncology (ASCO), an optimal cytoreduction is considered as no residual disease or
microscopic residual disease. For this reason, increasingly complex procedures including
the debulking of the upper abdomen have been implemented to achieve this goal. The
positive impact of no residual disease has been observed even in patients with stage IV
disease who would benefit from debulking surgery, requiring extensive upper abdominal
procedures, if no or small residual is obtained [1].
Involvement of cardiophrenic lymph nodes (CPLNs), that qualifies as stage IVB
disease, is quite common in advanced ovarian cancer and it is has been reported between
11–62% at preoperative CT scan. Cardiophrenic lymph nodes, also known as paracar-
diac or supradiaphgramatic lymph nodes, are located just above the diaphragm, and are
easily reached when the diaphragm is opened. Enlarged CPLNs could be predictive of
massive diaphragmatic involvement, however they are not a contraindication to the
attempt of cytoreductive surgery. The presence of pathological enlarged CPLNs is
usually related to a worst prognosis and the presence of an extensive abdominal
tumor burden. Furthermore, CPLNs’ involvement predicts the presence of carcinoma-
tosis of the upper abdomen in more than 90% of cases, and is associated with a reduced
chance of a complete optimal abdominal surgical debulking [2]. Why should they be
removed? Several surgical techniques have been described to remove CPLNs including
video-assisted thoracoscopic surgery (VATS), subxiphoid, and transdiaphragmatic
approaches. When performed by experienced surgeons in high-volume oncology cen-
ters, removal of CPLNs has been demonstrated feasible with no significant increase of
70

Enlarged Lymph Nodes Removed during Debulking? Yes 71
surgical time and blood loss [3]. Postoperative surgical morbidity associated with CPLN
removal has been reported as negligible or low and most likely related to diaphragmatic
surgery than to the dissection of the CPLNs themselves [3]. Moreover, adding this
procedure does not delay adjuvant chemotherapy [3]. The most frequent complication,
in accordance to procedure involving the diaphragm, is an asymptomatic pleural effu-
sion detected on postoperative imaging. CPLN removal in the case of absence of
diaphragmatic involvement is controversial. However, it should be considered that in
such an instance it would require only a small diaphragmatic incision and it’s likely
associated with much fewer complications compared to a procedure requiring a large
diaphragmatic resection.
No consensus exists on the dimension cut-off to define enlarged CPLNs. Different
criteria have been proposed starting from 5 mm in short axis (ESUR guidelines). Others
suggested the 7 mm cut-off and even, more than 10 mm has been considered. The
removal and histological evaluation of “enlarged” CPLNs will help define the best
radiological cut-off. Moreover, such a finding could confirm the predictivity of diaphrag-
matic involvement also in patients with no evidence of disease at preoperative CT scan,
and therefore the need of more extensive upper abdominal procedures in a potentially
frail population. Literature data of patients with FIGO stage III ovarian cancer with
enlarged CPLNs at preoperative imaging (CT scan or PET) show a significantly lower
rate of optimal debulking surgery, a shorter disease-free interval, and worse overall
survival (OS). Therefore, the presence (only radiological findings, not removed) of
abnormal CPLNs appears to have a significant negative impact on OS, mostly, in patients
with no gross residual disease (NGR) in the abdomen. The median OS of women with
abnormal CPLNs (not removed) and NGR was similar to patients who had abdominal
residual disease, losing the benefit of optimal abdominal surgery. Accordingly, in
a recent study, Luger et al. confirmed that enlarged (not removed) CPLNs had
a prognostic relevance for PFS (HR=2.02, 95% CI: 1.14–3.55, p=0.015) and OS
(HR=2.46, IQR=1.54–3.93; p=0.0001); nonetheless these patients still benefit from com-
plete intraabdominal tumor debulking in terms of PFS (HR=0.60, 95% CI: 0.38–0.94)
and OS (HR=0.59, 95% CI: 0.35–0.82) [2].The therapeutic role of resection of enlarged
CPLNs is not clear yet. A recent study did not demonstrate a significant impact on
survival of metastatic CPLNs removal. Nevertheless, these data are retrospective and
with a low number of cases. A large multicentric series should be advocated if
a prospective randomized trial is not feasible [4]. The presence of preoperative enlarged
CPLNs left in place at the time of surgery has been associated with an increased risk of
recurrence (81.5% in CPLNs positive vs. 57,4% in CPLNs negative); specifically with an
increased risk of thoracic recurrence (CPLN, pleura, parenchyma) therefore limiting
treatment options [5]. It can be argued that having left the CPLNs in place may have
affected the pattern of relapse and therefore it could be seen as a factor in favor of their
removal.
Conclusion
In conclusion, it is still unclear whether removal of suspicious CPLNs will improve the
oncological outcomes when NGR is obtained, however, given the minimal surgical effort
and the related low morbidity of such a procedure, that makes it feasible and safe, it seems
reasonable to be implemented when indicated.

72 Annalisa Garbi and Vanna Zanagnolo
References
1. Ataseven B, et al. Impact of abdominal wall lymph node resection in advanced ovarian
metastases on prognosis in epithelial cancer. Gynecol Oncol 2017;147
ovarian cancer. Int J Gynecol Cancer (2):262–266.
2016;26:1594–1600. 4. Prader S, et al. Pattern and impact of
2. Luger AK, et al. Enlarged cardiophrenic metastatic cardiophrenic lymph nodes in
lymph nodes predict disease involvement of advanced epithelial ovarian cancer. Gynecol
the upper abdomen and the outcome of Oncol 2019;152(1):76–81.
primary surgical debulking in advanced 5. Larish A, et al. Recurrence patterns
ovarian cancer. Acta Obstet Gynecol Scand in=patients with abnormal
2020;99(8):1092–1099. cardiophrenic lymph nodes at ovarian
3. Cowan RA, et al. Feasibility, safety cancer diagnosis. Int J Gynecol Cancer
and clinical outcomes of cardiophrenic 2020;30(4):504–508.

Debate
Should Enlarged
13B Supradiaphragmatic Lymph

Nodes be Routinely Removed
during Debulking Surgery
Procedures for Patients with
No
Javier F. Magrina, Kristina Butler, and Paul
Magtibay
Debate
Background
Because complete abdominal cytoreduction improved survival in advanced epithelial ovar-
ian carcinoma (EOC), there was great interest generated in evaluating whether complete
extra-abdominal debulking, such as enlarged supradiaphragmatic nodes (ESDN), resulted
in improved survival. Evidence suggests removal of ESDN at primary debulking does not
improve survival [1–5].
Incidence, Sites, and Size of Enlarged Supradiaphragmatic Nodes

There is no agreement to what constitutes ESDN. We know ESDN are common in stage IIIC
[1–3], but incidence varies according to the selected size and imaging modality. The
detection rate is almost double with positron emission tomography (PET) (67–76%)
[1,3,4] as compared to computed tomography (CT) (33–43%) [1,2]. Using a cut-off
>10 mm on the short axis eliminates many patients with metabolically active nodes on
PET because most are <10 mm [3]. Using the same cut-off on CT, only 11.1% have
ESDN [5].
Most with ESDN have multiple nodal sites (cardiophrenic, parasternal, mediastinal,
axillary, and subclavian) involved (76%) and only 14% are surgically accessible [3]. Forty-
five percent of patients with ESDN have parenchymal metastases in the liver, spleen, pleura,
or other extra-abdominal sites [5].
Not all ESDN are metastatic, only 67–94%, therefore routine removal is not advisable [4,6].
The size range of metastatic nodes is 0.3–2.9 cm [4,6], with a median of two positive nodes [6].
Patients with stage IV should be considered as a single group for therapeutic purposes
regardless of the type and location of extra-abdominal metastases because their survival is
73

74 Javier F. Magrina et al.
similar regardless of the location of the extra-abdominal metastases [3,4,7]. In 124 stage IV
patients, there was no significant difference in overall survival (OS) between 38 patients with
parenchymal metastases (18 months), 28 with extra-abdominal enlarged nodes (16
months), and 58 with pleural effusions (21.5 months) (p=0.7085) [7].
Enlarged supradiaphragmatic nodes are best treated with primary chemotherapy (PC)
(i.e., neoadjuvant) because it is effective for ESDN and their resection does not improve
survival.
1. Primary chemotherapy has multiple benefits.
(a) Primary chemotherapy identifies chemo-resistance and those unlikely to benefit
from cytoreduction.
(b) Enlarged supradiaphragmatic nodes are responsive to PC. A complete or
partial response was observed in 96% of 97 patients (complete 83%; partial
13%). The rate of response had no impact on progression-free survival
(PFS) (13.6 vs. 14.9 months, p=0.59) [3], suggesting removal would not
provide survival benefit.
(c) Isolated ESDN recurrences are rare, at 5% [4].
(d) Recurrences are abdominal in 80–85%, and only 2.4% are associated with
recurrence in ESDN [3,4,7].
2. Resection of ESDN does not improve survival.
A complete abdominal and thoracic debulking (involving thoracic surgeons) in 25
patients, resulted in similar PFS (p=0.425) and OS (p=0.465,) as compared to complete
abdominal debulking alone (n=151) [4].
3. There is no survival difference in stage IIIC with or without ESDN.
The median survival of 92 patients with ESDN was similar to 120 patients without
ESDN (45 vs. 50 months, p=0.09) [2]. Among 176 patients there was no difference in
PFS (p=0.671) or OS (p=0.525) for patients with or without ESDN [4].
Additionally, among 136 patients with complete abdominal debulking and enlarged
cardiophrenic nodes there was no significant difference in OS as compared to patients
without ESDN (38.4 vs. 69.6 months, p=0.08) [5].
4. Survival with single versus multiple sites of ESDN are similar.
In eight patients with a single cardiophrenic site, there was no difference in PFS
(p=0.22) or OS (p=0.56) versus 42 patients with multiple sites of ESDN [4].
What Should the Extent of Surgery be with Enlarged

Supradiaphragmatic Nodes?
The most influential factor in stage IVB survival is a complete abdominal debulking [7].
Unfortunately, it is uncommon in stage IVB because these patients have more advanced
abdominal disease than stage IIIC, usually with ascites, subdiaphragmatic carcinomatosis,
and high CA-125 [1,3,6,7].
Conclusion
In conclusion, because complete resection of extra-abdominal metastases does not improve
survival, it is hypothesized that stage IVB is a surrogate of aggressive tumor biology which
will persist regardless of the extent of resection.

Enlarged Lymph Nodes Removed during Debulking? No 75
Is there ever an Indication for Resection of Enlarged

Supradiaphragmatic Nodes?
Consider a rare patient with a single site of ESDN, surgically accessible, persistent after
primary chemotherapy, and with no residual abdominal disease after completion of an
interval debulking. This represents a site of unresponsive nodal disease for which there may
be an indication.
References
1. Hynninen J, et al. FDG PET/CT in staging of 4. Lee IO, et al. Prognostic significance of
advanced epithelial ovarian cancer: supradiaphragmatic lymph node metastasis
frequency of supradiaphragmatic lymph detected by (18)F-FDG PET/CT in advanced
node metastasis challenges the traditional epithelial ovarian cancer. BMC Cancer
pattern of disease spread. Gynecol Oncol 2018;18(1):1165. https://doi.org/10.1186/s1
2012;126(1):64–68. https://doi.org/10.1016/j 2885-018–5067–1
.ygyno.2012.04.023 5. Mert I, et al. Clinical significance of
2. Kolev V, et al. Prognostic significance of enlarged cardiophrenic lymph nodes in
supradiaphragmatic lymphadenopathy advanced ovarian cancer: implications for
identified on preoperative computed survival. Gynecol Oncol 2018;148(1):68–73.
tomography scan in patients undergoing https://doi.org/10.1016/j.ygyno.2017.10
primary cytoreduction for advanced .024
epithelial ovarian cancer. Int J Gynecol 6. Cowan RA, et al. Feasibility, safety and
Cancer 2010;20(6):979–984. https://doi.org/ clinical outcomes of cardiophrenic lymph
10.1111/IGC.0b013e3181e833f5 node resection in advanced ovarian cancer.
3. Laasik M, et al. Behavior of FDG-avid Gynecol Oncol 2017;147(2):262–266. https://
supradiaphragmatic lymph nodes in PET/ doi.org/10.1016/j.ygyno.2017.09.001
CT throughout primary therapy in advanced 7. Jamieson A, et al. Subtypes of stage IV
serous epithelial ovarian cancer: ovarian cancer; response to treatment and
a prospective study. Cancer Imaging 2019;19 patterns of disease recurrence. Gynecol
(1):27. https://doi.org/10.1186/s40644-019– Oncol 2017;146(2):273–278. https://doi.org/
0215–7 10.1016/j.ygyno.2017.05.023

Debate
Is there a Role
14A for Hyperthermic

Intraperitoneal
Chemotherapy in Front-line
Therapy for Ovarian Cancer?
Yes
S. Lot Aronson, Gabe S. Sonke, and Willemien J.
van Driel
Debate
Introduction
Ovarian cancer is the leading cause of mortality amongst gynecological cancers worldwide.
Despite progress in therapeutic strategies and surgical techniques, long-term survival rates have
not improved substantially over the last decades and remain poor. Standard treatment consists
of cytoreductive surgery (CRS) and platinum- and taxane-based chemotherapy, followed by
optional maintenance therapy with bevacizumab or poly-(ADP)-ribose polymerase (PARP)
inhibitors. Although response rates to first-line therapy are high, ovarian cancer recurs in most
patients within two years, for whom curative treatment is unavailable. In the search for new
strategies, hyperthermic intraperitoneal chemotherapy (HIPEC) is a next step forward, target-
ing the predominant site of ovarian cancer metastases and recurrence: the peritoneum.
From Intraperitoneal Chemotherapy to Hyperthermic Intraperitoneal

Chemotherapy
Advanced ovarian cancer is typically characterized by peritoneal dissemination, following
the route of peritoneal fluid, whereas lymphatic and hematogenous spreading occurs less
frequently. In 1955, Weisberger introduced intraperitoneal chemotherapy (IPC) for ovarian
cancer. The rationale was to achieve higher concentrations of chemotherapeutics within the
abdominal cavity, enhancing tumor deposit penetration, while limiting systemic toxic
effects due to the physiologic peritoneal-plasma barrier. In this way, locoregional chemo-
therapy targets microscopic, poorly vascularized lesions on the peritoneal surface, which are
relatively resistant to systemic therapy. The rationale was supported by extensive pharma-
cological data and a meta-analysis by Jaaback and others (2016), which showed significant
long-term improvement of survival in patients with primary advanced ovarian cancer, who
received intravenous paclitaxel plus intraperitoneal cisplatin [1]. As pharmacologic studies
have shown limited penetration depth (0.5–3 mm) of cytotoxic agents into the tumor
deposits, (near) complete CRS is a prerequisite for an optimal effect.
76

Chemotherapy in Front-line Therapy? Yes 77
Improved outcome by IPC came at the expense of increased toxicity, catheter-

related complications, and decreased quality of life, leading to premature termination
of the regimen in more than half of patients. These factors, together with challenging
patient selection and complex logistics, prevented IPC from becoming widely adopted.
In an effort to avoid treatment intolerance encountered with IPC, the search for novel
options for intraperitoneal chemotherapy administration continued.
Rationale for Hyperthermic Intraperitoneal Chemotherapy in Ovarian

Cancer
Experience in the use of HIPEC for pseudomyxoma peritonei, peritoneal mesotheli-
oma, and gastro-intestinal cancer has built up since the 1980s. The procedure of
a single intraoperative intraperitoneal administration of heated chemotherapy has
several clinical advantages over IPC. While formation of adhesions and fibrosis
impairs the distribution of IPC in the adjuvant setting, HIPEC enables optimal
distribution of cytotoxic agents within the abdominal cavity. Also, intraoperative
administration avoids delay between cytoreduction and chemotherapy, which is
known to significantly impact prognosis due to growth of residual cancer cells in
the time interval [2]. Furthermore, a single administration avoids complications
associated with repetitive administration over an indwelling catheter.
The rationale for addition of hyperthermia to IPC is based on several mechanisms
[2,3]. First, hyperthermia has direct lethal effect selectively on malignant cells through
heat-induced lysosomes, inhibition of oxidative metabolism, and selective vascular stasis.
Second, hyperthermia leads to transient induction of homologous recombination defi-
ciency that sensitizes tumor cells to chemotherapy that induces double-stranded DNA
breaks. Third, hyperthermia increases penetration of chemotherapeutic agents into tumor
deposits.
Clinical evidence for the benefit of HIPEC in ovarian cancer comes from the
pivotal phase 3 OVHIPEC-1 trial and is supported by several observational studies
that established safety and feasibility [4]. The OVHIPEC-1 trial by van Driel and
others included patients with stage III primary epithelial ovarian cancer who under-
went optimal or complete interval CRS [5]. Eligible patients had at least stable disease
after three cycles of neo-adjuvant carboplatin and paclitaxel and were randomized
during surgery to receive HIPEC with cisplatin or no additional intraoperative treat-
ment. Sodium thiosulphate was administered to prevent nephrotoxicity. The trial
showed a significant improvement in recurrence-free survival (10.7 vs. 14.2 months,
HR=0.66 [0.50–0.87]) and overall survival (33.9 vs. 45.7 months, HR=0.67 [0.48–0.94])
with addition of HIPEC. The likelihood of complete CRS and bowel surgery was
similar in both arms, indicating no difference in surgical quality. The higher number
of ileo- or colostomies in the HIPEC group probably reflects surgeons’ caution
regarding anastomotic leakage after HIPEC as reported in early publications.
However, the trial showed no important differences in postoperative complications
or adverse events and HIPEC did not delay the reinitiation of adjuvant chemotherapy.
Importantly, HIPEC did not adversely affect quality of life and cost-effectiveness
analysis indicated that addition of HIPEC was cost-effective in the Netherlands and
in countries with comparable healthcare systems [6].

78 S. Lot Aronson et al.
Conclusion
Long-term survival of women with advanced ovarian cancer is poor and the peritoneum is
the primary site of recurrence even after high-quality surgery in expert centers. HIPEC
therefore specifically targets microscopic residual disease at the peritoneal surface after
surgery. Mechanistic and pre-clinical data, early phase studies, and randomized evidence all
support the conclusion that HIPEC improves survival in women after interval CRS for
advanced ovarian cancer. Moreover, HIPEC is safe and cost-effective. Whether these
advantages apply to women undergoing primary CRS is the topic of the ongoing inter-
national OVHIPEC-2 trial (NCT03772028). Several unanswered questions remain, regard-
ing the administration procedure (temperature, dosing, duration, open vs. closed
technique), the additive effect of hyperthermia, integration with subsequent treatment,
and optimal patient selection. These knowledge gaps need more research, ultimately leading
to a uniform protocol and adoption into routine care, with the aim of improving survival
outcomes for women with advanced ovarian cancer.
References
1. Jaaback K, et al. Intraperitoneal 4. Huo YR, et al. Hyperthermic intraperitoneal
chemotherapy for the initial management of chemotherapy (HIPEC) and cytoreductive
primary epithelial ovarian cancer. Cochrane surgery (CRS) in ovarian cancer:
Database Syst Rev 2016;11:CD005340. http a systematic review and meta-analysis. Eur
s://doi.org/10.1002/14651858 J Surg Oncol 2015;41:1578–1589.
.cd005340.pub3 5. van Driel WJ, et al. Hyperthermic
2. de Bree E, et al. Pharmacological principles intraperitoneal chemotherapy in ovarian
of intraperitoneal and bidirectional cancer. N Engl J Med 2018;378:1363–1364.
chemotherapy. Pleura Peritoneum 6. Koole SN, et al. Cost effectiveness of interval
2017;2:47–62. cytoreductive surgery with hyperthermic
3. González-Moreno S, et al. Hyperthermic intraperitoneal chemotherapy in stage iii
intraperitoneal chemotherapy: rationale and ovarian cancer on the basis of a randomized
technique. World J Gastrointest Oncol phase iii trial. J Clin Oncol
2010;2:68–75. 2019;37:2041–2050.

Debate
Is there a Role
14B for Hyperthermic

Intraperitoneal
Chemotherapy in Front-line
Therapy for Ovarian Cancer?
No
Richard Schwameis, Luis M. Chiva, and Philipp
Harter
Debate
The hype around Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) started roughly
two decades ago when a randomized trial comparing surgery and HIPEC versus palliative
chemotherapy only in patients with colon cancer showed favorable results [1]. The prog-
nostic differences were limited to patients with complete resection, suggesting that surgery
played the main role. Unfortunately, there was no surgery-alone arm. Nevertheless, based
upon these data, some clinicians commenced adding HIPEC to cytoreductive surgery for
a variety of malignancies including ovarian cancer (OC).
Currently in the management of OC, data from two prospective randomized controlled
trials and several retrospective trials are available.
The OVHIPEC trial randomized 245 patients with FIGO stage III OC after three cycles of
carboplatin and paclitaxel to either HIPEC with 75 mg/m2 cisplatin or no HIPEC at the time of
interval debulking surgery (IDS) [2]. Subsequently, all patients received three additional cycles
of chemotherapy. Notably, this study showed a significant benefit in progression-free survival
(PFS) (14.2 vs. 10.7 months, p=0.003) and overall survival (OS) (45.7 vs. 33.9 months, p=0.02).
Although publicized very prominently, this study was the target of multiple criticisms.
First, the statistical plan was changed, while the study was already ongoing. In detail, the
statistical calculations were based upon the assumption that patients in the standard
treatment arm would have a PFS of 18 months and that by adding HIPEC an increase of
50% (18 to 24 months) could be achieved. Accordingly, a sample size calculation revealed
280 patients would be necessary to detect a hazard ratio of 1.5 with a 0.05 two-sided
significance level and a power of 80%. However, when the study recruited slowly, the sample
size was simply reduced to 240 patients. Furthermore, both study arms performed signifi-
cantly worse in terms of PFS than expected, which also reduced statistical validity.
Second, when comparing the original study protocol with the published paper, different
time points of study inclusion and randomization can be identified. While the protocol
initially allowed participant inclusion and randomization only prior to any treatment, this
was changed in an amendment to the protocol allowing randomization also just before IDS.
79

80 Richard Schwameis et al.
Therefore, there is a possibility that the timing of randomization might have biased the
surgeons performing the IDS in favor of the HIPEC arm. Unfortunately, the number of
patients randomized at the different time points was not reported.
Third, the limited number of 245 patients might have led to possible biases. For example,
regarding the OS statistics, the difference in death events was only 15 patients.
Unfortunately, patients were not stratified according to important factors such as tumor
grade, BRCA status or histologic type and therefore an imbalance of patients with histologic
types favoring the HIPEC arm occurred.
Fourth, patient recruitment took more than nine years, resulting in only three random-
ized patients per center per year. Within this time period treatment of OC changed
significantly (introduction of bevacizumab and PARP-inhibitors). This might have had
a significant impact, as other studies have shown a dramatically reduced benefit from
intraperitoneal chemotherapy in the era of bevacizumab treatment. Furthermore, study
center and surgeon selection were arbitrary without thorough quality assurance and no
information was given about the surgeon’s qualifications. Notably, in the largest participat-
ing center (National Cancer Institute Amsterdam, n=105) no significant beneficial effect of
HIPEC was observed. A beneficial effect of HIPEC was only observed in smaller centers,
including only 18 to 36 patients.
In addition, further points of criticism include incomplete reporting of HIPEC-
associated adverse events and toxicities, a missing general strategy of patient allocation to
either primary debulking surgery (PDS) or IDS and a remarkably high rate for colostomy in
the HIPEC arm.
Interestingly, Lim et al. also conducted a prospective randomized trial investigating the
impact of HIPEC in OC. This study included 184 patients with FIGO stage III and IV OC
undergoing PDS or IDS [3]. Patients were eligible if residual disease was <1 cm. In the
control arm, patients received intravenous chemotherapy, while patients in the study arm
received additional HIPEC using cisplatin 75 mg/m2. This study showed similar five-year
PFS rates (HIPEC arm: 20.9%; control arm: 16.0%, p=n.s.) and five-year OS rates (HIPEC
arm: 51.0%, control arm: 49.4%, p=n.s.) in both arms, respectively. In direct comparison
and in contrast to the OVHIPEC trial, patients of the IDS subgroup showed similar PFS and
OS rates (PFS: 20 vs. 19 months; OS: 54 and 51 months, for HIPEC and control arm,
respectively).Recently, the trial was published after a longer follow up confirming the results
in the ITT population, but now with a difference in IDS favoring HIPEC [Lim MC, Chang
SJ, Park B, et al. Survival After Hyperthermic Intraperitoneal Chemotherapy and Primary or
Interval Cytoreductive Surgery in Ovarian Cancer: A Randomized Clinical Trial. JAMA
Surg. 2022 May 1;157(5):374-383]. However, the primary endpoint was changed and
multiple questions regarding the methodology of analysis of the primary endpoint remain
open [Harter P, Bogner G, Chiva L. Statement of the AGO Kommission Ovar, AGO Study
Group, NOGGO, AGO Austria, Swiss AGO, BGOG, CEEGOG, and GEICO Regarding the
Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Epithelial Ovarian Cancer.
Le Bulletin du Cancer 2023 (accepted)
Additional evidence is provided by a prospective randomized trial in relapsed OC that
included 98 patients undergoing secondary cytoreductive surgery. In this study, HIPEC did
not shown any impact on perioperative morbidity, PFS, or OS [4].
Admittedly, there are retrospective trials showing a benefit of HIPEC in OC. A recent
systematic review included 22 trials and data from more than 1450 patients. This review
summarized the information on 493 patients that were treated with HIPEC in the first-line

Chemotherapy in Front-line Therapy? No 81
setting and of 957 patients at secondary debulking surgery. This review failed to show
a survival benefit and hence concluded that the use of HIPEC cannot be recognized as
a standard of care in ovarian cancer [5].
A randomized trial evaluating the role of HIPEC at primary debulking surgery in
primary OC (NCT03772028) is currently ongoing. However, we must be cautious that the
story of HIPEC in OC may follow a similar path to that of HIPEC in colorectal cancer.
Initially there was a trial showing a benefit (Verwaal et al.), however subsequently there have
been several prospective phase III trials failing to show a survival benefit of HIPEC, but in
contrast, more toxicity in the experimental arms [6,7,8].
Conclusion
In summary, there are insufficient data to support HIPEC in primary or relapsed ovarian
cancer. Furthermore, the possibility of a detrimental effect has still not been completely
evaluated nor ruled out.
References
1. Verwaal VJ, et al. Randomized trial of (HIPEC) in the treatment of advanced and
cytoreduction and hyperthermic recurrent ovarian cancer. Gynecol Oncol
intraperitoneal chemotherapy versus 2015;136(1):130–135.
systemic chemotherapy and palliative 6. Quénet F, et al. Cytoreductive surgery plus
surgery in patients with peritoneal hyperthermic intraperitoneal chemotherapy
carcinomatosis of colorectal cancer. J Clin versus cytoreductive surgery alone for
Oncol 2003;21(20):3737–3743. colorectal peritoneal metastases
2. van Driel WJ, et al. Hyperthermic (PRODIGE 7): a multicentre, randomised,
intraperitoneal chemotherapy in ovarian open-label, phase 3 trial. Lancet Oncol
cancer. N Engl J Med 2018;378(3):230–240. 2021;22(2):256–266.
3. Lim MC, et al. Randomized trial of 7. Goéré D, et al. Second-look surgery plus
hyperthermic intraperitoneal chemotherapy hyperthermic intraperitoneal chemotherapy
(HIPEC) in women with primary advanced versus surveillance in patients at high risk of
peritoneal, ovarian, and tubal cancer. J Clin developing colorectal peritoneal metastases
Oncol 2017;35(15,Suppl.): meeting abstract. (PROPHYLOCHIP-PRODIGE 15):
4. Zivanovic O, et al. Secondary cytoreduction a randomised, phase 3 study. Lancet Oncol
and carboplatin hyperthermic 2020;21(9):1147–1154.
intraperitoneal chemotherapy for 8. Klaver CEL, et al. Adjuvant hyperthermic
platinum-sensitive recurrent ovarian cancer: intraperitoneal chemotherapy in patients
an MSK Team Ovary Phase II Study. J Clin with locally advanced colon cancer
Oncol 2021;39(23):2594–2604. (COLOPEC): a multicentre, open-label,
5. Chiva LM, et al. A critical appraisal of randomised trial. Lancet Gastroenterol
hyperthermic intraperitoneal chemotherapy Hepatol 2019;4(10):761–770.

Debate
Is there a Role
15A for Intraperitoneal

Cytoreduction of Ovarian
Cancer?
Yes
Molly Morton, Tiffany Y. Sia, Laura M. Chambers,
Roberto Vargas, and Robert Debernardo
Debate
Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. Patients
diagnosed with advanced EOC often present with disease throughout the peritoneal cavity,
and surgical cytoreduction in combination with platinum- and taxane-based chemotherapy
are the backbone of initial treatment. Unfortunately, recurrence is common and is typically
associated with carcinomatosis, ascites, and worsening performance status. Once this occurs,
treatments are palliative in nature and outcomes are predicated upon response to subsequent
lines of chemotherapy, so long as the patient can continue to tolerate the cytotoxic treatments.
The rationale for administering chemotherapy directly into the peritoneal cavity is
supported by pharmacokinetic data as well as clinical evidence from both retrospective
and randomized clinical trials. Intraperitoneal (IP) administration of chemotherapy over-
comes the plasma-peritoneal barrier and directly treats peritoneal surfaces involved with
metastatic implants, allowing for a 20-fold higher drug concentration to be delivered
directly to the peritoneum and ovarian cancer implants compared to the plasma, sparing
systemic exposure to high concentrations of the drug.
With these principles in mind, several studies were developed to investigate the safety
and efficacy of IP therapy in treating EOC. In GOG114, patients with stage III EOC were
randomized to either a standard regimen of IV cisplatin and IV paclitaxel (135 mg/m2 over
24 hours) or high-dose IV carboplatin (AUC 9) for two cycles followed by the 24-hour IV
paclitaxel regimen and IP cisplatin [1]. Eligible patients had stage III disease and had
undergone optimal debulking (<1 cm residual disease). Patients in the IP arm had improved
PFS (28 vs. 22 months, p=0.01) and OS (63 vs. 52 months, p=0.05). Critics of the study
attributed the benefit to the treatment regimen’s differences, as the IP group received higher
doses and additional cycles [1]. Furthermore, 18% of patients in the IP arm received ≤2
cycles of IP therapy due to toxicity.
In a landmark study by Armstrong et al., GOG172 randomized patients with stage III
disease to either IV cisplatin and IV paclitaxel or IV paclitaxel with IP cisplatin (100 mg/m2)
82

Chemotherapy after Optimal Cytoreduction? Yes 83
and IP paclitaxel after undergoing optimal debulking [2]. As in GOG114, the paclitaxel
administration was over 24 hours. In patients treated with IP chemotherapy, significant
improvements in PFS (23.8 vs. 18.3 months, p=0.05) and OS were observed (65.6 vs. 49.7
months, p=0.03). Importantly, patients were assessed with an intention to treat analysis, and
the treatment effect was preserved despite fewer patients completing the regimen due to
toxicity and difficulty with treatment administration, with only 42% of patients in the IP
cohort completing treatment. A subsequent analysis found that aberrant tumor BRCA1
expression was an independent prognostic factor for median OS in women receiving IP
therapy (84 months IP vs. 47 months IV), suggesting a role of BRCA1 expression as
a biomarker for response [3].
In an exploratory analysis of GOG114 and GOG172 with a median follow-up of 10.7
years, Tewari et al. confirmed the long-term benefits of IP chemotherapy, demonstrating
an improvement in overall survival of 61.8 months in patients treated with IP chemo-
therapy compared to 51.4 months for IV therapy (p<0.05) [4]. Similarly, IP therapy was
associated with a 21% reduced risk of progression and 23% reduced risk of death.
Notably, in this analysis, the risk of death decreased by 12% for each IP cycle adminis-
tered (p<0.001). Multivariate analysis demonstrated that patients with clear cell and
mucinous ovarian cancer, gross residual disease, and fewer IP chemotherapy cycles had
worse OS.
Across all of these studies, patients who received IP chemotherapy had increased
frequency of G3/4 toxicities, including leukopenia, fatigue, thrombocytopenia, and gastro-
intestinal, neurologic, and renal adverse events. Although the reported quality of life in
GOG172 was decreased in patients who received IP chemotherapy prior to cycle four and
immediately after treatment, no differences were observed one year after completion of IP
therapy [2]. Furthermore, administration of IP therapy posed logistical challenges for
physicians and hospital systems, often requiring long administration times and inpatient
stays. For these reasons, many providers were hesitant to offer IP therapy despite a clear
improvement in PFS and OS across multiple randomized trials.
To address these concerns, modifications to the GOG172 protocol were made and
ultimately evaluated in GOG252. In this phase III trial, women with stage II through IV
EOC were randomized to one of three arms: dose dense IV paclitaxel and IV carboplatin (IV
carboplatin), dose dense IV paclitaxel and IP carboplatin (IP carboplatin), or a modification
of the original IP arm of GOG172 using IV paclitaxel (135 mg/m2 over three hours) in
combination with IP paclitaxel and a lower dose of IP cisplatin (75 mg/m2) (IP cisplatin) [5].
All arms included bevacizumab. The investigators found no difference in median PFS
between the three arms (24.9, 27.4, and 26.2 months, respectively). Subgroup analyses of
patients with optimal cytoreduction or no residual disease failed to show a difference
between arms. Additionally, median OS did not differ between groups (75.5, 78.9, and
72.9 months, respectively) [5]. The IP arms suffered higher rates of serious infections and
abdominal discomfort, and the IP cisplatin arm suffered increased rates of grade 3 or worse
hypertension as well as neurotoxicity. Critics of the study mention that use of bevacizumab
resulted in excellent PFS and OS in all subgroups, making it difficult to analyze smaller
differences in outcome between groups.
To further define the benefit of IP therapy without bevacizumab, the Intraperitoneal
Therapy for Ovarian Cancer with Carboplatin (iPocc) trial randomized women with stage II
to IV EOC to IV dose dense paclitaxel in combination with either IP carboplatin or IV
carboplatin, without bevacizumab. Unlike previous trials, the study included women with

84 Molly Morton et al.
residual disease, with 55% of enrolled patients with residual disease >2 cm after initial
surgery. The investigators found a PFS benefit with IP chemotherapy (23.5 months vs. 20.7
months), though median OS did not differ between groups (64.9 vs. 64.0 months) [6]. Rates
of adverse events were similar between the two arms except for catheter-related infections
which were more prevalent in the IP arm.
Conclusion
In conclusion, IP therapy should be considered in all patients following optimal cytoreduc-
tion for stage III ovarian cancer who are not candidates to receive bevacizumab. Although
IP therapy is complicated to administer and has been associated with increased toxicity, its
usage provides a durable PFS and OS benefit in EOC treatment which may be secondary to
the improved control of abdominopelvic disease. Further research must be performed to
elucidate biomarkers to predict improved response to IP therapy such as homologous
recombination deficiency status. Furthermore, as PARP inhibitor maintenance has become
part of upfront management of EOC, further work needs to be done to evaluate its
combination with IP chemotherapy.
References
1. Markman M, et al. Phase III trial of 4. Tewari D, et al. Long-term survival
standard-dose intravenous cisplatin plus advantage and prognostic factors associated
paclitaxel versus moderately high-dose with intraperitoneal chemotherapy
carboplatin followed by intravenous treatment in advanced ovarian cancer:
paclitaxel and intraperitoneal cisplatin in a gynecologic oncology group study. J Clin
small-volume stage III ovarian carcinoma: Oncol 2015;33(13):1460–1466. https://doi
an intergroup study of the Gynecologic .org/10.1200/JCO.2014.55.9898
Oncology Group, Southwestern Oncology 5. Walker JL, et al. Randomized trial of
Group, and Eastern Cooperative Oncology intravenous versus intraperitoneal
Group. J Clin Oncol 2001;19(4):1001–1007. chemotherapy plus bevacizumab in
https://doi.org/10.1200/JCO advanced ovarian carcinoma: an NRG
.2001.19.4.1001 Oncology/Gynecologic Oncology Groups
2. Armstrong DK, et al. Intraperitoneal study. J Clin Oncol 2019;37(16):1380–1390.
cisplatin and paclitaxel in ovarian cancer. https://doi.org/10.1200/JCO.18.01548
N Engl J Med 2006;354(1):34–43. https://doi 6. Fujiwara K, et al. A randomized phase 3 trial
.org/10.1056/NEJMoa052985 of intraperitoneal versus intravenous
3. Lesnock JL, et al. BRCA1 expression and carboplatin with dose-dense weekly
improved survival in ovarian cancer paclitaxel in patients with ovarian, fallopian
patients treated with intraperitoneal tube, or primary peritoneal carcinoma (a
cisplatin and paclitaxel: a Gynecologic GOTIC-001/JGOG-3019/GCIG, iPoccTrial).
Oncology Group Study. Br J Cancer Presented at the 2022 SGO Annual Meeting
2013;108(6):1231–1237. https://doi.org/10 on Womens’ Cancer; March 18–21, 2022;
.1038/bjc.2013.70 Phoenix, AZ. Abstract 241.

Debate
Is there a Role
15B for Intraperitoneal

Cytoreduction of Ovarian
Cancer?
No
Angeles Alvarez Secord and Laura J. Havrilesky
Debate
Intraperitoneal (IP) chemotherapy for women with optimally cytoreduced advanced ovar-
ian, tubal, and peritoneal cancer is a therapeutic relic and no longer has a role in the current
treatment of ovarian cancer. IP refers to the delivery of unheated chemotherapy into the
peritoneal cavity through a catheter connected to a surgically implanted port. To establish
our position against IP therapy, we argue that historical IP therapy survival outcomes are
not relevant in the current era of biologic therapy, demonstrate that IP therapy is too toxic,
and examine the challenging and costly logistics of delivering IP therapy.
The rationale for IP therapy is based on a favorable pharmacokinetic profile, direct
intraperitoneal drug delivery, and prolonged systemic exposure [1]. Historically, IP therapy
was supported by multiple randomized trials and an independent meta-analysis [1] demon-
strating improved progression-free survival (PFS) and/or overall survival (OS) outcomes
compared to intravenous (IV) chemotherapy alone. A National Cancer Institute alert reported
that IP therapy was associated with approximately 22% reduction in the risk of death (HR=0.79,
95% CI: 0.70–0.89) [1]. Furthermore, an ancillary analysis reported that IP therapy conferred
the longest survival outcomes, beyond ten years, of any ovarian cancer study [2]. Based on these
studies, we were strong proponents of IP therapy and routinely administered this treatment to
our patients. However, the irrefutable negative results from GOG0252, a randomized phase III
clinical trial evaluating IV and IP chemotherapy with bevacizumab in women with ovarian
cancer, clearly illustrated that IP therapy is not relevant in the current era of biologic therapy
[3]. GOG0252 included 1560 participants randomized to 21-day cycles of IV paclitaxel weekly +
IV carboplatin versus IV paclitaxel weekly + IP carboplatin versus IV paclitaxel day 1 + IP
cisplatin day 2 + IP paclitaxel day 8. The IP arms were developed to be more tolerable than the
proven but toxic GOG0172 IP regimen. Of note, bevacizumab every three weeks was included
in each arm, concurrent with chemotherapy and followed by 16 maintenance cycles. The
median PFS was similar in each group: 24.9 months in the IV arm, 27.4 months in the IV/IP
carboplatin arm, and 26.2 months in the IV/IP cisplatin arm. At the time of analysis, 51% of
patients had died and median OS was similar (75.5, 78.9, and 72.9 months, respectively).
85

86 Angeles Alvarez Secord and Laura J. Havrilesky
Despite the improvement in drug delivery and pharmacokinetic advantages, IP therapy at

tolerable doses does not translate to improved survival outcomes in the modern therapeutic
ovarian cancer landscape that increasingly includes maintenance regimens.
Intraperitoneal therapy is too toxic; this has always been a barrier to its widespread adoption
due to catheter-related issues, increased adverse effects due to IP administration, and increased
chemotherapy-induced toxicity. In GOG0172, 33% had catheter-related complications including
infection (n=21), blockage (n=9), leak (n=3), access issues (n=5), and vaginal drainage of IP fluid
(n=1). Another 27 women discontinued IP therapy due to possible catheter issues including
abdominal pain (n=4), bowel complications (n=4), and refusal (n=19). Women who received IP
chemotherapy were more likely to experience > grade 3 toxicities including leukopenia (76% vs.
64%, p<0.001), thrombocytopenia (12% vs. 4%, p<0.001), fatigue (18% vs. 4%, p=0.02), gastro-
intestinal (46% vs. 24%, p<0.001), infection (16% vs. 6%, p<0.001), hepatic (3% vs. <1%, p=0.05),
renal (7% vs. 2%, p=0.03), neurologic (19% vs. 9%, p<0.001), and abdominal pain (11% vs. 1%,
p<0.001) compared to IV [1]. Moreover, the “less toxic” GOG0252 IP regimens remained more
toxic than IV therapy, with significantly more > grade 3 infections (~17% vs. 10.2%), p=0.008).
The IP cisplatin group had higher frequency of > grade 3 hypertension (18.7% vs. 11.4%,
p<0.001), > grade 3 nausea/vomiting (10.8% vs. 4.7%, p<0.001), and > grade 2 CNS toxicity
(2% vs. 0.8%, p=0.58) [3]. Importantly, Wright et al. reported that IP therapy toxicity and
complications for IP chemotherapy were higher in the general population than reported in
clinical trials, leading to a higher frequency of emergency room visits and hospitalization [4].
Furthermore, in GOG0172 and GOG0252, IP therapy demonstrated significantly worse quality
of life (QoL) during therapy, extending up to one year [1,3]. In GOG0172, sensory neuropathy
was more likely to persist and be more severe in the IP cohort. Previously, many justified the
worse toxicity and QoL related to IP therapy with improved survival outcomes. However, the
negative PFS findings from GOG0252 have nullified that justification. IP therapy yields increased
frequency and severity of toxicity and impairs QoL without significantly enhancing survival
outcomes.
Finally, IP therapy is challenging and costly to deliver. IP therapy implementation has
always been difficult and often not feasible in community centers. Specific nursing skills are
required for port management and chemotherapy administration, and infusion times are
increased compared to conventional IV therapy. Even at the height of its popularity, IP
therapy remained underutilized at approximately 15%; and was only 41% at National
Comprehensive Cancer Centers [4], likely due to logistical barriers. The most effective IP
regimen was also costly due to the inpatient portion. Our group used a decision model to
compare the cost-effectiveness of IV carboplatin and paclitaxel, IV cisplatin and paclitaxel,
and IV/IP paclitaxel and cisplatin. Compared with IV outpatient therapy, inpatient IP
cisplatin/paclitaxel therapy was not cost-effective, with an incremental cost-effectiveness
ratio of $180,022 per quality-adjusted life year saved at a seven-year time horizon. We
predicted that an outpatient IV/IP paclitaxel cisplatin would be cost-effective if proven as
effective as the inpatient regimen [5]. GOG0252 subsequently incorporated a less costly
outpatient IP regimen, but unfortunately the effectiveness vanished.
Conclusion
In conclusion, despite four decades of research expended evaluating IP chemotherapy, the
data demonstrate that front-line IP therapy does not have a role in the current management
of ovarian cancer. These conclusions are drawn from the lack of survival improvement

Chemotherapy after Optimal Cytoreduction? No 87
reported in the GOG0252 trial, lack of relevance in an era of biologic therapy with
bevacizumab and PARPi, higher rate of toxicity associated with IP therapy, worse QoL
conferred by IP therapy, and costly challenges to delivery.
References
1. NCI alert (2006). Available from: https://w 2019;37(16):1380–1390. https://doi.org/10
ayback.archive-it.org/org-350/20211101182 .1200/JCO.18.01568
949/https://www.nlm.nih.gov/databases/ale 4. Wright JD, et al.
rts/ovarian_ip_chemo.html Utilization and toxicity of alternative
2. Tewari D, et al. Long-term survival delivery methods of adjuvant chemotherapy
advantage and prognostic factors for
associated with intraperitoneal ovarian cancer. Obstet Gynecol 2016;127
chemotherapy treatment in advanced (6):985–991.
ovarian cancer: a gynecologic oncology 5. Havrilesky LJ, et al. Gynecologic Oncology
group study. J Clin Oncol Group. Cost effectiveness of intraperitoneal
2015;33:1460–1466. compared with intravenous chemotherapy
3. Walker JL, et al. Randomized trial of for women with optimally resected stage III
intravenous versus intraperitoneal ovarian cancer: a Gynecologic Oncology
chemotherapy plus bevacizumab in Group study. J Clin Oncol 2008;26
advanced ovarian carcinoma.J Clin Oncol (25):4144–4450.

Debate
What is the Best Front-line
16A Maintenance Therapy

for HRD-positive Ovarian
Cancer?
Single-agent PARP Inhibitor
Debate
High-grade serous ovarian cancer (HGSOC) is the most frequent epithelial ovarian cancer
representing up to 85% of the patients with advanced disease (FIGO III–IV). Biologically,
almost all the patients harbor a TP53 mutation, and approximately 50% are deficient in the
homologous recombination (HR) system for DNA double-strand break repairs. This
molecular feature explains the sensitivity of HGSOC to DNA damaging agents, like plat-
inum analogs, and poly ADP ribose polymerase (PARP) inhibitors that induce synthetic
lethality in cells with HR deficiency. The most frequent cause of HR deficiency is inactivat-
ing mutation in the BRCA 1 or 2 gene, which is detected in the germline in about 15–18% of
patients, and exclusively in the tumor in an additional 5–7% of patients.
Maintenance therapy with oral PARP inhibitors (PARPi) has been demonstrated to
significantly expand the progression-free survival of patients with advanced HGSOC in
response to front-line platinum-based chemotherapy [1–4]. SOLO-1, PRIMA/ENGOT-
OV26/GOG-3012, and PAOLA-1 /ENGOT-OV25 trials achieved their primary endpoint
of PFS determined in the intent to treat population, leading to health authorities’ approvals
that have revolutionized the landscape of front-line ovarian cancer. In addition, there are
three more studies, ATHENA-MONO/GOG-3020/ENGOT-OV45, PRIME and VELIA that
provide more evidence of the effectiveness of PARPi in front-line maintenance therapy
[4-6]. Albeit positive results in the global population, veliparib and rucaparib were not
submitted to filing and are not available in the clinic.
Importantly, the significant benefit achieved with PARPi maintenance on PFS is highly
dependent on the status of BRCA and HR identified as genomic instability by Myriad MyChoice,
with the highest difference in outcome observed in patients with BRCA mutated tumors and
patients with BRCA wild type but HR-deficient tumors which are the focus of this controversy.
In patients with HR-proficient tumors only niraparib showed benefit but of less magnitude.
Currently, three options have been approved for patients with BRCAmut tumors
(olaparib, niraparib, or olaparib-bevacizumab) and only two options for patients with
BRCAwt/HRD tumors (niraparib or olaparib and bevacizumab). The reason for the con-
troversy we are discussing in this chapter is the lack of evidence from randomized trials
comparing single-agent PARPi versus PARP combined with bevacizumab. Both strategies
have shown similar benefits in terms of hazard ratio, but medians are not comparable due to
88

Best Front-line Maintenance: Single-agent PARP Inhibitor 89
the different patient populations included and the different tumor assessment schedule.
Nevertheless, several arguments in favor of the single-agent PARPi option can be argued:
• There is no clear evidence indicating that bevacizumab added to PARPi could improve
the outcome of HR-deficient tumors. The SOLO-1 and PAOLA-1 trials have recently
shown a clinically meaningful benefit in overall survival (OS) at 7 and 5 years, in the
BRCA mut and HR-deficient population (regardless of BRCAmut status), respectively
[7,8]. However, we still do not have the OS outcome of the niraparib monotherapy trials
in patients with BRCAwt, but HR-deficient tumors [3, 5]. On the other hand, a matched
indirect comparison of individual data of SOLO-1 patients and patients with BRCAmut
tumors from PAOLA-1 has indicated a potential additive effect. However, this analysis
compares events of two trials in which the frequency of tumor assessment was different
by protocol, every 12 weeks in SOLO-1 and every 24 weeks in PAOLA-1 [9]. In addition,
the role of bevacizumab alone in BRCAmut patients is not clear. In the exploratory
analysis of the GOG-218 trial, the HR for the BRCA1mut population was 0.82 (95% CI:
0.55–1.21) and for BRCA2mut was 1.10 (95% CI: 0.61–2.01), and it could only be
concluded that a benefit cannot be ruled out [10]. Fortunately, two ENGOT planned
randomized clinical trials comparing niraparib with niraparib plus bevacizumab,
NIRVANA/ENGOT-OV63 and AGO-OVAR 28/ ENGOT-OV57 trials, will probably
clarify this controversy.
• The controversy of single-agent PARPi versus the combination of PARPi and
bevacizumab leads to the debate of using biological agents as maintenance concurrently
or sequentially. There is no doubt that PARPi should be used in front-line, in patients
with HRD tumors, based on the increment of overall survival mentioned above.
However, bevacizumab can be used in the front-line and the recurrent setting, both in
patients for whom platinum is an option or not with the same HR. Unfortunately, many
patients with stage III–IV will relapse. If both agents (bevacizumab and PARPi) were
used in the front line, they would not have options for maintenance in the relapse. For
this reason, there is a need for intensive biomarker research that could help us in
identifying patients that may be cured within front-line with the combination of
bevacizumab and PARPi. In the meantime, for many patients, sequential use of
maintenance options is probably the most efficient approach. In addition, for some
health systems, the cost of the double combination may be unaffordable, and sequential
use of maintenance therapy will be preferred.
• The benefit of PARPi in patients with HR deficient (BRCAmut or BRCAwt) tumors is
unprecedented, durable over time and improves the OS, as shown by the long-term
follow-up of the SOLO-1 and PAOLA-1 trials [7,8]. This intervention may change the
natural history of the disease in many patients, and, for this reason, the physicians
should be adequately trained in the management of toxicity associated with these new
agents to keep the patients on treatment for the whole duration of maintenance,
preventing permanent therapy interruption. In this regard, physicians should be aware
that the discontinuation rate due to adverse events of PARPi inhibitors is around 2%, but
reaches 20% with the combination of olaparib and bevacizumab [1,2].
Conclusion
In summary, the combination of PARPi and bevacizumab in patients with HR-deficient
(BRCAmut or BRCAwt) tumors has produced revolutionary data. Still, the additional benefit

90 Antonio González-Martín
of bevacizumab added to single-agent PARP inhibitors has not yet been demonstrated and,
for most patients, single-agent PARPi should be considered the preferred option.
References
1. Moore K, et al. Maintenance olaparib in in ovarian cancer. N Engl J Med 2019;381
patients with newly diagnosed advanced (25):2403–2415.
ovarian cancer. N Engl J Med 2018;379 7. DiSilvestro P, Banerjee S, Colombo N
(26):2495–2505. et al. Overall Survival With Maintenance
2. Ray-Coquard I, et al. Olaparib plus Olaparib at a 7-Year Follow-Up in
bevacizumab as first-line maintenance in Patients With Newly Diagnosed
ovarian cancer. N Engl J Med Advanced Ovarian Cancer and a BRCA
2019;381:2416–2428. Mutation: The SOLO1/GOG 3004 Trial. J
Clin Oncol. 2023 Jan 20;41(3):609–617.
3. González-Martín A, et al. PRIMA/
ENGOT-OV26/GOG-3012 Investigators. 8. I.L. Ray-Coquard, A. Leary, S. Pignata,
Niraparib in patients with newly diagnosed et al. LBA29 Final overall survival (OS)
advanced ovarian cancer. N Engl J Med results from the phase III PAOLA-1/
2019;381(25):2391–2402. ENGOT-ov25 trial evaluating maintenance
olaparib (ola) plus bevacizumab (bev) in
4. Monk BJ, Parkinson C, Lim MC et al. A patients (pts) with newly diagnosed
Randomized, Phase III Trial to Evaluate advanced ovarian cancer (AOC). Annals of
Rucaparib Monotherapy as Maintenance Oncology, 2022; 33 (s7): S1396–S1397.
Treatment in Patients With Newly
Diagnosed Ovarian Cancer (ATHENA- 9. Vergote I, Ray-Coquard I, Anderson DM et
MONO/GOG-3020/ENGOT-ov45). J Clin al. Population-adjusted indirect treatment
Oncol. 2022 Dec 1;40(34):3952–3964. comparison of the SOLO1 and PAOLA-1/
ENGOT-ov25 trials evaluating
5. Ning Li, Jianqing Zhu, Rutie Yin et al. maintenance olaparib or bevacizumab or
Efficacy and safety of niraparib as the combination of both in newly
maintenance treatment in patients with diagnosed, advanced BRCA-mutated
newly diagnosed advanced ovarian cancer ovarian cancer. Eur J Cancer. 2021
using an individualized starting dose Nov;157:415–423.
(PRIME Study): A randomized, double-
blind, placebo-controlled, phase 3 trial 10. Norquist BM, et al. Mutations in
(LBA 5), Gynecologic Oncology, 2022; 166 homologous recombination genes and
(S1): 50-S51. outcomes in ovarian carcinoma patients in
GOG 218: an NRG Oncology/Gynecologic
6. Coleman RL, et al. Veliparib with first-line Oncology Group Study. Clin Cancer Res
chemotherapy and as maintenance therapy 2018;24(4):777–783.

Debate
What is the Best Front-line
16B Maintenance Therapy

for HRD-positive Ovarian
Cancer?
Bevacizumab plus PARP inhibitor
Hélène Vanacker, Olivia Le Saux, and Isabelle
Ray-Coquard
Debate
Epithelial high-grade ovarian carcinomas (HGOCs) have an overall poor prognosis due to
frequent presentation in advanced stage, rapid clinical evolution, and an over 70% risk of
relapse following completion of surgery and platinum-based chemotherapy. Two classes of
targeted therapies have aimed at improving these outcomes. (1) Bevacizumab was approved
in 2010 for front-line treatment and maintenance in all FIGO stages III–IV. Consequently,
standard therapy in the front-line setting has (until recently) included debulking surgery
and chemotherapy, with or without bevacizumab. Although in some countries bevacizumab
has been restricted to women at high risk for progression (stage IV/stage III with residual
disease, upfront inoperable stage III), the progression-free survival (PFS) benefit is also
observed in patients with no residual disease [1]. (2) The poly(ADP-ribose) polymerases
(PARP) inhibitors (PARPi), are oral targeted agents exploiting the particular biology of
HGOC. Indeed, at least half of HGOCs are characterized by a defect in DNA repair,
especially through homologous-recombination repair deficiency (HRD). So HRD signa-
tures have been developed to capture the HRD-positive phenotype even in those patients
and tumors that don’t have a BRCA mutation.
The efficacy of PARPi over placebo was consistently demonstrated in the platinum-
responsive front-line setting (SOLO1 and PRIMA/VELIA trials [2–4]), where PARPi showed
a differential benefit across different subgroups by biomarker status (BRCA+/HRD+/HRD-).
Indeed, the reduction in the risk of disease progression/death was consistently over 60% in
patients with BRCA mutations, between 35–50% in the HRD-positive-wildtype BRCA
population, as compared to less than 35% in HRD- tumors. However, all these trials tested
PARPi as single agent maintenance versus placebo. Only the PAOLA-1 trial [5] tested a front-
line double maintenance with bevacizumab + the PARPi olaparib, compared to a single
active agent bevacizumab/placebo maintenance control arm. The trial was positive for the
primary end point (PFS on ITT analysis) with a HR=0.59 (95% CI: 0.49–0.72), for the
bevacizumab + olaparib over bevacizumab + placebo.
Therefore, for patients who are possible candidates for bevacizumab (absence of medical
contraindications or access/availability issues), we support the use of bevacizumab + PARPi
in front-line maintenance therapy for HRD-positive HGOC. We feel the double
91

92 Hélène Vanacker et al.
Frontline maintenance in PRIMA, SOLO-1 and PAOLA-1 trials :primary analysis :median PFS (months)
PRIMA HRD+ population*

10,4 placebo vs Niraparib
HR = 0.43 (0.27–0.62)
21,9
PAOLA-1 HRD+ ‘Higher-risk disease’*
16 Beva.+ placebo vs Beva+Olaparib
HR = 0.37 (0.23–0.59)
36
HRD + PAOLA-1 ‘HRD+ Lower-risk disease’*
22,1 Beva.+ placebo vs Beva+Olaparib
HR = 0.11 (0.03–0.31)
... NR
10,9 PRIMA BRCAm population*

placebo vs Niraparib
22,1 HR = 0.40 (0.27–0.62)
19,4 PAOLA-1 BRCAm ‘Higher-risk disease’*
Beva.+ placebo vs Beva+Olaparib
36 HR = 0.37 (0.23–0.59)
BRCAmut.
22,9 PAOLA-1 BRCAm ‘Lower-risk disease’*
Beva.+ placebo vs Beva+Olaparib
... NR HR = 0.11 (0.03–0.31)
13,8 SOLO-1 (BRCAm) overall population*
placebo vs Olaparib
... NR
HR = 0.30 (0.23–0.41)
0 12 24 36 48
PRIMA placebo PRIMA niraparib

PAOLA higher risk bevacizumab PAOLA higher risk olaparib + bevacizumab
PAOLA lower risk bevacizumab PAOLA lower risk olaparib + bevacizumab
SOLO-1 placebo SOLO-1 olaparib
*Population definition:
PRIMA inclusion criteria: FIGO stage IV or III with upfront surgery and residual disease or neoadjuvant-chemotherapy (NACT), in CR/PR to platinum based CT
SOLO-1 inclusion criteria: BRCA-mutation and FIGO stage IV or III with upfront or interval surgery and platinum-based CT, in CR/PR/NED to platinum based CT
PAOLA-1 ‘Higher-risk disease’ subgroup: FIGO stage IV or III with upfront surgery and residual disease or NACT, in NED/CR/PR to platinum-based + bevacizumab CT
PAOLA-1 ‘Lower-risk disease’ subgroup: FIGO stage III receiving primary debulking surgery with no residual disease in NED/CR/PR to platinum-based + bevacizumab CT
Abbreviation CR complete response, NED: Non evidence of disease, PR partial response
Figure 16B.1 Front-line maintenance in PRIMA, SOLO-1, and PAOLA-1 trials; primary analysis PFS (months).
maintenance approach offers the greatest efficacy, highest potential for cure, with a good
safety profile and cost-effectiveness.
The association of bevacizumab + olaparib maintenance brought a never-reached
efficacy in the HRD-positive subgroup in the PAOLA-1 trial (Figure 16B.1). The pre-
specified exploratory analyses revealed a significant and meaningful PFS improvement
for patients with BRCA mutation (HR=0.31, 95% CI: 0.20–0.47), as well as in HRD-
positive/BRCA wild type population (HR=0.43, 95% CI: 0.28–0.46), with 20 months of
absolute benefit in median PFS. Of note, the population of PAOLA-1 was not selected
based on surgical outcome or highest platinum-sensitivity (Ca125 could be elevated at
inclusion) resulting in only 20% of patients in both arms having a complete response to
first-line therapy. All patients had first-line treatment including bevacizumab with
chemotherapy.
An additive effect of the antiangiogenic agent to PARPi seems supported by the
population-adjusted indirect comparison (PAIC) of PAOLA-1 and SOLO1 population
recently published [6] highlighting a 30% reduction in the risk of progression with bev-
acizumab + olaparib compared to olaparib alone. The combination of olaparib +

Best Front-line Maintenance: Bevacizumab and PARP inhibitor 93
bevacizumab reached a higher and long-lasting PFS benefit compared to olaparib alone,
bevacizumab alone or placebo, with a three-year progression-free rate (PFR) of 75.2%, 60%,
57%, and 27% respectively. Furthermore, the exploratory analysis of PAOLA-1 in the higher
risk group (FIGO stage IV or stage III disease with upfront surgery and residual disease or
neoadjuvant-chemotherapy), reached a median PFS of 36 months with the combination
compared to 15.9 months with bevacizumab alone. In a comparable population, PRIMA
reported a median PFS of 20.9 months for niraparib alone versus 10.4 months with placebo
(Figure 16B.1). Similarly, in patients with clinically lower-risk disease from PAOLA-1,
HRD-positive population benefitted from bevacizumab + olaparib with an impressive
HR=0.15 over bevacizumab, translating into a rate of 90% of patients still progression free
at two years with the combination. Hence, in both higher- or lower-risk disease, the front-
line combination maintenance is an important therapeutic window for patients with BRCA
and/or HRD-positive disease. Interestingly, such additive effect is also supported by data in
the relapsed setting where a superiority of the combination antiangiogenic + PARPi in PFS,
ORR, and OS (for over PARPi monotherapy have been reported, particularly in the HRD +
wtBRCA population.
The association is safe, since those two drugs have no overlapping adverse
events (AEs). The safety profile for the olaparib + bevacizumab arm was generally
similar to that observed in previous trials, with no increase of myelodysplastic
syndromes, nor increase in bevacizumab toxicity including all-grade or severe
hypertension [5].
Playing all the best cards first may be the optimum approach for the whole course of
patients with this disease! Analyses of PFS2 (survival on subsequent therapy following
progression on front-line therapy), were significantly longer in the HRD-positive popula-
tion treated with olaparib + bevacizumab compared to bevacizumab, The final overall
survival (OS) data strenghtenned the clinically meaningfull improvement of first line
olaparib = bevacizumab over bevacizumab in HRD-positive population witha median OS
of 65.5 vs 48.5 months (HR 0.62 95% CI: 0.45-0.85), even with a high proportion of patients
receiving a parp-inhibitor post progression (45.7% in the whole population of control arm)
(Ray-Coquard, ESMO 2022). Moreover, the PAICS analyses of SOLO1 and PALOA-1
underline a superior efficacy in terms of long-term progression-free rate and suggest that
a significant proportion of patients do not relapse after long-term follow-up and may even
be cured [6].
The cost-effectiveness of bevacizumab + PARPi maintenance and HRD-testing is
a legitimate concern. Recent cost-effectiveness analyses reported that combination mainten-
ance is in fact cost-effective in the case of BRCA-mutated and HRD-positive population, due
to their particular PFS benefit. Bevacizumab is much more cost-effective in first-line treatment
as compared to relapse. Finally, the cost of HRD-testing may be lowered by the development
of institutional testing and/or improved market access for commercially available assays.
Conclusion
Hence, our opinions are based on trends from currently available data on population-
matched analysis and subgroup analyses. All PFS, PFS2 ans OS data demonstrated a
significant and clinically meaningfull improvment for bevacizumab + olaparib over bev-
acizumab as fist line treatement even with a high proportion of subsequent PARPi which
may convince the scientific community. Overall, consistent with the FDA and EMA 2020’s

94 Hélène Vanacker et al.
recommendations, we definitely support the combination of bevacizumab and PARPi for

front-line maintenance for all eligible patients with HRD-positive advanced-HGOC.
References
1. González Martín A, et al. Exploratory ovarian cancer. N Engl J Med
outcome analyses according to stage and/or 2018;379:2495–2505.
residual disease in the ICON7 trial of 5. Ray-Coquard I, et al. Olaparib plus
carboplatin and paclitaxel with or without bevacizumab as first-line maintenance in
bevacizumab for newly diagnosed ovarian ovarian cancer. N Engl J Med
cancer. Gynecol Oncol 2019;152:53–60. 2019;381:2416–2428.
2. González-Martín A, et al. Niraparib in patients 6. Vergote I, et al. Population-adjusted
with newly diagnosed advanced ovarian indirect treatment comparison of the
cancer. N Engl J Med 2019;381:2391–2402. SOLO1 and PAOLA-1/ENGOT-ov25 trials
3. Coleman RL, et al. Veliparib with first-line evaluating maintenance olaparibor
chemotherapy and as maintenance therapy bevacizumab or the combination of both in
in ovarian cancer. N Engl J Med newly diagnosed, advanced BRCA-mutated
2019;381:2403–2415. ovarian cancer. Eur J Cancer
4. Moore K, et al. Maintenance olaparibin 2021;157:415–423. https://doi.org/10.1016/
patients with newly diagnosed advanced j.ejca.2021.08.023

Debate
When is the Best Time to Use
17A PARP Inhibitors for

Maintenance?
Front-line
Duaa H. Al-Rawi, Karen Cadoo, and Roisin
O’Cearbhaill
Debate
The development and use of poly(ADP-ribose) polymerase inhibitors (PARPi) in advanced
ovarian cancer (OC) have been an incredible clinical breakthrough. PARPi are FDA-
approved as front-line maintenance for BRCA1-/2-associated (olaparib or niraparib), hom-
ologous recombination deficient (HRD) (niraparib or olaparib with bevacizumab), and
homologous recombination proficient (HRP) (niraparib) advanced-stage high-grade ovar-
ian cancer (HGOC). Along with a third PARPi, rucaparib, they are also approved following
recurrence as both maintenance and treatment. Here we advocate for PARPi as front-line
maintenance for BRCA1-/2-associated (germline or somatic) and HRD tumors. We also
discuss our recommendations for patients with HRP tumors.
BRCA1 and BRCA2 are DNA damage signaling proteins fundamentally important for
HR-dependent repair. HRD cells are particularly sensitive to certain chemotherapeutics
such as platinum-based therapies; combined loss of the HR repair mechanism and PARP
results in synthetic lethality. HRD cells upregulate PARP1 and critically depend on PARP
for DNA replication. A commercially available assay called Myriad myChoice CDx utilizes
®
a genomic signature that combines loss of heterozygosity (LOH), telomeric allelic imbal-
ance, and large-scale state transitions loss to identify patients with HRD tumors (beyond
BRCA1/2) that may respond to PARPi.
SOLO1, PAOLA, and PRIMA examined PARPi switch maintenance after response to
front-line platinum-based therapy. SOLO1, a double-blinded, placebo-controlled, ran-
domized trial (RCT) in patients with BRCA1-/2-associated HGOC compared two years of
olaparib with placebo. An improved three-year median progression-free survival (mPFS)
of 60% versus 27% (HR=0.30) was observed with olaparib [1]. PAOLA, a RCT comparing
front-line maintenance olaparib plus bevacizumab with bevacizumab alone in advanced-
stage OC, demonstrated a mPFS of 37.2 months versus 21.7 months in the germline
BRCA1/2 subset; 28.1 months versus 16.6 months in the HRD subset (by Myriad
myChoice CDx); and 16.6 months versus 16.2 months in the HRP subset [2]. PRIMA
®
compared up to three years of niraparib with placebo in a higher risk group of patients
who responded to front-line platinum. The mPFS was 22.1 months versus 10.9 months in
the germline BRCA1/2 subset; 21.1 months versus 10.4 months in the HRD subset; and 8.1
months versus 5.4 months in the HRP subset [3]. Taken together, these RCTs demonstrate
strong evidence of benefit in patients with germline or somatic BRCA1/2 mutated and
95

96 Duaa H Al-Rawi et al.
HRD tumors. In PRIMA there was also a statistically significant but less compelling
benefit in patients with HRP tumors but no such benefit was seen in PAOLA1. Adverse
effects included fatigue, nausea, thrombocytopenia (more common with niraparib)
anemia and a rare (1–3%) but lethal risk of myelodysplastic syndrome or acute myeloid
leukemia (MDS/AML) across PARPi.
Several studies have examined PARPi in later lines of therapy. Patients continued
PARPi/placebo until disease progression or toxicity. In SOLO2 olaparib was studied as
post-platinum maintenance in patients with BRCA1-/2-associated platinum-sensitive OC
who had received at least two lines of platinum-based therapies. Study 19 enrolled all
comers with high-grade serous OC and at least two prior therapies to olaparib treatment.
A recent update to SOLO2 [4] at median follow-up of 65.7 months, showed a median
overall survival (OS) 51.7 and 38.8 months in the olaparib maintenance versus placebo
groups. This represented a nonsignificant but clinically meaningful difference despite 38%
of the placebo group receiving subsequent PARPi. In the subgroup analysis, OS was
reduced in patients who had received incremental numbers of prior therapies (56.3
months, 41.5 months, and 43.6 months in patients with two, three, four prior lines of
treatment, respectively). Alarmingly, 8% of patients in the olaparib group versus 4% in the
placebo group developed MDS/AML. These data posit three interesting observations; the
first is that there appears to be a reduction in the benefit from olaparib in patients who had
received more than two prior lines of treatment, arguing towards moving olaparib into
earlier lines of therapy for patients with BRCA1-/2-associated ovarian cancer; the second
is that the duration of benefit appears to extend beyond the conventional two years of
olaparib given as front-line maintenance; and finally the risk of leukemogenesis in
BRCA1-/2-associated OC appears to be augmented by receipt of PARPi later in the disease
course.
ARIEL2 assessed rucaparib in HGOC of all genetic backgrounds (HRD was character-
ized by LOH on FoundationOne CDX). NOVA, a RCT of niraparib maintenance versus
®
placebo in patients who had responded to second- or greater-line platinum-based therapy
included all genetic backgrounds [5]. QUADRA investigated niraparib treatment after at
least three prior lines of treatment and not necessarily platinum-sensitive. NOVA reported
a mPFS of 21 months versus 5.5 months in BRCA1-/2-associated tumors; 12.9 months
versus 5.5 months in HRD tumors (Myriad myChoice CDx); and 6.9 months versus 3.8
®
months in HRP tumors [5]. Interestingly, 20% of the HRP subgroup derived >18 months
benefit from niraparib maintenance.
To date, no trial has compared front-line PARPi maintenance to a later line of
therapy. However, if we extrapolate from SOLO2, in BRCA1/2 patients, there was
a reduction in response to PARPi between patients who received three or more lines
compared to two lines of prior therapy. Furthermore, the prolonged PFS noted in the
front-line maintenance trials may ultimately translate into enhanced survival and proffer
more cures. These bolster an argument towards moving PARPi to the front-line. The
data and the benefit in patients with HRP tumors are less compelling. We would argue
that PARPi could be better reserved for later line treatment in this patient subgroup
based on the prolonged benefit in patients with HRP tumors and low MDS/AML rate
noted in NOVA trial. Interestingly, ARIEL2 compared biopsies from patients at initial
surgery and prior to receiving PARPi and noted apparent rare changes in HR status
between the initial and pre-PARPi biopsies. In addition to preselection for patients with
platinum-responsive disease the conversion of tumors from HRP to HRD maybe explain

Best Time to Use PARP Inhibitors? Front-line 97
the prolonged benefit observed in the HRP patient subset in the NOVA trial. We
anticipate that further refinement of biomarkers of PARPi response will better identify
patients most likely to benefit from PARPi.
Conclusion
In conclusion, we favor utilizing PARPi in the front-line maintenance setting for patients
with BRCA1-/2-associated and HRD tumors given the profound PFS benefit noted in the
SOLO1, PAOLA1, and PRIMA trials. Further refinement of biomarkers of PARPi response
are needed to better identify patients who are most likely to derive benefit.
References
1. Moore K, et al. Maintenance olaparib in 4. Poveda A, et al. Olaparib tablets as
patients with newly diagnosed advanced maintenance therapy in patients with
ovarian cancer. N Engl J Med 2018;379 platinum-sensitive relapsed ovarian cancer
(26):2495–2505. and a BRCA1/2 mutation (SOLO2/
2. Ray-Coquard I, et al. Olaparib plus ENGOT-Ov21): a final analysis of a
bevacizumab as first-line maintenance in double-blind, randomised,
ovarian cancer. N Engl J Med 2019;381 placebo-controlled, phase 3 trial. Lancet
(25):2416–2428. Oncol 2021;22(5):620–631.
3. Gonzalez-Martin A, et al. Niraparib in 5. Moore KN, et al. Niraparib monotherapy for

patients with newly diagnosed advanced late-line treatment of ovarian cancer
ovarian cancer. N Engl J Med 2019;381 (QUADRA): a multicentre, open-label,
(25):2391–2402. single-arm, phase 2 trial. Lancet Oncol
2019;20(5):636–648.

Debate
When is the Best Time to Use
17B PARP Inhibitors for

Maintenance?
First Recurrence
Alvin Jun Xing Lee and Jonathan A. Ledermann
Debate
Poly ADP ribose polymerase (PARP) inhibitors have led to a step change in the management
of advanced ovarian cancer following the first approval of these inhibitors in 2014. PARP is an
enzyme needed for DNA repair and its inhibition results in the accumulation of single-strand
DNA breaks. PARP inhibitors were initially hypothesized to have maximum efficacy in
ovarian cancer with BRCA1/2 mutations or homologous recombination (HR) deficiency
(HRD) given the role of these pathways in repairing double-stranded DNA breaks. The
accumulation of both single-strand and double-strand breaks would result in synthetic
lethality and preferential cancer cell cytotoxicity with BCRA1/2 mutations and HRD being
a predictive biomarker of response. Here we present data that patients with recurrent ovarian
cancer will benefit from PARP inhibitors, given as maintenance therapy irrespective of BRCA
or HR status. This has been shown with olaparib, niraparib, and rucaparib; all three PARP
inhibitors are licensed for the treatment of recurrent ovarian cancer following a response to
platinum-based therapy in both BRCA-mutant and wild-type patients.
Two studies with olaparib demonstrate PFS and OS benefits in patients regardless of
BRCA mutations. Study 19 ] was a randomized, placebo-controlled, phase II trial to evaluate
maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-
grade serous ovarian cancer who had received two or more platinum-based regimens and
had had a partial or complete response to their most recent platinum-based regimen. The
study met its primary endpoint of improved median PFS (mPFS) in the overall population
(8.4 vs. 4.8 months, Hazard Ratio (HR)=0.35, 95% Confidence Interval (CI): 0.25–0.49),
BRCA mutant population (11.2 vs. 4.3 months, HR=0.18, 95% CI: 0.10–0.31) and BRCA
wild-type patients (7.4 vs. 5.5 months, HR=0.54, 95% CI: 0.34–0.85). Long-term follow-up
data in Study 19 [2] demonstrates an OS advantage following olaparib treatment (HR=0.73,
95% CI: 0.55‒0.95) irrespective of BRCA1/2 mutation status. Thirty-two patients (24%)
received maintenance olaparib for over two years with 15 (11%) receiving olaparib for over
six years. SOLO2 [3] was an international, multicentre, double-blind, randomized, placebo-
controlled, phase III trial evaluating olaparib in patients with recurrent ovarian cancer who
received at least two lines of chemotherapy previously with an aim to evaluate the tablet
formulation of olaparib and to confirm the efficacy in BRCA mutated ovarian cancer. The
median PFS for olaparib was 19.1 months and 5.5 months with placebo (HR=0.30, 95% CI:
0.22–0.41). The final OS data for SOLO2 demonstrated a long-term benefit with olaparib
versus placebo with an OS HR of 0.74 (95% CI: 0.54–1.00) unadjusted for the 38% of
patients in the placebo arm who subsequently received a PARPA inhibitor. At five years,
98

Best Time to Use PARP Inhibitors? First Recurrence 99
42.1% of olaparib patients were alive compared to 33.2% of patients receiving placebo.
Again, a prolonged benefit was seen in some patients with 22% of patients continuing on
olaparib after five years compared with 9% on placebo.
Homologous recombination deficiency testing was performed in NOVA and ARIEL3
trials in which niraparib and rucaparib respectively were given following platinum-based
therapy for recurrent ovarian cancer, and which confirmed a benefit of PARP inhibitors in
patients who do not have BRCA mutations. In NOVA [4] women were stratified into germline
BRCA (gBRCA) mutant and non-gBRCA groups. The non-gBRCA group was further divided
into HRD-positive (according to the Myriad myChoice HRD test) and HRD-negative.
Niraparib treatment improved PFS versus placebo in patients with mutant gBRCA (21.0 vs.
5.5 months, HR=0.27, 95% CI: 0.17–0.41), in the HRD-positive non-gBRCA cohort (12.9 vs.
3.8 months, HR=0.38, 95% CI: 0.24–0.59), and in the HRD negative group (6.9 vs. 3.8 months,
HR=0.58, 95% CI: 0.36–0.92). The ARIEL3 [5] trial used the T5 NGS assay (Foundation
Medicine) to determine HRD status, based on a loss of genomic heterozygosity (LOH). An
improvement in the median PFS was seen following rucaparib versus placebo in patients with
tumor BRCA mutations, 16.6 versus 5.4 months (HR=0.23, 95% CI: 0.16–0.34), in the LOH-
high cohort 13.6 versus 5.4 months (HR=0.32, 95% CI: 0.24–0.42), and in those with an LOH-
low score, 6.7 versus 5.4 months (HR=0.58, 95% CI: 0.40–0.85).
Following the success of these agents in recurrent ovarian cancer, the concept of switch
maintenance after chemotherapy was tested in the first-line setting. The three trials using
this approach were SOLO1 in which olaparib or placebo was given to patients with a BRCA
mutation, and two trials that enrolled a broader group of patients in response to or not
progressing after first-line treatment. They were PRIMA, comparing niraparib and placebo,
and PAOLA-1, in which olaparib or placebo was added to bevacizumab maintenance.
As we can see from these front-line studies, PARP inhibitors should not be used in first-
line maintenance for all patients. In particular, PAOLA-1 showed no benefit in the HRD-
negative/unknown population with a mPFS of 16.9 versus 16.0 months (HR=0.92, 95% CI:
0.72–1.17). Whilst some benefit was seen among this group in the PRIMA trial, it should be
noted that the population differed from PAOLA-1 in so far as all patients had demonstrated
a response to platinum-based therapy to enter the study. This confirms that as in the case of
patients with recurrent disease, the absence of HRD does not preclude a benefit from PARP
inhibitors, and that a response to platinum remains an important selection criterion for
benefit.
The key issue with front-line trials is how long patients benefit from a PARP inhibitor.
For this progression, rates are important, as failure of a front-line PARP inhibitor currently
precludes its use at relapse. In the non-BRCA mutated groups, particularly those with HR
proficiency, the failure rate was high. About 50% of patients progressed within 16 months of
randomization in PAOLA-1 and in PRIMA, 50% had progressed within about eight months
from diagnosis. Even among the BRCA wild-type HRD-positive group, 48% were not free of
progression at 24 months. Until survival data are seen, and in particular the outcome data
from patients who cross over to a PARP inhibitor at relapse, the question whether non-
BRCA-mutated patients might derive a greater benefit from the use of a PARP inhibitor at
relapse remains open. PFS2 is the time from randomization to second disease progression or
death. This is increasingly been used as a surrogate for OS in oncology clinical trials. In
PAOLA-1, the median PFS2 in the HRD-negative/unknown groups was 26.3 versus 28.1
months for olaparib/bevacizumab versus placebo/bevacizumab (HR=0.98, 95% CI: 0.77–
1.27), suggesting that there is unlikely to be an OS benefit from using PARP inhibitors

100 Alvin Jun Xing Lee and Jonathan A. Ledermann
upfront in HRD-negative patients. Given the PFS1 and PFS2 data, and that bevacizumab is
a widely available maintenance option following first-line chemotherapy in stage IV ovarian
cancer, patients with HRD-negative disease may derive the most benefit from bevacizumab
maintenance in the first-line followed by PARP inhibitors at first recurrence.
Conclusion
In conclusion, PARP inhibitors are widely approved for use as maintenance after the first
recurrence and patients benefit regardless of BRCA or HRD status. There is a long-term PFS
and OS benefit with some patients remaining on treatment beyond five years. Until there is
clear evidence that patients given PARP inhibitors after first-line treatment rather than at
recurrence live longer, the value of offering PARP inhibitors to all patients in the first-line
setting remains uncertain.
References
1. Ledermann J, et al. Olaparib maintenance and a BRCA1/2 mutation (SOLO2/
therapy in platinum-sensitive relapsed ENGOT-Ov21): a double-blind,
ovarian cancer. N Engl J Med 2012;366 randomised, placebo-controlled, phase 3
(15):1382–1392. trial. Lancet Oncol 2017;18(9):1274–1284.
2. Friedlander M, et al. Long-term efficacy, 4. Mirza MR, et al. Niraparib maintenance
tolerability and overall survival in patients therapy in platinum-sensitive, recurrent
with platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016;375
high-grade serous ovarian cancer treated (22):2154–2164.
with maintenance olaparib capsules 5. Coleman RL, et al. Rucaparib maintenance
following response to chemotherapy. Br treatment for recurrent ovarian carcinoma
J Cancer 2018;119(9):1075–1085. after response to platinum therapy
3. Pujade-Lauraine E, et al. Olaparib tablets as (ARIEL3): a randomised, double-blind,
maintenance therapy in patients with placebo-controlled, phase 3 trial. Lancet
platinum-sensitive, relapsed ovarian cancer 2017;390(10106):1949–1961.

Debate
What is the best front-line
18A maintenance therapy for

optimally debulked HRD-
negative advanced epithelial
ovarian cancer? Bevacizumab
Krishnansu S. Tewari
Debate
The biology of high-grade serous ovarian carcinoma encourages early dissemination
through activation of pro-angiogenic pathways [1]. Vascular endothelial growth factor
(VEGF) has been recognized as a key promoter of tumor angiogenesis and disease progres-
sion in this disease [1]. Over the past decade VEGF has also emerged as an important
therapeutic target. Nine phase 3 randomized clinical trials have each met their primary
endpoint with a statistically significant and clinically meaningful improvement in progres-
sion-free survival (PFS) through the incorporation of bevacizumab or other anti-angiogenic
molecules as compared to chemotherapy alone and/or placebo [1]. Five of these trials
studied the efficacy and tolerability of the anti-VEGF fully humanized monoclonal anti-
body, bevacizumab, and have directly led to US FDA approval and European Medicines
Agency approval of this agent for women with newly diagnosed disease, platinum-sensitive
relapsing disease, and platinum-resistant recurrent ovarian carcinoma [1].
Specifically, for patients with newly diagnosed advanced disease, in Gynecologic
Oncology Group protocol 0218, the integration of bevacizumab (15 mg/kg) with systemic
platinum- and taxane-based chemotherapy (beginning with cycle #2 following cytoreduc-
tive surgery) and continuing as a maintenance monotherapy (15 mg/kg q21d) confers a 5.8
month (18.2 vs. 12.8 months) improvement in PFS compared to chemotherapy alone:
stratified HR for progression or death 0.62; 95% CI: 0.52–0.75, two-sided p<0.0001 [2]. At
a median follow-up of 102.9 months and 375 deaths in the control arm, the final analysis of
overall survival did not attribute a survival benefit to bevacizumab [3].
In the ICON7 randomized trial of front-line bevacizumab, a survival benefit was
observed in an exploratory analysis of a high-risk subgroup (i.e., suboptimal stage III and
any stage IV) [1]. Although the placebo-controlled GOG-0218 was unable to validate the
European trials findings, the observed 10-month relative survival benefit (42.8 vs. 32.6
months) suggests that bevacizumab, when administered with and following chemotherapy,
may be beneficial for patients with stage IV disease by producing median survival rates that
approximate those observed with the more favorable stage III tumors [3].
All of the studies with bevacizumab were conducted in unselected patients. Because
validated serum and/or tissue factors that predict activity of anti-angiogenics have remained
elusive, enrolment in GOG-0218 was not enriched for a specific biomarker. Accordingly, the
101

102 Krishnansu S. Tewari
label granted by the US FDA on June 13, 2018 is for all patients with advanced disease who
do not have a contraindication to bevacizumab [1]. Black Box Warnings for bevacizumab
include wound healing, hemorrhage and gastrointestinal wall disruption; while potentially
catastrophic, bowel perforation has been largely avoided by withholding drugs to patients
with signs (physical or radiographic) or symptoms of small bowel obstruction or known
inflammatory bowel disease [1].
Poly-ADP-polymerase 1 inhibitors (PARPi) have also been developed as effective
maintenance strategies for newly diagnosed ovarian carcinoma, particularly the high-
grade serous histologic subtype. Because PARPi(s) prevent single-strand annealing of
DNA, they are most effective in tumors with homologous recombination deficiency
(HRD). Importantly, exploitation by PARPi(s) of the inability of HRD+ tumors to repair
double-strand DNA breaks leads to conversion of single-strand breaks to lethal double-
strand breaks with subsequent collapse at the replication fork.
Based on an astonishing PFS benefit observed among patients with HRD+ BRCA-
mutated (somatic or germline) tumors receiving maintenance therapy with olaparib in
the phase 3 randomized placebo-controlled SOLO-1 trial (NCT01844986), this agent was
approved by the US FDA on December 19, 2018 for primary maintenance therapy in this
population. Five-year follow-up data from this trial has demonstrated that olaparib con-
tinues to reduce the risk of disease progression or death compared to placebo (median 56.0
vs. 13.8 months) by 67% (HR=0.33, 95% CI: 0.25–0.43) with 48.3% of patients remaining
disease-free compared with 20.5% of patients on placebo [1]. Based on the phase 3
randomized PAOLA-1 trial (NCT02477644), on May 8, 2020 the FDA expanded the
indication of olaparib to include its combination with bevacizumab for first-line mainten-
ance treatment of patients with advanced HRD+ disease defined by either a deleterious or
suspected deleterious BRCA mutation and/or genomic instability according to Myriad’s
myChoice assay cut-off of >42. The rationale of combining anti-VEGF therapy with PARPi
is based on in vitro data which indicates that hypoxia may induce a BRCA-like phenotype.
PARPi(s) were designed to target HRD+ tumors and there is no argument that the data
in the HRD+ BRCA-mutated and HRD+ BRCA-wild type subpopulations are compelling.
A third randomized phase 3 trial, PRIMA (NCT02655016), studied maintenance therapy
with the PARPi, niraparib, and also demonstrated a PFS benefit in the overall intent-to-treat
population (HR=0.62, 95% CI: 0.50–0.76) [4]. Although exploratory analyses demonstrated
the treatment benefit was most pronounced in patients with somatic BRCA mutations
(HR=0.40, 95% CI: 0.27–0.62), followed by BRCA-wild type HRD+ tumors (HR=0.50, 95%
CI: 0.30–0.83), the FDA approved niraparib (200 mg daily) for primary maintenance
therapy for all-comers, regardless of molecular signature. Although niraparib reduced the
risk of disease progression or death by 32% (HR=0.68, 95% CI: 0.49–0.94) among patients
with homologous recombination-proficient (HR-proficient) tumors, these data are based
on pre-specified exploratory analyses, i.e., essentially a post-hoc retrospective study embed-
ded within PRIMA!
The field continues to advance and now in the third decade of the twenty-first century,
every patient with newly diagnosed advanced epithelial ovarian cancer should undergo
genetic counseling, genetic testing and when applicable tumor HRD testing. All patients
should be offered maintenance therapy, and for those with HR-proficient tumors, the
choices are between bevacizumab and niraparib. While the HR(s) are somewhat similar
(0.62 in GOG-0218 and 0.68 in PRIMA), certainly the prospectively derived median PFS of
18.2 months associated with bevacizumab maintenance in the non-enriched population of

Bevacizumab as the Appropriate Maintenance Therapy 103
GOG-0218 should resonate more strongly than the retrospectively derived median PFS of
8.1 months associated with niraparib in the HR-proficient subpopulation of PRIMA. Thus,
because the Devil’s in the details, there is no need to invoke the tired phrase of how cross-
trial comparisons are never valid. The FDA’s approval of niraparib for all-comers, fails to
provide clinical guidance, and has only created confusion.
Perhaps another reason to argue in favor of bevacizumab maintenance therapy lies in the
opportunity to realize the potential of immunotherapy in this disease. Ovarian carcinomas
are relatively cold (i.e., non-immunogenic), and thus far the activity of checkpoint inhib-
ition when administered as a monotherapy has been disappointing. However, because
VEGF has immunosuppressive effects in the tumor microenvironment where it inhibits
T-cell and dendritic cell function and reduces T-cell trafficking and infiltration into the
tumor bed [5], there is great interest in the possibility of additive or synergistic effects when
VEGF blockade is combined with immunotherapy. This hypothesis is particularly relevant
and applicable to the HR-proficient subgroups that lack the immunostimulatory neoanti-
gens generated through HRD-associated mutations including BRCA.
Conclusion
To summarize, bevacizumab is the appropriate maintenance therapy for women with HR-
proficient ovarian carcinoma who have responded to platinum- and taxane-based systemic
therapy. Unlike the findings concerning the HR-proficient subpopulation in PRIMA, the
data supporting bevacizumab arrive through prospective analysis and may even be associ-
ated with a survival benefit among women with stage IV disease. The inconvenience of a 30-
minute intravenous infusion every three weeks pales when framed against the potential for
grade 3–4 anemia and thrombocytopenia associated with niraparib (as well as the 1–2% risk
of potentially fatal myelodysplastic syndrome!). As stated earlier, the risk factors for
gastrointestinal wall disruption with bevacizumab have been identified. Consequently,
bevacizumab is the safer and more efficacious option. And that, as they say, is that.
References
1. Tewari KS, et al. Chapter 77: Ovarian 3. Tewari KS, et al. Final overall survival of
cancer. In: DeVita VT, Lawrence TS, a randomized trial of bevacizumab for
Rosenberg SA (Eds.), DeVita, Hellman , primary treatment of ovarian cancer. J Clin
and Rosenberg’s Cancer: Principles & Oncol 2019;37:2317–2328.
Practice of Oncology (11th edn.). 4. González-Martín A, et al. Niraparib in
Philadelphia, PA: Lippincott Williams & patients with newly diagnosed advanced
Wilkins; 2019. ovarian cancer. N Engl J Med
2. Burger RA, et al. Incorporation of 2019;381:2391–2402.
bevacizumab in the primary treatment of 5. Yi M, et al. Synergistic effect of immune
ovarian cancer. N Engl J Med checkpoint blockade and anti-angiogenesis
2011;365:2473–2483. in cancer treatment. Mol Cancer 2019;18:60.

Debate
What is the best front-line
18B maintenance therapy

for optimally debulked
HRD-negative advanced
epithelial ovarian cancer?
PARP Inhibitor
Francisco Grau, Lorena Fariñas-Madrid, and Ana
Oaknin
Debate
The integrated genomic analysis of high-grade serous ovarian cancer carried out by The
Cancer Genome Atlas Research Network (TCGA) identified two large subgroups of
patients, those harboring homologous recombination (HR) deficiency (50%), characterized
by genetic and epigenetic alterations of HR genes, most commonly the BRCA1 and BRCA2
genes, and those with an intact HR pathway, enriched in Cyclin E1 (CCNE1) amplifications.
These HR-proficient tumors are associated with inferior survival outcomes and poorer
response to PARP inhibitors (PARPi), in comparison with HR-deficient tumors [1,2].
Currently, two of the most used commercially available assays to test HR-deficiency
status, Myriad myChoice CDx and the Foundation Medicine’s FoundationFocus CDx, are
challenged by the reliable identification of HR-proficient tumors. Thus, some of those
tumors identified as HR-proficient by using these tests, contrary to expectations, may be
responsive to PARPi, as they may retain a certain degree of HR deficiency. This might
explain why both phase 3 trials, NOVA and ARIEL3 [3,4], assessing niraparib and rucaparib
respectively, in the platinum-sensitive recurrent disease setting, demonstrated a significant
improvement in PFS in the HR-proficient/LOH-low subgroups (HR=0.58, p=0.02, and
HR=0.58, p<0.001, respectively) . Similarly, PRIMA trial showed that the HRD-negative
population had statistically significant PFS benefit from niraparib (HR=0.68; 95% CI: 0.492–
0.944), in the first-line setting. Due to all that, and until the development of an accurate test
determining HR-proficiency, the HR-negative status may not preclude from using PARPi in
this subpopulation of advanced ovarian cancer.
Although PRIMA trial was run in high-risk “all-comers” advanced ovarian cancer
population, namely suboptimally primary debulked stage III, stage III under neoadjuvant
chemotherapy, and any stage IV ovarian cancer, patients included in this trial were highly
platinum-sensitive, as 69% of the population achieved a complete response to platinum-
based chemotherapy which may predict significant benefit from PARP inhibition. Thus,
using niraparib as maintenance treatment after a documented good response to platinum-
based chemotherapy in the first-line setting may still be an option.
104

PARP Inhibitor as the Appropriate Maintenance Therapy 105
From the perspective of optimizing the long-term sequential therapeutical strategy of

the HR-proficient patients, the administration of PARPi in the first-line setting may
represent an acceptable approach, even in comparison with the use of bevacizumab,
which demonstrated a meaningful PFS benefit even in those patients with no residual
disease [5,6]. HR-proficient patients represent a poor-prognosis population, with high
probability of relapse within the first six months after finishing first-line chemotherapy.
Besides, following disease recurrence, a response to subsequent platinum-based chemother-
apy is mandatory for receiving maintenance PARPi. Therefore, the first-line setting may be
the only opportunity for these patients to receive PARPi and provides the opportunity to
delay the onset of primary resistance to platinum. Conversely, the use of bevacizumab could
be postponed to the second-line based on data for patients with platinum-sensitive relapsed
disease and to the second- or third-line for platinum-resistant relapse [7,8].
Conclusion
In conclusion, HR-proficient advanced ovarian cancer population represents a relevant
unmet clinical need, in urgent need for novel therapeutical approaches to offer better
outcomes. In this regard, PARPi may still be an appropriate alternative treatment in this
subgroup.
References
1. Ray-Coquard I, et al. Olaparib plus ovarian cancer. N Engl J Med 2011 29;365
bevacizumab as first-line maintenance in (26):2473–2483.
ovarian cancer. N Engl J Med 2019;381 6. González Martín A, et al. Exploratory
(25):2416–2428. outcome analyses according to stage and/or
2. González-Martín A, et al. Niraparib in residual disease in the ICON7 trial of
patients with newly diagnosed advanced carboplatin and paclitaxel with or without
ovarian cancer. N Engl J Med 2019;381 bevacizumab for newly diagnosed ovarian
(25):2391–2402. cancer. Gynecol Oncol2019;152(1):53–60.
3. Mirza MR, et al. Niraparib maintenance 7. Aghajanian C, et al. OCEANS:
therapy in platinum-sensitive, recurrent a randomized, double-blind,
ovarian cancer. N Engl J Med 2016;375 placebo-controlled phase III trial of
(22):2154–2164. chemotherapy with or without bevacizumab
4. Ledermann JA, et al. Rucaparib for patients in patients with platinum-sensitive
with platinum-sensitive, recurrent ovarian recurrent epithelial ovarian, primary
carcinoma (ARIEL3): post-progression peritoneal, or fallopian tube cancer. J Clin
outcomes and updated safety results from Oncol 2012;30(17):2039–2045.
a randomised, placebo-controlled, phase 3 8. Pujade-Lauraine E, et al.Bevacizumab
trial. Lancet Oncol 2020;21(5):710–722. combined with chemotherapy for
5. Burger RA, et al. Incorporation of platinum-resistant recurrent ovarian cancer:
bevacizumab in the primary treatment of the AURELIA open-label randomized phase
III trial. J Clin Oncol 2014;32(13):1302–1308.

Debate
What is the Optimal
19A Therapeutic Option

for Platinum-resistant
Recurrent Ovarian Cancer
Single-agent Chemotherapy
David F. Cantú de León, Daniel Flores Alatriste,
and Milagros Pérez Quintanilla
Debate
Platinum resistance is a very common event during the natural history of epithelial ovarian
cancer (EOC); it is more prevalent as the number of treatment lines are given to patients, is
multifactorial, and evolves during time. Intrinsic platinum resistance is present in about 10–
15% of cases and is seen in nonserous histologic subtypes such as mucinous and clear cell
carcinomas [1].
The traditional definition of platinum resistance as reported in the previous GCIG
Ovarian Cancer Consensus Conference (OCCC) refers to a disease which relapses within
six months after finishing treatment with platinum. However, this definition has been
challenged during the sixth OCCC which discouraged the use of platinum-free interval as
the only criterion to define eligibility to clinical trial for patients with recurrent ovarian
cancer [2].
Treatment is challenging, patients have to be informed that management always is
considered palliative instead of curative, and potential toxicities, side effects, and risks
must be discussed. Progression-free survival (PFS) and overall survival (OS) may not be
the best endpoints in this subset of patients, as Health Related Quality of Life (HRQOL) and
Patient Reported Outcomes (PROs) may be more adequate metrics in these cases with
expected survival of less than 12 months. The choice of drug must be individualized to the
patient and must be based on previous treatments, toxicity, drug availability, cost, physician
experience, and patient preferences [3].
Several strategies are currently being investigated in an effort to improve outcome,
including improvement of drug delivery by developing antibody-drug conjugates (ADCs)
targeting several receptors, re-sensitizing the tumor by inhibiting DNA methylation,
modulating cell-cycle using specific checkpoint kinase inhibitors, improving immune
response by modulating tumor microenvironment, and optimizing the time for surgery,
which as a sole therapy could be very important in removing as much tumor as possible in
order to reduce the clonal diversity limiting the potential for sub-clonal populations to
progress and become resistant.
The use of single-agent chemotherapy is considered standard of care in those patients
that can be allocated to the definition of platinum-resistant. Four drugs are mainly used with
106

Optimal Therapy? Single-agent Chemotherapy 107
similar response rates: pegylated liposomal doxorubicin (PLD), paclitaxel, gemcitabine, and
topotecan. There is no preferred drug as first-line or subsequent therapy. The Cochrane
consortium included 1323 cases of platinum-resistant EOC in a systematic review and
concluded that topotecan, paclitaxel, and PLD have similar efficacy but with different
adverse effects. Treatment response rates range from 15–20%, PFS is less than four months,
and OS ranges between nine and 12 months [2].
Docetaxel and oral etoposide are other options that can be used as monotherapy.
Currently, the evidence of an objective benefit in platinum-resistant patients remains
weak, with response rates of 10–15% and PFS of three to four months.
Paclitaxel is one of the most commonly used cytotoxic agents. Its regimen was recently
modified because the weekly administration showed response rates of 13–50% and caused
less neurotoxicity, as compared with its every-three-week administration. Therefore, it has
become the control arm of several randomized trials in patients with platinum-resistant
EOC [4].
In a phase III multicenter trial, Ferrandina et al. compared gemcitabine versus PLD
treatment, considering time to progression as the primary endpoint. No significant differ-
ences were found between the two treatments. Another phase III trial of gemcitabine
compared with PLD was conducted by Mutch et al., recruiting patients experiencing
recurrence within six months. The primary endpoint was progression-free interval. No
differences were found either, with a similar OS in both groups.
Etirinotecan is a polymer conjugate of irinotecan with a longer half-life and fewer
cholinergic effects. The findings of phase II trials have shown response rates of up to
15.4% in patients with platinum-resistant EOC. This drug has also shown a PFS of 4.4
months and OS of 10 months.
Bevacizumab was approved by the FDA for patients with platinum-resistant EOC in
2014; its benefits have been demonstrated in several studies with objective response rates of
up to 20%. Candidate patients for bevacizumab are those who have received less than two
regimens, have not previously taken bevacizumab, and have no history of bowel obstruction
within six months. However, the most prominent activity is seen when bevacizumab is
combined with chemotherapy.
Poly ADP-ribose polymerase (PARP) inhibitors are among the novel effective agents in
the treatment of ovarian cancer. Olaparib, niraparib, and rucaparib are FDA approved as
therapy for platinum-resistant disease with BRCA mutation after three lines of treatment.
An objective response of 33% and an average response duration of 28 weeks were found in
a phase II trial involving 24 patients with platinum-resistant disease and BRCA mutation.
The QUADRA trial administered niraparib to BRCA mutation carriers with platinum-
resistant EOC. This trial showed a response rate of 34% and an average response duration of
7.9 months [3].
ARIEL 4 is a randomized study of rucaparib versus standard chemotherapy as second-
line treatment in patients with BRCA-mutated ovarian cancer. This study, which also
included platinum-resistant patients, demonstrated an improved PFS compared to standard
of care chemotherapy [5].
Endocrine therapy with tamoxifen versus chemotherapy in 138 platinum-resistant
patients revealed a PFS of 8.3 and 12.7 weeks respectively. In asymptomatic women with
elevated CA 125 levels, letrozole showed response rates >50% in tumor markers and
radiological response rates of 9% [5].

108 David F. Cantú de León et al.
Conclusion
In conclusion, platinum-resistant ovarian cancer is a complex and aggressive entity with
very limited treatment options, and is a prolific area of research in order to counteract the
different and multifactorial mechanisms of resistance. Cancer genome analysis has yielded
promising results that will lead to personalized and targeted treatments according to specific
genotypes. Monotherapy remains standard of care and must be carefully discussed with
patients in order to select the best option.
References
1. McMullen M, et al. New approaches for 4. Poveda AM, et al. Bevacizumab combined
targeting platinum-resistant ovarian cancer. with weekly paclitaxel, pegylated
Semin Cancer Biol 2020;2020:S1044–579X liposomal doxorubicin, or topotecan in
(20)30186–3. https://doi.org/10.1016/j platinum-resistant recurrent ovarian
.semcancer.2020.08.013 cancer: analysis by chemotherapy
2. Pujade-Lauraine E, et al. Management of cohort of the randomized phase III
platinum-resistant, relapsed epithelial AURELIA trial. J Clin Oncol
ovarian cancer and new drug perspectives. 2014;33:3836–3838.
J Clin Oncol 2019;37(27):2437–2448. https:// 5. Oronsky B, et al. A brief review of the
doi.org/10.1200/JCO.19.00194 management of platinum-resistant-
3. Lee JM, et al. New strategies in ovarian cancer platinum-refractory ovarian cancer. Med
treatment. Cancer 2019;125(Suppl. 24):4623– Oncol 2017;34(6):103. https://doi.org/10
4629. https://doi.org/10.1002/cncr.32544 .1007/s12032-017-0960-z

Debate
What is the Optimal
19B Therapeutic Option

for Platinum-resistant
Recurrent Ovarian Cancer?
Other
Olivia Lara and Bhavana Pothuri
Debate
The management of patients with platinum-resistant recurrent epithelial ovarian cancer
(EOC) poses a significant challenge. Traditionally treatment has involved the use of non-
platinum chemotherapeutic agents, including PEGylated liposomal doxorubicin (PLD),
topotecan, gemcitabine, and paclitaxel, used as monotherapy with response rates of 10–
15%, progression-free survival (PFS) of three to four months and overall survival (OS) of
approximately 12 months [1]. These agents have had limited efficacy and failed to demon-
strate a meaningful OS benefit at the risk of chemotherapy toxicity. Through advancements
in integrated genomic analysis, an increased understanding of the underlying molecular
characteristics of EOC has led to the development of various molecularly targeted strategies
designed to advance the field beyond single agent chemotherapy.
Bevacizumab, a recombinant humanized monoclonal antibody that targets vascular
endothelial growth factor, has single agent activity in EOC both as monotherapy and
when combined with chemotherapy. The AURELIA (Avastin Use in Platinum-Resistant
Epithelial OC) phase III study evaluated single agent chemotherapy with or without
bevacizumab in patients with platinum-resistant disease and noted a near doubling of the
PFS (3.4 vs. 6.7 months; hazard ratio (HR)=0.48; 95% confidence interval (CI): 0.38–0.60,
p<0.001) with the addition of bevacizumab. Median overall survival increased by three
months but was not statistically significant (13.3 vs. 16.6 months; HR=0.85, 95% CI: 0.66–
1.08, p<0.174) [2]. This led to the FDA approval of bevacizumab for use with chemotherapy
in patients with platinum-resistant EOC. This has spurred the integration of molecularly
targeted agents in the management of EOC and utilization of bevacizumab has become
a standard of care in the treatment of platinum-resistant ovarian cancer.
Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown evidence of their
efficacy in platinum-resistant patients as well. In a phase II study, which included 193
germline BRCA 1/2 mutation (gBRCAm) carriers with both platinum-sensitive and plat-
inum-resistant EOC, the tumor response was 31% (95% CI: 24.6–38.1) and stable disease
was seen in 40% of patients (95% CI: 33.4–47.7) [3]. Additionally in a phase Ib study of
olaparib, RECIST responses were confirmed in eight (33.5%) of 24 platinum-resistant
patients [4]. This has led to the FDA approval of olaparib as monotherapy for gBRCAm-
related ovarian cancer after three or more prior regimens. Study 10 and the ARIEL 2 trial
109

110 Olivia Lara and Bhavana Pothuri
investigated rucaparib in 106 gBRCAm and tumor BRCA mutated (tBRCAm) patients who
progressed on two prior therapies. Investigator-assessed objective response rate (ORR) was
66% (52/79; 95% CI: 54–76) in platinum-sensitive patients and 25% (5/20; 95% CI: 9–49) in
platinum-resistant patients. This led to the FDA approval of rucaparib for treatment
regardless of platinum sensitivity in gBRCAm and tBRCAm patients after two prior lines
of therapy. In the phase II Quadra trial of single-agent niraparib the ORR of gBRCAm
patients who had previously received three or more lines of therapy was 33% for platinum-
resistant disease (n=21) and 19% for platinum-refractory disease (n=16) [5]. In a phase II
trial investigating alterative combinations, olaparib was combined with cediranib in
gBRCAm patients. The ORR in platinum-resistant patients was 20% (95% CI: 11–38%)
with seven confirmed PRs. Median duration of response was six months and disease control
rate (DCR) 43% in platinum-resistant patients [6]. Confirmatory studies of the combination
olaparib and cediranib is currently under investigation in the NRG GY005 phase II/III trial
that recently completed accrual (Clinicaltrials.gov identifier: NCT02502266).
Immunotherapy has shown some antitumor activity in platinum-resistant patients; the
response rate with avelumab was 9.6% (12/125) and 9% (11/97) with pembrolizumab [7,8].
The TOPACIO/KEYNOTE-162 phase I and II trial evaluated pembrolizumab and niraparib
in platinum-resistant ovarian carcinoma irrespective of BRCA mutation status. In the
integrated phase I and II studies in ovarian carcinoma, ORR was 18% (95% CI: 11–29%),
with a disease control rate of 65% (95% CI: 54–74%). This included three (5%) with
complete response, eight (13%) with partial response, 28 (47%) with stable disease, and 20
(33%) with progressive disease [9]. In the phase II trial of Nivolumab and Ipilimumab in
recurrent or persistent ovarian cancer, platinum-resistant patients represented 62% of
patients and saw a favorable response to combination therapy [10]. In a single arm, phase
II study (ClinicalTrials.gov identifier: NCT02440425) the combination of pembrolizumab
and weekly paclitaxel has reported a preliminary response rate of 51% [11]. Results of
a phase II trial evaluating pembrolizumab in combination with bevacizumab and oral
metronomic cyclophosphamide showed an ORR of 37.5% which included platinum-
sensitive and platinum-resistant patients who received a median number of five prior
lines of chemotherapy (SGO Annual Conference 2019, Abstract LBA4). Immunotherapy
in platinum-resistant disease has yielded promising yet mixed results. Further combinations
including PLD and Atezolizumab are being studied in the ongoing phase II/III NRG GY009
study.
Finally, the use of novel therapeutics including antibody drug conjugates (ADC) have
shown clinical activity in platinum-resistant disease. In an ongoing phase I study, ADC
XMT-1536 demonstrated clinical responses and stable disease in platinum-resistant
patients. Of the 20 patients evaluated, two (10%) confirmed complete response and five
(25%) achieved partial responses for an objective response rate of 35% after treatment with
XMT-1536. Additionally eight (40%) of 20 patients achieved stable disease [12]. Additional
phase II trials are currently underway to determine the role of XMT-1536 in platinum-
resistant ovarian cancer. Mirvetuximab soravtansine is another ADC composed of
a humanized alpha-folate receptor (FRα)–binding monoclonal antibody with DM4,
a potent antimitotic agent. In 46 patients in the phase I expansion cohort with platinum-
resistant disease and FRα-positive tumors and up to five prior lines of systemic therapy, the
ORR was 26% and the median PFS was 4.8 months [13]. A phase III trial, Mirasol is
currently ongoing to confirm these findings. Other agents including ofranergene obadeno-
vec (VB-111), a targeted anti-cancer gene therapy, in combination with weekly paclitaxel

Optimal Therapy? Other 111
have shown interim favorable CA-125 tumor responses with an OS of 498 days compared to
172.5 days in the platinum-resistant group in phase III OVAL trial [14].
Conclusion
While the use of non-platinum single agent chemotherapy was once a standard of care for
patients with platinum-resistant EOC, the use of molecular targeted therapies has
changed the standard of care to include bevacizumab in these difficult-to-treat patients.
PARPi are effective in treating gBRCAm and tBRCAm patients with recurrent platinum-
resistant disease, and immunotherapy combinations as well as ADCs are being actively
investigated to determine if they can play a critical role in the treatment of platinum-
resistant ovarian cancer. Additional efforts are needed to understand the genomic events
driving resistant EOC to provide continued rational development of new therapies in
ovarian cancer.
References
1. Davis A, et al. “Platinum resistant” ovarian from the JAVELIN solid tumor trial. JAMA
cancer: what is it, who to treat and how to Oncol 2019;5:393–401.
measure benefit? Gynecol Oncol 2014;133: 8. Matulonis UA, et al. Antitumor activity
624–631. and safety of pembrolizumab in patients
2. Pujade-Lauraine E, et al. Bevacizumab with advanced recurrent ovarian cancer:
combined with chemotherapy for interim results from the phase 2
platinum-resistant recurrent ovarian KEYNOTE-100 study. J Clin Oncol
cancer: the AURELIA open-label 2018;36:5511.
randomized phase III trial. J Clin Oncol 9. Konstantinopoulos PA, et al. Single-arm
2014;32(13):1302–1308. https://doi.org/1 phases 1 and 2 trial of niraparib in
0.1200/JCO.2013.51.4489. combination with pembrolizumab in
3. Kaufman B, et al. Olaparib monotherapy in patients with recurrent platinum-resistant
patients with advanced cancer and ovarian carcinoma. JAMA Oncol
a germline BRCA1/2 mutation. J Clin 2019;5:1141–1149.
Oncol 2015;33:244–250. 10. Zamarin D, et al. Randomized phase ii
4. Fong PC, et al. Inhibition of poly trial of nivolumab versus nivolumab
(ADP-ribose) polymerase in tumors from and ipilimumab for recurrent or
BRCA mutation carriers. N Engl J Med persistent ovarian cancer: an NRG
2009;361:123–134. oncology study. J Clin Oncol
5. Moore KN, et al. QUADRA: a phase 2, open- 2020;38:1814–1823.
label, single-arm study to evaluate niraparib 11. Wenham RM, et al. Phase II trial of dose
in patients (pts) with relapsed ovarian cancer dense (weekly) paclitaxel with
(ROC) who have received ≥3 prior pembrolizumab (MK-3475) in platinum-
chemotherapy regimens. J Clin Oncol resistant recurrent ovarian cancer. 2016;34:
2018;36:5514. TPS5612-TPS.
6. Liu JF, et al. A phase 2 biomarker trial of 12. Richardson DL, et al. Phase I expansion
combination cediranib and olaparib in study of XMT-1536, a novel
relapsed platinum (plat) sensitive and plat NaPi2b-targeting antibody-drug conjugate
resistant ovarian cancer (ovca). J Clin Oncol (ADC): preliminary efficacy, safety, and
2018;36:5519. biomarker results in patients with
7. Disis ML, et al. Efficacy and safety of previously treated metastatic ovarian
avelumab for patients with recurrent or cancer (OC) or non-small cell lung cancer
refractory ovarian cancer: phase 1b results (NSCLC). J Clin Oncol 2020;38:3549.

112 Olivia Lara and Bhavana Pothuri
13. Moore KN, et al. Safety and activity of 14. Arend RC, et al. Clinical trial in
mirvetuximab soravtansine (IMGN853), progress: pivotal study of VB-111
a folate receptor alpha-targeting combined with paclitaxel versus
antibody-drug conjugate, in paclitaxel for treatment of
platinum-resistant ovarian, fallopian tube, platinum-resistant ovarian
or primary peritoneal cancer: a phase cancer (OVAL, VB-111-701/GOG-
i expansion study. J Clin Oncol 3018). J Clin Oncol 2020;38:TPS6097-
2017;35:1112–1118. TPS.

Debate
Should Patients with
20A Platinum-sensitive Recurrent

Ovarian Cancer Undergo
Secondary Cytoreduction
prior to Receiving
Platinum-containing
Second-line Chemotherapy?
Yes
Sarah Ehmann, Andreas du Bois, and Mareike
Bommert
Debate
Cytoreductive surgery is an important part in the treatment of ovarian cancer, in the
primary setting as well as in recurrence. One of the key prognostic factors which can be
influenced in ovarian cancer patient management is the surgical cytoreductive outcome, but
the ability to achieve complete resection and the right patient selection are of utmost
importance to prevent surgical morbidity and mortality.
The Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) published the Descriptive
Evaluation of perioperative Selection KriTeria for OPerability in recurrent OVARian cancer
(DESKTOP OVAR) series. The DESKTOP I trial created a predictive score for resectability
taking into account three factors: no residual disease after primary debulking surgery, good
performance status (PS), and ascites less than 500 mL in preoperative imaging. Localization
of recurrent disease and therapy-free interval did not show any impact for complete
resection in multivariate analysis [1]. The AGO score was successfully validated in the
DESKTOP II trial and showed in the subgroup of AGO score positive patients with first
recurrence a positive prediction regarding complete resectability in 76%. Surgery in AGO
score negative patients might also be an option, but it is an individual decision and this
endpoint was not addressed in the DESKTOP II trial. If complete resection was achieved
even in AGO score negative patients, the progression-free survival (PFS) was comparable to
AGO score positive patients [2]. MSKCC (Chi et al.) published selection criteria for offering
secondary cytoreductive surgery which included disease-free interval, the number of recur-
rence sites, and the presence of peritoneal carcinomatosis. Bristow et al. showed in a meta-
analysis that each 10% increase of complete resection rate in recurrent ovarian cancer
resulted in an overall survival benefit of three months.
113

114 Sarah Ehmann et al.
Worldwide, three prospective randomized multicenter trials in platinum-sensitive

recurrent ovarian cancer were conducted to compare secondary cytoreductive surgery
followed by platinum-based chemotherapy versus chemotherapy alone. The SOC-1 trial
opened in 2013, included 357 patients and its primary endpoint was PFS and overall survival
(OS). The iModel was used for patient selection and prediction of resection: it includes
stage, residual disease after primary surgery, progression-free interval (PFI), PS, CA125,
ascites at recurrence. The interim analysis showed a PFS benefit of 5.5 months (17.4 vs. 11.9)
favoring surgery with a complete resection rate was 76.7%. OS data are not mature yet [3].
The GOG 213 trial started in 2007 and 485 patients participated. Two primary analyses
were defined: chemotherapy with bevacizumab followed by bevacizumab maintenance
therapy versus chemotherapy alone and on secondary surgery versus no surgery if the
patient was also eligible for surgery. Its primary endpoint was OS. Focusing on the surgical
part of this trial the patients were deemed by the investigator to be amenable to complete
resection. Complete resection was reached in 63%. The median OS was 50.6 months in the
surgical group versus 64.7 months in the no surgery group without reaching statistical
significance (HR=1.29, 95% CI: 0.97–1.72, p=0.08) [4].
The DESKTOP III trial started in 2009 and had a standardized patient selection process
based on the AGO score as well as a careful selection of the participating centers. It was
a superiority trial with 407 patients and OS was the primary endpoint. Complete resection
in secondary cytoreduction was achieved in 75%. Median OS was 53.7 months with and 46.0
months without surgery (HR=0.76, 95% CI: 0.59–0.97, p=0.03). Analyzing and comparing
only patients with complete resection and patients without surgery an OS benefit of even
14.5 months was found (60.7 vs. 46.2 months), patients with surgery and incomplete
resection did even worse with an OS of 28.8 months [5].
Conclusion
In conclusion, the extraordinary OS benefit of more than 14 months in the DESKTOP III
trial was highest and exclusively seen in the cohort with complete resection, indicating the
importance of the right patient selection as well as the right selection of the center, with an
experienced team and interprofessional/interdisciplinary cooperation, to provide the best
treatment results for our patients. Therefore, an assessment of all patients with recurrent
ovarian cancer and a platinum-free interval of more than six months regarding their
eligibility for secondary cytoreduction should be performed. Tools such as AGO score,
imaging, patient, and tumor characteristics may be helpful for the identification of the right
cohort. The remaining 25% of patients with incomplete resection due to tumor spread or
other reasons should be evaluated for early initiation of platinum-based chemotherapy.
References
1. Harter P, et al. Surgery in recurrent ovarian Intergroup Study DESKTOP II. A Project of
cancer: the Arbeitsgemeinschaft the AGO Kommission OVAR, AGO Study
Gynaekologische Onkologie (AGO) Group, NOGGO, AGO-Austria, and MITO.
DESKTOP OVAR Trial. Ann Surg Oncol Int J Gynecol Cancer 2011;21:289–295. http
2006;13:1702–1710. https://doi.org/10.1245 s://doi.org/10.1097/IGC.0b013e31820aaafd
/s10434-006-9058-0 3. Zang R, et al. A randomized phase III
2. Harter P, et al. Prospective validation study trial of secondary cytoreductive surgery
of a predictive score for operability of in later recurrent ovarian cancer: SOC1/
recurrent ovarian cancer: the Multicenter SGOG-OV2. J Clin Oncol 2020;38:6001–

Secondary Cytoreduction before Chemotherapy? Yes 115
6001. https://doi.org/10.1200/JCO 5. Du Bois A, et al. Randomized phase III study to

.2020.38.15_suppl.6001 evaluate the impact of secondary cytoreductive
4. Coleman RL, et al. Secondary surgical surgery in recurrent ovarian cancer: final
cytoreduction for recurrent ovarian cancer. analysis of AGO DESKTOP III/ENGOT-ov20.
N Engl J Med 2019;381:1929–1939. https://d J Clin Oncol 2020;38:6000. https://doi.org/10
oi.org/10.1056/NEJMoa1902626 .1200/JCO.2020.38.15_suppl.6000

Debate
Should All Patients with
20B Platinum-sensitive Recurrent

Ovarian Cancer be Considered
for Secondary Cytoreduction
prior to Receiving Second-line
Platinum Chemotherapy?
No
Anca Chelariu-Raicu and Robert L. Coleman
Debate
Ardent support of secondary cytoreductive surgery as a strategy in the treatment paradigm
for patients with recurrent ovarian cancer has been levied for decades, largely by analogy to
primary cytoreduction [1]. The primary rationale follows that removal of as much tumor as
possible augments the effectiveness of subsequent chemotherapy and may enhance a more
favorable tumor microenvironment for natural immune surveillance. However, the merit of
this, as with any intervention, should be addressed in randomized clinical trials, if possible,
to control bias, and compared to appropriate reference treatment assessing clinically
relevant endpoints. This “tried and true” approach has been the foundation upon which
current treatment standards have been defined. In the setting of recurrent ovarian cancer,
a prolific expansion in efficacious therapies has been witnessed, challenging clinical trial
endpoints, such as overall survival (OS), which may not be reached years after an index
intervention [2].
When discussing role of surgery in recurrent ovarian cancer management, there are four
key elements that establish the framework for debate: (1) most appropriate clinical setting;
(2) patient candidacy/goal of surgery; (3) adjuvant therapy; (4) outcomes and endpoints.
Our contention in this debate is that while seemingly discordant results have been presented
among the three active clinical trials, the role of secondary cytoreduction is not clearly
defined, particularly in the setting of highly effective adjuvant treatment, increasingly
annotated by tumor genomic information [3–5].
Clinical Setting
We propose three subgroups of patients that are clinically relevant to the recurrent setting of
ovarian cancer: patients without front-line maintenance, patients who progressed after
front-line maintenance therapy with bevacizumab, and those who have progressed follow-
ing poly (ADP-Ribose) polymerase (PARP) inhibitor therapy with or without combination
116

Secondary Cytoreduction before Chemotherapy? No 117
bevacizumab. Herein, several key factors can be used to create an algorithm for an individ-
ual patient to evaluate potential response to systemic therapy: histologic type, platinum-free
interval, molecular signature, pre-existing toxicities, and the impact of treatment on quality
of life. In contrast, when considering a surgical approach, it is important to consider criteria
such as chance to achieve complete gross resection, volume of disease, extensive platinum-
free interval presence of ascites, and good performance status.
Goal of Surgery
In regards to surgical selection criteria, GOG-213 selected patients who were eligible for
platinum-based therapy and deemed as reasonable candidates for surgery, including no
extra-abdominal organ disease, ascites, and carcinomatosis. The pre-randomization stated
objective for consideration of study participation was complete gross resection (CGR).
However, DESKTOP III and SOC-1 trial used structured algorithms to provide guidance,
though with the same goal, complete gross resection. Therefore, given the discrepant
positive progression-free survival (PFS) results of these two trials relative to GOG-213,
one may call into question the lack of more specific selection criteria for patient selection in
GOG-213. However, it is important to note that the rate of CGR was numerically and
statistically similar across all three studies (67–76.7%). The parity of these CGR rates
minimizes one key variance often cited as a reason for the discordant observations seen in
the three trials. It must not be discounted that individualization of clinical trial participation
existed in each of these trials as patients matching eligibility criteria were not “required” to
participate and may not have been enrolled due to one or both patient and investigator
assessment factors, such as patient acceptance, medical safety of surgery, neoadjuvant
chemotherapy in the first-line, and low likelihood of CGR based on disease distribution.
Highlighting this point, in the SOC-1 trial, patients not meeting the iMODEL score were
allowed to undergo additional evaluation with PET-CT where two physicians could over-
ride the criteria to enroll the subject, reaching 11% of patients who were enrolled by
physician-directed individualization. In addition, while not stated in DESKTOP-III, 42%
of patients meeting AGO surgical criteria in DESKTOP-II, did not undergo surgery,
suggesting further patient individualization. Thus, championing discrepancy in trial results
as a matter specific selection algorithm alone would appear to be misguided.
Adjuvant Therapy
All three trials were conducted during a time when treatment for platinum-sensitive
recurrent ovarian cancer was changing, offering a greater variety of options, including
concomitant and maintenance therapy; options that at the least have demonstrated better
PFS, and in one, overall survival (OS). In contrast to GOG-213, which was designed to first
address the impact of bevacizumab added to paclitaxel and carboplatin followed by main-
tenance bevacizumab until progression on OS, few patients enrolled in DESKTOP III or
SOC-1 received any kind of maintenance therapy. This is critically important since the
surgical effect might have been diluted by adjuvant therapy, particularly where maintenance
was administered until disease progression. In a setting where prespecified and homoge-
neous chemotherapy is administered equally among the randomization cohorts, the effect of
surgery on PFS is easier to determine. However, even in the absence of bevacizumab,
platinum-based chemotherapy regimens have not demonstrated equipoise in formal
phase III investigation. Similarly, several trials investigating the efficacy of PARP inhibition,

118 Anca Chelariu-Raicu and Robert L. Coleman
for relapsed disease after complete or partial clinical response to platinum, demonstrated
substantial improvements in PFS, independent of secondary cytoreduction [6–8]. Further,
lack of a defined and balanced recurrence regimen strategy and the long anticipated post-
progression survivorship in this disease setting differentially challenges any clear assessment
of surgical treatment effect on OS. Despite this, the SOLO2 trial, which investigated the role
of maintenance olaparib in unselected women with BRCA-mutated tumors is the first trial
to report an improvement in median OS of 12.9 months [9]. Importantly, almost a third of
patients treated with olaparib survived more than five years.
Outcomes and Endpoints

Interestingly, the median PFS, OS, and three-year OS rate among the surgical arms in the
three trials are remarkably similar, highlighting some parity of prognostic factors.
Moreover, the morphology of the Kaplan-Meier survival curves, which are at least 80%
mature in GOG-213 and DESKTOP-III, are strikingly similar, demonstrating consistent
time-dependent event rates. What is clear from evaluation of these three trials is that
variance exists in the nonsurgical arms, with similarity observed in DESKTOP-III and
SOC1, and discrepancy in GOG-213. With respect to PFS, this might be anticipated based
on prior results of platinum-sensitive recurrence trials using bevacizumab, concomitantly
and in maintenance, and may suggest a differentially more important role for adjuvant
therapy (vs. surgical resection) in this population.
Conclusion
Taken together, each of the above-mentioned studies consists of an individual strength: the
value of maintenance therapy in GOG-213 and structured surgical algorithms applied for
patient selection in DESKTOP-III and SOC1. Although a trial investigating the role of
secondary cytoreduction enrolling patients after both rigorous selection criteria for surgery
and with an optimal (and biomarker directed) adjuvant therapy strategy would offer more
clarity to the question, the likelihood such a trial could be completed is low. Further, the
pace of drug discovery is swift and will continue to challenge treatment sequencing as newer
therapies with incremental benefit will be adopted. Nevertheless, we strongly contend that
continued investigation into innate and adapted tumor biology has the highest probability
to identify patient cohorts where a multimodality approach would optimize patient sur-
vivorship. Until this time, the indication for secondary cytoreduction should be carefully
considered.
References
1. Bristow RE, et al. Cytoreductive surgery for cytoreductive surgery in recurrent ovarian
recurrent ovarian cancer: a meta-analysis. cancer: final analysis of AGO DESKTOP III/
Gynecol Oncol 2009;112(1):265–274. ENGOT-ov20. J Clin Oncol (online) 2020;38.
2. Insitute NC. Cancer Stat Facts: Ovarian https://doi.org/10.1200/JCO.2017.35.15_SU
Cancer. 2020. PPL.5501
3. Coleman RL, et al. Secondary surgical 5. Zang R, et al. A randomized phase III trial of
cytoreduction for recurrent ovarian cancer. secondary cytoreductive surgery in later
N Engl J Med 2019;381(20):1929–1939. recurrent ovarian cancer: SOC1/SGOG-
4. duBois A, et al. Randomized phase III study OV2. J Clin Oncol 2020 (online). https://doi
to evaluate the impact of secondary .org/10.1200/jco.2020.38.15_suppl.6001

Secondary Cytoreduction before Chemotherapy? No 119
6. Coleman RL, et al. Rucaparib maintenance ovarian cancer and a BRCA1/2

treatment for recurrent ovarian carcinoma mutation (SOLO2/ENGOT-Ov21): a
after response to platinum therapy double-blind, randomised,
(ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet
placebo-controlled, phase 3 trial. Lancet Oncol 2017;18(9):1274–1284.
2017;390(10106):1949–1961. 9. Poveda A, et al. Final overall survival (OS)
7. Mirza MR, et al. Niraparib maintenance results from SOLO2/ENGOT-ov21: a phase
therapy in platinum-sensitive, recurrent III trial assessing maintenance olaparib in
ovarian cancer. N Engl J Med 2016;375 patients (pts) with platinum-sensitive,
(22):2154–2164. relapsed ovarian cancer and a BRCA
8. Pujade-Lauraine E, et al. Olaparib tablets mutation. J Clin Oncol (online) 2020;38. htt
as maintenance therapy in patients ps://doi.org/10.1200/jco.2020.38.15_suppl
with platinum-sensitive, relapsed .6002

Debate
Should Tertiary Debulking
21A for Patients with Recurrent

Ovarian Cancer be Performed?
Yes
Karin K. Shih
Debate
The role of surgical cytoreduction in the management of primary ovarian cancer is well
established. Unfortunately, the majority of patients develop recurrent disease. In the recur-
rent setting, the clinical benefit of surgical cytoreduction is debatable. The goal of treatment
of recurrent ovarian cancer is to prolong remission, improve quality of life, and improve
survival.
Recent results from randomized clinical trials evaluating the efficacy of surgical cytor-
eduction in the recurrent setting include results from the DESKTOP III trial [1]. In this
prospective randomized trial, patients with platinum-sensitive recurrent ovarian cancer
randomized to the surgery and chemotherapy arm had improved overall and progression-
free survival compared with patients randomized to chemotherapy alone. Residual disease
was a significant factor with patients who underwent complete gross resection [1] achieving
a median overall survival of 61.9 months versus 28.8 months for patients who had residual
disease after surgery versus 46 months for patients who received chemotherapy alone [1].
In contrast, results from the Gynecologic Oncology Group (GOG) 213 revealed no
improvement in outcome with secondary cytoreductive surgery as compared with chemo-
therapy alone [2]. There are significant differences in these two trials which may explain the
discordant findings. First, there was a substantial use of bevacizumab in GOG 213. Second,
the resectability of disease was determined by surgeons which may confound results in each
treatment arm. Moreover, the patient selection criteria in the DESKTOP III trial were
stricter, with patients undergoing R0 resection at primary surgery.
In patients who achieve remission after treatment for recurrent ovarian cancer, relapse is
common. In the tertiary recurrent setting, there are no randomized clinical trials to evaluate
the survival benefit with surgical cytoreduction. Retrospective data suggests improved
survival with appropriate patient selection (Table 21A.1). In a retrospective study of 77
patients, complete gross resection at tertiary cytoreductive surgery was significantly associ-
ated with disease-specific survival [3]. The median disease-specific survival of patients who
underwent complete gross resection was 60.4 months compared with 27.9 months for
patients with residual disease ≤ 0.5 cm and 13.6 months for patients with residual disease
> 0.5 cm. Factors that portend a favorable tumor biology such as a longer treatment-free
interval, platinum sensitivity, and single site of disease were associated with complete gross
resection at time of tertiary surgical cytoreduction. A larger multicenter retrospective study
at 14 centers evaluated 406 patients who underwent tertiary surgical cytoreduction [4]. The
120

Table 21A.1
N Treatment-free Extent of disease at No gross Overall survival and residual

interval tertiary cytoreductive residual disease disease
surgery
Shih et al. 77 patients Median 17 months 62.3% single site 72.7% 60.4 months (no gross residual)
2010 27.9 months (residual ≤ 0.5 cm)
13.6 months (residual > 0.5 cm)
Fotopolou 406 patients Median 18 months 72.9% confined to pelvis 54.4% 49 months (no gross residual)
et al. 2013 12 months (any residual disease)

Falcone 103 patients All patients ≥ 6 43.7% single site 68.9% 43 months (no gross residual)
et al. 2017 months 33 months (any residual disease)
63.1% (6–12 months)
36.9% (≥ 12 months)
122 Karin K. Shih
median time from first to second relapse was 18 months and median overall survival was 26
months. Patients with no gross residual disease at tertiary surgical cytoreduction had
a median overall survival of 49 months versus 12 months for patients with any tumor
residual. More recently, a retrospective analysis of 103 patients enrolled at MITO affiliate
centers included 103 patients who underwent tertiary surgical cytoreduction. The median
overall survival for the entire cohort was 39.5 months [5]. However, patients who had no
gross residual disease at tertiary surgical cytoreduction had median overall survival of 43
months, which was significantly higher than patients with any residual disease (33 months).
Factors predictive of complete surgical cytoreduction included single site of disease as well
as good performance status (ECOG = 0).
Patient selection is critical in evaluating the benefit of tertiary surgical cytoreduction.
Factors that suggest favorable tumor biology include longer treatment-free interval, platinum
sensitivity, single site of disease, and no residual disease at secondary surgical cytoreduction.
As evident in the results from the DESKTOP III trial, stringent patient selection criteria are
necessary to identify patients who will benefit from surgical cytoreduction in the recurrent
setting.
Conclusion
There is a role for surgical cytoreduction in the setting of tertiary recurrent ovarian cancer.
With appropriate patient selection, there may be a survival benefit with complete gross
resection and surgical cytoreduction should be considered.
References
1. Dubois A, et al. Randomized phase III study an updated series.Gynecol Oncol
to evaluate the impact of secondary 2010;117:330–335.
cytoreductive surgery in recurrent ovarian 4. Fotopoulou C, et al. Value of tertiary
cancer: final analysis of AGO DESKTOP III/ cytoreductive surgery in epithelial ovarian
ENGOT-ov20.J Clinical Oncol 2020;38:6000. cancer: an international multicenter
2. Coleman R, et al. Secondary surgical evaluation.Ann Surg Oncol 2013;20:1348–
cytoreduction for recurrent ovarian cancer. 1354.
N Engl J Med 2019;381:1929–1939. 5. Falcone F, et al. Tertiary cytoreductive
3. Shih K, et al. Tertiary cytoreduction in surgery in recurrent epithelial ovarian
patients in recurrent epithelial ovarian, cancer: a multicenter MITO retrospective
fallopian tube, or primary peritoneal cancer: study.Gynecol Oncol 2017;147:66–72.

Debate
Should Tertiary Debulking
21B be Performed for Patients

with Recurrent Ovarian
Cancer?
No
Debate
Surgery is considered a cornerstone in the treatment of advanced ovarian cancer. The
absence of macroscopic residual tumor at the end of surgery is associated with a better
outcome in primary debulking surgery and secondary cytoreduction for patients with a first
relapse. Despite the absence of randomized clinical trials in the front-line setting, nobody
questions the value of surgery in the initial management of primary advanced ovarian
cancer due to extensive data showing a clear benefit in overall survival of complete
cytoreduction after primary debulking surgery and interval debulking surgery. In the first
relapse, three randomized clinical trials have produced apparently contradictory results. It is
important to mention (for the best understanding of the question that we are dealing with),
that only the studies including clearly defined selection criteria for cytoreduction, AGO-
OVAR DESKTOP-III and SOC1, have produced a positive result in terms of progression-
free survival. In addition, the AGO-OVAR study has also shown a benefit in overall survival.
The main weakness and argument against tertiary debulking surgery is the absence of
good clinical evidence from randomized clinical trials, as we have for secondary cytoreduc-
tion, and even the lack of prospective series. To this author’s knowledge, all the evidence that
we have is from retrospective studies of highly specialized centers with high volume activity
and, expectedly, highly influenced by selection bias, choosing probably patients with more
“favorable” disease defined by longer disease-free interval, complete cytoreduction in prior
secondary surgery and fewer locations of disease [1–4].
Unsurprisingly, the largest retrospective studies published have consistently shown that
the achievement of complete cytoreduction in tertiary surgery is associated with
a significantly longer overall survival than if any residual tumor is left [1,3,4]. So, the first
question that the reader may raise is: do we have standardized criteria for selecting patients
more likely to achieve complete cytoreduction with no gross residual at tertiary surgery?
The answer is, unfortunately, not.
Many factors have been identified as predictors of complete cytoreduction at tertiary
surgery in the multivariate analysis of retrospective studies. Fotopoulos et al. found platinum
resistance, presence of positive lymph node at tertiary surgery, the persistence of tumor
residuals at secondary surgery, tumor involvement of middle and upper abdomen, and
presence of peritoneal carcinomatosis as significant risk factors for incomplete tumor resection
123

124 Antonio González-Martín
Table 21B.1 Retrospective studies of tertiary surgery with more than 100 patients
Fotopoulos1 Falcone3 Manning-Geist4

(Multicenter) (MITO) (MSKCC)
Date of publication 2013 2017 2021

Number of patients 406 103 114
Platinum-sensitive 38.2% 100% 88.6%
No gross residual at 38% 80.6% 67.6%
secondary surgery
Peritoneal carcinomatosis 51.9% 56.3%* 55.3%*
Isolated recurrence at NA 43.7% 44.7%
surgery
CGR rate 54.1% 68.9% 89.5%
Abbreviations: CGR = complete gross resection; NA = not available; * = multiple tumor sites.
in a multicenter retrospective study with 406 patients. On the other hand, Falcone et al. have
shown in a MITO retrospective study that the presence of a single lesion and a good perform-
ance status (ECOG 0) were the only independent predictors of complete surgical cytoreduction.
Interestingly, as summarized in Table 21B.1, the rate of complete cytoreduction of the
three largest retrospective studies with more than 100 patients have shown a consecutive
higher proportion of complete gross resection with best results in the most recently
published, that could be explained for a better patient selection with a higher proportion
of potentially good predictive factors for complete cytoreduction. In addition, we cannot
rule out the influence of advances in surgery and radiographic imaging over time. In this
regard, the retrospective series from Memorial Sloan Kettering by Manning-Geist et al.
demonstrated the value of skilled radiology in accurately identifying patients likely to
achieve a complete gross resection with high concordance between preoperative imaging
and intraoperative findings (only 18.7% of patients with predicted single-site disease on
imaging ultimately had three or more sites of disease).
As previously mentioned, the most potent factor that has been consistently identified as
a predictive factor for survival was the absence of gross residual tumor after tertiary surgery.
But we must also consider that tertiary surgery is not free of complications, with a reported
rate of severe complications and 30-day operative mortality ranging from 13–31.1%, and from
0–5.9%, respectively. For this reason, seeking a prospective predictive model for complete
gross resection at tertiary surgery allowing for a better selection of patients, as we have for the
secondary cytoreduction, should be a priority for the international Gynecologic Oncology
community. In addition, the value of complementary systemic chemotherapy and mainten-
ance therapy after tertiary surgery is not known and should be further explored, but data from
the retrospective studies suggest that it should not be skipped.
Conclusion
In conclusion, this author defends a position against the indiscriminative use of tertiary
surgery, without validated assessment criteria for patient selection and outside of special-
ized centers, but, as a clinician treating patients with recurrent disease, I recognize that

Tertiary Debulking? No 125
tertiary surgery may be considered in selected patients with a single site of recurrence, and
especially after a long treatment-free interval.
References
1. Fotopoulou C, et al. Value of tertiary 3. Falcone F, et al. Tertiary cytoreductive
cytoreductive surgery in epithelial ovarian surgery in recurrent epithelial
cancer: an international multicenter ovarian cancer: a multicentre MITO
evaluation. Ann Surg Oncol retrospective study. J Gynecol Oncol
2013;20:1348–1354. 2017;147:66–72.
2. Fanfani F, et al. Is there a role for tertiary 4. Manning-Geist BL, et al. Tertiary
(TCR) and quaternary (QCR) cytoreduction cytoreduction for recurrent ovarian
in recurrent ovarian cancer?Anticancer Res carcinoma: an updated and expanded
2015;35:6951–6956. analysis. J Gynecol Oncol 2021;162:345–352.

Debate
Is there a Role
22A for Immunotherapy

in Ovarian Cancer?
Yes
Claire F. Friedman
Debate
Epithelial ovarian carcinoma (EOC) remains a challenging malignancy to treat, with a five-
year overall survival rate of approximately 50%. Unfortunately, despite front-line therapy
including surgical resection and combination platinum-taxane chemotherapy, the vast
majority of patients will recur and ultimately die from disease. Thus, there is a great
unmet need for the development of novel complementary and augmentative therapeutic
approaches. Translational studies would suggest that EOC is an excellent candidate for
immuno-oncology (IO), given the high prevalence of tumor infiltrating lymphocytes at
diagnosis and associated improved survival [1]. A number of IO approaches have been
explored in EOC, with some promising data to date.
Checkpoint Inhibitors
Modest single agent activity has been seen for anti-PD-1 and anti-PD-L1 agents tested in
patients with EOC (Table 22A.1) [2], with objective response rates (ORRs) ranging from 8–
22%. The most promising data thus far has been seen in combination therapy. For example,
in patients treated with the combination of ipilimumab plus nivolumab, the ORR was 33%
in the nivolumab plus ipilimumab cohort, with a hazard of progression or death that was
significantly lower in the combination group (hazard ratio (HR)=0.528; 95% CI: 0.339–
0.821; two-sided p=.004) [3]. In addition to single-agent therapy checkpoint inhibitors
(CPI), given preclinical data that demonstrate synergy with poly-ADP-ribose polymerase
(PARP) inhibitors + anti-PD-1 combinations, there are several ongoing trials evaluating
combination therapy. In the TOPACIO/KEYNOTE-162 study (ClinicalTrials.gov
Identifier: NCT02657889), which enrolled patients with platinum-sensitive and resistant
recurrent disease, the overall ORR was 25%; among the 11 patients with a BRCA mutation,
the ORR was 45%. In contrast to these promising data, the JAVELIN Ovarian 100 study
(ClinicalTrials.gov Identifier: NCT02718417), which studied the efficacy and safety of
avelumab in combination with chemotherapy followed by maintenance avelumab in com-
bination with talazoparib in patients with advanced EOC, failed to meet its primary
endpoint of improved progression-free survival (PFS) and was discontinued early. Other
studies have completed enrollment but have not reported on data, including the ATHENA
study, which is assessing maintenance rucaparib plus nivolumab in EOC.
Lastly, there has also been interest in combining PD-1/PD-L1 blockade with anti-
angiogenesis drugs. Unfortunately, the addition of atezolizumab to a backbone of
126

Immunotherapy in Ovarian Cancer? Yes 127
Table 22A.1 Clinical trials of checkpoint blockade in epithelial ovarian cancer
Study name Drug Patient ORR Median

population PFS
PCD4989 g Atezolizumab Incurable or 22.2% 2.9 months

metastatic (95% CI:
EOC (n=12) 1.3, 5.5)
JAVELIN Avelumab Recurrent or 9.6% 2.6 months
refractory EOC (95% CI:
(n=125) 1.4–2.8)
KEYNOTE-028 Pembrolizumab PD-L1-positive 11.5% 1.9 months
advanced (95% CI:
metastatic 1.8–3.5)
EOC (n=26)
KEYNOTE-100 Pembrolizumab Cohort A received 8% 2.1 months
one to three prior (95% CI:
lines of treatment 2.1–2.2
with a platinum- cohort A,
free interval (PFI) or 2.1–2.6
treatment-free cohort B)
interval (TFI)
between three and
12 months; cohort
B received four to
six prior lines with
a PFI/TFI of ≥3
months
Nivolumab Advanced or 15% 3.5 months
relapsed, (95% CI:
platinum-resistant 1.7–3.9)
EOC (n=20)
NCT01611558 Ipilimumab Recurrent 10.3% NA
platinum-sensitive
EOC
NRG GY003 Nivolumab vs. EOC, one to three Nivolumab 2.0 and 3.9
ipilimumab prior lines of 12.2%, months,
plus nivolumab therapy, PFI <12 combination respectively
months (n=100) arm 31.4%
chemotherapy plus bevacizumab (ClinicalTrials.gov Identifier: NCT03038100) failed to

significantly prolong PFS in patients with newly diagnosed EOC. More promisingly, in
the phase II LEAP-005 basket study (ClinicalTrials.gov Identifier: NCT03797326), pembro-
lizumab plus the anti-angiogenic multikinase inhibitor lenvatinib demonstrated an ORR of
32.3% (95% CI: 16.7–51.4) in fourth line EOC. Median PFS for the ovarian cancer cohort
was 4.4 months and the estimated six-month PFS was 47.1%.

128 Claire F. Friedman
Beyond Immune Checkpoint Inhibitors : T Cell-based Therapy

Adoptive cellular transfer (ACT) is the infusion of lymphocytes either derived from
autologous tumor tissue or engineered to target tumor-specific antigens after activation
and expansion ex vivo. A patient’s T cells can either be engineered with a T-cell receptor
(TCR) or an artificial chimeric antigen receptor (CAR) recognizing the respective antigen.
Accordingly, binding of the TCR to a peptide antigen presented by the major histocompati-
bility complex (MHC) initiates signaling through the TCR/CD3 complex that is enhanced
by costimulatory receptor signaling. A CAR uses the same CD3/costimulatory signaling
pathway, however, binds the antigen independently of the MHC. A more recent strategy
utilizes CAR T cells for tumor targeting that are additionally engineered with cytokines that
are released upon CAR engagement, also known as a TRUCK (T-cells Redirected for
Universal Cytokine-Mediated Killing) [4].
The repertoire of potential targets for ACT in ovarian cancer has grown exponentially,
with potential targets including MUC16, mesothelin, and folate receptor. Clinical trials to
date have primarily been designed to establish the safety of this approach, with some early
signals of efficacy, including an ovarian cancer patient who achieved a partial response when
treated with gavocabtagene autoleucel, a TCR directed against mesothelin (ClinicalTrials.
gov Identifier: NCT03907852). There are multiple ongoing studies evaluating ACT in EOC
with the hope that this may be an effective IO strategy moving forward.
Biomarkers
Pd-L1
KEYNOTE 100 was the largest study to attempt to prospectively define a PD-L1 expression
cut point that would predict ORR to pembrolizumab among patients with recurrent EOC.
The cut points were set as a combined positive score (CPS) of < 1, CPS ≥ 1, or CPS > 10.
Among patients with from one to three prior lines of therapy, the ORR for each cut point
was 4.1% (95% CI: 0.9–11.5), 5.7% (95% CI: 1.9–12.8), and 10% (95% CI: 2.8–23.7),
respectively. Among patients with four to six prior lines of therapy, the ORR was 8.8%
(95% CI: 1.9–23.7), 10% (95% CI: 3.3–21.8), and 18.2% (95% CI: 5.2–40.3), respectively [2].
This study suggested that defining a cut point of CPS > 10 may enrich for responders to CPI
in EOC, but was not a perfect biomarker capable of discriminating responders from non-
responders. The use of PD-L1 IHC as a biomarker is made more complicated by the fact that
there may be significant differences in PD-L1 expression between primary tumor and
peritoneal metastases [5].
Histologic Subtype
Several clinical trials have revealed increased sensitivity of ovarian clear cell carcinoma
(OCCC) to CPI. In a phase II trial of nivolumab, two out of 20 cases of platinum-resistant
ovarian cancer with a complete response (CR) were OCCC. In the KEYNOTE 100 study, 19
patients were OCCC. The ORR was 15.8% (95% CI: 3.4–39.6%) in OCCC, compared to 8.5%
(95% CI: 5.5–12.4%) in the more common high-grade serous histology. Finally, in GY003,
patients with OCCC (n=12) had improved odds of response (OR=5.21, 95% CI: 1.37–19.77)
compared with the other histologic subtypes. These observations, although anecdotal and
with limited numbers, suggest increased sensitivity of OCCC to CPI [1].

Immunotherapy in Ovarian Cancer? Yes 129
Future Directions
While the data for single agent CPI in EOC are disappointing, early data from combination
studies and novel IO approaches such as ACT demonstrate the promise that these strategies
have in EOC. While there have not been FDA approvals of IO to date in this disease type,
and further work is needed to identify appropriate biomarkers to enrich the population of
EOC patients most likely to respond to this approach, there will be a future role for
immunotherapy in this disease.
References
1. Le Saux O, et al. Challenges for ovarian cancer: an NRG oncology study.
immunotherapy for the treatment of J Clin Oncol 2020;38:1814–1823.
platinum-resistant ovarian cancer. Seminars 4. Chmielewski M, et al. TRUCKS, the fourth-
in Cancer Biology 2020. generation CAR T cells: current
2. Borella F, et al. Immune checkpoint developments and clinical translation. Adv
inhibitors in epithelial ovarian cancer: an Cell Gene Ther 2020;3:e84
overview on efficacy and future perspectives. 5. Parvathareddy SK, et al. Differential
Diagnostics (Basel) 2020;10(3):E146. expression of PD-L1 between primary and
3. Zamarin D, et al. Randomized phase II trial metastatic epithelial ovarian cancer and its
of nivolumab versus nivolumab and clinico-pathological correlation. Sci Rep
ipilimumab for recurrent or persistent 2021;11:3750.

Debate
Is there a Role
22B for Immunotherapy

in Ovarian Cancer?
Not Yet
Tiffany Y. Sia and Dmitriy Zamarin
Debate
Immune checkpoint inhibitors (ICIs) have attracted attention recently and have received
fast-track approvals from the Food and Drug Administration (FDA) in multiple cancer
types, including cervical cancer and endometrial cancer. Normally, the expression of
immune checkpoint receptors such as programmed death 1 (PD-1) and cytotoxic
T lymphocyte-associated antigen 4 (CTLA-4) on T cells provides negative feedback mech-
anisms to prevent autoimmunity. Multiple cancers, including epithelial ovarian cancer
(EOC), exploit these mechanisms to inhibit T cell activation, allowing them to escape
immune detection. ICIs block immune checkpoint receptors, allowing for unchecked
activation of cancer-targeted T cells leading to tumor cell destruction. Despite the success
in various other cancer types, there are no approved immune therapies for ovarian cancer,
as response of EOC to ICIs thus far have been modest.
For example, in KEYNOTE 100, an early phase II study of pembrolizumab (anti-PD-1
antibody) monotherapy in 376 patients with recurrent EOC, the ORR was 8% with a disease
control rate of 37% [1]. This study also assessed expression of PD-L1 as a potential
biomarker and demonstrated that PD-L1 expression by combined positive score (CPS) >
10 was predictive of ORR, with ORR of 16.7% and 18.2% for CPS > 10 in less and more
heavily pretreated patients, respectively [1].
After moderate success with single agent ICIs, combination strategies to target different
parts of the immune-suppressive pathways have been explored. In a phase II randomized
trial of nivolumab with or without ipilimumab (anti-CTLA-4 antibody) in patients with
persistent or recurrent EOC, objective response rates were 12% and 33% for the nivolumab
and nivolumab plus ipilimumab groups, respectively [2]. Progression-free survival (PFS)
was 2.0 months and 3.9 months, respectively, demonstrating that though ORR was
increased, response to ICI had limited duration. Interestingly, there was a suggestion that
patients with clear cell carcinoma were more likely to respond to the combination, though
the numbers were small. Expression of PD-L1 was not found to be predictive of response in
either cohort.
A number of studies have also explored chemotherapy in combination with ICIs in EOC.
The recently published JAVELIN Ovarian 200 phase III trial compared avelumab (anti-PD-
L1 antibody) monotherapy, avelumab in combination with pegylated liposomal doxorubi-
cin (PLD), and PLD alone in 566 women with platinum-resistant or platinum refractory
EOC. Chemotherapies used in platinum-resistant EOC, including PLD, had previously been
130

Immunotherapy in Ovarian Cancer? Not Yet 131
shown to prime the immune system by enhancing antigen presentation, and were thought
to be able to enhance the efficacy of immune checkpoint blockade (ICB). Unfortunately, the
trial results did not show a benefit for either single-agent immunotherapy or for chemoim-
munotherapy for patients with platinum-resistant EOC compared to single agent PLD, with
an ORR of 4% for avelumab, 13% for avelumab with PLD, and 4% for PLD alone [3]. There
was no improvement in either PFS or overall survival (OS) with avelumab alone or in
avelumab plus PLD compared to single agent PLD. In a small subset of patients with tumors
expressing both CD8 and PD-L1 that was not defined a priori, combination of avelumab and
PLD therapy seemed to result in greater benefit than with monotherapy; however, the
results were underpowered for this subgroup analysis [3].
Most recently, the IMagyn500 study was conducted to evaluate the efficacy and safety of
ICI in combination with standard of care platinum-based chemotherapy and anti-VEGF
therapy in EOC. Over the course of two years, 1301 patients with previously untreated stage
III or IV EOC were randomized to atezolizumab (anti-PD-L1 antibody) plus bevacizumab
plus chemotherapy versus placebo plus bevacizumab and chemotherapy. Although OS data
for this trial are not yet mature, the trial showed no significant PFS improvement with ICB
plus bevacizumab plus chemotherapy compared to bevacizumab and chemotherapy alone
in the entire cohort and within the PD-L1 positive subgroup [4]. ORR were 93% in the
atezolizumab group versus 89% in the placebo group in this previously untreated patient
population.
Similarly, in the JAVELIN Ovarian 100 phase 3 trial, 998 patients with advanced
treatment-naïve EOC were randomized to receive standard front-line platinum-based
chemotherapy followed by avelumab maintenance, chemotherapy plus avelumab followed
by avelumab maintenance, or chemotherapy followed by observation [5]. The trial was
halted early as prespecified PFS futility boundaries were crossed, and PD-L1 status was not
predictive of benefit [5].
Conclusion
Overall, the studies above highlight that ICIs either alone or in combination with chemo-
therapy to date have failed to demonstrate substantial clinical benefit in the majority of
patients with EOC. Thus, we argue that outside of a clinical trial there is no clear evidence to
support the routine usage of ICIs either alone or in combination with chemotherapy in
EOC, even in a heavily pretreated platinum-resistant setting. We do note, however, that
a minority of patients with EOC appear to derive durable clinical benefit and that there are
some indicators or possibly increased responsiveness in some histologic subtypes such as
clear cell carcinoma [1,2,6]. With identification of biomarkers predictive of response to ICIs
in EOC, we remain hopeful that these drugs may play a role in therapy of some patients,
although the biomarkers that have been predictive of response to ICIs in other cancer types
(e.g., high tumor mutational burden, PD-L1 expression, homologous recombination defi-
ciency) to date have not been found to be useful in EOC [2,5].
Lastly, our advances in understanding of EOC biology and immunology make room for
further development of approaches aiming to address the resistance to ICIs. These include
combinations of ICIs with additional chemotherapy regimens such as metronomic cyclo-
phosphamide, anti-angiogenesis drugs, folate receptor antibodies, and PARP inhibitors. No
less exciting are other novel immunotherapeutic strategies for EOC targeting, including
bispecific antibodies, antibody-drug conjugates, cytokines, and adoptive cell therapies.

132 Tiffany Y. Sia and Dmitriy Zamarin
While many of these are still in the early stages of testing, we remain optimistic that
immunotherapy will eventually find its way into the treatment armamentarium of gyneco-
logic oncologists for most if not all ovarian cancers.
References
1. Matulonis UA, et al. Antitumor activity and 4. Moore KN, et al. Atezolizumab,
safety of pembrolizumab in patients with bevacizumab, and chemotherapy for newly
advanced recurrent ovarian cancer: results diagnosed stage III or IV ovarian cancer:
from the phase II KEYNOTE-100 study. placebo-controlled randomized phase III
Ann Oncol 2019;30(7):1080–1087. trial (IMagyn050/GOG 3015/
2. Zamarin D, et al. Randomized phase II trial ENGOT-OV39). J Clin Oncol 2021;39
of nivolumab versus nivolumab and (17):1842–1855.
ipilimumab for recurrent or persistent 5. Monk BJ, et al. Chemotherapy with or
ovarian cancer: an NRG oncology study. without avelumab followed by avelumab
J Clin Oncol 2020;38(16):1814–1823. maintenance versus chemotherapy alone in
3. Pujade-Lauraine E, et al. Avelumab alone patients with previously untreated epithelial
or in combination with chemotherapy ovarian cancer (JAVELIN Ovarian 100): an
versus chemotherapy alone in open-label, randomised, phase 3 trial. Lancet
platinum-resistant or platinum-refractory Oncol 2021;22(9):1275–1289.
ovarian cancer (JAVELIN Ovarian 200): 6. Hamanishi J, et al. Safety and antitumor
an open-label, three-arm, randomised, activity of anti-PD-1 antibody, nivolumab,
phase 3 study. Lancet Oncol 2021;22 in patients with platinum-resistant ovarian
(7):1034–1046. cancer. J Clin Oncol 2015;33(34):4015–4022.

Debate
What is the Best Management
23A Option for Malignant Bowel

Obstruction?
Surgery
Joanie M. Hope and Jill S. Whyte
Debate
Malignant bowel obstruction (MBO) is one of the toughest clinical challenges in gyneco-
logic oncology. Often the heralding sign of the “beginning of the end,” together doctor and
patient must decide whether to undergo palliative surgery motivated by the driving hope for
more quality time. There is minimal debate that conservative options including bowel rest,
nasogastric tube decompression, analgesics, and anti-secretory/motility agents should be
exhausted prior to considering surgery. The controversy arises when medical management
fails and the choice comes to accepting imminent death or attempting surgery to relieve
obstruction, restore oral nutrition, allow potential for further cancer directed therapy, and
achieve quality time.
Unfortunately, there are few rigorous clinical trials to guide management. Two
Cochrane reviews addressing the role of palliative surgery in MBO in gynecologic cancers
found only low-quality evidence comparing surgical and medical management and came to
no definitive conclusions [1,2]. Ample data establish that palliative bowel surgery is ridden
with complications and bad outcomes. Postoperative 30-day mortality after palliative bowel
surgery is reported at 4–40% and rates of significant perioperative morbidity such as
postoperative pain, bowel leaks, abscess, and sepsis are high, ranging from 5–86% [2].
Patients may end up in worse condition than had they not undergone surgery.
Nevertheless, palliative bowel surgery remains the only approach offering the possibility
of quality time in the face of recurrent malignant obstruction.
When conservative measures fail, a careful assessment of the potential role of surgery
should be performed. The decision to proceed with surgery is highly individualized and
must take into account location and cause of obstruction, performance status, prognosis,
and goals for care. The best surgical candidates are obstructed in a single location, naive to
prior bowel obstruction surgery, have few prior surgeries, chemotherapeutic options
remaining, and minimal if any ascites or carcinomatosis [2]. Unfortunately, women pre-
senting with MBO as a consequence of gynecologic cancer frequently do not meet these
criteria.
Laparotomy may be offered to patients deemed good surgical candidates with a site of
obstruction amenable to intervention. Both wisdom and technical prowess are critical for
best outcomes as malignant bowel surgeries are among the hardest embarked upon by
patient and gynecologic oncologist. The surgeon must be adept in adhesiolysis, bowel
resections, bypass, diversions, and stoma formation, all in the setting of carcinomatosis;
133

134 Joanie M. Hope and Jill S. Whyte
as well as be able to problem solve and make intra-operative choices from the bird’s eye
perspective of where the patient is in her overall cancer journey.
The choice to proceed with surgery requires exceptional doctor–patient communica-
tion. Hope for more time is a tremendous influencer for terminal cancer patients and their
families. It is incumbent upon gynecologic oncologists to take great care in how hope is
proffered when discussing whether to undergo surgery. The patient and her loved ones
cannot possibly foresee how significant the complications from malignant bowel surgery
can be. Risks and alternatives must be vividly explained. Although every case should be
approached individually, evidence based reasons to withhold surgery include: (1) recurrent
obstruction treated with recent surgery; (2) multiple sites of obstruction; (3) inability to
survive and heal from surgery; (4) rapidly growing disease likely to re-obstruct prior to
completion of healing; (5) lack of any viable treatment options in the setting of rapidly
growing disease; and (6) inability to consent and fully understand risk [1,2]. Additionally,
the presence of ascites, malnutrition (albumin < 3.5), and poor performance status (ECOG
2–4) are associated with high rates of perioperative morbidity and mortality [1].
That said, with a carefully selected patient and a highly skilled surgical team, good
outcomes are achievable in MBO surgery. A 2014 JAMA systematic review of 2347 articles
reported that surgery palliated obstructive symptoms in 32–100% of patients with resumption
of diet in 45–75% of cases [3]. While quality of life data and randomized controlled studies are
sorely missing, there are multiple case reports and retrospective data of patients who achieve
years of quality time following malignant obstruction surgery. We eagerly await the results of
a randomized controlled study comparing surgery to medical therapy for MBO [4].
Moving forward, recurrent gynecologic cancer is becoming ever more approachable as
a treatable chronic disease as the dualistic curative/terminal treatment paradigm is aban-
doned. Targeted biologic therapies, genetically driven personalized medicine, and immuno-
therapies are among the drugs revolutionizing cancer care. Many of these novel therapeutics
are oral agents, making a functional GI tract even more critical. This onslaught of novel
cancer therapy gives traction to the idea that if quality of life can be prolonged, science may
indeed deliver new treatment hope in the metric of months if not years.
Conclusion
In closing, the best management option for MBO refractory to conservative measures is
surgery, because surgery is the only way to offer real potential for quality, time, and ongoing
treatment. Unfortunately, not all patients with malignant obstructions can be treated with
surgery. In this very challenging conundrum, the rate-limiting step must be patient and not
surgeon factors. The complex skill set needed for malignant bowel surgery and the willing-
ness to operate when appropriate are essential components to state of the art gynecologic
cancer care. In an era where aggressive debulking surgery gives way to a growing number of
efficacious therapeutics, training future gynecologic oncologists in MBO surgical technique
becomes paramount, especially as the indication for MBO surgery may increasingly become
to offer meaningful life-prolonging therapy.
References
1. Cousins SE, et al. Surgery for the gynaecological and gastrointestinal cancer.
resolution of symptoms in malignant Cochrane Database Syst Rev 2016;1:
bowel obstruction in advanced CD002764.

Management for Bowel Obstruction? Surgery 135
2. Kucukmetin A, et al. Palliative surgery carcinomatosis: a systematic review. JAMA

versus medical management for bowel Surg 2014;149(4):383–392.
obstruction in ovarian cancer. Cochrane 4. SWOG S1316. Surgery or non-surgical
Database Syst Rev 2010;7:CD007792. management in treating patients with intra-
3. Paul Olson T, et al. Palliative surgery for abdominal cancer and bowel obstruction,
malignant bowel obstruction from ClinicalTrials.gov Identifier: NCT02270450.

Debate
23B Option for Malignant Bowel

Obstruction?
Percutaneous Endoscopic
Gastrostomy
Claire V. Hoppenot and S. Diane Yamada
Debate
A malignant bowel obstruction (MBO) in the setting of recurrent or progressive gynecologic
cancer is a terminal diagnosis. It is caused by progression of disease leading to carcinoma-
tosis or widespread cancer involving the bowel. Median survival after diagnosis ranges from
76 to 141 days [1–3]. Half of patients will never recover from an initial diagnosis of MBO; of
those who do, two thirds will have a recurrence of MBO symptoms [1].
In addition to a dismal prognosis, MBO is associated with pain and nausea, worsening
nutrition, and difficulty tolerating additional treatments [1]. Utilizing qualitative interviews
of 14 women with MBO (Hoppenot et al., personal communication) our group found that,
in addition to survival, women with MBO prioritized symptom control, good communica-
tion with their physician, support at home, and ability to receive future treatments. Along
similar lines, Lee et al. studied cohorts of gynecologic cancer patients with MBO before and
after initiating a program of supported self-management that involved close telephonic and
in-person follow-up from an interdisciplinary team [1]. Women after program initiation
were less likely to undergo surgery (11% vs. 21%), but more frequently received chemother-
apy (83% vs. 56%), which mirrors patient-identified goals from our qualitative study [1].
Patients were also less likely to have an Intensive Care Unit (ICU) admission and spent less
time admitted to the hospital [1]. Despite these less “aggressive” measures, survival was
longer in the intervention group by about five months.
Most importantly, a qualitative analysis of women who participated in the supported
self-management program suggests that participants were most grateful for assistance with
the medical and psychological effects of an MBO diagnosis [4]. In particular, they appreci-
ated the access to health professionals to answer questions and slowly developed a better
understanding of the implications of MBO as a terminal diagnosis [4].
The fact is that MBO secondary to recurrent gynecologic cancer is most commonly due
to the presence of widespread disease. On pre-operative imaging of patients with recurrent
gynecologic cancer, at least one third who underwent surgery for MBO had carcinomatosis
and ascites [3]. While surgery can mitigate obstructive symptoms, it cannot address the
carcinomatosis or ascites, leaving the patient at high risk of recurrent obstruction.
Additionally, despite aggressive interventions, surgical patients survive only a few months
longer than those who do not undergo surgery [2,3]. In the context of a terminal, incurable
136

Management for Bowel Obstruction? PEG 137
state, a focus on quality of life, not a few months length of life, may provide more benefit for
patients. Quality of life from the patient’s perspective is hard to measure, but surrogates
such as ICU care in the last days of life (24% for surgical patients vs. 12% for gastrostomy
tube (GT) patients, p<0.05) and death occurring in an acute care hospital (25% vs. 13%,
respectively) suggest that GT are associated with less suffering than surgery at the end of
life [2].
Gastrostomy tubes can control symptoms in medically refractory MBO to improve
quality of life. These tubes, placed endoscopically or by interventional radiology, allow for
venting of stomach contents to alleviate pain and nausea. A prospective study of GT for
MBO showed relief of symptoms in 77% of patients [5]. Median survival after GT placement
was about eight weeks and all deaths were due to disease progression [5]. Eighty-one percent
were discharged home [5]. Complications were mild, including peristomal infections (14%)
and intermittent catheter obstruction (8.4%) [5]. Rates of subsequent chemotherapy admin-
istration have ranged in the literature from 10–30%. In terms of quality of life measures
following GT, only 25 of 142 patients had follow-up scores calculated; 16 (64%) had an
improvement in overall quality of life, two (8%) had stable measures, and seven (28%) had
nonsignificant worsening [5]. GT are safe, effective for symptom relief, and well tolerated.
In terms of future treatments, it is also unclear whether surgery increases chance of
receiving further treatments, which patients valued, based on qualitative study. Although
patients selected for surgery had a longer survival after their first MBO, our retrospective
study of ovarian and uterine cancer patients showed similar rates of receiving chemotherapy
after either surgery or GT (about 50%) [3].
Additionally, frequent admissions for MBO incur substantial costs. Lee et al. estimated
the median cost for each admission to be over $8,000 in Canadian dollars [1]. In our
retrospective study of ovarian and uterine cancer patients, 54% of ovarian cancer patients
and 34% of uterine cancer patients were readmitted for MBO after a first admission [3].
Additional costs accrue from the higher level of care typically needed by surgical patients at
the end of life [2]. A SEER-Medicaid retrospective study showed that GTs were associated
with fewer readmissions compared to surgery (15% vs. 25%, p<0.05) and less need for ICU
care (12% vs. 24%, p<0.05) [2].
In addition to incurred costs, offering surgery can send mixed messages and detract
from patients’ need for palliative care support. In our retrospective study, surgical patients
were much less likely to have a palliative care consultation at the time of MBO (11% vs. 34%
in nonsurgical patients), despite a median survival of less than six months and a planned
palliative surgery [3]. In a large database study, palliative care referrals were again lower for
surgical patients (2% vs. 8% for GT patients) [2]. Even within a program of supported self-
management, patients sustained some uncertainty about prognosis after MBO [4]. It takes
counseling and time for patients to comprehend the poor prognosis associated with MBO,
and a focus on controlling symptoms and providing emotional and physical support stands
to benefit patients the most during this transition.
Conclusion
In the setting of MBO in recurrent and progressive gynecologic cancer, management should
focus on comfort care. For MBO symptoms refractory to medications, GTs are a safe and
effective option. Offering surgery provides limited benefit and can send mixed messages
about goals and options after a MBO diagnosis. A focus on symptom control with a GT and

138 Claire V. Hoppenot and S. Diane Yamada
close emotional and medical supportive care can help achieve measures that are important
to patients without compromising quality of life at the end of life.
References
1. Lee YC, et al. Optimizing care of malignant are there differences in outcome? Gynecol
bowel obstruction in patients with advanced Oncol 2019;154(1):177–182.
gynecologic cancer. J Oncol Pract 2019;15 4. Cusimano MC, et al. Supported
(12):e1066–1071. self-management as a model for end-of-life
2. Lilley EJ, et al. Survival, healthcare care in the setting of malignant bowel
utilization and end-of-life care in older obstruction: a qualitative study. Gynecol
adults with malignancy-associated Oncol 2020;157(3):745–753.
malignant bowel obstruction; comparative 5. Zucchi E, et al. Decompressive percutaneous
study of surgery, venting gastrostomy, or endoscopic gastrostomy in advanced cancer
medical management. Ann Surg 2018;267 patients with small-bowel obstruction is
(4):692–699. feasible and effective: a large prospective
3. Hoppenot C, et al. Malignant bowel study. Support Care Cancer
obstruction due to ovarian or uterine cancer: 2016;24:2877–2882.

Debate
What is the Optimal
24A Chemotherapy Regimen

for Ovarian Germ-cell Tumors?
Bleomycin, Etoposide, and
Cisplatinum (BEP)
Michael J. Seckl
Debate
Germ cell tumors predominantly arise in the gonads of children and young adults and are
important to recognize as they are exquisitely sensitive to chemotherapy and highly curable.
The behavior of the disease is likely different in pre-pubertal compared to post-pubertal
cases. Malignant ovarian germ cell tumors (MOGCTs) are very rare, with an incidence
between 1 in 250,000–500,000 women, and so studies to identify prognostic factors and
optimal treatments have been hampered by small numbers of cases [1]. In contrast,
testicular germ cell tumors (TGCTs) affect about 1:250 men and are the commonest cancer
in this age group [1]. Consequently, most of the treatment discoveries have been
made in the male disease where there have been sufficient cases to undertake larger and
often randomized controlled trials [2]. Some historical perspective is helpful to understand
how we have arrived at our current treatment paradigms in men before considering the
female disease.
Prior to the discovery of cisplatin in the mid-1970s, most patients with advanced
gonadal germ cell tumors that had spread beyond the affected primary site could not be
saved. Indeed, although a number of agents had some activity including the vinca alkaloids,
methotrexate, and bleomycin, the best hope for cure was in early stage (stage 1) surgically
resected disease. However, matters dramatically changed when Einhorn and Donohue
developed a regimen comprising bleomycin, etoposide, and cisplatin (BEP) which was
less toxic than their prior regimen of cisplatin, vinblastine, and bleomycin (PVB).
Subsequently, five-day BEP (etoposide 100 mg/m2 and cisplatin 20 mg/m2 days 1–5 with
bleomycin 30,000 IU days 1, 8, and 15 repeated every three weeks) has proven in multiple
randomized trials to be superior or at least not worse than more toxic alternative regimens
[2]. Much work has since focused on how to reduce toxicities which can be life-threatening
through, for example, the elimination of bleomycin or replacement of cisplatin with
carboplatin in seminomas (the male equivalent of dysgerminomas in women). This is
because bleomycin can cause pulmonary fibrosis and cisplatin (but much less so carbopla-
tin) can trigger severe nephrotoxicity, peripheral neuropathy, hearing impairment, small
vessel damage linked to high blood pressure, cardiac and cerebrovascular events. Helpfully,
in seminomas, randomized data have shown that omission of bleomycin from BEP does not
impair survival outcomes. Attention then switched to substituting cisplatin with carboplatin
and currently investigators are considering whether platinum and etoposide could be
139

140 Michael J. Seckl
replaced altogether with AUC 10 carboplatin alone. However, no randomized data exist in
patients with seminoma to prove this to be equivalent to either BEP or platinum etoposide
combinations [2].
For nonseminomatous TGCTs which are slightly less chemo-sensitive than seminomas,
there is recognition that four cycles of BEP is not sufficient to cure all poor risk cases defined
using The International Germ Cell Cancer Collaboration Group (IGCCCG) classification
system. Whilst several alternative approaches have been proposed including CBOP-BEP,
TIP, T-BEP, and high-dose chemotherapy, no randomized trial data exist that conclusively
indicate these therapies are superior to four cycles of BEP [2]. Fortunately, TGCT relapsing
after BEP chemotherapy can in 50–60% of cases be successfully salvaged with further
intensive chemotherapy and/or surgery [2].
In MOGCTs, nonrandomized small phase II studies demonstrated that BEP is clearly
active for both dysgerminomatous and nondysgerminomatous disease [1,3]. Arguments
still continue regarding the need for adjuvant BEP in stage IA/B or some IC MOGCTs [1,3].
However, a key question for the present debate is whether we can mirror what was learnt in
TGCTs by, for example, eliminating bleomycin for dysgerminomas or identifying poor risk
MOGCTs needing more intensified therapies? In considering these issues it is essential to
determine whether MOGCTs truly behave in a clinically and biologically identical fashion
to testicular disease. An indication that this might not be the case came from reports
showing that MOGCT relapsing after initial chemotherapy had dramatically lower salvage
rates of around 30% [4] unlike the 50–60% seen in the testicular equivalent [2]. Moreover,
data are emerging on how the distinct hormonal environment and genetic imprinting might
influence the molecular pathogenesis and behavior of female versus male germ cell tumors
[1,5]. At the very least, the clinical data suggest that in MOGCTs it is essential to optimize
initial chemotherapy to maximize chances of long-term cure. Thus, attempts to reduce BEP-
induced treatment toxicity by, for example, omitting bleomycin or switching cisplatin to
carboplatin needs to be done with extreme caution. Indeed, there is a strong argument that
treatment should be intensified in those women with advanced MOGCT who are more
likely to relapse. So, can these individuals be identified? Efforts have been made to adapt the
male IGCCCG system but currently, because of small MOGCT case numbers and inad-
equate power, there is no consensus apart from possibly stage IV disease where five-year
survival may be between 60–75% [1]. However, this is not sufficient to enable accurate
discrimination of patients for more intensified therapies.
Conclusion
In the future, our understanding of MOGCTs may be improved through centralization of
care so that larger numbers of cases can be collected and managed in a uniform manner and/
or be available for clinical trials. Currently though, in the absence of data to indicate that any
other chemotherapy is superior to three to four cycles of BEP, most investigators will
continue to recognize this as the standard of care for virtually all women with MOGCTs
of stage Ic or more.
References
1. Veneris JT, et al. Contemporary and remaining controversies. Gynecol Oncol
management of ovarian germ cell tumors 2020;158:467–475.

Optimal Chemotherapy Regimen? BEP 141
2. Alsdorf W, et al. Current 4. Reddy Ammakkanavar N, et al. High-

pharmacotherapy for testicular germ cell dose chemotherapy for recurrent ovarian
cancer. Expert Opin Pharmacother germ cell tumors. J Clin Oncol
2019;20:837–850. 2015;33:226–227.
3. Gershenson DM, et al. Management of rare 5. Oosterhuis JW, et al. Human germ cell
ovarian cancer histologies. J Clin Oncol tumours from a developmental perspective.
2019;37:2406–2415. Nat Rev Cancer 2019;19:522–537.

Debate
What is the Optimal
24B Chemotherapy Regimen

for Ovarian Germ-cell Tumors?
Other
Michael L. Friedlander
Debate
The notion that bleomycin, etoposide, and cisplatin (BEP) is the optimal chemotherapy
regimen for all ovarian germ cell tumors (OGCTs) is flawed as there are a number of equally
effective and potentially less toxic treatment regimens. The reductionist approach to
prescribe BEP to all patients with OGCTs is based on strong opinion rather than strong
evidence supported by well-designed randomized controlled trials in OGCTs. Indeed, there
are no randomized trials to guide the choice of chemotherapy regimens in women with
OGCTs and treatment guidelines have been extrapolated from clinical trials of males with
germ cell tumors [1]. OGCTs are rare in adults, but more commonly diagnosed in young
children and adolescents. OGCTs are highly curable and the focus over recent years has
been on minimizing toxicity of treatment and in particular the delayed effects. In this
regard, the pediatric trial groups are way ahead of gynecological/medical oncologists
managing adult patients with OGCTs [2]. However, before discussing a risk-stratified
approach to treatment of patients with OGCTs it is worthwhile to briefly review the
landmark randomized trials in testicular germ cell tumors as well as the few phase 2 trials
in OGCTs that have provided the evidence used to support treatment recommendations.
The major breakthrough in the management of germ cell tumors was the introduction of
cisplatin in the 1970s and the highly effective, albeit toxic regimen of PVB (cisplatin, vinblastine,
and bleomycin) reported by Einhorn and Donohue which was a transformational moment in
oncology [1]. PVB was soon supplanted by BEP after Williams et al. reported equivalent
efficacy, but with less toxicity than PVB in males with testicular cancer in 1987, and it became
the standard of care [1]. It was also highly effective in OGCTs, with cures reported in over 95%
of patients with stage 1 OGCTs and 75–80% of patients with stage 3 or 4 disease [2,3]. The
success of BEP was widely heralded for good reason and it was rapidly integrated into practice.
The acute toxicities were soon appreciated, but it took longer to learn of the late effects of BEP
which now assume high importance given that the majority of patients with OGCTs are likely
cured. The long-term side effects include secondary malignancies, cardiovascular disease,
hypertension, Raynaud’s phenomenon, pulmonary toxicity, nephrotoxicity, neurotoxicity,
deafness, decreased fertility, and psychosocial problems amongst others [1–5].
In view of the early as well as late adverse effects, there have been attempts to avoid
immediate treatment of patients with stage 1 OGCTs and rather than offer adjuvant BEP to
all patients, which is all too common, an alternative strategy is close surveillance and
treatment only for relapse [4].This does not impact on overall survival and has been
142

Optimal Chemotherapy Regimen? Other 143
standard of care for stage 1 testicular germ cell tumors for many years, as well as for
pediatric and young adolescent patients with OGCTs. There has been much effort in de-
escalating treatment, particularly in patients with advanced stage dysgerminomas. The
Gynecologic Oncology Group (GOG) were prescient when they designed a phase 2 trial
(GOG-116) which investigated carboplatin 400 mg/m2 and etoposide 120 mg/m2 days 1–3
every four weeks in 39 patients with stages 1b–3 dysgerminoma [3,5].No patients relapsed
despite the very modest dose of carboplatin and three days of etoposide every four weeks for
three cycles only. Unfortunately, the trial, reported in 2004, was closed early after the results
of two trials in males with nonseminomatous testicular cancer reported inferior outcomes
with carboplatin compared to cisplatin. However, the doses of carboplatin were low, with an
AUC 5 in one trial and 500 mg/m2 in the other and they did not include seminomas.
Seminomas and dysgerminomas are very different to other germ cell tumors with very high
response to carboplatin. Shah et al. reported the results of pooled data from six trials in the
Malignant Germ Cell Tumor International Consortium (MaGIC) which included 126
patients with advanced stage (stages 1c–4) dysgerminomas who were treated with either
carboplatin- or cisplatin-based chemotherapy [4]. Survival outcomes were equivalent with
a 96% five-year survival in both groups. More recently, a study of single agent carboplatin at
an AUC of 10 every three weeks for three to four cycles was reported to be highly effective in
males with good prognosis metastatic seminomas with a three-year overall survival of 96%
and three-year progression-free survival of 93.2%. A somewhat different approach in de-
escalation of chemotherapy in seminomas was taken in the SEMITEP study, where the
investigators used FDG PET scans to risk-stratify patients with metastatic seminoma after
two cycles of treatment – 72% had a negative PET scan after two cycles of cisplatin and
etoposide and ceased treatment and the 28% of patients who still had a positive PET-CT
received an additional two cycles of EP. The three-year PFS in the de-escalated arm was 90%
and the three-year overall survival was 100%.
Conclusion
Although BEP is an option for patients with nondysgerminomatous germ cell tumors, it is not
the only option and again a risk stratification is important. The risk of recurrence as well as
risk of acute/late toxicities should be considered as they impact on the selection of chemo-
therapy regimen. Unfortunately, we still do not have an optimal risk classification for OGCTs
unlike the IGCCC classification used to stratify patients with testicular cancers [4]. We need
more than FIGO stage to make rational decisions regarding treatment regimens, particularly
for patients with nondysgerminomas, rather than prescribe BEP for all regardless of risk.
Treatment options include four cycles of etoposide and cisplatin instead of BEP x 3, in patients
who are likely to have a good prognosis which is equivalent to BEP in males with good risk
metastatic nonseminomatous germ cell tumors and avoids the toxicity of bleomycin [1]. An
equally effective alternative is to substitute ifosfamide for bleomycin and to use three cycles
only. While over 90% of males with good risk metastatic disease are cured, the outcomes are
not as good for patients who fall into the intermediate or high-risk groups and who are treated
with BEP, and more effective regimens are being investigated [1].Although relatively few
patients with OGCTs fall into this category, their treatment should be discussed with a team
experienced with the management of high-risk germ cell tumors as they may be suitable for
clinical trials [4]. In conclusion, optimal management of patients with OGCTs requires a lot
more thought than simply prescribing BEP to all.

144 Michael L. Friedlander
References
1. Hanna N, et al. Testicular cancer: and late effects of treatment. Gynecol Oncol
a reflection on 50 years of discovery. J Clin 2016; 143(2):428–432.
Oncol 2014;32(28):3085–3092 4. Ray-Coquard I, et al. ESMO Guidelines
2. Newton C, et al. A multicentre retrospective Committee. Non-epithelial ovarian cancer:
cohort study of ovarian germ cell tumours: ESMO Clinical Practice Guidelines for
evidence for chemotherapy de-escalation diagnosis, treatment and follow-up. Ann
and alignment of paediatric and adult Oncol 2018;29(Suppl. 4):iv1–iv18
practice. Eur J Cancer 2019;113:19–27. 5. Veneris JT, et al. Contemporary
3. Gershenson DM, et al. Conundrums in the management of ovarian germ cell tumors
management of malignant ovarian germ cell and remaining controversies. Gynecol Oncol
tumors: toward lessening acute morbidity 2020;158(2):467–475.

Debate
What is the Optimal Adjuvant

for Primary Granulosa Cell
Tumor?
Bleomycin, Etoposide, and
Cisplatinum (BEP)
Olivia Le Saux, Hélène Vanacker, and Isabelle Ray-
Coquard
Debate
Adult granulosa cell tumors (AGCTs) are the most common type (85%) of granulosa cell
tumors (GCTs) accounting for about 2–5% of ovarian neoplasms. AGCTs are found mainly in
peri- and post-menopausal women, whereas juvenile granulosa cell tumors, which have
different tumor biology, usually develop in adolescents and young females. The majority of
GCT patients are diagnosed at an early stage and the disease is typically indolent. Surgical
management is the cornerstone of both initial and recurrent disease treatment for AGCTs. The
FIGO stage and age are the most often reported risk factors for recurrence. Consequently, for
patients with stage IC and higher disease, some clinical guidelines recommend adjuvant
chemotherapy, although the approach to such patients is controversial, and observation is
also an acceptable strategy for completely resected and well-staged disease [1]. Indeed,
although adjuvant chemotherapy has been associated with longer progression-free survival
(PFS) among those with advanced GCT, there is no evidence supporting an overall survival
(OS) benefit. As the benefit of postoperative treatment is unclear, practice is variable.
When chemotherapy is proposed, the most widely used platinum-based chemotherapy
is the combination of bleomycin, platinum, and etoposide (BEP) due to the high response
rate, reported by Gershenson et al. in 1996, of 83%, compared to 66% with platinum,
vinblastine, and bleomycin (PVB), the historical regimen [2].
The positive arguments in favor are:
• Bleomycin and etoposide are efficient drugs. The benefit of bleomycin was highlighted
in the study by Zambetti et al., which implemented PVB as a historical regimen of GCT
[3]. In this study, PVB reported higher response rates (66%) compared to other platinum
combination regimens without bleomycin (cisplatinum plus doxorubicin, or plus
hexamethylmelamine, or plus doxorubicin and cyclophosphamide). Moreover, BEP
showed superiority compared to EP in testicular germ cell tumors. The benefit of
etoposide was emphasized by Gershenson et al. who reported a higher response rate with
BEP versus PVB (83% vs. 66%). The added value of etoposide compared to vinblastine
was confirmed in an earlier study published in the New England Journal of Medicine by
145

146 Olivia Le Saux et al.
Williams et al. in 1987 in patients with testicular germ cell tumors which demonstrated
reduced toxicity and equivalent efficacy.
• To date, no trial has documented that carboplatin is equivalent to cisplatin in activity
in GCT [4]. In the retrospective series reported by Brown et al., taxanes were
administered with a platinum agent, either carboplatin or cisplatin, and no comparison
between the two agents was reported.
• BEP is the regimen associated with the strongest level of evidence (phase II study for
BEP vs. retrospective study for platinum + paclitaxel, the most commonly used
alternative). The GOG 115 trial was a single-arm phase II study to assess the efficacy and
toxicity of the combination of BEP for incompletely resected stages II–IV or recurrent
ovarian stromal malignancies [5]. Thirty-seven percent (14/38) of the patients
undergoing second look laparotomy had negative findings (primary endpoint). The six
complete responders were of long median duration (> 24 months). Myelotoxicity was
tolerable. Based on the results of this trial, surgery followed by BEP has become the
standard treatment option for patients with advanced ovarian GCT.
• Comparison between BEP and taxanes platinum-based regimens did not totally
conclude in favor of carboplatine + paclitaxel. An indirect comparison via a retrospective
review of all patients with sex cord stromal ovarian tumors seen at the M.D. Anderson
from 1985 to 2002 demonstrated activity of both regimens. In this study, focusing on
newly diagnosed disease, 11 patients received BEP (8/11 had residual disease after surgery)
and eleven patients received a taxane +/- platinum agent (2/11 had residual disease). The
authors reported a better (not statistically significant) ORR for BEP compared to taxanes
+/- platinum agents for patients with measurable recurrent disease (ORR=71% vs. 37%
respectively, p=0.677) [4]. There was also a trend towards increased median PFS for BEP
versus taxanes +/- platinum agents for patients with recurrent disease (11.2 months vs. 7.2
months, p=0.312). These results should be considered even more attentively as the
comparability of the two populations is to be confirmed (more residual disease, juvenile
histology, and more advanced FIGO stage in the BEP regimen group). More recently, the
randomized trial led by the Gynecologic Oncology Group and started in 2010 evaluating
BEP versus paclitaxel plus carboplatin (PC) in this population of patients failed to
demonstrate a benefit in favor of the PC regimen. This trial (NCT01042522) was closed
early for futility of PC (Brown et al., IGCS, 2020). Median age was 48 years, 87% had GCT,
the futility analysis was supported by 21 and 16 PFS events on the PC and BEP arms
respectively, with an estimated HR=1.12 [95% CI: 0.58–2.16] in favor of BEP. PC patients
had fewer grade ≥3 adverse events (PC 77% vs. BEP 90%). Differences included infections
(0 vs. 10%), and low neutrophil count (65% vs. 84%). One death not otherwise specified
occurred on PC regimen.
• In terms of feasibility, short duration of therapy of three cycles for BEP versus
six cycles for CP should be considered when comparing the two regimens as it
can be more convenient for patients.
• Trials analyzing BEP in GCT revealed significant bleomycin-related toxicity, including
deaths from bleomycin-related pulmonary fibrosis. Etoposide can also result in the
subsequent development of secondary malignancies. Nevertheless, none of the trials
reported on quality of life, and toxicity and adverse-event data were incompletely
reported, limiting the interpretation.

Table 25A.1 BEP regimen’s activity in this patient population
Study N of GCT Study Population ORR % PFS (mo) Overall survival

patients design median (95% CI) (mo) median
(95% CI)
Gershenson 6 Prospective IA, IIC, IIIC, or 83.3 14 (NA) 28 (NA)

(1996) [2] recurrent
GOG-115 (1999) [5] 48 Phase II Stage II, III, IV 40 66 (13, NR) NR (47, NR)
Brown (2005) [4] 20 Retrospective Newly diagnosed 71 46 (NA) 97 (NA)
Pautier (2008) [6] 20 Prospective Advanced ovarian 90 25 (NA) 46 (NA)
granulosa cell
tumors: initial
metastatic (n=5) or

recurrent (n=15)
Ray-Coquard 44 Prospective Newly diagnosed 84 in first line 65 (60–68) NR
(2010) [7] and first relapse 50 at first relapse
GOG-264 (2020) [8] 55 Randomized Newly diagnosed, NA 19.7 (10.4–52.7) NA
phase II stage IIA–IVB, ≤8
weeks after surgery
Abbreviations: NA = not available; NE = not reached.
148 Olivia Le Saux et al.
Conclusion
To conclude, for younger, fit patients, and more specifically juvenile histology, we typically
recommend using BEP as there is no reliable evidence for the superiority of PC, while we
prefer PC for patients >50 years old, due to toxicity concerns.
References
1. ESMO. Non-epithelial ovarian cancer: ovarian granulosa cell tumors and other
ESMO Clinical Practice Guidelines for stromal malignancies: a gynecologic
diagnosis, treatment and follow-up. Ann oncology group study. Gynecol Oncol
Oncol 2018;29:iv1–iv18. 1999;72:131–137.
2. Gershenson DM, et al. Treatment of 6. Pautier P, et al. Combination of bleomycin,
poor-prognosis sex cord-stromal tumors of etoposide, and cisplatin for the treatment of
the ovary with the combination of advanced ovarian granulosa cell tumors.
bleomycin, etoposide, and cisplatin. Obstet Int J Gynecol Cancer Off J Int Gynecol Cancer
Gynecol 1996;87:527–531. Soc 2008;18:446–452.
3. Zambetti M, et al. cis-platinum/vinblastine/ 7. Ray-Coquard I, et al. Management of rare
bleomycin combination chemotherapy in ovarian cancers: the experience of the
advanced or recurrent granulosa cell tumors French website «Observatory for rare
of the ovary. Gynecol Oncol 1990;36 malignant tumours of the ovaries» by the
(3):317–320. GINECO group: Interim analysis of the first
4. Brown J, et al. The activity of taxanes 100 patients. Gynecol Oncol 2010;119:53–59.
compared with bleomycin, etoposide, and 8. Brown J, et al. 125 Results of a randomized
cisplatin in the treatment of sex phase II trial of paclitaxel and carboplatin
cord-stromal ovarian tumors. Gynecol Oncol versus bleomycin, etoposide and cisplatin
2005;97:489–496. for newly diagnosed and recurrent
5. Homesley HD, et al. Bleomycin, etoposide, chemonaive stromal ovarian tumors.
and cisplatin combination therapy of Int J Gynecol Cancer 2020;30:A56.

Debate
What is the Optimal Adjuvant

for Primary Granulosa Cell
Tumor?
Carboplatin/Paclitaxel
Dib Sassine and Chrissy Liu
Debate
Patients with early-stage granulosa cell tumors (IA or IB) may be treated with surgical
therapy alone and expect an excellent prognosis. Patients with stage IC or greater disease,
recurrent granulosa cell tumors, and sub-optimally reduced disease may benefit from
adjuvant chemotherapy [1]. The type of adjuvant chemotherapy has been controversial
and varies based on clinical guidelines. The National Comprehensive Cancer Network
(NCCN) guidelines recommend platinum-based chemotherapy and endorses paclitaxel
and carboplatin (PC), etoposide and cisplatin, or bleomycin, etoposide, cisplatin (BEP)
[2]. In this debate the authors support the use of paclitaxel plus carboplatin based on (1) BEP
lacks durable activity, (2) PC demonstrates favorable outcomes in a retrospective analysis,
(3) PC has a better safety profile compared to BEP, (4) the dosing regimen for PC is more
convenient, and (5) there is insufficient data comparing PC to BEP.
Granulosa cell tumors (GCTs) represent up to 90% of malignant sex-cord stromal
tumors of the ovary. Usually, they are unilateral, large, and are prone to rupture that can
cause hemoperitoneum in about 10% of cases. They are divided into adult and juvenile type,
with the adult type being predominant [3]. While complete gross resection is the corner-
stone treatment of most GCT, adjuvant chemotherapy is suggested by certain specialists in
advanced cases (stage IC and above) as well as in the recurrent setting.
Bleomycin, Etoposide, and Cisplatin Has Not Demonstrated Durable

Remission in Patients
In 1999, the Gynecologic Oncology Group (GOG) investigated BEP in patients with
incompletely resected stage II–IV or recurrent sex cord stromal tumor (SCSTs), and
found that 37% (14/38) of patients who underwent second-look laparotomy had negative
findings [4]. Six complete responders had a 24.4 month median duration of response (DoR)
[4]. However, only one of seven patients with advanced disease experienced a durable
remission [4]. Despite being a single arm, small study, and requiring a dose reduction of
bleomycin due to two fatalities, the authors concluded that the modified BEP regimen is
tolerable and active, which led to the commonly used treatment option for patients with
advanced ovarian SCST. Gershenson and colleagues noted similar limitations in durable
149

150 Dib Sassine and Chrissy Liu
remission in a prior publication, where only one of seven patients with metastatic disease
experienced a durable remission (14%) [5].
While the most common chemotherapy regimen is BEP, carboplatin and paclitaxel have
shown to be effective. Brown et al. conducted a retrospective review of patients at MD
Anderson Cancer Center: in the primary adjuvant setting, 89% of patients with GCT were
disease free at completion of the treatment and almost 80% had durable remission, with
a median PFS not reached at 51 months. In the setting of measurable recurrent disease, the
response rate was 42% with a median follow-up of 100 months [6]. This study suggested that
a platinum and taxane combination is active in GCT [6].
Paclitaxel and Carboplatin Has a More Favorable Side-effect Profile

than Bleomycin, Etoposide, and Cisplatin
Brown and colleagues showed that patients on PC had fewer grade 3 or higher adverse events
than BEP (77% vs. 90%) [7]. Specifically, PC is associated with lower rates of infection (0% vs.
10%), neutropenia (65% vs. 84%), and leukopenia (22% vs. 40%) when compared to BEP [7].
In the trials conducted by Gershenson et al. and Homesley et al., two patients developed
pulmonary toxicity and two patients died as a result of bleomycin-related pulmonary fibrosis,
respectively [4,5]. Etoposide has been linked to the development of subsequent secondary
malignancies [6]. Although modifying doses and monitoring hematologic and pulmonary
function can lower the morbidity associated with BEP, there is still potential for serious
adverse effects. We think such toxicities should not be considered acceptable in this relatively
young population, especially in the setting of nondurable remission with BEP. On the other
hand, toxic effects in patients treated with PC for newly diagnosed or recurrent disease
included febrile neutropenia, anemia, thrombocytopenia, and hypersensitivity, which are
“largely acceptable” and treatable adverse events [6].
The dosing schedule for PC is more convenient. Paclitaxel 175 mg/m2 and carboplatin
AUC=6 IV are given once every three weeks for a total of six cycles. The BEP regimen
requires multiple infusions five days a week: bleomycin 20 units/m2 IV push on day 1,
etoposide 75 mg/m2 IV on days 1–5, and cisplatin 20 mg/m2 IV on days 1–5 every three
weeks for a total of three or four cycles. The burden from daily infusions, travel to the
infusion center, and treatment-related toxicity can negatively impact a patient’s quality of
life.
Conclusion
To date, there has been no successful head-to-head comparison between PC and BEP.
Brown and colleagues initiated a noninferiority trial evaluating BEP versus PC in newly
diagnosed advanced or recurrent chemotherapy-naïve SCST. This study was discontinued
at the interim futility analysis, as PC failed to improve PFS [7].
Because adult type GCTs are typically indolent and recur late, follow-up periods are
long, and analyzing overall survival of any adjuvant therapy is difficult in the setting of
GCT. Although there is a paucity of data, good response rates have been reported in
paclitaxel and carboplatin. One ongoing clinical trial is evaluating the use of PC versus
BEP in SCST surgery (NCT02429700) and is still recruiting, with PFS being the primary
outcome. Hopefully this study will potentiate the evidence for the use of PC in patients
with GCT.

Optimal Chemo Regimen? Carboplatin/Paclitaxel 151
References
1. DiSaia PJ, et al. Clinical Gynecologic 5. Gershenson DM, et al. Treatment of
Oncology (9th edn.). London: Elsevier, 2018. poor-prognosis sex cord-stromal tumors of
the ovary with the combination of
2. Network NCC. NCCN Guidelines bleomycin, etoposide, and cisplatin. Obstet
Version 1.2022 Ovarian Cancer. Gynecol 1996;87(4):527–531.
Published 2022.
6. Brown J, et al. The activity of taxanes
3. Young RH. Ovarian sex cord-stromal in the treatment of sex cord-stromal
tumours and their mimics. Pathology ovarian tumors. J Clin Oncol 2004;22
2018;50(1):5–15. (17):3517–3523.
4. Homesley HD, et al. Bleomycin, etoposide, 7. Brown JMA, et al. 125 Results of
and cisplatin combination therapy of a randomized phase II trial of paclitaxel and
ovarian granulosa cell tumors and other carboplatin versus bleomycin, etoposide and
stromal malignancies: a gynecologic cisplatin for newly diagnosed and recurrent
oncology group study. Gynecol Oncol chemonaive stromal ovarian tumors.
1999;72(2):131–137. Int J Gynecol Cancer 2020;30:A56.

Debate
26A Strategy for a Recurrent

Granulosa Cell Tumor?
Surgery
Alice Bergamini, Luca Bocciolone, and Gioriga
Mangili
Debate
Among patients diagnosed with stage I granulosa cell tumors (GCTs) of the ovary, 25% will
experience recurrent disease, after a median of four to six years from initial diagnosis [1].
GCTs are rare tumors and have a slow, indolent course, with recurrences registered even
after several decades from initial diagnosis [2].
Due to the rarity of this tumor type and the low number of events, data deriving from
randomized trials are lacking. For these reasons, strong evidence regarding the optimal
treatment of GCT recurrence is limited and mainly derives from small size retrospective
series.
The most recent NCCN clinical guidelines indicate either surgery, radiotherapy, hor-
monal therapy, or chemotherapy as possible options for the treatment of recurrent disease.
Conversely, ESMO Clinical Practice Guidelines consider surgery as the most effective
treatment for recurrent ovarian GCTs.
Several factors support surgery as the best therapeutic option for these patients, with
chemotherapy to be reserved in case of recurrent unresectable disease or when optimal
cytoreduction is not feasible.
Residual disease at primary surgery is known to be a prognostic factor for survival [3],
but also suboptimal cytoreduction at secondary debulking surgery is associated with
a decreased overall survival (OS). In a retrospective study of the MITO group, five-year
OS decreased from 87.4% in the case of no residual disease to 55.6% in the case of
suboptimal cytoreduction [4].
Hölscher et al. in 2009 made a comparison on the outcomes of GCT treatment before
and after 1988 and found a significant improvement in five-year and ten-years OS, from
55.8% to 89.1% and 42.8% to 85.2% respectively [5]. They concluded that these results could
be related to the continued advances made in the surgical field towards optimal tumor
resection with no residual disease.
Recurrences in GCTs are typically multifocal, similar to epithelial ovarian cancer. In
a retrospective study from Fotopolou et al., including 45 patients with relapsed GCT, 38.5%
had tumor on the pelvic side wall, 30.8% had bowel involvement, 5% showed tumor on the
liver, while 15.4% had tumor on the diaphragm, 15.4% on the abdominal wall, and 11.5% on
the omentum. Only 7.7% had mesenteric involvement [6]. Despite this pattern at relapse,
higher rates of optimal tumor cytoreduction have been reported when compared to
152

Management for Granulosa Cell Tumor? Surgery 153
epithelial ovarian cancer, as high as 85% [7,8]. Notably, most of the recurrences are
asymptomatic and incidentally diagnosed during follow-up [9]. These cases are therefore
generally associated with absence of large amounts of ascites, better performance status and
higher tolerance to complex surgical procedures compared to patients with epithelial
ovarian cancer.
Achieving optimal cytoreduction requires a complex multidisciplinary surgical
approach, often with extensive peritonectomy, bowel resections, splenectomy or liver
resections, and pancreatectomy [6]. Surgical complexity should be balanced in relation to
patient’s performance status.
Lymphadenectomy is not considered a standard procedure during primary surgery for
GCT, as lymph node metastases occur in only 4.5–5.5% of cases [6,7]. Abu Rustum et al.
reported that up to 15% of patients with first recurrence had positive retroperitoneal lymph
nodes [8]. Thus, status of the retroperitoneum should be assessed during second cytore-
ductive surgery, and bulky nodes should be removed.
The slow growth and indolent course of GCT supports surgery compared to chemo-
therapy for the treatment of recurrent disease that is considered poorly chemoresponsive.
From available retrospective data, chemotherapy administered after optimal secondary
surgery for recurrence does not seem to improve survival [4], but evidence is still
controversial.
In the retrospective experience deriving from MITO-9, 33% of patients with recurrent
GCT who had received surgery only as salvage treatment versus 37.5% of those treated with
surgery plus chemotherapy developed a second recurrence.
A recent retrospective study by Zhao et al. evaluated the outcome of 40 patients with
recurrent GCT. Three were treated with surgery alone, 31 with surgery plus chemotherapy,
and six by chemotherapy alone. Multivariate analysis showed that the administration of
chemotherapy following surgery and residual tumor at second cytoreductive surgery are the
only independent risk factors for PFS [10].
Conclusion
From the abovementioned evidence, we can conclude that surgery should be the primary
approach for patients with recurrent GCTs, with the aim of achieving optimal cytoreduc-
tion. Chemotherapy should be reserved in cases with suboptimal cytoreduction or unre-
sectable disease.
References
1. Thrall MM et al. Patterns of spread and 4. Mangili G, et al.Recurrent granulosa cell
recurrence of sex cord-stromal tumors of the tumors (GCTs) of the ovary: a MITO-9
ovary. Gynecol Oncol 2001;122:242–245. retrospective study. Gynecol Oncol 2013;130
2. Hines JF, et al. Recurrent granulosa cell (1):38–42.
tumor of the ovary 37 years after initial 5. Hölscher G, et al. Improvement of survival
diagnosis: a case report and review of the in sex cord stromal tumors – an
literature. Gynecol Oncol 1996;60 observational study with more than 25 years
(3):484–488. follow-up. Acta Obstet Gynecol Scand
3. Sun HD, et al. A long-term follow-up study 2009;88:440e8.
of 176 cases with adult type ovarian 6. Fotopolou C, et al. Adult granulosa cell
granulosa cell tumors. Gynecol Oncol tumors of the ovary: tumor dissemination
2012;124(2):244–249. pattern at primary and recurrent situation,

154 Alice Bergamini et al.
surgical outcome. Gynecol Oncol 9. Wang PH, et al. Outcome of patients

2010;119:285–290. with recurrent adult-type granulosa
7. Lee YK, et al. Characteristics of recurrence cell tumors – a Taiwanese Gynecologic
in adult-type granulosa cell tumos. Oncology Group study. Taiwan J Obstet
Int J Gynecol Cancer 2008;18:642–647. Gynecol 2015;54(3):253–259.
8. Abu-Rustum NR, et al. Retroperitoneal 10. Zhao D, et al. Characteristics and

nodal metastasis in primary and recurrent treatment results of recurrence in
granulosa cell tumors of the ovary. Gynecol adult-type granulosa cell tumor of ovary.
Oncol 2006;103:31. J Ovarian Res 2020;13(1):19.

Debate
26B Strategy for Recurrent

Granulosa Cell Tumor?
Chemotherapy
Amanika Kumar and Simrit Warring
Debate
When considering the best management of recurrent granulosa cell tumors (rGCTs),
surgery is certainly an essential part of treatment for patients due to the indolent nature
of this disease. However, given the long survivals and multiple recurrences many patients
will experience, chemotherapy is an important component of overall treatment. Systemic
therapy can increase the interval of time between surgeries, thereby potentially improving
overall survival (OS) and treatment-related morbidity and mortality.
Despite the rarity of disease and limited available data, there are several studies to
suggest efficacious chemotherapy regimens in rGCTs. The recommended first-line chemo-
therapy regimen has changed from VAC (vincristine, Adriamycin, and cyclophosphamide)
to BEP (bleomycin, etoposide, and cisplatin) and more recently to carboplatin and pacli-
taxel; hormonal agents have also been used effectively in rGCTs and immunotherapeutic
targets are of interest for future clinical trials.
Multiple small cohort studies have shown the efficacy of BEP in GCTs. In 1996,
Gershenson et al. studied BEP in nine patients with sex cord stromal tumors (SCSTs).
The studies showed a median progression-free survival (PFS) of 14 months and OS of
28 months [1], with 83% of patients demonstrating some response. Then Gynecologic
Oncology Group (GOG) 115 was reported in which 51.2% (n=41) patients with recurrent
disease and receiving BEP had a median PFS of 66 months [2]. Other follow-up cohort
studies show similar efficacy with median PFS of 25–66 months and OS of 28–97 months
[1–4], suggesting BEP to be an active chemotherapy regimen for advanced primary and
recurrent SCSTs (Table 26B.1).
More recently, taxane and platinum therapies have shown activity in GCTs with less
toxicity than BEP therapy. In the GOG187 phase II trial, 31 patients with recurrent SCSTs
received single-agent paclitaxel resulting in a 3.2% complete response and 25.8% partial
response with a median PFS of 10 months and OS of 73.6 months [5]. Ray-Coquard et al.
completed the first randomized control trial of SCSTs and found that 71% of patients were
progression-free at 6 months after treatment with weekly single-agent paclitaxel treatment
further validating taxane therapy as an option for treatment for SCSTs [6]. Brown et al.
compared BEP to taxane-based chemotherapies and showed that taxanes, alone or in
combination with platinum, are not inferior to BEP treatment in 30 patients with recurrent
measurable disease with median PFS of 7 months, median OS of 49 months, 7% complete
response, 30% partial response, 20% stable disease, and 40% progressed disease [3]. This
155

156 Amanika Kumar and Simrit Warring
Table 26B.1 Systemic treatment

of granulosa cell tumors
Therapy
BEP [1–4]
Taxane +/− platinum [3,5]
Bevacizumab [7]
Hormonal treatment [8]
suggests that taxane-based therapy is an effective and a less toxic approach for treatment of
SCSTs. GOG264 is an ongoing multi-institutional cooperative trial that randomizes newly
diagnosed patients with advanced stage SCSTs and chemo-naive patients with recurrent
SCSTs to either carboplatin/paclitaxel or BEP treatment.
Bevacizumab has also shown efficacy in GCT treatment. In a GOG phase II trial, 36
women with recurrent SCST (88.9% GCT) were given bevacizumab treatment with a 16.7%
partial response, 77.8% stable disease, 5.6% progressive disease, and median PFS of
9.3 months [7]. A more recent study compared the addition of bevacizumab to single-
agent paclitaxel and demonstrated no additional benefit in the rate of PFS at 6 months (72%
vs. 71%) [6].
Given these tumors express steroid hormone receptors, equally relevant with regards to
nonsurgical systemic treatment is the use of hormone therapy (HT), such as steroidal
progestins, selective estrogen receptor modulators, gonadotropin-releasing hormone agon-
ists, and aromatase inhibitors. In 31 patients who had all previously been treated with surgery,
a systematic review assessed the effectiveness of HT in GCT, which included letrozole,
tamoxifen, anastrozole, megestrol acetate, ganirelix, goserelin, medroxyprogesterone acetate,
and diethylstilbestrol. The findings revealed there was a 25.8% complete response, 45.2%
partial response, median PFS of 18 months (range 0–60 months), 12.9% with stable disease,
and 16.1% with progressive disease [8]. Additional hormonal therapies and agents targeted to
the estrogen pathway are an area of future research, including ribociclib, palbociclin, and
fulvestrant. Immunohistochemistry has been utilized to investigate potential biomarkers to
inform clinical trials in GCT. In 2019, Mills et al. argued against a significant role for
immunotherapy in the absence of additional stimulation to make targets further immuno-
genic, though they did suggest that many GCTs were potential candidates for anti-androgen
therapy [9]. There is currently an open label phase II clinical trial utilizing enzalutamide for
metastatic or advanced nonresectable GCT underway. In 2020, Pierini et al. published
findings on Forkhead Box L2 (FOXL2), a protein expressed by GCTs, showing promise as
an immunologic therapeutic target [10]. A combination anti-PD-L1 with FoxL2-TT vaccine
reduced tumor progression and improved survival in animal studies, suggesting potential
long-term benefits and serving as a foundation for immunotherapy clinical trials.
Conclusion
While chemotherapy has not shown strong OS benefit, the extension of PFS is meaningful
and can lead to longer intervals between surgery and perhaps an overall decrease in the total
number of surgeries a patient has in their lifetime. The intraoperative and postoperative

Management for Granulosa Cell Tumor? Chemotherapy 157
risks associated with multiple surgeries for recurrent GCTs are not insignificant and must
be considered when choosing best management for recurrences. There is ongoing research
to better understand the various systemic treatment approaches for GCTs including che-
motherapeutic agents, bevacizumab, HT, and immunotherapy. Overall, a multimodal
approach is essential for the effective treatment of recurrent GCTs with systemic chemo-
therapy being an important part of the treatment paradigm for this tumor.
References
1. Gershenson DM, et al. Treatment of 6. Ray-Coquard I, et al. Effect of weekly
poor-prognosis sex cord-stromal tumors of paclitaxel with or without bevacizumab
the ovary with the combination of on progression-free rate among
bleomycin, etoposide, and cisplatin. Obstet patients with relapsed ovarian sex
Gynecol 1996;87(4):527–531. cord-stromal tumors: the ALIENOR/
2. Homesley HD, et al. Bleomycin, etoposide, ENGOT-ov7 randomized clinical
and cisplatin combination therapy of trial. JAMA Oncol 2020;
ovarian granulosa cell tumors and other 6(12):1923–1930.
stromal malignancies: a Gynecologic 7. Brown J, et al. Efficacy and safety of
Oncology Group study. Gynecol Oncol bevacizumab in recurrent sex
1999;72(2):131–137. cord-stromal ovarian tumors: results of
3. Brown J, et al. The activity of taxanes a phase 2 trial of the Gynecologic
compared with bleomycin, etoposide, and Oncology Group. Cancer 2014;120
cisplatin in the treatment of sex (3):344–351.
cord-stromal ovarian tumors. Gynecol 8. van Meurs HS, et al. Hormone therapy in
Oncol 2005;97(2):489–496. ovarian granulosa cell tumors: a systematic
4. Pautier P, et al. Combination of bleomycin, review. Gynecol Oncol 2014;134
etoposide, and cisplatin for the treatment (1):196–205.
of advanced ovarian granulosa cell tumors. 9. Mills AM, et al. Emerging biomarkers in
Int J Gynecol Cancer 2008;18(3):446–452. ovarian granulosa cell tumors. Int J Gynecol
5. Burton ER, et al. A phase II study of Cancer 2019;29(3):560–565.
paclitaxel for the treatment of ovarian 10. Pierini S, et al. Ovarian granulosa cell
stromal tumors: an NRG Oncology/ tumor characterization identifies FOXL2 as
Gynecologic Oncology Group study. an immunotherapeutic target. JCI Insight
Gynecol Oncol 2016;140(1):48–52. 2020;5(16):e136773.

Debate
Is progression-free survival a
27A rational surrogate endpoint

in front-line ovarian cancer
clinical trials?
Yes
Daniel Margul and Thomas J. Herzog
Debate
Progression-free survival (PFS) is not only a rational surrogate in front-line ovarian cancer,
but is actually the preferred endpoint for the following reasons.
Front-line Ovarian Cancer Trials that Use Overall Survival as the Primary
Endpoint Are Problematic Because of the Very Long Survival After
Secondary Treatment for the First Recurrence/Progression
The number of approved agents for ovarian cancer has escalated rapidly, leading to
numerous active options for post-progression therapy, thereby diluting the relationship
between PFS and overall survival (OS). The result is that contemporary management of
ovarian cancer produces a relatively long post-progression survival (PPS). The disease
course includes undulating tumor burdens with multiple lines of interventions and therap-
ies leading to an OS to PFS ratio ranging from 2.5–4.1.
Primary and Secondary Cross-over Treatments

Primary cross-over is when a patient in the control arm receives the experimental agent in
a later line after coming off a trial for progression or toxicity. Novel treatments tested in
a specific trial may lead to a substantial increase in PFS, but due to crossover in subsequent
lines of therapy, no OS advantage is seen in the specific trial as the control group ends up
benefiting from the experimental agent in later lines of treatment. This effect was observed
in GOG 47 (doxorubicin/cyclophosphamide ± cisplatin) as patients randomized to doxo-
rubicin/cyclophosphamide frequently received cisplatin upon progression, confounding the
OS endpoint. Similarly, in GOG 132 (paclitaxel, cisplatin, or the combination of both
agents) cisplatin along or in combination yielded superior PFS; however, OS was similar
in all arms since the majority of patients in the single agent groups immediately received the
other agent after completion of the protocol or prior to progression. Secondary cross-over
occurs when a patient receives other active agents in later lines of treatment which may or
may not have been given to patients in the experimental arm of a specific trial. This
intervention also obscures the ability to demonstrate an OS effect.
158

PFS as a Rational Endpoint? Yes 159
Numbers Required for Enrollment Make Overall Survival Trials

Impractical
Due to the aforementioned long PPS time, powering studies to detect a treatment effect for
OS requires far greater sample sizes than for PFS. For example, if a novel treatment
improves PFS from six to nine months, a typical study with 80% power would require 280
patients. If PPS is not affected, the same study at 80% power would require 2440 patients to
preserve a statistically significant OS effect.
A Rapidly Evolving Clinical Landscape in the Era of Molecular Genomics

Makes Prolonged Overall Survival Trials Clinically Irrelevant
Drug development in recent years has rapidly evolved with the elucidation of molecular
and/or genetic etiologies of many cancers. Rapid discovery of actionable mutations is
outpacing our capacity to contemporaneously evaluate these targets. Time from study
conception to OS readout in front-line ovarian cancer often exceeds eight-plus years,
thereby making trial conclusions clinically irrelevant as the discovery is so dated relative
to the rapidly evolving standard of care if OS is the primary endpoint.
Progression-free Survival is a Valid Surrogate for Overall Survival when

Assessed Properly
Overall survival is clearly objective, but the subjectivity of PFS can be minimized. To
mitigate bias, clinical trials using PFS should blind the study treatments with placebo use
and/or incorporation of blinded independent central review. Assessment time bias should
be abrogated via assuring imaging and assessment visits are symmetrical in all study arms.
With these measures, most criticisms of PFS as an effective primary endpoint lose
credibility.
Recent approvals in front-line ovarian cancer by the United States Food and Drug Administration
Frontline Platinum Platinum Clear Cell,

Sensitive Resistant Mucinous,
LG-serous
OS Approve Approve Approve Approve

PFS (statistically significant) + Approve Approve Consider Consider
other (QoL/PRO)
PFS (statistically significant) Consider Consider Consider Consider
with clinically meaningful MOE
Objective Response Rate (with No No Consider Consider
supportive duration of
response)
Abbreviations: MOE = magnitude of effect, median difference between the experimental arm(s) relative to the
control.

160 Daniel Margul and Thomas J. Herzog
Regulatory Preference for Progression-free Survival

Virtually all recent approvals in front-line ovarian cancer by the US FDA have utilized PFS as
the primary end-point. The agency has embraced PFS, and it has codified this position in
workshop proceedings that describe the FDA position by line of therapy, as seen in Table 27A.1.
Notably, the FDA does require data to assure no diminution in OS when using PFS.
References
1. Herzog TJ, et al. Ovarian cancer clinical trial 3. Herzog TJ, et al. SGO guidance document
endpoints: Society of Gynecologic Oncology for clinical trial designs in ovarian cancer:
White Paper. Gynecol Oncol 2014;132 a changing paradigm. Gynecol Oncol
(1):8–17. 2014;135:3–7.
2. Broglio KR, et al. Detecting an overall 4. Herzog TJ, et al. FDA ovarian cancer clinical
survival benefit that is derived from trial endpoints workshop: Society of
progression-free survival. JNCI J Natl Gynecologic Oncology White Paper.
Cancer Inst 2009;101(23):1642–1649. Gynecol Oncol. 2017;147(1):3–10.

Debate
Is progression-free survival a
27B rational surrogate endpoint

in front-line ovarian cancer
clinical trials?
No
Eric Pujade-Lauraine, Benoit You, and Jean
Sebastien Frenel
Debate
As specified by the fifth Ovarian Cancer Consensus Conference (OCCC) consensus state-
ments [1], the endpoints in clinical trials need to demonstrate whether the treatment results in
clinical benefit. The authors will discuss here whether progression-free survival (PFS) is
a surrogate marker for patient clinical benefit in front-line ovarian cancer (OC) clinical trials.
Is the Progression-free Survival Criterion as Currently Assessed Clinically

Relevant?
The answer is clearly No. Clinical trials define PFS as the time interval between the date of
randomization (or first dose of protocol treatment) and disease progression (or death) accord-
ing to the latest version of the RECIST definition. RECIST disease progression is assessed
radiologically. The biomarker CA125 is only used to make the difference between complete and
partial remission depending on whether CA125 level falls within normal range or not.
Though radiographs have the merit to be potentially checked by several different
independent radiologists, it appears that the standard follow-up of ovarian cancer patients
in routine practice does not include systematic radiological examinations in most countries.
During surveillance after chemotherapy doctors indicate radiological examination mainly
based on patient symptoms or CA125 level evolution.
The appearance of symptoms at relapse is the critical signal for indicating a new
treatment. The main reason for waiting for the appearance of symptoms despite evidence
of disease progression on CA125 levels or radiologic examinations is that the objective of
treatment at relapse becomes palliative as the cure rate of patients with recurrent disease is
very low. And even worse, treating the patient on the basis of earlier signals such as a CA125
level increase may be deleterious for the quality of life of patients, exposing them to an
increased number of chemotherapy lines without prolonging their overall survival [2].
Based on the acknowledgement that RECIST progression may have no clinical impact
on treatment decision, most recent trials including maintenance treatment allow the patient
to pursue the treatment identically despite the observation of a RECIST radiologically
proven disease progression.
161

162 Eric Pujade-Lauraine, Benoit You, and Jean Sebastien Frenel
To sum-up, the current PFS criterion is an artificial construction which is not based on
routine practice patient follow-up nor on a clinically meaningful endpoint.
Is Progression-free Survival a Clinically Relevant Survival Landmark

for Patients Treated in Front-line?
The answer is clearly No.
The main objective of new experimental OC treatments in front-line is to increase
patient cure rate [1]. We have to recognize that overall survival (OS) superiority is difficult
to demonstrate due to long post-progression survival and cross-over. In addition, OS is an
endpoint which is more and more remote in advanced OC with the progress of first-line
therapy. The recent result disclosure of the AGO-Ovar 17 trial which has the merit of
a seven-year follow-up shows a median OS between 54 and 60 months of advanced stage
patients treated with chemotherapy plus bevacizumab and this before the introduction of
PARP inhibitors in first-line management [3].
Thus, the search for an OS surrogate marker appears justified. Does PFS fulfill the
requirements for an OS surrogate marker? The recent GCIG meta-analysis from 11,029
patients included in randomized first-line trials concluded that the correlation between PFS
and OS at the trial level was low, acknowledging the meta-analysis included very few
positive trials in terms of survival gain, which limits the conclusions that we can draw
from the outcomes [4]. In other words, demonstrating a reduction of PFS hazard ratio (HR)
in advanced ovarian cancer does not guarantee that a reduction in OS HR or an increase in
“cure rate” will be observed.
The recognition that PFS is such a poor surrogate marker of OS and a mediocre
indicator of first-line treatment clinical benefit has led to the addition of several other
criteria of efficacy in OC trials [1]. The authors will not outline here all the weaknesses of
PFS2; time to first subsequent treatment (TFST) and time to second subsequent treatment
(TSST), but thus far these metrics have added little to the interpretation of trial efficacy and
they have not yet proven their ability to compensate for the shortcomings of PFS in reliably
predicting clinical benefit.
Interestingly, some other surrogate markers have been proposed for patients in the neo-
adjuvant setting. Lecuru et al. have suggested that the ultimate goal for these patients could
be to combine RECIST response to chemotherapy at three cycles and complete resection at
interval surgery. These two criteria have a loose correlation between them and their
combination appears to be correlated to PFS and OS [5].
Is Prolonging the Time to Next Relapse (Progression-free Survival)

a Clinically Sound Objective?
This is doubtful. The main reason leading to the belief that prolonging the time without
relapse is beneficial for patients is based on the concept that rechallenging the patient with
chemotherapy is the worst thing that can happen for them. While there is plenty of evidence
that relapse is a particularly painful event, there are few prospective data evaluating the
quality of life (QoL) change when the patient resumes chemotherapy at relapse. The
question is particularly relevant when the patient is relapsing under a maintenance therapy
which has its own toxicity and thus may itself induce some QoL deterioration which could
be potentially worse or equal to that of chemotherapy.

PFS as a Rational Endpoint? No 163
To circumvent the inability of PFS superiority alone to adequately demonstrate clinical

patient benefit, the fifth OCCC requires that PFS should be supported by additional end-
points such as relevant patient-reported outcomes (PROs) [1]. The issue is that “relevant
PROs” tools correlated to patient well-being still need to be validated in OC. Recently,
a simple assessment called “TWIST,” time without symptoms or toxicity, has shown
clinically meaningful promise as a PRO tool [6]. However, there is not yet a consensus on
which symptoms and toxicity should be taken into account in the model and whether the
symptoms described by the doctor (CTCAE v5.0) or by the patient (specific OC QoL
questionnaires) should be assessed.
Conclusion
In conclusion, PFS is a second-best option as surrogate endpoint in front-line ovarian
cancer clinical trials. PFS is a criterion which is not clinically relevant, PFS is not correlated
with OS, and prolongation of PFS does not in itself mean a superior clinical benefit for the
patient. To try to palliate its numerous weaknesses in evaluating efficacy in OC, PFS is
currently surrounded by several additional criteria such as PFS2, TFST, TSST and assess-
ment of PROs. There is one exception to this grim picture of the lack of utility for PFS: when
the magnitude of PFS prolongation is clearly superior to the risks, such as with PARP
inhibitors in OC with homologous recombination deficiency [7].
References
1. Bookman MA, et al. Fifth Ovarian Cancer cancer: a systematic review and
Consensus Conference. Harmonising meta-analysis. JAMA Netw Open 2020;3(1):
clinical trials within the Gynecologic Cancer e1918939.
InterGroup: consensus and unmet needs 5. Lecuru F, et al. Surrogate endpoint of
from the Fifth Ovarian Cancer Consensus progression-free (PFS) and overall
Conference. Ann Oncol 2017;28(Suppl. 8): survival (OS) for advanced ovarian cancer
viii30–viii35. (AOC) patients (pts) treated with
2. Rustin GJ, et al. MRC OV05; EORTC 55955 neo-adjuvant chemotherapy (NACT):
investigators. Early versus delayed treatment Results of the CHIVA randomized phase
of relapsed ovarian cancer (MRC OV05/ II GINECO study. Ann Oncol 2019;30
EORTC 55955): a randomised trial. Lancet (Suppl. 5):3251.
2010;376(9747):1155–1163. 6. Friedlander M, et al.Health-related quality
3. Pfisterer J, et al. Optimal duration of of life and patient-centred outcomes with
bevacizumab combined with carboplatin olaparib maintenance after chemotherapy in
and paclitaxel in patients with primary patients with platinum-sensitive, relapsed
epithelial ovarian, fallopian tube or ovarian cancer and a BRCA1/2 mutation
peritoneal cancer. J Clin Oncol 2021;39 (SOLO2/ENGOT Ov-21): a
(15):5501. placebo-controlled, phase 3 randomised
4. Paoletti X, et al.Gynecologic Cancer trial. Lancet Oncol 2018;19(8):1126–1134.
InterGroup (GCIG) Meta-analysis 7. Moore K, et al. Maintenance olaparib in
Committee. Assessment of progression-free patients with newly diagnosed advanced
survival as a surrogate end point of overall ovarian cancer. N Engl J Med 2018;379
survival in first-line treatment of ovarian (26):2495–2505.

Section IV Endometrial Cancer
Debate
Fertility-sparing Surgery
28A in Early-stage Endometrial

Cancer is Safe and Does
not Compromise Oncological
Outcome
Yes
Enes Taylan and Kutluk Oktay
Debate
Endometrial cancer is the most common gynecologic malignancy in the United States, and the
standard-of-care for its treatment is total hysterectomy with bilateral salpingo-oophorectomy
(TH-BSO). Although the majority of patients are typically diagnosed after menopause, up to
6.5% of cases are seen in reproductive-age women at 45 years old or younger who may wish to
preserve their fertility. Moreover, the share of young women is expected to grow with the
increasing incidence of obesity, metabolic syndrome, and nulliparity due to delayed child-
birth, all of which are significant risk factors for endometrial cancer.
As a result, preserving fertility for a future chance of childbearing is increasingly
becoming an essential component of care in women with endometrial cancer. Therefore,
it is critical to provide timely fertility preservation counseling to reproductive-age women
with early-stage endometrial cancer who have not yet completed childbearing [1,2].
Conservative Fertility Preserving Surgery

Endometrial cancer tends to have more favorable outcomes in young women than in older
patients due to preponderance of well-differentiated (grade 1, endometrioid) endometrioid
subtype tumors with limited myometrial invasion. These tumoral lesions are typically
related to unopposed estrogen exposure of endometrium, and up to 55% will complete
regress with systemic or localized progestin therapy. Several recent studies have shown that
hysteroscopic resection of the localized endometrial tumor followed by levonorgestrel-
releasing intrauterine device (LR-IUD) placement or systemic progestin therapy is another
effective fertility-preserving strategy providing up to 88.9% complete response rate [1].
However, it should be noted that these treatment options should be considered in patients
with stage 1A disease, and only after an accurate pathological diagnosis of endometrioid
subtype is established. In addition, the risk of recurrence (5%) and potential future hyster-
ectomy should be kept in mind.
Another fertility-sparing surgical approach for women with early-stage endometrial
cancer is the preservation of ovaries at the time of hysterectomy. Recent studies have
165

Section IV Endometrial Cancer
Debate
Fertility-sparing Surgery
28A in Early-stage Endometrial

not Compromise Oncological
Outcome
Yes
Enes Taylan and Kutluk Oktay
Debate
Endometrial cancer is the most common gynecologic malignancy in the United States, and the
standard-of-care for its treatment is total hysterectomy with bilateral salpingo-oophorectomy
(TH-BSO). Although the majority of patients are typically diagnosed after menopause, up to
6.5% of cases are seen in reproductive-age women at 45 years old or younger who may wish to
preserve their fertility. Moreover, the share of young women is expected to grow with the
increasing incidence of obesity, metabolic syndrome, and nulliparity due to delayed child-
birth, all of which are significant risk factors for endometrial cancer.
As a result, preserving fertility for a future chance of childbearing is increasingly
becoming an essential component of care in women with endometrial cancer. Therefore,
it is critical to provide timely fertility preservation counseling to reproductive-age women
with early-stage endometrial cancer who have not yet completed childbearing [1,2].
Conservative Fertility Preserving Surgery

Endometrial cancer tends to have more favorable outcomes in young women than in older
patients due to preponderance of well-differentiated (grade 1, endometrioid) endometrioid
subtype tumors with limited myometrial invasion. These tumoral lesions are typically
related to unopposed estrogen exposure of endometrium, and up to 55% will complete
regress with systemic or localized progestin therapy. Several recent studies have shown that
hysteroscopic resection of the localized endometrial tumor followed by levonorgestrel-
releasing intrauterine device (LR-IUD) placement or systemic progestin therapy is another
effective fertility-preserving strategy providing up to 88.9% complete response rate [1].
However, it should be noted that these treatment options should be considered in patients
with stage 1A disease, and only after an accurate pathological diagnosis of endometrioid
subtype is established. In addition, the risk of recurrence (5%) and potential future hyster-
ectomy should be kept in mind.
Another fertility-sparing surgical approach for women with early-stage endometrial
cancer is the preservation of ovaries at the time of hysterectomy. Recent studies have
165

166 Enes Taylan and Kutluk Oktay
shown that preserving ovaries prevented menopause-associated morbidity and did not
increase the risk of endometrial cancer recurrence [1]. These patients can then attempt
having a child using in vitro fertilization (IVF) followed by embryo transfer to a gestational
surrogate.
Aromatase Inhibitor Protocols to Stimulate Ovaries for Oocyte

and Embryo Freezing
Over the past few decades, remarkable advances have been achieved in developing efficient
and safer controlled ovarian hyperstimulation (COH) protocols for oocyte retrieval to
cryopreserve oocytes or embryos in women with estrogen-sensitive cancer [2,3]. A major
concern with COH in women with endometrial cancer is that elevated systemic estrogen
levels can potentially worsen the prognosis. To overcome this, we developed an aromatase-
inhibitor protocol where letrozole is combined with reduced doses of gonadotropin stimu-
lation in assisted reproduction cycles. This protocol has been widely studied by the same
team in women with breast cancer and it has been shown to provide success rates that equal
or exceed the success rates with conventional protocols, without reducing the relapse-free
survival. Using the same novel protocol in a small case series, we generated embryos in
endometrial cancer patients who have had hysterectomy with ovarian preservation, and the
transfer of these embryos to gestational surrogates resulted in live births without comprom-
ising oncological treatment [4].
In women who may need TH-BSO, but there is insufficient time to wait for next menses
to start ovarian stimulation, we developed a “random start COH protocol” where the
letrozole-FSH protocol can be started at any time during the menstrual cycle. This strategy
provides successful retrieval of an adequate number of oocytes in less than two weeks
without causing any significant delay in the cancer treatment [5]. Later studies showed that
embryo quality is similar regardless when the ovarian stimulation is started during the
ovarian cycle.
Ovarian Tissue Cryopreservation and Transplantation

For women with endometrial cancer without evidence of ovarian involvement and who do
not have sufficient time for ovarian stimulation to cryopreserve oocytes or embryos, ovarian
tissue cryopreservation (OTC) and subsequent autotransplantation can be offered as an
alternative fertility-preserving surgery option. Quiescent primordial follicles, which are
embedded in the ovarian cortex and constitute the ovarian reserve, can be efficiently
cryopreserved without a need for ovarian stimulation or any regard to the day of menstrual
cycle. Having developed and performed the first successful procedures in 1999, our team
recently showed that auto-transplantation of frozen-thawed ovarian cortical tissues via
orthotopic or heterotopic approaches could efficiently establish ovarian function in patients
with various malignancies, including endometrial cancer, resulting in successful retrieval of
oocytes, generation of embryos, and live births [1,3].
Conclusions
The foregoing indicates that there are numerous fertility preservation options that can
preserve reproductive potential in young women with early-stage endometrial cancer. The
current literature on conservative surgery for early-stage cancer provides a good safety

Fertility-sparing Surgery is Safe: Yes 167
profile, however, larger studies with longer follow-up durations are still needed to establish
the safety of these strategies in oncological care. While the results obtained during the past
two decades with cancer patients indicate that oocyte and embryo freezing with aromatase
inhibitor protocols and ovarian tissue cryopreservation followed by auto-transplantation
are safe, specific data for endometrial cancer patients is limited. While all patients should be
counseled about the availability and success of fertility preservation approaches, the limita-
tions of the available data should also be disclosed to them. Judging from the progress
within the past two decades however, the potential for fertility preservation success looks
promising for women with endometrial cancer.
References
1. Taylan E, et al. Fertility preservation in 4. Azim A et al. Letrozole for
gynecologic cancers. Gynecol Oncol ovulation induction and fertility
2019;155:522–529. preservation by embryo
2. Oktay K, et al. Fertility preservation in patients cryopreservation in young women
with cancer: ASCO clinical practice guideline with endometrial carcinoma. Fertil
update. J Clin Oncol 2018;36:1994–2001. Steril 2007;88:657–664.
3. Oktay K, et al. Robot-assisted orthotopic 5. Sonmezer M, et al. Random-start

and heterotopic ovarian tissue controlled ovarian hyperstimulation for
transplantation techniques: surgical emergency fertility preservation in
advances since our first success in 2000. letrozole cycles. Fertil Steril 2011;95:2125.
Fertil Steril 2019;111:604–606. e9–2125.e11.

Debate
Fertility-sparing Treatment
28B for Early-stage Endometrial

Not Compromise Oncological
Outcome
No
Jessica E. Parker and David S. Miller
Debate
While the average age of patients diagnosed with endometrial cancer is 62 years old, around
4% of women are diagnosed under the age of 40. The gold standard treatment of endomet-
rial cancer is total hysterectomy, bilateral salpingo-oophorectomy, and retroperitoneal
lymph node assessment. This is, in many cases, curative but can be life-altering in women
desiring fertility. Fertility-sparing options include progestin treatment with oral agents such
as megestrol acetate, medroxyprogesterone, or a levonorgestrel-releasing intrauterine
device. The National Comprehensive Cancer Network (NCCN) supports these options in
well selected patients without any evidence of myometrial invasion who strongly desire
fertility [1]. However, this is not based on randomized or prospective trials but rather
retrospective data.
In one comprehensive review, a durable complete response to continuous progestin
therapy was seen in only 50% of patients [2]. However, the rate of recurrence even after
a complete response is relatively high at 35–40%. Most studies on response to progestin
treatment include endometrial intraepithelial neoplasia/complex atypical hyperplasia (EIN/
CAH) in their analysis as well, which is known to have a higher response rate and lower
recurrence rate than endometrial cancer, even with the 40% risk of underlying endometrial
cancer with an EIN/CAH preoperative diagnosis [1,2]. The impact of fertility-sparing treat-
ment on actual survival in endometrial cancer is not well reported. In the most recent study
and one of the largest published on this topic to date, younger age (<40 years) was associated
with a worse progression-free survival (PFS) (HR=3.96, p<0.001) on multivariate analysis.
This difference was no longer significant when patients who underwent fertility-sparing
therapy were excluded from the analysis (HR=1.17, p=0.71), suggesting that the difference
in PFS is directly attributed to fertility-sparing treatment. While overall survival was not
impacted by age, the importance of time without progression of disease, and therefore off
cancer treatment, has significant quality of life implications that should not be ignored [3].
The risks of continuous progestin therapy including venous thromboembolism, weight gain,
headaches, sleep disorders, and mood and libido changes should also be carefully weighed
when considering the medical implications as well as the quality of life of the patient.
168

Fertility-sparing Surgery is Safe: No 169
If gynecologic oncologists are to pursue fertility-sparing treatment for our patients

despite these risks and patients understand and accept them, we must consider the benefit
that may be ascertained by forgoing standard of care surgery. Studies evaluating outcomes
after progestin treatment for endometrial cancer or even EIN/CAH have revealed poor
pregnancy outcomes, with pregnancy rates of only 35% and live birth rates of 28% after
treatment. One recent study evaluated the addition of metformin to progestins in the
fertility-sparing treatment of endometrial intraepithelial neoplasia and cancer. The live
birth rate reported in this study was only 17%, and 81% of patients achieving live birth
required the use of assisted reproductive technology. It is important to note that the live
birth rate was even lower than the 22% risk of endometrial cancer recurrence. This was
despite a complete response rate of 69% and an overall response rate of 79% [4]. Another
study found an even lower rate of conception of 5% [3]. Therefore, pregnancy outcomes in
this population are low.
Outside of continuous progestin therapy, another option for fertility-sparing manage-
ment of endometrial cancer is hysterectomy with ovarian preservation. The NCCN suggests
that ovarian preservation for premenopausal women with stage 1A or 1B endometrial
cancer may be safe as it did not appear to increase cancer-specific mortality in one study
with follow-up of 16 years [1]. However, this presents a potentially fatal risk of missing
ovarian metastases or even synchronous ovarian primary cancer. One study of 102 patients
under the age of 45 years undergoing hysterectomy for presumed early-stage endometrial
cancer showed that 25% of these patients had a coexisting ovarian malignancy on final
pathology. Of these patients, 58% had inner myometrial invasion and 69% had well-
differentiated endometrial cancer. This suggests that the apparent low risk endometrial
cancer does not preclude coexisting ovarian cancer diagnosis [5]. In another study, the rate
of synchronous ovarian cancer was significantly higher in patients under the age of 40
compared with those between 41–60 years (9% vs. 1%, p<0.001). Similar to the prior study,
the majority of endometrial cancers with synchronous ovarian cancer had <50% myometrial
invasion (91%) and lacked lympho-vascular space invasion (82%). This presents a missed
opportunity for the patient and her family to treat this cancer as well as consider genetic
testing for familial syndromes associated with ovarian or endometrial cancer.
Conclusion
Based on the available evidence, one cannot definitively state that oncologic outcomes for
patients undergoing fertility-sparing treatment for endometrial cancer are the same as for
those patients undergoing standard of care surgical management. In fact, there appears to be
a lower PFS in these patients with a relatively low durable response rate and high recurrence rate.
Patients who decline the standard of care must be prepared to assume these risks with a small
likelihood of taking home a child. Therefore, patients should be counselled in a frank and honest
manner against fertility-sparing treatment in lieu of standard therapy in endometrial cancer.
References
1. National Comprehensive Cancer Network. 2. Gunderson CC, et al. Oncologic and
Uterine Neoplasms (Version 2.2020). reproductive outcomes with progestin therapy
Available from: www.nccn.org/profes in women with endometrial hyperplasia and
sionals/physician_gls/pdf/uterine.pdf [last grade 1 adenocarcinoma: a systematic review.
accessed September 19, 2020]. Gynecol Oncol 2012;125:477–482.

170 Jessica E. Parker and David S. Miller
3. Son J, et al. Endometrial cancer in young intraepithelial neoplasia or endometrial

women: prognostic factors and treatment cancer: little impact on response and low
outcomes in women aged <40 years. live-birth rates. Gynecol Oncol 2020;157
Int J Gynecol Cancer 2020;30:631–639. (2):348–356.
4. Acosta-Torres S, et al. The addition of 5. Walsh C, et al. Coexisting ovarian
metformin to progestin therapy in the malignancy in young women with
fertility-sparing treatment of women with endometrial cancer. Obstet Gynecol
atypical hyperplasia/endometrial 2005;106(4):693.

Debate
Sentinel Lymph Node
29A Mapping Should be the

Standard for Staging Patients
with High-grade Endometrial
Cancers
Yes
Patricia Rivera, Andrea Mariani, and Brooke A.
Schlappe
Debate
High-grade endometrial cancers consist of FIGO grade 3 endometroid, clear cell, and
papillary serous carcinomas and carcinosarcomas. These cancers are rare and given their
propensity to metastasize carry a poor prognosis. Lymph node (LN) metastasis has been
noted in up to 20–40% of patients with high-grade disease regardless of the depth of
myometrial invasion and as such LN evaluation is recommended for surgical staging
regardless of uterine factors. There is strong evidence that reveals LN evaluation via sentinel
lymph node (SLN) mapping versus complete lymphadenectomy (LND) to be non-inferior
in terms of detection of metastatic lymphatic disease and adverse outcomes. For this reason,
as well as the increased potential for injury to surrounding structures, lymphedema, and
lymphocyst formation with LND, SLN mapping should be the standard for staging patients
with high-grade endometrial cancers and is acceptable per the standard guidelines [1].
Opponents to SLN assessment cite two primary concerns which may theoretically lead to
worse oncologic outcomes with the use of this technique as compared to a full LND in high-
grade disease: (1) Limited ability to accurately detect metastatic disease, and (2) Loss of the
“therapeutic” removal of microscopic metastatic disease. The current available data do not
support these concerns.
Several studies support adequate detection of metastatic disease using a SLN algorithm.
In a prospective trial with evaluable high-risk disease, all patients underwent LN assessment
using a SLN algorithm followed by complete LND. Using the SLN algorithm, the detection
rate, sensitivity, false negative predictive value, and false negative rate were 89%, 95%, 1.4%,
and 5%, respectively [2]. In the largest prospective trial in endometrial cancer SLN assess-
ment, of which 28% of patients (n=101) had high-grade histologies, the sensitivity in
detection of metastatic disease and negative predictive value of the SLN algorithm was
97.5% and 99.6%, respectively [3]. These data confirm results from multiple retrospective
cohort studies and support the adequate detection of metastatic disease using the SLN
algorithm in patients with high-grade endometrial cancers.
171

172 Patricia Rivera et al.
A recent retrospective cohort study evaluating the use of a SLN algorithm versus LND in
serous and clear cell endometrial carcinoma demonstrated no difference in detection of
advanced stage disease with the SLN algorithm despite the removal of more LNs in those
who underwent a LND (median pelvic nodes removed 11 vs. 30 [p<0.001], median para-
aortic LNs removed 4 vs. 17 [p<0.001]) [4]. These data are consistent with the results of
other cohort studies comparing a SLN algorithm to LND in high-grade disease.
Several retrospective cohort studies demonstrate improved survival with increasing
number of LNs removed, supporting the theory that LND is therapeutic. These studies,
however, do not utilize a SLN algorithm which identifies metastatic disease with the removal
of fewer LNs. The improved survival in these studies likely comes from the improved
diagnosis of advanced stage disease, not the removal of microscopic nodal disease. This is
confirmed in several studies comparing oncologic outcomes in high-grade endometrial
cancer with the use of a SLN algorithm and a full LND. The previously mentioned
retrospective multicenter study compared outcomes of SLN mapping (n=118) with LND
(n=96) in patients with clear cell and serous endometrial carcinoma. There was no statistic-
ally significant difference in overall survival (OS) nor recurrence-free survival (RFS)
between the two cohorts [4]. Another multicenter study reviewed outcomes of SLN (n=
56) and LND (n=48) in patients with nonbulky stage IIIC endometrial cancer (46% were
high risk, defined as high-grade endometrioid with deep invasion or nonendometrioid)
there was no difference in OS between the SLN or LND cohorts [5]. Other single institution
retrospective studies confirm similar oncologic outcomes when a SLN algorithm is used in
high-grade endometrial cancer.
There does not appear to be an increased risk of nodal recurrences with the use of a SLN
algorithm. In the previously mentioned retrospective multicenter study, there was no clear
difference in the rates of nodal recurrence, though the numbers were too small for statistical
analysis. In a subset with negative LNs, the SLN cohort did have an increased risk of
progression (HR=3.12, 95% CI: 1.02, 9.57) but this was felt to be due to differences in
surveillance techniques between the cohorts [4]. Multinu et al. found no statistically
significant difference in the relative risks of any progression nor the risk of paraaortic
progression when SLN was compared to the LND, with paraaortic recurrences occurring in
4/48 of the LND cohort and 6/56 of the SLN cohort. There was no statistically significant
difference in lymphatic PFS in patients in the SLN cohort with 10 or fewer LNs removed
versus more than 10 LNs [5]. These data do not support the theory that LND is therapeutic.
Conclusion
Use of a SLN algorithm has proven to be non-inferior to LND in staging high-grade
endometrial cancer. With less morbidity and similar advanced stage detection rates, it
should be the standard for staging patients with high-grade endometrial cancer.
References
1. Holloway RW, et al. Sentinel lymph node 2. Soliman PT, et al. A prospective
mapping and staging in endometrial cancer: validation study of sentinel lymph
a society of gynecologic oncology literature node mapping for high-risk
review with consensus recommendations, endometrial cancer. Gynecol Oncol
Gynecol Oncol 2017;146:405–415. https://doi 2017;146:234–239. https://doi.org/10.1016/j
.org/10.1016/j.ygyno.2017.05.027 .ygyno.2017.05.016

Sentinel Lymph Node Mapping as Standard: Yes 173
3. Rossi EC, et al. A comparison of sentinel with serous and clear cell endometrial
lymph node biopsy to lymphadenectomy for carcinoma, Gynecol Oncol 2020;156:62–69.
endometrial cancer staging (FIRES trial): https://doi.org/10.1016/j
a multicentre, prospective cohort study, .ygyno.2019.11.002
Lancet Oncol 2017;18:384–392. https://doi 5. Multinu F, et al. Role of lymphadenectomy
.org/10.1016/S1470-2045(17)30068-2 in endometrial cancer with nonbulky lymph
4. Schlappe BA, et al. Multicenter study node metastasis: comparison of
comparing oncologic outcomes after lymph comprehensive surgical staging and sentinel
node assessment via a sentinel lymph node lymph node algorithm. Gynecol Oncol
algorithm versus comprehensive pelvic and 2019;155:177–185. https://doi.org/10.1016/j
paraaortic lymphadenectomy in patients .ygyno.2019.09.011

Debate
Sentinel Lymph Node
29B Mapping Should

be the Standard for Staging
Patients with High-grade
Endometrial Cancers
No
Camilla Yu, Payam Katebi Kashi, and Amanda N.
Fader
Debate
There is rationale for sentinel lymph node biopsy (SLNB) in endometrial cancer.
Randomized controlled trials (RCTs) have demonstrated that complete lymphadenectomy
in women with primary low-grade endometrial cancer (LGEC) who are at low risk for
metastatic disease increases perioperative morbidity without any clear influence on pro-
gression-free survival (PFS) or overall survival (OS). Unlike LGEC, those with high-grade
endometrial cancer (HGEC) are at increased risk for pelvic and para-aortic lymph node
metastases, with some studies citing up to 40% risk regardless of uterine factors. In order to
accurately tailor adjuvant treatments for women affected by HGEC, comprehensive pelvic
and para-aortic lymphadenectomy offers the most complete evaluation of the lymph node
basin and in a large, retrospective study, may also improve survival outcomes independent
of adjuvant therapy. Additionally, while limited prospective studies exist, there are currently
no RCTs studying oncologic outcomes of SLNB in women with HGEC.
The high rate of lymphatic dissemination in high-grade cancers as well as the lack of data
regarding long-term survival outcomes and therapeutic impact of SLNB versus complete
lymphadenectomy raise concerns for under-treatment of women with HGEC staged with
SLNB. Until these gaps are clarified, complete lymphadenectomy should remain the stand-
ard of care in the surgical staging of women with HGEC.
Background
Metastatic lymphatic disease is among the most important prognostic factors in endomet-
rial cancer. Historically, endometrial cancer has been staged via comprehensive pelvic and
aortic lymph node dissection. There are well defined risks to performing a comprehensive
lymphadenectomy, including a low risk of intraoperative vascular and nerve-related injuries
and a higher risk of lower extremity lymphedema. The use of SLNB in the staging of
apparent uterine-confined endometrial cancer has gained tremendous ground in the last
decade, with purported benefits such as a high sensitivity and low negative predictive value
174

Sentinel Lymph Node Mapping as Standard: No 175
in the hands of experienced surgeons, decreased surgical time and morbidity, as well as
a decreased risk of postoperative complications. However, many of the studies cited to
support SLNB in this setting focus on women with LGEC who have an overall very low risk
for nodal involvement and recurrence.
In contrast, HGEC, comprised of p53 aberrant tumors such as grade 3 endometrioid
subtypes, serous, papillary, and clear cell carcinomas as well as uterine carcinosarcoma,
carry an elevated risk for lymph node metastases (i.e., 20–40%), irrespective of uterine
factors, due to their biological aggressiveness. Compared to LGEC, those with HGEC often
require systemic adjuvant therapies and have a much worse prognosis. Additionally, among
those patients with non-endometrioid histologies who have lymphatic spread, 70% were
found to have para-aortic lymph node metastases [1]. Therefore, accurately identifying
patients with HGEC who have metastatic lymphatic disease is paramount, as it impacts
adjuvant therapy strategies and potential survival outcomes. The use of SNLB in the staging
of HGEC remains controversial.
Sentinel Lymph Node Studies in Endometrial Cancer Largely Focus

on Low-grade Endometrial Cancers
The vast majority of literature regarding SLNB in endometrial cancer is retrospective, and
demonstrates the feasibility and relative accuracy of SLNB in the setting of LGEC [2,3]. One of
the higher quality prospective studies, the multi-institutional FIRES trial, reported a 99.6%
(95% CI: 97.9–100) sensitivity and 97.2% (95% CI: 85–100%) negative predictive value (NPV)
in this technique. However, the study population was comprised primarily of women with
LGEC; only 28% of study subjects had HGEC, and therefore, the study was underpowered to
examine outcomes in this setting [4]. Since the publication of the FIRES trial, several other
studies have attempted to clarify the role of sentinel lymph node mapping HGEC. While the
sensitivities and mapping rates demonstrated in these studies are comparable to those found
in studies including both high- and low-grade endometrial cancers, most studies contain
small datasets with varying false negative rates, reaching as high as 22% as seen in one single
institution study [5]. These false negative rates may be further underestimated given the low
rate of para-aortic lymphadenectomies, and in particular those extending above the inferior
mesenteric artery, performed in studies validating SLNB protocols in women with HGEC.
The recently published SENTOR study, which included 156 patients, 80% of who had HGEC,
is the first prospective trial that is adequately powered to evaluate the accuracy of SNLB in
women with HGEC with sensitivity of 97.4% (95% CI: 93.6) and NPV of 99% (95% CI: 96–
100%) [6]. However, the SENTOR study was not adequately powered to evaluate long-term
survival outcomes, recurrence, and morbidity outcomes associated with SLNB alone. Given
the high propensity for lymphatic spread of HGEC, the use of SLNB in lieu of comprehensive
lymphadenectomy risks missing the presence of extra-uterine disease, potentially leading to
under-staging and under-treatment of disease.
Absence of Survival Data in Existing Sentinel Lymph Node Endometrial

Cancer Trials
In examining other solid tumor types, such as breast cancer and melanoma, SLNB has
become the standard of care after rigorous validation of techniques and outcomes data
through RCTs. A meta-analysis consisting of four RCTs in breast cancer patients

176 Camilla Yu et al.
demonstrated no long-term survival benefit to complete axillary node dissection compared

to SLNB [7]. Similarly, the MSLT-1 study, a phase III trial studying patients undergoing
wide local excision for melanoma, demonstrated improved disease-free survival outcomes
at 10 years for patients treated with SLNB compared to just wide local excision alone [8].
To date, there are no RCTs evaluating survival outcomes of women with HGEC staged
using SLNB alone compared to comprehensive lymphadenectomy (Table 29B.1) Although
two RCTs have demonstrated no therapeutic benefit of comprehensive pelvic and aortic
lymphadenectomy in women with endometrial cancer compared to hysterectomy alone,
these trials largely included low-risk, LGEC patients, and were not powered to examine PFS
and OS outcomes in women with HGEC. These two RCTs only examined the therapeutic
effect of pelvic lymphadenectomy and no para-aortic lymphadenectomies were performed
in either study. Furthermore, both RCTs utilized selective rather than systematic lympha-
denectomy. The ASTEC trial in particular was limited, with ≤9 lymph nodes removed in
35% of patients and ≤4 lymph nodes removed in 12% of patients in the lymphadenectomy
group. In both the ASTEC trial as well as the study by Benedetti-Panici et al., the rates of
adjuvant therapy in both study arms were similar, with almost equal numbers of patients
receiving adjuvant chemotherapy and/or radiation therapy, which further confound post-
operative and survival outcomes.
In contrast, the Japanese SEPAL study demonstrated a significantly longer overall
survival in a cohort of women with intermediate and high-risk endometrial cancer who
underwent systematic pelvic and aortic lymph node dissection compared to those undergo-
ing pelvic lymphadenectomy alone. On multivariate analysis, systematic lymphadenectomy
remained independently associated with improved survival even after controlling for adju-
vant chemotherapy. These data suggest that detecting positive lymph nodes may have led to
chemotherapy administration; chemotherapy alone may not be sufficient to treat para-
aortic disease [9,10].
Further evidence supporting a survival benefit of full lymphadenectomy is found in
a recent abstract presented at the Society for Gynecologic Oncology meeting in 2019.
Buskwofie et al. examined data from the National Cancer Database. This study identified
16,950 women diagnosed with type II uterine cancers between 2010–2015 and demon-
strated para-aortic lymph node metastases in 39% of patients who also had known positive
pelvic lymph nodes, and in 3% of patients without pelvic lymph node metastasis. This study
concluded that women treated with para-aortic lymphadenectomy were 12% less likely to
die from their disease (HR=0.88, 95% CI: 0.83–0.93) [11]. These data suggest that it is
essential to validate the use of SLN biopsy in women with HGEC through large RCTs before
considering a paradigm shift in the surgical staging of women with HGEC. Additionally,
randomized data is needed on perioperative outcomes associated with SLN biopsy com-
pared to comprehensive lymphadenectomy, especially pertaining to lymphedema.
A National Cancer Institute-NRG Oncology study is planned.
Conclusion
While the data supporting the use of SLNB in HGEC is preliminarily promising, the
question of clinical and survival benefit for patients remains. Ultimately, further investiga-
tion, ideally in a randomized trial setting, is required before universal adoption of SLNB as
a staging technique for women with HGEC. Until that time, if SLNB is to be employed, close
adherence to the NCCN SLN algorithm, which endorses complete lymphadenectomy for an

Table 29B.1 Summary of studies examining sentinel lymph nodes in endometrial cancer
Study Patients Tumor grade Histologic subtypes Statistical power to

designs with SLN examine oncologic
(Total) outcomes in HGEC?
LGEC╤ HGECπ Endometrioid Non-Endometrioid
n(%) n(%) EC n(%) EC n(%)
Prospective
studies
Cusimano et al. Prospective 156 30 (19) 126 (81) 65 (42) 91 (58) No

(SENTOR) 2020 [6] cohort
Soliman et al. Prospective 101 44 (44) 57 (56) 44 (44) 57 (56) No
Rossi et al. Prospective 293 254 (87) 39 (13) 252 (86) 41 (14) No
(FIRES) 2017 [4] cohort

Retrospective
studies
Tanner et al. Retrospective 52 0 52 (100) 14 (27) 38 (73) No
2017 [5]
Eriksson et al. Retrospective 642 450 (70) 192 (30) 642 (100) 0 (0) No
2016 [2]
RCT
No study None 0 0 0 0 0 None
Key: ╤ = low-grade endometrial cancer; π = high-grade endometrial cancer.
178 Camilla Yu et al.
unmapped hemi-pelvis as well as removal of abnormal-appearing lymph nodes, is critical in

order to minimize false negatives and potential poorer outcomes for women. If the recent
findings of the randomized surgical LACC trial in cervical cancer have proven anything, it is
that we should be cautious in our surgical approach to gynecologic cancer, not assume that
retrospective or underpowered prospective data is accurate, and look before we take
a surgical leap.
References
1. Mariani A, et al. Prospective assessment of 6. Cusimano MC, et al. Assessment of
lymphatic dissemination in endometrial sentinel lymph node biopsy vs
cancer: a paradigm shift in surgical staging. lymphadenectomy for intermediate- and
Gynecol Oncol 2008;109(1):11–18. high-grade endometrial cancer staging.
2. Eriksson AGZ, et al. Comparison of JAMA Surg 2021; 156(2):157–164.
a sentinel lymph node and a selective 7. Petrelli F, et al. Axillary dissection
lymphadenectomy algorithm in patients compared to sentinel node biopsy for the
with endometrioid endometrial carcinoma treatment of pathologically node-negative
and limited myometrial invasion. Gynecol breast cancer: a meta-analysis of four
Oncol 2016;140(3):394–399. randomized trials with long-term follow
3. Buda A, et al. Lymph node evaluation in up. Oncol Rev 2012;6(2):e20.
high-risk early-stage endometrial cancer: a 8. Morton DL, et al. Final trial report of
multi-institutional retrospective analysis sentinel-node biopsy versus nodal
comparing the sentinel lymph node (SLN) observation in melanoma. New Engl J Med
algorithm and SLN with selective 2014;370(7):599–609.
lymphadenectomy. Gynecol Oncol 9. Todo Y, et al. Survival effect of para-aortic
2018;150(2):261–266. lymphadenectomy in endometrial cancer
4. Rossi EC, et al. A comparison of sentinel (SEPAL study): a retrospective cohort
lymph node biopsy to lymphadenectomy analysis. Lancet 2010;375:1165–1172.
for endometrial cancer staging (FIRES 10. Frost JA, et al. Lymphadenectomy for the
trial): a multicentre, prospective, cohort management of endometrial cancer.
study. Lancet Oncol 2017;18(3):384–392. Cochrane Database Syst Rev 2015;2015(9):
5. Tanner EJ, et al. The utility of sentinel CD007585.
lymph node mapping in high-grade 11. Buskwofie A, et al. Role of paraaortic nodal
endometrial cancer. Int J Gynecol Cancer evaluation in women with uterine cancer.
2017;27(7):1416–1421. Gynecol Oncol 2019;154:105–106.

Debate
Molecular Profiling
30A Should be Done to Guide

the Management
of Endometrial Cancer?
Yes
Karen Cadoo
Debate
Molecular profiling is emerging as a critical tool for accurate stratification and treatment
planning in endometrial cancer (EC). Decision making and application of clinical trial
data has been challenged by the heterogenic biology and outcomes in ECs. We rely on
clinical variables to assess risk and determine optimal therapy, including patient age,
tumor stage and grade, and myometrial, lymphovascular, and cervical stromal invasion.
These variables provide imprecise estimates with the potential for both under and over
treatment of patients. Critically, intra observer variability affects classification and
therefore applicability of relevant data. It was shown, for example, that centralized
pathology review in the PORTEC-3 study changed clinico-pathological data in 43% of
patients [1].
With the integration of molecular data, we have the opportunity to be more precise
for our patients. We have learned from The Cancer Genome Atlas (TCGA) that ECs fall
into four distinct clusters or molecular subgroups [2]. Cluster one is defined by tumors
with a POLE ultramutated phenotype. These tumors often have a grade 3 and histolo-
gically aggressive appearance but in fact have a good prognosis. Accurate classification
and risk stratification of these tumors facilitates optimal management. We await further
data; however, it may be possible to de-escalate adjuvant therapy that would have been
prescribed based on clinical features in these cancers. In cluster two, tumors have
mismatch repair (MMR) deficiency /microsatellite instability (MSI) and are frequently
but not exclusively endometrioid cancers. Tumors are hypermutated, immunogenic,
and responsive to immunotherapy. This applies currently in the advanced disease
setting; ongoing clinical trials are exploring the role of immunotherapy in the adjuvant
setting. Cluster three ECs are genomically relatively stable and MMR proficient, with
a moderate number of mutations. This group does not have a surrogate marker for
identification and were classified by TCGA as copy number low. This is considered
a misleading term as they often harbour copy number alterations, leading to the
proposed terminology of “no specific molecular profile/ no surrogate marker profile.”
It is likely that further work will better define this subgroup in the future. Cluster three
tumors frequently have alterations in the PTEN/ PIK3CA pathway which have the
potential to be therapeutically targetable. Cluster four is characterized by extensive
179

180 Karen Cadoo
copy number alterations, few DNA methylation changes, and frequent TP53 mutations.
While these tumors are predominantly serous histologically, molecular data has shown
that 25% of high-grade endometrioid tumours share these characteristics, again high-
lighting that defining these tumors by their molecular profile is vital. Traditionally,
serous and clear cell EC have frequently been categorized together in clinical trials as
high grade, with the implication that prognosis and the impact of the intervention is
expected to be similar in both subtypes. However, clear cell cancers are distributed
across the four TCGA clusters, again with potential prognostic significance [3]. In fact,
all stages, grade, and histologic type of EC can be found across the TCGA subgroups.
We need to integrate this histomolecular data to accurately identify what the tumor
represents to avoid both under and over treatment in the adjuvant setting. While the
TCGA methodology is not practical for routine use, more pragmatic approaches have
been proposed using surrogate markers to identify molecular subgroups providing the
option to integrate into routine clinical care [4].
With integration of this more accurate tumor classification we will learn how to
better tailor therapy not just based on appropriate risk assessment but also predication of
how a given intervention may affect different subtypes. The ongoing PORTEC-4 study,
for example, is investigating the use of a molecular integrated risk profile to define
appropriate adjuvant therapy (NCT03469674). In addition, we have novel clinical trial
designs where eligibility for inclusion is molecularly rather than histology driven. This
also provides the opportunity to run clinical trials in rarer cancers and rare subtypes of
cancers, increasing the possibility for drug approvals and availability. Importantly,
molecularly driven studies have already led to drug approval on the basis of a genomic
biomarker with pembrolizumab being the first agnostic drug approval based on the
genomic biomarker of MMR deficient/MSI high tumor rather than a histology or disease
specific indication. For patients who have recurrent EC, molecular data and in particular,
next generation sequencing, may identify potential targets for therapy. In a study of
advanced EC patients undergoing next generation sequencing, 65% had a likely thera-
peutically actionable alteration. While patients who enrolled in a clinical trial and
benefitted from targeted therapy represented just 10% of patients in this study, the
proportion of EC patients who will benefit from this approach will become far higher
as routine sequencing is integrated into care and more molecularly driven clinical trials
become available.
Aside from the implications in terms of therapy planning in adjuvant and recurrent EC,
routine molecular profiling provides opportunities for our patients and their family mem-
bers for more accurate future cancer risk identification. Many women with EC are fortu-
nately cured of their disease. Identification of MMR deficient/MSI high EC acts as
a screening tool for Lynch syndrome. It is critical to identify women who have Lynch
syndrome, providing an important opportunity for reduction of future cancer risks in both
the patient and their family. It is also imperative to accurately classify the origin of MMR
deficiency. Previously women with MMR deficient EC, in the absence of MLH1 promoter
hypermethylation or an identified germline mutation to explain the immunohistochemical
loss, may have been considered to have occult Lynch syndrome. In these ECs with molecular
testing double somatic MMR mutations may be identified, providing reassurance in these
tumors that an occult germline mutation is unlikely. This avoids the emotional and financial
toll of intensive cancer screening for a high penetrance cancer predisposition mutation if it
is not required [5].

Molecular Profiling? Yes 181
Conclusion
Molecular profiling of all EC enables accurate stratification of risk and optimized therapy
planning and clinical trial enrollment. The identification of specific molecular subgroups
has changed the understanding of EC biology and it is continuing to evolve. Molecular
profiling is an essential tool for optimal patient care for all EC patients.
References
1. de Boer SM, et al; for PORTEC Study Group. 2017;243(2):230–241. https://doi.org/10
Clinical consequences of upfront pathology .1002/path.4947
review in the randomised PORTEC-3 trial 4. Stelloo E, et al. Improved risk assessment by
for high-risk endometrial cancer. Ann Oncol integrating molecular and
2018;29(2):424–430. https://doi.org/10.1093 clinicopathological factors in early-stage
/annonc/mdx753 endometrial cancer: combined analysis of
2. Cancer Genome Atlas Research Network, the PORTEC cohorts. Clin Cancer Res
Kandoth C, et al. Integrated genomic 2016;22(16):4215–4224. https://doi.org/10
characterization of endometrial carcinoma. .1158/1078-0432.CCR-15-2878
Nature 2013;497(7447):67–73. https://doi 5. Salvador MU, et al. Comprehensive paired
.org/10.1038/nature12113. Erratum in: tumor/germline testing for lynch syndrome:
Nature 2013;500(7461):242. bringing resolution to the diagnostic
3. DeLair DF, et al. The genetic landscape of process. J Clin Oncol 2019;37(8):647–657.
endometrial clear cell carcinomas. J Pathol https://doi.org/10.1200/JCO.18.00696

Debate
Molecular Profiling
30B Should be Done to Guide

the Management
of Endometrial Cancer?
No
Michael Wilkinson, Paul Downey, and Donal
J. Brennan
Debate
The treatment of endometrial carcinoma (EC) has been traditionally guided by microscopic
features, but the concept of molecular subtyping of endometrial cancer is nothing new. In
1983, Bokhman proposed that endometrial cancers be divided into two pathogenic groups:
type 1 endometrial tumors – low-grade, low-stage, good prognosis tumors classically
associated with PTEN mutations and activation of the PI3-kinase pathway (typically
endometrioid histology) – and type 2 endometrial tumors – high-grade, non-
endometrioid poorer prognosis tumors associated with p53 and Her2 mutations (classically
serous and clear cell histology) [1].
The more recent iteration of molecular profiling of endometrioid cancers (The Cancer
Genome Atlas (TCGA) and subsequently the ProMisE and TransPORTEC) is an evolving
piece of work (Figure 30B.1). Subtle differences have started to emerge between different
iterations of the molecular classification which appears to be reproducible, simple to apply,
and has clear prognostic implications. It has also recently been endorsed by the World
Health Organization who simultaneously removed other pathologic variants (e.g., secretory,
villoglandular, sertoliform, and microglandular from their classification of female genital
tumors) [2].
Advances in molecular classification of endometrial cancer certainly have the potential
to guide exciting developments in the twenty-first century, but whether the molecular
stratification of endometrial cancer ultimately reduces mortality from endometrial cancer
remains to be seen. Likewise, it is apparent that this is a dynamic area that may not yet
have reached a conclusion, for example where will L1CAM and CTNNB1 mutations fit
into this classification going forward? The pace of change in our evolving understanding
of molecular profiling is rapid, and incorporating routine molecular profiling into the
management of endometrial cancer may be premature at this point, particularly without
universal access to this technology. The focus at this point should be on appropriately
powered prospective randomized controlled trials (RCTs) designed to evaluate the utility
of these molecular stratifications, with a particular emphasis on their predictive rather
than their prognostic capacities. Currently the best data we have to support this approach
182

Molecular Profiling? No 183
ProMisE
Classification
(Four Groups)
Traditional 1. POLE
Pathology 2. MMR-D
(Two groups)
TCGA Classification 3. TP53 abnormal
(Four groups) 4. TP53 wildtype
1. Type I endometrial
cancer
(endometrioid) 1. POLE ultra-mutated
2. MSI Hypermutated TransPORTEC
2. Type II endometrial
cancer 3. Copy-number low Classification
(non-endometrioid) 4. Copy-number high (Four Groups)
1. POLE ultra-mutated
2. MSI Hypermutated
3. P53 mutated
4. No specific
molecular profile
Figure 30B.1 The molecular classifications of endometrial cancer.

This figure shows the evolution of the classification of endometrial cancer from the original classification on the left
of the figure to the newly adapted ProMisE and TransPORTEC classifications on the right.
is a post-hoc analysis of PORTEC3 and the only predictive signal suggests a benefit for
chemoradiotherapy in the p53 mutated group – which can be identified using immuno-
histochemistry [3].
As the clamour to introduce molecular subtyping increases, it is prudent to note that
this will not obviate the need for histopathologic assessment of all endometrial tumors,
which is required to establish the epithelial origin, out-rule a biphasic tumor, and
attribute the appropriate histological subtype (endometrioid vs. non-endometrioid).
Simultaneously, on the basis of hematoxylin and eosin (H&E) evaluation, this assessment
can stratify tumors into those with a low risk of recurrence, identify low-grade tumors
with intermediate recurrence risk (e.g., low-grade tumors with lympho-vascular space
invasion (LVSI) and tumors with a microcystic elongated and fragmented pattern of
invasion (MELF-like invasion)) and tumors that are potentially MMR deficient (endo-
metrial cancers with tumor infiltrating lymphocytes, tumors arising in the lower uterine
segment, and tumors with MELF-like invasion). An ad-hoc adoption of molecular
subtyping for all endometrial cancers will not replace these important observations.
The molecular classification of endometrial cancer has its origins in large-scale next-
generation sequencing – a technology that has promised a lot but delivered very little
in day-to-day oncological care. While there may be a place for targeted molecular
profiling, e.g., in the identification of less aggressive grade 3 ECs based on POLE
mutation status tumors, access to POLE sequencing has proven to be difficult outside
of a research setting, and numerous technical issues have been highlighted throughout
the literature. Furthermore, it is becoming increasingly obvious that not all POLE
mutations are equal. While some will argue that the identification of MMR-deficient
endometrial cancer may identify women who could respond to immunotherapy, access
to immunotherapy is restricted to high income countries. Until there is widespread
access to molecular profiling, the use of immunohistochemistry for MMR profiling, ER

184 Michael Wilkinson et al.
and p53 status should remain standard practice. We should remind ourselves that
multiple breast cancer molecular classifications have been developed over the last 15
years, all of which really have been focused on ER, PR, and Her2 status and proliferation
index [4].
The assessment of any proliferative endometrial lesion will always require conventional
histopathologic examination. Histomorphology using a simple H&E stain (with the add-
ition of selected immunohistochemistry) is widely available and can be implemented in
a cost-effective and reproducible manner in low- to middle-income settings. A low-tech
pathologic assessment often yields the only information required for treatment purposes for
the most common type of endometrial carcinomas – low grade endometrial cancer confined
to the inner half of the endometrium without LVSI. These tumors are typically cured by
surgery alone. Most of these patients will die of cardiovascular disease as a result of their co-
morbidities and additional prognostic or predictive molecular profiles are unlikely to add
value.
The implementation of molecular testing should not be to the detriment of standard
histomorphological assessment – this would be a major retrograde step with the potential
for significant clinical error. Histomorphological classification of endometrial cancer is
widely available worldwide and can be attained in a cost effective and reproducible
manner. Molecular profiling is a highly specialized investigation requiring skilled inter-
pretation, and adds considerable cost to cancer care. Its introduction to the management
of endometrial cancer will further alienate cancer centers in developing countries and
raise concerning ethical issues. While molecular profiling may have a role especially in
identifying good prognosis POLE mutated cancers (which would otherwise have
a potential for overtreatment) and in identifying an underlying familial cancer syndrome,
this is not required for most endometrial cancers, and we should wait for the results of
forthcoming RCTs. Until then, the focus should remain on improved training of gyneco-
logical pathologists worldwide to improve morphological assessment and provide appro-
priate immunohistochemistry assessment (IHC). Endometrial cancer affects women of all
socioeconomic classes and cultures worldwide. A globally standardized means of classify-
ing tumors is crucial for the delivery of equitable healthcare and research progression
worldwide.
Conclusion
Ultimately, until results of PORTEC-4A [5] and other ongoing RCTs are available and
demonstrate significant patient benefits in terms of improved overall survival or reduced
treatment-related morbidity, we should temper our enthusiasm. We should learn from
previous experience of over-enthusiastic adoption of new technologies which subsequently
failed in phase 3 randomized trials – from minimally invasive surgery for early-stage
cervical cancer to immunotherapy for ovarian cancer; gynecological oncology is littered
with examples of overzealous early adoption of new techniques before evidence of benefit is
available.
References
1. Bokhman JV. Two pathogenetic types of 2. International Agency for Research on
endometrial carcinoma. Gynecol Oncol Cancer. WHO Classification of Tumours.
1983;15(1):10–17. Female Genital Tumours (5th edn.). 2020.

Molecular Profiling? No 185
3. León-Castillo A, et al. Molecular cancer index: a TransATAC study. J Clin

classification of the PORTEC-3 trial for Oncol 2020;2020:Jco2000853.
high-risk endometrial cancer: impact on 5. van den Heerik A, et al. PORTEC-4a:
prognosis and benefit from adjuvant international randomized trial of molecular
therapy. J Clin Oncol 2020;38 profile-based adjuvant treatment for women
(29):3388–3397. with high-intermediate risk endometrial
4. Buus R, et al. Molecular drivers of oncotype cancer. Int J Gynecol Cancer 2020;30
DX, prosigna, endopredict, and the breast (12):2002–2007.

Debate
What is the Best Adjuvant
31A Therapy for Management

of Stage III Endometrial
Cancer?
Chemotherapy Alone
Daniela Matei
Debate
Regarded as a malignancy with high risk for local recurrence and highly responsive to
radiation, locally advanced endometrial cancer was traditionally approached with surgery,
followed by pelvic external beam radiotherapy (EBRT) aiming to sterilize potential residual
malignant sites in the tumor and lymphatic draining bed. Many studies have demonstrated
the efficacy of postoperative EBRT preventing pelvic and regional recurrences, however
more than a third of women with stage III endometrial cancer treated with surgery and
radiotherapy alone, experience failure at distant sites, ultimately succumbing to recurrent
disease. The recognition of nodal metastasis as a harbinger of future systemic recurrence has
brought interest to exploring chemotherapy as a treatment modality in this setting. The
Gynecologic Oncology Group (GOG) trial GOG-122 randomized phase III trial comparing
whole abdominal irradiation (WAI) to chemotherapy with doxorubicin and platinum
showed that administration of systemic treatment improved the overall survival (OS) by
10% compared to radiotherapy. This study put for the first time the spotlight on chemo-
therapy as a potential primary treatment approach for locally advanced endometrial cancer
[1]. However, 20% of patients treated with chemotherapy alone in this study experienced
loco-regional failure, raising the question whether a combined modality approach could
further improve outcomes for patients with stage III uterine cancer.
Several subsequent trials explored chemoradiation following surgery for this patient
population. GOG-184 compared two chemotherapy regimens (double vs. triple agent
combinations) together with volume directed EBRT and yielded a three-year progression-
free survival exceeding 60% for both groups [2]. While hailed as a successful approach,
toxicity was high in this study, with 20% of patients failing to complete the intended six
cycles of chemotherapy. Approximately 80% of the intended dose of chemotherapy was
given to those patients who completed chemo-radiotherapy. Grade 3 and 4 hematological
toxicity occurred in more than half of treated patients, while grade 3–4 gastrointestinal
adverse events were recorded in ~25% of women. Additionally, late grade 3 and 4 gastro-
intestinal toxicities were noted in 5% of patients treated on this study and worsening
neurotoxicity scores were detectable after chemo-radiation, being more significant in
women who received the platinum-containing regimen [2]. These observations underscore
the high level of acute and late toxicity associated with the combined treatment strategy.
186

Therapy for Stage III Endo? Chemotherapy Alone 187
Taking a different perspective, adjuvant chemo-radiotherapy was compared to EBRT

alone in patients with early-stage high risk and stage III endometrial cancer in PORTEC-3
trial. The combined regimen improved both OS and recurrence-free survival (RFS) over
radiotherapy alone in the mixed high-risk patient population examined in this study, of
which only half represented stage III endometrial cancer. This subgroup, at risk for both
local and systemic failure, drove most of the benefit form the combined approach in this
trial [3,4]. Despite these highly compelling results supporting use of a chemoradiation
strategy, the question as to whether the combined modality approach adds anything to
the benefits of systemic chemotherapy alone had not been addressed in either trial. Further,
the results of the PORTEC-3 clearly demonstrated the advantages conferred by chemother-
apy administration in patients with stage III endometrial cancer, but failed to dissect out
whether EBRT provided any additional benefit in this setting.
To address this remaining question, GOG-258 compared chemoradiation with systemic
chemotherapy alone in women with stage III/IVA endometrial cancer [5]. Although the
combined approach significantly reduced the rate of loco-regional relapse, contrary to
expectations, the study failed to demonstrate that the combination regimen was superior
to chemotherapy alone in prolonging RFS. At five years, 58% of patients were alive free of
disease recurrence on both arms of the study. The three-year RFS exceeded 60% for both
strategies, being comparable to the outcomes observed in GOG-184 where all patients
received chemo-radiotherapy, including a highly myelosuppressive three-drug regimen.
The lack of difference in outcome between patients receiving systemic treatment only and
multi-modality strategy was likely driven by an unexpected increase in rate of distant failure
in the group of patients receiving chemoradiotherapy. Whether the increase in visceral
metastases reflected the consequences of the inability to deliver full doses of chemotherapy
to those patients allocated to the multi-modality treatment strategy or to the delay in
initiating the systemic treatment remains controversial. Only 75% of patients allocated to
the chemoradiation arm completed the intended four cycles of chemotherapy. Coupled with
findings that patients receiving a combined therapeutic approach had an increased rate of
constitutional, gastrointestinal, renal/genitourinary, and musculoskeletal toxicities, and
reported worse quality of life scores, driven by more frequent gastrointestinal symptoms
in the group allocated to additional EBRT, the findings of this trial support omitting
radiotherapy for the treatment of women with endometrial cancer with nodal metastases.
Conclusion
It appears that for those patients whose tumors have escaped the containment of the uterus,
the risk of distant failure by far outweighs the danger of local recurrence, being the
dominant factor regulating survival. Addressing the risk of pelvic recurrence with EBRT
shifts the attention away from the far higher threat of distant metastasis, diminishes
tolerability and ability to deliver full doses of systemic treatment. With the cat out of the
bag in stage III endometrial cancer, chemotherapy wins all.
References
1. Randall ME, et al. Randomized phase III a Gynecologic Oncology Group study. J Clin
trial of whole-abdominal irradiation versus Oncol 2006;24:36–44.
doxorubicin and cisplatin chemotherapy in 2. Homesley HD, et al. A randomized phase III
advanced endometrial carcinoma: trial in advanced endometrial carcinoma of

188 Daniela Matei
surgery and volume directed radiation 4. de Boer SM, et al. Adjuvant

followed by cisplatin and doxorubicin with chemoradiotherapy versus radiotherapy
or without paclitaxel: a Gynecologic alone in women with high-risk endometrial
Oncology Group study. Gynecol Oncol cancer (PORTEC-3): patterns of recurrence
2009;112:543–552. and post-hoc survival analysis of
3. de Boer SM, et al. Adjuvant a randomised phase 3 trial. Lancet Oncol
chemoradiotherapy versus radiotherapy 2019;20:1273–1285.
alone for women with high-risk endometrial 5. Matei D, et al. Adjuvant chemotherapy plus
cancer (PORTEC-3): final results of an radiation for locally advanced endometrial
international, open-label, multicentre, cancer. N Engl J Med 2019;380:2317–2326.
randomised, phase 3 trial. Lancet Oncol
2018;19(3):295–309.

Debate
What is the Best Adjuvant
31B Therapy for Management

of Stage III Endometrial
Cancer?
Combined Chemotherapy
and Radiation Therapy
Stephanie M. de Boer and Catheryn M. Yashar
Debate
Stage III endometrial cancer (EC) comprises women with local and/or regional spread
of the tumor: invasion of the tumor to the serosa and/or adnexae (IIIA), vaginal and/
or parametrial involvement (IIIB) or metastases to pelvic and/or para-aortic lymph
nodes (IIIC). Stage III is considered high-risk EC (HREC) and identifies women at
increased risk of recurrence and EC-related death. Optimal adjuvant treatment has
been studied for decades. To optimize both locoregional and distant control, concur-
rent chemoradiotherapy was investigated. Two randomized trials (both including stage
III EC patients) were published in 2019; the Gynecologic Oncology Group (GOG)-258
trial and the Post-Operative Radiotherapy in Endometrial Carcinoma (PORTEC)-3
trial. In both trials chemoradiotherapy (CTRT) was investigated, compared with
chemotherapy (CT) alone in the GOG-258 trial and radiotherapy (RT) alone in the
PORTEC-3 trial.
In the PORTEC-3 trial, women with HREC were randomized to pelvic RT with or
without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m²
during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel
175 mg/m²). Of 660 eligible patients, 45% of women had stage III disease: 13% (n=83)
stage IIIA, 6% (n=42) stage IIIB, and 26% (n=170) stage IIIC. Updated survival analysis
with a median follow-up of 72 months showed a significant improvement of 5% in five-
year overall survival (OS; 81% vs. 76%, HR=0.70) and 7% in five-year recurrence-free
survival (RFS; 76% vs. 69%, HR=0.70) in favor of CTRT [1]. The benefit of chemother-
apy was most pronounced for women with stage III and/or serous cancers. For women
with stage III EC, a significant and clinically relevant benefit of 10% in OS (78% vs. 68%;
HR=0.63) and 12.5% in RFS (71% vs. 58%; HR=0.61) was found in favor of CTRT
compared to only 2% in OS and 4% in RFS for stages I–II EC. Both OS and RFS were
significantly improved for serous cancers with CTRT as well; five-year OS was 71%
(CTRT) versus 53% (RT; HR=0.48) and five-year RFS was 60% (CTRT) versus 48% (RT;
HR=0.42). Notably, the addition of chemotherapy to RT demonstrated increased toxicity
and lower quality of life during treatment and the first year thereafter. The persistence of
189

190 Stephanie M. de Boer and Catheryn M. Yashar
sensory neuropathy among women treated with chemotherapy is the most clinically
relevant and most bothersome long-term symptom, reported by 25% of women at two
years after treatment [2].
The GOG-258 trial randomly assigned 813 women with stages III–IVA EC (97%
stage III, 94% lymphadenectomy) to either pelvic RT with concurrent cisplatin and
adjuvant carboplatin and paclitaxel (in the same schedule as used in the PORTEC-3
trial), or chemotherapy alone (six cycles of carboplatin and paclitaxel given every three
weeks) [3]. With a median follow-up of 47 months overlapping RFS curves were
reported (five-year RFS: 59% CTRT vs. 58% CT). Significantly more pelvic and para-
aortic lymph node recurrences were reported in patients treated with chemotherapy
alone: HR=0.43 (95% CI: 0.28–0.66). Women treated with CTRT had a trend for more
distant recurrences as the first failure (HR=1.36, 95% CI: 1.00–1.86). It was not
reported how many women with pelvic or para-aortic lymph node recurrences in
the chemotherapy-alone arm had salvage radiotherapy. Grade 3, 4, or 5 acute adverse
events were reported in 202 patients (58%) in the CTRT group and 227 patients (63%)
in the chemotherapy-only group; A grade 4 or higher acute adverse event occurred in
48 patients (14%) in the chemoradiotherapy group and in 108 patients (30%) in the
chemotherapy-only group.
Comparing the stage III subgroup of the PORTEC-3 and the GOG-258 trial (97% stage
III), it is notable that the RT arm of the PORTEC-3 had a similar RFS (58%) compared with
both treatment arms of the GOG-258 (59% and 58%), while the RFS was 71% in the CTRT
arm of the PORTEC-3. In GOG-258, 73% of the trial participants were stage IIIC while in
PORTEC-3 58% of the stage III women had stage IIIC, so it is difficult to directly compare
these two groups.
These two randomized trials demonstrated that radiotherapy improved locoregional
control, even after lymphadenectomy. The addition of chemotherapy improved both OS
and RFS, especially for stage III and/or serous cancers: the question remains which patients
derive the most benefit from chemotherapy. HREC stage III is a very heterogeneous group
of tumors. Currently, decisions on adjuvant treatment are based on traditional histopatho-
logical factors. After the EC molecular classification was introduced by The Cancer Genome
Atlas (TCGA), a transition towards molecular-based classification was initiated [4]. This
molecular classification consists of four subclasses based on mutational burden and copy
number alterations with clear prognostic impact; p53-mutant (p53abn), POLE ultra-
mutated (POLEmut), mismatch-repair deficient (MMRd), or no specific molecular profile
(NSMP).
The TransPORTEC consortium investigated the TCGA-defined prognostic molecular
subgroups on 410 of 660 tumor tissues from patients enrolled in the PORTEC-3 trial [5].
The molecular classification had strong prognostic value with a five-year RFS of 98% for
POLEmut (12% of cases), 72% for MMRd (33%), 74% for NSMP (32%) and 48% for p53abn
(23%; p<0.001). Even among stage III patients, all four molecular subgroups were reported.
Women with p53abn EC had a significant benefit from CTRT (22% five-year RFS and 23%
five-year OS benefit), while POLEmut EC had excellent outcomes regardless of adjuvant
treatment received (100% vs. 97%). For women with MMRd EC no benefit of CTRT was
found (68% vs. 76%) and for women with NSMP EC a trend towards benefit from CTRT was
observed (80% vs. 68%). These results suggest that molecular factors should direct adjuvant
treatment in HREC.

Therapy for Stage III Endo? Combi Chemo & Radio 191
Conclusion
In conclusion, radiotherapy for stage III EC significantly improved locoregional control
and should therefore remain the backbone for management of stage III EC. The addition
of chemotherapy is beneficial for a subgroup of patients but comes at the expense of
increased adverse events and a (transient) impairment in quality of life. The EC molecular
classification should be incorporated in the risk stratification of these patients to identify
truly high-risk patients and those that derive the most benefit from chemotherapy. For
others treatment de-escalation should be considered or specific, targeted treatments may
be preferable.
References
1. de Boer SM, et al. Adjuvant 3. Matei D, et al. Adjuvant chemotherapy plus
chemoradiotherapy versus radiotherapy radiation for locally advanced endometrial
alone in women with high-risk endometrial cancer. N Engl J Med 2019;380
cancer (PORTEC-3): patterns of recurrence (24):2317–2326.
and post-hoc survival analysis of 4. Kandoth C, et al. Integrated genomic
a randomised phase 3 trial. Lancet Oncol characterization of endometrial carcinoma.
2019;20(9):1273–1285. Nature 2013;497(7447):67–73.
2. de Boer SM, et al. Toxicity and quality of life 5. León-Castillo A, et al. Molecular
after adjuvant chemoradiotherapy versus classification of the PORTEC-3 trial for
radiotherapy alone for women with high-risk high-risk endometrial cancer: impact on
endometrial cancer (PORTEC-3): an prognosis and benefit from adjuvant
open-label, multicentre, randomised, phase 3 therapy. J Clin Oncol 2020;38
trial. Lancet Oncol 2016;17(8):1114–1126. (29):3388–3397.

Debate
How Should Stage IA Serous
32A Papillary Endometrial Cancer

Confined to a Polyp
or the Endometrial Lining
be Managed?
Observation
Ryan M. Kahn and Ginger J. Gardner
Debate
Uterine papillary serous cancer (UPSC) accounts for only 10% of endometrial malignancies,
however, attributes to over 50% of endometrial cancer deaths annually [1]. USPC is
commonly more aggressive than the endometrioid subtype, with a higher propensity for
lymphovascular invasion as well as intraperitoneal and intra-abdominal spread at time of
diagnosis.
Despite the known increased aggressiveness and risk of relapse in USPC, a standardized
treatment paradigm for early-stage disease confined to the endometrium remains lacking.
There has been conflicting evidence on the benefit of adjuvant therapy in this population
and debate as to whether these patients require adjuvant therapy at all. As of 2021, the
National Comprehensive Cancer Network (NCCN) suggests observation, chemotherapy, or
radiotherapy all as acceptable management options following surgical staging for stage IA
USPC without myometrial invasion [2].
The appropriate surgical staging for USPC is critical. In addition to a total hysterectomy
and removal of the bilateral adnexa, this specifically includes peritoneal evaluation with
systematic intraoperative peritoneal survey, washings, omental tissue sampling, and nodal
assessment. Even in the absence of myometrial invasion, previous studies have demon-
strated UPSC rates of omental involvement up to 11% [3]. This highlights the necessity of
optimal staging in this population, as omental involvement could drastically change both
stage of disease and management.
In addition to guiding future adjuvant treatment decisions, studies have shown that
adequate surgical staging in patients with USPC could also lead to improved outcomes.
A 2016 retrospective review of 77 patients with stage IA USPC and clear cell endometrial
cancer by Velker et al. reported over 90% of recurrences (11/12) within the study had
occurred in patients that had either incomplete or suboptimal surgical staging [4]. When
stratified by staging adequacy, the five-year recurrence-free survival (RFS) was 97% in the
adequately staged cohort, compared with 68% in the suboptimally staged cohort
(p=0.01).
192

Management of Stage IA Endo Cancer? Observation 193
The previously described study by Velker et al. represents one of the largest initial series
of patients with stage IA UPSC who underwent observation as a primary treatment strategy.
Among the 77 patients with stage 1A uterine cancer (70% with USPC), 27 patients
underwent adjuvant therapy versus 50 patients who underwent observation with
a median follow-up time of 34 months (range 1–108) [4]. Congruent with previous studies,
myometrial involvement was an independent risk factor for increased recurrence rates with
22% (10/45) recurring among the myometrial invasion cohort versus 6% (2/32) recurring in
patients without invasion.
The five-year RFS rates among the observation and adjuvant treatment groups
were 84% and 63% respectively (p=0.27). Furthermore, when stratifying for those who
underwent observation alone, crude rates of recurrence were 25% (6/24) in those with
invasion versus 4% (1/26) in those without invasion. Ultimately, this led the authors to
conclude that it is reasonable to favor observation in USPC in the absence of
myometrial invasion [4]. It should be noted, there was a strong trend of increased
recurrence rates in patients with myometrial invasion who underwent observation
alone. Limitations in this study include the histologic heterogeneity with the combin-
ation of USPC with clear cell tumors.
Similar outcomes were reported in a 2013 Canadian population-based retrospective
cohort study of 127 patients with stage I UPSC by van der Putten et al. [3]. Median follow-up
time was 25 months (range 2–98 months). The five-year disease-free survival (DFS) rates
were 80.7% for those with stage I USPC without myometrial invasion and 74.4% for stage
I USPC with myometrial invasion. Among patients with stage IA disease with myometrial
invasion, the recurrence rates were 3% (1/35) for those who received chemoradiotherapy
(three cycles of adjuvant chemotherapy followed by radiation) versus 18% (4/21) for those
who either received observation or radiotherapy alone [3].
However, when stratifying for those without myometrial invasion, recurrence rates were
10% (3/30) after observation versus 18% (2/11) after adjuvant treatment (p=0.60). Based on
these results, the authors concluded that observation alone renders a favorable prognosis in
patients with stage IA USPC without myometrial invasion and therefore do not routinely
need to receive adjuvant therapy [3].
Expanding beyond using myometrial invasion as the sole determining factor for
treatment decisions in stage IA disease, a 2020 retrospective National Cancer Database
(NCDB) study by Mysona et al. developed a clinical scoring system to further classify stage
IA USPC patients that may or may not benefit from adjuvant therapy [5]. This study
included 1751 total patients with stage IA USPC; of which, 58% (1012/1751) received
chemotherapy while 34% (587/1751) underwent observation. Using a machine learning,
random survival forest algorithm, the authors developed a Cox regression model with risk
factors including age, CDCC scoring (Charlsen/Deyo Comorbidity Index), nodal status,
omentectomy, lymphovascular invasion, peritoneal cytology, and tumor size. Using
a binned scoring system, they were able to categorize by low-risk, moderate-risk, and
high-risk scores [5].
This random forest survival algorithm, which is publicly available online as a free-of-
cost clinical calculator, projected an overall survival (OS) of 87% for patients with stage IA
USPC receiving adjuvant chemotherapy versus 84% for those not receiving chemotherapy
(p=0.29) [5]. This method identified roughly one-third of patients within the study’s low-
risk cohort who would not benefit from chemotherapy and would be able to avoid the
associated risks and side effects of chemotherapy.

194 Ryan M. Kahn and Ginger J. Gardner
Conclusion
Ultimately, identifying the optimal treatment for women with stage IA UPSC without
myometrial invasion after surgery is critical. Until further studies show a benefit, observa-
tion should be performed for patients with no evidence of myometrial invasion at this time.
The previously described negative studies regarding stage IA USPC outcomes amongst
small populations on retrospective reviews need to be considered carefully. Prospective
randomized clinical trials are necessary to definitively show that observation can be equiva-
lent to adjuvant therapy in patients without myometrial invasion. In specific UPSC popula-
tions, clinicians must balance the unproven benefit of adjuvant treatments with the possible
toxicities and quality of life outcomes. Additional answers likely lie within an improved
molecular understanding of this disease. Just as there is an established association with
HER2 status and uterine serous carcinoma outcomes, further molecular classifications –
such as POLE mutations, p53 aberrancy, and copy-number repeats, among others – will
likely shed light on future directions and individualized treatment strategies for this clinical
conundrum.
References
1. del Carmen MG, et al. Uterine papillary 4. Velker V, et al. Role of adjuvant therapy
serous cancer: a review of the literature. for stage ia serous and clear cell
Gynecol Oncol 2012;127(3):651–661. uterine cancer: is observation a valid
2. Abu-Rustum NR, et al. NCCN Guidelines strategy? Int J Gynecol Cancer 2016;26
Insights: Uterine Neoplasms, Version 3.2021. ® (3):491–496.
J Natl Compr Canc Netw 2021;19(8):888–895. 5. Mysona DP, et al. Clinical calculator
3. van der Putten LJ, et al. Population-based predictive of chemotherapy benefit
treatment and outcomes of stage I uterine in stage 1A uterine papillary
serous carcinoma. Gynecol Oncol 2014;132 serous cancers. Gynecol Oncol 2020;156
(1):61–64. (1):77–84.

Debate
How Should Stage IA Serous
32B Papillary Endometrial Cancer

Confined to a Polyp
or the Endometrial Lining
be Managed?
Adjuvant Chemotherapy
Alessia Aloisi, Federica Tomao, and Eleonora
Zaccarelli
Debate
Uterine serous carcinoma is a rare, aggressive, high-risk histological subtype of endometrial
cancer. Although it represents less than 10% of all endometrial cancers, it accounts for more
than 50% of relapses and deaths attributed to endometrial carcinoma. This is most likely due
to a higher incidence of extrauterine disease at presentation, to higher rates of recurrence,
and a higher tendency for distant metastases compared to other histological subtypes.
A Gynecologic Cancer InterGroup review suggests that more than 50% of patients
affected by serous endometrial cancer is diagnosed at early stage (International
Federation of Gynecology and Obstetrics, FIGO, stage I); however, the overall survival
(OS) rates (range 65–85%) reported for these patients are much lower compared to the most
common endometrioid early-stage subtypes (>90%) [1].
The increased risk of recurrence, especially with distant metastasis, and the lower OS
warrant a consideration of adjuvant therapy even for patients with an early-stage disease.
Data from international literature, investigating the role of adjuvant chemotherapy in
a stage IA polyp-confined serous endometrial cancer, are inconsistent due to its rarity and to
the lack of prospective trials (most of the data are from retrospective studies and involve
small numbers of patients). Particularly, heterogeneous adjuvant treatment regimens
(radiotherapy, chemotherapy, combination of radiotherapy and chemotherapy) were inves-
tigated with mixed high-risk histologies and stages.
In this regard, there is no international consensus on what is the optimal adjuvant
treatment for stage IA serous endometrial cancer without myometrial invasion.
According to the European Society of Gynecologic Oncolgy (ESGO) and the National
Comprehensive Cancer Network (NCCN) Guidelines, 2020, patients can be treated either
with observation, vaginal brachytherapy or adjuvant chemotherapy (platinum/taxane com-
bination) with or without vaginal brachytherapy.
The largest single-center retrospective study conducted by Viswanathan et al. suggested
a survival benefit for the combination of chemotherapy and radiotherapy in uterine serous
195

196 Alessia Aloisi et al.
cancer [2]. However, a subgroup analysis of the NSGO9501/EORTC 55991 and MaNGO-
ILIADE III trials did not show a survival benefit for patients with early stage serous or clear-
cell tumors [3].
To date, the largest cohort of patients ever evaluated that reviewed 1709 patients with stage
I uterine serous carcinoma with no myometrial invasion selected from the National Cancer
Database, showed that adjuvant chemotherapy (with or without radiotherapy) is significantly
associated with a survival benefit (five-year OS 81.9% vs. 91.3%) [4]. However, some consider-
ations should be taken into account, such as absence of a central pathology review, lack of
information about residual tumor on the hysterectomy specimen or about cause of death, and
absence of data on the surgical staging for which staging misclassifications cannot be excluded.
According to a review of the literature [5], seven studies that included an overall cohort
of 160 patients reported oncologic outcomes on FIGO stage IA, polyp limited, serous
endometrial cancer. Only three of the studies required complete surgical staging in their
inclusion criteria. Among 160 patients, 13 women experienced a relapse, with a majority of
them recurring with extrapelvic metastases. Of these, seven were sent for observation, while
the remaining six were submitted to an adjuvant treatment (one patient underwent brachy-
therapy, one patient was submitted to EBRT, two to adjuvant chemotherapy + EBRT, and
two to adjuvant chemotherapy + vaginal brachytherapy). Overall, among 13 patients who
relapsed, only four had received chemotherapy as adjuvant treatment, though the statistical
significance of this association, due to the small number of cases analyzed, is aleatory.
Another multi-institutional retrospective review of data by Mahdi et al. examined the impact
of adjuvant therapy and pelvic radiation on pattern of recurrence and oncologic outcomes in
stage IA noninvasive uterine papillary serous carcinoma [6]. In this paper, adjuvant therapy was
associated with greater survival only in patients who did not undergo complete surgical staging.
Finally, data from the Cancer Genome Atlas (TCGA) network have shown that endo-
metrial cancer can be divided into four clinically significant molecular subtypes with
differing clinical prognoses: POLE ultramutated, microsatellite instability hypermutated
(MSI-H), copy number low, and copy number high. Patients with POLE-mutated tumors
usually have an excellent prognosis while those with copy-number-high tumors have poor
oncologic outcomes. The MSI-H and copy-number-low groups, instead, usually have
intermediate, stage-dependent prognoses.
Copy-number-high tumors, which are characterized by TP53 mutations, comprise some
high-grade endometrioid adenocarcinomas, some clear cell carcinomas, and all serous
cancers, confirming its bad prognosis [5]. Because of this new scenario, the current
knowledge about the indication regarding adjuvant treatment of endometrial cancer,
especially in nonendometrioid histotypes, might be completely changed in the near future.
Conclusion
In conclusion, the utility of adjuvant treatment in stage IA serous papillary endometrial cancer
confined to a polyp or the endometrial lining remains controversial and a clinical dilemma.
Observation has been reported as sufficient in most cases, even if adjuvant therapy could be
considered in nonstaged patients, when complete surgical staging is not feasible, in case of risk
factors such as positive peritoneal citology or large residual tumor on the hysterectomy
specimen or within clinical trials. Future prospective clinical trials, including the constantly
evolving molecular categorization, are needed to explore more effective treatment strategies for
this unique patient population.

Management of Stage IA Endo Cancer? Chemo 197
References
1. Boruta DM, et al.Management of women carcinoma confined to the endometrium.
with uterine papillary serous cancer: Int J Gynecol Cancer 2020;30(8):1089–1094.
a Society of Gynecologic Oncology (SGO) 5. Welp A, et al. Distant recurrence in
review. Gynecol Oncol 2009;115:142–153. a patient with polyp-confined stage IA
2. Viswanathan AN, et al. The importance of serous endometrial carcinoma
chemotherapy and radiation in uterine treated with adjuvant chemotherapy:
papillary serous carcinoma. Gynecol Oncol a case report and review of
2011;123:542–547. literature. Gynecol Oncol Rep
2019;31:100512.
3. Hogberg T, et al. Sequential adjuvant
chemotherapy and radiotherapy in 6. Mahdi H, et al. Adjuvant vaginal
endometrial cancer – results from two brachytherapy decreases the risk of
randomised studies. Eur J Cancer vaginal recurrence in patients with
2010;46:2422–2431. stage I non-invasive uterine papillary
serous carcinoma. A multi-institutional
4. Nasioudis D, et al. Adjuvant treatment for study. Gynecol Oncol
patients with FIGO stage I uterine serous 2015;136(3):529–533.

Debate
What is the Optimal Sequence
33A of Therapy for Patients

with Stage IIIC Endometrial
Carcinoma Treated
with Multimodal Therapy?
Sandwich Therapy
Lauren Thomaier Bollinger and Melissa A. Geller
Debate
For surgically staged stage III endometrial cancer, National Comprehensive Cancer Network
(NCCN) guidelines recommend systemic therapy ± external beam radiotherapy ± brachy-
therapy. Recent prospective data suggest that treatment with pelvic radiation prior to chemo-
therapy (CT) is not associated with a survival benefit compared to CT alone. A subset analysis
of PORTEC-3 did however demonstrate that patients with Stage III disease treated with
chemotherapy and radiation experienced longer five-year progression-free survival at 69%
versus 58% (p=0.03) [1]. The optimal sequencing of chemotherapy and radiation remains
a source of debate. “Sandwich” therapy consists of radiation therapy (whole pelvis ± para-
aortic ± brachytherapy) sandwiched between six total cycles of chemotherapy (typically,
carboplatin and paclitaxel). The “sandwich” modality evolved as a solution to reduce distant
recurrence and minimize locoregional recurrence while limiting toxicity in order to achieve
optimal therapeutic dosing of both radiation and chemotherapy. Multicenter and single
institution comparative retrospective studies have shown the superiority of sandwich therapy
compared to sequential therapy (adjuvant chemotherapy followed by radiation or radiation
followed by chemotherapy) for patients with stage III disease (Table 33A.1).
Multiple retrospective analyses show improved outcomes with “sandwiching” radiation
between chemotherapy. In a multicenter retrospective analysis of 265 patients with opti-
mally resected Stage IIIC recurrent endometrial cancer, 61 patients (23%) received “sand-
wich” adjuvant therapy. Combination adjuvant therapy resulted in a significantly lower risk
of death and progression compared to chemotherapy alone. Patients treated with the
“sandwich” method had a significantly superior overall survival (OS) compared to those
treated with either radiation followed by chemotherapy or chemotherapy followed by
radiation (p=0.04). Ninety-eight percent of patients treated with “sandwich” therapy were
alive at three years versus 90% and 82% of patients treated with sequential therapy [2].
There is also prospective evidence supporting “sandwich” therapy’s tolerability and
efficacy. We performed a prospective, single-arm phase II trial of 42 patients with Stage
III, IV and recurrent endometrial cancer who received three cycles of docetaxel (75 mg/m²)
and carboplatin (AUC 6) on an every 21-day schedule followed by involved field irradiation
198

Table 33A.1 Studies supporting the use of “sandwich” therapy for stage III endometrial cancer
Author PMID Year Design N % stage Findings

IIIC
Secord 23085460 2013 Retrospective, multicenter 265 Sandwich: superior three-year OS

et al. Combo CT+RT:61% (n=161*) 100% (98%) compared to RT+CT (90%) or
(USA) [2] - Sandwich: 38% (n=61) CT CT+RT (82%)
followed by RT and then CT RFS CT alone vs. combo CT+RT:
- Sequential: 16% (n=26) RT HR=2.2 (95% CI: 1.2–4.2; p=0.02)
followed by CT; 43% (n=68) CT OS CT alone vs. combo CT+RT:
followed by RT HR=4 (95% CI: 1.6–10, p=0.004)
- Concurrent:
2% (n=3) RT and CT; 1% (n=2) RT
and CT followed by CT
RT alone: 17% (n=45)
CT alone: 17% (n=46)
Geller et al. 21239048 2011 Prospective, single institution 42 KM estimates OS at one, three,

(USA) [3] Sandwich: three cycles of docetaxel 51% and five years: 95% (95% CI: 82–
(75 mg/m²) and carboplatin (AUC 6) 99%), 90% (95% CI: 75–96%), 71%
on a q21 day schedule followed by (95% CI: 45–86%)
involved field irradiation (45 Gy) ± KM estimates PFS at one, three,
brachytherapy and three additional and five years: 87% (95% CI: 72–
cycles of docetaxel and carboplatin 94%), 71% (95% CI: 51–83%), 64%
(95% CI: 42–80%)
Glasgow 27408749 2016 Long-term follow-up data of phase II 41 OS five years 70% (95% CI:
et al. trial 51% 53–82%)
(USA) [4] Sandwich: docetaxel (75 mg/m2) and PFS five years 66% (95% CI:
carboplatin (AUC = 6) every three 48–78%)
Table 33A.1 (cont.)
Author PMID Year Design N % stage Findings

IIIC
weeks for three cycles before and OS and PFS estimates remain high
after RT and in-field recurrences low
Frimer 30371562 2018 Prospective, single institution 132 Stage III disease OS probability
et al. stages I, II, III, or IV uterine serous 18% at two, five years: 74%, 44%
(USA) [5] carcinoma, completely resected OS far higher survival than what
Sandwich: CT (paclitaxel (175 mg/m2) has been reported in single-
and carboplatin (AUC 6–7.5) every modality trials
three weeks for three cycles) followed 81% completed six cycles of CT
by RT to 45 Gy (EBRT +/- HDR and RT
brachytherapy) followed by three Grades 3 and 4 hematologic

additional cycles of CT (carboplatin toxicities: 22% and 14% of cycles,
AUC 5–6) respectively
Grades 3 and 4 nonhematologic
toxicities: 6.9% of cycles
Abbreviations: AUC = area under curve; CT = chemotherapy; HDR = high-dose radiation; KM = Kaplan-Meier; OS = overall survival; PFS = progression-free
survival; RFS = recurrence-free survival; RT = radiotherapy.
* = mode of sequencing was unknown in one patient.
Optimal Sequence of Therapy? Sandwich Therapy 201
(45 Gy) ± brachytherapy followed by three additional cycles of docetaxel and carboplatin.
Just over half of these patients had stage IIIC disease and included unfavorable histologies.
Kaplan-Meier (KM) estimates at one, three, and five years for OS were 95% (95% CI: 82–
99%), 90% (95% CI: 75–96%), and 71% (95% CI: 45–86%) [3]. “Sandwich” therapy was well-
tolerated with only 14 (34%) and 16 (39%) patients exhibiting grade 3 and 4 hematologic
toxicities, respectively; lower than the toxicity reported in the chemoradiation arm of
PORTEC-3 [1]. In follow-up of our study after a median of five years, 15 of 41 patients
(37%) had died. The KM estimate for OS remained high at five years (70% (95% CI: 53–
82%)) with an estimated median OS of 8.2 years. There were no further pelvic recurrences
and only one distant recurrence in the cohort [4]. Frimer and colleagues similarly reported
acceptable toxicity, high survival (74% at two years) and high therapy completion rate (81%)
in a prospective study of patients with uterine serous carcinoma treated with “sandwich”
adjuvant therapy [5].
Conclusion
Despite mounting evidence to support its use, no prospective randomized trial has included
a treatment arm in which CT is given before radiotherapy or sequenced in a “sandwich”
fashion to maximize local and systemic control. Such a trial is necessary to determine the
most effective adjuvant treatment for patients with stage IIIC endometrial cancer.
References
1. de Boer SM, et al. Adjuvant for stage III, IV, and recurrent endometrial
chemoradiotherapy versus radiotherapy cancer. Gynecol Oncol 2011;121(1):112–117.
alone for women with high-risk endometrial 4. Glasgow M, et al. Long-term follow-up of
cancer (PORTEC-3): final results of an a phase II trial of multimodal therapy given
international, open-label, multicentre, in a “sandwich” method for stage III, IV, and
randomised, phase 3 trial. Lancet Oncol recurrent endometrial cancer. Gynecol Oncol
2018;19(3):295–309. Res Pract 2016;3:6.
2. Secord AA, et al. A multicenter evaluation of 5. Frimer M, et al. Adjuvant pelvic radiation
adjuvant therapy in women with optimally “sandwiched” between paclitaxel/
resected stage IIIC endometrial cancer. carboplatin chemotherapy in women with
Gynecol Oncol 2013;128(1):65–70. completely resected uterine serous
3. Geller MA, et al. A phase II trial of carcinoma: long-term follow-up of
carboplatin and docetaxel followed by a prospective phase 2 trial. Int J Gynecol
radiotherapy given in a “sandwich” method Cancer 2018;28(9):1781–1788.

Debate
What is the Optimal Sequence
33B of Therapy for Patients

with Stage IIIC Endometrial
Carcinoma Treated
with Multimodal Therapy?
Sequential
Nasuh Utku Dogan and Selen Dogan
Debate
Introduction
Endometrial cancer (EC) is the most common genital tumor in the developed world and in
the majority of cases, EC is diagnosed in early stage. Five to ten percent of EC patients
present at advanced stage with a poor prognosis. Surgery is the cornerstone of treatment and
curative in early stage; but in locally advanced stage, adjuvant treatment is required to
decrease risk of recurrence. Five-year survival rate is 96% in early disease while this
decreases to 67% in localized disease and falls to 17% in metastatic phase. There is no
optimal treatment for women diagnosed with stage III–IV EC. In the Gynecology Oncology
Group (GOG)-122 the superiority of chemotherapy over whole abdomen radiation was
demonstrated. Studies thereafter showed that combination of chemotherapy and radiation
improved survival compared to monotherapy either with chemotherapy or radiation.
Systemic treatment by means of chemotherapy improves overall survival in stage III disease
but is not good enough to prevent in particular pelvic recurrence, which can be seen in 18–
40% of cases. On the contrary, when external beam radiotherapy is given as a sole treatment,
there is a high rate of distant metastasis. Although the effect of combination treatment
proves to be effective, the optimal sequence of treatment is not clear. One approach is the
sandwich method (three cycles of chemotherapy followed by radiation and then three more
cycles of chemotherapy). Other regimes are six cycles of chemotherapy followed by radi-
ation (sequential treatment) or concomitant chemoradiotherapy. There are no randomized
trials comparing these regimes. In this chapter the authors evaluate the benefit of six cycles
of chemotherapy followed by pelvic radiotherapy (sequential regime) in stage IIIC disease.
Rationale for Adjuvant Multimodal Treatment in Stage IIIC Endometrial

Cancer
There are two recent randomized controlled trials assessing effects of combination therapy
compared to radiotherapy alone in advanced-stage EC. In the first study (PORTEC-3) there
202

Optimal Sequence of Therapy? Sequential 203
was a significant overall survival advantage in 660 high-risk EC patients (295 had stage III
disease) in favor of combination therapy compared to radiation alone. Radiation therapy
alone was associated with 68% five-year overall survival, while this was 78% for those
undergoing combination treatment. In the PORTEC-3 trial, the sequence of treatment
was external beam pelvic radiotherapy (concomitant chemoradiotherapy) followed by
adjuvant therapy in which there was a three-week break between two treatment modalities.
Interestingly, a subgroup analysis of stage III patients receiving chemoradiotherapy had
longer progression-free survival (PFS). The second study (GOG-258) included 715 patients
diagnosed with stage III disease and compared the effect of radiotherapy alone to combin-
ation treatment. There was no difference with respect to PFS, however a significant toxicity
in the combination arm of both studies was observed. In PORTEC-3 and GOG-258,
radiotherapy was given along with cis-platin as a radiosensitizer followed by administration
of four cycles of chemotherapy. Probably administration of chemotherapy in
a radiosensitizer dose was not good enough to control systemic disease. Moreover, four
cycles of adjuvant chemotherapy seem to be inadequate to prevent distant metastasis
compared to six cycles. The potential effects of multi-modal treatment are systemic disease
control by means of chemotherapy and local control of vaginal recurrences by radiotherapy.
But up to now there is no prospective data regarding the optimal sequencing and timing of
chemotherapy and adjuvant radiotherapy.
Series Comparing Different Treatment Schemes

Goodman et al. evaluated 5795 women diagnosed with stage III–IVA type I EC with various
adjuvant treatment schemes of which 26% received chemotherapy followed by radiation
therapy and 10% received radiation therapy followed by chemotherapy [1]. In multivariate
analysis, chemotherapy followed by radiation therapy was associated with longer overall
survival compared to other regimes including radiation therapy followed by chemotherapy,
radiation therapy alone, or chemotherapy alone. Moreover, when the cohort of women
diagnosed with IIIC disease were only included, chemotherapy followed by radiation
therapy was associated with longer five-year overall survival compared to radiation therapy
before chemotherapy. In a study with analysis of 105 patients with stage IIIC2 disease,
different adjuvant treatment regimens were compared [2]. In this group of patients, the type
of adjuvant therapy effected disease-free and overall survival. Patients having received
chemotherapy plus radiation therapy had a better prognosis compared to either chemo-
therapy or radiation therapy as a sole treatment. The combination therapy included mainly
chemotherapy followed by external beam radiation therapy. Particularly in endometrioid
histology, combination therapy was associated with longer locoregional or distant disease-
free survival. In another study in the United States, from the National Cancer Database,
6981 patients were identified with stage IIIC disease; 5116 received chemotherapy then
radiation therapy, 696 radiation therapy before chemotherapy, and 1196 received concomi-
tant chemoradiation between 2004–2015 [3]. Interestingly, the use of chemotherapy before
radiation therapy increased significantly from 39% to 75% between 2004 to 2015. In
a median follow-up of 43 months, there was no difference between chemotherapy-first
(then radiation) or radiation therapy first regimes. To note, when compared to these two
regimes, concomitant chemoradiation was associated with a 47% increased risk of mortality.
Lu et al. evaluated 51 stage III EC patients receiving multimodal therapy (either in sandwich
or sequential manner) [4]. The five-year overall survival, local, or distant progression-free

204 Nasuhh Utku Dogan and Selen Dogan
survival were all comparable between two groups with similar toxicity profiles. Though not
significant, there was a trend towards a higher grade III–IV hematologic toxicity in the
sandwich group [4]. In a study with 25 patients with stage IIIC disease, sequential therapy
was compared to the sandwich regime. More patients in the sandwich group experienced
grade III–IV neurologic and hematologic toxicity and undesired breaks in the course of
treatment compared to the sequential regime, particularly in IIIC2 disease [5].
Conclusion
Studies evaluating different combinations in locally advanced-stage EC are all heteroge-
neous. Large prospective studies are warranted to compare different combination regimes
including sandwich and sequential regimes; but inclusion of only stage IIIC disease is not
realistic as stage IIIC disease is relatively rare. Prognosis of stage IIIC disease is still poor,
with a high rate of distant recurrences pointing out need for a better systemic therapy. As
a conclusion, multimodal treatment should be given to all patients with stage III EC. Either
sandwich therapy or a sequential regime seem to be reasonable approaches; but sequential
regime, particularly for stage IIIC2, is well tolerated, with less toxicity and treatment breaks.
References
1. Goodman CR, et al. Association of 4. Lu SM, et al. Sequential versus
chemotherapy and radiotherapy sequence “sandwich” sequencing of adjuvant
with overall survival in locoregionally chemoradiation for the treatment of
advanced endometrial cancer. Gynecol stage III uterine endometrioid
Oncol 2019;153(1):41–48. adenocarcinoma. Gynecol Oncol 2015;137
2. Bogani G, et al. Role of adjuvant therapy in (1):28–33.
stage IIIC2 endometrial cancer. Int J Gynecol 5. Dogan NU, et al. Comparison of “sandwich
Cancer 2020;30(8):1169–1176. chemo-radiotherapy” and six cycles of
3. Latham AH, et al. Sequencing of therapy in chemotherapy followed by adjuvant
women with stage III endometrial radiotherapy in patients with stage IIIC
carcinoma receiving adjuvant combination endometrial cancer: a single center
chemotherapy and radiation. Gynecol Oncol experience. Arch Gynecol Obstet 2013;288
2019;155(1):13–20. (4):845–850.

Debate
Should an Attempt
34A at Debulking Grossly

Metastatic Endometrial
Cancer be Undertaken?
Yes
Brooke M. Lamparello and Joyce N. Barlin
Debate
Management of advanced endometrial cancer, including the role of surgical cytoreduction,
remains controversial. Debulking surgery is widely utilized in metastatic cancer due to
demonstrated physiologic and clinical survival benefits. Removal of large necrotic masses
can facilitate drug delivery to smaller tumors that maintain a good blood supply. Debulking
to minimal residual disease decreases the number of malignant cells present and improves
the ability of chemotherapeutic agents to reach tumor centers, decreasing the likelihood of
the development of drug-resistant cells. Further, by removing tumor burden that causes
clinical sequelae, such as bowel obstruction, nutritional and immunologic status can be
improved.
Owing to the low incidence and prevalence of stage IV endometrial cancer, research
investigating the role of surgical cytoreduction is retrospective. A meta-analysis of 14
retrospective studies, comprising 672 patients with advanced and recurrent endometrial
cancer of all histologies, showed a statistically significant association with median overall
survival (OS) and the proportion of patients undergoing surgical cytoreduction. Each
10% increase in the percentage of patients undergoing complete cytoreduction improved
survival by 9.3 months [1]. A retrospective study of 65 stage IVB endometrial cancer
patients with mixed histologies undergoing primary surgical debulking showed
a statistically significant survival advantage for optimal debulking compared to those
who had residual disease, 34.3 months versus 11.0 months, respectively [2]. This
improvement in survival retained statistical significance even when controlling for
other factors, including age, performance status, tumor histology, and adjuvant therapy.
In fact, the strongest predictor of survival was the volume of residual disease after
debulking surgery [2]. In a more homogeneous population of 58 patients with stage IV
endometrioid endometrial cancer and macroscopic disease, the extent of cytoreduction
achieved was a statistically significant prognostic factor in progression-free survival
(PFS) and OS [3]. Patients in this study with no residual disease had a median OS of
42.2 months compared with 19 months for patients with any residual disease, and 2.2
months for those that did not have cytoreductive surgery. Extent of residual disease and
adjuvant chemotherapy were also independently associated with OS when analyzed on
a multivariate level [3].
205

206 Brooke M. Lamparello and Joyce N. Barlin
The paucity of advanced metastatic endometrial cancer patients prohibits the devel-
opment of a randomized trial. In fact, many of the retrospective studies in metastatic
endometrial cancer spanned several decades. In contrast to endometrial cancer, most
ovarian cancer patients are diagnosed at an advanced stage, and surgical cytoreduction in
advanced ovarian cancer has been widely investigated and established as a valuable
cornerstone of treatment. The DESKTOP-III trial prospectively randomized 407 patients
with recurrent ovarian cancer to surgery (n=206) followed by chemotherapy, or no
surgery (n=201) with immediate chemotherapy. The median OS was 53.7 months versus
46.0 months in the surgery versus no surgery cohorts, respectively (95% CI: 0.58–0.96,
p=0.02) [4]. Given the similarity in patterns of metastasis, prospective ovarian cancer data
has been extrapolated to the advanced stage endometrial cancer population. This provides
additional support and justification for cytoreductive surgery in stage IV endometrial
cancer.
While the surgeon must consider the potential for surgical morbidity in a patient
population with advanced disease and a high likelihood of comorbidities, this does not
preclude these patients from the survival benefits of debulking surgery. In a retrospective
multi-institutional study, 426 patients with stage IVB endometrial cancer were divided by
initial treatment. One hundred and twenty-five patients underwent initial chemotherapy
treatment due to their poorer performance status and higher rates of comorbidities [5].
These patients had a decreased OS of 12 months compared to 21 months in the primary
surgery group (279 patients). However, 59 of the primary chemotherapy patients addition-
ally underwent surgical cytoreduction, and their OS curves were the same as those patients
in the primary surgery cohort. This suggests that patients who may be poor candidates for
debulking can benefit from chemotherapy followed by surgery. This data is further validated
by the numerous prospective randomized controlled trials within the advanced ovarian
cancer population that have shown neoadjuvant chemotherapy followed by cytoreductive
surgery as a valid therapeutic option for patients who are poor surgical candidates or
initially have unresectable disease.
Conclusion
Optimal cytoreductive surgery in grossly metastatic endometrial cancer is supported by
physiologic rationale and a clinically significant improvement in survival. The biological
benefits include reduction of tumor burden to improve clinical status, increase in chemo-
therapy drug delivery to the tumor, and decrease in the development of drug resistance.
Multiple retrospective studies have demonstrated an increased PFS and OS in stage IV
endometrial cancer patients with varying histologic subtypes. A meta-analysis in advanced
and recurrent endometrial cancer suggested that complete cytoreduction to no gross
residual disease is associated with superior OS outcomes. In the absence of readily achiev-
able prospective data in this rare cohort, results extrapolated from advanced-stage ovarian
cancer offer additional support for the benefits of debulking surgery. Furthermore, of the
prognostic factors favoring survival, the amount of residual tumor is the only factor that can
be directly influenced by the surgeon. A randomized prospective trial in metastatic endo-
metrial cancer to confirm or refute the clinical utility of surgical cytoreduction will require
a tremendous multi-institutional effort. However, until this is achieved, the current data
support surgical tumor debulking in advanced endometrial cancer in an effort to optimize
outcomes and improve survival.

Attempt at Debulking? Yes 207
References
1. Barlin JN, et al. Cytoreductive surgery for 4. Du Bois AA, et al. Randomized phase III
advanced or recurrent endometrial cancer: a study to evaluate the impact of secondary
meta-analysis. Gynecol Oncol cytoreductive surgery in recurrent ovarian
2010;118:14–18. cancer: final analysis of AGO DESKTOP
III/ENGOT-ov20. J Clin Oncol
2. Bristow RE, et al. Stage IVB endometrial 2020;38:6000).
carcinoma: the role of cytoreductive surgery
and determinants of survival. Gynecol Oncol 5. Eto T, et al. Status of treatment for the
2000;78(2):85–91. overall population of patients with stage IVB
endometrial cancer, and evaluation of the
3. Shih KK, et al. Surgical cytoreduction in role of preoperative chemotherapy:
stage IV endometrioid endometrial a retrospective multi-institutional study of
carcinoma. Gynecol Oncol 2011;122 426 patients in Japan. Gynecol Oncol
(3):608–611. 2013;131(3):574–580.

Debate
Should an Attempt
34B at Debulking Grossly

Metastatic Endometrial
Cancer be Undertaken?
No
Frederick M. Howard and Gini F. Fleming
Debate
Interest in debulking surgery for advanced uterine cancer arose in the 1980s after publication
of a number of case series demonstrating improved survival in women who had undergone
optimal or complete cytoreductive surgery. A 2010 meta-analysis of 14 retrospective series
(eight of which included women with stage IIIC disease, in whom outcomes are generally
better regardless of surgery, and in whom optimal debulking is more likely to be achieved)
evaluated the impact of extent of surgical debulking on outcomes in advanced or recurrent
endometrial cancer, and found that both optimal and complete cytoreduction were associated
with improved survival [1]. However, this should not be taken as evidence that debulking
should be attempted for stage IV endometrial cancer patients with grossly metastatic disease,
and may reflect a variety of confounders – in particular, optimally debulked patients likely had
lower pre-surgical disease burden. The presence of confounders is highlighted by the finding
of the same meta-analysis that receipt of chemotherapy was negatively associated with survival
(a 10.4 month decrease in survival per 10% increase in patients receiving chemotherapy),
which lies in direct conflict with data from randomized controlled trials.
In general, the fact that an improvement in survival is associated with positive outcomes
from a particular intervention does not prove that the intervention improves outcomes, as
outcomes of the intervention may be a surrogate marker for prognosis. For example,
numerous studies randomizing patients with cervical cancer to neoadjuvant chemotherapy
or no neoadjuvant chemotherapy found that while a good response to neoadjuvant chemo-
therapy among patients receiving neoadjuvant chemotherapy was associated with better
outcomes, the group randomized to receive neoadjuvant chemotherapy nonetheless fared
worse overall. Or, for a surgical example, results of the Gynecology Oncology Group (GOG)
213 (which randomly assigned women with platinum-sensitive recurrent ovarian cancer to
undergo surgical cytoreduction followed by chemotherapy or to receive chemotherapy
only) showed that among patients who underwent surgery, complete gross resection as
compared to incomplete resection was associated with longer overall survival (56.0 months
vs. 37.8 months) and longer progression-free survival. Yet overall, there was no benefit for
the group receiving surgery versus the group receiving no surgery. Indeed, surgery was
associated with a nonsignificant trend to worse overall survival (50.6 months vs. 64.7
months, p=0.08) [2].
208

Attempt at Debulking? No 209
Debulking surgery is utilized for a wide range of intraabdominal malignancies, includ-

ing gastrointestinal stromal tumors, well differentiated neuroendocrine carcinoma, peri-
toneal mesothelioma, and ovarian cancer. Although tempo of disease varies with histology
and grade, endometrial cancer generally is associated with a shorter survival than other
malignancies where peritoneal debulking is routine. In a case control series, stage IIIC
ovarian and stage IVB endometrial cancer patients undergoing primary cytoreduction were
matched for age and residual disease. Survival was significantly inferior in the endometrial
cancer patients with optimal cytoreductive surgery versus ovarian cancer patients with
optimal cytoreductive surgery (overall survival 57% at two years vs. 82% at two years) [3].
Any possible benefit from debulking surgery must also be weighed against the mortality
and morbidity of surgery. Relative to ovarian cancer, uterine cancer occurs in an older
population with higher levels of obesity and increased operative risk. In one retrospective
review of 85 patients with advanced endometrial cancer undergoing primary surgical
cytoreduction, the rates of minor and major (including bladder, bowel, and vascular injury)
postoperative complications were 36% and 13% respectively, and 4% of patients passed
away within 30 days of surgery [4]. Only 19 patients had stage IV disease, and 17 had
extrapelvic sites; the operative morbidity of achieving primary optimal cytoreduction in
patients with stage IV grossly metastatic disease may be higher. Indeed, complications were
more frequent in patients who had suboptimal cytoreduction, perhaps due to the higher
proportion of stage IV disease in that subgroup. This series, which was included in the
aforementioned meta-analysis, found a survival advantage to optimal versus suboptimal
cytoreduction. However, the survival analysis included 39 patients with stage IIIC disease
and only 19 with stage IV disease, and the authors found that after adjusting for stage the
survival advantage for optimal cytoreduction was no longer statistically significant.
Conclusion
In carefully selected patients with few comorbidities, minimal extrapelvic disease that
appears completely resectable, and slow growing tumors, complete cytoreduction may
improve survival. Moreover, hysterectomy can potentially reduce the risk of massive pelvic
hemorrhage, although radiation therapy and embolization can also palliate bleeding.
Surgical morbidity is, of course, decreased by the use of chemotherapy prior to surgery.
However, at this time we have no meaningful data supporting any survival benefit for the
broad use of debulking surgery for patients with grossly metastatic endometrial cancer, and
its routine use is not warranted in the absence of prospective randomized data.
References
1. Barlin JN, et al. Cytoreductive surgery for treatment paradigm result in similar
advanced or recurrent endometrial cancer: a outcomes? A case-control analysis. Gynecol
meta-analysis. Gynecol Oncol 2010;118:14–18. Oncol 2009;112:337–341. https://doi.org/10
https://doi.org/10.1016/j.ygyno.2010.04.005 .1016/j.ygyno.2008.10.009
2. Coleman RL, et al. Secondary surgical 4. Lambrou NC, et al. Optimal surgical
cytoreduction for recurrent ovarian cancer. cytoreduction in patients with stage III and
N Engl J Med 2019;381:1929–1939. https://d stage IV endometrial carcinoma: a study of
oi.org/10.1056/NEJMoa1902626 morbidity and survival. Gynecol Oncol
3. Landrum LM, et al. Stage IVB endometrial 2004;93:653–658. https://doi.org/10.1016/j
cancer: does applying an ovarian cancer .ygyno.2004.03.015

Debate
Should Secondary
35A Cytoreduction be Performed

for Recurrent Endometrial
Cancer?
Sometimes
Lea A. Moukarzel, Kevin Espino, and Chris Awtrey
Debate
Endometrial cancer is the most common gynecologic malignancy in the United States. The
primary form of treatment is surgical resection of the uterus, bilateral fallopian tubes and
ovaries, with or without complete or sentinel lymph node dissection. After which the
decision for adjuvant treatment is not only guided by stage, but most importantly by
tumor characteristics, i.e., tumor grade, histology, myometrial invasion, and more recently
molecular profiling. These factors also guide the decision on whether adjuvant therapy will
entail locoregional radiotherapy, chemotherapy, immunotherapy (currently under investi-
gation in the upfront setting), or a combination among them. Using these treatment
paradigms there is an 11–14% rate of recurrence with a median survival after recurrence
of 21–29 months [1,2].
One of the major challenges within the realm of treatment for endometrial cancer is that
for recurrent disease. Recurrent endometrial cancer represents a heterogeneous cohort of
cases with varying histologies, previous adjuvant therapy, time interval, as well as size and
pattern of disease recurrence. Therapeutic options vary significantly, and include surgical
resection, radiation therapy (RT), chemotherapy, hormonal therapy, immunotherapy, or
a combination among them. Traditionally, surgical resection for recurrent endometrial
cancer was limited to pelvic exenteration in previously irradiated patients presenting with
central pelvic recurrences. This has gradually been replaced with literature demonstrating
a utility in treating this disease with secondary cytoreductive surgery (SCS) for not only
central pelvic, but also other sites of disease recurrence.
Legge et al. and Moukarzel et al. demonstrated that SCS, not involving pelvic exenter-
ations, offers prolonged survival over other modalities of therapy when selected in the
appropriate patient [1,2]. Moukarzel et al. demonstrated that patients treated with SCS had
the longest median overall survival (OS) of 57.6 months (95% CI: 33.3–not reached)
resulting in an 80.9% two-year OS rate. These patients required a median of one additional
line of subsequent therapy. On multivariate analysis, after accounting for all significant
factors that differed across treatment modalities, SCS was an independent predictor of
improved survival. Compared with surgery, medical management with RT or chemother-
apy with or without radiation portended worse survival (HR=2.1, 95% CI: 1.3–3.5, p<0.012),
as did those treated with hormonal therapy (HR=2.3, 95% CI: 1.1–4.5, p=0.012).
210

Secondary Cytoreduction? Sometimes 211
Similar findings have been reported by others, suggesting that SCS for the treatment of
recurrence, even when nonexenterative, confers a significant survival benefit. This observa-
tion is partially due to appropriate patient selection for SCS. Thus far, there remains no well-
established prospectively validated selection criteria. However, findings from these
retrospective studies can help guide decision making. One criterion that has been repeatedly
shown in these studies to positively impact OS is achieving complete gross resection (CGR)
or optimal cytoreduction. In a meta-analysis, Barlin et al. demonstrated that for each 10%
increase in patients achieving CGR at debulking for advanced or recurrent EC, there was
a significant improvement in survival of 9.3 months [3].
Unfortunately, data is not as clear when it comes to delineating other selection criteria
for SCS. In their study, Moukarzel et al., proposed selection criteria based on factors that
were significantly more common in the population of patients selected for SCS as compared
to medical management [2]. They recommend that higher consideration for SCS should
occur in patients with the following features from time of diagnosis: age ≤70, time to
recurrence ≥19 months, grade 1/2 endometrioid or clear cell histology, early-stage (I/II)
disease; the following features from primary surgery: no residual disease, short length of stay
(LOS) (0–6 days), no more than two grade 3 complications, received adjuvant RT; and the
following feature from time of recurrence: single-site disease. Features that did not differ
statistically in distribution between patients selected for SCS versus medical management
should merit less consideration. These include BMI at initial diagnosis, adjuvant chemo-
therapy after primary surgery, size of recurrent tumor, and distant site of recurrent disease.
While the literature thus far can help guide decision making, due to the complexity of this
decision and need for treatment personalization it is recommended that these cases undergo
multidisciplinary tumor board assessment.
Summary and Recommendations

For vaginal recurrences in previously irradiated field, surgical resection should be con-
sidered as first-line therapy, followed by the consideration of adjuvant brachytherapy.
Currently, literature demonstrates that SCS are effective and less morbid than pelvic
exenterations. Vaginal recurrences in nonirradiated patients become more controversial,
as traditionally these patients are salvaged with RT. In PORTEC-1, among cases of isolated
vaginal recurrences in women without prior RT treatment, there was an 89% complete
remission and 65% five-year survival when treated with RT. However surgical cytoreduction
has also proven curative in this setting. Hardarson et al. showed comparable survival in
patients with surgical resection and RT, in previously nonirradiated patients [4]. More
specifically, surgical resection should be considered in large tumors, as tumor size signifi-
cantly influences the effect of radiation. Therefore, in patients who decline RT or are not
candidates for RT, SCS is a strong alternative in this setting.
As for women with locoregional-pelvic confined recurrences who are surgical candi-
dates and complete or optimal cytoreduction is deemed technically feasible, then SCS
should lead as primary modality of therapy with consideration of factors as previously
discussed. PORTEC-1 demonstrated that when extra-vaginal extension or pelvic lymph
involvement is present then RT no longer offers as promising results. If a patient is not
deemed a good candidate for SCS then RT should be considered if no history of prior RT,
while medical management would best suit those having already undergone RT. In addition,
the role of immunotherapy as an alternative option should be considered.

212 Lea A. Moukarzel et al.
Lastly, SCS can also play a role in the treatment of patients with distant disease, having
shown a two-year progression-free survival of 77% in this setting [2]. Tangjitgamol et al.
reported that the surgical resection of solitary, pulmonary, hepatic, and cerebral metastasis
is feasible and reported prolonged survival in patients with good performance status, long
disease-free interval, and clear margins [5].
Conclusion
In conclusion, the treatment of recurrent endometrial cancer remains a therapeutic chal-
lenge. However, it has become increasingly clear that with improved patient selection the
role of SCS offers tremendous impact on survival. Importantly, with the advancements in
the field of immunotherapy and the promising results for patients with endometrial cancer,
an important next step is to investigate how best to integrate it into the treatment paradigm.
References
1. Legge F, et al. Clinical outcome of recurrent (1):14–18. https://doi.org/10.1016/j
endometrial cancer: analysis of post-relapse .ygyno.2010.04.005
survival by pattern of recurrence and 4. Hardarson HA, et al. Vaginal vault
secondary treatment. Int J Gynecol Cancer recurrences of endometrial cancer in non-
2020;30(2):193–200. https://doi.org/10.1136 irradiated patients – radiotherapy or
/ijgc-2019-000822 surgery. Gynecol Oncol Rep 2015;11:26–30.
2. Moukarzel LA, et al. Non-exenterative https://doi.org/10.1016/j.gore.2015.01.002
surgical management of recurrent 5. Tangjitgamol S, et al. Role of surgical
endometrial carcinoma. Gynecol Oncol resection for lung, liver, and central
2021;162(2):268–276. https://doi.org/10 nervous system metastases in patients with
.1016/j.ygyno.2021.05.020 gynecological cancer: a literature review.
3. Barlin JN, et al. Cytoreductive surgery for Int J Gynecol Cancer 2004;14(3):399–422.
advanced or recurrent endometrial cancer: a https://doi.org/10.1111/j.1048-891x
meta-analysis. Gynecol Oncol 2010;118 .2004.14326.x

Debate
Should Secondary
35B Cytoreduction be Performed

for Recurrent Endometrial
Cancer?
Never
Marcela G. del Carmen
Debate
Background
Treatment options available to patients with recurrent endometrial cancer, including use
of systemic therapy and radiation, are selected based on patient- and tumor-related
factors, as well as previously delivered treatment, including use of radiation therapy
[1]. Historically, the role of surgical resection in the management of recurrent endomet-
rial cancer was limited to total pelvic exenteration (TPE) in select cases of isolated
vaginal apex recurrence and a previously irradiated area. Given that most patients who
develop recurrent endometrial cancer have diffusely metastatic disease, and would not be
appropriate candidates for TPE, many have adopted secondary debulking principles and
extrapolated from the data pertinent to treatment of recurrent epithelial ovarian cancer
(EOC) to support this strategy in the management of patients with metastatic recurrent
endometrial cancer [1]. As in the case of secondary cytoreduction in patients with
platinum-sensitive EOC, the data in recurrent endometrial cancer is limited to retro-
spective evidence and surgical effort intends to enhance response rates to salvage
systemic therapy. Importantly, cytoreduction in this setting was adopted prior to the
development of more promising adjuvant therapies, including innovation in targeted
approaches.
Available Evidence
In 1998, Scarabelli et al. published the first study, inclusive of 20 patients, evaluating the
role of cytoreductive surgery for recurrent endometrial cancer [2]. Complete micro-
scopic resection was attained in 65% of patients, with a reported improvement in
survival when compared to those with measurable disease after surgery (12 months
vs. undefined; p<0.01). Two patients had major complications and two deaths were
reported. In another retrospective study of 75 patients, cytoreduction to 1 cm or less was
achieved in 75%, with an improvement in overall survival of 53 months, compared to 9
months in those with residual disease >1 cm (p<0.05). The investigators also reported
a 31% rate of major complications and 8% mortality rate [3]. Bristow et al. reported on
213

214 Marcela G. del Carmen
outcomes of 61 patients with recurrent endometrial cancer, including those managed

with nonsurgical therapies [4]. When compared to the nonsurgical group, the 35
patients who underwent surgery had a longer median survival of 28 vs. 13 months,
respectively (p<0.0001). In 66% of patients treated surgically, complete cytoreduction
was attained and associated with improved median survival, when compared to patients
with a sub-optimal debulking effort. In a study of 27 patients, 18 of whom had
cytoreduction of recurrent endometrial cancer to <2 cm of residual disease, median
disease-specific survival was 43 months, compared to 10 months in those with >2 cm
residual disease [5]. In this study by Awtrey et al., there were no reported major
perioperative complications or mortality.
Limitations of Available Evidence

Secondary cytoreduction for patients with recurrent endometrial cancer was adopted from
the surgical treatment paradigm embraced by many as a management strategy for patients
with recurrent, platinum-sensitive EOC. Two randomized studies have evaluated the role of
secondary cytoreduction in the latter patient population with conflicting results. While
DESKTOP III reported an improvement in progression-free survival benefiting patients
randomized to cytoreductive surgery, data are not yet mature to inform on the impact on
overall survival. The Gynecology Oncology Group (GOG) 213 failed to show an improve-
ment in overall or progression-free survival benefitting patients with recurrent EOC
randomized to secondary cytoreduction. This level of evidence remains lacking to inform
on the utility of secondary debulking in patients with recurrent endometrial cancer. The
available data have significant limitations.
Given that the studies informing on the role of secondary cytoreductive surgery in the
treatment of patients with recurrent endometrial cancer are retrospective, inherent
selection bias presents a significant limitation. Furthermore, many of these studies
include small numbers of patients, from single institutions and have different definitions
for achieved optimal surgical effort. Adjuvant therapies available to patients after sec-
ondary surgical debulking are not standardized, have changed over time, and may indeed
have significant impact on patient overall and progression-free survivals. Lastly, most of
these retrospective studies report significant morbidity and mortality rates, which also
need to be considered in offering surgical therapy that carries an unlikely curative
outcome.
With the emergence of new systemic therapeutic options in the treatment of patients
with recurrent endometrial cancer, including discovery of molecular pathways offering
targeted therapeutic approaches, secondary cytoreductive surgery, informed solely based
on retrospective evidence and carrying a significant risk of perioperative morbidity and
mortality, should be abandoned.
Conclusion
The role of secondary debulking surgery in the treatment of recurrent endometrial cancer is
not justified based on the limited nature of available data and emergence of new systemic
therapeutic options.

Secondary Cytoreduction? Never 215
References
1. del Carmen MG, et al. Recurrent endometrial carcinoma. Cancer 2004;100(1):
endometrial cancer. Clin Obstet Gynecol 89–96.
2011;54(2):266–277. 4. Bristow RE, et al. Salvage cytoreductive
2. Scarabelli C, et al. Maximal cytoreductive surgery for recurrent endometrial
surgery as a reasonable therapeutic cancer. Gynecol Oncol 2006;103
alternative for recurrent endometrial (1):281–287.
carcinoma. Gynecol Oncol 1998;70(1):90–93 5. Awtrey CS, et al. Surgical resection of
3. Campagnutta E, et al. Surgical recurrent endometrial carcinoma. Gynecol
treatment of recurrent Oncol 2006;102:480–488.

Debate
Is Hormonal Therapy the Best
36A Therapy for Chemo-resistant

Endometrial Cancer?
Yes
Roni Nitecki and Pamela T. Soliman
Debate
Based on the knowledge that the uterus is an endocrine organ and the observations that
excess endogenous or exogenous estrogen was strongly linked to the development of
endometrial cancer, gynecologic oncologists have been using hormonal agents for decades.
The first report of progesterone as a therapeutic agent for endometrial cancer dates back to
1961. While hormonal therapy may be appropriate in different cancer stages for a variety of
indications, in the case of chemo-resistant endometrial cancer it is important to understand
the activity of hormonal therapy in the context of the existing therapeutic landscape.
Endometrial cancer is the most common gynecologic malignancy in the United States,
accounting for an estimated 65,620 new cases in 2020. The incidence and mortality of
uterine cancer have been on the rise for over a decade, but since 2009, the age-adjusted death
rate has been rising at 1.9% per year – double the rise of the incidence rate. With a five-year
relative survival of 81.2%, the majority of patients will have excellent prognosis. A subset,
however, present with advanced and recurrent disease that is rarely curable. This subset may
account for the rising death rate, as the majority of patients with advanced disease will
progress after first-line chemotherapy, and thereafter, treatment options are limited.
In the absence of a standard regimen, the Gynecologic Oncology Group (GOG) created
the 129 series, a group of phase II studies measuring response as the primary endpoint for
patients with recurrent or persistent disease who received one prior chemotherapy regimen.
Of this series, the only single agent considered active was paclitaxel with a response rate of
27% in 44 patients who were not exposed to prior taxane-based chemotherapy [1]. As the
modern most utilized first-line regimen is carboplatin plus paclitaxel, other chemothera-
peutic agents have been studied, and these have yielded disappointing response rates at the
cost of significant toxicity. In this setting, hormonal agents have been found to be particu-
larly useful given their moderate efficacy and favorable side-effect profile compared to
cytotoxic chemotherapy. There are a variety of hormonal strategies that can be broadly
categorized as progestins, selective estrogen receptor modifiers (SERMs, i.e., tamoxifen),
aromatase inhibitors, and combination strategies. Hormonal therapy is well tolerated. Side
effects are usually minor and include weight gain, edema, thrombophlebitis, possible
venous-thromboembolic disease, headache, and occasional hypertension.
While initial clinical trials of hormonal agents in patients with advanced or recurrent
endometrial cancer demonstrated response rates of 30–50%, larger studies with
more specific response criteria demonstrated more modest response rates in the range
216

Is Hormonal Therapy the Best? Yes 217
of 11–24%. A meta-analysis specifically examining the effect of different standardized

criteria on the association between hormonal therapies and response found that studies
utilizing RECIST or WHO found a mean response rate of 9.2%, while studies using GOG
criteria demonstrated an overall response rate of 20.5% [2]. In this setting, systematic
reviews have demonstrated conflicting evidence of the efficacy of hormonal therapy for
persistent or recurrent endometrial cancer, but the majority of evidence demonstrates
better response than chemotherapy, particularly in patients with low-grade steroid
hormone receptor positive (i.e., progesterone-receptor (PR) and estrogen-receptor
(ER)) tumors [2–4].
In a systematic review, Kokka and colleagues pooled six randomized trials encompassing
542 women who received various forms and combinations of hormonal therapies and
concluded that there was a dearth of evidence supporting hormonal therapy for advanced
or recurrent endometrial cancer [4]. It is important to note, however, that only one included
study compared hormonal therapy to chemotherapy, and three out of the six studies
included different hormonal regimens in both arms of the trial. In addition, significant
heterogeneity in stage of disease, prior treatment, histology, grade, and presence or absence
of hormonal receptors limited the study. In a more recent and representative systematic
review of 39 studies and 1937 patients, Ethier and colleagues combined randomized and
observational studies to quantify the overall response rates to hormonal therapy in patients
with advanced or recurrent endometrial cancer [2]. They found that hormonal therapy was
associated with an overall response rate of 21.6% and a clinical benefit rate (inclusive of
complete response, partial response, and stable disease) of 36.7%.
In comparing hormonal therapy regimens, Ethier and colleagues found that progestins,
tamoxifen, and combinations of progestins and tamoxifen were all associated with similar
response rates of 21–24%. The complete response rates appeared to be higher in tamoxifen-
containing regimens compared to single-agent progestin. In three studies examining aro-
matase inhibitors the mean overall response rate was only 9%. Notably, in the included
phase II trial of anastrozole, more than 25% of the patients had nonendometrioid histologic
subtypes, the majority had grade 3 tumors, and only 22% of the patients had estrogen
receptor (ER)- and progesterone receptor (PR)-positive tumors. In the subset of women
with low-grade tumors with endometrioid histology, the response rate was 30%.
The importance of steroid hormone receptors was demonstrated in an analysis of seven
studies (n=184) where the mean response rate was 26.6% in patients with ER-positive
tumors as compared to just 9.2% in six studies (n=119) reporting on patients with ER-
negative tumors [2]. Similarly, in pooled estimates of patients with PR-positive tumors
receiving hormonal therapy, the mean response rate was 35.5% compared to just 12.1% in
those with PR-negative tumors.
Finally, combination strategies including novel agents have shown promise. For
example, combining hormonal agents such as letrozole with mTOR inhibitors (everolimus)
had a reported response rate of 32% with a median duration of response of 12.5 months [5].
The addition of metformin to everolimus and letrozole has also demonstrated promise with
a clinical benefit rate of 50% and overall response rate of 28% in 54 patients with advanced
or recurrent endometrioid or mixed-endometrioid histology enrolled in a phase II study [6].
In this study, PR-positive tumor status was associated with 90% and 45% clinical benefit and
overall response rate respectively. Finally, in a randomized placebo-controlled phase II trial,
the addition of palbociclib, a CDK4/6 inhibitor, to letrozole resulted in a disease control rate
at 24 weeks of 64% versus 38% in patients receiving palbociclib versus placebo [7].

218 Roni Nitecki and Pamela T. Soliman
Conclusion
Ultimately, while the majority of data support the use of hormonal therapy from both an
efficacy and toxicity standpoint, the clinical benefit of endocrine therapy has not been
completely defined, as the presence of steroid hormone receptors has not been fully
incorporated in clinical trials and methods determining hormone receptor status have not
been standardized. Because of the low toxicity profile and modest efficacy, hormonal agents
should be considered in patients with recurrent endometrial cancer, particularly those who
are not eligible for clinical trials with well-differentiated hormone receptor positive disease.
In addition, histologic type should be considered in the decision making for recurrent
therapy as response rates to hormonal therapy are higher in those with endometrioid
tumors. With novel combination strategies of hormonal agents and improved stratification
by presence of hormonal receptors, we expect hormonal agents to become even more
valuable in the care of patients with chemo-resistant endometrial cancer.
References
1. Lincoln S, et al. Activity of paclitaxel as 5. Slomovitz BM, et al. Phase II study of
second-line chemotherapy in endometrial everolimus and letrozole in patients with
carcinoma: a Gynecologic Oncology Group recurrent endometrial carcinoma. J Clin
study. Gynecol Oncol 2003;88:277–281. http Oncol 2015;33:930–936. https://doi.org/10
s://doi.org/10.1016/S0090-8258(02)00068-9 .1200/JCO.2014.58.3401
2. Ethier J-L, et al. Is hormonal therapy 6. Soliman PT, et al. Metformin in women with
effective in advanced endometrial cancer? advanced or recurrent endometrioid
A systematic review and meta-analysis. endometrial cancer: a multi-center, single
Gynecol Oncol 2017;147:158–166. https://doi arm, phase II study. Clin Cancer Res
.org/10.1016/j.ygyno.2017.07.002 2020;26:581–587. https://doi.org/10.1158/1
3. Decruze SB, et al. Hormone therapy in 078-0432.CCR-19-0471
advanced and recurrent endometrial cancer: 7. Mirza MR, et al. LBA28 A randomised
a systematic review, Int J Gynecol Cancer double-blind placebo-controlled phase II
2007;17:964–978. https://doi.org/10.1111/j trial of palbociclib combined with
.1525-1438.2007.00897.x letrozole (L) in patients (pts) with
4. Kokka F, et al. Hormonal therapy in oestrogen receptor-positive (ER+)
advanced or recurrent endometrial cancer. advanced/recurrent endometrial cancer
Cochrane Database Syst Rev 2010 (online). (EC): NSGO-PALEO / ENGOT-EN3
https://doi.org/10.1002/14651858 trial. Ann Oncol 2020;31:S1160. https://
.CD007926.pub2 doi.org/10.1016/j.annonc.2020.08.2258

Debate
Is Hormonal Therapy the Best
36B Therapy for Chemo-resistant

Endometrial Cancer?
No
Julianne Lima and Susana Banerjee
Debate
For recurrent/advanced endometrial cancer (EC), carboplatin in combination with pacli-
taxel remains the current first-line standard of care globally. In the NRG Oncology/GOG209
phase III trial, the median progression-free survival (PFS) and overall survival (OS) was 13
months and 37 months respectively (NRG/GOG209) [1]. Whilst hormonal therapy (HT)
may be the preferred front-line systemic therapy for selected patients with low-grade EC
carcinomas without rapidly progressive disease [2], we argue that the efficacy in advanced/
recurrent EC post chemotherapy (i.e., chemo-resistant) is limited and alternative options
should now be considered in clinical practice.
Endometrial cancer is a group of diseases harboring different biological features.
Estrogen receptor (ER) was the first biomarker identified in EC with prognostic and
potentially predictive implications. The first classification of EC divided into type I or
type II tumors based primarily on ER positivity or negativity, respectively.
Response rates from different endocrine agents (HT) were reported in a meta-analysis of
39 studies (n=1837) showing a mean overall response rate (ORR) of 21.6%, clinical benefit
rate (CBR) of 36.7%, median PFS of 2.8 months, and OS of 10.2 months in the first-line
setting [3]. In the second-line setting, ORR and CBR were 18.5% and 35.8%, respectively.
However, the CBR was found to be significantly impacted by different timing of radiological
assessments ranging from four to 24 weeks. Although hormonal receptor positivity was
associated with higher ORR particularly amongst those treated with tamoxifen (CBR >50%),
these studies were highly heterogeneous in terms of outcomes and standard measurements
of benefit [3]. For example, only three studies used RECIST criteria [4]. In a multivariate
analysis, previous response to HT and tumors with grade 1 were found to be potential
predictors of response to subsequent HT lines [3]. The association between previous HT
and greater ORR raises the possibility of re-treatment of good responders to first-line
hormonal therapy, influencing the clinical activity in subsequent lines. A prospective
phase II single-arm study of anastrozole 1 mg/day for patients with endocrine-naïve ER
and/or PR positive advanced/recurrent EC showed PFS of 3.2 months (95% CI: 2.8–5.4),
44% CBR (defined as objective response and stable disease of three months) (n=82) includ-
ing 7% (n=6) who derived a partial response (PR) [5].
The concept of endocrine-sensitive EC has been taken further with the use of CDK4/6
inhibitors in combination with HT. The results of the PALEO/ENGOT-EN3, a phase II,
randomized, placebo-controlled trial which evaluated the combination of letrozole and
219

220 Julianne Lima and Susana Banerjee
palbociclib in patients with ER+ endometrioid, EC post-progression to chemotherapy or ≤1

line of endocrine therapy (MPA/megestrol acetate), reported a significant PFS increase of
five months for the combination compared to letrozole alone (8.3 vs. 3.0 months, HR=0.56,
95% CI: 0.32–0.98, p=0.041) [5]. It would be of interest to see the clinical activity according
to molecular profile including mismatch repair/microsatellite instability (MMR/MSI) sta-
tus. However, although the dualistic classification of EC has highlighted the concept of
potentially endocrine-driven tumors, HT alone has not been shown to improve PFS or OS
post first-line progression so far [6,7].
Limiting toxicities are less common with HT compared to other systemic treatment (e.g.,
vomiting, myelosuppression, hair loss), which in daily practice, makes hormonal therapy
a valid option for patients with contraindications to other systemic therapies including
chemotherapy and immunotherapy or among women whose performance status is 2 or
greater.
The new molecular classification from The Cancer Genome Atlas (TCGA) has evolved
the understanding of EC, reframing the classification of EC into four genomic categories,
and incorporating new molecular biomarkers with prognostic and potentially predictive
implications into practice [6].
The four molecular subtypes described are: p53-abnormal (p53abn), polymerase epsilon
mutation (POLEmut), mismatch repair-deficient (MMRd), and nonspecific molecular
profile (NSMP) [8]. Among those, endometrioid histology was the most common histotype
found on MMRd tumors and NSMP subtype was associated with endometrioid grade 1 and
2, hormone-receptor positive tumors [6]. Of note, endometrioid histotypes were found to be
related with estrogen/progesterone receptor pathways, less frequently described in serous-
like subtypes, in which HER2 amplification was found in approximately 30% of cases.
MMRd or microsatellite instability-high (MSI-H) tumors represent 25–30% of EC. In
recurrent/advanced EC post first-line chemotherapy, MMRd/MSI-H status is the first
biomarker to be linked to approval of therapy based on the clinical activity of PD-1/-L1
inhibitors, changing clinical practice. The extent of clinical benefit reported with immuno-
therapy so far is superior to HT alone as summarized below.
In the KEYNOTE-158 study, pembrolizumab monotherapy led to an ORR of 57% (8%
complete responses) in MSI-H EC. The median duration of response was not reached (2.9 –
27.0+ months) [9]. In 2017, pembrolizumab received the approval from the Food and Drug
Administration (FDA) as tissue-agnostic therapy for metastatic MSI-H/MMRd solid
tumors which included endometrial cancer in post first-line progression setting.
Analysis of the phase I expansion cohort of the anti-PD1 inhibitor, dostarlimab, within
the GARNET trial (NCT02715284) reported a response rate of 44.7% which included 10.7%
with complete response in patients with MMRd EC who had progressed on first-line
platinum-based chemotherapy and had not received more than two lines of therapy
[7,10]. At the time of reporting (median follow-up 16.3 months), the median duration of
response had not been reached. In 2021, FDA and European Medicines Agency (EMA)
approved dostarlimab for women with MMRd recurrent or advanced endometrial cancer
who have progressed on or following prior treatment with platinum-based chemotherapy.
In 2022, the results of the phase III, randomized trial of lenvatinib with pembrolizumab
(KEYNOTE-775) set a new standard of care for patients with advanced/recurrent disease
who have had prior chemotherapy. This study (n=827) showed superior PFS [6.6 vs. 3.8
months (HR=0.6, p<0.0001) in mismatch repair-proficient (MMRp) subgroup as well as the
overall population 7.2 vs. 3.8 months (HR=0.56, p<0.001)] with lenvatinib and

Is Hormonal Therapy the Best? No 221
pembrolizumab versus physician’s choice of chemotherapy (doxorubicin or weekly pacli-

taxel). Similarly, OS was improved (17.4 vs. 12 months (HR=0.68, p<0.001)) for the MMRp
subgroup and overall population (18.3 vs. 11.4 months (HR=0.62, p<0.001)) [11].
Subsequent analysis reported an improvement in PFS (10.7 vs. 3.7 months (HR=0.36,
p<0.0001) and OS (HR=0.37, p<0.0001) for lenvatinib and pembrolizumab compared to
chemotherapy in MMRd population as well. The benefit of this nonchemotherapy combin-
ation was seen across endometrioid, serous, and clear cell histologies [12].
Anti-HER2 therapies have also shown encouraging results. A randomized phase II study
of trastuzumab in combination with carboplatin and paclitaxel followed by maintenance,
which included stage III/IV and recurrent HER-2 positive serous uterine carcinomas,
reported a 54% reduction in the risk of disease progression compared to chemotherapy
alone (HR=0.46; 90% CI: 0.28–0.76, p=0.005) and significantly longer OS with the addition
of trastuzumab (29.6 months vs. 24.4 months (HR=0.58; 90% CI: 0.34–0.99; p=0.046).
Among the subgroup of patients with recurrent disease (n=17), an improvement in median
PFS (7.0 vs. 9.2 months, HR=0.12, 90% CI: 0.03–0.48, p=0.004) but not OS was noted.
Conclusion
In conclusion, post progression on chemotherapy, immunotherapy, and targeted therapies
including endocrine agents are valid choices in clinical practice. However, the efficacy with
approved immunotherapy approaches is higher than hormonal therapy alone and should be
considered the preferred choice if available. The combination of pembrolizumab and
lenvatinib is a new standard of care following first-line chemotherapy in MMRp EC (FDA
and EMA approval) and MMRd EC (EMA). Dostarlimab monotherapy is approved for
MSI-H/MMRd EC. HT is an option for patients with slow-growing disease, co-morbidities,
or worse performance status. Clinical trials should be considered for all patients with
recurrent EC who have received prior chemotherapy. Anti-HER2 options and other tar-
geted therapies (e.g., ATR inhibitors) are under investigation. In the meantime, new
strategies of endocrine manipulation under investigation are likely to open new horizons
for therapeutic sequencing and redefine individualized management for EC patients, in
particular post immunotherapy.
References
1. Miller DS, et al. Carboplatin and paclitaxel progesterone (PR) positive endometrial
for advanced endometrial cancer: final cancer: The PARAGON trial–ANZGOG
overall survival and adverse event analysis of 0903. Gynecol Oncol 2019;154(1):29–37.
a phase III trial (NRG Oncology/GOG0209). 5. Mirza MR, et al. A randomised double-blind
J Clin Oncol 2020;38(33):3841–3850. placebo-controlled phase II trial of
2. Concin N, et al. ESGO/ESTRO/ESP palbociclib combined with letrozole (L) in
guidelines for the management of patients patients (pts) with oestrogen
with endometrial carcinoma. Int J Gynecol receptor-positive (ER plus) advanced/
Cancer 2021;31(1):12–39. recurrent endometrial cancer (EC): NSGO-
3. Ethier JL, et al. Is hormonal therapy effective PALEO/ENGOT-EN3 trial. Ann Oncol
in advanced endometrial cancer? 2020;31(Suppl. 4):S1160. https://doi.org/10
A systematic review and meta-analysis. .1016/annonc/annonc325
Gynecol Oncol 2017;147(1):158–166. 6. Leon-Castillo A, et al. Molecular
4. Mileshkin L, et al. Phase 2 study of classification of the PORTEC-3 trial for
anastrozole in recurrent estrogen (ER)/ high-risk endometrial cancer: impact on

222 Julianne Lima and Susana Banerjee
prognosis and benefit from adjuvant therapy. v403ev404. https://doi.org/10.1093/anno

J Clin Oncol 2020;38:3388e3397. nc/mdz25
https://doi.org/10.1200/JCO.20.00549 10. Oaknin A, et al. Safety and antitumor activity
7. Oaknin A, et al. Clinical activity and safety of of dostarlimab in patients with advanced or
the anti-programmed death 1 monoclonal recurrent DNA mismatch repair deficient
antibody dostarlimab for patients with (dMMR) or proficient (MMRp) endometrial
recurrent or advanced mismatch repaire- cancer (EC): results from GARNET. Ann
deficient endometrial cancer: Oncol 2020;31(Suppl. 4):S1142–S1215.
a nonrandomized phase 1 clinical trial. JAMA 10.1016/annonc/annonc325
Oncol 2020;6v11:1766e1772. 11. Makker V, et al. Study 309–KEYNOTE-775
https://doi.org/10.1001/jamaoncol.2020.4515 Investigators. Lenvatinib plus
8. Fader AN, et al. Randomized phase II pembrolizumab for advanced endometrial
trial of carboplatin-paclitaxel compared cancer. N Engl J Med 2022;386(5):437–448.
with carboplatin-paclitaxel-trastuzumab 12. Colombo N, et al. Outcomes by histology
in advanced (stage III-IV) or and prior therapy with lenvatinib plus
recurrent uterine serous carcinomas that pembrolizumab vs treatment of physician’s
overexpress Her2/Neu (NCT01367002): choice in patients with advanced
updated overall survival analysis. endometrial cancer (Study 309/
Clin Cancer Res 2020;26(15):3928e3935. KEYNOTE-775). Ann Oncol 2021;32
9. Omalley D, et al. KEYNOTE 158. (Suppl. 5):S725–S772. https://doi.org/10
Ann Oncol 2019;30(Suppl. 5): .1016/annonc/annonc703

Debate
Is there a Role for Using
37A Immunotherapy
in Endometrial Cancer?
Yes
Ana Oaknin, Lorena Farinas-Madrid,
and J. Francisco Grau
Debate
Endometrial cancer (EC) is the most common gynecologic malignancy in post-menopausal
women. Although early-stage disease is associated with an excellent prognosis, to date
patients with advanced or recurrent disease have poor survival outcomes. While first-line
chemotherapy based on carboplatin/paclitaxel regimen is well established, for those patients
who progressed on or after this therapy, until recently, treatment alternatives (hormonal
therapy and single-agent chemotherapy) have been limited and scarcely active. As current
therapeutic alternatives do not satisfy the criteria to be defined as a “treatment of choice,”
new therapeutic approaches are needed in the setting of recurrent/advanced EC, and
immune checkpoint inhibitors (ICI) seems to be one of the most promising.
The Cancer Genome Atlas (TCGA) Research Project, and subsequently the ProMisE
classification, identified two EC subtypes as highly immunogenic: polymerase-ε (POLE)
mutated (7% of EC) and microsatellite instability-high/mismatch repair-deficient (MSI-H/
MMRd) (30% of EC) subgroups [1,2]. The POLE mutated subtype (7%), characterized by
hotspot mutations of the catalytic subunit of DNA POLE, and MMRd, featuring sporadic or
hereditary alterations in mismatch repair system genes (MLH1, MSH2, MSH6, PMS2),
harbor common distinctive biological features. Both of them feature higher mutational rates
resulting in a large number of neoantigens, and a greater number of CD8+ tumor-
infiltrating lymphocytes (TIL). This immune microenvironment leads to a tumoral adaptive
immune-resistance response, which is defined by the upregulation of immune checkpoint
proteins by tumor and immune cells, such as PD-(L)1/2. Beyond these two EC subtypes,
other molecular subgroups with low mutation loads also display a TIL-high phenotype. This
robust biological rationale has supported the clinical development of immunotherapy in
advanced or recurrent EC, regardless of the molecular subtypes.
Following early evidence of pembrolizumab activity in MMRd tumors that led to its
approval by the FDA, the open-label multi-cohort study KEYNOTE-158 confirmed pem-
brolizumab’s efficacy in MMRd EC patients [3].
Subsequently, several phase 1 and 2 clinical trials have assessed different anti-PD-1/PD-
L1 antibodies in the advanced/recurrent setting.
The GARNET trial, the largest EC patient dataset treated with ICI to date, evaluated the
efficacy of dostarlimab (anti-PD-1 antibody) in 108 patients with MMRd and 156 with
mismatch repair-proficient (MMRp) recurrent or advanced EC, respectively. The confirmed
223

224 Ana Oaknin et al.
objective response rate (ORR) was 43.5% and 14.1% in patients with MMRd and MMRp,
respectively. Both median overall survival (mOS) and median progression-free survival (mPFS)
have not yet been reached in either cohort [4]. The dostarlimab efficacy outcomes have led to its
approval by the FDA and EMA for MSI-H/MMRd EC that has progressed after prior platinum-
based therapy. Besides, other anti-PD-(L)1 monotherapies, namely durvalumab and avelumab,
have demonstrated consistent clinical activity in MMRd EC patients, with an ORR of 43% and
26.7%, respectively.
While the efficacy of anti-PD-(L)1 agents in MMRd EC has been clearly demonstrated,
their activity is not encouraging in the MMRp population. Therefore, new venues have been
explored to increase the anti-PD-(L)1 agents’ efficacy, such as the combination with anti-
angiogenic agents.
In this context, mature clinical data on the combination of pembrolizumab and the oral
multikinase inhibitor lenvatinib in women with previously treated EC have been already
reported in the randomized phase 3 study KEYNOTE-775/Study 309. This trial compared
the lenvatinib and pembrolizumab regimen with physician’s choice chemotherapy. A total of
827 patients with advanced or recurrent EC (84% had MMRp/Microsatellite stable tumors)
who had received at least one prior platinum-based regimen were enrolled. For the MMRp
cohort and the all-comers population, the combination of lenvatinib and pembrolizumab was
statistically and clinically superior to chemotherapy for both primary end-points (PFS and OS).
mPFS was 6.6 versus 3.8 months (Hazard Ratio (HR)=0.60, 95% Confidence Interval (CI): 0.50–
0.72, p<0.001), and 7.2 versus 3.8 months (HR=0.56, 95% CI: 0.47–0.66, p<0.001); and mOS was
17.4 versus 12.0 months (HR=0.68; 95% CI: 0.56–0.84; p<0.001) and 18.3 versus 11.4 months
(HR=0.62; 95% CI: 0.51–0.75, p<0.001) in the MMRp and overall population, respectively. An
exploratory analysis in the MMRd population also demonstrated better outcomes in favor of
the combination. Interestingly, the confirmed ORR in this cohort was 40.0% (95% CI: 28–53%),
which, acknowledging the limitations of cross-trials comparisons, seems to be similar to that
achieved with ICI monotherapy in an akin patient population [5]. Based on KEYNOTE-775
outcomes, the pembrolizumab and lenvatinib regimen was FDA Fapproved for patients with
previously treated advanced EC that are not MSI-H/MMRd and by the EMA, for all-comers.
Beyond these clinical activity outcomes, introducing immunotherapy in the EC landscape
treatment is somehow part of the precision oncology. Predictive biomarkers as MMR deficiency
determined by immunohistochemistry and Tumor Mutational Burden status seem to correlate
significantly with objective responses. Nevertheless, about half of patients with MMRd/MSI-H
tumors do not derive yet any benefit from anti-PD-(L)1 antibodies or combination therapies.
Selecting the most appropriate approach for advanced/recurrent EC requires a balance
in activity and safety profile. In this regard, the rate of immunotherapy discontinuation due
to adverse events ranges from 10% to 18% depending on monotherapy or combination
regimens. However, the broader knowledge in the immune-related adverse events and their
management is leading to a better tolerability.
Conclusion
The arrival of immunotherapy in the recurrent/advanced EC treatment landscape is leading
to a shift in the therapeutic paradigm of this poor prognosis population and should
currently be considered as a treatment of choice after failure to platinum therapy, regardless
of MMR status. Further investigation on predictive biomarker is mandatory to uncover
potential mechanisms of immune escape and better select the candidates to ICI.

Immunotherapy? Yes 225
References
1. Kandoth C, et al. Cancer Genome the KEYNOTE-158 Study. J Clin Oncol
Atlas Research Network,Integrated 2022;40(7):752–761.
genomic characterization of 4. Oaknin A, et al. Clinical activity and safety
endometrial carcinoma. Nature 2013;497 of the anti-programmed death 1 monoclonal
(7447):67–73. antibody dostarlimab for patients with
2. Talhouk A, et al. Confirmation of ProMisE: recurrent or advanced mismatch
a simple, genomics-based clinical classifier repair-deficient endometrial cancer:
for endometrial cancer. Cancer 2017; 123 a nonrandomized phase 1 clinical trial.
(5):802–813. JAMA Oncol 2020;6(11):1766–1772.
3. O’Malley DM, et al. Pembrolizumab in 5. Makker V, et al. Lenvatinib plus

patients with microsatellite instability-high pembrolizumab for advanced endometrial
advanced endometrial cancer: results from cancer. N Engl J Med 2022;386(5):437–448.

Debate
Is there a Role for Using
37B Immunotherapy
in Endometrial Cancer?
No
William A. Zammarrelli III and Vicky Makker
Debate
Immune checkpoint blockade (ICB) therapy has emerged as a valuable treatment modality
for previously treated advanced or metastatic endometrial cancer (EC) that is mismatch
repair deficient (dMMR) or microsatellite instability-high (MSI-H), with impressive and
durable response rates seen in a significant proportion of patients. Conversely, a substantial
proportion of patients with dMMR/MSI-H EC will not derive benefit from these therapies.
It is vitally important to understand the mechanisms behind these disparate responses, as
a one-size-fits-all approach, even within the dMMR/MSI-H EC subgroup, cannot be
employed. Responses to ICB therapy in mismatch repair proficient (pMMR) or microsatel-
lite stable (MSS) EC have been disappointing, and ICB monotherapy in this setting has not
shown efficacy. Additional disadvantages of ICB therapy for the management of EC include
the following: a lack of more definitive biomarkers predictive of response; the potential for
long-term toxicity, which can necessitate the need for lifelong hormone replacement; a risk
of serious sequalae (e.g., colitis, insulin-dependent diabetes mellitus); and extensive finan-
cial cost. Caution is warranted when considering this class of therapeutics for patients with
EC, as there are still unanswered questions regarding their optimal use.
Approximately 2–4% of all cancers are dMMR, and only 17–33% of advanced or
recurrent ECs are dMMR/MSI-H [1,2]. Studies of the anti-PD-1 (anti-programmed cell
death protein 1) monoclonal antibodies pembrolizumab and dostarlimab have shown
efficacy in dMMR EC, with objective response rates (ORR) of 45–57% and median durations
of response (mDORs) not reached at data cut-off [2,3]. The anti-PDL-1 (anti-programmed
death ligand 1) agents avelumab (ORR=27%) and durvalumab (objective tumor response
rate, 47%) have also shown efficacy in dMMR EC [4,5]. However, most recurrent ECs are
pMMR, and response rates to ICB therapy in this setting have ranged from 3–13%,
indicating a clear lack of efficacy when used as monotherapy [3–5].
Our understanding of the optimal use of immune checkpoint inhibitors in the treatment
of EC is confounded by the lack of definitive biomarkers of response, which is of paramount
importance in order to maximize efficacy and minimize toxicity. Tumor mutational burden
(TMB) and tumor-infiltrating leukocytes (TILs) do not uniformly correlate with response to
ICB therapy, and while mutations in Janus kinase 1 (JAK1) and ß2-microglobulin (B2 M)
may correlate with resistance, a clearer understanding of the chief mechanisms of response
and resistance are needed [5]. The identification of molecular and tumor microenvironment
factors that correlate with response is also imperative, as ICB therapy is associated with
226

Immunotherapy? No 227
grade 3 or higher immune-related adverse events in up to 19% of patients [2–5]. Other

important issues to address include the optimal timing and length of ICB therapy; ICB
rechallenge after initial response and progression; and racial disparities in access to ICB
treatment, treatment response, and adverse events.
Although chemotherapy may induce tumor vulnerability to immunotherapy secondary
to apoptosis and increased tumor antigen presentation, diminished response to ICB mono-
therapy after increasing lines of previous therapy have been shown in EC and other
malignancies. In the PHAEDRA study, the ORR of durvalumab treatment in patients
with EC was higher after first-line compared to second-line or beyond treatment (57% vs.
38%, respectively) [4]. The timing of ICB therapy may impact response, and exposure to
prior therapies may lead to changes in the tumor microenvironment, with a reduction of
host immune response, all leading to lower responses to ICB therapy. This is an important
consideration, as there are now multiple front-line phase 3 trials evaluating platinum-
taxane-based chemotherapy in combination with ICB therapy.
While ICB monotherapy appears to be a promising option for a select group of patients
with dMMR advanced or metastatic EC, the lack of efficacy in a significant proportion of
both dMMR and pMMR patients highlights the need to explore combination therapeutic
approaches. In the phase 3 KEYNOTE-775/Study 309 trial, one such combination –
lenvatinib plus pembrolizumab – compared to physician’s choice demonstrated statistically
significant improvements in overall survival (17.4 vs. 12 months, respectively), progression-
free survival (6.5 vs. 3.8 months, respectively), and ORR (30% vs. 15%, respectively)
following platinum-based chemotherapy and regardless of MMR status [6]. Based on
these findings, this combination was recently FDA approved for the treatment of patients
with advanced EC that is not MSI-H or dMMR who experience disease progression
following prior systemic therapy in any setting [6]. This landmark development has ushered
in a new era of therapeutics for EC.
Conclusion
As the incidence and disease-related mortality of this heterogeneous disease continue to
rise, ICB combination therapies exploiting signaling pathways that dominate the genetics of
EC must be more thoroughly explored and identified.
References
1. Cortes-Ciriano I, et al. A molecular portrait from GARNET. J Immunother Cancer 2022
of microsatellite instability across multiple (online). https://doi.org/10.1136/jitc-2021-
cancers. Nat Commun 2017;8:15180. 003777
2. Marabelle A, et al. Efficacy of 4. Antill Y, et al. Clinical activity of
pembrolizumab in patients with durvalumab for patients with advanced
noncolorectal high microsatellite instability/ mismatch repair-deficient and
mismatch repair-deficient cancer: results repair-proficient endometrial cancer.
from the phase II KEYNOTE-158 Study. A nonrandomized phase 2 clinical trial.
J Clin Oncol 2020;38(1):1–10. J Immunother Cancer 2021;9(6):e002255.
3. Oaknin A, et al. Safety and antitumor 5. Konstantinopoulos PA, et al. Phase II study
activity of dostarlimab in patients (pts) with of avelumab in patients with mismatch
advanced or recurrent DNA mismatch repair deficient and mismatch repair
repair deficient (dMMR) or proficient proficient recurrent/persistent endometrial
(MMRp) endometrial cancer (EC): results cancer. J Clin Oncol 2019;37(30):2786–2794.

228 William A. Zammarrelli III and Vicky Makker
6. Makker V, et al. A multicenter, open-label, with advanced endometrial cancer: Study

randomized phase 3 study to compare the 309/KEYNOTE-775. Society of Gynecologic
efficacy and safety of lenvatinib in Oncology 2021 Virtual Annual Meeting on
combination with pembrolizumab vs Women’s Cancer. Abstract 37/ID 11512.
treatment of physician’s choice in patients Presented March 19, 2021.

Debate
What is the Best

for Uterine Carcinosarcoma?
Carboplatin/Paclitaxel
Domenica Lorusso
Debate
Uterine carcinosarcoma (UCS), previously known as mixed mesodermal tumor, is a rare (2–
3% of uterine cancers) endometrial neoplasm in which both the adenomatous as well as the
stromal (mesenchymal) elements of the endometrium are malignant. The most frequent
epithelial element consists of a poorly differentiated serous carcinoma and the most
common sarcomatous component is represented by high-grade stromal sarcoma. For
several years mixed mullerian tumors were considered biphasic tumors with epithelial
and mesenchymal components; the current concept is that most UCSs are monoclonal
epithelial neoplasms with metaplastic degeneration. Accordingly, the precursor (stem) cell
is the origin of both the epithelial and mesenchymal components during histogenesis, but
the dominant epithelial component dictates the behavior of the tumor, thus suggesting that
drugs with proven efficacy against uterine epithelial tumors should represent the first
treatment choice [1].
The clinical behavior of UCS resembles that of Grade 3 endometrial endometrioid
adenocarcinoma with a worse prognosis. Disease stage is the most important prognostic
factor: only 40–60% of women with carcinosarcoma present with stage I or II disease, and
even when tumor is apparently confined to the uterus, metastases can be found in up to
60% [1].
Adjuvant chemotherapy is indicated in all stages of UCS even in stage I, as the
recurrence rate is as high as 50%. Adjuvant pelvic external irradiation or brachytherapy
reduces the rate of local recurrences without impacting on overall survival (OS) because
the recurrences are mostly distally [2].
Traditionally, when UCS was considered a biphasic neoplasm, the most common
chemotherapy agents used were platinum and ifosfamide with the aim of using the most
active available drugs against the epithelial and mesenchymal component of the neoplasia,
respectively. Unfortunately, in the metastatic setting, the combination registered moder-
ate activity with short progression-free survival (PFS) and duration of response, and
impressive toxicity particularly in terms of leukopenia, gastrointestinal and neurologic
toxicity [2].
Subsequently, paclitaxel was introduced in the treatment strategy. A GOG prospective
randomized phase III trial in 214 stage III–IV persistent or recurrent UCS patients reported
a significant five-month increase in OS for the ifosfamide-paclitaxel combination compared
to ifosfamide alone [3] with a 31% decrease in the hazard ratio (HR) for death and a 29%
229

230 Domenica Lorusso
decrease in HR for progression, consecrating ifosfamide-paclitaxel combination as the new

standard treatment.
Several studies found that carboplatin-paclitaxel is an effective regimen when used either
in the metastatic setting, where up to 54% objective response rate (ORR) was reported, or as
adjuvant treatment where a four-year PFS and OS of 67.9% and 76.0 %, respectively, were
reported. In all the published trials, the authors commonly concluded that the combination
of paclitaxel and carboplatin was a feasible and effective therapy for patients with UCS and
presented better tolerability and response rates compared with previous reports of ifosfa-
mide/cisplatin or ifosfamide/paclitaxel doublets [3].
A retrospective cohort study evaluated the activity and toxicity of cisplatin-ifosfamide
(group A) and carboplatin-paclitaxel (group B) as adjuvant treatments in 65 patients with
UCS. At a median follow-up of 30 months, the median PFS was 11.6 and 16.6 months
(p=0.20), and the median OS was 17.1 months and 35.1 months (p=0.14) for groups A and
B, respectively. No differences were identified among heterologous or homologous compo-
nents according to chemotherapy treatment and toxicity profiles widely differ between
treatment arms favoring the carboplatin-paclitaxel combination. The authors concluded
that because of the super imposable activity and the better toxicity profile, carboplatin-
paclitaxel could be considered a suitable alternative to cisplatin-ifosfamide in the treatment
of UCS [4].
At ASCO 2019 the results of a randomized phase III trial comparing paclitaxel-
carboplatin versus paclitaxel-ifosfamide in 449 patients with stage I–IV uterine and
ovarian CS were reported [5]. In the primary UCS cohort, median OS was 37 and 29
months for patients receiving paclitaxel/carboplatin and paclitaxel/ifosfamide, respect-
ively (HR=0.87, p<.01 for noninferiority). Additionally, the median PFS was 16 and 12
months for women who received paclitaxel/carboplatin and paclitaxel/ifosfamide,
respectively (HR=0.73; p=<.01 for noninferiority). The investigators reported increased
hematologic toxicity for the paclitaxel/carboplatin treatment, while neurologic toxicity
and genitourinary hemorrhage were significantly worse with paclitaxel/ifosfamide com-
bination. During treatment, both groups experienced a similar decline in quality of life
and increased neurotoxicity symptoms. A similar trend was observed in the smaller,
secondary cohort of patients with ovarian carcinosarcoma, with a 30-month median OS
in the paclitaxel/carboplatin arm versus 25 months in the paclitaxel/ifosfamide arm and
15-month median PFS for the paclitaxel/carboplatin arm versus 10 months for the
paclitaxel/ifosfamide arm. The authors concluded that paclitaxel/carboplatin was not
inferior to paclitaxel/ifosfamide based on the primary end-point OS, and paclitaxel/
carboplatin was associated with longer PFS and a more manageable toxicity profile
when compared with paclitaxel/ifosfamide and should be considered the new standard
treatment.
Conclusion
In conclusion, the epithelial nature of the tumor (suggesting that drugs with proven activity
toward epithelial cells should represent the first choice when establishing treatment), the
efficacy data coming from retrospective and prospective trials, the manageable toxicity
profile, and the comfortable 3-weekly schedule given in an outpatient setting, prompt the
author to conclude that carboplatin-paclitaxel should be considered the standard of care in
UCS treatment strategy.

Best Chemotherapy Regimen? Carboplatin/Paclitaxel 231
References
1. Denschlag D, et al. Uterine carcinosarcomas – 4. Lorusso D, et al. Carboplatin-paclitaxel
diagnosis and management. Oncol Res Treat versus cisplatin-ifosfamide in the treatment
2018;41(11):675–679. of uterine carcinosarcoma: a retrospective
cohort study. Int J Gynecol Cancer 2014;24
2. Menczer J. Review of recommended (7):1256–1261.
treatment of uterine carcinosarcoma. Curr
Treat Options Oncol 2015;16(11):53 5. Powell MA, et al. A randomized phase 3 trial
of paclitaxel (P) plus carboplatin (C) versus
3. Berton-Rigaud D, et al. Gynecologic Cancer paclitaxel plus ifosfamide (I) in chemotherapy-
InterGroup (GCIG) consensus review for naive patients with stage I–IV, persistent or
uterine and ovarian carcinosarcoma. recurrent carcinosarcoma of the uterus or
Int J Gynecol Cancer 2014;24(9 Suppl. 3): ovary: an NRG Oncology trial. JCO 2019;37
S55–60. (15):5500.

Debate
What is the Best

for Uterine Carcinosarcoma?
The Case for “Other” Regimens
Sara Bouberhan, Whitfield B. Growdon,
and Richard T. Penson
Debate
Carcinosarcomas have fascinated pathologists and clinicians alike since they were first
described by Virchow in 1863. Improved understanding of the molecular underpinnings
of these rare tumors has led to a treatment paradigm shift for women with uterine
carcinosarcoma away from a sarcoma-focused approach to that of a high-grade, metaplastic
carcinoma. In this regard, the reported Gynecologic Oncology Group (GOG)-261 clinical
trial established carboplatin and paclitaxel as the standard first-line treatment for women
with uterine carcinosarcoma (UCS). The doublet combination of carboplatin and paclitaxel
was well-tolerated and demonstrated favorable progression-free survival (PFS) and overall
survival (OS) when compared to ifosfamide and paclitaxel [1]. We agree that carboplatin
and paclitaxel should be strongly considered as a first-line treatment regimen for all women
with UCS.
While the combination of carboplatin and paclitaxel gives us another option for the
treatment of UCS, it provides only incremental benefits and does not improve OS. In the
primary uterine carcinosarcoma cohort of GOG-261, median OS, while numerically better
for paclitaxel/carboplatin, was not statistically different from paclitaxel/ifosfamide
(HR=0.87, p<.01 for noninferiority, p>.1 for superiority). While grade ≥3 toxicities
occurred in 90% of subjects receiving carboplatin/paclitaxel as opposed to 65% receiving
ifosfamide/paclitaxel, formal evaluations of quality of life were not different. The results of
GOG-261 confirm the observation that no advance in the last 10 years has resulted in
a meaningful improvement in OS for patients with UCS [1,2] highlighting the desperate
need for the development of alternative treatment approaches to improve outcomes for
women with this rare disease.
Molecular characterization of UCS commonly reveals several potentially actionable
mutations, including alterations in the phosphatidylinositol 3-kinase (PI3K) pathway,
ARID1A/B, ATM, BRCA2, ERBB2, and ERBB3 [3,4]. While TP53 is the most common
genetic aberration (>90%), approximately half of UCS have mutations in at least one PI3K
pathway genes [3]. Biomarker-driven combination studies with CDK inhibitors and PI3K
inhibitors show promise and could be applied to UCS in future studies. Alterations of
chromatin remodeling genes (ARID1A/B) or in histone H2A and H2B genes [4] suggest that
epigenetic modifiers may be effective, and we are presently investigating PLX2853 as an
orally active, small molecule inhibitor of BET bromodomain-mediated interactions in
232

Best Chemotherapy Regimen? Other 233
ARID1A mutated tumors. Perhaps the most exciting development has been the increase in
understanding of the epithelial-mesenchymal transition (EMT) that may be at the heart of
the metaplastic transformation of carcinomas into carcinosarcoma. We eagerly await
advances in therapeutics targeting the EMT process.
Tissue-of-origin agnostic treatment approaches may be another underexplored strategy
to treat UCS. While rare, microsatellite instability and POLE mutations have been reported
in UCS [3]. These patients may be candidates for treatment with pembrolizumab, and
testing for both microsatellite instability and tumor mutation burden is reasonable in the
recurrent disease setting. Several emerging treatment approaches studied in other tumor
types could be applied to UCS. Enhancer of zeste homolog 2 (EZH2) works as a master
regulator of cell cycle progression, autophagy, and apoptosis and may be a very good target
in carcinosarcoma. The role for immunotherapy in UCS has not yet been established, but
agents such as defactinib which targets FAK and PYK2 may reduce tumor survival signals
and make cold tumors immunologically hot.
Conclusion
The current status of therapy for carcinosarcomas is clearly inadequate and we cannot be
complacent about ineffective standards of care. We must apply advances from bench-to-
bedside research to develop a better regimen than carboplatin and paclitaxel. The lack of
clinical data to support regimens other than platinum-taxane and ifosfamide-based chemo-
therapy is notable. The rarity of UCS and its aggressive clinical course have made development
of carcinosarcoma-specific trials challenging. Moreover, many trials of novel and targeted
therapies all too often exclude UCS patients, focusing rather on the activity of novel therapies
in endometrioid or serous histology tumors. If new therapeutic strategies are to emerge,
women with UCS must be enrolled in dedicated clinical trials that seek to exploit the various
molecular signatures that are prevalent in these complex, metaplastic carcinomas.
References
1. Powell MA, et al. A randomized phase 3 trial 3. Cherniack AD, et al. Integrated molecular
of paclitaxel (P) plus carboplatin (C) versus characterization of uterine
paclitaxel plus ifosfamide (I) in carcinosarcoma. Cancer Cell 2017;31
chemotherapy-naive patients with s-IV, (3):411–423. https://doi.org/10.1016/j
persistent or recurrent carcinosarcoma of .ccell.2017.02.010
the uterus or ovary: an NRG Oncology trial. 4. Zhao S, et al. Mutational landscape of
J Clin Oncol 2022;40(9):968–977. uterine and ovarian carcinosarcomas
2. Berton-Rigaud D, et al. Gynecologic Cancer implicates histone genes in
InterGroup (GCIG) consensus review for epithelial-mesenchymal transition. Proc
uterine and ovarian carcinosarcoma. Natl Acad Sci U S A 2016;113
Int J Gynecol Cancer 2014;24(9 Suppl. 3): (43):12238–12243. https://doi.org/10.1073/
S55–60. pnas.1614120113

Debate
39A for Premenopausal Women

with Early-stage Uterine
Leiomyosarcoma Status Post
Uterine Leiomyomas?
Oophorectomy
Anastasios Tranoulis, Kavita Singh, and Janos
Balega
Debate
Oophorectomy Should be Considered as Standard for Patients
with Estrogen-/Progesterone- positive Leiomyosarcoma
Surgery represents the mainstay of treatment for uterine leiomyosarcomas (u-LMS) [1].
Resection of disease without fragmentation and with negative surgical margins seemingly
provides survival advantage [1]. For macroscopically uterus-limited disease, total abdom-
inal hysterectomy (TAH) should be considered as the standard management of choice [1].
Uterine leiomyosarcomas usually are discovered as incidental findings after hysterectomy
or myomectomy for presumed benign pathology (e.g., fibroid uterus). For peri-menopausal
or post-menopausal women, routine bilateral salpingo-oophorectomy (BSO) is usually
performed; however, amongst pre-menopausal women with uterus-limited disease, the
role of ovarian preservation (OP), as part of the staging process, remains to date a field of
contention. The Gynecologic Cancer InterGroup (GCIG) recommends that BSO is reason-
able and could also be offered in pre-menopausal women with apparent uterine-limited
LMS [1].
Overall, the risk of ovarian metastasis has been reported 4%, although most cases coexist
with peritoneal spread [1,2]. Recurrence rates even for early-stage disease are high, ranging
from 53% to 71% [2]. Estrogen and/or progesterone receptors have been found to be
positive in 40% to 70% of u-LMS [2]. The Memorial Sloan Kettering Cancer group reported
that the majority of u-LMS expressed estrogen (ER), progesterone (PR), and androgen (AR)
receptor [3]. After adjusting for stage, PR and AR status was found to be predictive of
a lower risk of recurrence. However, ER, PR, and AR were not found to be associated with
overall survival (OS) after adjustment for stage [2]. In a more recent study from the same
group, ER/PR expression was found to be associated with survival outcomes in 43 women
234

Management for Premenopausal Women? Oophorectomy 235
with high-grade uterine-limited LMS [4]. PR expression was associated with both improved
progression-free survival (PFS) and OS in the overall cohort analysis, whilst ER expression
was not statistically associated with either PFS or OS. Nonetheless, after adjusting for stage
(disease confined to the uterine body), ER expression was associated with improved PFS but
not OS, while PR expression maintained its association with PFS and approached significant
association with OS [4].
These findings suggest that ER/PR activation may play an important role in tumor
development in u-LMS. There is a growing body of evidence on the role of hormonal
treatment – especially of aromatase inhibitors – on patients with low disease burden
u-LMS [1,2]. Several studies have shown objective response rates and improvement in PFS
amongst women with u-LMS treated with aromatase inhibitors such as anastrozole or
letrozole [1,2]. ER/PR appear to have a pivotal role in regulating the growth and remodel-
ing of uterine smooth muscle, thus, necessitating a shift in the focus of future research into
understanding the potential role of targeting steroid hormone receptors as therapeutic
options in u-LMS. To this end, better understanding of the role of ER/PR may also guide
clinicians to decipher the circumstances under which oophorectomy may benefit the
outcome.
On the other hand, a retrospective review of 1395 u-LMS patients showed that OP did
not have a significant impact on OS, whilst independent predictors for PFS included age,
race, stage, grade, and primary surgery [5]. In their SEER (Surveillance, Epidemiology,
and End Results) review, Nasioudis et al. sought to ascertain the prognostic role of OP
amongst 800 women with apparent FIGO stage I u-LMS [6]. The authors reported that
approximately one third of all women did not undergo oophorectomy and that OP was
not associated with either worse OS or PFS. These findings are also supported from
smaller retrospective studies; yet, these are constrained by the small number of women
included in addition to the lack of controlling for age, FIGO stage, and adjuvant treat-
ment [6].
Conclusion
Currently, there is no consensus on the prognostic significance of OP in women with early-
stage u-LMS. In light of the limited quality of the available data, deriving only from
retrospective studies, the risks and benefits of OP should be thoroughly discussed with
the patient and OP may be offered only in selected cases with documented negative
endocrine receptor status until more robust evidence becomes available.
References
1. Hensley ML, et al. Gynecologic Cancer 3. Leitao MM, et al. Tissue microarray
InterGroup (GCIG) consensus review: immunohistochemical expression of
uterine and ovarian leiomyosarcomas. estrogen, progesterone, and androgen
Int J Gynecol Cancer 2014;9(Suppl. 3): receptors in uterine leiomyomata
S61–66. and leiomyosarcoma. Cancer
2. Zivanovic O, et al. A nomogram to 2004;101:1455.
predict post resection 5-year overall 4. Leitao MM, et al. O outcomes in patients
survival for patients with with newly diagnosed uterine
uterine leiomyosarcoma. Cancer leiomyosarcoma. Gynecol Oncol
2012;118:660–669. 2012;124:558–562.

236 Anastasios Tranoulis et al.
5. Kapp DS, et al. Prognostic factors and 6. Nasioudis D, et al. Safety of

survival in 1396 patients with uterine ovarian preservation in
leiomyosarcomas: emphasis on impact of premenopausal women with stage
lymphadenectomy and oophorectomy. I uterine sarcoma. J Gynecol Oncol
Cancer 2008;112:820–830. 2017;28(4):e46.

Debate
39B for Premenopausal Women

with Early-stage Uterine
Leiomyosarcoma Status Post
Uterine Leiomyomas?
Ovarian Preservation
Melissa K. Frey and Ryan M. Kahn
Debate
Uterine sarcomas are a rare subgroup of malignancies that comprise 3–7% of uterine
neoplasms and just nearly 1% percent of all gynecologic cancers [1]. Leiomyosarcomas
(LMS) of the uterus, which arise from the smooth muscle of the myometrium, are aggressive
malignancies with high rates of recurrence. Uterine LMS has been historically difficult to
diagnose pre-operatively. Both uterine leiomyoma and LMS share common presenting
symptoms including abnormal uterine bleeding, large pelvic masses, lower abdominal
pain, and abdominal distension. Because of this, the diagnosis of uterine LMS is commonly
made upon pathology evaluation after myomectomy or hysterectomy for suspected benign
disease.
The mainstay of local treatment for uterine LMS is complete tumor resection with
surgical excision. As the median age of diagnosis for uterine LMS is relatively young (54
years), many newly diagnosed women are premenopausal and must decide on ovarian
preservation [1]. Uterine LMS commonly expresses estrogen (ER) and progesterone (PR)
receptors; therefore, many have supported iatrogenic menopause through bilateral oophor-
ectomy to reduce the possibility of tumor recurrence and growth from stimulation of
endogenous steroid hormones. However, given the rarity of this tumor and inconclusive
data, the role of oophorectomy in premenopausal women with uterine LMS remains
controversial.
One of the initial studies investigating the prevalence of ER and PR receptors in uterine
LMS demonstrated that steroid receptor expression showed no significant association
with clinicopathologic outcomes [2]. Bodner et al. [2] reviewed 21 patients with uterine
LMS and found ER and PR positivity exhibited in 57% and 43% of cases, respectively.
Although a large portion of LMS cases exhibited positive ER and PR expression, the
presence of steroid receptors was not associated with any of the factors studied including
age of diagnosis, clinical stage, vascular involvement, disease recurrence, disease-free
237

238 Melissa K. Frey and Ryan M. Kahn
survival, and overall survival (p>0.05). That lack of association between receptor and
prognosis has led to the hypothesis that ER and PR are not the driving receptors for these
malignancies.
Similarly, Giuntoli et al. [3] evaluated the surgical management and associated out-
comes for uterine LMS. This case-control study comprised of 25 patients who maintained
ovarian function versus 25 matched cases who underwent bilateral salpingo-
oophorectomy (BSO). Kaplan–Meier analysis of disease-specific survival among the
matched ovarian preservation cases (mean >30 years) compared to controls (mean >30
years) demonstrated no significant difference (p=0.49) [3]. Likewise, mean recurrence-
free survival between ovarian preservation compared to the BSO cohort demonstrated no
significant difference (p=0.97) [3]. However, it should be noted that the exclusion criteria
for the case group included adjuvant pelvic radiation therapy, whereas 24% (6/25) of
women in the control group received some form of radiation therapy. This difference
could have led to potential bias favoring oophorectomy.
Nearly 15 years later, Nasioudis et al. [4] performed a large population-based study,
using the National Cancer Institute’s Surveillance, Epidemiology, and End Results data-
base, evaluating survival differences between uterine LMS patients undergoing ovarian
preservation versus BSO among premenopausal women diagnosed with stage I disease.
The search identified 800 women, aged <50 years, diagnosed between the timeframe of
1988–2013, with LMS limited to the uterus. Within this cohort, women with ovarian
preservation had better five-year overall survival (OS) rates as compared to the oophorec-
tomy group (72.8% vs. 68.9%). Likewise, women with ovarian perseveration had greater
cancer-specific survival (CSS) rates as compared to oophorectomy (74.2% vs. 70.8%).
However, these rates were not statistically significant (OS, p=0.078; CSS p=0.098).
Additionally, after controlling for age and FIGO staging, ovarian preservation was not
associated with a change in overall survival as compared to BSO (p=0.23) or cancer-
specific mortality (p=0.34) [4].
Another large-scale observational cohort study – conducted by Seagle et al. [1] investi-
gated 7455 cases of uterine LMS from the National Cancer Database reported between
1998–2013 [1]. Among all patients, 762 underwent hysterectomy without oophorectomy
(10.2%) [1]. Women with ovarian preservation were younger (median 46 years) as com-
pared to those with oophorectomy (median 55 years) (p<0.001). Ovarian preservation
demonstrated no difference in survival in event time ratio among women <51 years old at
diagnosis when compared to bilateral oophorectomy (p=0.48) [1]. This study demonstrates
that removal of bilateral ovaries may be safely omitted for early-stage uterine LMS.
Conclusion
Based on the current literature, there appears to be no added benefit of removing bilateral
ovaries following the diagnosis of early stage uterine LMS in premenopausal women. In
addition, there remains minimal data demonstrating any increased risk of recurrence or
tumor growth following ovarian preservation in this patient population. Given this, the
2019 European Society for Medical Clinical Practice Guidelines for uterine LMS recom-
mend that the added value of BSO is not established, particularly in pre-menopausal
women [5]. This form of management must be balanced with shared decision making and
extensive counseling. If the ovaries are preserved, close long-term follow-up is vitally
important.

Mx for Premenopausal Women? Ovarian Preservation 239
References
1. Seagle BL, et al. Prognosis and treatment of therapy. Gynecol Oncol 2003;89
uterine leiomyosarcoma: a National Cancer (3):460–469.
Database study. Gynecol Oncol 2017;145 4. Nasioudis D, et al. Safety of ovarian
(1):61–70. preservation in premenopausal women with
2. Bodner K, et al. Estrogen and progesterone stage I uterine sarcoma. J Gynecol Oncol
receptor expression in patients with uterine 2017;28(4):e46. https://doi.org/10.3802/jgo
smooth muscle tumors. Fertil Steril 2004;81 .2017.28.e46
(4):1062–1066. 5. ESMO/European Sarcoma Network
3. Giuntoli RL, et al. Retrospective review Working Group. Soft tissue and visceral
of 208 patients with leiomyosarcoma sarcomas: ESMO clinical practice guidelines
of the uterus: prognostic indicators, for diagnosis, treatment and follow-up. Ann
surgical management, and adjuvant Oncol 2014;25(Suppl. 3):iii102–112.

Debate
Should Primary Debulking
40A Surgery be Performed

for Metastatic
Leiomyosarcoma?
Yes
Sumer K. Wallace and Jamie N. Bakkum-Gamez
Debate
Surgical resection is the standard of care in the setting of early stage uterine leiomyosarcoma
(uLMS). Additionally, hysterectomy is often also the primary diagnostic procedure for
uterine-confined LMS given the limitations of imaging in the diagnostic setting and the
lack of any other biomarkers that differentiate uLMS from the more common benign
uterine leiomyoma. Although the majority of patients with uLMS have uterine-confined
disease, 30–40% of patients will have extrauterine disease at the time of presentation [1–3].
Limited ability to discern uLMS preoperatively on imaging may lead to encountering
unanticipated metastatic abdominopelvic disease. This may lead to consideration of add-
itional surgery for debulking of extrauterine disease discovered either during surgery or on
postoperative imaging. Primary surgery for uLMS consists of, at minimum, hysterectomy
and bilateral salpingectomy with consideration of bilateral oophorectomy, although uLMS
are typically not hormone-responsive sarcomas. Lymph node basins should be evaluated for
lymphadenopathy, but systematic lymphadenectomy is not required as the rate of uLMS
metastasis to lymph nodes is <5% [2]. Ideally, primary surgery would be performed after
a comprehensive workup such that all sites of uLMS metastases are known. This also ensures
that a primary surgical approach is appropriate for the patient. However, as previously
noted, apparent early stage uLMS is most often diagnosed after hysterectomy for presumed
benign leiomyomata. In this setting, operative details and postoperative imaging will guide
whether further surgical intervention is recommended, as stage is the most accurate
measure of prognosis [1,3].
Due to the poor prognosis for uLMS, adjuvant treatment is often recommended despite
the limited efficacy and paucity of overall survival (OS) benefit. Observation is the current
standard of care for stage I uLMS following R0 resection and it remains unknown whether
systemic therapy improves survival in stage I uLMS. Multi-modality treatment with surgery,
chemotherapy, and/or radiation is often utilized in the management of advanced stage
uLMS. Cytotoxic chemotherapy agents, such as doxorubicin, docetaxel, gemcitabine, and
ifosfamide, are active in uLMS and often recommended for treatment of advanced stage
disease; however, recurrence rates remain high despite adjuvant chemotherapy with no
demonstration of improved OS in the current literature [1,4]. Similarly, while adjuvant
radiation may improve local control, it has not been shown to increase OS [5]. As such,
240

Debulking for Metastatic Leiomyosarcoma? Yes 241
innovative and progressive therapeutic modalities that address frequent sites of spread, such
as metastases to the liver and lung, are important in the uLMS armamentarium.
Given the potential survival advantage associated with debulking, resection to R0 remains an
essential prognostic component of treatment planning for uLMS. However, the risks of surgical
complications and morbidity need to be balanced with the potential oncologic benefits. In the
setting of oligometastatic disease, surgery may only require a low complexity operation.
However, given the hematogenous spread pattern of LMS, surgical debulking may require
resection of hepatic or pulmonary metastases to achieve R0 resection. A recent review of the
literature confirmed the importance of complete surgical resection, when feasible, prior to
considering further treatment with chemotherapy or radiation [4]. This review reiterated the
lack of efficacy of chemotherapy and radiation in improving survival in uLMS patients, and
discussed the importance of surgical management for patients in which R0 resection can be
achieved. Additionally, based on retrospective and limited prospective data solely in uLMS,
women with disease that is amenable to complete surgical resection appear to fare better from
the oncologic standpoints of progression-free survival (PFS), OS and even cure [2,4]. Surgical
clinical trial data in uLMS alone is limited, with the majority of available data being retrospective
due to the rare nature of the disease. Therefore, primary surgical resection data in the setting of
metastatic uLMS is often extrapolated from clinical studies that include heterogeneous uterine
sarcoma histologies or LMS from various primary tissue origins. Burt et al. demonstrated that
resection of pulmonary metastases from primary LMS yielded improved OS when compared to
non-LMS sarcoma metastases (69.9 months and 23.9 months, respectively). Uterine LMS
comprised 42% of this study population, and pulmonary metastases from LMS were relatively
indolent in nature compared to other types of sarcoma metastases which may have contributed
to the improved OS [6]. While OS outcomes appear mixed, in good surgical candidates who are
deemed to have resectable disease, a maximal surgical cytoreduction effort that achieves an R0
resection offers improved PFS outcomes and potentially extends OS [2,3].
It is also important to recognize that there may be a role for palliative hysterectomy in
those with known metastatic disease and uterine symptoms of pain and/or bleeding in which
quality of life could be improved with hysterectomy. Such surgical management requires
weighing benefits with surgical risks, mode of hysterectomy, and assessment as to whether
surgery will impact the timing of initiation of systemic therapy for unresectable disease.
Conclusion
In summary, multimodality management of uLMS is often recommended with the goal of
optimizing OS in this highly lethal cancer. While current adjuvant therapy options seem to
have limited impact, and novel active systemic agents are desperately needed for metastatic
uLMS, upfront surgical excision of advanced stage uLMS amenable to R0 resection appears
to extend PFS and OS. Therefore, a comprehensive workup for metastatic disease is critical
in the setting of a new uLMS diagnosis so that individualized treatment, which may include
upfront aggressive surgical resection, can be considered.
References
1. Hensley ML, et al. Adjuvant gemcitabine 2. Dinh TA, et al. The treatment of uterine
plus docetaxel for completely resected stages leiomyosarcoma. Results from a 10-year
I–IV high-grade uterine leiomyosarcoma: experience (1990–1999) at the
results of a prospective study. Gynecol Oncol Massachusetts General Hospital. Gynecol
2009;112:563. Oncol 2004;92:648–652.

242 Sumer K. Wallace and Jamie N. Bakkum-Gamez
3. Leitao MM Jr, et al. Surgical cytoreduction radiotherapy in the treatment of uterine

in patients with metastatic uterine sarcomas stage I and II: a European
leiomyosarcoma at the time of initial Organisation for Research and Treatment of
diagnosis. Gynecol Oncol 2012;125 Cancer Gynaecological Cancer Group Study
(2):409–413. (protocol 55874). Eur J Cancer
4. Friedman CF, et al. Options for adjuvant 2008;44:808–818.
therapy for uterine leiomyosarcoma. Curr 6. Burt BM, et al. Repeated and aggressive
Treat Options Oncol 2018;19(2):7. pulmonary resections for leiomyosarcoma
5. Reed NS, et al. Phase III randomized study metastases extends survival. Ann Thorac
to evaluate the role of adjuvant pelvic Surg 2011;92:1207.

Debate
Should Primary Debulking
40B Surgery be Performed

for Metastatic
Leiomyosarcoma?
No
Beatrice Seddon
Debate
Gynecological sarcomas are rare tumors, with tumors of uterine origin being the most
common. Leiomyosarcoma is the most common subtype of uterine sarcoma, with 2383 new
diagnoses in England between 1985 and 2008 (approximately 100 cases per year), account-
ing for 54% of all uterine sarcomas and 86% of all gynecological leiomyosarcomas. Other
rarer sites of origin include leiomyosarcoma of the vulva, vagina, cervix, broad ligament and
ovary. The age-specific incidence rates are highest in women aged 50 to 64 years [1].
Approximately two thirds of women present with FIGO stage I disease, and approximately
20% with distant metastatic disease [2].
For patients presenting with localized disease, the most important component of
treatment is surgery, which for the commonest group of uterine tumors is a hysterectomy
[3]. Incidence of lymph node or ovarian metastases is low such that routine lymphadenect-
omy and removal of ovaries are not mandatory, and indeed do not improve survival [2]. For
patients with gynecological sarcomas presenting with metastatic disease, the question arises
as to whether these patients should have surgery to remove the primary tumor at diagnosis,
or whether they should receive palliative chemotherapy or radiotherapy for their metasta-
ses. There is some evidence that for patients with metastatic disease undergoing surgical
cytoreduction of disease at diagnosis, surgery is associated with improved progression-free
survival compared with patients not undergoing surgery [4].
There are arguments for and against surgery to remove the primary tumor in the
metastatic setting. Outcomes for patients presenting with metastatic disease are poor,
with median survival of 12 to 18 months, often less for patients with aggressive disease.
Therefore the priority for patients with rapidly progressing disease is often to start chemo-
therapy as soon as possible, in order to try to achieve some stability of the metastatic disease,
and thereby to prolong survival [5]. There may be the option following chemotherapy to
consider local therapy to the primary tumor, such as palliative radiotherapy. However,
primary tumors are frequently large and bulky, causing symptoms such as pelvic pain,
vaginal bleeding, and offensive vaginal disease, and these symptoms can be very difficult to
palliate, with either chemotherapy, or with radiotherapy as local therapy. For this reason, if
a patient presents with small-volume metastatic disease that is not obviously progressing
rapidly, consideration may be given to surgery to remove the primary tumor, and then to
243

244 Beatrice Seddon
consider chemotherapy postoperatively to treat the metastatic disease. The balance between
the need to remove the primary tumor surgically, and to treat progressing metastatic disease
in the first instance can be fine, and the judgement as to optimal treatment for an individual
patient difficult.
It is clear however, that surgery should only be undertaken if the disease can be
completely removed, with no macroscopic residual disease, as a debulking procedure
leaving overt residual disease gives the worst of both worlds, in that the disease will very
frequently grow back rapidly while the patient is recovering from surgery such that the
procedure has achieved nothing other than exposing the patient to a futile and potentially
morbid surgical procedure, and in the meantime the metastatic disease continues to grow.
There is also a risk that the patient is debilitated by surgery to the extent that they may no
longer be fit for palliative chemotherapy.
Conclusion
The key therefore is careful patient selection for surgical removal of the primary tumor at
diagnosis in the metastatic setting. This can be considered for patients with small-volume
metastatic disease that is not obviously progressing rapidly, for whom it is judged that
complete macroscopic removal of the primary disease can be achieved. However, patients
with rapidly progressing metastatic disease, and those for whom complete macroscopic
removal of the primary tumor is not possible, are unlikely to benefit from such surgery,
which should be avoided, and priority given to treatment with palliative chemotherapy or
radiotherapy.
References
1. Francis M, et al. Incidence and survival 3. Ghirardi V, et al. Role of surgery in
of gynecologic sarcomas in gynaecological sarcomas. Oncotarget
England. Int J Gynecol Cancer 2015;25 2019;10(26):2561–2575.
(5):850–857. 4. Leitao MM Jr., et al. Surgical cytoreduction in
2. Kapp DS, et al. Prognostic factors patients with metastatic uterine
and survival in 1396 patients with leiomyosarcoma at the time of initial diagnosis.
uterine leiomyosarcomas: emphasis on Gynecol Oncol 2012;125(2):409–413.
impact of lymphadenectomy and 5. George S, et al. Soft tissue and uterine
oophorectomy. Cancer 2008;112 leiomyosarcoma. J Clin Oncol 2018;36
(4):820–830. (2):144–150.

Debate
Should Secondary
41A Cytoreductive Surgery

be Offered to all Patients
with Optimally Resectable
Recurrent Uterine
Leiomyosarcoma?
Yes
Giovanni Aletti
Debate
Uterine sarcomas are rare gynecologic malignancies, being 3–7% of all uterine malignant
tumors, and approximately 1% of all female gynecologic cancers. Leiomyosarcomas
(LMS) encompass approximately 1% of all the uterine cancers. Leiomyosarcoma is the
most common uterine sarcoma, with an extremely aggressive clinical behavior.
Consequently, this neoplasm is associated with a poor prognosis and very high risk of
recurrence even among women with early-stage disease. The reported recurrence rates
range between 45% and 73%. The main sites of these recurrences are the abdomen or the
pelvis; a high proportion of uterine LMS will recur in the lung, with pulmonary metas-
tases. Typically, survival for patients with recurrent disease is extremely poor.
Unfortunately, the best management strategy for patients with recurrent uterine LMS
has yet to be defined. Management options for recurrent disease include additional
resection in operable patients, ablation, chemotherapy, radiation therapy, hormonal
therapy in selected patients, or a combination of these. The decision of the treatment
strategy should be taken in an interdisciplinary setting, involving gynecologic oncolo-
gists, medical oncologists, radiation therapists, interventional radiologists, and all spe-
cialists (thoracic surgeons, oncologic surgeons, etc.) involved in all the different
therapeutic options. Due to the paucity of data, and the different clinical presentations
of patients with recurrent LMS, treatment is proposed to each patient on an individual
basis, trying to maximize the potential benefits of each treatment by individualizing the
strategy. The main factors that guide the multidisciplinary team in this choice are
represented by the number of metastases and the anatomical locations of metastases,
the patient’s disease-free interval, the disease burden, the organ function, the different
prior therapies, the patient’s clinical condition and performance status, and the patient’s
preferences.
245

246 Giovanni Aletti
The question posed in the present chapter underlies two main issues:
- What is the rationale of secondary cytoreduction in recurrent uterine LMS?
- How can we define surgical candidates with optimally resectable recurrent
uterine LMS?
After elucidating these topics, we can definitely answer “yes” to the question posed in the
present chapter:
- Should secondary cytoreduction be offered to all patients with optimally resectable
recurrent uterine LMS?
Rationale for Secondary Cytoreduction in Recurrent Uterine

Leiomyosarcoma
The prognosis for patients with recurrent disease is poor, with five-year overall
survival (OS) of 40–60% [ 1,2]. Management options in this setting are limited and
poorly defined.
Options for Chemotherapy in Recurrent Disease

Patients with recurrent uterine LMS will often receive chemotherapy. Systemic chemother-
apy is often advocated for the treatment of recurrent uterine LMS, and doxorubicin is the
most active drug for this malignancy, with a reported response rate of 25%. Different
options for recurrent disease (depending also on previous chemotherapy regimens utilized)
include a combination of anthracycline with ifosfamide or dacarbazine or trabectedin, The
combination of gemcitabine and docetaxel, or single agents doxorubicin, trabectedin,
dacarbazine, pazopanib, high-dose ifosfamide, paclitaxel, etoposide. Unfortunately, these
regimens have been associated with modest activity in treating patients with recurrent
uterine LMS.
Due to these poor results, the first reason to consider secondary surgery for candidates
with resectable uterine LMS is the extremely poor alternative demonstrated in patients with
recurrent disease managed by non-surgical approaches.
Secondary Surgery in Patients with Recurrent Leiomyosarcoma

Pulmonary Metastasectomy
The concept of resection of isolated pulmonary metastases from uterine malignancies
(pulmonary metastasectomy) was introduced in 1930 by Torek, and has been validated by
several retrospective cohorts.
For example, in a relatively large retrospective study published by the Thoracic
Surgery Group at the Brigham and Women’s Hospital in Boston, 31 patients under-
went pulmonary metastasectomy for metastases from LMS, of which 15 patients
(48%) underwent repeated pulmonary metastasectomy. They compared the outcome
of these patients to a group of patients with pulmonary metastases from sarcomas
non LMS. Patients with LMS metastases had an improved overall survival as opposed
to those with non-LMS pulmonary metastases, with an overall survival of 70 months
versus 24 months (p=0.049). Furthermore, it is relevant to notice that a long-term
survival can be achievable for patients with isolated metastases from uterine LMS,
localized in the lung/s. Several studies confirmed the feasibility and the benefits of

Cytoreductive Surgery for Patients? Yes 247
pulmonary metastasectomy in selected groups of patients with recurrent uterine LMS.

Overall, resection of isolated lung metastases in patients with recurrent uterine LMS
has been associated with five-year survival of approximately 40%.
Secondary Cytoreduction
In this chapter we take into consideration patients with extra-pulmonary metastases from
uterine LMS, who are surgical candidates for secondary surgery.
Leitao and the Gynecologic Oncology Group at Memorial Sloan Kettering Cancer
Center [2] demonstrated the benefits of optimal resection of recurrent uterine LMS. They
retrospectively analyzed 41 patients with recurrent uterine LMS (17 local pelvic, 18 distant,
six both), who underwent surgical resection at time of first recurrence. A pulmonary
metastasectomy alone was performed in 13 cases. The disease-specific two-year survival
for all 41 patients was 71.2%. In univariate analysis, time to first recurrence and optimal
resection were significantly associated with longer overall survival. This study underlines
the importance of a complete resection of the distant metastases, even when they are
localized in the abdomen.
Giuntoli and the group at the Mayo Clinic [3] analyzed 128 patients with recurrent
uterine LMS. Management included secondary cytoreductive surgery in 63% (80/128)
of patients, chemotherapy in 55% (71/128) of patients and included radiation therapy
(discounting palliative radiation) in 26% (33/128) of patients. At univariate analysis,
secondary cytoreductive surgery was associated with significantly improved disease-
specific survival from time of first recurrence (p<0.001). Other factors including
greater than six-month disease-free interval, either local or distant recurrence, and
complete response were also associated with significantly improved outcome in uni-
variate analysis. At multivariate analysis, the presence of both distant and local
recurrence, the utilization of surgery for treatment of recurrent disease, and recur-
rence time greater than six months, were independently correlated with disease-
specific survival from the time of first recurrence (p≤0.05). They also reported that
optimal secondary surgical resection was associated with a significantly improved
survival.
Cybulska et al. recently reported the outcomes of patients with recurrent uterine
LMS treated again at Memorial Sloan Kettering Cancer Center [4]. In this study, the
authors analyzed the outcomes of patients who underwent secondary surgery, by
different sites of recurrence and by different surgical outcomes in terms of complete
gross resection (CGR). They identified 62 patients: 29 with abdominal/pelvic recur-
rence only, 30 with lung recurrence only, three with both sites of recurrences. Median
time to first recurrence was 15.8 months for patients with abdominal/pelvic recur-
rence, and 24.1 months lung-only recurrence (p=0.03). The median OS was 37.7
months for patients with abdominal/pelvic recurrence; 78.1 months for lung recur-
rence (p=0.02). Complete gross resection was obtained in 58 cases (93%), with gross
residual between 1–2 cm in two cases (3.5%) and RD > 2 cm in two cases (3.5%).
Median OS based on residual disease was 54.1 months, 38.7 months, 1.7 months,
respectively (p<0.001). The results of this study underlie the role and benefits of
secondary surgical resection of recurrent uterine LMS when a complete resection is
feasible.

248 Giovanni Aletti
Furthermore, lung-only recurrences were associated with a more favorable outcome,

and the resection of lung recurrence/s should definitely be considered as the best option
when the patient is amenable to complete surgical resection.
Surgical Candidates for Optimally Resectable Recurrent Uterine

Leiomyosarcoma
Given the rationale and the results of secondary cytoreduction for patients with recurrent
uterine LMS, the main issue is to define the subgroup of patients with two specific
characteristics:
1. High chance of performing a secondary complete gross resection
2. Minimizing peri-operative morbidity and mortality, avoiding a deterioration in the
quality of life.
In 2016, the Trans-Atlantic Retroperitoneal Sarcoma Working Group published
a consensus approach in the management of recurrent retroperitoneal sarcoma (RPS) [5].
While uterine LMS recurrences were not included in the statements, the approach described
can be extrapolated to patients with recurrent uterine LMS. Before considering secondary
cytoreduction, patients with recurrent RPS should be discussed at a multidisciplinary
meeting, involving surgical oncologists, medical oncologists, radiation oncologists, patho-
logists, and radiologists with expertise in sarcoma (in this case in uterine LMS). The
following data should be reviewed in detail:
- Specimens of the previous surgery
- Previous surgery/ies, systemic treatments, radiation therapy
- Current localization of the recurrence/s: the use of CT scan, and MRI as an ancillary
modality, are recommended
- Patient’s evaluation for symptoms, performance status
In case of intra-abdominal metastases, a complete resection is difficult to predict based
on imaging.
Extra peritoneal oligo metastatic recurrence/s, especially in the lung, can be better
assessed for complete resection. The delicate balance between the likelihood of completely
resecting the recurrence/s versus the risk of surgical complications and mortality should be
carefully considered on an individual basis in a multidisciplinary setting, in order to offer
the best option to each patient.
Conclusion
Secondary cytoreductive surgery should be offered to patients with recurrent uterine LMS
who are amenable of complete resection for these reasons:
1. In the case of complete resection, a survival advantage can be achieved. This is
particularly evident for lung-only recurrences.
2. Systemic treatments have shown discouraging results in recurrences that are not
manageable with surgery.
A careful multidisciplinary selection is of paramount importance to determine the best
approach on an individual basis.

Cytoreductive Surgery for Patients? Yes 249
References
1. Burt BM, et al. Repeated and aggressive leiomyosarcoma. Gynecol Oncol
pulmonary resections for leiomyosarcoma 2007;106:82–88.
metastases extends survival. Ann Thorac 4. Cybulska P, et al. Secondary surgical resection
Surg 2011;92:1202–1207. for patients with recurrent uterine
leiomyosarcoma. Gynecol Oncol 2019;154
2. Leitao MM, et al. Surgical resection
(2):333–337.
of pulmonary and extrapulmonary
recurrences of uterine leiomyosarcoma, 5. Trans-Atlantic RPS Working Group.
Gynecol Oncol 2002;87: Management of recurrent retroperitoneal
287–294. sarcoma (RPS) in the adult: a consensus
approach from the Trans-Atlantic RPS
3. Giuntoli RL, et al. Secondary cytoreduction Working Group. Ann Surg Oncol 2016; 23
in the management of recurrent uterine (11):3531–3540.

Debate
Should Secondary
41B Cytoreductive Surgery

be Offered to all Patients
with Optimally Resectable
Recurrent Uterine
Leiomyosarcoma?
No
Félix Blanc-Durand, Amandine Maulard, and
Patricia Pautier
Debate
After complete cytoreductive surgery of uterine leiomyosarcomas (uLMS), the risk of
recurrence within two years is around 40% and once metastatic, treatment has often been
palliative due to the dismal overall survival rates. Nearly 80% of all recurrences involve an
extra pelvic site (including lung and abdominal metastases) and overall prognosis is similar
for both pelvic and extra pelvic recurrences. It is well established that surgery of isolated
pulmonary recurrences offers improved overall survival and should be encouraged [1].
However, whether patients with recurrent uLMS benefit also from secondary cytoreductive
surgery (SCS) of extrapulmonary sites is not known.
Small retrospective studies have suggested that resection of extrapulmonary metastases
may also be beneficial for patients. Leitao et al. [2] reported on 37 patients with recurrent
uLMS who had undergone SCS with or without adjuvant chemotherapy and/or radiother-
apy. Importantly, the large majority of patients (29/37) had only pelvic or lung recurrences
and half of the population (18/37) received adjuvant therapy. In this heavily selected
population, with heterogeneous management, six patients (16.2%) had prolonged remission
without evidence of disease after a median follow-up of 25 months. Two out of these six
patients received adjuvant therapy and whether they subsequently developed extensive or
localized recurrences was not reported. Conversely, Nakamura et al. in 2018, in a small
subset of LMS(n=3) out of 18 uterine sarcomas, reported that two patients had prolonged
remission after SCS. Both presented with pelvic recurrences and benefited from complete
cytoreductive surgery. In this report, data on adjuvant treatment was not provided. Hoang
et al. [3] reported on three (13%) uLMS patients with complete remission after SCS. Details
on the type of recurrence and surgery were not reported but overall, the extent of surgical
250

Cytoreductive Surgery for Patients? No 251
resection, and the time to recurrence, were significantly associated with outcome. Bonvalot
et al., in 2005, reported a small randomized trial of intraperitoneal chemotherapy (with
doxorubicin and cisplatin) versus observation in patients with completely resected periton-
eal sarcomatosis in which half of the population had visceral sarcoma. Interestingly, median
local relapse-free survival was 12.5 months in both groups. Compared to median progres-
sion-free survival (PFS) observed in metastatic LMS (around six months) we can acknow-
ledge the benefit of optimal SCS in this selected population [4]. Finally, Díaz-Montes et al.
[5] reported numerically superior median disease-free survival for patients treated with SCS
(n=14) versus nonsurgical treatments (n=5) (5.3 months vs. 2.4 months respectively) and
notably, two uLMS patients with pelvic recurrences had long-term complete remission after
SCS + chemotherapy.
Beside these encouraging observations in heavily selected populations, most of these
studies agreed that recurrence within 12 months after initial treatment and suboptimal
surgical cytoreduction, as defined in the management of epithelial ovarian carcinomas, are
major prognostic markers associated with significantly worse disease-free and overall
survival rates. Moreover, patients with suboptimal surgery appear to have similar survival
rates compared to patients who do not have surgery [6]. Therefore, they may not be the best
candidates for SCS, especially considering surgical morbidity.
Most of these studies do not report on the use of chemotherapy (CT) after SCS that may
have biased the results. Systemic CT, in particular doxorubicin-containing regimens,
achieve overall response rates of 30% with median PFS of nine months. However, this
landscape is rapidly evolving. Very recently, at ESMO 2021, first-line doxorubicin +
trabectidine used for recurrent/metastatic uLMS and soft-tissue LMS demonstrated
improved overall response rates of 38% and disease control rate of 92% over doxorubicin
monotherapy, as well as significantly prolonged PFS (13.5 months vs. 7.4 months). To date,
this trial is the first one demonstrating significant survival benefit over the gold standard
doxorubicin for recurrent/metastatic uLMS. In this regard, the optimal place for extensive
extrapulmonary SCS versus standard systemic therapy is unknown. Regarding the activity
of a doxorubicin doublet, we can anticipate that “neoadjuvant” systemic therapy may better
select the best candidates for SCS, improving optimal resection rates as well as converting
primary unresectable diseases. Yet it should be stressed that response rates are not similar to
what is observed in ovarian carcinomas and some patients may progress under chemother-
apy and miss the opportunity for complete surgery. Moreover, chemotherapy for sarcoma
diseases is associated with significant toxicity and secondary surgery may be challenging.
Nevertheless, preoperative chemotherapy appears feasible and promising but reports con-
cerning its efficacy are scarce and limited to case reports. On the other hand, active CT done
on minimal residual disease may have a greater chance to be effective. In this regard, three
randomized trials tested adjuvant chemotherapy after initial surgery and two of them
demonstrated increased cure rates and one did not observe any benefit. Herein, this strategy
remains highly controversial.
Conclusion
To conclude, secondary cytoreductive surgery should be restricted to selected recurrent
uLMS, after multidisciplinary discussion, since the greatest benefit appears to be observed in
patients with localized pelvic and/or lung disease, late (>12 months) recurrence, in whom
optimal resection is considered. In addition, the best use of systemic therapy in this situation

252 Félix Blanc-Durand et al.
is unclear and dedicated prospective clinical trials comparing these sequences are needed.
Neoadjuvant chemotherapy may be an option for patients who cannot benefit from upfront
complete resection and this approach, along with complementary CT after surgery, should
also be discussed in specialized tumor boards depending on the number of metastatic
intraabdominal sites, and previous CT in the adjuvant or metastatic setting.
References
1. van Geel AN, et al. Surgical treatment of lung 4. Bonvalot S, et al. Randomized trial of
metastases: the European Organization for cytoreduction followed by intraperitoneal
Research and Treatment of Cancer-Soft chemotherapy versus cytoreduction alone in
Tissue and Bone Sarcoma Group study of 255 patients with peritoneal sarcomatosis. Eur
patients. Cancer 1996;77:675–682. https://doi J Surg Oncol 2005;31(8):917–923. https://doi
.org/10.1002/(sici)1097-0142(19960215)77: .org/10.1016/j.ejso.2005.04.010. PMID:
4<675::aid-cncr13>3.3.co;2-h 15975759
2. Leitao MM, et al. Surgical resection of 5. Díaz-Montes TP, et al. Efficacy of
pulmonary and extrapulmonary recurrences hyperthermic intraperitoneal chemotherapy
of uterine leiomyosarcoma. Gynecol Oncol and cytoreductive surgery in the treatment
2002;87:287–294. https://doi.org/10.1006/g of recurrent uterine sarcoma. Int J Gynecol
yno.2002.6840 Cancer 2018;28:1130–1137. https://doi.org/
3. Hoang HLT, et al. Prognostic factors and 10.1097/IGC.0000000000001289
survival in patients treated surgically for 6. Aalders J, et al. Postoperative external
recurrent metastatic uterine irradiation and prognostic parameters in
leiomyosarcoma. Int J Surg Oncol stage I endometrial carcinoma: clinical and
2014;2014:919323. https://doi.org/10.1155/ histopathologic study of 540 patients. Obstet
2014/919323 Gynecol 1980;56:419–427.

Section V Cervical Cancer
Debate
Is there a Role for Minimally
42A Invasive Radical

Hysterectomy
for Management of Cervical
Cancer?
Yes
Vanna Zanagnolo, Francesco Multinu, and Stefano
Bogliolo
Debate
The introduction of a minimally invasive (MIS) approach has had a dramatic impact on health
care management of gynecologic oncology patients, mainly for those with endometrial and
cervical cancer. Before the Laparoscopic Approach to Cervical Cancer (LACC) [1] trial results
became available, there was a paucity of adequately powered, prospective trials evaluating
oncological outcomes of MIS in cervical cancer patients. Guidelines from the National
Comprehensive Cancer Network (NCCN) and European Society of Gynaecological Oncology
(ESGO) indicated that either laparotomy or MIS were acceptable approaches to radical
hysterectomy (RH) in patients with early-stage cervical cancer.
In the LACC randomized trial, the investigators found a significant oncologic inferiority
(disease-free survival, pelvic recurrences) of minimally invasive radical hysterectomy com-
pared with open radical hysterectomy. The results were highly unexpected. Some speculated
that the use of intrauterine manipulators, the CO2 gas, or intra-corporeal colpotomy might
have accounted for those surprising outcomes. Nevertheless, since we are now dealing with
level I evidence, we have to learn from these results, starting by critically analyzing our own
data, trying to understand what could have gone wrong with the MIS approach, what can be
modified to prevent the negative impact of such an approach, and whether there is still room
for another, better designed, randomized trial.
Since the dissemination and publication of the LACC trial, guidelines from NCCN and
ESGO have changed and laparotomy is now recommended as the standard approach to radical
hysterectomy in patients with early-stage (IA2 to IIA) cervical cancer. The MIS approach can
still be performed for those patients with negative margins on their conization specimen and it
can still be considered after a thorough discussion with the patients of the available data.
A few recent studies have been published, all retrospective, mostly large series that
confirmed that the open approach was better than MIS in terms of progression-free survival
(PFS) and overall survival (OS), however in some of these studies OS was not significantly
different.
253

Section V Cervical Cancer
Debate
42A Invasive Radical

Hysterectomy
Cancer?
Yes
Vanna Zanagnolo, Francesco Multinu, and Stefano
Bogliolo
Debate
The introduction of a minimally invasive (MIS) approach has had a dramatic impact on health
care management of gynecologic oncology patients, mainly for those with endometrial and
cervical cancer. Before the Laparoscopic Approach to Cervical Cancer (LACC) [1] trial results
became available, there was a paucity of adequately powered, prospective trials evaluating
oncological outcomes of MIS in cervical cancer patients. Guidelines from the National
Comprehensive Cancer Network (NCCN) and European Society of Gynaecological Oncology
(ESGO) indicated that either laparotomy or MIS were acceptable approaches to radical
hysterectomy (RH) in patients with early-stage cervical cancer.
In the LACC randomized trial, the investigators found a significant oncologic inferiority
(disease-free survival, pelvic recurrences) of minimally invasive radical hysterectomy com-
pared with open radical hysterectomy. The results were highly unexpected. Some speculated
that the use of intrauterine manipulators, the CO2 gas, or intra-corporeal colpotomy might
have accounted for those surprising outcomes. Nevertheless, since we are now dealing with
level I evidence, we have to learn from these results, starting by critically analyzing our own
data, trying to understand what could have gone wrong with the MIS approach, what can be
modified to prevent the negative impact of such an approach, and whether there is still room
for another, better designed, randomized trial.
Since the dissemination and publication of the LACC trial, guidelines from NCCN and
ESGO have changed and laparotomy is now recommended as the standard approach to radical
hysterectomy in patients with early-stage (IA2 to IIA) cervical cancer. The MIS approach can
still be performed for those patients with negative margins on their conization specimen and it
can still be considered after a thorough discussion with the patients of the available data.
A few recent studies have been published, all retrospective, mostly large series that
confirmed that the open approach was better than MIS in terms of progression-free survival
(PFS) and overall survival (OS), however in some of these studies OS was not significantly
different.
253

254 Vanna Zanagnolo et al.
Different results were observed in a recently published Swedish nationwide population-

based cohort study [2]. The aim of the study was to compare OS and disease-free survival
(DFS) after open and robotic RH for women with cervical cancer stage IA1–IB who
underwent RH from January 2011 to December 2017; 864 women (236 open and 628
robotic) were included in the study. The five-year OS was 92% and 94% and DFS was
84% and 88% for the open and robotic cohorts, respectively. The recurrence pattern was
similar in both groups.
Based on these results, the authors designed and have opened to accrual the Robot-
assisted Approach to Cervical Cancer (RACC) study, a multi-centre open-label randomized
non-inferiority trial of robot-assisted laparoscopic surgery versus laparotomy in women
with early-stage cervical cancer (FIGO stage IB (IB3 excluded), IIA1) [3]. This trial aims to
compare the oncologic safety of robotic RH to conventional laparotomy and RH with the
primary outcome being five-year recurrence-free survival and secondary outcome being OS.
An International European Cohort Observational Study [4] comparing MIS versus open
surgery in patients with stage IB1 (FIGO 2009) cervical cancer was recently published. This
study included 1116 patients who underwent surgery in 126 centers from 29 ESGO
countries from 2013–2014. The primary outcome was 4.5 years DFS. With a median follow-
up of 59 months, the risk of relapse in the MIS group was significantly higher in patients
with cervical cancer stage IB1. The use of a uterine manipulator worsened the outcomes
among MIS patients. Patients with tumors <2 cm and those with a previous cone biopsy did
not demonstrate any difference in DFS. Patients who underwent MIS without use of
a manipulator had the same outcome as those undergoing open surgery. Protective maneu-
vers to avoid tumor spillage at the time of the vaginal colpotomy in MIS improved the DFS
in these patients.
In agreement with these results, Kohler at al. published a retrospective study [5] of 389
consecutive patients with initial FIGO stages identical to the LACC trial who underwent
combined laparoscopic-vaginal RH, with vaginal creation of a tumor covering vaginal cuff
without the use of any uterine manipulator. With a median follow-up period of >8 years, the
three-year OS and three-year DFS were 98.5% and 96.8%, respectively. These oncologic data
are nearly identical to the excellent results of open radical hysterectomy in the LACC trial,
but should be validated in further randomized trials.
Conclusion
Based on these results and the Swedish nationwide population-based cohort study, we can
speculate that the possible explanations for the findings in the LACC study could be the
use of intrauterine manipulators and the lack of implementation of protective procedures
to prevent cancer seeding at the time of colpotomy. But these speculations remain
conjectures and until further evidence becomes available, we are in a position that the
only level I evidence favors open surgery. As clinicians, the options we have now to
contemplate are: (1) a complete return to open surgery, (2) defining selection criteria
for those who can safely be treated with MIS with the implementation of protective
measures to prevent cancer seeding, or (3) participating in further clinical trials, such as
the RACC study. With further studies, selection criteria could be developed, based on the
presence or absence of risk factors, such as tumor size, previous cervical conization with
negative margins, and histotype, that would allow safe selection of those patients who can
safely be treated with MIS.

Minimally Invasive Radical Hysterectomy? Yes 255
References
1. Ramirez PT, et al. minimally invasive versus controlled trial. Int J Gynecol Cancer 2019;29
abdominal radical hysterectomy for cervical (6):1072–1076.
cancer. N Engl J Med 2018;379 4. Chiva L, et Al. SUCCOR study. An
(20):1895–1904. international European cohort
2. Alfonzo E, et al. No survival difference observational study comparing minimally
between robotic and open radical invasive surgery versus open abdominal
hysterectomy for women with early-stage radical hysterectomy in patients with stage
cervical cancer: results from a nationwide IB1 (FIGO 2009, <4 cm) cervical cancer
population-based cohort study. Eur J Cancer operated in 2013–2014. Int J Gynecol Cancer
2019;116:169–177. 2020;30:1269–1277.
3. Falconer H, et al. Robot-assisted approach to 5. Kohler C, et al. Laparoscopic radical

cervical cancer (RACC): an international hysterectomy with transvaginal closure of
multi-center, open-label randomized vaginal cuff – a multicenter analysis.
Int J Gynecol Cancer 2019;29(5):845–850.

Debate
42B Invasive Radical

Hysterectomy
Cancer?
No
Pedro T. Ramirez
Debate
The current recommended treatment for patients with early-stage cervical cancer is radical
hysterectomy with pelvic lymphadenectomy or sentinel lymph node mapping.
Traditionally, an approach by laparotomy was considered the standard until the introduc-
tion of the minimally invasive approach either by laparoscopy or robotic surgery.
Retrospective data on minimally invasive radical hysterectomy had shown better periopera-
tive results when compared to the open approach with no compromise in oncologic
outcomes. However, there are a number of flaws in these retrospective studies including
small sample size, comparisons to historical controls, unbalanced groups pertaining to
oncologic risk factors and follow-up times.
The only prospective randomized trial comparing open versus minimally invasive
radical hysterectomy (LACC trial) was published in October 2018 [1]. In that study,
patients with FIGO 2009 stage IA1 (LVSI)-IB1 cervical cancer and histologic subtype of
squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, were
included. The two groups were similar with regards to histologic subtypes, rate of
lymphovascular invasion, rates of parametrial and lymph node involvement, tumor
size, tumor grade, and use of adjuvant treatment. The primary outcome was the rate of
disease-free survival at 4.5 years. The investigators found that the rate of disease-free
survival was 86% with minimally invasive surgery and 96.5% with open surgery. In
addition, minimally invasive surgery was also associated with a lower rate of overall
survival (three-year rate, 93.8% vs. 99%). Of note, of the patients assigned to minimally
invasive surgery, 84.4% underwent laparoscopy and 15.6% robot-assisted surgery.
A subsequent study by Melamed et al. [2] evaluated 2461 patients (1236 open surgery
vs. 1225 minimally invasive surgery) in determining the effect of minimally invasive
surgery on all-cause mortality among women undergoing radical hysterectomy for
cervical cancer. Over a median follow-up of 45 months, the four-year mortality was
9.1% among women who underwent minimally invasive surgery and 5.3% among those
who underwent open surgery (p=0.002). The adoption of minimally invasive surgery
256

Minimally Invasive Radical Hysterectomy? No 257
coincided with a decline in the four-year relative survival rate of 0.8% per year after 2006
(p=0.01 for change of trend).
In a subsequent study, data from the LACC trial was evaluated to compare the incidence
of adverse events after minimally invasive versus open radical hysterectomy. In that study,
Obermair et al. [3] found that the incidence of intraoperative grade >2 adverse events was
12% in the minimally invasive group and 10% in the open surgery group (p=0.45) and the
overall incidence of postoperative grade >2 adverse events was 54% in the minimally
invasive group versus 48% in the open group (p=0.14). Of note, 1.4% of patients in the
minimally invasive group had wound complications versus 6% in the open surgery group
(p=0.004). However, the overall incidence of adverse events was similar between the groups.
Lastly, the most recent publication from LACC trial data was reported by Frumovitz et al.
[4], where the investigators reported on the quality-of-life comparison between the open
versus minimally invasive radical hysterectomy. Eligible patients completed validated
quality-of-life and symptom assessments one and six weeks before surgery and at one and
at three and six months after surgery, with one tool (Functional Assessment of Cancer
Therapy-Cervical [FACT-Cx]) also completed at additional timepoints up to 54 months
after surgery. The authors found no difference in the measures of quality of life between
open versus minimally invasive radical hysterectomy in the early (<6 weeks) or late (>3
months) phase of recovery.
Most recently, Nitecki et al. [5] published a systematic review and meta-analysis of
observational studies comparing minimally invasive (laparoscopic or robotic) and open
radical hysterectomy in patients with early cervical cancer. Study quality was assessed using
the Newcastle-Ottowa Scale with scores of at least 7 points that controlled for confounders
by tumor size or stage. In 9499 patients, the pooled hazard of recurrence or death was 71%
higher among patients who underwent minimally invasive radical hysterectomy compared
to those who underwent open surgery (HR=1.71, 95% CI: 1.36–2.15, p<0.001) and the
hazard of death was 56% higher (HR=1.56, 95% CI: 1.16–2.11, p=0.004). These results
provided further evidence to support the survival benefit associated with open radical
hysterectomy.
Conclusion
As a result of these studies, the National Comprehensive Cancer Network Guidelines
(NCCN), European Society of Gynecologic Oncology (ESGO) Guidelines, European
Society of Medical Oncology (ESMO) Guidelines, and the FIGO Guidelines have all
provided concrete recommendations indicating that open radical hysterectomy should
be the current standard of care in the management of patients with early cervical
cancer.
References
1. Ramirez PT, et al. Minimally invasive versus 3. Obermair A, et al. Incidence of adverse
abdominal radical hysterectomy for cervical events in minimally invasive vs open radical
cancer. N Engl J Med 2018;379:1895–1904. hysterectomy in early cervical cancer: results
2. Melamed A, et al. Survival after minimally of a randomized controlled trial. Am J Obstet
invasive radical hysterectomy for early-stage Gynecol 2020;222:249.e1–249.e10
cervical cancer. N Engl J Med 4. Frumovitz M, et al. Quality of life
2018;379:1905–1914. in patients with cervical cancer after

258 Pedro T. Ramirez
open versus minimally invasive 5. Nitecki R, et al. Survival after minimally

radical hysterectomy (LACC): invasive vs open radical hysterectomy for
a secondary outcome of a multicentre, early-stage cervical cancer: a systematic
randomised, open-label, phase 3, review and meta-analysis. JAMA Oncol
non-inferiority trial. Lancet Oncol 2020;6:1019–1027. https://doi.org/10.1001/j
2020;21:851–860. amaoncol.2020.1694

Debate
Is Radical Surgery
43A or Parametrectomy Needed

for Early-stage FIGO IA2
and Microscopic IB1 Cervical
Cancer?
Yes
Joo-Hyun Nam and Jeong-Yeol Park
Debate
Approximately 80% of cases of cervical cancer are diagnosed at an early stage, when it is
amenable to perform radical surgery. Radical surgery is characterized by parametrectomy,
which involves the excision of parametrial tissues, including the ventral (the vesicouterine
and vesicovaginal ligaments), lateral (the cardinal ligament), and dorsal (the uterosacral and
rectovaginal ligaments) parts of parametrial or paracervical tissues. Insufficient excision is
associated with an increased risk of cancer recurrence, whereas excessive excision is associ-
ated with an increased risk of surgical morbidity. The extent of parametrectomy should be
tailored according to the extent of the cancer.
It is unclear whether parametrectomy should be performed in stage IA2 and micro-
scopic IB1 cervical cancer because parametrectomy is associated with increased surgical
morbidity and the frequency of parametrial invasion is very low in small cancers. However,
the surrounding tissues are excised during cancer surgery not only because the tumor has
invaded the surrounding tissues but also because a sufficient tumor-free resection margin
must be secured. A sufficient tumor-free resection margin cannot be secured by removing
only the cervix, even in stage IA2 and microscopic IB1 cervical cancer. Therefore, the
current treatment guidelines recommend parametrectomy for stage IA2 and microscopic
IB1 cervical cancer.
The extent of parametrectomy can be adjusted according to tumor size and the degree of
cervical stromal invasion [1]. In stage IA2 and microscopic IB1 cervical cancer, type 2 or
type B hysterectomy is mainly performed. The rates of gastrointestinal and urologic
complications after type 2 or type B hysterectomy are much lower than those after type 3
or type C hysterectomy [1]. Therefore, surgery-related complications are not generally
a concern after type 2 or type B hysterectomy in stage IA2 and microscopic IB1 cervical
cancer.
Recent studies have reported the results of predicting the presence or absence of
parametrial invasion by a combination of factors such as tumor size, cervical stromal
invasion depth, lymphovascular space invasion, and lymph node metastasis [2]. However,
259

260 Joo-Hyun Nam and Jeong-Yeol Park
it is difficult to exactly determine these predictive factors before surgery. Another form of
parametrial involvement is parametrial lymph node metastasis or parametrial lymphovas-
cular space invasion, which differs from direct parametrial invasion and cannot be con-
firmed before surgery.
The absence of parametrial invasion and the need for parametrectomy are different
problems in small cervical cancers. The purpose of parametrectomy is to excise tumor
invasion and secure a sufficient tumor-free resection margin. Therefore, parametrectomy is
recommended for stage IA2 and microscopic IB1 cervical cancer without suspected para-
metrial invasion. Sufficient tumor-free resection margins should not be ignored, even in
small cervical cancers.
Thus far, no prospective randomized study has evaluated whether simple hysterec-
tomy is a safe treatment for stage IA2 and microscopic IB1 cervical cancer. In
retrospective studies, the prognosis of stage IA2 and small IB1 cervical cancer,
discovered incidentally after simple hysterectomy, was poor without additional para-
metrectomy or radiotherapy [3]. The largest retrospective study reported significantly
lower survival after simple hysterectomy (92.4%) than after radical hysterectomy
(95.3%) in stage IB1 cervical cancer (<2 cm; hazard ratio (HR)=1.55, 95% confidence
interval (CI): 1.18–2.03) [4]. A recent meta-analysis also suggested that simple hyster-
ectomy in women with stage IB1 cervical cancer may adversely affect survival [5].
Thus, simple hysterectomy or trachelectomy are insufficient for the treatment of stage
IB1 cervical cancer.
Conclusion
One recently completed clinical trial (the CONCERV trial) evaluated the safety of less
radical surgery in low-risk, early-stage cervical cancer, which is also being evaluated in
the following three ongoing clinical trials: the SHAPE trial (ClinicalTrials.gov,
NCT01658930), GOG-278 (ClinialTrials.gov, NCT01649089), and the LESSER trial
(ClinialTrials.gov, NCT02613286). In the CONCERV trial, the recurrence rate was 3%
in 100 patients with stage IA2–IB1 cervical cancer (<2 cm) with no lymphovascular space
invasion and depth of invasion <10 mm after a median follow-up of 25 months (range 0–
71 months). In the LACC trial, the recurrence rate was 0.7% in stage IB1 cervical cancer
after open radical hysterectomy [6]. A 3% difference may be statistically or clinically
significant. However, some surgeons may argue that the increase in morbidity due to
radical hysterectomy is not justified for a survival benefit of 3%. However, the morbidity
of type 2 or type B hysterectomy is much less than that of type 3 or type C hysterectomy;
thus, if the survival benefit is considered, tailored radical hysterectomy with small
parametrectomy is an appropriate treatment for stage IA2 or microscopic IB1 cervical
cancer.
References
1. Panici PB, et al. Tailoring the specimens for women with early-stage
parametrectomy in stages IA2-IB1 cervical cervical cancer. Obstet Gynecol
carcinoma: is it feasible and safe? Gynecol 2009;114:93–99.
Oncol 2005;96:792–798. 3. Park JY, et al. Management of occult
2. Frumovitz M, et al. Parametrial invasive cervical cancer found after simple
involvement in radical hysterectomy hysterectomy. Ann Oncol 2010;21:994–1000.

Radical Surgery or Parametrectomy Needed? Yes 261
4. Sia TY, et al. Trends in use and effect on review. Am J Obstet Gynecol 2021;224
survival of simple hysterectomy for (4):348–358.e5.
early-stage cervical cancer. Obstet Gynecol 6. Ramirez PT, et al. Minimally invasive
2019;134:1132–1143. versus abdominal radical hysterectomy for
5. Wu J, et al. Less-radical surgery for cervical cancer. N Engl J Med
early-stage cervical cancer: a systematic 2018;379:1895–1904.

Debate
Is Radical Surgery
43B or Parametrectomy Needed

for Early-stage FIGO IA2
and Microscopic IB1 Cervical
Cancer?
No
Zibi Marchocki and Allan Covens
Debate
Radical hysterectomy or radical trachelectomy with lymph node assessment are considered the
treatment of choice in patients with stages IA2 and IB1 cervical cancer (depending on fertility
wishes) [1]. However, not only is there no level 1 evidence to support this recommendation, but
also radical procedures are associated with significant morbidity. Complications, including
perioperative blood loss, bladder, rectal, and sexual dysfunction, as well as fistula formation,
adversely affect quality of life. All of those are mainly attributed to the parametrectomy causing
destruction of blood vessels and nerve plexuses. As cervical cancer is diagnosed earlier, and
women postpone pregnancy until later in life, the need for less radical and fertility-sparing
surgery has become more important. Traditionally the rationale for parametrectomy has been
to achieve clear margins or to remove potential sites of tumor spread. However, controversy
exists as most patients with lymph node involvement and a high proportion of those with
tumor invasion >10 mm will receive adjuvant treatment regardless of the radicality of surgery.
Prior studies demonstrated that in patients with favorable factors such as tumor size ≤2 cm,
depth of stromal invasion <10 mm, absence of lymphovascular space invasion and lymph node
involvement, the risk of parametrial involvement is less than 1% [2]. Therefore, it questions the
need and role for radical surgery (parametrectomy) in this group of patients. A number of
retrospective studies have demonstrated that in selected cases a less radical approach (without
parametrectomy) is a safe alternative.
Using the Surveillance, Epidemiology and End Results (SEER) database, Tseng and
colleagues compared 807 patients with stage IB1 cervical cancer treated with conization,
trachelectomy, or simple hysterectomy to 1764 patients treated with modified radical or
radical hysterectomy (lymph node assessment was performed in all groups) [3]. The authors
showed a very similar 10-year disease-specific survival between the two groups (93.5% for
less radical vs. 92.3% for more radical surgery, p=0.511). The largest retrospective study to
date, consisting of 1530 patients with stage IA and 3931 patients with stage IB1 treated with
simple and radical hysterectomies, compared simple and radical hysterectomy for stage IA2
and showed no difference in five-year survival rate (simple hysterectomy 97.6% vs. radical
95.1%, hazard ratio (HR)=0.70, 95% confidence interval (CI): 0.41–1.20) [4]. Interestingly,
262

Radical Surgery or Parametrectomy Needed? No 263
patients with stage IB1 disease had a 55% greater risk of death (HR=1.55, 95% CI: 1.18–2.03)
after simple hysterectomy compared with radical hysterectomy, with a five-year survival
rate of 92.4% and 95.3%, respectively. However, the increased hazard risk of 55% repre-
sented a five-year survival difference of 2.9%, which is below the threshold used in most
noninferiority oncologic trials (margins typically 5–8%). Additionally, many important
prognostic factors and survival outcomes were either missing or incomplete, rendering
the final study conclusion questionable. The standard-of-care pelvic lymphadenectomy was
omitted in 19% and 2% of stage IB1 patients treated by simple and radical hysterectomy
respectively, and more patients received adjuvant chemotherapy and radiation after simple
hysterectomy compared with radical hysterectomy (16% vs. 7% for chemotherapy, 9% vs.
3% for radiation). After adjusting for nodal assessment and receipt of adjuvant therapy, the
difference in survival was not statistically significant.
More recently Li and colleagues in a small retrospective study, examined 40 patients with
low-risk criteria (IA1 with lymphovascular space invasion (LVSI) to IB1, tumor size<2 cm on
the diagnostic specimen and no gross visible tumor at preoperative assessment, no radiological
evidence of metastasis, (squamous and adenocarcinoma or adeno-squamous histology) treated
with simple conization with pelvic lymphadenectomy and demonstrated a two-year recurrence-
free period in 97.5% of patients [5]. This is in line with the findings from a prospective,
multicenter trial (ConCerv) with 100 patients (IA2–IB1, no LVSI, depth of invasion <10 mm
and cone biopsy with negative margins) post-cervical conization or simple hysterectomy and
pelvic lymph node assessment [6]. The trial showed that after a median follow-up of 25 months
(range 0–71), recurrent disease was diagnosed in only three patients (3%).
Gynecologic Oncology Group (GOG) 278 (NCT01649089) and SHAPE (NCT01658930)
are “Gynecologic Oncology Group (GOG) 278 (NCT01649089) and SHAPE (NCT01658930)
are both closed to accrual and awaiting results.” accrual. GOG 278 is a prospective cohort
study evaluating the physical function and quality of life pre- and post-surgery in patients with
stage I (IA1 with positive LVSI) and IA2–IB1 <2 cm (with no radiological signs of metastases)
cervical cancer treated with nonradical surgery. In the SHAPE trial, women with early-stage
cervical cancer are randomized to radical or simple hysterectomy. Reassuringly, both trials
have been promising, with no safety concerns raised by the data safety monitoring committees
so far. Results from both trials are expected this year.
Conclusion
The recent trend towards less radical surgery represents the paradigm shift towards a less
radical approach. This is based on the growing evidence suggesting that in patients with
a low risk of parametrial involvement (tumor size ≤2 cm, depth of stromal invasion
<10 mm, absence of lymphovascular space invasion and lymph node involvement) non-
radical surgery (conization, trachelectomy, or hysterectomy) with lymph node assessment is
a safe alternative to radical surgery (parametrectomy).
References
1. National Comprehensive Cancer Network. 2. Covens A, et al. How important is removal
NCCN guidelines in oncology: cervical of the parametrium at surgery for carcinoma
cancer. Available at: www.nccn.org/profes of the cervix? Gynecol Oncol 2002;84
sionals/physician_gls/pdf/cervical.pdf. (1):145–149. https://doi.org/10.1006/gyno
Retrieved September 11, 2020. .2001.6493

264 Zibi Marchocki and Allan Covens
3. Tseng JH, et al. Less versus more radical cancer: a retrospective analysis
surgery in stage IB1 cervical cancer: and review of the literature.
a population-based study of long-term Gynecol Oncol 2020;158(2):231–235.
survival. Gynecol Oncol 2018;150:44–49. https://doi.org/10.1016/j
4. Sia TY, et al. Trends in use and effect on .ygyno.2020.05.035
survival of simple hysterectomy for 6. Schmeler K, et al. Concerv: a prospective
early-stage cervical cancer. Obstet Gynecol trial of conservative surgery for
2019;134:1132–1143. low-risk early-stage cervical cancer
5. Li X, et al. Simple conization and pelvic Int J Gynecol Cancer 2019;29:
lymphadenectomy in early-stage cervical A14–A15.

Debate
44A Option for Young Women

with Stage IB2 Cervical Cancer
Who Wish to Preserve
Fertility?
Abdominal Radical Trachelectomy
Michael Frumovitz
Debate
In 1998, Michel Roy and Marie Plante published the oft-cited criteria identifying appropri-
ate candidates for radical trachelectomy in women with cervical cancer [1]. These criteria
included:
1. Desire to preserve fertility
2. No clinical evidence of impaired fertility
3. Stage IA2 to IB (International Federation of Gynecology and Obstetrics)
4. Lesion size <2 cm
5. Limited endocervical involvement at colposcopic evaluation
6. No evidence of pelvic node metastasis
Over the last two decades, these “criteria” have transformed into guidelines and, for some,
into dogma. These criteria were originally developed to assess patients for possible vaginal
radical trachelectomy. Some of these factors are now routinely ignored such as “no clinical
evidence of impaired fertility” as many seemingly infertile patients have achieved pregnancy
after radical trachelectomy with assisted reproductive technologies. Others such as “limited
endocervical involvement on colposcopic evaluation” have been replaced by preoperative
imaging such as magnetic resonance imaging (MRI). MRI has a sensitivity of 82% and
a specificity of 93% in predicting an endocervical margin of ≤ or >5 mm between the tumor
and the internal os in radical trachelectomy candidates [2].
The “hard” cut-off of tumors <2 cm has been retained by many who perform the procedure.
However, this size limitation was proposed by those performing vaginal radical trachelectomies
likely due to the smaller amount of parametrium resected and the difficulty achieving an
adequate endocervical margin during the vaginal approach. As surgeons recognized that an
abdominal approach allowed for larger parametrial resections and easier assessment of where to
transect the cervix to obtain a tumor-free margin while retaining enough cervical stump for re-
anastomosis, they began to include women with tumors >2 cm in size.
Even with the ability to perform surgery that is more “radical” by the abdominal
approach, many believe performing this procedure in women with stage IB2 leads to
265

266 Michael Frumovitz
compromised oncologic outcomes. Although only retrospective data exist, systematic

reviews show an overall recurrence rate of 7% after abdominal radical trachelectomy for
women with tumors 2–4 cm in size which is comparable to that seen after radical hysterec-
tomy for women with similarly sized tumors [3]. Furthermore, it is seemingly equivalent to
the 10% recurrence rate seen after neoadjuvant chemotherapy followed by vaginal radical
trachelectomy in women with stage IB2 disease.
In 2006, Alexander Burnett proposed updated criteria that summarize the decision
making that most undertake when choosing appropriate candidates for radical trachelect-
omy for tumors 2–4 cm [4].
1. Can the cancer be safely and completely removed?
2. Does the woman wish to retain her uterus?
3. Is she informed of the risks, benefits, and alternatives to this procedure?
The main criteria of “can the cancer be safely and completely removed” truly focuses on
achieving the expected oncologic outcomes that are equivalent to radical hysterectomy in
these patients. The National Comprehensive Cancer Network (NCCN) guidelines acknow-
ledge that radical trachelectomy is “most validated” for tumors < 2 cm but also stipulates
that abdominal radical trachelectomy is an option for appropriately selected women with
stage IB2 tumors. In other words, NCCN guidelines state abdominal radical trachelectomy
is a reasonable fertility-sparing option in women with cervical cancers 2–4 cm in size in
whom the cancer can “be safely and completely removed.”
To these three criteria proposed by Burnett, I would add, “Does preoperative evaluation
(exam, pathology, and imaging) suggest little risk for completion hysterectomy or postop-
erative radiotherapy?” Although achieving optimal oncologic outcomes is the primary
consideration when making therapeutic recommendations to women with early-stage
cervical cancer, the “raison d’être” for performing fertility-sparing surgery is (obviously)
to spare fertility. A patient who is likely to have high-risk factors (positive margins, positive
nodes, or positive parametrium) or have intermediate risk factor (Sedlis Criteria) for
postoperative radiation should not be considered for either abdominal radical trachelect-
omy or neoadjuvant chemotherapy followed by vaginal radical trachelectomy. When
evaluating 246 patients from 10 published studies on abdominal radical trachelectomy in
women with stage IB2 cervical cancer, van Kol et al. [3] found that 204 (83%) ultimately had
a fertility-sparing procedure completed. This compared favorably to 69 (75%) out of 92
patients with stage IB2 cervical cancer who retained their uterus and ovaries and did not
need adjuvant radiation therapy after neoadjuvant chemotherapy followed by vaginal
radical trachelectomy.
That said, fertility-sparing procedures do not necessarily mean patients can still get
pregnant. For example, patients may encounter infertility due to cervical stenosis or
Asherman’s syndrome after a radical trachelectomy or decreased ovarian reserve and
ovulation after neoadjuvant chemotherapy. In this manner, there may be an improvement
in pregnancy rates for patients who undergo neoadjuvant chemotherapy and vaginal radical
trachelectomy when compared to abdominal radical hysterectomy. In one large review of
the literature, 19 (70%) of 27 women who attempted to conceive achieved pregnancy after
neoadjuvant chemotherapy followed by vaginal radical trachelectomy compared to preg-
nancies achieved in only 17 (21%) of 82 women who attempted to conceive after abdominal
radical trachelectomy [3]. Once pregnancy is achieved, however, pregnancy outcomes such
as term births and live births are similar between the two approaches. It is important to note

Mx to Preserve Fertility? Abdominal Trachelectomy 267
that these are very small sample sizes from retrospective studies so these results must be
interpreted with great caution.
Conclusion
Fortunately, we will have good prospective data on neoadjuvant chemotherapy and vaginal
radical trachelectomy. The CONTESSA/NEOCON-F study is currently enrolling 90 women
with stage IB2 cervical cancer in a prospective, phase II trial of neoadjuvant chemotherapy
followed by vaginal radical trachelectomy [5]. Outcomes include success rate of completing
fertility-sparing surgery without the need for radiation, response rate to chemotherapy,
overall survival, and pregnancy rates among other endpoints. The study is expected to
complete accrual in 2022 and report in 2025.
References
1. Roy M, et al. Pregnancies after recurrence rates. Gynecol Oncol
radical vaginal trachelectomy for 2019;155:515–521.
early-stage cervical cancer, Am J Obstet 4. Burnett AF. Radical trachelectomy with
Gynecol 1998;179:1491–1496. laparoscopic lymphadenectomy: review of
2. Bhosale PR, et al. Is MRI helpful in oncologic and obstetrical outcomes, Curr
assessing the distance of the Opin Obstet Gynecol 2006;18:8–13.
tumour from the internal os in 5. Plante M, et al. FIGO 2018 stage IB2
patients with cervical cancer below (2–4 cm) Cervical cancer treated with Neo-
FIGO Stage IB2? Clin Radiol adjuvant chemotherapy followed by fertility
2016;71:515–522. Sparing Surgery (CONTESSA); Neo-
3. van Kol KGG, et al. Abdominal radical Adjuvant Chemotherapy and Conservative
trachelectomy versus chemotherapy Surgery in Cervical Cancer to Preserve
followed by vaginal radical trachelectomy in Fertility (NEOCON-F). A PMHC, DGOG,
stage 1B2 (FIGO 2018) cervical cancer. GCIG/CCRN and multicenter study.
A systematic review on fertility and Int J Gynecol Cancer 2019;29:969–975.

Debate
44B Option for Young Women

with Stage IB2 Cervical Cancer
Who Wish to Preserve
Fertility?
Neo-adjuvant Chemotherapy
Followed by Fertility-sparing Surgery
Marie Plante
Debate
Upfront Radical Trachelectomy
The radical trachelectomy (RT) procedure is feasible but technically challenging in patients
with larger size lesions. Recurrence rates are clearly higher following the vaginal or laparo-
scopic approach (17–21%). Abdominal and robotic approaches appear to be better options
in terms of radicality. However, there is increasing concern over the minimally invasive
(MIS) approach in view of the reported increased risk of recurrence and death compared to
abdominal approach when a radical hysterectomy is performed (LACC trial). Logically, the
same concerns would apply if RT is performed by MIS particularly in the face of
a macroscopic cervical lesion. Therefore, upfront abdominal RT (ART) appears to be the
best option for patients with lesions >2 cm.
However, the reported rates of positive nodes in lesions measuring 2–4 cm is in the range
of 10–15%. Therefore, following upfront ART, the probability of patients requiring adju-
vant treatment because of positive nodes, or because of positive margins or parametrium
(Peters criteria) or in the presence of intermediate risk factors (Sedlis criteria) identified on
the final pathology of the trachelectomy specimen is significant (up to 26%). In most centers,
these patients would receive adjuvant (chemo)/radiation which would not only ruin fertility
potential but also ruin ovarian function in this young patient population. In a large series of
333 ART of which 132 had lesions >2 cm, up to 48% of patients required adjuvant treatment
because of unfavorable pathological findings.
Neo-adjuvant Chemotherapy Followed by Fertility-sparing Surgery

The rationale to offer neo-adjuvant chemotherapy (NACT) to women with larger cervical
cancer is to “cytoreduce” the size of the lesion in order to perform a less radical fertility-
sparing surgery (FSS), reduce the chances of requiring adjuvant treatment, and improve
268

Mx to Preserve Fertility? Chemo and Surgery 269
fertility and obstetrical outcome. The concept is based on the fact that cervical cancer is
a chemo-sensitive cancer with reported response rate >70%. Prior to initiating NACT,
a pelvic MRI is essential to carefully assess the size of the lesion and exclude extracervical/
extrauterine extension. In general, three cycles of platinum/paclitaxel combination are
given followed by a pelvic MRI to assess tumor response. In patients with complete or
optimal response (i.e., residual tumor <2 cm) a less radical FSS is performed (large coniza-
tion or simple trachelectomy). There is no clear evidence that more radical procedures in
good responders is associated with better oncologic outcomes. Considering the trend
towards less radical surgery in patients with small-volume tumors, it makes sense to offer
this option to patients with optimal response following NACT, considering its lower
surgical morbidity and excellent obstetrical results. Data from 264 cone/simple trachelec-
tomies shows a recurrence rate of 1.7% and live birth rate of 73% [1]. Conversely, patients
with suboptimal response to chemotherapy, (residual tumor >2 cm following NACT) have
poorer outcome, higher rates of recurrence, and should be treated more aggressively
(definitive chemoradiation or radical hysterectomy).
Available data on NACT/FSS for women with lesions measuring 2–4 cm remains limited
to small retrospective series [1]. A standardized approach with regards to the optimal
management of these patients will be conducted through a recently initiated prospective
international phase II trial (Contessa/Neocon-F trial) [2].
Comparison between the Two Options

A recent literature review comparing NACT/ Vaginal Radical Trachelectomy (VRT) versus
upfront ART specifically in patients with lesions measuring 2–4 cm was recently published
and confirms that both options have comparable oncologic outcome, but NACT/FSS is
definitively superior in terms of obstetrical outcome (Table 44B.1) [3].
Morbidity
The surgical morbidity of upfront ART is clearly superior compared to less radical proced-
ures (simple trachelectomy or conization). In addition to higher risks of infection and
bleeding, very serious complications such as uterovaginal anastomosis dehiscence and
Table 44B.1 Comparative oncologic and obstetrical outcome between NACT/VRT versus
ART in women with cervical cancer measuring 2–4 cm
NACT/VRT ART
n=92 n=246
Attempts to conceive 39% 40%

Chances of getting pregnant 21% 7%
Successful pregnancy 70% 21%
Live birth rate 63% 42%
Recurrence rate 10% 6.9%
Death rate 2.9% 3.4%
From van Kol et al. [3]

270 Marie Plante
uterine necrosis have been reported following ART. Extensive parametrial excision can also
impair fallopian tube motility, malfunction, or cause obstruction. Lastly, uterine atrophy
(secondary to uterine arteries ligation) may lead to Asherman’s syndrome and cervical
stenosis, all of which are associated with lower fertility and worse obstetrical outcome [4].
Oncologic Outcome
The oncologic outcome between the two options is actually comparable. In the van Kol
review, the recurrence rate was 10% versus 6.9% and the death rate was 2.9% versus 3.4% for
the NACT/FSS versus ART respectively (Table 44B.1) [3]. Fokom et al. calculated
a recurrence rate and mortality rate following NACT/FSS of 8.5% and 2.1% respectively
[1]. Bentivegna et al. also conducted an extensive systematic review and reported compar-
able recurrence rates of 4.3% versus 3.8% between the two procedures [5].
Fertility Outcome
Fertility preservation is better following NACT/FSS (ranging from 80–100%) compared to
ART. In a recent large series of 211 ART, only 17.4% of women who attempted to conceive
succeeded (fertility rate of only 7.2%); most infertility problems were related to cervical
stenosis and fallopian tube obstruction [4]. According to van Kol et al., chances of getting
pregnant following NACT/FSS were 21% compared to 7% following ART [3]. In
Bentivegna’s review, pregnancy rate was 77% following NACT/FSS versus 44% following
ART [5]. Although there is a potential risk of premature ovarian insufficiency following
NACT, this does not appear to be a major issue in most studies in terms of fertility.
Obstetrical Outcome
Obstetrical outcomes are clearly superior following NACT/FSS compared to ART. As can be
seen in Table 44B.1, successful pregnancy rate following NACT/FSS is 70% compared to
21% for ART with a live birth rate of 63% versus 42% in favor of NACT/FSS [3]. Pregnancies
following ART are associated with higher rates of obstetrical complications such as prema-
ture rupture of membranes and premature labor compared to simple trachelectomy or cone.
Obstetrical outcome according to the type of FSS shows a prematurity rate of 57% following
ART versus 15% after NACT/FSS [5].
Conclusion
A literature review comparing NACT/VRT versus upfront ART specifically in patients with
lesions measuring between 2–4 cm was recently published and confirms that both options
have comparable oncologic outcome, but NACT/FSS is definitively superior in terms of
obstetrical outcome (Table 44B.1) [3]. Since the ultimate objective of these young patients is
precisely to preserve fertility, NACT/FSS appears to be the best option. Even though upfront
ART is technically doable, it is associated with higher surgical morbidity and worse
obstetrical outcome.
Since a prospective randomized trial comparing both options is unlikely to ever be
conducted considering the rarity of those cases and the number of patients that would be
required to see a meaningful difference in outcome, we must currently rely on very
heterogeneous retrospective data with a variable level of evidence to guide management.
It is hoped that the Contessa/Neocon-F trial will provide solid data as to the oncologic
safety, fertility preservation, and obstetrical outcome with the NACT/FSS approach [2].

Mx to Preserve Fertility? Chemo and Surgery 271
References
1. Fokom Domgue J, et al. Conservative followed by vaginal radical trachelectomy in
management of cervical cancer: current stage 1B2 (FIGO 2018) cervical cancer.
status and obstetrical implications. Best A systematic review on fertility and
Pract Res Clin Obstet Gynaecol recurrence rates. Gynecol Oncol
2019;55:79–92. 2019;155:515–521.
2. Plante M, et al. FIGO 2018 stage IB2 (2– 4. Li X, et al. Reproductive and obstetric
4 cm) cervical cancer treated with neo- outcomes after abdominal radical
adjuvant chemotherapy followed by fertility trachelectomy (ART) for patients with
sparing surgery (CONTESSA); neoadjuvant early-stage cervical cancers in Fudan, China.
chemotherapy and conservative surgery in Gynecol Oncol 2020;157:418–422.
cervical cancer to preserve fertility 5. Bentivegna E, et al. Fertility results and
(NEOCON-F). Int J Gynecol Cancer pregnancy outcomes after conservative
2019;29:969–975. treatment of cervical cancer: a systematic
3. van Kol KGG, et al. Abdominal radical review of the literature. Fertil Steril
trachelectomy versus chemotherapy 2016;106:1195–1211(e5).

Debate
Should Adjuvant
45A Hysterectomy be Performed

for Patients with Locally
Advanced Cervical Cancer
Chemoradiotherapy?
Yes
Dib Sassine, Alexandra Diggs, and Yukio Sonoda
Debate
The utility of adjuvant hysterectomy (AH) after concurrent chemo-radiation (CCRT) for
the management of locally advanced cervical cancer (LACC) has been the subject of debate
for over 20 years. Up to 64% of hysterectomy specimens in patients who have received
CCRT have evidence of residual disease on pathology. In this setting, many gynecologic
oncologists see a benefit in AH to decrease rates of local recurrence [1].
In 2003, Keys et al. evaluated the role of AH in patients who received pelvic radiation
only for FIGO 1998 stage IB bulky cervical cancer. It demonstrated that patients with a large
tumor burden having lesions 4–6 cm may benefit from AH after pelvic radiation, without
increasing the rate of grade 3 or 4 adverse events [2].
To our knowledge, since these earlier studies, there have only been two additional
randomized controlled trials (RCTs) comparing the outcomes of CCRT alone versus
CCRT followed by AH [3,4].
A French trial attempted to investigate the therapeutic impact of AH after CCRT. The
trial included patients with stage IB2 and stage II who had received external beam radiation
therapy with concomitant cisplatin, followed by brachytherapy. Patients were randomized
AH versus no AH. It did not show any difference between both arms in terms of recurrence
and overall survival (OS). However, it is worth mentioning that the trial was underpowered
as it suffered from a failure of accrual, and had to close early after enrollment of only 61 of
the 320 planned patients [3].
A randomized trial from Mexico from 2014 aimed in turn to demonstrate that AH after
CCRT radically improved survival outcomes when compared with standard brachytherapy.
The study failed to show any difference in survival between both arms. The authors
acknowledged that the study design many have over-estimated the potential benefit of
radical hysterectomy and thus was underpowered. However, the trial did demonstrate
both the safety and feasibility of AH following CCRT [4].
272

Adjuvant Hysterectomy? Yes 273
Owing to the scarcity of well-designed RCTs showing a benefit to AH, most of the
available literature consists of retrospective data as well as single institution data.
A meta-analysis by Shim et al. published in Gynecologic Oncology in 2018, which
included the aforementioned RCTs and six observational studies, demonstrated that AH
following CCRT significantly decreased the risk of local recurrence by 44% (OR=0.56, 95%
CI: 0.33–0.96, p=0.034), but had no effect on rates of distant metastasis. This benefit was
again demonstrated in patients receiving combination external beam radiation therapy and
vaginal brachytherapy, with a pooled OR of 0.58 (95% CI: 0.41–0.83, p<0.05) favoring
CCRT + AH [5]. The same meta-analysis also concluded that there was no significant
difference in late adverse events (grade 3 or higher) between the two groups.
A more recent meta-analysis by Lu et al. in Oncology Letters (2021), including 12
retrospective studies and the aforementioned RCTs, reported no significant differences in
the cancer stage distribution between the two groups [6]. The CCRT + AH group had
a significantly improved OS and disease-free survival than the CCRT alone group (HR=0.72,
95% CI: 0.56–0.91, p=0.007, and HR=0.72, 95% CI: 0.56–0.93, p=0.01, respectively). The
incidence of recurrence was also significantly reduced in the CCRT + AH group compared
to CCRT alone (17.14% vs. 26.96%, OR=0.61, 95% CI: 0.47–0.79, p=0.0002). Importantly, all
of these statistically significant differences were observed only in pooled analyses of the
retrospective studies [6].
The majority of the locally advanced cervical cancers in the previously mentioned
studies were squamous cell carcinoma (SCC), as compared to adenocarcinoma, which
may be both more chemo-resistant and radio-resistant.
A retrospective study by Yang et al., looking at locally advanced adenocarcinoma of the
cervix, showed a significant improvement in PFS as well as OS in the group of patients who
underwent CCRT + AH compared to CCRT alone, (median PFS 48 months vs. 10 months,
HR=0.3431, 95% CI: 0.152–0.772, p=0.0097 and median OS 58 months vs. 36 months,
HR=0.3667, 95% CI: 0.139–0.964, p=0.0419 respectively [7].
Conclusion
Currently, retrospective data and subsequent meta-analyses are the only available data to
support the use of AH after CCRT for LACC. This data supports the practice of adjuvant
hysterectomy in patients with residual disease after CCRT, especially in the chemo-radio-
resistant and less common tumors such as AC. That being said, special attention should be
paid to assessing for distant metastases in these patients prior to proceeding with definitive
surgical management.
References
1. Yang J, et al. Completion hysterectomy after trial of the Gynecologic Oncology Group.
chemoradiotherapy for locally advanced Gynecol Oncol 2003;89(3):343–353.
adeno-type cervical carcinoma: updated 3. Morice P, et al. Results of the GYNECO 02
survival outcomes and experience in post study, an FNCLCC phase III trial comparing
radiation surgery. J Gynecol Oncol 2020;31 hysterectomy with no hysterectomy in
(2):e16. patients with a (clinical and radiological)
2. Keys HM, et al. Radiation therapy with and complete response after chemoradiation
without extrafascial hysterectomy for bulky therapy for stage IB2 or II cervical cancer.
stage IB cervical carcinoma: a randomized Oncologist 2012;17(1):64–71.

274 Dib Sassine et al.
4. Cetina L, et al. Brachytherapy versus radical 6. Lu W, et al. Chemoradiotherapy alone

hysterectomy after external beam vs. chemoradiotherapy and
chemoradiation with gemcitabine plus hysterectomy for locally advanced
cisplatin: a randomized, phase III study in cervical cancer: a systematic review and
IB2-IIB cervical cancer patients. Ann Oncol updated meta-analysis. Oncol Lett 2021;21
2013;24(8):2043–2047. (2):160.
5. Shim SH, et al. Impact of adjuvant 7. Yang J, et al. Extrafascial hysterectomy
hysterectomy on prognosis in patients with after concurrent chemoradiotherapy
locally advanced cervical cancer treated with in locally advanced cervical
concurrent chemoradiotherapy: a adenocarcinoma. J Gynecol Oncol 2016;27
meta-analysis. J Gynecol Oncol 2018;29(2):e25. (4):e40.

Debate
Should Adjuvant
45B Hysterectomy be Performed

for Patients with Locally
Advanced Cervical Cancer
Chemoradiotherapy?
No
Philippe Morice, Sebastien Gouy, and Cyrus
Chargari
Debate
Concomitant chemoradiation (CRT) followed by brachytherapy (BT) is considered as the
standard treatment for locally advanced cervical cancers in many countries. Adjuvant
hysterectomy in patients treated with primary radiation therapy had been the aim of endless
discussions. Adjuvant hysterectomy after such treatment had been widely used and evalu-
ated in numerous retrospective analyses during the last two decades. The theoretical
advantage is to remove any potential residual disease after CRT, thereby improving survival.
In a randomized trial conducted by Keys et al. comparing CRT and adjuvant hysterec-
tomy versus external radiation therapy (ERT) and adjuvant hysterectomy, the rate of
residual disease was lower in patients who received CRT compared to those treated with
ERT but was still reported to be 48% (vs. 59% in patients treated without concurrent
chemotherapy) [1]. This “high” rate should be evaluated with caution because it is strongly
correlated with the technical modalities of external radiation therapy and BT and also with
the timing of the surgery after the end of radiation therapy. Nevertheless, such a result was
the theoretical basis to consider a routine hysterectomy in this context to remove potential
residual cells that could explain recurrence or treatment failure.
Such a trial had been done before the major technical evolution of BT procedures and
development of 3D image-guided adaptive BT that is now the standard of care for this
technique, allowing dose escalations, which yield excellent local control while shielding
organs [2]. The other major issue that needs to be integrated in the evaluation of adjuvant
hysterectomy in this context is the morbidity of the pelvic surgery in this previously
irradiated area. In a prior study on morbidity caused by radical hysterectomy via laparo-
tomic approach after external radiation therapy for stage I or II cervical cancer, the rate of
major morbidity was almost 25% [3]. This rate was correlated with the radicality of the
hysterectomy (parametrial dissection) [3]. Such systematic radical hysterectomy should
275

276 Philippe Morice et al.
then surely be abandoned at least in patients with a “complete” clinical and radiological
response. In such cases, a “simple” hysterectomy is theoretically sufficient but even with
such a procedure, urological or intestinal morbidities could be observed due to the combin-
ation of the previous treatment and an additional pelvic dissection and de-vascularization of
the pelvic organs. The use of a laparoscopic approach could reduce the morbidity rate,
however, even lowering the morbidity rate does not justify the indication for this surgery
from an oncological point of view.
Only randomized trials could evaluate accurately the therapeutic impact of com-
pletion surgery after radiation therapy. One randomized trial (carried out before the
era of CRT) compared patients treated with initial radiation therapy and randomly
allocated to hysterectomy versus no hysterectomy (whatever the presence of residual
disease) but failed to demonstrate any benefit for overall survival with adjuvant
hysterectomy [4].
Fifteen years ago, we conducted a phase III trial in patients with “complete” response
following CRT and BT (evaluated between six to eight weeks after the end of the
treatment) comparing hysterectomy versus no hysterectomy, but the trial had to be closed
after three years due to lack of recruitment (only 61 patients were randomized).
Nevertheless, despite the lack of power for this study, hysterectomy had no impact on
survival rate [5].
According to the potential morbidity of adjuvant hysterectomy and unproved thera-
peutic impact of such a procedure, many teams and countries considered that such
a strategy is now obsolete and should be abandoned at least in patients having
a “complete” response after CRT and BT in locally advanced cervical cancer. Such surgery
could be potentially considered in countries having no or low access to high quality BT [6].
But this should not be an argument to abandon BT and to increase the use of hysterectomy
(and/or the dose of external radiation therapy) to replace it because such management will
have an impact on overall morbidity rates and furthermore recent major data from the
United States demonstrated clearly that omission of BT impacts negatively the survival of
patients in locally advanced cervical cancer [2].
Is there potentially a subgroup of patients in whom hysterectomy would be helpful? This
could be theoretically the case for patients with residual disease at the end of CRT and BT.
This situation of “real” residual tumor with remaining disease >1 cm is rare with the modern
techniques of external radiation therapy and BT (<10%). Thus, this surgery, in such
a context of residual disease, should be considered as a “salvage” surgery and not simply
as an adjuvant hysterectomy due to the possibly or requiring a radical hysterectomy or even
pelvic exenteration (with higher rates of major postoperative morbidities), in order to
optimize the rate of free surgical margins.
Additionally, patients who have a more “chemo-radio-resistant” disease also have
a higher rate of concurrent extra-cervical disease (nodal involvement, peritoneal dis-
ease), explaining the high rate of (pelvic and extra pelvic) recurrences in patients with
bulky residual disease following completion surgery at the end of treatment. This is
why, even if salvage surgery should be considered in these latter cases, we strongly
recommend a repeated complete radiological work-up is used (including new PET/CT
imaging, even if done initially before CRT is begun) to select the best candidates and
to exclude patients with obvious distant disease before such potentially radical surgery.

Adjuvant Hysterectomy? No 277
Conclusion
Finally, these considerations also raise the question of the best modalities to accurately
evaluate the presence of residual disease. Post-brachytherapy imaging, particularly using
magnetic resonance imaging (MRI), is the conventional approach with which to evaluate it,
but with the risk of false positives results. PET imaging or cone biopsies have also been
proposed to increase this accuracy, but the main issue for PET imaging is the delay in using
it after the end of treatment. Concerns regarding cone biopsies include morbidity (second-
ary bleeding) and accuracy. Currently, we have not yet determined the most accurate
procedure or combination of techniques to optimally predict the quality of response after
CRT and BT.
References
1. Keys HM, et al. Cisplatin, radiation and Gynecologic Oncology Group. Gynecol
adjuvant hysterectomy compared with Oncol 2003;89:343–353.
radiation and adjuvant hysterectomy for 5. Morice P, et al. Results of the GYNECO
bulky stage Ib cervical carcinoma. N Engl O2/108 phase III trial. Results of the
J Med 1999;341:708. GYNECO 02 study, an FNCLCC phase III
2. Chargari C, et al. Brachytherapy: an trial comparing hysterectomy with no
overview for clinicians. CA Cancer J Clin hysterectomy in patients with a (clinical
2019;69:386–401. and radiological) complete response after
3. Touboul C, et al. Prognostic factors and chemoradiation therapy for stage IB2 or
morbidities after completion surgery in II cervical cancer. Oncologist
patients undergoing initial chemoradiation 2012;17:64–71.
therapy for locally advanced cervical cancer. 6. Cetina L, et al. Brachytherapy versus radical
Oncologist 2010;15:405–415. hysterectomy after external beam
4. Keys HM, et al. Gynecologic Oncology chemoradiation with gemcitabine plus
Group. Radiation therapy with and without cisplatin: a randomized, phase III study in
extrafascial hysterectomy for bulky stage IB IB2-IIB cervical cancer patients. Ann Oncol
cervical carcinoma: a randomized trial of the 2013;24:2043–2047.

Debate
What is the Best Initial
46A Treatment for Stage IB3 to IIB

Cervical Cancer?
Neoadjuvant Chemotherapy
Followed by Radical Hysterectomy
Jolien Haesen, Rawand Salihi, and Ignace
B. Vergote
Debate
Neo-adjuvant chemotherapy (NACT) for cervical cancer reduces preoperatively the tumor
size and metastatic spread. In addition, long-term adverse events of radiochemotherapy
(CCRT), such as early menopause, dyspareunia, radio-enteritis and fistulas can be avoided.
A meta-analysis showed a significant benefit of neoadjuvant chemotherapy (NACT)
followed by surgery compared with radiotherapy alone. In addition, a better five-year
survival was observed with a short cycle (<14 days) NACT than with three-weekly regimens.
Two randomized phase III trials compared NACT followed by surgery with radioche-
motherapy (CCRT), and showed similar overall survival with both treatment strategies. In
both studies the disease-free survival for FIGO stage IB3 and stage IIA were also similar.
In conclusion, NACT followed by surgery can be considered as a valuable alternative for
CCRT in patients with cervical cancer FIGO stage IB3 or IIA, especially in premenopausal
patients.
Locally advanced cervical cancer, including FIGO IB3–IVA, is mainly treated by CCRT
followed by brachytherapy. Although in patients with stage IB3–IIB there is some evidence
that NACT followed by a radical hysterectomy (RH) might be an alternative.
By adding NACT to the treatment regimen, the tumor size can be reduced, making
inoperable tumors operable. In addition, better control of micro-metastatic disease can be
achieved. A meta-analysis showed a significant benefit of NACT followed by RH compared
with radiotherapy (without chemotherapy). In addition, a better five-year survival was
observed with a short cycle (<14 days) NACT than with three-weekly regimens [1].
Recently, two large randomized phase III studies compared NACT + RH versus CCRT
in cervical cancer FIGO stage IB3–IIB [2–3]. The first large single-center randomized
controlled trial reported by Gupta et al. included 635 patients randomized to NACT with
three-weekly carboplatin/paclitaxel followed by RH versus CCRT, and showed a five-year
disease-free survival of 69.3% and 76.7%, respectively (HR=1.38, p=0.038) [2]. However,
overall survival was 75.4% and 74.7%, respectively. Subgroup analyses of patients with FIGO
stage IB3 or IIA patients showed a similar disease-free survival with both treatment
strategies. The delayed toxicities at 24 months or later after treatment completion in the
278

Treatment? Chemo and Hysterectomy 279
NACT + RH group versus the CCRT group were rectal (2.2% vs. 3.5%, respectively), bladder
(1.6% vs. 3.5%, respectively), and vaginal (12.0% vs. 25.6%, respectively).
The EORTC 55994 study randomized 626 patients with cervical cancer FIGO stage IB3,
IIA2, and IIB between cisplatin-based NACT (in total at least 225 mg/m² cisplatinum)
followed by RH versus CCRT (80 Gy to high-risk PTV, with brachytherapy performed in
97% of patients). The primary endpoint, overall survival, was similar in both groups.
Progression-free survival at five years was 56.9% and 65.6% for NACT and CCRT, respect-
ively (p=0.021). However, in patients with FIGO stage IB3 (HR=0.89) NACT tended to be
better than CCRT. In addition, in patients younger than 50 years old, the progression-free
survival was similar with both treatment strategies. Long-term toxicity was lower in the
NACT + RH group (15%) versus the CCRT group (20%), with more specifically excess of
Chassagne grade 3–4 small bowel, colon, and vaginal complications in the CCRT group [3].
Although several studies have investigated the performance of different regimens of
NACT for locally advanced cervical cancer, the ideal regimen, number, and dosage of
NACT-courses remains uncertain. Paclitaxel – ifosfamide – cisplatinum three-weekly
(TIP) as NACT regime has been shown to be one of the most efficient, however, the
hematologic and nonhematologic toxicity is substantial [4]. As mentioned before, a meta-
analysis showed that short cycles (<14 days) should be preferred. Therefore, we investigated
a regimen with nine weekly dosages of paclitaxel (60 mg/m²) and carboplatin (AUC 2.7) and
observed similar response rates and a better tolerability than with the TIP regimen [5].
Conclusion
In conclusion, NACT followed by surgery can be considered as a valuable alternative for
CCRT in patients with cervical cancer FIGO stage IB3 or IIA, especially in premenopausal
patients. In addition, in regions with no or not enough radiotherapy resources, NACT
followed by surgery can be a valuable alternative for CCRT in FIGO IB3–IIB cervical cancer.
References
1. Tierney J. Neoadjuvant chemotherapy for Ib2–IIb cervical cancer, EORTC 55994.
locally advanced cervical cancer: J Clin Oncol 2019;37(15):5503.
a systematic review and meta-analysis of 4. Buda A, et al. Randomized trial of
individual patient data from 21 randomised neoadjuvant chemotherapy comparing
trials. Eur J Cancer 2003;39:2470–2486. paclitaxel, ifosfamide, and cisplatin with
2. Gupta S, et al. Neoadjuvant chemotherapy ifosfamide and cisplatin followed by radical
followed by radical surgery versus surgery in patients with locally advanced
concomitant chemotherapy and squamous cell cervical carcinoma: the
radiotherapy in patients with stage IB2, IIA, SNAP01 (studio neo-adjuvante portio)
or IIB squamous cervical cancer: Italian collaborative study. J Clin Oncol
a randomized controlled trial. J Clin Oncol 2005;23:4137–4145.
2018;36(16):1548–1555. 5. Salihi R, et al. Neoadjuvant weekly
3. Kenter G, et al. Results from neoadjuvant paclitaxel-carboplatin is effective in stage
chemotherapy followed by surgery I–II cervical cancer. Int J Gynecol Cancer
compared to chemoradiation for stage 2017;27(6):1256–1260.

Debate
What is the Best Initial
46B Treatment for Stage IB3 to IIB

Cervical Cancer?
Primary Chemoradiation
Sudeep Gupta, Amita Maheshwari, and Supriya
Chopra
Debate
The worldwide burden of cervical cancer continues to be high, with a substantial proportion
of patients presenting with locally advanced disease. These are either large tumors and/or
those which have infiltrated into vagina, parametrium, or other pelvic organs.
Historically, the first definitive treatment for invasive cervical cancer was radical hyster-
ectomy. The classical indications of an unresectable tumor are infiltration of pelvic side
walls and/or fixed pelvic lymph nodes. It is also known that radiation doses that are possible
to be safely delivered using a combination of external beam radiotherapy (EBRT) and
brachytherapy can cure many patients with advanced-stage cancer. One of the most
important advances in cervical cancer was the demonstration, about two decades ago,
that platinum-based chemotherapy delivered concurrently with radiotherapy could signifi-
cantly improve disease-free survival (DFS) and overall survival (OS) in patients with locally
advanced cervical cancer [1]. These results made concurrent chemoradiation (CTRT) the
standard of care [2].
Another promising treatment strategy that has been studied in patients with FIGO stage
IB2 (current stage IB3), IIA, and IIB disease, is neoadjuvant chemotherapy followed by
surgery (NACT-surgery). The results of two randomized phase III trials comparing CTRT
with NACT-surgery have now been presented [3,4]. Both studies have several similarities
and a few notable differences. The control arm of both studies was CTRT using weekly
cisplatin at a dose of 40 mg/m2 and radiotherapy delivered in appropriate doses and
durations. The investigational treatment in the Tata Memorial Hospital (TMH) study [3]
was three cycles of paclitaxel and carboplatin followed by type III radical hysterectomy, with
protocol defined cross-over to CTRT in case of suboptimal response. The investigational
treatment in the EORTC study [4] was neoadjuvant cisplatin-based chemotherapy, with
minimum cumulative planned dose of cisplatin >/= 225 mg/m2, followed by surgery.
Remarkably, 57% of the patients in both studies had stage IIB disease. The primary endpoint
of the TMH study was DFS while that of the EORTC study was OS, and both studies have
been reported with sufficient follow-up.
The results of both studies showed significantly higher five-year DFS with CTRT
compared with NACT-surgery, with absolute differences of 7.4% and 8.6% in TMH and
EORTC studies, respectively (Figure 46B.1). The DFS curves split apart early and stayed
apart during the entire course of follow-up. OS was not significantly different between the
280

Treatment? Primary Chemoradiation 281
(a)
1.0
DFS (probability) 0.8
0.6
0.4
HR for relapse or death as a result of cancer:
1.38 (95% CI, 1.02 to 1.87); log-rank P = .038
0.2
NACT plus surgery 5-year DFS, 69.3% (95% CI, 63.8 to 74.8)
CTRT 5-year DFS, 76.7% (95% CI, 71.6 to 81.8)
0 12 24 36 48 60 72 84
Times Since Random Assignment (months)
No. at risk:
NACT plus surgery 316 266 233 192 152 114 84 54
CTRT 317 282 261 210 167 116 85 60
(b) PFS
ITT population
100
90
80
70
60
50
40
30
20
Overall Score test: p = 0.011
10
0 (years)
0 2 4 6 8 10 12
O N Number of patients at risk: Treatment
144 314 202 169 122 93 64 NACT+Sy
119 312 230 202 145 105 75 CTRTx
Figure 46B.1 (A–D) Disease-free and overall survival in the TMH (A & C) and EORTC (B & D) studies [3,4].
two arms in both studies but there was a numerically superior (3.8%) five-year OS favoring
CTRT in the EORTC study (Figure 46B.1).
Subgroup analyses suggested that superior outcome with CTRT was concentrated in
patients with stage IIB disease. In terms of toxicity, the standout difference between the two

282 Sudeep Gupta, Amita Maheshwari, and Supriya Chopra
(c)
1.0
OS (probability) 0.8
0.6
0.4
HR for death: 1.025 (95% CI, 0.752 to 1.398);
log-rank P = .87
0.2
NACT plus surgery 5-year OS, 75.4% (95% CI, 70.1 to 80.7)
CTRT 5-year OS, 74.7% (95% CI, 69.4 to 80.0)
0 12 24 36 48 60 72 84
Times Since Random Assignment (months)
No. at risk:
NACT plus surgery 316 286 264 215 171 127 95 58
CTRT 317 297 277 223 176 120 86 60
(d) Overall survival

ITT population
100
90
80
70
60
50
40
30
20
Overall Score test: p = 0.253
10
0 (years)
0 2 4 6 8 10 12
O N Number of patients at risk: Treatment
104 314 244 212 156 116 78 NACT+Sy
94 312 262 228 162 119 84 CTRTx
Figure 46B.1 (cont.)
arms was higher vaginal toxicity in the CTRT arm after completion of treatment in both
studies and the higher gastrointestinal, bone marrow, and neurological toxicities during
treatment in the NACT-surgery arm in the EORTC study. Of note, in the NACT-surgery

Treatment? Primary Chemoradiation 283
arms of both studies, 24–28% of patients did not receive surgery while 27–44% patients
received radiotherapy or CTRT, as protocol-defined cross-over or adjuvant treatment.
The results of these two well conducted large randomized studies are remarkably
consistent and, in aggregate, suggest that CTRT results in superior outcomes compared
with NACT-surgery. Importantly, both studies were planned to prove the superiority of
NACT-surgery over CTRT and both failed to prove this in terms of their primary and
secondary endpoints. Further, almost one fourth of patients planned for NACT-surgery are
unable to undergo surgery and nearly one third or more require radiotherapy. While there
have been few, if any, advances in chemotherapy and surgery for cervical cancer, the
techniques of radiotherapy have rapidly progressed, and it is likely that in the current era,
the results would be tilted even more in favor of CTRT. Notably, with currently practiced
radiotherapy techniques, the incidence of short- and long-term toxicities is considerably
lower than that reported in these two studies [5]. The choice of platinum drug (carboplatin
or cisplatin) ultimately proved to be unimportant as was correctly speculated by us [3].
These results would ordinarily be sufficient to acknowledge CTRT as the standard of
care, which it is in most parts of the world. However, some centers have a long and well
entrenched practice of surgery in cervical cancer, even in advanced stages. To change
practice and give up long-held beliefs is difficult but must be done in the face of overwhelm-
ing evidence. It is often argued that radiotherapy resources are constrained in some
countries and therefore NACT-surgery is an acceptable alternative. This is an untenable
argument for two reasons. First, surgical expertise is equally scarce, if not more so, in these
same countries. Second, a considerable fraction of patients treated with NACT-surgery
strategy end up requiring radiotherapy and it would be a disservice to them to plan partial
and incomplete therapy. It would be more appropriate to enhance radiotherapy infrastruc-
ture and to implement referral networks that enable evidence-based treatment.
It has also been suggested that the superiority of CTRT is confined to patients with stage
IIB disease and that NACT-surgery is an appropriate alternative in stage IB2 (current stage
IB3) cancer. This is again untenable for two reasons. First, a substantial proportion (35.1%)
of stage IB2 patients in the NACT-surgery arm of the TMH study [Gupta S, personal
communication] ended up receiving radiotherapy, suggesting that NACT-surgery is often
inadequate in these patients. Second, the burden of proof in current era is on the advocates
of NACT-surgery and there is no indication from subgroup analysis of either study that this
treatment is superior in patients with stage IB2 cancer.
Conclusion
It is likely that the current ceiling of 70–75% DFS in stage IB3 and stage II cervical cancer
will be broken by integration of new treatments, like immunotherapy, with CTRT. Until this
is achieved, we should focus on increasing the accessibility and delivery of good quality
standard CTRT to these patients.
References
1. Chemoradiotherapy for Cervical Cancer meta-analysis of individual patient data
Meta-Analysis Collaboration. Reducing from 18 randomized trials. J Clin Oncol
uncertainties about the effects of 2008;26:5802–5812.
chemoradiotherapy for cervical 2. Koh WJ, et al. Cervical Cancer, Version
cancer: a systematic review and 3.2019, NCCN Clinical Practice Guidelines

284 Sudeep Gupta, Amita Maheshwari, and Supriya Chopra
in Oncology. J Natl Compr Canc Netw 4. Kenter G, et al. Results from neoadjuvant
2019;17(1):64–84. chemotherapy followed by surgery
3. Gupta S, et al. Neoadjuvant compared to chemoradiation for stage
chemotherapy followed by radical Ib2–IIb cervical cancer, EORTC 55994. 2019
surgery versus concomitant ASCO Annual Meeting; May 31 to June 4,
chemotherapy and radiotherapy in 2019; Chicago, IL: American Society of
patients with stage IB2, IIA, or IIB Clinical Oncology. Abstract 5503.
squamous cervical cancer: a randomized 5. Tan LT, et al. Image-guided adaptive
controlled trial. J Clin Oncol 2018;36 radiotherapy in cervical cancer. Semin
(16):1548–1555. Radiat Oncol 2019;29(3):284–298.

Debate
Is there a Role
47A for Immunotherapy

in Treatment of Cervical Cancer?
Yes
Chrisann Kyi and Dmitriy Zamarin1
Debate
Introduction
Cervical cancer (CC) is the most common gynecologic cancer worldwide. In the United States
annually, more than 13,800 new cases are diagnosed and 4290 expected to succumb to the
disease (SEER database, 2020). While early-stage disease CC can be cured with surgery or
chemoradiation, patients with metastatic and recurrent CC have poor prognosis and limited
treatment options after standard-of-care front-line platinum- and taxane-based chemother-
apy and bevacizumab. New treatment modalities and paradigms are needed. Several immu-
notherapeutic approaches have emerged as promising new strategies in the treatment of CC.
Rationale behind Immunotherapy in Cervical Cancer

Cervical Cancer is a Virally Driven Cancer
Cervical cancer is driven by high-risk human papillomavirus (HPV) infection, with onco-
genic HPV viral subtypes 16 and 18 accounting for more than ~70% of cases. While the
majority of individuals clear the initial infection, persistence of the viral oncoproteins E6
and E7 leads to inactivation of p53 and RB, resulting in progression through cell cycle and
carcinogenesis. As HPV-derived proteins represent a source of foreign antigens, HPV-
transformed cancer cells theoretically exhibit high immunogenicity, prompting recognition
and elimination by the immune system. However, HPV-related cancers have evolved
multiple mechanisms of evading the immune system, generating rationale for therapeutic
approaches targeting the mechanisms of immune evasion such as immune checkpoints or
therapies directed against HPV proteins.
Immune Checkpoint Inhibition in Cervical Cancer

Clinical trials have demonstrated clinical efficacy of PD-1 inhibition (pembrolizumab and
nivolumab) in the treatment of advanced and recurrent CC. KEYNOTE-158 was a phase II
study of pembrolizumab in metastatic and recurrent CC. Overall response rate (ORR) was
12.2% with responses observed only in PD-L1 positive (CPS≥1) cases. Based on
these results, the FDA approved pembrolizumab in recurrent and unresectable advanced
1
This study was supported in part by the MSK Cancer Center Support Grant P30 CA008748.
285

286 Chrisann Kyi and Dmitriy Zamarin
PD-L1+ CC in June 2018 [1]. CheckMate 358 was a phase I/II study of nivolumab in virus-
associated tumors, with ORR of 26.3% reported in CC [2]. Expansion cohorts of CheckMate
358 presented at the ESMO 2019 meeting demonstrated promising results of nivolumab in
combination with ipilimumab (CTLA-4 inhibitor), with ORR of 45.8% in patients with no
prior treatment and 36.4% in patients with prior systemic treatment, with median progres-
sion-free survival of 8.5 months and 5.8 months, respectively (Naumann et al., ESMO 2019),
highlighting that the utilization of immunotherapy earlier in the disease course may have
a potential to benefit a larger percentage of patients and possibly even prevent disease
recurrence. Ongoing or planned immune checkpoint inhibitor studies in CC are investigat-
ing combination with existing therapies (radiation therapy or chemotherapy) or combin-
ation therapy with other molecularly targeted drugs.
Immunotherapies Targeting HPV-related Genes

The viral oncoproteins E6 and E7 represent attractive targets for therapeutic cancer
vaccination. In patients with precancerous lesions (CIN 2/3), vaccination with VGX-3100,
a synthetic plasmid targeting HPV-16/HPV-18 E6 and E7 proteins, resulted in histopatho-
logic regression of CIN lesions in 48.2% of VGX-3100 recipients, compared with 30%
regression in the subjects treated with placebo (p=0.034) [3]. Unfortunately, various HPV-
directed vaccination strategies to date have not demonstrated a consistent signal of efficacy,
suggesting that in advanced disease, additional mechanisms of immune evasion (e.g.,
immune checkpoints) may need to be targeted to augment vaccine efficacy.
Adoptive cell therapies (ACT) refer to infusion of large numbers of ex vivo-expanded
antigen-specific T cells into patients and thus bypass the need for generation of HPV-
specific T cells in vivo. Several ACT approaches have been evaluated for therapy of CC,
including tumor infiltrating lymphocyte (TIL) therapy and therapy with engineered T cells
targeting HPV E6. In a study of nine patients with metastatic CC who received a single
infusion of TILs selected for HPV E6 and E7 reactivity, two patients experienced a complete
response, sustained for 22 and 15 months, and one patient experienced a partial response
[4]. Similarly, an ACT trial of engineered T cells expressing HPV-16 E6-targeted TCR
demonstrated two responses in 12 treated patients, providing a proof of concept that HPV-
targeted approaches can be an effective strategy in this disease [5].
Conclusion
Cervical cancers are in large part driven by HPV infection and their progression requires
acquisition of various immune evasion mechanisms. Though immunotherapies in CC to date
have benefited a minority of patients, the depth and durability of responses highlight the
power of the immune system to control and even eliminate this disease. New immune
checkpoint blockade combinations, ACT approaches, and utilization of these strategies earlier
in the disease setting will extend the benefit of these therapies in most if not all CC patients.
References
1. Chung HC, et al. Efficacy and safety of 2. Naumann RW, et al. Safety and
pembrolizumab in previously treated efficacy of nivolumab monotherapy
advanced cervical cancer: results from the in recurrent or metastatic cervical,
phase II KEYNOTE-158 study. J Clin Oncol vaginal, or vulvar carcinoma: results
2019;37:1470–1478. from the phase I/II Check Mate

Immunotherapy in Treatment? Yes 287
358 Trial. J Clin Oncol 4. Stevanovic S, et al. Complete regression of

2019;37:2825–2834. metastatic cervical cancer after treatment
3. Trimble CL, et al. Safety, efficacy, and with human papillomavirus-targeted
immunogenicity of VGX-3100, tumor-infiltrating T cells. J Clin Oncol
a therapeutic synthetic DNA vaccine 2015;33:1543–1550.
targeting human papillomavirus 16 and 18 5. Doran SL, et al. T-cell receptor gene
E6 and E7 proteins for cervical therapy for human
intraepithelial neoplasia 2/3: a randomised, papillomavirus-associated epithelial
double-blind, placebo-controlled phase 2b cancers: a first-in-human, phase I/II study.
trial. Lancet 2015;386:2078–2088. J Clin Oncol 2019;37:2759–2768.

Debate
Is there a Role
47B for Immunotherapy

in Treatment of Cervical Cancer?
No
Fernando Cotait Maluf, Daniele Xavier Assad,
and Angelica Nogueira-Rodrigues
Debate
Cervical cancer is responsible worldwide for 569,847 new cases and 311,365 deaths annually,
more than 85% of the deaths occurring in low- and middle-income countries. So far, few
advances have been seen in the treatment of locally advanced and metastatic disease.
Immuno-oncology, including adoptive T-cell therapy and immune checkpoint inhibition
(anti-CTLA-4 and anti-PD-1 and PD-L1), has emerged as a novel strategy to improve
outcomes in patients with many solid tumors including gynecologic malignancies such as
endometrial cancer. The role of immunotherapy is evolving in cervical cancer patients,
either in first-line for locally advanced and metastatic disease or as salvage therapy after
failure to platinum-based therapy. Based on evidence of human papillomavirus (HPV)-
induced immune evasion, immunotherapy may be an attractive strategy in this disease.
However, currently available data is limited and restricted to patients with metastatic or
recurrent (M/R) disease in the salvage setting.
Ipilimumab, a human monoclonal IgG1 k antibody against CTLA-4, was evaluated in
a phase I/II study in 42 M/R cervical cancer patients. Patients were treated with 10 mg/kg
every three weeks for a total of four cycles, followed by four additional cycles of
maintenance therapy every 12 weeks for patients with radiologic response or stabiliza-
tion. There was only one partial response and 10 patients had stable disease. The median
progression-free survival (PFS) was only 2.5 months and the median overall survival was
8.5 months [1].
Pembrolizumab, an anti-PD-1 antibody, was evaluated in 98 M/R cervical cancer
patients regardless of the PD-L1 status (KEYNOTE-158), at the dose of 200 mg intraven-
ously every three weeks for up to 24 months or until confirmed disease progression,
intolerable toxicity, or death. PD-L1-positivity, defined by PD-L1 combined positive score
≥1, was reported in 83% of patients. The overall response rate was only 12.2%, with
complete responses seen in three patients and partial response in nine patients; 17 patients
had stable disease and the disease control rate was 31%. All 12 responses were in patients
with PD-L1-positive tumors. Of those who experienced response, nearly 70% (9/12) had
a response lasting >9 months. A total of 12% of patients had grade 3/4 adverse events [2].
A second trial (KEYNOTE-028) evaluated pembrolizumab at the dose 10 mg/kg every two
weeks for up to 24 months in 24 PD-L1-positive patients with advanced or recurrent disease.
Overall response rate was 17%, all of them partial responses, with a median duration of only
288

Immunotherapy in Treatment? No 289
5.4 months [3]. Based on results of both nonrandomized studies, FDA granted approval for
the use of pembrolizumab in PD-L1-positive patients with metastatic or recurrent disease.
However, it remains unclear if PD-L1 is a reliable biomarker in this setting to discriminate
patients most likely to achieve a response. Also, the overall response rates in the enriched
PD-L1 population reported with pembrolizumab does not seem to be different from those
observed with second-line chemotherapy in the salvage setting such as irinotecan, topote-
can, capecitabine, gemcitabine, vinorelbine, and pemetrexed [4].
Another anti-PD-1 agent, nivolumab at the dose of 240 mg intravenously every two
weeks, was evaluated in a phase I/II study (CheckMate-358). CheckMate-358 is an ongoing
phase I/II study that is investigating nivolumab-based therapies in virus-associated cancers,
regardless of tumor cell PD-L1 expression. In a cohort with 19 advanced cervical patients
with ≤2 prior systemic therapies, the overall response rate of nivolumab alone was 26.3%,
with a disease control rate of 68% [5]. The CheckMate-358 study has also explored two
different regimens combining nivolumab and ipilimumab. A total of 91 patients who had
received up to two prior systemic therapies for M/R disease were randomized to either
nivolumab at 3 mg/kg every two weeks plus ipilimumab at 1 mg/kg every six weeks (nivo3 +
ipi1) or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg, given every three weeks for four
doses followed by nivolumab at 240 mg every two weeks (nivo1 + ipi3). In the nivo3 + ipi1
arm, median PFS was 13.8 months (95% CI: 2.1–not reached) in the patients not previously
treated with systemic therapy for M/R disease and 3.6 months (95% CI: 1.9–5.1) in those
with previous systemic therapy. In the nivo1 + ipi3 arm, the median PFS was 8.5. months
(95% CI: 3.7–not reached) in the patients with no prior systemic therapy and 5.8 months
(95% CI: 3.5–17.2) in those who had received prior systemic therapy. In the nivo3 + ipi1
arm, the objective response rate (ORR) was 31.6% in those patients who received no prior
systemic therapy and 23.1% in those with prior systemic therapy. The ORR in the nivo1 +
ipi3 arm were 45.8% and 36.4%, respectively. Although promising, this is a “pick a winner
cohort,” and CheckMate-358 continues to enroll patients with M/R cervical cancer for
mature conclusions [6].
An international phase III study is evaluating the role of cisplatin, paclitaxel, and
bevacizumab with or without atezolizumab (anti-PD-L1 antibody) in first-line therapy for
advanced cervical cancer with overall survival as the primary endpoint. The role of immune
checkpoint inhibitors has also been tested in locally advanced cervical cancer with durva-
lumab (anti-PD-L1 antibody), in a phase III study designed to compare durvalumab with
and following chemoradiotherapy versus chemoradiotherapy alone with PFS as the primary
endpoint. In the same scenario, pembrolizumab in addition to chemoradiotherapy has also
been evaluated.
Conclusion
Therefore, based on the actual data, the role of immunotherapy in cervical cancer at this
moment is uncertain. There are few phase I/II studies, no quality of life analysis, limited
responses for the majority of patients at high cost, and no clear superiority over second-line
chemotherapy (but obviously more expensive). Also, immunomediated toxicity is not
negligible and there is no definitive biomarker to discriminate efficacy and toxicity.
Lastly, the phase III trials either as first-line therapy for locally advanced or metastatic
disease or as salvage therapy are still ongoing in order to support a possible role of
immunotherapy in this setting with level 1 evidence.

290 Fernando Cotait Maluf et al.
References
1. Lheureux S, et al. Association of ipilimumab 4. Boussios S, et al. Management of patients
with safety and antitumor activity in women with recurrent/advanced cervical cancer
with metastatic or recurrent human beyond first line platinum regimens: where
papillomavirus–related cervical carcinoma. do we stand? A literature review. Crit Rev
JAMA Oncol 2018;4(7):e173776. Oncol/Hematol 2016;108:164–174.
2. Chung HC, et al. Efficacy and safety of 5. Naumann RW, et al. Safety and efficacy of
pembrolizumab in previously treated nivolumab monotherapy in recurrent or
advanced cervical cancer: results from the metastatic cervical, vaginal, or vulvar
phase II KEYNOTE-158 study. J Clin Oncol carcinoma: results from the phase I/II
2019;37(17):1470–1478. CheckMate 358 Trial. J Clin Oncol 2019;37
3. Frenel J-S, et al. Safety and efficacy of (31):2825–2834.
pembrolizumab in advanced, 6. Naumann RW, et al. Efficacy and safety of
programmed death ligand 1–positive nivolumab plus ipilimumab in patients with
cervical cancer: results from the phase Ib recurrent /metastatic cervical cancer: results
KEYNOTE-028 Trial. J Clin Oncol from Checkmate 358. Ann Oncol 2019;30
2017;35(36):4035–4041. (Suppl. 5):v851–v934.

Section VI Vaginal and Vulvar Cancer
Debate
Should the Subsequent
48A Management of Patients

with Vulvar Cancer
and a Positive Sentinel Lymph
Node be Complete Groin
Lymph Node Dissection
or Radiation Therapy?
Dissection
Lilian T. Gien
Debate
Vulvar cancer is a rare disease, representing 4% of gynecologic malignancies, with 90%
squamous cell histology. The most important prognostic factor for survival is lymph node
metastasis. Patients with negative groin nodes have an excellent five-year overall survival
(OS) rate (90%) versus those with groin metastasis (0–51%). The presence of groin metas-
tasis increases risk of groin recurrence which is fatal in almost all patients. Therefore, the
appropriate primary management of the groins at diagnosis of vulvar cancer is of utmost
importance.
Surgery remains the primary treatment for early-stage vulvar cancer, but has shifted
from radical to more limited surgery. Instead of complete inguinofemoral lymph node
dissection (IFLD), associated with high rates of lymphedema (30–70%) and wound break-
down (20–40%), groin assessment is now done by sentinel lymph node (SLN) biopsy. The
GROINSS-V study was an observational study of 403 women with early-stage (<4 cm)
vulvar cancer, depth of >1 mm and clinically nonsuspicious groin nodes, of which 276
patients had a negative SLN [1]. Isolated groin recurrence was 2.5% with median follow-up
of 105 months. Ten-year disease-specific survival was 91% in those SLN negative. There
were significantly lower wound breakdown, cellulitis, or lymphedema among those with
SLN biopsy compared to those with IFLD for positive nodes. Similarly, the Gynecologic
Oncology Group (GOG) protocol 173 was an observational study of 452 patients with
tumor size 2–6 cm who underwent a SLN biopsy and a complete IFLD [2]. SLN biopsy had
a sensitivity of 91.7%, and a false negative predictive value of 2% for those with tumors
<4 cm. Based on these two major studies, SLN biopsy is now the standard of care for vulvar
cancer, which has led to a substantial reduction in surgical morbidity.
291

Section VI Vaginal and Vulvar Cancer
Debate
48A Management of Patients

with Vulvar Cancer
Dissection
Lilian T. Gien
Debate
Vulvar cancer is a rare disease, representing 4% of gynecologic malignancies, with 90%
squamous cell histology. The most important prognostic factor for survival is lymph node
metastasis. Patients with negative groin nodes have an excellent five-year overall survival
(OS) rate (90%) versus those with groin metastasis (0–51%). The presence of groin metas-
tasis increases risk of groin recurrence which is fatal in almost all patients. Therefore, the
appropriate primary management of the groins at diagnosis of vulvar cancer is of utmost
importance.
Surgery remains the primary treatment for early-stage vulvar cancer, but has shifted
from radical to more limited surgery. Instead of complete inguinofemoral lymph node
dissection (IFLD), associated with high rates of lymphedema (30–70%) and wound break-
down (20–40%), groin assessment is now done by sentinel lymph node (SLN) biopsy. The
GROINSS-V study was an observational study of 403 women with early-stage (<4 cm)
vulvar cancer, depth of >1 mm and clinically nonsuspicious groin nodes, of which 276
patients had a negative SLN [1]. Isolated groin recurrence was 2.5% with median follow-up
of 105 months. Ten-year disease-specific survival was 91% in those SLN negative. There
were significantly lower wound breakdown, cellulitis, or lymphedema among those with
SLN biopsy compared to those with IFLD for positive nodes. Similarly, the Gynecologic
Oncology Group (GOG) protocol 173 was an observational study of 452 patients with
tumor size 2–6 cm who underwent a SLN biopsy and a complete IFLD [2]. SLN biopsy had
a sensitivity of 91.7%, and a false negative predictive value of 2% for those with tumors
<4 cm. Based on these two major studies, SLN biopsy is now the standard of care for vulvar
cancer, which has led to a substantial reduction in surgical morbidity.
291

292 Lilian T. Gien
The importance of adjuvant radiation was demonstrated in GOG37, where 114 patients
with positive groin nodes were randomized to adjuvant radiation therapy (RT) to the groin/
pelvis versus pelvic node resection. Survival was superior in the adjuvant RT group with the
most significant benefit in those with ≥2 positive groin nodes, demonstrating how RT is an
integral part of managing positive groin nodes in vulvar cancer. Therefore, although patients
with a negative SLN can avoid a full IFLD, for patients with a positive SLN, should the
subsequent management be a complete IFLD which can potentially introduce surgical morbid-
ity, or is it sufficient to offer adjuvant RT? Based on existing data, the standard of care remains
complete surgical dissection of the groin nodes in order to maximize patient survival.
In GOG88, patients with clinically negative groin nodes were randomized to full IFLD or
RT [3]. However, this trial was stopped early because the groin recurrence rate in the
radiation only arm was unacceptably high at 18.5%. This trial emphasized that resection of
clinically negative groins could not be substituted with radiation alone, and that surgical
resection of microscopic positive nodes remains necessary. There are several criticisms of
this trial, including the depth of treatment by RT resulting in insufficient dose of radiation to
the groin. Despite the criticisms however, no other randomized controlled trial (RCT) has
been done to re-evaluate this question, given the fatality associated with groin recurrence,
reluctance to randomize, and the rarity of this disease. A Cochrane Review of this topic was
completed in 2011, however GOG88 was the only RCT included. The conclusion of this
systematic review was that there is not enough evidence to prove that primary RT is as
effective to control tumors in the groin and surgery is the first-choice treatment for groin
nodes in early invasive vulvar cancer.
In the era of SLN biopsy, there is little data regarding the prognostic significance of the
size of the SLN metastasis. In an evaluation of the SLN positive patients in GROINSS-V, the
proportion of patients with non-SLN metastasis increased with size of SLN metastasis [4].
Disease-specific survival for patients with SLN metastasis >2 mm was lower than those with
metastasis ≤2 mm (69.5% vs. 94.4%, p=0.001). There was no size cut-off below which
chances of non-SLN metastasis were close to zero, concluding that all patients with SLN
metastasis necessitate additional groin treatment, regardless of the size of metastasis, and
for those with metastasis >2 mm this includes a full IFLD.
GROINSS-V II was a second multicentered international observational study that
evaluated whether adjuvant RT could be given for those with a positive SLN without
IFLD [5]. At the start of the study all patients with a positive SLN were included.
However, after interim analysis of 82 patients with metastatic SLN, there were nine groin
recurrences. Those at risk for groin recurrence had metastases >2 mm and/or extranodal
tumor growth. Therefore, the protocol was amended such that those with macrometastasis
received IFLD and RT whereas only patients with micrometastasis (≤ 2 mm) could receive
adjuvant RT without IFLD. There were 1544 eligible patients, 158 with micrometastatic
SLNs. The isolated groin recurrence rate was 1.7% after two years in patients with micro-
metastasis treated with adjuvant RT. Based on the recurrence rate with RT for macrometa-
static disease, radiotherapy with a total dose of 50 Gy was no safe alternative to IFLD.
Conclusion
A RCT is not possible in this patient population and decision guidelines will continue to be
based on prospective observational studies. GROINSS-V III is the next planned observa-
tional study, which asks the question of whether patients with macrometastatic disease in

Dissection or Radiation Therapy? Dissection 293
the SLN can avoid a full IFLD. All patients enrolled in this study will have adjuvant RT at an
increased dose of 56 Gy combined with concurrent chemotherapy, with the hypothesis that
the addition of cisplatin and increased radiation dose could potentially overcome the need
for IFLD in patients with a positive SLN >2 mm. However, the results of this study will not
be available for several years, and safety monitoring with interim analysis will be crucial. In
the meantime, the strongest data available in the literature support that the standard of care
for patients with a positive SLN is IFLD, which should not be substituted by RT.
References
1. Van der Zee AGJ, et al. Sentinel node 4. Oonk MHM, et al. Size of sentinel-node
dissection is safe in the treatment of metastasis and chances of non-sentinel-
early-stage vulvar cancer. J Clin Oncol node involvement and survival in
2008;26:884–889. early-stage vulvar cancer: results from
2. Levenback CF, et al. Lymphatic mapping GROINSS-V, a multicentre
and sentinel lymph node biopsy in women observational study. Lancet Oncol
with squamous cell carcinoma of the vulva: 2010;11:646–652.
a Gynecologic Oncology Group study. J Clin 5. Oonk MHM, et al. Radiotherapy instead
Oncol 2012;30:3786–3791. of inguinofemoral lymphadenectomy
3. Stehman FB, et al. Groin dissection vs groin in vulvar cancer patients with
radiation in carcinoma of the vulva: a metastatic sentinel node: results of
a Gynecologic Oncology Group study. GROINSS-V II. Int J Gynecol Cancer 2019;29
Int J Rad Oncol Biol Phys 1992;24:389–396. (Suppl. 4):A14.

Debate
48B Management of Patients

with Vulvar Cancer
Radiation Therapy
Ryan M. Kahn and Wui-Jin Koh
Debate
Squamous cell carcinoma (SCC) of the vulva is a rare disease accounting for nearly 6% of all
gynecologic malignancies, with an estimated 6300 newly diagnosed cases and 1500 deaths in
the United States in 2022 [1]. The traditional primary treatment of early-stage disease with
>1 mm of invasion consisted of radical excision of the tumor with elective inguinofemoral
lymphadenectomy (IFL). However, only 25–35% of women with early-stage disease will be
found to have lymph node metastases. Additionally, IFL has the potential to cause signifi-
cant morbidity. with a 30–70% risk of long-term lymphedema as well as infection or wound
breakdown in 20–40% of patients [2].
Recent evidence has shown that performing a sentinel lymph node (SLN) biopsy of the
inguinofemoral lymph node basin – a less invasive approach resulting in decreased mor-
bidity – is safe and feasible [2]. Long-term follow-up of the Groningen International Study
on Sentinel nodes in Vulvar cancer (GROINSS-V-I) demonstrated that SLN biopsy with
negative findings was associated with an isolated groin recurrence rate of 2.5% among 377
patients with unifocal disease over a median follow-up of 105 months, with a 10-year
disease-specific survival (DSS) of 91% [3] The Gynecologic Oncology Group (GOG)-173
study – a prospective, multi-institutional validation trial – demonstrated similar findings,
proving SLN biopsy is a reasonable alternative to IFL in select patients [4]. SLN biopsy has
now currently become the standard of care over IFL in patients with early-stage SCC of the
vulva – which includes patients with a unifocal tumor <4 cm as well as a negative clinical and
or radiologic groin examination. However, a standardized treatment paradigm following
the findings of a positive SLN remains lacking.
The known postoperative morbidity risks following IFL led to the follow-up study
(GROINSS-V-II), investigating whether inguinofemoral radiation therapy (RT) is a safe
294

Dissection or Radiation Therapy? Radiation Therapy 295
alternative to IFL in patients with positive SLN findings. This study was a prospective,
multicenter phase II single-arm study of patients with early-stage SCC of the vulva who
underwent primary local excision and a SLN biopsy. If the SLN was positive with
metastasis of any size, inguinofemoral RT was administered within six weeks after
surgery. The RT regimen consisted of a total dose of 50 Gray (Gy) in 25–28 fractions of
1.8–2 Gy, five fractions per week, which was considered an effective dose for subclinical
disease [5].
GROINSS-V-II study registered 1535 patients between the years of 2005–2016, with
SLN metastasis identified in 322 cases. The stopping rule was temporarily activated in
2010 as the isolated groin recurrence rate in the RT group exceeded the study’s
predefined threshold – among 10 patients with an isolated groin recurrence, nine had
SLN metastases of >2 mm and/or extracapsular spread. The protocol was then amended
so patients with SLN macrometastases were assigned to IFL as the standard of care
(with adjuvant RT for multiple LN involvement and/or extracapsular spread), whereas
patients with SLN micrometastases (≤2 mm) continued to receive inguinofemoral RT
alone [4]. At study conclusion, among 160 patients with SLN micrometastases, 126
received inguinofemoral RT alone per protocol, with a two-year ipsilateral isolated
groin recurrence rate of 1.6%. While adjuvant RT added low-grade acute morbidity
compared with SLN biopsy alone, chronic lymphedema was greatly decreased as
compared to IFL with rates of 11% versus 23% respectively at 12 months. Ultimately,
the authors of GROINSS-V-II concluded that inguinofemoral RT could spare patients
with early SCC of the vulva with SLN micrometastases from the long-term morbidity of
complete IFL [5].
The data is less clear for those with a macrometastasis (>2 mm) on SLN biopsy.
GROINSS-V-II suggested inadequate control with postoperative RT alone, without further
IFL. For the 162 patients with SLN macrometastases, the two-year groin recurrence rate was
22% in the RT cohort versus 6.9% in patients who underwent IFL with or without further RT
(p=0.011) [5]. However, the RT approach used in GROINS-V-II has been challenged as
possibly inadequate in coverage and dose for patients with a macrometastatic SLN [6]. It is
informative to note that in the GOG-101 study, patients with initially unresectable grossly
positive, fixed or ulcerated groin nodes underwent preoperative wide-field RT with concur-
rent 5FU and cisplatin, and demonstrated significant clinical response permitting resection
in 95% of cases, and complete histologic clearance of all nodal disease in 15 of 37 patients
[7]. The efficacy of appropriately designed adjuvant RT, with dose escalation and given with
concurrent cisplatin, is being evaluated in GROINSS-VIII for patients with macrometa-
static SLN.
Conclusion
Overall, the management of early-stage vulvar cancer has undergone major advances over
the past decade. In patients with early-stage disease, clinicians must balance the proven
benefits of adjuvant treatment options with the risks of toxicities and quality of life
outcomes. Based on data from GROINSS-V-II, patients with SLN micrometastasis of
≤2 mm benefit from inguinofemoral RT over complete groin lymph node dissection.
Further prospective trials are necessary to evaluate RT dose escalation in combination
with chemotherapy in hopes to establish future standardized guidelines, especially in the
adjuvant treatment of macroscopic SLN cases.

296 Ryan M. Kahn and Wui-Jin Koh
References
1. American Cancer Society. Cancer Facts & a Gynecologic Oncology Group study. J Clin
Figures 2022. Atlanta, GA: American Cancer Oncol 2012;30(31):3786–3791.
Society, 2022. 5. Oonk MHM, et al. Radiotherapy versus
2. Van der Zee AG, et al. Sentinel node inguinofemoral lymphadenectomy as
dissection is safe in the treatment of treatment for vulvar cancer patients with
early-stage vulvar cancer. J Clin Oncol micrometastases in the sentinel node: results
2008;26(6):884–889. of GROINSS-V II. J Clin Oncol 2021;39
(32):3623–3632.
3. Te Grootenhuis NC, et al. Sentinel nodes in
vulvar cancer: long-term follow-up of the 6. Glaser S, et al. Inguinal nodal radiotherapy
GROningen INternational Study on for vulvar cancer: are we missing the target
Sentinel nodes in Vulvar cancer again? Gynecol Oncol 2014;135(3):583–585.
(GROINSS-V) I. Gynecol Oncol 2016;140 7. Montana GS, et al. Preoperative
(1):8–14. chemo-radiation for carcinoma of the vulva
4. Levenback CF, et al. Lymphatic mapping with N2/N3 nodes: a Gynecologic Oncology
and sentinel lymph node biopsy in women Group study. Int J Radiat Oncol Biol Phys
with squamous cell carcinoma of the vulva: 2000;48(4):1007–1013.

Debate
What is the Best Treatment
49A for Stage I Vulvar Squamous

Cell Carcinoma with either
a Close or Positive Surgical
Margin?
Re-excision
Sabrina M. Bedell and Britt K. Erickson
Debate
To date there are no prospective studies that directly evaluate outcomes for re-excision
versus adjuvant radiation for close or positive margins in patients with stage I squamous cell
carcinoma of the vulva. However, given available evidence as well as consideration of
morbidities associated with radiotherapy, we suggest that re-excision is the preferred
method of management for stage I vulvar cancer with close or positive margins.
Observation may also be considered for patients with close margins.
Determining the true recurrence rates for patients with close or positive surgical
margins is challenging. Importantly, unlike other tumor types, local recurrence in vulvar
cancer is usually salvageable and distant recurrence is almost universally fatal. In the largest
early-stage prospective Gynecologic Oncology Group (GOG) study, the salvage rate for
local recurrence was 80% [1]. The majority of studies examining recurrence rates by margin
status combine all stages of disease, which majorly confounds survival. Studies that report
on only stage I tumors are limited by small sample size.
Additionally, the definition of “close margins” has changed over time. Historically, close
margins have been defined as less than 8 mm [2]. However, recent data demonstrate that for
patients with true stage I disease, 2–3 mm may better define those at increased risk of
recurrence [3]. Additionally, these studies suggest that other factors such as age and
presence of lichen sclerosis may be a more important predictor of recurrence compared
to margin status. The most recent NCCN guidelines define a pathologic close margin as 1–
8 mm [4].
In our series of 47 patients with stage I vulvar squamous cell carcinoma, which repre-
sents the largest series of stage I patients with sufficient treatment and survival outcome
data, we found no difference in the rate of recurrence between patients who received any
further treatment (vulvar radiation or re-excision) versus those who received no further
treatment [5]. Notably, there were no distance recurrences and of the seven local recur-
rences, one was lost to follow-up and the remaining six were salvaged with excision,
radiation, chemotherapy, or combination therapy. No patients died of disease.
297

298 Sabrina M. Bedell and Britt K. Erickson
Another multi-institutional cohort study evaluated outcomes following re-excision,

stratified by pathology of the re-excision specimen margin, and found that for patients
with stage I vulvar cancer, the mean time to recurrence was 58 months for those with VIN at
re-excision margins, versus 9.4 months for those that had carcinoma at re-excision margins.
Further, five of the six with local recurrences were salvaged with repeat excision and had no
evidence of disease at time of follow-up – the sixth patient had no further follow-up [6].
Thus, successful re-excision resulted in improved outcomes, and those with stage I disease
that did recur locally were often successfully salvaged with re-excision.
Adjuvant radiation has a host of morbid side effects including skin desquamation, pain,
necrosis, and urinary, bowel, and sexual dysfunction. Of the few studies that report on
complication rates for vulvar radiation, one indicates a conservative 42% rate of grade III
Radiation Therapy Oncology Group (RTOG) acute skin reactions and 13% rate of grade III
RTOG late skin reactions [7], while a second study indicates 100% rate of acute skin
desquamation (the equivalent of RTOG grade IV acute skin reaction), and 5.5% rate of
late skin reaction. It should be noted that in the latter study 22% of patients had died within
one year of treatment, limiting the ability to draw conclusions regarding long-term side
effects. The risk of long-term morbidity from adjuvant vulvar radiation is too high to be an
acceptable adjuvant treatment for stage I vulvar cancer.
In addition, adjuvant radiation complicates treatment of future recurrences by (1)
hampering healing following re-excision, and (2) eliminating radiation as a treatment
option at that time. Radiation causes depletion of dermal stem cells, fibroblast dysfunction,
defective collagen cross-linking, upregulation of pro-inflammatory cytokines, and micro-
vascular changes that all contribute to chronic fibrosis and poor wound healing. Multiple
strategies to improve wound healing of fibrotic tissue have been explored, but the only
reliable strategy thus far is the use of vascularized flaps from tissue outside of the radiation
field.
In contrast, re-excision likely reduces the risk of recurrence while minimizing morbid-
ity. Although re-excision can be associated with temporary wound breakdown, published
rates for wound breakdown and infection following modified vulvectomy are much lower
than radiation side effect rates, at approximately 18% [8].
Conclusion
In conclusion, although there is a potential for adjuvant vulvar radiation to decrease
recurrence, there is no data on the true risk reduction in stage I patients. The associated
long-term morbidity far outweighs the potential benefits. Efforts should be made to re-
excise close or positive margins for patients with stage I vulvar cancer and observation may
also be considered, particularly in cases of close margins. Radiation therapy should be saved
for the rare cases of positive margins or local recurrence that are not amendable to re-
excision.
References
1. Stehman F, et al. Early stage I carcinoma Oncology Group. Obstet Gynecol 1992;79
of the vulva treated with ipsilateral (4):490–497.
superficial inguinal lymphadenectomy and 2. Heaps JM, et al. Surgical-pathologic
modified radical hemivulvectomy: variables predictive of local recurrence in
a prospective study of the Gynecologic squamous cell carcinoma of the vulva.

Best Treatment? Re-excision 299
Gynecol Oncol 1990;38(3):309–314. https:// 6. Ioffe YJ, et al. Low yield of residual vulvar
doi.org/10.1016/0090-8258(90)90064-R carcinoma and dysplasia upon re-excision
3. Arvas M, et al. The role of pathological for close or positive margins. Gynecol Oncol
margin distance and prognostic factors after 2013;129(3):528–532. https://doi.org/10
primary surgery in squamous cell carcinoma .1016/j.ygyno.2013.02.033
of the vulva. Int J Gynecol Cancer 7. Faul CM, et al. Adjuvant radiation for vulvar
2018;28:623–631. carcinoma: improved local control.
4. Bradley K, et al. (Squamous Cell Carcinoma) Int J Radiat Oncol Biol Phys 1997;38
Vulvar Cancer. 2020. (2):381–389. https://doi.org/10.1016/S0360-
3016(97)82500-X
5. Bedell SM, et al. Role of adjuvant radiation
or re-excision for early stage vulvar 8. Gaarenstroom KN, et al. Postoperative
squamous cell carcinoma with positive or complications after vulvectomy and
close surgical margins. Gynecol Oncol inguinofemoral lymphadenectomy using
2019;154(2):276–279. https://doi.org/10 separate groin incisions. Int J Gynecol
.1016/j.ygyno.2019.05.028 Cancer 2003;13(4):522–527. https://doi.org/
10.1046/j.1525-1438.2003.13304.x

Debate
What is the Best Treatment
49B for Stage I Vulvar Squamous

Cell Carcinoma with either
a Close or Positive Surgical
Margin?
Adjuvant Radiation
Rachel C. Sisodia
Debate
Of the 6120 women who are projected to develop vulvar malignancy in 2021, the majority of
them will have disease which is confined to the vulva, of squamous cell etiology, and
potentially curable [1]. The cornerstone of management for women with localized disease
such as this is surgery. While surgery for vulva cancer was initially envisioned as an en-bloc
radical resection with bilateral inguinofemoral lymphadenectomy (Basset-Way radical
vulvectomy, 1912), over the decades, gynecologic oncologists have continued to improve
the operation in the pursuit of lessening morbidity for our patients. Currently, management
of a clinical stage I vulvar cancer is radical excision with a 1–2 cm negative margin on
normal tissue and an 8 mm margin on fixed tissue; clinical stage IB tumors will also undergo
nodal evaluation. Yet despite the desire for a less morbid, more conservative approach to
surgery, multiple retrospective studies have shown that in regard to vulvar cancer, tumor-
free margin matters. In a retrospective study of 135 patients with vulvar cancer, no patient
with an 8 mm or greater tumor-free margin recurred. However, 48% of the women with
a margin of less than 8 mm recurred, and local recurrence was associated with a 67% chance
of death from metastatic disease [2]. In addition, close or positive margins are common.
Given the frequency of close/positive margins, as well as the unacceptably high mortality
rate due to local recurrence, it is incumbent upon gynecologic oncologists to actively
manage close or positive margins in women with vulvar malignancy. Two choices are
available for the woman with concerning margin status after vulvar resection: re-excision
or radiation. Based on the increased morbidity with repeat excision, and the compromised
quality of life associated with resection of critical perineal structures (anus, clitoris, urethra,
vagina), radiotherapy is the most reasonable choice for management.
The role of adjuvant radiation in vulvar cancer has been studied for decades; since the
1990s, radiation oncologists and gynecologic oncologists have specifically studied its role in
women with close or positive surgical margins [3]. Radiation fields consist of 45 Gy to 60 Gy
to the area of the previous excision, and can be contoured to include the entire perineum,
inguinal and pelvic nodes if indicated [4]. In regard to efficacy, while adjuvant radiation
does not impact overall survival in women with negative margins, it is highly efficacious in
300

Best Treatment? Adjuvant Radiation 301
the patient with close or positive surgical margins. In a study of 257 women with primary
squamous cell carcinoma of the vulva, adjuvant radiation for women with close/positive
surgical margins improved five-year overall survival dramatically (67.6% vs. 29%, p=0.038),
bringing it equivalent to the overall survival rates seen in women with negative margins [3].
Furthermore, with the evolution of intensity modulated radiation therapy (IMRT), some of
the previous concerns about radiation toxicity (skin desquamation, vaginal stenosis, pain,
sexual dysfunction, and body image issues) can be ameliorated. In the largest study
examining patient-reported outcomes in a routine clinical population of women with vulvar
cancer, women who underwent radiation did not have statistically significantly different
rates of pain, bleeding, discharge, bowel or bladder function, quality of life, or overall health
than women who underwent a simple resection [4]. Furthermore, the single greatest
predictor of impaired or diminished quality of life was local recurrence [4]. As such, it
stands to reason that aggressively pursuing close or positive surgical margins with adjuvant
radiation is an acceptable trade-off to the patient to guarantee long-term survival and high
quality of life.
Conclusion
Finally, though radiation or re-excision has long been a mainstay of vulvar cancer treat-
ment, more recent investigations have called this paradigm into question. In an intriguing
manuscript by Grootenhuis et al. examining the specimens of 287 patients with primary
vulvar squamous cell carcinoma and a close (but not positive) margin, tumor-free margin
distance (≤8 mm, ≤ 5 mm, or ≤3 mm) did not impact the risk of local recurrence (HR=1.03,
95% CI: 0.99–1.06) [5]. However, local recurrence was seen more frequently in patients with
differentiated vulvar intraepithelial neoplasia (dVIN) (HR=2.76, 95% CI: 1.62–4.71) and/or
lichen sclerosis (HR=2.14, 95% CI: 1.11–4.12) in the margin, suggesting that local recur-
rence is more about tumor biology than a close margin. These findings are that of a single
retrospective study and do not yet change the standard of care, but they do highlight the
need for continued research into the pathogenesis and management of vulvar cancer. In the
interim, gynecologic oncologists will need to continue to use available therapies to help cure
women with vulvar cancer, and based on its high efficacy and manageable side-effect profile,
radiation continues to be the therapy of choice for close/positive margins after resection.
References
1. SEER Database: Vulvar Cancer. Available margins. J Cancer Res Clin Oncol
from: https://seer.cancer.gov/statfacts/html/ 2016;142:489–495.
vulva.html [last accessed November 9, 4. Alimena S, et al. Patient reported outcome
2022]. measures among patients with vulvar cancer
2. Heaps JM, et al. Surgical pathologic at various stages of treatment, recurrence
variables predictive of local recurrence in and survivorship. Gynecol Oncol
squamous cell carcinoma of the vulva. 2021;160:252–259.
Gynecol Oncol 1990;38 (3):309. 5. Grootenhuis NC, et al. Margin status
3. Ignatov T, et al. Adjuvant radiotherapy for revisited in vulvar squamous cell carcinoma.
vulvar cancer with close or positive surgical Gynecol Oncol 2019;154(2):266–275.

Debate
Should Adjuvant Radiation
50A be Given to Women with

Single Node Positive Vulvar
Cancer?
Yes
Rachel C. Sisodia
Debate
Vulvar cancer is a rare and poorly studied disease. While the majority of women will present
with disease localized to the vulva, a significant percentage will present with more advanced
disease involving at least one inguinal lymph node. In addition, lymph node involvement
often occurs quite early in disease course. In a sentinel study examining 177 cases of clinical
stage I vulvar squamous cell carcinomas examining depth of invasion as a predictor for
lymph node metastases, occult metastases were found in 10.5% of women with a depth of
invasion between 1.1 mm and 2 mm, and with risk increasing up to 42.9% when the depth of
invasion was more than 5 mm [1]. The presence of positive lymph nodes is considered the
single most important prognostic indicator for women with vulvar carcinoma, and is
associated with markedly reduced survival. As such, assessment of the inguinofemoral
nodes is part of all staging surgery for lesions that are clinically larger than 2 cm or have
more than 1 mm of invasion [2].
While there is ubiquitous agreement that macro-metastases or multiple involved nodes
must be treated for a patient to have a chance at survival, controversy exists over how to
manage women with a single positive node. Historically, it was believed that after undergo-
ing full lymphadenectomy, node-positive women should undergo radiation therapy or
chemoradiation. A sentinel report in the field, the AGO-CaRE-1 study, examined 447
women with node-positive vulvar cancer and demonstrated a statistically significant sur-
vival benefit with radiation as opposed to inguinal dissection alone (HR=0.63, 95% CI: 0.43–
0.91) [3]. While there was a trend for improved survival in women with one positive node
who were radiated, only women with two or more positive nodes met statistical significance
for a difference in survival rate. Further confounding the results of this study is the fact that
women had a drop in their overall survival even with one positive node. This finding
supports the idea that even a single positive node is a harbinger of worsened prognosis.
Both findings had also been reported in older studies [3]. Conversely, a large SEER database
study examining women with stage III, single-node positive vulvar cancer showed that
adjuvant radiation had a clear survival benefit over women receiving no further therapy,
with a five-year overall survival (OS) of 77% versus 61.2% (p =0.02). This effect was
particularly pronounced when the patient had <12 lymph nodes removed [4]. Of note,
given the uncertainty around radiation in the setting of one macro-metastases, we are
302

Adjuvant Radiation? Yes 303
currently unable to opine on the management of a patient found to have a micro-metastases

or isolated tumor cells on sentinel node biopsy. The GROningen International Study on
Sentinel nodes in Vulvar Cancer (GROINS-V-II)/Gynecologic Oncology Group 270 proto-
col, which is ongoing, seeks to provide insight to management of micro-metastases found
after sentinel node removal.
With such conflicting literature, what is the gynecologic oncologist to do in the patient
with a single positive groin node? While the literature allows for an argument to be made for
either adjuvant radiation or full lymphadenectomy alone, based on the above data the most
prudent course of action would be to perform radiation. While Mahner et al. was unable to
prove a statistically significant benefit in radiating patients with a single positive groin node,
there was a clear trend towards improved progression-free survival and OS with adminis-
tration of radiation after surgery [3]. Furthermore, even having one positive node correlates
with a lower OS (three-year OS, 7.8%) when compared to stage I or stage II disease. In
addition, a SEER review of 490 patients showed a benefit in disease-specific survival in
women with a single groin node that were radiated. Though this effect was greatest when
there were only a limited number of nodes removed (study comments on <12 cut-off), one
must understand that this cut-off was a statistical outcome of the study and difficult to
extrapolate to any one individual woman (who may have more or less lymphatic tissue).
Conclusion
For women with vulvar cancer, groin recurrence is a serious event which almost invariably is
fatal. As such, in an area where there is conflicting data, it is incumbent on the patient’s
physician to err on the side of being conservative. Until clearer data is available, patients
with a single positive groin node should be administered radiation therapy at curative
attempt.
References
1. Hacker NF, et al. Individualization of 3. Mahner S, et al. Adjuvant therapy in lymph
treatment for stage I squamous cell node positive vulvar cancer: the
vulvar carcinoma. Obstet Gynecol 1984;63 AGO-CaRE-1 study. J Natl Cancer Inst
(2):155. 2015;107(3):dju426.
2. National Comprehensive Cancer Network. 4. Parthasarathy A, et al. The benefit of
NCCN guidelines. Available from: www adjuvant radiation therapy in single node
.nccn.org/professionals/physician_gls/pdf/v positive squamous cell vulvar carcinoma.
ulvar.pdf Gynecol Oncol 2006;103:1095–1099.

Debate
Should Adjuvant Radiation
50B Therapy be Given to Patients

with Single Node Positive
Vulvar Cancer?
No
Aaron M. Praiss and Kaled M. Alektiar
Debate
Vulvar cancer is rare, accounting for <1% of all cancers in women and 6% of cancers of the
female reproductive tract. A total of 6330 new diagnoses of vulvar cancer and 1560 deaths
from vulvar cancer are estimated in 2022. Squamous cell carcinoma (SCC) is the most
common histology of vulvar cancer (>90%). Vulvar cancer metastasizes through three main
methods: local extension, lymphatic embolization to regional inguino-femoral lymph nodes
(IFLN), and hematogenous spread to distant sites. From an anatomic perspective, vulvar
lymphatics drain first into the superficial inguinal lymph nodes located within the femoral
triangle, and then beyond that into the pelvic nodal basins.
The most important prognostic factor for vulvar cancer is IFLN metastasis. Survival is
reduced to 50% in patients with positive IFLNs, and recurrences often occur within two
years of primary treatment. Five-year disease-specific survival ranges from 25–40% in
patients with positive IFLNs versus 70–93% in patients with negative IFLNs [1]. Risk of
IFLN metastases rises with increasing depth of invasion (DOI) of the primary tumor: <1%
risk for IFLN metastasis with DOI <1 mm, 6–12% risk for IFLN metastasis with DOI 1.1–
3 mm, and 15–20% risk for IFLN metastasis with DOI 3.1–5 mm.
The controversy regarding adjuvant radiotherapy for single IFLN positive vulvar
cancer started with Gynecologic Oncology Group (GOG) protocol 37 [2]. This prospect-
ive randomized trial from the 1980s investigated the value of pelvic lymphadenectomy
compared with pelvic and groin radiation therapy after vulvectomy and IFLN dissection.
Overall, this study demonstrated an improved two-year overall survival (OS) (68% vs.
54%, p=0.03) in favor of the radiotherapy group. More importantly, however, the number
of positive nodes impacted survival based on this data. Within the radiotherapy arm,
patients with one positive IFLN had a two-year survival of 80% versus 66% for those with
two or more positive IFLNs. Multiple trials since have further demonstrated improved
oncologic outcomes for patients with two or more positive IFLNs receiving adjuvant
radiotherapy.
Fast forward 30 years, and Mahner et al. further studied this controversy in the
AGO-CaRE-1 study [3]. This retrospective exploratory multicenter cohort study utilized
data from 29 gynecologic centers in Germany from 1998 to 2008. A total of 802 patients
with surgically proven negative IFLNs and 447 patients with positive IFLNs were
304

Adjuvant Radiation? No 305
Log-rank
HR (95 % CI) P value 2-year PFS (95 % CI) 3-year PFS (95 % CI)
(two-sided)
1 pos. LN 0.87 (0.53 to 1.42) 0.58 adj. Tx: 54.9 % (39.4 % to 67.9 %) 54.9 % (39.4 % to 67.9 %)
no adj. Tx: 47.0 % (34.5 % to 58.5 %) 43.6 % (31.2 % to 55.2 %)
no adj. Tx: 19.4 % ( 7.1 % to 36.2 %) 7.3 % ( 0.7 % to 25.3 %)
no adj. Tx: 17.9 % ( 4.4 % to 38.8 %) 12.0 % ( 2.0 % to 31.6 %)
>3 pos. LN 0.45 (0.25 to 0.82) 0.007 adj. Tx: 25.2 % (12.0 % to 40.8 %) 25.2 % (12.0 % to 40.8 %)
no adj. Tx: 6.6 % ( 0.5 % to 25.4 %) n/a
0.00 0.25 0.50 0.75 1.00 1.25 1.50

Hazard ratio for PFS: adjuvant vs. no adjuvant treatment
Figure 50B.1 Forest plot of progression-free survival in nodal subgroups with regards to adjuvant radiotherapy [3].
included in the final analysis, of which 38.5% had one positive IFLN and 22.8% had two
positive IFLNs. Progression-free survival (PFS) and OS decreased significantly with
increasing number of positive nodes. Three-year PFS ranged from 47.6% for one
positive IFLN to 21.2% for more than three positive IFLNS (p<0.001). OS followed
a similar trend with three-year OS ranging from 72.8% for one positive IFLN to 33.0%
for more than three positive IFLNs (p<0.001). More importantly, in multivariable
analysis, the OS hazard ratio for adjuvant radiotherapy in two positive IFLNs versus
single IFLN positive vulvar cancer was 2.52 (1.69, 5.24) p<0.001, indicating a significant
impact of adjuvant radiotherapy in patients with two or more positive IFLN vulvar
cancer. A forest plot of PFS by nodal subgroup also clearly demonstrates a lack of benefit
of adjuvant radiotherapy for the single IFLN positive group (Figure 50B.1) [3]. Even
though this study is retrospective, this is the largest study in this debate, demonstrating
no improved survival benefit for patients with one positive IFLN receiving adjuvant
radiotherapy or surveillance.
Two other recent studies have tried to address this question. Fons et al. were unable to
demonstrate a significant benefit of adjuvant radiotherapy in patients with single IFLN
positive disease, both with regards to PFS and OS [4]. Furthermore, recurrence rates were
comparable between the adjuvant radiotherapy and observation arms (39% vs. 32%). Using
the Surveillance Epidemiology and End Result database (SEER), Parthasarathy et al. dem-
onstrated improved outcomes for patients with single IFLN positive vulvar cancer receiving
adjuvant radiotherapy as compared to observation [5]. However, the SEER database study
lacked key information regarding size and location of the IFLNs.
It is important to note the poor survival for any node-positive cases (three-year OS,
33–72%) and high recurrence rates (30–40%) in all these studies. Beyond the question of
survival benefit from adjuvant radiotherapy in single IFLN positive vulvar cancer, there
are postoperative and postradiotherapy complications and quality of life concerns that
need to be considered in this patient population. Wound breakdown and infection are
reported to occur in up to 40% of patients after IFLN dissection, and lymphocyst forma-
tion and lymphedema are reported from 20% to 40%. The addition of adjuvant radiother-
apy can lead to further complications including gastrointestinal toxicity, desquamation,
fistula formation, and bone fractures. As such, weighing the risks and benefits of adjuvant
radiotherapy in single-node positive disease, one must consider quality of life altering
complications and long-term radiotherapy sequelae for what remains an unclear survival
benefit.

306 Aaron M. Praiss and Kaled M. Alektiar
Conclusion
Adjuvant radiotherapy for single positive IFLN vulvar cancer continues to be a controversial
topic, especially considering the crucial role IFLN metastases play in prognosis and survival
for patients with vulvar cancer. Looking ahead, in understanding the molecular landscape of
vulvar cancer, hopefully targeted and immuno-therapies will find a role in the treatment of
advanced stage vulvar cancer. In the meantime, multimodal techniques based on individual
disease status and patient quality of life preferences will be most important in the treatment
of this complex and rare cancer.
References
1. Woelber L, et al. Prognostic role of AGO-CaRE-1 study. J Natl Cancer Inst
lymph node metastases in vulvar cancer 2015;107(3):dju426.
and implications for adjuvant 4. Fons G, et al. Adjuvant radiotherapy in
treatment. Int J Gynecol Cancer 2012;22 patients with vulvar cancer and one intra
(3):503–508. capsular lymph node metastasis is not
2. Homesley HD, et al. Radiation therapy beneficial. Gynecol Oncol 2009;114
versus pelvic node resection for carcinoma (2):343–345.
of the vulva with positive groin nodes. Obstet 5. Parthasarathy A, et al. The benefit of
Gynecol 1986;68(6):733–740. adjuvant radiation therapy in single-node-
3. Mahner S, et al. Adjuvant therapy in lymph positive squamous cell vulvar carcinoma.
node-positive vulvar cancer: the Gynecol Oncol 2006;103(3):1095–1099.

Debate
Is Pelvic Exenteration
51A an Option for a Pelvic

Recurrence of a Vulvar/
Vaginal Melanoma
after Previous Radiation
Therapy?
Yes
John P. Geisler and Kelly J. Manahan
Debate
Many controversies exist in all aspects of gynecologic oncology. Some of these can be
answered by clinical trials because of higher incidence and prevalence of specific cancers.
However, some gynecologic cancers are infrequent, requiring observational studies and
logic to determine appropriate treatment plans. Vulvo-vaginal melanomas fall into this
category.
Although melanoma is the second most common histology of vulvar cancer, it is still
very uncommon [1]. Melanomas are malignant tumors which originate in melanocytes.
Vulvo-vaginal melanomas are classified into three categories: nodular, mucosal, and super-
ficial spreading [2]. While nodular melanomas are more common in the vagina, superficial
spreading and mucosal are more common in the vulva [2]. As a general rule, for patients
who are operative candidates, surgical excision is the initial treatment of choice. The overall
prognosis for vulvo-vaginal melanomas is significantly lower than for cutaneous melanoma
[3]. A Surveillance Epidemiology and End Results database review demonstrates that this
may occur because of the advanced depth of invasion and stage at initial presentation for
vulvo-vaginal melanomas. The extent of initial excision is guided by many factors: anatomic
location of the lesion, presence of locally advanced (or unresectable) disease, presence of
metastatic disease and depth of stromal invasion [4,5]. For example, an anterior pelvic
exenteration may be needed initially even for a small lesion of the anterior middle vagina
overlying the proximal urethra. Look and colleagues established that lymph node dissection
was more prognostic than therapeutic in vulvar melanomas [6].
Although melanomas are relatively radiation resistant, radiation is used on a case-by-
case basis, especially for lymph node metastatic disease [7]. Frumovitz and colleagues noted
that the use of radiation after wide local excision of vaginal melanomas decreased local
recurrence and increased mean overall survival from 16 to 29 months [5]. Unfortunately,
local recurrences were far less common than distant recurrence in this same study.
307

308 John P. Geisler and Kelly J. Manahan
How does the gynecologic oncologist approach a patient with a vulvar or vaginal melan-
oma that has recurred in the vulva or vagina after radiation? A repeat biopsy (not cytology) to
prove recurrence and to check for treatable mutations (i.e., BRAFv600 or KIT) is the first step.
The next step is to assess for the presence of metastatic disease. Multiple studies have
demonstrated that positron emission tomography/computed tomography (PET/CT) has the
best sensitivity for detection of metastases [8]. Once these steps are completed and the results
are known, an informed discussion can be undertaken with the patient and their caregivers. If
metastatic disease exists, undertaking an exenteration is not advisable, just as undertaking an
exenteration is not advisable if adequate resection margins cannot be achieved in the
previously radiated field. If treatable mutations exist in the tumor, especially a previously
untreated BRAFv600 or KIT mutation is present, systemic treatment is recommended over
ultra-radical surgery. Although a pelvic exenteration can be curative for patients with small
central recurrences without metastases, exenterations can affect quality of life and be challen-
ging to recover from both physically and psychologically [9]. Changes in techniques from the
use of robotic systems, for the supra-levator portion of the surgery, vascularized muscle-flaps
to fill the pelvis, J-pouches rather than end-to-end colo-coloanastamosis, and enhanced
recovery strategies all make an exenteration more tolerable in the well-chosen patient [10].
Conclusion
There are some clinical controversies in gynecologic oncology that even with large multi-
national cooperative groups will not be able to be answered with randomized trials. The use of
pelvic exenterations after radiation for recurrent vulvo-vaginal melanoma is one of these
clinical questions. Primary exenteration has been shown to be effective in well-chosen patients
[4,5]. In the absence of randomized trials, the gynecologic oncologist has to look at other
available data including other treatment options (immunotherapy, chemotherapy), the experi-
ence of the anesthesia, surgical, and postoperative teams, as well as the patient’s ability to cope
with the physical and psychological stressors of ultra-radical surgery. Until a randomized trial
shows no benefit, or better nonsurgical treatments evolve, pelvic exenteration for resectable,
central, recurrent vulvo-vaginal melanoma in a radiated pelvis should remain an option.
References
1. Boer FL, et al. Vulvar malignant melanoma: 4. Geisler JP, et al. Pelvic exenteration for
pathogenesis, clinical behaviour and malignant melanomas of the vagina or
management: review of the literature. Cancer urethra with over 3 mm of invasion. Gynecol
Treat Rev 2019;73:91–103. Oncol 1995;59:338–341.
2. Saito T, et al. Japan Society of 5. Frumovitz M, et al. Primary malignant
Gynecologic Oncology guidelines 2015 for melanoma of the vagina. Obstet Gynecol
the treatment of vulvar cancer and 2010;116:1358–1365.
vaginal cancer. Int J Clin Oncol 6. Look KY, et al. Vulvar melanoma
2018;23:201–234. reconsidered. Cancer 1993;72:143–146.
3. Mert I, et al. Vulvar/vaginal melanoma: an 7. Agrawal S, et al. The benefits of adjuvant
updated surveillance epidemiology and end radiation therapy after therapeutic
results database review, comparison with lymphadenectomy for clinically
cutaneous melanoma and significance of advanced, high-risk, lymph node-metastatic
racial disparities. Int J Gynecol Cancer melanoma. Cancer 2009;115:5836–5844.
2013;23:1118–1125.

Pelvic Exenteration an Option? Yes 309
8. Xing Y, et al. Contemporary diagnostic exenteration: interim results. Gynecol

imaging modalities for the staging and Oncol 2013;128:191–197.
surveillance of melanoma patients: a meta- 10. Schneider A, et al. Current developments
analysis. J Natl Cancer Inst 2011;103:129–142. for pelvic exenteration in gynecologic
9. Rezk YA, et al. A prospective study of oncology. Curr Opin Obstet Gynecol
quality of life in patients undergoing pelvic 2009;21:4–9.

Debate
Is Pelvic Exenteration
51B an Option for a Pelvic

Recurrence of a Vulvar/
Vaginal Melanoma
after Previous Radiation
Therapy?
No
Mario M. Leitao, Jr.
Debate
Until recently, therapy for any type of melanoma was limited, and outcomes were dismal in
those with advanced or recurrent disease. At a time when there were no viable options for
vulvovaginal melanomas, pelvic exenteration may have seemed like a good treatment
approach. Today, however, pelvic exenteration should not be considered in patients with
vulvovaginal melanomas, either newly diagnosed or recurrent . . . except possibly as a last
resort in rare, highly select cases. Due to the rarity of these tumors, data to direct treatment
are limited to case series, and although they are often treated as one entity, vulvar and
vaginal melanomas are different, with varying incidence and mortality rates.
Vulvovaginal melanomas are associated with worse overall survival (OS) compared to
vulvar carcinomas, as well as cutaneous melanomas [1]. The five-year OS rate for newly
diagnosed, locally advanced, American Joint Committee on Cancer (AJCC) stage II vulvar
melanoma is approximately 50%, and decreases with increasing stage. Vaginal melanomas
are associated with even worse outcomes, and many of the recurrences are distant. In the
primary setting, therefore, a highly morbid procedure with risk of postoperative mortality,
permanent stomas, and body disfigurement does not seem like a good approach. Overall
survival is even worse in patients with recurrence that requires exenteration, especially after
prior radiation, in whom the risk/benefit ratio is unfavorable. Surgical resection can be
considered in patients with recurrence in the vulva or vagina, and even the groins, if
a nonexenterative resection is possible.
Patients who present with newly diagnosed, locally advanced, or recurrent vulvovaginal
melanoma may be best treated with hypofractionated radiation therapy combined with
immunotherapy. This approach has been our standard of care since we treated a young
woman with vaginal melanoma using 3000 cGy external-beam radiation therapy in five
fractions, along with ipilimumab [2]. The patient experienced a pathologic complete
response and remains disease free, without recurrence, 100 months (8+ years) since her
initial diagnosis. The combination of radiation therapy and ipilimumab was prospectively
310

Pelvic Exenteration an Option? No 311
assessed in a single-arm study of 10 patients with locally advanced melanoma, of which only
one had mucosal melanoma [3]. A radiographic complete response was achieved in four out
of 10 patients. Three patients achieved a partial response. These three patients all underwent
a surgical resection for what was considered residual disease. Two of these three patients
achieved a pathologic complete response. The use of hypofractionated radiation therapy is
controversial and debatable. Some may prefer to use combination immunotherapy or
dabrafenib/trametinib (for BRAF V600E/K-mutated cases) without radiation.
The National Comprehensive Cancer Network (NCCN) does not recommend routine
molecular profiling for stage I and II resected melanomas but does recommend it for stage
III/IV, unresectable, and/or recurrent melanomas to help guide treatment [4]. This prin-
ciple would generally apply to vulvovaginal melanomas, but considering the rarity of these
tumors, it is reasonable to at least perform molecular analysis for KIT, BRAF, and NRAS in
all cases. Broader genomic analysis when obtaining molecular testing, if possible, may
provide a better understanding of this disease and also identify other potentially targetable
mutations and/or triage cases for select clinical trials. The value of routine testing for
programmed death-ligand 1 (PD-L1) expression in melanoma is unclear and not recom-
mended by the NCCN [4].
Nivolumab and pembrolizumab, anti-PD-1 (programmed cell death protein 1)
monoclonal antibodies, as well as other more recently developed anti-PD1 and PD-L1
agents, are preferred over ipilimumab. The anti-tumor activity of these agents is not
affected by the presence of BRAF mutations. Combination cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) and PD-1 therapies have higher responses but are more
toxic. Single-agent anti-PD-1 therapy is preferred with hypofractionated therapy, but
combinations are acceptable if radiation is not given. Patients with BRAF V600E or
V600 K mutations will benefit from targeted therapy using dual MAPK pathway inhib-
ition with a BRAF and a MEK inhibitor. This combination has an overall response rate
of 65%, with a median OS of 33.6 months in patients with metastatic and/or recurrent
cutaneous melanoma [5].
Conclusion
Resection of locally (vulva, vagina, pelvis, and/or groins) and metastatic recurrent melan-
oma may be an option in those in whom a negative-margin, limited-morbidity procedure is
possible [4,6]. There is an extensive body of literature on treatment options for recurrent
and metastatic melanoma that includes chemotherapeutics, radiation therapy, and other
available and novel agents. We recommend following published guidelines, such as those
provided by the NCCN [4]. Pelvic exenteration, even after prior pelvic radiation and
isolated to the pelvis, should not be considered outside a “last resort” option in very rare,
select cases. Such cases may include patients in whom disease remains truly confined to the
pelvis and has stabilized without further response to other therapies or in those who require
palliation of symptoms without other alternatives.
References
1. Mert I, et al. Vulvar/vaginal melanoma: an racial disparities. Int J Gynecol Cancer
updated Surveillance Epidemiology and End 2013;23:1118–1125.
Results Database review, comparison with 2. Schiavone MB, et al. Combined
cutaneous melanoma and significance of immunotherapy and radiation for treatment

312 Mario M. Leitao, Jr.
of mucosal melanomas of the lower genital 5. Dummer R, et al. Overall survival in patients
tract. Gynecol Oncol Rep 2016;16:42–46. with BRAF-mutant melanoma receiving
3. Salama AKS, et al. Ipilimumab and radiation encorafenib plus binimetinib versus
in patients with high risk resected or vemurafenib or encorafenib (COLUMBUS):
regionally advanced melanoma. Clin Cancer a multicenter, open-label, randomized,
Res 2021;27(5):1287–1295. phase 3 trial. Lancet Oncol
2018;19:1315–1327.
4. National Comprehensive Cancer Network.
Melanoma: cutaneous (Version 1.2021). 6. Wasif N, et al. Does metastatectomy
Available from: www.nccn.org/profes improve survival in patients with stage IV
sionals/physician_gls/pdf/cutaneous_mela melanoma? A cancer registry analysis of
noma.pdf outcomes. J Surg Oncol 2011;104:111–115.

Index
adjuvant carboplatin, 190 adult granulosa cell tumors AURELIA (Avastin Use in
cycles of, 51 (AGCT) Platinum-Resistant
adjuvant chemotherapy, 71, statistics for, 145 Epithelial OC) phase III
195–196 Agency for Healthcare study, 109
advanced ovarian cancer, 61 Research and Quality Avastin Use in Platinum-
for uterine carcinosarcoma, Safety Program for Resistant Epithelial
229–230 Improving Surgical Care OC, 109
high-risk stage I epithelial and Recovery, 5
ovarian cancer and, 47–48 aggressive cytoreduction basket or umbrella clinical
HIPEC and, 77 surgery trials, 31
mucinous ovarian for advanced ovarian cancer, BEP regimen, 139, 142–143,
carcinomas and, 44–46 58–60 146, 147, 150, 155, 232
regiment for primary AGO-CaRE-1 study, 302 for granulosa cell tumors
granulosa cell tumors, AGO-OVAR DESKTOP-III (GCTs), 145–146
149–150 trial, 123 modified, 149
treatment for early-stage American Cancer Registry, 21 remission and, 149
ovarian cancer, 49–50 American Cancer Society bevacizumab, 27, 76, 91,
treatment for primary guidelines, 19 101–103
granulosa cell tumor, 145 American College of plus chemotherapy, 131
Adjuvant ChemoTherapy in Obstetricians and Bevacizumab, 68
Ovarian Neoplasm Trial Gynecologists bevacizumab + PARPi
(ACTION), 42 (ACOG), 21 maintenance
adjuvant hysterectomy, American Joint Committee on cost-effectiveness of, 93
272–273, 275–277 Cancer (AJCC), 310 bilateral salpingo-
patients with primary American Society for Clinical oophorectomy (BSO), 13,
radiation therapy and, Pathology (ASCP), 21 165, 168, 238
275–277 American Society of biomarkers, 128
adjuvant radiation therapy, Anesthesiology, 6 BRAFv600 or KIT
240, 292 American Society of Clinical mutation, 308
after neoadjuvant Oncology (ASCO), 70 BRCA mutations, 29, 30,
chemotherapy, 266 American Society of Colon and 91–93, 98, 102,
side effects of, 298 Rectal Surgeons, 1 107, 126
treatment for single node angiography, NIR, 2 annual screening of
positive vulvar cancer, anti–PD-1 (programmed cell carriers, 14
302–303 death protein 1) BRCA 1 or 2 gene, 88
treatment for vulvar cancer, monoclonal BRCA 1/2 mutation
304–306 antibodies, 311 (gBRCAm) carriers, 109
treatment for vulvar Arbeitsgemeinschaft für BRCA and HR status, 88
squamous cell carcinoma, Gynäkologische BRCA status, 80
300–301 Onkologie (AGO), 51 BRCA1 and BRCA2
adjuvant radiotherapy, Arbeitsgemeinschaft mutations, 30
304–306 Gynäkologische BRCA1 mutation carriers,
adjuvant therapy Onkologie (AGO). 13–15
recurrent ovarian cancer, See AGO BRCA1/2 mutations, 98–100
117–118 ARID1A and PIK3CA BRCA2 mutation carriers,
sandwich, 198–201 mutations, 30 13–15
adoptive cellular transfer aromatase inhibitor protocols, ovarian cancer risks and,
(ACT), 128 166, 167 11–12, 13
313

314 Index
BRCA mutations(cont.) why parametrectomy is not Liquid-Based Cytology

salpingectomy for BRCA1 of recommended, 262–263 (LBC) for, 20
BRCA2 mutation carriers, cervical carcinomas. See also CIN3+, 16–17
13–15 cervical cancer clinical trial endpoints
BRCAmut tumors, 89 cervical cytology, cervical ovarian cancer trials and,
front-line maintenance cancer reduction and, 16 158–159
therapy for, 88–90 cervical neoplasia (CIN3+), clostridium difficile colitis, 1
breast cancer, 12, 14, 166, high-grade, 16 Cochrane Database systematic
175–176 Checkpoint Inhibitors review. See Cochrane
ER-positive, 14 (CPI), 128 Review
molecular classifications chemoradiation, 278 Cochrane Review, 4, 47, 52
of, 184 chemotherapy combination bowel
oophorectomy and death adjuvant, 47–48 preparation
from, 14 advantages of six cycles of, 50 data on, 2–3
breastfeeding, 13 comparison of toxicity of complete lymphadenectomy
cycles, 50 (LND), 171
CA-125 surveillance for granulosa cell CONCERV trial, 260
patients and, 26 tumors, 153 concomitant
cancer genetics, 29 for mucinous ovarian chemoradiation, 203
Cancer Genome Atlas (TCGA) carcinomas, 41–42 and adjuvant hysterectomy,
Research Project, 29, 104, frail patients and 275–277
179, 182, 190, 196, 223 neoadjuvant, 68 followed by brachytherapy
carbohydrate loading intraperitoneal, 76–77 (BT), 275–277
length of stay (LOS) and, 10 locally advanced concurrent
cardiophrenic nodes endometrial cancer, chemoradiation, 280
(CPLNs), 70 186–187 concurrent chemo-radiation
cervical cancer neoadjuvant, 67, 266, (CCRT), 272
best treatment for stage IB3- 268–269, 278–279 concurrent chemoradiotherapy
IIB, 278–279 platinum-and taxane-based, and adjuvant hysterectomy,
early stage, 259 52, 76 275–277
early-stage treatment of, 285 platinum-based, 50, 52, 91 CONTESSA/NEOCON-F
high-risk HPV screening for, recurrent uterine LMS, 246 study, 267, 269,
20–21 treatment for uterine 270
human papillomavirus carcinosarcoma, 229–230 controlled ovarian
(HPV) and infection as chemotherapy (HIPEC) hyperstimulation (COH)
a risk factor, 285 rationale for hyperthermic protocols, 166
immune checkpoint intraperitoneal, 77 cytology, 16–17, 21
inhibition in CC, 285–286 chemotherapy, adjuvant, cervical, 16
immunotherapies for HPV- 49–50, 61, 71 liquid-based screening, 20
related genes, 286 HIPEC and, 77 cytoreduction surgery. See
immunotherapy in mucinous ovarian cytoreductive surgery
treatment of, 288–289 carcinoma and, 44–46 cytoreductive surgery, 76,
in the United States, 20 primary granulosa cell 82–84
primary chemoradiation as tumor, 145 for advanced ovarian cancer,
treatment for, 280–283 regimen for granulosa cell 58–60
reduced incidence of, 16 tumors, 149–150 for recurrent ovarian cancer,
role of immunotherapy in chemotherapy, neoadjuvant, 113–114
treatment of, 285–286 58, 64, 66, 67, 117, 206, of uterine leiomyosarcomas
statistics, 20, 288 208, 252, 266, 268 (uLMS), 250–252
treatment of early-stage, 256 pregnancy after, 266 secondary, 116,
treatment options fro young reoccurrence rate after, 266 247–248
women, 265–267 stage IV ovarian cancer statistics for recurrent
when minimally invasive and, 104 endometrial cancer,
radical hysterectomy is treatment for cervical cancer, 213–214
not recommended, 278–279 cytotoxic chemotherapy
256–257 CIN 2+, 286 agents, 240

Index 315
cytotoxic T lymphocyte- metastatic lymphatic front line maintenance

associated antigen 4 disease, 174 therapy, 88
(CTLA-4), 130 molecular profiling for the high risk early stage, 45
management of, 182–184 maintenance therapy
debulking surgery multimodal therapy and, 102
for grossly metastatic treatment for, 202–204 management of, 251
endometrial cancer, pathogenic groups for, 182 platinum resistant recurrent,
208–209 rate of, 165 109–111
for metastatic rationale for SLNB in platinum-based
leiomyosarcoma, 240–241 treatment of, 171–172 chemotherapy for, 26
mortality rate, 209 recommended treatment treatment of platinum-
primary for, 168 resistant, 106–108
for advanced ovarian sandwich adjuvant therapy treatment of recurrent, 213
cancer, 55 for stage III, 198–201 treatments, 32
DESKTOP I trial, 113 secondary cytoreduction for European Society of
DESKTOP II trial, 113 recurrent, 213–214 Gynaecological Oncology
DESKTOP III trial, 27, 114, sentinel lymph node (ESGO), 70, 195, 253
117, 118, 120 mapping (SLN), 171–172 guidelines, 257
DNA copy number sentinel lymph node studies European Society of Medical
variations, 29 in, 175 Oncology (ESMO)
standard-of-care for, 165 guidelines, 257
epithelial ovarian cancer 49 statistics for, 202 EWOC-1 trial, 56
elective colorectal surgery, trials, 175–176 external beam radiotherapy
statistics about, 4 with synchronous ovarian (EBRT), 186
endocrine and immunologic cancer, 169
systems endometrial carcinomas (ECs). fallopian tubes, 62
response to surgical stress, 6 See endometrial cancer as the origin of cancer
endogenous hormone, endpoints in clinical trials, cells, 13
preservation of, 12 161–163 assessment of, 12
endometrial cancer Enhanced Recovery After obstruction of, 270
adjuvant chemotherapy, Surgery (ERAS) Society removal of, 13
195–196 guidelines, 4, 5 resection of, 210
adjuvant multimodal programs/protocols, 9 fertility preservation, 12,
treatment in Stage IIIC, enlarged supradiaphragmatic 165–167, 168–169
202–203 nodes (ESDN) and fertility-sparing
advanced stage extent of surgery, 74 surgeries, 270
prognosis, 202 incidence, sites, and size of, conservative, 165–166
average age of patients 73–74 obstetrical outcome, 270
diagnosis, 168 resection of, 74, 75 options, 166, 266
classification of, 182–184 treatment of, 74 fertility-sparing surgery,
deaths from UPSC, 192 Entrectinib, 30 165–167, 168–169
debulking grossly metastatic, EORTC 55994 study, 279 and neoadjuvant
208–209 EORTC trial, 23 chemotherapy, 268–269
debulking surgery for EORTC-Adjuvant conservative, 165–166
metastatic, 205–206 ChemoTherapy oncologic outcome, 270
debulking surgery for stage In Ovarian Neoplasm FIGO IA2
IV, 208–209 (ACTION) trials, 44 radical hysterectomy and,
high grade, 171 epithelial high-grade ovarian 262–263
hormonal therapy for carcinomas (HGOC) FIGO stage IB2, 280
chemo-resistant, 216–218 prognosis for, 91 FIGO stage IB3 or IIA, 101–103
immunotherapy treatment epithelial ovarian cancer, 33, FIRES trial, 175
for, 223–224, 226–227 41, 44, 50, 77, Food and Drug Administration
locally advanced, 186–187 130, 152 (FDA), 30
management of stage III, advanced, 73 Foundation Medicine’s Foun-
189–191 chemotherapy for early dationFocus CDx,
metastatic disease, 171 stage, 49–50 29, 104 ®

316 Index
frailty, 55 GOG-213, 26, 117, 118 hysterectomy

index (FI), 53 GOG-213 selected adjuvant, 272–273,
patients, 117 275–277
GARNET trial, 223 GOG-258 radiotherapy, 203 complete, 275–277
gastrostomy tubes (GT), GOG-258 trial, 189, 190 for uterine-confined
malignant bowel protocol, 101, 291, 304 LMS, 240
obstruction (MBO) and, SOC-1 trial, 117 radical, 256
136–138 study, 294
GCIG-EORTC trials, 51 trial, 49, 186, 189 IMagyn500 study, 131
genetic risk immune checkpoint blockade
for ovarian cancer, 11 hereditary ovarian cancer (ICB) therapy, 226
GOG 278 (NCT01649089), 263 syndromes, 11 immune checkpoint inhibitors
granulosa cell tumors (GCT) high-grade serous ovarian (ICI), 131–132
initial treatment for, cancer (HGSOC) immunohistochemistry (IHC),
145–146 front-line maintenance Fluorescence In Situ
granulosa cell tumors (GCTs) therapy for, 88–90 Hybridization (FISH), 29
BEP regimen for, homologous recombination immunotherapy
145–146 deficiency (HRD), 59, 77, in treating cervical
early stage, 149 84, 88, 91, 95, 98, 102, cancer, 285
juvenile, 145 131, 163 role of in treating cervical
management strategy of front-line maintenance cancer, 288–289
recurrent, 155–157 therapy and, 104–105 IMPACT study, 17
recurrent, 152–153 repair of, 29, 30 inguinofemoral lymph node
surgery as management of tumors, 29 dissection (IFLD)
recurrent, use of PARP inhibitors and, complete, 291
152–153 32–33 inguinofemoral
use of paclitaxel and homologous recombination lymphadenectomy (IFL)
carboplatin (PC) regimen proficient (HR-proficient) bilateral, 300
for, 149–150 tumors, 95, 102 elective, 294
GROINSS-V-II trial, 292, homologous recombination insulin resistance, 9–10
294–295 repair. See homologous carbohydrate loading and,
GROningen International recombination 6, 7
Study on Sentinel deficiency (HRD) perioperative hyperglycemia
nodes, 303 hormonal therapy, 210, and, 7
Groningen International Study 223, 245 International Collaborative
on Sentinel nodes in for treatment of recurrent Ovarian Neoplasm Trial 1
Vulvar cancer (GROINSS- disease, 152 (ICON1), 42, 44
V-I), 294 treatment for recurrent International European Cohort
Gynaecological Cancer endometrial cancer, 210, Observational
Intergroup (GCIG) 216–218, 219–221 study, 254
trial, 51 HRD-postive ovarian cancer International Federation of
gynaecological sarcomas, 243 front-line maintenance Gynecology and
Gynecologic Cancer therapy for, 88–90 Obstetrics (FIGO) staging
InterGroup (GCIG), Human Papilloma classification, 44
195, 234 Virus (HPV) International Germ Cell
gynecologic malignancies, 245 and women under 30, 20 Cancer Collaboration
Gynecologic Oncology Group HPV-negative women, Group (IGCCCG), 140
(GOG), 120, 146, 155, 216 16, 19 International Trial on Radical
270 protocol, 303 infection as a risk factor for Upfront Surgery in
GOG 0281, 38–39 cervical cancer, 285 Advanced Ovarian Cancer
GOG 0281 phase II/III screening for cervical cancer, (TRUST), 56
study, 35 20–21 intraperitoneal (IP)
GOG 213 trial, 114 hyperthermic intraperitoneal chemotherapy
GOG study, 297 chemotherapy (HIPEC), cons for use of, 85–87
GOG-157 trial, 49–50 79–81 surgical cytoreduction and,
GOG-199, 11 rationale for, 77 82–84

Index 317
JAVELIN Ovarian 100 phase 3 mechanical bowel multigene panel testing, 32

trial, 126, 130, 131 preparation (MBP) Myriad myChoice CDx, 29,
debate about, 4–5 ®
88, 95, 96, 99, 104
Kaplan-Meier survival curves, safety of, 1
118, 238 surgical site infections National Cancer Database,
KRAS mutations and, 1–2 42, 203
ovarian cancer and, 35 melanoma, pelvic exenteration National Cancer Institute’s
KRAS or BRAF mutations, 35 after radiation therapy, Surveillance,
310–311 Epidemiology, 238
Laparoscopic Approach to menopause National Comprehensive
Cervical Cancer (LACC) consequences of early Cancer Network (NCCN),
trial, 62, 253, 256 surgical, 14 42, 168, 192, 253, 311
laparoscopy, 67 premature, 11 guidelines, 195,
laparotomy, 67 metastasectomy, pulmonary, 257, 266
Larotrectinib, 30 246, 247 National Surgery Quality
LBC co-testing, 21 metastatic abdominopelvic Improvement Program
leiomyosarcomas disease, 240 (NSQIP) database, 2
debulking surgery for metastatic cancer, surgical review, 4
metastatic, 243–244 debulking for, 205–206 NCI-Kaiser Permanente real-
secondary cytoreductive microRNA (miRNA) world follow-up study, 19
surgery, 245–246 expression, 29 neoadjuvant carboplatin,
Liquid-Based Cytology MicroSatellite Instability 52, 77
(LBC), 20 (MSI), 30 neoadjuvant chemotherapy
locally advanced cervical minimally invasive radical (NACT), 58, 61, 64, 67,
cancer (LACC), 278 hysterectomy 117, 206, 252
management of, 272–273 survival, 253–254 adjuvant radiation therapy
low-grade serous carcinoma vs open hysterectomy, and, 266
of the ovary/peritoneum 256–257 cons of treating elderly
(LGSOC). See also ovarian Mitogen Activated Pathway patients with, 55–56
cancer Kinase (MAPK) followed by fertility-sparing
lymph node (LN) pathway, 35 surgery, 268–269
metastasis, 171 mixed mesodermal tumor, 229 frail patients and, 68
lymph node assessment, molecular profiling technique, outcomes from
168, 262 179–181, 182–184, 210 receiving, 208
lymphadenectomy, 302 BRCA and HRD-negative pregnancy after, 266
lympho-vascular space epithelial ovarian cancer, reoccurence rate after, 266
invasion (LVSI), 32–33 stage IV ovarian cancer
184 resected melanomas and, 311 and, 104
Molecular Tumor Boards treatment for IB3–IIB
maintenance therapy (MTB), 30 cervical cancer, 278–279
with bevacizumab, 76 mortality vaginal radical
with oral PARP age and, 14 trachelectomy and, 267
inhibitors, 76 cervical cancer incidence Newcastle-Ottowa Scale, 257
malignant bowel of, 20 Next Generation Sequencing
obstruction (MBO) from debulking surgery, 2 (NGS), 29, 32,
percutaneous endoscopic in BRCA1 and BRCA2 180, 183
gastrostomy for, carriers, 14 NIR angiography, 2
136–138 MRC OV05/ EORTC 55955 Nivolumab, 311
surgery for, 133–134 trial, 26 NSGO9501/EORTC 55991
survival rate after mucinous ovarian carcinomas/ trial, 196
gastrostomy tubes cancers NTRK1-2–3 fusions, 30
surgery, 137 adjuvant chemotherapy and, nutritional status
survival rate for, 136 44–46 importance of, 9
symptom control and, 136 prognosis for, 44
MaNGO-ILIADE III trial, 196 multi-center Olympia-MITO occult cancers, age distribution
MAPK pathway, 35 13 trial, 68 of, 14

318 Index
oly-ADP-polymerase 1 secondary cytoreductive best time to use for

inhibitors (PARPi) surgery for, 113–114 maintenance, 95
as maintenance strategy, 102 standard treatment for homologous recombination
Onclarity HPV study, 17 advanced, 64 deficient (HRD) tumors
OncoKb, 30 statistics of lifetime risk, 13 and, 32–33
oocyte retrieval, 166 substages of Stage I, 44 PARPi inhibitors. See PARP
oophorectomy, 12, 14–15 surgical selection criteria inhibitors
for uterine leiomyosarcoma, for, 117 patients, decisions of, 27
234–235 tertiary debulking for Pd-L1, 128
in premenopausal primary, 120–122 pelvic exenteration, 310–311
women, 237 treatment for early stages, 49 after pelvic recurrence of
premenopausal, 14 treatment for platinum vulvo-vaginal melanomas,
preventive, 14 resistant recurrent, 307–308
oophorectomy in, 13 109–111 pelvic high grade serous
oral antibiotic bowel treatment of platinum- carcinomas (HGSC)
preparations (OABP) resistant, 106–108 risk of, 11
clean colon and, 1 trials for early-stage, 51 pelvic radiation, 307
oral contraceptives, 13 younger age at diagnosis, 38 pembrolizumab, 311
ovarian cancer Ovarian Cancer Consensus percutaneous endoscopic
adjuvant therapy, 117–118 Conference (OCCC), 106 gastrostomy, 136–138
BRCA1 and BRCA2 and, 11 ovarian clear cell carcinoma platinum-based adjuvant
breastfeeding and oral (OCCC), 48, 128 chemotherapy, 42
contraceptive use and risk ovarian germ cell tumors platinum-based therapy,
reduction, 13 (OGCT), 139–140 eligibility for, 117
chemotherapy cycles for BEP for, 142–143 Poland, BRCA1 mutation
treatment of, 51 chemotherapy regimen, carriers in, 14
clinical settings and 142–143 POLE ultramutated
patients, 116 ovarian preservation, 234–235, phenotype, 179
genetic risk for, 11–12 237–238 poly (ADP-ribose) polymerase
individualize treatment ovarian tissue (PARP) inhibitors, 76,
for, 51 cryopreservation, 166 88–90, 91–94, 98–100, 116
long-term survival and ovaries, 13, 44, 210, 266 and platinum-resistant
advanced, 78 leaving intact, 13 ovarian cancer, 109
maintenance therapy for, 27 preservation of, 165 PARPi, 29–30, 95
maintenance therapy for removal of, 243 PORTEC-3 trial, 179, 187,
advanced, 50 removal of bilateral, 238 189–190, 198,
mortality rate, 76 stimulating, 166 203
optimal chemotherapy OVHIPEC trial, 77, 78, 79, 80 chemoradiation arm of, 201
regimen for, 142–143 OVO5 trial, 26 positive groin nodes, 292
PARP inhibitors as Post-Operative Radiotherapy
maintenance, 98–100 paclitaxel, 190 in Endometrial
platinum-based PAOLA-1 /ENGOT-OV25 Carcinoma (PORTEC)-3
chemotherapy for trial, 88 trial. See PORTEC-3 trial
treatment of, 50 PAOLA-1 trial, 91 premature menopause, 11
prevention of in women with papillary serous cancer premenopausal women
high risk, 13–15 (UPSC), observation and, oophorectomies in, 14,
recurrent, 114 192–194 237–238
recurrent early stage, 50 parametrectomy preoperative carbohydrate
residual disease and, 58 why not recommended, loading, 10
role of immunotherapies in, 262–263 preoperative fasting, 6–7
131–132 why use for early-stage PRIMA trial, 104
role of surgery in cervical cancer, 259–260 PRIMA/ENGOT-OV26/GOG-
management of, 116–118 PARP inhibitors, 27, See also 3012 trial, 88
salpingectomy to BRCA poly (ADP-ribose) PRIMA/VELIA trial, 91
mutation carriers, 13–15 polymerase (PARP) Primary Cytoreductive
screening tests for, 11 inhibitors Surgery [PCS]

Index 319
for treating ovarian for early-stage cervical predicting gross, 68

cancer, 61 cancer, 253–254 ways to minimize occurrence
primary debulking surgery, 68, radical trachelectomy, 268 of, 58
80, 113 candidates for, 265 risk-reducing bilateral
for advanced ovarian morbidity of, 269 salpingectomy (RRSO), 11
cancer, 59 radiotherapy, 202–203, RNA (mRNA) expression, 29
for gynecological sarcomas, 283, 297 Robot-assisted Approach to
243–244 adjuvant, 304–306 Cervical Cancer (RACC)
mechanical bowel prep for single IFLN positive study, 254
(MBP) before, 4–5 vulvar cancer, 304 RRESDO, 12
role of HIPEC at, 81 for uterine serous
survival rate after, 123 cancer, 196 salpingectomy
vs neoadjuvant locally advanced as a risk-reducing strategy,
chemotherapy (NACT), endometrial cancer and, 11–12
55, 58 186–187 BRCA1 of BRCA2 mutation
with advanced ovarian management of vulvar and, 13
cancer, 64–66 cancer, 300 salpingo-oophorectomy, 14
primary radiation therapy, recurrent granulosa cell age and, 14
adjuvant hysterectomy tumor, 152 bilateral, 13, 165, 168, 238
and, 275 without chemotherapy, 278 sandwich adjuvant therapy,
proctoscopy, 2 RECIST disease 198–201
progression free survival (PFS), progression, 161 Sanger sequencing or
79, 85, 101, 117, 118, 130, recurrent and metastatic Quantitative Polymerase
145, 235, 253, melanoma Chain Reaction, 29
288, 305 treatment options for, 311 secondary cytoreduction
AGO score and, 113 recurrent granulosa cell tumors in recurrent uterine LMS,
between NACT and PCS, 52 (rGCT). See granulosa cell 246–248
clinical trial endpoints and, tumors (GCTs) recurrent endometrial
158–159 recurrent low grade serous cancer, 213–214
endpoints in clinical trials ovarian cancer, 35 recurrent uterine LMS,
and, 161–163 recurrent ovarian and uterine 247–248
HRD-positive ovarian cancers SEER-Medicaid retrospective
cancer, 91 MBP and, 1 study, 137, 302, 305
median, 38, 219 recurrent ovarian cancer. See sentinel lymph node biopsy
ovarian cancer, 33, 47 ovarian cancer (SLNB)
ovarian germ cell tumors recurrent sex cord stromal endometrial cancer, 175
and, 143 tumor (SCSTs), 149 for groin assessment, 291
primary endpoint of, 88, 126 recurrent uterine LMS in endometrial cancer,
recurrent ovarian cancer, chemotherapy, 246 171–172
106, 120 reasons for doing secondary of the inguinofemoral lymph
ProMisE classifications, 223 cytoreduction node basin, 294
and TransPORTEC, 182 surgery, 248 sentinel lymph node mapping,
PTEN/ PIK3CA pathway, 179 secondary cytoreduction, 171–172, 175, 256
pulmonary metastasectomy, 247–248 SENTOR study, 175
246, 247 surgical candidates for, 248 serous ovarian cancers, high-
re-excision, 297–298 grade, 13
QUADRA trial, 107 treatment for vulvar serous tubal intraepithelial
quality-adjusted life years squamous cell carcinoma, carcinomas, 11–12, 13
(QALY), 33 300–301 sexually active women, HPV
residual disease, 70, 78, 80 and, 20
radiation therapy, 203, 311 abdominal, 71 SHAPE (NCT01658930), 263
treatment option for vulvar following upfront single agent CPI, in EOC
cancer, 294–295 cytoreductive surgery, 58 study, 129
radical hysterectomy in advanced or recurrent single node positive vulvar
cervical cancer stages IA2 ovarian and uterine cancer, adjuvant radiation
and IBI, 262–263 cancer, 1 for, 302–303

320 Index
small-molecule inhibitors, 30 treatment schemes, comparing vulva. See also vulvar cancer
SOC1, 118 types of, 203–204 squamous cell carcinoma
SOLO-1 trial, 88, 89, 91, 102 TRUST trial, 52, (SCC) of the, 294
squamous cell carcinomas, 273, 60, 62 vulvar cancer
300–301, 304, See also Tumor Mutational Burden adjuvant radiation therapy
vulvar cancer (TMB), 30 treatment for, 302–303,
best treatment options for 304–306
stage I, 297–298 U.S. NRG Gynecologic complete groin
FIGO 2009 stage IA1, 256 Oncology Group, 51 lymphadenectomy for,
of the vulva, 301 U.S. Preventative Task Force 291–293
vulva, 297–298 (USPTF), 21 inguino-femoral lymph node
STIC lesions, 11–12, 13 United States metastasis in, 304
surgery, goal of for ovarian cervical cancer in, 20 radiation therapy for,
cancer, 117 upfront radical trachelectomy 294–295
surgical cytoreduction debate about, 268 re-excision vs. adjuvant
intraperitoneal (IP) morbidity of, 269 radiation treatments,
chemotherapy after, UPSC. See uterine papillary 300–301
82–84 serous cancer single-node positive,
surgical resection, in uterine (UPSC) 304–306
leiomyosarcomas (uLMS), US FDA registration trials, 19 statistics on, 291, 294,
240–241 uterine carcinosarcoma 304–306
surgical site infections, 1 chemotherapy regimen for, surgery for early stage,
combinational therapy 229–230 291
and, 2 molecular characterization vulvar malignancy. See vulvar
MBP and rate of, 4 of, 232 cancer
Surveillance, Epidemiology other treatment options for, vulvar squamous cell
and End Results (SEER) 232–233 carcinomas
database, 262 uterine leiomyomas, 240 stage I, 302
systemic therapy, 198 ovarian preservation and, vulvar/vaginal
237–238 melanomas
Tata Memorial Hospital uterine leiomyosarcomas pelvic exenteration for,
(TMH) study, 280 (uLMS), 237–238 307–308
T-Cell based therapy, 128 management of for vulvovaginal melanomas
tertiary debulking surgery premenopausal women, overall survival and,
for advanced ovarian 234–235 310
cancer, 23 metastatic, 240–241 pelvic exenteration and,
for recurrent ovarian cancer, surgery for, 234 310–311
120–122 targeted therapy and, 240 pelvic reoccurrence of,
testicular germ cell tumors when cytoreductive surgery 307–308
(TGCT), 139 is not recommended,
TOPACIO/KEYNOTE-162 250–252 whole abdominal irradiation
study, 110, 126 uterine papillary serous cancer (WAI), 186
total abdominal hysterectomy (UPSC), 192–194
(TAH), 234 adjuvant chemotherapy, young women, 165
total hysterectomy, 168 195–196 cervical treatment for,
with bilateral salpingo- uterine sarcomas, 237, 241, 268–270
oophorectomy 243, 245, 250 endometrial cancer
(TH-BSO), 165 outcomes in, 165
total pelvic exenteration vaginal melanomas, 307–308 fertility-sparing options for,
(TPE), 213 outcomes of, 310 165, 166
Trans-Atlantic Retroperitoneal vaginal radical treatment options for
Sarcoma (RPS) Working trachelectomy, 267 cervical cancer in,
Group, 248 VELIA trial, 88 265–267

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50 Big Debates

Published online by Cambridge University Press

Published online by Cambridge University Press

Cambridge University Press is part of Cambridge University Press & Assessment,

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Section I: Perioperative Oophorectomy for Ovarian Cancer

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6B. In Patients with BRCA-negative 10A. Patients with Advanced Ovarian

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be Routinely Removed during 16B. What is the Best Front-line

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20A. Should Patients 24A. What is the Optimal

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Section IV: Endometrial Cancer Chemotherapy and Radiation

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35A. Should Secondary Cytoreduction Uterine Leiomyomas?

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with either a Close or Positive with Single Node Positive Vulvar

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Giovanni Damiano Aletti Jamie N. Bakkum-Gamez

Daniele Xavier Assad Ilaria Betella

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Surgery, Memorial Sloan Kettering Cancer Laura M. Chambers

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Nicoletta Colombo Paul Downey

Marcela G. del Carmen Britt K Erickson

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Hospital Universitari Vall d’Hebron, Vall Ginger J. Gardner

Olga T. Filippova John P. Geisler

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Dr. Sudeep Gupta Payam Katebi Kashi

Laura J. Havrilesky Wui-Jin Koh

Ryan M. Kahn Olivia Lara

Daniel S. Kapp Olivia Le Saux

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Jonathan A. Ledermann Gynecology, Mayo Clinic, Phoenix,

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Daniela Matei Lea A. Moukarzel

Joanie Mayer Hope Deepa Maheswari Narasimhulu

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Kutluk Oktay Pedro T. Ramirez

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University Medical Center, Durham, Hospital NHS Foundation Trust,

Karin K. Shih Kavita Singh

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University Hospital, LMU Munich, Center; and New York

Hélène Vanacker Thomas C. Wright

Ignace B. Vergote Juliet E. Wolford

Roberto Vargas S. Diane Yamada

Simrit Warring Jason Yap

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Eleonora Zaccarelli Vanna Zanagnolo

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1A Preparation be Performed before

Mechanical Bowel Preparation is a Commonly Used and Safe

Mechanical Bowel Preparation Decreases Postoperative Complications,

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1A Preparation be Performed before

Mechanical Bowel Preparation is a Commonly Used and Safe