Review

INTERNATIONAL JOURNAL OF
Improvement in radiation techniques for
GYNECOLOGICAL CANCER
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locally advanced cervical cancer during the
last two decades
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ijgc.bmj.com

Satoru Sagae ‍ ‍,1 Takafumi Toita ‍ ‍,2 Motoki Matsuura ‍ ‍,3 Manabu Saito,1 Takuma Matsuda,1
Nanaka Sato,1 Ayumi Shimizu,1 Toshiaki Endo,1,3 Miho Fujii ‍ ‍,1 David K Gaffney ‍ ‍,4
William Small Jr ‍ ‍5

ABSTRACT two decades have witnessed an expansion in radia-

For numbered affiliations see tion therapy options for the concurrent and sequential
Since the National Cancer Institute (NCI) alert of concurrent
end of article.
chemoradiotherapy, radiotherapy has been changed management of cervical cancer. These ideas include
from external beam radiotherapy plus brachytherapy to enhancing the radiation effect with concurrent chemo-
Correspondence to platinum-­based concurrent chemoradiotherapy. Therefore, therapy, standardization of radiation techniques, and
Dr Satoru Sagae, Women's
concurrent chemoradiotherapy plus brachytherapy has further advancements in radiation modalities, espe-
Medical Center, Tokeidai
become a standard treatment for locally advanced cervical cially with international collaboration. Therefore, to
Memorial Hospital, Sapporo,
Hokkaido, Japan; ​str-​sagae@​ cancer. Simultaneously, definitive radiotherapy has been promote the distribution and usefulness of radiation
outlook.​jp changed gradually from external beam radiotherapy plus
treatment globally one should review the following
low-­dose-­rate intracavitary brachytherapy to external
beam radiotherapy plus high-­dose-­rate intracavitary
issues: (1) Gynecologic Cancer InterGroup (GCIG) and
Received 21 December 2022 brachytherapy. Cervix cancer is uncommon in developed Cervical Cancer Research Network (CCRN) – these
Accepted 17 March 2023 countries; hence, international collaborations have been activities have aided the standardization of radia-
Published Online First critical in large-­scale clinical trials. The Cervical Cancer tion therapy; (2) improving external beam radiation
11 April 2023 therapy plus brachytherapy, with rapidly distributing
Research Network (CCRN), created from the Gynecologic
Cancer InterGroup (GCIG), has investigated various intensity-­
modulated radiation therapy, and three-­
concurrent chemotherapy regimens and sequential dimensional image-­guided adaptive brachytherapy;
methods of radiation and chemotherapy. Most recently, and (3) new modalities of radiation techniques, such
many clinical trials of combining immune checkpoint as stereotactic ablative body radiotherapy boost or
inhibitors with radiotherapy have been ongoing for MRI-­ guided linear accelerator (MRI-­ LINAC) using
sequential or concurrent settings. During the last decade,
adaptive radiotherapy. Herein, we explore the clin-
the method of standard radiation therapy has changed
from three-­dimensional conformal radiation therapy
ical benefit of these novel strategies currently being
to intensity-­modulated radiation therapy for external tested in clinical trials in cervical cancer and their
beam radiotherapy and from two-­dimensional to three-­ optimal use to improve radiation therapy.
dimensional image-­guided approaches for brachytherapy.
Recent improvements include stereotactic ablative body
radiotherapy and MRI-­guided linear accelerator (MRI-­ INTERNATIONAL COLLABORATION TO PERFORM
LINAC) using adaptive radiotherapy. Here we review the CLINICAL TRIALS
current progress of radiation therapy during the last two
decades. In 1999, the National Cancer Institute (NCI) of the
United States published a clinical alert indicating a
survival benefit for adding platinum-­based chemo-
INTRODUCTION therapy to radiotherapy in International Federation
For the definitive treatment of locally advanced of Gynecology and Obstetrics (FIGO) stages IB2–IVA.1
cervical cancer, definitive radiation therapy plus Meta-­analysis has confirmed the survival advantage
brachytherapy with concurrent cisplatin is the of chemoradiotherapy over radiotherapy alone.2 Also,
standard of care. After multiple clinical trials, radia- some studies have documented the rapid incor-
tion therapy and concurrent platinum-­based chemo- poration of platinum-­ based chemoradiotherapy as
therapy demonstrated an overall survival benefit standard treatment within a short period after the
© IGCS and ESGO 2023. compared with radiation therapy alone.1 However, NCI 1999 clinical alert. Concerning the benefit of
Re-­use permitted under CC BY. while concurrent chemoradiotherapy has improved concurrent chemoradiotherapy plus brachytherapy,
Published by BMJ. clinical outcomes, it is not without associated normal a meta-­analysis of individual patient data from 18
To cite: Sagae S, Toita T, tissue toxicity. In particular gastrointestinal toxicity randomized chemoradiotherapy trials for cervical
Matsuura M, et al. concerns are worsened, primarily when extended-­ cancer in 2008 showed a 6% improvement in
Int J Gynecol Cancer field irradiation treats para-­aortic metastasis. While 5-­year survival with chemoradiotherapy.3 In Japan,
2023;33:1295–1303. considering the benefit of radiation therapy, the past the Japanese Gynecologic Oncology Group (JGOG)

Sagae S, et al. Int J Gynecol Cancer 2023;33:1295–1303. doi:10.1136/ijgc-2022-004230 1295

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assessed the feasibility and acute toxicity of concurrent chemo- INTERNATIONAL OBSTACLES AND APPROACHES
radiotherapy plus brachytherapy with cisplatin in JGOG1066.4 The United States National Clinical Trials Network has recently
They showed concurrent chemoradiotherapy with high-­ dose-­ expanded beyond North America to include Canadian research
rate intracavitary brachytherapy and standard weekly delivery of bases, and international collaboration is anticipated for several
cisplatin was feasible with acceptable toxicity in Japanese patients United States-­based research bases. In addition, the current NRG
with cervical cancer and also revealed the excellent efficacy and Oncology group has expanded to other international sites in Asia
toxicity of concurrent chemoradiotherapy plus brachytherapy. and Europe. Specific to gynecologic malignancies, the GCIG was
Furthermore, Surveillance, Epidemiology, and End Results (SEER) formalized in 1997 as a collaborative network of international
analysis5 demonstrated overall survival improvement for cervical research groups performing clinical trials in gynecologic cancers. A
cancer patients treated in the era of concurrent chemoradiotherapy recent global survey of oncologists regarding the obstacles to inter-
plus brachytherapy. Therefore, concurrent chemoradiotherapy plus national clinical trials cited lack of funds as the most critical factor
brachytherapy as a standard of care for locally advanced cervical in low- and middle-­income countries. In addition, regulatory proce-
cancer was supported by population-­level evidence in this study. dures were ranked as the next most crucial impediment to clinical
Moreover, recently a randomized controlled trial of concurrent research in this setting. The GCIG surveyed the practice patterns of
chemoradiotherapy plus brachytherapy from India showed signif- radiotherapy in cervical cancer among member groups to describe
icantly better disease-­free survival and overall survival than radia- the therapeutic practice of treating cervical cancer.11 For the treat-
tion alone in women with stage IIIB cervical cancer.6 ment of advanced cervical cancer, pelvic external beam doses and
total doses to point A was 47 Gy and 79.1 Gy, respectively. More
than 80% of groups used concurrent chemoradiotherapy plus
brachytherapy, using weekly cisplatin. Among member groups
TRIALS OF CHEMORADIOTHERAPY PLUS BRACHYTHERAPY of the GCIG, radiotherapy practices were similar in terms of both
doses and the use of chemotherapy. These surveys belong in the
Clinical trials of concurrent chemoradiotherapy plus brachytherapy
age of two-­dimensional intracavitary brachytherapy, while in the
have been conducted using platinum compounds, such as weekly
current era of three-­dimensional intracavitary brachytherapy, a new
versus triweekly (TACO), and combinations of platinum with other
standardization and monitoring of these distributions are required.
drugs such as gemcitabine/cisplatin.7 Gemcitabine plus cisplatin
Furthermore, under the current rapid advancement of radiation
during concurrent chemoradiotherapy, followed by brachytherapy
techniques, including intensity-­ modulated radiation therapy as
and adjuvant gemcitabine/cisplatin chemotherapy, improved
external radiation, three-­dimensional image-­guided (MRI-­based)
survival outcomes but was associated with much higher toxicity
brachytherapy, the American Society for Radiation Oncology
than the standard treatment. The OUTBACK trial8 randomized
(ASTRO),12 NRG Oncology,13 and the international study group
patients with locally advanced cervical cancer to standard concur-
on MRI-­based brachytherapy in locally advanced cervical cancer
rent chemoradiotherapy plus brachytherapy with weekly cisplatin
(EMBRACE)14 propose recommendations of target delineation/
versus concurrent chemoradiotherapy plus brachytherapy with
organs at risk contouring and standardization of dose constraints. In
four cycles of adjuvant carboplatin and paclitaxel. With a median
the real world, penetration of techniques and an indication of possi-
follow-­up of 60 months, 5-­year overall survival was 72% adju-
bilities of new modalities for radiation techniques will be necessary
vant carboplatin and paclitaxel versus 71% control, and 5-­year
to monitor and survey the technical advantages.15 To successfully
progression-­free survival was 63% versus 61%. Grade >3 adverse
perform global clinical trials of cervical cancer, including concur-
events occurred in 81% of the adjuvant carboplatin and paclitaxel rent chemoradiotherapy plus brachytherapy and immuno-­oncology,
group compared with 62% of the control. It was concluded that novel standardization of radiotherapy will be resolutely required in
adjuvant chemotherapy after standard concurrent chemoradio- the future.16
therapy plus brachytherapy does not improve overall survival or
progression-­free survival and increases toxicity.
While concurrent chemoradiotherapy with a platinum agent and
brachytherapy has been the standard of care for multimodality THE CERVIX CANCER RESEARCH NETWORK (CCRN)
therapy in cervical cancer, novel strategies with targeted agents The GCIG established the Cervix Cancer Research Network (CCRN)
and immunotherapy have been actively tested in clinical trials in after its Cervical Cancer State of the Science Meeting held in
the definitive and metastatic setting. Radiation can activate the Manchester in 2009.17 The vision of the CCRN was to accredit
immune system when combined with immunotherapy, resulting individual sites to have a sufficiently high quality of treatment and
in a synergistic response. However, multiple controversies remain follow-­up and adequately trained staff and resourced infrastructure
regarding the treatment for locally advanced cervical cancer, to contribute to international trials according to good clinical prac-
including the optimal immunotherapy combination with radio- tice standards. The challenge facing the CCRN is that of funding.
therapy and durvalumab9 or pembrolizumab,10 and the radiotherapy The International Gynecologic Cancer Society (IGCS), recognizing
dose when given in the primary or metastatic setting. In the CALLA the potential of the CCRN, has generously donated an unrestricted
trial,9 durvalumab in combination with and following concurrent grant to the CCRN, which the CCRN has matched. The CCRN was
chemoradiotherapy plus intracavitary±interstitial brachytherapy designed to provide clinical trials to women in low- and middle-­
did not significantly improve progression-­free survival in patients resource settings.
with high-­risk locally advanced cervical cancer compared with In November 2014, a cervical cancer brainstorming meeting in
concurrent chemoradiotherapy plus brachytherapy alone (Table 1). Melbourne, Australia entitled “Advances and Concepts in Cervical

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Table 1 Current ongoing clinical trials of chemoradiotherapy for locally advanced cervical cancer
Trial name Phase Interventions Radiation details Primary endpoint Current status
OUTBACK Ⅲ Control: CCRT EBRT: 3D-­CRT OS ASCO 2021 Plenary8
NCT01414608 2012– Investigational: BT: 2D-­ICBT, 3D-­CT/MRI-­based CCRT+adjuvant CT vs
2018 CCRT+adjuvant CT IGBT CCRT
(paclitaxel+carboplatin) (IC/IS BT is not allowed) OS at 5 years: 72%
Enrollment: 926 vs 71% (HR 0.91)
participants PFS at 5 years: 63%
vs 61% (HR 0.87)
NS in OS and PFS
TACO Ⅲ Control: CCRT EBRT: 2D-/3D-­CRT OS Active, not recruiting
NCT01561586 2012– Investigational: CCRT BT: 2D-­ICBT, 3D-­CT/MRI-­based
2023 (triweekly CDDP) IGBT
Enrollment: 374 (IC/IS BT is not allowed)
participants
INTERLACE Ⅲ Control: CCRT EBRT: 3D-­CRT, IMRT OS Active, not recruiting
NCT01566240 2012– Investigational: NAC BT: 2D-­ICBT, 3D-­CT/MRI-­based
2026 (paclitaxel+carboplatin) IGBT
→CCRT (IC/IS BT if indicated)
Enrollment: 500
participants
CALLA Ⅲ Control: CCRT EBRT: 3D-­CRT or IMRT PFS IGCS 2022 Plenary9
NCT03830866 2019– Investigational: BT: 2D-­ICBT, 3D-­CT/MRI-­based Durvalumab+CCRT vs
2023 CCRT+durvalumab IGBT placebo+CCRT
(Concurrent→adjuvant) (IC/IS BT if indicated) HR 0.84 (95% CI
Enrollment: 770 0.65–1.08); p=0.174
participants N.S. in PFS
MK-­3475-­A18/ Ⅲ Control: CCRT EBRT: 3D-­CRT or IMRT PFS at 38 months J Clin Oncol 202010
KEYNOTE-­A18/ 2020– Investigational: BT: 2D-­ICBT, 3D-­CT/MRI-­based OS at 46 months Active, not recruiting
ENGOT-­cx11/ 2024 CCRT+pembrolizumab IGBT
GOG-­3047 (Concurrent→adjuvant) (IC/IS BT if indicated)
NT04221945 Enrollment: 980
participants
NRG-­GY006 Ⅲ Control: CCRT EBRT: 3D-­CRT or IMRT OS Active, not recruiting
NCT02466971 2016– Investigational: BT: 2D-­ICBT, 3D-­CT/MRI-­based
2023 CCRT+triapine IGBT
Enrollment: 450 (IC/IS BT if indicated)
participants
EMBRACE Ⅱ Ⅱ Control: CCRT EBRT: IMRT Local control for 5 Int J Radiat Oncol
NCT03617133 2016– (Historical: Retro-/ BT: 3D-­MRI-­based IGBT years, nodal control Biol Phys 201941
2031 EMBRACE) (IC/IS BT if indicated) for 5 years, systemic Active, not recruiting
Investigational: CCRT Increased use of IC/IS BT, control for 5 years,
Enrollment: 1000 reduction of vaginal source OS for 5 years,
participants loading, protocol for target and overall morbidity for
OAR contouring, EBRT dose 5 years, EORTC QoL
prescription and reporting, for 5 years
adaptation of EBRT nodal elective
CTV according to risk of nodal
and systemic recurrence,
use of IMRT and IGRT for EBRT
delivery, reduction of overall
treatment time

ASCO, American Society of Clinical Oncology; BT, brachytherapy; CCRT, concurrent chemoradiation therapy plus brachytherapy; CI,
confidence interval; CR, complete response; CRT, conformal radiotherapy; CT, computed tomography; CT, chemotherapy; CTV, clinical
target volume; 2D, two-­dimensional; 3D, three-­dimensional; EBRT, external beam radiotherapy; EORTC, European Organization for
Research and Treatment of Cancer; HR, hazard ratio; HR-­QoL, health-­related quality of life; ICBT, intracavitary brachytherapy; IC/IS,
intracavitary/interstitial; IGBT, image-­guided brachytherapy; IGCS, International Gynecologic Cancer Society; IMRT, intensity-­modulated
radiation therapy; MRI, magnetic resonance imaging; NAC, neoadjuvant chemotherapy; NS, no statistically significant improvement;
OAR, organs at risk; PFS, progression-­free survival; PR, partial response; QoL, quality of life.

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Cancer Trials: A Road Map for the Future” was held during the GCIG In 2012, the GCIG surveyed brachytherapy practice patterns25 to
meeting, and discussed the future direction of cervical cancer trials, determine current practice patterns concerning gynecologic high-­
including surgery, chemotherapy, radiation therapy, and molecular dose-­rate intracavitary brachytherapy among GCIG members in
issues.18 As a result, the GCIG had grown to include 28 member Japan/Korea, Australia/New Zealand, Europe, and North America.
groups, and there was significant worldwide interest in the CCRN. Among 72 responses, 61 respondents (85%) utilized a high-­dose-­
At that time, 17 different CCRN site visits were performed, and there rate. The fractionation patterns were varied, but the overall mean
were 10 approved CCRN sites. In addition, CCRN currently has three dose administered for cervical cancer was similar in Australia/
multinational publicly funded clinical trials using radiotherapy open New Zealand, Europe, and the United States. Members in Japan
for enrollment in low-, middle-, and high-­income countries. administered a significantly lower external beam dose and higher
The triweekly cisplatin-­based chemoradiation in locally advanced brachytherapy dose to the cervix. Furthermore, similar to the
cervical cancer (TACO) trial [NCT01561586], which investigators JGOG1066 study,4 high-­ dose-­rate intracavitary brachytherapy
developed from the Korean Gynecologic Oncology Group (KGOG) was planned with classical two-­dimensional images and point A
and the Thai Cooperative Group, compared weekly cisplatin cancer dose description. Then the results suggested that high-­dose-­rate
therapy to every-­ 3-­
week chemotherapy for locally advanced intracavitary brachytherapy would improve pelvic control using
cervical cancer. In addition, the concurrent chemoradiotherapy plus modern three-­ dimensional image-­ guided brachytherapy, which
brachytherapy with carboplatin and paclitaxel in patients with locally could deliver appropriate doses to the entire volume of the locally
advanced cervical cancer (OUTBACK) trial [NCT01414608]8 was advanced tumors without increasing the surrounding organs.
performed globally, as noted earlier. The induction chemotherapy
plus chemoradiation plus brachytherapy as first-­line treatment for Image-Guided Brachytherapy
locally advanced cervical cancer (INTERLACE) trial [NCT01566240] Although treatments were historically planned using two-­
is headed by the National Cancer Research Institute from the United dimensional films and the point-­based Manchester system in the
Kingdom. This trial evaluates the administration of neoadjuvant United States and Europe, technical advances have led to increased
chemotherapy before definitive chemoradiation therapy plus intra- use of CT or MRI for three-­dimensional volumetric planning.26 MRI
cavitary±interstitial brachytherapy (Table 1). provides a much better definition of tissues, allowing adaptive
In 2015, a CCRN report mentioned the global outreach effort.19 planning as the tumor regresses with each delivered fraction. In
In January 2016, in Bangkok, Thailand, a CCRN educational work- 2005, the Groupe Europeen de Curietherapie and the European
shop was held to distribute the advance of radiotherapy for cervical Society for Radiotherapy and Oncology (GEC-­ESTRO) published
cancer in Asia, with participating members from surrounding coun- guidelines for optimal MRI-­guided brachytherapy planning target
tries.20 Sixty-­two participants attended from 16 different countries. volumes.27 The total prescription dose is the combined external
This symposium evaluated progress, promoted new clinical trials beam and brachytherapy biologically effective dose delivered in
for the CCRN, and educated on brachytherapy in treating cervical 2 Gy fractions (EQD2). Image-­guided brachytherapy improves local
cancer. In addition, the CCRN held its second international educa- control and reduces normal tissue toxicity. In 2012, the French STIC
tional symposium in Mexico City with 90 participants from 15 Latin trial,28 the first prospective, non-­randomized trial to compare two-­
American countries in January 201721; the third and fourth annual dimensional versus three-­dimensional brachytherapy in treating
CCRN symposia were held in Romania22 and South Africa, respec- locally advanced cervical cancer, showed that three-­dimensional
tively. In addition, the CCRN has opted to hold meetings in regions brachytherapy was feasible and safe in routine practice. It improved
of the world with a high rate of cervix cancer. The CCRN symposium local control with half the toxicity observed with two-­dimensional
for Vietnam in 2020 was planned but canceled due to the COVID dosimetry. In 2017, the American Brachytherapy Task Group29
pandemic, with plans for the seminar to be accomplished in 2023.23 reported a pooled analysis of clinical outcomes for high-­dose-­rate
brachytherapy for cervical cancer, which showed an improvement
in outcomes with the use of image-­guided brachytherapy compared
with traditional point A dose prescriptions, and demonstrated that
ADVANCES IN EXTERNAL BEAM RADIATION THERAPY (EBRT) high-­dose-­rate brachytherapy is a safe, effective modality when
AND BRACHYTHERAPY (ICBT) combined with image-­guided brachytherapy. As reported in 2019,
Advances in Brachytherapy the international RetroEMBRACE study improved local control
In the 1990s and 2000s, brachytherapy was usually performed and reduced late toxicity for women with large tumors treated
using an intracavitary approach with intrauterine tandem and with image-­guided brachytherapy relative to historical controls.30
vaginal colpostats. However, depending on the patient and tumor Early results of the prospective, multi-­institutional EMBRACE study
anatomy, in patients with an intact cervix, the vaginal component have identified improved dose–volume thresholds for urinary and
of brachytherapy may be delivered using ovoids, ring, or cylinder rectal toxicity in women with locally advanced cervical cancer
brachytherapy (combined with the intrauterine tandem). Initially, receiving MRI-­guided brachytherapy. For patients with prominent
low-­dose-­rate intracavitary brachytherapy was standard. However, irregularly shaped tumors, sufficient dose coverage is difficult to
since the American Brachytherapy Society (ABS) recommended be achieved during whole dose constraint keeping organs at risk
high-­dose-­rate intracavitary brachytherapy in 2000,24 high-­dose-­ with the standard intracavitary brachytherapy. The therapeutic
rate has been recognized to have similar efficacy and toxicity. In advantage of hybrid intracavitary and interstitial brachytherapy has
addition, high-­ dose-­rate has apparent advantages compared been reported.31 In the EMBRACE I study, concurrent chemoradio-
with low-­dose-­rate, including decreased dose to staff by using a therapy with MRI-­based image-­guided brachytherapy was effective
remote afterloading system and capability in the outpatient setting. and stable for long-­term local control across all stages of locally

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advanced cervical cancer.32 The currently open EMBRACE II study variations in patient anatomy. Target nodal sites (regions) for the
[NCT03617133] further optimizes the therapeutic ratio using the definitive treatment of cervical cancer are the common iliac, internal
latest external beam radiation therapy and brachytherapy tech- iliac, external iliac, obturator, and presacral lymph nodes. Normal
niques using new dedicated applicators combined with conven- tissues, including the small bowel, bladder, rectum, sigmoid, pelvic
tional intracavitary and interstitial needles (Table 1). bones, and femoral heads, are also contoured. When para-­aortic
nodes are being treated, limiting the dose to the duodenum, kidney,
Intensity-Modulated Radiation Therapy (IMRT) spinal cord, and liver is appropriate.
Radiation therapy is the primary treatment for patients with locally In the post-­operative setting, more recent evidence suggests
advanced cervical cancer. However, traditional radiation therapy that intensity-­modulated radiation therapy may decrease toxicity
has adverse effects, including cystitis, proctitis, enteritis, small while maintaining excellent oncologic outcomes. In the randomized
bowel obstruction, and fistulas. Especially with external beam radi- Radiation Therapy Oncology Group (RTOG) 1203 study,38 intensity-­
ation therapy, conventional three-­dimensional conformal radiation modulated radiation therapy significantly reduced gastrointestinal
therapy showed a particular incidence of severe side effects on and genitourinary toxicity compared with the standard four-­field
the small bowel and bone marrow. Conversely, intensity-­modulated approach from the patient’s perspective. The PARCER trial39 also
radiation therapy treats areas of interest while limiting the dose to showed image-­guided intensity-­modulated radiation therapy with
normal tissues and may be a way to reduce toxicity from radia- reduced toxicity with no difference in disease outcomes, as well
tion therapy and possibly increase the dose and improve outcome. as the most current trial of positron emission tomography-­guided
For example, intensity-­modulated radiation therapy for irradiation bone marrow-­sparing intensity-­modulated radiation therapy for
of the para-­aortic nodal chain is also likely to decrease the risk locally advanced cervical cancer.40 Similarly, definitive concurrent
of toxicities compared with two-­ dimensional/three-­
dimensional chemoradiotherapy with intensity-­modulated radiation therapy plus
radiation therapy, while allowing dose escalation to intact positive brachytherapy is expected to be a promising strategy for locally
nodes, especially for patients receiving concurrent chemotherapy.33 advanced cervical cancer. Additionally, intensity-­modulated radia-
However, no data show that intensity-­modulated radiation therapy tion therapy significantly reduced acute gastrointestinal and genito-
improves disease-­specific survival or overall survival over two-­ urinary toxicities and chronic genitourinary toxicity in patients with
dimensional/three-­dimensional techniques. cervical cancer, which is strongly recommended by ASTRO.12
An up-­to-­date contouring atlas and guidelines for imaging during
intensity-­ modulated radiation therapy are needed. In addition, Intensity-Modulated Radiation Therapy plus Image-Guided
continuous upfront monitoring for both contouring and planning Brachytherapy
of patients34 and managing internal volume changes and motion Using image-­guided brachytherapy in cervical cancer, the clinical
is required, possibly with image-­guided radiotherapy.35 The dose-­ results of these innovations were presented based on the multicenter
calculation algorithms for intensity-­modulated radiation therapy EMBRACE I and RetroEMBRACE studies with large patient cohorts
shape the dose around target structures with multiple converging (n=1416, n=731, respectively).30 32 Image-­guided brachytherapy
beams or arcs. This approach makes it possible to reduce the dose for cervical cancer improves pelvic control and survival across all
delivered to the normal tissues that surrounde the target structures. stages. Improving pelvic control is more significant in advanced
However, intensity-­ modulated radiation therapy must address stages, but progress in survival is similar across stages. The Retro-
patient positioning, contouring, and set-­up reproducibility to avoid EMBRACE cohort study analyzed the failure patterns to investigate
errors with these highly conformal approaches. Given the tech- this discrepancy.30 Some 731 patients from 12 institutions treated
nical capacity to reduce treatment volumes to spare normal tissue, with chemoradiation therapy and MRI- or CT-­based image-­guided
a reproducible treatment planning set-­up and the careful use of brachytherapy were evaluated. In addition, this study analyzed the
relevant diagnostic imaging and thorough physical examination are pattern of failure at the time of the first relapse. After image-­guided
critical for optimal treatment planning. brachytherapy, the predominant failure is systemic, whereas the
Indeed, CT simulation aims to replicate the positioning that will principal failure with conventional brachytherapy is pelvic. As an
probably be encountered during daily treatment, given the possi- evolution of practice from EMBRACE-­I to -II,32 41 the importance
bility for large targets and organs at risk of movement due to rectum of technique, target selection, contouring, dose prescription, and
and bladder filling status. Moreover, appropriate internal margins dose-­planning in external beam radiation therapy for cervical
need to be added to the clinical target volume, especially for the cancer was emphasized as follows: EMBRACE-­I involved 1416
primary lesion, to form the internal target volume and subsequently patients with locally advanced cervical cancer treated with chemo-
to the planning target volume to keep adequate dose coverage radiation, including image-­ guided brachytherapy during 2008
for the clinical target volume. It is also essential to apply image-­ to 2015. EMBRACE II, which is now enrolled and has accrued
guided radiotherapy for daily intensity-­modulated radiation therapy 1000 patients, comprises a comprehensive, detailed strategy
delivery. Once CT simulation is complete and diagnostic imaging and accreditation procedure for external beam radiation therapy
is fused or otherwise carefully examined, the accurate delineation with target contouring, treatment planning, and image guidance,
of both target volumes and organs at risk is crucial to optimize performing three-­ dimensional conformal radiation therapy or
the probability of tumor control and minimize toxicity. There are intensity-­modulated radiation therapy as external beam radiation
consensus contouring guidelines for both intact and post-­operative therapy and two-­dimensional intracavitary brachytherapy or three-­
scenarios to assist with target volume segmentation.36 37 With the dimensional MRI-­ based image-­ guided brachytherapy (intracavi-
advent of three-­dimensional imaging, target structures should be tary±interstitial brachytherapy if indicated). External beam radia-
contoured to ensure radiotherapy field design reflects individual tion therapy planning target volumes (PTVs), treated volumes (V43

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Gy), and conformity index (CI; V43 Gy /PTV) will have been evalu- brachytherapy results, the use of brachytherapy is declining in
ated in both studies and compared. A similar report42 of intensity-­ the United States.46 Recently, the use of stereotactic ablative body
modulated radiation therapy/three-­ dimensional image-­ guided radiotherapy has rapidly increased in clinical practice for various
brachytherapy for cervical cancer from the United States was asso- cancers such as lung, kidney, and prostate. As a salvage/pallia-
ciated with improved survival and decreased gastrointestinal and tive option for locoregional and distant recurrences and oligo-
genitourinary toxicity in patients with cervical cancer compared metastatic cervical cancer,47 local control and toxicity associated
with those who received two-­dimensional external beam radiation with stereotactic ablative body radiotherapy seem reasonable for
therapy and brachytherapy. most clinical indications during short follow-­ ups, for example,
for some patients ineligible for brachytherapy.48 However, before
Extended-field irradiation and brachytherapy applying this strategy as an alternative to brachytherapy in defini-
Another approach is extended-­ field irradiation and intracavi- tive treatment in clinical practice, further investigation is necessary
tary brachytherapy with or without chemotherapy for patients regarding target volume delineation, the minimum dose required to
with positive para-­aortic or high common iliac lymph nodes. The control tumors, and patterns of internal organ motion (inter-/intra-­
RTOG 0116 trial43 was designed to test the toxicity of combined fractions). In addition, one phase II clinical trial evaluating stereo-
chemotherapy with extended-­ field irradiation and intracavitary tactic ablative body radiotherapy was closed early due to toxicity,
brachytherapy. Patients received extended-­field irradiation of 45 Gy and local control was only 70% at 2 years.49 Therefore, stereotactic
(1.8 Gy/fraction) in addition to intracavitary brachytherapy, which ablative body radiotherapy should not be used as a routine alter-
estimated 85 Gy low-­dose-­rate equivalent to the final point A dose. native to brachytherapy, although some clinical guidelines do not
The boosted irradiation was 54 to 59.4 Gy for the positive para-­ recommend it.34 The stereotactic ablative body radiotherapy boost
aortic and high common iliac lymph nodes. Cisplatin (40 mg/m2) for cervical tumors is still investigational, and the available data
was delivered weekly during external beam radiation therapy and suggest worse outcomes with non-­brachytherapy approaches.25
once with brachytherapy. Among 26 eligible patients with para-­ No studies have been published directly comparing stereotactic
aortic metastasis or high common iliac involvement, 16 (62%) ablative body radiotherapy with brachytherapy.
patients had a complete response for both local and nodal disease.
However, the acute and late grade 3/4 toxicity rate was 81% and MRI-LINAC Using Adaptive Radiotherapy
40%, respectively. This toxicity might be because of no use of Many image-­guided radiotherapy techniques have been developed,
intensity-­modulated radiation therapy. In conclusion, extended-­field but motion can be random and difficult to predict before treatment.
irradiation and intracavitary brachytherapy with cisplatin for para-­ In addition, MRI-­guided treatment planning is more complex for
aortic or highly common iliac node metastasis from cervical cancer external beam radiation therapy than for brachytherapy, requiring
were associated with significant acute and late toxicity. electron density information and a whole-­body contour for accu-
A recent study44 in 2018 was performed among eligible rate dose calculations. Nevertheless, many different technical solu-
patients with locally advanced cervical cancer and documented tions have been developed, including a combined MRI and cobalt
positive para-­aortic lymph nodes, extended-­field irradiation, and radiotherapy unit, an MRI scanner on rails, and a linear acceler-
brachytherapy with concurrent cisplatin 40 mg/m2 weekly for ator combined with an MRI scanner (MRI-­LINAC).50 50 Compared
6 weeks. Some 4–6 weeks after completing concurrent chemo- with CT, these approaches have potential benefits, including MRI
radiotherapy, patients were treated with four cycles of paclitaxel simulation allowing for more accurate and reproducible contouring,
135 mg/m2 and escalating doses of carboplatin with area under the improved visualization of the tumor for accurate localized dose
curve (AUC) 4 or 5. The therapeutic value of prophylactic extended-­ escalation, imaging during external beam radiation therapy to
field irradiation for patients with a high risk of para-­aortic lymph enable the management of inter- and intra-­fraction variations, and
node recurrence is another critical issue. Furthermore, extended-­ dose–response assessment with multiparametric MRI to guide
field, intensity-­modulated radiotherapy with concurrent chemo- further treatment. Therefore, with its superior soft-­tissue contrast,
therapy was tolerated well, with acceptable toxicities in patients MR-­guided radiation therapy can potentially reduce toxicity and
with cervical cancer and para-­aortic lymph node metastasis. More- potentiate dose escalation in external beam radiation therapy for
over, an Indian study45 in 2019 was undertaken to report the early cervical cancer.
toxicity with extended-­field, intensity-­modulated radiotherapy for
cervical cancer in their cohort of patients and determine dose–
volume parameters that predict over grade 2 hematological toxicity FUTURE DIRECTIONS
and diarrhea. Thus, extended-­ field, intensity-­modulated radio- Among radiotherapy plus chemotherapy, such as concurrent,
therapy was feasible for cervical cancer patients with para-­aortic adjuvant, and neoadjuvant styles, the control of distant metas-
lymph node involvement and associated with acceptable grade 3 tasis during or after radiotherapy is crucial, so many trials are
toxicity. ongoing. Unfortunately, the current OUTBACK trial8 did not show
any advantage of adjuvant chemotherapy with many difficulties in
understanding the results, such as patients' characteristics, stage,
NEW MODALITIES OF RADIATION TECHNIQUES used drug and dose, the timing between radiotherapy and chemo-
Stereotactic Ablative Body Radiotherapy therapy, and others. The ongoing TACO trial expects to show some
Currently, controversial issues exist as to whether high-­ evidence of concurrent chemotherapy compared with weekly and
quality external beam radiation therapy can be an alternative triweekly platinum. It might reveal some results with better disease
to brachytherapy for cervical cancer. Despite these excellent control, side effects, and quality of life during radiation therapy. The

1300 Sagae S, et al. Int J Gynecol Cancer 2023;33:1295–1303. doi:10.1136/ijgc-2022-004230

 Review

INTERLACE trial is also trying to show similar results of radiation have been tested in international clinical trials, and strate-
control under the setting of neoadjuvant chemotherapy. Therefore, gies of neoadjuvant chemotherapy before radiation therapy or
establishing the best way to add chemotherapy to radiotherapy is adjuvant chemotherapy after concurrent chemoradiotherapy
necessary to maximize disease control and minimize toxicities, so plus brachytherapy are ongoing. Moreover, numerous clinical
we need to generate more well-­designed trials globally that will trials of immune checkpoint inhibitors combined with concur-
define the position of chemotherapy in locally advanced cervical rent chemoradiotherapy plus brachytherapy are also ongoing.
cancer treatment (Table 1). External beam radiation therapy and brachytherapy have
Ongoing studies of concurrent chemoradiotherapy plus changed from three-­d imensional conformal radiation therapy
brachytherapy in combination with immune checkpoint inhibitors to intensity-­
m odulated radiation therapy and from two-­
in patients with locally advanced cervical cancer are assessing dimensional intracavitary brachytherapy to three-­d imensional
the sequence of treatments and overall efficacy and safety. For
image-­g uided brachytherapy. Current investigations include
example, recent results from the phase III CALLA trial9 showed
stereotactic ablative body radiotherapy or MRI-­L INAC using
that durvalumab, in combination with and following concur-
adaptive radiotherapy; however, there is no firm evidence
rent chemoradiotherapy plus brachytherapy, did not significantly
that these techniques are clinically advantageous. Radiation
improve progression-­free survival in patients with locally advanced
cervical cancer, with no new or unexpected toxicity. Furthermore, therapy continues to be the most attractive strategy to treat
the phase III ENGOT-­cx/KEYNOTE-­A18 trial10 evaluating the combi- locally advanced cervical cancer, with high local control rates.
nation of pembrolizumab with concurrent chemoradiotherapy However, some recent trials have indicated that the most
plus brachytherapy is ongoing, and the results of this trial are common site of the first failure is distant; hence, improved
highly anticipated. They will further elucidate whether immuno- systemic therapies are needed.
therapy combined with definitive concurrent chemoradiotherapy
plus brachytherapy can improve local control, pelvic control, and Author affiliations
1
Women’s Medical Center, Tokeidai Memorial Hospital, Sapporo, Hokkaido, Japan
survival in patients with locally advanced cervical cancer without 2
Radiation Therapy Center, Okinawa Chubu Hospital, Uruma, Okinawa, Japan
significantly increasing toxicities. 3
Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo,
EMBRACE II prescribes MRI-­ guided adaptive brachytherapy Hokkaido, Japan
with combined intracavitary±interstitial techniques and specific 4
Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah,
dose–volume constraints for adaptive targets and organs at risk Salt Lake City, Utah, USA
5
and image-­guided external beam radiotherapy for particular targets Department of Radiation Oncology, Loyola University Chicago, Stritch School of
and techniques (intensity-­ modulated radiation therapy, image-­ Medicine, Cardinal Bernardin Cancer Center, Maywood, Illinois, USA
guided radiation therapy, simultaneously integrated boost for lymph
Twitter William Small Jr @WilliamSmallJr
node boosting, and more para-­aortic radiotherapy) and concurrent
chemoradiotherapy plus brachytherapy. EMBRACE II intends to Acknowledgements The authors thank the members of the Japan Gynecologic
Oncology Group (JGOG), Gynecologic Cancer InterGroup (GCIG), and Cervical
benchmark excellent local, nodal, distant control and survival rates, Cancer Research Network (CCRN) for their contributions to developing clinical trial
morbidity, and quality of life outcomes and prospectively evaluate research for gynecologic cancer during the last two decades.
the evidence derived from the previous RetroEMBRACE30 and Contributors SS: conceptualization, methodology, investigation, writing-­original
EMBRACE I32 studies. These results will be used as a reference in draft, writing-­review and editing, project administration. TT: investigation, writing-­
many centers worldwide and in clinical studies reflecting clinical, original draft, writing-­review and editing. MM: writing-­original draft, writing-­review
and editing. MS, TM, NS, TE, MF: these authors made substantial contributions to
biological, and technical parameters of importance for further opti-
the drafting and revision of the manuscript for important intellectual content. DG,
mizing the therapeutic ratio for chemoradiotherapy and intracavi- WS: writing-­original draft, writing-­review and editing, supervision. All authors read
tary brachytherapy in locally advanced cervical cancer. and approved the final manuscript.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
CONCLUSIONS
Patient consent for publication Not applicable.
During the last two decades, radiation therapy has rapidly
Ethics approval Not applicable.
improved from external beam radiation therapy plus low-­
Provenance and peer review Not commissioned; externally peer reviewed.
dose-­r ate intracavitary brachytherapy to external beam radia-
tion therapy plus high-­d ose-­r ate intracavitary brachytherapy. Open access This is an open access article distributed in accordance with the
Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits
Since the NCI alert concerning concurrent chemoradiotherapy, others to copy, redistribute, remix, transform and build upon this work for any
definitive radiation therapy for locally advanced cervical purpose, provided the original work is properly cited, a link to the licence is given,
cancer has changed dramatically from external beam radi- and indication of whether changes were made. See: https://creativecommons.org/​
ation therapy plus brachytherapy alone to external beam licenses/by/4.0/.
radiation therapy with concurrent platinum-­ b ased chemo- ORCID iDs
therapy plus brachytherapy. In many countries, intensity-­ Satoru Sagae http://orcid.org/0000-0002-1802-1569
modulated radiation therapy is preferred over three-­ Takafumi Toita http://orcid.org/0000-0003-3907-0228
Motoki Matsuura http://orcid.org/0000-0002-6589-6480
dimensional conformal radiation therapy for gynecological Miho Fujii http://orcid.org/0000-0002-0785-2578
applications where the bladder, rectum, bowel, and bone David K Gaffney http://orcid.org/0000-0002-5752-1611
marrow are proximal. Various chemotherapeutic regimens William Small Jr http://orcid.org/0000-0002-1623-9863

Sagae S, et al. Int J Gynecol Cancer 2023;33:1295–1303. doi:10.1136/ijgc-2022-004230 1301

Review

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