Melanoma: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Melanoma
Version 3.2016
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Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.
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NCCN Guidelines Version 3.2016 Panel Members NCCN Guidelines Index

Melanoma Table of Contents
Melanoma Discussion
* Daniel G. Coit, MD/Chair ¶ Ryan C. Fields, MD ¶ Anthony J. Olszanski, MD †

Memorial Sloan Kettering Cancer Center Siteman Cancer Center at Barnes- Fox Chase Cancer Center
Jewish Hospital and Washington
* John A. Thompson, MD ‡ †/Vice-Chair University School of Medicine Patrick Ott, MD, PhD † ‡ Þ
Fred Hutchinson Cancer Research Dana-Farber/Brigham and Women's
Center/Seattle Cancer Care Alliance Martin D. Fleming, MD ¶ Cancer Center
The University of Tennessee
Alain Algazi, MD † Þ Health Science Center Aparna Priyanath Gupta, MD Þ
UCSF Helen Diller Family Robert H. Lurie Comprehensive Cancer
Comprehensive Cancer Center Brian Gastman, MD ¶ Center of Northwestern University
Case Comprehensive Cancer Center/
Robert Andtbacka, MD ¶ University Hospitals Seidman Cancer Center Merrick I. Ross, MD ¶
Huntsman Cancer Institute and Cleveland Clinic Taussig Cancer Institute The University of Texas
at the University of Utah MD Anderson Cancer Center
Rene Gonzalez, MD †
Christopher K. Bichakjian, MD ϖ University of Colorado Cancer Center April K. Salama, MD †
University of Michigan Duke Cancer Institute
Comprehensive Cancer Center Valerie Guild ¥
Aim at Melanoma Joseph Skitzki, MD ¶
William E. Carson, III, MD ¶ Roswell Park Cancer Institute
The Ohio State University Douglas Johnson, MD †
Comprehensive Cancer Center - Vanderbilt-Ingram Cancer Center Susan M. Swetter, MD ϖ
James Cancer Hospital and Stanford Cancer Institute
Solove Research Institute Richard W. Joseph, MD ‡ †
Mayo Clinic Cancer Center Kenneth K. Tanabe, MD ¶
Gregory A. Daniels, MD, PhD Þ ‡ Massachusetts General Hospital
UC San Diego Moores Cancer Center Julie R. Lange, MD, ScM ¶ Cancer Center
The Sidney Kimmel Comprehensive
Dominick DiMaio, MD ≠ Cancer Center at Johns Hopkins Javier F. Torres-Roca, MD §
Fred & Pamela Buffett Cancer Center Moffitt Cancer Center
Mary C. Martini, MD ϖ
Robert H. Lurie Comprehensive Cancer Vijay Trisal, MD ¶
Center of Northwestern University City of Hope Comprehensive
Cancer Center
† Medical oncology Miguel A. Materin, MD †
Þ Internal medicine Yale Cancer Center/Smilow Cancer Hospital Marshall M. Urist, MD ¶
ϖ Dermatology University of Alabama at Birmingham
¶ Surgery/Surgical oncology Comprehensive Cancer Center
≠ Pathology
¥ Patient advocacy
Continue NCCN
‡ Hematology/Hematology oncology Anita Engh, PhD
§ Radiotherapy/Radiation oncology Nicole McMillian, MS
* Writing committee member NCCN Guidelines Panel Disclosures
Fayna Ferkle, PharmD
NCCN Guidelines Version 3.2016 Sub-Committee NCCN Guidelines Index

Melanoma Discussion
Systemic Therapy Workup/Follow-up Recommendations Review

John A. Thompson, MD ‡ †/Lead Susan M. Swetter, MD ϖ/Lead Daniel G. Coit, MD ¶
Fred Hutchinson Cancer Research Stanford Cancer Institute Memorial Sloan Kettering Cancer Center
Center/Seattle Cancer Care Alliance
Merrick I. Ross, MD ¶/Co-Lead Kenneth K. Tanabe, MD ¶
Daniel G. Coit, MD ¶ The University of Texas Massachusetts General Hospital
Memorial Sloan Kettering Cancer Center MD Anderson Cancer Center Cancer Center
F. Stephen Hodi, Jr. MD † Robert Andtbacka, MD ¶ John A. Thompson, MD ‡ †

Dana-Farber/Brigham and Women’s Huntsman Cancer Institute Fred Hutchinson Cancer Research
Cancer Center at the University of Utah Center/Seattle Cancer Care Alliance
Richard W. Joseph, MD ‡ † Christopher K. Bichakjian, MD ϖ

Mayo Clinic Cancer Center University of Michigan
Comprehensive Cancer Center
Anthony J. Olszanski, MD †
Fox Chase Cancer Center Principles of Radiation Therapy
Robert Andtbacka, MD ¶/Lead
Susan M. Swetter, MD ϖ Huntsman Cancer Institute
Stanford Cancer Institute at the University of Utah
Vijay Trisal, MD ¶ Rene Gonzalez, MD †

City of Hope Comprehensive University of Colorado Cancer Center
Cancer Center
April K. Salama, MD †
Duke Cancer Institute
Javier F. Torres-Roca, MD §
Moffitt Cancer Center
† Medical oncology Continue

Þ Internal medicine
ϖ Dermatology
¶ Surgery/Surgical oncology
NCCN Guidelines Panel Disclosures
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®.
®
NCCN Guidelines Version 3.2016 Table of Contents NCCN Guidelines Index

Melanoma Discussion
NCCN Melanoma Panel Members Clinical Trials: NCCN believes that

Summary of the Guidelines Updates the best management for any cancer
patient is in a clinical trial.
Clinical Presentation and Preliminary Workup (ME-1) Participation in clinical trials is
especially encouraged.
Stage 0 (in situ), Stage IA, IB (ME-2)
Stage IB, Stage II (ME-3) To find clinical trials online at NCCN
Member Institutions, click here:
Stage III (ME-4) nccn.org/clinical_trials/physician.html.
Stage III In-Transit (ME-5)
NCCN Categories of Evidence and
Stage IV Metastatic (ME-6) Consensus: All recommendations
Follow-up (ME-7 and ME-8) are category 2A unless otherwise
Persistent Disease or True Local Scar Recurrence; Local, Satellite, and/or specified.
In-Transit Recurrence (ME-9) See NCCN Categories of Evidence
Nodal Recurrence (ME-10) and Consensus.
Distant Metastatic Disease (ME-11)
Principles of Biopsy and Pathology (ME-A)
NCCN Guidelines for Patients®
Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-B)
Principles of Complete Lymph Node Dissection (ME-C) available at www.nccn.org
Principles of Radiation Therapy for Melanoma (ME-D)
Systemic Therapy for Metastatic or Unresectable Disease (ME-E)
Management of Toxicities Associated with Immunotherapy and Targeted Therapy
(ME-F)
Staging (ST-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment.
Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical
circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or
warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may
not be reproduced in any form without the express written permission of NCCN. ©2016.
NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

Melanoma Discussion
Updates in Version 3.2016 of the NCCN Guidelines for Melanoma from Version 2.2016 include:
Global Changes:
• Workup language revised for various stages: "Imaging (CT scan PET/CT, MRI) to evaluate specific signs or symptoms" changed to
"Recommend imaging (CT scan PET/CT, MRI) only to evaluate specific signs or symptoms."
• Footnote "i" was added to clarify recommended modalities wherever imaging is mentioned: "Chest/abdominal/pelvic CT with contrast, brain
MRI with contrast, and/or FDG PET/CT. Neck CT with contrast if clinically indicated. Scans performed with contrast unless contraindicated.
Contrast not necessary for CT chest screening for lung metastases."
ME-5 ME-10
• After Primary Treatment, the recomendation "Imaging to assess • Workup for nodal recurrence: Recommendation revised:
treatment response" was added. "Recommend imaging for baseline staging and to evaluate specific
signs or symptoms (category 2B) (CT scan, PET/CT, MRI)."
ME-7 (Follow-up)
• Stage IA-IIA-NED: ME-11
Third bullet revised, "Routine radiologic imaging to screen for • Workup recommendation revised: "Recommend CT chest/abdomen/
asymptomatic..." pelvis ± MRI brain, and/or PET/CT imaging for baseline staging and
New bullet added: "Recommend imaging as indicated to investigate to evaluate specific signs and symptoms." Footnote "i" added.
specific signs or symptoms." This statement was previously part • Limited (Resectable) pathway;
of footnote "dd" "Common Follow-up Recommendations for All Treatment of Recurrence: Revised recommendation, "Resect or
Patients." Change was also made for Stage IIB-IV NED follow-up Observe or Systemic therapy; then repeat scans."
recommendadations on page ME-8. "Imaging to assess response or progression" was added after
ME-8 (Follow-up) "Observe or Systemic therapy."
• Stage IIB-IV NED: Revised "Consider chest x-ray, CT, brain MRI, and/
or PET/CT scans imaging every 3–12 mo (unless otherwise mandated MS-1
by clinical trial participation) to screen for recurrent/metastatic • The Discussion text has been updated to reflect the changes in the
disease (category 2B)". Footnote "i" also added. algorithm.
• Footnote "gg" is new: "Consider chest x-ray for surveillance of lung
metastases."
ME-9
• Local, satellite, and/or in-transit recurrence pathway
Workup recommendations revised:
◊◊"Recommend Consider baseline imaging for baseline staging
(category 2B)."
◊◊Recommend imaging to evaluate specific signs or symptoms
(category 2B) (CT scan, PET/CT, MRI)"
After "Treatment of recurrence," "Imaging to assess treatment
response" was added.
UPDATES
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN .
® ® Continued 1 OF 6

Melanoma Discussion
ME-4 ME-10
• Adjuvant treatment: "High-dose ipilimumab (category 2B)" added • Treatment for patients with disseminated (unresectable) distant
as an option for Stage III (sentinel node positive) and Stage III metastatic disease:
(clinically positive node[s]). "Systemic therapy" is now listed as a "preferred" option.
• Footnote s is new: "Adjuvant ipilimumab is associated with "Intralesional injection with T-VEC" added as an option for select
improvement in recurrence-free survival. Its impact on overall patients with corresponding footnote ii "T-VEC has shown a response
survival has not been reported. The recommended dose of rate (lasting ≥6 months) of 16% in highly selected patients with Stage IV-
ipilimumab (10 mg/kg) was associated with adverse events, M1a disease (skin, subcutaneous, and/or remote nodes)."
which led to the discontinuation of treatment in 52% of patients. ME-E (1 of 6) Systemic Therapy for Metastatic or Unresectable Disease
There was a 1% drug-related mortality rate." • For both first-line and second-line or subsequent targeted therapy, the
• Footnote t is new: "The clinical trial excluded patients with recommended combination regimens are listed as "preferred" over
sentinel lymph node metastases ≤1 mm in size and who did not single-agent therapy options.
undergo CLND. The decision to use ipilimumab should be based • First-line Therapy: "Vemurafenib/cobimetinib (category 1)" added as a
on risk of recurrence balanced against the risk of treatment- preferred treatment option.
related toxicity. It is unclear whether the decision should be • Second-line or Subsequent Therapy: "Vemurafenib/cobimetinib" added as
based on CLND." a treatment option
ME-5 • Footnote 3 revised: "Nivolumab/ipilimumab combination therapy is
• Primary Treatment for Stage III in-transit: "Intralesional injection associated with improved relapse-free survival compared with single-
with talimogene laherparepvec (T-VEC) (category 1)" added as an agent nivolumab or ipilimumab, at the expense of significantly increased
option with corresponding footnote z "T-VEC was associated with toxicity. Compared to single-agent therapy, the impact of nivolumab/
a response rate (lasting ≥6 months) of 16% in highly selected ipilimumab combination therapy on overall survival is not known. The
patients with unresectable metastatic melanoma. Efficacy was phase III trial of nivolumab/ipilimumab alone versus either nivolumab
noted in Stage IIIB, IIIC, and Stage IV-M1a disease and was more or nivolumab/ipilimumab monotherapy versus ipilimumab alone was
likely in patients who were treatment naive." conducted in previously untreated patients with unresectable stage III or
ME-8 IV melanoma."
• Treatment of Local, Satellite, and/or In-transit Recurrence: • Footnote 4 is new: "In previously untreated patients with unresectable
"Intralesional injection with T-VEC (category 1)" added as an Stage IIIC or Stage IV disease, the combination of vemurafenib/
option with corresponding footnote z. cobimetinib was associated with improved PFS and response rate when
ME-9 compared to vemurafenib alone. The impact on overall survival compared
• Treatment of nodal recurrence with unresectable or systemic to single-agent vemurafenib is unknown."
disease: • New references added for vemurafenib/cobimetinib combination therapy.
"Systemic therapy" is now listed as a "preferred" option. ME-F Management of Toxicities Associated with Immunotherapy and
Recommendation revised, "Palliative RT." Targeted Therapy
"Intralesional injection with T-VEC" added as an option with Page 1 of 2
corresponding footnote z. • Immunotherapy: Under "Ipilimumab" the first bullet was revised, "For
• Adjuvant Treatment for patients who have had a complete more information and specific wording of the black box warning, see the
lymph node dissection and/or a complete resection of the nodal full prescribiing information (www.fda.gov)."
recurrence: Page 2 of 2
"High-dose ipilimumab (category 2B)" added as a treatment • Targeted Therapy: Last bullet revised, "For more information on toxicities
option with corresponding footnote s. associated with dabrafenib with or without trametinib, or vemurafenib
"Biochemotherapy" revised as follows "Biochemotherapy for with or without cobimetinib, and for the management of these toxicities,
stages IIIB, IIIC." see the full prescribing information (www.fda.gov)." UPDATES
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Melanoma Discussion
Global Changes
• The footnote describing when and how to perform mutational analysis has been revised. (ME-6, ME-7, ME-8, ME-9)
ME-1
• Footnote c revised: "While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate
benign from malignant neoplasms, or melanomas at low- versus high-risk for metastasis, routine (baseline) genetic testing of primary
cutaneous melanomas (before or following SLNB) is not recommended outside of a clinical study (trial). Mutational analysis is recommended
if patients are being considered for either routine treatment or clinical trials, but is not recommended or patients who are otherwise NED."
• Footnote d is new: "In the absence of metastatic disease, BRAF testing of the primary cutaneous melanoma is not recommended."
• Footnote f revised: "Given lower reported rates of SLN positivity in pure desmoplastic melanoma, it is important that an experienced
dermatopathologist examine the entire lesion before making the decision to perform a SLNB. There is uncertainty regarding the diagnostic
criteria for, the probability of a positive sentinel node in, and the prognostic significance of the sentinel node in pure desmoplastic
melanoma. Multidisciplinary consultation including a dermatopathologist is recommended for determining staging and treatment options.
(Busam KJ. Desmoplastic Melanoma. Clin Lab Med 2011;31:321-330.)"
ME-2
• "Clinical Stage" revised: "Stage IA, IB (≤0.75 mm thick, any features) no ulceration, mitotic rate 0 per mm2); Stage IB (≤0.75 mm thick with
ulceration, and/or mitotic rate ≥1 per mm2."
• Footnote j revised: "SLNB is an important staging tool, but the impact of SLNB on overall survival is unclear but has not been shown to
improve disease-specific survival among all patients. Subset analysis of prospectively collected data suggest that SLNB is associated with
improvement in distant metastasis-free survival among patients with melanomas 1.2–3.5 mm thick, compared to patients with melanomas of
similar thickness who are initially observed and subsequently develop clinical nodal metastases."
ME-3
• "Clinical Stage" revised: "Stage IB (0.76–1.0 mm thick with ulceration or mitotic rate ≥1 per mm2) or Stage IB or II (>1 mm thick, any
characteristic feature, N0)."
ME-4
• Stage III (sentinel node positive)
Primary Treatment: Recommendation revised, "Discuss and offer complete lymph node dissection."
Adjuvant Treatment: Interferon alfa changed from category 2B to category 2A.
• Stage III (clinically positive node[s])
Workup: Bullet revised, "FNA preferred, if feasible, or core, incisional, or excisional biopsy lymph node biopsy."
Primary Treatment: Recommendation revised, "...complete therapeutic lymph node dissection."
Adjuvant Treatment:
◊◊Interferon alfa changed from category 2B to category 2A.
◊◊Biochemotherapy (category 2B) added as an option.
◊◊Recommendation revised, "...Consider RT to nodal basin in selected high-risk patients based on location..." (Also for ME-9)
Continued UPDATES
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Melanoma Discussion
ME-4 (continued)
• Footnote u is new: "For a list of biochemotherapy regimens, See Other Systemic Therapies (ME-E 2 of 6)."
• Footnote q revised: "The impact of complete lymph node dissection in patients with stage III (sentinel node positive) patients is unknown.
This will be clarified when results of MSLT-II are published. CLND contributes to staging. Its impact on regional disease control and overall
survival is the focus of ongoing clinical trials. Factors that predict non-sentinel lymph node positivity include sentinel node tumor burden,
number of positive nodes, and thickness/ulceration of the primary tumor. See Principles of Complete Lymph Node Dissection (ME-C)."
• Footnote r revised: "Interferon can be given as high-dose alfa interferon for one year or as peginterferon alfa-2b for up to 5 years. Adjuvant
interferon has been shown to improve DFS (category 1); its impact on overall survival remains unclear (category 2B) but there is no impact
on overall survival." (Also for ME-9)
• Footnote t revised: "Adjuvant nodal basin RT is associated with reduced lymph node field recurrence but has no impact on shown no
improvement in relapse-free or overall survival., and Its benefits must be weighed against potential toxicities the increased probability of long-
term skin and regional toxicities and potential reduced quality of life."
ME-5
• Fourth column: After "Primary Treatment" the statement "If free of disease" was divided into two pathways "If free of disease by surgery"
and "If free of disease by other treatments." For the latter, "Clinical trial" or "Observation" are recommended as adjuvant treatment options.
ME-6
• Footnote y revised: "...Obtain tissue for genetic analysis from either biopsy of the metastasis (preferred) or archival material if the patient is
being considered for targeted therapy or if the tissue mutation status is relevant to eligibility for participation in a clinical trial."
ME-7
• Follow-up for Stage IIB-IV NED
Third bullet revised: "Consider chest x-ray, CT, brain MRI, and/or PET/CT scans..."
Recommendation removed: "Consider brain MRI annually (category 2B)"
• Footnote aa revised: "The frequency of follow-up and intensity of cross-sectional imaging should be based on the conditional probability of
recurrence at any point in time after initial treatment. Follow-up recommendations listed here are for surveillance for recurrence in patients
with no evidence of disease."
Continued UPDATES
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Melanoma Discussion
ME-8
• Local, satellite, and/or in-transit recurrence
Workup: First bullet revised, "FNA or biopsy FNA preferred, if feasible, or core, incisional, or excisional biopsy."
Fourth column after "Treatment of Recurrence" the statement "If free of disease" was divided into two pathways: "If free of disease by
surgery" and "If free of disease by other treatments". For the latter, "Clinical trial" or "Observation" were recommended as adjuvant
treatment options.
ME-9
• Nodal recurrence:
Workup
◊◊First bullet revised: "FNA (preferred) or lymph node biopsy FNA preferred, if feasible, or core, incisional, or excisional biopsy."
Corresponding new footnote dd added: "Biopsy preferred if recurrence is unresectable."
◊◊Bullet removed: "Pelvic CT if inguinofemoral nodes clinically positive."
Adjuvant Treatment:
◊◊Interferon alfa changed from category 2B to category 2A.
◊◊Biochemotherapy for stages IIIB, IIIC (category 2B) added as an option.
ME-10
• Distant metastatic disease
Workup
◊◊First bullet revised: "FNA (preferred) or lymph node biopsy FNA preferred, if initial resection is planned. Biopsy (core, excisional, or
incisional) preferred if initial therapy is to be systemic."
For disseminated (unresectable) disease with brain metastases, recommendation revised: "Consider palliative resection and/or..."
ME-A Principles of Biopsy and Principles of Pathology

• Footnote 3 revised: "While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate
benign from malignant neoplasms, or melanomas at low- versus high-risk for metastasis, routine (baseline) genetic testing of primary
cutaneous melanomas (before or following SLNB) is not recommended outside of a clinical study (trial). Mutational analysis is recommended
if patients are being considered for either routine treatment or clinical trials, but is not recommended or patients who are otherwise NED."
• Footnote "4" is new: "In the absence of metastatic disease, BRAF testing of the primary cutaneous melanoma is not recommended."
ME-C Principles of Complete Lymph Node Dissection
• Second bullet revised: "In the groin, consider elective iliac and obturator lymph node dissection if clinically positive superficial
inguinofemoral nodes or ≥3 superficial inguinofemoral nodes are positive (category 2B)."
Continued UPDATES
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Melanoma Discussion
ME-D Principles of Radiation Therapy for Melanoma ME-E Systemic Therapy For Metastatic or Unresectable Disease
Page 1 of 3 Page 1 of 6 (continued)
• "Regional disease" recommendation revised: "Adjuvant treatment in Footnote 3 is new: "Nivolumab/ipilimumab combination therapy
selected patients following resection of clinically appreciable nodes is associated with improved relapse-free survival compared
(category 2B) if LDH <1.5 x upper limit of normal AND..." with single agent nivolumab or ipilimumab, at the expense of
• Footnote 1 revised: "Interactions between radiation therapy and significantly increased toxicity. Compared to single agent therapy,
systemic therapies (eg, BRAF inhibitors, and interferon alfa-2b, the impact of nivolumab/ipilimumab combination therapy on overall
immunotherapies, and checkpoint inhibitors) need to be very survival is not known. The phase III trial of nivolumab alone versus
carefully considered as there is potential for increased toxicity." nivolumab/ipilimumab versus ipilimumab alone was conducted
• Footnote 3 revised: "Adjuvant nodal basin RT is associated with in previously untreated patients with unresectable stage III or IV
reduced lymph node field recurrence but has no impact on shown no melanoma."
improvement in relapse-free or overall survival. Its benefits must be Footnote 5 is new: "Consider second-line agents if not used first-
weighed against potential toxicities the increased probability of long- line and not of the same class.
term skin and regional toxicities and potential reduced quality of life." Page 2 of 6
• Footnote 4 revised: "Adjuvant whole brain radiation following • Page title changed from "Systemic Therapy for Metastatic or
resected melanoma brain metastasis is controversial and should be Unresectable Disease" to "Other Systemic Therapies."
considered on an individual patient basis. An ongoing randomized • Subheading title changed: "Cytotoxic Regimens for Metastatic Disease."
clinical trial (ANZMTG 01-07, ACTRN12607000512426, NCT01503827) • Subheading title changed: "Biochemotherapy for Metastatic Disease."
is currently investigating adjuvant whole brain radiation (Fogarty This section was extensively revised.
G, Morton RL, Vardy J, et al. Whole brain radiotherapy after local • New section added: "Biochemotherapy for Adjuvant Treatment of High-
treatment of brain metastases in melanoma patients--a randomised Risk Disease."
phase III trial. BMC Cancer. 2011;11:142.)." "Dacarbazine, cisplatin, vinblastine, IL-2, and interferon alfa-2b
Page 2 of 3 (category 2B)" added as the recommended regimen.
• Primary Disease: New reference added "Hedblad MA, Mallbris L. • Footnote 1 regarding cytotoxic regimens and biochemotherapy
Grenz ray treatment of lentigo maligna and early lentigo maligna is new: "In general, options for front-line therapy for metastatic
melanoma. J Am Acad Dermatol 2012;67:60-68." melanoma include immunotherapy or targeted therapy."
ME-E Systemic Therapy For Metastatic or Unresectable Disease Page 3 of 6, Page 4 of 6, Page 5 of 6, and Page 6 of 6
Page 1 of 6 The reference section was extensively revised to reflect the changes in
• This section was reorganized and extensively revised including: the algorithm.
The "Metastatic or unresectable disease" treatment pathways for ME-F Management of Toxicities Associated with Immunotherapy and
"BRAF V600 wild type" and "BRAF V600 mutant" were combined into Targeted Therapy
one algorithm. • This section was previously entitled "Principles of Immunotherapy
Nivolumab/ipilimumab was added to the list of options for "First-line and Targeted Therapy."
therapy" and "Second-line or subsequent therapy." • This section was reorganized and extensively revised.
UPDATES
® ® 6 OF 6
NCCN Guidelines Version 3.2016 NCCN Guidelines Index

Melanoma Discussion
CLINICAL PATHOLOGY PRELIMINARY CLINICAL STAGE

PRESENTATION REPORTa,c,d WORKUP
Breslow thickness
Stage 0 in situ
+
(ME-2)
Ulceration status
(present or absent)
Inadequateb Rebiopsy + • H&P with
Dermal mitotic rate (#/mm2) Stage IA, Stage IB
Suspicious attention to
+ (ME-2)
pigmented Biopsya locoregional
lesion Assess deep and peripheral area, draining
margin status lymph nodes
Melanoma + Stage IB, Stage II
• Complete skin
confirmedb Microsatellitosise (ME-3)
exam
(present or absent) • Assessment of
+ melanoma-
Clark level (for nonulcerated related risk Stage III
lesions where mitotic rate is factorsg (ME-4) and (ME-5)
not determined,
for lesions ≤1 mm)
+ Stage IV Metastatic
Pure desmoplasiaf if present (ME-6)
aSee Principles of Biopsy and Pathology (ME-A).
bIf diagnostic biopsy is inadequate for treatment decisions, rebiopsy may be appropriate.
cWhile there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate benign from malignant neoplasms, or melanomas at
low versus high risk for metastasis, routine (baseline) genetic testing of primary cutaneous melanomas (before or following SLNB) is not recommended outside of a
clinical study (trial).
dIn the absence of metastatic disease, BRAF testing of the primary cutaneous melanoma is not recommended.
eMicrosatellitosis is defined in the CAP 2013 melanoma protocol (version 3.3.0.0) as “the presence of tumor nests greater than 0.05 mm in diameter, in the reticular
dermis, panniculus, or vessels beneath the principal invasive tumor but separated from it by at least 0.3 mm of normal tissue on the section in which the Breslow
measurement was taken" (Harrist TJ, Rigel DS, Day CL Jr, et al. “Microscopic satellites” are more highly associated with regional lymph node metastases than is
primary melanoma thickness. Cancer 1984;53:2183-2187).
fThere is uncertainty regarding the diagnostic criteria for, the probability of a positive sentinel node in, and the prognostic significance of the sentinel node in pure
desmoplastic melanoma. Multidisciplinary consultation including a dermatopathologist is recommended for determining staging and treatment options.
gRisk factors for melanoma include family history of melanoma, prior primary melanoma, and other factors such as atypical moles/dysplastic nevi.
Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ME-1

Melanoma Discussion
CLINICAL STAGE WORKUPc,d PRIMARY TREATMENT ADJUVANT TREATMENT

• H&P
Stage 0 in situ
• Routine imaging/lab tests not
recommended
Stage IA, IB • Recommend imagingi only Wide excisionl
(≤0.75 mm thick, to evaluate specific signs or
any features)h symptoms See
Follow-Up
• H&P Wide excisionl (ME-7)
• Routine imaging/lab (category 1)
Stage IA tests not Discuss and
Sentinel
(0.76–1.0 mm thick, recommended consider
node
no ulceration, • Recommend sentinel node Wide excisionl negative
mitotic rate 0 per mm2)h imagingi only to biopsyj,k (category 1)
evaluate specific with sentinel
signs or symptoms node biopsym Sentinel
(category 2B) See Stage III Workup and
node
Primary Treatment (ME-4)
positive
hIn general, SLNB is not recommended for primary melanomas ≤0.75 mm thick, unless there is significant uncertainty about the adequacy of microstaging.
For melanomas 0.76 to 1.0 mm thick, SLNB may be considered in the appropriate clinical context. In patients with thin melanomas (≤1.0 mm), apart from
primary tumor thickness, there is little consensus as to what should be considered “high-risk features” for a positive SLN. Conventional risk factors for a
positive SLN, such as ulceration, high mitotic rate, and lympovascular invasion (LVI), are very uncommon in melanomas ≤0.75 mm thick. When present,
SLNB may be considered on an individual basis.
cWhile there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate benign from malignant neoplasms, or melanomas at
low versus high risk for metastasis, routine (baseline) genetic testing of primary cutaneous melanomas (before or following SLNB) is not recommended outside of a
clinical study (trial).
dIn the absence of metastatic disease, BRAF testing of the primary cutaneous melanoma is not recommended.
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck CT with contrast if clinically indicated. Scans performed with contrast unless contraindicated.
Contrast not necessary for CT chest screening for lung metastases.
jDecision not to perform SLNB may be based on significant patient comorbidities, patient preference, or other factors.
kSLNB is an important staging tool, but has not been shown to improve disease-specific survival among all patients. Subset analysis of prospectively collected data
suggest that SLNB is associated with improvement in distant metastasis-free survival among patients with melanomas 1.2–3.5 mm thick, compared to patients with
melanomas of similar thickness who are initially observed and subsequently develop clinical nodal metastases.
lSee Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-B).
mSentinel lymph nodes should be evaluated with multiple sectioning and immunohistochemistry.


Melanoma Discussion
CLINICAL STAGE WORKUPc,d PRIMARY TREATMENT ADJUVANT TREATMENT

If Stage IB, IIA:
Clinical trial
(if available)
Stage IB Wide excisionl or
(0.76–1.0 mm thick • H&P
(category 1) Observation
with ulceration or • Routine imaging/lab See
mitotic rate ≥1 per tests not Discuss and Follow-Up
If Stage IIB, IIC:
mm2) recommendedo offer sentinel Sentinel (ME-7 and
Clinical trial
or • Recommend node node ME-8)
(if available)
Stage IB or II imagingi only to biopsyj,k,n negative
evaluate specific Wide excisionl or
(>1 mm thick, (category 1) Observation
any feature, N0)h,n signs or symptoms
with sentinel or
node biopsym Interferon alfap
Sentinel (category 2B)
node See Stage III Workup and
positive Primary Treatment (ME-4)
hIn general, SLNB is not recommended for primary melanomas ≤0.75 mm thick, unless there is significant uncertainty about the adequacy of microstaging. For melanomas
0.76 to 1.0 mm thick, SLNB may be considered in the appropriate clinical context. In patients with thin melanomas (≤1.0 mm), apart from primary tumor thickness, there is
little consensus as to what should be considered “high-risk features” for a positive SLN. Conventional risk factors for a positive SLN, such as ulceration, high mitotic rate,
and LVI, are very uncommon in melanomas ≤0.75 mm thick. When present, SLNB may be considered on an individual basis.
nMicrosatellitosis, when present in the initial biopsy or wide excision specimen, defines at least N2c and at least stage IIIB disease. SLN status does have prognostic
significance in these patients, with a positive SLN upstaging a patient to N3, stage IIIC. However, the importance of SLNB in the management and outcome of these
patients has not been clearly defined. Regardless of SLN status, these patients should be managed as stage III in discussions of workup, adjuvant therapy, and follow-up.
cWhile there is interest in newer prognostic molecular techniques such as gene expression kSLNB is an important staging tool, but has not been shown to improve disease-specific
profiling to differentiate benign from malignant neoplasms, or melanomas at low survival among all patients. Subset analysis of prospectively collected data suggest that
versus high risk for metastasis, routine (baseline) genetic testing of primary cutaneous SLNB is associated with improvement in distant metastasis-free survival among patients
melanomas (before or following SLNB) is not recommended outside of a clinical study with melanomas 1.2–3.5 mm thick, compared to patients with melanomas of similar
thickness who are initially observed and subsequently develop clinical nodal metastases.
(trial). lSee Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-B).
dIn the absence of metastatic disease, BRAF testing of the primary melanoma is not
mSentinel lymph nodes should be evaluated with multiple sectioning and
recommended. immunohistochemistry.
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/ oConsider nodal basin ultrasound prior to SLNB for melanoma patients with an equivocal
CT. Neck CT with contrast if clinically indicated. Scans performed with contrast unless regional lymph node physical exam. Nodal basin ultrasound is not a substitute for SLNB.
contraindicated. Contrast not necessary for CT chest screening for lung metastases. Negative nodal basin ultrasound is not a substitute for biopsy of clinically suspicious
jDecision not to perform SLNB may be based on significant patient comorbidities, patient lymph nodes. Abnormalities or suspicious lesions on nodal basin ultrasound should be
preference, or other factors. confirmed histologically.
pHigh-dose alfa interferon for one year has been shown to improve disease-free survival
(DFS) (category 1); its impact on overall survival remains unclear (category 2B).

Melanoma Discussion
CLINICAL/ WORKUPq PRIMARY TREATMENT ADJUVANT TREATMENT

PATHOLOGIC STAGE
Clinical trial
• Consider imagingi for
or
baseline staging
Stage III Discuss and offer Observation
(category 2B)
(sentinel node complete lymph node or
• Recommend imagingi to
positive) dissectionr Interferon alfas
evaluate specific signs or
or
symptoms
High-dose ipilimumabt,u (category 2B)
Clinical trial
or (See
Observation Follow-up
or (ME-8)
Interferon alfas
• FNA preferred, if feasible, or
or
core, incisional, or excisional
Wide excision of primary High-dose ipilimumabt (category 2B)
Stage III biopsy
tumorl (category 1) or
(clinically positive • Recommend imagingi for
+ complete therapeutic Biochemotherapyv
node[s]) baseline staging and to
lymph node dissection (category 2B)
evaluate specific signs or
and/or
symptoms
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck Consider RT to nodal basin in selected
CT with contrast if clinically indicated. Scans performed with contrast unless contraindicated. high-risk patients based on location,
Contrast not necessary for CT chest screening for lung metastases. size, and number of involved nodes,
lSee Principles of Surgical Margins for Wide Excision of Primary Melanoma (ME-B).
qMutational analysis is recommended if patients are being considered for either routine treatment and/or macroscopic extranodal
or clinical trials, but is not recommended for patients with cutaneous melanoma who are extensionw,x (category 2B)
otherwise NED.
rCLND contributes to staging. Its impact on regional disease control and overall survival is the
focus of ongoing clinical trials. Factors that predict non-sentinel lymph node positivity include
sentinel node tumor burden, number of positive nodes, and thickness/ulceration of the primary uThe clinical trial excluded patients with sentinel lymph node metastases ≤1 mm in size
tumor. See Principles of Complete Lymph Node Dissection (ME-C). and who did not undergo CLND. The decision to use ipilimumab should be based on
sInterferon can be given as high-dose alfa interferon for one year or as peginterferon alfa-2b for risk of recurrence balanced against the risk of treatment-related toxicity. It is unclear
up to 5 years. Adjuvant interferon has been shown to improve DFS (category 1); but there is no whether the decision should be based on CLND.
impact on overall survival. vFor biochemotherapy, see Other Systemic Therapies (ME-E 2 of 6).
tAdjuvant ipilimumab is associated with improvement in recurrence-free survival. Its impact on wAdjuvant nodal basin RT is associated with reduced lymph node field recurrence but has
overall survival has not been reported. The recommended dose of ipilimumab (10 mg/kg) was shown no improvement in relapse-free or overall survival. Its benefits must be weighed
associated with adverse events, which led to the discontinuation of treatment in 52% of patients. against potential toxicities.
There was a 1% drug-related mortality rate. xSee Principles of Radiation Therapy for Melanoma (ME-D).


Melanoma Discussion
CLINICAL/ WORKUPq PRIMARY TREATMENT ADJUVANT TREATMENT

PATHOLOGIC • Clinical trial (preferred)
STAGE • Local therapy options:
Complete surgical excision to
clear margins, if feasiblez
Intralesional injection options:
• FNA preferred, if ◊◊Talimogene laherparepvec
feasible, or core, (T-VEC)aa
incisional, or Clinical trial
(category 1)
excisional biopsy or
◊◊BCG, IFN, or IL-2 (all category If free of
Stage III • Recommend imagingi Observation
2B) disease by
in-transity for baseline staging or (See
Local ablation therapy surgery
and to evaluate Interferon alfas Follow-up
(category 2B)
specific signs or (category 2B) (ME-8)
Topical imiquimod for superficial
symptoms dermal lesions (category 2B)
Imagingi If free of
Consider RTx for unresectable Clinical trial
to assess disease
disease (category 2B) or
treatment by other
• Regional therapy options: Observation
response treatments
Isolated limb infusion/perfusion
(ILI/ILP) with melphalan
• Systemic therapybb
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck CT with contrast if clinically indicated. Scans performed with contrast
unless contraindicated. Contrast not necessary for CT chest screening for lung metastases.
qMutational analysis is recommended if patients are being considered for either routine treatment or clinical trials, but not recommended for patients with cutaneous
melanoma who are otherwise NED.
sInterferon can be given as high-dose alfa interferon for one year or as peginterferon alfa-2b for up to 5 years. Adjuvant interferon has been shown to improve DFS
(category 1); but there is no impact on overall survival.
xSee Principles of Radiation Therapy for Melanoma (ME-D).
yIn-transit metastasis is defined as intralymphatic tumor in skin or subcutaneous tissue more than 2 cm from the primary tumor but not beyond the nearest regional
lymph node basin. (Definition from CAP 2012 Melanoma Protocol [version 3.2.0.0])
zConsider sentinel node biopsy for resectable in-transit disease (category 2B). Sentinel lymph nodes should be evaluated with multiple sectioning and
immunohistochemistry.
aaT-VEC was associated with a response rate (lasting ≥6 months) of 16% in highly selected patients with unresectable metastatic melanoma. Efficacy was noted in
Stage IIIB, IIIC, and Stage IV-M1a disease and was more likely in patients who were treatment naive.
bbSee Systemic Therapy for Metastatic or Unresectable Disease (ME-E 1 of 6)


Melanoma Discussion
CLINICAL/ WORKUP
PATHOLOGIC
STAGE
• Biopsy preferred over FNA if archival tissue

not available for genetic analysiscc See Treatment for Limited (Resectable)
Stage IV
• LDH or Disseminated (Unresectable) Disease
Metastatic
• Recommend imagingi for baseline staging ME-11)
and to evaluate specific signs and symptoms
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck CT with contrast (if clinically indicated). Scans performed with contrast
unless contraindicated. Contrast not necessary for CT chest screening for lung metastases.
ccInitial clinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Obtain tissue for genetic analysis from either biopsy of the
metastasis (preferred) or archival material if the patient is being considered for targeted therapy or if the mutation status is relevant to eligibility for participation in a
clinical trial.


Melanoma Discussion
CLINICAL/PATHOLOGIC FOLLOW-UP RECURRENCEee

STAGE Persistent
disease or true
(See ME-9)
local scar
recurrenceee
Stage 0 in situ See Common Follow-up Recommendations for All Patientsdd
Local, satellite,
• See Common Follow-up Recommendations for All Patientsdd and/or in-transit (See ME-9)
• H&P (with emphasis on nodes and skin) recurrencecc,ff
every 6–12 mo for 5 y, then
annually as clinically indicated
Stage IA - IIA NED
• Routine imaging to screen for asymptomatic recurrent/
metastatic disease is not recommended Nodal
(See ME-10)
• Recommend imagingi as indicated to investigate specific recurrencecc
signs or symptoms
ddCommon Follow-up Recommendations for All Patients: Distant

• At least annual skin exam for life (See ME-11)
recurrencecc
• Educate patient in regular self skin and lymph node exam
• Routine blood tests are not recommended
• Regional lymph node ultrasound may be considered in patients with an equivocal lymph node physical
exam, patients who were offered but did not undergo SLNB, patients in whom SLNB was not possible (or not
successful), or patients with a positive SLNB who did not undergo complete lymph node dissection (CLND). At
this point, nodal basin ultrasound has not been shown to be a substitute for SLNB or CLND.
• Follow-up schedule is influenced by risk of recurrence, prior primary melanoma, and family history of
melanoma, and includes other factors such as atypical moles/dysplastic nevi and patient/physician concern.
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck CT with contrast if clinically indicated. Scans performed with contrast unless contraindicated.
ccInitialclinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Obtain tissue for genetic analysis from either biopsy of the
metastasis (preferred) or archival material if the patient is being considered for targeted therapy or if the mutation status is relevant to eligibility for participation in a
clinical trial.
eePersistent disease or true local scar recurrence is defined by presence of in situ and/or radial growth phase.
ffLocal, satellite recurrence without in situ or radial growth phase, with deep dermal or subcutaneous fat recurrence within the melanoma scar or satellite metastasis
adjacent to the melanoma scar.


Melanoma Discussion
CLINICAL/PATHOLOGIC FOLLOW-UP RECURRENCEee

STAGE Persistent
disease or true
(See ME-9)
local scar
recurrenceee
• See Common Follow-up Recommendations for All Patientsdd
• H&P (with emphasis on nodes and skin)
every 3–6 mo for 2 y, then
every 3–12 mo for 3 y, then Local, satellite,
annually as clinically indicated and/or in-transit (See ME-9)
• Recommend imagingi as indicated to investigate specific signs recurrencecc,ff
Stage IIB - IV NED
or symptoms
• Consider imagingi,gg every 3–12 mohh (unless otherwise
mandated by clinical trial participation) to screen for recurrent/ Nodal
metastatic disease (category 2B) (See ME-10)
recurrencecc
• Routine imaging to screen for asymptomatic recurrent/
metastatic disease is not recommended after 3–5 years
ddCommon Follow-up Recommendations for All Patients:
• At least annual skin exam for life Distant
• Educate patient in regular self skin and lymph node exam (See ME-11)
recurrencecc
• Routine blood tests are not recommended
• Regional lymph node ultrasound may be considered in patients with an equivocal lymph node physical
exam, patients who were offered but did not undergo SLNB, patients in whom SLNB was not possible (or not
successful), or patients with a positive SLNB who did not undergo complete lymph node dissection (CLND). At
this point, nodal basin ultrasound has not been shown to be a substitute for SLNB or CLND.
• Follow-up schedule is influenced by risk of recurrence, prior primary melanoma, and family history of
melanoma, and includes other factors such as atypical moles/dysplastic nevi and patient/physician concern.
hhThe
frequency of follow-up and intensity of cross-sectional imaging should
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/
be based on the conditional probability of recurrence at any point in time after
CT. Neck CT with contrast if clinically indicated. Scans performed with contrast unless
contraindicated. Contrast not necessary for CT chest screening for lung metastases. initial treatment. Follow-up recommendations listed here are for surveillance for
ccInitial clinical recurrence should be confirmed pathologically whenever possible recurrence in patients with no evidence of disease.
eePersistent disease or true local scar recurrence is defined by presence of in situ
or if clinically indicated. Obtain tissue for genetic analysis from either biopsy of the
metastasis (preferred) or archival material if the patient is being considered for and/or radial growth phase.
ffLocal, satellite recurrence without in situ or radial growth phase, with deep dermal
targeted therapy or if the mutation status is relevant to eligibility for participation in
a clinical trial. or subcutaneous fat recurrence within the melanoma scar or satellite metastasis
ggConsider chest x-ray for surveillance of lung metastases. adjacent to the melanoma scar.


Melanoma Discussion
WORKUP TREATMENT OF RECURRENCE ADJUVANT TREATMENT

Recommendations
• Biopsy to confirma Re-excise tumor site to appropriate should be based
Persistent
• Workup appropriate margins (See ME-B) on pathologic
disease or true
to primary tumor Consider lymphatic mapping/SLNB stage of
local scar
characteristics according to primary tumor recurrence; follow
recurrenceee
(See ME-2) characteristics Guidelines as in
(ME-2)
• Clinical trial (preferred)
• Local therapy options:
Complete surgical excision to clear
• FNA preferred, if
margins, if feasiblez
feasible, or core, Clinical trial
Intralesional injection options:
incisional, or or
◊◊T-VECaa (category 1) If free of
Local, satellite, excisional biopsycc Observation
◊◊BCG, IFN, or IL-2 (all category 2B) disease by
and/or • Consider imagingi or
Local ablation therapy (category 2B) surgery
in-transit for baseline staging Interferon alfas
Topical imiquimod for superficial
recurrenceff (category 2B) (category 2B)
dermal lesions (category 2B)
• Recommend imagingi Imagingi
Consider RTx for unresectable If free of
Clinical trial
to evaluate specific to assess disease
disease (category 2B) or
signs or symptoms treatment by other
• Regional therapy options: Observation
ILI/ILP with melphalan response treatments
aSee Principles of Biopsy and Pathology (ME-A).
• Systemic therapybb
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck
CT with contrast if clinically indicated. Scans performed with contrast unless contraindicated.
sInterferon can be given as high-dose alfa interferon for one year or as peginterferon alfa-2b
bbSee Systemic Therapy for Metastatic or Unresectable Disease (ME-E 1 of 6).
for up to 5 years. Adjuvant interferon has been shown to improve DFS (category 1); but there ccInitial clinical recurrence should be confirmed pathologically whenever possible or if
is no impact on overall survival.
xSee Principles of Radiation Therapy for Melanoma (ME-D). clinically indicated. Obtain tissue for genetic analysis from either biopsy of the metastasis
zConsider sentinel node biopsy for resectable in-transit disease (preferred) or archival material if the patient is being considered for targeted therapy or if
(category 2B). Sentinel lymph nodes should be evaluated with multiple sectioning and the mutation status is relevant to eligibility for participation in a clinical trial.
eePersistent disease or true local scar recurrence is defined by presence of in situ and/or
immunohistochemistry.
aaT-VEC was associated with a response rate (lasting ≥6 months) of 16% in highly selected radial growth phase.
ffLocal, satellite recurrence without in situ or radial growth phase, with deep dermal or
patients with unresectable metastatic melanoma. Efficacy was noted in Stage IIIB, IIIC, and
Stage IV-M1a disease and was more likely in patients who subcutaneous fat recurrence within the melanoma scar or satellite metastasis adjacent
were treatment naive. to the melanoma scar.


Melanoma Discussion
WORKUP TREATMENT OF RECURRENCE ADJUVANT TREATMENT

Clinical trial
No previous Complete lymph or
dissection node dissectionjj Observation
or
• FNA preferred,
Interferon alfas
if feasible, or
or
core, incisional,
Complete High-dose ipilimumabt
or excisional
resection (category 2B)
biopsycc,ii
Nodal Excise recurrence; if or
• Recommend
recurrence previously incomplete Biochemotherapy
imagingi for
Resectable lymph node (category 2B)v
baseline staging
dissection, complete and/or
and to evaluate
lymph node dissection Consider RT to nodal
specific signs or
Incomplete basin in selected
symptoms
Previous Systemic therapy high-risk patients
resection
dissection (preferred)bb based on location,
Unresectable or size, and number of
iChest/abdominal/pelvic CT with contrast, brain MRI with or Clinical trial involved nodes, and/or
contrast, and/or FDG PET/CT. Neck CT with contrast if Systemic or macroscopic
clinically indicated. Scans performed with contrast unless Palliative RTx
contraindicated. Contrast not necessary for CT chest disease extranodal extensionw,x
screening for lung metastases. or (category 2B)
sInterferon can be given as high-dose alfa interferon for one year or as Intralesional injection with T-VECaa
peginterferon alfa-2b for up to 5 years. Adjuvant interferon has been shown to or
improve DFS (category 1); but there is no impact on overall survival.
tAdjuvant ipilimumab is associated with improvement in recurrence-free survival. Best supportive care (See NCCN
Its impact on overall survival has not been reported. The recommended dose Guidelines for Palliative Care)
of ipilimumab (10 mg/kg) was associated with adverse events which led to the
discontinuation of treatment in 52% of patients. There was a 1% drug-related
mortality rate.
vFor biochemotherapy, see Other Systemic Therapies (ME-E 2 of 6).
wAdjuvant nodal basin RT is associated with reduced lymph node field recurrence bbSee Systemic Therapy for Metastatic or Unresectable Disease (ME-E 1 of 6).
ccInitial clinical recurrence should be confirmed pathologically whenever possible
but has shown no improvement in relapse-free or overall survival, and its benefits
must be weighed against potential toxicities. or if clinically indicated. Obtain tissue for genetic analysis from either biopsy of the
xSee Principles of Radiation Therapy for Melanoma (ME-D). metastasis (preferred) or archival material if the patient is being considered for
aaT-VEC was associated with a response rate (lasting ≥6 months) of 16% in targeted therapy or if the mutation status is relevant to eligibility for participation in a
highly selected patients with unresectable metastatic melanoma. Efficacy was clinical trial.
iiBiopsy preferred if recurrence is unresectable.
noted in Stage IIIB, IIIC and Stage IV-M1a disease and was more likely in jjSee Principles of Complete Lymph Node Dissection (ME-C).
patients who were treatment naive.

Melanoma Discussion
WORKUP TREATMENT OF METASTATIC DISEASE

No evidence
of disease Clinical trial
Resect
Treat as disseminated or
Residual disease
pathway (below) Observation
(See Follow-up
Limited or No evidence on ME-8)
(Resectable) of disease
• FNA preferred, if Negative
initial resection is for
Observe Imagingi other Resect
planned. Biopsy
or to assess disease
(core, excisional Treat as
Systemic response or Residual disease
or incisional) Positive disseminated
therapybb progression
preferred if initial for pathway
Distant therapy is to be other (below)
metastatic systemiccc disease
Systemic therapy
disease • LDH
(preferred)bb
• Recommend
or
imagingi for
Clinical trial
baseline staging
or
and to evaluate Without brain Intralesional injection
specific signs and metastases with T-VECkk
symptoms
and/or
Disseminated Consider palliative
x
(Unresectable) Consider palliative resection and/or RT resection and/or RTx
With brain
for patients with brain metastases for symptomatic patients
metastases
(See NCCN Guidelines for CNS Cancers) or
iChest/abdominal/pelvic CT with contrast, brain MRI with contrast, and/or FDG PET/CT. Neck CT with contrast if clinically indicated. Scans Best supportive care
performed with contrast unless contraindicated. Contrast not necessary for CT chest screening for lung metastases. (See NCCN Guidelines
xSee Principles of Radiation Therapy for Melanoma (ME-D).
for Palliative Care)
bbSee Systemic Therapy for Metastatic or Unresectable Disease (ME-E 1 of 6).
ccInitial clinical recurrence should be confirmed pathologically whenever possible or if clinically indicated. Obtain tissue for genetic analysis from either biopsy of the
metastasis (preferred) or archival material if the patient is being considered for targeted therapy or if the mutation status is relevant to eligibility for participation in a clinical
trial.
kkT-VEC has shown a response rate (lasting ≥6 months) of 16% in highly selected patients with Stage IV-M1a disease (skin, subcutaneous, and/or remote nodes).


Melanoma Discussion
PRINCIPLES OF BIOPSY PRINCIPLES OF PATHOLOGY3,4

• Excisional biopsy (elliptical, punch, or saucerization) with 1–3 mm • Biopsy to be read by a pathologist experienced in pigmented lesions.
margins preferred. Avoid wider margins to permit accurate • Minimal elements to be reported should include Breslow thickness
subsequent lymphatic mapping. (mm), histologic ulceration (present or absent), dermal mitotic rate
• The orientation of the biopsy should be planned with definitive per mm2,5 Clark level (encouraged for lesions ≤1 mm, optional for
wide excision in mind (eg, parallel to lymphatics). lesions >1 mm), and peripheral and deep margin status of biopsy
• Full-thickness incisional or punch biopsy1 of clinically thickest (positive or negative).
portion of lesion acceptable, in certain anatomic areas • Microsatellitosis (present or absent)6
(eg, palm/sole, digit, face, ear) or for very large lesions. • Encourage consistent reporting of these additional factors
• Shave biopsy1,2 may compromise pathologic diagnosis and (compatible with American Academy of Dermatology
complete assessment of Breslow thickness, but is acceptable recommendations7):
when the index of suspicion is low. Location
Regression
Tumor-infiltrating lymphocytes (TILs)
Vertical growth phase (VGP)
Angiolymphatic invasion
Neurotropism
Histologic subtype
Pure desmoplasia, if present, or specify pure vs. mixed
desmoplastic with spindle cell and/or epithelioid cells
• Consider use of comparative genomic hybridization (CGH) or
1Ifclinical evaluation of incisional biopsy suggests that microstaging is fluorescence in situ hybridization (FISH) for histologically equivocal
inadequate, consider narrow margin excisional biopsy.
2For lentigo maligna melanoma in situ, a broad shave biopsy may help to lesions.8
optimize diagnostic sampling.
3While there is interest in newer prognostic molecular techniques such as gene
expression profiling to differentiate benign from malignant neoplasms, or 6Microsatellitosis

melanomas at low versus high risk for metastasis, routine (baseline) genetic is defined in the CAP 2013 melanoma protocol (version 3.3.0.0) as
“the presence of tumor nests greater than 0.05 mm in diameter, in the reticular dermis,
testing of primary cutaneous melanomas (before or following SLNB) is not
panniculus, or vessels beneath the principal invasive tumor but separated from it by at
recommended outside of a clinical study (trial). least 0.3 mm of normal tissue on the section in which the Breslow measurement was
4In the absence of metastatic disease, BRAF testing of the primary cutaneous
taken” (Harrist TJ, Rigel DS, Day CL Jr, et al. “Microscopic satellites” are more highly
melanoma is not recommended. associated with regional lymph node metastases than is primary melanoma thickness.
5Dermal mitotic rate should be determined using the “hot spot” technique and
Cancer 1984;53:2183-2187).
expressed as number of mitoses per square millimeter. (Piris A, Mihm Jr. MC, 7Bichakjian C,Halpern AC, et al. Guidelines of care for the management of primary
Duncan LM. AJCC melanoma staging update: impact on dermatopathology cutaneous melanoma. J Am Acad Dermatol 2011;65:1032-1047.
practice and patient management. J Cutan Pathol 2011;38:394-400). 8CGH may be more accurate than FISH in identifying relevant genetic mutations.

Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ME-A

Melanoma Discussion
PRINCIPLES OF SURGICAL MARGINS FOR

WIDE EXCISION OF PRIMARY MELANOMA
Tumor Thickness Recommended Clinical Margins2
In situ1 0.5–1.0 cm
≤1.0 mm 1.0 cm (category 1)
1.01–2 mm 1–2 cm (category 1)
2.01–4 mm 2.0 cm (category 1)
>4 mm 2.0 cm (category 1)
• Margins may be modified to accommodate individual anatomic or functional considerations.
1For large melanoma in situ (MIS), lentigo maligna type, surgical margins >0.5 cm may be necessary to achieve histologically negative margins; techniques for more
exhaustive histologic assessment of margins should be considered. For selected patients with positive margins after optimal surgery, consider topical imiquimod (for
patients with MIS) or RT (category 2B).
2Excision recommendations are based on measured clinical margins taken at the time of surgery and not gross or histologic margins, as measured by the pathologist
(category 1).

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Melanoma Discussion
PRINCIPLES OF COMPLETE LYMPH NODE DISSECTION
Adequacy of regional lymph node dissection:
• An anatomically complete dissection1 of involved nodal basin is required.

• In the groin, consider elective iliac and obturator lymph node dissection if clinically positive
inguinofemoral nodes or ≥3 inguinofemoral nodes are positive (category 2B).
• Iliac and obturator lymph node dissection is indicated if pelvic CT is positive (category 2A) or if Cloquet’s
node is positive (category 2B).
• For primary melanomas of the head and neck with clinically or microscopically positive lymph nodes in
the parotid gland, a superficial parotidectomy and appropriate neck dissection of the draining nodal
basins is recommended.
1Anatomic boundaries of lymph node dissection should be described in operative report.

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Melanoma Discussion
PRINCIPLES OF RADIATION THERAPY FOR MELANOMA

Consider RT in the following situations:1
PRIMARY DISEASE
• Adjuvant treatment in selected patients with factors including, but not limited to deep desmoplastic melanoma with narrow margins,
extensive neurotropism, or locally recurrent disease.
REGIONAL DISEASE2
• Adjuvant treatment in selected patients following resection of clinically appreciable nodes (category 2B)3 if
Extranodal tumor extension AND/OR
◊◊Parotid: ≥1 involved node, any size of involvement
◊◊Cervical: ≥2 involved nodes and/or ≥3 cm tumor within a node
◊◊Axillary: ≥2 involved nodes and/or ≥4 cm tumor within a node
◊◊Inguinal: ≥3 involved nodes and/or ≥4 cm tumor within a node
• Palliative
Unresectable nodal, satellite, or in-transit disease
METASTATIC DISEASE
• Brain metastases (See NCCN Guidelines for Central Nervous System Cancers)
Stereotactic radiosurgery either as adjuvant or primary treatment
Whole brain radiation therapy, either as adjuvant (category 2B) or primary treatment4
• Other symptomatic or potentially symptomatic soft tissue and/or bone metastases2
1Interactionsbetween radiation therapy and systemic therapies (eg, BRAF inhibitors, interferon alfa-2b, immunotherapies, checkpoint inhibitors) need to be very
carefully considered as there is potential for increased toxicity.
2A wide range of radiation dose/fractionation schedules is effective. Hypofractionated regimens may increase the risk for long-term complications.
3Adjuvant nodal basin RT is associated with reduced lymph node field recurrence but has shown no improvement in relapse-free or overall survival. Its benefits must be
weighed against potential toxicities.
4Adjuvant whole brain radiation following resected melanoma brain metastasis is controversial and should be considered on an individual patient basis.
Note: All recommendations are category 2A unless otherwise indicated. Continue

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Melanoma Discussion

(References)
Primary Disease
• Chen JY, Hruby G, Scolyer RA, et al. Desmoplastic neurotropic melanoma: a clinicopathologic analysis of 128 cases. Cancer 2008;113:2770-2778.
• Guadagnolo BA, Prieto V, Weber R, et al. The role of adjuvant radiotherapy in the local management of desmoplastic melanoma. Cancer.
2014;120:1361-1368.
• Hedblad MA, Mallbris L. Grenz ray treatment of lentigo maligna and early lentigo maligna melanoma. J Am Acad Dermatol 2012;67:60-68.
• Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer. 2014;120:1369-1378.
• Farshad A, Burg G, Panizzon R, et al. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of
radiotherapy using Grenz or soft X-rays. Br J Dermatol Jun 2002;146:1042-1046.
• Harwood AR. Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma. Int J Radiat Oncol Biol Phys
1983; 9:1019-21.
• Johanson CR, Harwood AR, Cummings BJ, Quirt I. 0-7-21 radiotherapy in nodular melanoma. Cancer 1983;51:226-232.
Regional Disease
• Agrawal S, Kane JM, 3rd, Guadagnolo BA, et al. The benefits of adjuvant radiation therapy after therapeutic lymphadenectomy for clinically advanced,
high-risk, lymph node-metastatic melanoma. Cancer 2009;115:5836-5844.
• Beadle BM, Guadagnolo BA, Ballo MT, et al. Radiation therapy field extent for adjuvant treatment of axillary metastases from malignant melanoma. Int J
Radiat Oncol Biol Phys 2009;73:1376-1382.
• Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after
therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol 2012;13:589-597.
• Chang DT, Amdur RJ, Morris CG, Mendenhall WM. Adjuvant radiotherapy for cutaneous melanoma: comparing hypofractionation to conventional
fractionation. Int J Radiat Oncol Biol Phys 2006;66:1051-1055.
• Lee RJ, Gibbs JF, Proulx GM, Kollmorgen DR, et al. Nodal basin recurrence following lymph node dissection for melanoma: implications for adjuvant
radiotherapy. Int J Radiat Oncol Biol Phys 2000;46:467-474.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Continue
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Melanoma Discussion

(References)
Metastatic Disease
• Atkins MB, Sosman JA, Agarwala S, et al. Temozolomide, thalidomide, and whole brain radiation therapy for patients with brain metastasis from
metastatic melanoma: a phase II Cytokine Working Group study. Cancer 2008;113: 2139-2145.
• Huguenin PU, Kieser S, Glanzmann C, et al. Radiotherapy for metastatic carcinomas of the kidney or melanomas: an analysis using palliative end
points. Int J Radiat Oncol Biol Phys 1998;41:401-405.
• Liew DN, Kano H, Kondziolka D, et al. Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article. J Neurosurg
2011;114:769-779.
• Olivier KR, Schild SE, Morris CG, et al. A higher radiotherapy dose is associated with more durable palliation and longer survival in patients with
metastatic melanoma. Cancer 2007;110:1791-1795.
• Overgaard J, von der Maase H, Overgaard M. A randomized study comparing two high-dose per fraction radiation schedules in recurrent or metastatic
malignant melanoma. Int J Radiat Oncol Biol Phys 1985;11:1837-1839.
• Sause WT, Cooper JS, Rush S, et al. Fraction size in external beam radiation therapy in the treatment of melanoma. Int J Radiat Oncol Biol Phys
1991;20:429-432.
• Anker CJ, Ribas A, Grossmann AH, et al. Severe liver and skin toxicity after radiation and vemurafenib in metastatic melanoma. J Clin Oncol
2013;31:e283-287.
• Peuvrel L, Ruellan AL, Thillays F, et al. Severe radiotherapy-induced extracutaneous toxicity under vemurafenib. Eur J Dermatol 2013;23:879.-881
• Fogarty G, Morton RL, Vardy J, et al. Whole brain radiotherapy after local treatment of brain metastases in melanoma patients--a randomised phase III
trial. BMC Cancer 2011;11:142.

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Melanoma Discussion
SYSTEMIC THERAPY FOR METASTATIC OR UNRESECTABLE DISEASE

FIRST-LINE PERFORMANCE SECOND-LINE OR
THERAPY1 STATUS (PS) SUBSEQUENT THERAPY5
• Anti PD-1 monotherapy
Pembrolizumab2
Nivolumab2
• Nivolumab/ipilimumab2,3
• Ipilimumab (category 1)2,6
• Immunotherapy • Targeted therapy if BRAF mutated
Anti PD-1 monotherapy Combination therapy (preferred)
◊◊Pembrolizumab 2 ◊◊Dabrafenib/trametinib2
PS 0–2 ◊◊Vemurafenib/cobimetinib2,4
◊◊Nivolumab
(category 1)2 Disease Single-agent therapy
Nivolumab/ipilimumab 2,3
progression ◊◊Vemurafenib2
• Targeted therapy if BRAF mutated; ◊◊Dabrafenib2
or
preferred if clinically needed for early • High-dose IL-27
Metastatic or Maximum • Biochemotherapy8
response clinical
unresectable (category 2B)
Combination therapy (preferred)
disease ◊◊Dabrafenib/trametinib 2 benefit • Cytotoxic agents8
(category 1) from BRAF • Imatinib for tumors with activating
◊◊Vemurafenib/cobimetinib 2,4 targeted mutations of C-KIT
(category 1) therapy • Clinical trial
Single-agent therapy
◊◊Vemurafenib (category 1)2 Consider best supportive care
◊◊Dabrafenib (category 1)2 PS 3–4 (See NCCN Guidelines for
• Clinical trial Palliative Care)
1The choice of a treatment is based on evaluation of the individual patient.
2See Management of Toxicities of Immunotherapy and Targeted Therapy
(ME-F)
3Nivolumab/ipilimumab combination therapy is associated with improved 5Consider second-line agents if not used first line and not of the same class.
relapse-free survival compared with single-agent nivolumab or ipilimumab, 6Re-induction with ipilimumab may be considered for select patients who experienced
at the expense of significantly increased toxicity. Compared to single-agent
therapy, the impact of nivolumab/ipilimumab combination therapy on overall no significant systemic toxicity during prior ipilimumab therapy and who relapse after
survival is not known. The phase III trial of nivolumab/ipilimumab versus initial clinical response or progress after stable disease >3 months.
7High-dose IL-2 should not be used for patients with inadequate organ reserve, poor
either nivolumab or ipilimumab monotherapy was conducted in previously
untreated patients with unresectable stage III or IV melanoma. performance status, or untreated or active brain metastases. For patients with small
4In previously untreated patients with unresectable Stage IIIC or Stage IV brain metastases and without significant peritumoral edema, IL-2 therapy may be
disease, the combination of vemurafenib/cobimetinib was associated with considered (category 2B). Therapy should be restricted to an institution with medical
improved PFS and response rate when compared to vemurafenib alone. The staff experienced in the administration and management of these regimens.
8For a list of cytotoxic regimens and biochemotherapy regimens, see (ME-E 2 of 6).
impact on overall survival compared to single-agent vemurafenib is unknown.
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Melanoma Discussion
OTHER SYSTEMIC THERAPIES
Cytotoxic Regimens for Metastatic Disease1

• Dacarbazine
• Temozolomide
• Paclitaxel
• Albumin-bound paclitaxel
• Carboplatin/paclitaxel
Biochemotherapy for Metastastic Disease1
• Dacarbazine or temozolomide, and cisplatin or
carboplatin, with or without vinblastine or nitrosourea,
and IL-2 and interferon alfa-2b (category 2B)
Biochemotherapy for Adjuvant Treatment of High-Risk Disease
• Dacarbazine, cisplatin, vinblastine, IL-2, and interferon alfa-2b
(category 2B)
1In general, options for front-line therapy for metastatic melanoma include immunotherapy or targeted therapy.

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Melanoma Discussion
SYSTEMIC THERAPY FOR METASTATIC OR UNRESECTABLE DISEASE (REFERENCES)
Immunotherapy
Pembrolizumab
• Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma
(KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16:908-918.
• Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015;372:2521-2532.
• Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced
melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014;384:1109-1117.
• Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. N Eng J Med 2013;369:134-144.
Nivolumab
• Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4
treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015;16:375-384.
• Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-330.
Ipilimumab
• Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol
2012;13:459-465.
• Weber JS, Kahler KC, Hauschild A. Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab. J Clin Oncol
2012;30:2691-7.
• Hodi FS, O’Day SJ, McDermott DF, Weber RW, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med
2010;363:711-723.
• Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med
2011;364:2517-2526.
Nivolumab/Ipilimumab
• Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med
2015;373:23-34.
• Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-
2017.

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Melanoma Discussion
Targeted Therapy (Combination Therapy)

Dabrafenib/Trametinib
• Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a
multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015; 386:444-451.
• Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med
2015;372:30-39.
• Johnson DB, Flaherty KT, Weber JS, et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant
melanoma experiencing progression with single-agent BRAF inhibitor. J Clin Oncol 2014;32:3697-3704
• Sanlorenzo M, Choudhry A, Vujic I, et al. Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF
monotherapy in melanoma. J Am Acad Dermatol 2014;71:1102-1109 e1101.
Vemurafenib/Cobimetinib
• Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014;371:1867-1876.
• Ribas A, Gonzalez R, Pavlick A, et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAF(V600)-mutated melanoma: a
phase 1b study. Lancet Oncol 2014;15:954-965.
• Pavlick AC, Ribas A, Gonzalez R, et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in
BRAF-mutant melanoma. ASCO Meeting Abstracts 2015;33:9020.
Targeted Therapy (Single-agent Therapy)

Vemurafenib
• Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366:707-
714.
• Chapman reference under Vemurafenib with: McArthur GA, Chapman PB, Robert C, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and
BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 2014;15:323-
332.
Dabrafenib
• Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-
MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:1087-1095.
• Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised
controlled trial. Lancet 2012;380:358-365.

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Melanoma Discussion

Targeted Therapy (Single-agent Therapy)
Imatinib for tumors with activating mutations of C-KIT
• Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral,
and chronically sun-damaged skin. J Clin Oncol 2013;31:3182-3190.
• Carvajal RD, Antonescu CR, Wolchok, JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;395:2327-2334.
High-dose IL-2
• Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose
bolus interleukin 2. JAMA 1994;271:907-913.
• Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients
treated between 1985 and 1993. J Clin Oncol 1999;17:2105-2116.
• Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term
survival update. Cancer J Sci Am 2000;6 Suppl 1:S11-14.
• Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer
Res 2008;14:5610-5618.

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Melanoma Discussion
OTHER SYSTEMIC THERAPIES (REFERENCES)

Cytotoxic Regimens for Metastatic Disease Biochemotherapy for Metastatic Disease
Dacarbazine Dacarbazine or temozolomide, and cisplatin or carboplatin, with or without
• Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy for vinblastine or nitrosourea, and IL-2 and interferon alfa-2b
metastatic melanoma: thirty-year experience overview. • Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with
J Exp Clin Cancer Res 2000;19:21-34. concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and
Temozolomide interleukin-2 for patients with metastatic melanoma. J Clin Oncol 1998;16:1752-
• Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of 1759.
temozolomide versus dacarbazine in the treatment of patients with advanced • Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus
metastatic malignant melanoma. J Clin Oncol 2000;18:158-166. chemotherapy for metastatic melanoma: results from a phase III randomized trial. J
Paclitaxel Clin Oncol 2002;20:2045-2052.
• Wiernik PH and Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst • O'Day SJ, Boasberg PD, Piro L, et al. Maintenance biotherapy for metastatic
Monogr 1993;15:185-187. melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor
Albumin-bound paclitaxel improves survival for patients responding to induction concurrent biochemotherapy.
• Hersh EM, O'Day SJ, Ribas A, et al. A phase 2 Clinical trial of nab-Paclitaxel Clin Cancer Res 2002;8:2775-2781.
in previously treated and chemotherapy-naïve patients with metastatic • Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy compared with
melanoma. Cancer 2010;116:155-163. biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18
• Kottschade LA, Suman VJ, Amatruda T, et al. A phase II trial of nab- trials involving 2,621 patients. J Clin Oncol 2007;25:5426-5434.
paclitaxel (ABI-007) and carboplatin in patients with unresectable stage iv • Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy
melanoma: a north central cancer treatment group study, N057E(1). Cancer with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with
2011;117:1704-1710. cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant
Paclitaxel/carboplatin melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J
• Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin Clin Oncol 2008;26:5748-5754.
as second-line therapy for patients with metastatic melanoma. Cancer
2006;106:375-382. Biochemotherapy for Adjuvant Treatment of High Risk Disease
• Agarwala SS, Keilholz U, Hogg D, et al. Randomized phase III study of Dacarbazine, cisplatin, vinblastine, IL-2, and interferon alfa-2b
paclitaxel plus carboplatin with or without sorafenib as second-line treatment • Flaherty LE, Othus M, Atkins MB, et al. Southwest Oncology Group S0008: a phase
in patients with advanced melanoma. J Clin Oncol (Meeting Abstracts). III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine,
2007;25(18_suppl):8510. plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup
• Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, study of cancer and leukemia Group B, Children's Oncology Group, Eastern
randomized, placebo-controlled study of sorafenib in combination with Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol
carboplatin and paclitaxel as second-line treatment in patients with 2014;32:3771-3778.
unresectable stage III or stage IV melanoma. J Clin Oncol 2009;27:2823-
2830.
• Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of E2603: A double-
blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P)
with or without sorafenib (S) in metastatic melanoma. J Clin Oncol (ASCO
Meeting Abstracts) 2010. 28:(suppl; abstr):8511.
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Melanoma Discussion
MANAGEMENT OF TOXICITIES ASSOCIATED WITH IMMUNOTHERAPY AND TARGETED THERAPY

Immunotherapy
• Anti-PD1 Agents (pembrolizumab or nivolumab)
Pembrolizumab and nivolumab may cause immune-mediated adverse reactions. Grade 3–4 toxicities are less common than with
ipilimumab, but require similar expertise in management. The most common adverse events (>20% of patients) include fatigue, rash,
pruritus, cough, diarrhea, decreased appetite, constipation, and arthralgia. Depending on the severity of the reaction, pembrolizumab and
nivolumab should be discontinued.
For moderate to severe immune-mediated pneumonitis, colitis, hepatitis, hypophysitis, nephritis, and hyperthyroidism, anti-PD1 therapy
should be discontinued and systemic steroids should be administered.
Immune-mediated dermatitis sometimes responds to topical corticosteroids. For patients who do not respond, consider referral to a
dermatologist or provider experienced in the diagnosis and management of cutaneous manifestations of immunotherapy.
Infliximab 5 mg/kg is preferred for treatment of severe immune-related colitis that does not respond promptly (within 1 week) to therapy
with high-dose steroids. A single dose of infliximab is sufficient to resolve immune-related colitis in most patients.
For patients with preexistent hypophysitis due to ipilimumab, pembrolizumab may be administered if patients are on appropriate
physiologic replacement endocrine therapy.
For more information on toxicities associated with pembrolizumab and nivolumab and the management of these toxicities, see the full
prescribing information (www.fda.gov).
• Ipilimumab
Ipilimumab has the potential for significant immune-mediated complications. Although no longer required by the FDA, the Risk Evaluation
and Mitigation Strategy program and/or experience in use of the drug as well as resources to follow the patient closely are essential
for safe use of ipilimumab. Patient management information may be viewed at (http://www.fda.gov/downloads/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/UCM249435.pdf). For more information and specific wording of the black box
warning, see the full prescribing information (www.fda.gov)
For moderate to severe immune-mediated toxicity, ipilimumab should be discontinued and systemic steroids should be administered. See
the prescribing information (www.fda.gov)
Immune-mediated dermatitis sometimes responds to topical corticosteroids. For patients who do not respond, consider referral to a
dermatologist or provider experienced in the diagnosis and management of cutaneous manifestations of immunotherapy.
Infliximab 5 mg/kg is preferred for treatment of severe immune-related colitis that does not respond promptly (within 1 week) to therapy
with high-dose steroids. A single dose of infliximab is sufficient to resolve immune-related colitis in most patients.
For severe hepatotoxicity refractory to high-dose steroids, mycophenolate is preferred over infliximab as second-line therapy.
Ipilimumab should be used with extreme caution, if at all, in patients with serious underlying autoimmune disorders.
• Combination Therapy
Clinically significant (grade 3 and 4) immune-related adverse events are seen more commonly with nivolumab/ipilimumab combination
therapy compared to ipilimumab or nivolumab monotherapy. This emphasizes the need for careful patient education, selection, and
monitoring.
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Melanoma Discussion
MANAGEMENT OF TOXICITIES ASSOCIATED WITH IMMUNOTHERAPY AND TARGETED THERAPY
Targeted Therapy (BRAF or combined BRAF/MEK inhibitors)

• Dermatologic: Regular dermatologic evaluation and referral to a dermatologist or provider experienced in the diagnosis and management of
cutaneous manifestations of targeted therapy is recommended. BRAF inhibitors are associated with cutaneous squamous cell carcinoma,
extreme photosensitivity, and other dermatologic toxicities, which occur much less often with concurrent MEK inhibitors.
• Pyrexia: Pyrexia (defined as a temperature of 38.5 °C or greater) is a common (~55%) side effect of combining BRAF and MEK inhibitors
and occurs less frequently with BRAF monotherapy (~20%). The pyrexia is episodic, and onset is often 2 to 4 weeks following the start of
therapy with a median duration of 9 days. Pyrexia may be associated with chills, night sweats, rash, dehydration, electrolyte abnormalities,
and hypotension. Stopping or holding dabrafenib and trametinib at the onset of pyrexia will often interrupt the episode, and treatment
can be resumed with full-dose dabrafenib and trametinib upon cessation of pyrexia and pyrexia-related symptoms. Upon re-exposure to
dabrafenib and trametinib, repeat pyrexia events can occur, but grade >3 events are uncommon (21%). In occasional instances of prolonged
or severe pyrexia not responsive to discontinuation of dabrafenib and trametinib, low-dose steroids (prednisone 10 mg/day) can be used.
Patients with pyrexia should be advised to use antipyretics as needed and increase fluid intake.
• For more information on toxicities associated with dabrafenib with or without trametinib, or vemurafenib with or without cobimetinib, and
for the management of these toxicities, see the full prescribing information (www.fda.gov).

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NCCN Guidelines Version 3.2016 Staging NCCN Guidelines Index

Melanoma Discussion
Table 1 Regional Lymph Nodes (N)

American Joint Committee on Cancer (AJCC) NX
Patients in whom the regional lymph nodes cannot be assessed
TNM Staging System for Melanoma (7th ed., 2010) (eg, previously removed for another reason)
Primary Tumor (T) N0 No regional metastases detected
TX
Primary tumor cannot be assessed (eg, curettaged or severely N1-3 R
egional metastases based upon the number of metastatic
regressed melanoma) nodes and presence or absence of intralymphatic metastases
T0 No evidence of primary tumor (in transit or satellite metastases)
Tis Melanoma in situ Note: N1-3 and a-c sub categories are assigned as shown below:
T1 Melanomas 1.0 mm or less in thickness N Classification No. of Metastatic Nodes Nodal Metastatic Mass
T2 Melanomas 1.01–2.0 mm N1 1 node a: micrometastasis*

b: macrometastasis**
T3 Melanomas 2.01–4.0 mm
N2 2–3 nodes a: micrometastasis*
T4 Melanomas more than 4.0 mm b: macrometastasis**
Note: a and b sub categories of T are assigned based on ulceration and c: in transit met(s)/
number of mitoses per mm2 as shown below: satellite(s) without
metastatic nodes
T classification Thickness (mm) Ulceration Status/Mitoses
N3 4 or more metastatic nodes,
T1 ≤1.0 a: w/o ulceration and or matted nodes, or in transit
mitosis <1/mm2 met(s)/satellite(s) with meta-
b: with ulceration or static node(s)
mitoses ≥1/mm2
T2 1.01–2.0
a: w/o ulceration *Micrometastases are diagnosed after sentinel lymph node biopsy and
b: with ulceration completion lymphadenectomy (if performed).
T3 2.01–4.0
a: w/o ulceration **Macrometastases are defined as clinically detectable nodal metastases
b: with ulceration confirmed by therapeutic lymphadenectomy or when nodal metastasis
exhibits gross extracapsular extension.
T4 >4.0
a: w/o ulceration
b: with ulceration
Continue
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC
Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media, LLC (SBM). (For complete information and data supporting the
staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this
information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-1
NCCN Guidelines Version 3.2016 Staging NCCN Guidelines Index

Melanoma Discussion
Distant Metastasis (M) Pathologic Staging**

M0 No detectable evidence of distant metastases Stage 0 Tis N0 M0
M1a Metastases to skin, subcutaneous, or distant lymph nodes Stage IA T1a N0 M0
M1b Metastases to lung Stage IB T1b N0 M0
M1c Metastases to all other visceral sites or distant metastases to T2a N0 M0
any site combined with an elevated serum LDH Stage IIA T2b N0 M0
T3a N0 M0
Note: Serum LDH is incorporated into the M category as shown below: Stage IIB T3b N0 M0
M Classification Site Serum LDH T4a N0 M0
M1a Distant skin, subcutaneous, Normal Stage IIC T4b N0 M0
or nodal mets Stage IIIA T(1–4)a N1a M0
T(1–4)a N2a M0
M1b Lung metastases Normal Stage IIIB T(1–4)b N1a M0
T(1–4)b N2a M0
M1c All other visceral Normal T(1–4)a N1b M0
metastases T(1–4)a N2b M0
Any distant metastasis Elevated T(1–4)a N2c M0
Stage IIIC T(1–4)b N1b M0
Anatomic Stage/Prognostic Groups T(1–4)b N2b M0
T(1–4)b N2c M0
Clinical Staging*
Any T N3 M0
Stage 0 Tis N0 M0 Stage IV Any T Any N M1
Stage IA T1a N0 M0
Stage IB T1b N0 M0 **Pathologic staging includes microstaging of the primary melanoma and
T2a N0 M0 pathologic information about the regional lymph nodes after partial or
Stage IIA T2b N0 M0 complete lymphadenectomy. Pathologic Stage 0 or Stage IA patients are
T3a N0 M0 the exception; they do not require pathologic evaluation of their lymph
Stage IIB T3b N0 M0 nodes.
T4a N0 M0 Used with the permission of the American Joint Committee on Cancer (AJCC),
Stage IIC T4b N0 M0 Chicago, Illinois. The original and primary source for this information is the
Stage III AnyT ≥N1 M0 AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer
Stage IV Any T Any N M1 Science+Business Media, LLC (SBM). (For complete information and data
supporting the staging tables, visit www.springer.com.) Any citation or quotation
*Clinical staging includes microstaging of the primary melanoma and of this material must be credited to the AJCC as its primary source. The
clinical/radiologic evaluation for metastases. By convention, it should be inclusion of this information herein does not authorize any reuse or further
used after complete excision of the primary melanoma with clinical distribution without the expressed, written permission of Springer SBM, on
assessment for regional and distant metastases. behalf of the AJCC.
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. ST-2

Melanoma Discussion
Discussion Completion Lymph Node Dissection After Positive SLNB ........ MS-18
Therapeutic Lymph Node Dissection ....................................... MS-20
Palliative Lymph Node Dissection ........................................... MS-20
NCCN Categories of Evidence and Consensus Elective Pelvic Lymph Node Dissection ................................... MS-20
Morbidity of Lymph Node Dissection ....................................... MS-21
Category 1: Based upon high-level evidence, there is uniform NCCN
Technical Aspects of Lymph Node Dissection ......................... MS-21
consensus that the intervention is appropriate. NCCN Recommendations ....................................................... MS-21
Adjuvant Systemic Therapy for Melanoma .................................. MS-22
Category 2A: Based upon lower-level evidence, there is uniform
Low-Dose and Intermediate-Dose Interferon ........................... MS-22
NCCN consensus that the intervention is appropriate. High-Dose Interferon and Pegylated Interferon ....................... MS-24
Biochemotherapy .................................................................... MS-25
Category 2B: Based upon lower-level evidence, there is NCCN
High-dose Ipilimumab .............................................................. MS-26
consensus that the intervention is appropriate. NCCN Recommendations ....................................................... MS-26
Adjuvant Radiation Therapy ........................................................ MS-27
Category 3: Based upon any level of evidence, there is major NCCN
Adjuvant Radiation for Desmoplastic Neurotropic Melanoma .. MS-27
disagreement that the intervention is appropriate. Adjuvant Radiation for Preventing Nodal Relapse ................... MS-28
Adjuvant Radiation for Brain Metastases ................................. MS-29
All recommendations are category 2A unless otherwise noted.
NCCN Recommendations ....................................................... MS-29
Treatment for Stage III In-transit Disease ................................... MS-30
Local Therapy ......................................................................... MS-30
Table of Contents Regional Therapy: Isolated Limb Perfusion and Infusion ......... MS-33
Overview....................................................................................... MS-2 NCCN Recommendations ....................................................... MS-34
Delivery of High-Quality Cancer Care ........................................ MS-3 Treatment for Distant Metastatic Disease (Stage IV) .................. MS-35
Clinical Presentation and Preliminary Workup .............................. MS-4 Systemic Therapy for Advanced Melanoma ............................ MS-35
Biopsy: NCCN Recommendations ............................................. MS-4 Palliative Radiation Therapy .................................................... MS-54
Diagnosis, Prognostic Factors, and Clinical Staging .................. MS-4 NCCN Recommendations ....................................................... MS-55
Pathology Report: NCCN Recommendations ............................ MS-7 Follow-up .................................................................................... MS-61
Preliminary Workup: NCCN Recommendations ......................... MS-7 Surveillance Modalities ............................................................ MS-61
Further Workup and Pathologic Staging ....................................... MS-8 Patterns of Recurrence ........................................................... MS-62
Laboratory Tests and Imaging ................................................... MS-8 Risk of Developing a Second Primary Melanoma .................... MS-63
Sentinel Lymph Node Biopsy..................................................... MS-9 Long-term Impact of Surveillance ............................................ MS-63
Biopsy of Palpable Lymph Nodes ............................................ MS-14 Patient Education .................................................................... MS-64
NCCN Recommendations ....................................................... MS-14 NCCN Recommendations ....................................................... MS-64
Treatment of Primary Melanoma ................................................. MS-16 Treatment of Recurrence ............................................................ MS-66
Wide Excision .......................................................................... MS-16 NCCN Recommendations ....................................................... MS-66
Alternatives to Excision: Topical Imiquimod or Radiation ......... MS-17 Summary .................................................................................... MS-68
NCCN Recommendations ....................................................... MS-18 References ................................................................................. MS-69
Lymph Node Dissection .............................................................. MS-18
Version 3.2016, 07/07/16 © National Comprehensive Cancer Network, Inc. 2016, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®. MS-1

Melanoma Discussion
Overview 84% of patients with melanoma initially present with localized disease,
In 2016, an estimated 76,380 patients will be diagnosed with and about 9% with regional disease, and 4% with distant metastatic disease.15 In
10,130 patients will die of melanoma in the United States.1 However, general, the prognosis is excellent for patients who present with
these figures for new cases may represent a substantial underestimate, localized disease and primary tumors 1.0 mm or less in thickness, with
as many superficial and in situ melanomas treated in the outpatient 5-year survival achieved in more than 90% of patients.14 For patients
setting are not reported. The incidence of melanoma continues to with localized melanomas more than 1.0 mm in thickness, survival rates
increase dramatically, at an overall rate of 33% for men and 23% range from 50% to 90%, depending on tumor thickness, ulceration, and
women from 2002 to 2006.2 Melanoma is increasing in men more mitotic rate.14 The likelihood of regional nodal involvement increases
rapidly than any other malignancy, and in women more rapidly than any with increasing tumor thickness, as well as the presence of ulceration
other malignancy except lung cancer.3 Based on data from 2009 to and mitotic rate.16-19 When regional nodes are involved, survival rates
2011, the lifetime risk of developing cutaneous melanoma is 1 in 34 for are roughly halved. However, within stage III, 5-year survival rates
women and 1 in 53 for men.1 The median age at diagnosis is 59 years. range from 20% to 70%, depending primarily on the nodal tumor
On average, an individual loses 20.4 years of potential life as a result of burden.14 Historically, long-term survival in patients with distant
melanoma mortality compared to 16.6 years for all malignancies.4 metastatic melanoma, taken as a whole, has been less than 10%.
However, even within stage IV, some patients have a more indolent
Risk factors for melanoma include skin type, personal history of prior clinical course that is biologically quite distinct from most patients with
melanoma, multiple clinically atypical moles or dysplastic nevi, a advanced disease. Furthermore the impact of emerging effective
positive family history of melanoma,5-8 and rarely, inherited genetic systemic therapies on the survival of patients with stage IV melanoma,
mutations. Genetic counseling could be considered for individuals with a either at presentation or recurrence, has made long-term remission
strong family history of invasive melanoma with or without pancreatic possible for a larger proportion of patients.
cancer. In addition to genetic factors, environmental factors including
excess sun exposure and UV-based artificial tanning contribute to the There is increasing appreciation of the variations in specific genetic
development of melanoma.9-11 The interaction between genetic alterations among distinct clinical subtypes of melanoma. The currently
susceptibility and environmental exposure is illustrated in individuals described clinical subtypes of cutaneous melanoma are: non-chronic
with an inability to tan and fair skin that sunburns easily who have a sun damage (non-CSD): melanomas on skin without chronic sun-
greater risk of developing melanoma.12,13 However, melanoma can induced damage; CSD: melanomas on skin with chronic sun-induced
occur in any ethnic group and also in areas of the body without damage signified by the presence of marked solar elastosis; and acral:
substantial sun exposure. melanomas on the soles, palms, or sub-ungual sites. Melanocytes exist
outside of the skin as well, and can give rise to non-cutaneous
As with nearly all malignancies, the outcome of melanoma depends on melanomas on mucosal membranes, the uveal tract of the eye, or
the stage at presentation.14 In the United States, it is estimated that leptomeninges.20 Mucosal melanomas most often occur in the head and

Melanoma Discussion
neck sinuses and oral cavity, anorectum, vulva, and vagina, but can initial diagnostic workup and treatment of mucosal melanoma of the
arise in any of the mucosal membranes lining the gastrointestinal and head and neck can be found in the NCCN Guidelines for Head and
urogenital tracts.21 Neck Cancers. For systemic therapy of stage IVB or IVC mucosal
melanoma of the head or neck, however, the NCCN Guidelines for
Different subtypes of melanoma have been found to have very different Head and Neck Cancers points to the NCCN Guidelines for Melanoma
genetic profiles, some of which have different therapeutic implications. recommendations for systemic therapy for metastatic or unresectable
In an analysis of 102 primary melanomas, the non-CSD subtype was disease. The NCCN Guidelines currently do not include
found to have the highest proportion of BRAF mutations (56%) recommendations for initial diagnosis and treatment of early-stage uveal
compared to CSD, acral, and mucosal subtypes (6%, 21%, and 3%, melanoma or anogenital mucosal melanoma.
respectively).22 On the other hand, incidence of KIT aberrations was
28%, 36%, and 39% in CSD, acral, and mucosal subtypes, respectively, Delivery of High-Quality Cancer Care
but 0% in non-CSD subtypes. NRAS mutations were found in 5% to A key component to delivery of high-quality cancer care is discussing
20% of the subtypes. with patients their options for diagnostic workup, treatment, and follow-
up.26 The goal of these conversations should be two-fold: 1) capturing
By definition, the National Comprehensive Cancer Network (NCCN)
all the case-specific information that should be considered when
practice guidelines cannot incorporate all possible clinical variations and
evaluating options, and 2) ensuring that the patient understands all the
are not intended to replace good clinical judgment or individualization of
potential benefits and risks associated with different clinical approaches
treatments. Exceptions to the rule were discussed among the panel
so they can make informed decisions. Adherence to the guidelines does
members while developing these guidelines. A 5% rule (omitting
not mean limiting decisions about patient care exclusively to NCCN-
specific recommendations for clinical scenarios that comprise less than
recommended guidelines, but that all the recommended options are
5% of all cases) was used to eliminate uncommon clinical occurrences
discussed with the patients. The clinical team should document the
or conditions from these guidelines. The NCCN Melanoma Panel
rationale for the clinical approach selected. An essential feature of high-
strongly supports early diagnosis and appropriate treatment of
quality care is that clinical decisions are informed by a variety of case-
melanoma, including participation in clinical trials where available.
specific factors (eg, patient characteristics and preferences, disease
Mucosal and uveal melanomas differ significantly from cutaneous characteristics, medical history), such that for some patients the best
melanoma in presentation, genetic profile, staging, response to clinical approach may not be an option listed in the guidelines. The
treatment, and patterns of progression.23-25 Ideally, mucosal and uveal guidelines include language such as “discuss and consider” and
melanoma should be treated as diseases distinct from cutaneous “consider and offer” to indicate situations in which conversations with
melanoma, with care tailored to the individual. The NCCN Guidelines for the patient are especially important because the optimal option is not
Melanoma do not include recommendations for the diagnostic workup clear (eg, insufficient clinical data) and/or strongly depends on case-
or treatment of early-stage mucosal or uveal melanoma. Guidelines for specific factors (eg, data show that the approach is beneficial only to a

Melanoma Discussion
subset of patients with specific features). Whereas “discuss and diagnosed by shave biopsy during screening in a dermatologist office,
consider” indicates that the recommended option may be beneficial for and that any diagnosis is better than none even if microstaging may not
some patients, “consider and offer” indicates that the recommended be complete.
approach is likely beneficial for most patients.
Diagnosis, Prognostic Factors, and Clinical Staging
Clinical Presentation and Preliminary Workup In general, cutaneous melanomas are categorized as follows: localized
Biopsy: NCCN Recommendations disease with no evidence of metastases (stage I–II), regional disease
Patients presenting with a suspicious pigmented lesion optimally should (stage III), and distant metastatic disease (stage IV). The AJCC
undergo an excisional biopsy (elliptical, punch or saucerization), analyzed 38,918 patients to determine factors significantly predictive of
preferably with 1- to 3-mm negative margins. The orientation of the survival for patients with cutaneous melanomas.14,27-29 This and other
excisional biopsy should always be planned with definitive treatment in studies have shown that in addition to patient-specific factors of age and
mind (eg, a longitudinal orientation in the extremities, parallel to gender, tumor-specific factors of Breslow tumor thickness, ulceration,
lymphatics). With the increasing use of lymphatic mapping and sentinel and mitotic rate were found to be the three most important
node biopsy, biopsies should also be planned so as not to interfere with characteristics independently predictive of outcome by multivariate
this procedure. In this regard, wider margins for the initial diagnostic analysis.14,28-34
procedure should be avoided.
Mitotic rate is an indicator of tumor proliferation and is measured as the
Excisional biopsy may be inappropriate for certain sites (including the number of mitoses per mm2. The latest AJCC Staging Manual
face, palmar surface of the hand, sole of the foot, ear, distal digit, or recommended the “hot spot” technique for calculating the mitotic
subungual lesions) or for very large lesions. In these instances, a rate.27,35 Several other studies have also confirmed the prognostic
full-thickness incisional or punch biopsy of the clinically thickest portion importance of mitotic rate in patients with primary cutaneous
of the lesion is an acceptable option. These procedures should provide melanoma.28-33,36-40 In the evidence-based derivation of the 2010 AJCC
accurate primary tumor microstaging, without interfering with definitive staging system, mitotic rate greater than or equal to 1 per mm2 was
local therapy. If the initial biopsy is inadequate to make a diagnosis or to independently associated with worse disease-specific survival (DSS),
accurately microstage the tumor (based on evaluation by a especially in patients with melanoma less than or equal to 1.0 mm
dermatopathologist) for treatment planning, re-biopsy with narrow thick.14 As such, mitotic rate has replaced Clark level as a criterion for
margin excision should be considered. Shave biopsy may compromise upstaging patients with melanomas less than or equal to 1.0 mm in
pathologic diagnosis and complete assessment of Breslow thickness. thickness from IA to IB.
However, it is acceptable in a low suspicion setting. For example, a
Reporting detection of microscopic satellites in the initial biopsy or wide
broad shave biopsy may help to optimize accurate diagnosis of lentigo
excision specimen is also important for AJCC staging, as this defines at
maligna. Panelists recognized that melanomas are commonly
least N2c, stage IIIB disease. The 2013 College of American

Melanoma Discussion
Pathologists have defined a microsatellite as the presence of tumor selected gene mutations for histologically equivocal lesions. CGH is a
nests greater than 0.05 mm in diameter, in the reticular dermis, more comprehensive technique than FISH that may offer higher
panniculus, or vessels beneath the principal invasive tumor but sensitivity and specificity in identifying relevant copy number changes,
separated from it by at least 0.3 mm of normal tissue on the section in as suggested by a small study on atypical Spitz tumors.47
which the Breslow measurement was taken.41,42 It is usually not
possible to detect microscopic satellites with less than a complete In addition to CGH and FISH, a number of diagnostic or prognostic
excisional biopsy. genetic tests for melanoma are in development.48-52 One of these
commercially available gene expression profiling tests was developed
The American Academy of Dermatology (AAD) Task Force to help predict the biologic behavior of atypical melanocytic lesions
recommends the inclusion of additional factors such as vertical growth with indeterminate histopathology (eg, melanocytic or Spitz tumors of
phase (VGP), tumor-infiltrating lymphocytes (TIL), and regression in the uncertain malignant potential).50 Although there is a tremendous
report.43,44 These factors are less consistently independently predictive clinical need for this technology, the challenges of developing a truly
of outcome.31,32,45,46 discriminant test are substantial. Even in the presence of sentinel
lymph node metastasis these indeterminate neoplasms can
The AAD also recommends that pathologists should note cases of pure demonstrate a strikingly benign biologic behavior, making it
desmoplastic melanoma (as opposed to the presence of desmoplasia exceedingly difficult to define a true positive (fully malignant lesion).53-
admixed with spindle cell and/or epithelioid cells) as this may impact 58 Furthermore, as the very few events in this low-risk group tend to be
decisions about further diagnostics and treatment.43 late, long-term follow-up is required to validate the prognostic
significance of this test.
Some melanocytic proliferations can be diagnostically challenging.
Examples include atypical melanocytic proliferation, melanocytic tumor Another currently commercially available gene expression profiling test
of uncertain malignant potential, superficial melanocytic tumor of is being marketed to supplement prognostic information derived from
uncertain significance, atypical Spitz tumor, and atypical cellular blue the primary tumor and sentinel lymph nodes.48,49 This technique was
nevus. These lesions are more frequently seen in younger patients, and developed to discriminate patients at low risk versus high risk for
when suspected, referral to a pathologist with expertise in atypical metastatic disease based on the differential expression of 28 genes.
melanocytic lesions is recommended. In cases where melanoma is The gene set was developed from a relatively high-risk training set of
included in the differential diagnosis, the pathology report should patients and tested in a different relatively high-risk validation set of
include prognostic elements as for melanoma. patients. This gene expression profile has been validated as
independently predictive of outcome when compared to AJCC stage or
Molecular Characterization of the Primary Tumor
sentinel lymph node status.48,49 This test has not been directly
Comparative genomic hybridization (CGH) or fluorescence in situ
evaluated in the context of all known prognostic characteristics of
hybridization (FISH) may be helpful in detecting the presence of
localized melanoma.59 Furthermore, its independent prognostic value

Melanoma Discussion
has yet to be confirmed in a large population of patients with average- In-transit metastasis is defined as intralymphatic tumor in skin or
to low-risk melanoma. subcutaneous tissue more than 2 cm from the primary tumor but not
beyond the nearest regional lymph node basin.41 The presence of
Gene expression profiling for melanoma could be an enormously microsatellites, clinically evident satellites, and/or regional intransit
valuable contribution to understanding the biology of the disease. disease is all part of the biologic continuum of regional lymphatic
However, the difficulty of embracing gene expression profiling as an involvement, and these are all associated with a prognosis similar to
independent predictor of outcome is illustrated by the inconsistency of that of patients with clinically positive nodes. This is recognized in the
results across studies aimed at defining the most predictive gene sets staging system with the designation of stage IIIC.
for melanoma.49,51,60-62 Comparison of the gene signatures identified in
these studies show minimal overlap in specific genes thought to be Clinical Characterization of Metastatic Disease
predictive of outcome. The identification and validation of a prognostic Among patients with distant metastatic melanoma (stage IV), the site of
gene expression profile is a complicated multi-step and often multi- metastases is the most significant predictor of outcome. The three risk
study process, and there are many ways in which specifics of study categories recognized by the AJCC are skin, soft tissue, and remote
design and methodology can impact the end result.63-66 The lack of nodes (M1a); visceral-pulmonary (M1b); and visceral-nonpulmonary
overlap in gene signatures identified as prognostic for melanoma is (M1c).14,27 Elevated lactate dehydrogenase (LDH), likely a surrogate for
likely due to substantial differences in study design and methodology. overall tumor burden, is also an independent predictor of poor outcome
Efforts to develop gene expression profiling prognostic assays for in patients with stage IV disease and has been incorporated into the
other types of cancer have also resulted in limited or partial overlap in AJCC staging system; patients with distant metastases to any site and
the “gene signature” identified by different studies.67-70 elevated LDH are in the highest risk category (M1c).71,87,88 The
prognosis for patients with metastatic melanoma has dramatically
Pathology of Nodal and Regional Disease improved with the emergence of several effective systemic therapies
Among patients with nodal metastases (stage III), the clinical nodal associated with improved overall survival (OS) and long-term survival in
status (nonpalpable vs. palpable) and the number of metastatic nodes some patients (See Systemic Therapy for Advanced Melanoma). It is
are the most important predictors of survival.71,72 The AJCC staging unclear whether the factors prognostic for outcome will also change.
system has recognized this difference in prognosis among patients with
pathologic stage III melanoma.14 For patients with a positive sentinel Molecular Characterization of Metastatic Disease
lymph node, prognostic factors include number of positive nodes, tumor Several targeted therapies have been developed for patients with
burden in the sentinel node, primary tumor thickness, mitotic rate and melanoma harboring specific mutations (See Systemic Therapy for
ulceration, and patient age.28,73-80 For patients with clinically positive Advanced Melanoma, sub-sections BRAF-targeted Therapies and
nodes, prognostic factors include number of positive nodes, extranodal Other Targeted Therapies). Patients with metastatic melanoma with
extension, primary tumor ulceration, and patient age.28,81-86 activating mutations of BRAF, an intracellular signaling kinase in the
mitogen activated protein kinase (MAPK) pathway,89-91 have been

Melanoma Discussion
shown to be likely to respond to BRAF inhibitors.92-95 Likewise, patients mutations for histologically equivocal lesions. While there is interest in
with metastatic melanoma with activating mutations in KIT, a receptor newer prognostic molecular techniques such as gene expression
tyrosine kinase, have been shown to be more likely to respond to profiling to help differentiate benign from malignant neoplasms, or to
imatinib, a tyrosine kinase inhibitor, compared with patients without help distinguish melanomas at low- versus high-risk for metastasis,
activating KIT mutations.96-98 A number of tests have been developed routine (baseline) genetic testing of primary cutaneous melanomas
for detecting BRAF and KIT mutations common in metastatic (before or following sentinel lymph node biopsy [SLNB]) is not
melanoma. The sensitivity and accuracy of these tests vary, and recommended outside of a clinical study.
improved assays are in development.99-110 For both BRAF and KIT
mutations, studies have investigated the intra- and inter-tumoral For stage III patients, the NCCN Melanoma Panel recommends
homogeneity, and found that mutation status can change during reporting the number of positive nodes, the total number of nodes
disease progression, such that recurrences or metastases may have examined, and the presence or absence of extranodal tumor extension.
mutations not present in the primary tumor.111-115 Pathologists are now In addition, the panel recommends recording the size and location of
strongly encouraged to test for and report the presence or absence tumor present in a positive sentinel node.
gene mutations (BRAF, KIT) that may impact treatment options in
For stage IV patients, the clinician is responsible for reporting the
patients with metastatic melanoma.
number and sites of metastatic disease. In addition to histologic
Pathology Report: NCCN Recommendations confirmation of metastatic disease whenever possible, pathologists are
now strongly encouraged to test for and report the presence or absence
For the pathology report, the NCCN Melanoma Panel recommends at a
of gene mutations (BRAF, KIT) that may impact treatment options in
minimum the inclusion of Breslow thickness, ulceration status, mitotic
patients with metastatic melanoma. Because these inhibitors of BRAF
rate (#/mm2), deep and peripheral margin status (positive or negative),
or KIT are recommended only for patients with advanced disease,
presence or absence of microsatellites, pure desmoplasia if present,
BRAF and c-KIT mutational analyses are clinically useful only for
and Clark level for nonulcerated lesions 1.0 mm or less where mitotic
patients with advanced disease considering these molecular targeted
rate is not determined. Ideally, mitotic rate should be reported for all
therapies. In the absence of metastatic disease, testing of the primary
lesions, as it is emerging as an independent predictor of outcome.
cutaneous melanoma for BRAF mutation is not recommended.
When pure desmoplastic melanoma is suspected, multidisciplinary
consultation including an experienced dermatopathologist is Preliminary Workup: NCCN Recommendations
recommended for determining staging and treatment options.
After the diagnosis of cutaneous melanoma has been confirmed,
The panel agreed that recording of additional parameters identified by detailed personal and family history, including any personal history of
the AAD task force would be helpful, but not mandatory. CGH or FISH prior melanoma or dysplastic nevi, should be obtained. In the physical
should be considered to detect the presence of selected gene examination of patients with invasive melanoma, physicians should pay
special attention to the locoregional area and lymph node drainage

Melanoma Discussion
basin(s) of the established melanoma. A complete dermatologic  Stage III with clinically detected (palpable) positive nodes,
examination is recommended for all patients with newly-diagnosed microscopic satellitosis (from assessment of the primary lesion),
melanoma. and/or in-transit disease
 Stage IV (distant metastatic disease)
Patients can be clinically staged after histopathologic microstaging of
the primary tumor, and a complete history and physical examination Further Workup and Pathologic Staging
(H&P) as described above. Patients are staged according to the AJCC
Laboratory Tests and Imaging
criteria. Patients with in-situ melanoma are stage 0. Patients with
invasive (not in-situ) melanoma and clinically negative nodes are stage There are several reasons to embark on a further imaging and
I-II. The NCCN Guidelines have further stratified clinical stage I patients diagnostic workup to determine the extent of disease in the melanoma
into three groups based on risk of lymph node involvement. patient. One is to establish a set of baseline images against which to
compare future studies in a patient at risk for relapse. Another is to
Patients with palpable regional nodes, as well as those with in-transit detect clinically occult disease that would affect immediate treatment
disease or microsatellites are clinical stage III. decisions. A third reason is to define homogeneously staged patients for
inclusion into clinical trials. Although patients greatly value the negative
Patients with distant metastases are clinical stage IV, and should be result of a cross-sectional imaging study, physicians need to be
further assigned to a substage by recording all sites of metastatic cautious about over interpreting the significance of the findings,
disease and the serum LDH (within normal limits or elevated). recognizing that all tests have relatively insensitive lower limits of
resolution. Finally, any test carries the very real possibility of detecting
Based on preliminary workup and clinical staging patients are stratified
findings unrelated to the melanoma, findings that can lead to morbid
into one of six groups for further workup and treatment:
invasive biopsy procedures, or at the very least substantial patient
 Stage 0 (melanoma in situ); or stage IA or IB with thickness 0.75 anxiety while awaiting results of interval follow-up studies.
mm or less, regardless of other features (eg, ulceration, mitotic
The yield of routine blood work and imaging studies in screening
rate)
patients with clinical stage I-II melanoma for asymptomatic distant
 Stage IA with thickness 0.76 to 1.0 mm, with no ulceration, and
metastatic disease is very low. Screening blood tests are very
mitotic rate 0 per mm2
insensitive, and the findings of cross-sectional imaging for patients with
 Stage IB with thickness 0.76 to 1.0 mm with ulceration or mitotic clinical stage I-II are often nonspecific, with frequent false-positive
rate greater than or equal to 1 per mm2; or stage IB or II with findings unrelated to melanoma.116-118
thickness 1.0 mm thick, any feature (eg, with or without
ulceration, any mitotic rate), and clinically negative nodes The yield of imaging studies has been more extensively evaluated in the
context of patients with stage III melanoma. In patients with a positive

Melanoma Discussion
SLN, the yield of cross-sectional imaging in detecting clinically occult Another large meta-analysis suggested that PET/CT was superior over
distant metastatic disease ranges from 0.5% to 3.7%.119-122 True CT in detecting distant metastases.134 Other recent studies in patients
positive findings are most often found in patients with ulcerated thick with stage III or IV melanoma have reported similar results, and
primary tumors and a large tumor burden in their sentinel nodes. In indicated that additional information provided by PET/CT may impact
asymptomatic patients with clinically positive nodes, the yield of routine treatment decisions in up to 30% of patients, with the greatest impact
cross-sectional imaging is a bit higher than in patients with positive seen in surgical management.132,135
sentinel nodes, reported at 4% to 16%.123-125 All of these series also
report a significant incidence of indeterminate or false-positive Another consideration for baseline imaging is the impact on early
radiologic findings that are unrelated to the melanoma. detection of central nervous system (CNS) metastases. Early detection
and treatment of subclinical CNS metastases is important because 1)
These retrospective studies report minimum estimates, as it is very clinically symptomatic CNS metastases are associated with significant
difficult to define a study population of truly “imaging-naïve” high-risk morbidity and poor survival, and 2) outcomes after treatment are
stage II and stage III patients. It is probable that, among the entire markedly better in patients with lower CNS tumor burden and/or
denominator of stage III patients, some would have been defined as asymptomatic metastases.126,136-144 Although CNS recurrence is rare in
stage IV based on imaging before the study cohort was assembled. patients who present with stage I-IIIB melanoma (≤5%), patients with
Furthermore, as a substantial proportion of clinical stage III patients will stage IIIC disease have an appreciable risk (11%).126 Although the yield
ultimately develop distant metastases,126 the inability of cross-sectional of baseline CNS imaging may be low, it may be useful for comparison
imaging studies to detect metastatic disease at diagnosis of stage III is with follow-up scans in patients at risk of CNS recurrence.
a relatively poor predictor of future events.
Sentinel Lymph Node Biopsy
PET scanning has attracted interest as a means of enhancing detection SLNB is a minimally invasive staging procedure developed to further
of subclinical metastatic disease. Most investigators have described risk-stratify patients with clinical stage I-II melanoma according to the
very low yield and poor sensitivity in detecting metastatic disease in presence or absence of subclinical nodal metastases. Patients with
patients with clinically localized melanoma.127-130 In patients with stage positive SLNB are at higher risk of recurrence, and might be candidates
III disease, PET/CT scan may be more useful. In particular, PET/CT for complete lymph node dissection (CLND) and/or adjuvant systemic
scans can help to further characterize lesions found to be indeterminate therapy.145 The utility of SLNB for staging depends on a thorough
on CT scan, and can image areas of the body not studied by the routine understanding of 1) the technical aspects of the procedure that lead to
body CT scans (ie, arms and legs).131,132 A systematic review of 17 successful identification and pathologic examination of a sentinel node;
diagnostic studies documented PET sensitivity ranging from 68% to 2) the low rate of complications associated with the procedure; 3) the
87% and specificity ranging from 92% to 98% for stage III and IV likelihood of sentinel node positivity; 4) the sensitivity of the test
melanoma compared to sensitivity ranging from 0% to 67% and
specificity ranging from 77% to 100% for stage I and II melanoma.133

Melanoma Discussion
(likelihood of false positives and false negatives); and 5) the prognostic be interpreted with caution. These “nodal nevi” can masquerade as
significance of sentinel lymph node status. metastatic disease, when in fact long-term outcomes in patients with
nodal nevi are similar to those of patients with negative SLNs.157 When
Techniques of Sentinel Lymph Node Biopsy there is any doubt about the significance of abnormal melanocytes in a
SLNB is almost always performed at the time of initial wide excision; the sentinel node, review by an experienced dermatopathologist is
validity of performing this technique after definitive wide excision has recommended.
not been extensively studied. There is at least a theoretical concern that
the relevant draining lymphatics could have been disturbed by the wide Although the concept is simple, and the technical aspects of SLNB are
excision, especially if rotation flaps or skin grafts were used for very robust, with similar results reported from many centers around the
reconstruction, degrading the accuracy of the SLNB procedure. world using innumerable variations of the basic technique, the
successful identification and characterization of the sentinel node
The technique for SLNB consists of preoperative dynamic depends on dedicated and meticulous cooperation among nuclear
lymphoscintigraphy, intraoperative identification using isosulfan blue or medicine, surgery, and pathology.
methylene blue dye, and a gamma probe to detect radiolabeled lymph
nodes.73,146-149 Many studies have reported high rates of successful Complications of Sentinel Lymph Node Biopsy
sentinel lymph node detection using this robust technique SLNB is associated with a low complication rate (5% in the Sunbelt
(>95%).19,73,146-149 SPECT scanning may enhance the accuracy of this Melanoma trial; 10% in MSLT-1).158-165 Two prospective randomized
technique in anatomically challenging regions, such as the head and trials have shown that the complication rate is significantly lower with
neck, or when a faintly visible sentinel node might be otherwise SLNB compared with completion lymph node dissection.158,159 The most
overshadowed by the intense radioactivity at the primary injection common complications associated with SLNB are wound dehiscence
site.150,151 and infection, seroma/hematoma, and lymphedema; other associated
complications are nerve injury and thrombophlebitis, deep vein
Meticulous pathologic examination of all sentinel nodes is essential to thrombosis, and hemorrhage.158-160,162-167 Allergic reactions to the blue
maximize the probability of detecting all SLNs with microscopic disease. dye used in SLNB have also been reported.159,161,162 Risk of
When micrometastases are not identified by routine hematoxylin and complications, particularly lymphedema, is higher for SLNB of the groin
eosin (H&E) staining, serial sectioning and immunohistochemical compared with the axilla or neck 158,165,168
staining (eg, with HMB-45 and/or Melan-A) has been shown to identify
additional patients with positive sentinel nodes.152-154 As the presence of Rates and Predictors of Sentinel Lymph Node Positivity
even scattered clusters of melanoma cells in a sentinel node is clinically Depending on a variety of factors described below, 5% to 40% of
relevant, the AJCC was unable to determine a sentinel node tumor patients undergoing SLNB will be upstaged from clinical stage I-II to
burden too low to report as metastatic disease.27,155,156 On the other pathologic stage III, based on subclinical micrometastatic disease in the
hand, the presence of bland or benign-appearing melanocytes should SLN.18,73,147-149,169-174 Multivariate analyses have identified factors

Melanoma Discussion
independently predictive of a positive SLN. The correlation between metastasis). The final long-term results of this trial were recently
increased primary tumor thickness and SLN positivity is well reported, and provide the best available data regarding the utility of
established.18,45,148,169,171,172,175-177 Due in part to the low probability of SLNB, as described in the following sections.173
finding a positive sentinel node in patients with thin primary melanomas
(≤1 mm), the utility of SLNB in this population is controversial and is Accuracy of Sentinel Lymph Node Biopsy
discussed below in SLNB in Thin (≤1 mm) Melanoma. Both retrospective analyses and data from MSLT-I have been evaluated
to determine the false negative rate of SLNB, or the probability of
In addition to Breslow thickness, other primary lesion characteristics missing a positive sentinel node if present. The false-negative rate is
(eg, Clark level, mitotic rate, ulceration, lymphovascular invasion, VGP, strictly defined as the number of patients with nodal recurrences after
anatomic site, tumor infiltrating lymphocytes, regression) and patient negative SLNB (false negatives), divided by the total number of patients
characteristics (eg, sex, age) have been assessed for their association with nodal involvement, including false negatives and patients with a
with SLN status in patients with primary melanomas thicker than 1 mm. positive SLNB (true positives). Using this definition, MSLT-I and
For each of these factors, however, their prognostic value is unclear retrospective series have reported false-negative rates of up to
due to results varying between studies.177-182 For example, results vary 20%.73,147,149,170,173,174,182,185
regarding the prognostic significance of patient age for predicting
likelihood of SLN positivity, but most studies show higher risk of SLN Prognostic Value of the Sentinel Node
involvement in younger patients.18,45,148,171,175,176,183 An AJCC database Retrospective analyses have indicated that among patients with
analysis of patients with cutaneous melanoma, no clinically detectable clinically node negative localized melanoma undergoing SLNB, the
LN metastases (n = 7756), and SLNB showed that age was an status of the sentinel node is the most important prognostic factor, both
independent predictor of SLN positivity, with higher rates of SLN for disease progression and DSS.71,73,172,182,185,186 Primary tumor
positivity in younger patients (<20 y), but that younger patients lived thickness is also an independent predictor of progression and survival;71
longer, nonetheless.184 High age (>80 y) was associated with lower however, and one study has shown that the prognostic value of SLN
rates of SLN positivity, but nonetheless this group had lower survival positivity is greater for patients with tumor thickness >1 mm.187 The
rates. Analysis of a SEER database yielded similar results.180 prognostic value of SLN status in patients with thin primary melanomas
is discussed further in the next section.
MSLT-1: Prospective Randomized Trial on SLNB
MSLT-I, an international, multicenter, phase III trial, was initiated in Prospective data from MSLT-I confirm the prognostic value of SLN
1994 to evaluate the impact of initial management with SLNB on the status in patients with primary tumors ≥1.2 mm thick; among patients
DSS of patients presenting with localized melanoma. Patients were screened with SLNB, DSS was significantly worse in those with versus
treated by wide excision, followed by either SLNB (and immediate without sentinel node involvement.173 Sentinel lymph node status was
lymphadenectomy if SLN positive) or followed by observation of the also the strongest predictor of disease-free survival (DFS) by
nodal basin (and lymphadenectomy upon clinical detection of nodal multivariate analysis.

Melanoma Discussion
Among patients with SLN positivity, the SLN burden (number of positive Utility of SLNB in Patients with Unusual Presentations
SLNs, size and location of tumor in the SLN[s]) is prognostic for SLNB in Thin (≤1 mm) Melanoma
recurrence and survival.74-80 Among patients with thin melanoma selected for SLNB, rates of SLN
positivity are low, around 5% in most studies (Table 1). Primary tumor
Therapeutic Value of SLNB thickness is the single factor that most consistently predicts SLN
SLNB has limited therapeutic value. Although MSLT-1 largely confirmed positivity (Table 2), in large part because other high-risk features such
the known role of SLNB as a very important staging test, SLNB did not as ulceration and high mitotic rate are seen so infrequently. A review by
improve DSS compared with nodal basin observation, regardless of Andtbacka and Gershenwald188 reported an overall SLN metastasis rate
primary lesion thickness. SLNB did improve DFS by 7% and 10% for of 2.7% in patients with melanoma thinner than 0.75 mm. In patients
patients with intermediate thickness (1.2–3.5 mm) or thick (>3.5 mm) with melanoma 0.75 to 1.0 mm thick, 6.2% of patients selected to
primary lesions, respectively. Improvements in DFS were due in large undergo SLNB were found to have a positive SLN.
part to the higher rate of nodal relapse in the nodal basin observation
group. Other than thickness, individual studies have inconsistently identified
additional factors to be predictive of a positive SLN among patients with
In a prespecified retrospective subset analysis of patients who thin melanoma.188 These include Clark level, mitotic rate, ulceration,
developed nodal metastases from intermediate-thickness (1.2–3.5 mm) lymphovascular invasion, VGP, and TIL.16,17,19,45,71,186,189-198 For thin
melanoma, MSLT-I confirmed a survival advantage to those with melanomas the significance of tumor regression as a predictor is
microscopic versus macroscopic disease at the time of detection and controversial, though most studies have reported no
removal (10-year DSS for those detected by SLNB versus nodal basin association.17,191,192,195,199
observation: 62% vs. 41.5%, P = .006). A similar survival advantage
was not seen in patients with thick (>3.5 mm) melanomas and positive One multi-institutional review of 1250 patients with thin melanomas (≤1
nodes. mm) found that less than 5% of melanomas thinner than 0.75 mm had
positive SLNs regardless of Clark level and ulceration status.190
In summary, although SLNB improved survival for the subgroup of
patients having both intermediate thickness primary lesions and lymph However, another review found that for patients with thin melanomas
node involvement, the study population as a whole did not benefit and at least one risk factor (ulceration, Clark level IV, nodular growth,
because SLNB did not improve survival in other subgroups (patients mitosis, regression, or age ≤40 years), the SLN positivity rate was as
with thick primary lesions and/or who did not develop lymph node high as 18%.200
metastasis).
In patients with thin melanoma the prognostic value of SLNB results is
The therapeutic value of SLNB for patients with thin melanomas (1.2 unclear. A number of studies have associated SLN positivity with worse
mm or less) was not specifically addressed in the MSLT-I trial.

Melanoma Discussion
disease-free or melanoma-specific survival in patients with thin primary Table 2. Effect of Thickness on Rate of Positive SLN in Thin
melanomas,186,191,201 while others have reported no association.192,193 Melanomas (≤1 mm)
Primary Tumor Thickness
Table 1. Rate of Positive SLN in Thin Melanomas (≤1 mm) <0.75 mm 0.75–1.0 mm
Total Positive SLN Positive SLN
Study Positive SLN
Patients
Study n/N % n/N %
N n %
Bleicher 2003 202 2/118 1.7% 6/154 3.9%
Statius Muller 2001 147 104 7 6.7%
Kesmodel 2005 19 1/91 a 1.1% 8/90 a 8.9%
Rousseau 2003 148 388 16 4.1%
Puleo 2005 196 20/409 4.9%
Bleicher 2003 202 272 8 2.9%
Ranieri 2006 191 2/86 2.3% 10/98 10.2%
Olah 2003 149 89 12 13%
Wong 2006 192 0/73 0% 8/150 5.3%
Oliveira 2003 16 77 6 7.8%
Wright 2008 186 16/372 4.3% 15/259 5.8%
Borgognoni 2004 170 114 2 1.8%
Vermeeren 2010 204 0/39 b 0% 5/39 b 12.8%
Stitzenberg 2004 195 146 6 4.1%
Murali 2012 193 3/113 2.7% 26/290 9.0%
Sondak 2004 18 42 4 9.5%
Venna 2013 189 7/170 c 4.1% 27/280 c 9.6%
Puleo 2005 196 409 20 4.9%
Total 31/1062 2.9% 125/1769 7.1%
Kruper 2006 171 251 13 5.2% SLN, sentinel lymph node
Ranieri 2006 191 184 12 6.5% a
Subgroups were primary tumor thickness <0.76 mm, 0.76–1.0 mm; all had
Cascinelli 2006 172 145 6 4.1% VGP
b
Subgroups were primary tumor thickness ≤0.75 mm, 0.76–1.0 mm
Nowecki 2006 174 260 17 6.5% c
Subgroups were primary tumor thickness <0.8 mm, ≥0.8 mm
Wong 2006 192 223 8 3.6% SLNB in Desmoplastic Melanoma
Wright 2008 186 631 31 5.0% Although estimates vary across studies, rates of SLN positivity tend to
Murali 2012 193 432 29 6.7% be lower with pure desmoplastic melanoma compared with mixed
Mozzillo 2013 201 492 24 4.9% desmoplastic or other types of melanoma.205-214 Moreover, several
Venna 2013 189 450 34 7.6% studies have shown that among patients with desmoplastic melanoma,
Cooper 2013 203 189 3 1.6% SLN positivity does not consistently correlate with DSS.209,211,214
Total 4898 258 5.3% Variability in results may be due in part to lack of standardized criteria
SLN, sentinel lymph node for defining pure desmoplastic melanoma.215-218 Assignment may vary
between pathologists and across institutions. In the setting of these
conflicting reports, the role of SLNB in patients with pure desmoplastic
melanoma remains controversial.

Melanoma Discussion
Biopsy of Palpable Lymph Nodes Sentinel Lymph Node Biopsy

The NCCN Melanoma Panel does not recommend SLNB for patients
Fine-needle aspiration (FNA), with or without ultrasound guidance, has
with in situ melanoma (stage 0). The panel discussed at length the
been shown to have high sensitivity and specificity for detecting
lower limit of probability of sentinel node positivity that should prompt a
melanoma in enlarged lymph nodes (detected clinically or by
discussion of SLNB for stage I melanoma. According to data discussed
imaging).219-221
above, Breslow thickness is the main factor associated with SLN
Full Workup and Pathologic Staging: NCCN Recommendations positivity.
Practices among the NCCN Member Institutions vary greatly with In general, the panel does not recommend SLNB for stage IA or IB
respect to the appropriate workup of a melanoma patient. In the lesions that are very thin (≤0.75 mm) unless there is considerable
absence of compelling data beyond the retrospective series cited uncertainty about the adequacy of microstaging. Conventional risk
above, for the most part, recommendation for the appropriate extent of factors such as ulceration, high mitotic rate, and lymphovascular
workup is based on non-uniform consensus within the panel. invasion are very uncommon in melanomas 0.75 mm thick or less. In
the rare event that a conventional high-risk feature is present, the
Stage 0, I, and II
decision about SLNB should be left to the patient and the treating
Workup
physician. For patients with stage IA melanomas that are 0.76 to 1.0
The panel stressed the importance of a careful physical examination of
mm thick without ulceration, and with mitotic rate 0 per mm2, SLNB
the primary site, the regional lymphatic pathways and lymph node
should be considered in the appropriate clinical context.
basin, and the remainder of the skin. Although nodal basin ultrasound is
not a substitute for SLNB, the procedure should be considered for SLNB should generally be discussed and offered for patients with
patients with an equivocal regional lymph node physical exam prior to higher-risk stage IB (>1 mm thick or 0.76–1.0 mm thick with ulceration
SLNB. Abnormalities or suspicious lesions on nodal basin ultrasound or mitotic rate ≥1 per mm2) or stage II melanoma.
should be confirmed histologically.
Any discussion of the SLNB procedure in patients with stage I or II
Routine cross-sectional imaging (CT, PET/CT, or MRI) is not melanoma should reflect what is known about the prognostic value of
recommended for these patients. Despite the very low yield of cross- SLNB on various clinical endpoints, its defined accuracy and false
sectional imaging, there was increasing disagreement about what negative rate, the potential morbidity of the procedure, and what (if
consensus-based recommendations should be made for clinically node anything) will be done differently once the SLN status is known.
negative patients at the higher risk end of the spectrum. There was
uniform consensus that imaging studies were indicated to investigate Meticulous pathologic examination of all sentinel nodes is mandatory.
specific signs or symptoms. Routine blood tests are not recommended When micrometastases are not identified by routine H&E staining, serial
for patients with melanoma in situ or stage I and II disease. sectioning and immunohistochemical staining should be performed.

Melanoma Discussion
There is no sentinel node tumor burden too low to report as metastatic Stage III Workup
disease, including even scattered clusters of melanoma cells. On the Stage III Sentinel Node Positive
other hand, the presence of bland or benign-appearing melanocytes Most panel members acknowledged the low yield of screening CT or
should be interpreted with caution. When any doubt is present, review PET/CT scans in patients with a positive sentinel lymph node. Based on
by an experienced dermatopathologist is recommended. the results of the studies reported in the literature and the absence of
conclusive data, there was consensus that cross-sectional imaging
In patients who otherwise would be candidates for SLNB, the decision could be considered at baseline for staging (category 2B) or to assess
to not perform SLNB may be based on significant patient comorbidities specific signs or symptoms (category 2A).
or individual patient preference. There is controversy regarding the
diagnostic criteria for, the probability of a positive sentinel node in, and Stage III with Clinically Positive Node(s)
the prognostic significance of the sentinel node in pure desmoplastic For patients presenting with clinical stage III disease who have clinically
melanoma. Clinicians may consider forgoing SLNB on confirmed pure positive node(s), all panel members believe it is appropriate to confirm
desmoplastic melanoma. Multidisciplinary consultation including a the suspicion of regional metastatic disease, preferably with FNA, or
dermatopathologist is recommended for determining staging and with core, incisional, or excisional biopsy of the clinically enlarged lymph
treatment options. node. If FNA is non-diagnostic in the setting of high clinical suspicion,
excisional biopsy, planned with therapeutic lymph node dissection
The validity of SLNB in accurately staging patients after prior wide (TLND) in mind, is appropriate. Clearly, in patients without an
excision is unknown. As such, wide excision before planned SLNB is antecedent history of melanoma, this would have been the initial
discouraged, although patients may be considered for the procedure on diagnostic test. At a minimum, a pelvic CT scan is recommended in the
an individual basis if they present for that discussion after initial wide setting of inguinofemoral lymphadenopathy to rule out associated pelvic
excision. or retroperitoneal lymphadenopathy. Most of the panel also endorsed
baseline cross-sectional imaging for staging purposes and to evaluate
The panel discussed the appropriate management of clinically negative
specific signs or symptoms.
lymph nodes in patients at risk for regional metastases, in the event that
SLNB is unavailable. Based on the results of three prospective Stage III In-transit
randomized trials, the panel does not recommend routine elective lymph For the small group of patients presenting with stage III microsatellitosis
node dissection for this group. Wide excision alone or referral to a or in-transit disease, the workup outlined above for clinical stage III
center where lymphatic mapping is available are both acceptable nodal disease, including histologic confirmation of the in-transit
options in this situation. While nodal basin ultrasound surveillance metastasis, and cross-sectional imaging, is appropriate.
would seem to be another reasonable option in this setting, its value
has not been defined in prospective studies. SLNB may be considered for patients with resectable solitary in-transit
stage III disease (category 2B recommendation). However, while SLNB

Melanoma Discussion
may be a useful staging tool, its impact on the OS of these patients Although LDH is not a sensitive marker for detecting metastatic disease,
remains unclear. Likewise for patients with microsatellitosis, while SLN the panel recognizes its prognostic value. It is recommended that serum
positivity would upstage the disease to N3, stage IIIC, its significance in LDH be obtained at diagnosis of stage IV disease. Other blood work
treatment decisions has not been clearly defined. may be done at the discretion of the treating physician.
Since patients with stage IIIC have an appreciable risk of symptomatic Treatment of Primary Melanoma
CNS recurrence, and symptomatic CNS metastasis are associated with Wide Excision
significant morbidity and poor survival, baseline CNS imaging should be
Surgical excision is the primary treatment for melanoma. Several
considered in these high-risk patients.
prospective randomized trials have been conducted in an effort to
Stage IV Workup define optimal surgical margins for primary melanoma (Table 3).
For patients presenting with stage IV distant metastatic disease, all
In an international prospective study carried out by WHO, 612 patients
panel members agree it is appropriate to confirm the suspicion of
with primary melanomas not thicker than 2.0 mm were randomized to
metastatic disease with either FNA or core, incisional, or excisional
wide excision with 1 cm or ≥3 cm margins.222,223 At a median follow-up
biopsy of the metastases. Genetic analyses (eg, BRAF or KIT mutation
of 90 months, local recurrence, DFS and OS rates were similar in both
status) are appropriate for patients being considered for treatment with
groups. Similarly, Swedish and French randomized trials confirmed that
targeted therapy, or if mutational status is relevant to eligibility for
survival was not compromised by narrower margins in melanomas
participation in a clinical trial. To ensure that adequate metastatic
thinner than 2 mm.224,225
material is available for mutational analysis, biopsy (core, excisional, or
incisional) is preferred if initial therapy is to be systemic and archival A multicenter European trial randomized 936 patients with melanoma
tissue is not available. However, the panel also recognized that brain thicker than 2.0 mm to wide excision with 2 or 4 cm margins.226 The 5-
metastases are typically treated without histologic confirmation. year OS rate was similar in the two groups. This is in keeping with
previous trials that found no survival benefits with margins wider than 2
Panelists encourage baseline chest/abdominal/pelvic CT with or without
cm for thicker lesions.227,228 A systematic review and meta-analysis of
PET/CT in patients with stage IV melanoma. Because patients with
the first three trials shown in Table 3 reported that surgical excision
metastatic melanoma have a high incidence of brain metastases, brain
margins of at least 1 cm and no more than 2 cm are adequate.229
MRI or CT scan with contrast should be performed at presentation with
stage IV disease. Brain MRI is also recommended if patients have even A recent update on the UK-based prospective trial of 1- versus 3-cm
minimal symptoms or physical findings suggestive of CNS involvement, margins in patients with melanomas greater than 2 mm thick showed
or if results of imaging would affect decisions about treatment. that at a median follow-up of 8.8 years, wider margin was associated
with statistically significantly improved melanoma-specific survival (see
Table 3 footnote).230 OS was not significantly different between the

Melanoma Discussion
treatment groups. Although this is the only prospective trial that has by Mohs surgery, 9-mm surgical margins resulted in removal of 99% of
shown a wider margin to be associated with a survival advantage, this is melanomas while 6-mm margins removed 86%.241 Retrospective
not practice-changing finding. The current recommendations are for 2- analyses have also shown that >5 mm margins are often needed for
cm margins in this population, and this trial did not demonstrate complete histologic clearance of melanoma in situ, particularly for the
superiority of 3-cm over 2-cm margins. lentigo maligna subtype.240,242-244 Mohs micrographic surgery or staged
excision with or without immunohistochemical staining aimed at
Recent large retrospective analyses are generally supportive of the complete surgical excision with meticulous margin control have
margin recommendations that were based on prospective randomized demonstrated high local control rates in lentigo maligna.245-247
trials.231-236
Alternatives to Excision: Topical Imiquimod or Radiation
Table 3. Studies That Evaluated Surgical Margins of Wide
Excision of Melanoma Although surgical excision remains the standard of care for in situ
Follow- melanoma, it is sometimes not feasible due to comorbidity or
Thickness Margin cosmetically sensitive tumor location. Topical imiquimod has emerged
Study Year N up LR OS
(mm) (cm)
(years) as a treatment option, especially for lentigo maligna.248-264 Topical
WHO222,223 1991 612 8 ≤2 1 vs. ≥3 NS NS imiquimod was associated with high rates of clinical and histologic
Sweden224 2000 989 11 >0.8–2.0 2 vs. 5 NS NS clearance (70%–100%) and low recurrence rates (0%–4%) in most
Intergroup227 2001 468 10 1–4 2 vs. 4 NS NS studies, whether used as first-line treatment (as monotherapy or prior to
France225 2003 326 16 ≤2 2 vs. 5 NS NS excision) or second-line treatment for incompletely excised lentigo
UK230,237 2016 900 8.8 >2 1 vs. 3 NS NSa maligna, or adjuvant therapy for lesions excised with narrow margins.
Sweden226 2011 936 6.7 >2 2 vs. 4 NS NS However, long-term, comparative studies are still needed.
LR, local recurrence; OS, overall survival; NS, non-significant
a
Analysis after a median follow-up of 5.7 years showed no significant difference Radiotherapy has also been used selectively for lentigo maligna. In a
in overall survival or melanoma-specific survival, but analysis after a median systematic review of retrospective studies reporting outcomes for
follow-up of 8.8 years showed significantly better melanoma-specific survival patients with lentigo maligna treated with definitive primary RT, there
for patients with 3-cm vs. 1-cm excision margins (unadjusted HR 1.24 [95% CI
1.01–1.53]; P = .041) but no significant improvement in overall survival were 18 recurrences in a total of 349 assessable patients (5%), after a
(unadjusted HR 1.14 [95% CI, 0.96–1.36]; P = .14). median follow-up of 3 years, and disease progressed to lentigo maligna
melanoma in 5 cases (1.4%).265 There were 8 in-field recurrences (5
Management of lentigo maligna and in situ melanoma may present lentigo maligna, 3 lentigo maligna melanoma) out of 171 assessable
unique problems because of the characteristic, yet unpredictable, patients (4.7%), and 5 marginal recurrences out of 123 assessable
subclinical extension of atypical junctional melanocytic hyperplasia, patients (4.1%). The retrospective studies used a variety of radiation
which may extend several centimeters beyond the visible margins.238-240 protocols, including superficial RT and Grenz rays, but there were no
In a prospective study of 1,120 patients with melanoma in situ treated

Melanoma Discussion
clear trends to indicate the optimal approach. Another large For melanomas 1.0 mm or less, wide excision with a 1-cm margin is
retrospective study (not included in the aforementioned meta-analysis) recommended (category 1). Wide excision with a 1- to 2-cm margin is
tested Grenz ray radiation in a mixed population of patients with lentigo recommended for melanomas measuring 1.01 to 2 mm in thickness
maligna and early lentigo maligna melanoma.266 Complete clearance (category 1). For melanomas measuring more than 2 mm in thickness,
without relapse was observed in 83% of 350 patients who received RT wide excision with 2-cm margins is recommended (category 1). Surgical
as primary therapy, and in 90% of 71 patients who received RT after margins may be modified to accommodate individual anatomic or
partial excision. cosmetic considerations. The panel recognized that 1- to 2-cm margins
might be acceptable in anatomically difficult areas where a full 2-cm
Since tumor border delineation for lentigo maligna is smaller on clinical margin would be difficult to achieve.
exam than with Wood lamp or digital epiluminescence microscopy,
collaboration with a dermatologist who can perform these procedures is Lymph Node Dissection
necessary to help prevent these marginal failures.267 Completion Lymph Node Dissection After Positive SLNB
NCCN Recommendations Traditionally, all patients with a positive SLNB have been advised to
proceed to CLND. This is in part an extension of the observation that, in
The clinical/surgical margins discussed below refer to those taken at the
historical prospective trials, among patients with a positive node,
time of surgery and do not necessarily correlate with gross
survival was better in those patients where the node was removed when
pathologic/histologic margins measured by pathologists.
clinically occult by elective lymph node dissection rather than when
For in situ melanoma, a measured margin of 0.5 to 1 cm around the clinically apparent by TLND.268 There are a number of other theoretical
visible lesion should be obtained. For large in situ lentigo maligna reasons for recommending CLND to this patient population. These
melanoma, surgical margins greater than 0.5 cm may be necessary to include the known probability of residual positive non-sentinel lymph
achieve histologically negative margins. In the absence of prospective nodes (NSLNs), the prognostic value of additional positive NSLNs,
clinical trials testing margins for standard excision, this margin range is improved regional nodal basin control after CLND, the lower morbidity
recommended based on panel consensus, data from retrospective of CLND rather than TLND, and the potential to improve long-term DSS
studies, and results from the large prospective study described above by early aggressive nodal basin intervention. Arguments against CLND
that showed that increasing Mohs microsurgery margins from 6 mm to 9 include the cost and morbidity of the procedure,269-274 and the fact that
mm significantly improved the rate of complete histologic clearance. the procedure has never been demonstrated to offer clinical benefit to
More exhaustive histologic assessment of margins such as staged this group of patients, a group already defined as at increased risk of
excision for lentigo maligna melanoma should be considered. For systemic disease based on the presence of their positive SLNB. Over
selected patients with positive margins after optimal surgery, topical the last 25 years, much has been learned about the natural history of
imiquimod or RT can be considered as non-standard options (category patients with a positive sentinel node to inform many of the points cited
2B). above. More importantly, two pivotal prospective randomized trials have

Melanoma Discussion
been conducted to directly address the impact of CLND on a number of Table 4. Rates of Positive Non-Sentinel Lymph Nodes
these clinical endpoints.275,276 Patients with Patients with Positive
Study
CLND, n NSLN, n (%)
Likelihood of Non-Sentinel Lymph Node Positivity McMasters 2002 302 272 45 (16%)
Among patients with a positive sentinel node, published studies have Dewar 2004 291 146 24 (16%)
revealed additional positive non-sentinel nodes in approximately 20% of Sabel 2005 278 221 34 (15%)
the CLND specimens (Table 4). Factors most predictive of additional Kettlewell 2006 303 105 34 (32%)
non-sentinel node involvement include the largest size of the SLN Cascinelli 2006 172 176 33 (19%)
metastasis,77,79,172,277-289 the number of SLNs involved,79,155,278,283,290 the
Govindarajan 2007 279 127 20 (16%)
distribution of metastasis in the SLN (subcapsular vs.
Gershenwald 2008 288 343 48 (16%)
parenchymal),172,291,292 and primary tumor characteristics of
Cadili 2010 77 606 142 (24%)
thickness277,278,281,285-288,293,294 and ulceration.155,281,283,293,294 Several
Leung 2013 293 329 79 (24%)
scoring systems have been developed to predict the likelihood of
Wevers 2013 295 130 30 (23%)
positive non-sentinel nodes based on SLN biopsy findings, primary
tumor, and patient characteristics,288,295-299 although the utility of each of Pasquali 2014 304 1,538 353 (23%)
these systems has been debated based on subsequent Bertolli 2015 285 146 23 (16%)
analyses.80,281,283,300,301 Rutkowski 2015287 473 132 (28%)
Kim 201579 111 13 (12%)
Total 4723 1010 (21%)
CLND, complete lymph node dissection; NSLN, non-sentinel lymph node
Prognostic Value of Complete Lymph Node Dissection
A number of retrospective studies have evaluated the prognostic value
of NSLN involvement in patients who had a CLND after a positive SLN
(no palpable lymph nodes). Compared to those without NSLN
involvement detected by CLND, those with positive NSLN(s) have
higher rates of recurrence80,273,293 and poorer DFS,305 melanoma-
specific survival, and OS.80,172,287,293,304-306 In fact, in the studies that
evaluated the clinical importance of NSLN positivity by multivariate
analysis, it was consistently one of the most important independent
predictor of DSS.273,293,304-306 Other factors identified to be independently
associated with recurrence and survival include the number of positive

Melanoma Discussion
NSLNs81,273,287 as well as the non-CLND factors of the primary tumor MSLT-II is a much larger international prospective randomized trial in
(site,273 Breslow thickness,80,287,301 and ulceration80,273,287), the nodal which patients with a positive SLNB were randomized to undergo either
basin involved,273 and the SLN burden (number of positive SLNs, size immediate completion lymph node dissection or nodal basin ultrasound
and location of tumor in the SLN[s]).77,79,80,301 surveillance (clinicaltrials.gov/show/NCT00297895). This trial, which
has completed accrual, should further clarify the issue of whether CLND
The challenge of using the probability of NSLN positivity as a rationale has an impact on outcome.
to proceed to CLND is that patients with a positive NSLN are at much
higher risk for distant metastases. This is a population that intuitively Therapeutic Lymph Node Dissection
may be much less likely to benefit from additional treatment of the In patients with clinically involved lymph nodes but no distant disease,
regional nodal basin. TLND is associated with 5-year survival rates of 30% to 50%,
depending on number of lymph nodes involved, extracapsular
Therapeutic Value of CLND
extension, and high-risk features of the primary tumor (Breslow
The impact of completion lymph node dissection on regional control and
thickness, ulceration, site).71,81,82,310-317 At present, there is no non-
survival in the setting of a positive SLN has not been clearly
surgical therapy that has been shown to provide similar results (for
demonstrated. Results from a few retrospective studies in patients with
survival).
positive SLNB have shown that treatment with CLND versus
observation may be associated with improved recurrence-free survival, Palliative Lymph Node Dissection
but is not significantly associated with improved OS or melanoma-
On occasion, lymph node dissection may be indicated for patients with
specific survival.307-309 Two ongoing trials are designed to assess the
distant metastatic disease in order to achieve regional nodal basin
therapeutic value of CLND for patients with positive sentinel lymph
control.
nodes (but no palpable nodes).
Elective Pelvic Lymph Node Dissection
DeCOG-SLT is a phase III prospective randomized trial
(https://clinicaltrials.gov/ct2/show/record/NCT02434107) in which Among patients with positive inguinofemoral nodes and no clinical or
melanoma patients with a positive SLNB were randomized to undergo radiologic evidence of positive pelvic nodes, there is some controversy
immediate CLND (n = 241) or observation with nodal basin ultrasound as to the role of elective ileo-obturator lymph node dissection.310,318-321 In
surveillance (n = 242). At a mean follow-up of 34 months, CLND was these patients, the probability of clinically occult positive pelvic nodes is
not associated with any improvement in recurrence-free survival, increased when there are clinically positive inguinofemoral nodes, three
distant-metastasis-free survival, or melanoma-specific survival.275 An or more inguinofemoral nodes involved, or when Cloquet’s node is
interesting subset analysis in this trial suggested that CLND was not positive.322-327 Again, the impact of elective pelvic lymphadenectomy on
associated with clinical benefit in patients with either high or low SLN survival in this specific patient cohort is unknown.328
tumor burden.

Melanoma Discussion
Morbidity of Lymph Node Dissection with distant metastatic disease) to limit the morbidity of the procedure. A
The value CLND for providing prognostic information and regional number of investigators have attempted to evaluate this issue.269,284,333-
338
control must be weighed against morbidity of the procedure. Many
studies have reported complication rates for between 40% to 60%,269,329
NCCN Recommendations
but others have reported lower rates, between 20% to 40%.158,159,271
Potential complications associated with CLND include wound If the sentinel node is negative, regional lymph node dissection is not
dehiscence or infection, hematoma/seroma, neuropathy, lymphocele indicated. For patients with stage III disease based on a positive SLN, a
formation, and lymphedema.158,159,269-272,311,317,329-331 Lymphedema and CLND of the involved nodal basin should be discussed and offered, in
neuropathy can be persistent postoperative problems.270-272,331 Most the context of all of the points raised above, including the probability of
studies report lymphoedema rates between 20% to 30%, but some a positive NSLN, the prognostic value of the NSLN status, the morbidity
studies have reported lymphedema in up to 50% of of the procedure, and the fact that one prospective randomized
patients.86,269,271,272,331 Risk factors for complications during or after controlled trial has shown no benefit in any clinically relevant endpoint.
lymph node dissection include obesity and increased age.331,332 The risk The impact of CLND on plans for adjuvant therapy or clinical trial
and severity of complications may depend on the location of the nodal enrollment should also be considered.
basin undergoing lymph node dissection, with the groin being the
Patients presenting with clinically positive nodes without radiologic
highest risk location, especially for lymphedema.158,271,274,317,331
evidence of distant metastases should undergo wide excision of the
Technical Aspects of Lymph Node Dissection primary site (if present) and CLND of the involved nodal basin. In the
setting of inguinal lymphadenopathy, a pelvic dissection is
CLND consists of an anatomically thorough dissection of the involved
recommended if the PET/CT or pelvic CT scan reveals iliac and/or
nodal basin. The extent of lymph node dissection is often modified
obturator lymph node involvement (category 2A) or if a positive
according to the anatomic area of lymphadenopathy. There is some
Cloquet’s lymph node is found on intraoperative frozen section
controversy on how best to define an adequate lymph node dissection.
(category 2B). Pelvic dissection also should be considered for clinically
One measure of the completeness of a regional lymph node dissection
positive inguinal-femoral nodes or if three or more inguinofemoral nodes
is the number of lymph nodes examined. There is not uniform
are involved (category 2B). For primary lesions in the head and neck
agreement on the number of lymph nodes needed to define an optimal
with clinically or microscopically positive lymph nodes in the parotid
CLND in a given lymph node basin.
gland, a superficial parotidectomy alone is insufficient and the panel
It is unknown whether the extent of lymph node dissection can safely be recommends appropriate neck dissection of the draining nodal
modified according to the indication for the lymph node dissection basins.339
(CLND due to positive sentinel lymph node, TLND for palpable lymph
However, the NCCN panel felt that available retrospective evidence to
node(s), palliative lymph node dissection regional control in patients
date was insufficient to mandate that a specific number of nodes be

Melanoma Discussion
required to deem a lymph node dissection adequate for any designated defined as 5 to 10 MU/d subcutaneously (SC) for 3 to 5 d/wk, has also
lymph node basin. As a measure of quality control to ensure adequacy been compared with observation as adjuvant therapy for resected, high-
of lymphadenectomy, the committee recommended that the operative risk melanoma. As with low-dose IFN, prospective randomized studies
note fully describe the anatomic boundaries of the lymph node showed that intermediate-dose adjuvant IFN did not improve survival,
dissection. and results for relapse-free survival were inconsistent across trials
(Table 5).
Adjuvant Systemic Therapy for Melanoma
For adjuvant treatment of melanoma in patients rendered free of
disease by surgery, most traditional chemotherapy approaches have
proven to be ineffective. Adjuvant interferon (IFN), particularly high-dose
IFN, has been widely used in patients with melanoma, and as described
below, a large body of clinical evidence has amassed. Results from
recent and ongoing trials support two new types of adjuvant treatment
for melanoma: 1) biochemotherapy, a combination of high-dose IFN,
interleukin-2 (IL-2), and chemotherapy; and 2) immune checkpoint
inhibitors.340,341 Prospective clinical trials are evaluating targeted
therapies as well as regimens combining multiple types of therapy (eg,
IFN, chemotherapy, immune checkpoint inhibitors, targeted therapies)
for use as adjuvant treatment for melanoma.342-357
Low-Dose and Intermediate-Dose Interferon

Low-dose adjuvant IFN typically has been administered subcutaneously
at 3 MU/d for 3 d/wk. Various intervals and durations of low-dose IFN
have been compared with observation in patients with fully resected
non-metastatic melanoma at high-risk for recurrence (Table 5). In these
trials patients with stage III in-transit disease were either explicitly
excluded or very unlikely to have been included. Prospective
randomized trials have shown that low-dose adjuvant IFN was not
associated with statistically significant improvements in survival, and
with a few notable exceptions also did not provide statistically significant
improvement in relapse-free survival (Table 5). Intermediate-dose IFN,

Melanoma Discussion
Table 5. Low-Dose or Intermediate-Dose Adjuvant Interferon

IFN Patients, n Statistically Significant Impact of IFN
Triala References IFN Doseb
type IFN Obs Relapse-free Survivalc Survivald
Italian Skin Cancer Foundatione Rusciani 1997358 Low 2b 84 70 Yes; P < .0001f No
Austrian Malignant Melanoma Group Pehamberger 1998359 Lowg 2a 143 150 Yes; P = .02 No
French Cooperative Group on Melanoma Grob 1998360 Low 2a 244 243 Yes; P = .035 Trend: P = .059
Overall: No
Scottish Melanoma Group Study Cameron 2001361 Low 2b 49 47 No
2-y rate: Yes; P < .05
WHO Melanoma Programme Cascinelli 2001362 Low 2a 225 219 No No
AIM HIGH – UK Coordinating Committee
Hancock 2004363 Low 2a 338 336 No No
on Cancer Research
EORTC 18871 and DKG-80-1 Kleeberg 2004364 Very low 2b 240 244 No No
Kirkwood 2000365
ECOG 1690 Low 2b 215 212 No No
Kirkwood 2004366
EORTC 18952 Eggermont 2016367 Intermediate 2b 1109 279 Noh Noh
DeCOG trial Garbe 2008368 Low 2a 148 148 Yes; P = .018 Yes; P = .005
Nordic IFN trial Hansson 2011369 Intermediate 2b 571 284 Yes; P = .034i No
IFN, interferon; NR, not reported; Obs, observation
a
All prospective, randomized, multicenter studies comparing adjuvant interferon with observation in patients with fully resected non-metastatic cutaneus melanoma
at high-risk for recurrence.
b
Low-dose IFN regimen: 3 MU SC 3 x/wk, for various intervals and durations; very-low-dose IFN regimen: 1 MU SC every other day; intermediate-dose IFN
regimens: 10 MU SC 3–5 x/wk for 4 weeks, then 5–10 MU SC 3 x/wk.
c
Relapse-free survival, relapse-free interval, recurrence-free survival, disease-free survival, progression-free survival, or metastasis rate.
d
Overall survival or melanoma-specific survival.
e
Included only stage I and II.
f
No significant improvement for patients with stage I or Breslow thickness
<1.5 mm.
g
IFN regimen: 3 MU SC daily for 3 weeks, then 3 x/wk.
h
Subgroup analyses showed that the longer IFN regimen (25 months) was associated with statistically significant improvement (P < .001) in relapse-free survival,
distant metastasis-free survival, and overall survival for patients with ulcerated primary lesions.
i
Exploratory subset analysis showed that largest effects were in patients with highest disease burden before resection (stage III, more involved lymph nodes), and
non-ulcerated primary tumor.

Melanoma Discussion
Pegylated IFN was also tested as an adjuvant therapy with potentially

High-Dose Interferon and Pegylated Interferon
better risk-benefit profile. The EORTC 18991 phase III randomized trial
High-dose IFN generally includes one month of IV induction with 20 compared pegylated IFN-alfa-2b with observation in 1256 patients with
MU/m2/d for 5 d/wk followed by 11 months of intermediate-dose completely resected stage III melanoma (without distant or in-transit
subcutaneous maintenance IFN with 10 MU/m2/d for 3 d/wk. This metastases). The pegylated IFN regimen included induction with 6
regimen has been evaluated in five large prospective randomized µg/kg SC per week for 8 weeks followed by maintenance with 3 µg/kg
clinical trials in patients with fully resected non-metastatic melanoma at SC per week for an intended duration of five years.376 Pegylated IFN
high risk for recurrence (Table 6). The smallest of these trials, ECOG improved recurrence-free survival compared with observation (4-year
E2696, was the only one to specifically allow recruitment of patients recurrence-free survival: 45.6% vs. 38.9%, P = .01); however, there was
with in-transit disease. Results from these trials vary, but nonetheless no statistically significant effect on OS. Based on these data, pegylated
suggest that high-dose adjuvant IFN can provide statistically significant IFN alfa received approval by the U.S. Food and Drug Administration
improvement in relapse-free and sometimes OS, at least at early time- (FDA) in 2011 as an adjuvant therapy option for patients with melanoma
points. However, both of these effects appear to diminish with longer- involving regional lymph nodes. After extended follow-up, however, the
follow-up (Table 6). The variability of results suggests that clinical effect on recurrence-free survival had only borderline statistical
benefit from adjuvant high-dose IFN may be limited to a subset of significance (7-year recurrence-free survival: 39.1% vs. 34.6%; HR,
patients, but it remains unclear which if any subsets of patients are most 0.87; 95% CI, 0.76–1.00; P = .055).377 There were no statistically
likely to benefit. Of note, ECOG 1690 showed that high-dose but not significant effects on distant metastasis-free survival (DMFS) and OS.
low-dose IFN significantly improved relapse-free survival compared with Subset analysis showed that patients more likely to benefit from
observation (Tables 5 and 6).365 pegylated IFN were those with microscopic nodal metastasis (not
clinically palpable) either limited to 1 node or associated with an
In an attempt to reduce toxicities associated with adjuvant high-dose
ulcerated primary lesion.
IFN, randomized trials have compared different dose schedules and
durations.370-375 Results differ across trials, however, so it is unclear
which schedules, if any, provide greater clinical benefit than the
standard regimen.

Melanoma Discussion
Table 6. High-Dose Interferona

IFN Patients, n Median Statistically Significant Impact of IFN
Trialb References
type IFN Obs Follow-up Relapse-free Survivalc Survivald
Kirkwood 1996378 6.9 y Yes; P = .0023 Yes; P = .0237
ECOG 1684 2b 143 137
Kirkwood 2004366 12.6 y Yes; P = .02 No
ECOG 1690 2b 215 212
Kirkwood 2004366 6.6 y Trend; P = .09 No
ECOG 1694 2b 440 440e
ECOG E2696 2b 72f 35f
Kirkwood 2004366 2.8 y No No
Sunbelt Trial McMasters 2016380 2b 112 106 5.9 y No No
c
IFN, interferon; NR, not reported; Obs, observation Relapse-free survival for ECOG trials, disease-free survival for Sunbelt Trial.
a
High-dose IFN regimen: 20 MU/m2/d IV for 5 d/wk for 4 weeks, then 10 d
Overall survival or melanoma-specific survival.
MU/m2/d SC for 3 d/wk for 48 weeks. e
Control was GM2-KLH21 vaccine (GMK) instead of observation.
b f
All prospective, randomized, multicenter studies comparing adjuvant interferon Treatment arms: A, GMK + High-dose IFN alfa-2b (n = 36); B: GMK alone;
with observation in patients with fully resected cutaneus non-metastatic then GMK + high-dose IFN alfa-2b (n = 36); C: GMK alone (n = 35); P = .03
melanoma at high risk for recurrence. for relapse-free survival from B versus C using Cox regression analysis.
Biochemotherapy showed improved median recurrence-free survival of 4.0 years

For patients with completely resected high-risk stage III disease, compared with 1.9 years for high-dose IFN alfa-2b (HR, 0.75 with 95%
biochemotherapy may be an appropriate adjuvant treatment option. CI, 0.58–0.97; P = .03). Median OS and 5-year OS rate were not
Biochemotherapy may be generally defined as any regimen that significantly different between the two treatment groups. Although the
includes both chemotherapy and immunotherapy, usually IFN and/or IL- overall percent of patients who experienced grade 3–5 adverse events
2. Adjuvant biochemotherapy with cisplatin, vinblastine, dacarbazine, IL- (AEs) was similar between treatment arms (76% for biochemotherapy
2, and IFN was compared with high-dose IFN alfa-2b monotherapy in vs. 64% for IFN-alfa-2a), the toxicity profiles for each regimen were
the SWOG S0008 phase 3 randomized trial.340 Eligible patients had fully different. IFN-alfa-2a was associated with significantly higher rates of
resected stage III cutaneous melanoma, including all except for the liver enzyme elevations, and biochemotherapy was associated with
lowest risk substage, stage IIIA-N1a (non-ulcerated primary tumor with significantly higher rates of hypotension and hematologic,
micrometastasis in one sentinel lymph node). Patients were more likely gastrointestinal, and metabolic toxicities.
to complete the 9-week biochemotherapy course versus the 52-week
course of IFN-alfa-2b (80% vs. 43% completion rate, P < .001). After a
median follow-up of 7.2 years, patients treated with biochemotherapy

Melanoma Discussion
High-dose Ipilimumab mg/kg every 12 weeks for up to 3 years or until documented disease
Immune checkpoint inhibitors, a relatively new class of therapies, target recurrence or unacceptable toxicity.341,381 In contrast, for treatment of
molecules involved in T-cell activation to promote immune responses unresectable or metastatic disease, the recommended ipilimumab dose
needed to fight cancer (See Checkpoint Immunotherapy Treatment is much lower (3 mg/kg) and the treatment duration much shorter (every
Administration section below). Ipilimumab, a monoclonal antibody three weeks for a total of four doses).381 Ipilimumab is associated with a
directed to the immune checkpoint receptor CTLA-4, has been shown to variety of immune-related adverse events (irAEs), and the frequency
significantly improve PFS and OS in patients with unresectable or and severity of these toxicities has been shown to increase with
metastatic melanoma (See Ipilimumab: Efficacy section below), and dose.382-385 A meta-analysis including 1265 patients from 22 clinical
originally received FDA approval in 2011 for treatment of patients with trials found that the risk of developing an irAE (any grade) was three-
metastatic melanoma. Based on its efficacy for treating metastatic fold higher with ipilimumab 10 mg/kg versus 3 mg/kg.383
disease, the phase 3 double-blind, randomized, multicenter,
In EORTC 18071, grade 3–4 AEs were more common with ipilimumab
international EORTC 18071 trial compared adjuvant high-dose
versus placebo (54% vs. 25%), as were irAEs (grade 3: 37% vs. 2%;
ipilimumab (10 mg/kg) to placebo in patients with completely resected
grade 4: 6% vs. <1%).341 Fatal ipilimumab-related AEs occurred in 5
stage III melanoma. Eligible patients included those with stage IIIA
patients (1%), and included colitis with gastrointestinal perforation (n =
disease (if N1a, at least one metastasis >1 mm), or with stage IIIB-C
3), myocarditis (n = 1), and multi-organ failure with Guillain-Barre
disease but no in-transit metastases. All patients had their primary
syndrome (n = 1).
tumor excised with adequate margins and complete regional
lymphadenectomy, but none had received systemic therapy for NCCN Recommendations
melanoma.341 The trial demonstrated improved recurrence-free survival:
For patients with node-negative, early-stage melanoma who are at risk
median 26.1 months with ipilimumab versus 17.1 months with placebo
for recurrence (stage IB or stage II, ≤1.0 mm thick with ulceration or
(HR stratified by stage = 0.75; P = .0013).341,381 Based on these results,
mitotic rate ≥1 per mm2, or >1.0 mm thick), postoperative management
the FDA approved high-dose ipilimumab for adjuvant treatment of
options include participation in a clinical trial or observation. For patients
patients with cutaneous melanoma with pathologic involvement of
with node-negative stage IIB or IIC disease, postoperative treatment
regional lymph nodes >1 mm diameter who have undergone complete
options include participation in a clinical trial, observation, or high-dose
resection, including total lymphadenectomy.381 The approved indication
IFN alfa (category 2B).
mostly mirrors the trial inclusion criteria, but also includes patients with
stage III in-transit disease and those who had received prior systemic For all patients with stage III melanoma, postoperative management
therapy for melanoma.341,381 options include participation in a clinical trial and observation. For those
with completely resected stage III melanoma, additional postoperative
Adjuvant ipilimumab was tested and FDA approved with a prolonged
management options may include high-dose or pegylated IFN,
high-dose regimen: 10 mg/kg every 3 weeks for 4 doses, followed by 10
biochemotherapy, or high-dose ipilimumab. Selection of an active

Melanoma Discussion
adjuvant treatment for these patients depends on many factors, resected stage IIIB-C; or 3) resected nodal recurrence. Enthusiasm for
including patient preference, patient age and comorbidities, and risk of this approach is tempered by the high rates of severe toxicities
recurrence. associated with the recommended adjuvant dose and duration of
treatment. The decision to recommend a course of adjuvant ipilimumab
Interferon should be informed by careful consideration of a patient’s individual risk
Due to the inconsistency of results, NCCN does not recommend use of recurrence and their ability to tolerate and manage toxicities. The
low-dose or intermediate-dose IFN. subset of patients with stage IIIA disease in this trial was small; the
benefit of high-dose adjuvant ipilimumab in this particular subset is less
Adjuvant high-dose and pegylated IFN are both appropriate options for
well defined. CLND was required for ipilimumab treatment in the trial;
patients with completely resected stage III disease. This
however, it is not clear that patients opting out of CLND should
recommendation is category 2A for patients with either positive sentinel
necessarily be excluded from consideration of this option, as ipilimumab
nodes or clinically positive nodes. There is panel consensus that high-
has demonstrated efficacy in treating metastatic disease, including
level evidence supports IFN therapy for improving relapse-free survival
nodal metastases.
in these patients, but that the effect of IFN on OS did not achieve
statistical significance with long-term follow-up. Adjuvant high-dose IFN Biochemotherapy
is a potentially toxic therapy that is not being used in all institutions, but Based on the results of SWOG S0008, biochemotherapy is another
panelists agree that it still may have a role in certain settings. The adjuvant option for patients with completely resected stage III disease.
clinical trials cited above included very few patients with in-transit Although the trial included some patients with stage III sentinel node-
disease. Hence, adjuvant IFN is a category 2B recommendation for positive disease and patients with stage III in-transit disease, the panel
patients with completely resected stage III in-transit disease. Decisions voted against including biochemotherapy as an adjuvant treatment
about adjuvant IFN treatment should be made on an individual basis, option for these pathways based the toxicity and limited benefit
after a thorough discussion with the patient about the potential benefits restricted to recurrence-free survival but not OS.
and side effects of therapy. If the decision is made to use adjuvant IFN,
the best available evidence suggests that options include using either Adjuvant Radiation Therapy
high-dose IFN with a planned duration of up to a year, or pegylated IFN Adjuvant Radiation for Desmoplastic Neurotropic Melanoma
with a planned duration of up to five years.
Adjuvant radiation therapy (RT) is rarely necessary following adequate
High-dose Ipilimumab excision of a primary melanoma. One exception may be desmoplastic
Based on results of EORTC 18071, adjuvant high-dose ipilimumab is neurotropic melanoma (DNM), which tends to be locally aggressive. In a
included as an adjuvant treatment option for select patients. NCCN retrospective series of 128 patients with DNM (84% stage II), patients
acknowledges high-dose ipilimumab monotherapy as an adjuvant who did and did not receive adjuvant radiation had a similar incidence of
treatment option for 1) resected stage IIIA with metastases >1 mm; 2) local failure (7% with RT vs. 6% without) despite worse prognostic

Melanoma Discussion
features in the radiated group (thicker tumors, deeper Clark level extension. At a median follow-up of 5 years, regional recurrence
invasion, and narrower excision margins).218 The authors concluded occurred in only 10% of the patients selected to receive adjuvant RT,
that radiation should be considered for patients with inadequate compared to 41% of the non-radiated patients. Adjuvant radiation was
margins, which in this series occurred predominately in the head and associated with improved locoregional control on multivariate analysis
neck region. A multicenter retrospective analysis in 277 patients with (P < .0001). Of note, treatment-related morbidity was significantly
primary stage I-III desmoplastic melanoma treated with wide excision increased with RT (5-year rate of 20% vs. 13%, P = .004), particularly
with or without SLNB showed that adjuvant RT was associated with lymphedema. Subsequent smaller retrospective analyses have also
improved local control, particularly in patients with positive excision shown that adjuvant RT after surgery is associated with improved nodal
margins or primary melanoma with Breslow thickness >4 mm or located basin control in patients with who are at high risk of regional
in the head and neck region. 386 Another retrospective study of patients recurrence.392,393 One retrospective analysis suggested that the benefit
with resected recurrent desmoplastic melanoma (n = 130) also showed of RT for regional control may be associated with doses of at least 50
that adjuvant RT was associated with improved local control but not Gy.394 Interpretation of these results should take into consideration
DMFS.387 The association of RT with improved local control was selection bias and many other potential forms of bias inherent in
particularly evident in those with pure desmoplastic melanoma or those retrospective studies.
with perineural invasion. The utility of RT for local control of
desmoplastic melanoma is further supported by the results from another The only prospective randomized phase III trial of adjuvant nodal basin
single-institution retrospective analysis (n = 95) showing a trend toward RT versus observation in patients at risk for nodal relapses recently
improved relapse-free survival in patients who received RT in addition reported final results. This trial included 250 patients with nonmetastatic
to surgery.388 Results from these four and one smaller retrospective disease and palpable lymphadenopathy at diagnosis or as an isolated
study389 suggest that adjuvant RT improves local control in patients with palpable site of relapse.395 Eligible patients were required to have an
desmoplastic melanoma, a hypothesis that is being tested in an ongoing LDH <1.5 times the upper limit of normal, as well as 1 parotid, 2
phase III trial comparing adjuvant RT with observation following cervical or axillary or 3 groin positive nodes, a maximum nodal
resection of neurotropic melanoma of the head and neck diameter 3 cm in neck, 4 cm in the axilla or groin, or nodal
(NCT00975520).390 extracapsular extension.396 Patients were treated with
lymphadenectomy followed by either adjuvant radiation (48 Gy in 20
Adjuvant Radiation for Preventing Nodal Relapse fractions) to the nodal basin or observation.395 After a mean of follow-up
Radiation has a role in controlling nodal relapse in patients at risk. The of 73 months, lymph node field recurrence was significantly less
largest retrospective review investigating the role of RT was performed frequent in the adjuvant radiation group (HR = 0.54; 95% CI, 0.33–0.89;
by Agrawal et al.391 Six hundred fifteen patients were evaluated who P = .021) for all nodal basins.395 Although not primary endpoints,
met the specific criteria portending a “high risk” of regional nodal relapse-free survival and OS showed no statistically significant
relapse, based on lymph node number, size, location, and extracapsular differences for patients treated with adjuvant RT versus observation.

Melanoma Discussion
Adjuvant radiation was associated with frequent grade 2 to 4 toxicities prospective randomized trial setting is needed to assess the impact of
primarily affecting the skin or subcutaneous tissue, but also including WBRT on melanoma brain metastases, especially in the context of
pain, nerve damage, and joint AEs. emerging data supporting the use of systemic therapy in patients with
melanoma brain metastases.
Various fractionation schemes for postoperative adjuvant radiation have
been evaluated in retrospective studies.386,397-401 Hypofractionated There are no good prospective randomized trials testing adjuvant SRS
radiotherapy appears to be equally as effective as standard following surgery for patients with brain metastases from melanoma, but
fractionation. These studies have shown moderate toxicity associated SRS is being increasingly used in an effort to reduce the risk of
with adjuvant RT. While some doses/schedules may be better tolerated, neurocognitive toxicities associated with WBRT.
prospective analyses are needed to establish the optimal regimen.
NCCN Recommendations
Adjuvant Radiation for Brain Metastases Most patients with in situ or early-stage melanoma will be cured by
Adjuvant radiation is also used after surgery for melanoma brain primary excision alone. However, patients with desmoplastic
metastases. Prospective randomized trials have compared adjuvant melanomas, especially those with extensive neurotropism, are at high
whole-brain radiation therapy (WBRT) with observation, given after risk for local recurrence, especially if margins are suboptimal. Adjuvant
surgery or stereotactic radiosurgery (SRS) in patients with brain radiation following surgery may be considered to improve local control.
metastases from various types of cancer.402-408 All but one of these
studies showed that adjuvant WBRT reduces intracranial recurrence, Adjuvant RT may be considered for select patients with clinically
and some studies also show improved duration of functional positive nodes and features predicting a high risk of nodal basin
independence and reduced mortality due to intracranial progression and relapse. The NCCN panel discussed at length the value of adjuvant RT
neurologic causes. However, these trials included very few patients with in patients at high risk of recurrence. Panelists agreed that high-level
melanoma—likely less than 60 patients all together—and did not report evidence indicates that adjuvant RT is useful in delaying or preventing
results specifically from patients with melanoma. The largest of these nodal relapse. However, some institutions argued that the increased
prospective randomized trials included 18 patients with melanoma, and incidence of late RT-related toxicity could potentially outweigh the
showed that adjuvant WBRT after resection or SRS reduced intracranial benefit of reducing nodal basin recurrence. This, coupled with the
progression but did not lead to statistically significant improvements in statistically insignificant trend towards worse OS in the RT arm resulted
OS or duration of functional independence.408 A few retrospective in substantial heterogeneity of opinion among panel members as to the
studies have reported outcomes for patients with brain metastases from role of adjuvant nodal basin RT. Patient characteristics that suggest
melanoma treated with adjuvant WBRT after either surgery or SRS, but potential use of radiation are those used as entry criteria in the phase III
data from these analyses are insufficient for evaluating the clinical value trial described above.396 The use of adjuvant RT for these patients is a
of adjuvant WBRT for patients with melanoma.409,410 Further study in a category 2B recommendation, reflecting nonuniform panel consensus
on its value. Careful patient selection based on location, size, number of

Melanoma Discussion
positive nodes, and gross (instead of histologic) extranodal extension is 3) Systemic therapy: Systemic treatments have antitumor effects on
critical. The benefits of adjuvant RT must be weighed against the existing in transit lesions and may help delay/prevent further
increased likelihood of long-term skin and regional toxicities that can regional or subsequent systemic recurrence.
affect quality of life. Consideration should be given to potential
Many different treatment options, mostly locoregional, are available to
interactions between radiation and systemic therapy.
patients presenting with stage III in-transit metastases. The choice of
The current data regarding adjuvant RT, either WBRT or SRS, for therapy depends on the patient’s health status and tumor burden,
resected brain metastases are insufficient to formulate a specific defined by the size, location, and number of tumor deposits. Since the
recommendation. Adjuvant RT should be considered for these patients tempo of spread of in-transit disease is not always known at
on a case-by-case basis. With the advent of more effective systemic presentation, it may be reasonable to start with conservative local
therapy, melanoma patients are living longer than in the past, and may therapies and move to regional/systemic therapy if response to local
be more susceptible to the long-term neurocognitive toxicity of WBRT. therapy is short-lived.
For adjuvant therapy of recurrent disease, see Treatment of Local Therapy

Recurrence. Excision to clear margins is the mainstay of treatment for limited
resectable in-transit metastasis. Although in-transit disease has a high
Treatment for Stage III In-transit Disease probability of clinically occult regional nodal involvement, and a positive
The tumor burden, time course of appearance, and duration of in-transit sentinel node in the presence of in-transit metastasis portends a more
disease is variable. In some patients, in-transit lesions remain confined ominous prognosis, the impact of SLNB on outcome remains
to a region of the body for many years. This may occur in isolation or in unknown.411
combination with other sites of metastatic disease. A major concern in
For patients for whom resection is not feasible, prior resections have
patients in which in-transit disease occurs in isolation is the high
been unsuccessful, or who refuse surgery, non-surgical local
probability of subsequent development of visceral metastasis.
approaches for treating stage III in-transit melanoma include
Therapies for isolated in-transit disease can be organized as:
intralesional injections, local ablation therapy, topical imiquimod, and
1) Local therapy: Local treatments reduce the morbidity of in-transit RT.
lesions but have a low/variable effect on the appearance of new
Intralesional Injections
lesions.
A variety of agents have been tested as intralesional injections for
2) Regional therapy: Regional therapies treat the entire lymphatic melanoma. Key results from those showing he most promise are
basin and may not only eliminate visible tumors but also prevent summarized in Table 7.
outgrowth of new lesions in the region.

Melanoma Discussion
Talimogene Laherparepvec For T-VEC, common toxicities (treatment-emergent in ≥20%, any grade)
Intralesional or perilesional injection of melanoma metastases with were fatigue, chills, pyrexia, nausea, flu-like illness, injection-site pain,
granulocyte macrophage colony-stimulating factor (GM-CSF) has and vomiting.417 Treatment-related toxicities of grade 3-4 occurred in
shown modest response rates or stable disease in several small clinical 11% of patients, and included injection-site reactions (eg, cellulitis, pain,
studies.412-415 These studies and others led to the development of peripheral edema) and systemic toxicities (fatigue, vomiting, and other
talimogene laherparepvec (T-VEC), an agent that uses a modified flu-like symptoms).
herpes simplex virus to induce tumor cell lysis and to deliver localized
expression of GM-CSF to injected lesions.416 A recent phase 3 trial in Interleukin-2
select patients with unresectable stage IIIB-IV melanoma randomized Intralesional injection with IL-2 is supported by a number of clinical
subjects to intralesional injection T-VEC versus subcutaneous injection studies (Table 7). The complete response rate in IL-2 injected lesions
of GM-CSF.417 Patients were required to have at least one cutaneous, may be as high as 70%. Although response rates are higher in
subcutaneous, or nodal lesion or aggregation of lesions >10 mm in cutaneous lesions, good response rates have been observed in
diameter, bidimensionally measurable disease, and limited distant subcutaneous lesions as well.419 Intralesional injection of IL-2 is far less
metastatic disease (with specific definitions). T-VEC produced clinically toxic than high-dose IV IL-2. Grade 1-2 adverse effects are common but
significant durable response rates (DRRs) in injected tumors, and a manageable, and grade 3-4 toxicities are extremely rare.419-421
bystander effect on some uninjected non-visceral and visceral tumors Intralesional IL-2 is usually associated with an injection site
(Table 7).418 At a median follow-up of 44 months (range 32–59 months), inflammatory reaction with local swelling, erythema, pain, and
patients treated with T-VEC compared with GM-CSF showed a higher sometimes necrosis. Common systemic effects include fever and other
DDR (16.3% vs. 2.1%, P < .001) and overall response rate (26.4% vs. flu-like symptoms (chills, fatigue, nausea, and emesis, and sometimes
5.7%, P < .001; complete response in 11% vs. <1%).417 stomach pain, diarrhea, and headache) that are usually mild and often
respond to analgesics.419,420,422
Exploratory subset analyses showed that the effect of T-VEC on
response was greater for patients with less advanced disease. Patients Less Common Intralesional Injection Agents
IFN has been used as an intralesional injection agent for treating in-
with stage IIIB or IIIC disease had a DRR of 33% with T-VEC compared
transit melanoma, although there is very little published evidence to
with 0% for GM-CSF. For patients with stage IV-M1a disease, the effect
support this approach (case reports and one small retrospective
of T-VEC on DRR was smaller (16.0% vs. 2.3%). For patients with
study423).
stage IV-M1b or -M1c disease, however, the effects of T-VEC on DRR
and OS were small and not statistically significant. The effect of T-VEC Intralesional Bacillus Calmette-Guérin (BCG) has been shown to
on DRR was far more profound in patients with previously untreated provide at least transient complete or partial responses in most injected
metastatic disease (23.9% vs. 0%) than for those with previously lesions, with much higher response rates in cutaneous versus
treated metastatic disease (9.6% vs. 5.6%). subcutaneous metastases (Table 7).424-426 Although initial response

Melanoma Discussion
rates are high for injected lesions, intralesional BCG is associated with metastases by intralesional injection (using PV-10, a 10% w/v Rose
a number of significant local and occasional systemic adverse Bengal saline solution).428,429 It has similar activity to other intralesional
effects.425-427 BCG injection has been largely supplanted by other local agents, but is not currently available outside of the clinical trial setting
injection options and is rarely used in clinical practice. (NCT02288897).
Rose Bengal, a photosensitizing dye, is an investigational agent in

development as another method for chemoablation of melanoma
Table 7. Intralesional Injection

Response Rates
Injection Agent Key Published Clinical Studies
Injected Lesions Uninjected Lesions
 ≥50% decrease in size:
Talimogene
 Phase III trial417,418 ≥50% decrease in size: 64%  32% of non-visceral
laherparepvec (T-VEC)
 15% of visceral
 >5 non-comparative studies, including several phase II CR: 67%–96%
No responses seen in two
Interleukin-2 trials419,420 and retrospective/observational analyses430-433  80% for dermal
phase 2 trials
 2014 systematic reviews and meta-analysis421  73% for subcutaneous
CR:
Bacillus Calmette-Guérin  >10 prospective pilot/retrospective studiesa Occasional responses
 90% for dermal
(BCG)  1 prospective randomized study426 observed
 45% for subcutaneous
 Phase I trial428
Rose Bengal OR: 46%–58% OR: 27%
 Phase II trial429
CR, complete response, defined as the percent of lesions that disappeared; NR, not reported; OR, objective response, defined as the percent of lesions showing
partial or complete response.
a
Most included fewer than 30 patients. See Krown et al. 1978,425 Morton et al. 1974,434and Table 5 in Tan et al. 1993,424 a pooled analysis of 15 studies.
Other Local Therapies this technique has largely been supplanted by more contemporary
Local Ablation approaches.
The efficacy of laser ablation, primarily carbon dioxide laser ablation, for
treatment of melanoma metastases, is reported in a number of non- Topical Therapy
In patients with in-transit/locally metastatic disease, case reports
comparative retrospective analyses (15–100 patients/study).435-441
suggest that imiquimod monotherapy can provide partial and complete
Ablation can be effectively achieved with minimal toxicity,435,437,438,441 but
responses in patients with cutaneous metastases, but is less likely to be

Melanoma Discussion
effective on deep dermal or subcutaneous metastases.442-446 Other approaches are limited to patients with regional metastases confined to
studies have shown that imiquimod used in combination with another an extremity.
local therapy can provide high rates of durable response in patients with
locally metastatic melanoma.444,447-453 ILP, the first of these techniques to be developed, was introduced in the
late 1950s and has been refined and modified to improve response
Topical immunotherapy using diphencyprone (DPCP), also known as rates and minimize toxicities.471,472 Although other agents have been
diphenylcyclopropenone, has been studied in patients with in-transit used for ILP, and many have yet to be tested, melphalan (L-
melanoma, either alone or in combination with other concomitant phenylalanine mustard) is the cytotoxic agent most commonly used,
therapies. As with topical imiquimod, supporting evidence for this often in combination with either actinomycin D or TNF-alfa.472-475
approach comes primarily from case studies reporting remarkable Response rates after ILP have improved as the method has been
responses in some patients.454-461 One retrospective study included 50 refined. A large systematic review (n = 2018 ILPs, 22 trials) found that
patients with in-transit cutaneously metastatic melanoma treated for at for patients with unresectable stage IIIB-IIIC metastatic melanoma of
least one month with DPCP.462 Complete clearance of cutaneous the limbs, studies published between 1990 and 2008 reported a median
disease was observed in 46% of patients, and another 38% showed overall response rate of 90% (range 64%–100%) and a median
partial response. DPCP is not FDA approved for this indication but may complete response rate of 58% (range, 25%–89%).474 Median complete
be available in the context of clinical trials. response rate varied somewhat depending on the agents used, ranging
from 47% with single-agent melphalan, 45% to 65% for
Radiation melphalan/actinomycin D combination, and up to 70% with
RT may be used for selected patients with unresectable symptomatic
melphalan/TNF-alfa combination.474 These response rates are mostly
regional recurrences for whom there are no better options. A wide
derived from retrospective series, and the differences reported depend
variety of dose schedules has been employed. See Palliative Radiation
on definitions of response often spanning decades and on patient
Therapy.
selection factors. The reported differences in response rates may not be
Regional Therapy: Isolated Limb Perfusion and Infusion clinically significant. For example, a prospective randomized clinical trial
directly comparing hyperthermic ILP with single-agent melphalan to
For patients with regionally recurrent melanoma not suitable for local or
combination melphalan and TNF-alfa did not show a significant
topical therapy, regional administration of cytotoxic chemotherapy with
difference in response rate.476 TNF-alfa is currently unavailable for use
either isolated limb perfusion (ILP) or isolated limb infusion (ILI) is
in the United States.
designed to administer high doses to an affected extremity while
avoiding toxicities associated with systemic drug exposure. These Disadvantages to ILP include the technical complexity and invasiveness
approaches also allow delivery of chemotherapy under hyperthermic of the procedure, which make it challenging (or contraindicated) in
conditions, suggested by some studies to improve efficacy of cytotoxic elderly and frail patients, and difficult to use again in the same patient in
agents,463-468 but also associated with increased toxicity.469,470 These the event of recurrence or progression.477 This approach should only be

Melanoma Discussion
performed in centers with the expertise to manage both the procedure local, regional, or systemic therapies can be considered. If the patient
and the potential complications. has a limited number of in-transit metastases, particularly dermal
lesions, which are not amenable to complete surgical excision,
In the 1990s ILI was developed as a simpler and less invasive intralesional local injections should be considered. Patients with least
approach,478 amenable to repeated applications,479 and safe for use in one cutaneous, subcutaneous, or nodal lesion or aggregation of lesions
elderly patients.480 Melphalan is commonly used for ILI, often with >10 mm in diameter, may be appropriate candidates for intralesional
actinomycin D.481 Addition of papaverine for cutaneous vasodilation has injection with T-VEC. Intralesional injection with T-VEC is a
been shown to increase response rate but also the risk of regional recommended option for patients with unresectable stage III in-transit
toxicity.482,483 ILI is associated with lower rates of toxicity and morbidity disease based on improved durable and overall response rate
compared with ILP, but retrospective comparisons of response and compared to injection with GM-CSF alone. If T-VEC is not available,
survival with ILP versus ILI have shown varying results.482,484-488 An intralesional injection with IL-2 is another option, as is injection with
analysis of seven studies, including 576 patients, primarily with stage III BCG or IFN. All of these options are category 2B recommendations.
disease, treated with melphalan/actinomycin D combination via ILI,
showed an overall response rate of 73%, with complete response in Based on non-comparative studies, laser ablation, topical imiquimod, or
33% (range, 26%–44% across studies), partial response in 40% (33%– RT are category 2B options that may help for palliation or to establish
53%), and stable disease in 14%.481 A smaller pooled analysis of two regional control for selected patients with unresectable in-transit
additional studies (N = 58), one a non-comparative phase II study disease. Topical imiquimod can be considered as an option in very low-
(NCT00004250), showed similar overall response rates for stage IIIB volume cutaneous metastases.
versus stage IIIC disease (48% vs. 40%), and similar 5-year survival
rates (38% vs. 52%).489 Complete responses were achieved in 25% of For patients with multiple regional in-transit metastases confined to an
patients, partial responses in 20%. extremity, regional chemotherapy by hyperthermic perfusion or infusion
is an option. Although ILP and ILI can be technically challenging, they
NCCN Recommendations can result in high initial and durable regional response rates when
Treatment in the context of a clinical trial is the preferred option for in- administered properly.
transit disease. For those with a single or a small number of resectable
With the advent of more effective systemic therapy, this approach is
in-transit metastases, complete surgical excision with histologically
increasing be considered as a first-line treatment option for regionally
negative margins is preferred, if feasible. In the patient undergoing
recurrent melanoma. See Systemic Therapy for Advanced Melanoma
curative resection of a solitary in-transit metastasis, SLNB can be
for treatment options.
considered (category 2B).
If a complete surgical excision to clear margins is not feasible, treatment

in the context of a clinical trial is generally the preferred option. Other

Melanoma Discussion
Given the number of options available, clinical judgment and checkpoints exploited by cancers to decrease immune activity. For
multidisciplinary consultation is often helpful to determine the order of example, activation of T helper cells upon binding to antigens on the
therapies. antigen-presenting cell (APC) can be modulated by other receptor-
ligand interactions between the two cells. Cytotoxic T lymphocyte
Treatment for Distant Metastatic Disease (Stage IV) antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) are
Systemic Therapy for Advanced Melanoma two examples of receptors on T-cells that upon ligand binding trigger a
The therapeutic landscape for metastatic melanoma is rapidly changing signalling cascade that inhibits T-cell activation, limiting the immune
with the recent development of novel agents, which have demonstrated response.505-508 Antibodies against these receptors (eg, ipilimumab,
better efficacy than traditional chemotherapy. The first generation of nivolumab, pembrolizumab) prevent receptor-ligand interaction,
novel targeted and immunotherapy agents (ie, vemurafenib, dabrafenib, removing the inhibition of T-cell activation and ‘releasing the brake’ on
ipilimumab) demonstrated significantly improved response rates and the immune response.509-511
outcomes compared with conventional therapies. Subsequently, a
Ipilimumab
number of ongoing or recently completed phase II and phase III trials Ipilimumab is a monoclonal antibody directed against the immune
testing new immunotherapies, targeted therapies, and combination checkpoint receptor CTLA-4. Two phase III trials in patients with
regimens have yielded noteworthy results.93,417,490-501 A second unresectable stage III or stage IV melanoma support the use of
generation of effective agents and combination regimens are now ipilimumab for advanced disease (Table 8). Results from these trials
available for treatment of advanced unresectable or metastatic showed that ipilimumab improved response rates, response duration,
melanoma. PFS, and OS in patients with previously treated or previously untreated
advanced disease.512,513 Most importantly, extended follow-up showed
Checkpoint Immunotherapy
that ipilimumab resulted in long-term survival in approximately 20% of
The immune system may be capable of identifying and destroying
patients (5-year OS: 18% vs. 9% for dacarbazine),514 consistent with
certain malignant cells, a process called immunosurveillance.
findings from phase II trials.515,516,517 Safety results from these trials
Conditions or events that compromise the immune system can lead to
showed that ipilimumab is associated with a substantial risk of irAEs,
cancer cells escaping immunosurveillance.502-504 Once cancer cells
including grade 3-4 events (Table 8) and drug-related deaths (7 in
have escaped immunosurveillance and have begun to proliferate, their
CA184-002).512 Even higher rates of grade 3-4 irAEs were observed in
genetic and phenotypic plasticity enables them to develop additional
patients treated with ipilimumab in CA184-024 (Table 8), possibly due to
mechanisms by which the nascent tumor can evade, thwart, or even
the high dose used (10 mg/kg), or due to combination therapy with
exploit the immune system.502-504 Immunotherapies are aimed at
dacarbazine, or both.513 Combination therapy with ipilimumab and
augmenting the immune response to overcome or circumvent the
dacarbazine therefore is not used in clinical practice, and the FDA-
immune evasion mechanisms employed by cancer cells and tumors.
recommended dose of ipilimumab is 3 mg/kg rather than 10 mg/kg.381
Some of the most effective immunotherapies target immune
Immune-related AEs associated with ipilimumab and other checkpoint

Melanoma Discussion
inhibitor regimens are detailed in the Toxicity of Checkpoint frequency and types of ipilimumab-related irAEs seemed similar for
Immunotherapies section. reinduction as for initial treatment, and patients who experienced
toxicities during the initial round of therapy did not necessarily
Given that treatment options may be limited for heavily pretreated experience the same irAEs upon reinduction.518
patients who have progressed after checkpoint inhibitor therapy, it is
noteworthy that reinduction therapy with ipilimumab was administered to Although the pivotal phase III ipilimumab trials excluded patients with
a small number of patients in CA180-002 who had progressed after active CNS metastases, results from an open-label, phase II study
showing initial clinical benefit (responses or stable disease lasting ≥3 (CA184-042; Table 8) showed a modest CNS disease control rate and
months). Disease control (CR, PR, or SD) was achieved upon acceptable toxicity in patients with brain metastases.136
ipilimumab reinduction in most of these patients (20/31).512,518 The
Table 8. Ipilimumab Trials in Advanced Melanomaa

Trial Patients Responsec
Grade 3-4
Name and Phase Tx CNS Treatment Arms PFSd OSd
b Rate Onset Duration irAEse
References Design Naive Mets
 Ipi + gp100 (n = 403) 6% P = .04 3.3 17%g 2.8 P < .05h 10.0 P < .001
CA184-002 III
None 12%f  Ipi (n = 137) 11% P = .001 3.2 60%g 2.9 P < .001h 10.1 P = .003
}10%–15%
NCT00094653512 RDB
 gp100 (n = 136) 2% 2.7 0g 2.8 6.4 3%
CA184-024 III  DTIC + ipi (n = 250) 15% NR 19.4 NR 11.2 38%
100% None P = .09 P = .03 P = .0006g P < .001
NCT00324155513 RDB  DTIC + pbo (n = 252) 10% NR 8.1 NR 9.1 4%
CA184-042 II  Ipi, ASXi (n = 51) 10% NR NR 1.4 7.0 NR
≥71% 100%
NCT00623766136 OL  Ipi, Sxi (n = 21) 5% NR NR 1.2 3.7 NR
ASX, patients with asymptomatic brain metastases; CNS Mets, percent of patients with central nervous system metastases at baseline; CR, complete response;
DTIC, dacarbazine; gp100, gp100 peptide vaccine; ipi, ipilimumab; irAEs, immune-related adverse events; Sx, patients with symptomatic brain metastases; NR,
not reported; OL, open-label; pbo, placebo; R, randomized; RDB, randomized, double-blind; Tx, treatment.
a e
Unresectable stage III or stage IV melanoma. Percent of patients who experienced any type of treatment-related irAE of
b
Percent of patients with previously untreated advanced disease. grade 3 or 4.
c f
Response rate is the percentage of patients who achieved complete or partial Patients with active CNS metastases were excluded from the trial.
g
response. Time to onset is the median time to response, given in months. Percent of patients with response duration >24 months.
h
Response duration is given as the median, in months, unless otherwise Although median PFS was similar across arms. P values for PFS and OS refer
indicated. P values are for comparisons with the control arm. to differences in Kaplan-Meier survival distributions.
d i
Median PFS and OS are given in months. Median duration, P value, and HR Results were reported for patients with asymptomatic versus symptomatic
were determined using the Kaplan-Meier method. brain metastases.

Melanoma Discussion
Anti-PD-1 Agents nivolumab, improves response and PFS compared with chemotherapy
While anti CTLA 4 therapy seems to interfere primarily with the or ipilimumab (monotherapy), and is associated with lower risk of AEs
feedback mechanism at the interface between T cell and antigen- (Table 9).500 Results from KEYNOTE-006 showed that pembrolizumab
presenting dendritic cell, anti-PD-1 inhibitors are thought to interfere also improved OS compared with ipilimumab.500 The efficacy and
primarily with the feedback mechanism at the interface of T cell and safety of pembrolizumab did not appear to be significantly affected by
tumor cell.519 the dose level (2 mg/kg vs. 10 mg/kg) and frequency (every 2 weeks
[Q2W] or every three weeks [Q3W]), and all the regimens tested in
Pembrolizumab
these trials improved response and outcomes compared with
Randomized trials in patients with unresectable stage III or stage IV
controls.495,500,520
metastatic disease have shown that pembrolizumab (monotherapy), like
Table 9. Pembrolizumab Trials in Advanced Melanomaa
Trial Patients Responsed
Grade
BRAF Treatment Arms PFSe OSe 3-4
Name and Phase Tx Brain
b V600 c Rate Onset Duration AEsf
Mut
KEYNOTE-001 I  Pembro 2 mg/kg (n = 89) 26% 2.8 ND 5.1 58% 15%
Noneg 18% 9%
NCT01295827520 R, OL, E  Pembro 10 mg/kg (n = 84) 26% 2.8 ND 3.2 63% 8%
 Pembro 2 mg/kg (n = 180) 21% P < .0001 3 ND 2.9i P < .0001 ND 11%
KEYNOTE-002 II
None g 23% NR  Pembro 10 mg/kg (n = 181) 25% P < .0001 3.5 ND 2.9 P < .0001
i ND 14%
NCT01704287495 R, OL
 Chemoh (n=179) 4% 3 37 2.7 ND 26%
 Pembro Q2W (n = 279) 34% P < .001 2.8 8.3 5.5 P < .001 74% P < .0005 13%
KEYNOTE-006 III
34% 36% 9%  Pembro Q3W (n = 277) 33% P < .001 2.8 ND 4.1 P < .001 68% P = .0036 10%
NCT01866319500 R, OL
 Ipi (n = 278) 12% 2.9 ND 2.8 58% 20%
BRAF V600 Mut, percent of patients with a mutation in BRAF at V600; Chemo, chemotherapy; CNS Mets, percent of patients with central nervous system
metastases at baseline; E, expansion; ipi, ipilimumab; Mut, mutated; ND, not determined because longer follow-up is needed; NR, not reported; OL, open label;
pembro, pembrolizumab; Q2W, every 2 weeks; Q3W, every 3 weeks; R, randomized.
a f
Unresectable stage III or stage IV melanoma. Percent of patients who experienced any type of treatment-related AE of grade
b
Previously untreated advanced disease. 3 or 4.
c g
Patients with active CNS metastases were excluded from the trials. All were previously treated with ipilimumab and progressed; patients with BRAF
d
Response rate is the percentage of patients that achieved complete or partial mutations were also previously treated with BRAF or MEK inhibitors, or both.
h
response. Time to onset is the median time to response, given in months. Investigator’s choice chemotherapy.
i
Response duration is given as the median, in months, unless otherwise Median PFS and HRs varied by method of assessment; for all analyses
indicated. P values are for comparisons with the control arm. P < .0001.
e
Median PFS is given in months. OS is given as 1-year rate. Median duration, P
value and HR were determined using the Kaplan-Meier method.

Melanoma Discussion
The results of Checkmate 066 and 067 demonstrated that in the first-
Nivolumab
Two phase III clinical trials have demonstrated nivolumab efficacy in line setting nivolumab is a better option than chemotherapy or
previously untreated unresectable stage III or stage IV melanoma ipilimumab for patients with unresectable or metastatic disease. An
(Table 10). Results from Checkmate 066 showed that nivolumab ongoing trial, Checkmate 037, has shown that nivolumab also improves
improved response rate, PFS, and OS compared with chemotherapy. response rate compared with chemotherapy in patients with previously
The percent grade 3-4 AEs was lower with nivolumab compared to treated unresectable stage III or stage IV melanoma (Table 10).490
chemotherapy.496 Remarkably, the survival curve suggests that Safety results suggest that nivolumab may be better tolerated than
nivolumab may lead to long-term survival in at least 50% of patients. chemotherapy in heavily pretreated patients with advanced disease.490
Results from Checkmate 067 showed that nivolumab (monotherapy) Further follow-up is needed to verify whether nivolumab improves PFS
improved response rate and PFS compared with single-agent or OS in patients with previously treated advanced disease.
ipilimumab, and was associated with lower toxicity.492

Melanoma Discussion
Table 10. Nivolumab Trials in Advanced Melanomaa

Trial Patients Responsed
BRAF Grade
Name and Phase Tx CNS Treatment Arms PFSe OSe
b V600 c Rate Onset Duration 3-4 AEsf
Mut
CheckMate 066 III  Nivo (n = 210) 40% 2.1 ND 5.1 73% 12%
100% 0% 3.6% P < .001 P < .001 P < .001
NCT01721772496 RDB  DTIC (n = 208) 14% 2.1 6 2.2 42% 18%
 Nivo + ipi (n = 314) 57% P < .001 2.8 ND 11.5 P < .001 ND 55%
CheckMate 067 III
100% 32% 3.6%  Nivo (n = 316) 44% P < .001 2.8 ND 6.9 P < .001 ND 16%
NCT01844505492 RDB
 Ipi (n = 315) 19% 2.8 ND 2.9 ND 27%
CheckMate 069 II  Nivo + ipi (n = 95) 59% ~3 ND 8.5-NDi ND 54%
100% 23% 3%g P < .001 P < .001
NCT01927419499 RDB  Ipi (n = 47) 11% ~3 ND 2.7-4.4i ND 24%
CheckMate 037 III 19%g  Nivo (n = 272) 31% 2.1 ND 4.7 ND 9%
0% 22% NS
NCT01721746 490 R, OL 14%g  Chemoh (n = 133) 8% 3.5 3.5 4.2 ND 31%
BRAF V600 Mut, percent of patients with a mutation in BRAF at V600; Chemo, Response duration is given as the median, in months, unless otherwise
chemotherapy; CNS Mets, percent of patients with central nervous system indicated. P values are for comparisons with the control arm.
e
metastases at baseline; CR, complete response; DTIC, dacarbazine; ipi, Median PFS is given in months. OS is given as 1-year rate. Median duration,
ipilimumab; nivo, nivolumab; PR, partial response; ND, not determined P value, and HR were determined using the Kaplan-Meier method.
f
because longer follow-up is needed; NS, not statistically significant; OL, open- Percent of patients who experienced any type of treatment-related AE of grade
label; RDB, randomized, double blind. 3 or 4.
a g
Unresectable stage III or stage IV melanoma. Patients with a history of brain metastases.
b h
Previously untreated advanced disease. Investigator’s choice chemotherapy: single-agent dacarbazine or
c
Patients with active CNS metastases were excluded from the trials. carboplatin/paclitaxel combination.
d i
Response rate is the percentage of patients that achieved complete or partial Reported separately for patients with BRAF V600 mutation and BRAF wild-
response. Time to onset is the median time to response, given in months. type disease.
single-agent ipilimumab. Both these trials also showed substantially

Anti-CTLA-4/Anti-PD-1 Combination Therapy
As shown in Table 10, results from two randomized trials demonstrated increased toxicity with immune checkpoint combination therapy versus
that ipilimumab/nivolumab combination therapy significantly improved monotherapy.
response and PFS compared with ipilimumab monotherapy in patients
with previously untreated unresectable stage III or stage IV
disease.492,499 Further follow-up is needed to determine whether
nivolumab/ipilimumab combination therapy improves OS compared with

Melanoma Discussion
Anti-PD-1 Therapy in Patient Subpopulations Before or After Anti-CTLA-4 Therapy

Ongoing studies are aimed at determining the efficacy of sequential
BRAF Mutation Status
Subgroup analyses in the Checkmate and KEYNOTE trials showed monotherapy with ipilimumab and PD-1 inhibitor. Preliminary results
that both patients with BRAF mutant tumors and those with BRAF wild- from a randomized phase II trial show similar safety but improved
type tumors derived clinical benefit from anti-PD-1 therapy compared response for patients treated with nivolumab followed by ipilimumab
with controls (single-agent ipilimumab or chemotherapy).490,492,495,500 compared with patients who received these therapies in the reverse
Likewise, subgroup analyses in CheckMate 067 and 069 showed order.525
improved efficacy with nivolumab/ipilimumab combination therapy
Checkpoint Immunotherapy Treatment Administration
compared with ipilimumab monotherapy regardless of BRAF mutation The ipilimumab treatment regimen of 3 mg/kg every three weeks for
status.492,499 four doses is well supported by clinical trial data and approved by the
FDA.381,512,513 For anti-PD-1 agents, however, there are fewer data to
PD-L1 Expression
To determine whether the PD-1 ligand (PD-L1) could be used to identify support the optimal dose and duration of treatment. Tables 11 through
candidates for anti-PD-1 therapy, PD-L1 expression was assessed in 13 summarize the treatment dosing and duration used in the pivotal
tumor samples from patients in the CheckMate and KEYNOTE trials, trials supporting anti-PD-1 agents for use in unresectable or metastatic
and expression level cutoffs were chosen to divide patients into “PD-L1 melanoma. The FDA-recommended dosing regimen for single-agent
positive” and “PD-L1 negative” subgroups.490,492,496,499,521 Across trials nivolumab matches that used in all 3 phase III trials shown in Table 11:
results showed that for both subgroups, anti-PD-1 monotherapy 3 mg/kg every 2 weeks until disease progression or unacceptable
provided clinical benefit compared with controls (single-agent toxicity.490,492,496,526 The FDA-recommended dosing for pembrolizumab is
ipilimumab or chemotherapy), and nivolumab/ipilimumab combination 2 mg/kg every 3 weeks until disease progression or unacceptable
therapy improved efficacy compared with ipilimumab. The apparent toxicity.527 The FDA-recommended dosing regimen for
prognostic value of PD-L1 may have been limited by the expression nivolumab/ipilimumab combination therapy is nivolumab 1 mg/kg
assays and cutoffs used in these studies. Although PD-L1 expression followed by same-day ipilimumab 3 mg/kg, every 3 weeks for 4 doses;
continue to be developed, in current form they are not sufficiently then single-agent nivolumab 3 mg/kg every 2 weeks until disease
reproducible, widely available, nor discriminative for screening patients progression or toxicity.381,526
with melanoma.
Although the product labels for nivolumab and pembrolizumab indicate
Brain Metastases that treatment should continue until disease progression or
In the CheckMate and KEYNOTE trials, 3% to 19% of patients had unacceptable toxicity,526,527 the published trials allowed shorter or longer
brain metastases (Tables 9 and 10). Ongoing trials have been designed treatment in certain situations. Discontinuation is common among
to specifically address the safety and efficacy of anti-PD-1 in patients patients treated with anti-PD-1 therapy, and hence clinical experience
with melanoma brain metastases.522-524 with treatment beyond one year is currently limited. For the trials listed

Melanoma Discussion
in the tables, results published thus far (median follow-up <2 years) indicate whether anti-PD-1 treatment beyond two years is needed to
show discontinuation rates of 45% to 77% in patients treated with anti- maintain disease control. Studies are needed to explore this question
PD-1 therapy. In the KEYNOTE-002 study, pembrolizumab was and test whether switching to lower-frequency maintenance therapy is
administered for a maximum of 24 months. Further follow-up should sufficient to maintain long-term clinical benefit.
Table 11. Nivolumab Treatment Regimens
Trial Dosing Treatment Duration
CheckMate 066 496
 Until disease progression or unacceptable toxicity.
CheckMate 067492 3 mg/kg Q2W  Patients who had clinical benefit could opt for treatment beyond progression, provided
CheckMate 037490 they had not experienced substantial AEs.
Table 12. Pembrolizumab Treatment Regimens

 Until disease progression or unacceptable toxicity.
KEYNOTE-002495 2 mg/kg or 10 mg/kg Q3W  Patients with PD at 12-week scan could opt to continue until confirmation of PD at next
scan.
 Until disease progression, unacceptable toxicity, or 24 months.
KEYNOTE-006500 10 mg/kg Q2W or Q3W
 Patients with CR lasting ≥6 months could discontinue after an additional 2 treatments.
Table 13. Ipilimumab/Nivolumab Combination Treatment Regimens

CheckMate 067492 1 mg/kg nivo + 3 mg/kg ipi  Until disease progression or unacceptable toxicity.
(same day), Q3W for 4 doses;
 Patients who had clinical benefit could opt for treatment beyond progression, provided
then 3 mg/kg nivo
CheckMate 069499 monotherapy Q2W they had not experienced substantial AEs.
Ipi, ipilimumab; nivo, nivolumab; Q2W, once every 2 weeks; Q3W, once every 3 weeks
system is active throughout the body, and irAEs can occur in any
Toxicity of Checkpoint Immunotherapies
Immunotherapy-associated AEs tend to be inflammatory or autoimmune organ.528,535 Unlike chemotherapy, which directly kills or damages cells,
in nature, often due to reduction in self-tolerance, proliferation of immunotherapy acts indirectly by altering complex multi-step immune
activated T-cells, and pro-inflammatory reactions (release of cytokines) processes. Therefore, it is not surprising that for immunotherapy the
in normal (non-cancerous) organs and tissues.528-534 The immune incidence and severity of toxicities may not correlate well with dose;

Melanoma Discussion
rather than reducing dose, withholding or discontinuing treatment is pembrolizumab both include specific warnings regarding pneumonitis
often the recommended method for AE management. and nephritis.381,526,527,538
Most of the treatment-related AEs associated with ipilimumab, Safety data from randomized clinical trials have shown that single-agent
nivolumab, and pembrolizumab are autoimmune in nature (Table 14). nivolumab or pembrolizumab are associated with less toxicity compared
For ipilimumab alone or in combination with anti-PD-1, the most with ipilimumab monotherapy (Table 14). Although the proportion of
common AEs are cutaneous toxicities (rash, pruritus, and vitiligo), patients who experienced treatment-related AEs of any grade was
gastrointestinal toxicities (diarrhea/colitis), and fatigue. Aside from these similar with anti-PD-1 agents (monotherapy) versus ipilimumab,
3 types of toxicities, the most common high-grade toxicities observed in treatment-related AEs associated with anti-PD-1 monotherapy were
clinical trials are endocrinopathies (eg, hypophysitis, hypo- or less likely to be grade 3-4 (Table 14), and less likely to lead to treatment
hyperthyroidism), and hepatitis (eg, elevated ALT/AST).381 However, discontinuation.492,500
retrospective analyses suggest that clinical trial results may have
underestimated the frequency of endocrinopathies.533,536,537 Other less Although there are no data from prospective randomized trials directly
common toxicities of concern are also shown in Table 14. Many of comparing nivolumab versus pembrolizumab, these agents appear to
these toxicities are more frequent with combination ipilimumab plus anti- have similar safety profiles (Table 14). Both anti-PD-1 monotherapies
PD-1 regimens. Gastrointestinal and cutaneous AEs tend to manifest were associated with notably less diarrhea and pruritus but more
earlier in treatment, whereas the onset tends to be later for hypothyroidism compared with ipilimumab.492,500
endocrinopathies and other rarer toxicities of concern (eg, hepatic,
Safety results from randomized phase II-III trials showed that
renal, and respiratory; Table 15).
combination therapy with nivolumab and ipilimumab was associated
AE rates with anti-PD-1 monotherapy are lower than for ipilimumab with higher rates of toxicity compared with single-agent ipilimumab or
single-agent or in combination with anti-PD-1 inhibitor (Table 14). nivolumab (Table 14).492,499 Ipilimumab/nivolumab combination therapy
Fatigue and arthralgia are the most frequent AEs in patients treated with increased the total number of patients with treatment-related AEs of any
anti-PD-1 monotherapy.492,495,496,500 Pneumonitis and nephritis, although grade, and notably increased the occurrence of grade 3-4 AEs (Table
occurring in less than 5% of patients treated with anti-PD-1 14) and AEs leading to treatment discontinuation (36% vs. 8%, 15%).
monotherapy, may be more common with anti-PD-1 versus ipilimumab For all the toxicities commonly observed with immune checkpoint
monotherapy. Safety guidelines in the FDA labels for nivolumab and inhibitors, grade 3-4 AEs occurred more frequently with combination
therapy compared with either monotherapy (Table 14).

Melanoma Discussion
Table 14. Checkpoint Immunotherapies: Treatment-Related Toxicitiesa,b

Study: CheckMate 067 and 069492,499 KEYNOTE-006500
Ipilimumab +
Agent: Ipilimumab Nivolumabb Ipilimumab Pembrolizumab
Nivolumab
Grade: 3–4 Any 3–4 Any 3–4 Any 3–5 Any 3–5 Any
All types 24–27% 86–93% 16% 82% 54–55% 91–96% 20% 73% 10–13% 73–80%
Diarrhea 6–11% **** 2% ** 9–11% ***** 3% ** 1–3% **
Colitis 7–9% * 1% 8–17% ** 6% * 1–2%
Rash ≤2% *** 1% *** 5% **** 1% * 0 *
Pruritus <1% **** 0 ** 1–2% **** <1% *** 0 *
Vitiligo 0 * <1% * 0 * 0 0 *
Fatigue ≤1% **** 1% *** 4–5% **** 1% ** <1% **
Nausea 1–2% ** 0 * 1–2% *** <1% * <1% *
Vomiting <1% * <1% * 1–3% ** 0 * <1%
Decreased appetite <1% * 0 * <1% ** 0 * 0 *
Pyrexia <1% ** 0 * 1–3% ** 0 0
Arthralgia 0 * 0 * <1% * 1% * <1% *
Myalgia 0 *
b NR NR 0b * <1% <1% *
Asthenia 0 *
b NR NR 0b * 1% * <1% *
Headache <1% * 0 * ≤2% * 0 0
Dyspnea 0 * <1% 1–3% * <1% <1%
Elevated ALT/AST ≤2% 1% 6–11% ** 1% <1% *
Hypophysitis 2–4% * <1% 2% * 1% <1%
Elevated lipase (pancreatitis) 2% b NR NR 9%b * NR NR NR NR
Hypothyroidism 0 ** 0 * <1% ** 0 <1% *
Hyperthyroidism 0 0 ≤1% * <1% 0 *
Pneumonitis ≤2% <1% 1–2% * <1%c <1%c
Nephritis 0b,d NR NR 1% 0d 0d
The percent of patients affected by specific AEs (any grade) was rounded to the nearest 10%, then assigned one asterisk (*) for every 10% of patients effected.
NR, not reported.
a
Aside from nephritis, specific AEs listed occurred in ≥10% of patients for at least one checkpoint immunotherapy regimen.
b
Data available from only one of two trials.
c
Any cause (not only treatment related).
d
Nephritis includes elevated blood creatinine and renal failure.

Melanoma Discussion
Table 15: Kinetics and Characteristics of Immune-Related Adverse Events Associated with Ipilimumaba
IrAE Management Techniques
Time to Onsetb,d Time to Resolutionb,d IrAE Resolution Ratec,d
Employedd
 Ipilimumab stopped
 Corticosteroids (IV, oral)
Median: 3 to 8 weeks Median: 3 to 8 weeks  Infliximab for refractory cases
Gastrointestinal 540,542 385,492,499,541,542 88-100%  Budesonide
(diarrhea, colitis)
383,385,539-547 Range: <3 to 20 weeks Range: <1 to 34 weeks 385,492,499,540,542,544,545
 Antidiarrheals, antiemetics, antacids
539,540,542,547-549 542,547
 Hydration (IV)
 Colectomy for extremely serious or
persistent cases
Cutaneous  Ipilimumab stopped
Range: ≤4 to 10 weeks Median: 3.3 to 12.4 74-85%
(rash, pruritus, vitiligo)  Corticosteroids (topical, oral)
383,545 weeks 492,499,541 492,499,544,545
383,541,543-545
 Antihistamines
Endocrine 25-29%e,383,492
Median: 8.4 to 11 Median: 10.5 to 15
(hypophysitis, By axesf: 0/28 (0%) for  Ipilimumab stopped
weeks 536,537 weeks536
hypothyroidism, adrenal insufficiency to  Corticosteroids (IV)
Range: 5 to 36 weeks Range: 1 to 92 weeks
hyperthyroidism) 536,542,545,550-552 385,536,542,545 19/24 (79%) for enlarged  Hormone replacement therapy
383,533,536,537,542,543,545,550-552 pituitary536,551,552
 Ipilimumab stopped
 Corticosteroids
 Immunosuppressive therapies
(tacrolimus, mycophenolate,
Hepatic Range: <3 to 11.6
Range: 4 to 26 weeks 23/24 (96%) antithymocyte globulin) for refractory
(elevated ALT/AST) weeks 385,492,541,545,553,555 385,492,545,550,553,555
385,541-543,545,550,553-555 542,545,550,553,555 cases
 Cotrimoxazole and valganciclovir
prophylaxis against opportunistic
infection during immunosuppressant
treatment
Renal
Range (n=6): 6 to 12 Median (n=3): 4.6 weeks 8/8 (100%)  Ipilimumab stopped
(elevated creatinine, renal
weeks 556 492 492,556
 Corticosteroids
failure)556,557
Respiratory 11/14 (79%)  Corticosteroids (IV, oral)
Range (n=8): 4.7 to Range: 1.4 to 24 weeks 492,499,542,549
(pneumonitis, dyspnea,  Cotrimoxazole IV
35.6 weeks 542 492,499,542,549
cough)542,549  IgG for humoral immune defect

Melanoma Discussion
a
Combined results from small sets of patients from clinical trials, retrospective analyses, or case studies
b
For time to onset and time to resolution, median(s) provided are from studies with at least 10 patients with the irAE of interest, and ranges include data from
studies with fewer patients. The number of patients with the irAE of interest (n) is provided for data based on fewer than 10 patients.
c
Resolution rate was defined as the percent of patients with “significant improvement” or improvement to grade 1 or lower out of the total number of patients in
which the irAE was actively managed and sufficient follow-up was available. For common irAEs, management and resolution data were available for larger sample
sizes (ie, 2 or more studies with ≥10 patients with the irAE of interest), so the range of resolution rates is reported. For rarer irAEs for which the data on
management and resolution are more limited, data from multiple smaller studies were combined to report the total number of patients in which the irAE resolved
(n) out of the total number of patients in in which the irAE was actively managed and sufficient follow-up was available (N).
d
Management techniques listed were used in studies that reported on irAE resolution, and may include methods that are no longer recommended. Data on irAE
resolution is based on patients whose irAEs that were managed using some or all of the methods listed.
e
Resolution rates from studies reporting the percent of patients for whom all their endocrinopathies resolved.
f
Resolution rates from studies reporting separately on different signs, including pituitary enlargement and specific hormonal insufficiencies.
Management of Immune-related Toxicities particularly challenging cases of gastrointestinal and hepatic

Much of the management of irAEs associated with checkpoint irAEs.540,545-547,549,560,561 Based on a growing number of case reports, the
immunotherapies has evolved in centers using these agents in the immunosuppressant infliximab can provide rapid improvement in
context of clinical trials. Aside from one randomized controlled trial patients with serious or steroid-refractory colitis.383,539-543,546-549,561-563 For
testing prophylactic budesonide (described below), management many cases reported only one dose of infliximab was needed to
recommendations are based on published expert opinion or results from dramatically improve symptoms.547 Merrill, 2014 #1858,548,549,561-563 Several
small sets of patients from clinical trials, retrospective analyses, or case immunosuppressants have been used in attempts to manage high-
studies. Table 15 shows combined results from publications reporting grade liver toxicities: tacrolimus, mycophenolate, 6-mercaptopurine, and
irAE management techniques used and the observed resolution rate antithymocyte globulin.541,542,553-555 Case reports have shown that
and timing. These studies found that with the exception of administering mycophenolate plus steroids can reverse ipilimumab-
endocrinopathies, most irAEs resolved when managed by withholding associated severe (grade ≥3) hepatotoxicity.541,542,553
ipilimumab and administering corticosteroids.383,540,542-545,553,556 Although
oral corticosteroids have been shown to reverse ipilimumab-associated Endocrinopathies associated with ipilimumab have proved more difficult
diarrhea and colitis, results of a phase II placebo-controlled randomized to manage, and require hormone replacement therapy in addition to
trial showed that prophylactic oral budesonide does not reduce the corticosteroids (Table 15). Compared with other irAEs associated with
incidence of moderate to severe diarrhea (grade ≥2) or any other irAE in ipilimumab, endocrinopathies were less likely to fully reverse and took
patients receiving ipilimumab (10 mg/kg every 3 weeks) for longer to resolve.533,536,537,551 Patients with endocrinopathies frequently
unresectable stage III or stage IV metastatic melanoma.558,559 required ongoing hormone replacement,383,533,536,550,551 emphasizing the
importance of early detection to minimize long-term sequelae.
Reports indicate that many high-grade or refractory irAEs have been Endocrinopathies often presented as headache, fatigue or asthenia, but
successfully managed using high-dose oral or IV corticosteroids, and sometimes presented with a variety of other symptoms.
that immunosuppressants have been used successfully in some 383,533,537,543,545,551,564 Affected areas are often the hypothalamic-pituitary-

Melanoma Discussion
adrenal axis, thyrotropin axis, and gonadal axis, and were frequently (dacarbazine; Tables 16–18). For both vemurafenib (Table 16) and
associated with enlargements of the pituitary gland detected by dabrafenib (Table 17), efficacy in patients with previously-treated
MRI383,533,536,537,542,551,552. advanced disease, including patients who received prior ipilimumab, is
supported by single-arm open-label trials (NCT00949702, BREAK-2)
BRAF-targeted Therapies showing response rates, median PFS, and median OS similar to those
Approximately half of patients with metastatic cutaneous melanoma from the phase III trials (BRIM-3, BREAK-3). Phase III trial results show
harbor an activating mutation of BRAF, an intracellular signaling kinase that time to response for BRAF inhibitors (median ~1.5 months) was
in the MAPK pathway.89-91 Most BRAF-activating mutations occurring in shorter than with chemotherapy (Table 17), and when compared to data
melanomas are at residue V600, usually V600E but occasionally V600K from other trials, appears to be shorter than for checkpoint
or other substitutions.90,565 BRAF inhibitors have been shown to have immunotherapy (median 2.1–3.5 months; Tables 8–10 and 16–18).
clinical activity in melanomas with BRAF V600 mutations. Inhibitors of Responses to BRAF inhibitor monotherapy were relatively short lived,
MEK, a signalling molecule downstream of BRAF, may potentiate these however, with median duration ~5 to 7 months (Tables 16–17).
effects. Recent efficacy and safety data from large randomized trials Likewise, PFS and OS Kaplan-Meier curves for vemurafenib and
testing BRAF and MEK inhibitors have significantly impacted the dabrafenib show little or no decline during the first few months of
recommended treatment options for patients with BRAF-mutation treatment (~1.5 months for PFS, ~3 months for OS), and then abruptly
positive advanced melanoma. begin to decline.93,94 Both dabrafenib and vemurafenib have been tested
in non-comparative trials (NCT01307397, BREAK-MB) as single-agent
BRAF Inhibitor Monotherapy
Vemurafenib and dabrafenib were developed to inhibit BRAF with therapy in patients with asymptomatic brain metastases (Table 16–17).
mutations at V600.566-568 For patients with previously untreated stage IV Response rates for vemurafenib (24%)494 and dabrafenib (31%–38%,
or unresectable stage III melanoma, phase III trials (BRIM-3, BREAK-3) Table 17) were lower than for patients without brain metastases, but are
have shown that monotherapy with either of these agents improves nonetheless notable in the context of this difficult to treat population.
response rates, PFS, and OS compared with chemotherapy

Melanoma Discussion
Table 16. Vemurafenib Monotherapy in Advanced Melanomaa: Key Trials

AEs by
Gradee
Treatment Arms PFSd OSd
Name and Phase Tx BRAF Brain
Rate Onset Duration 3 4 5
References Design Naiveb V600E (K) Mets
BRIM-3 III  Vem (n = 337) 48% 1.5 NR 6.9 13.6 65% 6% 2%
100% 91% (9%)f NRg P < .001 P < .0001 P = .0008
NCT0100698092,93 R, OL  DTIC (n = 338) 5% 2.7 NR 1.6 9.7 33% 9% 2%
IV
NCT01307397494 50% Allh 23%g  Vem (N = 3222) 34%i NR 7.3 5.6 12.0 45% 3% 3%
OL
II 92% 53%
NCT00949702a569 None <1%  Vem (N = 132) NR 6.7 6.8 15.9 60% 4% <1%
OL (8%)f (40%)
BRAF V600 Mut, percent of patients with a mutation in BRAF at V600; Brain Mets, percent of patients with brain metastases at baseline; DTIC, dacarbazine; Mets,
metastases; NR, not reported; R, randomized; OL, open label; vem, vemurafenib.
a e
Unresectable stage III or stage IV melanoma; NCT00949702 included only Percent of patients with AE of any cause (treatment or otherwise). None of
stage IV melanoma. these trials reported rates for treatment-related AEs.
b f
Previously untreated advanced disease. Two patients (<1%) had BRAF V600D.
c g
Response rate is the percentage of patients that achieved complete or partial Patients with active CNS metastases were excluded from the trials.
h
response. Time to onset is the median time to response, given in months. All treated patients had a BRAF V600 mutation.
i
Response duration is given as the median, in months, unless otherwise Response rate was 24% for patients with brain metastases
f
indicated. P values are for comparisons with the control arm. Data in parentheses indicate the percent of patients with BRAF V600K
d
Median PFS is given in months. OS is given as 1-year rate. Median duration, mutation.
P value, and HR were determined using the Kaplan-Meier method.

Melanoma Discussion
Table 17. Dabrafenib Monotherapy in Advanced Melanomaa: Key Trials

BRAF Treatment Grade
Name and Phase Tx Brain PFSd OSd
V600E Arms Rate Onset Duration 3-4 AEse
References Design Naiveb Mets
(K)
BREAK-2 II 83% 59% 5.2 6.3 13.1
16% 0% Dab (n = 92) 1.3 27%
NCT01153763 570 OL (17%) f (13%) (5.3) (4.5) (12.9)
BREAK-3 III Dab (n = 187) 50% 1.5 5.5 5.1 18.2 53%g
100% 100% 0% P < .0001 HR = 0.76
NCT0122788994,95 R, OL DTIC (n = 163) 5% NR ND 2.7 15.6 44%g
BREAK-MB II 81% 31-38% 4.6-6.5i 3.7-3.8 7.2-7.6
52% 100%h Dab (n = 172) NR 22%
NCT01266967571 OL (19%)f (0-28%) (2.9-3.8i) (1.9-3.7) (3.8-5.0)
BRAF V600 Mut, percent of patients with a mutation in BRAF at V600; Brain Mets, percent of patients with brain metastases at baseline; dab, dabrafenib; DTIC,
dacarbazine; ND, not determined because longer follow-up is needed; NR, not reported; OL, open label; R, randomized.
a e
Stage IV melanoma; BREAK-3 also included unresectable stage III. Percent of patients who experienced any type of treatment-related AE of
b
Previously untreated advanced disease. grade 3 or 4.
c f
Response rate is the percentage of patients that achieved complete or partial Data in parentheses the percent of patients with BRAF V600K mutation.
g
response. Time to onset is the median time to response, given in months. Percent of patients with AEs of grade 2 or greater. Rates of adverse events of
Response duration is given as the median, in months, unless otherwise grade ≥3 were not reported.
h
indicated. P values are for comparisons with the control arm. Patients with active CNS metastases were excluded from the trial.
d i
Median PFS is given in months. OS is given as 1-year rate. Median duration, Intracranial duration of response.
P-value and HR were determined using the Kaplan-Meier method.
response rates for vemurafenib (48%, 53%) and dabrafenib (50%) from
BRAF/MEK Inhibitor Combination Therapy
Despite high initial response rates, half of the patients treated with phase II-III trials.569 92,94 Moreover, in an open-label, phase II study,
BRAF-targeted monotherapies relapse within around 6 months, due to trametinib failed to induce objective responses in 40 patients previously
development of drug resistance.94,569,572 Alternate methods for targeting treated with a BRAF inhibitor.573
the MAP kinase pathway are being explored as options for overcoming
Although MEK inhibitor monotherapy has limited utility for treating
resistance to BRAF inhibitor therapy. Trametinib and cobimetinib are
advanced metastatic melanoma, phase III trials have now demonstrated
oral small-molecule inhibitors of MEK1 and MEK2, signaling molecules
that combination therapy with a BRAF and MEK inhibitor has better
downstream of BRAF in the MAP kinase pathway. Results from a phase
efficacy than BRAF inhibitor monotherapy for previously untreated
III randomized trial (NCT01245062) showed that in patients with BRAF-
unresectable or metastatic disease (Table 18).491,497,501 When compared
mutated metastatic melanoma not previously treated with BRAF
with either single-agent dabrafenib or single-agent vemurafenib,
inhibitors, trametinib improves PFS and OS compared with
combination therapy with dabrafenib and trametinib improved response
chemotherapy.572 Although trametinib response rate (22%) was
rate, duration of response, PFS, and OS.491,497 Likewise, combination
significantly better than chemotherapy (8%, P = .01), it was lower than

Melanoma Discussion
therapy with vemurafenib and cobimetinib improved response and PFS (although similar time to response) compared with patients who had not
compared with single-agent vemurafenib.501 Further follow-up is needed received prior BRAF inhibitor treatment.498,574 A subset analysis in one
to determine whether vemurafenib/cobimetinib also improves OS. of these studies (NCT01072175) showed that patients who had rapidly
progressed on first-line BRAF inhibitor therapy (time to progression <6
Few clinical data are available regarding the efficacy of BRAF/MEK months) derived little or no clinical benefit from second-line BRAF/MEK
inhibitor combination therapy in patients with previously treated inhibitor combination therapy compared with patients whose resistance
advanced melanoma. Results from phase I/II studies (Table 18) showed to first-line BRAF inhibitor monotherapy occurred at ≥6 months
that in patients who had progressed on previous BRAF inhibitor (response rate: 0% vs. 25%; median PFS: 1.8 months vs. 3.9 months,
treatment, dabrafenib/trametinib combination therapy were associated P = .018).498
with a relatively poor response rate and duration, PFS, and OS,

Melanoma Discussion
Table 18. BRAF/MEK Inhibitor Combination in Advanced Melanomaa: Key Trials

AEs
BRAF Treatment Arms PFSd OSd Grade
Name and Phase Tx Brain
b V600E Rate Onset Duration ≥3e
(K)
Vem + cobi, dose
BRIM-7574,575 Ib 93% escalation:
49% NRf NRh
NCT01271803 OL (7%)  BRAFi naïve (n = 63) 87% 1.4 12.5 13.8 28.5
 Prior vemg (n = 33) 15% 1.5 6.7 2.8 8.4
I/II 86%
NCT01072175498 Nonei 14%  Dab + tram (n = 71) 14% NR 7.8 3.6 10-11.8 51%
OL (14%)
COMBI-d491 III 85%  Dab + tram (n = 211) 69% NR 12.9 11.0 25.1 32%j
100% NRf P = .0014 P = .0004 P = .0107
NCT01584648 RDB (15%)  Dab + pbo (n = 212) 53% NR 10.6 8.8 18.7 32%j
COMBI-v497 III 90%  Dab + tram (n = 352) 64% NR 13.8 11.4 ND 52%
100% NRf P < .001 P < .001 P = .005
NCT01597908 R, OL (10%)  Vem (n = 352) 51% NR 7.5 7.3 17.2 63%
Co-BRIM501 III 70%  Vem + cobi (n = 247) 68% ~1.8 ND 9.9 81%l 65%
100% 1%f P < .001 P < .001 P = .046
NCT01689519 RDB (11%)k  Vem + pbo (n = 248) 45% ~1.8 7.3 6.2 73%l 59%
BRAF V600 Mut, percent of patients with a mutation in BRAF at V600; Brain Mets, percent of patients with brain metastases at baseline; BRAFi naïve, patients
without prior BRAF inhibitor treatment; Dab, dabrafenib; cobi, cobimetinib; Mets, metastases; NR, not reported; OL, open label; pbo, placebo; R, randomized;
RDB, randomized double blind; tram, trametinib; vem, vemurafenib.
a f
Unresectable stage III or stage IV melanoma. Patients with active brain metastases were excluded from the trial.
b g
Patients with previously untreated advanced disease. Patients who had recently progressed on vemurafenib.
c h
Response rate is the percentage of patients that achieved complete or partial AE rates depended on dose.
i
response. Time to onset is the median time to response, given in months. All patients progressed on prior BRAF inhibitor.
j
Response duration is given as the median, in months, unless otherwise Treatment-related AEs.
k
indicated. P values are for comparisons with the control arm. All patients had BRAF V600 mutation, but for 20% the exact mutation was
d
Median PFS and median OS are given in months. Median durations, P value, unknown.
l
and HR are per Kaplan-Meier analysis. P values and HRs are for comparisons Median OS was not reached for either arm; rates show the 9-month survival
with the control arm. rate.
e
Percent of patients with AE of any cause (treatment or otherwise).
BRAF and MEK Inhibitor Safety myalgia, pyrexia and chills, cutaneous events, alopecia, and cutaneous
In phase III trials common toxicities associated with BRAF inhibitor AEs (Table 19).93,94,491,497,501 Skin complications occurred with notable
monotherapy (vemurafenib or dabrafenib) were fatigue, arthralgia or prevalence, severity, and variety, including not only rash, pruritus, and

Melanoma Discussion
photosensitivity, but also keratoacanthomas, cutaneous squamous cell the particular BRAF/MEK inhibitor combination and BRAF inhibitor
carcinomas (cSCC), papillomas, hyperkeratoses, and actinic keratoses monotherapy being compared. Of note, consistent across all phase III
(Table 19). Safety analyses of phase III trials showed that the risk of trials and other studies, BRAF/MEK inhibitor combination therapy was
toxicity (all grade, grade 3–4) was similar for BRAF/MEK inhibitor associated with lower rates of alopecia and hyperproliferative cutaneous
combination therapy compared with single-agent BRAF inhibitor therapy AEs compared with BRAF inhibitor monotherapy (Table 19).576 Cross-
(Table 19). For each phase III trial comparing BRAF/MEK inhibitor trial comparisons suggest that diarrhea, elevated ALT/AST, elevated
combination therapy with single-agent BRAF inhibitor therapy, Table 19 creatinine kinase, rash, and photosensitivity were more prevalent with
shows rates for the most common AEs. As expected, BRAF/MEK vemurafenib/cobimetinib combination therapy, whereas pyrexia was
inhibitor combination therapy increased the occurrence of some of the more prevalent with dabrafenib/trametinib combination therapy (Table
most common toxicities, but the specific toxicities affected depends on 19).

Melanoma Discussion
Table 19: BRAF and MEK Inhibitors: Toxicitiesa

Studies: COMBI-da,491 Combi-v497 Co-BRIM501
Dabrafenib/ Dabrafenib/ Vemurafenib/
Agent: Dabrafenib Vemurafenib Vemurafenib
Trametinib Trametinib Cobimetinib
Grade: 3b Any 3c Any 3d Any 3e Any 3-4g Any 3-4h Any
All types 30% 90% 32% 87% 57% 99% 48% 98% 58% 87% 63% 96%
Systemic AEs:
Fatigue <1% *** ~ 2% *** 2% *** ~ 1% *** 3% *** ~ 4% ***
Asthenia 1% ** ~ 1%f **
Arthralgia/Myalgia 0 ** ~ <1% ** 4% ***** > 1% ** 5% **** > 2% ***
Hypertension 9% **
f < 14% ***
Headache 0 ** ~ 0 ** <1% ** < <1%f ***
Pyrexia 2% *** << 7% ***** 1% ** << 4% ***** 0 ** ~ 2% ***
Chills <1% * < 0 *** 0 * << 1% ***
Gastrointestinal AEs:
Vomiting <1% * ~ <1% * 1% ** < 1% *** 1% * < 1% **
Nausea <1% ** ~ 0 ** 1% **** ~ <1% **** 1% ** < 1% ****
Diarrhea 1% * ~ <1% ** <1% **** > 1% *** 0 *** << 6% ******
Constipation 0f * 0 *
Cough 0 * < 0 **
Elevated ALT/AST <1% < 2-3% * 3-4%f ** > 1-3%f * 6% ** < 8-11% **
Elevated creatinine kinase <1% * > 0% 0 << 10% ***
Peripheral edema 0 < 1% * <1% * ~ <1% *
Alopecia 0 *** >> 0 * <1% **** >> 0 * 0 *** > 0 *
Cutaneous AEs:
Rash <1% ** ~ 0 ** 9% **** >> 1% ** 5% **** ~ 6% ****
Pruritus 0 * ~ 0 * <1% ** > 0 *
Dry skin 0 * ~ 0 * <1% ** > 0 *
Photosensitivity reaction <1% ** >> 0 0 ** < 2% ***
Hyperkeratosis <1% *** >> 0 * 1% *** >> 0 2% *** > 0 *
Hand-foot syndrome <1% *** >> <1% * <1% *** >> 0
Skin papilloma 0 ** > 0 1% ** >> 0
cSCC and
9% * > 3% 17%f ** >> 1% 5-8% * > 1%
keratoacanthomas
The percent of patients affected by specific AEs (any grade) was rounded to the nearest 10%, then assigned one asterisk (*) for every 10% of patients effected.
Symbols show the whether the percent of patients experiencing the AE was similar in both arms (~), greater in one arm (> or <), or much greater in one arm (>> or
<<).

Melanoma Discussion
a
AE rates shown are for all AEs, regardless of whether or not they were treatment related, except for COMBI-d, for which rates of treatment-related events were
reported.
b
Grade 4 events occurred in 3 patients: thrombocytopenia, febrile neutropenia, and hypokalemia. A grade 5 event occurred in 1 patient: bile duct adenocarcinoma.
c
A grade 4 event occurred in 1 patient: pancytopenia.
d
Grade 5 events occurred in 3 patients (<1%): acute coronary syndrome, cerebral ischemia, and pleural infection (n=1 each).
e
Grade 5 events occurred in 3 patients (<1%): cerebral hemorrhage (n=2) and brain stem hemorrhage (n=1).
f
One patient experienced a grade 4 adverse event of this type.
g
Grade 5 events occurred in 3 patients (1.3%): fatigue (and progressive disease; n=1), cardiac failure (n=1), and pulmonary embolism (n=1).
h
Grade 5 events occurred in 6 patients (2.3%): fatigue and asthenia (n=1), cardiac arrest (n=1), cerebral hemorrhage (and progressive disease, n=1), hemiparesis
(and progressive disease, n=1), pneumonia (n=1), and not specified (n=1).
Other Targeted Therapies: Imatinib phase III randomized trial comparing sequential biochemotherapy
KIT (commonly known as c-KIT) mutations have been associated most (dacarbazine, cisplatin, and vinblastine [CVD] with IL-2 and IFN
commonly with mucosal and acral subtypes of melanoma.22 Phase II administered on a distinct schedule) with CVD showed
studies testing imatinib, an inhibitor of mutated c-KIT, in patients with biochemotherapy improved response rates (48% vs. 25%) and survival
KIT-mutated or KIT-amplified metastatic melanomas demonstrated 20% (median 11.9 months vs. 9.2 months).590 In a phase III randomized
to 30% overall response rate and 35% to 55% disease control rate.96-98 intergroup trial (E3695), biochemotherapy (CVD plus IL-2 and IFN
Unfortunately, most of these responses were of limited duration. These alpha-2b) produced a slightly higher response rate and progression
phase II studies included a significant portion of patients with non- free-survival than CVD alone, but it was not associated with either
cutaneous melanoma (46%–71% mucosal). The results show trends improved quality of response or OS, and was substantially more
toward better response in mucosal melanoma compared with acral/CSD toxic.591 Biochemotherapy should not be administered in centers that do
subtypes, and toward better response for patients with KIT mutations not have substantial clinical experience and infrastructure to manage
versus amplifications alone.97,98 Like BRAF inhibitors, patient selection toxicities. Additional attempts to decrease toxicity of biochemotherapy
by molecular screening is essential to identify patients who might by administering subcutaneous outpatient IL-2 did not show a
potentially benefit; previous studies on unselected patients yielded no substantial benefit of biochemotherapy versus chemotherapy
meaningful responses.577,578 alone.585,592,593 A meta-analysis also showed that although
biochemotherapy improved overall response rates, there was no
Biochemotherapy survival benefit for patients with metastatic melanoma.594
Biochemotherapy is the combination of chemotherapy and biological
agents. In phase II-III trials, biochemotherapy (dacarbazine or Interleukin-2
temozolomide, cisplatin, and vinblastine or nitrosourea, plus IFN-alfa High-dose IL-2 has been used extensively to treat metastatic melanoma
and IL-2) produced overall response rates of 21% to 64% and CR rates in first-line and second-line settings. Although overall response rates
of 7.5% to 21% in patients with metastatic melanoma.579-589 A small are modest (<20%), those that achieve a complete response (<10%)

Melanoma Discussion
tend to have extremely durable responses and high rates of long-term Little consensus exists regarding optimal standard chemotherapy for
survival 595-597 Thus, although median OS is usually 11 to 12 months, patients with metastatic melanoma, which most likely reflects the low
approximately 10% of patients achieve long-term survival (>5 level of activity of older FDA-approved agents.611,612
years).595,597-599 In one retrospective analysis of 305 patients who
received IL-2 monotherapy for previously treated measurable metastatic Palliative Radiation Therapy
disease, complete response was achieved in 4%, with median duration Contrary to common perception that melanoma is radio-resistant,
of response >176 months (range, 12 months to >253 months).595 Of the radiation often achieves palliation of symptomatic metastatic disease.613-
615 Clinically significant regression of radiated lesions of up to 60% has
12 patients with CR, 10 survived at least 13 years.
been reported in carefully-selected patients.616,617
High-dose IL-2 is associated with significant toxicities. Safe and
effective administration requires careful selection of patients, close SRS is gaining importance in the management of CNS metastases from
monitoring, and adherence to administration and AE management melanoma. Retrospective studies have shown 1-year local tumor
protocols.600 High-dose IL-2 therapy should be restricted to institutions control rates from 72% to 100% for patients with limited CNS disease,
with medical staff experienced in the administration and management of but lower rates for patients with multiple or large (>2 cm) tumors.618-623
these regimens. With the increasing use of stereotactic radiation, the value of WBRT in
patients with melanoma brain metastases is increasingly unclear and
Cytotoxic Therapy controversial. Virtually all the information available about the impact of
Common cytotoxic agents being used in patients with metastatic RT for melanoma brain metastases comes from retrospective studies. It
melanoma include dacarbazine,601,602 temozolomide,595-597,602,603 and is almost impossible to separate out the impact of patient selection from
paclitaxel with or without carboplatin.604-608 These have demonstrated the effect of treatment. Results from recent retrospective studies
modest response rates less than 20% in first-line and second-line comparing patients who received SRS versus those who received
settings. WBRT are especially compromised by selection bias because WBRT is
more likely to be used in patients with more extensive disease.623,624 In
Traditional paclitaxel formulation is solvent-based. Albumin-bound
clinical practice, the use of SRS in patients with a limited number of
paclitaxel, also known as nab-paclitaxel, is a solvent-free formulation
small brain tumors is gaining wider acceptance because studies have
bound by stable albumin particles that has lower toxicity and higher
demonstrated late adverse effects of WBRT on cognitive function.407,625-
bioavailability. This formulation yielded response rates of 22% to 26% in 627 Prospective randomized studies are needed to determine the best
phase II trials among chemotherapy-naïve patients with metastatic
approach to radiation for melanoma brain tumors.
melanoma.609,610
Combining Radiation with Systemic Therapy
Some systemic therapy regimens may increase toxicity when given
concurrently with radiation. A number of case studies have reported that

Melanoma Discussion
BRAF inhibitors vemurafenib and dabrafenib have radiosensitizing order of administration.639.641,644,647 Abscopal responses in non-irradiated
effects,628-636 and a retrospective analysis by Hecht and colleagues637 tumors have been observed, but prospective trials are needed to
found that 57% of 70 patients receiving concomitant therapy confirm these effects because the delayed kinetics of ipilimumab
experienced acute or late toxicities. Case reports indicate that response complicate interpretation of retrospective data.641,648-650
radiosensitization reactions can also occur in patients treated with RT
and subsequent BRAF inhibition.634-636 Radiodermatitis was the most NCCN Recommendations
common of these toxicities, with acute events (grade ≥2) occurring in Multidisciplinary tumor board consultation is encouraged for patients
36% of patients treated with concomitant RT plus dabrafenib or with stage IV metastatic melanoma. Treatment depends on whether
vemurafenib.637 Acute dermatitis has also been reported in patients disease is limited (resectable) or disseminated (unresectable) as
treated with WBRT and BRAF inhibitor therapy (either concurrent or outlined below.
sequential).632,633 In the retrospective study by Hecht and colleagues,637
BRAF inhibitor therapy was associated with increased risk of acute Resection, if feasible, is recommended for limited metastatic disease. In
dermatitis among patients treated with WBRT (44% vs. 8%; P = .07). In selected patients with a solitary site of visceral metastatic melanoma, a
contrast, a retrospective study by Gaudy-Marqueste and colleagues638 short period of observation or systemic treatment followed by repeat
found no evidence of radiodermatitis in 30 patients who received SRS scans may be appropriate to rule out the possibility that the visceral
and BRAF inhibitor therapy. A variety of other toxicities have been metastasis is the first of many metastatic sites, and to better select
reported to be associated with RT plus BRAF inhibitor treatment; those patients for surgical intervention. Following observation or treatment,
reported in more than one patient include follicular cystic proliferation patients with resectable solitary sites of disease should be reassessed
(13%), hearing disorder (4%), and dysphagia (2%). for surgery. If completely resected, patients with no evidence of disease
(NED) can be observed or offered adjuvant treatment on clinical trial.
Results from retrospective studies suggest that for patients with There is panel consensus that adjuvant IFN alpha monotherapy outside
metastatic melanoma (including brain metastases), combining of a clinical trial is inappropriate for resected stage IV disease.
checkpoint immunotherapy (ipilimumab or nivolumab) with radiation of Alternatively, limited metastatic disease can be treated with systemic
CNS or non-CNS metastases does not significantly increase the risk of therapy either in the context of a clinical trial (preferred) or as a
toxicity.139,639-645 However, multiple retrospective studies on ipilimumab standard of care. Residual disease following incomplete resection for
and one on nivolumab failed to show that adding checkpoint limited metastases is treated as described below for disseminated
immunotherapy provided additional clinical benefit in patients receiving disease.
RT for brain metastases, at least in terms of response rates and
OS.139,639,640,643,646 Several analyses found that concurrent or close Disseminated disease can be managed by systemic therapy, clinical
proximity of RT and systemic therapy treatment improved response trial, intralesional injection with T-VEC, or best supportive care (see the
rates and OS, although results are inconsistent regarding the optimal NCCN Guidelines for Palliative Care). In addition, symptomatic patients

Melanoma Discussion
may receive palliative resection and/or radiation. A number of options mediated toxicities. Treatment selection should therefore be informed
are available for systemic therapy. by consideration of the patient’s overall health, medical history,
concomitant therapies, comorbidities, and compliance with proactive
First-line Systemic Therapy monitoring and management of AEs.
For first-line therapy of unresectable or metastatic disease,
recommended treatment options include checkpoint immunotherapy, For patients with BRAF-mutant metastatic disease, BRAF-targeted
BRAF-targeted therapy for patients with BRAF-mutated disease, or therapy first-line options include BRAF/MEK inhibitor combination
clinical trial. therapy with dabrafenib/trametinib or vemurafenib/cobimetinib, or
single-agent BRAF inhibitor therapy with vemurafenib or dabrafenib. All
Checkpoint immunotherapy options in this setting include anti-PD-1 of these regimens are category 1 based on results from phase 3 trials in
monotherapy with pembrolizumab (category 2A) or nivolumab (category the first-line setting (ie, BRIM-3, BREAK-3, COMBI-d, COMBI-v,
1) or nivolumab/ipilimumab combination therapy (category 2A). CoBRIM). Both vemurafenib and dabrafenib are FDA approved as
Checkpoint inhibitors have been shown to be effective regardless of single-agent therapy for treatment of patients with metastatic or
BRAF mutation status. The NCCN Panel considers all recommended unresectable melanoma with BRAF V600E mutation as detected by an
checkpoint immunotherapy options appropriate for both BRAF mutant FDA-approved test.651,652 Dabrafenib/trametinib and
and BRAF wild-type metastatic disease. There is interest in PD-L1 as a vemurafenib/cobimetinib combination therapy regimens are FDA
predictive biomarker for response to anti-PD-1 therapy, but to date it approved for the treatment of patients with unresectable or metastatic
has not been discriminant enough to be used to inform treatment melanoma with BRAF V600E or V600K mutations, as detected by and
decisions in clinical practice. FDA-approved test.652-654 The Cobas 4800 BRAF V600 mutation test, a
test for detecting the BRAF V600E mutation, received FDA approval as
Although ipilimumab is FDA approved for treatment of unresectable or
a companion diagnostic for selecting patients for treatment with
metastatic melanoma, including both treatment-naïve and previously
vemurafenib. The THxID BRAF Kit, a test for detecting BRAF V600E or
treated disease, single-agent ipilimumab monotherapy is no longer an
V600K mutations, received FDA approval as a companion diagnostic for
NCCN-recommended first-line therapy option due results from the
selection of patients for treatment with dabrafenib and trametinib. The
CheckMate 067 phase III trial showing improved outcomes with anti-
NCCN Panel recommends that BRAF mutational status should be
PD-1 monotherapy or nivolumab/ipilimumab combination therapy
tested using an FDA-approved test or by a facility approved by Clinical
compared with ipilimumab monotherapy.
Laboratory Improvement Amendments (CLIA). The NCCN panel
Selection between Anti-PD-1 monotherapy and nivolumab/ipilimumab recommends that tissue for genetic analysis be obtained from either
combination therapy should be informed by the consideration that biopsy of a metastasis (preferred) or from archival material. The NCCN
although combination therapy has been shown to provide somewhat panel considers single-agent BRAF inhibitor monotherapy and
better PFS, it is associated with a much higher risk of serious immune- BRAF/MEK inhibitor combination therapy as appropriate treatment

Melanoma Discussion
options for metastatic disease with any type of activating BRAF Second-line or Subsequent Therapy
mutation (includes V600E, V600K, V600R, V600D, and others). For patients who progress on first-line therapy or achieve maximum
Although trametinib is FDA approved for single-agent use to treat clinical benefit from BRAF-targeted therapy (if BRAF mutated), options
patients with unresectable or metastatic melanoma with BRAF V600E for second-line therapy depend on ECOG performance status. Patients
mutation,654 trametinib monotherapy is no longer an NCCN- with poor performance (PS 3-4) should be offered best supportive care.
recommended treatment option due to relatively poor efficacy compared Patients with PS 0-2 have a variety of options depending on their BRAF
with BRAF inhibitor monotherapy and BRAF/MEK inhibitor combination status and treatment history. Based on the positive results from phase
therapy. Among the recommended BRAF-targeted therapy options, the III trials supporting the recommended first-line therapies, these
BRAF/MEK inhibitor combination is preferred over BRAF inhibitor checkpoint immunotherapy and BRAF-targeted therapy regimens have
monotherapy based on results from phase III trials in the first-line been incorporated into the guidelines in the setting of second-line or
setting showing improved outcomes and similar risk of toxicity (COMBI- subsequent therapy for qualifying patients: nivolumab, pembrolizumab,
d, COMBI-v, and CoBRIM). nivolumab/ipilimumab combination, dabrafenib, vemurafenib,
dabrafenib/trametinib, or vemurafenib/cobimetinib combination. Due to
For patients with documented BRAF V600 mutations, selection between lack of phase III trial data in patients with previously treated metastatic
first-line checkpoint immunotherapy and BRAF-targeted therapy can be disease, however, these regimens are category 2A (rather than
difficult given the lack of comparative phase III clinical trials. Clinical category 1) recommended options for second-line or subsequent
trials are underway to address unanswered questions regarding the systemic therapy. As described in previous sections, results from phase
optimal sequencing and/or combination of these agents. The II or phase IV trials in patients with previously-treated advanced disease
recommendation for first-line systemic therapy should be informed by support second-line or subsequent systemic therapy for some of these
the tempo of disease, and the presence or absence of cancer-related options (eg, vemurafenib, dabrafenib, pembrolizumab).
symptoms. Given that responses to checkpoint immunotherapy can
take longer to develop, BRAF-targeted therapy may be preferred in In addition to the checkpoint immunotherapy regimens recommended
cases where the disease is symptomatic or rapidly progressing or the for first-line, second-line, and subsequent treatment of metastatic
overall health of the patient appears to be deteriorating. Patients with disease, single-agent ipilimumab is an option in patients who have
low-volume, asymptomatic metastatic melanoma may be good received prior systemic therapy for metastatic disease. This
candidates for checkpoint immunotherapy, as there may be time for a recommendation is based on the results from the pivotal phase III trial
durable antitumor immune response to emerge. Safety profiles and AE (CA184-002) in patients with previously-treated unresectable stage III or
management approaches differ significantly for BRAF-targeted therapy stage IV melanoma.
versus checkpoint immunotherapy; treatment selection should therefore
be informed by consideration of the patient’s overall health, medical Of the recommended options for second-line and subsequent therapy,
history, concomitant therapies, comorbidities, and compliance. the NCCN panel recommends considering only those agents that are
not the same or of the same class as agents the patient received

Melanoma Discussion
previously. Patients treated with ipilimumab who experience stable As described above, FDA-recommended dosing regimens indicate that
disease of three months’ duration after week 12 of induction or partial treatment should continue until disease progression or unacceptable
response or CR, who subsequently experience progression of toxicity for all 3 of the approved regimens containing anti-PD-1 agents:
melanoma, may be offered re-induction with up to four doses of nivolumab, pembrolizumab, and nivolumab/ipilimumab combination
ipilimumab at 3 mg/kg every three weeks. Although anti-CTLA-4 therapy. Due to the lack of data with long-term anti-PD-1 treatment, the
(ipilimumab) and anti-PD-1 (nivolumab, pembrolizumab) agents are optimal treatment duration is unknown. In the absence of unacceptable
both checkpoint immunotherapies, they are not considered the same toxicity, it is common practice to continue anti-PD-1 therapy until
class of agent because they target different molecules. For patients who maximal response. Although there is no standard definition for maximal
previously received ipilimumab, subsequent treatment with anti-PD-1 response, it is commonly defined as no additional tumor regression on
therapy is a recommended option, and vice versa. Patients who at least 2 consecutive scans taken at least 12 weeks apart. Treatment
previously progressed or achieved maximal response on BRAF inhibitor after maximal response is controversial. Continuing anti-PD-1 treatment
therapy are unlikely to benefit from BRAF/MEK inhibitor combination for one 12-week cycle after maximal response has been achieved is not
therapy. Likewise, patients who progressed or achieved maximal uncommon in clinical practice. NCCN-recommended dosing regimens
response on BRAF/MEK inhibitor combination therapy are unlikely to are listed in Table 20.
respond to BRAF inhibitor monotherapy or to a different BRAF/MEK
inhibitor combination. For patients who have progressed on checkpoint Table 20. NCCN Recommended Dosing Regimens
immunotherapies (and BRAF-targeted therapy if BRAF mutated), Therapy Recommended Regimen
additional options to consider for second-line or subsequent therapy Ipilimumab 3 mg/kg Q3W for up to 4 doses
include high-dose IL-2, biochemotherapy (category 2B), cytotoxic Nivolumab monotherapy 3 mg/kg Q2W for up to 2 years
agents, and imatinib for tumors with activating mutations of c-KIT. It is Nivolumab combination therapy 1 mg/kg Q3W for 4 doses,
not known which of these options may provide benefit, as data (with ipilimumab) then 3 mg/kg Q2W for up to 2 years
supporting these approaches largely predate the development Pembrolizumab 2 mg/kg Q3W for up to 2 years
checkpoint inhibitor and BRAF-targeted therapies. Safety
Management of Immune-related Toxicities
Immune Checkpoint Inhibitor Administration
Much of the management of irAEs has evolved in centers using these
Ipilimumab is FDA approved for treatment of unresectable or metastatic
agents in the context of clinical trials. As such, the following
melanoma at a dose of 3 mg/kg of body weight, administered every 3
recommendations for management of irAEs represent a consensus of
weeks for a total of 4 doses, consistent with the dosing regimen in the
experienced experts rather than evidence-based guidelines.
phase III trials described.381 NCCN Member Institutions recommend the
use of ipilimumab at the FDA-approved dose and schedule. Treatment-related AEs occur in a high percentage of patients treated
with anti-CTLA-4 or anti-PD-1 agents, and grade 3-4 related AEs occur

Melanoma Discussion
in as many as 20% of patients receiving single-agent therapy and in with the care team are essential for identifying and effectively managing
~50% receiving ipilimumab monotherapy or nivolumab/ipilimumab irAEs.
combination therapy. Careful selection of patients and AE monitoring
and management are therefore critical to safe administration of all of A recommended management approach for many moderate to severe
these agents. Among other factors, patient selection should take into irAEs is withholding or discontinuing treatment and administering
consideration age, comorbidities (eg, disease processes whose systemic corticosteroids. Diarrhea is the most common grade 3-4 irAE
manifestations might be confused with immune-related toxicities), associated with checkpoint immunotherapy; severe cases were treated
concomitant medications (eg, immunosuppressive therapies), and by high-dose corticosteroids. For severe enterocolitis that does not
overall performance status. Patients with underlying autoimmune respond to systemic corticosteroids (within 1 week), the NCCN panel
disorders are generally excluded from treatment with checkpoint recommends infliximab 5 mg/kg; a single dose is sufficient to resolve
immunotherapies. severe colitis in most patients.381,526,547 Merrill, 2014 #1858,548,549,561-563
Budesonide is not recommended for prophylactic treatment of
The product labels for ipilimumab, nivolumab, and pembrolizumab enterocolitis. Infliximab may be used as a second-line approach for
provide specific guidelines for monitoring and management of managing other types of severe steroid-refractory irAEs. For severe
irAEs.381,526,527 Clinicians need to educate themselves about the pattern hepatotoxicity refractory to high-dose corticosteroids, the addition of
of toxicities and recognition of these toxicities, as well as management mycophenolate is recommended instead of infliximab. This
strategies. Formal training programs are strongly recommended, along recommendation is based on the concern for possible hepatotoxicity
with careful and frequent consultation of 1) the relevant package inserts; from infliximab.656 While patients are on combination agent immune
2) other FDA-approved materials with detailed descriptions of the signs suppression therapy (eg, prednisone plus mycophenolate), they may be
and symptoms of irAEs associated with ipilimumab and detailed at risk for opportunistic infection, and should be considered for
protocols for management; and 3) standard institutional protocols for pneumocystis prophylaxis (See NCCN Guidelines for Cancer-
monitoring and managing irAEs.381,655 Associated Infections, INF-6). Immune-mediated dermatitis sometimes
responds to topical corticosteroids, but systemic steroids may be
There are two broad categories of irAE monitoring and management: needed for reactions that do not respond to topical application.526 The
one for ipilimumab-containing regimens and one for anti-PD-1 NCCN panel also recommends referral or consultation with a
monotherapy. dermatologist or provider experienced in cutaneous irAEs.
Ipilimumab-containing Regimens Endocrinopathies often require hormone replacement therapy, even

Close monitoring of potentially lethal irAEs in patients receiving
after corticosteroids have been tapered off.341,381,383,499,512,526,527,544
ipilimumab is essential.538 In addition to proactive questioning of
Clinicians should actively screen for symptoms of hypophysitis because
symptoms, patient and nursing education and frequent communication
the signs are subtle, often presenting as headache or asthenia.

Melanoma Discussion
Anti-PD-1 Monotherapy toxicities between ipilimumab and high-dose IL-2 therapy, especially in
AE monitoring and management for patients receiving anti-PD-1 the gastrointestinal tract.
monotherapy is similar to that for ipilimumab-containing regimens. As
noted above, the frequency of grade 3-4 AEs requiring management is Treatment of Patients with Brain Metastases
lower with anti-PD-1 monotherapy compared with ipilimumab-containing For patients with brain metastases, treatment of the CNS disease
regimens. For patients with preexistent hypophysitis due to ipilimumab, usually takes priority in an effort to delay or prevent intratumoral
anti-PD-1 therapy may be administered if patients are on appropriate hemorrhage, seizures, or neurologic dysfunction. Treatment of
physiologic replacement endocrine therapy. melanoma brain metastases is based on symptoms, number of lesions
present, and location of the lesions, as described in the NCCN
Management of BRAF Inhibitor Toxicities Guidelines for Central Nervous System Cancers. SRS and/or WBRT
For patients on BRAF inhibitor therapy, the panel recommends regular
may be administered either as the primary treatment or as an adjuvant
dermatologic evaluation with referral to a dermatologist to monitor for
following surgical resection. Compared with WBRT, SRS may have
skin complications. Although dabrafenib is not associated with
better long-term safety and allow earlier documentation of stable CNS
significant photosensitivity, regular skin evaluation and referral to a
disease, thus allowing earlier access to systemic agents and clinical
dermatologist is still recommended as secondary skin lesions can
trials that require stable CNS disease. For patients with BRAF mutation
develop. Fever is common in patients receiving dabrafenib and should
who present with systemic and CNS disease, BRAF or BRAF/MEK
be managed by treatment discontinuation and use of anti-pyretics such
inhibitor systemic therapy is sometimes offered as first-line therapy, with
as acetaminophen and/or NSAIDs. After resolution of fever, resumption
radiation used as consolidation as needed. After treatment of the brain,
of dabrafenib or dabrafenib/trametinib at reduced dose may be tried.
options for management of extracranial sites are the same as for
Patients treated by vemurafenib or dabrafenib should also be educated
patients without brain metastases. Ipilimumab therapy is associated
to report joint pain and swelling.
with the potential for long-term disease control outside the CNS.
Management of Interleukin-2 and Biochemotherapy Toxicities
In patients with both brain and extracranial metastases, systemic
Caution is warranted in the administration of high-dose IL-2 or
therapy may be administered during or after treatment of the CNS
biochemotherapy due to the high degree of toxicity reported. Some
disease, with the exception of high-dose IL-2, which has low efficacy in
patients may attempt biochemotherapy for palliation or to achieve a
patients with previously untreated brain metastases and which may
response that may render them eligible for other therapies. In any case,
worsen edema surrounding the untreated metastases. There is
if such therapy is considered, the NCCN panel recommends patients to
disagreement on the value of IL-2 therapy in patients with small brain
receive treatment at institutions with relevant expertise.
metastases but no significant peritumoral edema; IL-2 may be
Contraindications for IL-2 include inadequate organ reserve, poor
considered in selected cases (category 2B). Interactions between RT
performance status, and untreated or active brain involvement.
and systemic therapies need to be very carefully considered as there is
Additionally, panelists raised concerns over potential synergistic

Melanoma Discussion
potential for increased toxicity, particularly with concurrent or sequential abdominal ultrasound; detection by brain MRI or other imaging methods
BRAF-targeted therapy and radiation. was rare.660,662,664-666 Even in prospective trials where laboratory tests
were conducted regularly, detection of recurrence by blood work results
Follow-up was extremely rare.126,664
In the absence of clear data, opinions vary widely regarding the
appropriate follow-up of patients with melanoma. There is debate about Recurrences detected by patients or physician clinical exams are
the appropriate surveillance methods and frequency of exams or other usually local, regional satellite or in-transit, or nodal, and less commonly
tests. As yet, there are no data to support that pre-symptomatic distant.126,664 Recurrences detected by imaging, on the other hand, are
detection of visceral metastasis improves patient outcomes. While the more likely distant and nodal; local or in-transit recurrences are rarely
obvious immediate clinical goal for ongoing surveillance of patients with detected by imaging.126,664 These findings, combined with the low
NED is for identification of relapse or a second primary melanoma, it is percentage of recurrences identified by imaging some
important to consider the long-term impact of ongoing surveillance in studies,660,662,665,666 suggest that imaging can be used sparingly for
terms of improved survival, patient quality of life, and exposure to risks surveillance, especially in patients who present with early-stage
associated with some surveillance methods.657-659 melanoma who are less likely to recur with systematic disease.
Surveillance Modalities Imaging Methods: Sensitivity, Selectivity, and Safety

Studies on medical imaging have reported low yield, significant false
Modalities that have been tested for follow-up in melanoma patients
positivity (often associated with increased patient anxiety and medical
include patient self-exam or reporting of symptoms, clinical physical
costs related to further work-up), and risks of cumulative radiation
exam, blood tests, and various imaging modalities (eg, chest x-ray,
exposure.657,658,667-673 A large meta-analysis compared ultrasound
ultrasound, CT, PET/CT, MRI). The utility of these modalities has been
imaging, CT, PET, and PET/CT for the staging and surveillance of
evaluated in retrospective and observational studies terms of the
patients with melanoma.134 Data from 74 studies containing 10,528
proportion of lesions (recurrences and second primary melanomas)
patients were included. For both staging and surveillance purposes,
detected by the surveillance methods employed. These studies have
ultrasound was found to be associated with the highest sensitivity and
shown that most recurrences are detected by the patient or during
specificity for lymph node metastases, while PET/CT was superior for
physical exam in the clinic. The proportion of recurrences detected by
detecting distant metastases. The safety of CT and PET/CT is a
patients varies across studies (17%–67%), as does the proportion of
significant concern, however, because large population-based studies
recurrences detected by physician’s physical exams (14%–55%), but
have shown that cumulative radiation exposure from repeated CT and
clearly both of these modalities are essential for effective surveillance
nuclear imaging tests may be associated with an increased risk of
during follow-up.660-666 Imaging tests detected 7% to 49% of
cancer.658,659,674
recurrences.126,660,662-666 Imaging methods that detected recurrences
included CT scanning, lymph node ultrasound, chest x-ray, or

Melanoma Discussion
Nodal basin ultrasound has emerged as a modality for surveillance in stage III substage at initial presentation is associated with a greater
patients who are eligible for, but do not undergo, SLNB or in whom the proportion of distant recurrences.
procedure is not technically successful or feasible. Surveillance
ultrasound is often used in patients with a positive sentinel node who Timing of Recurrence
have elected not to undergo CLND. This approach has been In general, earlier stage melanoma recurs less often, but over a longer
demonstrated to be safe in one prospective randomized trial that time period, while later stage melanoma recurs more often and over a
compared nodal basin ultrasound surveillance to CLND in patients with shorter time period. For all stages of melanoma, the risk of recurrence
a positive sentinel node.275 Results from a similar but much larger trial is generally decreases with time (from diagnosis), although it does not
eagerly awaited. 276 reach zero at any time.126,661,662,664,676 Studies indicate that the risk of
recurrence plateaus at between 2% to 5%.126,661,678,679 Late recurrence
Patterns of Recurrence (more than 10 years after diagnosis) is well documented, especially for
In order to design an efficient and effective follow-up schedule, the patients initially presenting with early-stage melanoma.678-680 Data from
overall stage-specific risk of relapse, median time to initial relapse, and several studies suggest that the time it takes for the risk of recurrence to
the likely location of recurrences must be understood. reach its low plateau depends on the stage of disease at first
presentation. In a retrospective study of patients who initially presented
Stage-specific Probability of Recurrence with stage I melanoma (N = 1568), 80% of the 293 recurrences
The likelihood of recurrence is dependent on the stage of the primary developed within the first 3 years, but some recurrences (<8%) were
disease at presentation. With increasing stage at first presentation, risk detected 5 to 10 years after the initial treatment.661 A prospective study
of recurrence increases and the distribution of recurrences found that for patients with stage I or II at initial presentation, the risk of
changes.126,661,664,675,676 Recurrence rates for completely excised recurrence reached a low level by 4.4 years after initial diagnosis.664 For
melanoma in situ are sufficiently low that patients are considered cured patients initially presenting with stage III disease, the risk of recurrence
following excision, with the exception that certain subtypes may recur reached low levels after only 2.7 years.664 A retrospective study in
locally (ie, lentigo maligna).243,244,246,677 patients initially presenting with stage III disease calculated the time
until the risk of relapse dropped to 5% or less, and found that this time
For patients who present with stage I-II melanoma and who are shortened as the substage at presentation increased (from stage IIIA to
rendered free of disease after initial treatment, recurrences are IIIC).126 Recurrences to distant sites occur over a longer timeframe than
distributed as follows: approximately 15% to 20% are local or in/transit, local or regional recurrences, and all types of recurrence (local,
~50% in regional lymph nodes, and 29% at distant metastatic regional, and distant) develop more quickly in patients who had more
sites.675,676 In patients who present with stage III melanoma, advanced disease at initial presentation.126,676 Nonetheless, over 95% of
recurrences are more likely to be distant (~50%), with the remainder observed regional nodal and distant recurrences were detected within 3
divided between local sites and regional lymph nodes.126 Increasing

Melanoma Discussion
years for stage IIIA and IIIB melanoma, and within 2 years for IIIC could permit the earlier detection of recurrent disease at a time when it
melanoma.126 might be more amenable to potentially curative treatment. This rationale
for follow-up is particularly appropriate for patients at risk for a second
In summary, patients who have more advanced disease at first primary melanoma, patients who have not undergone SLNB at risk for
presentation are more likely recur, and will recur more quickly. Patients nodal recurrence, or in those patients with a positive sentinel node who
with less advanced disease at presentation are less likely to recur, and elected not to undergo completion lymphadenectomy.
will recur more slowly, with especially long delays associated with
development of recurrences at distant sites. In patients who have Several other reasons for a structured follow-up program include
already had one recurrence, subsequent recurrences tend to occur at provision of ongoing psychosocial support, identification of familial
progressively shorter intervals.676 kindreds, screening for second non-melanoma primary malignancies,
patient education, and documentation of the results of treatment.686-688
Risk of Developing a Second Primary Melanoma
Patients cured of an initial primary melanoma are at increased risk for Survival after Recurrence
developing a second primary melanoma. Although rates vary, most Earlier detection of recurrence is assumed to be beneficial because
studies have reported that ~2% to 10% of patients with first primary lower tumor burden and younger age are associated with improved
melanomas develop second primary melanomas.661,664,681-684 The risk of treatment response rates and survival. However, this concept has not
developing a second primary melanoma generally decreases with time been proven, even with the use of more effective therapies for
from diagnosis of the first primary melanoma.685 About one third of advanced melanoma. Prospective randomized trials are needed to
second primary melanomas are identified at the same time or within the assess whether surveillance improves survival, and to determine the
first 3 months of the diagnosis of the first melanoma,681 and about half optimal frequency and duration of follow-up surveillance. In the absence
are diagnosed within the first year.682 For patients who have already of such trials, the patterns and risk factors of survival after recurrence
developed 2 primary melanomas, the risk of developing a third is higher can help inform design of appropriate surveillance schedules.
(16% by 1 year, 31% by 5 years).682 Second primary melanomas are
Risk Factors for Survival After Recurrence
likely to occur at the same body region as the original lesion,684 and are Survival after recurrence is generally poor, and depends on the stage of
usually thinner than the original lesion,682,686 possibly due to increased disease at first presentation, site(s) of recurrence, stage of recurrence,
clinical surveillance. The probability of developing a second primary disease-free interval, tumor thickness, ulceration, and response to initial
melanoma is increased by the presence of atypical/dysplastic nevi and therapy for the recurrence. 675,679,689-691 Survival nodal or distant
a positive family history of melanoma.682,686 metastatic recurrences also depend on the diameter of largest
metastasis, number of metastases, and presence of visceral
Long-term Impact of Surveillance
metastases.675,690
It is difficult to document the effect of intensive surveillance on the
outcome of patients with melanoma. A structured follow-up program

Melanoma Discussion
Patient Quality of Life and Emotional Well-Being NCCN Recommendations

An additional consideration when designing a follow-up schedule is the Follow-up recommendations described in this section are for
impact of surveillance on the patient’s quality life. Whereas normal surveillance for recurrence in patients with NED. Recommendations for
exam results can have a positive effect on a patient’s emotional well- assessment of disease response to therapy is described in the specific
being, follow-up visits can also cause stress associated with traveling to treatment sections or left to the discretion of the practitioner.
a clinic, the exam experience, and waiting for results. A meta-analysis
of 15 studies reporting on psychosocial outcomes in patients with early NCCN recommendations for follow-up are largely based on
stage (I/II) melanoma found that although anxiety with follow-up is retrospective studies, generally well-accepted clinical practice, and
common, patients value reassurance, information, and psychosocial panel consensus, and thus are not overly prescriptive. The panel felt
support.692 It was not uncommon for follow-up exams or imaging to be that a recommendation for lifetime dermatologic surveillance for patients
primarily motivated by patient request with melanoma at a frequency commensurate with risk is appropriate.
Risk assessment should include likelihood of relapse, metastasis, or
Psychosocial support for patients not only impacts their quality of life, second primary melanoma or other skin cancer. Clinical discretion is
but may also impact clinical outcomes. Patients in one randomized recommended for determining the appropriate follow-up schedule on a
study who participated in a structured psychiatric group intervention case-by-case basis. The panel recommends the development of
shortly after their diagnosis and initial surgical treatment showed a trend institutional protocols for follow-up, which can be consistent with the
toward decreased recurrence and significantly better survival than those broad parameters of the guidelines despite differing between institutions
without the psychiatric group intervention.687 Of note, improvement in due to institutional structure, resources and processes, and
active-behavioral coping over time was correlated with improved characteristics of the population served. As there is a lifetime increased
outcomes. risk of subsequent melanoma and non-melanoma skin cancers, lifelong
dermatologic surveillance at a frequency consistent with risk is
Patient Education
appropriate.
Skin cancer preventive education should be promoted for patients with
melanoma and their families.693,694 There is increasing evidence that To balance cost with clinical efficacy, the follow-up schedule should
regular sunscreen use may diminish the incidence of subsequent depend on a variety of patient- and disease-specific factors associated
melanoma.695 Patients can be made aware of the various resources that with risk of recurrence, risk of second primary melanoma, and
discuss skin cancer prevention. A list of useful resources is provided by probability that the recurrence or second primary can be effectively
the National Council on Skin Cancer Prevention at treated. Although the optimal duration of follow-up remains
http://www.skincancerprevention.org/resources. controversial, it is probably not cost effective to follow all patients
intensively for metastatic disease beyond five years.

Melanoma Discussion
It is important to highlight that most recurrences are detected through possible or not successful, or patients with a positive SLNB who did not
patient-reported symptoms and physician- or patient-reported physical undergo CLND. Nodal basin ultrasound is not a substitute for SLNB or
exam findings, rather than by imaging surveillance. The follow-up CLND.
schedule should consider the utility of these different surveillance
methods in different settings. Whereas physical exam and recording of Routine blood testing to detect recurrence is not recommended.
symptoms should be emphasized for patients who present with stage Appropriate workup, including radiologic imaging, should be promptly
I/II melanoma, imaging may be incorporated into the follow-up of obtained in the setting of concerning signs and/or symptoms of
asymptomatic patients who present with more advanced disease or recurrence.
have other risk factors for recurrence.
Follow-up schedule should be tailored by risk of recurrence, prior
Common Recommendations for All Patients primary melanoma, and family history of melanoma, and includes other
Skin examination and surveillance at least once a year for life is factors such as atypical moles, moles/dysplastic nevi, and
recommended for all patients with melanoma, including those who are patient/physician concern.
rendered NED after treatment of stage 0, in situ melanoma. Annual
Specific Recommendations
exams should be conducted with care, as regular clinical examination
has the highest diagnostic benefit; it is the most cost-effective method Stage IA-IIA
For patients with stage IA to IIA melanoma, a comprehensive H&P with
for early detection of treatable disease and provides additional
specific emphasis on the regional nodes and skin should be performed
diagnostic benefit by enabling imaging directed by symptoms or clinical
every 6 to 12 months for five years and annually thereafter as clinically
findings. Patients with risk factors associated with increased risk of
indicated. The consensus of the panel is that imaging to screen for
subsequent primary melanomas, such as prior multiple primary
asymptomatic recurrence/metastatic disease is not useful for these
melanomas, family history of melanoma, and the presence of
patients.
atypical/dysplastic nevi, should be enrolled in more intensive
surveillance programs, and may benefit from adjuncts such as high- Stage IIB-IV
resolution total body photography. Coordination among the clinical team For patients with stage IIB-IV melanoma, a comprehensive H&P should
is recommended so that the yearly exam (and any further testing) is not be performed every 3 to 6 months for 2 years; then every 3 to 12
duplicated across specialties. Clinicians should educate all patients months for 3 years; and annually thereafter, as clinically indicated.
about regular post-treatment self-exam of their skin and of their lymph Surveillance interval should be tailored to substage and based on
nodes if they had stage IA to IV melanoma (and are NED). assessment of risk factors for recurrence. In the absence of meaningful
data on the association of rigorous routine surveillance imaging with
Regional lymph node ultrasound may be considered for patients with an improved long-term outcome for stage IIB-IIC, the recommendations
equivocal lymph node physical exam, patients who were offered but did remain controversial. Periodic surveillance CNS imaging for 3 years
not undergo SLNB, patients in whom SLNB was indicated but was not

Melanoma Discussion
might avert some of the substantial morbidity incurred by stage IIIC All of the available data on risk of recurrence, surveillance, and survival
patients who present with symptomatic CNS recurrence. Brain MRI are based on patients treated in the era of older, generally ineffective
surveillance beyond three years, however, has low yield and therefore chemotherapy, and not the current targeted therapies or checkpoint
is less likely to be useful. immunotherapies. Prospective analyses are necessary to determine
whether the use of newer targeted therapies and immunotherapies will
Although not recommended at baseline, in the absence of firm data, the impact surveillance recommendations in asymptomatic high-risk
panel acknowledged that surveillance chest x-ray, CT, brain MRI, patients.
and/or PET/CT every 3 to 12 months (unless otherwise mandated by
clinical trial participation) could be considered to screen for recurrent Treatment of Recurrence
disease at the discretion of the physician (category 2B). Because most NCCN Recommendations
recurrences manifest within the first 3 years (depending on stage and
Persistent Disease or Local Scar Recurrence
other risk factors), routine imaging to screen for asymptomatic
The panel recognized the distinction between true local scar recurrence
recurrence is not recommended beyond 3 to 5 years.
after inadequate initial excision (which most likely represents locally
Prior brain metastases increase risk of new brain metastases, and persistent disease) and local recurrence after adequate initial excision,
treatment success increases with decreasing brain tumor burden; (which likely represents dermal lymphatic disease appearing in
therefore more frequent surveillance with brain MRI is recommended for proximity to the wide excision scar).696 In the former situation, defined
these patients with prior brain metastases. by the presence of in situ and/or radial growth phase, the prognosis
after re-excision is related to the microstaging of the recurrence,
Tailoring the Follow-up Schedule: Key Considerations whereas the latter scenario is prognostically similar to recurrent regional
The frequency of follow-up and intensity of cross-sectional imaging disease.
should be based on the conditional probability of recurrence at any
point in time after the patient is rendered free of disease, as well as the For persistent disease or true local scar recurrence after inadequate
options for treatment. Surveillance for patients at higher risk should be primary therapy, a biopsy is required for confirmation. Guidelines for this
more frequent than for those at lower risk, especially for the first two biopsy should be the same as for primary tumors. The workup should
years. be similar to that of the primary tumor based on microstaging
characteristics. Re-excision to appropriate margins is recommended,
The intensity and interpretation of cross-sectional imaging should also with or without lymphatic mapping and SLNB according to primary
be influenced by the potential for false positives, the desire to avoid tumor characteristics. Adjuvant treatment should be based on
unnecessary treatment, patient anxiety, the potential adverse effects of pathologic stage of the recurrence, and should be similar to that of
cumulative radiation exposure, and medical costs, as well as treatment primary tumors of equivalent stage.
options available in the event that asymptomatic recurrence is detected.

Melanoma Discussion
Local, Satellite, and/or In-Transit Recurrence surgery, an additional adjuvant therapy option is high-dose IFN alfa
Initial clinical recurrence should be confirmed pathologically whenever (category 2B).
possible or if clinically indicated. Pathology should be confirmed by FNA
cytology, if feasible, or core, incisional, or excisional biopsy. Local or Regional Nodal Recurrence
satellite recurrences are in the deep dermis or subcutaneous fat within For patients presenting with regional nodal recurrence, the clinical
the melanoma scar or satellite metastasis adjacent to the melanoma diagnosis should be confirmed by FNA (preferred) or core, incisional, or
scar. By definition they are recurrences after initial adequate wide excisional biopsy. Tissue from the recurrence (preferred) or archival
excision, and lack in situ or radial growth phase. Tissue from the tissue should be assessed for mutation status if the patient is being
recurrence (preferred) or archival tissue should be assessed for considered for targeted therapy or enrollment in a clinical trial that
mutation status if the patient is being considered for targeted therapy or includes mutation status as an eligibility criterion. Baseline imaging (CT
enrollment in a clinical trial that includes mutation status as an eligibility and/or PET/CT or MRI) is recommended for staging and to evaluate
criterion. Baseline imaging (CT and/or PET/CT or MRI) is recommended specific signs or symptoms (category 2B).
for staging and to evaluate specific signs or symptoms (category 2B).
For patients who have not undergone prior lymph node dissection or
Participation in a clinical trial should be considered in all cases of local, had an incomplete lymph node dissection, a CLND is advised. If the
satellite, or in-transit recurrence. In the absence of extra-regional patient underwent a previous CLND, excision of the recurrence to
disease, complete surgical excision to clear margins is recommended negative margins is recommended if possible. After complete resection
whenever feasible. Lymphatic mapping with SLNB may be considered of nodal recurrence, options for adjuvant treatment include a clinical
in patients with resectable in-transit disease on an individual basis trial, observation, or, in patients who were not previously treated,
(category 2B). The prognostic significance of a positive SLNB in high-dose or pegylated IFN alfa, high-dose ipilimumab (category 2B), or
patients with established local regional recurrence is unclear. biochemotherapy (category 2B). Adjuvant radiation to the nodal basin
may also be considered in selected high-risk patients based on size,
Options for treatment of unresectable local, satellite, or in-transit location, and number of involved nodes, and/or macroscopic extranodal
recurrences include intralesional injection with T-VEC, ILP or ILIwith extension (category 2B). For patients with incompletely resected nodal
melphalan, or systemic therapy (as recommended for metastatic recurrence, unresectable disease, or systemic disease, options include
disease). The following are category 2B alternatives: intralesional systemic therapy (preferred), clinical trial, palliative RT, intralesional
injections with BCG, IFN alfa, or IL-2, topical imiquimod (for superficial injection with T-VEC, or best supportive care (see NCCN Guidelines for
dermal lesions), local ablation therapy, or RT. Palliative Care).
After CR to any of these modalities, options include participation in a

clinical trial or observation. For those rendered free of disease by

Melanoma Discussion
Distant Recurrence
For patients presenting with distant recurrence, the workup and
treatment options are similar to those outlined previously for patients
presenting initially with stage IV metastatic disease.
Summary
The NCCN Guidelines for Melanoma represent an effort to distill and
simplify an enormous body of knowledge and experience into fairly
simple management algorithms. In general, treatment recommendations
for primary tumors are based on better data than the recommendations
for treating recurrent disease. These guidelines are intended as a point
of departure, recognizing that all clinical decisions about individual
patient management must be tempered by the clinician’s judgment and
other factors, such as local resources and expertise as well as the
individual patient’s needs, wishes, and expectations. Furthermore, the
NCCN Guidelines for Melanoma undergo annual revision and are
continually updated as new data become available.

Melanoma Discussion
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines Version 3.2016 Panel Members NCCN Guidelines Index

* Daniel G. Coit, MD/Chair ¶ Ryan C. Fields, MD ¶ Anthony J. Olszanski, MD †

NCCN Guidelines Version 3.2016 Sub-Committee NCCN Guidelines Index

Systemic Therapy Workup/Follow-up Recommendations Review

F. Stephen Hodi, Jr. MD † Robert Andtbacka, MD ¶ John A. Thompson, MD ‡ †

Richard W. Joseph, MD ‡ † Christopher K. Bichakjian, MD ϖ

Vijay Trisal, MD ¶ Rene Gonzalez, MD †

† Medical oncology Continue

NCCN Guidelines Version 3.2016 Table of Contents NCCN Guidelines Index

NCCN Melanoma Panel Members Clinical Trials: NCCN believes that

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

ME-A Principles of Biopsy and Principles of Pathology

NCCN Guidelines Version 3.2016 Updates NCCN Guidelines Index

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL PATHOLOGY PRELIMINARY CLINICAL STAGE

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL STAGE WORKUPc,d PRIMARY TREATMENT ADJUVANT TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL STAGE WORKUPc,d PRIMARY TREATMENT ADJUVANT TREATMENT

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL/ WORKUPq PRIMARY TREATMENT ADJUVANT TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL/ WORKUPq PRIMARY TREATMENT ADJUVANT TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

• Biopsy preferred over FNA if archival tissue

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL/PATHOLOGIC FOLLOW-UP RECURRENCEee

ddCommon Follow-up Recommendations for All Patients: Distant

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

CLINICAL/PATHOLOGIC FOLLOW-UP RECURRENCEee

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

WORKUP TREATMENT OF RECURRENCE ADJUVANT TREATMENT

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

WORKUP TREATMENT OF RECURRENCE ADJUVANT TREATMENT

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

WORKUP TREATMENT OF METASTATIC DISEASE

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

PRINCIPLES OF BIOPSY PRINCIPLES OF PATHOLOGY3,4

expression profiling to differentiate benign from malignant neoplasms, or 6Microsatellitosis

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 3.2016 NCCN Guidelines Index

T2 Melanomas 1.01–2.0 mm N1 1 node a: micrometastasis*