NCCN Guidelines® Insights: Melanoma: Cutaneous, Version 2.2021

Featured Updates to the NCCN Guidelines

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  • 1 Stanford Cancer Institute;
  • | 2 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 3 University of Wisconsin Carbone Cancer Center;
  • | 4 Memorial Sloan Kettering Cancer Center;
  • | 5 UC San Diego Moores Cancer Center;
  • | 6 Massachusetts General Hospital Cancer Center;
  • | 7 UCLA Jonsson Comprehensive Cancer Center;
  • | 8 Fred & Pamela Buffett Cancer Center;
  • | 9 University of Michigan Rogel Cancer Center;
  • | 10 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 11 St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;
  • | 12 Yale Cancer Center/Smilow Cancer Hospital;
  • | 13 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 14 Huntsman Cancer Institute at the University of Utah;
  • | 15 AIM at Melanoma;
  • | 16 O'Neal Comprehensive Cancer Center at UAB;
  • | 17 Vanderbilt-Ingram Cancer Center;
  • | 18 Mayo Clinic Cancer Center;
  • | 19 Abramson Cancer Center at the University of Pennsylvania;
  • | 20 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 21 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 22 University of Colorado Cancer Center;
  • | 23 City of Hope National Medical Center;
  • | 24 Fox Chase Cancer Center;
  • | 25 Dana-Farber/Brigham and Women's Cancer Center;
  • | 26 The University of Texas MD Anderson Cancer Center;
  • | 27 Duke Cancer Institute;
  • | 28 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 29 Roswell Park Comprehensive Cancer Center;
  • | 30 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 31 Moffitt Cancer Center; and
  • | 32 National Comprehensive Cancer Network.

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-017-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/89579; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: April 10, 2021; Expiration date: April 10, 2022

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for Melanoma: Cutaneous
  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Melanoma: Cutaneous

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

Susan M. Swetter, MD, Panel Chair, has disclosed no relevant financial relationships.

John A. Thompson, MD, Panel Vice Chair, has disclosed receiving consulting fees from AVEO Pharmaceuticals, Inc., Calithera, Neoleukin, Regeneron Pharmaceuticals, Inc., and sanofi-aventis US; and serving as a scientific advisor for and receiving stock options for Alpine Immune Sciences.

Mark R. Albertini, MD, Panel Member, has disclosed receiving grant/research support from Bristol Myers Squibb, Apeiron Biologics, Array BioPharma, and Merck Sharpe & Dohme.

Genevieve Boland, MD, PhD, Panel Member, has disclosed receiving grant/research support from Olink Proteomics and Palleon Pharmaceuticals, and serving as a scientific advisor for Nektar Therapeutics.

Alison Durham, MD, Panel Member, has disclosed no relevant financial relationships.

Ryan C. Fields, MD, Panel Member, has disclosed no relevant financial relationships.

Brian Gastman, MD, Panel Member, has disclosed receiving grant/research support from Merck & Co., Inc., Alkermes, IntillBio, and NeoImmune Tech; serving on the product/speakers bureau and receiving equity interest/stock options in Castle Biosciences; and receiving consulting fees from Castle Biosciences, Iovance, and Quest Imaging.

Douglas Johnson, MD, Panel Member, has disclosed serving as a scientific advisor for Bristol Myers Squibb Company, Merck & Co., Inc., and Novartis Pharmaceuticals Corporation; receiving grant/research support from Bristol Myers Squibb Company and Incyte Corporation; and receiving consulting fees from Janssen Pharmaceutica Products, LP, Catalyst Biopharma, Iovance, and Oncosec.

Giorgos Karakousis, MD, Panel Member, has disclosed receiving grant/research support from Merck & Co., Inc.

Kim Margolin, MD, Panel Member, has disclosed receiving consulting fees from ImaginAb, Oncosec, Werewolf, Tentarix, Xilio, and Mizuno; and serving as a scientific advisor for Pfizer and Checkmate Pharmaceuticals.

Patrick A. Ott, MD, PhD, Panel Member, has disclosed receiving grant/research support from AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb Company, Genentech, Inc., GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Oncorus, Xencor, and Pfizer Inc.; and serving as a scientific advisor for Merck & Co., Inc.

Merrick I. Ross, MD, Panel Member, has disclosed receiving consulting fees and honoraria from Amgen Inc., Merck & Co., Inc., and Novartis Pharmaceuticals Corporation; serving as a scientific advisor for Amgen Inc. and Merck & Co., Inc.; and serving on the product/speakers bureau for Merck & Co., Inc.

April K. Salama, MD, Panel Member, has disclosed serving as a scientific advisor for Novartis Pharmaceuticals Corporation, Iovance, Pfizer Inc., and Regeneron Pharmaceuticals, Inc.

Rohit Sharma, MD, Panel Member, has disclosed no relevant financial relationships.

Jeffrey Sosman, MD, Panel Member, has disclosed receiving consulting fees from Genentech, Inc., and Nektar Therapeutics; and serving as a scientific advisor for and receiving honoraria from Bristol Myers Squibb.

Nicole R. McMillian, MS, CHES, Guidelines Coordinator, NCCN, has disclosed no relevant financial relationships.

Anita M. Engh, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed no relevant financial relationships.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.

This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.

Overview

In 2021, an estimated 106,110 individuals will be diagnosed with cutaneous melanoma in the United States and about 7,180 will die of metastatic melanoma.1 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma: Cutaneous includes recommendations for biopsy of pigmented lesions suspected to be cutaneous melanoma, and workup, treatment, and follow-up recommendations for patients with pathologically confirmed lesions. These guidelines cover management of all stages of cutaneous melanoma, from melanoma in situ (MIS) through stage IV disease, including recurrent disease. They do not address noncutaneous melanoma, such as uveal and mucosal types, which differ significantly in presentation, genetic profiles, staging, patterns of progression, and response to treatment.24

Overview of Staging and Treatment of Cutaneous Melanoma

Cutaneous melanomas are categorized as follows: localized disease with no evidence of regional or distant metastases (stages 0–II), regional nodal/in-transit disease (stage III), and distant metastatic disease (stage IV). Primary treatment of most newly-diagnosed melanomas includes wide excision (WE) of the primary melanoma, sentinel lymph node biopsy (SLNB) for pathologic staging in appropriate patients with eligible tumor thickness, and additional treatment of regional or distant metastatic disease if present. For patients with resected stage III–IV melanoma, adjuvant systemic immune and targeted therapies are an important means of improving disease-free survival.

Revisions to Pathology Recommendations

Patients presenting with a suspicious pigmented skin lesion should undergo a biopsy to establish a definitive diagnosis of cutaneous melanoma; complete/excisional biopsy is preferred to maximize histopathologic exam and microstaging of the primary tumor. Complete biopsy should be performed with narrow (1–3 mm margins) around the concerning lesion and may be full thickness (eg, fusiform/elliptical, disk, or punch techniques) or involve shave removal into the deep reticular dermis via the saucerization technique.5 Breslow depth of the initial biopsy, along with other histologic factors (ulceration, high mitotic rate, lymphovascular invasion) is used to determine whether SLNB is warranted in clinically node-negative patients, with the caveat that SLNB should optimally be performed at the time of WE. Importantly, both primary tumor thickness and ulceration status are incorporated across the AJCC staging manual 8th edition (AJCC-8) stage III categories.6 In recent updates to the NCCN Guidelines for Melanoma: Cutaneous, the recommendations for elements to be included in the pathology report have been revised to more closely reflect those listed as key factors in national and international dermatopathology guidelines, as illustrated in supplemental eTable 1 (available with this article at JNCCN.org).58 In addition, the description of some of these pathology report elements and guidance for how to measure and record them have been modified in recent updates to the NCCN Guidelines, as described in greater detail subsequently.

Mitotic Rate

Dermal mitotic rate measures the proportion of cells undergoing mitosis and is an indicator of tumor proliferation. The AJCC-8 recommends recording mitotic rate (using the “hot spot” technique to determine the number of mitosis per mm2), since it remains an independent prognostic factor for melanoma specific survival (MSS) across all thickness categories.6 For instance, a mitotic rate ≥11/mm2 reduces 5-year MSS of patients with node-negative T1–T4 melanoma to 84%.9 The NCCN panel has systematically reviewed the many studies that evaluated the relationship between primary tumor mitotic rate in T1 melanoma and likelihood of SLN positivity in patients and noted that whereas results varied across studies that compared presence/absence of mitosis or used low mitotic index cutoff values,1028 studies consistently found that mitotic index >2/mm2 was significantly associated with a higher risk of SLN positivity in thin melanoma.2937 As such, the NCCN Guidelines have been updated to reflect that for T1a lesions (Breslow depth <0.8 mm, nonulcerated), mitotic index >2/mm2 is one of several adverse features that may increase the risk of nodal metastasis and should be considered when discussing SLNB as part of the primary workup (ME-2, footnote l, available at NCCN.org).

Satellite Lesions: Microscopic and Macroscopic

Lymphatic metastasis within or adjacent to the melanoma biopsy site or subsequent WE scar are termed satellite metastasis, whereas those located between the primary tumor and the regional lymph node basin are termed in-transit metastasis. Both confer a stage III diagnosis, as do microsatellites,6,38,39 which are observed histopathologically in either the biopsy or WE specimen.6,9 An analysis of the AJCC-8 worldwide database that included patients with and without synchronous regional nodal disease showed that survival outcomes were similar for patients with microsatellites, macroscopic satellites, and in-transit metastases, with all 3 conferring worse survival.9 Other studies corroborate that the presence of microsatellites, clinical satellites or in-transit metastasis are associated with poorer outcomes (relapse-free survival [RFS], disease-specific survival [DSS], and overall survival [OS]), even among patients with synchronous nodal disease.36,4044 Evidence of microsatellites, clinical satellites, and in-transit metastases is a critical element of initial workup and should be included in pathology reports on biopsy or WE specimens, as should any macroscopic satellites on the gross tumor specimen (ME-B, 2 of 3, page 366).

In AJCC-8, the presence of microsatellites, clinical satellites or in-transit metastasis upstages patients with and without regional nodal disease,6 resulting in an N (node) classification of N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes (0, 1 or ≥2, respectively; see AJCC Staging Tables, ST-2 and ST-4, in these guidelines, at NCCN.org).

In patients with clinical stage I/II melanoma, the presence of microsatellites has also been linked to higher rates of SLN positivity,10,20,44,45 and a positive SLNB upstages a patient to at least N2c, stage IIIC.9,4648 For these reasons the NCCN Guidelines recommendations for workup and management of patients with microsatellites (ME-4), clinical satellites, or in-transit disease (ME-7) differ from those for patients without regional disease (ME-1 and ME-2) or who have regional disease limited to lymph nodes (ME-5 and ME-6; all pages available in these guidelines at NCCN.org).

In contrast to the findings from the analysis of the AJCC-8 database, several studies across various subpopulations reported higher MSS rates for patients with stage III melanoma based on microsatellitosis alone,47,48 compared with those with satellite/in-transit metastasis46,49 or those with a positive SLNB.9,50 In addition, patients with stage III melanoma based on the presence of microsatellites alone (without regional nodal disease) were not included in the prospective randomized trials testing adjuvant therapy for resected stage III cutaneous melanoma.5155 For these reasons, the NCCN Guidelines recommendations for adjuvant treatment consideration differ for those with stage III based on microsatellitosis (ME-4) versus those with stage III based on nodal or clinical satellite/in-transit disease (ME-5 through ME-7; available at NCCN.org).

Lymphovascular/Angiolymphatic Invasion

Lymphovascular invasion (LVI) refers to the presence of melanoma cells within the lumina of blood vessels (termed vascular invasion) or lymphatics (termed lymphatic invasion), or both.68 None of the analyses of the AJCC staging database identified LVI as a significant prognostic factor for survival,9,56,57 although results from other studies varied.22,42,43,5865 A number of studies have found LVI to be an independent predictor of SLN positivity,15,23,28,36,47,63,66 so it is listed as one of the adverse features to be considered when discussing SLNB as part of the primary workup for patients with Stage I, T1a disease (ME-2, footnote l, available at NCCN.org). CAP and ICCR include LVI as a core element, the AJCC encourages reporting, and the AAD Guidelines list it as an optional element to report. The NCCN Guidelines encourage consistent synoptic reporting of LVI or angiolymphatic invasion (ME-B 2 of 3, page 366).

Regression

In some cases the primary tumor may show signs of regression, a process in which the host immune system has recognized and destroyed all or part of the tumor.6,8 The prognostic relevance of this feature is controversial, with some studies showing no correlation between regression and outcomes (SLN status, disease-free survival [DFS], recurrence, metastasis, survival), other studies showing regression to be associated with poor prognosis (DFS, metastasis, survival), and still others showing regression associated with favorable outcomes (lower SLN positivity and improved DFS and MSS).67,68

The NCCN Guidelines encourage reporting of regression if it is extensive (>75%) or extending beneath the measured Breslow thickness (ME-B 2 of 3, page 366). The presence of regression could impact accurate measurement of Breslow thickness, so in some cases surgeons may take it into account when deciding on WE margins or whether to perform SLNB (eg, on tumors <0.8 mm thick), although there are no published data to support this approach.

Other Histologic Features of Importance

Some studies suggest that neurotropism (perineural invasion) may increase the chance for local recurrence in the setting of “pure” desmoplastic melanoma.69,70 The NCCN Guidelines encourages reporting of neurotropism, noting that extensive neurotropism is one of the risk factors for local recurrence in desmoplastic melanoma used to identify cases where adjuvant radiation may be considered, along with head and neck location, and/or close histologic margins (category 2B; ME-H 1 of 7, footnote b; available at NCCN.org).

Although CAP still lists tumor infiltrating lymphocytes as a core element for cutaneous melanoma excision specimens,7 it is a noncore or nonessential element in other guidelines (supplemental eTable 1).5,6,8 In v1.2021, the NCCN panel removed tumor infiltrating lymphocytes from the list of features encouraged for reporting due to concerns about reproducibility and lack of prognostic value.

Studies that have included vertical growth phase as a variable have produced very mixed results regarding its association with LN metastasis29,30,32,71 and other outcomes, with most studies finding that it is not an independent prognostic for RFS or survival.62,7275 Likewise, the NCCN panel removed vertical growth phase from the list of reportable features, as this variable does not appear to have independent prognostic value or impact management decisions.

Histologic Subtype

Traditional clinicopathologic growth patterns (ie, superficial spreading, nodular, lentigo maligna and acral lentiginous) have evolved according to the site of origin (epithelium- versus non-epithelium-derived), role of cumulative sun damage (CSD; high-, low-, or non-CSD-related), and frequency of BRAF, NRAS, and other oncogenic mutations.76 These melanoma subtypes have been incorporated into the 2018 WHO classification of skin tumors77 to denote differences in terms of molecular drivers, pathogenesis, and natural history. The prognostic value of histologic subtype is controversial, with varying results across studies.10,37,42,46,47,62,63,73,74,7887 The AJCC staging system and much of the data informing management is primarily based on the common superficial spreading and nodular subtypes, so consideration of alternative management approaches may be appropriate for patients with less common subtypes. For example, lentigo maligna melanoma may be associated with subclinical peripheral extension beyond visible margins, so may require wider surgical margins or alternative surgical approaches and tissue processing to clear histologically.88,89

Desmoplastic melanoma is characterized by malignant spindle cells separated by prominent fibrocollagenous or mixed fibromyxoid stroma.6,8 “Pure” desmoplastic melanoma is defined as desmoplastic component occupying >90% of a dermal invasive tumor. Mixed desmoplasia defined by typical features of desmoplastic melanoma (desmoplastic component) mixed with densely cellular tumor foci without fibrosis and desmoplasia (nondesmoplastic component), with desmoplastic melanoma areas occupying 10%–90% of the invasive melanoma.90 In v1.2021, the NCCN Guidelines were updated to include the definition of pure desmoplastic melanoma as >90% of invasive melanoma associated with prominent stromal fibrosis.

Compared with mixed desmoplasia or other melanoma subtypes, studies consistently show that “pure” desmoplastic melanoma is associated with improved DSS, and a lower likelihood of nodal metastasis (including lower rates of SLN positivity).81,90101 However, due to variability across studies in the rate of SLN positivity,69,81,91,93104 the role of SLNB in patients with pure desmoplastic melanoma remains controversial. Although adjuvant radiation to the primary melanoma site is generally not recommended due to low risk of recurrence after adequate WE, some desmoplastic melanomas are at increased risk of local recurrence, and adjuvant radiation to the primary site may be considered, as noted above (category 2B).

Histologic Margin Status

Histologic margin status in the biopsy and WE specimens (to include whether the peripheral and deep margin are involved/positive or uninvolved/negative) is a key element for reporting among pathology guidelines (supplemental eTable 1). Consistent with CAP,7 ICCR,8 and AAD,5 the NCCN Guidelines recommend recording whether in situ and/or invasive melanoma is present at the peripheral and/or deep margins on the biopsy or excision specimen. For histologically negative margins on the WE specimen, ICCR and CAP guidelines do not require reporting the microscopically measured distances between tumor and labeled lateral or deep margins, and this measurement should not generally impact clinical decision-making (see “WE for Invasive Cutaneous Melanoma,” page 370). However, narrow pathologic margins (particularly of the invasive component) are associated with higher risk of local recurrence, and this information may warrant consideration of further surgical resection (ME-E, page 367).

Management of Primary Melanoma

WE Management of Melanoma In Situ: Lentigo Maligna or Acral Lentiginous Subtypes

For both in situ and invasive primary melanoma, WE is the primary treatment, although no randomized trials have assessed surgical margins for MIS, and those assessing surgical margins for invasive cutaneous melanoma mostly included patients with superficial spreading or nodular melanoma subtypes (supplemental eTable 2). Management of 2 subtypes of MIS—lentigo maligna (LM) and acral lentiginous type—present surgical challenges because of subclinical extension of tumor cells, location in anatomically constrained sites (eg, face, palms, soles), in addition to the presence of atypical/actinic melanocytic hyperplasia in the LM subtype (high-CSD melanoma) which often confounds histologic assessment of margin status.88,105117 For this reason, surgery with complete circumferential peripheral and deep margin assessment (CCPDMA) has been studied in MIS to improve histologic clearance and decrease the chance of local recurrence (typically persistent disease-type, with in situ and/or radial growth phase).88,89,109,111,112,115,118131 Mohs micrographic surgery (MMS) and staged excision with formalin-fixed, paraffin-embedded (ie, permanent) sections are types of CCPDMA, though these techniques have not yet been prospectively studied in comparison with conventional WE for MIS or invasive CM for local control. The NCCN Guidelines were updated to clarify that for MIS, LM and acral lentiginous types, surgical margins >0.5 cm may be needed and techniques for comprehensive histologic margin assessment may be considered. Published data also suggest a role for CCPDMA in LM with a minimally invasive (T1a) component,132,133 as reflected on ME-E (page 367). For MIS, identification of an invasive component in the central debulking specimen is not uncommon, so the NCCN Guidelines have been updated to indicate that if MMS is performed, permanent section analysis should be performed to provide complete pathologic staging.88,124

WE for Invasive Cutaneous Melanoma

Although much if not all of the melanoma may have been removed by the initial biopsy, WE provides a wider and deeper excision to prevent local recurrence. Multiple prospective randomized trials have been conducted in an effort to define optimal peripheral surgical margins for WE of primary invasive (but not in situ) melanoma (supplemental eTable 2) and have demonstrated that WE with sufficient margins results in very high rates of local control (>96%). These prospective randomized trials are considered category 1 level of evidence for the NCCN recommendations regarding clinical (peripheral) margin extent for WE of primary invasive melanoma, as shown on ME-E (page 367). These trials defined clinical margins as the distance between the incision and the grossly visible edge of the tumor, as measured by the surgeon at the time of surgery. The NCCN Guidelines excision recommendations regarding peripheral margin size are therefore based on clinical margins taken at the time of surgery, not gross or histologic margins measured by the pathologist (ME-E, footnote b).

Concerns have been raised regarding the applicability of these randomized controlled trial (RCT) results across all melanomas, since these trials included mainly superficial and nodular melanoma subtypes on the trunk and extremities and very few patients with lesions on the head or neck (supplemental eTable 2) or other anatomic locations where wide margins would not be possible (ie, acral sites). Large retrospective analyses have attempted to evaluate the relationship between margin size and outcomes using patient populations that include patients with invasive primary melanoma on the head and neck.83,85,87,134139 Of those that evaluated surgical margins,85,134138 multivariable analyses showed that the width of clinical margins (1 vs 2 cm for melanomas 1–2 mm thick,137,138 or 2–4 mm thick,85 or 1–4 mm thick134) did not impact local/intransit RFS, overall RFS, DFS, or MSS. In studies that evaluated histopathologic excision margins (minimum distance between the surgical edge and the invasive component of the melanoma), multivariable analyses sometimes found that narrower peripheral histologic margins were associated with increased risk of local recurrence, locoregional recurrence, and overall DFS, but results were not entirely consistent across studies.83,85,87,138 Results from multivariable analyses more consistently showed that peripheral histopathologic margins were not correlated with MSS or OS.83,85,138 Based on these analyses, the NCCN Guidelines were updated to clarify that although peripheral resection margins may be modified to accommodate individual anatomic or functional considerations, narrower than recommended margins may increase the risk for local recurrence (ME-E, bullet 1, page 367), and footnote language has been added to indicate that narrower peripheral histologic margins have been associated with higher rates of local recurrence for invasive melanoma, though not worse MSS.83,85,87,138

Evidence relating narrower margins to outcomes is based on retrospective studies, and the NCCN Guidelines have been updated to note that the safety and efficacy of narrower surgical margins has not been evaluated through prospective randomized trials. At least one large retrospective analysis found that narrower than recommended surgical margins is associated with increased likelihood of positive or equivocal histopathologic margins,140 although predicting histopathologic margin width based on surgical margins is not entirely straightforward.141 The NCCN Guidelines have been updated to caution that narrower than recommended surgical margins may increase the likelihood of margin positivity and local recurrence, and may warrant further surgical resection.

Due to the challenges of obtaining the recommended WE margins in sites with anatomic or functional constraints and the local recurrence risk if narrower surgical margins are used, surgical techniques and processing to provide comprehensive pathologic assessment prior to surgical repair have been investigated, including MMS and staged excision with permanent sections.109,111,119,120,125,133,142145 However, while there are multiple prospective randomized trials supporting conventional WE with the recommended margins (supplemental eTable 2), there have been no prospective comparisons of different excision methods, including conventional WE, MMS, and staged excision with permanent sections. Available retrospective studies in invasive melanoma suggest that MMS or staged excision may result in similar low recurrence rates as conventional WE,119,120,143,144,146,147 but prospective, randomized trial data are needed for confirmation. The NCCN Guidelines have been updated to clarify that MMS is not recommended for primary treatment of invasive cutaneous melanoma. However, because the RCTs supporting WE largely excluded patients with lesions in anatomically constrained areas, and there are no high-quality data to inform surgical method for lesions in these areas, the NCCN Guidelines have been updated to indicate that MMS may be considered selectively for MIS (LM and acral lentiginous types) and for minimally invasive (T1a) LM melanoma in anatomically constrained areas, along with other surgical methods that provide comprehensive histologic assessment, such as staged excision with permanent sections for dermatopathology review.

Sentinel Lymph Node Biopsy

Cutaneous melanoma typically presents with a clinically localized primary lesion.1 Most regional nodal melanoma presents microscopically (ie, clinically occult) and is detected via SLNB.9,50 Patients with a positive SLNB are at higher risk of recurrence and may now be followed with nodal basin ultrasound surveillance (where radiologic expertise is available) without completion lymph node dissection, given lack of improved MSS in 2 RCTs assessing the merits of completion lymph node dissection following a positive SLNB vs clinical observation with nodal ultrasound.148150 Although SLNB is considered minimally invasive, it is not without risks of complications. In general, if a patient’s risk of a positive SLN is <5% (ie, T1a melanoma), NCCN does not recommend SLNB; if a patient’s risk of a positive SLN is 5%–10% (ie, T1b melanoma), NCCN recommends discussing and considering SLNB; and if the probability of a positive SLN is >10% (T2a-T4b melanoma), NCCN recommends that SLNB should be discussed and offered. NCCN panel considerations regarding SLNB, including information from initial biopsy of the primary lesion that is used to determine appropriateness of SLNB are summarized in supplemental eTable 3 and should take into account patient age, functional status, and life expectancy. The use of prognostic gene expression profiling (GEP) tests (before or after SLNB) requires further investigation across large, prospectively-enrolled cohorts of unselected patients. Given the low probability of metastasis in stage I melanoma and a higher proportion of false-positive results,151154 the NCCN panel concluded that currently available GEP tests should not replace pathologic staging procedures, be used to determine SLNB eligibility, or guide clinical-decision making in this subset of patients (see ME-2A, footnote d, and ME-F 1 of 3; available in these guidelines at NCCN.org). Principles of nuclear medicine, surgery, and pathology pertaining to SLNB have also been recently revised (ME-F 2 and 3; available in these guidelines at NCCN.org).

Treatment of Unresectable Stage III or Distant Metastatic Disease (Stage IV): Updates to Systemic Therapy Options

Anti–PD-1/Anti–CTLA-4 Combinations

For several years, combination therapy with nivolumab/ipilimumab has been a recommended option for first-line or second- or subsequent-line systemic therapy for unresectable or distant metastatic disease, based on the results from Checkmate-067 and Checkmate-069 (supplemental eTable 4). These trials both used nivolumab 1 mg/kg (NIVO1) plus ipilimumab 3 mg/kg dosing (IPI3), which is associated with a high rates of grade 3–4 treatment-related adverse events (TRAEs) as shown in supplemental eTable 4. Investigators have explored new combinations of anti–PD-1 and anti–CTLA-4 in an attempt to reduce the rate of grade 3–5 toxicity while preserving the antitumor efficacy of combination therapy. One such approach is the use of “full dose” anti–PD-1 (eg, nivolumab 3 mg/kg [NIVO3]) in combination with a lower dose of anti–CTLA-4 (eg, ipilimumab 1 mg/kg [IPI1]). The randomized double-blind Checkmate 511 trial showed that this approach (NIVO3/IPI1) significantly reduced the rate of high-grade TRAEs compared with NIVO1/IPI3 (supplemental eTable 4; P=.006 for grade 3–5 TRAEs). Based on these results, the NCCN Guidelines now indicate that while NIVO1/IPI3 is an FDA approved regimen,155 NIVO3/IPI1 is associated with lower rates of immune-related toxicity, although longer follow-up is needed to determine equivalence of therapeutic efficacy between the 2 dosing regimens (ME-J 1 of 4, available in these guidelines at NCCN.org).

Several trials are exploring “full dose” pembrolizumab (2 mg/kg or 200 mg) in combination with lower-dose ipilimumab (IPI1) for patients with unresectable or distant metastatic disease (supplemental eTable 4). Like the trials testing nivolumab/ipilimumab, these trials included an option for single-agent anti–PD-1 therapy after the 4 doses of combination therapy. The phase IB open label trial (KEYNOTE-029) showed that in patients with advanced melanoma, and no prior checkpoint immunotherapy, pembrolizumab combined with low-dose ipilimumab resulted in a high response rate, long duration of response (84% of responses lasted at least 36 months), and long PFS and OS (supplemental eTable 4). These results appear to be on par with results from similar patient populations treated with nivolumab/ipilimumab combination in randomized trials (supplemental eTable 4, see results from Checkmate 067 and Checkmate 069). The rate of grade 3–4 TRAEs (47%) is similar to or lower than that seen for NIVO1/IPI3 across trials (range, 48%–59%; but higher than that seen for NIVO/IPI1 [33%] in Checkmate 511 (supplemental eTable 4)}. Because KEYNOTE-029 is a single-arm study, the NCCN panel voted to include pembrolizumab/low-dose ipilimumab in the first-line setting as an “other recommended regimen”, category 2B (ME-I, 1 of 8; available at NCCN.org).

Another single-arm trial (NCT02743819, phase II) tested pembrolizumab/low-dose ipilimumab in patients with advanced melanoma and recent progression on an anti–PD-1 agent and no prior ipilimumab treatment (supplemental eTable 4). In an analysis of 70 patients (67 evaluable for response), 31% responded, with a median PFS of 4.7 months and 21% of patients experiencing a grade 3–4 TRAE (supplemental eTable 4). The NCCN panel voted to include this combination as a category 2A preferred option for patients who have progressed on prior anti–PD-1 therapy (ME-I, 1 of 8; available in these guidelines at NCCN.org).

BRAF/MEK Inhibitors Plus Checkpoint Immunotherapy Triplet Combinations

For patients with unresectable or distant metastatic disease harboring a BRAF V600-activating mutation, selection between first-line immune checkpoint inhibitors or BRAF/MEK inhibitor therapy can be difficult given the lack of comparative phase II/III clinical trials. The advantage of BRAF/MEK inhibitor therapy is high response rates (65%–70%; see supplemental eTable 5), and relatively rapid time to response (reflects time to first tumor response assessment: 6 weeks in BRIM-7, 8 weeks in other trials).156159 Although the median duration of response to BRAF/MEK inhibitor therapy is in the range of 12.0 to 18.6 months (supplemental eTable 5), there have been concerns dating back to the era of BRAF monotherapy, when response durations were much shorter, that targeted therapy may not elicit immunologic memory required for durable antitumor responses. For anti–PD-1–based immune checkpoint inhibitor therapy, response rates in trials are between 35%–40% for single-agent therapy and around 60% for anti–PD-1/ipilimumab combination therapy (see supplemental eTable 4). Reponses to immune checkpoint inhibitors can take time to develop in some patients, with late responses observed over a year after starting treatment, and initial partial responses that may convert to complete responses after long-term follow-up (see trials in supplemental eTable 4). Responses to immune checkpoint inhibitors appear to be highly durable in this setting, with large trials reporting median duration of response for anti–PD-1 containing regimens ranging from 22 months to several years (supplemental eTable 4).

Several trials are currently assessing whether the high likelihood of response seen with BRAF/MEK inhibitor therapy and the durability of response see with immune checkpoint inhibitors can both be achieved in patients with activating BRAF V600 mutations. Results have recently been reported from a number of randomized phase II-III trials testing triplet combinations of BRAF, MEK and a PD-1 (eg, pembrolizumab, spartalizumab) or PD-L1 inhibitors (eg, atezolizumab) as first-line systemic therapy for unresectable stage III or stage IV cutaneous melanoma (supplemental eTable 6). These trials found that the triplet combinations did not improve response rate compared with BRAF/MEK inhibitor doublets. However, the triplet combinations did improve the duration of response compared with the doublets (supplemental eTable 6, footnote d). In both IMspire150 and KEYNOTE-022, the triplet combination improved PFS, although in KEYNOTE-022 this was not apparent in the prespecified analysis after 9.5 months follow-up (supplemental eTable 6). COMBI-I showed a nonsignificant trend toward improved PFS with the triplet regimen compared with BRAF/MEK inhibition alone. In all 3 trials, there was no clear benefit in OS, although longer follow-up may be needed. Until mature OS data are published, it is therefore not clear that triplet regimens are preferred over sequential BRAF/MEK inhibitor therapy followed by immune checkpoint inhibitor therapy (or the converse order). Whereas KEYNOTE-022 and COMBI-I both show higher rates of grade 3–5 TRAEs with the triplet versus the doublet regimen, IMspire150 showed similarly high rates of grade 3–4 TRAEs across arms (supplemental eTable 6), but reported more immune-mediated AEs in the triplet versus doublet arms (63% vs 51%). IMsprire150 showed similar rates of discontinuation due to TRAEs across arms. The NCCN panel voted to include both triplet regimens as “other recommended” first-line systemic therapy options for patients with metastatic or unresectable cutaneous melanoma who have a BRAF V600-activating mutation, with vemurafenib/cobimetinib/atezolizumab as category 2A and dabrafenib/trametinib/pembrolizumab as category 2B.

Summary and Conclusions

Advances in melanoma diagnosis, prognosis, and therapy will continue with ongoing investigation of various molecular techniques (eg, GEP and circulating tumor DNA [ctDNA] assays) to more accurately define the risk of relapse. Prospective investigation is required using large contemporary data sets and compared with optimized phenotypic models to support use of molecular tests for SLNB eligibility, therapeutic decisions regarding adjuvant therapy, indications for imaging surveillance, and intensity of patient follow-up. Ongoing investigation of sequential and combination regimens of targeted and immune therapy, including novels agents, holds promise in prolonging survival in patients with advanced disease.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

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

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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