eBulletin Newsletter

NCCN Flash Updates: NCCN Guidelines Updated for Melanoma: Cutaneous

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Melanoma: Cutaneous. These NCCN Guidelines^® are currently available as Version 1.2024.

Link directly to the Updates section of the NCCN Guidelines: Melanoma: Cutaneous

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.

General

• The recommendation "Observation" now links to Follow-up/surveillance recommendations (ME-11) and/or Systemic Therapy Considerations

(ME-J 2 of 4), which lists the follow-up/surveillance recommendations.

• The systemic therapy regimen "Dabrafenib/trametinib for patients with BRAF V600-activating mutation" changed to "Dabrafenib/trametinib if BRAF V600 mutation positive."
• The term "immune therapy" changed to "immunotherapy" throughout the Guidelines.
• A new section for "Principles of Neoadjuvant Therapy" was added (ME-I).

Table of Contents

• New listings added
  • For melanomas in other sites, see:
    • Eye(s): NCCN Guidelines for Melanoma: Uveal
    • Vulvovaginal Melanoma: NCCN Guidelines for Vulvar Cancer
    • Mucosal Melanoma: NCCN Guidelines for Head and Neck Cancer

ME-1A

• Footnote d revised: Repeat narrow-margin excisional biopsy is generally not indicated if the initial specimen meets criteria for sentinel lymph node biopsy (SLNB), unless the initial biopsy is inadequate for diagnosis or microstaging recommended if an initial partial biopsy is inadequate for diagnosis or microstaging but should not be performed if the initial specimen meets criteria for sentinel lymph node biopsy (SLNB) staging.
• Footnote f revised: "...or in-transit metastasis should undergo warrant a thorough discussion to consider a dermal primary versus metastatic process. Baseline metastatic workup with imaging (CT chest/abdomen/pelvis or FDG-PET/CT)...
• Footnote h revised: "... or wide excision specimen, describe whether presence of in situ or invasive melanoma is present at the peripheral and/or deep margins should be noted. For histologically negative margins... This measurement should does not generally impact clinical decision-making..."
• Footnote m revised: Pathology reporting of extensive versus focal neurotropism (ie, involving only a single nerve vs. multiple nerves and/or size of involved nerves present, absent, indeterminate) may help guide clinical decision-making (ie, further excision or adjuvant radiation therapy [RT]).

ME-2

• Footnote n revised: "...This would include clinical stage IA, T1a melanoma (Breslow depth of <0.8 mm, nonulcerated) without other adverse features, unless there is significant uncertainty about the adequacy of microstaging (due to positive deep margins or limited sampling of a larger lesion). If a patient’s risk of a positive SLNB is 5%–10%, NCCN recommends discussing and considering SLNB. This would include clinical stage IB, T1b melanoma (Breslow depth <0.8 mm with ulceration or 0.8–1 mm with or without ulceration), or T1a lesions with Breslow depth ≥0.5 mm >0.5 mm and other adverse features (age ≤42 years, head/neck location, lymphovascular invasion, and/or mitotic index rate ≥2/mm²), with additive increased risk when multiple adverse features are present (Shannon AB, et al. J Am Acad Dermatol 2023;88:52-59). Readily available, no-cost risk calculators (eg, melanomarisk.org.au; https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis) may aid clinicians in discussion of risk versus benefit of SLNB in these scenarios Ongoing prospective investigation will further inform the utility of GEP tests and multivariable nomograms/risk calculators (eg, melanomarisk.org.au/snlland; https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis for SLNB risk prediction.

ME-2A

• Footnote o revised: "...GEP testing should not guide clinical decision-making in this subgroup. On an individual basis, the likelihood of a positive SLNB may be informed by the use of multivariable nomograms/risk calculators. Ongoing prospective investigation will further inform the use of GEP tests for SLNB risk prediction In addition, the likelihood of a positive SLNB may be informed by the use of multivariable nomograms/risk calculators. Ongoing prospective investigation will further inform the utility of GEP tests and multivariable nomograms/risk calculators for SLNB risk prediction (eg, melanomarisk.org.au/snlland; https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis). See Principles of Molecular Testing (ME-C). (Freeman SC, et al. J Am Acad Dermatol 2023;89:967-973) (Also for ME-3A)
• Footnote s revised: SLNB is an important staging tool. While SLNB itself has not been shown to improve disease-specific survival (DSS), it is associated with improved regional nodal disease control (Crystal JS, et al. JAMA Surg 2022;157:835-842). A positive SLNB would upstage a patient to stage III. A positive SLNB upstages melanoma to stage III and is associated with significantly decreased disease-specific survival (DSS) melanoma-specific survival (MSS) (Montcreif MD, et al. J Clin Oncol 2022;40:3940-3951). While SLNB has not been proven to provide therapeutic benefit, it is associated with improved control of regional nodal disease (Crystal JS, et al. JAMA Surg 2022;157:835-842). SLNB status may aid adjuvant therapy decisions in clinically node-negative patients. Adjuvant therapy has mainly been shown to mainly improve relapse-free survival (RFS) (over overall survival [OS]) in selected patients with high-risk stage II and III disease melanoma. (Also for ME-3A)

 

ME-3

• Stage IB (T2a) or II (T2b or higher); Adjuvant Treatment: Recommendation revised,
  • "For pathological stage IIB or IIC
    • Pembrolizumab (category 1)
    • Nivolumab (category 1)

and/or Locoregional Primary tumor site radiation therapy (RT) to reduce local recurrence (category 2B)"

• Footnote x revised: "... SLNB should be considered in patients with microsatellitosis, especially if it will alter disease management decisions."
• Footnote y: Placement of footnote "y" moved from page ME-3A to ME-3.

ME-3A

• Footnote z revised: "...prior to consideration of adjuvant pembrolizumab or nivolumab—to enhance risk/benefit patient discussions and optimize locoregional disease control."
• Footnote aa revised: Adjuvant pembrolizumab and nivolumab is are active in reducing relapse events for resected stage IIB and IIC melanoma. However, longer follow-up is needed to evaluate the impact of adjuvant pembrolizumab or nivolumab on OS. Clinicians considering adjuvant pembrolizumab or nivolumab therapy for stages IIB or IIC disease should have a detailed discussion with the patient to weigh the pros and cons of treatment benefit versus toxicity. Factors to be considered, in addition to stage, include patient’s age, performance status, personal/family history of autoimmune disease, and tolerance for risk of lifelong immunotoxicities.

ME-4

• Microscopic satellites in wide excision specimen and Sentinel node negative; SLNB not performed: Consider delayed SLNBif not previously performed

• Adjuvant treatment revised for first and second pathways:
  • The recommendation Adjuvant PD-1 immunotherapy changed to Systemic therapy.
  • Single-agent nivolumab and pembrolizumab were preference stratified as preferred regimens
  • Dabrafenib/trametinib if BRAF V600 mutation positive was added as an adjuvant treatment option. This is a category 2A, preferred regimen.

ME-4A

• Footnote cc revised: "Patients with stage IIIB melanoma based on microsatellites alone (without satellite, in-transit, or nodal disease) demonstrate more favorable survival compared with those with a positive SLNB (Bartlett EK. J Surg Oncol 2019;119:200-207; Karakousis GC, et al. Ann Surg Oncol 2019;26:33-41). Because patients who were microsatellite-positive, but SLN-negative, microsatellite-positive patients were not studied in adjuvant therapy trials, the results of these trials may not be applicable to this subgroup.
• Footnote dd added: If BRAF V600 mutation positive, other BRAF/MEK inhibitor combinations can be considered in the event of unacceptable toxicities to dabrafenib/trametinib or based on side effect profiles.
• Footnote removed: Primary lesion microsatellitosis with no clinical satellite, in-transit, or nodal disease.

ME-5

• Stage III sentinel node–positive disease
  • Primary Treatment revised: Observation without additional nodal surgery, and with mandatory radiographic nodal surveillance (preferred) Active nodal basin ultrasound (US) or other radiographic surveillance without completion lymph node dissection (CLND) (preferred) or CLND, only in select patients.
  • Adjuvant Treatment; Options; Preferred regimens: Dabrafenib/trametinib for patients with if BRAF V600 activating mutation positive.
  • Footnote nn is new: Adjuvant dabrafenib/trametinib and pembrolizumab were tested in AJCC 7th Edition stage IIIA with SLN metastasis >1 mm or stage IIIB/C disease. Adjuvant nivolumab was studied in AJCC 7th Edition stage IIIB/C disease (category 1 for all agents). Clinical efficacy
    of these agents has been demonstrated across AJCC 8th Edition stage III disease.

ME-5A

• Footnotes modified
  • Footnote dd: For patients with If BRAF V600 mutation positive, Oother BRAF/MEK inhibitor combinations can be considered in the event of unacceptable toxicities to dabrafenib/trametinib or based on side effect profiles.
    (Also for ME-6A, ME-7A, ME-8A, ME-14A, ME-15A, ME-16A, ME-17A)
  • Footnote ee: "For patients with a positive SLNB(s), the presence of microsatellites in the initial biopsy of the primary tumor or wide excision specimen will upstage the patient melanoma to at least IIIC...."
  • Footnote ff: "For patients with clinically positive node(s), the presence of microsatellites in the initial biopsy of the primary tumor or wide excision specimen upstages patients the melanoma to a minimum of stage IIIC. While this microsatellitosis does not change..." (Also for ME-6A)
  • Footnote hh: For patients with a positive sentinel node SLNB, two prospective randomized phase III studies have demonstrated no improvement in MSS or OS in patients undergoing CLND compared to those who underwent nodal basin US surveillance although only one study (MSLT-II) included primary melanomas on the head and neck. CLND did provide additional prognostic information as well as and improvement in regional control/recurrence, at the expense of increased morbidity, including wound complications and long-term lymphedema. Factors that predict non-SLN positivity include mitotic rate, lymphovascular invasion, head/neck location, sentinel node tumor burden..."
  • Footnote ii: Nodal US surveillance is preferred if institutional expertise is available. Alternative imaging modalities (eg, CT, MRI, FDG-PET/CT), are acceptable.
  • Footnote jj: "...two prospective randomized trials (MSLT-II and DeCOG; ie, every 4 months during the first 2 years, then every 6 months during years 3 through 5), although synchronizing frequency of nodal US with cross-sectional imaging may also be acceptable..."
  • Footnote kk: Nodal basin US/imaging surveillance may not be preferred over CLND in all cases (eg, patient preference due to the logistics of surveillance, when primary tumor histology and SLN tumor burden suggest a higher likelihood of additional, and/or when adjuvant therapy is not pursued). Active nodal basin surveillance with imaging and clinical exam is recommended over CLND. In very select, uncommon scenarios (eg, inability to adhere to clinical and imaging surveillance, or when primary tumor characteristics and SLN tumor burden predict a higher likelihood of additional positive nodes), CLND should be considered and discussed.
  • Footnote mm: In patients with very-low-risk stage IIIA disease (non-ulcerated primary ≤2 mm thickness, SLN metastasis <1 mm), (T1a/b–T2a/N1a or N2a), the toxicity of adjuvant therapy may outweigh the benefit. Patients with T1b–T2a/N1a or N2a pathologic stage IIIA melanoma and SLN tumor deposits ≥0.3 mm in maximum dimension are at higher risk of disease progression and may benefit from adjuvant systemic therapy. Stage IIIA patients with SLN deposits <0.3 mm in maximum dimension demonstrate 5-year melanoma-specific survival similar to those with pathologic stage IB (T2aN0) melanoma, with consideration for less intensive radiologic surveillance and follow-up (Moncrieff MD, et al. J Clin Oncol 2022;40:3940-3951).
  • Footnote pp: "...CLND has no impact on DSS MSS or OS, it is unclear whether CLND should generally not be a factor in the decision...
• Footnotes removed
  • Adjuvant dabrafenib/trametinib and pembrolizumab are category 1 options for patients with AJCC 7th Edition stage IIIA with SLN metastasis >1 mm or stage IIIB/C disease. Adjuvant nivolumab is a category 1 option for patients with AJCC 7th Edition stage IIIB/C disease.
  • Randomized clinical trials testing adjuvant anti-PD-1 therapy included patients with sentinel node-positive disease at higher risk of recurrence: those with ulcerated primary (ie, nivolumab, pembrolizumab) or an SLN metastasis >1 mm (pembrolizumab).
  • The randomized clinical trial testing adjuvant dabrafenib/trametinib combination therapy for patients with BRAF V600E/K mutation included patients with sentinel node-positive disease at higher risk of recurrence: those with ulcerated primary and/or SLN metastasis >1 mm.

ME-6

• Stage III (clinically positive[s]); Primary Treatment
  • The recommendation "Neoadjuvant therapy options" was added with the following regimens:
    • Preferred regimens
      • Pembrolizumab
      • Nivolumab/ipilimumab
    • Other recommended regimens
      • Nivolumab
      • Nivolumab and relatlimab
    • Useful in certain circumstances
      • Dabrafenib/trametinib if BRAF V600 mutation positive
  • After the list of neoadjuvant therapy options, "Wide excision of primary tumor(category 1)+ TLND" was added.
  • The recommendation "Neoadjuvant therapy, preferably in the context of a clinical trial" was removed.
• Stage III (clinically positive[s]); Adjuvant Treatment
  • Locoregional therapy option modified: "Consider RT to nodal basin in selected patients at high risk patients for nodal recurrence based on..."

ME-6A

• The following footnotes changes were made:
  • Footnote qq modified: Patients with extensive clinically evident nodal or in-transit disease are at high risk for metastatic progression and have increased risks of perioperative morbidity. Multiple clinical trials have investigated neoadjuvant therapy, including single/combination checkpoint inhibitors, BRAF/MEK inhibitors, and intralesional therapies either alone or in combination with checkpoint inhibitors (see references below).
    Clinical trials have also been designed to study pathologic response after neoadjuvant treatment and its effect on RFS. A randomized phase 2 trial of 313 patients (naïve to prior immunotherapy) showed event-free survival (EFS) at 2 years of 72% (95% confidence interval [CI], 64 to 80) for neoadjuvant pembrolizumab for 3 cycles followed by surgery and adjuvant pembrolizumab compared with 49% (95% CI, 41 to 59) in the up-front surgery and adjuvant therapy group. At present, there is no consensus regarding the recommended agents to use, duration of neoadjuvant therapy, extent of subsequent surgery, or how pathologic response to neoadjuvant therapy might impact the choice of adjuvant therapy outside the context of a prospective study.
    The SWOG1801 trial randomized 313 patients with resectable stage III–IV melanoma to 3 doses of neoadjuvant pembrolizumab 200 mg every 3 weeks followed by adjuvant pembrolizumab, vs. adjuvant pembrolizumab; both groups received surgical excision. The neoadjuvant arm was associated with improved event-free survival (EFS) at 2 years (72% vs. 49%, P < .01). Additional studies with 1–3 doses of anti-PD-1–based regimens given prior to surgery (either monotherapy or in combination with CTLA-4 or LAG-3 blockade) have also demonstrated high pathologic response rates and toxicities largely consistent with their use in the metastatic setting. Receipt of prior (neo)adjuvant therapy likely decreases the likelihood of response to neoadjuvant therapy of a similar class. (For neoadjuvant therapy references, see ME-6B)
    • The references associated with this footnote were moved to a separate page.
    • The changes for this footnote were also made for ME-16A and ME-17A.
  • Footnote rr modified: "Prospective trials supporting the systemic therapy options on MELSYS (1 of 7) as neoadjuvant therapy are ongoing. Patients should be monitored for best response..." (Also for ME-16A, ME-17A)
  • Footnote tt is new: Major pathologic response (MPR) following 2 doses of nivolumab/ipilimumab is associated with >90% 3-year RFS with no additional adjuvant therapy; optimal adjuvant therapy is not clear but can include anti-PD-1 monotherapy or observation (for MPR), or anti-PD-1 or dabrafenib/trametinib (for those lacking MPR). (Tetzlaff MT, et al. Ann Oncol 2018;29:1861-1868). (Also for ME-16A, ME-17A)
  • Footnote uu is new: Ipilimumab 1 mg/kg + nivolumab 3 mg/kg was associated with similar pathologic response and RFS rates, and lower toxicities compared with ipilimumab 3 mg/kg + nivolumab 1 mg/kg. (Also for ME-16A, ME-17A)
  • Footnote vv is new: If immunotherapy is contraindicated, dabrafenib and trametinib could be considered for a short course (4–12 weeks) of preoperative therapy. However, this approach has not been studied in comparison with adjuvant dabrafenib and trametinib.
    ME-6B

• A new page was added with references for neoadjuvant therapy.

ME-7

• The layout of this page was significantly revised. (Note: The changes below were also made for local/satellite in-transit recurrence on page ME-14)
  • Stage III (clinical satellite/in-transit); Limited resectable disease
    • Initial treatment
      • Neoadjuvant systemic therapy (For regimens, see ME-6) added as an option.
      • After neoadjuvant systemic therapy, Complete excision to clear margins added.
      • Modified: Systemic therapy (See adjuvant treatment ME-7 First-Line therapy MELSYS-1)
    • Subsequent treatment recommendation modified: See Initial Treatment for Unresectable/Borderline resectable disease (ME-8)
    • Adjuvant treatment; Bottom pathway; NED after systemic therapy; Modified: Observation (ME-11), (ME-J 2 of 4) or continue same class of systemic therapy. (Also for ME-8)
  • Stage III (clinical satellite/in-transit); bottom pathway revised: Unresectable/borderline resectable disease (Also for ME-8)

ME-7A

• Footnote aaa is new: Most neoadjuvant clinical trials included no or few satellite/in-transit lesions. However, given their high degree of activity in other stage III/IV settings, similar therapeutic options can be considered as with clinically positive nodal disease. (Also for ME-14A)
• Footnote bbb is new: When systemic therapy is given, a neoadjuvant approach is generally favored; however, when patients experience excellent clinical/pathologic responses, complete excision may not be necessary, particularly when clinically morbid. (Also for ME-14A, ME-16A, ME-17A)
• Footnote ccc modified: For low-volume in-transit disease, the high risk of toxicities associated with certain combination regimens (nivolumab/ipilimumab or nivolumab and relatlimab) may outweigh the benefit. (Also for ME-8A, ME-14A, ME-15A)
• Footnote eee is new: A course of 6 doses of T-VEC followed by surgery was compared to surgery alone in 150 patients. Neoadjuvant T-VEC was associated with improved RFS at 2 years (29.5% vs. 16.5%). Based on modest efficacy in lymph node or distant metastatic disease, this approach is only considered in patients with in-transit disease. (Dummer R, et al. Nat Med 2021;27:1789-1796.) (Also for ME-14A)

ME-8

• The layout of this page was significantly revised. (Note: The changes below were also made for local/satellite in-transit recurrence on page ME-15)
• Stage III (clinical satellite/in-transit); Unresectable/borderline resectable disease
  • Initial treatment; Local therapy options
    • Intralesional injection options; Preference stratification for the noted regimens was moved to the algorithm. Previously the stratification was in footnotes.
      • Preferred regimens: T-VEC(category 1)
      • Useful in certain circumstances: IL-2 (category 2B)
    • Topical imiquimod for superficial dermal lesions (category 2B) was removed as an option.
  • Adjuvant treatment
    • NED after local or regional therapy; Consider adjuvant systemic therapy options (category 2B); The adjuvant systemic therapy regimens were clarified as:
      • Preferred regimens
        • Nivolumab
        • Pembrolizumab
        • Dabrafenib/trametinibif BRAF V600 mutation positive

ME-8A

• Footnote jjj modified: "...Efficacy was noted demonstrated in AJCC 7th Edition stage IIIB and IIIC disease, and was more likely to be seen in patients who were treatment naïve. T-VEC has shown similar efficacy across clinically detected/macroscopic AJCC 8th edition stage III disease." (Also for ME-15A, ME-17A)
• Footnote removed: These options have been preference stratified as "Preferred Regimens." (Also for ME-15A)
• Footnote removed: These options have been preference stratified as "Useful In Certain Circumstances." (Also for ME-15A, ME-17A)

ME-11

• Stage IIB–IV NED; Follow-up; Bullet 3 modified: Routine blood tests are not recommended, unless indicated for post-treatment monitoring.
• Footnote qqq modified: "...recommendations listed here are for surveillance for recurrence in patients who are asymptomatic patients with no clinical evidence of disease."

ME-14

• The layout for this page was significantly revised.

ME-15

• Local satellite/in-transit recurrence; Unresectable/borderline resectable disease
  • NED after local or regional therapy; Adjuvant treatment
    • Consider adjuvant systemic therapy options (category 2B); The adjuvant systemic therapy regimens were clarified as:
      • Preferred regimens
        • Nivolumab
        • Pembrolizumab
        • Dabrafenib/trametinibif BRAF V600 mutation positive
      • Useful in certain circumstances
        • Ipilimumab if prior exposure to anti-PD-1 therapy

ME-16

• Nodal recurrence; Treatment of recurrence
  (Note: The changes below were also made for disease limited to nodal recurrence; Biopsy to confirm on page ME-17)
  • The recommendation "Neoadjuvant therapy options" was added with the following regimens:
    • Preferred regimens
      • Pembrolizumab
      • Nivolumab/ipilimumab
    • Other recommended regimens
      • Nivolumab
      • Nivolumab and relatlimab
    • Useful in certain circumstances
      • Dabrafenib/trametinib if BRAF V600 mutation positive
  • After the list of neoadjuvant systemic therapy options, "Excision of the recurrence/TLND" was added.
  • The recommendation "Neoadjuvant therapy, preferably in the context of a clinical trial" was removed.
• Nodal recurrence; Adjuvant Treatment
  • Locoregional therapy option modified: "Consider RT to nodal basin in selected patients at high risk patients for nodal recurrence
    based on..."

ME-17

• Disease limited to nodal recurrence; Biopsy to confirm; Resectable; Treatment of recurrence
  • Recommendation revised: Excise recurrence and, if previously incomplete, perform complete/TLND

ME-17A

• Footnote sss modified: "Disease is defined as technically unresectable (ie, involvement of a major neurovascular structure) or clinically unresectable (ie, remote distant nodal disease)..." (Also on ME-16A)

ME-18

• Distant metastatic disease
  • Oligometastatic pathway; Treatment of Metastatic Disease
    • Revised: Metastasis-directed therapy options
    • Residual disease pathway: Revised, Treat as distant metastatic disease widely disseminated pathway (below)
    • Negative for other disease pathway: "Treat as disseminated pathway (below)" added as an option
    • Adjuvant treatment options; Under "Other recommeded regimens" revised: For patients with If BRAF V600-activating mutation positive
      (all category 2B)
  • Widely disseminated
    • Bullets revised under "Options include"
      • Consider palliative resection and/or RT and/or intralesional T-VECfor symptomatic extracranial disease
      • Bullet removed: "For limited extracranial lesions: intralesional T-VEC"

ME-18A

• Footnote xxx revised: "... IV–M1a disease (skin, subcutaneous, and/or remote nodes). Similar efficacy has been demonstrated in AJCC 8th Edition stage IV–M1a disease."

MELSYS-1 Systemic Therapy for Metastatic or Unresectable Disease

• First-line Therapy; Other recommended regimens: bullet 1 revised: Combination targeted therapy if BRAF V600-activating mutation positive
  (The same change was made in second-line or subsequent therapy)
• Second-line or subsequent therapy; Useful in certain circumstances;
  • 7th bullet revised: Combination BRAF/MEK + PD(L)-1 checkpoint inhibitors
    (eg, dabrafenib/trametinib + pembrolizumab or vemurafenib/cobimetinib + atezolizumab if BRAF V600 mutation positive)
  • Cytotoxic agents (MELSYS 2 of 7)

MELSYS-1A

• Footnote i modified: The combination nivolumab and relatlimab-rmbw is associated with higher progression-free survival (PFS) but more frequent and more severe toxicity than nivolumab alone. Nivolumab and relatlimab-rmbw showed a 9%–12% objective response rate in patients with PD-1/PD-L1 refractory disease.
• Footnote m modified: "...and OS compared to BRAF inhibitor monotherapy. Similar efficacy has been demonstrated across AJCC 8th Edition unresectable stage III or stage IV disease."
• Footnote o modified: "...combination immunotherapy. Otherwise nivolumab/ipilimumab/nivolumab is preferred first-line over BRAF/MEK
  therapy due to OS benefit.

MELSYS-1A (continued)

• Footnote r is new: A 94-patient trial randomized patients to ipilimumab and nivolumab vs. ipilimumab alone following progression on anti-PD-1 therapy. The combination was associated with higher response rates (28% vs. 8%) and 6-month PFS (35% vs. 13%).
• Footnote w is new: Despite FDA approval in the first-line setting, these triplet regimens are recommended for second-line or subsequent therapy due to excessive toxicity with minimal additive benefit.
• Footnote removed: For cytotoxic therapy recommendations, see (MELSYS 2 of 7).

MELSYS (3 of 7) to (MELSYS 7 of 7)

• The references were updated in the following sections
  • Immunotherapy: Pembrolizumab/Low-dose ipilimumab
  • Targeted Therapy (combination therapy)
    • Dabrafenib/Trametinib
    • Vemurafenib/Cobimetinib
    • Vemurafenib/Cobimetinib + Atezolizumab
    • Pembrolizumab/Lenvatinib

ME-A Risk Factors for Development of Single or Multiple Primary Melanomas

• Bullet 2 modified: Age >50 years
• Footnote a modified: "...as those are covered elsewhere in the algorithm. Cutaneous melanoma is not a risk factor for uveal melanoma."

ME-B 1 of 3 Principles of Biopsy of a Suspicious Pigmented Lesion

• 1st bullet modified: "Excisional/complete biopsy (elliptical, punch, or saucerization/deep shave removal) (saucerization/deep shave removal, punch [for small diameter lesions], or elliptical excision) with..."
• New bullet added: "Superficial/tangential shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but is acceptable when the index of suspicion is low. However, a broad shave biopsy may be optimal for histologic assessment for melanoma in situ (MIS), lentigo maligna (LM) type (ie, melanoma on skin with high cumulative sun damage [CSD])." Note: This bullet was previously part of the third bullet.
• New bullet added: If shave removal or tangential shave biopsy shows residual tumor/pigment at the base, a deeper biopsy (punch or elliptical) should be performed immediately and submitted in a separate container to the pathologist, noting that the shave specimen was transected.
• 6th bullet modified: Appropriate bBiopsy of the nail matrix should be performed for suspected subungual melanoma and requires expertise in biopsy of the nail apparatus.
• Last bullet modified: Repeat narrow-margin excisional biopsy is recommended if an initial partial biopsy is inadequate for diagnosis or microstaging but should not be performed if the initial specimen meets criteria for SLNBgenerally not indicated if the initial specimen meets criteria for SLNB, unless the initial biopsy is inadequate for diagnosis or microstaging.

ME-B 2A of 3

• Footnote b revised: CAP 04/2020 (08/2021 [4.3.0.1]) histopathologic elements required for accreditation purposes in the wide excision specimen include: macroscopic satellite nodules, histologic subtype, thickness, ulceration, microsatellites, margins (deep/peripheral - positive or negative for invasive or in situ melanoma), mitotic rate, lymphovascular invasion, and neurotropism, and regression.
• Footnote f revised: For histologically positive margins on the biopsy or wide excision specimen, describe whether presence of in situ or invasive melanoma is present at the peripheral and/or deep margins should be noted. For histologically negative margins on the wide excision 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 does not generally impact clinical decision-making.
• Footnote i revised: Pathology reporting of extensive versus focal neurotropism (ie, involving only a single nerve vs. multiple nerves and/or size of involved nerves present, absent, indeterminate) may help guide clinical decision-making (ie, further excision or adjuvant RT).

ME-B 3 of 3

• References were updated.

ME-C 1 of 8 Principles of Molecular Testing

• General: Page title revised: Molecular Technologies for Cutaneous Melanoma Diagnosis, and Prognostication, and SLNB Risk Prediction
• Bullet 2 revised: Prognostic/predictive testing
  • Arrow bullets revised
    • Despite commercially available GEP tests being marketed to risk stratify cutaneous melanomas, current GEP platforms do not provide clinically actionable prognostic information when combined or compared with known clinicopathologic (CP) factors (eg, sex, age, primary tumor location, thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and/or SLNB status) or multivariable nomograms/risk calculators. Furthermore, the clinical utility of these tests to inform treatment recommendations and predict patient outcomes and improve health outcomes by prompting an intervention, has not been established.
    • Various studies of prognostic GEP tests suggest their role as an independent predictor of worse outcome. However, GEP is not superior to Breslow thickness, ulceration, or SLN status studies to date have not demonstrated added benefit beyond comprehensive CP variables, and it remains unclear whether available GEP tests are reliably predictive of outcome across the risk spectrum of cutaneous melanoma. Validation studies on prospectively collected, independent cohorts (similar to those performed in breast cancer) are necessary to define the clinical utility of molecular prognostic GEP testing as an adjunct to AJCC staging and other known prognostically significant CP variables or as part of the multidisciplinary decision-making process to guide surveillance imaging, SLNB, and adjuvant therapy.
    • Existing and emerging GEP tests and other molecular techniques (ie, circulating tumor DNA tests) should be prospectively compared to determine their clinical utility, including with no-cost, contemporary, multivariable SLNB risk prediction models (eg, melanomarisk.org.au or https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis) models that incorporate readily available CP variables. Prospective study of the utility of predictive GEP for SLNB risk, in conjunction with well-established CP factors, is ongoing.

ME-C 3 of 8

• 4th bullet; Methods of mutation testing; New arrow sub-bullet added: PCR testing can also be done for rapid assessment of BRAF V600E/K mutation status.

ME-C 4 of 8

• 2nd bullet;4th dash sub-bullet revised: "...outcome with nivolumab monotherapy compared to nivolumab/ipilimumab/nivolumab combination..."

ME-C 5 of 8

• Biomarkers with potential utility for immunotherapy; third diamond sub-bullet; fourth arrow sub-bullet revised: "...Low PD-L1 expression may be a marker for worse outcome with nivolumab monotherapy compared to nivolumab/ipilimumab/nivolumab combination.."

ME-C 7 of 8

• Reference 31 is new: Hieken T, Egger ME, Angeles CV, et al. Merlin_001: A prospective registry study of a primary melanoma gene-signature to predict sentinel node (SN) status and determine its prognostic value for more accurate staging of SN-negative melanoma patients [abstract]. J Clin Oncol 2022;40(Suppl): Abstract TPS9606.

ME-D 1 of 5 Principles of Imaging

• Imaging modalities include; bullet 3 revised: Brain MRI with and without IV contrast

ME-D 2 of 5

• Workup (Baseline)
  • Stage 0, IA, IB, and II; first arrow sub-bullet modified: Baseline cross-sectional imaging with or without brain imaging is not recommended unless needed for surgical planning or prior to initiation of adjuvant therapy (for stage IIB/IIC)
• Stage IIIA (sentinel node positive); Revised: Consider cross-sectional imaging for baseline staging or prior to initiation of adjuvant therapy.
• Stage IIIB/C/D:
  • Revised: Perform cross-sectional imaging with or without brain imaging for baseline staging or prior to initiation of therapy.
  • Bullets in this section were reorganized.

ME-D 3 of 5

• Treatment Response Assessment
  • New bullet added: For patients receiving neoadjuvant therapy, cross-sectional imaging is recommended after 6 to 12 weeks to exclude residual or metastatic disease and assess for surgical planning.
  • 3rd bullet revised: For active treatment other than complete surgical resection, assessment of response is appropriate and should include clinical examination and/or imaging (cross-sectional ± brain). For patients receiving active non-surgical treatment, imaging throughout treatment at clinically appropriate intervals is recommended in the following clinical settings:
  • New bullet added: For patients receiving active systemic therapy, imaging throughout treatment at clinically appropriate intervals (eg, every 2–6 months) is recommended in the following clinical settings:
  • Stage III (clinical satellite or in-transit local satellite/in-transit disease) primary or local, satellite, and/or in-transit recurrence disease
  • Nodal recurrence disease in previously dissected nodal bed that is unresectablef or incompletely resected
• Footnote e revised: Intralymphatic metastases can be characterized as clinically or pathologically detectable satellite metastases (visible or microscopic cutaneous and/or subcutaneous metastases occurring within 2 cm of the primary melanoma) or in-transit metastases (regional cutaneous and/or subcutaneous metastases identified at a distance >2 cm from the primary melanoma). The 2-cm cutoff is consistent with AJCC staging definitions. Satellite and in-transit metastases are biologically and prognostically similar. Local satellite/in-transit metastasis lacks in situ or radial growth phase, and is defined by intralymphatic deep dermal or subcutaneous fat recurrence within the melanoma scar or satellite metastasis adjacent to the melanoma scar. Satellite and in-transit metastases are biologically and prognostically similar.
• Footnote removed: Local satellite/in-transit recurrence without in situ or radial growth phase, with intralymphatic deep dermal or subcutaneous fat recurrence within the melanoma scar or satellite metastasis adjacent to the melanoma scar. Satellite and in-transit metastases are
  biologically and prognostically similar.

ME-D 4 of 5

• Follow-up (surveillance for recurrence in patients with NED)
• 2nd bullet; 2nd arrow sub-bullet revised: "...It would be appropriate for the frequency of clinical exam and US/imaging surveillance to be consistent with the two prospective randomized trials (MSLT-II and DeCOG): every 4 months during the first 2 years, then every 6 months during years 3 through 5, although synchronizing frequency of nodal US with cross-sectional imaging may also be acceptable."
  • Stage IIB–IV (NED); Diamond sub-bullets revised
    • Periodic brain MRI for up to 3 years may be appropriate to screen for asymptomatic brain metastases in high-risk patients who had stage IIIC IIIB or higher without prior central nervous system (CNS) metastases.
    • There is non-uniform application of chest x-ray in surveillance and monitoring of patients with advanced high-risk stage II melanoma across NCCN Member Institutions; cross-sectional imaging is preferred.

ME-D 5 of 5

• Reference 11 is new: Dieng M, Lord SJ, Turner RM, et al. The impact of surveillance imaging frequency on the detection of distant disease for patients with resected stage III melanoma. Ann Surg Onc 2022;29:2871-2881.

ME-E 1 of 2 Principles of Surgical Margins for Wide Excision of Primary Melanoma

• 2nd bullet: For invasive melanoma, wide excision involves removal of all tissue to the level of the fascia, which is typically preserved unless involved by tumor. Peripheral resection margins may be modified to accommodate individual anatomic or functional considerations. However, The safety and efficacy of narrower surgical margins have not been prospectively studied in a randomized controlled manner. However, narrower-than-recommended margins may increase the risk for margin positivity and/or local recurrence. The safety and efficacy of narrower surgical margins is being prospectively studied in a randomized controlled trial (NCT03860883) to compare 1-cm versus 2-cm margins for stage II melanoma (1–2 mm with ulceration [T2b] and >2 mm [T3a-T4b]). However, this trial excludes patients with melanoma distal to the metacarpophalangeal joint (including subungual melanoma), on the nasal tip, eyelids, or ear, and on noncutaneous sites.
• 3rd bullet: The gold standard for histologic assessment of excised melanoma is use of permanent sections. If Mohs micrographic surgery (MMS) is performed, permanent section analysis of the central debulking specimen is strongly recommended to provide complete staging information. Consider delay of complex reconstruction or wound closure until histologic margin assessment is complete. If complex reconstruction is anticipated, wound closure should generally be delayed until histologic margin assessment is complete.
• 4th bullet revised: Mohs micrographic surgery (MMS) is not recommended for primary treatment of invasive cutaneous melanoma when standard clinical margins can be obtained. It may be considered selectively for minimally invasive (T1a) melanomas in anatomically constrained areas (ie, face, ears, acral sites) along with other surgical methods that provide comprehensive histologic assessment, such as staged excision with permanent sections for dermatopathology review.If MMS is performed, the central debulking specimen should be analyzed histologically via permanent sections (preferred) or frozen sections with immunostaining, to provide complete staging information.

ME-E 2 of 2

• New References added:
  • Maurichi A, Barretta F, Patuzzo R, et al. Association of Excision Margin Size With Local Recurrence and Survival in Patients With T1a Melanoma at Critical Structures. JAMA Dermatol 2023;159:587-595.
  • Etzkorn JR, Sobanko JF, Elenitsas R, et al. Low recurrence rates for in situ and invasive melanomas using Mohs micrographic surgery with melanoma antigen recognized by T cells 1 (MART-1) immunostaining: tissue processing methodology to optimize pathologic staging and margin
    assessment. J Am Acad Dermatol 2015;72:840-850. Erratum in: J Am Acad Dermatol 2018;78:235-235.e1.

ME-F 1 of 3 Principles of Sentinel Lymph Node Biopsy (SLNB)

• General Principles
  • 6th bullet; 2nd arrow sub-bullet revised: "...or T1a lesions with Breslow depth ≥0.5 mm >0.5 mm..."
  • 6th bullet; 5th arrow sub-bullet: Prognostic GEP testing to differentiate melanomas at low versus high risk for metastasis should not replace pathologic staging procedures. Currently available GEP tests should not be used to determine SLNB eligibility. Readily available, no-cost risk calculators (eg, melanomarisk.org.au; https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis) may aid clinicians in discussion of risk versus benefit of SLNB Ongoing prospective investigation will further inform the utility of GEP tests and multivariable nomograms/risk calculators (eg, melanomarisk.org.au/snlland; https://www.mskcc.org/nomograms/melanoma/sentinel_lymph_node_metastasis) for SLNB risk prediction.

ME-F 2 of 3

• Principles of Nuclear Medicine; 4th bullet revised: "...a higher dose of radiocolloid should be used and the case surgery should be performed..."

ME-F 3 of 3

• Principles of Pathology
  • 2nd bullet revised: SLN(s) are fixed in formaldehyde and embedded in paraffin for subsequent analysis. SLN(s) are usually not sent for frozen section analysis, but there are certain scenarios where this may be appropriate, such as unexpected findings at the time of SLNB that would affect immediate subsequent care.
  • Bullet removed: SLN(s) are usually not sent for frozen section analysis, but there are certain scenarios where this may be appropriate, such as unexpected findings at the time of SLNB that would affect immediate subsequent care.

ME-G Principles of Completion/Therapeutic Lymph Node Dissection

• Adequacy of Regional Lymph Node Dissection
  • 3rd bullet revised: In the axilla, for clinically involved nodal disease, dissection of levels I–III is generally recommended has historically been recommended; however, the need for level III nodal dissection has not been formally evaluated in the setting of newer neoadjuvant or adjuvant approaches.
  • 5th arrow sub-bullet revised: In the groin, the presence of clinically positive inguinofemoral nodes, ≥3 microscopically positive (subclinical) inguinofemoral nodes, or a positive Cloquet’s node may increase the likelihood of occult external iliac or obturator microscopic nodal disease. However, there is no known survival benefit of prophylactic lymphadenectomy for clinically/radiographically uninvolved pelvic nodal basins. The decision on whether to perform a pelvic lymph node dissection (external iliac and obturator basins) in conjunction with an inguinofemoral lymph node dissection should be governed by careful review of preoperative imaging studies. This decision should be made jointly by a multidisciplinary team, given the advances in modern imaging and neoadjuvant or adjuvant therapies.

ME-H 1 of 7 Principles of Radiation Therapy

• Primary Disease; Adjuvant Therapy
  • Last diamond sub-bullet: 30 Gy in 5 fractions over 2 2–2.5 weeks (twice per week or every other day, prescribing 90% of the dose [27 Gy] to encompass the target volume such that a dose of ≤30 Gy is delivered to the target volume)

ME-H 3 of 7

• Distant Metastatic Disease; Brain Metastases
  • 4th arrow sub-bullet; Palliative whole brain RT (WBRT): The sub-bullets under "Common WBRT regimens include" were revised as follows:
    • 30 Gy in 10 fractions over 2 weeks
    • 37.5 Gy in 15 fractions over 3 weeks
    • 20 Gy in 5 fractions over 1 week
    • Standard doses include 30 Gy in 10 fractions and 20 Gy in 5 fractions. WBRT can be done with or without hippocampal avoidance (HA) + memantine. HA-WBRT (plus memantine) 30 Gy in 10 fractions is preferred for patients with a better prognosis (≥4 months) and no metastases within 5 mm of the hippocampi.
    • For patients with poor predicted prognosis and with symptomatic brain metastases, standard WBRT of 20 Gy in 5 fractions is a reasonable option. If WBRT is given, for patients with a better prognosis, consider memantine during and after WBRT for a total of 6 months.

ME-H 7 of 7

• New references added
  • Brown PD, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase III trial NRG Oncology CC001. J Clin Oncol 2020;38:1019-1029.
  • Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomized trial. Lancet 2004;363:1665-1672.
  • Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013;15:1429-1437.

ME-J 1 of 4 Systemic Therapy Considerations

• Considerations for Selection of Systemic Therapy for Unresectable or Metastatic Disease
  • 1st bullet revised: Randomized clinical trials are ongoing to compare front-line systemic targeted therapy (BRAF/MEK) to immune therapy with checkpoint inhibitors. Results will help define the best approach for initial therapy. A randomized clinical trial comparing front-line systemic targeted therapy (BRAF/MEK) to immune therapy with checkpoint inhibitors confirmed the superiority of first-line immunotherapy, regardless of BRAF mutation status.
    • 1st arrow sub-bullet: Considerations for deciding between anti-PD-1/ipilimumab or nivolumab and relatlimab combination versus anti-PD-1 alone.
  • Reference 1 is new: Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-Mutant melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol 2023;41:186-197.

ME-J 2 of 4

• When to Stop or Switch Therapies
  • 2nd bullet; second arrow sub-bullet: As the average time to response varies between 6 and 12 weeks depending upon the therapy, it is reasonable to continue immunotherapy for an additional treatment interval (6–10 weeks) in some patients with tumor growth who are tolerating therapy and doing well clinically. Since average time to response ranges from 6 to 12 weeks in most patients who are asymptomatic, depending on the clinical situation, it is reasonable to continue immunotherapy beyond progression for an additional interval of 6 to 10 weeks, with short-interval imaging. Some patients may have true progression at 16 weeks or sooner, and this judgment is based on the volume or size of tumor progression, number of new lesions, organ involvement, and/or tumor-related symptoms.

ME-K Management of Toxicities Associated With Targeted and Immune Therapies

• Page title revised: Management of Toxicities Associated With Targeted Therapy and Immune Therapies
• Targeted Therapy (BRAF or combined BRAF/MEK inhibitors); Pyrexia, bullet revised: "...or severe pyrexia not responsive to discontinuation of BRAF/MEK inhibitors, low-dose corticosteroids (prednisone 10 mg/day) can be used..."
• New section added: Immune Checkpoint Inhibitor Therapy: See NCCN Guidelines for Management of Immunotherapy-Related Toxicities

ME-L 1 of 5 Principles of Brain Metastases Management

• Selection of Initial Treatment Modality (Brain-Directed vs. Systemic)
  • New arrow sub-bullet added: For patients with symptomatic brain metastases initially requiring corticosteroids, surgical resection, SRS, or BRAF/MEK inhibition, it may be useful to reduce steroid dose prior to transitioning to immunotherapy.

 

ABBR-1

The abbreviations page was updated to reflect the changes in the algorithm.

 

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