Cutaneous Melanoma Treatment & Management

Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No overall survival (OS) benefit was demonstrated for adjuvant chemotherapy, nonspecific immunotherapy, radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy. ^[85]  High-dose IFN alfa-2b was the first US Food and Drug Administration (FDA)‒approved adjuvant therapy for high-risk cutaneous melanoma (currently defined as stages IIB, IIC, and III) to prevent relapse and death but has been supplanted by newer immune approaches. The landscape has changed dramaticially for adjuvant, neoadjuvant and systemic therapeutic approaches for stage III and IV melanoma, with the advent of modern immunotherapies via immune checkpoint blockade and targeted therapies against specific oncogenic mutations.

Current adjuvant immunotherapies/targeted therapies for resected stage III melanoma

Ipilimumab (Yervoy) is an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and was approved in 2015 for the adjuvant treatment of stage III melanoma, including pathologic involvement of regional lymph nodes larger than 1 mm, followed by complete lymph node resection. Approval for adjuvant therapy was based on results from the EORTC 18071 study that was conducted in 951 high-risk patients with stage III melanoma who had undergone a complete lymph node dissection. ^[86] Recurrence-free survival (RFS) was significantly higher in the ipilimumab group compared with the placebo group at 1 year (63.5% vs 56.1%), at 2 years (51.5% vs 43.8%), and at 3 years (46.5% vs 34.8%), as was median RFS was in the ipilimumab group (26.1 vs 17.1 months). However, the initial FDA-approved regimen for adjuvant ipilimumab (10 mg/kg q3wk for 4 doses then every 3 months for up to 3 y) was significantly higher in dose and duration than that approved for patients with unresectable stage III and IV melanoma (3mg/kg q3week for 4 doses), making toxicity and tolerability problematic. High dose ipiliumumab was demonstrated to not only improve recurrence-free survival, but also overall survival (11% at 5 years) in resected stage III melanoma patients ^[87] , though with significant risk of immune-related adverse events; it is thus seldom used in the adjuvant setting.

The phase 3 ECOG (E1609) trial assessed the use of low (3 mg/kg) versus high-dose ipilimumab compared with high-dose IFN in 1,670 patients with resected stage IIIB and IV melanoma randomized (1:1:1) between 2011 and 2014. ^[88] Treatment related adverse events grade ≥ 3 were higher in the high-dose ipilimumab arm (58%) vs low-dose arm (37%), leading to treatment discontinuation in over 50% of patients on the higher-dose. In comparison to high dose IFN, low-dose ipilimumab showed improved OS (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044), while high-dose ipilimumab did not achieve statistical significance in this regard. In situations where adjuvant ipilimumab may be considered, the low dose regimen (3 mg/kg) is thus recommended over the high-dose regimen. ^[38]

Two adjuvant trials showed increased RFS for resected stage III melanoma with combination MAP kinase inhibitor therapy (dabrafenib/trametinib) ^[89]  and for resected stage III and IV melanoma with nivolumab (Opdivo) therapy (over low-dose ipilimumab) ^[90] , resulting in FDA approval in 2017 for anti-PD1 monotherapy and for dabrafenib/trametenib in 2018. In the Checkmate 238 trial, significantly lower immune-related adverse events (14.4% vs 45.9%) were noted on adjuvant nivolumab compared with adjuvant ipilimumab, making it the preferred treatment immunotherapy option over ipilimumab. However, overall survival at 4-years of follow-up on the study was similar in both groups (77.9% with nivolumab and 76.6% with ipilimumab), with fewer deaths than anticipated. ^[91]

Adjuvant pembrolizumab (Keytruda) was approved for resected stage III melanoma in 2019 based on results of the EORTC trial showing increased RFS compared to placebo (75.4% vs 61.0% at median follow-up of 15 months) in patients with resected stage III melanoma who were treated with 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year), with similar favorable toxicity and efficacy profile to nivolumab. ^[92] The impact of adjuvant pembrolizumab on OS has not yet been reported.

The use of adjuvant BRAF inhibitor dabrafenib (150 mg twice daily) and MEK inhibitor trametinib (150 mg twice daily) for 12 months was studied in 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations. Improved 3-year RFS (58%) was noted in the combination MAP kinase group (58%) compared with the placebo group (39%), with similar safety/toxicity profile to that observed in unresected stage III and IV studies. ^[89] Other BRAF/MEK inhibitor combinations may be used (i.e. vemurafenib/cobimetinib or encorafenib/binimetinib) for unacceptable side effects on dabrafenib/trametinib.

Ongoing close clinical observation with periodic surveillance imaging is also an option for resected stage III melanoma, though anti-PD1 monotherapy and dual BRAF/MEK inhibitors are associated with fewer side effects and much greater efficacy than prior adjuvant therapies. These studies highlight the importance of accurate pathologic staging of cutaneous melanoma with SLNB in appropriate patients, since upstaging disease to stage III would result in eligibility for potentially life-saving adjuvant therapy.

Melanoma vaccines

Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. Vaccines remain a theoretically attractive therapeutic option due to low associated toxicity (eg, fatigue, myalgias, local inflammatory skin reactions). Numerous melanoma-associated antigens have been identified, and which of these are the most important in eliciting the necessary cytotoxic and humoral responses to kill melanoma cells remains unclear. In addition, HLA haplotype restriction (mainly to the A2 allele) limits the use of peptide vaccines in many patients. Vaccine trials have been conducted in the setting of advanced disease (stages III and IV) and not for melanoma prevention.

Vaccine types include whole cell preparations, cell lysates, gangliosides, peptides/proteins, dendritic cell vaccines, and DNA vaccines. Melanoma vaccines may be autologous (killed cell and recombinant types), allogeneic, shed from tumor, defined antigen-directed or genetically engineered, and either polyvalent or univalent in nature. Enhanced delivery systems, such as dendritic cell preparations, DNA-plasmid vectors, and intranodal infusion, have been studied to enhance immunogenicity and host response. Biologic response modifiers such as granulocyte macrophage colony-stimulating factor, IL-2, IL-12, and IFN gamma are often integrated into vaccine strategies.

As yet, no large, phase III randomized trial has demonstrated an OS advantage for vaccine-treated melanoma patients. However, a phase III trial of gp100:209-217(210M) peptide vaccine in combination with high-dose IL-2 showed significant improvement in response rate and progression-free survival compared with IL-2 alone and provided the first evidence of clinical benefit for vaccine strategies in patients with melanoma. ^{[93, 94, 95]} Vaccine strategies remain challenging in melanoma but continue to be investigated.

BRAF and MEK inhibitors for advanced melanoma (unresectable stage III and IV)

The mitogen-activated protein kinase (MAPK) signaling pathway (RAS/RAF/MEK/ERK) has been found to be constitutively activated in up to 80-90% of melanomas, with the most common mutations in either NRAS (15-30% of melanomas) or BRAF (50-70% of melanomas). Drugs that target this pathway, including multikinase inhibitors, which decrease BRAF activity, are highly effective in treating metastatic melanoma. ^{[96, 97, 98]}

Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF(V600E). The drug is indicated for the treatment of unresectable or metastatic melanoma with BRAF(V600) mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib and other BRAF inhibitors are contraindicated in patients with wild-type BRAF melanoma.

The BRAF Inhibitor in Melanoma (BRIM)–3 study results showed vemurafenib improved progression-free and overall survival compared with standard chemotherapy in patients with advanced melanoma with no previous treatment. Results found vemurafenib had a 74% reduction in the risk for progression (or death) compared with patients receiving dacarbazine chemotherapy (hazard ratio, 0.26; P< .001). Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, the estimated OS rate was 84% (95% CI, 78-89) in the vemurafenib group and 64% (95% CI, 56-73) in the dacarbazine group. ^[97] Vemurafenib continued to be associated with improved median OS in the BRIM-3 trial after extended follow-up through August 2015, although convergence of survival curves after about 3 years was attributabed to crossover from dabrafenib to vemurafenib and receipt of other cancer therapies. ^[99]

Adverse effects from vemurafenib monotherapy are largely cutaneous and include photosensitivity, which appears to be driven by UV-A light, ^[100] alopecia, xerosis, follicular hyperkeratosis (keratosis pilaris‒like), rash, and potential development of cutaneous squamous cell carcinoma (SCC), particularly the keratoacanthoma type. The keratinocyte proliferations observed with BRAF inhibition, ranging from benign papillomas to SCC, tend to appear early in the course of treatment and are likely driven by paradoxical activation of the MAPK pathway. Reports of atypical melanocytic proliferations in patients on selective BRAF inhibitors, including new primary melanomas and dysplastic nevi, highlighted the need for routine skin examination in all treated individuals. ^[101]

Dabrafenib (Taflinar) is a BRAF inhibitor that inhibits the mutant BRAF protein in melanomas with either the V600E or V600K genotype. A phase III study demonstrated high clinical response rates and improved progression-free survival in BRAF(V600E) metastatic melanoma patients who received dabrafenib compared with dacarbazine. ^[102] Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastasis. Dabrafenib appears similar to vemurafenib in terms of efficacy but may be associated with less photosensitivity, although it is associated with increased pyrexia; it was FDA approved in 2013. ^[103]

A subsequent phase III open-label trial assessing the use of an oral selective MEK inhibitor, trametinib (Mekinist), versus dacarbazine in 322 patients with metastatic melanoma (unresectable stage IIIC or IV) demonstrated improved rates of progression-free and OS in patients with the BRAF(V600E) or BRAF(V600K) mutation. ^[104] At 6 months, OS was 81% in the trametinib group and 67% in the chemotherapy group, despite allowances for cross-over from the chemotherapy group to the trametinib group following disease progression (hazard ratio for death, 0.54; 95% CI, 0.32-0.92, P = .01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group, although secondary skin neoplasms, including cutaneous SCCs, were not noted.

Trametinib was FDA approved in May 2013 as a single agent, though it is seldom used as monotherapy. The combination of BRAF and MEK inhibitors (dabrafenib/trametinib) showed higher response rates and more durable clinical benefit than monotherapy with either agent ^{[105, 106]} and was FDA approved in  2014. Combination BRAF/MEK inhibition is considered first-line therapy over BRAF monotherapy.

Two phase III trials (COMBI-v and coBRIM) demonstrated that combination therapy with a BRAF inhibitor and a MEK inhibitor is more efficacious than therapy with a BRAF inhibitor alone, with longer progression-free survival, resulting in FDA approval in 2014 for vemurafenib/dabrafenib as first-line therapy over BRAF inhibitor monotherapy, and for vemurafenib/cobimetinib in 2015. Extended follow-up of the phase Ib BRIM7 trial showed median OS in BRAFi-naive pts on combination therapy of 31.8 months, with landmark OS rate plateauing at 39.2% at years 4 and 5 of follow-up. ^[107] Similar favorable long-term (5-year) results were noted in the coBRIM study. ^[108]

Encorafenib (BRAFTOVI) and binimetinib (MEKTOVI) were FDA approved in 2018 as combination therapy based on the results of phase 3 COLUMBUS trial showing improved PFS (14.9 months) in 577 treatment naive patients or those who had progressed on or after previous first-line immunotherapy, compared to vemurafenib monotherapy (7.3 months) at medial follow-up of 16.6 months, with improved tolerability on the combined regimen. ^[109] Subsequent interim OS analysis at median follow-up of 36.8 months showed median OS of 33.6 months with encorafenib plus binimetinib vs 16.9 months with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p< 0·0001), demonstrating clinical meaningful efficacy and improved tolerability. ^[110] Combination BRAF/MEK inhibition is the standard of care for BRAF mutant advanced melanoma, particularly in the setting of rapidly progressing and/or high-volume metastasis. ^[111]

Immunotherapies for advanced melanoma (unresectable stage III and IV)

The fixed dose combination of nivolumab/relatlimab (Opdualag) is indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody.  The combination results in increased T-cell activation compared to activity of either antibody alone. 

Approval in March 2022 was based on the RELATIVITY-047 phase 2/3 global trial  which found a median progression-free survival (PFS) of 10.1 months among 355 patients randomly assigned to the combination therapy compared with 4.6 months among 359 patients who received nivolumab alone (HR, 0.75; P = .0055). ^[178]  

Ipilimumab (Yervoy) is a monoclonal antibody against CTLA-4, which inhibits T-cell inactivation, allowing expansion of melanoma-specific cytotoxic T cells. Ipilimumab, a CTLA-4 blocker, was the first drug to demonstrate an OS in stage IV melanoma and was FDA approved in 2011 for patients with unresectable stage III and IV melanoma.

In the pivotal phase III trial, ipilimumab (3 mg/kg q3wk for 4 treatments) was shown to enhance T-cell response in HLA-A2–positive patients and prolong OS in patients with metastatic melanoma compared with a glycoprotein 100 (gp 100) peptide vaccine (median OS, 10.1 vs 6.4 months, respectively; hazard ratio for death 0.66; P = .003). Durable responses were observed for over 2 years in 9 (60%) of 15 of ipilimumab responders, suggesting a durable response benefit that has been demonstrated to be independent of HLA status. ^[112] Results of a phase III trial comparing dacarbazine plus ipilimumab (administered at 10 mg/kg ) versus dacarbazine alone also demonstrated improved median OS in the ipilimumab-treated group (11.2 vs 9.1 months), with a consistent survival benefit noted at years 1, 2, and 3 of follow-up. ^[113]

As noted, the use of both low- and high-dose ipilimumab is tempered by potential severe immune-related adverse events, primarily enterocolitis and hypophysitis, which require prompt initiation of high-dose corticosteroids and/or other immune response modifiers, as well as hormone replacement for hypophysitis (including hypopituitarism and adrenal insufficiency) alteration. Dermatitis, pruritus, and potential vitiligo may also be seen with ipilimumab therapy, emphasizing the importance of dermatologic consultation for management of associated skin conditions.

Enhanced antitumor activity was also demonstrated with human monoclonal antibodies against the programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, or its ligand, PD-L1. Objective responses, durable tumor regression, and prolonged stabilization of disease were demonstrated in patients with a variety of advanced cancers, including non–small-cell lung cancer, renal cell cancer, and melanoma following treatment with the anti–PD-L1 antibody BMS-936559, with reduced toxicity in comparison to ipilimumab. Objective responses (complete or partial) were observed in 9 (17%) of 52 of melanoma patients, generating enthusiasm for these agents in patients with metastatic disease. ^{[114, 115]}

Accelerated FDA approval of the PD1 inhibitor pembrolizumab (Keytruda) was granted in 2014 for patients with advanced or unresectable melanoma following progression on prior therapies, including ipilimumab and BRAF inhibitors. ^[116] , and later approved as first-line therapy in 2015, based on demonstration of superior survival and lower toxicity compared with ipilimumab in the phase 3 KEYNOTE-006 trial. ^[117] Concurrent studies of the PD1 inhibitor nivolumab (Opdivo) showed similar durable tumor remission and long-term safety, with median OS of 16.8 months and 1- and 2-year survival rates of 62% and 43%, respectively, in patients with advanced, treatment-refractory melanoma. ^[118] The use of nivolumab in previously untreated BRAF wild-type melanoma patients showed significantly improved OS at 1 year compared with dacarbazine (72.9% vs 42.1%, respectively), with objective response rates of 40% versus 13.9%, respectively, resulting in FDA approval of nivolumab in March 2015. ^[119] Subsequent documented superior progression-free survival over ipilimumab in the CheckMate 067 trial resulted in similar FDA approval as a first-line agent for metastatic melanoma. Both anti-PD-1 agents are considered first-line monotherapy in patients with advanced (unresectable stage III and IV) melanoma and now for adjuvant therapy in resected, stage II melanoma, as noted above. ^[120] Known adverse effects include induction of immunobullous disease, especially pemphigoid, as well as eruptive keratoacanthomas similar to those seen with BRAF therapy. ^{[121, 122, 123, 124]} .

The combination of ipilimumab and PD1 inhibitors (has shown even greater efficacy for PFS and OS in patients with advanced melanoma and more rapid response rates (akin to targeted therapy) than single agent immune checkpoint inhibitors, but it is associated with increased toxicity. ^[125] In 2015, the FDA approved the combination regimen of nivolumab 1 mg/kg plus ipilimumab mg/kg for 4 doses q3 weeks followed by nivolumab 3 mg/kg q2 weeks in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma based on results from the Checkmate 067 trial. ^{[126, 127]}  Long-term follow-up (6.5 years) has shown a compelling benefit of dual immune checkpoint inhibition with ipilimumab and nivolumab, with median OS  of 72 months for the combination regimen compared with 36.9 months for nivolumab monotherapy and 19.9 months for ipilimumab monotherapy. ^[128] However, since increased immune-related adverse events occur on the combined regimen, appropriate patient selection, careful monitoring during treatment, and prompt initiation of appropriate therapy are warranted.

In October 2015, the FDA approved talimogene laherparepvec, commonly known as T-VEC (Imlygic), a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and produce the immune stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). ^[129] It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.

Approval was based on results from the OPTiM study, a randomized, controlled trial conducted in adults with unresectable regionally or distantly metastatic melanoma. ^[130] The study enrolled 436 patients, of which 295 patients treated with talimogene laherparepvec were compared with 141 patients treated with GM-CSF. The primary endpoint was the durable response rate, defined as the rate of complete response plus partial response continuously lasting at least 6 months and beginning within the first 12 months. Secondary endpoints included OS and the overall response rate.

The durable response rate was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P< .001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 months (range, 1.2-16.7 months) in the arm receiving talimogene laherparepvec.

The overall response rate was also higher with talimogene laherparepvec (26.4% vs 5.7%; P< .001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (< 1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio, 0.42). Median OS was 23.3 months and 18.9 months, respectively (hazard ration, 0.79; P = .051), which just missed being statistically significant.

Additional immunotherapy and targeted therapy regimens are being actively investigated, including the combination of nivolumab and relatlimab, which inhibits lymphocyte-activation gene 3 (LAG-3) ^[131] . The combination of targeted therapy and immunotherapy (in BRAF-mutated melanoma) with vemurafenib/cobimetinib plus the PD-L1 inhibitor atezolizumab ^[132]  was FDA approved in 2020, although the triple regimen is associated with more toxicity compared with dual BRAF/MEK inhibition. For melanomas with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, targeted therapy with larotrectinib ^[133]  or entrectinib ^[134] were FDA approved in 2018 and 2019, respectively, although NTRK fusions are uncommon in cutaneous melanoma (< 1%), including acral melanoma (2.5%), compared to the spitzoid melanoma subtype (21-29%). ^[135]

Surgery is the primary mode of therapy for localized cutaneous melanoma.

Surgical margins for primary melanoma

The narrowest efficacious margins for cutaneous melanoma have yet to be determined. Surgical margins of 5 mm are currently recommended for melanoma in situ, although wider (1 cm) margins may be needed to achieve clear histologic margins in certain subtypes (lentigo maligna and acral lentiginous) that are characterized by subclinical extension. ^[136] Margins of 1 cm are recommended for melanomas less than or equal to 1 mm in depth and are now being studied for thicker melanomas T2b-T4. ^[137] For melanoma in situ (LM and ALM subtypes) and thin (T1) on anatomically constrained sites (i.e., head and acral sites), tissue sparing may be critical, and surgical techniques that provide complete margin assessment via Mohs micrographic surgery or staged excision with permanent sections may be appropriate. However, Mohs surgery is not recommended in either the NCCN or AAD melanoma guidelines for surgical resection of invasive cutaneous melanoma when standard clinical margins can be obtained.

Randomized prospective studies showed that 2-cm margins are generally appropriate for tumors of intermediate thickness (1-4 mm Breslow depth), although 1-cm margins have been proven effective for tumors of 1- to 2-mm thickness. ^{[138, 139]} Margins of 2 cm are recommended for cutaneous melanomas greater than 4 mm in thickness (high-risk primaries) to prevent potential local recurrence in or around the scar site.

A 2004 prospective study of melanoma greater than or equal to 2 mm thickness (median depth 3 mm) from the United Kingdom suggested that narrower margins (1 cm) result in higher locoregional recurrence compared with wider margins (3 cm), although no difference was noted in melanoma-specific survival between the two groups. ^[140] However, this study was criticized for combining satellite, in-transit, and regional nodal recurrences as the primary endpoint and by excluding SLNB (which would have demonstrated existing occult regional nodal metastasis at the time of wide local excision). Likewise, because a 2-cm margin is as efficacious as a 4-cm margin for melanomas of 1-4 mm depth, a 3-cm margin has been deemed unlikely to prove more beneficial than a 2-cm margin.

A retrospective study of high-risk primary melanomas (>4 mm thickness, median depth 6 mm) showed that excisional margins greater than 2 cm have no effect on local recurrence, disease-free relapse, or OS rates; therefore, a 2-cm margin is likely appropriate in this subgroup. ^[141]

In a multicenter randomized controlled trial in 9 European countries from 1992 to 2004, 936 patients with clinical stage IIA–IIC cutaneous melanoma >2.0 mm were treated with 2- vs 4-cm resection margins. At a median overall follow-up of 19·6 years, 621 deaths were reported, 304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group; 397 deaths were attributed to cutaneous melanoma, 192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78–1·16, p=0·61). This large study with nearly 2 decades of follow-up support the use of a maximum of 2 cm surgical margins for thicker (T3-T4) melanoma. ^{[142, 143]}  As noted, a randomized trial is in progress to determine differences in disease-free survival using a 1 vs 2 cm for patients with primary cutaneous melanoma with Breslow thickness > 2.0 mm or 1.0-2.0 mm with ulceration (T2b-pT4b).

Mohs micrographic surgery has also been proposed for cutaneous melanoma and has the advantage of providing visualization of 100% of peripheral and deep margins microscopically (i.e., complete circumferential peripheral and deep margin assessment). While studies have shown no increased local recurrence for Mohs micrographic surgery compared with historical controls, much of the data stem from thinner tumors that have a lower risk of locoregional recurrence and distant metastasis. ^[144] A recent review of published data regarding Mohs micrographic surgery and staged excision for cutaneous melanoma demonstrated serious or critical bias in 1 or more ROBINS-I criteria, specifically noting that definitions of local recurrence rate were generally poorly or not defined and that longer follow-up, clear tumor classifications, and prospective, randomized study designs are necessary in future research. ^[145]

Dissection

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and sentinel node biopsy serve as the most effective and accurate means of staging the regional lymph node basin(s) in patients with melanoma greater than 1 mm in depth and in those less than or equal to 1 mm in depth with adverse features (eg, ulceration, lymphovascular invasion, high mitotic rate—particularly for tumors 0.8-1.0 mm in thickness).

SLNB for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying individuals with occult regional nodal metastasis through localization of the first-draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (ie, a negative sentinel node obviates the need for further lymph node dissection). Both of these concepts were borne out in initial and subsequent studies of the staging technique. ^[146]

Preoperative radiographic mapping (lymphoscintigraphy) and vital blue dye injection around the primary melanoma or biopsy scar (at the time of wide local excision/reexcision) is performed to identify and remove the initial draining regional node(s).

The sentinel node is examined for the presence of micrometastasis using both routine histology and immunohistochemistry; if present, a therapeutic or completion lymph node dissection (CLND) has traditionally been performed, although recent data have shown no evidence of improved OS in patients who underwent CLND versus clinical observation following SLNB. A negative sentinel node biopsy result prevents the morbidity associated with an unnecessary lymphadenectomy.

Sentinel node status (positive or negative) is widely regarded as the most important prognostic factor for recurrence and the most powerful predictor of survival in melanoma patients. In a study of 612 patients with cutaneous melanoma (stage I/II), negative results from SLNB were associated with a nearly 60% increase in 3-year disease-free survival compared with positive SLNB results. ^[147]

Current AJCC melanoma staging and National Comprehensive Cancer Network clinical practice guidelines advocate pathologic staging of the regional lymph nodes for cutaneous melanoma of greater than 1 mm depth along with microstaging of the primary melanoma as the most complete means of staging. ^{[69, 83]}

SLNB provides the most reliable and accurate means of detecting occult regional nodal micrometastasis in clinically appropriate patients with primary melanomas and provides a more accurate determination of patient prognosis compared to clinical staging. However, it has not demonstrated an impact on overall survival in various RCTs. ^[148] The results of the Multicenter Selective Lymphadenectomy Trial (MSLT), the Florida Melanoma Trial, and the Sunbelt Melanoma Trial have not demonstrated that SLNB provides a therapeutic benefit in patients with cutaneous melanoma, although low rates of sentinel lymph node positivity in all studies limit their power to detect an overall survival difference.

The final analyses of the MSLT-1 was published in 2014. ^[149] This analysis of the subset of 1270 patients with intermediate-thickness melanoma (1.2-3.5 mm) demonstrated no overall (melanoma-specific) survival differences in the group that underwent SLNB at the time of primary excision of the melanoma versus the group that underwent wide local excision alone. However, immediate lymphadenectomy in the setting of a positive sentinel lymph node was associated with improved 10-year survival compared with delayed lymph node dissection in patients who developed macroscopic nodal metastasis following primary excision alone (62.1% vs 41.5%, respectively). The risk of death was reduced by nearly one half in this subset (hazard ratio, 0.56; 95% CI, 0.37-0.84; P = .0006) in the node-positive subset of patients who underwent immediate versus delayed lymph node dissection for regional nodal metastasis. The treatment-related difference persisted when patients with false-negative SLNB results were included in the final analysis (10-year melanoma-specific survival 56% vs 41.5%, respectively, hazard ratio, 0.67; 95% CI, 0.46-97; P = .04), However, OS rates did not differ in the subset of patients with thick melanoma (>3.5 mm).

The potential therapeutic benefit of early removal of micrometastasis in the regional nodal basin as well as the merits of CLND following a positive SLNB continue to be analyzed in various studies worldwide. Two prospective randomized trials showed that immediate CLND following a positive SLNB increases rate of regional disease control but does not impact melanoma specific survival. ^[38] to forego CLND in most cases of a positive SLNB and incorporate the use of nodal basin ultrasound surveillance as an alternative. However, these studies had few cases of head and neck melanomas, and there may be an advantage of improved nodal basin control for primary melanomas with high risk features and/or large tumor burden within the sentinel lymph node(s), Incorporation of newer molecular techniques, such as gene expression profiling, may aid in determining the therapeutic benefit and selection of the most appropriate patients for both SLNB and CLND. See the Medscape article The Role of Sentinel Node Biopsy in Skin Cancer for further information.

Dermatologist, as follows:

• For clinical/dermoscopic evaluation and surveillance of individuals at increased risk of developing melanoma based on mole phenotype, family history, sun sensitivity, and other factors
• For clinical assessment and biopsy of suspicious skin lesions to diagnose melanoma
• For surgical or topical treatment of cutaneous melanoma
• For long-term follow-up of patients with cutaneous melanoma to assess for disease recurrence
• For lifelong skin surveillance to detect possible new primary melanoma
• For early detection of melanoma, including use of total body photography in patients with atypical mole patterns

Surgical oncologist, as follows:

• For sentinel node biopsy, typically performed at the time of wide local excision and following preoperative lymphoscintigraphy
• For surgical and/or intralesional treatment of regional lymph node disease and soft tissue and/or in-transit recurrence (stage III disease)
• For palliative surgical treatment of visceral and CNS metastasis

Medical oncologist, as follows:

• To discuss adjuvant systemic therapy with approved agents or clinical trials: Patients with high-risk resected melanoma who are eligible for adjuvant therapy (usually stage III melanoma) should be referred to a medical oncologist or melanoma specialist soon after surgery in order to optimize the chances for appropriate adjuvant therapy or clinical trial entry. Patients with unresectable stage III or IV melanoma should be referred primarily to medical oncologists for initiation of first-line therapy with targeted agents, immune checkpoint inhibitors, or clinical trial consideration.
• To discuss and initiate treatment of metastatic melanoma (stage IV) with systemic therapy

Nuclear medicine specialist, as follows:

• For preoperative lymphoscintigraphy if SLNB is performed
• For PET-CT scan interpretation

Pathologist/dermatopathologist, as follows:

• For accurate histologic microstaging of primary melanoma and atypical melanocytic neoplasms that may mimick melanoma
• For proper processing and evaluation of nodal tissue from SLNB for micrometastasis
• For confirmation of the diagnosis of recurrent/metastatic disease

Radiation oncologist, as follows:

• For consideration of local adjuvant therapy for high-risk desmoplastic melanoma for improved local control, as detailed in current NCCN guidelines
• For consideration of adjuvant treatment of selected patients with resected bulky regional nodal metastasis per current NCCN guideline recommendations
• For palliative treatment of distant metastatic disease, particularly bony metastasis or brain involvement (whole brain radiotherapy or stereotactic radiosurgery)

Neurosurgeon, as follows:

• For evaluation and treatment of resectable brain metastasis

Patients should be monitored regularly after a diagnosis of cutaneous melanoma, particularly in the setting of thicker tumors, because most metastases occur in the first 1-3 years after treatment of the primary tumor. Annual skin examinations are recommended for life because an estimated 4-8% of patients with a history of melanoma develop new primary melanoma, generally within the first 3-5 years following diagnosis. ^[150] The risk of new primary melanoma increases in the setting of increased nevus count; multiple clinical atypical/dysplastic nevi and/or germline mutation in CDKN2A/p16; family history of melanoma; lighter skin/sun sensitivity; and male sex. ^[151] Individual patient risk factors should be taken into account in the determining the frequency of dermatologic surveillance.

The diagnosis of recurrent/metastatic disease depends on a routine evaluation schedule that varies according to the AJCC melanoma stage (based on tumor thickness, presence or absence of histologic ulceration, and regional lymph node status determined by SLNB), and the following additional factors:

• Mitotic rate in the primary tumor
• Results of the examination of the melanoma scar site – for local recurrence (persistent disease type with in situ component vs satellite (lymphatic) metastatic recurrence
• Results of the examination of regional and distant lymph node basins
• Mole pattern and examination findings from the entire cutaneous surface for new primaries