Cutaneous Melanoma Treatment & Management

Updated: Apr 29, 2019
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Treatment

Medical Care

Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No overall survival (OS) benefit has been demonstrated for adjuvant chemotherapy, nonspecific (passive) immunotherapy (including interferon [IFN] and now ipilimumab), radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy. [69] IFN alfa-2b was the first US Food and Drug Administration (FDA)‒approved adjuvant therapy for high-risk melanoma (currently defined as stages IIB, IIC, and III), which is associated with a 40-80% chance of relapse and death.

Adjuvant IFN-alfa trials

In the United States, three prospective, multicenter, randomized, controlled trials have been conducted to assess the effect of adjuvant high-dose IFN alfa-2b on relapse-free survival (RFS) and OS rates in patients with high-risk melanoma (primary tumors ≥4 mm depth and regional nodal disease). The Eastern Cooperative Oncology Group (ECOG) trial 1684 showed an 11% increase (26% to 37%) in RFS rates at 5 years in the IFN-alfa treatment group compared with the observation arm. Similarly, this trial showed an increase in 5-year OS rates from 37% to 46% (median OS, 2.78 to 3.82 y) in the treatment arm compared with observation. [70]

The confirmatory Intergroup trial (ECOG 1690) again showed an increase in the estimated 5-year RFS rates from 35% in the observation arm to 44% in the high-dose IFN-alfa arm. No significant benefit in the RFS rate was associated with low-dose IFN. Important to note, no difference in the OS rate was seen in the IFN-treated groups (high- or low-dose) compared with the observation arm. [71] Despite further data analysis that suggested postrelapse salvage therapy with an IFN-alfa–containing regimen may have confounded the OS results (ie, "crossover effect"), the ECOG 1690 trial is largely viewed as a negative study for high-dose IFN effects on OS.

The last Intergroup trial (ECOG 1694) compared the use of standard high-dose IFN alfa with GM2 ganglioside vaccine (GMK). The study was closed prematurely because a significant benefit was observed for IFN alfa over GMK for both RFS and OS rates. Hazard ratio analysis revealed that the likelihood of disease relapse and death in patients treated with high-dose IFN was reduced by one third compared with GMK. [72]

A pooled analysis of the three ECOG/Intergroup trials (with median follow-up ranging from 2.1-12.6 y) revealed that RFS, but not OS, was significantly prolonged for patients treated with high-dose IFN versus observation. [73] A subsequent systematic review and meta-analysis showed a modest benefit in OS in four of 14 comparisons but combined multiple low-, intermediate-, and high-dose regimens. [74] However, a more recent systematic review of seven randomized controlled trials demonstrated no OS benefit between adjuvant high-dose IFN and observation, although a meta-analysis of disease-free survival showed a significant benefit for high-dose IFN over control. [75]

A European Organization for Research and Treatment of Cancer (EORTC) randomized, phase III trial of adjuvant pegylated IFN alfa-2b (Peg-Intron) (PEG-IFN) in patients with resected stage III melanoma similarly showed no OS benefit but almost 12% improvement in RFS, although largely restricted to patients with microscopic lymph node involvement. [76] Long-term results of this trial at 7.6 years median follow-up demonstrated a slightly diminished impact on RFS, with a 7-year RFS rate of 39.1% in the PEG-IFN arm compared with 34.6% in the observation arm; however, no difference was observed in OS with longer follow-up. The subgroup of patients with ulcerated primary tumors and sentinel lymph node metastasis appeared to show the most consistent benefit from adjuvant treatment with PEG-IFN. [77]

The potential benefits of high-dose IFN (given in either the pegylated form or standard year-long regimen) must be weighed against its substantial tolerability and toxicity issues, including commonly associated flulike symptoms and potential for significant adverse reactions.

New adjuvant immunotherapies/regimens for resected stage III melanoma

Ipilimumab (Yervoy), an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was approved in October 2015 for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes larger than 1 mm who have undergone complete resection, including total lymphadenectomy. 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. [78] Recurrence-free survival 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%). Patients in the ipilimumab group were 25% less likely to experience melanoma recurrence than those in the placebo group (P = .0013). Median recurrence-free survival was also improved in the ipilimumab group (26.1 vs 17.1 months). The FDA-approved regimen for adjuvant ipilimumab (10 mg/kg q3wk for 4 doses then every 3 months for up to 3 y) for provides significantly higher dosing and duration than that approved for patients with unresectable stage III and IV melanoma. Since immune-related adverse events are dose-related with CTLA-4 antibody therapy, [79] the risks of high-dose adjuvant ipilimumab must be weighed against its improvement in RFS alone, with no improvement in OS demonstrated thus far. Pending analysis of the phase 3 ECOG E1609 trial assessing the use of low (3 mg/kg) versus high-dose ipilimumab compared with high-dose IFN in patients with resected stage IIIB and IV melanoma will help to establish the efficacy of low-dose ipilimumab in the adjuvant setting. CTLA-4 single-nucleotide variants may be predictive of the biologic response. [80]

The anti–programmed-death-receptor-1 (PD-1) agent pembrolizumab was approved in September 2014 for unresected stage III and IV melanoma and has demonstrated efficacy in ipilimumab-refractory advanced melanoma. [81, 82, 83, 84] An additional PD-1 inhibitor, nivolumab, was approved in October 2015, and both PD-1 blockers are now considered first-line monotherapy in patients with advanced (unresectable stage III and IV) melanoma and are now being studied for adjuvant therapy in resected, earlier-stage melanoma. [85] Known adverse effects include induction of immunobullous disease, especially pemphigoid, as well as eruptive keratoacanthomas similar to those seen with BRAF therapy. [86, 87, 88, 89]

Adjuvant biochemotherapy is also a consideration for resected stage III melanoma, based on results from a phase 3 SWOG S0008 trial using a 9-week regimen consisting of cisplatin, vinblastine, dacarbazine, interleukin (IL)–2, and IFN, compared with the standard 52-week regimen of high-dose IFN alfa-2b in patients with resected stage III melanoma. [90] Patients with the lowest risk category, with a single regional nodal micrometastasis and no ulceration of the primary melanoma (N1a), were excluded from the study. Improved RFS was noted in biochemotherapy-treated patients compared with those on high-dose IFN (4 years vs 1.9 years, respectively, 95% confidence interval [CI], 0.58-0.97), although median and 5-year OS rates did not significantly differ between the treatment groups. However, substantial toxicity associated with the biochemotherapy regimen is expected to limits its use in clinical practice.

Melanoma vaccines

Melanoma vaccines are a theoretically attractive alternative to chemotherapy or immunotherapy with systemic cytokines because they are typically associated with relatively little toxicity (eg, fatigue, myalgias, local inflammatory skin reactions). Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. 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. Most current trials for melanoma vaccines are for advanced disease (stages III and IV); trials aimed at prevention are not yet available.

Vaccine types include whole cell preparations, cell lysates, gangliosides, peptides/proteins, dendritic cell vaccines, and DNA vaccines. Melanoma vaccines may be (1) autologous (killed cell and recombinant types), allogeneic, shed from tumor, defined antigen-directed, or genetically engineered and (2) either polyvalent or univalent in nature. Enhanced delivery systems, such as dendritic cell preparations, DNA-plasmid vectors, and intranodal infusion, are under active study 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 provides the first evidence of clinical benefit for vaccine strategies in patients with melanoma. [91, 92, 93] Vaccine strategies remain challenging in melanoma but continue to be studied.

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. [94, 95, 96]

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. [95]

Adverse effects from vemurafenib monotherapy are largely cutaneous and include photosensitivity, which appears to be driven by UV-A light, [97] 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, highlight the need for routine skin examination in all treated individuals. [98]

Dabrafenib (Taflinar) is a newer 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. [99] 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 May 2013. [100]

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. [101] 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. The combination of BRAF and MEK inhibitors (dabrafenib/trametinib) has shown higher response rates and more durable clinical benefit than monotherapy [102, 103] and was FDA approved in January 2014. Combination BRAF/MEK inhibition is now 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. Combination therapy is the standard of care for BRAF mutant advanced melanoma, particularly in the setting of rapidly progressing and/or high-volume metastasis. [104]

Immune checkpoint inhibitors for advanced melanoma (unresectable stage III and IV)

Ipilimumab 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. [105] 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. [106]

However, 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 has also been 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. [107, 108]

Accelerated FDA approval of the PD1 inhibitor pembrolizumab (Keytruda) was granted in September 2014 for patients with advanced or unresectable melanoma following progression on prior therapies, including ipilimumab and BRAF inhibitors. [109] , although it was approved as first-line therapy in December 2015, based on demonstrated superior survival and lower toxicity compared with ipilimumab in the phase 3 KEYNOTE-006 trial. [110]

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. [111] 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. [112] Subsequent documented superior progression-free survival over ipilimumab in the CheckMate 067 trial has resulted in similar FDA approval as a first-line agent for metastatic melanoma.

The combination of ipilimumab and PD1 inhibitors has shown even greater efficacy in patients with advanced melanoma, but it is associated with increased toxicity. [113] The FDA approved the combination regimen of nivolumab plus ipilimumab in September 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. [114] 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). [115] 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. [116] 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.

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Surgical Care

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, and margins of 1 cm are recommended for melanomas less than or equal to 1 mm in depth (low-risk primaries). [117] In some settings of melanoma in situ, tissue sparing may be critical, and Mohs margin-controlled excision may be appropriate. A 2012 prospective study of 1120 melanoma in situ cases revealed that Mohs surgery, with 9-mm margins of normal-appearing skin around the melanoma, resulted in complete removal of almost 99% of lesions and was superior to 6 mm margins, which cleared only 86% of all tumors. [118] However, Mohs surgery is not recommended in either the NCCN or AAD melanoma guidelines for surgical resection of invasive cutaneous melanoma.

Randomized prospective studies show that 2-cm margins are 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. [119, 120] 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. [121] 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. [122]

In a recently concluded multicenter randomized controlled trial in 9 European countries from 1994 to 2002, 936 patients with clinical stage IIA–C cutaneous melanoma thicker than 2 mm were allocated 1:1 for wide excision with either 2- or 4-cm resection margin. With median follow up of 6.7 years, the overall 5-year survival in both groups was 65%, suggesting that a 2-cm resection margin is sufficient and safe for patients with cutaneous melanoma thicker than 2 mm. [123]

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. While studies have shown no increased local recurrence for Mohs surgery compared with historical controls, much of the data stem from thinner tumors with a lower risk of local recurrence and metastasis. [124] Mohs surgery may have certain "niche" indications, including melanomas located the head, neck, hands, or feet. Mohs surgery may prove useful in completely removing subclinical tumor extension in certain subtypes of melanoma in situ, such as lentigo maligna and acral lentiginous melanoma in situ.

Elective lymph node dissection

Prophylactic lymph node dissection for primary cutaneous melanoma of intermediate thickness initially was believed to confer a survival advantage on patients with tumors of 1-4 mm in depth. However, subsequent prospective randomized clinical trials have shown no survival benefit for elective lymphadenectomy for melanomas of varying thicknesses on the extremities and marginal, if any, benefit for nonextremity melanomas. [125, 126]

The 10-year follow-up data from two of the trials conducted by the World Health Organization and the Melanoma Intergroup suggested a survival benefit for certain subsets of patients studied. Patients with occult metastasis detected at the time of wide local excision who underwent immediate elective lymph node dissection had a significantly better 5-year survival rate (48%) compared with those who underwent delayed (therapeutic) lymph node dissection when lymphadenopathy became apparent clinically (27%). [127] However, the differences in OS rates for all patients who had delayed lymph node dissection were not statistically significant compared with the immediate node dissection group.

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 0.76-1 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. [128]

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. [129]

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. [54, 67]

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, its impact on overall survival has yet to be determined. [130] 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. [131] 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. 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.

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Consultations

Dermatologist, as follows:

  • For clinical assessment and biopsy of suspicious skin lesions to diagnose melanoma

  • For long-term follow-up of most patients with cutaneous melanoma

  • For surveillance of individuals at increased risk of melanoma based on mole phenotype, family history, sun sensitivity, and other factors

  • For early detection of suspicious pigmented lesions, particularly in patients at increased risk of melanoma

  • For surgical or topical treatment of cutaneous melanoma

  • For lifelong skin surveillance to detect possible new primary melanoma

Surgical oncologist, as follows:

  • For sentinel node biopsy, typically performed at the time of wide local excision and following preoperative lymphoscintigraphy

  • For surgical 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 chemotherapy, high-dose IL-2, concurrent biochemotherapy, or clinical trials, as indicated clinically

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

  • For evaluation of nodal tissue from SLNB for micrometastasis

  • For confirmation of the diagnosis of disseminated 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 resected regional nodal metastasis with extracapsular extension 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 for resectable brain metastasis

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Long-Term Monitoring

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. [132] The risk of new primary melanoma increases in the setting of increased nevus count; multiple clinical atypical/dysplastic nevi; family history of melanoma; fair skin/sun sensitivity; prior in situ, nodular, and lentigo maligna melanoma; and male sex. [133] Additionally, individual patient risk factors should be taken into account in the determining the frequency of dermatologic surveillance.

The diagnosis of recurrent/metastatic disease and new primary melanoma depends on a routine evaluation schedule that varies according to the following:

  • Tumor depth

  • The presence of histologic ulceration

  • Mitotic rate in the primary tumor

  • Regional lymph node status

  • Results of the examination of the melanoma scar

  • Results of the examination of regional and distant lymph node basins

  • The presence of hepatosplenomegaly upon abdominal examination

  • Mole pattern and examination findings from the entire cutaneous surface for new primaries

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