Cutaneous Melanoma Treatment & Management

Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No overall survival benefit has been demonstrated for adjuvant chemotherapy, nonspecific (passive) immunotherapy (including interferon), radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy.^[59] Adjuvant interferon (IFN) alfa-2b is the only adjuvant therapy approved by the US Food and Drug Administration for high-risk melanoma (currently defined as stages IIB, IIC, and III), which is associated with a 40-80% chance of relapse and death. The immunotherapy agent, ipilimumab, biologic response modifiers (eg, granulocyte macrophage colony-stimulating factor [GM-CSF]), and various melanoma vaccines are currently being studied in the adjuvant setting for resected stage III and IV melanoma.

Interferon alfa trials

In the United States, 3 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.^[60]

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. Importantly, no difference in the OS rate was seen in the IFN-treated groups (high- or low-dose) compared with the observation arm.^[61] 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 most recent Intergroup trial (ECOG 1694) compared the use of standard high-dose IFN alfa with GM2 ganglioside vaccine (GMK). The study was closed prematurely due to a significant benefit 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.^[62]

A pooled analysis of the 3 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.^[63] The authors concluded there is "strong evidence for improved RFS and evidence for moderate improvement in OS based on two prospective randomized studies (E1684 and E1694), but not in the pooled analysis" and called for further analysis of predictors of both response and relapse to improve the therapeutic value of high-dose IFN therapy. An EORTC randomized, phase III trial of adjuvant pegylated interferon alfa-2b (Peg-Intron) in patients with resected stage III melanoma similarly showed no OS benefit but almost 12% improvement in RFS, though largely restricted to patients with microscopic lymph node involvement.^[64]

In any case, the potential benefits of high-dose IFN must be weighed against its substantial tolerability and toxicity issues, including the yearlong duration of therapy, commonly associated flulike symptoms, and potential for significant adverse reactions.

Data from 2006 suggest that high-dose IFN-induced autoimmunity, as manifested clinically by new-onset vitiligo, and/or serologically by the development of autoantibodies (antithyroid, antinuclear, and anticardiolipin), is associated with prolonged RFS and OS in melanoma patients.^[65] The apparent prognostic significance of autoimmunity during high-dose IFN treatment warrants further study.

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, interleukin (IL)–2, IL-12, and IFN gamma are often integrated into vaccine strategies.

As yet, no large, phase III randomized trial has demonstrated an overall survival advantage for vaccine-treated melanoma patients. However, a recent 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.^{[66, 67, 68]}

BRAF inhibitors

BRAF mutations could have important implications in terms of survival. Prospective studies are needed, but BRAF inhibitors in preliminary studies have been found to be effective in treating metastatic melanoma.^{[69, 70]}

Vemurafenib (Zelboraf) was approved by the US Food and Drug Administration (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 has not been studied 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 overall survival rate was 84% (95% confidence interval [CI], 78-89) in the vemurafenib group and 64% (95% CI, 56-73) in the dacarbazine group.^[70]

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 ≤1 mm in depth (low-risk primaries).^[71] In some settings, tissue sparing may be critical, and Mohs margin-controlled excision may be appropriate.

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.^{[72, 73]} 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 suggests 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 2 groups.^[74] However, this study has been criticized for combining satellite, in-transit, and regional nodal recurrences as the primary end point 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 is 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.^[75]

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.^[76]

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.^[77] 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. Subsequently, 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.^{[78, 79]}

The 10-year follow-up data from 2 of the trials conducted by the World Health Organization and the Melanoma Intergroup now suggest a survival benefit for certain subsets of patients studied. In particular, patients in the World Health Organization trial who had occult metastasis detected at the time of wide local excision and immediate elective 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%).^[80] 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/dissection

Lymphatic mapping and sentinel node biopsy have helped to solve the dilemma of whether to perform regional lymphadenectomy in the absence of clinically involved nodes in patients with thicker melanomas (≥1 mm in depth) and in those of less than 1 mm depth with adverse features (eg, ulceration, lymphovascular invasion, mitotic rate ≥1/mm²).

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.^[81]

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) is performed. 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.^[82]

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.^{[46, 57]}

Sentinel lymph node biopsy 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.^[83] The results of the ongoing Multicenter Selective Lymphadenectomy Trial (MSLT), the Florida Melanoma Trial, and the Sunbelt Melanoma Trial should help to determine whether SLNB provides a therapeutic benefit in patients with cutaneous melanoma.

The third of 5 planned analyses of the MSLT-1 has been published.^[84] This interim analysis of the subset of 1269 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 5-year survival compared with delayed CLND in patients who developed macroscopic nodal metastasis following primary excision alone (72% vs 52%, respectively). The risk of death was reduced by one half (hazard ratio, 0.51; 95% confidence interval, 0.32-0.81; P = .004) in the node-positive subset of patients who underwent immediate versus delayed CLND for regional nodal metastasis. OS rates did not differ.

Longer follow-up with continued analysis of MSLT-1 and other important SLNB trials will help to elucidate the potential therapeutic benefit of early removal of micrometastasis in the regional nodal basin. See the Medscape Reference article The Role of Sentinel Node Biopsy in Skin Cancer for further information.

• Dermatologist

  • For clinical assessment and biopsy of suspicious skin lesions
  • 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

  • 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

  • To discuss adjuvant therapy with IFN alfa, experimental melanoma vaccines, or other clinical trials: Patients should be referred to a medical oncologist or melanoma specialist soon after the melanoma diagnosis and treatment in order to optimize the chances for appropriate adjuvant therapy or clinical trial entry.
  • 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

  • For preoperative lymphoscintigraphy if SLNB is performed
  • For PET scan interpretation
• Pathologist/dermatopathologist

  • 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

  • For consideration of local adjuvant treatment of resected regional nodal metastasis with extracapsular extension or resected intransit metastasis
  • For palliative treatment of distant metastatic disease, particularly bony metastasis or brain involvement (whole brain radiotherapy or stereotactic radiosurgery)
• Neurosurgeon - For evaluation for resectable brain metastasis