Malignant Melanoma Treatment & Management

Surgery is the definitive treatment for early stage melanoma. A wide local excision with sentinel lymph node biopsy and/or elective lymph node dissection (LND) is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease.^[18]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma.

Because less than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival, these patients are classified as high risk and should be considered for adjuvant therapy.

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.^[19] Multiple iterations of a genetic algorithm using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry on 246 serial primary melanomas yielded a consistent 5-marker solution. A favorable prognosis was predicted by the following criteria:

• ATF2 ln(non-nuclear/nuclear AQUA score ratio) greater than -0.052
• p21(WAF1) nuclear compartment AQUA score greater than 12.98
• p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) -0.083 or less
• Beta-catenin total AQUA score greater than 38.68
• Fibronectin total AQUA score 57.93 or less

Primary tumors that met at least 4 of these 5 conditions were considered low risk. Validation of the score showed that tumors in the high-risk group (those that met 3 or fewer conditions) were associated with significantly reduced survival (hazard ratio, 2.72; 95% confidence interval, 1.12-6.58; P = .027).

Interferon alfa

A large multicenter study, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival using high-dose interferon alfa-2b (IFN) and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).^[20] On the basis of ECOG-1684, the Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.

A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = .006) but not overall survival (P = .42).^[21]

Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.

To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomly assigned to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.^[22]

On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome. In their prospective, randomized, multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months.^[23]

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.^[24]

Granulocyte-macrophage colony-stimulating factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high risk melanoma. Spitler et al treated 46 patients with resected stage III or IV melanoma with a subcutaneous dose of 125 mg/m² for 2 weeks on and 2 weeks off for a year and found that the improvement in progression-free survival over historical controls was 37 vs 12 months.^[25] Based on this promising result, a trial was done to test the efficacy of this regimen compared with placebo and a vaccine (ECOG-4697). The results of the trial are still pending at this time.

BRAF mutations

BRAF mutations are present in 40-60% of melanomas. When detected, this mutation can help to guide treatment. In a multicenter, phase 1, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032).^[26] Two patients had a complete response, and 24 had a partial response.

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.

Phase 3 trial results for the investigational BRAF inhibitor vemurafenib demonstrated a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation compared with dacarbazine, the only chemotherapeutic drug currently approved by the US Food and Drug Administration (FDA) for this disease.^[27] In addition, the overall survival rate at 6 months in the vemurafenib group was 84% relative to 64% in the dacarbazine group.^[27] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve the BRAF V600E mutation. Moreover, a response to vemurafenib in 4 of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.^[27]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.^[27] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Treatment of patients with advanced-stage melanoma (stage IV) has not improved significantly in recent years.

Currently, there are no standard systemic therapeutic regimens that offer significant prolongation of survival for most patients with metastatic melanoma without significant risk of toxicities.

At this time, no combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate.^[28]

Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens.^[29]

A study by Carvajal et al found that among patients with advanced melanoma who had alternations in the type III transmembrane receptor tyrosine kinase KIT, treatment with imatinib mesylate resulted in clinically significant response in a subset of patients.^[30]

Dacarbazine

DTIC was the first drug approved for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%.^[31] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists currently use temozolomide as their first-line drug for melanoma.

Biologic therapies now are being used alone and with chemotherapy regimens in the treatment of patients with advanced-stage melanoma. To date, studies do not show that IFN and interleukin-2 added to DTIC is better than DTIC alone.

Interleukin 2

The second drug approved by the Food and Drug administration (FDA) was interleukin 2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell derived growth factor and used as a lymphokine-activated cell killer therapy.

A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg administered every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patient with soft tissue and lung metastases. The overall median survival was 11.4 months.^[32]

The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for this type of treatment, patients must have normal results on pulmonary function testing, brain MRI, and cardiac stress testing, plus adequate renal and hepatic function.

Carboplatin and paclitaxel

Carboplatin and paclitaxel have been tested in 2 small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This sometimes is being used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.

However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.^{[33, 34]}

Thymosin alpha 1

Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses.

Maio et al evaluated the efficacy and safety of Talpha1 when combined with DTIC and IFN alfa and found that their results suggested that Talpha1 has activity in patients with metastatic melanoma. The authors’ investigation was a randomized study of 488 patients with the disease. Tumor responses were higher in the DTIC/IFN/Talpha1 (3.2mg) (10 responses) and DTIC/Talpha1 (3.2 mg) (12 responses) groups than in the DTIC/IFN control group (4 responses).^[35]

Vaccines

Melanoma vaccines and gene therapy are 2 additional treatment options that may become available.^[36]

A 2007 review found no clear evidence that the addition of immunotherapy to chemotherapy increases survival in metastatic melanoma and recommended that combined immunotherapy and chemotherapy be limited to clinical trials.^[37] Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies. Vaccines have not been successful as a treatment for metastatic melanoma but are still a reasonable area of research in the adjuvant setting.

External-beam radiation

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.^[18]

Anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody directed at a down-regulatory receptor on activated T-cells.^[38] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T-cells.

Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently underway.^[39] Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. Ipilimumab blocks CTLA-4 to a potentiate T-cell response. In a phase 3 study, 676 patients with HLA2-positive patients with unresectable stage III or IV melanoma who disease progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy. The median overall survival was 10 months among patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab-plus-gp100 arm. Because of these findings, ipilimumab has been approved as a treatment for metastatic melanoma.^[39]

In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival among patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, they had more grade 3 and 4 toxicity.^[40]

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.

The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than it was in patients who did not take the drug.^[41]

The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against UVR exposure, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15. This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.^[42] Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.^[43]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.

A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.^[15]

Follow-up for stage 0 in situ is as follows:

• At least annual skin examination for life
• Educate patient in monthly self skin examination

Follow-up for stage IA is as follows:

• History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
• At least annual skin examination for life
• Educate patient in monthly self skin and lymph node examination

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

• H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
• Chest radiography, LDH, and CBC every 6-12 mo (optional)
• Routine imaging is not recommended for stage IB or IIA disease
• CT scans to follow up for specific signs and symptoms
• Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
• At least annual skin examination for life
• Educate patient in monthly self skin and lymph node examination