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Melanoma Treatment (Professional) (cont.)

Stage IV and Recurrent Melanoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Stage IV melanoma is defined by the American Joint Committee on Cancer's TNM classification system:[1]

  • Any T, any N, M1

Standard Treatment Options for Patients With Stage IV and Recurrent Melanoma

Standard treatment options for patients with stage IV and recurrent melanoma include the following:

  1. Palliative local therapy.
  2. Systemic therapy.
  3. Chemotherapy.
  4. Immunotherapy.
  5. Biochemotherapy.
  6. Signal transduction inhibitors.

Palliative local therapy

Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or occasionally the brain may be palliated by resection with occasional long-term survival.[2,3,4]

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[5,6] (Refer to the PDQ summary on Pain for more information.) The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A phase I and II clinical trial (MCC-11543) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.

Systemic therapy

Melanoma has been refractory to most standard systemic therapy. The two approved treatments, dacarbazine (DTIC) and interleukin-2 (IL-2), have not demonstrated an impact on overall survival (OS) in randomized trials. Attempts over the past two decades to develop novel regimens (e.g., multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] combinations of chemotherapy and immunotherapy or biochemotherapy;[7,12,13,14,15,16,17] vaccines; antisense bcl-2 oligonucleotide oblimersen; a reactive-oxide species inhibitor, elesclomol; and others) have also not impacted OS.[18]

However, drug development in melanoma is changing. Significant strides have been made in cataloguing the genetic abnormalities that permit the formation and dissemination of melanoma and in better understanding immunologic checkpoints. The discovery of activating mutations in BRAF in 2002 [19] was followed by the discovery of other mutations, which allowed melanoma to be classified into a group of diseases, and created the opportunity to develop therapies that target the activating molecules and their pathways. The most frequently mutated pathway, the mitogen-activated protein (MAP) kinase pathway, involves the BRAF, NRAS and KIT genes. The single most frequent mutation is in the BRAF gene, with 60% to 70% of malignant melanomas harboring a single nucleotide transversion. In smaller subsets of melanoma, activating mutations may occur in NRAS (15%–20%), c-kit (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), CDK4 (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.

Advances in immunotherapy include development of novel monoclonal antibodies such as anti-CTLA-4 and anti-PD-1, which can prevent down regulation of T cells and modifications in adoptive cell transfer (ACT). Pilot data of ACT regimens have yielded promising results when incorporating lymphodepletion in single-institution studies, but confirmatory trials are needed.

Finally, antiangiogenesis agents in conjunction with relevant therapies for melanoma are under active development. Because of the rapid development of novel therapies, all newly diagnosed patients should be considered candidates for clinical trials.


The objective response rate to DTIC and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%.[7,8,9,20] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response.[7,20] A randomized trial of DTIC versus temozolomide showed an OS of 6.4 months versus 7.7 months, respectively (hazard ratio [HR] = 1.18; 95% confidence interval [CI] 0.92–1.52). These data suggested similarity to DTIC; however, no benefit in survival has been demonstrated for either DTIC or temozolomide, and therefore, temozolomide did not receive approval from the U.S. Food and Drug Administration.[21][Level of evidence: 1iiA] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[7,8,22]


IL-2. Response to IL-2 regimens is in the 10% to 20% range.[11,23,24] Approximately 5% of patients may obtain a complete remission and be long-term survivors; however, phase III confirmatory trials have not been conducted. Attempts to improve on this therapy have included the addition of lymphokine-activated killer cells (i.e., autologous lymphocytes activated by IL-2 ex vivo) and tumor-infiltrating lymphocytes (TIL) (i.e., lymphocytes derived from tumor isolates cultured in the presence of IL-2). A report suggests that ACT with lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and high-dose IL-2 have improved durable response rates in a single-institution study.[25][Level of evidence: 3iiiDiv] There are no confirmatory phase III trials.

Ipilimumab. A total of 676 patients with previously treated, unresectable stage III or stage IV disease, who were HLA-A*0201-positive patients, were entered into a three-arm, multinational, randomized, double-blind trial comparing ipilimumab with or without glycoprotein 100 (gp100) peptide vaccine to the gp100 vaccine plus placebo.[26] Patients were stratified by baseline metastases and prior receipt or nonreceipt of IL-2 therapy. Of the patients, 82 had metastases to the brain at baseline. The median OS was 10 months and 10.1 months among patients receiving ipilimumab alone or with the gp100 vaccine, respectively, versus 6.4 months for patients receiving the vaccine alone (HR = 0.68; P <.001; HR = 0.66; P <.003). An analysis at 1 year showed that among those patients treated with ipilimumab, 44% and 45% of them were alive compared to 25% of the patients who received vaccine only. Grade 3 to grade 4 immune-related adverse events occurred in 10% to 15% of patients treated with ipilimumab. These immune-related adverse events most often included diarrhea or colitis, and endocrine-related events (i.e., inflammation of the pituitary) and required cessation of therapy and institution of anti-inflammatory agents such as corticosteroids or in four cases, infliximab (i.e., an anti-tumor necrosis factor-alpha antibody). There were 14 deaths related to study drugs (2.1%) and seven were associated with immune-related adverse events.[26][Level of evidence: 1iA]


A published data meta-analysis of 18 randomized trials (15 of which had survival information) comparing chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrates no impact on OS.[27][Level of evidence:1iiA]

Signal transduction inhibitors

Sorafenib. The multikinase inhibitor sorafenib (Nexavar) has activity against both the vascular endothelial growth factor signaling and the Raf/MEK/ERK pathway at the level of Raf kinase. However, two large, multicenter, placebo-controlled, randomized trials of carboplatin and taxol plus or minus sorafenib showed no improvement over chemotherapy alone as either first-line treatment or second-line treatment.[28,29]

BRAF inhibitors. Thirty-two patients with metastatic melanoma characterized by the BRAF V600E mutation were entered into the phase II component of a phase I and II trial and received PLX4032, an orally available inhibitor of mutated BRAF, at the recommended phase II dose of 960 mg twice daily. The number of prior treatments ranged from zero to more than three regimens. Twenty-four patients had a partial response and two had a complete response (i.e., an 81% response rate), with responses lasting from 2 months to 18 months and with four responses ongoing. The most common side effects included the following:[30]

  • Arthralgia.
  • Rash.
  • Nausea. (Refer to the PDQ summary on Nausea and Vomiting for more information.)
  • Photosensitivity.
  • Fatigue. (Refer to the PDQ summary on Fatigue for more information.)
  • Cutaneous squamous cell carcinoma.
  • Pruritus. (Refer to the PDQ summary on Pruritus for more information.)
  • Palmar-plantar dysesthesias.

There were no grade 4 adverse events.[30][Level of evidence: 3iiiDiv] A randomized phase III trial of DTIC versus PLX4032 (NCT01006980) is ongoing with patients who have unresectable stage III and stage IV melanoma but who have not received prior therapy for advanced disease. The primary endpoint is OS, and accrual is expected to be completed shortly.

A number of phase II trials of signal transduction inhibitors that have potential for the treatment of melanoma are ongoing, including single-agent trials or combination trials of MEK, AKT, and PI3 kinase inhibitors. (Information about ongoing clinical trials is available from the NCI Web site.)

Kit inhibitors. A number of phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-kit mutation. (Information about ongoing clinical trials is available from the NCI Web site.)

Treatment Options Under Clinical Evaluation for Patients With Stage IV and Recurrent Melanoma

Treatment options under clinical evaluation for patients with stage IV and recurrent melanoma include the following:

  1. Patients who have mutations and are receiving antiangiogenesis agents should be considered appropriate candidates for clinical trials evaluating immunotherapy and signal transduction inhibitors. Although it is expected that novel therapies will be approved over the next year, the vast majority of patients are not cured, and clinical trials remain a compelling option for treatment, especially those trials that provide combinations of therapies.
  2. Palliative radiation therapy for bone, spinal cord, or brain metastases.
  3. Complete surgical resection of all known disease (SWOG-9430 [NCT00002860]).
  4. Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences.[31] Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.[32,33]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV melanoma and recurrent melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


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