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Melanoma Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Stage III Melanoma

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

  • Any T, N1, M0
  • Any T, N2, M0
  • Any T, N3, M0

Standard Treatment Options for Patients With Stage III Melanoma

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  1. Wide local excision of the primary tumor with 1 cm to 3 cm margins, depending on tumor thickness and location.[2,3,4,5,6,7,8] Skin grafting may be necessary to close the resulting defect.
  2. High-dose or pegylated interferon alpha-2b as adjuvant treatment for patients who have undergone a complete surgical resection but are considered to be at high risk for relapse.
  3. Ipilimumab for patients with unresectable disease.
  4. Vemurafenib for patients with unresectable disease who test positive for the BRAF V600 mutation in a U.S. Food and Drug Administration-approved test.

Adjuvant Treatment Options for Patients With Resected Stage III Disease

Prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon do not improve overall survival (OS). Agents that have demonstrated improved OS in patients with recurrent or metastatic disease are now being tested in clinical trials of adjuvant therapy in patients at high risk for relapse after surgical resection of tumor. These trials include: NCT01274338, NCT01667419, and NCT01682083.

  1. High-dose interferon. High-dose interferon alpha-2b was approved in 1995 for the adjuvant treatment of patients with melanoma who have undergone a complete surgical resection but who are considered to be at a high risk of relapse. Evidence was based on a significantly improved relapse-free survival (RFS) and marginally improved OS that were seen in the completed EST-1684 trial. Subsequent large, randomized trials have not been able to reproduce a benefit in OS.
    • A multicenter, randomized, controlled study, (EST-1684), compared a high-dose regimen of interferon alpha-2b (20 mU/m2 of body surface per day given intravenously for 5 days a week every week for 4 weeks, then 10 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 48 weeks) to observation.[9] This study included 287 patients at high risk for recurrence after potentially curative surgery for melanoma (patients with melanoma >4 mm thick without involved lymph nodes or patients with melanomas of any thickness with positive lymph nodes). Patients who had recurrent melanoma involving only the regional lymph nodes were also eligible. At a median follow-up of 7 years, this trial demonstrated a significant prolongation of RFS (P = .002) and OS (P = .024) for patients receiving high-dose interferon.

      The median OS for patients who received the high-dose regimen of interferon alpha-2b was 3.8 years compared with 2.8 years for those in the observation group.[9][Level of evidence: 1iiA] A subset analysis of the stage II patients, however, failed to show any benefit from high-dose interferon in terms of RFS or OS. Because the number of stage II patients was small in this subset analysis, it is difficult to draw meaningful conclusions from this study for this specific group.

    • A subsequent multicenter, randomized, controlled study (EST-1690) conducted by the same investigators compared the same high-dose regimen of interferon alpha-2b to either a low-dose regimen (3 mU/m2 of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation.[10] The stage entry criteria for this trial were the same as for the initial study. This three-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant RFS advantage was shown for all patients who received high-dose interferon (including the clinical stage II patients) when compared with the observation group (P = .03); however, no statistically significant RFS advantage was seen for low-dose interferon when compared with the observation group. The 5-year estimated RFS rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose interferon nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR], 1.0; P = .995).[10][Level of evidence: 1iiA]
    • Pooled analyses of the two high-dose arms versus the two observation arms from both studies (EST-1684 and EST-1690) suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.[10][Level of evidence: 1iiA]
    • E-1697, a randomized, multicenter, national trial evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm in thickness or with any thickness and positive sentinel nodes. This trial was closed at interim analysis because of the lack of benefit from treatment with interferon.

    Clinicians should be aware that the high-dose regimens have significant toxic effects.

  2. Pegylated Interferon. Pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the FDA in 2011 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy. Approval was based on EORTC-18991, which randomly assigned 1,256 patients with resected stage III melanoma to observation or weekly subcutaneous pegylated interferon alpha-2b for up to 5 years. RFS, as determined by an Independent Review Committee, was improved for patients receiving interferon (34.8 months vs. 25.5 months in the observation arm; HR, 0.82; 95% confidence interval [CI], 0.71–0.96; P = .011). No difference in median OS between the arms was observed (HR, 0.98; 95% CI, 0.82–1.16).[11][Level of evidence: 1iiDii] One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.
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