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Melanoma Treatment (PDQ®)

Health Professional Version
Last Modified: 03/19/2014

Stage III Melanoma

Standard Treatment Options for Patients With Stage III Melanoma
Adjuvant Treatment Options for Patients With Resected Stage III Disease
Treatment Options for Patients With Unresectable Stage III Disease
Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma
Current Clinical Trials

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
  1. Wide local excision of the primary tumor with 1 cm to 3 cm margins, depending on tumor thickness and location.[2-8] 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.

Treatment Options for Patients With Unresectable Stage III Disease
  1. Ipilimumab. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)

  2. Vemurafenib for patients who test positive for the BRAF V600 mutation by an FDA-approved test. (Refer to the Standard Treatment Options for Patients with Stage IV and Recurrent Melanoma section of this summary for more information.)

  3. Local therapy for extremity melanoma. For patients with in-transit and/or satellite lesions (stage IIIC) of the extremities, hyperthermic isolated limb perfusion (ILP) with melphalan (L-PAM) with or without tumor necrosis factor-alpha (TNF-alpha) has resulted in high tumor response rates and palliative benefit.[4] No impact on OS has been convincingly demonstrated in randomized controlled studies.[12,13]

Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma
  • Clinical trials exploring the following:
    • Adjuvant therapy after local control of the tumor in high-risk tumors.
    • Intralesional therapies for local control of lesions.
    • Isolated limb perfusion for unresectable extremity melanoma.
    • Systemic therapy for unresectable disease.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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.

References
  1. Melanoma of the skin. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 325-44. 

  2. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.  [PUBMED Abstract]

  3. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988.  [PUBMED Abstract]

  4. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.  [PUBMED Abstract]

  5. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000.  [PUBMED Abstract]

  6. Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001.  [PUBMED Abstract]

  7. Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998.  [PUBMED Abstract]

  8. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993.  [PUBMED Abstract]

  9. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996.  [PUBMED Abstract]

  10. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000.  [PUBMED Abstract]

  11. Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372 (9633): 117-26, 2008.  [PUBMED Abstract]

  12. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004.  [PUBMED Abstract]

  13. Lens MB, Dawes M: Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol 4 (6): 359-64, 2003.  [PUBMED Abstract]