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Melanoma Treatment (Professional) (cont.)

Stage III 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 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

Standard treatment options for patients with stage III melanoma include the following:

  • 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.

Clinical trials exploring adjuvant therapy after control of the primary tumor with standard therapy are especially appropriate because of the higher rate of treatment failure in this group.

Adjuvant Treatment Options for Patients With Resected Stage III Disease

Adjuvant treatment options for patients with resected stage III disease include the following:

  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 overall survival (OS) that were seen in EST-1684. Subsequent large, randomized trials have not been able to reproduce a benefit in OS.
    • A multicenter, randomized controlled study, (E-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 (E-1684 and E-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 mo) 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. Low-dose interferon. Several randomized trials using lower doses of interferon have been conducted in the adjuvant setting. To date, no consistent evidence is available that intermediate doses or low doses of interferon improve RFS or OS.[11]
  3. Pegylated Interferon. Pegylated interferon alpha-2b, which is characterized by a longer half-life and can be administered subcutaneously, was approved by the U.S. Food and Drug Administration 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).[12][Level of evidence: 1iiDii] One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.
  4. Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival.[13]

Treatment Options for Patients With Unresectable Stage III Disease

Treatment options for patients with unresectable disease include the following:

  • Patients with unresectable disease are entered into trials recruiting stage IV patients. See stage IV section for clinical trial results and treatment options.

Treatment Options Under Clinical Evaluation for Patients With Stage III Melanoma

Treatment options under clinical evaluation for patients with stage III melanoma include the following:

  1. EORTC-18071 (NCT00636168), in collaboration with centers in the United States, is conducting a phase III randomized trial of ipilimumab versus placebo in patients with high-risk stage III melanoma who have undergone an adequate surgical resection. The Eastern Cooperative Oncology Group is preparing to launch a U.S. adjuvant trial (E4697) of ipilimumab in stage III and stage IV patients who have resectable disease.
  2. 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] Results from a multicenter, randomized, phase II study showed no benefit from adding interferon-gamma to a regimen of L-PAM plus TNF-alpha.[14] Clinical trials such as the ACOSOG-Z0020 and MSKCC-99047 trials, for example, have evaluated ILP using L-PAM in combination with TNF or other chemotherapeutic agents.
  3. Intratumoral injections of replication-competent oncolytic viruses of unresectable lesions are being tested in national clinical trials.

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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  11. 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.
  12. 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.
  13. Meisenberg BR, Ross M, Vredenburgh JJ, et al.: Randomized trial of high-dose chemotherapy with autologous bone marrow support as adjuvant therapy for high-risk, multi-node-positive malignant melanoma. J Natl Cancer Inst 85 (13): 1080-5, 1993.
  14. Liénard D, Eggermont AM, Koops HS, et al.: Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study. Melanoma Res 9 (5): 491-502, 1999.
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