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Melanoma Treatment (PDQ®)

  • Last Modified: 09/19/2014

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Resectable Stage III Melanoma Treatment

Standard Treatment Options for Resectable Stage III Melanoma
        Excision
Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma
Current Clinical Trials



Standard Treatment Options for Resectable Stage III Melanoma

Standard treatment options for resectablestage III melanoma include the following:

  1. Excision with or without lymph node management.
Excision

The primary tumor may be treated with wide local excision with 1-cm to 3-cm margins, depending on tumor thickness and location.[1-7] Skin grafting may be necessary to close the resulting defect.

Lymph node management

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and SLNB can be considered to assess the presence of occult metastases in the regional lymph nodes of patients with primary tumors larger than 1 mm to 4 mm, potentially identifying individuals who may be spared the morbidity of regional lymph node dissections (LNDs) and individuals who may benefit from adjuvant therapy.[3,8-12]

To ensure accurate identification of the sentinel lymph node (SNL), lymphatic mapping and removal of the SLN should precede wide excision of the primary melanoma.

Multiple studies have demonstrated the diagnostic accuracy of SLNB, with false-negative rates of 0% to 2%.[8,12-17] If metastatic melanoma is detected, a complete regional lymphadenectomy can be performed in a second procedure.

Complete lymph node dissection (CLND)

Patients can be considered for CLND if the sentinel node(s) is microscopically or macroscopically positive for regional control or considered for entry into the Multicenter Selective Lymphadenectomy Trial II to determine whether CLND affects survival. SLNB should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping.

Adjuvant Therapy

Interferon alpha-2b

Prospective, randomized, multicenter treatment trials have demonstrated that high-dose interferon alpha-2b and pegylated interferon, both approved for the adjuvant treatment of patients at high risk for relapse, can improve relapse-free survival (RFS) but 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.

Evidence (high-dose alpha interferon):

  1. A multicenter, randomized, controlled study (EST-1690) compared a high-dose interferon alpha regimen with either a low-dose regimen of interferon alpha-2b (3 mU/m2 of body surface per day given subcutaneously three times per week for 104 weeks) or observation. The stage entry criteria for this trial included patients with stage II and III melanoma. This three-arm trial enrolled 642 patients.[14][Level of evidence: 1iiA]
    • 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).

    • No statistically significant RFS advantage was seen for patients who received low-dose interferon when compared with the observation group.

    • The 5-year estimated RFS rate was 44% for the high-dose interferon group, 40% for the low-dose interferon group, and 35% for the observation group.

    • Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR], 1.0; P = .995).

    • Pooled analyses (EST-1684 and EST-1690) of the high-dose arms versus the observation arms suggest that treatment confers a significant RFS advantage but not a significant benefit for survival.

  2. A randomized, multicenter, national trial, ECOG-1697 [NCT00003641], evaluated high-dose intravenous interferon for a short duration (1 month) versus observation in patients with node-negative melanoma at least 2 mm thick 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.

Pegylated interferon alpha-2b

In 2011, 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 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including complete lymphadenectomy.

Evidence (pegylated interferon alpha-2b):

  1. Approval of pegylated interferon alpha-2b was based on EORTC-18991 [NCT00006249], 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.[15][Level of evidence: 1iiDii]
    • 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).

    • One-third of the patients receiving pegylated interferon discontinued treatment because of toxicity.

Treatment Options Under Clinical Evaluation for Resectable Stage III Melanoma

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

  1. Adjuvant therapy that can impact OS.

  2. Intralesional therapies.

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. 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]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. 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]

  8. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000.  [PUBMED Abstract]

  9. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.  [PUBMED Abstract]

  10. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998.  [PUBMED Abstract]

  11. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998.  [PUBMED Abstract]

  12. Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012.  [PUBMED Abstract]

  13. 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]

  14. 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]

  15. 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]

  16. 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]

  17. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011.  [PUBMED Abstract]