Treatment Option Overview
Melanomas that have not spread beyond the site at which they developed are highly curable. Most of these are thin lesions that have not invaded beyond the papillary dermis (Clark level I–II; Breslow thickness ≤1 mm). The treatment of localized melanoma is surgical excision with margins proportional to the microstage of the primary lesion; for most lesions 2 mm or less in thickness, this means 1 cm radial re-excision margins.[1,2]
Melanomas with a Breslow thickness of 2 mm or more are still curable in a significant proportion of patients, but the risk of lymph node and/or systemic metastasis increases with increasing thickness of the primary lesion. The local treatment for these melanomas is surgical excision with margins based on Breslow thickness and anatomic location. For most melanomas more than 2 mm to 4 mm in thickness, this means 2 cm to 3 cm radial excision margins. These patients should also be considered for sentinel lymph node biopsy followed by complete lymph node dissection if the sentinel node(s) are microscopically or macroscopically positive. Sentinel node biopsy should be performed prior to wide excision of the primary melanoma to ensure accurate lymphatic mapping. Patients with melanomas that have a Breslow thickness more than 4 mm should be considered for adjuvant therapy.
Some melanomas that have spread to regional lymph nodes may be curable with wide local excision of the primary tumor and removal of the involved regional lymph nodes.[3-6] A completed, multicenter, phase III randomized trial (SWOG-8593) of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to disease-free survival (DFS) or overall survival (OS) when compared to surgery alone. Systemic treatment with high dose and pegylated interferon alpha-2b are approved for the adjuvant treatment of patients who have undergone a complete surgical resection but are considered to be at high risk for relapse. Prospective, randomized, controlled trials with both agents have not shown an increase in OS when compared with observation.[8-10] Clinicians should be aware that high-dose and pegylated interferon regimens have substantial side effects, and patients should be monitored closely. Adjuvant therapy with lower doses of interferon have not been consistently shown to have an impact on either relapse-free survival or OS. Therapies that have impacted OS in patients with recurrent or metastatic disease are now being tested as adjuvant therapy in clinical trials, including NCT01274338, NCT01667419, and NCT01682083.
Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and OS in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. These single agents are rarely curative; however, clinical trials that incorporate these agents are testing combinations in an attempt to prevent development of drug resistance. Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with a demonstrated BRAF V600E mutation by an FDA-approved test. Clinical trials are testing targeted therapies in the smaller patient subsets (e.g., those with mutations in NRAS, c-KIT, CDK4, GNAQ or GNA11). Information about ongoing clinical trials is available from the NCI Web site.
Interleukin-2 (IL-2) was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0% –8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.
Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20%, with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[12-16] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase III trial with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.
Patients with all stages of melanoma may be considered candidates for ongoing clinical trials. Information about ongoing clinical trials is available from the NCI Web site.References
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- 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]
- 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]
- Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
- Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000. [PUBMED Abstract]
- Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004. [PUBMED Abstract]
- 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]
- Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011. [PUBMED Abstract]