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 with high-dose interferon.

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.[3,4,5,6] In a prospective randomized controlled trial (EST-1684), adjuvant high-dose interferon was shown to increase relapse-free survival (RFS) and overall survival (OS) when compared to observation.[7] A subsequent randomized trial (EST-1690) conducted by the same group of investigators using the same high-dose interferon regimen confirmed the RFS but not the OS advantage.[8] A third randomized trial (SWOG-8593) again demonstrated both a disease-free survival (DFS) and OS advantage to high-dose interferon when compared to a ganglioside vaccine.[9] Clinicians should be aware that high-dose 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 RFS or OS.[10] Adjuvant chemotherapy does not improve survival. A multicenter phase III randomized trial of patients with high-risk primary limb melanoma did not show a benefit from isolated limb perfusion with melphalan in regard to DFS or OS when compared to surgery alone.[11]

Melanoma that has spread to distant sites is rarely curable with standard therapy, though high-dose interleukin-2 (IL-2) has been reported to produce durable responses in a small number of patients.[12,13] In patients with systemic metastasis confined to one anatomic site, long-term survival is occasionally achieved by complete resection of all metastatic disease.[14,15,16,17] All patients with distant metastasis are appropriately considered candidates for clinical trials exploring new forms of treatment, including combination chemotherapy, biological response modifiers (such as specific monoclonal antibodies, interferons, IL-2, or tumor necrosis factor-alpha), vaccine immunotherapy, or biochemotherapy (chemoimmunotherapy).

Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.[18]

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:

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991.
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.
3. 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.
4. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998.
5. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000.
6. 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.
7. 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.
8. 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.
9. Kirkwood JM, Ibrahim J, Lawson DH, et al.: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19 (5): 1430-6, 2001.
10. 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.
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.
12. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999.
13. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000.
14. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000.
15. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000.
16. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.
17. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.
18. Wang TS, Lowe L, Smith JW 2nd, et al.: Complete spontaneous regression of pulmonary metastatic melanoma. Dermatol Surg 24 (8): 915-9, 1998.