Current Clinical Trials

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 following clinical stage groupings:

• Any T, N1, M0
• Any T, N2, M0
• Any T, N3, M0

Standard treatment options:

• Wide local excision of the primary tumor 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.

  A multicenter, randomized controlled study (EST-1684) has 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.[8] 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 relapse-free survival (P = .002) and overall survival (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.[8][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 relapse-free survival 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) by the same investigators compared the same high-dose regimen of interferon-alpha to either a lower dose regimen (3 mU/m² of body surface per day given subcutaneously 3 times a week every week for 104 weeks) or observation.[9] The stage entry criteria for this trial were the same as for the initial study. This 3-arm trial entered 642 patients. At a median follow-up of 52 months, a statistically significant relapse-free survival 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 relapse-free survival advantage was seen for low-dose interferon when compared to the observation group. The 5-year estimated relapse-free survival rates for the high-dose interferon, low-dose interferon, and observation groups were 44%, 40%, and 35%, respectively. Neither high-dose nor low-dose interferon yielded an OS benefit when compared with observation (hazard ratio [HR] = 1.0; P = .995).[9][Level of evidence: 1iiA]

  Pooled analyses of the two high-dose arms versus the two observation arms from both studies suggest that treatment confers a significant relapse-free survival advantage but not a significant benefit for survival.[9][Level of evidence: 1iiA]

  Another multicenter prospective trial randomized patients with resected stage IIB or III melanoma to receive either the same high-dose interferon-alpha-2b regimen or a vaccine of conjugated GM2 melanoma antigen (GM2-KLH/QS-21)(GMK).[10] Of the 880 randomly assigned patients, 774 patients were eligible for efficacy analysis. This trial was closed after an interim evaluation indicated the inferiority of the GMK vaccine compared to treatment with interferon. A statistically significant relapse-free survival was found for high-dose interferon (HR = 1.47; P = .0015), as was a statistically significant OS benefit (HR = 1.52; P = .009). (In the intent-to-treat analysis, relapse-free survival [HR = 1.49]; OS [HR = 1.38].)

  Clinicians should be aware that the high-dose regimens have significant toxic effects.

  Several randomized trials using lower doses of interferon have been conducted in the adjuvant setting. To date, no consistent evidence is available that intermediate or low doses of interferon improve relapse-free survival or OS.[11]

  Autologous bone marrow transplantation with high-dose chemotherapy has not been shown to improve survival.[12]

Treatment options under clinical evaluation:

• Because of the higher rate of treatment failure in this group, clinical trials exploring adjuvant chemotherapy and/or adjuvant biologic therapy, or immunologically active agents to prevent recurrences after control of the primary tumors with standard therapy are especially appropriate for newly diagnosed patients.

  An ongoing phase III trial (ECOG-1697) is evaluating the effect of 1 month of high-dose adjuvant interferon-alpha-2b versus observation on relapse-free survival and OS in patients with melanomas more than 1.5 mm in thickness, with or without a single microscopically positive lymph node. Another ongoing phase III trial (EORTC-18991) is evaluating adjuvant phenylated interferon-alpha-2b versus observation. Results are pending from a phase III study (EORTC-18952) that randomly assigned patients with stage II or stage III disease to adjuvant intermediate high-dose interferon-alpha-2b versus intermediate low-dose interferon-alpha-2b versus observation.




• For patients with high-risk stage III disease, phase III clinical trials such as the SWOG-S0008 and MDA-ID-95196 trials, for example, are evaluating interferon-alpha-2b versus chemoimmunotherapy.



• 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.[3] Results from a multicenter randomized phase II study showed no benefit from adding interferon-gamma to a regimen of L-PAM plus TNF-alpha.[13] Clinical trials such as the ACOSOG-Z0020 and MSKCC-99047trials, for example, are evaluating ILP using L-PAM in combination with TNF or other chemotherapeutic agents.



• A recently completed phase I/II study (MCC-11543) evaluated interferon-alpha-2b in combination with radiation therapy; results are pending.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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. 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]
   
   
9. 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]
   
   
10. Kirkwood JM, Ibrahim JG, Sosman JA, et al.: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol 19 (9): 2370-80, 2001.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    

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