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 IV melanoma is defined by the following clinical stage grouping:

• Any T, any N, M1

Standard treatment options:

• Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or occasionally the brain may be palliated by resection with occasional long-term survival.[1-3] Radiation therapy may provide symptomatic relief for metastases to brain, bones, and viscera.

  Advanced melanoma is refractory to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Although advanced melanoma is relatively resistant to therapy, several biologic response modifiers and cytotoxic agents have been reported to produce objective responses.

  The objective response rate to dacarbazine (DTIC) and the nitrosoureas, carmustine (BCNU) and lomustine, is approximately 10% to 20%.[4-7] Responses are usually short-lived, ranging from 3 to 6 months, though long-term remissions can occur in a limited number of patients who attain a complete response.[4,7] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[4,5,8]

  Phase II studies of three-drug combinations showed higher response rates (ranging from 22% to 45%) than were seen with single agents.[4,5] Randomized trials comparing two-drug or three-drug combination regimens with DTIC alone have not consistently demonstrated any advantage for the combination, though these trials had limited sample sizes and insufficient power to detect small but clinically relevant differences in response or survival.[4]

  The addition of tamoxifen to the three-drug combination regimen of cisplatin, BCNU, and DTIC (i.e., the Dartmouth regimen) showed high response rates in phase II studies, with a 20% complete response rate in several trials.[4] A phase III trial testing the three drugs with and without tamoxifen showed no benefit for the addition of tamoxifen, and the response rates in both study arms were once again in the 20% to 30% range.[9]

  One trial directly compared DTIC alone to the three-drug regimen plus tamoxifen.[6] Results from this trial indicated no difference in tumor response or overall survival (OS) between the two treatment groups. The tumor response rate to DTIC was 10.2% compared with 18.5% for the three-drug combination plus tamoxifen (P = .09). Pending the outcome of further randomized, controlled trials, no combination regimen has yet been proven to be superior to DTIC alone.

  The two biologic therapies that appear most active against melanoma are interferon-alpha and interleukin-2 (IL-2). Response rates for interferon range from 8% to 22%, and long-term administration on a daily or a three-times-per-week basis appears superior to once per week or more intermittent schedules.[10] Response to IL-2 regimens is similar and is in the 10% to 20% range.[11-13] Attempts to improve on this with the addition of lymphokine-activated killer cells (autologous lymphocytes activated by IL-2 ex vivo) and by tumor-infiltrating lymphocytes (lymphocytes derived from tumor isolates cultured in the presence of IL-2) have not improved response rates or durable remissions sufficiently to merit the expense and complexity of this therapy. Phase II studies testing combinations of interferon and IL-2 have demonstrated high response rates, but a phase III comparison of interferon and IL-2 compared with IL-2 alone in 85 patients did not show any benefit for the combination.[8]

  Combinations of chemotherapy and biologics (chemoimmunotherapy or biochemotherapy) have been tested against chemotherapy alone. Four small phase III studies comparing DTIC and interferon with DTIC alone yielded conflicting results.[4] In a larger randomized trial involving 271 patients, 258 eligible patients received either DTIC alone; DTIC plus interferon; DTIC plus tamoxifen; or DTIC, interferon, and tamoxifen (2 × 2 factorial design).[14] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic effects were increased in the groups who received interferon.[14][Level of evidence: 1iiA] IL-2 has also been combined with cisplatin in several phase II trials [15-17] with encouraging response rates, but data supporting an improvement in survival are lacking. One prospective trial randomly assigned 102 patients to either chemotherapy (DTIC, cisplatin, and tamoxifen) alone or chemotherapy plus IL-2 and interferon-alpha-2b.[18] No statistically significant differences were found in objective response rate or OS between the treatment groups, and toxic side effects were increased in the group that received biochemotherapy.

  A meta-analysis of 20 randomized trials (involving 3,273 patients) that compared single-agent DTIC to combination chemotherapy with or without immunotherapy found that the combination of DTIC and interferon-alpha produced a tumor response rate 53% greater (95% confidence interval, 1.10–2.13) than that seen with DTIC alone;[19] however, no difference in OS was found.

  Ongoing phase II and III trials such as the EORTC-18951, UCCRC-9372, SFMH-BB-IND-5301, and E-E3695 trials, for example, are comparing complex biochemotherapy regimens (interferon, IL-2, and chemotherapy) to chemotherapy alone. Pending the results of these and future trials, no proof exists that biochemotherapy is superior to chemotherapy.

Treatment options under clinical evaluation:

1. Patients should be considered appropriate candidates for clinical trials evaluating new forms of chemotherapy and/or biologic therapy (specific monoclonal antibodies, interleukin, and interferons) or vaccines.
2. Palliative radiation therapy for bone, spinal cord, or brain metastases.
3. Complete surgical resection of all known disease (SWOG-9430).

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV 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. 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.  [PUBMED Abstract]
   
   
2. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.  [PUBMED Abstract]
   
   
3. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001.  [PUBMED Abstract]
   
   
4. Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.  [PUBMED Abstract]
   
   
8. Sparano JA, Fisher RI, Sunderland M, et al.: Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in patients with advanced melanoma. J Clin Oncol 11 (10): 1969-77, 1993.  [PUBMED Abstract]
   
   
9. Rusthoven JJ, Quirt IC, Iscoe NA, et al.: Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 14 (7): 2083-90, 1996.  [PUBMED Abstract]
   
   
10. Agarwala SS, Kirkwood JM: Interferons in melanoma. Curr Opin Oncol 8 (2): 167-74, 1996.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Rosenberg SA, Yang JC, Topalian SL, et al.: Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271 (12): 907-13, 1994 Mar 23-30.  [PUBMED Abstract]
    
    
14. Falkson CI, Ibrahim J, Kirkwood JM, et al.: Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 16 (5): 1743-51, 1998.  [PUBMED Abstract]
    
    
15. Demchak PA, Mier JW, Robert NJ, et al.: Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. J Clin Oncol 9 (10): 1821-30, 1991.  [PUBMED Abstract]
    
    
16. Flaherty LE, Robinson W, Redman BG, et al.: A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma. Cancer 71 (11): 3520-5, 1993.  [PUBMED Abstract]
    
    
17. Atkins MB, O'Boyle KR, Sosman JA, et al.: Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma. J Clin Oncol 12 (8): 1553-60, 1994.  [PUBMED Abstract]
    
    
18. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 17 (3): 968-75, 1999.  [PUBMED Abstract]
    
    
19. Huncharek M, Caubet JF, McGarry R: Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res 11 (1): 75-81, 2001.  [PUBMED Abstract]
    
    

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