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.)

Recurrent melanoma is resistant to most standard systemic therapy, and all newly diagnosed patients should be considered candidates for clinical trials. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Surgery is the most efficacious therapy for isolated recurrence in sites where it can be accomplished (including lymph node, skin, brain, lung, liver, and gastrointestinal sites).[1-3] 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%.[2,4-6] 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.[4,6] Other agents with modest single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[2,4]

Phase II studies of three-drug combinations showed higher response rates (ranging from 22%–45%) than were seen with single agents.[2,4] 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 for both study arms were once again in the 20% to 30% range.[7]

One trial directly compared DTIC alone with the three-drug regimen plus tamoxifen.[5] 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.[8] Response to IL-2 regimens is similar and is in the 10% to 20% range.[9-11] 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 these therapies. 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.[12]

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).[13] No statistically significant differences were found in response rates, time-to-treatment failure, or survival among the different groups. Toxic side effects were increased in the groups that received interferon.[13][Level of evidence: 1iiA]

IL-2 has also been combined with cisplatin in several phase II trials [14-16] 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.[17] 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.[18] No difference in OS was found, however.

Two ongoing phase III trials (E-E3695 and SWOG-S0008) 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.

For patients with recurrent melanoma presenting in the extremities as in-transit or satellite metastases, surgical resection remains standard treatment for limited-volume disease. For multiple in-transit and/or satellite lesions, hyperthermic isolated limb perfusion (ILP) with melphalan has been associated with overall tumor response rates of approximately 80% to 90%, with complete response rates ranging from 7% to 82%.[19,20] Small, single-institution studies have suggested that the addition of tumor necrosis factor-alpha (TNF-alpha) to melphalan-based ILP may further increase complete response rates (54%–90%).[20-24] A prospective, randomized multicenter study (ACSOG-Z0020) comparing hyperthermic ILP with melphalan alone to ILP with melphalan plus TNF demonstrated no statistically significant difference in 3-month complete response rates (25% melphalan vs. 26% melphalan plus TNF) or overall response (64% melphalan vs. 69% in melphalan plus TNF).[25][Level of evidence: 1iiDiv] Furthermore, ILP with melphalan plus TNF was associated with increased adverse events, including musculoskeletal complications of the perfused extremity resulting in two toxicity-related amputations.

Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that patients with multiple brain metastases, bone metastases, and spinal cord compression may achieve symptom relief and some shrinkage of the tumor with radiation therapy.[26,27] The most effective dose-fractionation schedule for palliation of melanoma metastatic to the bone or spinal cord is unclear, but high-dose-per-fraction schedules are sometimes used to overcome tumor resistance. A recently completed phase I and II clinical trial (MCC-11543) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma, and results are pending.

Treatment options:

1. Resection of isolated single or localized metastases from skin, visceral, or brain sites in selected patients is sometimes associated with prolonged survival.
2. Hyperthermic isolated limb perfusion for in-transit and/or satellite extremity recurrences.[25] Isolated limb infusion is being studied as a minimally invasive regional chemotherapy technique for extremity recurrences.[28,29]
3. Palliative radiation therapy for bone, spinal cord, or brain metastases.
4. Palliative biologic therapy and/or chemotherapy in phase I and II clinical trials.
5. Palliative treatment with interleukin-2 or interferon can occasionally result in prolonged survival.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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. Wong JH, Skinner KA, Kim KA, et al.: The role of surgery in the treatment of nonregionally recurrent melanoma. Surgery 113 (4): 389-94, 1993.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999.  [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. 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]
   
   
6. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. Agarwala SS, Kirkwood JM: Interferons in melanoma. Curr Opin Oncol 8 (2): 167-74, 1996.  [PUBMED Abstract]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    
12. 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]
    
    
13. Falkson G, Gelman RS, Pandya KJ, et al.: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16 (5): 1669-76, 1998.  [PUBMED Abstract]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. Skene AI, Bulman AS, Williams TR, et al.: Hyperthermic isolated perfusion with melphalan in the treatment of advanced malignant melanoma of the lower limb. Br J Surg 77 (7): 765-7, 1990.  [PUBMED Abstract]
    
    
20. Fraker DL, Alexander HR, Ross M, et al.: A phase III trial of isolated limb perfusion for extremity melanoma comparing melphalan alone versus melphalan plus tumor necrosis factor (TNF) plus interferon-gamma (IFN). [Abstract] Society of Surgical Oncology 55th Annual Cancer Symposium, Denver Co, 2002. A-1, S-8, 2002. 
    
    
21. Liénard D, Lejeune FJ, Ewalenko P: In transit metastases of malignant melanoma treated by high dose rTNF alpha in combination with interferon-gamma and melphalan in isolation perfusion. World J Surg 16 (2): 234-40, 1992 Mar-Apr.  [PUBMED Abstract]
    
    
22. 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]
    
    
23. Fraker DL, Alexander HR, Andrich M, et al.: Treatment of patients with melanoma of the extremity using hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor, and interferon gamma: results of a tumor necrosis factor dose-escalation study. J Clin Oncol 14 (2): 479-89, 1996.  [PUBMED Abstract]
    
    
24. Vaglini M, Belli F, Ammatuna M, et al.: Treatment of primary or relapsing limb cancer by isolation perfusion with high-dose alpha-tumor necrosis factor, gamma-interferon, and melphalan. Cancer 73 (2): 483-92, 1994.  [PUBMED Abstract]
    
    
25. Cornett WR, McCall LM, Petersen RP, et al.: Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020. J Clin Oncol 24 (25): 4196-201, 2006.  [PUBMED Abstract]
    
    
26. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15 (4): 859-64, 1988.  [PUBMED Abstract]
    
    
27. Herbert SH, Solin LJ, Rate WR, et al.: The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 67 (10): 2472-6, 1991.  [PUBMED Abstract]
    
    
28. Lindnér P, Doubrovsky A, Kam PC, et al.: Prognostic factors after isolated limb infusion with cytotoxic agents for melanoma. Ann Surg Oncol 9 (2): 127-36, 2002.  [PUBMED Abstract]
    
    
29. Brady MS, Brown K, Patel A, et al.: A phase II trial of isolated limb infusion with melphalan and dactinomycin for regional melanoma and soft tissue sarcoma of the extremity. Ann Surg Oncol 13 (8): 1123-9, 2006.  [PUBMED Abstract]
    
    

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