Early data suggest that mucosal or acral melanomas with activating mutations or amplifications in c-KIT may be sensitive to a variety of c-KIT inhibitors.[34,35,36] Phase II and phase III trials are available for patients with unresectable stage III or stage IV melanoma harboring the c-KIT mutation.
The objective response rate to DTIC and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[2,37,38,39] 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 CR.[37,39] A randomized trial compared IV DTIC with temozolomide (TMZ), an oral agent that hydrolyzes to the same active moiety as DTIC; OS was 6.4 months versus 7.7 months, respectively (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between DTIC and TMZ, no benefit in survival has been demonstrated for either DTIC or TMZ and therefore, demonstration of similarity did not result in approval from the FDA.[Level of evidence: 1iiA] An extended schedule and escalated dose of TMZ was compared with DTIC in a multicenter trial randomly assigning 859 patients ( EORTC-18032 [NCT00101218]). No improvement was seen in OS or PFS for the TMZ group, and this dose and schedule resulted in more toxicity than standard dose, single-agent DTIC.[Level of evidence: 1iiA]
The design of two recent randomized, phase III trials in previously untreated patients with metastatic melanoma included DTIC as the standard therapy arm. Vemurafenib (in BRAF V600 mutant melanoma) and ipilimumab showed superior OS compared with DTIC in the two separate trials.
Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[37,38]
Palliative local therapy
Melanoma metastatic to distant, lymph node-bearing areas may be palliated by regional lymphadenectomy. Isolated metastases to the lung, gastrointestinal tract, bone, or sometimes the brain, may be palliated by resection with occasional long-term survival.[15,16,17]
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.[41,42] (Refer to the PDQ summary on Pain for more information.) 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 phase I and II clinical trial (MCC-11543 [NCT00005615]) evaluated adjuvant radiation therapy plus interferon in patients with recurrent melanoma and results are pending.
A published data meta-analysis of 18 randomized trials (15 of which had survival information) that compared chemotherapy with biochemotherapy (i.e., the same chemotherapy plus interferon alone or with IL-2) demonstrated no impact on OS.[Level of evidence:1iiA]