A randomized trial compared IV DTIC with TMZ, an oral agent; OS was 6.4 months for DTIC versus 7.7 months for TMZ (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; therefore, demonstration of similarity did not result in approval of TMZ by 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]
Two randomized, phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib  and ipilimumab ) included DTIC as the standard therapy arm. Both 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.[23,24]
Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[27,28] combinations of chemotherapy and tamoxifen,[29,30,31] and combinations of chemotherapy and immunotherapy [5,6,27,32,33,34,35]) have not demonstrated an improvement in OS.
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) reported no impact on OS.[Level of evidence:1iiA]
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.[33,34,35]
Although melanoma is a relatively radiation-resistant tumor, palliative radiation therapy may alleviate symptoms. Retrospective studies have shown that symptom relief and some shrinkage of the tumor with radiation therapy may occur in patients with the following:[37,38]
- Multiple brain metastases.
- Bone metastases.
- Spinal cord compression.