Chemotherapy

Dacarbazine was approved in 1970 based on objective response rates. Phase III trials indicate an objective response rate of 10% to 20%, with rare complete responses observed. An impact on OS has not been demonstrated in randomized trials.[6,21,42-44] When used as a control arm for recent registration trials of ipilimumab and vemurafenib in previously untreated patients with metastatic melanoma, dacarbazine was inferior for OS.

Temozolomide, an oral alkylating agent that hydrolyzes to the same active moiety as dacarbazine, appeared to be similar to dacarbazine (IV administration) in a randomized phase III trial with a primary end point of OS. However, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.[43]

The objective response rate to dacarbazine and the nitrosoureas, carmustine and lomustine, is approximately 10% to 20%.[42,45-47] Responses are usually short-lived, ranging from 3 to 6 months, although long-term remissions can occur in a limited number of patients who attain a complete response.[45,47]

A randomized trial compared IV dacarbazine with temozolomide, an oral agent. OS was 6.4 months for dacarbazine versus 7.7 months for temozolomide (HR, 1.18; 95% CI, 0.92–1.52). While these data suggested similarity between dacarbazine and temozolomide, no benefit in survival has been demonstrated for either dacarbazine or temozolomide. Therefore, evidence of similarity did not result in FDA approval of temozolomide.[43][Level of evidence A1]

An extended schedule and escalated dose of temozolomide was compared with dacarbazine in a multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) (EORTC-18032 [NCT00101218]) that randomly assigned 859 patients. No improvement was seen in OS or PFS for the temozolomide group, and this dose and schedule resulted in more toxicity than standard-dose, single-agent dacarbazine.[48][Level of evidence A1]

Two randomized phase III trials in previously untreated patients with metastatic melanoma (resulting in FDA approval for vemurafenib [21] and ipilimumab [6]) included dacarbazine as the standard therapy arm. Both vemurafenib (in BRAF V600–altered melanoma) and ipilimumab showed superior OS compared with dacarbazine in the two separate trials.

Other agents with modest, single-agent activity include vinca alkaloids, platinum compounds, and taxanes.[45,46]

Attempts to develop combination regimens that incorporate chemotherapy (e.g., multiagent chemotherapy,[49,50] combinations of chemotherapy and tamoxifen,[51-53] and combinations of chemotherapy and immunotherapy [9,10,39-41,49,54]) 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.[55][Level of evidence A1]