Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview

Dacarbazine (DTIC) is the only single-agent approved by the Food and Drug Administration for treating metastatic melanoma. With DTIC as single agent, an approximately 20% objective response rate can be achieved with median response duration of 5 to 6 months and complete response rates of 5%. Current status of DTIC single agent and DTIC-based combination chemotherapy has been extensively reviewed in this article. Moreover, future directions including new combination chemotherapies and/or new therapeutical approaches have been considered. The addition to DTIC of agents such as cisplatin, nitrosoureas and tubular toxins has been reported to yield high response rates, up to 40%, in single-institution phase II trials. Historically, promising combination regimens like BOLD (bleomycin, vincristine, lomustine and DTIC) and CVD (cisplatin, vinblastine and DTIC) have induced responses on metastatic lesions to the liver, bone and brain, commonly unresponsive to DTIC alone, even though have failed to produce impact on patient survival. Several other studies have suggested a significant enhancement of antitumor effect associated with the addition of tamoxifen to various cytotoxic regimens. The four-drug combination CBDT (cisplatin, carmustine, DTIC and tamoxifen) or "Dartmouth regimen" has yielded high response rates, up to 55%, with continuous, maintained, complete responses, up to 82 months, in a subset of patients, that is considerably longer than observed with other combinations. Some authors recommend CBDT as reference therapy, even though recently presented results of a randomized phase III trial of CBDT versus DTIC alone, show no statistical difference in survival between the two groups. While a survival benefit from DTIC-based chemotherapy or DTIC alone has never been shown in metastatic melanoma patients and, therefore, the survival has remained unchanged over the past 30 years, some long term survivors have been reported with the "Dartmouth regimen" and/or with high dose interleukin-2 (IL-2) based regimens whose role is going to be defined in prospective randomized phase III trials. On the other hand, the better understanding of the mechanisms responsible for melanoma chemoresistance and the development of new therapeutical strategies could change the scenario in the next future.