Cytotoxic Chemotherapy

The management of patients with stage IV or metastatic melanoma remains a challenge, with few randomized, controlled trials showing significant survival advantage with the use of single or combination chemotherapeutic regimens. As a monotherapy, dacarbazine is generally considered one the most active agents, with response rates of 10-20% and median response duration of 4 to 6 months. In recent years, dacarbazine has become much of a fixture in current chemotherapeutic regimens, featured in combinations with various cytotoxic agents, IFNs, and interleukins. FDA approval has, in fact, been granted for dacarbazine therapy, along with interleukin (IL)-2, for the treatment of metastatic melanoma, with better success rates in metastases local to skin, subcutaneous tissues, and lymph nodes, but little to no overall survival benefit compared with other agents or no treatment. The prognosis for all melanoma metastases remains bleak, with median survival of 6 to 10 months.

The cytotoxic agents thought to have the greatest antitumor effects against metastatic melanoma include dacar-bazine, platinum analogues, nitrosoureas, and tubular toxins, with response rates ranging from 12 to 25%.29 Newer phase I and II studies have emerged in recent years examining the use of taxanes (paclitaxel, docetaxel) and temozolomide, an analogue of dacar-bazine.30-32 Temozolomide, which degrades into the active metabolite of dacarbazine, carries the advantages of being orally absorbed and crossing relatively well into central nervous system, reaching cerebrospinal fluid levels of up to 30% of those in plasma.33 This agent is therefore currently being scrutinized for activity in the prevention of CNS-related melanoma progression, a contributing factor in up to 95% of patient deaths.34-36 Temozolomide has also been included in several other phase I and II studies combined with other cytotoxic agents or recombinant cytokines (IFN, IL-2), and very recently with thalidomide (which is also orally bioavailable with antiangiogenic effects) or in conjunction with radiotherapy.37-40 Gogas et al have evaluated temozolo-mide in conjunction with docetaxel in a study of 65 patients (62 evaluable), administering both agents every 4 weeks for a maximum of six cycles. A total of 5 complete and 12 partial responses were reported, with median response duration of 9.5 months.30

Combination chemotherapy regimens for metastatic melanoma have produced response rates of up to 30 to 50% in single-institution phase II trials.29 Various combinations involving dacarbazine and nitrosoureas, dacarbazine and cisplatin, or cisplatin and vinblastine29,41 have also shown variable efficacy in combination with IFN, interleukins, and/or tamoxifen, though not significantly better than dacarbazine alone. Tamoxifen and other antiestrogens have been studied since the presence of estrogen-binding activity in melanoma was demonstrated. As a single agent, tamoxifen has shown little benefit, but may potentiate the action of cytotoxic chemotherapy agents in combination regimens. Though a significantly improved median survival rate using tamoxifen with dacarbazine has been reported,42 later studies have not confirmed the advantage of adding high-dose tamoxifen to dacarbazine-based regimens, with or without IFN.43-45

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