Temozolomide; A novel regional perfusion agent for the treatment of advanced extremity melanoma

5129 Isolated limb perfusion (ILP) with melphalan is a well established treatment for regionally advanced melanoma confined to an extremity. While complete response rates exceed 60%, many still respond poorly and about one-third of the complete responders develop a subsequent local recurrence at a median time of 13 months. Temozolomide is a novel methylating agent that has shown promising antitumor activity against metastatic melanoma when administered orally in recent clinical trials, with relatively little toxicity. We set out to determine if temozolomide could be utilized intra-arterially as a regional chemotherapeutic agent for patients with advanced extremity melanoma. ILP was performed using a nude rat xenograft model of subcutaneously injected human DM6 melanoma cells. Temozolomide was solubilized in a 10% solution of dimethyl sulfoxide and 0.9% saline. At total temozolomide doses between 750 mg/kg and 1000 mg/kg, all treated rats showed marked tumor regression by post-operative day eight, with 38% decrease in mean tumor volume and minimal limb toxicity. Temozolomide doses at or exceeding 3000 mg/kg produced frequent toxicity-related limb necrosis. By comparison, rats treated systemically with temozolomide (300 mg/kg) showed no tumor regression. The efficacy of temozolomide ILP was also significantly higher than that of melphalan ILP at equitoxic doses, as only one of five rats treated with melphalan (27 mg/kg) demonstrated tumor regression. By post-operative day 14, the tumor volume of temozolomide treated animals was always less than or equal to the original tumor volume. In contrast, the tumors of rats treated with either melphalan or saline had 315% greater volume than baseline by day 14, with no significant difference between either group. These data suggest that ILP with temozolomide can be an effective treatment for regionally advanced extremity melanoma. In addition, temozolomide appears to be markedly superior to melphalan, the agent currently utilized for clinical ILP.