RANDOMIZED PLACEBO-CONTROLLED MULTICENTER EVALUATION OF DIETHYLDITHIOCARBAMATE FOR CHEMOPROTECTION AGAINST CISPLATIN-INDUCED TOXICITIES

Purpose: Diethyldithiocarbamate (DDTC) blocks cisplatin-induced toxici ties in animal models without inhibiting antitumor effects. DDTC chemo protection wets tested in a randomized, multicenter, double-blind comp arison versus placebo (PB) in patients with lung or ovarian cancer. Pr imary end points were nephrotoxicity, ototoxicity, neuropathy, and com pletion of therapy. Patients and Methods: Between April 1990 and Febru ary 1992, 221 patients were registered with small-cell lung cancer (SC LC), non-small-cell lung cancer (NSCLC), or ovarian cancer. Cisplatin (100 mg/m(2)) and cyclophosphamide (in ovarian cancer) or etoposide (i n lung cancer) were administered with either DDTC (1.6 g/m(2) over 4 h ours) or PB intravenously, every 4 weeks for a planned six cycles. Res ults: At an interim safety analysis, data were available for 195 patie nts from the combined lung and ovarian cancer populations (PB, 99 pati ents; DDTC, 96 patients). Withdrawal for chemotherapy-induced toxiciti es occurred in 9% of PB-treated patients and 23% of DDTC-treated patie nts (P=.008). The mean cisplatin delivered dose-intensity (DDI) was 23 mg/m(2)/wk on both arms. However, the mean cisplatin cumulative dose delivered (CDD) was 379 mg/m(2) on the PB arm, compared with 247 mg/m( 2) on the DDTC arm (P=.0001). At the time of interim analysis, 28% of PB-treated patients had completed all six cycles of therapy, compared with only 6% of DDTC-treated patients (P<.001). Although, clinical hea ring loss, neuropathy, emesis, and myelosuppression were equivalent in the two treatment arms, DDTC-treated patients had more nephrotoxicity as determined by changes in serum creatinine concentration. Toxicitie s related to DDTC infusion included transient hypertension, flushing, and hyperglycemia. DDTC did not compromise response rates in either ru mor type. Conclusion: This study did not demonstrate a significant che moprotective effect against cisplatin-induced toxicities with the DDTC dose schedule tested. Patients who received DDTC received lower cumul ative doses of cisplatin, but were more likely to be withdrawn from tr eatment early due to chemotherapy-related toxicities.