Dose intensification of platinum compounds with glutathione protection as induction chemotherapy for advanced ovarian carcinoma

Based on previous clinical experience indicating the tolerability and effic acy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach includ ing a combination of high-dose cisplatin plus carboplatin as induction chem otherapy of advanced ovarian carcinoma and intervention surgery. Fifty cons ecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) car boplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemothera py, the patients underwent surgical reevaluation with debulking, when possi ble, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m( 2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assess ed for response and toxicity. The toxicity was moderate with lack of signif icant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicit y was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy ). The efficacy of the present protocol was also documented by overall surv ival (median survival >48 months), which appeared to be better than expecte d with the current therapy in this group with advanced/bulky disease. The i mpressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The r esults of this study should be placed in context with current platinum-base d therapy including paclitaxel.