Efficacy and safety of high-dose cisplatin and cyclophosphamide with glutathione protection in the treatment of bulky advanced epithelial ovarian cancer

Abstract

Recent efforts to improve the response rates in advanced ovarian cancer with the use of high-dose cisplatin have been limited by unacceptable toxicity. Based on experimental and clinical studies indicating that reduced glutathione (GSH) is a protective agent against cisplatin-induced toxicity, a new high-dose regimen including GSH as a chemoprotector was designed in an attempt to improve the efficacy and therapeutic index of cisplatin. A total of 40 consecutive patients with stage III (bulky) and IV ovarian carcinoma were treated with cisplatin (40 mg/m2 daily for 4 consecutive days) and cyclophosphamide (600 mg/m2 i.v. on day 4). The treatment was repeated every 3-4 weeks for five courses unless progression or severe toxicity occurred. Before each cisplatin administration, patients received GSH (1,500 mg/m2) i.v. over 15 min, with a standard i.v. hydration (2,000 ml fluid) without diuretics. Debulking surgery was initially attempted in 18 patients and, after 2-3 courses, in 16 patients; it could not be carried out in 6 patients. Three patients were not evaluable for response because they prematurely discontinued their treatment. In all, 23 patients (62%) achieved complete clinical remission (negative second-look laparotomy in 16), with an overall (complete + partial) response rate of 86%; 2 patients achieved disease-free status following second surgery. Nausea/vomiting was the most severe acute toxic effect; myelosuppression was acceptable. Renal impairment was effectively prevented by GSH. Neurotoxicity that was not associated with motor dysfunction was the most significant cumulative toxicity in patients (24/32) receiving 4-5 courses. The results of this study indicate that the use of GSH is a safe new method for high-dose cisplatin administration. This regimen is well-tolerated and very effective in ovarian cancer patients with bulky disease and warrants further evaluation.

Renal Toxicity Associated with Weekly Cisplatin and Gemcitabine Combination Therapy for Treatment of Advanced Biliary Tract Cancer

“…Generally, cisplatin is concentrated at higher levels in the dorsal root ganglion cells and causes apoptosis of sensory neurons [42,43]. Various attempts have been reported to reduce the neuropathy associated with cisplatin, and some agents have been reported to be promising for neuroprotection [44,45]. Among these medications, the incidence of clinical neuropathy was reported at 44% after a cumulative cisplatin dose of 400 mg/m 2 and at 88% after 600 mg/m 2 [16].…”

Dose‐Dependent Protection by Lipoic Acid against Cisplatin‐Induced Nephrotoxicity in Rats: Antioxidant Defense System

“…Other toxic effects of cisplatin also markedly increased with higher doses of cisplatin (Bodenner et al 1986;Hamers et al 1993;Rybak et al 1995). Nephroprotection by various chemotherapeutic agents is being evaluated against higher doses of cisplatin in clinical practice (Cozzaglio et al 1990;Di Re et al 1990;Fontanelli et al 1992). Therefore, this study evaluates the nephroprotective effects of a biological antioxidant lipoic acid against the toxic renal effects that occur with higher doses of cisplatin in rats.…”

In Vitro Ototoxicity of aminoglycosides and platin derivatives. A semi-automatic assay for sensory hair cell damage in explanted rat organ of corti

“…GSH is reported to diminish cisplatin-induced neurotoxicity, and patients treated with cisplatin in combination with GSH (doses ranging from 1.5 to 3 g/m 2 ) exhibit a less severe neuropathic syndrome with no negative interference of its anticancer activity in these patients (Cavaletti et al, 1996;Colombo et al, 1995;Di Re et al, 1993). Experimental studies performed on rats have shown that GSH provides protection against the cisplatininduced slowing of sensory nerve conduction velocity without interfering with the antitumour ecacy of this drug (Hamers et al, 1993).…”