High-Dose Cisplatin with Glutathione Protection in Gynecologic Malignancies

Cisplatin is one of the most effective antitumor agents currently available for the treatment of malignant disease. It has a broad range of antitumor activity, but it is most recognized for its efficacy in the treatment of testicular and ovarian cancer1,2. Many other genito-urinary and gynecologic tumors have found responsive to the drug3. Cisplatin with or without an alkylating agent is currently regarded as a standard treatment for epithelial ovarian cancer. A dose-intensity analysis of various chemotherapy regimens used in the treatment of ovarian cancer supports a dose-response relationship for cisplatin, since it was found to be the only drug whose dose intensity correlated significantly with response rates4. Clinical and experimental observations of a dose-response effect for cisplatin have stimulated the search for new approaches for dose intensification and escalation. However, the use of high-dose cisplatin is associated with major toxicities which limit treatment duration1,5. The use of intensive hydration protocols and hypertonic saline has allowed a dose escalation of cisplatin beyond 120 mg/m2 with acceptable nephrotoxicity1. However, peripheral neuropathy and ototoxicity have emerged as dose-limiting complications of high-dose therapy that affect more than 50% of treated patients1,6. The severity of these side effects remains a major obstacle to wide-spread use of high doses. Thus, clinical experience with the use of cisplatin doses of more than 100 mg/m2 is still limited in the treatment of advanced epithelial ovarian cancer.