High-dose cisplatin with sodium thiosulfate protection.

Nephrotoxicity frequently limits the dose of cisplatin to less than 120 mg/m2 per injection. Sodium thiosulfate is a neutralizing agent for cisplatin that protects against renal damage. To determine whether injection of thiosulfate would permit larger doses of cisplatin to be administered, a fixed 9.9-g/m2 dose of thiosulfate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulfate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225 mg/m2 before dose-limiting toxicities were encountered. Comparison of cisplatin pharmacokinetics in patients treated with 202.5 mg/m2 plus thiosulfate to those in patients treated with 100 mg/m2 without thiosulfate indicated that there were no changes in the elimination rate constant, volume of distribution, or total body clearance of cisplatin. The total drug exposure for the plasma was approximately twofold at the higher cisplatin dose. This study demonstrates that concurrent administration of thiosulfate permits at least a twofold increase in dose and total exposure to cisplatin.