High Dose Cisplatin: Modulation of Toxicity

Abstract

Dose escalation of cisplatin is theoretically attractive due to the steep dose-response curve for antitumor activity. However, the dose-response relationship for cisplatin toxicity appears to be equally steep. A high dose regimen of 40 mg/m² for 5 days in 3% saline (200 mg/m²/28 day cycle) results in dose limiting peripheral neuropathy and myelosuppression, and is associated with accumulation of ultrafiltrate platinum species. A pharmacokinetically designed regimen delivering the same projected dose intensity on a divided dose schedule (100 mg/m² on day 1 and 8) avoids ultrafiltrate accumulation. In a phase II study in non-small cell lung cancer (NSCLC), this dose schedule resulted in a reduced incidence and severity of neuropathy and absence of severe myelosuppression. At a mean cumulative cisplatin dose of 525 mg/m²/patient, mean delivered dose intensity was 94% of projected (47.2 mg/m²/week). An encouraging response rate and median survival time in NSCLC were also observed, suggesting a positive clinical impact of enhanced dose intensity. A subsequent SWOG study comparing the 5 day high dose cisplatin regimen and the day 1 and 8 regimen in metastatic melanoma confirmed reduced toxicity of the latter dose schedule. Nephrotoxicity and ototoxicity were similar in both groups, but severe myelosuppression and neurotoxicity were confined to patients on the 5 day schedule.

Diethyldithiocarbamate (DDTC) is a chelating agent with preclinical data supporting reduction in cisplatin toxicity without loss of antitumor activity. In a phase I study, we evaluated the pharmacokinetics, schedule dependence, and toxicity pattern of high dose cisplatin in combination with DDTC rescue. Twenty-two patients with advanced cancer received cisplatin, 100 mg/m² in a 3% saline over 1–3 hours on days 1 and 8, followed by DDTC, 4 g/m² over 1–3 hours, beginning 0–45 minutes after cisplatin. Pharmacokinetic studies showed plasma DDTC levels predicted to achieve optimal chemoprotection (>400uM) in 62% of infusions and no change in total or ultrafiltrate platinum levels. Cisplatin toxicity was compared to a retrospective control group receiving the identical cisplatin regimen without DDTC rescue. Ototoxicity and neurotoxicity were less common in the DDTC group compared to controls, and protection correlated with timing of DDTC rescue (cisplatin-DDTC interval of < 4 hours). DDTC is currently undergoing prospective evaluation as a cisplatin chemoprotector in two phase III double-blind, placebo controlled multicenter clinical trials.