High-dose cisplatin in patients with advanced malignancies

Area of Science:

• Oncology
• Pharmacology
• Nephrology

Background:

• Cisplatin (CDDP) is a cornerstone chemotherapy agent.
• Dose escalation of CDDP is limited by toxicities, particularly nephrotoxicity and ototoxicity.
• Aggressive supportive care strategies may allow for higher CDDP dosing.

Purpose of the Study:

• To evaluate the safety and tolerability of escalating doses of cisplatin (CDDP) with intensive supportive care.
• To determine dose-limiting toxicities at higher CDDP dose levels.
• To assess the efficacy of aggressive hydration and mannitol in mitigating CDDP-related toxicities.

Main Methods:

• A dose-escalation study involving 12 patients treated with cisplatin at three dose levels (180, 220, and 200 mg/m2 daily).
• Intensive intravenous hydration and mannitol administration were employed as supportive measures.
• Patients received varying durations and schedules of CDDP based on dose level.
• Toxicities, including ototoxicity, nephrotoxicity, and myelosuppression, were closely monitored.

Main Results:

• Ototoxicity was the dose-limiting toxicity at 220 mg/m2 (level II).
• Myelosuppression (leukopenia and thrombocytopenia) was dose-limiting at 200 mg/m2 daily (level III).
• Transient, asymptomatic elevations in serum creatinine were observed at lower dose levels, but no significant nephrotoxicity or need for dialysis occurred.
• Ototoxicity and nephrotoxicity were absent at the 200 mg/m2 daily dose level.
• Nausea and vomiting were frequent but manageable.

Conclusions:

• Higher doses of cisplatin can be administered with aggressive supportive care, but dose-limiting toxicities emerge.
• The optimal dosing strategy involves balancing efficacy with manageable toxicities.
• At 200 mg/m2 daily, myelosuppression becomes dose-limiting, while ototoxicity and nephrotoxicity are avoided, suggesting this as a potentially feasible dose for further investigation.