High-dose cisplatin in patients with advanced malignancies

Abstract

A study was conducted to determine if cisplatin (CDDP) can be given at higher doses than usual, utilizing aggressive supportive measures. Twelve patients were entered into three dose levels of CDDP: level I, 180 mg/m2 given as a short infusion; level II, 220 mg/m2 also given as a short infusion; level III, 200 mg/m2 divided in five daily doses, each infused over 6 hours. In all cases, CDDP was dissolved and given in 250 ml of a 5% saline solution. For levels I and II, intravenous hydration with 200 to 250 ml/hour D51/2NS with potassium and magnesium supplements, was started 24 hours before therapy and continued for 3 to 4 days after, longer if nausea persisted. Mannitol was given before (25% solution, 50 ml bolus) and after (20% solution, 500 ml over 3 hours) CDDP. At level III hydration with the same intravenous (IV) fluids was begun the day before therapy and continued without interruption at 200 to 250 ml/hour for a minimum of 24 hours after the completion of the 5 days of chemotherapy. Each daily dose of CDDP was preceded by injection of mannitol (25% solution, 50 ml bolus) and accompanied by a 6‐hour infusion of 1000 ml 20% mannitol. Three patients received five CDDP courses at level I; 4 patients, seven courses at level II; and 5 patients, seven courses at level III. Ototoxicity was dose‐limiting in three patients at level II. Transient elevation of serum creatinine was seen following two courses at level I and two courses at level II. The renal impairment was asymptomatic in all cases; dialysis was not needed. At level II, leukocyte nadir counts between 1.0 and 2.0 × 103/mm3 were seen following two courses and between 2.0 and 3.0 × 103/mm3 following three courses. Platelet nadir counts below 50 × 103/mm3 were recorded after four courses and between 50 and 100 × 103/mm3 after one course. Nausea and vomiting occurred frequently, but were tolerable. At level III, myelosuppression was dose‐limiting. Nadir leukocyte counts between 1.0 and 2.0 × 103/mm3 followed four courses and between 2.0 and 3.0 followed one course. Nadir platelet counts below 50 × 103/mm3 were seen after three courses; two patients required prophylactic platelet transfusions. Nadirs between 50 and 100 × 103 platelets/mm3 followed three further courses. Ototoxicity and nephrotoxicity did not occur at level III. Responses were seen in all three dose levels in patients with prostate carcinoma, non‐small cell lung cancer, adenocarcinoma of the esophagus, and malignant fibrous histiocytoma. It was concluded that CDDP at a dose of 200 mg/m2, divided in five daily fractions, is tolerable and can be introduced into Phase II trials.

Comparative Adverse Effect Profiles of Platinum Drugs

“…• age 60 years or older [SI] • the size of the individual dose [48] • cumulative cisplatin dose [52] • high renal cortical platinum concentrations compared with renal medullary and hepatic concentrations [52] • single dose compared with daily x 5 administration schedules [53] • pretreatment serum uric acid levels ~476 Jlmol/L (8 mg/dl) [54] • pretreatment serum albumin levels ~30 gIL [54] • peak plasma platinum concentrations >6 mglL. [55,56] Severe nephrotoxicity may occur when cisplatin is given together with aminoglycoside or cephalosporin antibiotics.…”

Protective effects of vitamins E, B and C andl-carnitine in the prevention of cisplatin-induced ototoxicity in rats

“…8 In such patients treated with cisplatin, ototoxicity is known to be the chief side effect that decreases patients' quality of life and constrains the treatment protocol. 16 Unlike nephrotoxicity, which can be controlled by hydration and diuretics, ototoxicity develops cumulatively and irreversibly. 17 Therefore, research aiming to prevent cisplatinassociated ototoxicity is ongoing.…”

Protection against Cisplatin-Induced Toxicities byN-Acetylcysteine and Sodium Thiosulfate as Assessed at the Molecular, Cellular, and in Vivo Levels

“…Ototoxicity is the primary dose-limiting factor in CDDP therapy (Blumenreich et al, 1985) that both reduces quality of life and restricts treatment protocols. CDDP-induced nephrotoxicity can be alleviated with hydration using crystalloid therapy but can still be dose limiting.…”