High‐dose cisplatin in patients with advanced malignancies

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 D₅ 1/2 NS 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 mgl/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 x 10³/mm³ were seen following two courses and between 2.0 and 3.0 x 10³/mm³ following three courses. Platelet nadir counts below 50 x 10³/mm³ were recorded after four courses and between 50 and 100 x 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 x 10³/mm³ followed four courses and between 2.0 and 3.0 followed one course. Nadir platelet counts below 50 x 10³/mm³ were seen after three courses; two patients required prophylactic platelet transfusions. Nadirs between 50 and 100 x 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.