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Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein-bound plasma platinum levels. To determine the dose-limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose-limiting toxicity was found to be leukopenia: 42% of patients receiving the 5-day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high-dose regimens for response and toxicity are indicated.

Synchronously administered cis-platinum (cis-DDP) and radiation therapy have been used to treat unresectable squamous cell carcinomas of the head and neck. The purpose of this study was to evaluate the efficacy and tolerance of preoperative adjuvant cis-DDP plus radiation therapy in operable stage III and IV head and neck cancers. Radiation therapy (4,500 rad) was delivered in 180-rad daily fractions. Cis-DDP (20 mg/M2) was given before radiotherapy on days 1-4 and 21-24. Eighteen patients began therapy; 16 completed the combined regimen. Toxicity included stomatitis and WBC below 2,500/mm3. One patient died from therapy of a cerebrovascular accident. Sixteen patients (89%) achieved a complete or partial response to therapy. Complete responses were observed in 13 of 18 primary tumors (72%), and in all three patients with cervical lymphadenopathy. Complete responses were noted for lesions of the nasopharynx, oral cavity, pharynx, hypopharynx, and larynx, for all histologic grades of squamous cell carcinoma. Twelve patients underwent curative surgery. Site-related morbidity occurred in two patients (15%) and a third patient developed postoperative pneumonia. Five of 10 resected primary tumors with preoperative complete responses were pathologically negative for tumor. Concurrent bolus cis-DDP and radiation therapy are well-tolerated and result in impressive tumor reduction. Morbidity after subsequent curative surgery is low, and histologic complete responses are frequent.(ABSTRACT TRUNCATED AT 250 WORDS)

Total and filterable platinum in plasma were monitored for seven courses (five patients, 25 mg/m2/day) using continuous 5-day infusions and one 30-minute infusion at a similar dose level (120 mg/m2). Maximum filterable (non-protein-bound) platinum levels (0.1-0.3 mg/L) for the extended infusions were ten to 40 times lower than that for the short-term infusion (4.0 mg/L). Filterable drug exposure as measured by the area under the [Pt]filterable-time curve is greater for the extended infusions (9.6 mg X hr/L) than that for the short-term infusion (4.8 mg X hr/L). Renal excretion of cisplatin (% of dose excreted/24-hour period after the beginning of the infusion) was measured for four courses of continuous 5-day infusions and for the 30-minute infusion. Urine excretion rates were lower for the continuous infusion (5%-8% of dose/24-hour period during the infusion) compared to the short-term infusion (33% of dose/24-hour period after the beginning of the 30-minute infusion).