Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors

The human central nervous system pharmacology of cis-diamminedichloroplatinum (CDDP) was studied, and trials were initiated of CDDP as a radiosensitizer in the treatment of malignant primary brain tumors. Samples were assayed for platinum using X-ray-dispersive fluorescence spectrometry. Platinum was barely detectable in cerebrospinal fluid from two patients and was not detectable (< 0.10 μg/ml) in cerebrospinal fluid from three patients receiving CDDP, 100 to 120 mg/sq m. Six patients were given CDDP, 20 to 25 mg/sq m i.v. during or before resection of intracerebral tumor. Potentially cytotoxic and radiosensitizing tumor platinum concentrations were attained. Autopsy tissue samples were obtained from two patients who had received CDDP, 20 to 120 mg/sq m i.v., and two who had received intracarotid (i.c.) CDDP, 60 to 100 mg/sq m, therapeutically 0 hr to 102 days antemortem, and surgical tissue specimens were obtained from one patient who had received CDDP, 120 mg/sq m i.v. 180 days previously and from one who had received i.c. CDDP, 75 mg/sq m, 2 days previously. Platinum was quantifiable at concentrations from 0.33 to 2.97 μg/g. Platinum concentrations in edematous brain tissue adjacent to tumor were generally lower than platinum concentrations in intracerebral tumor. Brain platinum concentration decreased with increasing distance from intracerebral tumor, and platinum varied from undetectable to 0.63 μg/g (median, 0.33 μg/g) in autopsy brain tissue from five patients who had received CDDP, 50 to 120 mg/sq m i.v., 2 to 165 days antemortem. The extent to which central nervous system pharmacology of an antineoplastic agent affects its activity against intracerebral neoplasms remains unclear. Fifteen patients with malignant brain tumors received CDDP, 40 mg/sq m/week i.v., during cranial irradiation, and some received 105 to 120 mg/sq m every 3 weeks after cranial irradiation. Close follow-up was necessary, and some weekly treatments needed to be omitted in individual patients. During the weekly CDDP, gastrointestinal, scalp, and renal toxicities and hypomagnesemia were noted but were tolerable. Only one patient developed myelosuppression. Ototoxicity may have been enhanced. Postirradiation CDDP, 105 to 120 mg/sq m every 3 weeks, caused substantially more gastrointestinal toxicity and may have caused central nervous system toxicity in four patients, although other factors probably contributed. It is too early to evaluate effect on survival.