A Pilot Clinical and Pharmacokinetic Study of Intracarotid Cisplatin and Bleomycin

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Abstract
Fifteen patients with progressive primary malignant or metastatic brain tumors were treated on a clinical and pharmacokinetic study with intracarotid cisplatin and bleomycin. Toxicity was tolerable and consisted mainly of nausea and vomiting. Neurologic toxicity included focal seizures (1), leukoencephalopathy (1), and motor weakness (1). Five patients had improvement in CT scans and four patients had stabilization of disease. Recommended dosage for future clinical trials are cisplatin 60 mg/m2 and bleomycin 100 units. Pharmacokinetics of intracarotid cisplatin revealed the jugular vein concentration was twice the peripheral vein level at the end of infusion. Cisplatin is a drug which has demonstrated in vitro activity against malignant gliomas (1). Clinical trials with intravenous administration of cisplatin has shown definite, although limited antitumor activity against primary brain tumors (2,3,4) and metastatic brain tumors (5,6). To enhance its antitumor effect, cisplatin has been administered by the intracarotid route (7,8,9). The results appear encouraging, but neurological and ophthalmological toxicity may occur (8). In our initial study with intracarotid cisplatin, 35 patients with malignant brain tumors (23 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation ± chemotherapy were treated. Of 20 evaluable patients with primary tumors, 6 responded to therapy and 5 had stable disease. Five of 10 evaluable patients with brain metastases responded and 2 had stable disease. For responding primary brain tumor patients the median time to progression was 33 weeks. The recommended dose for intracarotid cisplatin was 60-75 mg/m2 administered every 3-4 weeks (7,8). Higher cisplatin doses produced more central neurological toxicity. There is limited data on the central nervous system pharmacology of cisplatin. Certain studies have found only low platinum concentrations in normal brain and cerebrospinal fluid (10, 11) but higher concentrations are found in brain tumors after intravenous or intracarotid administration (10). As part of our studies with intracarotid cisplatin alone or when combined with other drugs, we have investigated the pharmacology of intracarotid cisplatin. Bleomycin was used with cisplatin for several reasons. Intracerebral bleomycin therapy has improved survival in a rat brain tumor model (9) gliosarcoma (12). In addition, bleomycin has shown antitumor activity in tissue cultures of human glioma cell lines (13). In this in vitro study, growth inhibition occurred in 7 of 15 brain tumors at bleomycin concentration of 10 mU/ml. Bleomycin has been administered postoperatively and intravenously in patients with brain tumors with some response (14). We report here our results of a pilot clinical and pharmacokinetic trial of intracarotid cisplatin and bleomycin.