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Reduced Systemic Drug Exposure by Combining Intraarterial cis-Diamminedichloroplatinum(II) with Hemodialysis of Regional Venous Drainage

Clinical Neurosurgery Section, Surgical Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke [E. H. O., W. C. C.], Biomedical Engineering and Instrumentation Branch, Division of Research Services [R. L. D.], Kidney Disease Section, National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases [H. A. A.], Neurology Nursing Service, The Clinical Center [H. D. D.], Arthritis Nursing Service, The Clinical Center [K. M. J.], Department of Diagnostic Radiology, The Clinical Center [J. L. D.], NIH, Bethesda, Maryland 20205; and Division of Developmental Therapeutics, University of Maryland Cancer Center, Baltimore, Maryland [M. J. E.]

During cancer chemotherapy toxicity to normal tissues often limits the tolerable dose. To increase drug delivery to tumor while maintaining tolerable systemic exposure, regional treatments, such as intraarterial drug delivery, have been used. Despite intraarterial delivery, systemic toxicity often remains the dose-limiting sensitivity. If systemic drug exposure could be reduced after intraarterial infusion, the intraarterial dose could be increased, which should increase the therapeutic response. We compared the pharmacokinetic advantage after cisplatin infusion into the internal carotid artery to that obtained after infusing cisplatin into the internal carotid artery during extracorporeal removal of cisplatin from the jugular blood by hemodialysis.

Four patients with malignant gliomas received intracarotid cisplatin, 100 mg/m² over 60 min, every 4 weeks. During one treatment, while cisplatin was infused into the internal carotid artery, the jugular blood was dialyzed extracorporeally at 300 ml/min and returned to the inferior vena cava.

Seventy to 96% of the free platinum that entered the dialyzer was removed. By aspirating blood from the jugular vein at 300 ml/min, 30–79% of the ipsilateral carotid blood was collected for extracorporeal circulation. Hemodialysis of the cerebral venous drainage during intracarotid infusion reduced the systemic exposure to cisplatin by 51–61% when compared to the exposure from internal carotid artery infusion without hemodialysis. The pharmacokinetic advantage (brain/body exposure ratio) was increased from 3 to 5/1 during internal carotid artery infusion alone to as much as 15/1 during treatment combining intracarotid infusion with hemodialysis of the jugular blood.

Systemic toxicity now limits the dose of cisplatin that can be administered safely. Increased tumor exposure without increased systemic toxicity may be possible with the technique described and greater doses of cisplatin. Assuming no associated local toxicities, the results of the current study indicate that the dose of intracarotid cisplatin can be increased while maintaining tolerable systemic exposure.

¹ To whom requests for reprints should be addressed, at Clinical Neurosurgery Section, Surgical Neurology Branch, National Institute of Neurological and Communicative Disorders and Stroke, Building 10, Room 3E68, NIH, Bethesda, MD 20892.

Received 5/12/86. Revised 11/18/86. Accepted 12/11/86.