Clinical evaluation of long-term, continuous-infusion doxorubicin
Garnick, M.B.; Weiss, G.R.; Steele, G.D.; Israel, M.; Schade, D.; Sack, M.J.; Frei, E.
Cancer Treatment Reports 67(2): 133-142
1983
ISSN/ISBN: 0361-5960 PMID: 6825120 Document Number: 201044
Preclinical and clinical pharmacology evaluations of continuous-infusion doxorubicin (ADR ), utilizing a totally implantable s.c. drug delivery system (Infusaid, Metal Bellows Corp) were performed. The preclinical studies in dogs established the compatibility of ADR solutions in contact with the titanium and stainless steel components of the Infusaid pump, the long-term stability of ADR at physiologic temperatures, and the reliability of pump function and flow under the conditions of clinical use. In preclinical studies in dogs, myelosuppression was the dose-limiting toxicity at a dosage of 0.15 mg/kg per day and was a rapidly reversible phenomenon followed by rebound thrombocytosis and leukocytosis. In the phase I investigation, 14 patients with cancer resistant to standard therapies were treated. The Infusaid pump was surgically implanted in the infraclavicular fossa or epigastrium; the Silastic delivery catheter was placed in the subclavian vein in 13 patients and the external carotid artery in 1 patient. During the study, 174 pump refills with ADR were completed without refill-related extravasation of drug or infection at the injection site. Based on animal toxicity data, the starting dose was 1 mg/m2 per day with escalation by 1-mg/m2 per day increments every 3 wk. Dose-limiting toxic effects were myelosuppression, conjunctivitis, and oral mucositis. Alopecia was also observed. Technical complications were observed in 9 patients and are described. Potentially serious intravascular thromboses related to the subclavian catheter were detected in 3 patients. Endomyocardial biopsies were performed in 2 patients who had achieved a cumulative ADR dose of 682 and 652 mg/m2; cardiotoxicity scores of 1 and 2A (Stanford Scoring System), respectively, were recorded. Urine and plasma pharmacology studies using high-performance liquid chromatography were performed in all patients to monitor ADR, adriamycinol, and aglycone metabolites. Of the total anthracycline infused over a 24-h period, 5.4% was recovered in the urine (range, 0.7%-16%). Plasma levels were undetectable in all but 2 patients in whom drug levels were transiently measurable. The results support the use of the Infusaid drug delivery system as a feasible method of long-term infusion of ADR. Based on the toxicity data, a starting dosage for continuous infusion ADR at 4.0 mg/m2 per day is proposed.