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J Thorac Cardiovasc Surg 1996;112:1542-1548
© 1996 Mosby, Inc.

GENERAL THORACIC SURGERY

ISOLATED LUNG PERFUSION WITH MELPHALAN FOR THE TREATMENT OF METASTATIC PULMONARY SARCOMA

From the Thoracic Oncology Laboratory/Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, N.Y.

Received for publication May 6, 1996 Revisions requested June 24, 1996; revisions received August 9, 1996 Accepted for publication August 13, 1996. Address for reprints: Michael Burt, MD, PhD, Memorial Sloan-Kettering Cancer Center, Department of Surgery, 1275 York Ave., New York, NY 10021.

Abstract

Objective: Isolated lung perfusion allows the delivery of high-dose chemotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat. Melphalan activity in this model was investigated.
Methods: Toxicity study: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was determined by survival after contralateral pneumonectomy. Pharmacokinetics study: Nineteen rats were treated with melphalan administered either by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg). Lung, pulmonary effluent, and serum melphalan were analyzed by high-pressure liquid chromatography. Efficacy study: On day 0, 41 rats received an intravenous injection of 5 x 10⁶ methylcholanthrene induced sarcoma cells. On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion with 2 mg of melphalan (n = 12). Isolated lung perfusion with buffered hetastarch in sodium chloride (Hespan, n = 11) was used as control. On day 14, pulmonary nodules were counted.
Results: Toxicity: Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg. Pharmacokinetics: Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 ± 34.3 µg/gm lung) than in the intravenous treatment groups (6.9 ± 1.9 µg/gm lung and 3.3 ± 0.9 µ g/gm lung, respectively) (p = 0.0002). Efficacy: Significantly fewer left lung nodules were found in animals receiving melphalan by means of isolated lung perfusion (7 ± 10) than in the groups receiving intravenous melphalan (60 ± 21) or buffered hetastarch by isolated lung perfusion (84 ± 52) (p = 0.01 and p = 0.0001, respectively).
Conclusion: Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat. (J THORAC CARDIOVASC SURG 1996;112:1542-8)

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