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

Objective: Isolated lung perfusion allows the delivery of high-dose ch emotherapy to the perfused lung and is an efficacious modality in the treatment of pulmonary metastases in the rat, Melphalan activity in th is model was investigated, Methods: TOXICITY STUDY: Maximum tolerated dose of melphalan delivered by means of isolated lung perfusion was de termined by survival after contralateral pneumonectomy, PHARMACOKINETI CS STUDY: Nineteen rats were treated with melphalan administered eithe r by isolated lung perfusion (2 mg) or intravenously (2 mg or 1 mg), L ung, pulmonary effluent, and serum melphalan were analyzed by high-pre ssure liquid chromatography. EFFICACY STUDY: On day 0, 41 rats receive d an intravenous injection of 5 x 10(6) methylcholanthrene induced sar coma cells, On day 7, rats either received intravenous melphalan (2 mg [n = 10]; 1 mg [n = 8]) or underwent left isolated lung perfusion wit h 2 mg of melphalan (n = 12), Isolated lung perfusion with buffered he tastarch in sodium chloride (Hespan, n = 11) was used as control, On d ay 14, pulmonary nodules were counted. Results: TOXICITY: Maximum tole rated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg, PHARMACOKINETICS: Left lung melphalan level was significant ly higher in the isolated lung perfusion group (62.2 +/- 34.3 mu g/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 mu g/gm lu ng and 3.3 +/- 0.9 mu 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 hetasta rch by isolated lung perfusion (84 +/- 52) (p = 0.01 and p = 0.0001, r espectively). Conclusion: Isolated lung perfusion with melphalan is sa fe and effective in the treatment of pulmonary sarcoma metastases in t he rat.