Isolated lung perfusion with melphalan for the treatment of metastatic pulmonary sarcoma

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 10(6) 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 mu g/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 mu g/gm lung 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 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.