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



RESULTS
Maximum tolerated dose of melphalan delivered buy means of isolated lung perfusion was 2 mg.


RESULTS
Left lung melphalan level was significantly higher in the isolated lung perfusion group (62.2 +/- 34.3 microg/gm lung) than in the intravenous treatment groups (6.9 +/- 1.9 microg/gm lung and 3.3 +/- 0.9 microg/gm lung, respectively) (p = 0.0002).


RESULTS
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).


CONCLUSIONS
Isolated lung perfusion with melphalan is safe and effective in the treatment of pulmonary sarcoma metastases in the rat.
Nawata
S
S
Thoracic Oncology Laboratory/Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, N.Y. 10021, USA.
Abecasis
N
N
Ross
H M
HM
Abolhoda
A
A
Cheng
H
H
Sachar
K S
KS
Burt
M E
ME
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D008748:Methylcholanthrene; D010477:Perfusion; D051381:Rats; D011916:Rats, Inbred F344; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000556:secondary
D018906:Antineoplastic Agents, Alkylating; D008748:Methylcholanthrene; D008558:Melphalan