Isolated lung perfusion with melphalan: pharmacokinetics and toxicity in a pig model.
BACKGROUND
In patients with unresectable lung cancer or pulmonary metastases, isolated lung perfusion (ILP) has been described as an alternative method to deliver high-dose chemotherapy to the lungs, thereby minimizing systemic toxicity. Pharmacokinetics of ILP have not been extensively investigated. Therefore, we studied the feasibility of ILP with melphalan in a pig model with emphasis on pharmacokinetics and acute lung damage.


METHODS
Five pigs underwent ILP with melphalan. Blood and tissue samples were obtained for determination of melphalan levels. Tissue biopsies were taken for microscopic evaluation of lung damage.


RESULTS
During ILP, no hemodynamic effects of importance were noted. No systemic leakage of melphalan was observed in any of the animals. Compared with normal lung tissue, microscopic examination of lung tissue after perfusion without melphalan showed pulmonary edema. Directly after melphalan perfusion additional hemorrhagic areas were seen; however, electron microscopy displayed no irreversible endothelial damage.


CONCLUSIONS
This study on pigs proved to be a well reproducible model for ILP with melphalan. Pharmacokinetics show a safety profile with no systemic toxicity, which could justify further patient studies, necessary to determine its effect on pulmonary metastases in humans, especially in case of adjuvant therapy after surgical resection or in unresectable disease.
Department of Surgical Oncology and Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands.
A
A
van der Elst
S J
SJ
Oosterling
M A
MA
Paul
A M A
AM
Vonk
R W
RW
Sparidans
J R M
JR
van der Sijp
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D010478:Chemotherapy, Cancer, Regional Perfusion; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D013552:Swine
D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan