Modified In Vivo Lung Perfusion for Local Chemotherapy: A Preclinical Study With Doxorubicin.

ABSTRACT

BACKGROUND: In vivo lung perfusion (IVLP) is a promising adjuvant treatment of lung metastases, allowing the localized delivery of drugs to the lungs without systemic exposure. Previous experimental and clinical data resulted in variable efficacy and frequent toxicity. Our objectives were to demonstrate the feasibility and safety of a novel protective IVLP technique coupled with the delivery of sarcoma-based chemotherapy to the lung. METHODS: The left pulmonary artery and veins in pigs were cannulated and clamped. Left lung IVLP was performed for 4 hours. Doxorubicin (Dox) at a standard clinical dose of 75 mg/m(2) was used, followed by 150 and 225 mg/m(2). Dox 75 mg/m(2) combined with ifosfamide (Ifos) 6 g/m(2) was also tested. After IVLP, blood reperfusion was allowed for 4 hours. Lung physiology was assessed and biopsy samples were obtained for histologic assessment of acute lung injury (ALI), inflammatory profile, and cell death. Lung tissue levels, perfusate, and plasma levels of Dox were measured during the procedure. RESULTS: Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p = 0.36, respectively). Tissue levels of Dox were 70.3 µg/g homogeneously distributed in the lung (p = 0.12). No drug was detected systemically. Dox 150 mg/m(2) and 225 mg/m(2) showed incremental ALI. CONCLUSIONS: IVLP for 4 hours with Dox 75 mg/m(2) alone or combined with Ifos was well tolerated, without measurable ALI. High drug levels in perfusate and lung tissue were found without systemic leakage. A dose-related toxicity was observed with increases in Dox doses.