Pierre-Benoît Pagès, Mauricio Pipkin, Yui Watanabe, Daisuke Nakajima, Ricardo Zamel, Shaf Keshavjee, Marcelo Cypel
Institutions : Laboratoire de chirurgie thoracique Latner, institut de recherche de l’hôpital général de Toronto, réseau universitaire de santé, Toronto, Ontario, Canada
Objectives : In-Vivo Lung Perfusion is a promising technique to deliver high dose chemotherapy to the lung without systemic leakage. Oxaliplatin in combination with 5 Flurouracil is the standard chemotherapy regimen for metastatic colorectal cancer. Our objective was to evaluate the dose limiting toxicity and the maximum tolerated dose of Oxaliplatin and 5 Fluorouracil when delivered through In-Vivo Lung Perfusion in a pig model.
Methods : Sixteen pigs underwent In-Vivo Lung Perfusion in the left lung for 4 hours. Oxaliplatin was administered at the following doses: 85 (group 1), 170 (Group 2) and 255 mg/m² (Group 3) in combination with 5 Fluorouracil at the dose of 400 mg/m² for the three groups. Group 4 was a control group without chemotherapy and group 5 received the same dose of chemotherapy as group 1 but intravenously. After lung perfusion, blood reperfusion was allowed for 4 hours. Lung physiology was assessed during the 2 periods, lung biopsies, perfusate and blood samples were taken for histological assessment, cytokines profiles and measurement of drugs concentration.
Results : After reperfusion, animals from group 3 showed significant decreased of PaO2/FIO2 as compared to control group (366.85 ±36.66 mmHg vs 201.05 ±29.79 mmHg; p=0.005), high level of platinium elements in tissue as compared to group 1 (11314 ±1943.7 ng/g vs 3411 ±820.1 ng/g, p=0.0016), and increased of IL1-beta and TNF-alpha in the lung and in the blood as compared to group 4, (respectively p=0.02 and p=0.01).
Conclusion : The dose limiting toxicity was defined for group 3 dose, and the maximum tolerated dose was defined for group 2 dose.