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- Title
Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs.
- Authors
Pagès, Pierre-Benoit; Derangere, Valentin; Bouchot, Olivier; Magnin, Guy; Charon-Barra, Céline; Lokiec, François; Ghiringhelli, François; Bernard, Alain
- Abstract
OBJECTIVES: Colorectal cancer is the third most commonly diagnosed cancer worldwide, with up to 25% of patients presenting with metastases at the time of diagnosis. Despite pulmonary metastasectomy many patients go on to develop pulmonary recurrence, which might be linked to the presence of lung micrometastases. In this setting, the adjuvant administration of high-dose chemotherapy by isolated lung perfusion (ILP) has shown encouraging results. However, the tolerance to and efficacy of modern gemcitabine (GEM)-based chemotherapy regimens during adjuvant ILP remain unknown. We conducted a dose-escalating preclinical study to evaluate the immediate and delayed toxicity of GEM in a pig model to define dose-limiting toxicity (DLT) and maximum tolerated concentration. METHODS: Twenty-three pigs were given increasing concentrations of GEM during ILP, and were awakened at the end of the procedure. The concentrations of GEM were 40, 80, 160, 320, 640 and 1280 μg/ml. Serum and lung samples were taken to measure GEM concentrations. Pulmonary damage was evaluated by histological examination and cleaved caspase-3 detection. Immediate and delayed (1 month) toxicity were recorded. RESULTS: All of the animals underwent successful ILP with GEM. No systemic leak was observed. The three pigs that received a concentration of GEM of 1280 μg/ml died of hypoxia after lung recirculation at the end of the procedure. Eleven pigs survived for 1 month. Major lung toxicity was observed for the concentration of GEM of 640 μg/ml, both at the end of the procedure and after 1 month. DLT was defined at the concentration of 640 μg/ml and the maximum tolerated dose (MTD) was defined at the concentration of 320 μg/ml. CONCLUSIONS: ILP with GEM is a safe and reproducible technique in this large-animal model, which includes 1 month of survival. The MTD in this pig model was a concentration of GEM of 320 μg/ml.
- Subjects
CANCER chemotherapy; DRUG dosage; RISK of metastasis; COLON cancer treatment; ANTINEOPLASTIC agents
- Publication
European Journal of Cardio-Thoracic Surgery, 2015, Vol 48, Issue 2, p228
- ISSN
1010-7940
- Publication type
Article
- DOI
10.1093/ejcts/ezu441