Journal Article

Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs

Pierre-Benoit Pagès, Valentin Derangere, Olivier Bouchot, Guy Magnin, Céline Charon-Barra, François Lokiec, François Ghiringhelli and Alain Bernard

in European Journal of Cardio-Thoracic Surgery

Published on behalf of European Association for Cardio-Thoracic Surgery

Volume 48, issue 2, pages 228-235
Published in print August 2015 | ISSN: 1010-7940
Published online November 2014 | e-ISSN: 1873-734X | DOI: https://dx.doi.org/10.1093/ejcts/ezu441
Acute and delayed toxicity of gemcitabine administered during isolated lung perfusion: a preclinical dose-escalation study in pigs

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  • Cardiothoracic Surgery
  • Respiratory Medicine and Pulmonology
  • Anatomy
  • Cardiovascular Medicine

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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.

Keywords: Isolated lung perfusion; Gemcitabine; Lung metastases; Colorectal cancer

Journal Article.  4850 words.  Illustrated.

Subjects: Cardiothoracic Surgery ; Respiratory Medicine and Pulmonology ; Anatomy ; Cardiovascular Medicine

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