Isolated Lung Perfusion as an Adjuvant Treatment of Colorectal Cancer Lung Metastases: A Preclinical Study in a Pig ModelReport as inadecuate




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Background

The lung is a frequent site of colorectal cancer CRC metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion ILP. We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP.

Methods

First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early operative and delayed 1 month tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria.

Results

In vitro, gemcitabine GEM was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular 20 µg-ml or high 100 µg-ml concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent.

Conclusions

GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.



Author: Pierre-Benoit Pagès , Olivier Facy, Pierre Mordant, Sylvain Ladoire, Guy Magnin, Francois Lokiec, Francois Ghiringhelli, Alain B

Source: http://plos.srce.hr/



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