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

Abstract

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

Noninvasive Quantification of Solid Tumor Microstructure Using VERDICT MRI

“…This acute effect could also potentially be due to antivascular effects caused by apoptosis of endothelial cells (32,33). Gemcitabine has been found to induce a transient pulmonary constriction within 30 minutes of administration into an isolated lung perfusion model, which is further suggestive of a direct vascular effect (34). Thus, the increase in pseudo-diffusion measured by VERDICT could either be due to a tumor-specific effect or due to systemic vascular toxicity.…”

Modified in vivo lung perfusion allows for prolonged perfusion without acute lung injury

“…16 Histologic signs of hemorrhagic edema were found in both the control and melphalan-treated groups, 17 raising the question of the potential role that the perfusion circuit may have in causing injury. More recently, Pages and colleagues 18 performed IVLP for 30 minutes in 50-kg pigs, with a perfusion flow that ranged from 500 to 600 mL/min (adjusted to a PA pressure of around 25 mm Hg) and found that the control group had even greater histologic injury compared with lungs perfused with gemcitabine. This again highlights that IVLP itself without drugs was injurious.…”