Isolated lung perfusion with gemcitabine for the treatment of pulmonary metastases : Experimental study in a rat model

Abstract

Isolated lung perfusion is an experimental surgical technique for the treatment of pulmonary metastases in order to improve the current 5-year survival of approximately 40 % after surgical resection of manually palpable metastases. Several drugs have been tested in animals models and five phase I studies on this subject have been performed now. Efficacy results are disappointing probably due to the invasive nature of the treatment which implies just one or two sessions per patient. Furthermore, only single-agent therapy have been studied yet. This thesis focuses on a relatively new anticancer (pro)drug gemcitabine which is an deoxycytidine analogue. Due to several self-potentiating mechanisms this drug inhibits cell proliferation efficiently and it is a very interesting drug to combine with other drugs resulting in synergistic activity. Clinical anticancer activity has been described against colon, pancreas, ovary, breast carinoma and NSCLC. Acute and chronic toxicity, pharmacokinetic parameters and efficacy are studied. In preparation of less invasive models, first-pass effect of lung tissue during isolated lung perfusion gemcitabine is investigated. Toxicity studies showed a higher maximally tolerated dose without major lung fibrosis compared with intravenous treatment resulting in significantly higher lung levels. Efficacy studies proved significant survival benefit compared to either untreated controls and intravenously treated rats. Blood flow occlusion has been studied in order to perfuse lung tissue without clamping the pulmonary veins. Significantly higher lung levels and significantly lower serum levels of gemcitabine were measured compared to systemic infusion. These findings open a way to less invasive catheterization models with balloon catheters which can be performed for several times per patient in preparation for surgery of manually palpable metastases. Combinations of gemcitabine, cisplatin and melphalan were studies in order to find synergistic activity. Major survival benefit was observed after isolated lung perfusion with gemcitabine combined with melphalan. Smaller synergistic action was shown after treatment with cisplatin and melphalan. Based on these results, a phase I trial will start studying the combination therapy with gemcitabine and melphalan. A recent phase I study with melphalan in our center showed the maximally tolerated dose of melphalan in isolated lung perfusion to be 45 mg. Gemcitabine will be added to this dose in dose-escalating schedule.