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Project

High-dose locoregional chemotherapy in the lung: towards a less invasive percutaneous technique.

Surgical resection of lung metastases is a widely accepted procedure but due to local and distant recurrences reported 5-year survival rates are only 30 to 40%. Reoperations are feasible but often patients become inoperable due to insufficient pulmonary reserve and for this reason new treatment modalities are being investigated. The maximal dose of intravenous chemotherapy is limited due to systemic side-effects, mainly haematological. As is the case with isolated limb and liver perfusion, isolated lung perfusion has the advantage of selectively delivering an agent into the lung while diverting the venous effluent. Phase I and phase II studies have shown that isolated lung perfusion is feasible and may decrease local recurrence rate. However, it remains an invasive technique and less invasive alternative methods are being investigated. Pulmonary artery infusion is such a technique by injecting a cytostatic drug directly in the pulmonary artery without control of the venous effluent. This offers the advantage of high drug exposure in lung parenchyma with some controlled systemic exposure. In this way, isolated lung perfusion is combined with classical intravenous chemotherapy, which may offer an additional advantage to control distant systemic spread. Pulmonary artery infusion is mostly performed with a balloon catheter inflated in the pulmonary artery, so-called blood flow occlusion. The pulmonary circulation is temporarily arrested to allow a better uptake of the injected drug in the lung parenchyma. This represents a minimally invasive, endovascular technique, which can be repeated several times and which can also be applied in patients who cannot tolerate one-lung ventilation or initially, have inoperable lung metastases or even primary lung cancer. In the present research proposal, a minimally invasive and percutaneous method and device of use will be developed and tested in vitro to occlude and infuse/perfuse a lung locoregionally in large animals and patients. Devices and method are tested in vitro. Results are discussed in a design review whereby the parties concerned will jointly decide whether or not the objectives have been met which will conclude the investigation under this application. Regarding subsequent investigations, pulmonary infusion will be evaluated in a pig model of blood flow occlusion with injection of gemcitabine as this drug was found to be most promising in the experimental rodent setting. Pharmacokinetics will be determined specifically looking at lung and systemic concentrations. Afterwards, a phase I trial will be performed in patients with inoperable lung metastases or primary lung cancer. When the dose-limiting toxicity and maximum tolerated dose have been determined, a phase II trial may be designed similar to what as has been performed for isolated lung perfusion. By combining both worlds of high locoregional and distant exposure of chemotherapeutic drugs, we hope to improve the overall and disease-free survival rate of our patients with lung metastases or primary lung cancer.
Date:1 Oct 2018 →  30 Sep 2019
Keywords:LUNG PERFUSION, ENDOVASCULAR TECHNIQUE, CHEMOTHERAPY, LUNG METASTASEN
Disciplines:Animal biology, Morphological sciences, Oncology, Orthopaedics, Surgery, Nursing, Veterinary medicine, Other veterinary sciences, Other agricultural, veterinary and food sciences