Isolated lung perfusion for the treatment of pulmonary metastases an experimental study in the rat

The lung is a common site of metastatic involvement and 5-year survival rates after complete surgical resection of lung metastases vary between 16 and 42%. As isolated limb or liver perfusion, isolated lung perfusion offers a new therapeutic option to deliver high-dose chemotherapy with minimal systemic side-effects (chapter 1). In our laboratory isolated lung perfusion was studied in a model of pulmonary metastatic adenocarcinoma in the rat and compared with intravenous chemotherapy. To improve results, techniques for intubation and anesthesia were modified and a new approach of catheterization of the pulmonary artery was developed (chapter 2). In a first series of experiments isolated lung perfusion was studied in a model of bilateral pulmonary metastases. Left isolated lung perfusion with melphalan and tumor necrosis factor was evaluated with the contralateral side serving as control (chapter 3). Toxicity, pharmacokinetic and toxicity studies were performed. Left lung melphalan levels were significantly higher after isolated lung perfusion compared to intravenous injection and significantly fewer left lung nodules were found. Tumor necrosis factor didn't show any significant effect in our model. In a second series of experiments long-term survival was evaluated after isolated lung perfusion with melphalan in a model of unilateral pulmonary metastases (chapter 4). All animals treated with melphalan intravenously died of massive tumor replacement of the left lung with a median survival time of 38 days. Rats undergoing isolated lung perfusion with melphalan had a significantly longer median survival time of 84 days (p < 0.0004). The left lung of three of the rats perfused with melphalan was even tumor-free at 3 months. In conclusion, isolated lung perfusion is effective in a rat model of pulmonary metastatic adenocarcinoma. Clinical studies are necessary to determine its effect on pulmonary metastases in man, especially in case of unresectable disease or possibly as adjuvant therapy after surgical resection.