Colorectal cancer, which causes approximately 10% of cancer deaths in the United States, is the third leading cause of cancer-related mortality; death usually results from uncontrolled metastatic disease. Approximately 25% of patients with colorectal cancer will develop metastatic disease exclusively or largely confined to the liver. Untreated patients with liver metastases share a poor prognosis with an average survival of 12 months. In contrast, patients whose liver metastatic lesions are surgically treated have an average 5-year survival rate of 40%, but only 10-15% of initial colorectal liver metastases are considered resectable. The unresectable cases of liver metastatic disease can be treated with isolated hepatic perfusion (IHP), which involves a method of complete vascular isolation of the liver to allow treatment of liver tumors with toxic systemic doses of chemotherapeutic agents, biologic agents, and mild hyperthermia. We recently completed a phase I trial defining the safe dose of oxaliplatin delivered with IHP. In this grant proposal, we will apply IHP using the chemotherapeutic agent oxaliplatin, the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat advanced colorectal liver metastases. The specific aims of this project are to investigate this multimodality approach as to (1) the mechanism of the synergy between the three treatment modalities, and the efficacy of this treatment, (2) preclinical evaluation of multimodality treatment, and (3) clinical trials of multimodality treatment. The proposed studies for the first aim will employ biochemical and molecular techniques to investigate the mechanisms of cell death. For the second aim, we will employ IHP in a syngeneic rat hepatic metastasis model of colorectal carcinoma. The third aim will evaluate the therapeutic advantage of this treatment on patients. We believe that the successful outcome of this study will support the application of this multimodality approach to colorectal hepatic metastases.