Colorectal carcinoma occurs in 150,000 new patients a year. Sixty percent of these patients will develop liver metastases. This application is one of four interactive applications submitted with the goal of improving long term survival for patients with colorectal carcinoma metastatic to the liver. Close collaboration will exist between this project for clinical trials and three others: (1) Dr. Fong's project using animals to characterize cellular proliferation (both normal hepatocytes and tumor cells) following liver resection and to quantitate with 124I-IUDR PET the growth of hepatic metastases; (2) Dr. Bertino's project for laboratory studies of drug resistance mechanisms, new drugs, and new gene therapies; and (3) Dr. Jhanwar's project to study genetic alterations in metastatic colorectal carcinoma. Based on the applicant's earlier work, three consecutive studies with hepatic arterial infusion (HAI) that produced median survivals of 22 to 27 months, she has the following future aims: (1) to complete a prospective randomized trial evaluating the role of HAI in the adjuvant setting; (2) to evaluate the efficacy and tolerability of HAI used in conjunction with systemic CPT-11 in two separate cohorts of patients, one of which will have undergone cryotherapy of their liver lesions (in conjunction with Dr. Fong's project, PET scans will be obtained before and after cryosurgery to document residual disease and response); and (3) to test new drugs such as AG337 (a thymidylate synthase inhibitor), new gene strategies, and other new therapies acting on leads from Dr. Bertino's laboratory findings. Hepatic tissue samples will be obtained from all patients to test prognostic factors for response and to explore resistance mechanisms and genetic alterations. Metastatic colorectal cancer is a significant health problem. Adjuvant therapy after a liver resection is a reasonable approach and understanding the kinetics of DNA synthesis and cell division in liver regeneration, using PET scanning and MR spectroscopy, may provide new insights into the optimal timing of adjuvant therapies. Cryosurgery and newer hepatic arterial therapies are therapeutic modalities that can be used in patients in whom liver resection is impossible.
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