Until recently non-surgical therapeutic options for patients with cancer of the colon and rectum have been quite limited. The fluorinated pyrimidine 5-fluorouracil has been the basis of chemotherapeutic regimens used for metastatic or adjuvant therapy, in conjunction with pelvic radiation for patients with rectal cancer. Several new classes of chemotherapeutic agents and new routes of administration are now available in need of systematic testing. This project will execute four phase I/II trials for patients with advanced rectal cancer and five phase I/II trials for patients with metastatic or recurrent colorectal cancer. The unifying clinical hypothesis of these nine trials is that the introduction of oral analogues of fluorinated pyrimidine, camptothecin, and platinum agents to multi-modality regimens for rectal cancer and to salvage regimes for metastatic disease will improve clinical outcomes and the therapeutic ration for these patients. This project will test specific hypotheses, based on the basic science studies of investigators in Projects 2 and 3 regarding the relationship between tumor response and the status and degree of expression of genes implicated in the MMR-Pathway of tumor progression (Project 3) and the Aneuploid Pathway of tumor progression (Project 2). If these hypotheses are confirmed, the status of such genes as hMSH2, hMSH6, and Hmlh1 (MMR-pathway) and PLA2G2A (Aneuploid Pathway) in the sampled tumors of patients in these trials will be tested as eligibility criteria for subsequent clinical trials. These studies should provide a firm foundation for the integration of molecular genetic analysis as an important element of the therapeutic decision-making process for patients with cancer of the colon and rectum.
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