The goal of this interactive R01 (I-R01) is to improve the long-term survival of patients with colorectal carcinoma metastatic to the liver. This will be accomplished by close collaboration between the clinical trials (Kemeny - I-R01), studies of drug resistance and genetics of colorectal cancer (Bertino - I-R01) and the diagnostic uses of monoclonal antibodies (Cohen - I-R01). Based on our previous work with hepatic arterial infusion (HAI) of FUDR and leucovorin which produced a median survival of greater than 29 months and a 4-year survival of 24%, we have the following aims: 1) to increase response rate and number of complete responses with HAI; 2) to test an adjuvant protocol after liver resection using HAI and systemic therapy; 3) to develop a salvage protocol for patients whose tumor does not respond to first line regional therapy; and 4) to determine if NMR spectroscopy will be able to predict response and/or toxicity.
Under aim 1) we have initiated a new Phase II trial of FUDR, leucovorin and dexamethasone to increase response and decrease toxicity. Mitomycin C, which has been shown to have an additive effect with FUDR infusion (Bertino - I-R01), will be added to our best protocol.
Under aim 2) we have initiated a new adjuvant study after liver resection to see if the addition of HAI to systemic therapy will improve the results over systemic therapy alone. Monoclonal antibodies for detection of occult disease will be used prior to surgery in an attempt to improve patient selection (Cohen - I-R01). both occult bone marrow metastases and occult intra-abdominal disease will be assessed and related to clinical outcome. Tumor tissue from these patients will be analyzed for drug resistance and cytogenetics and these will be correlated with patient survival and recurrence (Bertino - I-R01).
Under aim 3) two agents that show promise for HAI use: teroxirone, an alkylating agent, and fluorouridine (FUR), an old drug (toxic when used systemically, but may be selective when given by HAI) will be tested. FUR has a high hepatic extraction; we will test teroxirone extraction. both drugs are effective against colon cancer cell lines (Bertino - I-R01).
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