Primary cancers of the liver and metastatic cancer to the liver are responsible for over one million deaths a year. For either primary or metastatic tumors, liver resection represents the only potentially curative treatment. However, in the majority of patients, tumor recurs, indicating that microscopic disease undetected at the time of liver resection is responsible for such failures. This R01 is one of four submissions in an Interactive Research Project Grants (IRPG) whose goal is to improve survival of patients with liver cancer. Using resources shared with the current submission, including animal models, central isotope facility, Positron Emission Tomography (PET) facility, Magnetic Resonance (MR) facility, and patients, the other three submissions seek to I) identify novel chemotherapeutic treatments (Bertino-RO1), 2) identify novel radiotherapeutic approaches (Macapinlac RO1, Kemeny RO1), 3) determine utility of PET in monitoring tumor response to treatment (Macapinlac RO1), and 4) determine route and agents for adjuvant therapy after liver resection (Kemeny RO1). The current submission attempts to examine the biological determinants for the optimal timing of adjuvant therapy after resection of liver tumors. After resection of up to 90% of liver substance, a rapid regenerative process results in restoration of the liver to its original size. This regenerative process may stimulate growth of microscopic residual tumor within the non-resected portions. Adjuvant chemotherapy strives to eradicate microscopic residual tumor. Theoretically, earlv adjuvant therapy is desirable since antitumor effects may be optimized by the minimal volume of residual tumors, and by enhanced proliferation of residual tumor triggered by the local milieu underlying liver regeneration. However, clinicians are reluctant to institute adjuvant therapy within the first four weeks after liver resection for fear that adjuvant therapy may alter the course of liver regeneration that is the basis for recovery. Animal studies suggest that the majority of new hepatocyte DNA synthesis and cell division occur early after liver resection. However, such data are not available for man mainly due to the invasive nature of prior assessments of DNA synthesis and cellular proliferation. We propose studies using 124I-IUdR administration and whole body PET scanning as a tool for assessing DNA synthesis in vivo in man. We propose to use MR?pectroscopy as a non-invasive assessment of changes in energy metabolism during liver regeneration in man that may coincide with mitosis. We also intend to determine in animal models if relative hepatocyte and tumor proliferation rates are difThrentially stimulated by hepatectomy, and whether measurement of these by PET or MR correlate to toxicities and antitumor effects of early adjuvant therapies. Thus, the specific goals of this application are to determine the comparative cellular proliferative rates of hepatocyte versus residual tumor afier liver resection, to determine if these changes in proliferative rates can be determined non-invasively in vivo, with the hope that an adjuvant strategy exploiting the differential changes in tumor and hepatocyte proliferation may provide the basis for future therapy in man.
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