Contrasting effects of extended low dose versus standard dose shorter course UFT chemotherapy on microscopic versus macroscopic established tumors: Implications for optimal postoperative adjuvant chemotherapy

Given such differences as relative tumor burden, the optimal dose and schedule for postoperative adjuvant chemotherapy of microscopic disease might be expected to differ significantly from therapy of advanced higher volume disease. We investigated this hypothesis by determining the optimal dose and schedule of the 5-FU pro-drug, UFT, for treatment of early versus later stage disease models of the Lewis lung carcinoma (LLC). Postoperative adjuvant therapy of early stage disease was modeled by intravenous injection of LLC cells and initiating therapy one day later, thus simulating the presence of micrometastases at the time of surgery. As a model of ‘late’ stage disease, a LLC fragment was implanted subcutaneously and UFT therapy was initiated when the tumor was firmly established and had grown to >5 mm in size. A number of UFT dosing protocols were evaluated such as short-term (daily, for 7 days) maximum tolerated dosing (MTD), e.g. 31 mg/kg/day, or a much longer-term (e.g., daily, for up to 60 days) repetitive dosing using doses such as 24 mg/kg/day (the MTD) or lower. The long-term consecutive administration of UFT at relatively low minimally toxic dose levels is a superior dosing regimen in the postoperative adjuvant chemotherapy model; in contrast, the short-term higher dose protocols were superior for treatment of more advanced, established cancer. In addition, the efficacy of UFT in an adjuvant setting is more effective when drug administration is continued for longer periods and when treatment is initiated at progressively earlier time points, after disease establishment.