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Phase I Study of Preoperative Oral Uracil and Tegafur Plus Leucovorin and Radiation Therapy in Rectal Cancer

From the Departments of Gastrointestinal Medical Oncology and Digestive Diseases, Radiation Oncology, Surgical Oncology, and Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ; and Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD.

Address reprint requests to Paulo M. Hoff, MD, Department of Gastrointestinal Medical Oncology and Digestive Diseases, Box 78, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; email phoff{at}mdanderson.org

PURPOSE: Preoperative combined-modality therapy for rectal cancermay allow for sphincter preservation, while decreasing recurrencerates and improving the overall prognosis. Oral chemotherapy withuracil and tegafur (UFT) plus leucovorin (LV) may reduce costs andcomplications associated with protracted infusions offluorouracil. Our goal was to evaluate the safety of UFT plus LVcombined with preoperative radiation and determine themaximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFTplus LV in this setting.

PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectalcancer received escalating doses of UFT (starting at 250mg/m²/d, with50-mg/m²/d increments between consecutivecohorts) and fixed doses of LV (90 mg/d). The UFT and LV combinationwas given 5 days per week concurrently with a 5-week course ofpreoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery wasperformed 4 to 6 weeks after radiation and was followed by four 35-daycycles of fixed doses of UFT and LV (28 days of therapy eachcycle).

RESULTS: Fifteen patients weretreated, and 13 received the full preoperative chemotherapy. Allplanned radiation was delivered successfully. The MTD of UFT withradiation was 350 mg/m²/d with 90 mg/d ofLV. Diarrhea was the DLT. Sphincter-preserving surgery was performedin 12 of 14 patients. One patient had progressive disease beforesurgery. Pathologic evaluation of 14 resected specimens showed acomplete response in three cases.

CONCLUSION: Preoperative chemoradiation with oral UFT plus LV isfeasible and well tolerated and should be furtherinvestigated.

The views expressed are the result of independent work and do not represent the views of the United States Food and Drug Administration or the United States government. Work described herein was performed while Richard Pazdur was an employee of The University of Texas M.D. Anderson Cancer Center.

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