PREOPERATIVE TREATMENT OF PATIENTS WITH LOCALLY ADVANCED UNRESECTABLERECTAL ADENOCARCINOMA UTILIZING CONTINUOUS CHRONOBIOLOGICALLY SHAPED 5-FLUOROURACIL INFUSION AND RADIATION-THERAPY

BACKGROUND. This study was designed to determine the efficacy and maxi mally tolerated dose of 5-fluorouracil when administered by chronobiol ogically shaped prolonged infusion in combination with radiation thera py in patients with both locally advanced and unresectable rectal carc inoma. METHODS. Eighteen sequential patients determined clinically to have either locally advanced or unresectable rectal carcinoma were tre ated by 4500 centigray (cGy) or 5580 cGy, respectively, combined with continuous chronobiologically modulated 5-FU infusion starting at 250 mg/m(2)/day, with the dose escalating in each cohort of 5 patients if no Grade 3 or higher toxicity was observed in each cohort. Imaging stu dies were obtained prior to and after completion of treatment. RESULTS . All 18 patients completed the full course of radiation therapy and a ll were subsequently resectable for potential cure. The maximum tolera ted dose of 5-FU was 275/m(2)/day for 5 weeks. Seven patients had a sp hincter-sparing procedure, and ten patients underwent an abdominoperin eal resection, all with clear margins. Five complete pathologic respon ses (28%) were obtained. The average follow-up time was 12 months with a range of 6 to 37 months. With the exception of two patients, one of whom declined surgery and one of whom died of widespread disease, all of the patients have remained free of disease. CONCLUSIONS. The combi nation of radiation therapy and continuous chronobiologically shaped 5 -FU infusion at a dose of up to 275/m(2)/day is well tolerated and app ears to be more effective in downsizing and possibly downstaging local ly advanced and unresectable rectal carcinoma than radiation therapy a lone. Longer follow-up will determine whether ultimate disease free an d overall survival are improved by this method. (C) 1996 American Canc er Society.