Preoperative treatment of patients with locally advanced unresectable rectal adenocarcinoma utilizing continuous chronobiologically shaped 5-fluorouracil infusion and radiation therapy.

BACKGROUND: This study was designed to determine the efficacy and maximally tolerated dose of 5-fluorouracil when administered by chronobiologically shaped prolonged infusion in combination with radiation therapy in patients with both locally advanced and unresectable rectal carcinoma. METHODS: Eighteen sequential patients determined clinically to have either locally advanced or unresectable rectal carcinoma were treated by 4500 centigray (cGy) or 5580 cGy, respectively, combined with continuous chronobiologically modulated 5-FU infusion starting at 250 mg/m2/day, with the dose escalating in each cohort of 5 patients if no Grade 3 or higher toxicity was observed in each cohort. Imaging studies were obtained prior to and after completion of treatment. RESULTS: All 18 patients completed the full course of radiation therapy and all were subsequently resectable for potential cure. The maximum tolerated dose of 5-FU was 275/m2/day for 5 weeks. Seven patients had a sphincter-sparing procedure, and ten patients underwent an abdominoperineal resection, all with clear margins. Five complete pathologic responses (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 combination of radiation therapy and continuous chronobiologically shaped 5-FU infusion at a dose of up to 275/m2/day is well tolerated and appears to be more effective in downsizing and possibly downstaging locally advanced and unresectable rectal carcinoma than radiation therapy alone. Longer follow-up will determine whether ultimate disease free and overall survival are improved by this method.

Circadian rhythm modulated 5-FUdR infusion with Megace in the treatment of advanced pancreatic cancer.

Thirteen patients with advanced pancreatic carcinoma were treated with circadian rhythm modulated infusion of 5-FUdR and Megace. Treatment was initiated at a dose of 0.15 mg/kg/day for 14 days every 28 days and was increased or decreased by 0.025 mg/kg/day with each subsequent cycle until maximum tolerated dose (MTD) was achieved. Megace (200 mg) was administered daily in divided doses. One-third of the patients were able to complete > or = 6 cycles of treatment, one-half could only complete < or = 2 cycles, and the remainder managed 3-4 cycles. No patients had regression of disease, but a small number, who were able to receive 6-7 months of treatment, achieved stable disease in the short term. In conclusion, treatment was fairly well tolerated. However, increased dose intensity by this method did not significantly increase response rate. In only a few patients was disease stabilized for a brief period. Megace did not materially improve nutritional status. CA-19-9 levels did not correlate well with disease activity.