Phase I study of 5-fluorouracil and leucovorin by continuous infusion chronotherapy and pelvic radiotherapy in patients with locally advanced or recurrent rectal cancer.

PURPOSE

To determine the maximal tolerated dose of chronomodulated 5-fluorouracil (5-FU) and leucovorin (LV) given concurrently with radiotherapy in patients with rectal cancer.

METHODS AND MATERIALS

Forty-five patients with T3, T4 or recurrent rectal cancer received concurrent radiotherapy to a minimal dose of 4500 cGy. Chemotherapy was administered by a programmable pump in chronomodulated fashion, with 62.5% of the total dose given within 7 hours around 9:30 pm. The starting doses were LV at 5 mg/m2/d and 5-FU at 150 mg/m2/d. LV was escalated in 5-mg/m2 increments to 20 mg/m2/d; 5-FU was then escalated in 25 mg/m2 increments to the maximal tolerated dose.

RESULTS

Diarrhea and stomatitis were dose limiting, with Grade 3 or worse toxicity occurring in 16% and 5% of patients, respectively. Thirty-seven patients (84%) received their scheduled dose of radiotherapy (range, 4500-6000 cGy). Thirty-two patients had clinical T3 disease; all were treated with definitive surgery; 23 (71%) underwent sphincter-sparing surgery with complete resection in 28 (87%). Ten patients (31%) had no evidence of tumor in the pathologic specimen.

CONCLUSION

Preoperative chemoradiotherapy in rectal cancer using chronomodulated 5-FU and LV is feasible. The recommended Phase II dose is 5-FU 200 mg/m2 and LV 20 mg/m2 daily for 5 weeks.