Preoperative 5-fluorouracil, low-dose leucovorin, and concurrent radiation therapy for rectal cancer

A Phase I trial was performed to determine the maximum tolerated dose of concurrent preoperative radiation therapy (5040 cGy) and 2 cycles (bolus daily times 5) of 5-fluorouracil (5-FU) and low-dose leucovorin (LV) (20 mg/m2), followed by surgery and 10 cycles of postoperative 5-FU/LV in patients with primary or recurrent rectal cancer.

Twenty-four patients were entered into the study. Preoperatively, the initial dose of 5-FU was 325 mg/m2. 5-FU was escalated 50 mg/m2, while the dose of LV and radiation therapy remained constant. Chemotherapy and radiation began concurrently on day 1. The postoperative chemotherapy was not dose escalated; 5-FU, 425 mg/m2, and LV, 20 mg/m2. The median follow-up was 10 months (range, 4-19 months).

The resectability rate with negative margins in the 23 patients who underwent surgery was 100%. One patient refused surgery. The pathologic complete response rate was 13% (3 of 23). An additional four patients had negative nodes and a microscopic foci of tumor in the bowel wall. Therefore, the total clinical complete response rate was 30% (7 of 23). The maximum tolerated dose of 5-FU for the preoperative combined modality segment was 375 mg/m2; therefore, the recommended Phase II dose level is 325 mg/m2. The incidence of Grade 3+ toxicity for the 22 patients treated at the recommended 5-FU dose level (325 mg/m2) during the preoperative combined modality segment was as follows: diarrhea, 14%; erythema, 5%; hematologic, 10%; and total, 18%. The median nadir counts were leukocyte count, 3.7 (range, 1.5-5.9); hemoglobin count, 12.2 (range, 10.2-14.3); and platelet count (times 1000), 165 (range, 92-237).

With this regimen, the recommended doses of chemotherapy in the combined modality segment are slightly higher than those recommended in arm 2 of the Intergroup postoperative adjuvant rectal trial 0114. This regimen will serve both as the preoperative arm of the Intergroup randomized trial of preoperative versus postoperative combined modality therapy for resectable rectal cancer (INT R9401) as well as the basis for the combined modality segment of NSABP RO-3.