PREOPERATIVE 5-FLUOROURACIL, LOW-DOSE LEUCOVORIN, AND CONCURRENT RADIATION-THERAPY FOR RECTAL-CANCER

Background. A Phase I trial was performed to determine the maximum tol erated dose of concurrent preoperative radiation therapy (5040 cGy) an d 2 cycles (bolus daily times 5) of 5-fluorouracil (5-FU) and low-dose leucovorin (LV) (20 mg/m(2)), followed by surgery and 10 cycles of po stoperative 5-FU/LV in patients with primary or recurrent rectal cance r. Methods. Twenty-four patients were entered into the study. Preopera tively, the initial dose of 5-FU was 325 mg/m(2). 5-FU was escalated 5 0 mg/m(2), while the dose of LV and radiation therapy remained constan t. Chemotherapy and radiation began concurrently on day 1. The postope rative chemotherapy was not dose escalated; 5-FU, 425 mg/m(2), and LV, 20 mg/m(2). The median follow-up was 10 months (range, 4-19 months). Results. The resectability rate with negative margins in the 23 patien ts who underwent surgery was 100%. One patient refused surgery. The pa thologic complete response rate was 13% (3 of 23). An additional four patients had negative nodes and a microscopic foci of tumor in the bow el wall. Therefore, the total clinical complete response rate was 30% (7 of 23). The maximum tolerated dose of 5-FU for the preoperative com bined modality segment was 375 mg/m(2); therefore, the recommended Pha se II dose level is 325 mg/m(2). The incidence of Grade 3+ toxicity fo r the 22 patients treated at the recommended 5-FU dose level (325 mg/m (2)) during the preoperative combined modality segment was as follows: diarrhea, 14%; erythema, 5%; hematologic, 10%; and total, 18%. The me dian nadir counts were leukocyte count, 3.7 (range, 1.5-5.9); hemoglob in count, 12.2 (range, 10.2-14.3); and platelet count (times 1000), 16 5 (range, 92-237). Conclusions, With this regimen, the recommended dos es of chemotherapy in the combined modality segment are slightly highe r than those recommended in arm 2 of the Intergroup postoperative adju vant rectal trial 0114. This regimen will serve both as the preoperati ve arm of the Intergroup randomized trial of preoperative versus posto perative combined modality therapy for resectable rectal cancer (INT R 9401) as well as the basis for the combined modality segment of NSABP RO-3.