PURPOSE:This study examines the effect of 5‐fluorouracil administration during preoperative irradiation on rectal cancer tumor proliferation.PATIENTS AND METHODS:One hundred and fifty‐three patients with locally advanced rectal cancer received 45 to 50 Gy of preoperative irradiation with (103 patients) and without (50 patients) concurrent 5‐fluorouracil, followed by surgery. Pretreatment tumor biopsies and postirradiation surgical specimens were scored for proliferative activity by assaying the extent of Ki‐67 and proliferating cell nuclear antigen immunostaining and the number of mitoses per ten high‐powered fields. Postirradiation specimens were also assessed for downstaging.RESULTS:Although 5‐fluorouracil did not improve downstaging rates, marked decreases in the activity of all three markers of proliferation (mitotic counts, Ki‐67, and proliferating cell nuclear antigen immunostaining) were seen in rectal cancers of patients receiving the drug. No significant decreases were noted in patients undergoing irradiation only.CONCLUSION:The addition of 5‐fluorouracil to preoperative irradiation resulted in a more complete inactivation of the proliferating population. Frequency of downstaging, however, was unaffected. Thus, the quiescent cell population appears to represent a substantial barrier to further downstaging. New treatment strategies should be aimed at controlled recruitment of quiescent tumor cells at the time of irradiation.