BACKGROUND:Neoadjuvant CRT may lead to significant tumor regression in patients with rectal cancer. Different CRT regimens with consolidation chemotherapy may lead to increased rates of complete tumor regression. The purpose of this study was to understand tumor metabolic activity following two different neoadjuvant CRT regimens using sequential PET/CT imaging in two different intervals following RT. METHODS:Patients with cT2-4 N0-2 M0 rectal cancer treated by standard CRT (54Gy and 2 cycles of 5FU-based chemotherapy) or extended CRT (54Gy and 6 cycles of 5FU-based chemotherapy) underwent sequential PET/CT imaging at baseline, 6 weeks and 12 weeks from radiation completion. RESULTS:99 patients undergoing standard CRT were compared to 12 patients undergoing CRT with consolidation chemotherapy. Patients treated with consolidation CRT had increased rates of complete clinical or pathological response (66 % vs. 23 %; p < 0.001). SUVmax variation between baseline and 6 weeks (88 % vs. 63 %; p < 0.001) and between baseline and 12 weeks (90 % vs. 57 %; p < 0.001) were significantly more pronounced among patients undergoing extended CRT with consolidation chemotherapy. An increase in SUVmax between 6 and 12 weeks was observed in 51 % of patients undergoing standard and 18 % of patients undergoing consolidation CRT (p = 0.04). CONCLUSIONS:Most of the reduction in tumor metabolism after neoadjuvant CRT occurs within the first 6 weeks from RT completion. In patients undergoing CRT with consolidation chemotherapy, tumors are less likely to regain metabolic activity between 6 and 12 weeks. Therefore, assessment of tumor response may be safely postponed to 12 weeks in patients undergoing extended CRT with consolidation chemotherapy. TRIAL REGISTRATION:NCT00254683.