Vascular endothelial growth factor (VEGF) has a crucial role in tumor angiogenesis, and its inhibition by bevacizumab (BEV) leads to normalization of tumor vessels increasing tumor oxygenation and drug delivery. However, the clinical benefits of current anti-VEGF treatments have thus far been rather modest, stimulating interest in developing novel effective ways to combine anti-VEGF drugs and chemotherapy (CT) and in the identification of valid predictive biomarkers of clinical benefit. We have previously shown that pre-operative oxaliplatin (OXA), raltitrexed (RTX), fluorouracil (5FU), and folinic acid (LFA) during pelvic radiotherapy (RT) have high rate of complete (TRG1) or subtotal (TRG2) tumor regression in locally advanced rectal cancer. In this study in order to demonstrate the relevance of the timing of BEV added to primary CT and RT we evaluate two different schedules of treatment. Changes of CECs and glucose metabolism, evaluated by flow cytometry and FDG-PET respectively, were used as early surrogate markers of tumor response. Thirty-two patients (inclusion criteria: cT4, cN+, cT3≤ 5 cm from the anal verge and/or +ve CRM, M1 resectable/initially unresectable) received 3 biweekly courses of OXA (100 mg/m2)/RTX (2.5 mg/m2) on day 1, and 5FU (800 mg/m2)/LFA (250 mg/m2) on day 2 during pelvic RT (45 Gy). In schedule A (16 pts) BEV (5 mg/kg) was given biweekly from day −14 for 4 courses, while in schedule B (16 pts) it was given from day −4 for 2 courses. Toxicity was graded with NCI-CTC version 3. According to the Simon's two-stage design, assuming an hypothesis of a 50% TRG1 (α error=0.05, β error=0.20), at least 6/16 TRG1 should be obtained (first stage) to continue pts accrual. Grade ¾ neutropenia was the most common adverse event with the schedule A (7 pts, 44%), but it was considerably lower with the schedule B (2 pts, 13%). Pre-treatment basal CEC amounts showed increased levels in the pts samples compared to the healthy controls. Notably, a significant difference of CEC levels, compared to basal levels, was observed 2 days after CT-RT between the two schedules of treatment (median +6% and −84% in schedule A and B, respectively, p<0.05). Likewise, a major reduction of median tumor metabolic volume was observed in schedule B compared to schedule A (−75% vs −50%, p<0.05). Furthermore, while in the schedule A only 2 (12%) pts obtained a TRG 1, in the schedule B the number of TRG 1 required by statistical design was already reached in the first 13 treated pts (7 pts; 54%). Overall these data suggest the relevance of the BEV schedule to optimize the feasibility and efficacy of combination treatment, as well as the potential role of CEC evaluation and FDG-PET for the early prediction of response to anti-angiogenesis therapeutical approaches.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3721.