Abstract LB-219: Neoadjuvant multidisciplinary phase II study (BRANCH) of an early bevacizumab schedule plus chemo-radiation therapy in rectal cancer: efficacy, safety, and biomarkers.
Authors: Avallone Antonio , Gennaro Elena Di , Delrio Paolo , Aloj Luigi , Tatangelo Fabiana , Pecori Biagio , Leone Alessandra , Caracò Corradina , Moccia Tania , Iaffaioli Vincenzo R. , Romano Giovanni , Lastoria Secondo , Budillon Alfredo 
Published: August 2012

Abstract
BACKGROUND: The benefits of combining bevacizumab (BEV) plus chemotherapy have thus far been rather modest, stimulating interest in developing novel effective combination schedule as well as valid predictive biomarkers. Several evidences support the hypothesis that BEV can normalize the abnormal tumor vasculature, resulting in more efficient delivery of drugs and oxygen to cancer cells and that this effect seems to be transient and with a relatively narrow therapeutic window. In BRANCH study (NCT01481545) we assess the safety and efficacy of an experimental schedule of early (4 days before) BEV added to neoadjuvant chemotherapy (CT) and radiotherapy (RT) in poor-risk locally advanced rectal cancer (pLARC) patients (pts) and explore the potential of circulating endothelial cells (CECs) and tumor lesion glycolysis (TLG) as surrogate markers of pathological response. PATIENTS AND METHODS: 46 pts (cT4, cN+, cT3≤ 5 cm from the anal verge and/or positive circumferential margin, M1 resectable) received 3 biweekly courses of oxaliplatin (100 mg/m2)/raltitrexed (2.5 mg/m2) on day 1, and 5-FU (800 mg/m2)/folinic acid (250 mg/m2) on day 2 during pelvic RT (45 Gy). BEV (5 mg/kg) was given biweekly 4 days before beginning of CT/RT for 2 courses. Toxicity was graded with NCI-CTC v.3. Pathological response was defined using a modified Mandard tumor regression grade (TRG). According to the Simon's two-stage design, assuming an hypothesis of a 50% TRG1 (complete tumor regression) (α error=0.05, β error=0.20), at least 6/16 TRG1 should be obtained to continue accrual to 46 pts. CECs were quantified at baseline (BL) before BEV, at several time points thereafter during treatment and before surgery, by flow cytometry. TLG, was evaluated at BL, on day 10 and before surgery, by FDG-PET. Statistical analysis was by Mann-Whitney test. RESULTS: TRG1 required by statistical design was reached in the first 16 pts and in the final 46 pts: 23 TRG1 (50%), 14 TRG2 (30%) and 8 TRG3-4 (17%). One pt refused surgery. Grade ¾ neutropenia was the most common adverse event (13/46 pts, 28%). TLG reduction on day 10 vs BL was significantly higher in responders TRG1-2 compared to non-responders TRG3-4 pts (median -72%, range -90%+31% vs -38%, range -45%+25%; p &lt; 0.05). Median CECs at BL were higher in TRG1-2 vs TRG3-4 pts (median 0.22/µl, range 0-3.98 vs 0/µl, range 0-0.174; p=0.009). Moreover, in TRG1-2 pts CECs were significantly reduced on day 10 vs BL (median 0.014/µl, range 0-2.29; p=0.002). This pattern was not seen in TRG3-4 pts with a tendency toward increased levels (median 0.316/µl, range 0-2.64; p=0.097). CONCLUSIONS: Early schedule of BEV plus CT and RT appears safe and active yielding high rate of TRG1 and TRG2 responses in pLARC. Early FDG-PET and CECs evaluation emerged as potential biomarkers for treatment selection to be incorporated in design of future studies with this regimen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-219. doi:1538-7445.AM2012-LB-219