A phase II study of neoadjuvant bevacizumab plus capecitabine and concomitant radiotherapy in patients with locally advanced rectal cancer.

Abstract PURPOSE: To assess safety and activity of neoadjuvant bevacizumab, capecitabine and standard radiotherapy in locally advanced rectal cancer as well as potential predictive biomarkers. PATIENTS AND METHODS: The multicentric phase II study enrolled 43 patients who received bevacizumab infusion (5 mg/kg) every 2 weeks for 4 cycles; oral capecitabine at 825 mg/m(2) twice a day for 5.5 weeks with external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks). We determined certain biomarkers before and after therapy for correlation with response. RESULTS: Post-operative histologic examination revealed no residual cancer cells in 6 of the 43 patients (14%; 95% confidence limits 3.60-24.31%). In another 22 patients (51.2%) a varying percentage of cancer cells in residual areas of fibrosis/ necrosis was found, corresponding to Mandard TRG 2 or 3 classification. Tumor resection with negative circumferential margin was achieved in 38/40 (95%) operated patients. Sphincter-sparing surgery was obtained in 31 (72.1%) patients. Primary tumor and lymph nodes downstaging was observed in 15 (34.9%) and 16 (37.2%) cases, respectively. Neoadjuvant therapy was safe and well tolerated. The most frequent side effects were G1-2 diarrhea, proctitis, rectal bleeding and hypertension. No biomarker tested was significantly predictive of both pathological complete response and disease-free survival. Pre-treatment CD-34 vessel density, post-treatment Ki-67 labeling index and VEGFR-2 cancer cells expression significantly correlated with residual tumor area. CONCLUSIONS: The schedule of neoadjuvant therapy tested was safe and active. Pre-treatment vessel density by the panendothelial marker anti CD-34 antibody, post-treatment Ki-67 labeling index and VEGFR-2 expression were significantly associated to residual tumor area. The biomarkers correlations warrant further evaluation in prospective clinical trials.