Abstract LB-304: Evaluation of the effects of anti-VEGF therapy in a multidisciplinary phase I/II study of neoadjuvant bevacizumab with chemoradiation therapy in rectal cancer

Abstract

Abstract Background: A phase I/II study of neoadjuvant bevacizumab with 5-fluorouracil and radiation therapy in patients with locally advanced rectal cancer is underway to assess the clinical benefits of bevacizumab enhancement of chemo-radiation therapy. Methods: 24 patients with endoscopic ultrasound or surface coil MRI staged T3/T4 non-metastatic rectal cancer were enrolled from 2001-2007. All patients completed 4 cycles of neoadjuvant therapy including: 1) bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; 2) peripheral venous infusion 5-FU (225 mg/m2/24 hours) administration each treatment week of cycles 2 - 4; 3) external beam irradiation delivery (50.4 Gy in 28 fractions over 5.5 weeks); and 4) surgery 7 to 9 weeks after completion of all neoadjuvant therapy. Correlative studies are undertaken before and during the trial. We collected serial tumor biopsies, PET-FDG scans, and analyzed blood and urine for potential biomarkers. Results: Histologic examination showed no residual primary cancer in 5 patients (ypT0). Of 19 patients with residual disease, microscopic disease usually occurred as malignant glands embedded in fibrosis (ypT1 in 3 patients, ypT2 in 4 patients, ypT3-4 in 12 patients). Downstaging was seen in 12/22 tumors. Nine patients had microscopic nodal metastases. Bevacizumab alone and combined treatment were both associated with increased plasma VEGF, PlGF and SDF1alpha levels in analyzed patients (P<0.01 at all 4 timepoints compared to baseline). Viable CECs were decreased by VEGF blockade at day 3 (P<0.01 compared to baseline), and CEC levels correlated with histologic tumor response (T3 vs T0, p <0.05). Laser-capture micro-dissection identified a set of genes changed by anti-VEGF therapy in cancer cells as well as in tumor-associated macrophages. Actuarial 4 year local control and disease-free are 100% and 88%, respectively. Conclusions: Addition of bevacizumab at a dose of 5 mg/kg to standard chemo-radiation shows activity and the combined regimen yields promising results.