Correlation of blood and physiologic markers with effect of bevacizumab (BV) with chemoradiation therapy in rectal cancer (RC)

Abstract

4096 Background: A phase I/II study of neoadjuvant BV with 5-fluorouracil (5-FU) and radiation therapy (RT) in patients with locally advanced RC tested the hypothesis that standard therapy plus inhibition of VEGF results in clinical benefit and that this effect is correlated with a set of angiogenic biomarkers. Methods: 25 patients with endoscopic US or surface coil MRI staged T3/4 RC were enrolled on this trial from 2002. Patients received 4 cycles of neoadjuvant therapy consisting of: 1) BV infusion on day 1 (cycles 1–4); 2) infusional 5-FU (225 mg/m2/24 hours, cycles 2–4); 3) external beam RT (50.4 Gy in 28 fractions, cycles 2–4; and 4) surgery 7–9 weeks after completion of neoadjuvant therapy. Correlative studies were undertaken to explore the biomarker value of angiogenic markers for this neoadjuvant therapy regimen in RC. Results: Histologic examination of the surgical specimen showed no residual cancer in the primary site in 5 patients (20%), 8 patients had rare scattered tumor cells (32%) and 6 patients exhibited more fibrosis than residual tumor (24%). In 14 patients all the lymph nodes were negative for malignancy, whereas 11 patients had microscopic nodal metastases. 3-year actuarial overall survival, disease free survival, and local control of these 25 patients were 100%, 88%, and 100%, respectively. There were no acute grade 4 toxicity events. The change in PlGF on BV alone and the pretreatment sVEGFR-1 in plasma correlated significantly (p<0.05) with extent of primary tumor regression. Presurgery CECs correlated with the extent of PET-FDG uptake decrease and was significantly higher in patients with residual disease compared to patients with pathCR (p<0.05). Changes in plasma VEGF and in tumor interstitial pressure correlated significantly (p<0.05) to extent of nodal regression in the surgical specimen. Conclusions: BV with standard chemo- radiation yields promising clinical results. The biomarkers identified in this study are the first ones shown to correlate with tumor response to combination of anti-VEGF and cytotoxic therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Dyax, Pfizer, Takeda AstraZeneca, Genentech