A Prospective Study of Bevacizumab and Neoadjuvant Concurrent Chemoradiation in Locally Advanced Esophageal Squamous Cell Carcinoma: Paradoxical Increase in Circulating Vascular Endothelial Growth Factor-A and Effect on Outcome

Abstract

In the prior prospective biomarker study, high serum vascular endothelial growth factor-A (VEGF-A) was associated with a poor prognosis. We conducted a prospective phase II trial of adding Bevacizumab, an anti-VEGF-A monoclonal antibody, to neoadjuvant concurrent chemoradiation (neoCCRT) for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC). This prospective biomarker study aims to evaluate the expressions of angiogenesis-associated circulating biomarkers before and after neoCCRT and compare clinical outcomes for patients receiving platinum/5-fluorouracil (PF) with or without Bevacizumab. Patients with biopsy-proven resectable non-T4 LA-ESCC were enrolled for the prospective phase II trial investigating PF-neoCCRT plus Bevacizumab (BPF group). A parallel patient cohort enrolled in a prospective biomarker study receiving PF-neoCCRT was included in the present analysis as the control group (PF group). Radiotherapy was delivered with 40 Gy in 20 fractions. All patients had restaging workups after enoCCRT and underwent radical esophagectomy if the disease remained resectable. Serums were collected before and after neoCCRT. The serum concentrations of angiogenesis-associated biomarkers were determined by the multiplex enzyme-linked immunosorbent assay. Survival analyses were performed by the Kaplan-Meier method. The t-test and log-rank test were used to compare differences in biomarker expression and survival between groups. From 2016 to 2019, 43 patients (BPF/PF group: 21/22) were enrolled in the study. Twenty patients in each group had serum samples available for biomarker analysis. 15 out of 21 patients in the BPF group and 20 out of 22 patients in the PF group underwent radical esophagectomy. Six patients in the BPF group and nine patients in the PF group achieved pathological complete responses. The median overall survival for the BPF and PF group was 20.8 months and not-reached, respectively (hazard ratio = 1.33, long rank p = 0.58). In the BPF group, the serum VEGF-A level was significantly increased from an average value of 446 pg/mL to 723 pg/mL after neoCCRT (p = 0.037), while its level was decreased from 815 ng/mL to 380 pg/mL in the PF group (p = 0.104). In addition, the expression value of circulating Angiopoietin-1 was not changed in the BPF group (before neoCCRT, mean value = 828 pg/mL; after neoCCRT, mean value 762 pg/mL, p = 0.67). In contrast, serum Angiopoietin-1 level was reduced from an average value of 659 pg/mL before neoCCRT to 271 pg/mL after neoCCRT (p = 0.002) in the PF group. The addition of Bevacizumab to PF-neoCCRT did not improve pathological or survival outcomes in patients with resectable LA-ESCC. Adding a single dose of Bevacizumab paradoxically increases circulating VEGF-A while maintaining the Angiopoietin-1 serum level after neoCCRT. Further investigation by using additional VEGF-A inhibition may be required to achieve sustained angiogenesis blocked for tumor control.