Bevacizumab-Induced Tumor Vasculature Normalization and Sequential Chemotherapy in Colorectal Cancer: An Interesting and Still Open Question

Abstract

Bevacizumab is a recombinant fully humanized IgG1 targeting the Vascular Endothelial Growth Factor A (VEGF-A). The rationale of its use in oncology relies on the critical role of VEGF-Ainduced neo-angiogenesis in the growth of many solid tumors (1–3). Since its discovery, many evidences suggested that it did not display direct antitumor action but rather contributes to improve the effects of associated chemotherapy. In fact, following bevacizumab administration, intratumoral vessels become morphologically more organized, and hypoxia and interstitial fluid pressure reduce (“vasculature normalization”); as a consequence, chemotherapy drug delivery into tumor masses ameliorates (4). Avallone et al. published the first randomized phase III study (OBELICS study) comparing the sequential administration of bevacizumab before standard oxaliplatin-based chemotherapy versus a traditional concomitant regimen in metastatic colorectal cancer (CRC) (5). The intent was to optimize bevacizumab and chemotherapy association by administering the chemotherapy in the “normalization window” and ameliorate the antitumor effects. The “normalization window” is the time window during which the anarchist texture of tumor vasculature becomes macroscopically more linear and less dense (1–4) (Figure 1). The authors fail to meet the primary end-point based on a difference in objective response rate (ORR) between the two arms. The odds ratio of response for experimental (ORR: 56.5%) versus standard arm (ORR: 57.4%) was 0.96 (95% CI: 0.55–1,68, P=0.89). We would add insights and prompt discussion making hypotheses on the causes of failure. This is important for scientific discussion and for planning future trials.