Abstract

Vascular endothelial growth factor (VEGF) pathway targeting agents have been combined with other anticancer drugs, leading to improved efficacy in carcinoma of the cervix, stomach, lung, colon and rectum, ovary, and breast. Vessel normalization induced by VEGF pathway targeting agents influences tumor drug uptake. Following bevacizumab treatment, preclinical and clinical studies have shown a decrease in tumor delivery of radiolabeled antibodies and two chemotherapeutic drugs. The decrease in vessel pore size during vessel normalization might explain the decrease in tumor drug uptake. Moreover, the addition of bevacizumab to cetuximab, or panitumumab in colorectal cancer patients or to trastuzumab in breast cancer patients, did not improve efficacy. However, combining bevacizumab with chemotherapy did increase efficacy in some cancer types. Novel biomarkers to select patients who may benefit from combination therapies, such as the effect of an angiogenesis inhibitor on tumor perfusion, requires innovative trial designs and large clinical trials. Small imaging studies with radiolabeled drugs could be used in the interphase to gain further insight into the interplay between VEGF targeted therapy, vessel normalization and tumor drug delivery.

Highlights

  • Angiogenesis is a hallmark of cancer that enables tumor growth [1]

  • Results from numerous phase 3 trials combining VEGF receptors (VEGFR) tyrosine kinase inhibitors (TKI) with chemotherapy showed only marginal to no increased antitumor efficacy (Table 1)

  • In metastatic breast cancer sunitinib had no effect on progression-free survival (PFS) or overall survival (OS) when combined with chemotherapy as first- and second-line therapy [27, 28]

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Summary

Introduction

Angiogenesis is a hallmark of cancer that enables tumor growth [1]. Vascular endothelial growth factor A (VEGF-A) is a key player in the process of tumor angiogenesis, and the VEGF pathway has been an important focus for anti-cancer drug development [2, 3]. In the randomized phase 3 HORIZON II trial, combination of cediranib with chemotherapy led to a clinically irrelevant increase of 0.3 months in PFS (HR 0.84, P = .012), and had no effect on OS as first-line therapy in mCRC patients [26]. In metastatic breast cancer sunitinib had no effect on PFS or OS when combined with chemotherapy as first- and second-line therapy [27, 28].

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