Colorectal cancer (CRC) is one of the commonest cancers in the world. During the last decade,
the development of targeted therapies has given cancer treatment a novel direction in management
of metastatic CRC (mCRC) and has enriched the therapeutic armamentarium in the management of this
disease. In mCRC, targeting angiogenesis via the vascular endothelial growth factor (VEGF) pathway
has been of particular interest based on the favourable survival benefit demonstrated by bevacizumab in
clinical trials. More recently, large phase III studies have shown clinical efficacy for the new antiangiogenic
agents aflibercept and regorafenib. However, the results of pre-clinical and clinical studies
of other anti-angiogenic agents have been disappointing.
Furthermore, the benefits from angiogenic inhibitors (AIs) in an unselected patient population are modest.
Research into predictive biomarkers is therefore essential, but has, to date, been unsuccessful. Nevertheless,
aflibercept and regorafenib have been shown to benefit both bevacizumab naive and refractory
patients, suggesting that acquired resistance to AIs can be potentially reversed. This review describes
the most recent advances in development of AIs in mCRC with particular focus on aflibercept
and regorafenib, the existing challenges for the evaluation of these agents in clinical practice and potential
strategies in designing clinical trials that could lead to the discovery of clinically meaningful biomarkers.
Keywords: Colorectal cancer, angiogenesis, angiogenesis inhibitors, biomarkers, vascular endothelial growth factor (VEGF),
bevacizumab, aflibercept, regorafenib.
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