Introduction It has long been recognized that

Introduction It has long been recognized that angiogenesis is critical to the growth, progression, and metastasis of many solid tumor types [1], and thus, drugs targeting the angiogenic pathway have been a topic of clinical investigation in the oncology community for many years. Angiogenesis is regulated by numerous signaling pathways, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and the angiopoietins [2], [3]. Several antiangiogenic agents have been approved worldwide for various oncology indications (Table 1), including monoclonal 1,2-Dimyristoyl-sn-glycerol (eg, bevacizumab [BV], ramucirumab) and multi-targeted tyrosine kinase inhibitors (TKIs; eg, regorafenib, sorafenib, sunitinib, nintedanib) (Fig. 1). While many of these agents have demonstrated promising clinical activity, some (particularly BV, regorafenib, and ziv-aflibercept) have also been associated with serious safety concerns, such as bleeding, thrombosis, gastrointestinal perforation, and impaired wound healing. Therefore, surgical and medical oncologists need to be cautious when using these products either before and/or after surgery. Many of these complications can affect the planning of surgical procedures or may require emergency surgical intervention [4].
Surgical complications associated with the use of antiangiogenic agents The use of some antiangiogenic agents has been linked to various surgical complications, particularly impaired wound healing. Because angiogenesis is a critical step in the wound healing process, agents that inhibit angiogenesis may potentially interfere with wound healing by impairing neovascularization, disturbing platelet-endothelial cell interaction, and reducing VEGF-mediated migration and proliferation of endothelial cells [5] Other consequences of VEGF/VEGFR inhibition include bleeding and thrombosis (Fig. 2) [6]. Therefore, it is logical that the administration of an antiangiogenic agent during the time when surgical wound healing is dependent on angiogenesis would increase the risk of surgical wound complications, which may include dehiscence, surgical site bleeding, and/or wound infection. Preclinical data also support this theory and suggest that VEGF-targeted therapies can impair wound healing [7]. The sections below discuss surgical complications reported in the literature for patients receiving antiangiogenic therapy across tumor types, with the majority of data being related to BV use in particular since it has been the most widely used anti-angiogenic agent. In addition, it is thought that the unique longer half-life of BV (∼20 days) relative to other VEGF receptor (VEGFR) inhibitors and targeted therapies may lead to a greater risk of wound healing complications with this agent [8]. While the focus of this review article is primarily on BV due to more extensive published data with this agent, these potential risks must also be taken into consideration when administering other agents targeting the angiogenesis pathway. In addition, while many of the more recently approved antiangiogenics, such as TKIs, have not been specifically linked to impaired wound healing and/or other surgical-related complications in the published literature, they should be used with caution when surgery is part of the overall oncology treatment strategy especially since long-term experience with these agents is limited.
Optimal timing between antiangiogenic therapy and surgery A common theme in much of the literature regarding surgical complications is related to the timing between antiangiogenic therapy and surgery; however, the optimal time-period to hold antiangiogenic therapy prior to and/or after surgery to avoid these complications is somewhat unclear. Since the half-life of BV is approximately 20 days [55], most physicians suggest avoiding BV for ≥4 weeks before or after most major surgeries, or 2 weeks for smaller surgeries (such as port-a-cath placement and vascular access). Due to their shorter half-life, surgery can usually be done earlier with other VEGFR inhibitors, but washout is still recommended [8]. More specifically, in the case of RCC, data suggest a washout period of about 3 days for sorafenib and 1 week for sunitinib, in comparison with up to 5–7 weeks for BV before surgery [56], [57]. Another case series in RCC suggests a washout period of at least 2 weeks between TKIs and surgery [36].