Background: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have been widely used in a variety of solid malignancies. Concerns have arisen regarding the risk of severe infections (≥grade 3) with use of these drugs, but the contribution of VEGFR-TKIs to infections is still unknown.
Methods: The databases of PubMed and abstracts presented at oncology conferences’ proceedings were searched for relevant studies from January 2000 to December 2014. Summary incidences, Peto odds ratio (Peto OR), and 95% confidence intervals (CIs) were calculated by using either random-effects or fixed-effects models according to the heterogeneity of included studies.
Results: A total of 16,488 patients from 27 randomized controlled trials were included. The risk of developing severe (Peto OR 1.69, 95% CI: 1.45–1.96, P<0.001) and fatal infections (Peto OR 1.78, 95% CI: 1.13–2.81, P=0.013) was significantly increased in patients treated with VEGFR-TKIs when compared to controls. Exploratory subgroup analysis showed no effect of tumor types, phase of trials, or agent used on the Peto OR of severe infections. When stratified according to specific infectious events, the risks of high-grade febrile neutropenia, pneumonia, fever, and sepsis were increased compared with controls, with Peto ORs of 1.57 (95% CI: 1.30–1.88, P<0.001), 1.79 (95% CI: 1.29–2.49, P<0.001), 5.35 (95% CI: 1.47–19.51, P=0.011), and 3.68 (95% CI: 1.51–8.99, P=0.004), respectively. Additionally, VEGFR-TKIs significantly increased the risk of fatal sepsis (OR 3.66, 95% CI: 1.47–9.13, P=0.005) but not fatal pneumonia (OR 1.34, 95% CI: 0.80–2.25, P=0.26).
Conclusion: The use of VEGFR-TKIs significantly increases the risk of developing severe and fatal infectious events in cancer patients. A close monitoring for any signs of infections is recommended for patients treated with VEGFR-TKIs.


Keywords: VEGFR-TKIs, infections, cancer, randomized controlled trials, meta-analysis 


INTRODUCTION

Tumor angiogenesis is a complex process that is crucial for tumor growth, invasion, and metastasis.1–3 During the past decades, many new agents targeting vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have proven to be a successful strategy in patients with cancer. Until now, the US Food and Drug Administration has approved a number of VEGFR tyrosine kinase inhibitors (TKIs) in multiple indications: sunitinib, sorafenib, pazopanib, and axitinib have been approved for patients with metastatic renal cell carcinoma (RCC).4–8 Moreover, sunitinib has been approved for pancreatic neuroendocrine tumors9 and refractory gastrointestinal stromal tumors (GISTs),10 and sorafenib has been approved for advanced hepatocellular carcinoma (HCC)11 and radioiodine-refractory differentiated thyroid carcinoma.12 Additionally, vandetanib has been approved for symptomatic or progressive medullary thyroid cancer,13 and regorafenib has been approved for refractory advanced colorectal cancer14 and GISTs.15

However, the toxicity profiles of VEGFR-TKIs are unique compared with the adverse effects typically associated with traditional cytotoxic anticancer therapies. They include mucocutaneous adverse events,16–19 liver dysfunction,20–23 gastrointestinal perforation,24,25 and cardiovascular toxicities.26–33Additionally, severe infections (≥grade 3) associated with VEGFR-TKIs have been reported in randomized controlled trials (RCTs). However, the incidence has varied substantially among clinical trials, and there has been no systematic attempt to synthesize the data in order to define the overall incidence and risk of infections associated with these drugs. Therefore, we conducted a systematic review and meta-analysis of RCTs to determine the overall risk of developing severe infection in cancer patients treated with these drugs.