Increased risk of Severe Infections in Cancer Patients Treated With Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: A Meta-Analysis

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The use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) significantly increases the risk for developing severe and fatal infections in patients with cancer, a recent study published in the journal OncoTargets and Therapy has shown.

VEGFR-TKIs, such as axitinib, pazopanib, regorafenib, sorafenib, and sunitinib, are widely used for the treatment of a variety of solid tumors, including colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer. However, concerns have arisen surrounding the association between these agents and the risk of severe infections. Therefore, researchers at The General Hospital of Tianjin Medical University in China sought to evaluate the contribution of VEGFR-TKIs to the risk of infections.

For the meta-analysis, researchers analyzed data from 27 randomized controlled trials that included a total of 16,488 patients. Results showed that the risk for severe and fatal infections was significantly higher in patients who received VEGFR-TKIs compared with controls. Subgroup analyses demonstrated no difference in risk between patients with different tumor types or agent used.

The findings suggest that health care professionals should closely monitor patients treated with VEGFR-TKIs for any signs of infection, particularly those with non-small cell lung cancer and colorectal cancer.

OncoTargets and Therapy
OncoTargets and Therapy

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 


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.  

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