Use Of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Analysis of Anti-Angiogenesis-Related Adverse Events Associated with Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitors (VEGFR-TKIs) in Patients with Metastatic Renal Cell Carcinoma.

Limited studies have evaluated anti-angiogenesis-related adverse events involving oral vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in metastatic renal cell carcinoma using real-world data. This study aimed to investigate the incidence, patterns, and impact on the dose intensity of anti-angiogenesis-related adverse events associated with the use of VEGFR-TKIs in patients with metastatic renal cell carcinoma using real-world data. This cross-sectional study included patients with a diagnosis of metastatic renal cell carcinoma who received axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib at a tertiary hospital in South Korea. We categorized the patients into those who had not previously received a VEGFR-TKI (VEGFR-TKI-naive) and those who had previously received a VEGFR-TKI (VEGFR-TKI-experienced). Anti-angiogenesis-related adverse events were defined as hypertension, proteinuria, bleeding, thrombosis, hypothyroidism, and left ventricular dysfunction, which were rated "possible" or higher based on a causality assessment scale. Among a total of 988 patients, 674 patients were VEGFR-TKI-naïve and 314 patients were VEGFR-TKI-experienced. Anti-angiogenesis-related adverse events of any grade and severe adverse events occurred in 65.1 and 34.6% of VEGFR-TKI-naïve patients and 54.8 and 36.0% of VEGFR-TKI-experienced patients, respectively. Regardless of treatment history, the most common adverse event was hypertension, with 48.6% in VEGFR-TKI-naïve patients and 35.0% in VEGFR-TKI-experienced patients. For VEGFR-TKI-experienced patients, the overall rate of anti-angiogenesis-related adverse events for sorafenib (24.3%) was lower than that for other VEGFR-TKIs (p < 0.05). Patients experiencing anti-angiogenesis-related adverse events were 1.6 times more likely to receive a low relative dose intensity. More than half and more than one-third of patients with renal cell carcinoma receiving VEGFR-TKIs experienced any and severe anti-angiogenesis-related adverse events, respectively. The relative dose intensity of VEGFR-TKI treatment was associated with anti-angiogenesis-related adverse events.

Thyroid dysfunction related to vascular endothelial growth factor receptor tyrosine kinase inhibitors: A real-world study based on FAERS.

The adverse events of thyroid dysfunction caused by the use of vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) have not been confirmed in a real-world investigation. The aim of this study was to evaluate the relationship between thyroid dysfunction and treatment using Food and Drug Administration (FDA)-approved VEGFR-TKIs. Four data-mining algorithms were employed to detect thyroid dysfunction signals for VEGFR-TKIs, using data in the FDA Adverse Event Reporting System (FAERS) database from 68 quarters. MySQL Workbench and R were used to conduct statistical analysis. We identified 32679 reports of thyroid dysfunction, of which 1567 listed VEGFR-TKIs as the primary suspected drugs. All four algorithms showed that the strength of the signals for hypothyroidism were greater than those for hyperthyroidism, for all the VEGFR-TKIs. In most cases, the median appearance time was within 100days of initiation of VEGFR-TKIs therapy, except in the case of ponatinib. This indicated the need to actively identify and manage thyroid dysfunction during the early stages of VEGFR-TKIs treatment. This study systematically identified the pharmacovigilance signals of thyroid dysfunction associated with the use of VEGFR-TKIs, using the FAERS database.

NCMP-01. THE ROLE OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR INHIBITORS IN PREVENTING CEREBRAL RADIATION NECROSIS: A RETROSPECTIVE COHORT STUDY

Abstract INTRODUCTION Radiation necrosis (RN) is a potential complication after radiation therapy to primary brain tumors and brain metastases. The pathophysiology of RN is not well understood but it is hypothesized that vascular endothelial growth factor (VEGF) plays an important role. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse cerebral radiation necrosis METHODS We retrospectively studied a cohort of 102 patients with renal cell carcinoma (RCC) and brain metastases seen at The Ohio State University James Cancer Center between 01/01/2011 and 04/30/2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS The cumulative incidence of RN in our cohort is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, p= 0.741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 versus 315 days, p=0.315). One patient developed RN after stopping cabozantinib. Three other patients developed RN while on cabozantinib. Two patients developed RN while on pazopanib, and 3 patients developed RN while on sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS VEGFR TKIs do not consistently prevent or reverse cerebral radiation necrosis and do not seem to have the efficacy that bevacizumab has against RN.

Risk of hand-foot skin reaction associated with vascular endothelial growth factor–tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients

Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P<.001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P<.001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. High heterogeneity in most studies. High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.

Cardiovascular Toxicities with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer Patients: A Meta-Analysis of 77 Randomized Controlled Trials.

Use of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) has led to considerable improvements in the clinical outcome of patients with various tumor types. However, VEGFR-TKIs may be associated with increased incidence of cardiovascular toxicities. We conducted this meta-analysis to systematically review the risk of cardiovascular toxicities with VEGFR-TKIs in cancer patients. The relevant studies of the randomized controlled trials in cancer patients treated with VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until April 2018. A total of 77 randomized controlled trials and 27,353 patients were included. The current meta-analysis suggests that the use of VEGFR-TKIs significantly increases the risk of developing cardiovascular toxicities, such as all-grade and high-grade hypertension, all-grade bleeding, and all-grade cardiac dysfunction. Hypertension was the most common cardiovascular toxicity. There was no significant increased risk of all-grade and high-grade thromboembolism, high-grade bleeding, and high-grade cardiac dysfunction associated with these agents. The available data suggest that the use of VEGFR-TKIs is associated with a significantly increased risk of cardiovascular toxicities in cancer patients. Clinicians should be aware of this risk and perform regular cardiovascular monitoring.

Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis.

A meta-analysis was conducted to systematically review the risk of hand-foot skin reaction (HFSR) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with cancer. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with VEGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till May 2017. Twenty-one RCTs and 9552 patients were included. The current analysis suggested that the use of VEGFR-TKIs increased the risk of all-grade HFSR (7.04;95%CI, 5.33-9.30;p<0.00001) and high-grade (≥grade 3) HFSR (21.62;95%CI, 15.19-30.78;p<0.00001). On subgroup analyses, the risk ratio (RR) of all-grade HFSR varies significantly according to cancer type, whereas the RR of high-grade HFSR did not. The risk of all-grade and high-grade HFSR did not affect by drug types, treatment line, median age and treatment duration.

Efficacy and safety of vascular endothelial growth factor receptor tyrosine kinase inhibitors in the treatment of advanced thyroid cancer: a meta-analysis of randomized controlled trials.

BackgroundWe performed a systematic review and meta-analysis to determine the efficacy and safety of the US Food and Drug Administration approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in the treatment of advanced thyroid cancer.Patients and methodsWe included prospective randomized controlled trials that compared VEGFR-TKIs with placebo for advanced thyroid cancer. The endpoints included safety (fatal adverse events [FAEs], treatment discontinuation, and any severe [grade 3 or 4] adverse events [AEs]) and efficacy (objective response rate, progression-free survival, and overall survival). The pooled relative risk (RR) or hazard ratio (HR) was calculated by using either random-effects or fixed-effects models according to the heterogeneity of included studies.ResultsA total of 1,614 advanced thyroid cancer patients from five randomized controlled trials were identified for analysis. Compared with placebo alone, VEGFR-TKIs significantly increased the risk of treatment discontinuation (RR: 3.80, 95% confidence interval [CI]: 2.56–5.65, P<0.001) and any severe AEs (RR: 2.63, 95% CI: 1.72–4.03, P<0.001), but not of FAEs (RR: 1.24, 95% CI: 0.65–2.39, P=0.52). The use of VEGFR-TKIs in advanced thyroid cancer was associated with a significant improvement in objective response rate (RR: 8.73, 95% CI: 1.72–44.4, P=0.009) and progression-free survival (HR: 0.41, 95% CI: 0.27–0.61, P<0.001), with a tendency to improve overall survival (HR: 0.83, 95% CI: 0.68–1.01, P=0.06).ConclusionThe use of small-molecule VEGFR-TKIs in advanced thyroid cancer did significantly increase the risk of treatment discontinuation and any severe AEs, but not of FAEs, compared with placebo alone. It is important for physicians to weigh the risk of toxicities as well as the potential survival benefits associated with VEGFR-TKI treatment in advanced thyroid cancer patients.

Increased risk of severe infections in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis.

BackgroundVascular 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.MethodsThe 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.ResultsA 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).ConclusionThe 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.

Viruses and cancer, cats and cattle: A tribute to Bill Jarrett

We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine-kinase inhibitors (VEGFR-TKIs).We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies.The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8–12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19–2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86–1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all-grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high-grade hemorrhagic events.While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events.

Meta-analysis of randomized control trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors.

349 Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs. Methods: MEDLINE and PubMed databases were searched for articles published from January 1966 to February 2011. Eligible studies were limited to trials of US Food and Drug Administration– approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results: In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P .023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed. Conclusions: In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients.

Meta-Analysis of Randomized Controlled Trials for the Incidence and Risk of Treatment-Related Mortality in Patients With Cancer Treated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

Purpose Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become the cornerstone in the treatment of several malignancies. These drugs have also been associated with an increase in the risk of potentially life-threatening adverse events, such as arterial thrombotic events, bleeding, congestive heart failure, and others. We performed an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in patients with cancer treated with VEGFR TKIs. Methods MEDLINE and PubMed databases were searched for articles published from January 1966 to February 2011. Eligible studies were limited to trials of US Food and Drug Administration–approved VEGFR TKIs (pazopanib, sunitinib, and sorafenib) that reported on patients with cancer with any primary tumor type, randomized design, and adequate safety profile. Statistical analyses were conducted to calculate the summary incidence, relative risk (RR), and 95% CIs by using random-effects or fixed-effects models on the basis of the heterogeneity of included studies. Results In all, 4,679 patients from 10 randomized controlled trials (RCTs) were included, with 2,856 from sorafenib, 1,388 from sunitinib, and 435 from pazopanib trials. The incidence of FAEs related to VEGFR TKIs was 1.5% (95% CI, 0.8% to 2.4%) with an RR of 2.23 (95% CI, 1.12 to 4.44; P = .023) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between different VEGFR TKIs or tumor types. No evidence of publication bias was observed. Conclusion In a meta-analysis of RCTs, the use of VEGFR TKIs was associated with an increased risk of FAEs compared with control patients.