Risks of Proteinuria Associated with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Abstract

BackgroundVascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) have emerged as an effective targeted therapy in the treatment of cancer patients, the overall incidence and risk of proteinuria associated these drugs is unclear. We performed a systematic review and meta-analysis of published clinical trials to quantify the incidence and risk of proteinuria associated with VEGFR-TKIs.MethodologyDatabases from PubMed, Web of Science and abstracts presented at ASCO meeting up to May 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on proteinuria. Statistical analyses were conducted to calculate the summary incidence, Odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.Principal FindingsA total of 6,882 patients with a variety of solid tumors from 33 clinical trials were included in our analysis. The incidence of all-grade and high-grade (grade 3 or higher) proteinuria was 18.7% (95% CI, 13.3%–25.6%) and 2.4% (95% CI, 1.6%–3.7%), respectively. Patients treated with VEGFR-TKIs had a significantly increased risk of all-grade (OR 2.92, 95%CI: 1.09–7.82, p = 0.033) and high-grade proteinuria (OR 1.97, 95%CI: 1.01–3.84, p = 0.046) when compared to patients treated with control medication. No evidence of publication bias was observed.ConclusionsThe use of VEGFR-TKIs is associated with a significant increased risk of developing proteinuria. Physicians should be aware of this adverse effect and should monitor cancer patients receiving VEGFR-TKIs.

Adverse events risk associated with anti-VEGFR agents in the treatment of advanced nonsmall-cell lung cancer

“…However, VEGF plays multiple roles in physiologic processes, and thus its inhibition could have potentially serious systemic consequences. Although previous researches have shown that anti-VEGFR agents significantly increases the risk of developing anti-VEGF adverse events, including hypertension, [39–41] hemorrhage, [42,43] proteinuria, [44,45] gastrointestinal perforation, [46] congestive heart failure, [47–49] and thromboembolic events. [50–53] , the risk of these adverse events in advanced NSCLC remains unknown.…”

Lenvatinib for the treatment of radioiodine-refractory follicular and papillary thyroid cancer

“…Two to ten percent of this event fulfilled G3 criteria according to common terminology criteria for adverse events [42,45,47]. Total risk of all grade proteinuria assessed by meta-analysis, published by Zhang et al, was 11.6% for sorafenib compared with 13.5 and 10.0% for pazopanib and vandetanib, respectively [54].…”

“…Hypertension, proteinuria, gastrointestinal perforation, thrombosis and CHF belong to possible VEGF inhibitionrelated consequences [52][53][54][55][56][57]. Keizer et al constructed a pharmacokinetic-pharmacodynamics (PK-PD) model for hypertension and proteinuria applied in patients who were given lenvatinib.…”

“…Proteinuria was also a side effect of other VEGFR-TKIs administered in thyroid cancer [20,58]. However, the risk of proteinuria varies between different TKIs [54]. Elevated urine protein excretion (all grade) was present in 39 --58% of thyroid cancer patients treated with lenvatinib.…”

Tumor angiogenesis revisited: Regulators and clinical implications

“…Some adverse effects are shared with conventional chemotherapeutic agents while others are unique and not typically observed with cytotoxic drugs. Specific toxicities associated with VEGF axis inhibition using VEGF‐ligand or VEGFR inhibitors include cardiovascular effects (hypertension, thromboembolism, left ventricular dysfunction, cerebrovascular effects) as well as noncardiovascular effects (proteinuria, bleeding/hemorrhage, delayed wound healing, gastrointestinal perforation, fatigue, and dysphonia) . Other rare class effects of VEGF axis inhibition comprise reversible posterior leukoencephalopathy (RPLS), osteonecrosis of the jaw (ONJ), and microangiopathic hemolysis.…”