A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib

Patel, Tejas; Morgan, Jeffrey A.; Demetri, George D.; George, Suzanne; Maki, Robert G.; Quigley, Michael; Humphreys, Benjamin D.

doi:10.1093/jnci/djm311

Cited by 167 publications

(97 citation statements)

References 6 publications

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“…25 Several cases of nephrotic proteinuria have been reported in patients who were treated with sorafenib or sunitinib. 26,27 Proteinuria induced by VEGF inhibition may involve multiple pathways. VEGF is constitutively produced by podocytes with a function of activating VEGF receptor 2 on glomerular capillary endothelial cells, and its inhibition may cause a loss of endothelial fenestrations and podocytes and reduced proliferation of endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Kim²,

Baer³

et al. 2010

Journal of the American Society of Nephrology

202

127

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Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum-and non-platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P ϭ 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.

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Section: Discussionmentioning

confidence: 99%

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Kim²,

Baer³

et al. 2010

Journal of the American Society of Nephrology

202

127

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“…Fortunately, the incidence of renal toxicity by sorafenib was low [66], except for its use in combination with bevacizumab [67,68]. Blockade of the VEGF pathway and impairment of glomerular capillary endothelial cells may account for this complication.…”

Section: Renal Toxicitymentioning

confidence: 99%

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Gao

2015

Basic Clin Pharma Tox

144

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Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine-resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in longterm efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.Over the past few years, targeted therapy utilizing multi-tyrosine kinase inhibitors (TKIs) has been widely used for treatment of cancers. TKIs are designed to block specific cancer cell processes and are usually better tolerated than most conventional chemotherapeutic drugs. Sorafenib is the first orally active TKI approved by the Food and Drug Administration (FDA). Sorafenib mainly targets vascular endothelial growth factor (VEGFR1-3) and Raf kinases. Other reported targets include K-Ras, BRAF, V599E mutant BRAF, platelet-derived growth factor receptor-b (PDGFR-b), FMS-like tyrosine kinase 3 (FLT3), c-Kit and RET, and several other receptor tyrosine kinases (RTKs) via various modes of action, such as inhibition of the Ras/Raf/MAPK and PI3K/AKT/mTOR signalling pathways [1][2][3]. The anticancer activity of sorafenib thus results from a dual inhibitory effect towards angiogenesis and tumour cell proliferation. Sorafenib also possesses the function of inducing apoptosis in cancer cells by inhibiting the phosphorylation of initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukaemia-1(Mcl-1) [4].In 2007, sorafenib was approved by the FDA for the treatment of advanced hepatocellular cancer (HCC) [5,6] and metastatic renal cell cancer (RCC) [7,8]. Oral administration of sorafenib is associated with improved quality of life and prolonged overall survival of patients [9]. Recently, the most positive phase III results were observed in well-differentiated radioiodine-resistant thyroid cancer (DTC) [10], resulting in the increased use of sorafenib to treat patients with DTC.

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“…Endothelial dysfunction is considered to be a direct effect of VEGF signaling inhibition. VEGF upregulates endothelial nitric oxide synthase and prostacyclin, leading to nitric oxide (NO) production via the phosphoinositide 3-kinase/Akt and mitogen-activated protein kinase pathways [34]. Inhibition of VEGF signaling could lead to a decrease in NO and prostacyclin activity, altering vasodilatory ability and leading to increased vascular resistance and blood pressure.…”

Section: Pathogenesismentioning

confidence: 99%

“…It is reversible with cessation of the implicated agent, although rarely residual neurological deficits can persist [42]. Another syndrome of hypertension, proteinuria, and features of thrombotic microangiopathy (TMA) has been reported in association with sunitinib, sorafenib, and bevacizumab, either combined or as single agents [34,42]. The TMA was mostly localized to the kidney without all patients exhibiting thromobocytopenia, hemolytic anemia with schistocytosis, and renal dysfunction [42].…”

Section: Clinical Manifestations and Managementmentioning

confidence: 99%

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

et al. 2011

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Summary. The introduction of molecularly targeted anticancer therapies has brought the promise of longer survival times for select patients with cancers previously considered untreatable. However, it has also brought new toxicities that require understanding and management, sometimes for long periods of time. Vascular endothelial growth factor inhibitors are associated with a broad range of adverse effects, with vascular toxicity being particularly serious. This review focuses on the current understanding of the pathophysiology and mechanisms of macrovascular toxicities (hypertension, hemorrhage, and thromboembolism), their incidence and severity, the current clinical management, and implications in the advanced cancer setting. Movement of these agents into the early disease setting will alter the impact of these toxicities.Search Strategy and Selection Criteria. Information for this review was collected by searching PubMed/ Medline and American Society of Clinical Oncology abstract databases. The medical subject heading terms used included toxicity, hypertension, thromboembolism, hemorrhage, intestinal perforation, risk factors, pharmacokinetics, and metabolism, combined with free text search terms including, but not limited to, VEGF inhibitor*, bevacizumab, sunitinib, and sorafenib. Articles published in English before March 2010 were included, in addition to information from case reports and pharmaceutical agent package inserts. The Oncologist 2011;16:432-444

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A Preeclampsia-like Syndrome Characterized by Reversible Hypertension and Proteinuria Induced by the Multitargeted Kinase Inhibitors Sunitinib and Sorafenib

Cited by 167 publications

References 6 publications

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

Bevacizumab Increases Risk for Severe Proteinuria in Cancer Patients

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Noncardiac Vascular Toxicities of Vascular Endothelial Growth Factor Inhibitors in Advanced Cancer: A Review

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