Incidence and risk of hypertension associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a comprehensive network meta-analysis of 72 randomized controlled trials involving 30013 patients

Liu, Bo; Ding, Fengxia; Yang, Liu; Geng, Xin; Lin, Tao; He, Dawei; Zhang, Yuanyuan; Zhang, Deying; Wei, Guanghui

doi:10.18632/oncotarget.11813

Cited by 43 publications

(33 citation statements)

References 104 publications

(56 reference statements)

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“…Among patients receiving the TKIs, the total incidence of all-grade or highgrade hypertension was 23.0% and 4.4%, respectively; sunitinib, pazopanib, cabozantinib, vandetanib, motesanib, regorafenib, cediranib, and sorafenib were associated with the highest risk. 53 A separate study involving 1120 patients treated with TKIs observed a rapid and significant increase in systolic and diastolic BP after initiation of therapy, with a median onset of 29 days after first dose. Risk factors for treatment-induced hypertension in that cohort were preexisting hypertension, body mass index .25, and age .60 years.…”

Section: Tyrosine Kinase Inhibitors Of Vegf Signalingmentioning

confidence: 99%

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Estrada

Maldonado

Mallipattu

2019

JASN

142

153

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Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition's mediation of key downstream signaling pathways, specifically MAPK/ ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.

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Section: Tyrosine Kinase Inhibitors Of Vegf Signalingmentioning

confidence: 99%

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Estrada

Maldonado

Mallipattu

2019

JASN

142

153

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“…27,58 Hypertension is a known AE for TKIs. 81,82 The incidence ASSESSMENT OF CLINICAL EFFECTIVENESS NIHR Journals Library www.journalslibrary.nihr.ac.uk of diarrhoea in patients receiving vandetanib treatment for MTC appears to be similar to that reported for patients receiving vandetanib treatment for other cancers, 83 but the rates of any grade or high-grade severity rash and hypertension appear to be higher for vandetanib in MTC patients than in most other cancer patients, 84,85 which might be attributable to longer treatment duration. 85 It should be noted that patients with MTC have a substantial disease burden.…”

Section: Safety Outcomesmentioning

confidence: 66%

“…Hypertension is a known AE of TKIs. 81,82 The incidence rates of rash and hypertension appear to be higher for vandetanib in MTC patients than in most other cancer patients, 84,85 which might be attributable to a longer treatment duration. 85 ASSESSMENT OF CLINICAL EFFECTIVENESS NIHR Journals Library www.journalslibrary.nihr.ac.uk…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model

Tappenden

Hamilton

Kaltenthaler

et al. 2019

Health Technol Assess

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BackgroundMedullary thyroid cancer (MTC) is a rare form of cancer that affects patients’ health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq®; Ipsen, Paris, France) and vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC.Objectives(1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.Data sourcesPeer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers’ submissions.Review methodsA systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.ResultsThe systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower.LimitationsThe intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.ConclusionsThe identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.Future research priorities(1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.Study registrationThis study is registered as PROSPERO CRD42016050403.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…While concerns regarding increased blood pressure are of lesser concern in the context of transient inhibition, such as would be performed for management of viral disease and acute thrombotic events, this issue may affect enthusiasm for pursuing PLD2 inhibition in the setting of long-term cancer or neurodegenerative treatment. In particular for cancer, some therapeutics, for example, VEGFR tyrosine kinase inhibitors, are independently associated with a substantially elevated risk of hypertension development 48 , and thus use of a PLD2 inhibitor in parallel with them could result in synergistic adverse effects. Nonetheless, murine studies do not always predict the outcomes of complex signaling pathways in humans.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway

Nelson

Jiang

Gadbery

et al. 2017

Sci Rep

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The Phospholipase D (PLD) superfamily is linked to neurological disease, cancer, and fertility, and a recent report correlated a potential loss-of-function PLD2 polymorphism with hypotension. Surprisingly, PLD2 −/− mice exhibit elevated blood pressure accompanied by associated changes in cardiac performance and molecular markers, but do not have findings consistent with the metabolic syndrome. Instead, expression of endothelial nitric oxide synthase (eNOS), which generates the potent vasodilator nitric oxide (NO), is decreased. An eNOS inhibitor phenocopied PLD2 loss and had no further effect on PLD2 −/− mice, confirming the functional relationship. Using a human endothelial cell line, PLD2 loss of function was shown to lower intracellular free cholesterol, causing upregulation of HMG Co-A reductase, the rate-limiting enzyme in cholesterol synthesis. HMG Co-A reductase negatively regulates eNOS, and the PLD2-deficiency phenotype of decreased eNOS expression and activity could be rescued by cholesterol supplementation and HMG Co-A reductase inhibition. Together, these findings identify a novel pathway through which the lipid signaling enzyme PLD2 regulates blood pressure, creating implications for on-going therapeutic development of PLD small molecule inhibitors. Finally, we show that the human PLD2 polymorphism does not trigger eNOS loss, but rather creates another effect, suggesting altered functioning for the allele.

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Incidence and risk of hypertension associated with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: a comprehensive network meta-analysis of 72 randomized controlled trials involving 30013 patients

Cited by 43 publications

References 104 publications

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model

Phospholipase D2 loss results in increased blood pressure via inhibition of the endothelial nitric oxide synthase pathway

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