Mechanisms of Hypertension Associated With BAY 43-9006

Veronese, Maria Luisa; Mosenkis, Ari; Flaherty, Keith T.; Gallagher, Maryann; Stevenson, James P.; Townsend, Raymond R.; O’Dwyer, Peter J.

doi:10.1200/jco.2005.02.0503

Cited by 300 publications

(196 citation statements)

References 24 publications

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“…Hypertension, a known complication of VEGFR signalling inhibition, is likely related with several factors, including diminished nitric oxide and prostacyclin synthesis (Scotland et al, 2005), diminished endothelial baroreceptor response (Yang et al, 2002), small artery and arteriole rarefaction (Ciuffetti et al, 2003) as well as increased vascular stiffness (Veronese et al, 2006). To our knowledge, this is the first clinical trial among malignant glioma patients to note an association between hypertension after VEGF-targeted therapy and improved outcome.…”

Section: Discussionmentioning

confidence: 89%

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

et al. 2009

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BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg À1 bevacizumab biweekly and 50 mg m À2 etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2a (HIF-2a) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade X3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

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Section: Discussionmentioning

confidence: 89%

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

et al. 2009

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“…However, patients can develop seizures and impaired vision acutely, so the diagnosis of posterior reversible leukoencephalopathy syndrome (PRES) needs to be considered. This is rare (Ͻ1% of patients treated with VEGFI therapy) and has been reported with bevacizumab, sorafenib, sunitinib, and vatalanib [40]. PRES can occur within 24 hours and up to months after VEGF inhibition.…”

Section: Clinical Manifestations and Managementmentioning

confidence: 99%

“…Lastly, increased arterial stiffness within the proximal and distal blood vessels may also contribute to the pathogenesis of hypertension [39]. In patients treated with sorafenib, increased aortic wall stiffness has been a postulated mechanism of hypertension, especially in the absence of underlying renovascular causes or blood volume-related changes [40].…”

Section: Pathogenesismentioning

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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“…Incidence ranges from 15% to 60%, depending on drug-and patient-related factors still being defined (10)(11)(12)(13)(14). Early and aggressive initiation of antihypertensive therapy can help maintain the treatment schedule (15) and reduce complications (16,17).…”

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confidence: 99%

Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition

Sunshine¹,

Dallabrida²,

Durand³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.

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Mechanisms of Hypertension Associated With BAY 43-9006

Abstract: Treatment with BAY 43-9006 is associated with a significant and sustained increase in BP. The lack of significant change in circulating factors suggests that these humoral factors had little role in the increase in BP.

Cited by 300 publications

References 24 publications

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study

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

Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition

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