Vascular Cardio-Oncology: Vascular Endothelial Growth Factor inhibitors and hypertension

Versmissen, Jorie; Colafella, Katrina M Mirabito; Koolen, Stijn L.W.; Danser, A.H. Jan

doi:10.1093/cvr/cvz022

Cited by 71 publications

(68 citation statements)

References 133 publications

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“…The rise of plasma VEGF-A, VEGF-D, PlGF levels and decrease in shedding of Tie-2 during treatment are consistent with literature and indicate that dovitinib effectively blocks angiogenesis via the angiopoietin (Ang)/Tie-2 and VEGFR signaling pathways [17,18]. More than half of dovitinibtreated patients developed grade 3-4 hypertension, which is an on-target effect of VEGFR inhibition previously associated with treatment efficacy [19]. Despite the high rate of treatment-emergent toxicity resulting in dose reduction and/or interruption, shrinkage of viable tumor mass occurred in a considerable number of patients.…”

Section: Discussionsupporting

confidence: 84%

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study

et al. 2021

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Background. Hepatocellular carcinoma (HCC) recurrence rates following locoregional treatment are high. As multireceptor tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptors (VEGFR) are effective in advanced HCC, we assessed the efficacy and safety of neoadjuvant systemic treatment with dovitinib in early and intermediate stage HCC. Methods. Twenty-four modified Child-Pugh class A early and intermediate stage HCC patients received neoadjuvant oral dovitinib 500 mg daily (5 days-on/2-days-off) during 4 weeks, followed by locoregional therapy. Primary endpoints were objective response rates and intratumoral blood flow changes. Secondary endpoints were safety, pharmacodynamical plasma markers of VEGFR-blockade, time to progression (TTP) and overall survival (OS). Results. mRECIST overall response rate was 48%, including 13% complete remission, and despite dose reduction/interruption in 83% of patients, intratumoral perfusion index decreased significantly. Grade 3-4 adverse events, most frequently (on-target) hypertension (54%), fatigue (25%) and thrombocytopenia (21%), occurred in 88% of patients. Plasma VEGF-A, VEGF-D and PlGF increased significantly, while sTie-2 decreased, consistent with VEGFR-blockade. Following neoadjuvant dovitinib, all patients could proceed to their original planned locoregional treatment. No delayed toxicity occurred. Seven patients (3 early, 4 intermediate stage) underwent orthotopic liver transplant after median 11.4 months. Censoring at transplantation, median TTP and OS were 16.8 and 34.8 months respectively; median cancer-specific survival not reached. Conclusion. Already after a short 4-week dovitinib treatment period, intratumoral blood flow reduction and modest antitumor responses were observed. Although these results support use of systemic neoadjuvant strategies, the poor tolerability indicates that dovitinib dose adaptations are required in HCC. The Oncologist 2021;9999:• •

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Section: Discussionsupporting

confidence: 84%

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study

et al. 2021

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“…Most published literature on this topic recommends using either dihydropyridine calcium channel blockers (CCB) or RAS inhibition as first line treatment for hypertension. 27,38,[42][43][44][45] VEGF: vascular endothelial growth factor; CCB: calcium channel blocker; ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; Cycle: chemotherapy cycles. *This algorithm is based on the NCI guidelines 42 ; however, other recommendations suggest less stringent blood pressure control.…”

Section: Targeted Cancer Therapiesmentioning

confidence: 99%

“…44,47,48 CCBs are also effective, but for patients on TKIs, non-dihydropyridine CCB should be avoided as they inhibit the cytochrome p450 system that metabolizes TKIs and can therefore potentially worsen hypertension. 45 Beta blockers can be started second or third line if needed, or earlier if there is another indication for their use. Diuretics have also been used, but require caution given the frequency of vomiting, diarrhea, and poor appetite caused by the other chemotherapeutics frequently administered with VEGF inhibitors.…”

Section: Targeted Cancer Therapiesmentioning

confidence: 99%

“…Most published literature on this topic recommends using either dihydropyridine calcium channel blockers (CCB) or RAS inhibition as first line treatment for hypertension. 27,38,42–45 The current evidence suggests that the RAS does not play a substantial role in the pathogenesis of hypertension caused by VEGF inhibitors, so it would seem that RAS inhibition should not provide much benefit. In one retrospective study of patients with renal cell cancer on TKIs, angiotensin-converting enzyme inhibitors and aldosterone receptor blockers were not associated with a blood pressure decline while CCB and potassium sparing diuretics were.…”

Section: Overview Of Hypertension With Anti-cancer Agentsmentioning

confidence: 99%

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Onco-hypertension: Overview of hypertension with anti-cancer agents

Ruf

Yarandi

Ortiz-Melo

et al. 2021

Journal of Onco-Nephrology

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Onco-hypertension is an emerging field investigating the relationship between hypertension and cancer. This paper details one part of this relationship—the effect of anti-cancer agents on blood pressure. We review the evidence linking targeted therapies, immunotherapy, traditional chemotherapies, and hormonal agents with hypertension. Proposed pathophysiological mechanisms vary by drug but include endothelial dysfunction, altered sodium homeostasis, and nephrotoxicity. Despite growing interest in the field, there is a paucity of data on the clinical significance of treatment related hypertension and the optimal management strategy. This should be a focus of future studies.

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“…Vascular damage in the cardiovascular system can be caused not only by anti-angiogenic chemotherapy (inhibitors of vascular endothelial growth factor (VEGFi), but also by anti-tumor antibiotics (bleomycin and anthracyclines) ( 5 , 6 ). The first line of treatments includes monoclonal antibodies (e.g., bevacizumab), and multiple kinase inhibitors such as sunitinib, a multi-targeted inhibitor, or sorafenib ( 7 ). In addition, plant alkaloids (taxanes, vinca alkaloids), alkylating agents (cisplatin, cyclophosphamide), antimetabolites (5-fluorouracil), and radiation therapy also foster vascular damages ( 8 ) ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

Updates on Anticancer Therapy-Mediated Vascular Toxicity and New Horizons in Therapeutic Strategies

Hsu

Mammadova

Benkirane‐Jessel

et al. 2021

Front. Cardiovasc. Med.

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Vascular toxicity is a frequent adverse effect of current anticancer chemotherapies and often results from endothelial dysfunction. Vascular endothelial growth factor inhibitors (VEGFi), anthracyclines, plant alkaloids, alkylating agents, antimetabolites, and radiation therapy evoke vascular toxicity. These anticancer treatments not only affect tumor vascularization in a beneficial manner, they also damage ECs in the heart. Cardiac ECs have a vital role in cardiovascular functions including hemostasis, inflammatory and coagulation responses, vasculogenesis, and angiogenesis. EC damage can be resulted from capturing angiogenic factors, inhibiting EC proliferation, survival and signal transduction, or altering vascular tone. EC dysfunction accounts for the pathogenesis of myocardial infarction, atherothrombosis, microangiopathies, and hypertension. In this review, we provide a comprehensive overview of the effects of chemotherapeutic agents on vascular toxicity leading to hypertension, microvascular rarefaction thrombosis and atherosclerosis, and affecting drug delivery. We also describe the potential therapeutic approaches such as vascular endothelial growth factor (VEGF)-B and prokineticin receptor-1 agonists to maintain endothelial function during or following treatments with chemotherapeutic agents, without affecting anti-tumor effectiveness.

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Vascular Cardio-Oncology: Vascular Endothelial Growth Factor inhibitors and hypertension

Cited by 71 publications

References 133 publications

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study

Neoadjuvant Treatment with Angiogenesis-Inhibitor Dovitinib Prior to Local Therapy in Hepatocellular Carcinoma: A Phase II Study

Onco-hypertension: Overview of hypertension with anti-cancer agents

Updates on Anticancer Therapy-Mediated Vascular Toxicity and New Horizons in Therapeutic Strategies

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