The Role of Angiogenesis Inhibitors in Hypertension: Following “Ariadne’s Thread”

The Role of Angiogenesis Inhibitors in Hypertension: Following “Ariadne’s Thread” Abstract Arterial hypertension (HT) is one of the most frequently recorded comorbidities among patients under antiangiogenic therapy. Inhibitors of vascular endothelial growth factor and vascular endothelial growth factor receptors are most commonly involved in new onset or exacerbation of pre-existing controlled HT. From the pathophysiology point of view, data support that reduced nitric oxide release and sodium and fluid retention, microvascular rarefaction, elevated vasoconstrictor levels, and globular injury might contribute to HT. The purpose of this review was to present recent evidence regarding the incidence of HT induced by antiangiogenic agents, to analyze the pathophysiological mechanisms, and to summarize current recommendations for the management of elevated blood pressure in this field. blood pressure; cancer, angiogenesis, chemotherapy; hypertension Arterial hypertension (HT) is considered one of the most commonly seen comorbidities in patients with malignancy due to the use of chemotherapeutic agents.1 Before the introduction of antiangiogenic medications, the prevalence of HT in oncological patients was similar to the general population. Nevertheless, increased use of these agents along with consequent prolonged survival of cancer patients contributed to the new onset or worsening of pre-existing HT.2 After initiation of treatment, the vast majority of oncological patients have an absolute increase in blood pressure (BP), with a subset development of HT that ranges from 11% to 43%. Drug-related HT might occur from initiation of antiangiogenic therapy until a year after treatment onset.3,4 The incidence and severity of HT are influenced by patient age, specific medications used and dosage, cancer type, history of HT, and pre-existing cardiovascular risk factors.5,6 Given the fact that the increased BP levels might be responsible for therapy withdrawal, HT management is crucial in order to avoid interruption of treatment.7 Among newer cancer therapies, antiangiogenic drugs are the most frequently involved in new onset or exacerbation of pre-existing but controlled HT. In particular, inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) have received the most attention.8–10 Management of HT in cancer patients treated with antiangiogenic agents resembles the Greek myth of Theseus and Minotaur; the hero had to follow Ariadne’s thread in order to retrace the path and get out of the labyrinth. In this context, the complexity of HT requires a stepwise approach including close collaboration of oncologists and cardiologists, repeated BP measurements, and cardiovascular profile assessment to avoid temporary or permanent interruption of chemotherapy and to achieve optimal HT control. The purpose of this review was to present recent evidence connecting HT to antiangiogenic factors and to summarize current recommendations of HT management in this field. Angiogenesis Angiogenesis is the process of new blood vessel sprouting from pre-existing blood vessels and is essential for tumor growth and metastasis. Usually, the level of angiogenic factor expression reflects cancer aggressiveness.11–13 Both activator and inhibitor molecules are implicated in the angiogenesis process. Numerous proteins have been identified as angiogenic activators such as VEGF, fibroblast growth factor, angiogenin, transforming growth factor-α, transforming growth factor-β, tumor necrosis factor-α, platelet-derived endothelial growth factor (PDGF), granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor. On the other hand, proteins that inhibit angiogenesis include angiostatin, endostatin, interferon, platelet factor 4, thrombospondin, prolactin 16 kD fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3.13,14 The most important pathway of the angiogenesis process is mediated by VEGF and its tyrosine kinase receptors (VEGFR-1, -2, and -3). There are 5 different VEGF isoforms (A, B, C, D, and placenta growth factor) with VEGF-A being the most clinically relative protein-promoting angiogenesis through binding mainly to VEGFR-2 (Table 1).10,15 Table 1. Antiangiogenic agents and FDA-approved indications Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Abbreviations: FDA, food and drug administration; RCC, renal cell carcinoma. View Large Table 1. Antiangiogenic agents and FDA-approved indications Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Abbreviations: FDA, food and drug administration; RCC, renal cell carcinoma. View Large Pathophysiology of HT The exact mechanism of HT induced by antiangiogenic drugs is not well understood yet. Several theories have been proposed suggesting that multiple mechanisms contribute to the development of HT. Impaired endothelial function along with microvascular rarefaction and glomerular injury might be implicated in HT secondary to antiangiogenic therapy (Figure 1). Figure 1. View largeDownload slide Pathophysiology of HT induced by antiangiogenic agents. Abbreviations: ET-1, endothelin-1; NO, nitric oxide; sFlt-1: soluble Fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factors; VEGFR, vascular endothelial growth factor receptor. Figure 1. View largeDownload slide Pathophysiology of HT induced by antiangiogenic agents. Abbreviations: ET-1, endothelin-1; NO, nitric oxide; sFlt-1: soluble Fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factors; VEGFR, vascular endothelial growth factor receptor. Endothelial dysfunction VEGF exerts pleiotropic effects on endothelial cells including migration and invasion into the basement membrane and proliferation.14 Thus, VEGF inhibition induces endothelial dysfunction leading to an imbalance between endothelium-derived relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2) and endothelium-derived contractile factors such as endothelin-1 (ET-1).16,17 It is well established that activation of VEGFR by VEGF prompts the expression of nitric oxide synthase by endothelial cells and PGI2 resulting in vasodilation due to NO release via phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Therefore, VEGF and VEGFR inhibition and subsequent vasoconstriction might be a critical mechanism underlying treatment-induced HT. Additionally, impaired NO production promotes sodium and fluid retention and further elevations of BP.18–20 Soluble VEGFR-1, also known as soluble Flt-1, is a variant of VEGFR lacking the transmembrane and cytoplasmic domains and is expressed by endothelial cells, monocytes, and placenta.21,22 Available data support that soluble Flt-1 is overexpressed in several tumors types23,24 and binds VEGF causing endothelial dysfunction, decreasing angiogenesis, impairing capillary repair, and increasing proteinuria.25,26 Moreover, elevated levels of the potent vasoconstrictor ET-1 have been detected in patients treated with the VEGFR inhibitor sunitinib.27 According to a study, soluble Flt-1 infusion in mice augmented ET-1–mediated vasoconstriction contributing to BP elevation.28 Apart from vasoconstriction, ET-1 activates vascular NADPH oxidase resulting in oxidative stress through enhanced reactive oxygen species production.29,30 Microvascular rarefaction It is defined as a decrease in the number of perfused capillaries in an area of tissue. Angiogenesis inhibition might result in microvascular rarefaction leading to increased vascular resistance and HT. In a small study of 18 oncological patients treated with bevacizumab, microvascular rarefaction and raised BP were observed in all individuals.19,20,31 Glomerular injury Angiogenesis inhibition might generate renal thrombotic microangiopathy and subsequent glomerular injury, but the exact mechanisms are not clear yet. In vitro, VEGF induces the formation of fenestrations in glomerular endothelial cells that are requisite for the permeability of the glomerular filtration barrier. Thus, the inhibition of VEGF might result in the loss of the healthy fenestrated phenotype and the development of thrombotic microangiopathy and microvascular injury.32 Antiangiogenic Agents and HT The association of HT with antiangiogenic drugs is a matter of emerging clinical concern. After initiation of therapy, severe BP rises could lead to the permanent discontinuation of these agents.33 Numerous studies aimed to investigate the overall incidence of HT among oncological patients receiving antiangiogenic factors (Table 2). Of note, in all studies, patients were either normotensives or controlled hypertensives before the initiation of treatment. The majority of trials used the Common Terminology Criteria for Adverse Events (CTCAE) to classify hypertensive events (Table 3). According to these criteria, the term “all-grade” refers to all grades from 1 to 4, while the term “high-grade” refers solely to any grade between 3 and 4, respectively.34 Table 2. Studies that investigated the incidence of all-grade and high-grade HT among cancer patients treated with antiangiogenic agents Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Abbreviations: CCC, cholangiocarcinoma; CRC, colorectal cancer; GC, gastric cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HT, hypertension; NA, nonavailable; NSCLC, non-small cell lung carcinoma; PC, pancreatic cancer; RCC, renal cell carcinoma; SCLC, small cell lung cancer; TC, thyroid cancer; UC, urothelial carcinoma. View Large Table 2. Studies that investigated the incidence of all-grade and high-grade HT among cancer patients treated with antiangiogenic agents Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Abbreviations: CCC, cholangiocarcinoma; CRC, colorectal cancer; GC, gastric cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HT, hypertension; NA, nonavailable; NSCLC, non-small cell lung carcinoma; PC, pancreatic cancer; RCC, renal cell carcinoma; SCLC, small cell lung cancer; TC, thyroid cancer; UC, urothelial carcinoma. View Large Table 3. Classification of HT according to CTCAE criteria and treatment indications Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Abbreviations: CTCAE, common terminology criteria for adverse events; HT, hypertension. View Large Table 3. Classification of HT according to CTCAE criteria and treatment indications Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Abbreviations: CTCAE, common terminology criteria for adverse events; HT, hypertension. View Large Bevacizumab Bevacizumab is a monoclonal antibody that targets VEGF molecule.35 There is evidence that patients treated with bevacizumab have a 3-fold higher risk of HT.36 A retrospective study of 154 patients treated with bevacizumab showed that 35% of them experienced HT secondary to therapy after a median time of 11 weeks.37 HT was most likely to occur in patients with pre-existing HT. Indeed, 8 in 10 individuals experienced an exacerbation of pre-existing HT. Likewise, the increased risk of bevacizumab-induced HT was revealed in a meta-analysis that included 12,656 oncological patients. The incidence of all-grade HT in patients receiving bevacizumab was 23.6% with 7.9% of them being high-grade. The relative risk of all-grade and high-grade HT was 3.02 and 5.28, respectively, compared with controls. The risk of high-grade HT also varied among patients with different tumor type with significantly increased risk observed in patients with renal cell carcinoma (RCC), non-small cell lung cancer, pancreatic cancer, and colorectal cancer.38 Sunitinib Sunitinib is a potent inhibitor of VEGFR-1 and -2, PDGF receptor-a and -b, fetal liver tyrosine kinase receptor 3 (FLT3), and c-Kit (stem-cell factor [SCF] receptor).39 In a meta-analysis of 5,000 patients treated with sunitinib, the calculated summary incidence of all-grade HT was 21.6%, whereas the incidence of high-grade HT was 6.8%. In addition, the risk of HT varied with tumor type and dosing schedule of therapy being significantly higher in patients with RCC and continuous daily-dosing schedule.40 Moreover, among 181 patients with metastatic RCC, 33% of them developed HT after initiating sunitinib.41 Sorafenib Sorafenib is a multikinase inhibitor of VEGFR-1, -2, and -3, RET receptor tyrosine kinase, RAF kinase, and PDGF receptor-b.42 In 2 meta-analyses, the overall incidence of sorafenib-induced high-grade HT among oncological patients was 4.3% and 6%, respectively.43,44 Additionally, among 4,600 cancer patients, 23.4% of them developed all-grade HT and 5.7% of them developed high-grade HT. No significant difference was noted between individuals with RCC or non-RCC malignancy.45 Axitinib Axitinib is a highly selective inhibitor of VEGFR-1, -2, and -3.46 In a total of 1,148 cancer patients, the overall incidence of all-grade and high-grade HT after initiating therapy was 40.1% and 13.1%, respectively. The risk was significantly higher in subjects with RCC.47 In another study of 52 oncological patients treated with axitinib, 63.5% of them developed HT after 5-year follow-up.48 There is evidence that the risk of HT is greater in patients treated with axitinib compared with sorafenib. Indeed, 2 studies confirmed this ascertainment. In the first one, the incidence of axitinib-induced HT was 49%, whereas the incidence of sorafenib-induced HT was 29%.49 The other study included 723 patients that were randomly allocated to receive axitinib or sorafenib. HT was developed in 42% of subjects treated with axitinib, whereas 30% of them treated with sorafenib.50 Pazopanib Pazopanib is a multityrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGF receptor-a and -b and c-Kit.51 In a cohort of normotensive oncological patients treated with pazopanib, 33% of them developed HT.52 Similarly, a more recent study revealed that 57% of individuals treated with pazopanib developed HT after the initiation of therapy. The incidence of a new onset event was 17% within a median time of 19 days.53 Ramucirumab Ramucirumab is a VEGFR-2 inhibitor that blocks the binding of VEGF.54 Among 3,851 cancer patients, the risk of all-grade and high-grade HT was greater in subjects treated with ramucirumab compared with control group (20% vs. 7% for all-grade HT; 9% vs. 3% for high-grade HT).55 A meta-analysis also showed that the risk of ramucirumab-induced all-grade and high-grade HT was 11–38% and 6–16%, respectively, whereas the incidence in the control group was significantly lower. In addition, patients with gastric and metastatic colorectal cancer were more likely to develop HT.56 Regorafenib Regorafenib inhibits VEGFR-1, -2, and -3, PDGF-b, fibroblast growth factor receptor-1, c-Kit, RET protein, and BRAF protein.57 A meta-analysis that included 5 clinical trials revealed that the pooled incidence of all-grade and high-grade HT in patients treated with regorafenib was 44% and 13%, respectively. Moreover, the risk varied with tumor type and was higher among patients with gastrointestinal stromal tumors (56%) and RCC (49%).58 Aflibercept Aflibercept is a recombinant fusion protein that blocks VEGFRs and is a more potent VEGF blocker than bevacizumab.59 According to a meta-analysis that included 4,451 patients with metastatic colorectal cancer, the use of aflibercept was associated with a significantly increased risk of all-grade (42.4%) and high-grade (17.4%) HT.60 Cabozantinib Cabozantinib is a tyrosine kinase inhibitor targeting VEGFR-2. A study that included patients with thyroid cancer revealed that the risk of all-grade and high-grade HT was greater in group of subjects treated with cabozantinib compared with control group (33% vs. 5% for all-grade HT; 8% vs. 1% for high-grade HT).61 In a more recent trial, patients with metastatic RCC were randomly assigned 1:1 to cabozantinib or everolimus, a nonangiogenesis inhibitor. The incidence of HT was higher among individuals receiving cabozantinib (37% vs. 7% for all-grade HT; 15% vs. 3% for high-grade HT).62 Lenvatinib Lenvatinib is an inhibitor of VEGFR-1, -2, and -3, fibroblast growth factor receptor-1, -2, -3, and -4, PDGF receptor-a, RET, and c-Kit.63 The safety and efficacy of lenvatinib were evaluated in SELECT trial where the risk of HT was higher among patients received lenvatinib compared with controls (68% vs. 9% for all-grade HT; 42% vs. 2% for high-grade HT).64,65 Vandetanib Vandetanib is an agent that selectively targets VEGFR, RET protein, and epidermal growth factor receptor. In a study that included patients with locally advanced or metastatic medullary thyroid cancer, individuals treated with vandetanib were at greater risk of HT compared with controls (32% vs. 5%).66 Therefore, available data conclude that the use of antiangiogenic agents acts as an additional risk factor contributing to the increased incidence of HT in oncological patients. HT as a Predictive Factor to Antiangiogenic Therapy There is evidence suggesting that HT might be considered as a clinical marker predicting the efficacy of antiangiogenic therapy. In this context, response evaluation criteria in solid tumors (RECIST) criteria were updated the previous decade. It is a set of published rules that define when cancer patients improve (respond), stay the same (stable), or worsen (progression) during treatment.67 In a cohort of patients with metastatic RCC on sunitinib, the development of HT was correlated with higher response to therapy.68 These findings were consistent with another study that included individuals with the same type of cancer treated with bevacizumab. Patients that did not develop HT had greater degree of progressive disease and shorter time to disease progression.69 Furthermore, a retrospective study that evaluated individuals with metastatic colorectal cancer treated with bevacizumab showed that 73% of patients with bevacizumab-induced HT presented response to treatment and 98% achieved disease control. Conversely, only 18% of controls presented response, and 64% of them achieved disease control.70 However, more data are needed in order to clarify the clinical significance of such observational studies. Management of HT National Cancer Institute (NCI) issued recommendations for the BP management among patients receiving antiangiogenic agents and set the goal of 140/90 mm Hg.71 European Society of Cardiology (ESC) also published a position paper on cancer treatment and cardiovascular toxicity including HT. The recommended goal was <140/90 mm Hg or lower in case of overt proteinuria.72 However, these values are not yet in accordance with the recently published guidelines for HT management in the general population that target lower than 130/80 mm Hg.73 The primary goal in this setting is to optimize risk assessment, monitoring, and safe administration of antiangiogenic drugs. The pretreatment assessment includes repeated BP measurements along with history, physical examination, and laboratory tests to estimate the cardiovascular risk profile of each patient. Pain relief and stress management are mandatory for adequate BP evaluation.71,72 Once therapy has been started, BP should be monitored weekly during the first cycle and then at least every 2 or 3 weeks. After the first cycle is completed and a stable BP has been achieved, BP control might be managed with routine clinical evaluations or home BP monitoring. Initiation of antihypertensive drugs should be considered when BP is higher than 140/90 mm Hg or there is an increase in diastolic BP of at least 20 mm Hg compared with pretreatment values. Temporary interruption of antiangiogenic agents might be necessary if HT is difficult to control or patients are symptomatic because of the excess BP elevation. Once BP control is achieved, therapy can be restarted to succeed maximum cancer efficacy (Figure 2).71 Figure 2. View largeDownload slide Management of HT in oncological patients. Abbreviations: CV: cardiovascular, HT: hypertension. Figure 2. View largeDownload slide Management of HT in oncological patients. Abbreviations: CV: cardiovascular, HT: hypertension. Early detection of HT and sufficient management of BP elevations are critical to avoid severe complications. Hence, aggressive pharmacological management is recommended. However, there are no clear data regarding the superiority of any class of antihypertensive drug for HT management in oncological patients. Although there are inconclusive data concerning the renin levels during antiangiogenic therapy,27,74 renin–angiotensin system (RAS) inhibitors are frequently the initial treatment of choice unless there are obvious contraindications.71,72,75 A retrospective study that evaluated patients with bevacizumab-induced HT revealed that quinapril, an angiotensin-converting enzyme inhibitor (ACE-I), achieved better BP control than other antihypertensive agents.37 Another study showed that the majority of oncological patients were successfully managed with amlodipine within 7 days.76 Thus, calcium channel blockers might constitute an alternative choice. Nonetheless, nondihydropyridine calcium channel blockers (verapamil and diltiazem) should be avoided when sunitinib or sorafenib is used due to pharmacokinetic interactions, since they are inhibitors of CYP3A4 system that is implicated in the metabolism of both sunitinib and sorafenib.75 Furthermore, ACE-I and beta-blockers are the preferred antihypertensive medications among patients with heart failure or at risk of heart failure or left ventricular dysfunction. Drugs that increase NO release, such as the beta1-blocker nebivolol, may be considered for BP control. Other vasodilator beta-blockers, such as carvedilol, can also be used.72 Given the relationship between VEGF and NO, nitrates or phosphodiesterase inhibitors might be an alternative mechanistic treatment as NO donors.75 Lifestyle modifications should be also encouraged including weight loss, if needed, aerobic exercise, diet low in total and saturated fat, salt restriction, and limitation in alcohol consumption.75 In addition, some agents such as nonsteroidal anti-inflammatory drugs (including cyclooxygenase 2 inhibitors), adrenal steroid hormones, erythropoietin, oral contraceptive hormones, and sympathomimetics (methylphenidate) that are commonly prescribed by oncologists might also increase BP. Even though there is no evidence that HT is more frequent or more severe in patients treated with the abovementioned drugs, while on antiangiogenic therapy, elevated doses of antihypertensive drugs or more frequent BP measurements are recommended.71,72 To date, there are no adequate data suggesting the prophylactic use of antihypertensive drugs in normotensive patients before initiating therapy with antiangiogenic agents. A prospective clinical study that included 126 patients treated with cediranib revealed that antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. However, severe HT (systolic BP >180 mm Hg or diastolic BP >110 mm Hg) occurred in only 1 patient received prophylaxis vs. 18 that did not receive prophylaxis.77 Further studies are required in this field. Conclusions The vicious circle between cancer and high BP is an evolving matter of concern considering the high prevalence of both conditions. Among newer cancer therapies, antiangiogenic agents are the most frequently involved in the development of HT implicating multiple pathophysiological mechanisms. Thus, HT management remains crucial in order to avoid treatment withdrawal. Collaboration of oncologists and cardiologists is imperative to prevent and manage HT guaranteeing best patients’ outcomes. Disclosure The authors declared no conflict of interest. References 1. Dreyfus B , Kawabata H , Gomez A . Selected adverse events in cancer patients treated with vascular endothelial growth factor inhibitors . Cancer Epidemiol 2013 ; 37 : 191 – 196 . Google Scholar CrossRef Search ADS PubMed 2. Souza VB , Silva EN , Ribeiro ML , Martins WdeA . Hypertension in patients with cancer . Arq Bras Cardiol 2015 ; 104 : 246 – 252 . Google Scholar PubMed 3. Milan A , Puglisi E , Ferrari L , Bruno G , Losano I , Veglio F . Arterial hypertension and cancer . Int J Cancer 2014 ; 134 : 2269 – 2277 . Google Scholar CrossRef Search ADS PubMed 4. Small HY , Montezano AC , Rios FJ , Savoia C , Touyz RM . Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome . Can J Cardiol 2014 ; 30 : 534 – 543 . Google Scholar CrossRef Search ADS PubMed 5. Izzedine H , Massard C , Spano JP , Goldwasser F , Khayat D , Soria JC . VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management . Eur J Cancer 2010 ; 46 : 439 – 448 . Google Scholar CrossRef Search ADS PubMed 6. Hamnvik OP , Choueiri TK , Turchin A , McKay RR , Goyal L , Davis M , Kaymakcalan MD , Williams JS . Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway . Cancer 2015 ; 121 : 311 – 319 . Google Scholar CrossRef Search ADS PubMed 7. Azizi M , Chedid A , Oudard S . Home blood-pressure monitoring in patients receiving sunitinib . N Engl J Med 2008 ; 358 : 95 – 97 . Google Scholar CrossRef Search ADS PubMed 8. Hurwitz H , Fehrenbacher L , Novotny W , Cartwright T , Hainsworth J , Heim W , Berlin J , Baron A , Griffing S , Holmgren E , Ferrara N , Fyfe G , Rogers B , Ross R , Kabbinavar F . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med 2004 ; 350 : 2335 – 2342 . Google Scholar CrossRef Search ADS PubMed 9. Gurevich F , Perazella MA . Renal effects of anti-angiogenesis therapy: update for the internist . Am J Med 2009 ; 122 : 322 – 328 . Google Scholar CrossRef Search ADS PubMed 10. Kerbel RS . Tumor angiogenesis . N Engl J Med 2008 ; 358 : 2039 – 2049 . Google Scholar CrossRef Search ADS PubMed 11. Folkman J . Tumor angiogenesis: therapeutic implications . N Engl J Med 1971 ; 285 : 1182 – 1186 . Google Scholar CrossRef Search ADS PubMed 12. Cao Y , Arbiser J , D’Amato RJ , D’Amore PA , Ingber DE , Kerbel R , Klagsbrun M , Lim S , Moses MA , Zetter B , Dvorak H , Langer R . Forty-year journey of angiogenesis translational research . Sci Transl Med 2011 ; 3 : 114rv3 . Google Scholar PubMed 13. Nishida N , Yano H , Nishida T , Kamura T , Kojiro M . Angiogenesis in cancer . Vasc Health Risk Manag 2006 ; 2 : 213 – 219 . Google Scholar CrossRef Search ADS PubMed 14. Rajabi M , Mousa SA . The role of angiogenesis in cancer treatment . Biomedicines 2017 ; 5 : 34 . Google Scholar CrossRef Search ADS 15. Koch S , Claesson-Welsh L . Signal transduction by vascular endothelial growth factor receptors . Cold Spring Harb Perspect Med 2012 ; 2 : a006502 . Google Scholar CrossRef Search ADS PubMed 16. Tio RA , Wijpkema J , Tan ES , Asselbergs FW , Hospers GA , Jessurun GA , Zijlstra F . Reduction of endothelial dysfunction following VEGF gene therapy . Neth Heart J 2005 ; 13 : 139 – 141 . Google Scholar PubMed 17. Winnik S , Lohmann C , Siciliani G , von Lukowicz T , Kuschnerus K , Kraenkel N , Brokopp CE , Enseleit F , Michels S , Ruschitzka F , Lüscher TF , Matter CM . Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis—implications for cardiovascular safety . Int J Cardiol 2013 ; 168 : 2453 – 2461 . Google Scholar CrossRef Search ADS PubMed 18. Keefe D , Bowen J , Gibson R , Tan T , Okera M , Stringer A . Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review . Oncologist 2011 ; 16 : 432 – 444 . Google Scholar CrossRef Search ADS PubMed 19. Robinson ES , Khankin EV , Karumanchi SA , Humphreys BD . Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker . Semin Nephrol 2010 ; 30 : 591 – 601 . Google Scholar CrossRef Search ADS PubMed 20. Hayman SR , Leung N , Grande JP , Garovic VD . VEGF inhibition, hypertension, and renal toxicity . Curr Oncol Rep 2012 ; 14 : 285 – 294 . Google Scholar CrossRef Search ADS PubMed 21. Barleon B , Reusch P , Totzke F , Herzog C , Keck C , Martiny-Baron G , Marmé D . Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors . Angiogenesis 2001 ; 4 : 143 – 154 . Google Scholar CrossRef Search ADS PubMed 22. Hornig C , Barleon B , Ahmad S , Vuorela P , Ahmed A , Weich HA . Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids . Lab Invest 2000 ; 80 : 443 – 454 . Google Scholar CrossRef Search ADS PubMed 23. Yamaguchi T , Bando H , Mori T , Takahashi K , Matsumoto H , Yasutome M , Weich H , Toi M . Overexpression of soluble vascular endothelial growth factor receptor 1 in colorectal cancer: association with progression and prognosis . Cancer Sci 2007 ; 98 : 405 – 410 . Google Scholar CrossRef Search ADS PubMed 24. Toi M , Bando H , Ogawa T , Muta M , Hornig C , Weich HA . Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer . Int J Cancer 2002 ; 98 : 14 – 18 . Google Scholar CrossRef Search ADS PubMed 25. Kendall RL , Wang G , Thomas KA . Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR . Biochem Biophys Res Commun 1996 ; 226 : 324 – 328 . Google Scholar CrossRef Search ADS PubMed 26. Maynard SE , Min JY , Merchan J , Lim KH , Li J , Mondal S , Libermann TA , Morgan JP , Sellke FW , Stillman IE , Epstein FH , Sukhatme VP , Karumanchi SA . Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia . J Clin Invest 2003 ; 111 : 649 – 658 . Google Scholar CrossRef Search ADS PubMed 27. Kappers MH , van Esch JH , Sluiter W , Sleijfer S , Danser AH , van den Meiracker AH . Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels . Hypertension 2010 ; 56 : 675 – 681 . Google Scholar CrossRef Search ADS PubMed 28. Amraoui F , Spijkers L , Hassani Lahsinoui H , Vogt L , van der Post J , Peters S , Afink G , Ris-Stalpers C , van den Born BJ . SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice . PLoS One 2014 ; 9 : e91897 . Google Scholar CrossRef Search ADS PubMed 29. Dong F , Zhang X , Wold LE , Ren Q , Zhang Z , Ren J . Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1 . Br J Pharmacol 2005 ; 145 : 323 – 333 . Google Scholar CrossRef Search ADS PubMed 30. Li L , Fink GD , Watts SW , Northcott CA , Galligan JJ , Pagano PJ , Chen AF . Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension . Circulation 2003 ; 107 : 1053 – 1058 . Google Scholar CrossRef Search ADS PubMed 31. Mourad JJ , des Guetz G , Debbabi H , Levy BI . Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation . Ann Oncol 2008 ; 19 : 927 – 934 . Google Scholar CrossRef Search ADS PubMed 32. Eremina V , Jefferson JA , Kowalewska J , Hochster H , Haas M , Weisstuch J , Richardson C , Kopp JB , Kabir MG , Backx PH , Gerber HP , Ferrara N , Barisoni L , Alpers CE , Quaggin SE . VEGF inhibition and renal thrombotic microangiopathy . N Engl J Med 2008 ; 358 : 1129 – 1136 . Google Scholar CrossRef Search ADS PubMed 33. Abi Aad S , Pierce M , Barmaimon G , Farhat FS , Benjo A , Mouhayar E . Hypertension induced by chemotherapeutic and immunosuppresive agents: a new challenge . Crit Rev Oncol Hematol 2015 ; 93 : 28 – 35 . Google Scholar CrossRef Search ADS PubMed 34. SERVICES., U.S.D.O.H.A.H., Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 35. Midgley R , Kerr D . Bevacizumab—current status and future directions . Ann Oncol 2005 ; 16 : 999 – 1004 . Google Scholar CrossRef Search ADS PubMed 36. Dai F , Shu L , Bian Y , Wang Z , Yang Z , Chu W , Gao S . Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials . Clin Drug Investig 2013 ; 33 : 779 – 788 . Google Scholar CrossRef Search ADS PubMed 37. Pande A , Lombardo J , Spangenthal E , Javle M . Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab . Anticancer Res 2007 ; 27 : 3465 – 3470 . Google Scholar PubMed 38. Ranpura V , Pulipati B , Chu D , Zhu X , Wu S . Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis . Am J Hypertens 2010 ; 23 : 460 – 468 . Google Scholar CrossRef Search ADS PubMed 39. Le Tourneau C , Raymond E , Faivre S . Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST) . Ther Clin Risk Manag 2007 ; 3 : 341 – 348 . Google Scholar CrossRef Search ADS PubMed 40. Zhu X , Stergiopoulos K , Wu S . Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis . Acta Oncol 2009 ; 48 : 9 – 17 . Google Scholar CrossRef Search ADS PubMed 41. Rautiola J , Donskov F , Peltola K , Joensuu H , Bono P . Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma . BJU Int 2016 ; 117 : 110 – 117 . Google Scholar CrossRef Search ADS PubMed 42. Worden F , Fassnacht M , Shi Y , Hadjieva T , Bonichon F , Gao M , Fugazzola L , Ando Y , Hasegawa Y , Park DJ , Shong YK , Smit JW , Chung J , Kappeler C , Meinhardt G , Schlumberger M , Brose MS . Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer . Endocr Relat Cancer 2015 ; 22 : 877 – 887 . Google Scholar CrossRef Search ADS PubMed 43. Funakoshi T , Latif A , Galsky MD . Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis . J Hum Hypertens 2013 ; 27 : 601 – 611 . Google Scholar CrossRef Search ADS PubMed 44. Li Y , Li S , Zhu Y , Liang X , Meng H , Chen J , Zhang D , Guo H , Shi B . Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis . J Clin Hypertens (Greenwich) 2014 ; 16 : 177 – 185 . Google Scholar CrossRef Search ADS PubMed 45. Wu S , Chen JJ , Kudelka A , Lu J , Zhu X . Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis . Lancet Oncol 2008 ; 9 : 117 – 123 . Google Scholar CrossRef Search ADS PubMed 46. Escudier B , Gore M . Axitinib for the management of metastatic renal cell carcinoma . Drugs R D 2011 ; 11 : 113 – 126 . Google Scholar CrossRef Search ADS PubMed 47. Qi WX , He AN , Shen Z , Yao Y . Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis . Br J Clin Pharmacol 2013 ; 76 : 348 – 357 . Google Scholar CrossRef Search ADS PubMed 48. Rini BI , de La Motte Rouge T , Harzstark AL , Michaelson MD , Liu G , Grünwald V , Ingrosso A , Tortorici MA , Bycott P , Kim S , Bloom J , Motzer RJ . Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib . Clin Genitourin Cancer 2013 ; 11 : 107 – 114 . Google Scholar CrossRef Search ADS PubMed 49. Hutson TE , Lesovoy V , Al-Shukri S , Stus VP , Lipatov ON , Bair AH , Rosbrook B , Chen C , Kim S , Vogelzang NJ . Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial . Lancet Oncol 2013 ; 14 : 1287 – 1294 . Google Scholar CrossRef Search ADS PubMed 50. Motzer RJ , Escudier B , Tomczak P , Hutson TE , Michaelson MD , Negrier S , Oudard S , Gore ME , Tarazi J , Hariharan S , Chen C , Rosbrook B , Kim S , Rini BI . Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial . Lancet Oncol 2013 ; 14 : 552 – 562 . Google Scholar CrossRef Search ADS PubMed 51. Cella D , Beaumont JL . Pazopanib in the treatment of advanced renal cell carcinoma . Ther Adv Urol 2016 ; 8 : 61 – 69 . Google Scholar CrossRef Search ADS PubMed 52. Bible KC , Suman VJ , Molina JR , Smallridge RC , Maples WJ , Menefee ME , Rubin J , Karlin N , Sideras K , Morris JC III , McIver B , Hay I , Fatourechi V , Burton JK , Webster KP , Bieber C , Traynor AM , Flynn PJ , Cher Goh B , Isham CR , Harris P , Erlichman C ; Endocrine Malignancies Disease Oriented Group, Mayo Clinic Cancer Center, and the Mayo Phase 2 Consortium . A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H . J Clin Endocrinol Metab 2014 ; 99 : 1687 – 1693 . Google Scholar CrossRef Search ADS PubMed 53. Pinkhas D. Thai H , Smith S . Assessment of pazopanib-related hypertension, cardiac dysfunction and identification of clinical risk factors for their development . Cardiooncology . 2017 ; 3 : 5 . Google Scholar PubMed 54. Fala L . Cyramza (ramucirumab) approved for the treatment of advanced gastric cancer and metastatic non-small-cell lung cancer . Am Health Drug Benefits 2015 ; 8 : 49 – 53 . Google Scholar PubMed 55. Wang J , Wang Z , Zhao Y . Incidence and risk of hypertension with ramucirumab in cancer patients: a meta-analysis of published studies . Clin Drug Investig 2015 ; 35 : 221 – 228 . Google Scholar CrossRef Search ADS PubMed 56. Roviello G , Pacifico C , Corona P , Generali D . Risk of hypertension with ramucirumab-based therapy in solid tumors: data from a literature based meta-analysis . Invest New Drugs 2017 ; 35 : 518 – 523 . Google Scholar CrossRef Search ADS PubMed 57. Wilhelm SM , Dumas J , Adnane L , Lynch M , Carter CA , Schütz G , Thierauch KH , Zopf D . Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Int J Cancer 2011 ; 129 : 245 – 255 . Google Scholar CrossRef Search ADS PubMed 58. Wang Z , Xu J , Nie W , Huang G , Tang J , Guan X . Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis . Eur J Clin Pharmacol 2014 ; 70 : 225 – 231 . Google Scholar CrossRef Search ADS PubMed 59. Chung C , Pherwani N . Ziv-aflibercept: a novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer . Am J Health Syst Pharm 2013 ; 70 : 1887 – 1896 . Google Scholar CrossRef Search ADS PubMed 60. Qi WX , Shen Z , Tang LN , Yao Y . Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis . Clin Drug Investig 2014 ; 34 : 231 – 240 . Google Scholar CrossRef Search ADS PubMed 61. Elisei R , Schlumberger MJ , Müller SP , Schöffski P , Brose MS , Shah MH , Licitra L , Jarzab B , Medvedev V , Kreissl MC , Niederle B , Cohen EE , Wirth LJ , Ali H , Hessel C , Yaron Y , Ball D , Nelkin B , Sherman SI . Cabozantinib in progressive medullary thyroid cancer . J Clin Oncol 2013 ; 31 : 3639 – 3646 . Google Scholar CrossRef Search ADS PubMed 62. Choueiri TK , Escudier B , Powles T , Mainwaring PN , Rini BI , Donskov F , Hammers H , Hutson TE , Lee JL , Peltola K , Roth BJ , Bjarnason GA , Géczi L , Keam B , Maroto P , Heng DY , Schmidinger M , Kantoff PW , Borgman-Hagey A , Hessel C , Scheffold C , Schwab GM , Tannir NM , Motzer RJ ; METEOR Investigators . Cabozantinib versus everolimus in advanced renal-cell carcinoma . N Engl J Med 2015 ; 373 : 1814 – 1823 . Google Scholar CrossRef Search ADS PubMed 63. Frampton JE . Lenvatinib: a review in refractory thyroid cancer . Target Oncol 2016 ; 11 : 115 – 122 . Google Scholar CrossRef Search ADS PubMed 64. Fala L . Lenvima (lenvatinib), a multireceptor tyrosine kinase inhibitor, approved by the FDA for the treatment of patients with differentiated thyroid cancer . Am Health Drug Benefits 2015 ; 8 : 176 – 179 . Google Scholar PubMed 65. Schlumberger M , Tahara M , Wirth LJ . Lenvatinib in radioiodine-refractory thyroid cancer . N Engl J Med 2015 ; 372 : 1868 . Google Scholar CrossRef Search ADS PubMed 66. Wells SA Jr , Robinson BG , Gagel RF , Dralle H , Fagin JA , Santoro M , Baudin E , Elisei R , Jarzab B , Vasselli JR , Read J , Langmuir P , Ryan AJ , Schlumberger MJ . Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial . J Clin Oncol 2012 ; 30 : 134 – 141 . Google Scholar CrossRef Search ADS PubMed 67. Eisenhauer EA , Therasse P , Bogaerts J , Schwartz LH , Sargent D , Ford R , Dancey J , Arbuck S , Gwyther S , Mooney M , Rubinstein L , Shankar L , Dodd L , Kaplan R , Lacombe D , Verweij J . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer 2009 ; 45 : 228 – 247 . Google Scholar CrossRef Search ADS PubMed 68. Rixe O , Billemont B , Izzedine H . Hypertension as a predictive factor of Sunitinib activity . Ann Oncol 2007 ; 18 : 1117 . Google Scholar CrossRef Search ADS PubMed 69. Bono P , Elfving H , Utriainen T , Osterlund P , Saarto T , Alanko T , Joensuu H . Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma . Ann Oncol 2009 ; 20 : 393 – 394 . Google Scholar CrossRef Search ADS PubMed 70. Dionisio de Sousa IJ , Ferreira J , Rodrigues J , Bonito N , Jacinto P , Marques M , Ribeiro J , Pais A , Gervasio H . Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer . ESMO Open 2016 ; 1 : e000045 . Google Scholar CrossRef Search ADS PubMed 71. Maitland ML , Bakris GL , Black HR , Chen HX , Durand JB , Elliott WJ , Ivy SP , Leier CV , Lindenfeld J , Liu G , Remick SC , Steingart R , Tang WH ; Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee . Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors . J Natl Cancer Inst 2010 ; 102 : 596 – 604 . Google Scholar CrossRef Search ADS PubMed 72. Zamorano JL , Lancellotti P , Rodriguez Muñoz D , Aboyans V , Asteggiano R , Galderisi M , Habib G , Lenihan DJ , Lip GYH , Lyon AR , Lopez Fernandez T , Mohty D , Piepoli MF , Tamargo J , Torbicki A , Suter TM ; ESC Scientific Document Group . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) . Eur Heart J 2016 ; 37 : 2768 – 2801 . Google Scholar CrossRef Search ADS PubMed 73. Whelton PK , Carey RM , Aronow WS , Casey DE Jr , Collins KJ , Dennison Himmelfarb C , DePalma SM , Gidding S , Jamerson KA , Jones DW , MacLaughlin EJ , Muntner P , Ovbiagele B , Smith SC Jr , Spencer CC , Stafford RS , Taler SJ , Thomas RJ , Williams KA Sr , Williamson JD , Wright JT Jr . 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018, 71:e13-e115 . 74. Veronese ML , Mosenkis A , Flaherty KT , Gallagher M , Stevenson JP , Townsend RR , O’Dwyer PJ . Mechanisms of hypertension associated with BAY 43-9006 . J Clin Oncol 2006 ; 24 : 1363 – 1369 . Google Scholar CrossRef Search ADS PubMed 75. Nazer B , Humphreys BD , Moslehi J . Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension . Circulation 2011 ; 124 : 1687 – 1691 . Google Scholar CrossRef Search ADS PubMed 76. Mir O , Coriat R , Ropert S , Cabanes L , Blanchet B , Camps S , Billemont B , Knebelmann B , Goldwasser F . Treatment of bevacizumab-induced hypertension by amlodipine . Invest New Drugs 2012 ; 30 : 702 – 707 . Google Scholar CrossRef Search ADS PubMed 77. Langenberg MH , van Herpen CM , De Bono J , Schellens JH , Unger C , Hoekman K , Blum HE , Fiedler W , Drevs J , Le Maulf F , Fielding A , Robertson J , Voest EE . Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors . J Clin Oncol 2009 ; 27 : 6152 – 6159 . Google Scholar CrossRef Search ADS PubMed © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

The Role of Angiogenesis Inhibitors in Hypertension: Following “Ariadne’s Thread”

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Oxford University Press
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© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0895-7061
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1941-7225
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Abstract

Abstract Arterial hypertension (HT) is one of the most frequently recorded comorbidities among patients under antiangiogenic therapy. Inhibitors of vascular endothelial growth factor and vascular endothelial growth factor receptors are most commonly involved in new onset or exacerbation of pre-existing controlled HT. From the pathophysiology point of view, data support that reduced nitric oxide release and sodium and fluid retention, microvascular rarefaction, elevated vasoconstrictor levels, and globular injury might contribute to HT. The purpose of this review was to present recent evidence regarding the incidence of HT induced by antiangiogenic agents, to analyze the pathophysiological mechanisms, and to summarize current recommendations for the management of elevated blood pressure in this field. blood pressure; cancer, angiogenesis, chemotherapy; hypertension Arterial hypertension (HT) is considered one of the most commonly seen comorbidities in patients with malignancy due to the use of chemotherapeutic agents.1 Before the introduction of antiangiogenic medications, the prevalence of HT in oncological patients was similar to the general population. Nevertheless, increased use of these agents along with consequent prolonged survival of cancer patients contributed to the new onset or worsening of pre-existing HT.2 After initiation of treatment, the vast majority of oncological patients have an absolute increase in blood pressure (BP), with a subset development of HT that ranges from 11% to 43%. Drug-related HT might occur from initiation of antiangiogenic therapy until a year after treatment onset.3,4 The incidence and severity of HT are influenced by patient age, specific medications used and dosage, cancer type, history of HT, and pre-existing cardiovascular risk factors.5,6 Given the fact that the increased BP levels might be responsible for therapy withdrawal, HT management is crucial in order to avoid interruption of treatment.7 Among newer cancer therapies, antiangiogenic drugs are the most frequently involved in new onset or exacerbation of pre-existing but controlled HT. In particular, inhibitors of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFR) have received the most attention.8–10 Management of HT in cancer patients treated with antiangiogenic agents resembles the Greek myth of Theseus and Minotaur; the hero had to follow Ariadne’s thread in order to retrace the path and get out of the labyrinth. In this context, the complexity of HT requires a stepwise approach including close collaboration of oncologists and cardiologists, repeated BP measurements, and cardiovascular profile assessment to avoid temporary or permanent interruption of chemotherapy and to achieve optimal HT control. The purpose of this review was to present recent evidence connecting HT to antiangiogenic factors and to summarize current recommendations of HT management in this field. Angiogenesis Angiogenesis is the process of new blood vessel sprouting from pre-existing blood vessels and is essential for tumor growth and metastasis. Usually, the level of angiogenic factor expression reflects cancer aggressiveness.11–13 Both activator and inhibitor molecules are implicated in the angiogenesis process. Numerous proteins have been identified as angiogenic activators such as VEGF, fibroblast growth factor, angiogenin, transforming growth factor-α, transforming growth factor-β, tumor necrosis factor-α, platelet-derived endothelial growth factor (PDGF), granulocyte colony-stimulating factor, placental growth factor, interleukin-8, hepatocyte growth factor, and epidermal growth factor. On the other hand, proteins that inhibit angiogenesis include angiostatin, endostatin, interferon, platelet factor 4, thrombospondin, prolactin 16 kD fragment, and tissue inhibitor of metalloproteinase-1, -2, and -3.13,14 The most important pathway of the angiogenesis process is mediated by VEGF and its tyrosine kinase receptors (VEGFR-1, -2, and -3). There are 5 different VEGF isoforms (A, B, C, D, and placenta growth factor) with VEGF-A being the most clinically relative protein-promoting angiogenesis through binding mainly to VEGFR-2 (Table 1).10,15 Table 1. Antiangiogenic agents and FDA-approved indications Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Abbreviations: FDA, food and drug administration; RCC, renal cell carcinoma. View Large Table 1. Antiangiogenic agents and FDA-approved indications Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Agent FDA-approved indications Bevacizumab (Avastin) Colorectal cancer Non-small cell lung cancer Glioblastoma multiforme RCC Cervical cancer Ovarian cancer Fallopian tube cancer Peritoneal cancer Sunitinib (Sutent) Gastrointestinal stromal tumor RCC Pancreatic cancer Sorafenib (Nexavar) Advanced RCC Hepatocellular carcinoma Thyroid cancer Axitinib (Inlyta) RCC Pazopanib (Votrient) RCC Soft tissue sarcoma Ramucirumab (Cyramza) Stomach cancer Non-small cell lung cancer Regorafenib (Stivarga) Colorectal cancer Gastrointestinal stromal tumor Hepatocellular carcinoma Aflibercept (Zatrap) Colorectal cancer Cabozantinib (Cabometyx, Cometriq) Thyroid cancer Lenvatinib (Lenvima) Thyroid cancer Advanced RCC Vandetanib (Caprelsa) Thyroid cancer Abbreviations: FDA, food and drug administration; RCC, renal cell carcinoma. View Large Pathophysiology of HT The exact mechanism of HT induced by antiangiogenic drugs is not well understood yet. Several theories have been proposed suggesting that multiple mechanisms contribute to the development of HT. Impaired endothelial function along with microvascular rarefaction and glomerular injury might be implicated in HT secondary to antiangiogenic therapy (Figure 1). Figure 1. View largeDownload slide Pathophysiology of HT induced by antiangiogenic agents. Abbreviations: ET-1, endothelin-1; NO, nitric oxide; sFlt-1: soluble Fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factors; VEGFR, vascular endothelial growth factor receptor. Figure 1. View largeDownload slide Pathophysiology of HT induced by antiangiogenic agents. Abbreviations: ET-1, endothelin-1; NO, nitric oxide; sFlt-1: soluble Fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factors; VEGFR, vascular endothelial growth factor receptor. Endothelial dysfunction VEGF exerts pleiotropic effects on endothelial cells including migration and invasion into the basement membrane and proliferation.14 Thus, VEGF inhibition induces endothelial dysfunction leading to an imbalance between endothelium-derived relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2) and endothelium-derived contractile factors such as endothelin-1 (ET-1).16,17 It is well established that activation of VEGFR by VEGF prompts the expression of nitric oxide synthase by endothelial cells and PGI2 resulting in vasodilation due to NO release via phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Therefore, VEGF and VEGFR inhibition and subsequent vasoconstriction might be a critical mechanism underlying treatment-induced HT. Additionally, impaired NO production promotes sodium and fluid retention and further elevations of BP.18–20 Soluble VEGFR-1, also known as soluble Flt-1, is a variant of VEGFR lacking the transmembrane and cytoplasmic domains and is expressed by endothelial cells, monocytes, and placenta.21,22 Available data support that soluble Flt-1 is overexpressed in several tumors types23,24 and binds VEGF causing endothelial dysfunction, decreasing angiogenesis, impairing capillary repair, and increasing proteinuria.25,26 Moreover, elevated levels of the potent vasoconstrictor ET-1 have been detected in patients treated with the VEGFR inhibitor sunitinib.27 According to a study, soluble Flt-1 infusion in mice augmented ET-1–mediated vasoconstriction contributing to BP elevation.28 Apart from vasoconstriction, ET-1 activates vascular NADPH oxidase resulting in oxidative stress through enhanced reactive oxygen species production.29,30 Microvascular rarefaction It is defined as a decrease in the number of perfused capillaries in an area of tissue. Angiogenesis inhibition might result in microvascular rarefaction leading to increased vascular resistance and HT. In a small study of 18 oncological patients treated with bevacizumab, microvascular rarefaction and raised BP were observed in all individuals.19,20,31 Glomerular injury Angiogenesis inhibition might generate renal thrombotic microangiopathy and subsequent glomerular injury, but the exact mechanisms are not clear yet. In vitro, VEGF induces the formation of fenestrations in glomerular endothelial cells that are requisite for the permeability of the glomerular filtration barrier. Thus, the inhibition of VEGF might result in the loss of the healthy fenestrated phenotype and the development of thrombotic microangiopathy and microvascular injury.32 Antiangiogenic Agents and HT The association of HT with antiangiogenic drugs is a matter of emerging clinical concern. After initiation of therapy, severe BP rises could lead to the permanent discontinuation of these agents.33 Numerous studies aimed to investigate the overall incidence of HT among oncological patients receiving antiangiogenic factors (Table 2). Of note, in all studies, patients were either normotensives or controlled hypertensives before the initiation of treatment. The majority of trials used the Common Terminology Criteria for Adverse Events (CTCAE) to classify hypertensive events (Table 3). According to these criteria, the term “all-grade” refers to all grades from 1 to 4, while the term “high-grade” refers solely to any grade between 3 and 4, respectively.34 Table 2. Studies that investigated the incidence of all-grade and high-grade HT among cancer patients treated with antiangiogenic agents Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Abbreviations: CCC, cholangiocarcinoma; CRC, colorectal cancer; GC, gastric cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HT, hypertension; NA, nonavailable; NSCLC, non-small cell lung carcinoma; PC, pancreatic cancer; RCC, renal cell carcinoma; SCLC, small cell lung cancer; TC, thyroid cancer; UC, urothelial carcinoma. View Large Table 2. Studies that investigated the incidence of all-grade and high-grade HT among cancer patients treated with antiangiogenic agents Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Study Year Patients Agent Dosage Cancer type All-grade HT % High-grade HT % Pande et al. 2007 154 Bevacizumab 5–15 mg/kg CRC, SCLC, RCC, PC 35 16 Ranpura et al. 2010 12,656 Bevacizumab 2.5–5 mg/kg CRC, NSCLC, RCC, PC,breast, mesothelioma 23.6 7.9 Zhu et al. 2009 4,999 Sunitinib 37.5–50 mg NSCLC, RCC, GIST,GC, UC 21.6 6.8 Rautiola et al. 2016 181 Sunitinib 25–50 mg RCC 33 NA Wu et al. 2008 4,599 Sorafenib 800 mg RCC, other solid cancers 23.4 5.7 Funakoshi et al. 2013 4,722 Sorafenib NA RCC, NSCLC, HCC,TC, prostate, melanoma NA 6 Li ei al. 2014 13,555 Sorafenib 800 mg RCC, NSCLC, HCC, breast, prostate, TC, sarcoma melanoma, CCC, gallbladder 19.1 4.3 Qi et al. 2013 1,148 Axitinib 10 mg RCC, NSCLC, breast, melanoma, PC, TC 40.1 13.1 Rini et al. 2013 52 Axitinib NA RCC 63.5 13.5 Hutson et al. 2013 285 Axitinib, Sorafenib 10 mg, 800 mg RCC 49, 29 14, 1 Motzer et al. 2013 723 Axitinib, Sorafenib 10 mg, 800 mg RCC 42, 30 17, 12 Bible et al. 2014 35 Pazopanib 800 mg TC 51 3 Pinkhas et al. 2017 35 Pazopanib 400–800 mg RCC 57 49 Wang et al. 2015 3,851 Ramucirumab NA NA 20 9 Roviello et al. 2017 4,297 Ramucirumab NA GC, CRC, HCC, NSCLC 11–38 6–16 Wang et al. 2014 1,069 Regorafenib 160 mg HCC, GIST, RCC, CRC 44 13 Qi et al. 2014 4,451 Aflibercept NA NA 42.4 17.4 Elisei et al. 2013 330 Cabozantinib 140 mg TC 33 8 Choueiri 2015 658 Cabozantinib 60 mg RCC 37 15 Schlumberger et al. 2015 261 Lenvatinib 24 mg TC 68 42 Wells et al. 2012 331 Vandetanib 300 mg TC 32 9 Abbreviations: CCC, cholangiocarcinoma; CRC, colorectal cancer; GC, gastric cancer; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HT, hypertension; NA, nonavailable; NSCLC, non-small cell lung carcinoma; PC, pancreatic cancer; RCC, renal cell carcinoma; SCLC, small cell lung cancer; TC, thyroid cancer; UC, urothelial carcinoma. View Large Table 3. Classification of HT according to CTCAE criteria and treatment indications Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Abbreviations: CTCAE, common terminology criteria for adverse events; HT, hypertension. View Large Table 3. Classification of HT according to CTCAE criteria and treatment indications Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Grade Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Stage Prehypertension 120– 139/80–89 mm Hg Stage 1 HT 140–159/90–99 mm Hg or symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg if previously normal Stage 2 HT ≥160/100 mm Hg Life-threatening consequences (i.e., malignant HT, transient or permanent neurologic deficit, hypertensive crisis) Death Therapy medical intervention indicated medical intervention indicated urgent intervention indicated Abbreviations: CTCAE, common terminology criteria for adverse events; HT, hypertension. View Large Bevacizumab Bevacizumab is a monoclonal antibody that targets VEGF molecule.35 There is evidence that patients treated with bevacizumab have a 3-fold higher risk of HT.36 A retrospective study of 154 patients treated with bevacizumab showed that 35% of them experienced HT secondary to therapy after a median time of 11 weeks.37 HT was most likely to occur in patients with pre-existing HT. Indeed, 8 in 10 individuals experienced an exacerbation of pre-existing HT. Likewise, the increased risk of bevacizumab-induced HT was revealed in a meta-analysis that included 12,656 oncological patients. The incidence of all-grade HT in patients receiving bevacizumab was 23.6% with 7.9% of them being high-grade. The relative risk of all-grade and high-grade HT was 3.02 and 5.28, respectively, compared with controls. The risk of high-grade HT also varied among patients with different tumor type with significantly increased risk observed in patients with renal cell carcinoma (RCC), non-small cell lung cancer, pancreatic cancer, and colorectal cancer.38 Sunitinib Sunitinib is a potent inhibitor of VEGFR-1 and -2, PDGF receptor-a and -b, fetal liver tyrosine kinase receptor 3 (FLT3), and c-Kit (stem-cell factor [SCF] receptor).39 In a meta-analysis of 5,000 patients treated with sunitinib, the calculated summary incidence of all-grade HT was 21.6%, whereas the incidence of high-grade HT was 6.8%. In addition, the risk of HT varied with tumor type and dosing schedule of therapy being significantly higher in patients with RCC and continuous daily-dosing schedule.40 Moreover, among 181 patients with metastatic RCC, 33% of them developed HT after initiating sunitinib.41 Sorafenib Sorafenib is a multikinase inhibitor of VEGFR-1, -2, and -3, RET receptor tyrosine kinase, RAF kinase, and PDGF receptor-b.42 In 2 meta-analyses, the overall incidence of sorafenib-induced high-grade HT among oncological patients was 4.3% and 6%, respectively.43,44 Additionally, among 4,600 cancer patients, 23.4% of them developed all-grade HT and 5.7% of them developed high-grade HT. No significant difference was noted between individuals with RCC or non-RCC malignancy.45 Axitinib Axitinib is a highly selective inhibitor of VEGFR-1, -2, and -3.46 In a total of 1,148 cancer patients, the overall incidence of all-grade and high-grade HT after initiating therapy was 40.1% and 13.1%, respectively. The risk was significantly higher in subjects with RCC.47 In another study of 52 oncological patients treated with axitinib, 63.5% of them developed HT after 5-year follow-up.48 There is evidence that the risk of HT is greater in patients treated with axitinib compared with sorafenib. Indeed, 2 studies confirmed this ascertainment. In the first one, the incidence of axitinib-induced HT was 49%, whereas the incidence of sorafenib-induced HT was 29%.49 The other study included 723 patients that were randomly allocated to receive axitinib or sorafenib. HT was developed in 42% of subjects treated with axitinib, whereas 30% of them treated with sorafenib.50 Pazopanib Pazopanib is a multityrosine kinase inhibitor targeting VEGFR-1, -2, and -3, PDGF receptor-a and -b and c-Kit.51 In a cohort of normotensive oncological patients treated with pazopanib, 33% of them developed HT.52 Similarly, a more recent study revealed that 57% of individuals treated with pazopanib developed HT after the initiation of therapy. The incidence of a new onset event was 17% within a median time of 19 days.53 Ramucirumab Ramucirumab is a VEGFR-2 inhibitor that blocks the binding of VEGF.54 Among 3,851 cancer patients, the risk of all-grade and high-grade HT was greater in subjects treated with ramucirumab compared with control group (20% vs. 7% for all-grade HT; 9% vs. 3% for high-grade HT).55 A meta-analysis also showed that the risk of ramucirumab-induced all-grade and high-grade HT was 11–38% and 6–16%, respectively, whereas the incidence in the control group was significantly lower. In addition, patients with gastric and metastatic colorectal cancer were more likely to develop HT.56 Regorafenib Regorafenib inhibits VEGFR-1, -2, and -3, PDGF-b, fibroblast growth factor receptor-1, c-Kit, RET protein, and BRAF protein.57 A meta-analysis that included 5 clinical trials revealed that the pooled incidence of all-grade and high-grade HT in patients treated with regorafenib was 44% and 13%, respectively. Moreover, the risk varied with tumor type and was higher among patients with gastrointestinal stromal tumors (56%) and RCC (49%).58 Aflibercept Aflibercept is a recombinant fusion protein that blocks VEGFRs and is a more potent VEGF blocker than bevacizumab.59 According to a meta-analysis that included 4,451 patients with metastatic colorectal cancer, the use of aflibercept was associated with a significantly increased risk of all-grade (42.4%) and high-grade (17.4%) HT.60 Cabozantinib Cabozantinib is a tyrosine kinase inhibitor targeting VEGFR-2. A study that included patients with thyroid cancer revealed that the risk of all-grade and high-grade HT was greater in group of subjects treated with cabozantinib compared with control group (33% vs. 5% for all-grade HT; 8% vs. 1% for high-grade HT).61 In a more recent trial, patients with metastatic RCC were randomly assigned 1:1 to cabozantinib or everolimus, a nonangiogenesis inhibitor. The incidence of HT was higher among individuals receiving cabozantinib (37% vs. 7% for all-grade HT; 15% vs. 3% for high-grade HT).62 Lenvatinib Lenvatinib is an inhibitor of VEGFR-1, -2, and -3, fibroblast growth factor receptor-1, -2, -3, and -4, PDGF receptor-a, RET, and c-Kit.63 The safety and efficacy of lenvatinib were evaluated in SELECT trial where the risk of HT was higher among patients received lenvatinib compared with controls (68% vs. 9% for all-grade HT; 42% vs. 2% for high-grade HT).64,65 Vandetanib Vandetanib is an agent that selectively targets VEGFR, RET protein, and epidermal growth factor receptor. In a study that included patients with locally advanced or metastatic medullary thyroid cancer, individuals treated with vandetanib were at greater risk of HT compared with controls (32% vs. 5%).66 Therefore, available data conclude that the use of antiangiogenic agents acts as an additional risk factor contributing to the increased incidence of HT in oncological patients. HT as a Predictive Factor to Antiangiogenic Therapy There is evidence suggesting that HT might be considered as a clinical marker predicting the efficacy of antiangiogenic therapy. In this context, response evaluation criteria in solid tumors (RECIST) criteria were updated the previous decade. It is a set of published rules that define when cancer patients improve (respond), stay the same (stable), or worsen (progression) during treatment.67 In a cohort of patients with metastatic RCC on sunitinib, the development of HT was correlated with higher response to therapy.68 These findings were consistent with another study that included individuals with the same type of cancer treated with bevacizumab. Patients that did not develop HT had greater degree of progressive disease and shorter time to disease progression.69 Furthermore, a retrospective study that evaluated individuals with metastatic colorectal cancer treated with bevacizumab showed that 73% of patients with bevacizumab-induced HT presented response to treatment and 98% achieved disease control. Conversely, only 18% of controls presented response, and 64% of them achieved disease control.70 However, more data are needed in order to clarify the clinical significance of such observational studies. Management of HT National Cancer Institute (NCI) issued recommendations for the BP management among patients receiving antiangiogenic agents and set the goal of 140/90 mm Hg.71 European Society of Cardiology (ESC) also published a position paper on cancer treatment and cardiovascular toxicity including HT. The recommended goal was <140/90 mm Hg or lower in case of overt proteinuria.72 However, these values are not yet in accordance with the recently published guidelines for HT management in the general population that target lower than 130/80 mm Hg.73 The primary goal in this setting is to optimize risk assessment, monitoring, and safe administration of antiangiogenic drugs. The pretreatment assessment includes repeated BP measurements along with history, physical examination, and laboratory tests to estimate the cardiovascular risk profile of each patient. Pain relief and stress management are mandatory for adequate BP evaluation.71,72 Once therapy has been started, BP should be monitored weekly during the first cycle and then at least every 2 or 3 weeks. After the first cycle is completed and a stable BP has been achieved, BP control might be managed with routine clinical evaluations or home BP monitoring. Initiation of antihypertensive drugs should be considered when BP is higher than 140/90 mm Hg or there is an increase in diastolic BP of at least 20 mm Hg compared with pretreatment values. Temporary interruption of antiangiogenic agents might be necessary if HT is difficult to control or patients are symptomatic because of the excess BP elevation. Once BP control is achieved, therapy can be restarted to succeed maximum cancer efficacy (Figure 2).71 Figure 2. View largeDownload slide Management of HT in oncological patients. Abbreviations: CV: cardiovascular, HT: hypertension. Figure 2. View largeDownload slide Management of HT in oncological patients. Abbreviations: CV: cardiovascular, HT: hypertension. Early detection of HT and sufficient management of BP elevations are critical to avoid severe complications. Hence, aggressive pharmacological management is recommended. However, there are no clear data regarding the superiority of any class of antihypertensive drug for HT management in oncological patients. Although there are inconclusive data concerning the renin levels during antiangiogenic therapy,27,74 renin–angiotensin system (RAS) inhibitors are frequently the initial treatment of choice unless there are obvious contraindications.71,72,75 A retrospective study that evaluated patients with bevacizumab-induced HT revealed that quinapril, an angiotensin-converting enzyme inhibitor (ACE-I), achieved better BP control than other antihypertensive agents.37 Another study showed that the majority of oncological patients were successfully managed with amlodipine within 7 days.76 Thus, calcium channel blockers might constitute an alternative choice. Nonetheless, nondihydropyridine calcium channel blockers (verapamil and diltiazem) should be avoided when sunitinib or sorafenib is used due to pharmacokinetic interactions, since they are inhibitors of CYP3A4 system that is implicated in the metabolism of both sunitinib and sorafenib.75 Furthermore, ACE-I and beta-blockers are the preferred antihypertensive medications among patients with heart failure or at risk of heart failure or left ventricular dysfunction. Drugs that increase NO release, such as the beta1-blocker nebivolol, may be considered for BP control. Other vasodilator beta-blockers, such as carvedilol, can also be used.72 Given the relationship between VEGF and NO, nitrates or phosphodiesterase inhibitors might be an alternative mechanistic treatment as NO donors.75 Lifestyle modifications should be also encouraged including weight loss, if needed, aerobic exercise, diet low in total and saturated fat, salt restriction, and limitation in alcohol consumption.75 In addition, some agents such as nonsteroidal anti-inflammatory drugs (including cyclooxygenase 2 inhibitors), adrenal steroid hormones, erythropoietin, oral contraceptive hormones, and sympathomimetics (methylphenidate) that are commonly prescribed by oncologists might also increase BP. Even though there is no evidence that HT is more frequent or more severe in patients treated with the abovementioned drugs, while on antiangiogenic therapy, elevated doses of antihypertensive drugs or more frequent BP measurements are recommended.71,72 To date, there are no adequate data suggesting the prophylactic use of antihypertensive drugs in normotensive patients before initiating therapy with antiangiogenic agents. A prospective clinical study that included 126 patients treated with cediranib revealed that antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. However, severe HT (systolic BP >180 mm Hg or diastolic BP >110 mm Hg) occurred in only 1 patient received prophylaxis vs. 18 that did not receive prophylaxis.77 Further studies are required in this field. Conclusions The vicious circle between cancer and high BP is an evolving matter of concern considering the high prevalence of both conditions. Among newer cancer therapies, antiangiogenic agents are the most frequently involved in the development of HT implicating multiple pathophysiological mechanisms. Thus, HT management remains crucial in order to avoid treatment withdrawal. Collaboration of oncologists and cardiologists is imperative to prevent and manage HT guaranteeing best patients’ outcomes. Disclosure The authors declared no conflict of interest. References 1. Dreyfus B , Kawabata H , Gomez A . Selected adverse events in cancer patients treated with vascular endothelial growth factor inhibitors . Cancer Epidemiol 2013 ; 37 : 191 – 196 . Google Scholar CrossRef Search ADS PubMed 2. Souza VB , Silva EN , Ribeiro ML , Martins WdeA . Hypertension in patients with cancer . Arq Bras Cardiol 2015 ; 104 : 246 – 252 . Google Scholar PubMed 3. Milan A , Puglisi E , Ferrari L , Bruno G , Losano I , Veglio F . Arterial hypertension and cancer . Int J Cancer 2014 ; 134 : 2269 – 2277 . Google Scholar CrossRef Search ADS PubMed 4. Small HY , Montezano AC , Rios FJ , Savoia C , Touyz RM . Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome . Can J Cardiol 2014 ; 30 : 534 – 543 . Google Scholar CrossRef Search ADS PubMed 5. Izzedine H , Massard C , Spano JP , Goldwasser F , Khayat D , Soria JC . VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management . Eur J Cancer 2010 ; 46 : 439 – 448 . Google Scholar CrossRef Search ADS PubMed 6. Hamnvik OP , Choueiri TK , Turchin A , McKay RR , Goyal L , Davis M , Kaymakcalan MD , Williams JS . Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway . Cancer 2015 ; 121 : 311 – 319 . Google Scholar CrossRef Search ADS PubMed 7. Azizi M , Chedid A , Oudard S . Home blood-pressure monitoring in patients receiving sunitinib . N Engl J Med 2008 ; 358 : 95 – 97 . Google Scholar CrossRef Search ADS PubMed 8. Hurwitz H , Fehrenbacher L , Novotny W , Cartwright T , Hainsworth J , Heim W , Berlin J , Baron A , Griffing S , Holmgren E , Ferrara N , Fyfe G , Rogers B , Ross R , Kabbinavar F . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer . N Engl J Med 2004 ; 350 : 2335 – 2342 . Google Scholar CrossRef Search ADS PubMed 9. Gurevich F , Perazella MA . Renal effects of anti-angiogenesis therapy: update for the internist . Am J Med 2009 ; 122 : 322 – 328 . Google Scholar CrossRef Search ADS PubMed 10. Kerbel RS . Tumor angiogenesis . N Engl J Med 2008 ; 358 : 2039 – 2049 . Google Scholar CrossRef Search ADS PubMed 11. Folkman J . Tumor angiogenesis: therapeutic implications . N Engl J Med 1971 ; 285 : 1182 – 1186 . Google Scholar CrossRef Search ADS PubMed 12. Cao Y , Arbiser J , D’Amato RJ , D’Amore PA , Ingber DE , Kerbel R , Klagsbrun M , Lim S , Moses MA , Zetter B , Dvorak H , Langer R . Forty-year journey of angiogenesis translational research . Sci Transl Med 2011 ; 3 : 114rv3 . Google Scholar PubMed 13. Nishida N , Yano H , Nishida T , Kamura T , Kojiro M . Angiogenesis in cancer . Vasc Health Risk Manag 2006 ; 2 : 213 – 219 . Google Scholar CrossRef Search ADS PubMed 14. Rajabi M , Mousa SA . The role of angiogenesis in cancer treatment . Biomedicines 2017 ; 5 : 34 . Google Scholar CrossRef Search ADS 15. Koch S , Claesson-Welsh L . Signal transduction by vascular endothelial growth factor receptors . Cold Spring Harb Perspect Med 2012 ; 2 : a006502 . Google Scholar CrossRef Search ADS PubMed 16. Tio RA , Wijpkema J , Tan ES , Asselbergs FW , Hospers GA , Jessurun GA , Zijlstra F . Reduction of endothelial dysfunction following VEGF gene therapy . Neth Heart J 2005 ; 13 : 139 – 141 . Google Scholar PubMed 17. Winnik S , Lohmann C , Siciliani G , von Lukowicz T , Kuschnerus K , Kraenkel N , Brokopp CE , Enseleit F , Michels S , Ruschitzka F , Lüscher TF , Matter CM . Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis—implications for cardiovascular safety . Int J Cardiol 2013 ; 168 : 2453 – 2461 . Google Scholar CrossRef Search ADS PubMed 18. Keefe D , Bowen J , Gibson R , Tan T , Okera M , Stringer A . Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review . Oncologist 2011 ; 16 : 432 – 444 . Google Scholar CrossRef Search ADS PubMed 19. Robinson ES , Khankin EV , Karumanchi SA , Humphreys BD . Hypertension induced by vascular endothelial growth factor signaling pathway inhibition: mechanisms and potential use as a biomarker . Semin Nephrol 2010 ; 30 : 591 – 601 . Google Scholar CrossRef Search ADS PubMed 20. Hayman SR , Leung N , Grande JP , Garovic VD . VEGF inhibition, hypertension, and renal toxicity . Curr Oncol Rep 2012 ; 14 : 285 – 294 . Google Scholar CrossRef Search ADS PubMed 21. Barleon B , Reusch P , Totzke F , Herzog C , Keck C , Martiny-Baron G , Marmé D . Soluble VEGFR-1 secreted by endothelial cells and monocytes is present in human serum and plasma from healthy donors . Angiogenesis 2001 ; 4 : 143 – 154 . Google Scholar CrossRef Search ADS PubMed 22. Hornig C , Barleon B , Ahmad S , Vuorela P , Ahmed A , Weich HA . Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids . Lab Invest 2000 ; 80 : 443 – 454 . Google Scholar CrossRef Search ADS PubMed 23. Yamaguchi T , Bando H , Mori T , Takahashi K , Matsumoto H , Yasutome M , Weich H , Toi M . Overexpression of soluble vascular endothelial growth factor receptor 1 in colorectal cancer: association with progression and prognosis . Cancer Sci 2007 ; 98 : 405 – 410 . Google Scholar CrossRef Search ADS PubMed 24. Toi M , Bando H , Ogawa T , Muta M , Hornig C , Weich HA . Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer . Int J Cancer 2002 ; 98 : 14 – 18 . Google Scholar CrossRef Search ADS PubMed 25. Kendall RL , Wang G , Thomas KA . Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR . Biochem Biophys Res Commun 1996 ; 226 : 324 – 328 . Google Scholar CrossRef Search ADS PubMed 26. Maynard SE , Min JY , Merchan J , Lim KH , Li J , Mondal S , Libermann TA , Morgan JP , Sellke FW , Stillman IE , Epstein FH , Sukhatme VP , Karumanchi SA . Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia . J Clin Invest 2003 ; 111 : 649 – 658 . Google Scholar CrossRef Search ADS PubMed 27. Kappers MH , van Esch JH , Sluiter W , Sleijfer S , Danser AH , van den Meiracker AH . Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels . Hypertension 2010 ; 56 : 675 – 681 . Google Scholar CrossRef Search ADS PubMed 28. Amraoui F , Spijkers L , Hassani Lahsinoui H , Vogt L , van der Post J , Peters S , Afink G , Ris-Stalpers C , van den Born BJ . SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice . PLoS One 2014 ; 9 : e91897 . Google Scholar CrossRef Search ADS PubMed 29. Dong F , Zhang X , Wold LE , Ren Q , Zhang Z , Ren J . Endothelin-1 enhances oxidative stress, cell proliferation and reduces apoptosis in human umbilical vein endothelial cells: role of ETB receptor, NADPH oxidase and caveolin-1 . Br J Pharmacol 2005 ; 145 : 323 – 333 . Google Scholar CrossRef Search ADS PubMed 30. Li L , Fink GD , Watts SW , Northcott CA , Galligan JJ , Pagano PJ , Chen AF . Endothelin-1 increases vascular superoxide via endothelin(A)-NADPH oxidase pathway in low-renin hypertension . Circulation 2003 ; 107 : 1053 – 1058 . Google Scholar CrossRef Search ADS PubMed 31. Mourad JJ , des Guetz G , Debbabi H , Levy BI . Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation . Ann Oncol 2008 ; 19 : 927 – 934 . Google Scholar CrossRef Search ADS PubMed 32. Eremina V , Jefferson JA , Kowalewska J , Hochster H , Haas M , Weisstuch J , Richardson C , Kopp JB , Kabir MG , Backx PH , Gerber HP , Ferrara N , Barisoni L , Alpers CE , Quaggin SE . VEGF inhibition and renal thrombotic microangiopathy . N Engl J Med 2008 ; 358 : 1129 – 1136 . Google Scholar CrossRef Search ADS PubMed 33. Abi Aad S , Pierce M , Barmaimon G , Farhat FS , Benjo A , Mouhayar E . Hypertension induced by chemotherapeutic and immunosuppresive agents: a new challenge . Crit Rev Oncol Hematol 2015 ; 93 : 28 – 35 . Google Scholar CrossRef Search ADS PubMed 34. SERVICES., U.S.D.O.H.A.H., Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. 2010. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 35. Midgley R , Kerr D . Bevacizumab—current status and future directions . Ann Oncol 2005 ; 16 : 999 – 1004 . Google Scholar CrossRef Search ADS PubMed 36. Dai F , Shu L , Bian Y , Wang Z , Yang Z , Chu W , Gao S . Safety of bevacizumab in treating metastatic colorectal cancer: a systematic review and meta-analysis of all randomized clinical trials . Clin Drug Investig 2013 ; 33 : 779 – 788 . Google Scholar CrossRef Search ADS PubMed 37. Pande A , Lombardo J , Spangenthal E , Javle M . Hypertension secondary to anti-angiogenic therapy: experience with bevacizumab . Anticancer Res 2007 ; 27 : 3465 – 3470 . Google Scholar PubMed 38. Ranpura V , Pulipati B , Chu D , Zhu X , Wu S . Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis . Am J Hypertens 2010 ; 23 : 460 – 468 . Google Scholar CrossRef Search ADS PubMed 39. Le Tourneau C , Raymond E , Faivre S . Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST) . Ther Clin Risk Manag 2007 ; 3 : 341 – 348 . Google Scholar CrossRef Search ADS PubMed 40. Zhu X , Stergiopoulos K , Wu S . Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: systematic review and meta-analysis . Acta Oncol 2009 ; 48 : 9 – 17 . Google Scholar CrossRef Search ADS PubMed 41. Rautiola J , Donskov F , Peltola K , Joensuu H , Bono P . Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma . BJU Int 2016 ; 117 : 110 – 117 . Google Scholar CrossRef Search ADS PubMed 42. Worden F , Fassnacht M , Shi Y , Hadjieva T , Bonichon F , Gao M , Fugazzola L , Ando Y , Hasegawa Y , Park DJ , Shong YK , Smit JW , Chung J , Kappeler C , Meinhardt G , Schlumberger M , Brose MS . Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer . Endocr Relat Cancer 2015 ; 22 : 877 – 887 . Google Scholar CrossRef Search ADS PubMed 43. Funakoshi T , Latif A , Galsky MD . Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis . J Hum Hypertens 2013 ; 27 : 601 – 611 . Google Scholar CrossRef Search ADS PubMed 44. Li Y , Li S , Zhu Y , Liang X , Meng H , Chen J , Zhang D , Guo H , Shi B . Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis . J Clin Hypertens (Greenwich) 2014 ; 16 : 177 – 185 . Google Scholar CrossRef Search ADS PubMed 45. Wu S , Chen JJ , Kudelka A , Lu J , Zhu X . Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis . Lancet Oncol 2008 ; 9 : 117 – 123 . Google Scholar CrossRef Search ADS PubMed 46. Escudier B , Gore M . Axitinib for the management of metastatic renal cell carcinoma . Drugs R D 2011 ; 11 : 113 – 126 . Google Scholar CrossRef Search ADS PubMed 47. Qi WX , He AN , Shen Z , Yao Y . Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis . Br J Clin Pharmacol 2013 ; 76 : 348 – 357 . Google Scholar CrossRef Search ADS PubMed 48. Rini BI , de La Motte Rouge T , Harzstark AL , Michaelson MD , Liu G , Grünwald V , Ingrosso A , Tortorici MA , Bycott P , Kim S , Bloom J , Motzer RJ . Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib . Clin Genitourin Cancer 2013 ; 11 : 107 – 114 . Google Scholar CrossRef Search ADS PubMed 49. Hutson TE , Lesovoy V , Al-Shukri S , Stus VP , Lipatov ON , Bair AH , Rosbrook B , Chen C , Kim S , Vogelzang NJ . Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial . Lancet Oncol 2013 ; 14 : 1287 – 1294 . Google Scholar CrossRef Search ADS PubMed 50. Motzer RJ , Escudier B , Tomczak P , Hutson TE , Michaelson MD , Negrier S , Oudard S , Gore ME , Tarazi J , Hariharan S , Chen C , Rosbrook B , Kim S , Rini BI . Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial . Lancet Oncol 2013 ; 14 : 552 – 562 . Google Scholar CrossRef Search ADS PubMed 51. Cella D , Beaumont JL . Pazopanib in the treatment of advanced renal cell carcinoma . Ther Adv Urol 2016 ; 8 : 61 – 69 . Google Scholar CrossRef Search ADS PubMed 52. Bible KC , Suman VJ , Molina JR , Smallridge RC , Maples WJ , Menefee ME , Rubin J , Karlin N , Sideras K , Morris JC III , McIver B , Hay I , Fatourechi V , Burton JK , Webster KP , Bieber C , Traynor AM , Flynn PJ , Cher Goh B , Isham CR , Harris P , Erlichman C ; Endocrine Malignancies Disease Oriented Group, Mayo Clinic Cancer Center, and the Mayo Phase 2 Consortium . A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H . J Clin Endocrinol Metab 2014 ; 99 : 1687 – 1693 . Google Scholar CrossRef Search ADS PubMed 53. Pinkhas D. Thai H , Smith S . Assessment of pazopanib-related hypertension, cardiac dysfunction and identification of clinical risk factors for their development . Cardiooncology . 2017 ; 3 : 5 . Google Scholar PubMed 54. Fala L . Cyramza (ramucirumab) approved for the treatment of advanced gastric cancer and metastatic non-small-cell lung cancer . Am Health Drug Benefits 2015 ; 8 : 49 – 53 . Google Scholar PubMed 55. Wang J , Wang Z , Zhao Y . Incidence and risk of hypertension with ramucirumab in cancer patients: a meta-analysis of published studies . Clin Drug Investig 2015 ; 35 : 221 – 228 . Google Scholar CrossRef Search ADS PubMed 56. Roviello G , Pacifico C , Corona P , Generali D . Risk of hypertension with ramucirumab-based therapy in solid tumors: data from a literature based meta-analysis . Invest New Drugs 2017 ; 35 : 518 – 523 . Google Scholar CrossRef Search ADS PubMed 57. Wilhelm SM , Dumas J , Adnane L , Lynch M , Carter CA , Schütz G , Thierauch KH , Zopf D . Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Int J Cancer 2011 ; 129 : 245 – 255 . Google Scholar CrossRef Search ADS PubMed 58. Wang Z , Xu J , Nie W , Huang G , Tang J , Guan X . Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis . Eur J Clin Pharmacol 2014 ; 70 : 225 – 231 . Google Scholar CrossRef Search ADS PubMed 59. Chung C , Pherwani N . Ziv-aflibercept: a novel angiogenesis inhibitor for the treatment of metastatic colorectal cancer . Am J Health Syst Pharm 2013 ; 70 : 1887 – 1896 . Google Scholar CrossRef Search ADS PubMed 60. Qi WX , Shen Z , Tang LN , Yao Y . Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis . Clin Drug Investig 2014 ; 34 : 231 – 240 . Google Scholar CrossRef Search ADS PubMed 61. Elisei R , Schlumberger MJ , Müller SP , Schöffski P , Brose MS , Shah MH , Licitra L , Jarzab B , Medvedev V , Kreissl MC , Niederle B , Cohen EE , Wirth LJ , Ali H , Hessel C , Yaron Y , Ball D , Nelkin B , Sherman SI . Cabozantinib in progressive medullary thyroid cancer . J Clin Oncol 2013 ; 31 : 3639 – 3646 . Google Scholar CrossRef Search ADS PubMed 62. Choueiri TK , Escudier B , Powles T , Mainwaring PN , Rini BI , Donskov F , Hammers H , Hutson TE , Lee JL , Peltola K , Roth BJ , Bjarnason GA , Géczi L , Keam B , Maroto P , Heng DY , Schmidinger M , Kantoff PW , Borgman-Hagey A , Hessel C , Scheffold C , Schwab GM , Tannir NM , Motzer RJ ; METEOR Investigators . Cabozantinib versus everolimus in advanced renal-cell carcinoma . N Engl J Med 2015 ; 373 : 1814 – 1823 . Google Scholar CrossRef Search ADS PubMed 63. Frampton JE . Lenvatinib: a review in refractory thyroid cancer . Target Oncol 2016 ; 11 : 115 – 122 . Google Scholar CrossRef Search ADS PubMed 64. Fala L . Lenvima (lenvatinib), a multireceptor tyrosine kinase inhibitor, approved by the FDA for the treatment of patients with differentiated thyroid cancer . Am Health Drug Benefits 2015 ; 8 : 176 – 179 . Google Scholar PubMed 65. Schlumberger M , Tahara M , Wirth LJ . Lenvatinib in radioiodine-refractory thyroid cancer . N Engl J Med 2015 ; 372 : 1868 . Google Scholar CrossRef Search ADS PubMed 66. Wells SA Jr , Robinson BG , Gagel RF , Dralle H , Fagin JA , Santoro M , Baudin E , Elisei R , Jarzab B , Vasselli JR , Read J , Langmuir P , Ryan AJ , Schlumberger MJ . Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial . J Clin Oncol 2012 ; 30 : 134 – 141 . Google Scholar CrossRef Search ADS PubMed 67. Eisenhauer EA , Therasse P , Bogaerts J , Schwartz LH , Sargent D , Ford R , Dancey J , Arbuck S , Gwyther S , Mooney M , Rubinstein L , Shankar L , Dodd L , Kaplan R , Lacombe D , Verweij J . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) . Eur J Cancer 2009 ; 45 : 228 – 247 . Google Scholar CrossRef Search ADS PubMed 68. Rixe O , Billemont B , Izzedine H . Hypertension as a predictive factor of Sunitinib activity . Ann Oncol 2007 ; 18 : 1117 . Google Scholar CrossRef Search ADS PubMed 69. Bono P , Elfving H , Utriainen T , Osterlund P , Saarto T , Alanko T , Joensuu H . Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma . Ann Oncol 2009 ; 20 : 393 – 394 . Google Scholar CrossRef Search ADS PubMed 70. Dionisio de Sousa IJ , Ferreira J , Rodrigues J , Bonito N , Jacinto P , Marques M , Ribeiro J , Pais A , Gervasio H . Association between bevacizumab-related hypertension and response to treatment in patients with metastatic colorectal cancer . ESMO Open 2016 ; 1 : e000045 . Google Scholar CrossRef Search ADS PubMed 71. Maitland ML , Bakris GL , Black HR , Chen HX , Durand JB , Elliott WJ , Ivy SP , Leier CV , Lindenfeld J , Liu G , Remick SC , Steingart R , Tang WH ; Cardiovascular Toxicities Panel, Convened by the Angiogenesis Task Force of the National Cancer Institute Investigational Drug Steering Committee . Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors . J Natl Cancer Inst 2010 ; 102 : 596 – 604 . Google Scholar CrossRef Search ADS PubMed 72. Zamorano JL , Lancellotti P , Rodriguez Muñoz D , Aboyans V , Asteggiano R , Galderisi M , Habib G , Lenihan DJ , Lip GYH , Lyon AR , Lopez Fernandez T , Mohty D , Piepoli MF , Tamargo J , Torbicki A , Suter TM ; ESC Scientific Document Group . 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) . Eur Heart J 2016 ; 37 : 2768 – 2801 . Google Scholar CrossRef Search ADS PubMed 73. Whelton PK , Carey RM , Aronow WS , Casey DE Jr , Collins KJ , Dennison Himmelfarb C , DePalma SM , Gidding S , Jamerson KA , Jones DW , MacLaughlin EJ , Muntner P , Ovbiagele B , Smith SC Jr , Spencer CC , Stafford RS , Taler SJ , Thomas RJ , Williams KA Sr , Williamson JD , Wright JT Jr . 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018, 71:e13-e115 . 74. Veronese ML , Mosenkis A , Flaherty KT , Gallagher M , Stevenson JP , Townsend RR , O’Dwyer PJ . Mechanisms of hypertension associated with BAY 43-9006 . J Clin Oncol 2006 ; 24 : 1363 – 1369 . Google Scholar CrossRef Search ADS PubMed 75. Nazer B , Humphreys BD , Moslehi J . Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension . Circulation 2011 ; 124 : 1687 – 1691 . Google Scholar CrossRef Search ADS PubMed 76. Mir O , Coriat R , Ropert S , Cabanes L , Blanchet B , Camps S , Billemont B , Knebelmann B , Goldwasser F . Treatment of bevacizumab-induced hypertension by amlodipine . Invest New Drugs 2012 ; 30 : 702 – 707 . Google Scholar CrossRef Search ADS PubMed 77. Langenberg MH , van Herpen CM , De Bono J , Schellens JH , Unger C , Hoekman K , Blum HE , Fiedler W , Drevs J , Le Maulf F , Fielding A , Robertson J , Voest EE . Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors . J Clin Oncol 2009 ; 27 : 6152 – 6159 . Google Scholar CrossRef Search ADS PubMed © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

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American Journal of HypertensionOxford University Press

Published: Sep 1, 2018

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