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Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome. Feliers, D. VEGF regulation of endothelial nitric oxide synthase in glomerular endothelial cells. Kidney Int. Sandoo, A. The endothelium and its role in regulating vascular tone. Open Cardiovasc. Neagoe, P. Kappers, M. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels.
Hypertension 56 , — Regorafenib induces rapid and reversible changes in plasma nitric oxide and endothelin Management of antiangiogenic therapy-induced hypertension. Hypertension 60 , — Pandey, A. Our study has demonstrated that bevacizumab is associated with a significantly increased risk of high-grade hypertension, with an incidence of 7.
The clinical significance of severe hypertension is evident because of associated cardiovascular complications. Indeed, severe hypertension can require hospitalization or discontinuation of bevacizumab in up to 1. In addition to bevacizumab, other angiogenesis inhibitors such as sunitinib and sorafenib, which block the activity of VEGF receptors, are also associated with high-grade hypertension.
Based on our previous studies, the incidences of high-grade hypertension for sunitinib and sorafenib were 6. Thus, it appears that the absolute risk of high-grade hypertension induced by these angiogenesis inhibitors is remarkably similar. Efforts are ongoing to understand the mechanism of hypertension associated with angiogenesis inhibitors.
The binding of VEGF to its corresponding receptors can enhance microvascular permeability, initiate cell division and migration, and impede apoptosis and senescence. Appropriate VEGF expression in endothelial cells and podocytes of kidneys maintains a normal glomerular structure and function. Disruption of the VEGF signaling pathway leads to inhibition of nitric oxide synthase, thereby reducing nitric oxide and prostacyclin synthesis.
This in turn renders a vasoconstrictive effect and decreased sodium ion renal excretion, resulting in elevated blood pressure. In addition, hypertension may be related to vascular rarefaction, a functional decrease in the number of arterioles and capillaries generating an increase in peripheral vascular resistance. We also explored the relationship between bevacizumab dose and high-grade hypertension. Here, we showed that RRs of high-grade hypertension were 4.
It is possible that our study may be limited in power to detect a small difference due to the much lower incidence of high-grade hypertension in comparison with all-grade hypertension. Alternatively, it can be speculated that the development of high-grade hypertension may have a distinct mechanism involving VEGF or its receptor polymorphism resulting in differential sensitivity to anti-VEGF effect of bevacizumab.
This is consistent with the observation that a particular VEGF genotype was correlated with hypertension in patients with metastatic renal cell carcinoma undergoing the therapy of sunitinib. Our study demonstrated that the risk of high-grade hypertension associated with bevacizumab varies among patients with different tumor type, with significantly increased risks observed in patients with renal cell carcinoma RR: 8.
The higher RR in patients with renal cell carcinoma can be secondary to decreased glomerular filtration because of nephrectomy commonly performed in these patients.
Although it was not statistically significant, a particularly high RR of It is possible that breast cancer patients, who would receive a wide array of adjuvant therapies with known cardiovascular side effects, may be more prone to the anti-VEGF effect of bevacizumab.
Interestingly, the development of grade 2 and 3 hypertension was correlated with better disease control in advanced CRC patients undergoing bevacizumab-based therapy.
However, this does not exclude the possibility that a correlation might exist for all-grade hypertension or at patient level.
Further prospective large trials with standard blood pressure measurement may be able to resolve this issue. There are no specific guidelines for the treatment of bevacizumab-associated hypertension. The packet insert recommends permanently discontinuing bevacizumab in patients with hypertensive crisis or hypertensive encephalopathy, and temporarily suspending bevacizumab in patients with severe hypertension that is not controlled with medical management.
Lifestyle modification may be considered for patients with hypertension. No clear recommendation for an antihypertensive agent can be made because there is a lack of controlled studies addressing the subject.
Our study has several limitations. The findings described here are affected by the limitations of individual trials included in the analysis. Other classification methods proposed by European Society of Hypertension may also better define blood pressure variation Second, these studies were conducted at various institutions across the country, and hence may contribute bias related to instruments, recording of blood pressure, different protocols followed by different institutions resulting in potential bias of reported incidences.
The reported incidence of high-grade hypertension had significant heterogeneity among the included studies. Nevertheless, we have minimized its influence by using a random-effects model to calculate the overall incidence of high-grade hypertension. Despite these differences, RRs reported by all of the studies were remarkably nonheterogenous.
Third, these studies were conducted at major academic institutions for patients with adequate major organ function, and may not reflect general patient population in the community or those patients with organ dysfunction. Therefore, conclusions from these studies may not be applied to general patient population in community or patients with organ dysfunction. Fourth, this is a meta-analysis at study level; therefore confounding variables at the patient level cannot be assessed properly and incorporated into the analysis.
In addition, we were not able to find any meaningful correlation between high-grade hypertension and study level covariants such as follow-up duration, cancer types, bevacizumab dose, and number of subjects by logistic regression.
Fifth, although we were not able to detect significant publication bias on the P values from Begg's and Egger's test, and also searched unpublished abstracts from ASCO conferences to reduce publication bias, it may not be sufficient to identify unpublished results to eliminate publication bias.
Finally, even though our analysis showed that bevacizumab did not significantly increase the risk of hypertensive crisis RR: 3. In summary, our study has shown that the addition of bevacizumab to concurrent antineoplastic therapy significantly increased the risk of high-grade hypertension in cancer patients. The risk was associated with both low and high doses of bevacizumab, and may vary among patients with different tumors.
It is important for physicians and patients to recognize the risk, and treat it adequately in order to prevent cardiovascular complications. Future studies are recommended to investigate risk reduction and to optimize bevacizumab-based therapy.
It has not played any role in the design, collection, analysis, interpretation, and writing of the study. Three authors including V. The corresponding author had access to all raw data, and maintained final responsibility to submit the manuscript for publication. Cavallaro U , Christofori G : Molecular mechanisms of tumor angiogenesis and tumor progression.
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Lancet ; : — Oncology ; 69 Suppl 3 : 25 — J Clin Oncol ; 22 : — J Clin Oncol ; 27 : — Zhu X , Wu S , Dahut WL , Parikh CR : Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis ; 49 : — These comorbidities include coronary artery disease, diabetes, obstructive sleep apnea, and underlying hypertension [ 54 ]. In patients with well-controlled hypertension and appropriate management of other vascular risk factors, re-introduction of VSP-TKI may be possible with close BP monitoring.
Ibrutinib is a distinct small molecule TKI which acts not via VSP but by selectively and irreversibly inhibiting Bruton tyrosine kinase BTK and preventing chemokine-induced adhesion and migration. The mechanism of hypertension and its management strategies are yet to be clarified.
Bortezomib and second-generation proteasome inhibitor PI , carfilzomib, are used in the treatment of multiple myeloma MM. Both have been implicated in drug-induced hypertension with carfilzomib more often than bortezomib [ 77 , 78 ]. The proposed mechanism for cardiovascular adverse effect is abnormal accumulation of ubiquitinated proteins from proteasome inhibition resulting in cellular toxicity and endothelial damage [ 79 ].
Another study analyzing the safety profile of carfilzomib from four Phase II trials demonstrated an aggregated Long-term real-world data on the incidence and management of hypertension associated with carfilzomib and ixazomib are not yet available. Cyclophosphamide, ifosfamide, busulfan, and cisplatin are commonly used in the treatment of hematologic malignancies lymphoma, leukemia and solid organ malignancies head and neck cancers and genitourinary cancers.
The predominant mechanism for arterial hypertension is suspected to be oxidative damage to endothelial cells, increased intimal thickness, and abnormal vascular remodeling [ 84 ]. Other postulated mechanisms include nephrotoxicity with associated sodium retention [ 85 ].
No antihypertensive medication is decisively superior over others for the management of hypertension associated with alkylating agents. Glucocorticoids are commonly used in anticancer regimens, especially for hematologic malignancies, such as lymphoma and MM. Steroids cause new-onset or worsening hypertension by promoting sodium and water retention, exerting its intrinsic vasoconstricting properties, and increasing sensitivity to endogenous vasopressors.
The mainstay of BP control for these patients is dose reduction or drug discontinuation. However, if a patient requires high-dose steroids, diuretics may be added for BP control since it targets the main mechanism of fluid retention. In the context of cancer management, calcineurin inhibitors cyclosporin and tacrolimus are commonly used for immunosuppression post-transplant for graft vs. It is also sometimes used for autoimmune diseases associated with cancers, such as autoimmune hemolytic anemia and pure red cell aplasia.
The proposed mechanism of hypertension includes changes in sympathetic activity, increased proximal tubule sodium reabsorption, renal dysfunction with distal tubule ENaC epithelial sodium channel activation, decrease in NO production, RAAS activation and altered renal prostaglandin PG synthesis [ 91 , 93 , 94 ]. In a recent observational study on the efficacy of different antihypertensive medications for cyclosporine-induced hypertension among renal transplant patients, all anti-hypertensives reduced systolic BP effectively.
However, beta-blockers and ACEIs were associated with increased graft failure [ 96 ]. Compared to cyclosporin, tacrolimus has been associated with a lower incidence of hypertension [ 97 ]. Low-dose amlodipine has equal efficacy as other anti-hypertensives with minimal side effects [ 98 ].
ACEIs are associated with a slight decrease in GFR, hyperkalemia, and elevation of uric acid levels when used for cyclosporin-induced hypertension [ 99 ]. Similarly, diuretics can elevate uric acid levels and precipitate acute gout. Also, diuretics can lead to hypomagnesemia, which increases the risk of arrhythmias. Thus, caution must be exercised, and close monitoring is required when prescribing loop diuretics. Since tacrolimus causes hypertension by targeting the sodium-chloride transporter in the distal convoluted tubule, thiazide diuretics are especially effective [ ].
Interestingly, a recent study has shown that probiotic Lactobacillus fermentum also reduces the incidence of tacrolimus-induced hypertension by preventing oxidative stress, NOS uncoupling, and resultant endothelial dysfunction [ ].
Mycophenolate mofetil, another immunosuppressive agent, has been associated with hypertension but to a much lesser extent compared to calcineurin inhibitors. The incidence of hypertension is thought to be dose-dependent [ ], and the hypertension responds well to ARBs, especially losartan [ ]. Abiraterone acetate is an oral hormonal agent used in the treatment of metastatic castration-resistant prostate cancer [ ].
It inhibits CYP17, a key enzyme that catalyzes the biosynthesis of androgens, more specifically dehydroepiandrosterone DHEA from hydroxyprognenolone [ ]. As a result of CYP17 inhibition, abiraterone decreases serum levels of testosterone and other androgens. Steroid precursors can be diverted to mineralocorticoid production, resulting in fluid retention and subsequent hypertension [ ]. In a meta-analysis of patients with metastatic prostate cancer on abiraterone, new-onset hypertension was significantly higher in the abiraterone group compared with placebo [ ].
To prevent this mineralocorticoid toxicity, it is often prescribed with prednisone. In patients who cannot tolerate prednisone, mineralocorticoid antagonists, such as spironolactone, can be considered.
Copanlisib is a phosphoinositol-3 kinase inhibitor approved for relapsed follicular lymphoma. It has been frequently associated with hyperglycemia and hypertension. Thus, it requires pre- and post-infusion monitoring and close follow-up. Taxanes are widely used for the treatment of a variety of solid tumor cancers in both adjuvant and metastatic settings. Paclitaxel is used for breast, ovarian, bladder, prostate, and esophageal cancers. Docetaxel has been approved to treat breast, lung, prostate, head and neck, and stomach cancers.
The mechanism of action of taxanes is to affect microtubules, resulting in cell cycle arrest and aberrant mitosis. They have been associated with endothelial dysfunction [ , ]. When paclitaxel is used in combination with bevacizumab for breast and lung cancer, the incidence of hypertension has been shown to increase [ , ]. Docetaxel has rarely been associated with hypertension. The possible mechanisms behind EPO-induced hypertension include increased blood viscosity, direct vasoconstricting properties, increased sensitivity to endogenous vasopressors within smooth muscle cells, and vascular remodeling [ ].
Daratumumab and elotuzumab, relatively novel monoclonal antibodies used for the treatment of RRMM, have also been associated with hypertension. Grade 3 hypertension was reported in up to 6. BP assessment is usually performed in the outpatient office setting. In-clinic measurements may be subject to error due to a variety of factors including individual technique, equipment, measurement method, and time constraints.
Office BP measurements can be affected by important confounders, such as pain- or anxiety-driven sympathetic overactivity and temporary medications, such as NSAIDs or steroids. Studies have shown that patients with cancer may have a higher prevalence of both white coat hypertension and masked hypertension [ ]. As such, it is crucial to incorporate out-of-clinic BP measurements, which include ambulatory and HBPM, in the management of the oncologic patient.
Patients with cancer have traditionally been excluded in the large-scale hypertension trials. Figure 1 illustrates a reasonable stepwise approach to identify and manage hypertension in the context of cancer treatment with the overarching goal of reducing the burden of CVD in this at-risk population. Randomized clinical trials with a focus on optimal BP goals and management in oncologic patients are needed to better inform contemporary clinical practice.
Algorithm for blood pressure assessment and management in patients newly diagnosed with cancer. Many studies have highlighted that the overall survival in patients with cancer is as much dependent on their comorbidities as it is on the stage of cancer at the time of diagnosis [ , , , ].
Cancer-related therapies are known to cause secondary hypertension as a side effect. New onset or worsening hypertension is a well-known potential adverse effect of VEGF inhibitors as well as other antineoplastic therapies. Indeed, elevated BP can be used as a surrogate biomarker for the optimal anti-tumor effect of VEGF inhibitors [ 68 , 69 ]. Importantly, the treatment of resultant hypertension does not compromise the outcome of cancer treatment [ ].
Given the rapid development of new treatment regimens that counter the growth and spread of cancer and increase the longevity of patients, there is an urgent need to tackle non-cancer-related comorbid medical conditions, such as hypertension, that may interfere with successful cancer treatment. Management of underlying cancer and non-cancer comorbidities must go hand in hand, and the joint efforts of the oncologist, cardio-oncologist, and primary care provider are critical to provide optimal care in these patients.
The composite goal is to reduce cardiovascular events while achieving maximum benefits from cancer therapy. Timely screening for hypertension, early diagnosis and prompt initiation of intervention, regular home BP monitoring, and close follow-up can reduce the burden of cardiovascular complications, leading to an improvement in the quality of life and overall survival in patients with cancer.
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Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.
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