Etiology and management of hypertension in patients with cancer.

Background

Recent advances in antineoplastic therapies have resulted in a significant improvement in overall and disease-free survival in patients with cancer. Better strategies for early detection and effective treatment have transformed cancer from a fatal disease to a chronic condition [ 1 ] . However, the quality of life of these patients often remains low because of toxicities that may arise from cancer therapies. Importantly, cardiovascular toxicities, if severe, may lead to the premature discontinuation of effective treatment [ 2 ] . Cancer therapies have been associated with cardiomyocyte damage, heart failure, ischemia, hypertension, and rhythm disturbances [ 1 ] . In a study by Patnaik et al., among sixty-three thousand women with breast cancer who were followed for nine years, cardiovascular disease (CVD) was the primary cause of death, followed by breast cancer. Intriguingly, of the women who died of CVD, only 25% had a documented history of CVD at the time of their cancer diagnosis [ 3 ] .

As with the other cardiovascular side effects of cancer drugs, hypertension is important to recognize and treat [ 4 ]. Hypertension is a well-established risk factor for heart failure and atherosclerotic cardiovascular disease (ASCVD) in the general population as well as in patients with cancer. Hypertension increases the risk of death from stroke, heart disease, and other vascular conditions. Recent data suggest that the presence of hypertension, particularly poorly-controlled hypertension, significantly increases the risk for chemotherapy-induced cardiomyopathy and heart failure [ 4 , 5 ]. Effective treatment of hypertension allows patients to tolerate maximum doses of the planned chemotherapy, yielding better control of the tumor [ 6 ].

The objectives of this review are as follows: 1) to review the classes of antineoplastic drugs that can potentially cause hypertension, summarizing the incidence, mechanism, management for each class of cancer drug; 2) to discuss other potential causes of hypertension in patients with cancer aside from cancer treatment; 3) to review the role of poorly controlled hypertension in exacerbating anthracycline and trastuzumab-induced cardiomyopathy and heart failure; 4) to discuss the importance of blood pressure (BP) control in the oncologic patient; and 5) to discuss the recommended target BP range for cancer patients and survivors.

The relationship between cancer and hypertension

Various classes of medications used for the treatment of cancer have been associated with the development of new hypertension or exacerbation of previously well-controlled hypertension. Furthermore, hypertension has been associated with an increased likelihood of developing certain cancers and with higher cancer-related mortality. The relationship between cancer and hypertension was first suggested by Dyer et al. in 1975 [ 7 ] . 1233 men were followed for 14 years in a prospective study, which demonstrated an association of higher systolic and diastolic blood pressures with higher cancer-related mortality [ 7 ] . In a large prospective pooled cohort study, hypertension, both treated and untreated, was associated with an increased likelihood of developing cancer compared with normotensive individuals. Additionally, there was a similar increased risk of cancer mortality in patients with hypertension (7–15%) compared with normotensive patients [ 8 ] .

Certain types of cancers have been associated with hypertension. Hypertensive men are at a higher risk of developing prostate cancer, and hypertensive women are at a higher risk of developing endometrial and breast cancers [ 4 ]. Hypertension is also a known risk factor for renal cancer [ 9 ]. In a study by Colt et al., hypertension increased the risk of renal cancer by two-fold in Caucasian and up to three-fold in African American patients. This risk increased to four times in African American patients if they were diagnosed with hypertension for more than 25 years [ 10 ].

In a prospective cohort study by Stocks et al. of approximately 577,800 adults followed for 12 years, there was an association between hypertension and cancer incidence in men and between hypertension and higher cancer mortality in both men and women. In men, the absolute 20-year risk for development of cancer increased from 13.7% in a normotensive patient to 15.6% in a hypertensive patient. This study also noted a statistically significant positive association between hypertension and mortality from cancers of oropharynx, pancreas, rectum, lung, prostate, and bladder in men, and pancreas, breast, and malignant melanoma in women [ 11 ] . Grossman et al. analyzed 47,000 patients and concluded that systolic hypertension was associated with an increased risk of mortality from cancer by 23% [ 12 ].

The underlying mechanism remains unclear. Animal models suggest dysregulation of apoptosis due to elevated blood pressures [ 8 ] . Another hypothesis is that angiotensin II, which is elevated in hypertensive patients, can stimulate the production of vascular endothelial growth factor (VEGF), which in turn augments cancer-related angiogenesis [ 13 ]. Finally, patients with hypertension may have other risk factors, such as advanced age, smoking, obesity, and sedentary lifestyle, which increase the risk for cancer development and cancer-related mortality.

The role of hypertension in increasing the risk for anthracycline- and trastuzumab-induced cardiomyopathy

Anthracycline-based chemotherapy is well known to potentially cause irreversible damage to the heart in a dose-dependent manner [ 14 , 15 ]. Recent data suggest that the presence of hypertension, particularly poorly-controlled hypertension, significantly increases the risk for chemotherapy-induced cardiomyopathy and heart failure [ 4 , 5 ]. One of the earliest studies indicating this association was a retrospective analysis of 4018 patients published in 1979, which found that patients with underlying heart disease, hypertension, or both were at a higher risk for developing doxorubicin-induced heart failure [ 16 ] . In a retrospective study by Hershman et al., patients with diffuse large B-cell lymphoma (DLBCL) receiving doxorubicin-based chemotherapy versus other chemotherapy were analyzed. After adjusting for cardiac risk factors, doxorubicin was associated with a higher risk of heart failure. Among patients receiving doxorubicin, both hypertension and diabetes were strongly associated with the development of heart failure [ 17 ] . Pre-existing hypertension has been demonstrated to be an independent risk factor for the development of anthracycline cardiotoxicity and heart failure (hazard ratio = 1.8; p < 0.01) [ 18 ]. The patients with hypertension had a 58% higher risk of developing CHF than those without hypertension [ 18 ].

The mechanism of anthracycline-induced cardiotoxicity is postulated to be multifactorial involving the generation of reactive oxygen species, mitochondrial dysfunction, cardiomyocyte injury, and impaired repair mechanism [ 19 – 22 ]. Although most of the myocardial injury is thought to occur at the time of anthracycline exposure, it can also occur many years later. Long-lived hydroxy metabolites or secondary alcohol metabolites may accumulate in the cardiac myocytes as “anthracycline signatures”, which can lead to calcium channel inactivation, disruption of cellular metabolism, and redox imbalance [ 15 ]. Salvatorelli et al. have shown that even low-dose anthracycline therapy can potentially lead to heart failure through the same mechanism, and epirubicin has a better side effect profile than doxorubicin due to less generation of secondary metabolites [ 23 ].

Any previous stressors or damage to the heart can intensify anthracycline-induced cardiotoxicity [ 24 ]. Hypertension leads to increased systemic vascular resistance, which in turn leads to pressure overload. Increased left ventricular wall stress results in the release of growth factors and cytokines, which then leads to concentric remodeling and hypertrophy. Hypertension-mediated cytokine activation can also increase the rate of downstream cell apoptosis, leading to ventricular dysfunction [ 25 ]. These mechanisms together with the cytotoxic factors of anthracyclines may accelerate the development of heart failure [ 24 ]. In 2014, Szmit et al. studied patients with lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). They found that patients with preexisting hypertension more frequently developed left ventricular dysfunction compared with patients without hypertension. In turn, this caused the hypertension subgroup to have more delays in subsequent treatment, more reductions of doxorubicin doses, and early discontinuation of chemotherapy [ 26 ].

Similarly, trastuzumab-associated cardiotoxicity has been demonstrated to be exacerbated by the presence of underlying hypertension. In patients with breast cancer receiving trastuzumab with or without anthracycline, the risk factors for the development of congestive heart failure are age > 65 years, diabetes, hypertension, obesity, and smoking history [ 27 , 28 ]. One of the key mechanisms for myocardial injury in these patients is the alteration in nitric oxide (NO) synthesis and release from vascular endothelial cells [ 29 ]. Patients with hypertension have increased systemic vascular resistance, which increases myocardial wall stress. Among patients receiving trastuzumab therapy, inhibition of human epidermal growth factor receptor (HER2) activity in cardiomyocytes interrupts the HER2/neuregulin pathway, which is central to NO synthesis and sarcomere preservation [ 30 ]. Disruption of this pathway reduces NO bioavailability with a concomitant increase in angiotensin-II and reactive oxygen species (ROS) [ 31 ]. These processes, in addition to the preexisting myocardial stress from underlying hypertension, culminate in endothelial dysfunction, which is a well-established contributor to the development of congestive heart failure.

Therefore, preexisting hypertension may worsen the overall prognosis of patients undergoing anthracycline-based chemotherapy and/or trastuzumab. Effective treatment of hypertension allows the patients to tolerate maximum doses of the planned cancer therapy, yielding better control of the tumor [ 6 ].

Cancer therapies with the potential to cause hypertension

Various classes of medications used for the treatment of cancer have been associated with the development of new hypertension or exacerbation of previously well-controlled hypertension (Table 1 ). In this section, we discuss the classes of antineoplastic and other drug therapies commonly used in cancer treatment that can potentially cause hypertension. For each drug class, we summarize the incidence, mechanism, and management from the available literature (Table 2 ). Table 1 List of anticancer drugs commonly associated with hypertension VEGF inhibitors TKI Proteosome inhibitors Alkylating agents Miscellaneous Bevacizumab Sorafenib Bortezomib Cyclophosphamide Steroids Ramucirumab Sunitinib Carfilzomib Ifosfamide Abiraterone Aflibercept Lenvatinib Ixazomib Busulfan Recombinant human erythropoietin Axitinib Cisplatin Cyclosporin Ibrutinib Tacrolimus Cabozantinib Paclitaxel Pazopanib Copanlisib Nintedanib Daratumumab Regorafinib Elotuzumab VEGF Vascular endothelial growth factor, TKI Tyrosine kinase inhibitor Table 2 Mechanism and incidence of hypertension associated with cancer drug class and proposed treatment recommendation Cancer Drug Class Mechanism of Hypertension Incidence of Hypertension Recommended Treatment VEGF inhibitors endothelial dysfunction, decrease in nitric oxide and prostacyclin I, increase in endothelin, vascular remodeling, capillary rarefaction, decreased renal excretion of sodium All Grade: 17–80% Grade 3–4: 6–9% CCB (e.g., amlodipine) ACEI (e.g., lisinopril) TKI decrease in NOS activity, activation of RAAS All Grade: 17–47% Grade 3–4: 4–6% ACEI CCB Proteasome inhibitors angiotensin-induced hypertension, aortic vascular remodeling All Grade: 3–15% ACEI or ARB (e.g., losartan) Alkylating agents oxidative damage to endothelial cells, increased intimal thickness, abnormal vascular remodeling, sodium retention All Grade: 36–50% ACEI or ARB Steroids promoting sodium and water retention, intrinsic vasoconstricting properties, enhanced sensitivity to endogenous vasopressors All Grade: up to 13% a Diuretics (e.g., hydrochlorothiazide) Mineralocorticoid antagonists (e.g., spironolactone) Calcineurin inhibitors and other immunosuppressive agents sympathetic overactivity, increased renal sodium reabsorption (distal tubule ENaC activation), decrease in NO production, RAAS activation, altered renal PG synthesis All Grade: 30–80% CCB Thiazide diuretics (especially for Tacrolimus) Taxanes endothelial dysfunction, enhanced toxicity of bevacizumab and anthracyclines NA ACEI or ARB CCB Abiraterone increase in steroid precursors with mineralocorticoid properties (sodium and fluid retention) NA Mineralocorticoid antagonists Diuretics Recombinant human erythropoietin increased blood viscosity, direct vasoconstricting properties, increased sensitivity to endogenous vasopressors All Grade: 30–35% CCB a Data on the incidence of steroid-induced hypertension comes mainly from pediatric population treated for acute lymphocytic leukemia (ALL) VEGF vascular endothelial growth factor, TKI tyrosine kinase inhibitor, NOS nitric oxide synthase, RAAS renin-angiotensin-aldosterone system, ENaC epithelial sodium channel, PG prostaglandin, CCB calcium channel blockers, ACEI angiotensin converting enzyme inhibitors, ARB angiotensin II receptor blocker, NA not available

VEGF signaling pathway (VSP) inhibitors

Angiogenesis is one of the central pathophysiological mechanisms involved in the growth and spread of tumors [ 32 ]. Vascular endothelial growth factor (VEGF), which is found in endothelial cells, fibroblasts, renal epithelial cells, and tumors, is among the most important mediators of angiogenesis [ 33 ]. VEGF binding to VEGF receptors (VEGFR) activates multiple intracellular downstream signaling pathways, including phosphoinositide 3-kinase/AKT, endothelial nitric oxide synthase (eNOS), and prostacyclin. These pathways are important for vasodilation and maintaining the integrity of the vasculature through endothelial cell survival, proliferation, and permeability [ 34 ].

VSP inhibitors are classified into three categories based on their site of action on the VEGF pathway: 1) VEGF ligand binders that prevent binding of VEGF to VEGFR [ 35 ]; 2) small molecule tyrosine kinase inhibitors (TKIs) that interrupt intracellular pathways [ 36 ]; and 3) soluble decoy receptors acting as “VEGF trap” [ 37 ].

VEGF inhibitors

The most widely used VEGF inhibitor is bevacizumab, a humanized monoclonal antibody (mAb) targeting VEGF-A, approved by the FDA in 2004. It is commonly used to treat advanced solid organ cancers, such as colon and other gastrointestinal malignancies, non-small cell lung cancer (NSCLC), renal cell cancer (RCC), and gynecologic malignancies, among others. Other drugs in this class include ramucirumab, mAb directed against VEGFR-2, and aflibercept, a soluble decoy receptor that binds to VEGF-A, VEGF-B, and placental growth factor, preventing them from binding and activating native VEGFR.

Hypertension is the most commonly reported cardiovascular side effect of VEGF inhibitors with incidence ranging from 17 to 80% in the literature [ 38 ]. The grades of hypertension resulting as a side effect of cancer therapy is reviewed in Table 3 . In a meta-analysis of more than 21,900 patients from 72 clinical trials who were treated with bevacizumab-based therapy, all-grade hypertension was documented in 25.3% of patients, and grade 3 or 4 hypertension was noted in 8.2% [ 40 ]. In another meta-analysis of 3155 patients with non-small cell lung cancer, the incidence of all-grade hypertension was reported to be 19.55% and that of high-grade hypertension 6.95% [ 41 ]. The risk factors for high-grade hypertension were older age (> 75 years old), African-American race, higher dose of bevacizumab, drug interaction with other medications, and type of malignancy (i.e., renal tumors) [ 42 ]. Table 3 Grades of hypertension resulting as a side effect of cancer therapy per the NCI Common Terminology Criteria for Adverse Events (CTCAE) [ 39 ] Grade of Hypertension Severity Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Systolic BP 120–139 mmHg or diastolic BP 80–89 mmHg Grade 2 Moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental ADL Systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg; Recurrent or persistent elevation ( > 24 h); Symptomatic increase by > 20 mmHg (diastolic) or to > 140/90 mmHg if previously WNL; Monotherapy is indicated Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Systolic BP > 160 mmHg or diastolic BP > 100 mmHg; Medical intervention is indicated; Requires more intensive therapy than previously used or more than one drug Grade 4 Life-threatening consequences; urgent intervention indicated Life-threatening consequences (malignant hypertension, transient or permanent neurological deficit, hypertensive crisis); Urgent intervention is indicated Grade 5 Death related to AE Death Adapted from Cancer Institute N. Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Published Nov,2017

Although the exact mechanism of VEGF inhibitor-induced hypertension is not entirely understood, potential mechanisms have been proposed [ 43 , 44 ]: oxidative stress and endothelial dysfunction [ 45 ], an imbalance between vasodilators (decrease in nitric oxide and prostacyclin I) and vasoconstrictors (increase in endothelin) [ 46 ], vascular remodeling, capillary rarefaction [ 47 ] and decreased renal excretion of sodium [ 48 ]. In addition, VEGF inhibitors can cause autonomic system toxicity and sympathetic dysregulation, resulting in hypertension [ 49 ].

Hypertension induced by bevacizumab often occurs early after treatment initiation. Controlling pre-existing hypertension is recommended before initiating therapy with bevacizumab [ 50 ]. The treating oncologist must perform a thorough history and exam and order appropriate cardiovascular workup before starting bevacizumab. Plummer et al. published a consensus statement on the management of hypertension in patients receiving bevacizumab for ovarian and cervical cancer [ 51 ]. They recommend that bevacizumab can be safely initiated in patients only if BP is < 160/100 mmHg. If office BP is > 160/100 mmHg, then home blood pressure monitoring (HBPM) is advised. If BP is > 150/95 mmHg on four consecutive days, then treatment hold should be considered, and amlodipine 5 mg may be initiated for BP control [ 51 ]. Traditionally, BP has been monitored weekly, especially in the first cycle, then at an interval of every 2–3 weeks. All patients are strongly advised to maintain BP < 140/90 mmHg. In case of discrepancies between home and clinic BP, HBPM is preferred to decide on further dosing of bevacizumab. A study by Shah et al. demonstrated that a lower dose of bevacizumab was not associated with hypertension and proteinuria [ 52 ]. In the case of high-grade hypertension necessitating additional anti-hypertensives, angiotensin converting enzyme inhibitors (ACEI) may be used [ 51 ]. These recommendations were also supported by Cameron et al., who suggested maintaining BP < 140/90 mmHg while on bevacizumab therapy with weekly HBPM and regular urinalysis for proteinuria [ 53 ].

Consistent with the recent AHA hypertension guidelines, a BP target of < 130/80 mmHg is generally recommended among patients on VEGF inhibitors [ 54 ]. Although amlodipine and ACEIs are the preferred first-line choices, adding a beta-blocker to ACEI therapy in patients with heart failure or cardiomyopathy helps improve prognosis by preventing cardiac remodeling [ 55 ]. Preclinical data have suggested that nifedipine may increase VEGF levels [ 56 ]; however, it did not reduce the antitumor activity of VEGF inhibitors. In addition, newer data suggest that nifedipine can effectively reverse BP elevation associated with VSP inhibitors. Non-dihydropyridine calcium channel blockers (CCB), such as verapamil and diltiazem, are generally avoided in these patients because they inhibit CYP3A4, which metabolizes VEGF inhibitors, leading to potentially high drug levels [ 57 , 58 ].

If a patient develops hypertensive urgency or crisis while on bevacizumab, then subsequent dosing is contraindicated, and an alternative treatment regimen is recommended [ 6 ]. Bevacizumab-related hypertension often resolves when the treatment course is stopped or completed. It is important to have the patient follow up in four weeks after treatment completion to adjust or discontinue antihypertensive therapy depending on BP readings. In one study, hypertension resolved in more than 82% of patients with a median duration of 87 days after the last dose of bevacizumab [ 59 ]. Once BP normalizes, annual or biannual monitoring is usually sufficient.

Aflibercept, a VEGF trap, has also been associated with an increased incidence of all-grade hypertension in patients with RCC and requires BP management along similar lines as bevacizumab discussed above [ 60 ].

Small molecule tyrosine kinase inhibitors

Small molecule tyrosine kinase inhibitors (TKI), such as sorafenib, sunitinib, lenvatinib, and axitinib, are used for the treatment of a variety of solid tumors, including RCC, hepatocellular carcinoma, metastatic melanoma, gastrointestinal stromal tumors (GIST), and neuroendocrine pancreatic neoplasms. Other drugs in this class include pazopanib, cabozantinib, nintedanib among others. The drugs in this class of multikinase inhibitors act by interrupting downstream intracellular VEGF signaling pathways and inhibit angiogenesis [ 61 ].

Hypertension is one of the most reported adverse events documented in 17–47% of patients receiving VSP-TKIs. The postulated mechanisms for hypertension involve decreased renal NO bioavailability via downregulation of soluble guanylate cyclase activity, inhibition of intrarenal NOS activity, activation of the renin-angiotensin-aldosterone system, and decreased fractional sodium excretion [ 62 ]. In a systematic review and meta-analysis of sorafenib-induced hypertension, the incidence of new-onset all-grade hypertension was 19.1% and high-grade hypertension was 4.3% [ 63 ]. In clinical trials, sunitinib was associated with hypertension in 17–24% [ 64 , 65 ]. In an observational study on patients with GIST treated with TKIs, the incidence of new-onset or worsening hypertension was 33.3% with sorafenib and 22.7% with sunitinib. However, more patients developed grade 3 or 4 hypertension on sunitinib compared to sorafenib [ 66 ]. Similar findings were reported in a review looking at the safety profile of TKIs in patients with RCC, where it was reported that sorafenib has a better side effect profile than sunitinib. Among all TKIs, axitinib was associated with the highest rates of hypertension [ 67 ].

Several studies have demonstrated that TKI-induced hypertension may serve as a biomarker of efficacy in patients with metastatic RCC. Patients who developed the adverse events of hypertension, neutropenia, and thrombocytopenia on sunitinib had a longer progression-free survival (PFS) and overall survival (OS) [ 68 , 69 ]. In another study on patients with metastatic RCC on sunitinib, patients receiving angiotensin system inhibitors for hypertension had better PFS and OS compared with patients on other anti-hypertensive medications [ 70 ]. VSP-TKIs are associated with up to a 3–8% incidence of cardiotoxicity, and the addition of ACEIs or beta-blockers for hypertension is beneficial [ 54 ]. Newer treatment options like NO donors have shown promising results for TKI-induced hypertension, and further studies are underway [ 71 ].

Hypertension associated with VSP-TKIs usually does not require treatment interruption, and concomitant anti-hypertensive therapy is often sufficient. Those patients who develop hypertensive crisis or refractory hypertension may require treatment cessation. The increase in BP induced by VSP-TKIs appears to be reversible once the drug is discontinued [ 72 – 74 ]. In a study of sunitinib in patients with metastatic RCC or GIST and in rats, the rise in BP was reversible after sunitinib withdrawal [ 75 ]. Whether it is safe to rechallenge a patient with a VSP-TKI once BP is better controlled remains to be answered. Rechallenge may be feasible once the underlying risk factors for vascular toxicity are screened and treated. 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. Ibrutinib has also been observed to cause new-onset or worsening hypertension in 18% of patients and grade 3 or 4 hypertension in 6% of patients with CLL [ 76 ]. The mechanism of hypertension and its management strategies are yet to be clarified.

Proteasome inhibitors

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 ].

In Phase III of the ENDEAVOR trial, 16% of patients on carfilzomib and 6% on bortezomib developed hypertension [ 78 ]. Another study analyzing the safety profile of carfilzomib from four Phase II trials demonstrated an aggregated 14.3% of patients developing new-onset or worsening hypertension in patients with MM [ 80 ].

In Phase I/II clinical trials, > grade 3 hypertension was reported in 5% of all treatment-naïve patients with MM on ixazomib, a third generation PI [ 81 ]. Similar incidence (6%) was reported in patients with relapsed/refractory MM (RRMM) in a Phase III trial [ 82 ]. Long-term real-world data on the incidence and management of hypertension associated with carfilzomib and ixazomib are not yet available. Since the PIs have also been associated with cardiac dysfunction, ACEI or ARB can provide both cardio-protective and anti-hypertensive effect [ 83 ].

Alkylating agents

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 ]. Studies among testicular cancer survivors have shown that the use of cisplatin-based chemotherapy resulted in an increased incidence of hypertension as a late effect in up to 50% of survivors [ 53 , 86 ]. No antihypertensive medication is decisively superior over others for the management of hypertension associated with alkylating agents. However, ACEIs and ARBs are preferred as first-line agents for BP control due to their reno-protective properties [ 87 ].

Glucocorticoids

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. Glucocorticoid-induced hypertension has been reported in up to 13% of patients [ 88 ]. 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. Mineralocorticoid antagonists and ACEIs/ARBs may also be beneficial [ 89 ].

Non-antineoplastic immunosuppressive agents

In the context of cancer management, calcineurin inhibitors (cyclosporin and tacrolimus) are commonly used for immunosuppression post-transplant for graft vs. host disease. It is also sometimes used for autoimmune diseases associated with cancers, such as autoimmune hemolytic anemia and pure red cell aplasia. Hypertension is a common adverse effect of calcineurin inhibitors with reported incidence rate ranging from 30 to 80% [ 90 – 92 ]. 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 ]. The National Kidney Foundation/Kidney Disease Outcomes Quality Initiative recommends maintaining BP < 130/80 mmHg in kidney transplant recipients on chronic immunosuppressive agents [ 95 ]. 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 [ 100 ]. 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 [ 101 ].

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 [ 102 ], and the hypertension responds well to ARBs, especially losartan [ 103 ].

Other antineoplastic agents

Abiraterone acetate is an oral hormonal agent used in the treatment of metastatic castration-resistant prostate cancer [ 104 ]. It inhibits CYP17, a key enzyme that catalyzes the biosynthesis of androgens, more specifically dehydroepiandrosterone (DHEA) from 17-hydroxyprognenolone [ 105 ]. 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 [ 106 ]. 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 [ 107 ]. 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. Depending on the patient’s BP response, dose modification or drug discontinuation may be required [ 108 , 109 ].

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 [ 110 , 111 ]. When paclitaxel is used in combination with bevacizumab for breast and lung cancer, the incidence of hypertension has been shown to increase [ 112 , 113 ]. Docetaxel has rarely been associated with hypertension.

Recombinant human erythropoietin (RhuEPO) has been recommended by the American Society of Clinical Oncology (ASCO)/American Society of Hematologists (ASH) for patients with cancer and anemia after comprehensive risk-benefit assessment [ 114 ]. There has been a decrease in its use over the last decade because of its side effect profile, including systemic hypertension (reported in up to 35% of patients) and thromboembolic events [ 115 , 116 ]. 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 [ 117 ]. CCB is a good choice for BP control but when anti-hypertensives are ineffective, EPO discontinuation is advised.

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 6.6% of patients on daratumumab during the CASTOR Phase III trial [ 118 ]. The incidence of all-grade and ≥ grade 3 hypertension increased when daratumumab was used in combination with carfilzomib [ 119 ]. Elotuzumab used in combination with lenalidomide/dexamethasone was associated with only 1.3% of ≥ grade 3 hypertension in the ELOQUENT-2 trial [ 120 ].

Blood pressure assessment in patients with cancer

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 [ 121 ]. As such, it is crucial to incorporate out-of-clinic BP measurements, which include ambulatory and HBPM, in the management of the oncologic patient.

Target blood pressure goal in patients with cancer

Patients with cancer have traditionally been excluded in the large-scale hypertension trials. Based on the best available evidence, the 2017 ACC/AHA Hypertension guidelines outline a series of recommendations that are generally applied to the care of the oncologic patient [ 122 ].

Patients who have an estimated 10-year ASCVD risk of ≥10%, or who have additional cardiovascular comorbidities such as type 2 diabetes mellitus or chronic kidney disease, should be treated to a goal BP < 130/80 mmHg. Patients who have an estimated 10-year ASCVD risk of ≤10% with no additional cardiovascular comorbidities should be treated to a goal BP < 140/90 mmHg, though it may be reasonable to treat these patients to a goal BP < 130/80 mmHg as well [ 122 ]. 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. Fig. 1 Algorithm for blood pressure assessment and management in patients newly diagnosed with cancer. BP, blood pressure; HBPM, home blood pressure monitoring; VSP, VEGF signaling pathway; PI, proteasome inhibitor; CCB, calcium channel blockers; DHP, dihydropyridine; ACEI, angiotensin converting enzyme inhibitors; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; IHD, ischemic heart disease; NSAID, non-steroidal anti-inflammatory drug; EPO, erythropoietin; DBP, diastolic blood pressure

Conclusion

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 [ 123 – 126 ]. 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 [ 127 ]. For patients without other cardiovascular risk factors, BP goal is < 140/90 mmHg; whereas for patients who are at high cardiovascular risk, BP goal < 130/80 mmHg should be achieved.

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.

Abbreviations

Cardiovascular disease

Blood pressure

Home blood pressure monitoring

VEGF signaling pathway

Vascular endothelial growth factor

Vascular endothelial growth factor receptor

Food and Drug Administration

Diffuse large B-cell lymphoma

Reactive oxygen species

Nitric oxide

Human epidermal growth factor

Non-small cell lung cancer

Renal cell cancer

American College of Cardiology

American Heart Association

Angiotensin converting enzyme inhibitors

Dihydropyridine

Cytochrome P450 3A4

VEGF signaling pathway tyrosine kinase inhibitors

Gastrointestinal stromal tumors

Progression-free survival

Overall survival

Bruton tyrosine kinase

Chronic lymphocytic leukemia

Multiple myeloma

Epithelial sodium channel

Angiotensin II receptor blocker

Renin angiotensin aldosterone system

Glomerular filtration rate

Recombinant human erythropoietin

Calcium channel blocker

Atherosclerotic cardiovascular disease

Non-steroidal anti-inflammatory drug

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

Not Applicable.

Authors’ contributions

AK and TM made substantial contribution to the article design and conception of the work. TM, MS and JT contributed to the acquisition of data and drafting of the manuscript. AK and TM made major contribution to analysis, interpretation and editing of the manuscript. AK and JT made critical revisions, and all authors read and approved the final manuscript.

Funding

There was no funding source for this study.

Availability of data and materials

Not Applicable.

Declarations

Ethics approval and consent to participate

Not Applicable.

Consent for publication

Not Applicable.

Competing interests

The authors declare that they have no competing interests.

References

1. Bloom MW Hamo CE Cardinale D Ky B Nohria A Baer L Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging Circ Heart Fail 2016 9 e002661 10.1161/CIRCHEARTFAILURE.115.002661 26747861 PMC4709035

2. Definition of cardiotoxicity - NCI Dictionary of Cancer Terms - National Cancer Institute [Internet]. [cited 2020 Aug 8]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cardiotoxicity

3. Patnaik JL Byers T DiGuiseppi C Dabelea D Denberg TD Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: A retrospective cohort study Breast Cancer Res. BioMed Central 2011 13 R64 10.1186/bcr2901 PMC3218953 21689398

4. Tini G Sarocchi M Tocci G Arboscello E Ghigliotti G Novo G Brunelli C Lenihan D Volpe M Spallarossa P Arterial hypertension in cancer: the elephant in the room Int J Cardiol 2019 281 133 139 10.1016/j.ijcard.2019.01.082 30718135

5. Mouhayar E Salahudeen A Hypertension in Cancer patients Tex Heart Inst J 2011 38 3 263 265 21720467 PMC3113122

6. de Souza VB Silva EN Ribeiro ML Martins W de a. hypertension in patients with cancer Arq Bras Cardiol 2015 104 3 246 252 10.5935/abc.20150011 25742420 PMC4386854

7. Dyer AR Berkson DM Stamler J Lindberg HA Stevens E HIGH BLOOD-PRESSURE: a RISK FACTOR FOR CANCER MORTALITY ? Lancet 1975 305 1051 1056 10.1016/S0140-6736(75)91826-7 48728

8. Harding JL Sooriyakumaran M Anstey KJ Adams R Balkau B Brennan-Olsen S Hypertension, antihypertensive treatment and cancer incidence and mortality J Hypertens 2016 34 149 155 10.1097/HJH.0000000000000770 26630217

9. Milan A Puglisi E Ferrari L Bruno G Losano I Veglio F Arterial hypertension and cancer Int J Cancer 2014 134 2269 2277 10.1002/ijc.28334 23784914

10. Colt JS Schwartz K Graubard BI Davis F Ruterbusch J Digaetano R Hypertension and risk of renal cell carcinoma among white and black Americans Epidemiology 2011 22 797 804 10.1097/EDE.0b013e3182300720 21881515 PMC3188386

11. Stocks T Van Hemelrijck M Manjer J Bjørge T Ulmer H Hallmans G Blood pressure and risk of cancer incidence and mortality in the metabolic syndrome and Cancer project Hypertens Dallas Tex 1979 2012 59 802 810 10.1161/HYPERTENSIONAHA.111.189258 22353615

12. Grossman E Messerli FH Boyko V Goldbourt U Is there an association between hypertension and cancer mortality? Am J Med 2002 112 479 486 10.1016/S0002-9343(02)01049-5 11959059

13. Koene RJ Prizment AE Blaes A Konety SH Shared risk factors in cardiovascular disease and cancer Circulation 2016 133 1104 1114 10.1161/CIRCULATIONAHA.115.020406 26976915 PMC4800750

14. Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA, Ma J, Landstrom AP, Morrison AC, Ater JL. Hypertension susceptibility loci are associated with Anthracycline-related Cardiotoxicity in long-term childhood Cancer survivors. Sci Rep. 2017;7(1):9698. 10.1038/s41598-017-09517-2. 10.1038/s41598-017-09517-2 PMC5575079 28851949

15. Minotti G Menna P Salvatorelli E Cairo G Gianni L Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity Pharmacol Rev 2004 56 2 185 229 10.1124/pr.56.2.6 15169927

16. von Hoff DD Layard MW Basa P Davis HL Von Hoff AL Rozencweig M Risk factors for doxorubicin-induced congestive heart failure Ann Intern Med 1979 91 5 710 717 10.7326/0003-4819-91-5-710 496103

17. Hershman DL RB MB Eisenberger A Tsai WY Grann VR Jacobson JS Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma J Clin Oncol Off J Am Soc Clin Oncol 2008 26 3159 3165 10.1200/JCO.2007.14.1242 18591554

18. Pinder MC Duan Z Goodwin JS Hortobagyi GN Giordano SH Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer J Clin Oncol Proc Am Soc Clin Oncol 2007 25 25 3808 3815 10.1200/JCO.2006.10.4976 17664460

19. Lipshultz SE Rifai N Sallan SE Lipsitz SR Dalton V Sacks DB Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury Circulation 1997 96 2641 2648 10.1161/01.CIR.96.8.2641 9355905

20. Seidman A Hudis C Pierri MK Shak S Paton V Ashby M Cardiac Dysfunction in the Trastuzumab Clinical Trials Experience J Clin Oncol 2002 20 1215 1221 10.1200/JCO.2002.20.5.1215 11870163

21. Horenstein MS Vander Heide RS L’Ecuyer TJ Molecular basis of anthracycline-induced cardiotoxicity and its prevention Mol Genet Metab 2000 71 436 444 10.1006/mgme.2000.3043 11001837

22. Tokarska-Schlattner M, Zaugg M, Zuppinger C, Wallimann T, Schlattner U. New insights into doxorubicin-induced cardiotoxicity: The critical role of cellular energetics. J Mol Cell Cardiol. 2006;41(3):389–405. 10.1016/j.yjmcc.2006.06.009 16879835

23. Salvatorelli E Menna P Chello M Covino E Minotti G Low-dose Anthracycline and risk of heart failure in a pharmacokinetic model of human myocardium exposure: analog specificity and role of secondary alcohol metabolites J Pharmacol Exp Ther American Society for Pharmacology and Experimental Therapeutics 2018 364 2 323 331 10.1124/jpet.117.246140 29222131

24. Kuriakose RK, Kukreja RC, Xi L. Potential therapeutic strategies for hypertension-exacerbated Cardiotoxicity of anticancer drugs. Oxid Med Cell Longev. 2016;2016:8139861. 10.1155/2016/8139861. 10.1155/2016/8139861 PMC5086499 27829985

25. Hunter JJ Chien KR Signaling pathways for cardiac hypertrophy and failure. Epstein FH, editor. N Engl J med Massachusetts Medical Society 1999 341 1276 1283 10.1056/NEJM199910213411706 10528039

26. Szmit S Jurczak W Zaucha JM Drozd-Sokołowska J Spychałowicz W Joks M Długosz-Danecka M Torbicki A Pre-existing arterial hypertension as a risk factor for early left ventricular systolic dysfunction following (R)-CHOP chemotherapy in patients with lymphoma J Am Soc Hypertens 2014 8 11 791 799 10.1016/j.jash.2014.08.009 25455004

27. Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, D'Amico R. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2014;2014(6):CD006242. 10.1002/14651858.CD006242.pub2. 10.1002/14651858.CD006242.pub2 PMC6464904 24919460

28. Gunaldi M Duman BB Afsar CU Paydas S Erkisi M Kara IO Sahin B Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: an observational single-Centre study J Oncol Pharm Pract Off Publ Int Soc Oncol Pharm Pract 2016 22 2 242 247 10.1177/1078155214567162 25567518

29. Sandoo A Kitas GD Carmichael AR Endothelial dysfunction as a determinant of trastuzumab-mediated cardiotoxicity in patients with breast cancer Anticancer Res 2014 34 3 1147 1151 24596352

30. Pentassuglia L Sawyer DB The role of Neuregulin-1beta/ErbB signaling in the heart Exp Cell Res 2009 315 4 627 637 10.1016/j.yexcr.2008.08.015 18801360 PMC2667947

31. Gordon LI Burke MA Singh ATK Prachand S Lieberman ED Sun L Naik TJ Prasad SVN Ardehali H Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways J Biol Chem 2009 284 4 2080 2087 10.1074/jbc.M804570200 19017630 PMC2629107

32. Viallard C Larrivée B Tumor angiogenesis and vascular normalization: alternative therapeutic targets Angiogenesis. 2017 20 4 409 426 10.1007/s10456-017-9562-9 28660302

33. Hein TW Rosa RH Ren Y Xu W Kuo L VEGF Receptor-2-linked PI3K/Calpain/SIRT1 activation mediates retinal arteriolar dilations to VEGF and shear stress Invest Ophthalmol Vis Sci 2015 56 9 5381 5389 10.1167/iovs15-16950 26284543 PMC4544352

34. Zhao Y Adjei AA Targeting angiogenesis in Cancer therapy: moving beyond vascular endothelial growth factor Oncologist 2015 20 6 660 673 10.1634/theoncologist.2014-0465 26001391 PMC4571783

35. Simons M Gordon E Claesson-Welsh L Mechanisms and regulation of endothelial VEGF receptor signalling Nat Rev Mol Cell Biol 2016 17 10 611 625 10.1038/nrm.2016.87 27461391

36. Kamli H Li L Gobe GC Limitations to the therapeutic potential of tyrosine kinase inhibitors and alternative therapies for kidney Cancer Ochsner J 2019 19 2 138 151 10.31486/toj.18.0015 31258426 PMC6584192

37. Sarwar S Bakbak B Sadiq MA Sepah YJ Shah SM Ibrahim M Do DV Nguyen QD Fusion proteins: Aflibercept (VEGF trap-eye) Dev Ophthalmol 2016 55 282 294 10.1159/000439008 26501481

38. 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 5 534 543 10.1016/j.cjca.2014.02.011 24786444

39. Cancer Institute N Common Terminology Criteria for Adverse Events (CTCAE) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 2017

40. Zhao T Wang X Xu T Xu X Liu Z Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: a systematic review and comprehensive meta-analysis Oncotarget. 2017 8 31 51492 51506 10.18632/oncotarget.18190 28881662 PMC5584263

41. Chen J Lu Y Zheng Y Incidence and risk of hypertension with bevacizumab in non-small-cell lung cancer patients: a meta-analysis of randomized controlled trials Drug Des Devel Ther 2015 9 4751 4760 26316712 10.2147/DDDT.S87258 PMC4547635

42. Yeh ETH Bickford CL Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management J Am Coll Cardiol 2009 53 24 2231 2247 10.1016/j.jacc.2009.02.050 19520246

43. Versmissen J Mirabito Colafella KM Koolen SLW Danser AHJ Vascular cardio-oncology: vascular endothelial growth factor inhibitors and hypertension Cardiovasc Res 2019 115 5 904 914 10.1093/cvr/cvz022 30726882

44. Pandey AK Singhi EK Arroyo JP Ikizler TA Gould ER Brown J Mechanisms of VEGF-Inhibitor Associated Hypertension and Vascular Disease Hypertens Dallas Tex 1979 2018 71 e1 e8 10.1161/HYPERTENSIONAHA.117.10271 PMC5825002 29279311

45. Syrigos KN Karapanagiotou E Boura P Manegold C Harrington K Bevacizumab-induced hypertension: pathogenesis and management BioDrugs Clin Immunother Biopharm Gene Ther 2011 25 159 169 10.2165/11590180-000000000-00000 21627340

46. Gressett SM Shah SR Intricacies of bevacizumab-induced toxicities and their management Ann Pharmacother 2009 43 3 490 501 10.1345/aph.1L426 19261963

47. Li M Kroetz DL Bevacizumab-induced hypertension: clinical presentation and molecular understanding Pharmacol Ther 2018 182 152 160 10.1016/j.pharmthera.2017.08.012 28882537 PMC5785435

48. Frey MK Dao F Olvera N Konner JA Dickler MN Levine DA Genetic predisposition to bevacizumab-induced hypertension Gynecol Oncol 2017 147 3 621 625 10.1016/j.ygyno.2017.09.017 28969913

49. McIntyre WF, Oqab Z, Hopman WM, Hammad N, Baranchuk A. Hypertension due to antiangiogenic cancer therapy with VEGF inhibitors: is autonomic nervous system toxicity another possible mechanism? Can J Cardiol. 2014;30(12):1733. 10.1016/j.cjca.2014.08.023 25475480

50. Anonymous. Avastin. Eur Med Agency. 2018; [cited 2020 Aug 8]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/avastin .

51. Plummer C Michael A Shaikh G Stewart M Buckley L Miles T Ograbek A McCormack T Expert recommendations on the management of hypertension in patients with ovarian and cervical cancer receiving bevacizumab in the UK Br J Cancer 2019 121 2 109 116 10.1038/s41416-019-0481-y 31182765 PMC6738076

52. Shah SR Gressett Ussery SM Dowell JE Marley E Liticker J Arriaga Y Verma U Shorter bevacizumab infusions do not increase the incidence of proteinuria and hypertension Ann Oncol Off J Eur Soc Med Oncol. 2013 24 4 960 965 10.1093/annonc/mds593 23175623

53. Cameron AC Touyz RM Lang NN Vascular complications of Cancer chemotherapy Can J Cardiol 2016 32 7 852 862 10.1016/j.cjca.2015.12.023 26968393 PMC4989034

54. Touyz RM Herrmann J Cardiotoxicity with vascular endothelial growth factor inhibitor therapy NPJ Precis Oncol 2018 2 1 13 10.1038/s41698-018-0056-z 30202791 PMC5988734

55. Blanter JB Frishman WH The preventive role of angiotensin converting enzyme inhibitors/angiotensin-II receptor blockers and β-adrenergic blockers in Anthracycline- and Trastuzumab-induced Cardiotoxicity Cardiol Rev 2019 27 5 256 259 10.1097/CRD.0000000000000252 31008768

56. Miura S-I Fujino M Matsuo Y Tanigawa H Saku K Nifedipine-induced vascular endothelial growth factor secretion from coronary smooth muscle cells promotes endothelial tube formation via the kinase insert domain-containing receptor/fetal liver kinase-1/NO pathway Hypertens Res Off J Jpn Soc Hypertens 2005 28 2 147 153 10.1291/hypres.28.147 16025742

57. Izzedine H Ederhy S Goldwasser F Soria JC Milano G Cohen A Khayat D Spano JP Management of hypertension in angiogenesis inhibitor-treated patients Ann Oncol Off J Eur Soc Med Oncol 2009 20 5 807 815 10.1093/annonc/mdn713 19150949

58. Kružliak P Novák J Novák M Vascular endothelial growth factor inhibitor–induced hypertension: from pathophysiology to prevention and treatment based on long-acting nitric oxide donors Am J Hypertens 2014 27 1 3 13 10.1093/ajh/hpt201 24168915

59. Corr BR Breed C Sheeder J Weisdack S Behbakht K Bevacizumab induced hypertension in gynecologic cancer: does it resolve after completion of therapy? Gynecol Oncol Rep 2016 17 65 68 10.1016/j.gore.2016.06.002 27617286 PMC5004251

60. Qi W-X Shen Z Tang L-N Yao Y Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis Clin Drug Investig 2014 34 4 231 240 10.1007/s40261-014-0174-5 24493142

61. Goodman VL Rock EP Dagher R Ramchandani RP Abraham S Gobburu JVS Booth BP Verbois SL Morse DE Liang CY Chidambaram N Jiang JX Tang S Mahjoob K Justice R Pazdur R Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma Clin Cancer Res Off J Am Assoc Cancer Res. 2007 13 5 1367 1373 10.1158/1078-0432.CCR-06-2328 17332278

62. Valent P Hadzijusufovic E Hoermann G Füreder W Schernthaner G-H Sperr WR Kirchmair R Wolf D Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML Leuk Res 2017 59 47 54 10.1016/j.leukres.2017.05.008 28549238 PMC7115818

63. 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 Conn 2014 16 3 177 185 10.1111/jch.12273 PMC8031967 24621095

64. Haas NB Manola J Uzzo RG Flaherty KT Wood CG Kane C Jewett M Dutcher JP Atkins MB Pins M Wilding G Cella D Wagner L Matin S Kuzel TM Sexton WJ Wong YN Choueiri TK Pili R Puzanov I Kohli M Stadler W Carducci M Coomes R DiPaola RS Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial Lancet Lond Engl 2016 387 10032 2008 2016 10.1016/S0140-6736(16)00559-6 PMC4878938 26969090

65. Eechoute K van der Veldt AAM Oosting S MHW K Wessels JAM Gelderblom H Polymorphisms in endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) predict sunitinib-induced hypertension Clin Pharmacol Ther 2012 92 503 510 22948895 10.1038/clpt.2012.136

66. Fu Y Wei X Lin L Xu W Liang J Adverse reactions of sorafenib, sunitinib, and imatinib in treating digestive system tumors Thorac Cancer 2018 9 5 542 547 10.1111/1759-7714.12608 29575544 PMC5928375

67. Bæk Møller N, Budolfsen C, Grimm D, Krüger M, Infanger M, Wehland M, et al. Drug-induced hypertension caused by multikinase inhibitors (Sorafenib, Sunitinib, Lenvatinib and Axitinib) in renal cell carcinoma treatment. Int J Mol Sci. 2019;20(19). 10.3390/ijms20194712. 10.3390/ijms20194712 PMC6801695 31547602

68. 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 1 110 117 10.1111/bju.12940 25252180

69. Donskov F Michaelson MD Puzanov I Davis MP Bjarnason GA Motzer RJ Goldstein D Lin X Cohen DP Wiltshire R Rini BI Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients Br J Cancer 2015 113 11 1571 1580 10.1038/bjc.2015.368 26492223 PMC4705883

70. Izzedine H Derosa L Le Teuff G Albiges L Escudier B Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma Ann Oncol Off J Eur Soc Med Oncol. 2015 26 6 1128 1133 10.1093/annonc/mdv147 25795198

71. León-Mateos L Mosquera J Antón AL Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors Redox Biol 2015 6 421 425 10.1016/j.redox.2015.09.007 26386874 PMC4588456

72. Kollmannsberger C Soulieres D Wong R Scalera A Gaspo R Bjarnason G Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects Can Urol Assoc J 2007 1 2 Suppl S41 S54 10.5489/cuaj.67 18542784 PMC2422945

73. Ewer MS Suter TM Lenihan DJ Niculescu L Breazna A Demetri GD Motzer RJ Cardiovascular events among 1090 cancer patients treated with sunitinib, interferon, or placebo: a comprehensive adjudicated database analysis demonstrating clinically meaningful reversibility of cardiac events Eur J Cancer 2014 50 12 2162 2170 10.1016/j.ejca.2014.05.013 24930624

74. Brose MS Frenette CT Keefe SM Stein SM Management of Sorafenib-Related Adverse Events: a Clinician’s perspective Semin Oncol 2014 41 S1 16 10.1053/j.seminoncol.2014.01.001 24576654

75. Kappers Mariëtte HW van Esch Joep HM Wim S Stefan S Jan DAH van den Meiracker Anton H Hypertension induced by the tyrosine kinase inhibitor Sunitinib is associated with increased circulating Endothelin-1 levels Hypertension Am Heart Assoc 2010 56 675 681 10.1161/HYPERTENSIONAHA.109.149690 20733093

76. Roeker LE Sarraf Yazdy M Rhodes J Goodfriend J Narkhede M Carver J Mato A Hypertension in patients treated with Ibrutinib for chronic lymphocytic leukemia JAMA Netw Open 2019 2 12 e1916326 10.1001/jamanetworkopen.2019.16326 31790561 PMC6902749

77. Laubach JP Moslehi JJ Francis SA San Miguel JF Sonneveld P Orlowski RZ Moreau P Rosiñol L Faber EA Jr Voorhees P Mateos MV Marquez L Feng H Desai A van de Velde H Elliott J Shi H Dow E Jobanputra N Esseltine DL Niculescu L Anderson KC Lonial S Richardson PG A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma Br J Haematol 2017 178 4 547 560 10.1111/bjh.14708 28466536 PMC6812508

78. Dimopoulos MA Goldschmidt H Niesvizky R Joshua D Chng W-J Oriol A Orlowski RZ Ludwig H Facon T Hajek R Weisel K Hungria V Minuk L Feng S Zahlten-Kumeli A Kimball AS Moreau P Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial Lancet Oncol 2017 18 10 1327 1337 10.1016/S1470-2045(17)30578-8 28843768

79. Hasinoff BB Patel D Wu X Molecular mechanisms of the Cardiotoxicity of the proteasomal-targeted drugs Bortezomib and Carfilzomib Cardiovasc Toxicol 2017 17 3 237 250 10.1007/s12012-016-9378-7 27388042

80. Siegel D Martin T Nooka A Harvey RD Vij R Niesvizky R Badros AZ Jagannath S McCulloch L Rajangam K Lonial S Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies Haematologica. 2013 98 11 1753 1761 10.3324/haematol.2013.089334 23935022 PMC3815177

81. Kumar SK Berdeja JG Niesvizky R Lonial S Laubach JP Hamadani M Stewart AK Hari P Roy V Vescio R Kaufman JL Berg D Liao E di Bacco A Estevam J Gupta N Hui AM Rajkumar V Richardson PG Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study Lancet Oncol. 2014 15 13 1503 1512 10.1016/S1470-2045(14)71125-8 25456369

82. Moreau P Masszi T Grzasko N Bahlis NJ Hansson M Pour L Sandhu I Ganly P Baker BW Jackson SR Stoppa AM Simpson DR Gimsing P Palumbo A Garderet L Cavo M Kumar S Touzeau C Buadi FK Laubach JP Berg DT Lin J di Bacco A Hui AM van de Velde H Richardson PG Oral Ixazomib, Lenalidomide, and dexamethasone for multiple myeloma N Engl J Med 2016 374 17 1621 1634 10.1056/NEJMoa1516282 27119237

83. Wu P Oren O Gertz MA Yang EH Proteasome inhibitor-related Cardiotoxicity: mechanisms, diagnosis, and management Curr Oncol Rep 2020 22 7 66 10.1007/s11912-020-00931-w 32514632

84. Soultati A Mountzios G Avgerinou C Papaxoinis G Pectasides D Dimopoulos M-A Papadimitriou C Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications Cancer Treat Rev 2012 38 5 473 483 10.1016/j.ctrv.2011.09.002 21982720

85. Nuver J Smit AJ Sleijfer DT van Gessel AI van Roon AM van der Meer J Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer Eur J Cancer Oxf Engl 1990 2004 40 701 706 10.1016/j.ejca.2003.12.012 15010071

86. Valentová M Mladosievicová B Coronary heart disease and hypertension as late effects of testicular cancer treatment--a minireview Klin Onkol Cas Ceske Slov Onkol Spolecnosti 2011 24 18 22 21542272

87. Navis G Faber HJ de Zeeuw D de Jong PE ACE inhibitors and the kidney. A risk-benefit assessment Drug Saf 1996 15 3 200 211 10.2165/00002018-199615030-00005 8879974

88. Goodwin JE Geller DS Glucocorticoid-induced hypertension Pediatr Nephrol Berl Ger 2012 27 7 1059 1066 10.1007/s00467-011-1928-4 21744056

89. Baid S Nieman LK Glucocorticoid excess and hypertension Curr Hypertens Rep 2004 6 6 493 499 10.1007/s11906-004-0046-0 15527696

90. Arslansoyu Camlar S Soylu A Kavukçu S Cyclosporine in pediatric nephrology Iran J Kidney Dis 2018 12 6 319 330 30595561

91. Morales JM Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation Kidney Int Suppl 2002 62 S81 S87 10.1046/j.1523-1755.62.s82.16.x 12410861

92. Bursztyn M Zelig O Or R Nagler A Isradipine for the prevention of cyclosporine-induced hypertension in allogeneic bone marrow transplant recipients: a randomized, double-blind study Transplantation. 1997 63 7 1034 1036 10.1097/00007890-199704150-00025 9112363

93. Zhai Y-J Wu M-M Linck VA Zou L Yue Q Wei S-P Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol-4,5-bisphosphate and mediates cyclosporine A-induced hypertension Biochim Biophys Acta Mol basis Dis 1865 2019 1915 1924 10.1016/j.bbadis.2018.08.027 31109455

94. Schlaich MP Grassi G Sympathoexcitation in calcineurin inhibitor-induced hypertension: villain or innocent bystander? J Hypertens 2010 28 9 1809 1810 10.1097/HJH.0b013e32833e0e74 20699713

95. Divac N Naumović R Stojanović R Prostran M The role of immunosuppressive medications in the pathogenesis of hypertension and efficacy and safety of antihypertensive agents in kidney transplant recipients Curr Med Chem 2016 23 19 1941 1952 10.2174/0929867323666151221150052 26687832

96. Marienhagen K Lehner F Klempnauer J Hecker H Borlak J Treatment of cyclosporine induced hypertension: results from a long-term observational study using different antihypertensive medications Vasc Pharmacol 2019 115 69 83 10.1016/j.vph.2018.06.012 29933079

97. Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev. 2006;(4):CD005161. 10.1002/14651858.CD005161.pub2. 10.1002/14651858.CD005161.pub2 PMC8865611 17054241

98. Chanard J Toupance O Lavaud S Hurault de Ligny B Bernaud C Moulin B Amlodipine reduces cyclosporin-induced hyperuricaemia in hypertensive renal transplant recipients Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc 2003 18 2147 2153 10.1093/ndt/gfg341 13679494

99. Vergoulas G Antihypertensive agents and renal transplantation Hippokratia. 2007 11 3 12 19582170 PMC2464259

100. Lazelle RA McCully BH Terker AS Himmerkus N Blankenstein KI Mutig K Renal deletion of 12 kDa FK506-binding protein attenuates Tacrolimus-induced hypertension J Am Soc Nephrol JASN 2016 27 5 1456 1464 10.1681/ASN.2015040466 26432904 PMC4849833

101. Toral M, Romero M, Rodríguez-Nogales A, Jiménez R, Robles-Vera I, Algieri F, Chueca-Porcuna N, Sánchez M, de la Visitación N, Olivares M, García F, Pérez-Vizcaíno F, Gálvez J, Duarte J. Lactobacillus fermentum Improves Tacrolimus-Induced Hypertension by Restoring Vascular Redox State and Improving eNOS Coupling. Mol Nutr Food Res. 2018:e1800033. 10.1002/mnfr.201800033. 10.1002/mnfr.201800033 29851248

102. Manzia TM De Liguori CN Orlando G Toti L De Luca L D’Andria D Use of mycophenolate mofetil in liver transplantation: a literature review Transplant Proc 2005 37 6 2616 2617 10.1016/j.transproceed.2005.06.073 16182764

103. Fujihara CK Vieira JM Sena CR Ventura BH Malheiros DM Zatz R Early brief treatment with losartan plus mycophenolate mofetil provides lasting renoprotection in a renal ablation model Am J Nephrol 2010 32 2 95 102 10.1159/000315137 20551627

104. Pinto F Calarco A Totaro A Sacco E Volpe A Racioppi M Androgen-deprivation therapy in prostate cancer: clinical evidence and future perspectives Urologia. 2010 77 2 71 83 10.1177/039156031007700201 20890863

105. Vasaitis TS Bruno RD Njar VCO CYP17 inhibitors for prostate cancer therapy J Steroid Biochem Mol Biol 2011 125 1-2 23 31 10.1016/j.jsbmb.2010.11.005 21092758 PMC3047603

106. Veccia A Maines F Kinspergher S Galligioni E Caffo O Cardiovascular toxicities of systemic treatments of prostate cancer Nat Rev Urol 2017 14 4 230 243 10.1038/nrurol.2016.273 28117849

107. Iacovelli R Verri E Cossu Rocca M Aurilio G Cullurà D De Cobelli O The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer Eur J Cancer Oxf Engl 1990 2015 51 1970 1977 10.1016/j.ejca.2015.06.106 26169016

108. Curigliano G Shah RR Safety and tolerability of Phosphatidylinositol-3-kinase (PI3K) inhibitors in oncology Drug Saf 2019 42 2 247 262 10.1007/s40264-018-0778-4 30649751

109. Greenwell IB Ip A Cohen JB PI3K inhibitors: understanding toxicity mechanisms and management Oncol Williston Park N 2017 31 821 828 29179250

110. Canela M-D Noppen S Bueno O Prota AE Bargsten K Sáez-Calvo G Jimeno ML Benkheil M Ribatti D Velázquez S Camarasa MJ Fernando Díaz J Steinmetz MO Priego EM Pérez-Pérez MJ Liekens S Antivascular and antitumor properties of the tubulin-binding chalcone TUB091 Oncotarget. 2017 8 9 14325 14342 10.18632/oncotarget.9527 27224920 PMC5362409

111. Schwartz EL Antivascular actions of microtubule-binding drugs Clin Cancer Res Off J Am Assoc Cancer Res 2009 15 8 2594 2601 10.1158/1078-0432.CCR-08-2710 PMC2745203 19351751

112. Sandler A Gray R Perry MC Brahmer J Schiller JH Dowlati A Lilenbaum R Johnson DH Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer N Engl J Med 2006 355 24 2542 2550 10.1056/NEJMoa061884 17167137

113. Miller K Wang M Gralow J Dickler M Cobleigh M Perez EA Shenkier T Cella D Davidson NE Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer N Engl J Med 2007 357 26 2666 2676 10.1056/NEJMoa072113 18160686

114. Hoque S Chen BJ Schoen MW Carson KR Keller J Witherspoon BJ Knopf KB Yang YT Schooley B Nabhan C Sartor O Yarnold PR Ray P Bobolts L Hrushesky WJ Dickson M Bennett CL End of an era of administering erythropoiesis stimulating agents among veterans administration cancer patients with chemotherapy-induced anemia PLoS One 2020 15 6 e0234541 10.1371/journal.pone.0234541 32584835 PMC7316310

115. Schoen MW Hoque S Witherspoon BJ Schooley B Sartor O Yang YT Yarnold PR Knopf KB Hrushesky WJM Dickson M Chen BJ Nabhan C Bennett CL End of an era for erythropoiesis-stimulating agents in oncology Int J Cancer 2020 146 10 2829 2835 10.1002/ijc.32917 32037527

116. Forbes CA Worthy G Harker J Kleijnen J Kutikova L Zelek L van Belle S Dose efficiency of erythropoiesis-stimulating agents for the treatment of patients with chemotherapy-induced anemia: a systematic review Clin Ther 2014 36 4 594 610 10.1016/j.clinthera.2014.02.007 24656152

117. Vaziri ND Mechanism of erythropoietin-induced hypertension Am J Kidney Dis Off J Natl Kidney Found 1999 33 5 821 828 10.1016/S0272-6386(99)70413-0 10213636

118. Palumbo A Chanan-Khan A Weisel K Nooka AK Masszi T Beksac M Spicka I Hungria V Munder M Mateos MV Mark TM Qi M Schecter J Amin H Qin X Deraedt W Ahmadi T Spencer A Sonneveld P Daratumumab, Bortezomib, and dexamethasone for multiple myeloma N Engl J Med 2016 375 8 754 766 10.1056/NEJMoa1606038 27557302

119. Chari A Martinez-Lopez J Mateos M-V Bladé J Benboubker L Oriol A Arnulf B Rodriguez-Otero P Pineiro L Jakubowiak A de Boer C Wang J Clemens PL Ukropec J Schecter J Lonial S Moreau P Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma Blood. 2019 134 5 421 431 10.1182/blood.2019000722 31113777 PMC6676132

120. Dimopoulos MA Lonial S White D Moreau P Palumbo A San-Miguel J Shpilberg O Anderson K Grosicki S Spicka I Walter-Croneck A Magen H Mateos MV Belch A Reece D Beksac M Bleickardt E Poulart V Sheng J Sy O Katz J Singhal A Richardson P Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth Br J Haematol 2017 178 6 896 905 10.1111/bjh.14787 28677826 PMC6084289

121. Costa LJM Varella PCS Del Giglio A White coat effect in breast cancer patients undergoing chemotherapy Eur J Cancer Care (Engl) 2003 12 4 372 373 10.1046/j.1365-2354.2003.00416.x 14982318

122. Whelton PK Carey RM Aronow WS Casey DE Collins KJ Dennison Himmelfarb Cheryl, et al. 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 Am Heart Assoc 2018 71 e13 115 10.1161/HYP.0000000000000065 29133356

123. Minlikeeva AN Freudenheim JL Cannioto RA Szender JB Eng KH Modugno F History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium Cancer Causes Control CCC 2017 28 5 469 486 10.1007/s10552-017-0867-1 28293802 PMC5500209

124. Williams B Mancia G Spiering W Agabiti Rosei E Azizi M Burnier M Clement DL Coca A de Simone G Dominiczak A Kahan T Mahfoud F Redon J Ruilope L Zanchetti A Kerins M Kjeldsen SE Kreutz R Laurent S Lip GYH McManus R Narkiewicz K Ruschitzka F Schmieder RE Shlyakhto E Tsioufis C Aboyans V Desormais I Authors/Task Force Members: 2018 ESC/ESH guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension J Hypertens 2018 36 10 1953 2041 10.1097/HJH.0000000000001940 30234752

125. Iachina M Jakobsen E Møller H Lüchtenborg M Mellemgaard A Krasnik M Green A The effect of different comorbidities on survival of non-small cells lung cancer patients Lung. 2015 193 2 291 297 10.1007/s00408-014-9675-5 25516286

126. Piccirillo JF Tierney RM Costas I Grove L Spitznagel EL Prognostic importance of comorbidity in a hospital-based cancer registry JAMA. 2004 291 20 2441 2447 10.1001/jama.291.20.2441 15161894

127. Goldstein D Rosenberg JE Figlin RA Townsend RR McCann L Carpenter C Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma? Eur J Cancer Oxf Engl 1990 2016 53 96 104 10.1016/j.ejca.2015.10.006 26702763