Hypertension induced by chemotherapeutic and immunosuppresive agents: A new challenge

https://doi.org/10.1016/j.critrevonc.2014.08.004Get rights and content

Highlights

  • Hypertension is a common adverse effect of certain anti neoplastic therapy.

  • We reviewed the literature for studies that reported the effect of anti neoplastic agents on blood pressure in patients with malignancies.

  • 30% of patients treated for cancer will have concomitant hypertension, and crucial chemotherapy can sometimes be stopped due to new onset or worsening severe hypertension.

  • Hypertension in this group of patients, if untreated, can alter cancer management and result in dose reductions or termination of treatments as well as life-threatening end organ damage.

Abstract

Background

Hypertension is a common adverse effect of certain anti neoplastic therapy. The incidence and severity of hypertension are dependent mainly on the type and the dose of the drug.

Methods

We reviewed the literature for studies that reported the effect of anti neoplastic agents on blood pressure in patients with malignancies. The medical databases of PubMed, MEDLINE and EMBASE were searched for articles published in English between 1955 and June 2012. The effects of specific agents on blood pressure were analyzed.

Results and conclusions

Hypertension is a prevalent adverse effect of many of the new chemotherapy agents such as VEGF inhibitors. Approximately 30% of patients treated for cancer will have concomitant hypertension, and crucial chemotherapy can sometimes be stopped due to new onset or worsening severe hypertension. The importance of a timely diagnosis and optimal management of HTN in this group of patients is related to the facts that HTN is a well established risk factor for chemotherapy-induced cardiotoxicity and if left untreated, can alter cancer management and result in dose reductions or termination of anti-cancer treatments as well as life-threatening end organ damage.

Introduction

Hypertension in cancer patients is a common phenomenon. Factors that cause hypertension in the general population also afflict those with cancer; however, the incidence of hypertension in cancer patients is influenced heavily by the type of chemotherapy used. High blood pressure has often led to treatment limitation and even life-threatening events [1], [2], [3], [4], thus demonstrating the importance of blood pressure (BP) control in this cohort of patients. In cancer patients, the etiology of hypertension is influenced by the type of chemotherapy, radiation therapy, and by the malignancy itself. Not only must the physician choose an antihypertensive medication, but he or she must also take into consideration the drug interactions that may accompany the treatment. The aim of this review is to evaluate the literature on hypertension in cancer patients and to survey the various chemotherapy treatments causing hypertension.

Section snippets

Epidemiology

The prevalence of hypertension in cancer patients is approximately 28% [4], [5], which is similar to the general population. However, the incidence of de novo hypertension is less defined in this cohort. It is accepted that the most common cause of new onset hypertension in those being treated for cancer is the chemotherapy itself. The incidence of de novo hypertension induced by VEGF is between 17% and 80% [6], [7]. Alkylating agents are associated with a 36% incidence of hypertension, while

Pathophysiology

Complex and poorly understood mechanisms are implicated in the origin and pathophysiology of hypertension [10], [11]. These processes include increased sympathetic nervous system activity, psychosocial stress, overproduction of sodium-retaining hormones and vasoconstrictors, chronic excess sodium intake, increased or inappropriate renin secretion inducing increased production of angiotensin II and aldosterone [11], [12], alterations in expression of the kallikrein-kinin system, endothelial

Diagnosis

The diagnosis of hypertension should follow the Joint National Commission (JNC) recommendations and is generally based on documenting BP readings of 140/90 mmHg or more on three separate occasions at least 1 week apart in patients less than 60 years of age (150/90 for patients above 60 years old) [13]. The pretreatment assessment entails repeated BP measurements, a history and physical examination to assess certain risk factors, and laboratory tests to detect end organ damage [14]. Patients

Management

The primary goal in managing hypertension is to reduce morbidity and minimize risks of end organ damage [16], [17]. More importantly, appropriate management of blood pressure will allow continuation of a necessary cancer therapy that might otherwise be discontinued. In the absence of specific data to guide therapy, management should focus on appropriate and timely diagnosis of hypertension, identifying potential secondary/reversible causes, and adequately treating elevated BP to achieve the

Angiogenesis inhibitors

The use of angiogenesis inhibitors over the past few years has risen dramatically, given their proven efficacy in decreasing mortality in cancer patients [1], [2], [3], [4]. Several agents have been approved for marketing worldwide and are divided into two separate classes based on the mechanisms of action leading to a similar effect on angiogenesis: Bevacizumab, a VEGF monoclonal antibody, and the small-molecule tyrosine kinase inhibitors such as Sorafenib, Sunitinib, and Pazopanib. HTN is one

Conclusion

With the development of new chemotherapy agents and subsequent improvement in mortality in those with cancer, the incidence of hypertension has increased in this patient population. Hypertension is a common side effect of many of these new therapies such as VEGF inhibitors. Because more than 30% of patients with cancer will have hypertension and often crucial chemotherapy is stopped solely for that reason, we advise that a protocol be established to assess high-risk patients’ prophylactic

Funding

No source of funding.

Conflicts of interest

No conflicts of interest to disclose.

Reviewers

Felipe Nonato Albuquerque, 3210 Riverdale Ave Apt-5j, Bronx, NY, United States.

Michael S. Ewer, M.D., J.D., Professor of Medicine, UT MD Anderson Cancer Center, Cardiology, 1515 Holcombe Blvd, Houston, TX 77030, United States.

Dr. Simon Abi Aad completed his medical degree at the Holy Spirit University in Kaslik, Lebanon. His postgraduate training included a research internship at the MD Anderson Cancer Center, Department of Cardiology, internal medicine residency at the Mount Sinai – St. Luke's Roosevelt Hospital Center. His clinical and research activities cover anti neoplastic therapy side effects and toxicities. He has a special interest in leukemia and potential targets for treatment associated with it.

References (67)

  • N.D. Vaziri

    Mechanism of erythropoietin-induced hypertension

    Am J Kidney Dis

    (1999)
  • J.J. Mourad et al.

    Blood pressure rise following angiogenesis inhibition by Bevacizumab. A crucial role for microcirculation

    Ann Oncol: Off J Eur Soc Med Oncol/ESMO

    (2008)
  • A.Y. Khakoo et al.

    Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor

    Cancer

    (2008)
  • M. Schmidinger et al.

    Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma

    J Clin Oncol

    (2008)
  • K.L. Snider et al.

    Cardiovascular toxicities: clues to optimal administration of vascular endothelial growth factor signaling pathway inhibitors

    Target Oncol

    (2009)
  • L. Brookes

    National Health and Nutrition Examination Survey (NHANES) data on hypertension

  • B. Escudier et al.

    Sorafenib in advanced clear-cell renal-cell carcinoma

    N Engl J Med

    (2007)
  • B.I. Rini et al.

    Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib

    J Natl Cancer Inst

    (2011)
  • P.W. Wijermans et al.

    An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2′-deoxycytidine (decitabine) in 177 patients

    Ann Hematol

    (2005)
  • J.A. Whitworth et al.

    Cushing, cortisol, and cardiovascular disease

    Hypertension

    (2000)
  • R.E. Klabunde

    Cardiovascular physiology concepts

    (2005)
  • S. Oparil et al.

    Pathogenesis of hypertension

    Ann Intern Med

    (2003)
  • D.A.Z.A. Calhoun et al.

    Etiology and pathogenesis of systemic hypertension

  • M. Ganetsky et al.

    Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant

    J Med Toxicol

    (2011)
  • M.L. Maitland et al.

    Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors

    J Natl Cancer Inst

    (2010)
  • M. Jain et al.

    Chemotherapy agents and hypertension: a focus on angiogenesis blockade

    Curr Hypertens Rep

    (2007)
  • S. Lewington et al.

    Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies

    Lancet

    (2002)
  • R. Jain

    Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer

    Nat Rev Cancer

    (2008)
  • J.F. Piccirillo et al.

    Prognostic importance of comorbidity in a hospital-based cancer registry

    JAMA

    (2004)
  • E. Grossman et al.

    Secondary hypertension: interfering substances

    J Clin Hypertens (Greenwich)

    (2008)
  • B. Nazer et al.

    Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension

    Circulation

    (2011)
  • K.N. Syrigos et al.

    Bevacizumab-induced hypertension: pathogenesis and management

    BioDrugs

    (2011)
  • S.W. Graves et al.

    Endogenous digoxin-like immunoreactive factor and digitalis-like factor associated with the hypertension of patients receiving multiple alkylating agents as part of autologous bone marrow transplantation

    Clin Sci (Lond)

    (1989)
  • Cited by (35)

    • Hypertension and renal disease during anti-cancer therapies

      2022, Cardio-Oncology Practice Manual: A Companion to Braunwald's Heart Disease
    • Intriguing relationship between antihypertensive therapy and cancer

      2019, Pharmacological Research
      Citation Excerpt :

      It was reported that AH was present in 37% cancer patients [1,2]. However, anticancer therapy itself represents an important risk factor for AH development [3,4]. Before chemotherapy AH was present in 29% of cancer patients and after chemotherapy AH prevalence increased to 36%–80% [1,2].

    • Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 2

      2017, Journal of the American College of Cardiology
      Citation Excerpt :

      Early diagnosis and treatment is essential because HTN is a major risk factor for the development of chemotherapy-induced cardiotoxicity (2). In addition, suboptimal blood pressure control may lead to premature discontinuation of chemotherapy, thus affecting cancer therapy directly (2,3). Bevacizumab, sorafenib, and sunitinib target the vascular endothelial growth factor signaling pathway (VSP) to achieve their therapeutic efficacy at the expense of increased blood pressure (4) (Table 1).

    • Hypertension in Oncology and Stem Cell Transplant Patients

      2023, Pediatric Hypertension: Fifth Edition
    View all citing articles on Scopus

    Dr. Simon Abi Aad completed his medical degree at the Holy Spirit University in Kaslik, Lebanon. His postgraduate training included a research internship at the MD Anderson Cancer Center, Department of Cardiology, internal medicine residency at the Mount Sinai – St. Luke's Roosevelt Hospital Center. His clinical and research activities cover anti neoplastic therapy side effects and toxicities. He has a special interest in leukemia and potential targets for treatment associated with it.

    Dr. Elie Mouhayar, Associate Professor of Medicine, Department of Cardiology at the UT/MD Anderson Cancer Center in Houston, Texas. He completed his medical degree at the Lebanese University in Beirut, Lebanon. His postgraduate training included a clinical fellowship in cardiology at Geisinger Medical Center. He is board certified in internal medicine, cardiology and vascular medicine. He is the Associate Medical Director of the Cardiopulmonary Center and the Medical Director of the Non-Invasive Vascular Laboratory at the university of Texas/MD Anderson Cancer Center. He serves as a collaborator on several ongoing clinical trials. He has a special interest in pericardial and peripheral arterial diseases and in the early detection and management of cardio-toxicity as a result of conventional or targeted chemotherapy.

    View full text