Elsevier

The Lancet Oncology

Volume 10, Issue 4, April 2009, Pages 391-399
The Lancet Oncology

Review
Cardiovascular toxicity caused by cancer treatment: strategies for early detection

https://doi.org/10.1016/S1470-2045(09)70042-7Get rights and content

Summary

Cardiovascular toxicity is one of the most devastating complications of cancer treatment and can arise during or shortly after treatment, or even several years later. Identification of the left ventricular ejection fraction (LVEF) is the most common method to screen for toxic effects on the heart; however, this approach underestimates cardiac damage and additional strategies for the monitoring of treatment-induced cardiotoxicity are being explored. Guidelines for monitoring have been formulated for several cancer treatments; however, appropriate underlying evidence is still largely absent. In this Review, we summarise conventional and contemporary methods for early detection of cardiotoxicity and designate a level of evidence for the basis of each method.

Introduction

Methods for detection and treatment of different types of cancer have developed impressively in the past 20 years. Life-expectancy for patients with cancer is steadily improving, with an age-adjusted 10-year survival of 70% for breast cancer, 80% for Hodgkin's disease, and 90% for testicular cancer.1 Around 3 million patients are diagnosed with cancer in Europe each year, which means there is a large group at risk of treatment-related complications.2 Long-term complications include development of second malignancies and cardiovascular disease, but up to now, the incidence and extent of these complications in adults are largely unknown. By contrast, studies of childhood cancer survivors have produced many more data on long-term complications of treatment.3

In trials of adjuvant anthracycline-based treatment for breast cancer, 5-year incidence of chronic heart failure is between 0% and 3Ā·2%, depending on the combination regimen and cumulative dose of anthracycline.4 However, long-term follow up of cardiovascular morbidity and mortality is not available. A large meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, in which 42ā€ˆ000 patients with breast cancer participated in 78 randomised trials, found that patients treated with radiotherapy had a high rate of non-breast cancer mortality, mainly from heart-disease (rate ratio 1Ā·12). This high rate of heart disease was observed during the first 5 years after treatment and continued for up to 15 years.5 However, data are partly based on outdated radiation-techniques in use from 1976 until 1995.

10 years ago, we reviewed methods for detection of anthracycline-induced cardiotoxicity.6 Improvements have since resulted in more sensitive monitoring strategies (Figure 1, Figure 2). Changes in cancer treatment have introduced both, more as well as less, potentially cardiotoxic regimens, through the increased use of anthracyclines, platinum compounds, radiation therapy, and introduction of monoclonal antibodies such as trastuzumab and bevacizumab.

Although monitoring guidelines exist for several potentially cardiotoxic treatments, little data are available to formulate evidence-based screening and follow-up recommendations for treatment-induced cardiotoxicity. In 2007, the American Society of Clinical Oncology (ASCO) Survivorship Expert Panel clearly stated the need for such recommendations.7

In this Review, we give an update of the methods available for early detection of cardiac damage caused by cancer treatment. Each method is assigned a level of evidence backing up its applicability, according to the system used by the Oxford Centre of Evidence Based Medicine (panel 1).8 Level 1a evidence is viewed as definite and level 5 as weak. Most studies reviewed in this paper were not designed to assess the sensitivity of monitoring strategies as a primary goal, which implies that level of evidence is based on indirect evidence or retrospective data.

Section snippets

Detection of treatment-induced cardiotoxicity

Cardiac function is monitored during a potentially cardiotoxic cancer treatment to identify patients who are susceptible to this toxicity as early as possible and prevent morbidity and mortality. Efforts to prevent further complications include intensified monitoring, initiation of preventive measures, or changes to cancer treatments. Detection of possible toxicity should not result in holding back an essential treatment, which would compromise effectiveness.

Mitani and colleagues9 did a

LVEF

Measurement of LVEF with multiple gated acquisition (MUGA) scintigraphy and echocardiography,12 gives an assessment of systolic cardiac function and is the most common method of monitoring cardiac function during cancer treatment. However, LVEF can underestimate actual cardiac damage13 because of the compensatory reserve of the myocardium that enables adequate ventricular output even in the presence of dysfunctional myocytes. With left ventricular dysfunction, deterioration of diastolic cardiac

Methods for assessment of cardiovascular function

Strategies for early detection of potential cardiovascular damage from cancer treatment will be addressed. Advantages, disadvantages, and level of evidence behind each strategy are summarised in panel 2.

Conclusion

The identification of patients who are at an increased risk of cardiovascular damage caused by cancer treatment can be achieved by detection of early changes in cardiovascular function and estimation of a baseline risk of late morbidity (figure 3).16, 17, 18, 19 Current guidelines and monitoring strategies for detection of cardiovascular toxicity caused by cancer treatment are mostly derived from medium-level evidenceā€”true even for MUGA scintigraphy (panel 2).

LVEF is the most widely used

Search strategy and selection criteria

Articles for this Review were found through searches of PubMed and Embase by use of the terms ā€œcardiovascular toxicityā€, ā€œcardiotoxicityā€, ā€œcancer treatmentā€, ā€œchemotherapyā€, ā€œbiochemicalā€, ā€œendothelial damageā€, ā€œgenetic variationsā€, ā€œelectrocardiographyā€, ā€œechocardiographyā€, ā€œMultiple Gated Acquisition Scanā€, ā€œMagnetic Resonance Imagingā€, ā€œPositron Emission Tomographyā€, and ā€œSingle Photon Emission Tomographyā€. Trials with highest quality study design were selected. Only studies of

References (73)

  • B Marchandise et al.

    Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics

    Am Heart J

    (1989)
  • L Kapusta et al.

    Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines

    Ultrasound Med Biol

    (2001)
  • H Nakamae et al.

    QT dispersion as a predictor of acute heart failure after high-dose cyclophosphamide

    Lancet

    (2000)
  • H Steen et al.

    Cardiac troponin T at 96 hours after acute myocardial infarction correlates with infarct size and cardiac function

    J Am Coll Cardiol

    (2006)
  • T Suzuki et al.

    Elevated B-type natriuretic peptide levels after anthracycline administration

    Am Heart J

    (1998)
  • FY de Vos et al.

    Endothelial cell effects of cytotoxics: balance between desired and unwanted effects

    Cancer Treat Rev

    (2004)
  • F Fichtner et al.

    Bleomycin induces IL-8 and ICAM-1 expression in microvascular pulmonary endothelial cells

    Exp Toxicol Pathol

    (2004)
  • H Ishii et al.

    Bleomycin induces E-selectin expression in cultured umbilical vein endothelial cells by increasing its mRNA levels through activation of NF-kappaB/Rel

    Toxicol Appl Pharmacol

    (2002)
  • J Nuver et al.

    Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer

    Eur J Cancer

    (2004)
  • S Beauclair et al.

    Role of the HER2 [Ile655Val] genetic polymorphism in tumorogenesis and in the risk of trastuzumab-related cardiotoxicity

    Ann Oncol

    (2007)
  • FM Bengel et al.

    Assessment of cardiac sympathetic neuronal function using PET imaging

    J Nucl Cardiol

    (2004)
  • RA Valdes Olmos et al.

    Assessment of anthracycline-related myocardial adrenergic derangement by [123I]metaiodobenzylguanidine scintigraphy

    Eur J Cancer

    (1995)
  • MA de Korte et al.

    (111)Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: A clue to uncover the mechanisms of trastuzumab-related cardiotoxicity

    Eur J Cancer

    (2007)
  • N Fallah-Rad et al.

    Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy

    J Cardiovasc Magn Reson

    (2008)
  • D Pulte et al.

    Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990ā€“2004

    J Natl Cancer Inst

    (2008)
  • M Clarke et al.

    Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials

    Lancet

    (2005)
  • JR Carver et al.

    American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects

    J Clin Oncol

    (2007)
  • B Philips et al.

    Oxford Centre for Evidence-based Medicine Levels of Evidence

  • SA Hunt et al.

    ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society

    Circulation

    (2005)
  • W Landier et al.

    Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Late Effects Committee and Nursing Discipline

    J Clin Oncol

    (2004)
  • A Jannazzo et al.

    Monitoring of anthracycline-induced cardiotoxicity

    Ann Pharmacother

    (2008)
  • MS Ewer et al.

    Left ventricular ejection fraction and cardiotoxicity: is our ear really to the ground?

    J Clin Oncol

    (2008)
  • R Jurcut et al.

    Detection and monitoring of cardiotoxicity-what does modern cardiology offer?

    Support Care Cancer

    (2008)
  • TM Suter et al.

    Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial

    J Clin Oncol

    (2007)
  • S Zhou et al.

    Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin

    Cancer Res

    (2001)
  • SM Swain et al.

    Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials

    Cancer

    (2003)
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