Monitoring chemotherapy-induced cardiotoxicity: Role of cardiac nuclear imaging

doi:10.1016/j.nuclcard.2006.03.002

Journal of Nuclear Cardiology

Volume 13, Issue 3, June 2006, Pages 415-426

https://doi.org/10.1016/j.nuclcard.2006.03.002 Get rights and content

Cardiotoxicity may result from a range of chemotherapeutic agents. The prevalence of cardiotoxicity from certain cytotoxic agents is reported to be significantly high. In addition to serious side effects and increased long-lasting morbidity and mortality, dose limitation and suboptimal usage is an important adverse effect. Nuclear cardiac imaging has played a quintessential and important role in identifying patients at risk and in the prevention and reduction of cardiac injury resulting from cytotoxic agents. Despite exploring a number of other diagnostic imaging or biochemical tools for identification of cardiac injury, nuclear cardiac imaging in the form of radionuclide angiocardiography continues to be the most suitable and cost-effective tool for reducing the prevalence of cases of cardiac dysfunction resulting from chemotherapy. This article reviews the prevalence, mechanisms, and prevention strategies for cardiotoxicity associated with some of the commonly known cytotoxic agents and the role of nuclear cardiac imaging in its monitoring and prevention, along with recent advances in this area.

Section snippets

Anthracyclines

Anthracyclines (doxorubicin, daunorobucin, epirubicin, idarubicin, and so forth) are commonly used antineoplastic agents in a wide variety of hematologic and solid tumors.4, 5 Anthracyclines are highly potent anticancer agents. Cardiotoxicity is a well-known side effect of anthracyclines.⁶ As per recent estimates, by the year 2010, 1 in 200 adults in the United States will be a survivor of some form of childhood cancer.⁷ Because anthracyclines constitute the regimen for many of the common

Acute and early toxicity

Acute or subacute cardiotoxicity with anthracyclines occurs during or immediately after infusion and usually is self-limiting with discontinuation of therapy (eg, electrocardiographic abnormalities such as nonspecific ST-T changes and QT prolongation, pericarditis–myocarditis syndrome, and ventricular dysfunction with CHF).

Chronic and late-onset toxicity

Although late-onset cardiotoxic effects are noted after months to years, some of these chronic effects may start with early cardiac abnormalities that can progress over a period of time to overt cardiac dysfunction. Chronic effects persist after discontinuation of the anthracyclines and the clinical symptoms may include all signs of cardiomyopathy such as electrophysiologic changes, decrease of left ventricular function, changes in exercise capacity, and overt signs of CHF. Estimates based on

Risk factors

Cumulative dose,¹¹ dose schedule,12, 13 female sex,14, 15 age, prior irradiation,¹⁶ concomitant administration of other chemotherapeutics,17, 18 and underlying heart disease have been associated with early and late-onset cardiotoxicity.¹⁹ Of these, the cumulative dose seems to be the most important factor. The usual dose of doxorubicin is 55 to 75 mg/m² every 3 weeks. At a cumulative dose of more than 450 to 550 mg/m² of doxorubicin, cardiomyopathy and CHF occur most frequently (Figure 1). Von

Mechanism

A number of mechanisms including free radical–mediated myocardial injury, myocyte death from calcium overload,22, 23, 24 alteration in adrenergic function, and inhibition of protein synthesis have been postulated as plausible mechanisms of doxorubicin cardiotoxicity. However, the exact mechanism of doxorubicin cardiotoxicity is not clear. Although the mechanism of anthracycline cardiotoxicity may be multifactorial, of all the hypotheses, oxidative injury from the production of oxygen free

Prevention

For more than 2 decades researchers have struggled to develop strategies to ameliorate or prevent doxorubicin cardiotoxicity. Reducing cumulative dose and frequent surveillance have been among the most effective strategies until now. A number of antioxidant and free radical scavengers have been developed for experimental and clinical studies, but without consistent benefit.²⁹ These strategies have been devised based on the concept of free radical injury and relative weaker defense system of the

Monitoring and detection of cardiotoxicity

Along with attempts to reduce or prevent cardiotoxicity by developing newer forms of anthracyclines and other chemotherapeutic agents and other pharmacologic agents, the need arises for identifying patients at unusually higher risk for developing CHF. Detection of myocardial injury before irreversible functional impairment is the most logical approach for the prevention of doxorubicin-induced heart failure. This approach would allow maximum doses of doxorubicin to be administered without the

Endomyocardial biopsy examination

Endomyocardial biopsy examination is an invasive and expensive technique requiring interpretation by a skilled histopathologist. Endomyocardial biopsy examination requires a small sample of right ventricular myocardium to be obtained for histopathologic analysis. Although endomyocardial biopsy examination provides a histologic diagnosis along with grading of severity of disease (based on the Billingham score), it has multiple shortcomings.62, 63 The changes of doxorubicin cardiotoxicity are

Equilibrium radionuclide angiocardiography

Equilibrium radionuclide angiocardiography (ERNA) has been a reliable and reproducible test for monitoring and evaluation of left ventricular function in patients undergoing doxorubicin chemotherapy.66, 67 It is among the earliest and most widely used methods for this purpose. Change in left ventricular ejection fraction (LVEF) precedes overt heart failure in patients undergoing doxorubicin cardiotoxicity. Serial monitoring using ERNA allows the detection of a predetermined decrease in LVEF

Stress ERNA

Several investigators explored the role of exercise ERNA in detecting early cardiotoxicity.72, 73, 74 Studies suggested a failure to increase the LVEF by 5% or more during exercise RNA over the resting ejection fraction as an indication for risk of developing subsequent cardiomyopathy. Although initial studies showed exercise ERNA to be more sensitive than rest ERNA, specificity in the absence of serial testing was a concern. In addition, several healthy patients failed to increase the ejection

Diastolic dysfunction

Although resting ejection fraction as determined by ERNA has been standard practice, other variables have been tested for their use in predicting subsequent heart failure. Diastolic dysfunction has been examined by means of both echocardiographic and by radionuclide angiocardiography.75, 76, 77, 78 A reduction in peak filling rate was suggested as an early marker of anthracycline-induced cardiotoxicity.⁷⁷ A decrease in peak filling rate was purported to occur earlier than reduction in ejection

Echocardiography

Echocardiography is another imaging modality commonly used for the evaluation of cardiac function and structure in patients, especially pediatric, undergoing anthracycline cardiotoxicity. Although it is used frequently, serial measurement of cardiac function is limited by a greater degree of variability that impairs its value in predicting heart failure. Echocardiographic studies based on ERNA guidelines have reported poor sensitivity of echo in detecting anthracycline-induced cardiac

Neuronal Imaging

Beyond the conventional methods, several newer agents have been evaluated in predicting heart failure caused by doxorubicin cardiotoxicity. Iodine-123–labeled metaiodobenzylguanidine (I-123 MIBG), an agent used for neuronal imaging in heart failure, has been proposed for understanding the contribution of abnormal adrenergic function in pathogenesis of doxorubicin cardiotoxicity (Figure 3).81, 82, 83, 84, 85 MIBG, a guanethidine analog, shares type I adrenergic neuroreceptor uptake storage and

Acknowledgment

The authors have indicated they have no financial conflicts of interest.

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ReviewMonitoring chemotherapy-induced cardiotoxicity: Role of cardiac nuclear imaging

Section snippets

Anthracyclines

Acute and early toxicity

Chronic and late-onset toxicity

Risk factors

Mechanism

Prevention

Monitoring and detection of cardiotoxicity

Endomyocardial biopsy examination

Equilibrium radionuclide angiocardiography

Stress ERNA

Diastolic dysfunction

Echocardiography

Neuronal Imaging

Acknowledgment

Cancer Treat Rev

Int J Radiat Oncol Biol Phys

Ann Oncol

Biochem Pharmacol

Biochem Pharmacol

J Card Fail

Free Radic Biol Med

J Card Fail

J Mol Cell Cardiol

Ann Oncol

Ann Oncol

Ann Oncol

Am Heart J

Am J Cardiol

Am Heart J

Am J Med

Am J Cardiol

J Am Coll Cardiol

J Nucl Cardiol

J Nucl Cardiol

J Nucl Cardiol

J Am Coll Cardiol

J Nucl Cardiol

Cardiovascular complications of cancer therapydiagnosis, pathogenesis, and management

Circulation

Health profiles in 5836 long-term cancer survivors

Int J Cancer

Anthracyclines in the treatment of cancer. An overview

Drugs

The anthracyclineswill we ever find a better doxorubicin?

Semin Oncol

Doxorubicin-induced cardiomyopathy

N Engl J Med

Epidemiology of anthracycline cardiotoxicity in children and adults

Semin Oncol

Congestive heart failure in patients treated with doxorubicina retrospective analysis of three trials

Cancer

Cardiac toxicity 4 to 20 years after completing anthracycline therapy

JAMA

Late cardiotoxicity after treatment for a malignant bone tumor

Med Pediatr Oncol

Risk factors for doxorubicin-induced congestive heart failure

Ann Intern Med

Doxorubicin administration by continuous infusion is not cardioprotectivethe Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol

J Clin Oncol

Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion

Ann Intern Med

Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer

N Engl J Med

Clinical cardiotoxicity following anthracycline treatment for childhood cancerthe Pediatric Oncology Group experience

J Clin Oncol

Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancerNSABP B-31

J Clin Oncol

Adriamycin cardiomyopathy—risk factors

Cancer

The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia

N Engl J Med

Cardiotoxicity from intensive chemotherapy combined with radiotherapy in breast cancer

Br J Cancer

Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin

Cancer Res

Adriamycin-induced free radical formation in the perfused rat heartimplications for cardiotoxicity

Cancer Res

Prevention of anthracycline cardiotoxicity by iron chelation

Review
Monitoring chemotherapy-induced cardiotoxicity: Role of cardiac nuclear imaging