Review Article
Non-invasive imaging and monitoring cardiotoxicity of cancer therapeutic drugs

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Abstract

Cardiotoxicity due to administration of cancer therapeutic agents such as anthracyclines and herceptin are well described. Established guidelines to screen for chemotherapy-related cardiotoxicity (CRC) are primarily based on serial assessment of left ventricular (LV) ejection fraction (EF). However, other parameters such as LV volume, diastolic function, and strain may also be useful in screening for cardiotoxicity. More recent advances in molecular imaging of apoptosis and tissue characterization by cardiac MRI are techniques which might allow early detection of patients at high risk for developing cardiotoxicity prior to a drop in EF. This comprehensive multi-modality review will discuss both the current established imaging techniques as well as the emerging technologies which may revolutionize the future of screening and evaluation for CRC.

Introduction

Cardiotoxicity is an unfortunate but well-established adverse effect of various chemotherapeutic agents, particularly anthracyclines and herceptin. Anthracyclines are used regularly in chemotherapeutic regimens to treat a variety of malignancies, including leukemia, lymphoma, neuroblastoma, sarcoma, ovarian cancer, breast cancer, and gastric cancer. While the exact mechanism of anthracycline-related cardiomyopathy (ARC) is poorly understood, a commonly accepted theory involves myocardial damage caused by mitochondrial injury and free radical formation.1,2 The risk of cardiomyopathy increases with a higher cumulative anthracycline dose: 3% with dose of 400 mg/m2, 7% for a dose of 550 mg/m2, and 18% for a dose of 700 mg/m2.3 However, there are patients who received doses exceeding 1 g/m2 who did not develop cardiomyopathy, which implies that there are clearly other factors involved. It is possible that patients metabolize the drugs differently, with some being more sensitive to the generation of anthracycline-induced free-radical formation than others.4 Many patients receive additional agents, such as taxanes, which are known to increase production of toxic anthracycline metabolites.5 Radiation therapy may also increase the incidence of ARC.6,7

Many patients with invasive breast cancer that overexpresses the human epidermal growth factor (HER-2) receptor receive regimens that include herceptin, a monoclonal antibody targeting the HER-2/neu receptor. The role of herceptin in the development of heart failure has not been elucidated, however, the loss of protective HER-2-mediated signaling pathways in response to stress8 may sensitize the myocardium to cellular injury from anthracyclines,9 as a higher incidence of cardiomyopathy was observed in regimens that involved concurrent herceptin and anthracycline administration compared to those receiving herceptin after completing anthracycline treatment (27% vs 7%, respectively).10,11

The prevalence of clinical heart failure was initially reported to be 2.2% in a large retrospective analysis of over 4,000 patients who received anthracycline-based chemotherapy with a mortality of 71% attributed to heart failure.3 However, that study was performed in 1979, prior to the widespread use of modern heart failure medical therapies and the implementation of routine screening for left ventricular (LV) dysfunction prior to and after dosing anthracyclines. A more recent long-term follow-up study of patients who received anthracyclines suggests that prior studies may have underestimated the number of patients developing heart failure, as they observed a 63% prevalence of LV dysfunction after more than 10 years of follow-up for those who received more than 500 mg/m2 cumulative dose, in contrast to an 18% prevalence in those who had received less than 500 mg/m2.7 Perhaps more concerning is that up to half of patients who develop LV dysfunction after receiving an anthracycline and/or herceptin may not be on medical therapy or have even had a cardiology consultation.12 Although treatment of anthracycline-induced cardiomyopathy with carvedilol and enalapril has shown some promise in small studies,13, 14, 15 45% of patients have no improvement in LV function with medical therapy.16 Conversely, cardiotoxicity due to herceptin is considered to be reversible if a prompt diagnosis is made, with discontinuation of herceptin and initiation of medical treatment for heart failure.17 A scheme for classification of cardiotoxicity based on differences in underlying mechanism and reversibility has been developed (Table 1).18 Thus an early diagnosis of cardiotoxicity and the ability to predict which patients are more likely to suffer cardiotoxicity are important for preventing chronic heart failure in patients receiving these agents.

Section snippets

Imaging to Detect Cardiotoxicity

The current guidelines for monitoring patients receiving anthracyclines proposed by Schwartz et al in 198719 recommends obtaining a baseline ejection fraction (EF) by equilibrium radionuclide imaging, with subsequent imaging studies before consideration of any additional doses and specific criteria for drug discontinuation based on interval change in LV function (Figure 1). In patients with a normal resting EF > 50%, a drop in LVEF of >10% or to <50% is considered an indication for

Radionuclide Imaging

For serial measurements of LVEF, quantification by equilibrium radionuclide angiocardiography (ERNA) is more reproducible than echocardiographic visual assessment,28 and has long been considered the gold-standard for CRC screening. Perhaps the single largest study involving monitoring for CRC involved serial ERNA or single-photon emission computed tomography (SPECT) in 1,487 patients receiving doxorubicin.19 Using this method of screening, 19% of patients will be at high risk for developing

Positron Emission Tomography (PET)

The utility of PET imaging in cancer patients has focused on diagnosis of metastatic lesions and response to chemotherapy. However, fluorine-18-fluorodeoxyglucose (FDG) PET imaging can be useful in diagnosing and monitoring response to treatment of primary cardiac lymphoma, which will be apparent as hypermetabolic areas within the myocardium,46,47 FDG-PET has also been able to evaluate for metastatic pericardial involvement.48 There has been limited investigation applying cardiac PET to monitor

Echocardiography

Perhaps the most readily available modality for assessment to screen for cardiotoxicity with serial measurements of LVEF, echocardiography can provide supplemental information that cannot be obtained from SPECT, such as evaluation for valvular disease or pericardial constriction, which are known adverse effects of mediastinal radiation. Recently, a restrictive cardiomyopathy with endocardial calcification has been described by echocardiography in a patient who received an anthracycline-based

CMR Imaging

CMR is recognized by the ACC/AHA as method to screen for CRC.79 However, it is less widely used for routine screening for CRC, in part likely due to more widespread availability of echocardiography and SPECT. However, there are some potential advantages of CMR. Particularly in obese patients for whom echocardiography yields suboptimal images, CMR is an excellent modality for obtaining accurate serial measurements of LV function, and is considered the gold standard for measuring LV function.80

Molecular Imaging of Apoptosis

Molecular imaging agents targeting annexin A5 to detect apoptosis have been developed for multiple imaging modalities including SPECT, echo, and CMR. Non-invasive imaging using 11In or 99mTc-labeled annexin A5 has been used to monitor response of tumors to treatment, as annexin A5 binds to phosphatidylserine, a cell membrane phospholipid which is exposed during apoptosis.97,98 There has been interest in using annexin as a target to image apoptosis in the myocardium as an indicator of

Conclusion

Given recent advances in non-invasive cardiac imaging to screen for CRC over the last decade, there is a critical need to re-evaluate the current reliance on LVEF in determining which patients are at high risk for developing cardiomyopathy. The yearly cost of caring for a patient with heart failure due to CRC is offset several times over by the cost of screening an at-risk population by ERNA.29 Screening in a population without established risk factors for CRC is not cost-effective104; however,

Disclosures

Ronny S. Jiji, None; Christopher M. Kramer, Research support (significant), Siemens Healthcare; Michael Salerno, AHA research support.

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