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The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.
Advances in cancer therapy have allowed for increasing numbers of long-term cancer survivors but have also generated increasing potential and significance of cardiovascular complications.
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Involvement of cardiovascular disease specialists has therefore become advisable from the initial assessment through survivorship, and this integrative approach has been coined “cardio-oncology.”
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Cardiotoxicity related to cancer therapy is currently defined by a decrease in cardiac function and categorized into 2 types: irreversible injury type (type 1) or reversible dysfunction type (type 2).
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Monitoring and management algorithms for either type of chemotherapy-induced cardiomyopathy are evolving around the central paradigm of early recognition and early treatment.
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Radiation-induced cardiotoxicity encompasses a broad spectrum of cardiac diseases that potentiates any chemotherapy-induced cardiotoxicity.
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Treatment of cardiovascular conditions of patients with cancer generally follows the American Heart Association/American College of Cardiology guidelines with some particular nuances.
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Preventive efforts should be considered for patients at an estimated high risk for cancer therapy–induced cardiotoxicity, with the preferred drugs being angiotensin-converting enzyme inhibitors and the specific β-blockers carvedilol or nebivolol.
Over the past decades, there has been a tremendous improvement in the survival rates of a number of cancers and a steady increase in the number of cancer survivors (see Supplemental Figure 1 and Supplemental Table 1 [available online at http://www.mayoclinicproceedings.org]). As a result, an increasing number of patients with cancer are now being followed not only by oncologists or hematologists but also by general practitioners. Cardiovascular complications are not uncommonly encountered in these patients with potentially profound impact on morbidity and mortality, and thus their recognition and management has become an important element in the overall care for patients with cancer.
Furthermore, there is an intriguing geographic overlap in the prevalence of cancer and cardiovascular disease (see Supplemental Figure 2 [available online at http://www.mayoclinicproceedings.org]) and expansion of cancer therapies to more elderly individuals with a greater burden of comorbidities.
ICARO (Italian CARdio-Oncologic) Network Adjuvant trastuzumab cardiotoxicity in patients over 60 years of age with early breast cancer: a multicenter cohort analysis.
Hence, an increasing number of patients with preexisting cardiovascular diseases are now being considered for cancer therapy, which adds another level of complexity. Involvement of cardiologists has thus become more and more advisable not only to most optimally manage cardiovascular complications of cancer therapy but also to assist in the overall care of patients with cancer from the initial assessment to survivorship. This integrative approach has been termed cardio-oncology,
and herein we will reflect on this emerging field. An overview of cancer therapy–induced cardiotoxicity is provided in the first part and practical steps to its evaluation, management, and prevention in the following parts. The content is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.
Part 1: Chemotherapy and Radiation Therapy–Induced Cardiotoxicity
The armamentarium for the treatment of various cancers has increased substantially over the past decades, with a gradual change from a cell cycle kinetics–based approach to more specific targeting of crucial signaling pathway(s). In most cases, these are cell proliferation pathways, which are regulated by receptor and nonreceptor tyrosine kinases, leading to the development of a wide range of inhibitors. The extent to which this would interfere with normal cardiovascular function has often not been well anticipated, but such “off-target” effects have become clinically relevant and revealing with regard to the functional role of signaling pathways in the cardiovascular system. A comprehensive list of currently used cancer drugs with a propensity for cardiovascular toxicities is provided in Table 1, along with their Food and Drug Administration–approved cancer indications.
Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon: an unexpectedly frequent complication.
Coronary vasospasm, myocardial ischemia and infarction, arrhythmias, ECG changes including ventricular ectopy, hypotension
Advanced colon cancer, anal cancer, gastrointestinal cancers, pancreatic cancer, hepatobiliary cancers, breast cancer, bladder cancer, head and neck cancers, and as a radiation sensitizer in several tumors
Lung cancer, bladder cancer, sarcomas, testicular cancer, ovarian cancer, head and neck cancer, metastatic breast cancer, cancer of unknown origin, esophageal cancer
Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon: an unexpectedly frequent complication.
Considering the spectrum of cardiovascular effects, a distinction can be made between those agents that primarily affect cardiac function (eg, anthracyclines and trastuzumab), vascular function (eg, 5-fluorouracil and capecitabine), or both (eg, bevacizumab and sunitinib). Radiation therapy leads to an all-encompassing form of injury to the myocardium, the pericardium, the valvular apparatus, and the coronary vasculature from the epicardial to the microvascular level, though modern approaches appear to reduce cardiovascular damage compared with older techniques. The focus herein will be on cardiotoxicity, and vascular toxicities will be discussed only as much as they relate to this topic.
Chemotherapy-Induced Cardiotoxicity
To organize the broad spectrum of cardiotoxicity due to chemotherapy, an operational classification system was introduced by Ewer and Lippman
(see Supplemental Table 2 [available online at http://www.mayoclinicproceedings.org]). This system is based on the presence of structural abnormalities and extent of functional reversibility. Accordingly, a distinction can be made between an injury type (type 1 chemotherapy-induced cardiotoxicity) and a dysfunction type (type 2 chemotherapy-induced cardiotoxicity). Given that cardiac magnetic resonance imaging (MRI) has provided evidence for scar formation in patients with presumed type 2 cardiotoxicity and appropriate heart failure therapy led to an improvement in presumed type 1 cardiotoxicity, the outlined classification pattern may not be as much of an absolute as perceived.
The one used in recent times was developed by the Cardiac Review and Evaluation Committee of trastuzumab-associated cardiotoxicity, and it defines chemotherapy-induced cardiotoxicity as a decrease in left ventricular ejection fraction (LVEF) by 5% or more to less than 55% in the presence of symptoms of heart failure (diagnosed by a cardiologist) or an asymptomatic decrease in LVEF by 10% or more to less than 55%.
Induction of cardiomyocyte injury is a key distinguishing feature of this type of chemotherapy-induced cardiotoxicity, with anthracyclines as the prototype class of drugs in this category. Given the imposition of structural changes, it has become widely accepted that this type of cardiotoxicity is not reversible. Moreover, anthracycline-induced cardiomyopathy has been considered to be associated with a prognosis that is worse than that for ischemic or dilated cardiomyopathies and possibly even for the primary cancer for which it was given.
Although anthracycline-induced cardiomyopathy was found to be rarely and never fully reversible when recognized and treated late, resolution can be noted with close surveillance and prompt institution of therapy early on (Figure 1).
Figure 1Illustration of the percentage of patients with an improvement in left ventricular ejection fraction to greater than 50%, depending on the timing of the initiation of heart failure therapy after the diagnosis of anthracycline-induced cardiomyopathy (A) and survival free of cardiac events for patients with an improvement in left ventricular ejection fraction less than (partial responders) or greater than 50% (responders) (B).
Traditionally, a distinction has been made between an acute and a chronic form of anthracyline-induced cardiotoxicity. The acute form develops at the time (or within 1 week) of administration of anthracyclines and resembles an acute toxic myocarditis with myocyte damage (pyknotic debris), inflammatory infiltrates, and interstitial edema.
It manifests primarily with electrocardiographic (ECG) changes (20%-30%) and arrhythmias (up to 3%), and occasionally with reversible cardiac dysfunction, even acute heart failure and peri-/myocarditis. The aforementioned clinically much more recognized type is the chronic form of anthracycline-induced cardiotoxicity with early onset within 1 year or late onset more than 1 year after completion of therapy.
This type is marked by cardiac dysfunction rather than ECG abnormalities. On histology, cytoplasmic vacuolization due to swelling of the sarcoplasmic reticulum and mitochondria can be noted, as well as disruption of organelles, myocyte death, myofibrillar loss, and/or myofibrillar disarray.
Studies on the exact mechanisms responsible for the cardiotoxicity of anthracyclines have remained without a unifying explanation. The prevailing theory has been the “iron and free-radical hypothesis.”
Accordingly, reductases in cardiomyocytes catalyze the addition of an electron to the quinone moiety of anthracyclines, which leads to the formation of a semiquinone that then regenerates the quinone state by reducing molecular oxygen to superoxide anion and its dismutation product hydrogen peroxide (the so called “redox cycling”).
The propensity toward toxicity is significantly increased when these products interact with low-molecular iron, generating a surge of oxidative stress (Fenton reaction). The oxidative modification of proteins and lipids as well as genomic and mitochondrial DNA damage are the downstream consequences.
Uncoupling of the electron transport chain with impairment of oxidative phosphorylation and adenosine triphosphate synthesis contributes further to mitochondrial dysfunction and damage.
Finally, the inhibition of topoisomerase 2-β in cardiomyocytes has recently been proposed as an additional, if not key, mediator of anthracycline-induced cardiomyopathy.
Anthracyclines thereby induce DNA damage and impair its repair, which are the mechanisms responsible for tumor cell death. In crucial distinction, however, it is the inhibition of topoisomerase 2-α in cancer cells.
It develops as an acute myopericarditis, which (usually) does not take the course of chronic injury and hence does not meet all criteria for a type 1 pattern. Similarly, the tyrosine kinase inhibitor sunitinib manifests cardiotoxicity that meets some, but not all, of the above criteria and has, in fact, been considered to represent a type 2 pattern.
Mechanistically, sunitinib inhibits adenosine monophosphate–activated protein kinase, which interferes with the ability of the cardiomyocyte to adapt to energy demands with untoward consequences for cardiac function.
Furthermore, other studies suggest that the inhibition of the platelet-derived growth factor receptor pathway and the vascular endothelial growth factor (VEGF) receptor pathway leads to hypoxia, hypoxia-inducible genes, and a pattern of myocardial hibernation rather than infarction.
This type of treatment-induced cardiotoxicity is marked by the absence of structural abnormalities and reversibility on cessation of therapy. Trastuzumab (Herceptin) is the prototype drug, and the key pathophysiological mechanism is interference with the HER-2/ErbB2–regulated signaling pathways in cardiomyocytes.
These are key stress, adaption, and survival pathways, which explains why the incidence of cardiotoxicity is extremely high when trastuzumab is given in close temporal relationship with anthracyclines.
Furthermore, mice with a cardiac-specific deletion of the ErbB2 receptor develop a dilated cardiomyopathy and are unable to tolerate high afterload (blood pressure) challenges.
As not all HER-2/ErbB2 pathway inhibitors, however, share the same potential for cardiomyopathy, the ultimate consequences are dictated by the net effect on multiple downstream targets.
Another example of a drug that can cause type 2 treatment-induced cardiotoxicity is bevacizumab. In contrast to the aforementioned drugs, the cardiomyocyte does not appear to be the primary culprit. Rather, bevacizumab binds to and prevents VEGF from interacting with its receptor(s), which reside primarily on endothelial cells. Still, cardiotoxicity including clinical heart failure has been reported with this drug.
Reversibility of cardiac dysfunction has been noted, suggesting that no structural damage to the cardiomyocytes is induced, though histological confirmation is lacking.
The underlying mechanisms likely include interference with endothelial function, impairment of endothelial-myocardial coupling, and capillary rarefaction.
Radiation therapy entails the use of high-energy particles, x-rays, or γ-rays that fragment cellular DNA and thereby interfere with cell proliferation and viability. This affects cancer cells in particular, given their high metabolic and proliferation index. The effect on normal cells and tissues is related to their particular susceptibility and the extent of ionizing radiation exposure. For instance, radiation therapy to the chest can harm the cardiovascular system, and even more so if doses exceed 30 Gy.
Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease.
This had been the case with mantle field radiation and is still the case with involved field radiation therapy in patients with Hodgkin lymphoma (up to a total dose of 20-35 Gy). Doses for adjuvant radiation therapy in patients with breast cancer can be even higher (in the order of 45-50 Gy). Modifications of radiation protocols, careful radiation field planning, and techniques such as breath holding have been implemented to reduce the radiation dose to the cardiovascular structures. As outlined in recent studies and not without controversy, however, there may not be a threshold level below which radiation therapy is safe to the heart and the vascular system.
From a current practice standpoint though, radiation-induced heart disease remains of significance, as most patients seen today are those who had higher exposures 20 to 30 years ago.
Radiation therapy induces a spectrum of cardiotoxicities that differ considerably from chemotherapy-induced cardiotoxic effects and affect all layers of the heart. Acute pericarditis used to be the most frequent complication, but advances reduced its incidence from 25% to 2%.
Chronic pericarditis still develops with a clinical incidence of 3% at 20 years and 12% at 30 years in those who underwent chest radiation at a dose of 35 Gy or greater.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.
Similar fibrotic changes can be noted in the endocardium and the valve apparatus, initially causing retraction and regurgitation and over time (>20 years) also stenosis, especially of the left-sided valves.
Capillary rarefaction has also been noted, and injury to the endothelium is considered an integral part of radiation-induced heart disease. The theory has been that microvascular insufficiency leads to ischemia and cardiomyocyte death with replacement fibrosis; however, this has not been substantiated by histological observations.
Instead, barrier breakdown of the endothelium with microhemorrhage and aggravation of (radiation-induced) oxidative stress and inflammation seems to be an important pathomechanism.
Furthermore, extravasation of albumin can lead to amyloid formation and predisposition to sudden cardiac death. These recent observations add another dimension to the restrictive cardiomyopathy phenotype observed after radiation therapy. They may also have important implications for the early detection of radiation-induced cardiotoxicity and the identification of patients at risk of malignant cardiac arrhythmias.
How the combination of anthracycline-based chemotherapy and radiation therapy affects these aspects remains to be defined. Alterations in cardiac function and valve disease are most profound though with combined therapies.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.
In contrast, the incidence of radiation-induced pericardial disease is not increased by concomitant anthracycline therapy and only limited, inconclusive data are available for coronary artery disease (CAD).
Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE−/− mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage.
A dose correlation has been noted and hence coronary artery segments with the highest degree of exposure are at greatest risk of disease. For mantle and even involved field radiation, this is the proximal left main and right coronary artery.
For left- and right-sided breast cancer radiation, this is the mid left anterior descending artery and proximal to mid right coronary artery, respectively.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.
An intriguing aspect is that radiation therapy has a long-reaching effect despite a confined exposure period. This points to the induction of a smoldering process that continues after the initiating stimulus, and similar to the mechanisms discussed for anthracycline-induced cardiomyopathy, this may be mitochondrial DNA damage and perturbed mitochondrial function.
Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans.
DNA damage and activation of key proinflammatory pathways such as the nuclear factor κB pathway has been pointed out for traditional cardiovascular risk factors as well, which may explain why traditional cardiovascular risk factors can affect the type and extent of atherosclerosis after chest radiation.
Mitochondrial DNA damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans.
Part 2: Evaluation for Cancer Therapy–Induced Cardiotoxicity
A multidisciplinary approach incorporating cardiology and oncology expertise is needed to evaluate and manage short- and long-term effects of cancer treatments enumerated above.
The following sections are devoted to discuss the principles of practice of cardio-oncology before, during, and after chemo- and/or radiation therapy (Figure 2).
Figure 2Outline of a general cardio-oncology algorithm. abn = abnormal; CAD = coronary artery disease; CXR = chest x-ray; CV = cardiovascular; ECG = electrocardiogram; f/u = follow-up; HTN = hypertension; QTc = corrected QT.
Cardiovascular Evaluation of Patients Before and During Cancer Therapy
Before the initiation of cancer therapy, a thorough patient history and physical examination should be performed to determine the baseline cardiovascular risk. Traditionally, there has been considerable variation in the use of adjunctive tests such as ECG or echocardiography, directed mainly by the cardiotoxicity profile of the planned treatment regimen and individual practice styles. However, it is advisable to standardize the assessment of patients with cancer and to stratify them in their cardiotoxicity risk profile routinely. Such an approach allows for a universal standard of care for all patients, facilitates communication across disciplines, and aids in treatment decisions and follow-up planning. Recent meta-analyses support operational models that incorporate underlying patient-related risk factors.
However, full assessment should also include the cardiac toxicity potential of cancer therapies (as suggested in Figure 3) and the anticipated therapeutic benefit of the anticancer regimen. Whether and which additional tests would further refine this risk assessment remains unanswered at present.
Figure 3Outline of a putative risk assessment, monitoring, and management model for patients undergoing chemotherapy. The central concept is that patient- and medication-related risk factors can be used to generate an overall risk score that can then be used to determine monitoring intervals and thresholds for preventive strategies. Such models need to be accounted for the fact that not all chemotherapeutic agents and patient-related risk factors weigh the same, and hence the ultimate prediction models will need to be more stratified and will need to be verified. ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; cTn = cardiac troponin; ECG = electrocardiogram; HTN = hypertension; PAD = peripheral arterial disease; TTE = transthoracic echocardiography.
Once patients have begun receiving treatment, it must be further decided which patients require cardiovascular follow-up. This depends on the baseline cardiovascular risk profile, the specific cancer treatment regimen, and the development of cardiac symptoms and/or events. Monitoring protocols were developed and validated for patients undergoing anthracycline-based therapy in the 1970s and 1980s (Figure 4).
These were based on radionucleotide angiogram (ventriculogram) (RNA, also known as multiple-gated acquisition or MUGA scan), and the pivotal observation that a decrease in LVEF noted by this technique would precede clinically overt heart failure.
Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: seven-year experience using serial radionuclide angiocardiography.
Figure 4Established algorithm for the monitoring of patients undergoing anthracycline-based chemotherapy. A variation of this algorithm is the reassessment before each cycle after administering 250 to 300 mg/kg2 in those at high risk. LVEF = left ventricular ejection fraction.
Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy: seven-year experience using serial radionuclide angiocardiography.
Radionucleotide angiogram (ventriculogram) is operator independent and highly reproducible but has been largely replaced by echocardiography. Historically, change in LVEF by 2-dimenisonal (2D) transthoracic echocardiography (TTE) has been reported as high as 10%. However, LVEF assessment by contrast-enhanced 2D TTE or 3D TTE is superior in this regard and comparable to that by RNA and cardiac MRI.
Analysis of left ventricular volumes and function: a multicenter comparison of cardiac magnetic resonance imaging, cine ventriculography, and unenhanced and contrast-enhanced two-dimensional and three-dimensional echocardiography.
Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance: are they interchangeable?.
As such, the algorithms validated for RNA may be applied to TTE imaging using these newer echocardiographic techniques. Widespread availability, feasibility, lack of radiation exposure, and acquisition of additional cardiac imaging information (valvular, pericardial, and hemodynamic data) make echocardiography an attractive option for serial imaging, even though service fees might be higher.
Of particular interest is strain imaging, which is a measure of regional deformation of the myocardium. It is currently mainly obtained by angle-independent 2D speckle tracking echocardiography, which can evaluate all 3 domains of myocardial mechanics (longitudinal, circumferential, and radial) and derive data for deformation and rate of deformation for each myocardial segment.
Two-dimensional speckle tracking echocardiography has been used in multiple independent studies, reporting changes in cardiac (mechanical) function before a decrease in LVEF and even before changes in diastolic function after chemotherapy.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction.
The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
Xu YH J, Pellikka P, Ansell S, Cha S, HR V. Early changes in 2D-speckle tracking echocardiography may predict a decrease in left ventricular ejection fraction in lymphoma patients undergoing anthracycline chemotherapy. J Am Soc Echocardiogr. 2013;26(6):B52.
The degree of change in strain imaging is quite consistent across different laboratories and studies, and a greater than 10% change in global longitudinal strain after completion of anthracycline-based chemotherapy relative to baseline is predictive of a future decrease in LVEF.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
Conceivably, but subject to further studies, abnormal strain values before cancer therapy may signal higher baseline risk for chemotherapy-induced cardiotoxicity.
Based on the above discussion, it seems appropriate to include strain imaging in monitoring algorithms for cardiotoxicity. The dynamics after a cumulative dose of 200 mg/m2 of doxorubicin may be particularly instructive and have been suggested to serve as a benchmark, with reassessment after each additional 50 to 100 mg/m2 thereafter.
After completion of therapy, reassessment is recommended at 6 and 12 months and as early as 3 months for those at highest risk, for example, after doxorubicin equivalent doses exceed 400 mg/m2.
The aforementioned observation of clinical outcome as a function of time to treatment (Figure 1) would support expansion of these efforts to even earlier time points as would the outlined data on strain imaging.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
Importantly, how well changes in these imaging parameters predict the development of clinical heart failure has not been established. Also, how these algorithms should be modified for other drugs, for instance, trastuzumab, remains to be defined. Changes in strain values, however, have been found to precede changes in LVEF by a minimum of 3 months in this setting as well.
The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
One unique aspect of trastuzumab is the prolonged (1-year) treatment duration. Algorithms are in place, with LVEF as a central evaluation parameter; there is no guidance yet on how to interpret changes in strain imaging data over time (Figure 5). One may argue that the recognition of abnormalities in these echocardiographic parameters should prompt the initiation of effective cardiac therapies with continuation rather than suspension of cancer therapy as long as LVEF is preserved and signs and symptoms of heart failure are absent. Specific guidelines addressing the use of strain imaging in patients with cancer are to be released by the American Society of Echocardiography in the near future. The current (2012) clinical practice guidelines by the European Society for Medical Oncology are summarized in Supplemental Tables 3 and 4 (available online at http://www.mayoclinicproceedings.org).
Regarding the use of circulatory biomarkers, only cardiac troponin (cTn) has stood the test of time whereas brain natriuretic peptides and C-reactive protein have not and emerging data on myeloperoxidase are yet to be confirmed.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
The replacement, additive, or synergistic role of cTn in the outlined monitoring algorithms also requires further investigation. With anthracycline-based protocols, cTn serum concentrations increase during and early after completion of chemotherapy but their predictive value for a future decrease in LV function is not superior to that obtained with strain imaging.
Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy.
With trastuzumab, new cTn elevation is mainly seen with the first or second cycle and only early and persistent elevations seem to carry the greatest prognostic weight.
These data are intriguing if trastuzumab is to lead only to myocardial dysfunction and not myocardial injury.
Cardiovascular Evaluation of Patients After Cancer Therapy
After completion of cancer therapy, follow-up recommendations are to be individualized according to the overall survival prognosis of the underlying malignancy, the specific anticancer therapy administered, each patient’s unique cardiovascular risk and comorbidity profile, and whether they suffered adverse cardiac effects during therapy. Goals of management should be explained and managed together with other subspecialists involved in the cancer care of the patient.
Serial, long-term postexposure cardiac surveillance does not pertain to drugs that are associated with acute but not chronic injury patterns in the absence of any persistence of complications after completion of therapy. One example is cyclophosphamide, and even if acute cardiotoxicity were to occur, ongoing follow-up would not be necessary after recovery. Similarly, cardiotoxicity has not been reported to develop late after completion of trastuzumab therapy, and hence there is no need to continue with cardiac monitoring after completion of therapy (which is typically for a duration of 12 months). The need for posttreatment cardiovascular follow-up is hence confined to only those patients who have ongoing cardiovascular disease processes or are at risk of late cardiotoxicity.
Patients with breast cancer and lymphoma who have undergone anthracycline-based therapy and patients who have had mediastinal radiation therapy are prime candidates for long-term cardiac surveillance programs (ideally integrated into cancer survivorship programs). A recently published expert consensus statement from the European Association of Cardiovascular Imaging and the American Society of Echocardiography recommends evaluation based on signs and symptoms and echocardiographic surveillance starting 5 years after treatment in high-risk patients and 10 years in all other patients. High-risk patients should also receive a functional noninvasive stress test within 5 to 10 years of completion of chest radiation therapy (Figure 6).
European Society of Cardiology Working Groups on Nuclear Cardiology and Cardiac Computed Tomography and Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
J Am Soc Echocardiogr.2013; 26 ([published correction appears in J Am Soc Echocardiogr. 2013;26(11):1305. Bergler, Jutta [corrected to Bergler-Klein, Jutta]]): 1013-1032
Figure 6Monitoring algorithm of patients after radiation therapy. CAD = coronary artery disease; CMR = cardiac magnetic resonance; LV = left ventricular; US = ultrasound.
European Society of Cardiology Working Groups on Nuclear Cardiology and Cardiac Computed Tomography and Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
J Am Soc Echocardiogr.2013; 26 ([published correction appears in J Am Soc Echocardiogr. 2013;26(11):1305. Bergler, Jutta [corrected to Bergler-Klein, Jutta]]): 1013-1032
Intriguingly, even in the highest-risk group of patients with Hodgkin lymphoma who received 35 Gy or more of radiation to the chest, treadmill exercise ECGs do not reflect the burden of CAD.
Moreover, stress echocardiography and nuclear stress test can be quite discordant in their results—the former being more sensitive to abnormalities at rest and the latter being more sensitive to stress-related abnormalities.
However, it should be noted that these results do not reflect the technological advances which have been made, specifically as they relate to the use of ultrasound-enhancing contrast agents in stress echocardiography. Still, stenoses greater than 70% are noted on coronary angiography much more frequently than suggested by stress tests, and left main disease alone is found in more than 10% of the patients with Hodgkin disease more than 10 years after chest radiation therapy.
As outlined above, the disease process may be more regional in patients undergoing radiation therapy for breast cancer and the yield of nuclear stress testing may thus be higher in these patients.
For CAD evaluation after mediastinal radiation therapy, one must therefore consider the type and extent of therapy as well as baseline cardiac status along with strengths and limitations of various test modalities.
Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease.
Computed tomography angiography and perfusion to assess coronary artery stenosis causing perfusion defects by single photon emission computed tomography: the CORE320 study.
Radiation exposure has been a concern, but recently developed CT scanners have led to dose reduction. The role of cardiac MRI remains to be defined, but it is an excellent method to reliably assess ventricular structure and function and can be used for perfusion stress imaging. However, it poses significant logistic and financial challenges. For detection of cardiomyopathy, there is evidence that stress tests that assess exercise capacity and reserve are of superior yield, unmasking otherwise unrecognized (subclinical) impairment.
One subgroup of patients in need of particular attention are women with a history of chemo- or radiation therapy who are pregnant or are planning to become pregnant, as the pregnancy can unmask “smoldering” (subclinical) cardiomyopathy. The recommendation of the Children’s Oncology Group is that these patients should be evaluated by a cardiologist if they received a cumulative anthracycline dose of 300 mg/m2 or more, a radiation dose to the heart or surrounding tissues of 30 Gy or more, or any chest radiation plus an anthracycline or high-dose cyclophosphamide. These recommendations have been incorporated into the Mayo Clinic Lymphoma Survivorship Program (see Supplemental Table 5 [available online at http://www.mayoclinicproceedings.org]).
Part 3: Management of Cancer Therapy–Induced Cardiotoxicity
Management of patients who sustain cardiotoxicity during or after cancer therapy should be in keeping with the American Heart Association/American College of Cardiology heart failure guidelines.
American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
The efficacy of angiotensin-converting enzyme (ACE) inhibitors as first-line therapy was elegantly exhibited in patients with breast cancer who developed a significant decrease in LVEF and heart failure after epirubicin-based chemotherapy. Neither diuretics nor digoxin but prompt administration of ACE inhibitor therapy restored LV systolic function.
While such data are not available for angiotensin receptor blockers, these should still be considered in those with contraindications to ACE inhibitors. The precise role of aldosterone receptor antagonists (eg, spironolactone) in the treatment of chemotherapy-induced cardiomyopathy is currently unknown, but may be considered in those with NYHA class >1 symptoms and an LVEF of 35% or less.
American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
β-Blockers are the second main class of drugs for patients with chemotherapy-induced cardiomyopathy. This is supported by reports on the initiation of carvedilol after the initial successful commencement of low-dose enalapril with up-titration of both drugs as tolerated in patients who were found to have an LVEF of 45% or less after completion or during chemotherapy without any other identifiable cause.
Over the course of 3 years, this combined intervention restored LVEF to greater than 50% in 42% and partially improved it by 10% to less than 50% in another 13% of the patients. Intriguingly, clinical outcome was equally poor in those with a partial response and the 45% of the patients with no response (Figure 1).
As outlined before, timing from completion of anthracycline-based chemotherapy to initiation of heart failure therapy was identified as the crucial determinant of the response rate (Figure 1).
These observations substantiate the paradigm shift to the early detection and early treatment of chemotherapy-induced cardiotoxicity.
Hemodynamic device support may become necessary if medical therapy fails. Acute hemodynamic support can be temporarily lifesaving as in those with acute myopericarditis owing to cyclophosphamide.
Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry.
One unique aspect is the relatively high rate of biventricular failure in these patients compared with those receiving left ventricular assist device therapy for other indications.
Increased need for right ventricular support in patients with chemotherapy-induced cardiomyopathy undergoing mechanical circulatory support: outcomes from the INTERMACS Registry.
The most severe forms of heart failure are usually observed in patients receiving both chemotherapy and radiation therapy because of the profound injury and in those of young age.
Two key processes have been noted in children developing cardiotoxicity: reduction in contractility and/or increase in afterload. These have not been described in adults but may be of significance for the choice of therapy.
At present, it is unknown whether the medical therapies outlined above are necessary for agents that cause type 2 cardiotoxicity. Initial studies on trastuzumab-associated cardiomyopathy reported improved cardiac function after withholding therapy alone.
This has remained the primary approach common to all published management algorithms for trastuzumab-associated cardiotoxicity. However, HER-2 inhibition is a vital element in the treatment of patients with breast cancer overexpressing this receptor, and thus “drug holiday” is of concern.
Herceptin Adjuvant (HERA) Trial Study Team 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.
Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study.
It is currently undefined whether institution of cardioactive medication is necessary and would allow continuation of therapy without concerns for cardiac adverse effects. As the Akt/PKB signaling pathway is one of the key pathways affected by HER-2/ErbB2 signaling and is involved in trastuzumab-associated cardiotoxicity, up-regulation of this pathway in the heart may be of merit. Intriguingly, statins and nebivolol induce potent up-regulation of this pathway.
Whether such strategies would be counterproductive to the anticancer effects of therapy, however, remains an unanswered question.
The treatment of patients with radiation-induced heart disease is challenged by the multiplicity of processes and the high propensity for surgical intervention over time. One aspect often not considered is the fact that radiation therapy to the chest increases the level of complexity for open heart operation and risk of complications.
The internal mammary artery (IMA) is often not a prime bypass conduit in these patients owing to radiation damage. Furthermore, radiation-induced left subclavian artery disease may cause both a traditional steal phenomenon and flow limitation to the left IMA. Aortic calcification may pose significant challenges to aortocoronary (saphenous and arterial) bypasses. Assessment of the ascending aorta, aortic arch, and IMAs is recommended if these patients are considered for coronary artery bypass grafting.
Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease.
Given the surgical challenges in these patients, percutaneous coronary intervention might be preferred over coronary artery bypass grafting whenever possible.
A “heart team” approach should be pursued, and a comprehensive risk and benefit assessment should be made. As with patients with CAD in general, medical therapy remains the cornerstone of treatment. However, experimental data indicate that although radiation induces an inflammatory and thrombotic phenotype, conventionally used drugs such as statins and clopidogrel are not effective, though clopidogrel seems more favorable.
Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice.
Similarly, neither aspirin nor the newer nitric oxide–donating aspirin reduces the amount of plaque development in radiation-induced atherosclerosis despite efficacy for age-related atherosclerosis.
Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice.
Another important consideration is that these patients may require more than 1 open heart surgery (eg, bypass surgery and valve replacement). Postradiation mediastinal fibrosis poses a challenge at baseline and limits the number of redo surgeries. It is therefore advisable, if surgery is pursued, to address as many cardiac disease processes as comprehensively as possible in one operation and to use alternative interventions when possible until surgery becomes the only remaining option.
Furthermore, it is important to consider the propensity for constrictive pericarditis in these patients. If a patient is considered for pericardectomy, evaluation for the coexistence of restrictive cardiomyopathy is necessary because radiation therapy can also cause myocardial and endocardial fibrosis. Removal of the pericardium will unmask the presence of underlying restrictive cardiomyopathy without providing much symptom relief. Thus, hemodynamic catheterization is advised to differentiate between a primarily constrictive or restrictive process. Cardiac MRI might help to define the burden of cardiac fibrosis, especially in those with equivocal hemodynamic findings. It can also outline the pericardium, but in most cases there is no inflammation and these patients do not benefit from anti-inflammatory therapy.
A high level of clinical suspicion for arrhythmia needs to be maintained in patients after radiation therapy to the chest because interstitial fibrosis may lead to ventricular tachycardias and degeneration of the conduction system may cause bradyarrhythmias.
Late calcification of the mitral-aortic junction causing transient complete atrio-ventricular block after mediastinal radiation of Hodgkin lymphoma: multimodal visualization.
Treatment of these ultimate complications should be in keeping with current guidelines.
Part 4: Prevention of Cancer Therapy–Induced Cardiotoxicity
The poor prognosis of cancer therapy–induced heart disease and the lack of a universal response to the institution of therapy argue for a preventive approach. This has to be based on the premise that the perceived benefit is greater than the perceived risk in terms of both adverse effects and reduction of the anticancer effects. Ideally, these approaches should be supported by prospective randomized trials that also define target subsets of patients at varying levels of risk.
This has been the case for dexrazoxane, the drug with the best level of evidence for the prevention of chemotherapy-induced cardiotoxicity. In a meta-analysis of 8 trials with more than 1500 patients, dexrazoxane reduced the incidence of clinical heart failure by more than 80% (relative risk, 0.18; 95% CI, 0.10-0.32; P<.0001).
These and other observations have raised enough concerns that dexrazoxane may reduce the antitumor efficacy of the primary cancer therapy. For this reason, its Food and Drug Administration– and European Medicines Agency–approved use is only for patients with metastatic breast cancer who may benefit from further anthracycline therapy after having already received 300 mg/m2.
Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.
Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging: a prospective randomized controlled study with 6-month follow-up.
Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up.
Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone.
Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction.
Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.
This is important as experimental studies have found that not all β-blockers provide cardioprotection from chemotherapy-induced cardiotoxicity. Nonselective β-blockers such as propranolol may, in fact, potentiate cardiotoxicity, likely related to inhibition of β-2 activity.
In contrast, β-blockers with proven evidence for cardioprotection in this setting include carvedilol and nebivolol whereas the effect of metoprolol appears neutral.
Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging: a prospective randomized controlled study with 6-month follow-up.
Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up.
Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.
Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging: a prospective randomized controlled study with 6-month follow-up.
Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up.
Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone.
Long-term protective effects of the angiotensin receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress and myocardial dysfunction.
In keeping with the reported benefit in the treatment of patients with chemotherapy-induced heart failure, ACE inhibitors have been the first ones tested and contended. The ACE inhibitor After Anthracycline study in survivors of pediatric cancer did not find any significant long-term benefit.
However, the qualifying enrollment criteria included a broad spectrum of cardiac abnormalities and treatment was not commenced until at least 2 years after discontinuing anthracycline therapy.
Still, a prospective randomized controlled study comparing monotherapy with enalapril or metoprolol to placebo in patients undergoing adriamycin, bleomycin, vinblastine, and dacarbazine or rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone therapy for Hodgkin or non-Hodgkin lymphoma, respectively, did not find any benefit in the prevention of clinical or subclinical cardiotoxicity.
Cardioprotective effect of metoprolol and enalapril in doxorubicin-treated lymphoma patients: a prospective, parallel-group, randomized, controlled study with 36-month follow-up.
At the other end of the spectrum, confined only to those with cTnI elevation within 3 days of initiation of high-dose chemotherapy, initiation of enalapril therapy was of remarkable benefit.
The surveillance intensity of such a protocol, however, may pose a barrier for general use, even though it underscores the merit of defining a high risk–high yield patient population.
With regard to combination therapies, the preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies (OVERCOME) trial was conducted with universal consideration of enalapril and carvedilol for all patients referred for intensive chemotherapy or stem cell transplant.
Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
The study remained positive in its primary end point of the prevention of LVEF reduction at 6 months and even outlined a benefit in terms of the combined secondary end point of death or heart failure.
Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
No interaction was observed in terms of the primary end point and cTnI or brain natriuretic peptide elevation; however, LVEF benefits remained largely confined to patients with acute leukemia.
Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies).
This observation thus supports the limitation of preventive strategies to those patients at highest presumed risk of cardiotoxicity on the basis of treatment-related and patient-related factors as outlined in the beginning (Figure 3). This is in keeping with the European Society for Medical Oncology guidelines (see Supplemental Table 3), which recommend ACE inhibitors as first-line agents; however, as outlined above and summarized in Table 2, carvedilol, nebivolol, and statins should be considered as well.
Obviously, patients already receiving these therapies should continue with them. The exception, however, as implied, is that efforts should be made to switch patients from β-blockers other than carvedilol and nebivolol to these specific agents, given their evidence-based level of benefit for the prevention of chemotherapy-induced cardiomyopathy.
Conclusion
Advances in cancer therapy and the outcome limiting effect of cardiovascular adverse effects have generated a growing need for cardio-oncology. With this, the paradigm has shifted toward early recognition and treatment of cardiotoxicity and even pre-cancer therapy cardiovascular risk assessment and prevention. The key practical steps in the cardio-oncology approach outlined in this review comprise the following:
Step 1:
Ongoing interaction between cardiologists, oncologists or hematologists, and general practitioners in a “cardio-oncology team” approach, ideally with the development of “cardio-oncology clinics” staffed by dedicated specialists. These efforts should be linked to and even start with evaluation efforts of potential cardiotoxic adverse effects of chemotherapeutic agents.
Step 2:
Clinical screening of patients with cancer for underlying or developing cardiovascular disease, followed by stratified evaluation and management based on patient presentation relative to the timing of cancer therapy, that is, before, during, or after (Figure 2).
Step 3:
Before cancer therapy, cardiotoxicity risk stratification should be pursued, which then guides further follow-up (Figure 3 and Supplemental Table 3).
Step 4:
During cancer therapy, specific surveillance algorithms have been formulated for the 2 most notorious drugs known to cause cardiotoxicity, that is, anthracycline and trastuzumab (Figures 4 and 5 and Supplemental Table 4), but may include others.
Step 5:
After cancer therapy, clinical and echocardiographic screening for cardiotoxicity depends on estimated cardiovascular risk and any cardiovascular toxicity observed during treatment (Figure 6 and Supplemental Table 5).
Step 6:
Consideration of cardiovascular medications with reported benefit to be instituted as a preventive or therapeutic measure for chemotherapy-induced cardiotoxicity as patients qualify. These include carvedilol, nebivolol, ACE inhibitors and angiotensin receptor blockers, and/or statins; additional cardiovascular treatments are required on the basis of standard of care.
Step 7:
Treatment of radiation-induced heart disease is to follow standard practice guidelines, with the recognition that exposure was to the entire heart with the potential for multilevel involvement; treatment approaches thus need to be integrative and individualized with a cautious approach to surgical interventions.
These steps aim to minimize the burden of cardiovascular morbidity and mortality in patients with cancer who are treated with cardiotoxic agents and thus to improve their clinical outcome and survivorship. They will need to be applied on an individual basis and require ongoing reevaluation as the field of cardio-oncology continues to evolve.
Acknowledgments
We are deeply indebted to Dr Thomas Gerber for the critical review of this manuscript.
Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon: an unexpectedly frequent complication.
Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease.
Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.
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