Cancer Survivorship: Cardiotoxic Therapy in the Adult Cancer Patient; Cardiac Outcomes With Recommendations for Patient Management

Cancer Survivorship: Cardiotoxic Therapy in the Adult Cancer Patient; Cardiac Outcomes With Recommendations for Patient Management Richard M. Steingart,a Nandini Yadav,a Carlos Manrique,a Joseph R. Carver,b and Jennifer Liua Many types of cancer are now curable or, if not cured, becoming a chronic illness. In 2012, it was estimated that there were more than 13,500,000 cancer survivors in the United States. Late outcomes of these survivors are increasingly related to cardiovascular disease, either as a consequence of the direct effects of cancer therapy or its adverse effects on traditional cardiac risk factors (eg, obesity, hypertension, dyslipidemia, and diabetes mellitus). This article describes the therapies that have led to advances in cancer survival and the acute and chronic cardiovascular toxicities associated with these therapies. Recommendations are made for the surveillance and management of cancer survivors. Published guidelines on the subject of cardio-oncology are reviewed in light of clinical experience caring for these patients. To supplement this cancer-related knowledge base, appropriateness criteria and guidelines for cardiac care in the general population were extrapolated to cancer survivors. The result is a series of recommendations for surveillance and management of cardiovascular disease in cancer survivors. Semin Oncol 40:690-708 & 2013 Elsevier Inc. All rights reserved.

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n 2005 the American Society of Clinical Oncology (ASCO) convened an expert panel to develop guidelines for the ongoing cardiac surveillance and care of adult and pediatric survivors of cancer. Ultimately the proposed guideline document was not issued by ASCO “in light of the lack of direct, high quality evidence on the benefits and harms of screening for cardiac late effects.” The document was subsequently published in 2007 as a clinical evidence review that summarized the then-current literature regarding late cardiac effects among cancer survivors.1 Since that report, a multitude of articles have been published that consistently show a relationship between specific cancer treatments and cardiac toxicity, yet without the emergence of universally accepted guidelines for long-term care. The need for management guidelines for survivors is magnified by a

Memorial Sloan-Kettering Cancer Center, New York, NY. Abramson Cancer Center, Philadelphia, PA. The authors have no financial disclosures or conflicts of interest to report. Address correspondence to Richard M. Steingart, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. E-mail: [email protected] 0093-7754/ - see front matter & 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2013.09.010 b

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the exponential expansion of this patient group.2–4 Based on the current evidence, the Heart Failure Association of the European Society of Cardiology provides recommendations for screening, treatment, and follow-up of cardiac disease in cancer patients.5 In addition, Cardiology-Oncology Clinical Practice Guidelines have been developed by the European Society of Medical Oncology.6,7 Both groups focus largely on minimizing cardiac toxicity during cancer treatment, with some advice regarding issues of cardiac disease in survivors. They have reinforced the current knowledge base that anthracyclines, radiation, and the newer targeted molecular agents are associated with cardiac toxicity and that the detection of potential cardiac toxicity needs to be an integral part of treatment and follow up. Continued controversy persists about cardiac toxicity definitions, incidence, detection, monitoring, and treatment of late effects in survivors of cancer. As a result, the surveillance for late cardiac effects in cancer survivors has not changed appreciably. There are multiple explanations for the lack of guidelines including: an absence of randomized clinical trial evidence that demonstrates an improvement in outcome, lack of expert consensus, a belief that cancer therapy-induced cardiac toxicity is fundamentally different from other forms of cardiac disease, concerns that discovery of cardiac toxicity will reduce

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the effectiveness of cancer care, a reluctance by professional societies to endorse care recommendations not derived from a traditional evidence-base, lack of a financial infrastructure to support systematic research in the hybrid field of cardio-oncology, and failure to demonstrate the cost-effectiveness of aggressive cardiac surveillance and treatment for providers and purchasers of health care. These are not trivial concerns. At the more granular clinic level, healthcare professionals caring for cancer survivors face daunting problems. Patients and providers are at times physically, mentally, and emotionally overwhelmed by the course of cancer, its therapy, and the multiplicity of late effects. Clinical presentations of cardiac disease in the cancer patient may be confusing. Cardiac disease occurs at a younger age and is set in the background of diminished exercise tolerance, fatigue, chronic chest pain, and dyspnea that may be related to the underlying malignancy. Appropriate care often involves the coordination of multiple specialists practicing in different institutions. This updated clinical evidence review with recommendations for surveillance and management of cancer survivors was undertaken to re-stimulate interest in guideline development. We hope to expand the dialogue on these issues beyond the highly specialized cardio-oncology community.8 This review summarizes new evidence on cardiac issues in cancer survivors in the context of a modern cardiovascular disease (CVD) classification that emphasizes the importance of risk factors for heart disease and recognizing asymptomatic disease before symptomatic cardiac dysfunction appears.9 In addition, better tools have evolved for cardiac assessment, including biomarkers and imaging technologies.10,11 Earlier detection of cardiac abnormalities with biomarkers and accurate imaging techniques may stimulate low-risk and inexpensive interventions (eg, exercise)12 that can prevent the development of symptomatic disease without significantly impeding cancer therapy. With acknowledgment that data from randomized controlled trials are lacking, there is a great deal of practice experience that should be shared, and an enlarging scientific evidence-base from observational and epidemiologic sources.8,13 There are now carefully conceived appropriateness criteria designed to reduce the variability and cost of caring for patients with heart disease, largely ischemic and hypertensive heart disease.14,15 These principles can reasonably be extrapolated to the cancer survivorship population. While the results of randomized controlled trials are eagerly awaited,16,17 formulating surveillance and management recommendations now will help to standardize, organize, and improve the current practice of cardiac care in cancer

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survivors, educate care providers, stimulate prospective research on the subject, and serve as talking points when major medical societies undertake guideline writing. This review begins with a brief description of the acute cardiac toxicities of cancer treatment followed by a detailed description of the late cardiac effects and recommendations for cardiac management. For convenience, cardiovascular surveillance and treatment recommendations are organized by the type of cancer. In the adult, the most abundant sources of information on cardiac outcomes are from survivors of breast cancer and lymphoma. Also included are sections on thoracic, germ cell, and prostate cancers, and sarcoma. Although cardiotoxic agents also are used in the treatment of gynecological tumors, space limitations precluded their inclusion. This article contains some principles derived from the childhood cancer survivorship literature but does not address childhood cancer in any detail. This subject has been well covered elsewhere.18 The literature review methodology published by the ASCO expert panel in 2007 was used to conduct a search for articles published from February 2006 through August 2012.1 Results were supplemented with hand searching of important papers published during the preparation of this article, selected reviews, and personal files. Additional articles for background information were obtained for reference. In consideration of making recommendations regarding the reasonable use of cardiac services for cancer survivors, we examined appropriate use criteria (AUC) published by the American College of Cardiology Foundation (ACCF).14,15,19,20 AUC defines patient subgroups where the available medical evidence supplemented by expert opinion make it reasonable to perform testing in a particular clinical situation.14 For example, the most common appropriate indications for echocardiography include initial evaluation of symptoms potentially caused by suspected cardiac disease, prior testing concerning for heart disease, evaluation for valvular disease, and evaluation of a heart failure indication. All of these indications are relevant for a cancer survivorship population. Furthermore, the risk standards recommended by the ACCF panels were adapted to this purpose. For example, for coronary artery disease (CAD) hard events (myocardial infarction [MI] or CAD death) based on Adult Treatment Panel III (ATP III) global risk assessment, a greater than 10% ten-year incidence of a coronary event is defined as intermediate or high risk for older men, as is a greater than 6% ten-year incidence of a coronary event for women and younger men (Table 1). Table 2 contains pretest probability of CAD categories derived from patient age, gender, and

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Table 1. Classification of the Risk for Hard Cardiac Events (MI or CAD death) in Asymptomatic patients (Framingham Risk Score),132 and for the Presence of Obstructive CAD ●

Thresholds for further tests based on ACCF AUC intermediate- or high-risk criteria for hard cardiac events in asymptomatic patients ○ 410% ten-year incidence of a hard cardiac event for older men ○ 46% ten-year incidence of a hard cardiac event for women and younger men ○ CAD equivalents such as diabetes mellitus, peripheral arterial disease also can define high risk

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Thresholds for further testing based on pretest probability for CAD by age, gender, and symptoms ○ Intermediate pretest probability: Between 10% and 90% pretest probability of CAD ○ High pretest probability: 490% pretest probability of CAD

Abbreviations: MI, myocardial infarction; CAD, coronary artery disease; ACCF, American College of Cardiology Foundation; AUC, appropriate use criteria.

symptoms, useful when considering testing symptomatic patients for CAD beyond the basic clinical evaluation. If the published literature for a cancer survivor suggests an intermediate or higher level of risk, further testing to evaluate for the presence and severity of CAD would be considered appropriate. Similarly, ACCF AUC criteria for pursuing a cardiovascular evaluation for heart failure and valvular heart disease were applied to cancer survivors. In the sections that follow, the justification for applying ACCF AUC criteria to cancer patients is presented.14,15,21 We also include relevant recommendations for cancer survivor management from the European Society for Medical Oncology,7 the Heart Failure Association of the European Society of Cardiology,5 the National Comprehensive Cancer Network (NCCN) Treatment Guidelines,22 the Children’s Oncology Group (COG) Long-Term Follow-Up Guidelines,23 the ACCF/American Heart Association (AHA) Perioperative Evaluation Guidelines,24,25 and the ACCF/AHA Heart Failure Guidelines section on patients with cancer.9

ACUTE CARDIOVASCULAR TOXICITIES OF CANCER THERAPIES A full description of the acute toxicities of cancer therapies has recently been well summarized elsewhere.26–28 Below is a summary of the acute cardiovascular toxicities of cancer therapies relevant to long-term cancer survivors, emphasizing those agents widely employed in the survivorship population. This is an extraordinarily complicated subject because of the wide ranging effects of even so-called targeted cancer therapies (eg, multi-kinase inhibitors), the interactions with other cancer therapies, the effects of cancer on the cardiovascular, immune, inflammatory, and clotting systems, and of course the patient milieu (eg age, prior and ongoing coexisting disease) into which these therapies are delivered.

Anthracyclines Among the chemotherapeutic agents, anthracyclines, a product of Streptomyces, are the most impor-

Table 2. Pretest Probability of Coronary Artery Disease by Age, Gender, and Symptoms14 Age (yr)

Gender

Typical/Definite Angina Pectoris

Atypical/Probable Angina Pectoris

Non-anginal Chest Pain

o39

Men Women Men Women Men Women Men Women

Intermediate Intermediate High Intermediate High Intermediate High High

Intermediate Very low Intermediate Low Intermediate Intermediate Intermediate Intermediate

Low Very low Intermediate Very low Intermediate Low Intermediate Intermediate

40–49 50–59 460

Asymptomatic Very Very Low Very Low Very Low Low

low low low low

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tant to understand for the proper management of cardiac effects in survivors. Their anti-tumor actions include inhibition of topoisomerase II, an enzyme that regulates the uncoiling of DNA strands and in doing so induces breaks in DNA and ultimately cell death. Anthracyclines also lead to the creation of toxic reactive oxygen species (ROS) and intercalate into DNA preventing macromolecule synthesis. They increase cardiac oxidative stress-associated apoptosis. Myocyte mitochondria are particularly vulnerable to ROS. Genetic polymorphisms affecting ROS generation and degradation correlate with risk for anthracycline related cardiotoxicity. Polymorphisms in anthracycline metabolism also are associated with cardiac toxicity, and some research suggests that toxic anthracycline metabolites (eg, doxorubicinol) can be detected in cardiomyocytes years after administration.28 Recently, in an animal model, a strong linkage has been discovered between cardiotoxicity and topoisomerase IIβ activity in the heart.29 Clinical presentations of toxicity during or after initial infusions (“acute”) can include arrhythmias, heart block, heart failure, pericarditis-myocarditis syndrome, and cardiac ischemia.30 Toxicity occurring beyond the early weeks of treatment (“subacute”) is almost universally limited to myocardial dysfunction and its sequelae. Pre-existing CVD, hypertension, mediastinal radiotherapy (RT), and the use of other cardiotoxic non-anthracycline agents (trastuzumab, taxanes) can increase the risk of subacute and late (41 year) cardiotoxicity of anthracyclines. The elderly and children are at particular risk for development of anthracyclineinduced cardiomyopathy.31 Although there is an accepted direct relationship of cardiotoxicity with cumulative anthracycline dose, cardiotoxicity has been reported in patients who have received total doses o100 mg/m2 of doxorubicin and there are patients who have received doses 4550 mg/m2 who never develop cardiotoxicity; there is neither a uniformly “safe” dose nor a “toxic” dose of any of the anthracyclines. That said, acute cardiotoxicity is uncommon in women treated for breast cancer with standard cumulative dosing at 240 mg/m2. Risk is not increased with dose dense administration.32 After a cumulative doxorubicin dose of 240 mg/m2, asymptomatic decline in left ventricular ejection fraction (LVEF) during therapy (grade 2 toxicity: EF below lower limit of normal or declining of EF Z20% from baseline) was detected by prospective monitoring using either echocardiography or multi-gated acquisition scan (MUGA) in 6.6% of women.33 The incidence of overt heart failure was 1%–2% after anthracycline therapy in a trial of more than 3,000 patients with primary breast cancer.34 Recent studies demonstrate that cardiac biomarkers and twodimensional echo speckle strain imaging detects

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subclinical LV systolic abnormalities during anthracycline therapy even at low doses before changes occur in heart function measured by conventional methods.31,35,36

5-Fluorouracil The most severe acute cardiac complications of 5-fluorouracil (5FU) are heart failure, arrhythmia, and myocardial ischemia. Typically, patients with 5FU cardiotoxicity present with chest discomfort with or without electrocardiographic changes compatible with myocardial ischemia. In addition, impairment of cardiac contractility, elevation of N terminal pro brain naturetic peptide (NTproBNP)37 and rhythm disturbances have been described.38 These complications are reversible in the majority of cases after cessation of 5FU. Estimates of their incidence in large studies are reported between 1.2% and 1.6% of patients, but there is considerable variability in the published reports.26 A number of mechanisms have been proposed to explain 5FU cardiotoxicity, including coronary spasm, injury to the vascular endothelium, endothelin-1 release, and/or reduced activity of the cardiac enzymes superoxide dismutase and glutathione peroxidase.39,40 5FU cardiac toxicity is more prevalent in patients with a cardiac history in comparison to patients with no cardiac history (4.5% v 1.1%) and in patients exposed to mediastinal RT.38

Vascular Endothelial Growth Factor Signaling Pathway Inhibitors The term VSPI (vascular endothelial growth factor [VEGF] signaling pathway inhibitors) is used to describe agents that, within their typical therapeutic range, block the downstream signaling of the soluble ligand, VEGF, and its primary cognate receptor on endothelial cells, VEGFR2. Anti-angiogenic therapies have been associated with important acute systemic cardiovascular toxicities during or soon after their administration such as hypertension, LV systolic dysfunction, heart failure, myocardial ischemia, and MI.41 QT interval prolongation has also been reported. Agents currently approved by the US Food and Drug Administration (FDA) include bevacizumab (an antibody that blocks VEGF receptors on the cell surface); sunitinib, sorafenib, pazopanib, and vandetanib (small molecule inhibitors that block the kinase activity of VEGFR2); and several other kinases inhibitors that have effects on cellular function and survival in a variety of tissues, including the myocardium.41 Hypertension is a class effect of all these agents.42 Acute LV dysfunction has been best documented with the use of sunitinib.43 Guidelines on the use of these agents call for careful monitoring and control of blood pressure during therapy, and a sensitivity to the possibility of heart failure and acute

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ischemic syndromes during and after therapy particularly in patients with cardiovascular risk factors or established CVD.41,42

Trastuzumab The human epidermal growth factor receptor 2 (HER2) oncogene encodes a transmembrane tyrosine kinase receptor that promotes cell proliferation and survival. HER2 overexpression/amplification is seen in 20%–30% of breast cancers and is associated with an aggressive cancer phenotype. To date, trastuzumab is the most commonly used anti-HER2 therapy and thus the most studied. Trastuzumab, a monoclonal antibody to HER2, has consistently demonstrated a 40%–50% reduction in the recurrence of breast cancer and a 30% reduction in the risk of death from breast cancer.44 Anti-HER2 therapy is currently the standard of care for the treatment of HER2-positive breast cancer. However, its ability to potentiate anthracycline-induced cardiotoxicity is well recognized. In a recent Cochrane review, breast cancer mortality was reduced by one third, but the risk of cardiac toxicity was five times higher for women receiving trastuzumab than women receiving standard therapy.44 If 1,000 women were given standard chemotherapy (with no trastuzumab) then about 900 would survive and five would have experienced heart toxicities. If 1,000 women were treated with standard chemotherapy and trastuzumab for 1 year, 33 more women will have their lives prolonged, 95 more women will not experience cancer return, and 21 more than the chemotherapy-alone group would have cardiac toxicity due to the drug.44 When trastuzumab was used concomitantly with doxorubicin, the overall rate of cardiotoxicity was 27%, with severe heart failure developing in 16% of the patients.44 When given sequentially in the adjuvant trials, the cardiotoxicity has been substantially less. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, the incidence of severe heart failure was 4.3% and asymptomatic decrease in LVEF that required discontinuation of the trastuzumab occurred in 14% of patients.45 In other large randomized studies, the incidence of overt heart failure during trastuzumab therapy in the adjuvant setting is o4%.5,46 In contrast to anthracycline-induced cardiac toxicity, trastuzumabassociated cardiac toxicity does not appear to be dose-related, is frequently reversible, and is often manifested by asymptomatic LVEF decline.47 Endomyocardial biopsies performed in patients with trastuzumab-associated cardiac toxicity do not reveal the ultrastructural changes including loss of myofibrils and vacuolization of cytoplasm typically observed in biopsy specimens from patients with

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anthracycline-induced cardiomyopathy. However, there are concerns regarding the completeness of recovery of trastuzamab-related cardiac toxicity, and ultimately, concerns about the risk for developing clinically significant LV dysfunction in survivors.48

Tyrosine Kinase Inhibitors Through reversible phosphorylation, kinases regulate multiple signaling pathways that control metabolism, cell cycle progression, cell proliferation and cell death, differentiation and survival.49 There are currently nine FDA-approved small molecule adenosine triphosphate (ATP)-competitive inhibitors that target a range of kinases and three inhibitors of mammalian target of rapamycin (mTOR) working through an inhibitory protein–protein interaction. In general the majority of the approved agents appear to be well-tolerated from a cardiac safety perspective. However, with few exceptions the true risk of cardiotoxicity during treatment is not known because thorough clinical assessments of LV function have not been done before or after drug approval. The only approved kinase inhibitor that is clearly associated with clinical cardiotoxicity is sunitinib where in one study 18% of patients treated for gastrointestinal stromal tumors developed either heart failure or a decline in LVEF of Z15 points.43 The only other large study of cardiotoxicity with a small molecule kinase inhibitor was with lapatinib where assessment of cardiotoxicity is problematic as it is used with trastuzumab, a known cardiotoxic agent.50

Cisplatin/Carboplatin Acute cardiovascular toxicities have infrequently been reported with cisplatin, and almost never with carboplatin.26 Although clinically manifest acute cardiac or vascular toxicity is relatively rare, cisplatin has acute toxic effects on the endothelium,51 the long-term consequences of which may be responsible for the high rates of premature vascular disease years after administration. Arterial and venous thrombosis are noted in case reports of cisplatin, as are arrhythmogenic electrolyte disturbances or fluid overload, in turn related to renal toxicity and or the large volume of fluid typically administered with this agent.

Mediastinal Radiotherapy Radiation pericarditis may be one of the earliest cardiac complications of mediastinal RT and was historically the most common cardiovascular manifestation of radiation, typically manifesting a few weeks after treatment. Modern methods of radiation delivery at lower doses (including equally weighted anterior and posterior beams) with use

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of shielding methods (like subcarinal blocking) have decreased the incidence from 20% to 2.5%, with the incidence being proportional to dose and treatment volume.52,53 Pericardial fibrosis occurs due to microcirculatory damage causing ischemia and formation of fibrinous exudates. Acute pericarditis usually occurs during the early phases of mediastinal RT. Clinically it is similar to other types of pericarditis with pleuritic chest pain, friction rub, and diffuse ST wave changes on electrocardiogram. This is usually due to the necrosis and inflammation of the mass beside the pericardium rather than damage to the pericardium itself. It is usually benign and can be treated with antiinflammatory drugs. Radiation should not be stopped, but the dose can be adjusted. Delayed pericarditis occurs a few months to years after completion of radiation. Most cases resolve spontaneously, but a few cases progress to constrictive pericarditis.54 Radiotherapy including the mediastinum is associated with the development of coronary disease. Proposed mechanisms are: capillary network damage leading to ischemia, epicardial artery damage similar to atherosclerosis, and a sustained inflammatory response through activation of nuclear factor (NF)-κB.55 Radiation results in cardiac valvular retraction causing at first regurgitation and eventual calcification with stenosis.54 Left-sided valves are more commonly affected; the aortic valve is most commonly involved due to its anterior location followed by the mitral valve. Right-sided valvular disease is less common. The valvular lesions worsen over time as the fibrotic process progresses and may not become clinically evident until a decade or two after treatment. Radiation myocarditis is seen with highdose radiation. Pathology reveals fibrosis without inflammation. Abnormalities of systolic and diastolic function can be seen acutely. Conduction and or rhythm abnormalities can be seen immediately and late after RT and can include heart block and persistent tachycardia. As with coronary disease, late valve and conduction system damage from RT are important survivorship concerns. All of these cardiac toxicities are proportional to the radiation dose delivered and the exposed cardiac volume. Contemporary RT techniques have decreased both dose and volume delivered compared to treatment in the past that generated most of the existing literature and probably overestimates the cardiac risks of current treatment.

Hematopoietic Cell Transplantation Hematopoietic cell transplantation (HCT) is an important therapeutic modality for the treatment of

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disorders including multiple myeloma, Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute myeloid leukemia, immunoglobulin light chain (AL) amyloidosis, and Waldenstro ¨m macroglobulinemia. The acute and long-term complications seen in patients after HCT depend on the source of the stem cells, the hematopoietic progenitor cell donor, prior exposure to chemotherapy including anthracyclines, and preparative regimens using high-dose chemotherapy and total body irradiation.56 Respiratory failure, infection, secondary malignancies, and chronic graft-versus-host disease in allogeneic HCT survivors are the most common cause of non-relapse morbidity and mortality after HCT.57–59 Cardiac risk factors and CVD are being seen more frequently in survivors due to improvement in transplant outcomes, with a long-term threefold risk of CVD complications compared with an age-matched population.60

CARDIOVASCULAR ISSUES BY CANCER TYPE Breast Cancer Survivors Currently, there are an estimated 2.6 million breast cancer survivors living in the United States. Most women now presenting with early-stage breast cancer can be expected to be cured of their disease. Many of these women receive multi-agent treatment that can potentially cause acute and late cardiac abnormalities and will be living long enough to experience clinically relevant cardiac toxicity from their treatment. Breast cancer survivors have an increased risk of CVD, which may adversely impact survival more than breast cancer itself, especially in women 465 years of age.61–63 LV dysfunction and myocardial ischemia are the two most clinically relevant late cardiac outcomes in breast cancer survivors.

LV Dysfunction and Heart Failure Recent evidence indicates that no safe threshold dose exists for late anthracycline-induced cardiotoxicity regardless of which compound is used, particularly when combined with other agents. While few women experience acute cardiotoxicity (heart failure or reduced LVEF) during anthracycline treatment, changes in LV function may not be clinically evident until many years later. There have been several studies demonstrating lower LVEF in women treated with an anthracycline-based regimen compared to women treated with a non–anthracyclinebased regimen 5 to 10 years after therapy.64,65 A study using claims data from the Surveillance Epidemiology and End Results (SEER) Medicare database found that among women aged 66–70 treated for breast cancer from 1992–2002, there was an

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almost 10% absolute difference in the rate of overt heart failure by 10 years in anthracycline-treated patients compared with those who did not receive any chemotherapy (38.4% v 29%).66 Although the abnormalities in LVEF generally improve spontaneously or with treatment in women with acute trastuzumab cardiotoxicity, a clinically significant proportion of women who develop cardiotoxicity on anti-HER2 therapy appear to have sustained decrements in LVEF following completion of therapy.48 Furthermore, a recent analysis of the SEER Medicare database found that the addition of trastuzumab to anthracycline chemotherapy increased the long-term risk of heart failure or cardiomyopathy by 2.4-fold compared to no adjuvant therapy more than 3 years after treatment.13

Coronary Ischemia and Myocardial Infarction Older methods of left sided breast RT, administered prior to 2001, are associated with an increased risk of CAD.55 In a retrospective cohort study of female Medicare recipients diagnosed from 1992– 2000 elderly breast cancer patients with pre-existing MI and congestive heart failure were less likely to receive radiation than patients without those diagnoses. Radiation was not associated with MI events during the follow-up period. Furthermore, among patients who underwent RT after 1992, women with left-sided tumors were not more likely than those with right-sided tumors to experience MI. Although the presence of cardiac risk factors increased the likelihood of an MI after breast cancer therapy, these factors did not increase the likelihood of RT-induced cardiac toxicity. Radiation was shown to exacerbate chemotherapy induced heart failure, but there was no association between RT, chemotherapy, and ischemic events. 67 Jagsi et al performed a similar analysis of cardiac events in 828 patients with early breast cancer (all ages) treated with breast-conserving surgery and radiation. With a median follow-up of 6.8 years, 1.4% of patients had at least one MI and 2.4% of patients had at least one MI or CAD requiring intervention. The median age for first cardiac event was 75.9 years and the median interval from radiation to first cardiac event was 3.7 years. Multivariate analysis showed age, diabetes, active smoking, and laterality of RT to be significantly associated with risk of MI. Age and active smoking were predictors of MI or CAD requiring intervention.68 Stokes et al analyzed whether regional node radiation added to cardiac and cerebrovascular events in 4,929 women treated with breast/chest wall radiation for early-stage breast cancer and monitored for a median of 11.7 years. The incidence of cardiac–cerebrovascular events was 5% in those who had locoregional

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radiation in addition to breast/chest wall radiation versus 3.5% for those with breast/chest wall RT alone.69 An increased risk of late stress test abnormalities in the distribution of the left anterior descending coronary artery has been reported in breast cancer patients receiving left-sided chest irradiation.55,70 The clinical significance of this finding is unknown. Contemporary RT techniques minimize the heart volume in the field by using breath-holding techniques and prone positioning, with a resultant substantial reduction in radiation exposure to the left ventricle and the coronary arteries, and thus a lower likelihood of inducing myocardial or vascular damage. Several studies have shown no association between RT and increased clinical cardiovascular risk in women with breast cancer who received RT after the early to mid 1990s regardless of tumor laterality, patient’s age or baseline cardiac risk factors after more than 10 years of follow-up.67,71,72 However, in a recently published analysis of a large European database, exposure of the heart to ionizing radiation during RT for breast cancer was shown to increase the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from RT than other women.73

Breast Cancer Survivors: Recommendations for CVD Surveillance and Prevention CVD and breast cancer share several common risk factors such as obesity and physical inactivity. Most women will have at least one cardiovascular risk factor at the time of their breast cancer diagnosis74 and their increased risk for CVD is compounded by the direct cardiotoxic effects of the cancer treatment. In addition, lifestyle changes related to the cancer or cancer treatment such as fatigue and physical inactivity may further adversely affect the cardiovascular system and increase the long-term risk for cardiovascular morbidity and mortality, a phenomenon Jones and colleagues described as “the multiple-hit hypothesis.”75 Thus, a preventive heart health strategy should start prior to the initiation of treatment.76,77 During treatment, the patient’s symptomatic status and physical examination should be closely monitored for evidence of cardiotoxicity and cardiac risk estimated (Table 1). The ACCF AUC considers serial evaluations of LVEF appropriate during therapy in patients receiving cardiotoxic agents.14 The NCCN guidelines call for monitoring of LV function at baseline and at 3, 6, and 9 months of trastuzumab therapy.22 The European Society of Medical Oncology (ESMO) recommendations are consistent with

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this, and additionally call for monitoring of cardiac function at 12 and 18 months after the initiation of anthracyclines and or trastuzumab, with increased vigilance for patients over the age of 59. Long-term monitoring of LV function is suggested for patients treated with 4240 mg/m2 of doxorubicin. The ESMO recommendations call for patients with metastatic disease to be monitored at baseline and then infrequently.7 However, it should be recognized that the clinical course of metastatic breast cancer can vary greatly such that this recommendation should be individualized according to each patient’s circumstance. Echocardiography is now the method of choice for monitoring cardiac structure and function due to its relatively low cost, the absence of ionizing radiation, and the extensive information it can provide beyond calculation of the LVEF including valvular function, chamber size, diastolic properties, pulmonary artery pressure, and pericardial disease. Nonspecific complaints, particularly of new onset, such as fatigue, dyspnea, edema, palpitations should raise the possibility of CHF in women treated with cardiotoxic breast cancer therapy and consideration should be given to the appropriate use of echocardiography and biomarkers to elucidate the cause of these symptoms14 (Table 3). Newer imaging modalities such as cardiac MRI and two-dimensional echo strain imaging along with cardiac biomarkers may be useful for the surveillance of cardiotoxicity during and post-treatment even among asymptomatic patients, but further investigation in larger populations is needed for validation.78 These tools are certainly helpful to clarify the cause of symptoms. Initial evaluation of hypertension, with or without symptoms, is considered an appropriate indication for echocardiography.14 A cardiovascular consultation by a physician familiar with cardiac disease in the cancer patient should be considered

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when the cardiac diagnosis is elusive or signs and symptoms prove resistant to initial intervention. For patients with known cardiomyopathy or heart failure referral to a cardiologist and follow up exams when clinical signs or symptoms suggest a change in status, or to monitor heart failure therapy may be appropriate. The value of routine cardiac imaging surveillance yearly or less frequently in the presence of known cardiomyopathy is considered uncertain, but not inappropriate.14 In women with known LV dysfunction following anthracycline-based chemotherapy with or without trastuzumab, standard drug therapies for heart failure have been shown to improve symptoms and LV function, particularly when cardiac dysfunction is detected during or early after treatment.79 That is, with earlier detection, anthracycline-related cardiotoxicity can be successfully managed.80 Even in advanced anthracycline related heart failure, therapeutic interventions have proven effectiveness. Rickard et al81 reported that select patients with anthracycline related cardiomyopathy demonstrated significant improvements in EF and reverse ventricular modeling with cardiac resynchronization therapy similar to patients with non ischemic cardiomyopathy. A particularly difficult issue is how best to manage New York Heart Association (NYHA) clinical class I patients whose LVEF has fallen within the normal range or just to or below the lower limit of normal during or after treatment with cardiotoxic therapy. Some recommend treatment with angiotensinconverting enzyme inhibitors (ACEI) and/or beta blockers,9 while a case can be made for expectant observation.82 A normal BNP level, normal LVEF response to exercise, and/or a normal longitudinal myocardial strain measured by echocardiography may help reinforce the decision for watchful waiting. Watchful waiting should include educating the

Table 3. When to Assess LV Function in the Cancer Patient14 ● ●

●

● ●

Baseline and serial evaluations of LVEF during therapy in patients receiving cardiotoxic agents. Evaluation of LV function 12 and 18 months after the initiation of anthracyclines and or trastuzumab, with increased vigilance for patients over the age of 59. Patient with nonspecific complaints such as fatigue, dyspnea, edema, palpitations should raise the possibility of heart failure during cardiotoxic therapy, particularly if of new onset. Consider biomarkers. Patients with hypertension. Patients who have received chest radiation 420 Gy, total body irradiation, combined chemoradiation. See COG guidelines for detailed recommendations for assessment of LV function and valvular disease following cancer therapy in children and young adults. These can reasonably be applied to the older adult as well.

Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; COG, Children’s Oncology Group; EF, ejection fraction; LV, left ventricular.

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patient about the signs and symptoms of heart failure and urging early reporting. If cardiotoxic therapy is ongoing, assessment of LV function before each subsequent dose of the agent(s) is appropriate.14 When cardiotoxic therapy is complete, assessing LV function once or twice per year for several years following treatment could be considered appropriate.14 Once stability has been documented over several years, it is probably reasonable to further space out the measurement of LV function to every 3–5 years. Of course, continued vigilance regarding signs and symptoms of heart disease is indicated. After therapy has been initiated for symptomatic or asymptomatic LV dysfunction related to cancer treatment, the optimal duration of therapy is unknown. If LV function has normalized, cancer treatment is complete, and there are no other indications for cardiac therapy, discontinuing heart failure drugs with careful follow up is a reasonable approach. This clinical conundrum could be informed by a randomized controlled trial. With regard to an appropriate search for ischemic heart disease, particularly among women with cardiac risk factors and/or a history for left-sided chest radiation therapy administered prior to 2001, a careful chest pain/discomfort history should be obtained. If age, symptoms, and risk factors suggest an intermediate or high likelihood for coronary disease (Table 1), stress testing for diagnostic and prognostic purposes should be considered as appropriate.15 Even among asymptomatic women, if the global CAD risk assessment using the Framingham score suggests more than a low likelihood for a coronary event in the ensuing 10 years, further cardiac testing could also be viewed as appropriate (Table 1). Shapiro et al83 studied the role of presurgical cardiac evaluation in 83 women with breast cancer who had received o240 mg/m2 of doxorubicin as part of their neoadjuvant protocol within a year prior to breast surgery. All patients had a negative cardiac history, were asymptomatic and had a normal echocardiogram prior to chemotherapy. They reported no anesthesia related complications intra- or postoperatively.83 The ACC/AHA guidelines do not recommend preoperative stress testing in patients without active cardiac disease undergoing low risk (breast surgery) procedures.24,25

Testicular Cancer Survivors The risk of CVD is increased in survivors of testicular cancer, and CVD occurs at a younger age than in the general population.84 The reported incidence of CAD in survivors of testicular cancer ranges from 5.6% to 6.7% with relative risks of 1.35 to as high as 7.1.85 Potential mechanisms for

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treatment-induced CVD include direct vascular damage of the therapy and indirect effects through gradual development of CVD risk factors, including hypertension, hyperlipidemia, and the metabolic syndrome, all of which are more common in testicular cancer survivors than controls.1 Administration of testosterone replacement to hypogonadal patients, particularly those with the metabolic syndrome, has been suggested. Discovery of genetic polymorphisms in the androgen receptor gene, such as leptin receptor gene, 9p21 (for CAD), or genes increasing the risks of diabetes and dyslipidemia, may improve prediction of which patients will develop CAD after cancer treatment.85 The limited data available on the natural history of atherosclerotic CVD in testicular cancer survivors support the use of accepted guidelines for primary heart disease prevention in these patients.51 Patients undergoing treatment should be made aware of their future risk for CVD and encouraged to establish care with a physician familiar with their increased likelihood of developing CVD. During routine annual examinations, particular attention should be given to symptoms and signs that suggest the presence of CAD. If the history suggests an intermediate or high likelihood for CAD, stress testing is considered appropriate14,15 (Table 1). The patient’s prior exposure to vascular toxic chemotherapy weighs in favor of further evaluation when there is doubt about appropriateness using the above criteria. For asymptomatic patients with high Framingham risk scores, even after a normal initial stress test, follow-up examination after 2 or more years is considered appropriate by ACCF AUC.15 Patients should be given recommendations for adopting a hearthealthy diet and exercise, achieve a target body mass index of o25, and advised to stop smoking. They should be counseled regarding signs and symptoms that could suggest an acute ischemic syndrome and how to respond.

Prostate Cancer Survivors In a SEER Medicare study, subjects receiving androgen-deprivation therapy (ADT) had 1.2 times the risk of cardiovascular morbidity as those not receiving such therapy, after controlling for age, stage, grade, race, comorbidity score, pretreatment cardiac disease, treatment type, and measures of socioeconomic status.86 Several mechanisms may explain the increase in risk for cardiovascular morbidity in men rendered hypogonadal as a result of ADT. Aside from testosterone’s potential direct dilatory effects on vascular walls, low serum testosterone has been associated with a significant decrease in total cholesterol and low-density lipoprotein, and a decrease in serum high-density lipoprotein. Higher

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serum testosterone levels are associated with lower levels of visceral adiposity. Hypogonadism has been associated with hyperinsulinemia and a prothrombotic state. A prothrombotic effect was also associated with diethylstilbestrol treatment (another hormonal therapy for advanced prostate cancer) perhaps due to an effect on the coagulation cascade. For men being treated with ADT for metastatic disease, physicians should focus on interventions that may mitigate cardiovascular risks. Since the risk was highest during the first 12 months of ADT, counseling at the time of the initiation of therapy will likely achieve maximum benefit.86 Recommendations regarding the evaluation for ischemic heart disease outlined above apply, with the understanding that prostate cancer is often an indolent disease in older men (Table 1).

Intrathoracic Malignancies Intrathoracic malignancies including lung and esophageal cancer have a lower 5-year survival rate compared with breast cancer and the other malignancies covered in this review. Overall esophageal cancer 5-year survival is 17% (37% for localized malignancy and 3% for distant disease) and 16% for lung cancer (52% for localized malignancy and 4% for distant disease).4 Multi-modality therapy (chemotherapy and radiation) is common in the treatment for these malignancies. The 5- and 10-year incidences of radiation induced cardiac toxicity are estimated at 10% and 30%, respectively.1 However, due to the low rate of long-term survival in these patients, making recommendations for the evaluation of late effects from these therapies is challenging. Nevertheless, with improvements in chemotherapeutic strategies and new radiation techniques, further improvement of survival can be anticipated.87

Lung Cancer Lung cancer is one the most common malignancies in the world, and is the leading cause of cancer death in men and women.4 More than 90% of all lung cancers are classified as either non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). Therapeutic recommendations vary by cancer type. While currently applied treatments for lung cancer have shown survival benefits, the toxic effects associated with chemoradiation could potentially affect the quality of life of patients after therapy.41 The conditions reported include cardiomyopathy with or without overt heart failure, endothelial dysfunction and high incidence of CAD, and conduction disorders, as well as pericardial and valvular diseases.1,88

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Platinum-based regimens including cisplatin or carboplatin in combination with etoposide or other drugs are common chemotherapeutic agents used for this type of tumor.22 Platinum-based protocols used for other tumors have been associated with chronic endothelial damage, obesity, hypertension, and lipid abnormalities which increase the risk of premature atherosclerosis, both coronary artery and peripheral vascular disease, in survivors of other cancers.89 Hardy et al investigated the risk for developing cardiovascular complications in 34,209 patients older than 65 years with NSCLC selected from the SEER data base.90 Of these, 31.2% received no chemotherapy or radiation, 68.2% received chemotherapy and/or radiation as part of treatment. Advanced age, particularly in the presence of multiple cardiovascular risk factors, was associated with complications from ischemic heart disease. Patients receiving chemotherapy had a significantly increased risk for ischemic heart disease, cardiac dysfunction, and heart failure. Patients who were treated with radiation (without chemotherapy) also had an increased risk for cardiac dysfunction, in particular when radiation was administered to the left lung compared with the right lung. However, the chemoradiation group had the highest risk for cardiac dysfunction compared to the chemotherapy-only and radiation-only treatment groups. They also had a higher risk for developing conduction disorders and heart failure. Pericardial damage has been described as the most frequent adverse cardiac effect of thoracic radiation, but all cardiac structures are at risk.1,53,91 In another study, an increased incidence of new onset or aggravation of supraventricular tachycardia, bradycardia, pericarditis, pericardial effusion, congestive heart failure, and angina was seen with radiation.92 Atrial fibrillation is a common early complication of surgical resection of lung cancer with a significant impact on the hospital course. Further, in a multivariable analysis among 5-year survivors, postoperative atrial fibrillation was the strongest independent predictor of reduced long-term survival.93 The precise incidence of radiation induced atherosclerosis is difficult to establish in the lung and esophageal cancer population because of the high prevalence of “native” CAD in this group. Although reports of acute ischemic events following and attributable to chemoradiation are uncommon, radionuclide stress perfusion defects have been reported following radiation for thoracic tumors. Such defects were not predictive of future cardiac complications.92 Chemoradiation for lung cancer also has been associated with LV dysfunction. There are conflicting reports regarding the role of cardiac biomarkers during treatment for intra-thoracic

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malignancies. Nellessen et al studied 23 patients with lung or breast cancer and found relatively subtle increases in cardiac biomarkers including Troponin I and BNP during therapy, raising the possibility that they could identify subgroups of patients at potential risk for cardiac abnormalities secondary to cancer therapy.94 Other groups have not shown significant variation in biomarkers suggestive of cardiac damage during contemporary radiation and/or non-anthracycline chemotherapy.95,96

Esophageal Cancer Surgery has been the therapeutic approach of choice for patients with localized esophageal malignancies. However, data from recent studies support the use of chemoradiation as neoadjuvant or adjuvant therapy and in nonoperative therapeutic strategies with improvement in 5-year survival. Importantly, though, chemoradiation is associated with a higher incidence of treatment related toxicity.97–99 Cisplatin, 5FU, and taxane-based regimens among others, along with new radiation techniques are commonly used in locally advanced unresectable and metastatic esophageal cancer. In a retrospective study Ishikura et al87 evaluated long-term toxicity in 139 patients with squamous cell cancer of the thoracic esophagus after chemoradiation that included cisplatin, 5FU, and concurrent RT (60 Gy). They reported a median survival time of 21 months and 5-year survival rate of 29% with no acute cardiotoxic events. However, late toxicity included pericarditis in 16 patients (median time of onset, 15–17 months), grade 4 heart failure in 2 patients (23 and 35 months after therapy, respectively), and MI in two patients at 30 and 40 months after therapy. Mukherjee et al reported a significant reduction in LVEF of approximately 10% in 12 of 15 patients following chemoradiation for mid and lower esophageal carcinoma without evidence of acute coronary events. Patients received a total dose of 45–50 Gy in 25 fractions and chemotherapy included cisplatin and 5FU.100 Hatakenaka et al101 reported acute cardiac dysfunction using sensitive imaging techniques after therapy for mid and lower thoracic malignancies. Patients received cisplatin- and 5FU-based chemotherapy associated with low and high doses of radiation (40–41.4 Gy and 55.4–71 Gy, respectively). Early systolic and diastolic LV function impairment were detected, and were more significant after high-dose chemoradiation.101 As reported in patients treated for lung cancer, the limited number of patients with distal esophageal cancers who underwent RT had a higher incidence of perfusion defects by myocardial perfusion imaging.92,102,103 However, there was no

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evidence presented that these defects are predictive of future, clinically important events.

Thoracic Malignancies: Recommendations for CVD Surveillance and Prevention Because of the overlap of risk factors for thoracic malignancies and CVD, and the cardiotoxic potential of chemoradiation, cancer survivors are at higher risk for cardiac events.104 Diagnosis is problematic due to the overlap in clinical presentation between thoracic malignancies and CVD (eg, chest pain, shortness of breath, arrhythmias or other electrocardiogram abnormalities). Cardiac imaging and biomarkers have an essential role in the investigation of symptoms like chest pain, dyspnea, and cough.95 Clinical decision-making is complicated in this setting because the patient’s life expectancy may be limited, they may be frail from their cancer and its treatment, and the treatments for cancer and CVD may work at cross purposes (eg, chemotherapyrelated thrombocytopenia and antiplatelet therapy for CVD). For those with a relatively favorable cancer prognosis, the general principles for the management of cardiac disease in cancer survivors outlined above should apply (Tables 1 and 3).

Lymphoma Survivors HL, NHL, and leukemia account for 7.7% of the estimated new cancer cases in the US, and for 7.5% of the cancer related deaths in the US per year.4 In the latest US cancer statistics report, HL represents more than 10% of lymphomas diagnosed annually, accounting for more than 9,000 new cases and approximately 1,190 deaths in United States per year.4 Children, young adults (around 20 years old), and older patients (465 years) are the most commonly affected, with a 5-year relative survival rate of 86%. Annually, 70,130 new cases of NHL are diagnosed in the United States and about 18,940 deaths are reported annually. Middle-aged and older patients are most often affected with an estimated 5year survival rate of 70%, depending on histological subtype and disease stage. Standard therapeutic approaches for hematologic malignancies include multi-agent chemotherapy regimens with or without radiation, and HCT in selected patients. Long-term complications related to therapy of hematologic malignancies include second malignancies, CVD, endocrine dysfunction, and neurologic and psychiatric complications. Cardiac toxicities among survivors include premature and accelerated atherosclerosis of the coronary arteries and other vessels, myocarditis, systolic and diastolic dysfunction, valvular damage, conduction abnormalities, autonomic dysfunction including baroreflex failure, and pericarditis.1,105

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The following discussion focuses on HL given the cardiotoxic exposures, high intermediate- and longterm survival rates, and a robust follow-up literature. Swerdlow et al compared the risk of cardiac mortality in a cohort of 7,033 HL patients with the general population of England and Wales; 62% were male, 35% were treated before 1981, and 31% were younger than 25 years of age when first treated. Follow-up averaged 11.1 years.106 The relative risk of death from MI was significantly increased, more than twofold compared with the general population. The absolute excess risk of death from MI was more than three times higher in males than in females. The relative risk of death from MI decreased sharply with older age at first treatment.106 Heidenreich et al107 reported a progressive increase in valvular disease with time following radiation in HL survivors. Patients who had received radiation more than 20 years before evaluation had a significant increase in mild or more severe aortic regurgitation (60% v 4%), and aortic stenosis (16% v 0%) compared to those who had received irradiation within 10 years.107 More recently, Aleman et al108 evaluated the longterm cardiovascular complications in 1,474 5-year HL survivors younger than 41 years at treatment. Patients were treated between 1965 and 1995, with a median follow-up of 18.7 years. Different radiation techniques were used throughout the time periods of study. Chemotherapeutic regimens also were modified over the years, switching the initial regimen MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) to anthracycline-containing regimens such as ABVD (doxorubicin, bleomycin, vinblastine, and dactinomycin) or MOPP/ABV. They observed a three- to fivefold increased incidence of MI and heart failure with a median time between treatment and diagnosis of CVD of 19 years. Valvular disorders and CAD/MI were the most common events at 5 years. In a multivariate analysis, mediastinal radiation was associated with two- to sevenfold increased risk of valvular disorders, CAD, and heart failure. Combined anthracycline regimens with mediastinal radiation showed further increase of heart failure and valvular disorders, with a 25-year cumulative incidence of 7.9% for heart failure or cardiomyopathy. Galper et al109 studied 1,279 patients with HL treated with mediastinal radiation for the incidence of cardiac events. Compared with the general population, there was a 3.2-fold increased risk of requiring coronary artery bypass surgery, a 1.6-fold risk of needing percutaneous transluminal coronary angioplasty, and a 9.2-fold risk of requiring valve surgery. After adjusting for confounding factors including treatment variables, only older age and male sex were predictive of undergoing a cardiac procedure.109 Recognizing these complications, in recent years there has been a shift

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away from the use of radiation in HL with greater emphasis on the use of chemotherapy. Cardiovascular risk factors including hypertension, dyslipidemia, smoking, and diabetes mellitus, as well as preexisting cardiac disease, are important contributors to the risk of long-term cardiovascular complications after HL treatment.105,108,110 Glanzmann et al reported significant associations between ischemic heart disease and mediastinal radiation (total doses between 30 and 42 Gy) among patients who also had traditional cardiac risk factors.111 There was a relative risk of 4.2 for fatal MI and 6.7 for MI or sudden death. In other studies, hypertension and dyslipidemia were associated with CAD in HL survivors,105 and diabetes mellitus and smoking history were predictive of cardiac hospitalization.112 It follows that cardiovascular risk factors should be aggressively controlled in these patients.105,113,114 Several reports have suggested the effective role of exercise in improving cancer survivor’s quality of life.115,116 Moser et al reported the long-term risk of CVD after treatment for aggressive NHL.117 They studied patients with NHL in Holland and Belgian treated with at least six cycles of doxorubicin-based chemotherapy. The risk of chronic heart failure was markedly increased with 208 excess cases per 10,000 patient-years, whereas the risk of CAD matched the general population. Risk of stroke was raised especially after additional radiation. Preexisting hypertension, NHL at a young age, and salvage treatment increased the risk of all cardiovascular events; the effect of RT was dose-dependent.117

Lymphoma: Recommendations for CVD Surveillance and Prevention Cardiac screening is recommended prior to initiation of chemoradiation, especially if anthracyclines are part of the protocol.107,118 Baseline electrocardiogram and echocardiogram are recommended. Dose adjustment should be considered if LVEF o50% and protocols should be modified using cardioprotective strategies including changes of the infusion schedules and incorporation of contemporary approaches using RT at a lower dose to a smaller volume.119 This is a risk-benefit assessment and the recommendation to change the cancer treatment regimen because of a low LVEF has to also consider the risk of compromising the cure of the HL. The Children’s Oncology Group (COG) recommendations include yearly follow-up of symptoms and physical examination for patients who were exposed to radiation Z20 Gy to chest, total body irradiation, cardiotoxic chemotherapy, or combined chemoradiation. Electrocardiograms should be repeated as clinically indicated. Echocardiograms

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should be repeated based on age at treatment, radiation dose, and cumulative anthracycline dose. In patients who received anthracyclines as part of the cancer regimen, an echocardiogram should be repeated every 1 to 5 years based on age at treatment, radiation dose, and cumulative anthracycline dose.18 In addition, the COG recommends the monitoring of fasting glucose and lipid profile every 2 years. Healthy lifestyle including diet modification and physical activity (aerobic exercise) is encouraged. Cardiology consultation is recommended 5 to 10 years after radiation to evaluate risk of CAD, or after cardiotoxic chemotherapy to evaluate subclinical cardiac impairment (patients who received anthracyclines Z300 mg/m2, chest radiation Z40 Gy or 30 Gy chest radiation plus anthracyclines), or for patients with abnormalities on screening. Cardiovascular evaluation should be sought for patients planning pregnancy. During pregnancy, periodic cardiovascular evaluation should be done, especially during the third trimester, labor, and delivery due to the risk of cardiac failure.18 In the same way, yearly examination of carotid pulses and auscultation for carotid bruits is recommended for patients who required mediastinal, cervical, supraclavicular, or mantle radiation, or total body irradiation with a dose 440 Gy. Finally, the COG recommended a carotid Doppler study 10 years after completion of radiation to the neck as a baseline. Further refinement of the COG recommendations based on current imaging techniques and the use of biomarkers is also a fertile area for future research. According to recent NCCN Clinical Practice Guidelines in Oncology, HL patients should be encouraged to undergo counseling on issues regarding survivorship and long-term treatment effects. These issues include secondary malignancies, cardiac disease, reproduction, health habits, and psychosocial issues. Close follow-up by the oncologist should be assured especially during the first 5 years with subsequent annual monitoring because of the risk for late complications, including secondary cancers and cardiovascular problems. In the light of increased long term risk of CVD, the NCCN recommends a baseline stress test or echocardiogram at 10 years after treatment and annual blood pressure monitoring, even in asymptomatic individuals. The NCCN panel also recommends aggressive medical management of cardiovascular risk factors.120,121 The ESMO122 guidelines recommend aggressive interventions to reduce cardiovascular risk factors, and a baseline echocardiogram before treatment with further monitoring of cardiac function after administration of half the planned dose of anthracycline, or after administration of a cumulative dose of doxorubicin 300 mg/m2, epirubicin 450 mg/m2, or mitoxantrone 60 mg/m2. Subsequent ventricular

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function monitoring is recommended 4 and 10 years after anthracycline therapy in patients who were treated at less than 15 years of age, and for patients treated at age older than 15 years but with cumulative dose of doxorubicin of 4240 mg/m2 or epirubicin 4360 mg/m2.122

Sarcoma With the introduction of multimodality treatment the 10-year survival has reached approximately 50% for patients with Ewing sarcoma or osteosarcoma.123 Chronic or late cardiac toxicity in the treatment of sarcoma is primarily due to doxorubicin, which is given at relatively high doses particularly for patients with osteosarcoma. Most currently used regimens include cumulative doxorubin dose of 375–480 mg/m2. Studies have reported heart failure in as many as 4% of patients and asymptomatic LV dysfunction in up to 27% of doxorubicin-treated survivors of bone tumor.124 Survivors of sarcoma have poorer general health status compared to age and gender matched populations.125 Long-term survivors have demonstrated reduced musculoskeletal function related to the regional therapy with diminished activity levels.126 Sarcoma survivors o40 years of age were four times as likely to have the metabolic syndrome as compared to age- and gender-matched reference populations.127 Although the metabolic syndrome is a well-recognized late complication after cancer treatment, the etiology and its effect on cardiovascular risk in cancer survivors are not well known. Growth hormone deficiency and other endocrinopathies due to complications of the cancer treatment, as well as lifestyle factors, have been implicated as potential causes.128–130 The higher prevalence and earlier onset of metabolic syndrome plus diminished cardiac reserve and physical inactivity place sarcoma survivors at increased risk for cardiovascular morbidity and mortality. The AHA guidelines for primary prevention of CVD call for risk factor screening in adults beginning at age 20 with assessment of smoking status, alcohol intake, and physical activity.131 Regular check-ups should occur at least every 2 years with recording of blood pressure, body mass index, waist circumference, and pulse, as well as fasting serum lipid profile and blood glucose and the risk for CVD estimated (Table 1). Recommendations for surveillance after anthracycline exposure are congruent with those proposed for HL survivors. RT to the heart or vasculature is usually not an issue for patients treated for osteosarcoma.

CONCLUSIONS The critical imperative of identifying patients with risk factors for CVD and/or patients who harbor

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early and often asymptomatic CVD has been a recent and important landmark in the journey to control CVD in the general population.9,131 In these patients, early intervention has proven to be the best therapy. It is reasonable to apply the same principles accepted for “garden-variety” CVD to the cancer survivor population who clearly are at risk for CVD and often harbor subclinical and clinical CVD. Cancer patients and their clinicians should maintain a vigilant watch for signs and symptoms that suggest CVD, as it is clear that CVD is a common problem that can impact the quality of life of these patients. If complaints of fatigue, dyspnea, edema and pain are dismissed as nonspecific after-effects of cancer therapy, opportunities to effectively diagnose and treat CVD will be missed. Current algorithms using clinical acumen and basic and advanced cardiac testing for the evaluation and treatment of vascular, myocardial and valvular disease should be thoughtfully applied to cancer survivors, keeping in mind that cancer and its treatment will only increase the risk for CVD compared with the general population. The first priority in cancer survivors should be effective relief of symptoms and improved quality of life. Prolonging the life of cancer survivors through the management of CVD and its risk factors is a realistic goal.

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