Cardiac Outcomes in Survivors of Pediatric and Adult Cancers

Accepted Manuscript Cardiac outcomes in survivors of pediatric and adult cancers Paul C. Nathan, MD, MSc, Eitan Amir, PhD, ChB, MB, Husam Abdel-Qadir, MD PII:

S0828-282X(16)00191-4

DOI:

10.1016/j.cjca.2016.02.065

Reference:

CJCA 2052

To appear in:

Canadian Journal of Cardiology

Received Date: 24 November 2015 Revised Date:

1 February 2016

Accepted Date: 22 February 2016

Please cite this article as: Nathan PC, Amir E, Abdel-Qadir H, Cardiac outcomes in survivors of pediatric and adult cancers, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.02.065. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Cardiac outcomes in survivors of pediatric and adult cancers

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Paul C. Nathan MD, MSc1, 2, 3, Eitan Amir PhD, ChB, MB3, 4,5, Husam Abdel-Qadir MD3,6

Division of Hematology/Oncology, The Hospital for Sick Children

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Department of Pediatrics, University of Toronto

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Institute for Health Policy, Management and Evaluation, University of Toronto

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Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre

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Department of Medicine, University of Toronto

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Division of Cardiology, Women’s College Hospital

Corresponding author: Paul Nathan MD, MSc

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The Hospital for Sick Children

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416-813-7743

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555 University Avenue, Toronto, ON M5G 1X8

[email protected]

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Abstract Over 80% of children and 60% of adults with cancer will become long-term survivors, emphasizing the importance of late effects of cancer therapy. Cardiotoxicity due to

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chemotherapy and radiation is a frequent cause of serious morbidity and premature mortality in survivors. Anthracyclines, a core component of many treatment regimens, have been implicated as a principal cause of irreversible cardiomyopathy. Approximately 60% of anthracycline-treated

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children will develop echocardiographic evidence of cardiac dysfunction, and 10% of those treated with high-dose anthracyclines will develop congestive heart failure within the 20 years

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after therapy. Adults treated with trastuzumab are at risk for a cardiomyopathy which is usually reversible. As many as 12% of adults treated with trastuzumab and 20% of those who have also received an anthracycline will develop cardiotoxicity within 5 years. Risk factors for cardiomyopathy include patient (e.g. age, sex, genetic predisposition) and treatment

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characteristics (e.g. cumulative anthracycline dose). Radiotherapy to a field involving the heart increases the risk for cardiomyopathy, coronary artery disease, valvular dysfunction, arrhythmias and pericardial disease. Surveillance guidelines are available to guide long-term cardiac follow-

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up of childhood cancer survivors, but not for survivors of adult cancers; however, periodic follow-up to detect cardiac dysfunction may be reasonable. Modifiable cardiac risk factors like

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hypertension, smoking and dyslipidemia interact with cancer therapies to increase the risk of cardiac disease, emphasizing the importance of risk-factor control. Coordination of care between oncologists and cardiologists would optimize care for those individuals at high risk of cardiotoxicity who would benefit from appropriate surveillance and treatment strategies.

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Summary Survivors of cancer are at significant risk for cardiac disease, particularly cardiomyopathy as a

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consequence of chemotherapy exposure. This paper discusses cardiac outcomes in long-term cancer survivors, the risk factors for the development of cardiac disease, and the guidelines for follow-up in patients exposed to cardiotoxic chemotherapy or radiation. It summarizes some of

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the available interventions for survivors with sub-clinical or clinical cardiac disease, and

emphasizes the importance of healthy lifestyle choices and treatment of modifiable cardiac risk

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factors in this population.

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The growing population of cancer survivors With contemporary therapies, over 80% of children diagnosed with cancer will become long-term survivors.1 There are almost 400,000 childhood cancer survivors alive in the United

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States,2 with the survivor population in Canada approximating 40,000. Childhood cancer

survivors (CCS) are at significant risk of serious morbidity and premature mortality as a result of their cancer therapy;3,4 80% of survivors will develop one or more severe or life-threatening

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chronic health conditions by the age of 45 years.5 Of those children that survive 5 years from their initial cancer diagnosis, almost 10% will die in the next 10 years.6 Although cancer

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recurrence is the primary cause of mortality early in the survivor period, second malignant neoplasms and cardiac and pulmonary disease account for greater proportions of premature deaths over time.7 In fact, cardiac disease is the third leading cause of premature death in CCS (after cancer recurrence and second malignant neoplasms), with a 7-fold increased risk of

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premature cardiac death compared to the general population. The relative risk of cardiac death remains elevated even in CCS who have survived for more than 25 years after their primary cancer.7

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There are similar concerns within the population of adult cancer survivors. In 2009, there were an estimated 810,045 Canadians who had been diagnosed with a malignancy in the

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preceding ten years. This equates to approximately 1 in 40 adult Canadians being a cancer survivor.8 As a result, assessment of the risk-benefit of specific cancer therapies is now expected to factor in their long-term impact on survivors’ health.9 In malignancies with a large survivor population such as breast cancer, the most common cause of death among older patients is cardiovascular disease.10

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Cardiac outcomes in survivors of childhood cancer Cardiac toxicity in CCS is caused mainly by anthracycline chemotherapy agents (most

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commonly doxorubicin and daunomycin) which are administered to more than 50% of children with cancer.11 Although observed frequencies vary between studies, up to 60% of children

treated with an anthracycline will develop at least some subclinical cardiac dysfunction.12 These

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abnormalities are progressive in a significant proportion of patients.13-15 The risk of congestive heart failure (CHF) in children exposed to a cumulative anthracycline dose greater than 300

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mg/m2 approaches 10% by 20 years after their cancer therapy,16 but even children exposed to lower doses are at significantly increased risk for CHF.12,17 Compared to their siblings, CCS have a 15-fold increased risk of developing CHF.18

Cardiac disease in cancer survivors extends beyond damage to the myocardium. Cancer

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treatments that include radiation therapy to a field that includes the heart can impact any of the cardiac structures. Thus, survivors treated with radiation are at increased risk for coronary artery disease (CAD), valvular abnormalities, arrhythmias and pericardial disease.17 Among adult

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survivors of childhood cancer (median age at assessment, 32 years) assessed as part of the St Jude Lifetime Cohort Study,5 57% of those treated with radiation to a field that involved the

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heart were found to have a valvular abnormality, most frequently mild to moderate tricuspid regurgitation or mitral valve regurgitation. Fourteen percent of survivors treated with an anthracycline, anthraquinone, or radiation had developed a conduction disorder. By age 45 years, 5.3% of survivors in the Childhood Cancer Survivor Study, only 39% of whom had received an anthracycline and 26% chest-directed radiotherapy, had developed severe or life threatening CAD or had died of a myocardial infarction.19

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Cardiac outcomes in survivors of adult cancers A paradigm for Cancer Therapeutics-related Cardiac Dysfunction (CTRCD) has been

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proposed in adults, with classification into an irreversible Type I form, and a Type II form that is believed to be reversible with timely intervention (Figure 1).20 However, this simple

dichotomization is most useful as a framework to conceptualize the spectrum of CTRCD rather

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than an absolute distinction between two non-overlapping entities. Anthracyclines are the

chemotherapy agents most commonly associated with Type I CTRCD. In a seminal study, CHF

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was observed in 88 (2.2%) of 3941 doxorubicin-treated patients (median dose 183 mg/m2).21 In contrast to children in whom CHF is usually a late occurrence, CHF was recognized at a median of 23 days (mean 30 days) after the last administered dose of chemotherapy in this adult cohort. The most potent predictor of heart failure was the cumulative doxorubicin dose; the median dose

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was 390 mg/m2 in patients who developed heart failure and 180 mg/m2 in those who did not. The incidence of CHF was 3% in patients who received <400mg/m2, 7% in patients who received 400-550 mg/m2, and 18% at higher doses. However, the risk may have been underestimated due

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to limited follow-up and lack of image-based assessment of subclinical left ventricular (LV) dysfunction. More recent observational studies that reflect contemporary practices (which limit

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doxorubicin dosing to <500 mg/m2) have reported a 5-year cumulative incidence of heart failure and/or cardiomyopathy of up to 4.3% in breast cancer patients who have received anthracyclines without trastuzumab.22 The risk increases markedly with age, with ten-year incidence rates of up to 32% in cohorts of women aged over 65 years at the time of anthracycline exposure. The other major risk factors for CTRCD in adults are the presence of pre-existing cardiac disease, exposure

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to other chemotherapy or chest irradiation, and other recognized risk factors for cardiovascular disease in the general population (e.g. diabetes, hypertension and dyslipidemia).

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Trastuzumab is the agent most associated with reversible Type II CTRCD23, although this reversibility has been questioned,24 particularly as greater numbers of patients survive long

enough to accumulate more common forms of cardiac injury (as described in the “multiple-hit

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hypothesis” below). The risk factors for CTRCD due to trastuzumab also include age and other population risk factors for cardiovascular disease. However, prior anthracycline exposure leads

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to a particularly high risk. At a median follow-up of 10.3 years, the BCIRG 006 trial reported a 2% incidence rate of grade 3/4 left ventricular dysfunction in patients who had received doxorubicin, cyclophosphamide, docetaxel and trastuzumab and 0.4% in patients who received docetaxel, carboplatin and trastuzumab (i.e. no anthracyclines).25,26 However, population-based studies report 5-year trastuzumab-related cardiac toxicity rates of 12% without anthracycline

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exposure and 20% with combined therapy.22,27 In cohorts of women aged >65 years, the corresponding incidence rates at 3 years were 32% and 42% respectively.

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As in children, thoracic irradiation has also been implicated in various forms of cardiac injury. While there is a small risk of short-term complications such as pericarditis, most

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radiation-induced cardiovascular disease only becomes apparent after decades of follow-up. In a study of 415 patients (median age at treatment 25 years) who received chest radiation therapy for Hodgkin’s lymphoma, 10.4% developed CAD at a median time of 9 years after treatment, 7.4% developed carotid or subclavian stenosis at a median of 17 years, and 6.2% developed clinically important valvular dysfunction at a median of 22 years. Valve surgery was required 8 times more often than in age-matched patients, while cardiac revascularization was required 1.6-fold more often.28 When cardiac surgery is needed, it is associated with a higher risk of complications 7

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compared to patients who have not been treated with thoracic irradiation. In an observational study of matched cohorts, 55% of patients with radiation-associated cardiac disease died after cardiac surgery versus 28% of the matched controls (hazard ratio 2.47).29 Ultimately, left-sided

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thoracic irradiation translates to a higher risk of cardiovascular death: in a cohort of women with mean follow-up of 28 years after breast cancer, radiation was associated with a 1.8-fold higher risk of cardiac death and a 1.3-fold risk of vascular death.30 In women treated with radiation for

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breast cancer, rates of major coronary events have been shown to increase linearly with mean dose to the heart by approximately 7% per Gray of radiation.31 The risk of cardiovascular disease

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after radiotherapy is further increased by exposure to other cardiotoxic chemotherapy agents. Smoking is another important risk factor, and is associated with a three-fold increase in the risk of radiation-associated cardiac disease.32

Endocrine therapy to suppress circulating sex hormones is a highly effective therapy for

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the majority of male prostate cancer and female breast cancer patients. It is usually considered less toxic than other types of cancer therapy. However, prolonged exposure to these agents (typically multiple years) mandates attention to the risk of adverse effects. In men with prostate

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cancer, treatment with orchiectomy or Gonadotropin-Releasing Hormone (GnRH) agonists may

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increase the risk of diabetes and atherosclerotic cardiovascular disease, including myocardial infarction and stroke,33,34 although this increased risk has not been consistently observed.35 There may also be a higher risk of cardiovascular death, 33 34 although this appears limited to those with prior myocardial infarction or pre-existing heart failure.33 In women with breast cancer, tamoxifen is associated with an elevated risk of venous thromboembolism that usually manifests within the first years of exposure, and is less likely to be a long term concern in survivors.36 Among post-menopausal women, aromatase inhibitors have become the preferred endocrine 8

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therapeutic option. However, these agents have been associated with an increased risk of hypertension, dyslipidemia, and endothelial dysfunction, which translates into a higher risk of myocardial infarction at 3-4 years of follow-up.37 In addition, they increase the risk of

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osteoporosis, fractures, and musculoskeletal complaints, which can aggravate the weight gain and physical inactivity that is commonly observed in breast cancer survivors. This can indirectly

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increase cardiovascular risk in the long term (Figure 2).

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Predicting which survivors of childhood cancer are at elevated risk for cardiomyopathy To date, predicting which CCS are at elevated risk for cardiac toxicity has been based predominantly on clinical and demographic factors (e.g. cumulative anthracycline dose, radiation therapy involving the heart, younger age at treatment, female gender, longer follow-up, and CHF during therapy12-14,21,38-41). This only accounts for a proportion of the considerable inter-

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individual variability in susceptibility to cardiac injury. Clinicians have generally relied on these established clinical risk factors to counsel patients and families about risk, and to guide longterm surveillance. Recently, Chow and colleagues created and validated a tool to predict risk for

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developing CHF in CCS.42 They developed three models that vary in the amount of treatment

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information required to generate an estimate of risk. Their “simple model” used gender, age (younger or older than 5 years), anthracycline treatment (yes/no) and chest radiation (yes/no) to develop a risk score, while their “standard model” and “heart dose model” incorporated data about anthracycline dose and radiation dose to the heart. However, other factors impact risk, particularly genetic variability between subjects. Most published genetic studies have focused on variations in the pathways associated with anthracycline absorption, distribution, metabolism, and excretion (ADME) or myocyte response 9

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to oxidative stress, and have identified several genetic aberrations in these pathways that modify the risk for cardiac toxicity.43-49 Inquiry has expanded to include pathways that regulate myocardial response to injury, since these contribute to progressive cardiac remodeling and

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dysfunction even after the initiating insult has been removed. Potential candidates include genes in neurohormonal pathways, pathways of myocardial energy metabolism, structural or

sarcomeric genes, ion channel genes, cell hypertrophy, cell death, angiogenesis, and fibrosis.50-54

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The complexity of pathways associated with anthracycline toxicity has limited the use of

genomic data for guiding therapy, although some research groups have created risk prediction

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models that combine clinical factors with data about genetic variants to estimate the risk for cardiac toxicity at the initiation of cancer therapy.55 Such models might ultimately be useful for informing modifications in anthracycline dosing or the addition of cardiac protectant agents such

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as dexrazoxane.

Predicting which survivors of adult cancer are at elevated risk for cardiomyopathy Cancer survivors who have been exposed to therapies with known cardiovascular risk but

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who have not developed overt CTRCD are considered to be in Stage A heart failure, namely, “at risk for heart failure but without detectable cardiac structural abnormalities” (see below).56 For

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most survivors of adult cancers, cardiovascular disease is believed to occur as a consequence of multiple insults rather than chemotherapy in isolation.57 In this “multiple-hit hypothesis”, the cardiotoxic regimen is only one of several insults that cumulatively overwhelm the defence and repair mechanisms of the heart. The development of clinically overt CHF or a decline in left ventricular ejection fraction (LVEF) after cancer therapy identifies survivors of adult cancers that require closer and more 10

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prolonged follow-up. However, reliance on diagnosing cardiac injury in this manner results in detection of cardiotoxicity late in its natural history. LVEF can remain normal early in the course of anthracycline cardiomyopathy, even when biopsy studies demonstrate evidence of myocardial

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damage such as apoptosis and interstitial fibrosis.58 Declines in LVEF occur after the heart has exhausted compensatory mechanisms for the underlying cardiac injury, and CHF can occur even in the face of normal LVEF.59,60 Thus, initiating medical interventions after detection of

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abnormal LVEF or clinical heart failure may be too late to arrest the course of heart failure, increasing the risk of heart transplantation or early mortality.61 This has led to growing interest in

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newer echocardiographic techniques (such as strain) that can detect cardiac injury in cancer patients prior to declines in LVEF.62 Several studies have demonstrated that worsening strain values in adult patients receiving cancer therapy can predict future declines in LVEF .63 There are limited data describing an increased prevalence of strain abnormalities in adult survivors of

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breast cancer,64 but no data specific to this setting confirming that abnormal strain parameters predict worse outcomes after completion of therapy. Data in children are limited, but there have been several recent publications on the use of this approach in the CCS population.65-68 Whether

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survivors with abnormal strain parameters are at increased risk for developing clinical cardiac dysfunction, and whether earlier medical intervention based on abnormal strain can alter the

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natural history of the disease, remains to be established. However, a meta-analysis of studies of adult patients with cardiac disease from other causes demonstrates that abnormal strain is associated with approximately double the risk of mortality for every standard deviation increase in strain values, a stronger association than observed with abnormalities in LVEF.69 In parallel to new imaging techniques, cardiac biomarkers have provided a potential avenue for earlier detection of cardiac toxicity prior to the development of overt cardiac 11

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dysfunction. Most of the data are limited to adults in the peri-treatment setting. Of relevance to the survivorship population is the observation that a persistent troponin elevation 30 days after the last chemotherapy dose identifies a survivor population at extremely high risk - 84% of this

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group developed cardiac toxicity within mean follow-up period of 20 months.70 The same

researchers demonstrated in a different study that among trastuzumab-treated women, a decline

the drug, identifying a lower-risk group of survivors.71

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in LVEF without concurrent troponin elevation is very likely to recover after discontinuation of

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In contrast to survivors of childhood cancer, there are no risk prediction tools for estimation of cardiovascular risk that are specific to survivors of adult cancers; available tools focus on evaluation of risk prior to initiation of chemotherapy.72,73 A pragmatic solution would be to begin with cardiac risk scores for the general population such as the modified Framingham risk score recommended by the Canadian Cardiovascular Society for cardiovascular

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atherosclerotic events,74 or the Framingham General cardiovascular risk score for coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure.75 The practitioner would then increase the risk estimate by a factor equivalent to the hazard ratio reported for the

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cardiotoxic regimen that the patient has received. Treatment decisions about cardiovascular risk

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reduction and intensity of follow-up can be based on this modified risk estimate. For example, data on thoracic radiation therapy predicts an approximately two-fold increase in the risk of atherosclerotic cardiac events. This means a radiation-treated patient whose modified Framingham risk score predicts an 8% event rate (low-risk) should be treated as a moderate risk patient as their anticipated event rate would be closer to 16%. Patients with asymptomatic LV dysfunction at the end of cancer therapy can be managed with the knowledge that asymptomatic LV dysfunction in settings outside cancer therapy is associated with a four to five-fold increase 12

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in the risk of progression to symptomatic CHF compared to individuals with normal LV function .76

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Prevention and treatment of CTRCD As the substantial cardiovascular risk associated with cancer therapy has become widely recognized, there has been increased focus on interventions to mitigate this risk. These include

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interventions targeted at primary prevention (the adoption of strategies to protect against cardiac damage before it occurs, such as modification of anthracycline doses based on individual risk,

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use of less cardiotoxic anthracycline analogues, and administration of cardioprotective agents) as well as secondary prevention, which is focused on treating cardiac damage before it manifests clinically. Interventions aimed at the early detection of cardiovascular injury and its management before and during the administration of cancer therapy are discussed in detail in another article in this issue. Among FDA-approved medications, angiotensin converting enzyme (ACE) inhibitors

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or angiotensin receptor blockers (ARBs) have the best evidence for efficacy in prevention of heart failure or declines in LV function. There is also a strong body of evidence supporting the use of dexrazoxane, although its use is limited by the United States Food and Drug

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Administration and the European Medicine Agency to patients with metastatic breast cancer

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receiving high anthracycline doses. In fact, the European Medicines Agency recommended that use of the drug be prohibited in children because of concern that it increased the risk for the development of second malignant neoplasms,77 particularly in children who received concurrent etoposide or cranial radiation therapy. However, systematic reviews of the pediatric78 and adult79 literature have not demonstrated an increased risk for second malignant neoplasms. As described above, survivors of adult cancer have a higher incidence of cardiovascular disease well beyond the period of active cancer therapy, particularly if they have received chest 13

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radiation or prolonged aromatase inhibitor therapy. Thus, the emphasis on cardioprotection should extend beyond the early time period during and immediately after cancer therapy. The American College of Cardiology (ACC) and American Heart Association (AHA) have

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developed a classification of heart failure stages that classifies a patient’ s trajectory from being at risk for heart failure but without detectable cardiac structural abnormalities (Stage A) to

intractable symptomatic heart failure (Stage D).56 Patients with asymptomatic cardiac structural

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abnormalities are classified as being in Stage B, while those with symptomatic heart failure that responds to treatment are classified as being in Stage C. There is a substantial and irreversible

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decline in prognosis as patients move from one stage to the next. There are well-established guidelines for the management of survivors with Stages B-D heart failure, which are detailed in relevant guidelines from the Canadian Cardiovascular Society 80and analogous societies in the United States and Europe. These recommendations extend to patients with CTRCD, and are

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summarized in Supplementary Table S1.

A unique issue in survivors of pediatric and adult cancers is the choice of treatment for cancer recurrence or a second malignant neoplasm, which often requires an individualized

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decision that acknowledges the trade-offs between the competing risks of death and morbidity

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from the malignancy and cardiovascular disease. Unfortunately, cancer patients are less likely to be treated effectively for clinically overt cardiovascular disease in spite of well-defined and widely disseminated practice guidelines. For example, one study reported that less than 50% of cancer patients with myocardial infarction received routine interventions such as aspirin or statins.81 Another study showed similarly poor rates of guideline-recommended therapy after development of cardiac dysfunction among anthracycline or trastuzumab-treated patients. Only 54% of those patients received a cardiology consultation.82 The limiting step may be recognition 14

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of the presence of asymptomatic LV dysfunction. A recently published consensus document for the management of CTRCD calls for assessment of LVEF (preferably with echocardiography, including an assessment of global longitudinal strain) at the end of chemotherapy and at six

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month follow-up. However, there is little high-quality data demonstrating substantial benefit in reducing CTRCD with early intervention among asymptomatic patients receiving contemporary adjuvant chemotherapy regimens. The available data regarding the potential benefit of early

Cardiac surveillance in survivors

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facilitate informed personalized decision-making.

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initiation of therapy in and outside the cancer setting 83,84 should be discussed with patients to

Guidelines for surveillance for cardiac dysfunction in childhood cancer survivors have been published by several groups across North America, Europe and Asia.85-87 For example, the

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Children’s Oncology Group, a North American consortium of over 200 pediatric cancer centres, have published guidelines that recommend a surveillance echocardiogram (or MUGA) every 1, 2 or 5 years, depending on three risk factors: (1) age at treatment; (2) cumulative anthracycline

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dose; and (3) receipt of chest radiation. Several groups have evaluated the cost effectiveness of

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this surveillance approach.88,89 Wong and colleagues determined that these guidelines (versus no screening) extend life expectancy by 6 months and reduce the incidence of heart failure by 18% at 30 years.88 However, less frequent screenings are more cost effective than the guidelines while maintaining 80% of the health benefits. The International Late Effects of Cancer Guidelines Harmonization Group has completed an initiative to harmonize several clinical practice guidelines that were developed independently by different pediatric oncology groups.90 These guidelines, available at 15

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www.ighg.org/guidelines/topics/cardiomyopathy/recommendations/ , state that surveillance is recommended for survivors treated with high dose anthracyclines (≥250 mg/m2), chest radiation ≥35 Gray, or the combination of anthracyclines and radiation. Surveillance may also be

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reasonable for survivors treated with lower doses of anthracyclines or radiation. The committee endorsed screening that begins no later than 2 years after the completion of cardiotoxic therapy and occurs every 5 years. They noted that more frequent screening is reasonable in higher risk

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survivors.

There are no analogous well-accepted guidelines for follow-up of adult survivors,

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although the American Society of Clinical Oncology (ASCO) is developing such a document. The Society for Cardiac Angiography and Interventions has published an executive summary of a consensus statement document on cardio-oncology patients in the cardiac catheterization laboratory.91 This document presents an algorithm that calls for yearly follow-up, along with

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surveillance using ankle brachial indices and non-invasive cardiac imaging to detect occult vascular disease in survivors who received targeted therapeutics known to increase vascular risk. They also recommend a schedule for surveillance echocardiography and non-invasive

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assessment for coronary disease in survivors who have received thoracic radiation. We propose a schematic for the assessment and follow-up of adult receiving cardiotoxic cancer therapies in

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Figure 3.

Interaction between modifiable cardiac risk factors and cardiac late effects Despite a revolution in cancer therapy that has heralded an era of targeted cancer

therapies, it is likely that anthracyclines will remain a core component of chemotherapy regimens for the foreseeable future. Genetic profiling or risk prediction tools are not sufficiently robust to

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inform clinicians as to which patients should avoid anthracycline agents or be treated with reduced doses to avoid cardiac toxicity. Consequently, the population of cancer survivors at risk for anthracycline-induced cardiac dysfunction will continue to grow. Although surveillance may

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identify survivors with sub-clinical cardiac disease, it is essential that health care providers target modifiable risk factors for cardiac disease in this population. Factors such as smoking,

hypertension and the metabolic syndrome have been definitively linked to a risk for coronary

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artery disease in the general population, and contribute to this morbidity in cancer survivors as well. These risk factors have also been linked to the development of cardiomyopathy. The

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Childhood Cancer Survivor Study demonstrated that by age 50 years, survivors are significantly more likely than their siblings to be hypertensive (40% vs. 26%) or have dyslipidemia (23% vs. 14%).19 Of major concern was the observation that hypertensive survivors were at significantly increased risk for all major cardiac events (CAD, CHF, valvular disease, arrhythmias),

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particularly in those that had received chest radiation. Thus, treatment of hypertension and other modifiable cardiac risk factors should be a focus of long-term follow-up care. Unfortunately, survivors of various malignancies are less likely to receive treatment directed at cardiovascular

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risk factors57,92,93 highlighting an area of potential improvement in the care of at-risk survivors. Smoking substantially increases the risk of CHF 94-96 and interacts with chest radiation in a

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multiplicative manner, making it crucial for a cancer survivor to avoid tobacco. There should be enhanced emphasis on moderation in alcohol consumption given the association of alcohol excess with a higher risk of cardiovascular events, particularly in women.94 Finally, cancer survivors should adopt recommended dietary habits with increased intake of vegetables, whole grains, fish, olive oil and nuts given demonstrated efficacy in reduction of cardiovascular disease

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in general, and heart failure in particular, 97,98 above and beyond the anticipated impact on

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reduction of cancer recurrence risk.

Future perspectives

As highlighted above, there has been an increasing research and clinical focus on the

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cardiovascular health of cancer survivors, whether treated as children or adults. Unfortunately, there are many gaps in knowledge, including an incomplete understanding of which patients are

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at greatest risk, uncertainty about the optimal strategies for surveillance including how best to image the heart in this population, and lack of clarity as to what are the most effective interventions for primary and secondary prevention of cardiac disease. The bulk of the research in this area has yielded estimates of the incidence of cardiac

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pathology in cancers with the largest survivorship populations (hematologic, breast, prostate, childhood cancers as a group) and methods for risk stratification in the peri-treatment setting. Unfortunately, many of the decisions made regarding cardiac surveillance and interventions to

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prevent or treat cardiac dysfunction in cancer survivors are based on extrapolation of data derived from the general cardiology literature. However, cancer survivors are a unique patient

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population with different comorbid health conditions and competing risks compared to the general public - cancer recurrence, second malignant neoplasms, and other therapy-related complications such as osteoporosis may impact cardiac health and available treatment options should cardiac disease develop. Moreover, the nature of cardiac injury after cancer therapy is different from most forms of cardiac disease in that the cardiotoxic exposure is for the most part self-limited, in contrast to common causes of heart failure such as atherosclerosis and

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hypertension. There is a need for more specific data on the incidence of cardiac pathology in survivors of other common, but less-studied adult malignancies (such as colon cancer). Importantly, patient management will benefit from data to guide risk stratification in patients

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after completion of treatment, as well as studies designed specifically to evaluate treatment of asymptomatic cardiac dysfunction in cancer survivors before and after the development of

declines in LVEF. Ultimately, patients undergoing cardiotoxic cancer therapies as well as cancer

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survivors who have been exposed to such therapies will benefit from the coordination of their care by a multi-disciplinary team that includes oncologists, cardiologists, allied health care

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providers and each patient’s primary care physician.

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Figures titles Figure 1: Type I and II Cancer Therapeutics-related Cardiac Dysfunction (CTRCD)100

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Figure 2: The interplay between cardiovascular disease, cancer, their risk factors, and their treatments in determining the health of cancer survivors

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Figure 2 was modified from an earlier version that was designed with input from Dr. Geoffrey M. Anderson.

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Figure 3: Proposed surveillance and risk stratification of adults receiving cardiotoxic therapies as part of cancer therapy with curative/adjuvant intent

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2. Phillips SM, Padgett LS, Leisenring WM, et al. Survivors of childhood cancer in the United States: prevalence and burden of morbidity. Cancer Epidemiol Biomarkers Prev 2015;24:653-63.

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3. Geenen MM, Cardous-Ubbink MC, Kremer LCM, et al. Medical Assessment of Adverse Health Outcomes in Long-term Survivors of Childhood Cancer. JAMA 2007;297:2705-15.

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4. Armstrong GT, Pan Z, Ness KK, Srivastava D, Robison LL. Temporal trends in causespecific late mortality among 5-year survivors of childhood cancer. J Clin Oncol 2010;28:122431. 5. Hudson MM, Ness KK, Gurney JG, et al. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 2013;309:2371-81. 6. Mertens AC, Yong J, Dietz AC, et al. Conditional survival in pediatric malignancies: analysis of data from the Childhood Cancer Survivor Study and the Surveillance, Epidemiology, and End Results Program. Cancer 2015;121:1108-17.

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100.

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• Cellular dysfunctionType

II

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Type I

Trastuzumab) • No typical(e.g. anthracycline-like biopsy changes

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(e.g. Doxorubicin)

• Not cumulative dose-related

• Cellular death

• Generally reversible

• Permanent damage

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• Cumulative dose-related

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(resolve with time)

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• Typical anthracycline biopsy changes noted

Cancer death

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Advanced cancer

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Cardiotoxic cancer therapy

Less CV primary prevention

CV risk factors

Suboptimal lifestyle choices

Cancer risk factors

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Cancer diagnosis

CV disease

Suboptimal CV treatment

Preventable/ Premature CV morbidity and mortality

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Patient specific risk factors

Intended cancer therapy

Anthracycline dose >240 mg/m2 Left-sided/mediastinal irradiation High chest radiation dose Trastuzumab exposure Concurrent exposure to >1 cardiotoxic treatment

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Age >60 years Female Known CVD pre-treatment CV risk factors pre-treatment Pre-treatment LVEF <53%

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Pre-treatment assessment Risk-appropriate surveillance plan Consider baseline assessment (+/- during treatment): • LVEF assessment (preferably with strain) • Troponin measurement

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Cancer treatment

Risk of LV dysfunction Consider serial LVEF assessments Frequency of assessment and role of strain unclear

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Post-treatment assessment (if appropriate*) Prediction of risk of future CVD Risk of coronary disease

Primary / secondary prevention Role of surveillance stress testing or imaging unclear

Surveillance for other toxicities Valvular disease Pericardial constriction Extra-cardiac vascular disease

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* Post-treatment assessment may not be needed for all patients, especially those who have a low risk of CV disease (e.g. young patients with no evidence of cardiac dysfunction at end of therapy, patients treated with trastuzumab alone, or at one year after therapy with a doxorubicin-equivalent anthracycline dose <240mg/m2)

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CV: cardiovascular; CVD: cardiovascular disease; LVEF: left ventricular ejection fraction