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Canadian Journal of Cardiology

Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy

Published:April 07, 2016DOI:https://doi.org/10.1016/j.cjca.2016.02.078

      Abstract

      Modern treatment strategies have led to improvements in cancer survival, however, these gains might be offset by the potential negative effect of cancer therapy on cardiovascular health. Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors. This guideline, authored by a pan-Canadian expert group of health care providers and commissioned by the Canadian Cardiovascular Society, is intended to guide the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to cancer treatment. It includes recommendations and important management considerations with a focus on 4 main areas: identification of the high-risk population for cardiotoxicity, detection and prevention of cardiotoxicity, treatment of cardiotoxicity, and a multidisciplinary approach to cardio-oncology. All recommendations align with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Key recommendations for which the panel provides a strong level of evidence include: (1) that routine evaluation of traditional cardiovascular risk factors and optimal treatment of preexisting cardiovascular disease be performed in all patients before, during, and after receiving cancer therapy; (2) that initiation, maintenance, and/or augmentation of antihypertensive therapy be instituted per the Canadian Hypertension Educational Program guidelines for patients with preexisting hypertension or for those who experience hypertension related to cancer therapy; and (3) that investigation and management follow current Canadian Cardiovascular Society heart failure guidelines for cancer patients who develop clinical heart failure or an asymptomatic decline in left ventricular ejection fraction during or after cancer treatment. This guideline provides guidance to clinicians on contemporary best practices for the cardiovascular care of cancer patients.

      Résumé

      Les stratégies modernes de traitement du cancer ont permis d’améliorer le taux de survie, mais ce gain pourrait être contrecarré par les possibles effets négatifs du traitement anticancéreux sur la santé cardiovasculaire. En effet, il est maintenant reconnu que la cardiotoxicité liée au traitement anticancéreux constitue la principale cause de morbidité et de mortalité à long terme chez les survivants du cancer. Ces lignes directrices, dont l’élaboration par un groupe pancanadien d’experts en soins de santé a été mandatée par la Société canadienne de cardiologie, ont pour but d’orienter le traitement des patients cancéreux atteints d’une maladie cardiovasculaire établie ou à risque de subir des effets toxiques liés au traitement anticancéreux. On y trouve des recommandations et d’importantes considérations pour la prise en charge des patients qui ont été réparties en quatre volets distincts, soit la reconnaissance de la population à risque élevé de cardiotoxicité, le dépistage et la prévention de la cardiotoxicité, le traitement de la cardiotoxicité et l’approche multidisciplinaire de la cardio-oncologie. Toutes les recommandations contenues dans les lignes directrices sont conformes aux critères du système GRADE (Grading of Recommendations Assessment, Development, and Evaluation system). Les principales recommandations auxquelles le groupe d’experts a accordé un niveau de preuve élevé sont les suivantes : 1) l’évaluation systématique des facteurs de risque cardiovasculaire traditionnels de même que le traitement optimal d’une cardiopathie préexistante doivent être effectués chez tous les patients avant, pendant et après le traitement anticancéreux; 2) le traitement antihypertenseur doit être instauré, poursuivi et/ou ajusté conformément aux lignes directrices du Programme éducatif canadien sur l’hypertension, chez les patients souffrant déjà d’hypertension ou chez ceux qui développent ce problème au cours du traitement anticancéreux; et 3) les patients cancéreux qui présentent une insuffisance cardiaque clinique ou un déclin asymptomatique de leur fraction d’éjection ventriculaire gauche au cours du traitement anticancéreux ou après ce dernier doivent être évalués et pris en charge conformément aux lignes directrices actuelles sur le traitement de l’insuffisance cardiaque de la Société canadienne de cardiologie. Ces lignes directrices ont pour objectif de faire connaître aux professionnels de la santé les meilleures pratiques actuelles en matière de soins cardiovasculaires destinés aux patients atteints de cancer.
      Approximately 40% of Canadians will be diagnosed with cancer in their lifetime. In the past 2 decades significant gains have been made in cancer detection and treatment. Between 2001 and 2010, age-standardized mortality rates in women with cancer have declined by 1.2% per year and in men with cancer by 1.8% per year (Canadian Cancer Society; www.cancer.ca). Improvement in survivorship, however, can come at a cost. Although the number of cancer survivors is increasing at twice the rate of new cancer diagnoses,
      • de Moor J.S.
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      Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care.
      extended follow-up from registry data, in selected populations, has shown that death from cardiovascular causes is more frequent than death from cancer.
      • Patnaik J.L.
      • Byers T.
      • DiGuiseppi C.
      • Dabelea D.
      • Denberg T.D.
      Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study.
      • Hanrahan E.O.
      • Gonzalez-Angulo A.M.
      • Giordano S.H.
      • et al.
      Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma.
      Cardiotoxicity is now recognized as a leading cause of long-term morbidity and mortality among cancer survivors.
      • Daher I.N.
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      • Bhatia N.
      • Durand J.B.
      The prevention of cardiovascular disease in cancer survivors.
      Cardio-oncology is a new discipline, which has developed in response to the need for optimal strategies to manage this at-risk population. This guideline, commissioned by the Canadian Cardiovascular Society (CCS), and endorsed by the Canadian Cardiac Oncology Network is intended to optimize the care of cancer patients with established cardiovascular disease or those at risk of experiencing toxicities related to their cancer treatment.
      The methodology and processes for development of this guideline are well described on the CCS Web site (www.ccs.ca). Recommendations are aligned with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system,
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      Adding “value” to clinical practice guidelines.
      which has been adopted by the CCS Guidelines Committee to promote quality and rigour in guideline development.
      The objectives of this guideline are to provide recommendations on 4 key topics within cardio-oncology, specifically: (1) the patient population at highest risk for cardiovascular toxicity related to cancer therapy; (2) strategies for detection and prevention of cardiotoxicity; (3) treatment of cardiotoxicity; and (4) the need for a multidisciplinary approach in the management of individuals who experience cardiotoxicity related to their cancer therapy.

      Identifying the High-Risk Population

      Cancer and cardiovascular disease: The multiple hit hypothesis

      The multiple hit hypothesis is a framework for understanding cancer therapy-induced cardiac dysfunction. This framework suggests that traditional atherosclerotic risk factors and cardiac disease, in combination with cardiotoxic cancer therapy, can overwhelm cardiac reserve and lead to cardiac dysfunction (Fig. 1).
      • Jones L.W.
      • Haykowsky M.J.
      • Swartz J.J.
      • et al.
      Early breast cancer therapy and myocardial injury.
      • Cardinale D.
      • Bacchiani M.
      • Colombo A.
      • et al.
      Strategies to prevent and treat cardiovascular risk in cancer patients.
      The childhood cancer survivorship study reported that when hypertension and other cardiac risk factors operate on a cardiovascular system exposed to cancer therapy, survivors have a high risk of cardiac disease (Table 1).
      • Armstrong G.T.
      • Oeffinger K.C.
      • Chen Y.
      • et al.
      Modifiable risk factors and major cardiac events among adult survivors of childhood cancer.
      • Oeffinger K.C.
      • Mertens A.C.
      • Sklar C.A.
      • et al.
      Chronic health conditions in adult survivors of childhood cancer.
      • Meachem L.R.
      • Chow E.J.
      • Ness K.K.
      • et al.
      Cardiovascular risk factors in adult survivors of pediatric cancer – a report from the Childhood Cancer Survivor Study.
      Such observations appear to validate this hypothesis as a suitable framework to understand, evaluate, prevent, and treat cancer therapy-induced cardiac dysfunction in adults.
      Figure thumbnail gr1
      Figure 1Preexisting cardiovascular disease and cardiac risk factors combine with chemotherapy and targeted therapy to produce subclinical and clinical cardiovascular disease, during and long after cancer therapy. This model for cancer therapy-induced cardiotoxicity emphasizes multiple risk factors, each of which is a potential target for intervention. Whether such intervention translates into clinical benefit requires further study.
      Modified from Jones et al.
      • Jones L.W.
      • Haykowsky M.J.
      • Swartz J.J.
      • et al.
      Early breast cancer therapy and myocardial injury.
      and Cardinale et al.
      • Cardinale D.
      • Bacchiani M.
      • Colombo A.
      • et al.
      Strategies to prevent and treat cardiovascular risk in cancer patients.
      with permission from Elsevier.
      Table 1Risk of cardiac disease and cardiac risk factors in long-term survivors of childhood cancer vs healthy siblings (Childhood Cancer Survivor Study)
      CAD
      • Oeffinger K.C.
      • Mertens A.C.
      • Sklar C.A.
      • et al.
      Chronic health conditions in adult survivors of childhood cancer.
      Heart failure
      • Oeffinger K.C.
      • Mertens A.C.
      • Sklar C.A.
      • et al.
      Chronic health conditions in adult survivors of childhood cancer.
      Hypertension
      • Meachem L.R.
      • Chow E.J.
      • Ness K.K.
      • et al.
      Cardiovascular risk factors in adult survivors of pediatric cancer – a report from the Childhood Cancer Survivor Study.
      Diabetes
      • Meachem L.R.
      • Chow E.J.
      • Ness K.K.
      • et al.
      Cardiovascular risk factors in adult survivors of pediatric cancer – a report from the Childhood Cancer Survivor Study.
      Dyslipidemia
      • Meachem L.R.
      • Chow E.J.
      • Ness K.K.
      • et al.
      Cardiovascular risk factors in adult survivors of pediatric cancer – a report from the Childhood Cancer Survivor Study.
      RR (95% CI)10.4 (4.1-25.9)15.1 (4.8-47.9)1.9 (1.6-2.2)1.7 (1.2-2.3)1.6 (1.3-2.0)
      n10,39710,397859985998599
      CAD, coronary artery disease; CI, confidence interval; RR, relative risk.

      Patient- and treatment-related risk factors for cardiotoxicity from cancer therapy

      Risk factors for cancer therapy-induced cardiac dysfunction are well established for chemotherapy (eg, anthracyclines), several targeted therapies (eg, trastuzumab), and radiation therapy (Supplemental Tables S1-S6). Limited experience, variable definitions, and inconsistent monitoring of cardiac function have hindered evaluation of risk factors for cardiotoxicity associated with newer cancer therapies. In general, patients with preexisting cardiovascular disease, multiple, or poorly controlled cardiovascular risk factors, advanced age, and exposure to multiple cardiotoxic agents are at highest risk for cancer therapy-induced cardiotoxicity. These toxicities, which might include left ventricular (LV) dysfunction, hypertension, myocardial ischemia, arterial thrombosis, and arrhythmias are discussed in greater detail in the following sections.

      LV dysfunction

      Risk factors for anthracycline-induced heart failure (HF) and asymptomatic LV dysfunction are well established (Supplemental Tables S1-S6). High-risk patients include those at the extremes of age, non-Caucasian individuals, women, and those with preexisting cardiac disease and established cardiovascular risk factors. Anthracycline-induced cardiotoxicity is largely irreversible, such that cumulative lifetime dose is one of the most important risk factors for LV dysfunction
      • Swain S.M.
      • Whaley F.S.
      • Ewer M.S.
      Congestive heart failure in patients treated with doxorubicin. A retrospective analysis of three trials.
      ; as such, contemporary chemotherapy regimens have evolved to minimize anthracycline exposure, particularly in the adjuvant setting. LV dysfunction associated with targeted therapies has been most extensively evaluated in the breast cancer population treated with trastuzumab; in the adjuvant setting, cardiotoxicity associated with these agents appears to be largely reversible.
      • Smith I.
      • Procter M.
      • Gelber R.D.
      • et al.
      HERA study team 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.
      • Ewer M.S.
      • Vooletich M.T.
      • Durand J.B.
      • et al.
      Reversibility of trastuzumab-related cardiotoxicity: new insights based on clinical course and response to medical treatment.
      At highest risk of LV dysfunction are those aged older than 50 years, with underlying heart disease or hypertension, baseline ejection fraction between 50% and 55%, and those who have received anthracycline therapy.
      • Perez E.A.
      • Suman V.J.
      • Davidson N.E.
      • et al.
      Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial.
      • Suter T.M.
      • Procter M.
      • van Veldhuisen D.J.
      • et al.
      Trastuzumab-associated cardiac adverse effects in the Herceptin adjuvant trial.
      There is less information available on the short- and long-term effect of novel targeted therapies (eg, regorafenib) on cardiovascular health (Supplemental Tables S1-S6).
      Baseline assessment of LV function, before treatment, with agents associated with the development of LV dysfunction, is a necessary component of established monitoring protocols for treatment-related cardiotoxicity.
      • Keefe D.L.
      Trastuzumab-associated cardiotoxicity.
      • Hensley M.L.
      • Hagerty K.L.
      • Kewalramani T.
      • et al.
      American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants.
      • Curigliano G.
      • Cardinale D.
      • Suter T.
      • et al.
      Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.

      Hypertension

      A number of novel targeted cancer therapies are associated with hypertension (Supplemental Tables S1-S6). Therapy-associated hypertension was first described for the antiangiogenic agent sunitinib and might relate to reduced function of nitric oxide synthase, endothelial dysfunction, and disruption of normal capillary function in nontumour tissue.
      • Nazer B.
      • Humphreys B.D.
      • Moslehi J.
      Effects of novel angiogenesis inhibitors for the treatment of cancer on the cardiovascular system: focus on hypertension.
      • Small H.Y.
      • Montezano A.C.
      • Rios F.J.
      • et al.
      Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: understanding and managing a new syndrome.
      Other antiangiogenic agents that might contribute to or worsen hypertension include: bevacizumab
      • Saltz L.B.
      • Clarke S.
      • Díaz-Rubio E.
      • et al.
      Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
      and regorafenib
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      • Van Cutsem E.
      • Sobrero A.
      • et al.
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      in colorectal cancer, and sorafenib
      • Escudier B.
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      • Stadler W.M.
      • et al.
      Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III Treatment Approaches in Renal Cancer Global Evaluation trial.
      and axitinib
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      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      in renal cell carcinoma.

      Myocardial ischemia/arterial thrombosis

      Fluoropyrimidines, including 5-flurouracil and capecitabine, are the most well established cause of coronary arterial spasm leading to acute myocardial ischemia during cancer therapy. Patients with preexisting coronary artery disease (CAD) and those receiving concomitant cisplatin therapy or previous mediastinal irradiation are at highest risk (Supplemental Tables S1-S6). Chest radiation is an important cause of accelerated CAD leading to increased long-term coronary events. However, with modern delivery techniques, the mean radiation cardiac volume exposure dose has decreased with a lifetime risk of major coronary events of 0.05%-3.5%. Risk factors for major coronary events among breast cancer survivors include exposure at a young age, combination with other cardiotoxic agents, and presence of traditional cardiovascular risk factors (Supplemental Tables S1-S6). There are early and late effects of chest radiation that lead to radiation-induced heart disease (RIHD), including pericardial disease, myocardial fibrosis, cardiomyopathy, CAD, valvular disease, and arrhythmias in the setting of myocardial fibrosis.
      • Taunk N.K.
      • Haffty B.G.
      • Kostis J.B.
      • Goyal S.
      Radiation-induced heart disease: pathologic abnormalities and putative mechanisms.
      RIHD morbidity and mortality can be attenuated through careful control of cardiovascular risk factors, lifestyle modification, and avoiding cardiotoxic cancer treatment.
      • Jaworski C.
      • Mariani J.A.
      • Wheeler G.
      • Kaye D.M.
      Cardiac complications of thoracic irradiation.
      Antiangiogenic agents (eg, bevacizumab) have been associated with an increased incidence of arterial thromboembolism, especially in patients older than the age of 65 years with vascular disease.
      • Choueiri T.K.
      • Schutz F.A.
      • Je Y.
      • Rosenberg J.E.
      • Bellmunt J.
      Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials.
      As with LV dysfunction, the rate of arterial thrombotic events with this group of agents is less well established.

      Arrhythmias

      Fluoropyrimidine therapy can cause ventricular arrhythmias as a consequence of myocardial ischemia. Novel cancer therapies, such as tyrosine kinase inhibitors, can prolong the QT interval leading to ventricular arrhythmias. High-risk patients include those with congenital long QT syndrome, history of torsades de points, or baseline corrected QT (QTc) interval > 450 ms. The use of supportive medications for cancer therapy (eg, antiemetics, antidepressants) in combination with cancer treatments can lead to QT prolongation, and careful review of drug interactions should be considered standard of care for all patients who receive cancer treatment.
      • 1.
        We recommend evaluation of traditional cardiovascular risk factors and optimal treatment of cardiovascular disease, as per current CCS guidelines, be part of routine care for all patients before, during, and after receiving cancer therapy (Strong Recommendation, Moderate-Quality Evidence).
      • 2.
        We recommend that patients who receive potentially cardiotoxic cancer therapy undergo evaluation of LV ejection fraction (LVEF) before initiation of cancer treatments known to cause impairment in LV function (Weak Recommendation, Moderate-Quality Evidence).

      Detection and Prevention of Cardiotoxicity

      The most widely applied modality used to detect chemotherapy-induced cardiotoxicity is serial determination of LV function measured before and during cancer therapy.
      • Plana J.C.
      • Galderisi M.
      • Barac A.
      • et al.
      Expert consensus for multi-modality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      The frequency of imaging varies according to the goals of cancer therapy (eg, curative vs palliative) and the type of therapeutic regimen used. The most commonly used marker of LV function is LVEF, regardless of which imaging modality is used. Although the imaging modality chosen should adapt to local institutional expertise, transthoracic echocardiography is the method of choice in view of its wide availability, reproducibility, and versatility. Moreover, transthoracic echocardiography does not expose the patient to radiation and provides additional information on abnormalities of the right ventricle, pericardium, and heart valves.
      • Daher I.N.
      • Kim C.
      • Saleh R.R.
      • et al.
      Prevalence of abnormal echocardiographic findings in cancer patients: a retrospective evaluation of echocardiography for identifying cardiac abnormalities in cancer patients.
      There are currently no consistent recommendations on the frequency and modality with which cardiac imaging should be performed in patients at risk of LV dysfunction related to cancer therapy. Existing surveillance protocols are on the basis of methodology from clinical trials and expert opinion.
      • Curigliano G.
      • Cardinale D.
      • Suter T.
      • et al.
      Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.
      In the case of trastuzumab however, there appears to be consensus in the adjuvant setting to assess LV function at baseline and every 3 months during therapy.
      • Jones A.L.
      • Barlow M.
      • Barrett-Lee P.J.
      • et al.
      Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

      Echocardiographic evaluation

      Although 2-dimensional (2-D) measurement of LVEF has been widely used, its reproducibility is limited with the ability to reliably detect differences only > 10% in LVEF. Because this is the same magnitude of change that is used to adjudicate cardiotoxicity, the sensitivity of 2-D echocardiography for the diagnosis of chemotherapy-induced cardiotoxicity has been questioned.
      • Jacobs L.D.
      • Salgo I.S.
      • Goonewardena S.
      • et al.
      Rapid online quantification of left ventricular volume from real-time three-dimensional echocardiographic data.
      • Otterstad J.E.
      • Froeland G.
      • St John Sutton M.
      • Holme I.
      Accuracy and reproducibility of biplane two-dimensional echocardiographic measurements of left ventricular dimensions and function.
      • Thavendiranathan P.
      • Grant A.D.
      • Negishi T.
      • et al.
      Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
      Three-dimensional (3-D) echocardiography has emerged as the preferred technique for monitoring cardiac function and for the detection of cardiotoxicity.
      • Plana J.C.
      • Galderisi M.
      • Barac A.
      • et al.
      Expert consensus for multi-modality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      Specifically in cancer patients, it has been shown to be more accurate for the detection of chemotherapy-induced cardiotoxicity
      • Armstrong G.T.
      • Plana J.C.
      • Zhang N.
      • et al.
      Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging.
      and has the best reproducibility.
      • Plana J.C.
      • Galderisi M.
      • Barac A.
      • et al.
      Expert consensus for multi-modality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.
      For patients with suboptimal image quality using 2-D echocardiography, the use of myocardial contrast agents might be useful.
      • Yu E.H.
      • Sloggett C.E.
      • Iwanochko R.M.
      • Rakowski H.
      • Siu S.C.
      Feasibility and accuracy of left ventricular volumes and ejection fraction determination by fundamental, tissue harmonic, and intravenous contrast imaging in difficult-to-image patients.
      Contrast agents should be used when 2 contiguous LV segments from any apical view are not visualized on noncontrast images.
      • Mulvagh S.L.
      • Rakowski H.
      • Vannan M.A.
      • et al.
      American Society of Echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography.

      Complementary imaging modalities for LVEF assessment

      There is extensive experience on the efficacy of radionuclide angiography scans (mulitigated acquisition scan [MUGA]) for the identification of asymptomatic declines in LVEF among cancer patients. MUGA scans have consistently been shown to be more reproducible and accurate than standard 2-D echocardiography and have better correlations with 3-D imaging methods such as cardiac magnetic resonance (CMR) imaging and 3-D echocardiography.
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      • Burgess M.I.
      • Ray S.G.
      • et al.
      Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable?.
      • Naik M.M.
      • Diamond G.A.
      • Pai T.
      • Soffer A.
      • Siegel R.J.
      Correspondence of left ventricular ejection fraction determinations from two-dimensional echocardiography, radionuclide angiography and contrast cineangiography.
      • Walker J.
      • Bhullar N.
      • Fallah-Rad N.
      • et al.
      Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging.
      The inability to assess other cardiac structures, and the required radiation exposure, limit the widespread use of this technique.
      In addition to echocardiography and MUGA scans, CMR imaging might be useful for the noninvasive assessment of LV volumes and LVEF in the cancer setting.
      • Walker J.
      • Bhullar N.
      • Fallah-Rad N.
      • et al.
      Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging.
      • Fallah-Rad N.
      • Lytwyn M.
      • Fang T.
      • Kirkpatrick I.
      • Jassal D.S.
      Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy.
      • Zeglinski M.
      • Ludke A.
      • Jassal D.S.
      • Singal P.K.
      Trastuzumab-induced cardiac dysfunction: A ‘dual-hit’.
      CMR imaging is considered the gold standard for the noninvasive assessment of LV systolic function.
      • Strohm O.
      • Schultz-Menger J.
      • Pilz B.
      • et al.
      Measurement of left ventricular dimensions and function in patients with dilated cardiomyopathy.
      In addition to accurate and highly reproducible determination of LV volumes and systolic function.
      • Thavendiranathan P.
      • Wintersperger B.J.
      • Flamm S.D.
      • Marwick T.H.
      Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review.
      • Grothues F.
      • Smith G.C.
      • Moon J.C.
      • et al.
      Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy.
      CMR imaging is also useful for the detection of myocardial edema, perfusion abnormalities, and cardiac fibrosis. The role of these advanced CMR imaging techniques in the assessment of cardiotoxicity is currently evolving.
      Because LV volumes and LVEF values differ significantly across techniques, the imaging modality and method used to determine LVEF should be maintained during treatment and for surveillance after treatment. Importantly, the digital images obtained to calculate LVEF regardless of imaging modality used should be compared with previous ones to minimize interobserver variability.

      Subclinical LV dysfunction evaluation using novel echocardiographic techniques

      Although LVEF remains the best surrogate for systolic function, it is a late marker of cardiotoxicity and one that is highly dependent on preload and afterload conditions. Detecting a decreased LVEF after cancer therapy might be a late finding; therefore, earlier markers of myocardial dysfunction are needed. Echocardiographic myocardial strain analysis, using 2-D speckle tracking imaging, has shown promise in this regard. Global longitudinal strain is a useful early marker predictive of a further decrease in LVEF.
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging and cardiac MRI in predicting early left ventricular dysfunction in patients with HER-2 positive breast cancer treated with adjuvant Trastuzumab therapy.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      • Thavendiranathan P.
      • Poulin F.
      • Lim K.D.
      • et al.
      Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review.
      For patients with available baseline strain measurements, a relative percentage reduction in global longitudinal strain of < 8% from baseline is not meaningful whereas those with > 15% reduction from baseline are very likely to be abnormal.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.

      Utility of cardiac biomarkers for the early detection of chemotherapy-mediated cardiotoxicity

      Although not routinely used in clinical practice, cardiac biomarkers are a reliable diagnostic tool for the early identification, and monitoring of cardiotoxicity. In the breast cancer setting, troponin is a sensitive and specific marker for myocardial injury in chemotherapy-treated patients, and is an early predictor of LV systolic dysfunction.
      • Cardinale D.
      • Sandri M.T.
      • Martinoni A.
      • et al.
      Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy.
      • Sandri M.T.
      • Cardinale D.
      • Zorzino L.
      • et al.
      Minor increases in plasma troponin I predict decreased left ventricular ejection fraction after high-dose chemotherapy.
      Several studies have confirmed that the administration of anticancer drugs, specifically anthracyclines, induce subclinical myocardial injury, which can be associated with increasing levels of B-type natriuretic peptide (BNP).
      • Horacek J.M.
      • Pudil R.
      • Jebavy L.
      • et al.
      Assessment of anthracycline-induced cardiotoxicity with biochemical markers.
      Conversely, in a recent study on human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients treated with combined doxorubicin and trastuzumab, troponin T, C-reactive protein, and BNP were not able to predict early LV systolic dysfunction, which ultimately developed in 25% of the study population.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      Further prospective studies are warranted to evaluate the potential use of cardiac biomarkers, including troponin and C-reactive protein, to identify a subset of patients at highest risk of developing cardiac dysfunction during and after chemotherapy.
      • Cardinale D.
      • Colombo A.
      • Torrisi R.
      • et al.
      Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation.
      • Ky B.
      • Putt M.
      • Sawaya H.
      • et al.
      Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab.
      • 3.
        We recommend the same imaging modality and method be used to determine LVEF before, during, and after completion of cancer therapy (Suggestion, Low-Quality Evidence).
      • 4.
        We suggest that myocardial strain imaging be considered a method for early detection of subclinical LV dysfunction in patients treated with potentially cardiotoxic cancer therapy (Suggestion, Low-Quality Evidence).
      • 5.
        We suggest that serial use of cardiac biomarkers (eg, BNP, troponin) be considered for early detection of cardiotoxicity in cancer patients who receive cardiotoxic therapies implicated in the development of LV dysfunction (Weak Recommendation, Moderate-Quality Evidence).
      Values and preferences. We prefer the use of 3-D echocardiography, whenever feasible and technically satisfactory, for LVEF determination because of its enhanced reproducibility and accuracy.

      Drug therapy in primary prevention

      Primary prevention strategies can be considered for HF, ischemia, arrhythmia, hypertension, or arterial thromboembolism. Primary prevention might include universal treatment of all patients who receive potentially cardiotoxic cancer therapy
      • Bosch X.
      • Rovira M.
      • Sitges M.
      • et al.
      Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the overcome trial (prevention of left ventricular dysfunction with enalapril and carvedilol in patients submitted to intensive chemotherapy for the treatment of malignant hemopathies).
      or early detection of subclinical cardiac injury with targeted treatment.
      • Negishi K.
      • Negishi T.
      • Haluska B.A.
      • et al.
      Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection.
      The former is attractive because it has the potential to prevent any myocardial injury from occurring and does not rely on repeated surveillance. The corollary however, is that primary prophylaxis might unnecessarily expose patients to treatment-related side effects in the absence of any clear benefit.
      Much of the literature on prevention of HF has been generated in subsets of patients treated with anthracyclines.
      • Kalam K.
      • Marwick T.H.
      Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis.
      This has included predominantly breast cancer, but also sarcoma, lymphoma, and leukemia patients. Drugs that have been tested for primary prevention include: β-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and dexrazoxane. Overall, the evidence in support of primary prevention is quite limited because of small study size, variable follow-up, and variable end points; in some studies patients already had HF at the time of medication initiation. However, an important strength of the limited data is that they predominantly come from randomized controlled trials.
      • Vejpongsa P.
      • Yeh E.T.
      Prevention of anthracycline-induced cardiotoxicity.
      On the basis of a recent meta-analysis, in which trials with similar characteristics were combined, the relative risk reduction for LV dysfunction and/or HF with dexrazoxane ranged from 55% to 73% (n = 1163), β-blockers 37%-84% (n = 458), statins 23%-87% (n = 241), and angiotensin antagonists 71%-96% (n = 244) compared with placebo.
      • Kalam K.
      • Marwick T.H.
      Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis.
      Although these data are promising, it is unclear whether they are sufficient to support universal adoption of cardioprotection. Some studies have shown significant intolerance to cardiac medications necessitating discontinuation in approximately one-third of the patients.
      • Negishi K.
      • Negishi T.
      • Haluska B.A.
      • et al.
      Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection.
      This is a particular concern for patients who are at low risk for cardiotoxicity. Unfortunately, there are currently no robust methods for pretreatment risk stratification that would allow for selective treatment of patients who are at high risk for cardiotoxicity. There are currently several ongoing studies such as Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research (MANTICORE) 101,
      • Pituskin E.
      • Haykowsky M.
      • Mackey J.R.
      • et al.
      Rationale and design of the multidisciplinary approach to novel therapies in cardiology oncology research trial (MANTICORE 101-breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI.
      Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA),
      • Heck S.L.
      • Gulati G.
      • Ree A.H.
      • et al.
      Rationale and design of the prevention of cardiac dysfunction during an adjuvant breast cancer therapy (PRADA) trial.
      Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcomes (SUCCOUR) (http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=SUCCOUR&isBasic=True), and ELEVATE (https://clinicaltrials.gov/ct2/show/NCT01708798), which should provide further guidance on the optimal primary prevention approach.
      Currently, there are no data on primary prevention strategies for myocardial ischemia, hypertension, arrhythmias, or arterial thromboembolism in patients who receive cancer therapies. The most significant challenge in articulating a primary prevention strategy is the relative paucity of tools to identify patients at high risk of adverse cardiovascular outcomes. However, general principles should apply until more robust data become available. This includes guideline- and evidence-based treatment of underlying ischemia before initiation of cancer therapy, use of radiation treatment strategies to minimize cardiac injury, treatment of preexisting hypertension, and management of underlying cardiac arrhythmias and conduction system disease.
      • 6.
        We suggest that in patients deemed to be at high risk for cancer treatment-related LV dysfunction, an ACE inhibitor or angiotensin receptor blocker, and/or β-blocker, and/or statin be considered to reduce the risk of cardiotoxicity (Weak Recommendation, Moderate-Quality Evidence).

      Prevention related to RIHD

      The underlying mechanisms of RIHD are related to micro- and macrovascular damage, which leads to clinical manifestations such as pericarditis, CAD, acute myocardial infarction, valvular heart disease, and cardiomyopathy.
      • Lancellotti P.
      • Nkomo V.T.
      • Badano L.P.
      • et al.
      Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      Darby et al. reported that the risk of major coronary events increased linearly with the mean radiation dose to the heart. This increased risk was observed as early as 5 years after radiotherapy and continued for 3 decades.
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      The most important factors influencing RIHD are dose to the heart and the target volume.
      Several modern radiation techniques have been introduced with the aim of reducing the radiation dose to the heart. Modern 3-D conformal radiotherapy planning and intensity-modulated radiotherapy have been reported to reduce radiation dose to the heart, especially in patients with unfavourable cardiac anatomy.
      • Mast M.E.
      • van Kempen-Harteveld L.
      • Heijenbrok M.W.
      • et al.
      Left-sided breast cancer radiotherapy with and without breath-hold: does IMRT reduce the cardiac dose even further?.
      Active breathing control helps patients to reproducibly perform breath-holding during radiotherapy with the aim of reducing the dose to the whole heart and the proximal portion of the left anterior descending coronary artery.
      • Mast M.E.
      • van Kempen-Harteveld L.
      • Heijenbrok M.W.
      • et al.
      Left-sided breast cancer radiotherapy with and without breath-hold: does IMRT reduce the cardiac dose even further?.
      • Zellars R.
      • Bravo P.E.
      • Tryggestad E.
      • et al.
      SPECT analysis of cardiac perfusion changes after whole-breast/chest wall radiation therapy with or without active breathing coordinator: results of a randomized phase 3 trial.
      It is important to explore the risk:benefit ratio and individualize treatment decisions, taking into consideration other factors, such as smoking, diabetes, or history of ischemic heart disease.
      • Darby S.C.
      • Ewertz M.
      • McGale P.
      • et al.
      Risk of ischemic heart disease in women after radiotherapy for breast cancer.
      • Harris E.E.
      • Correa C.
      • Hwang W.T.
      • et al.
      Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment.
      • 7.
        We suggest that modern radiotherapy techniques (eg, 3-D conformal radiotherapy, intensity-modulated radiotherapy) be used during planning mediastinal and chest radiation to reduce the risk of short- and long-term cardiotoxicity (Weak Recommendation, Moderate-Quality Evidence).

      Treatment of Cardiotoxicity

      Despite the beneficial effects of many anticancer drugs, cardiotoxic complications of these treatments might require specific interventions. Herein, we broadly categorize the most common complications of anticancer treatment, including hypertension arrhythmias, ischemia, and LV dysfunction, and describe an approach to management.

      Hypertension

      The treatment of hypertension in the setting of malignancy will vary depending on the underlying cause and the overall goals of care.
      Before considering treatment with an anticancer agent known to cause hypertension (eg, anti-vascular endothelial growth factor inhibitors or multitargeted tyrosine kinase inhibitors), assessment and treatment of baseline cardiovascular risk factors, per established guidelines,
      • Daskalopoulou S.S.
      • Rabi D.M.
      • Zarnke K.B.
      • et al.
      The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
      is recommended. Baseline blood pressure (BP) measurements should be measured at ≥ 2 initial clinic visits to account for, and rule out, transient hypertension. When diagnosed, treatment of hypertension should follow established Canadian Hypertension Education Program guidelines.
      • Daskalopoulou S.S.
      • Rabi D.M.
      • Zarnke K.B.
      • et al.
      The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
      With respect to choice of antihypertensive agent, there are currently no studies to suggest the superiority of any given drug in the cardio-oncology setting. Treatment for cancer patients can be started with a diuretic, β-blocker, ACE inhibitor, angiotensin receptor blocker, or calcium channel blocker accordingly.
      • Daskalopoulou S.S.
      • Rabi D.M.
      • Zarnke K.B.
      • et al.
      The 2015 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
      The choice of agent should be tailored to the individual clinical situation including consideration for potential drug-drug interactions. Careful attention to volume status and renal function, at baseline and through the course of therapy are warranted, because this will affect the choice of an antihypertensive agent and the need for dose adjustments. After initiation of treatment with an antihypertensive agent, weekly monitoring of BP is recommended during the first cycle of therapy, and then every 2-3 weeks for the duration of cancer therapy.

      Arrhythmia

      Arrhythmias represent a less common effect of cancer drugs. Although there might be direct effects of chemotherapy and radiation therapy, there are also many other preexisting patient factors that independently predispose to arrhythmia. Importantly, cancer itself creates an arrhythmogenic milieu. It can be difficult to determine whether one anticancer agent is responsible for an arrhythmia, when multidrug regimens are used. In addition, arrhythmias might coexist in the setting of other cardiotoxic effects (ie, LV systolic dysfunction, ischemia, hypertension), rather than directly related to the administration of the chemotherapeutic agent itself.
      Evaluation and management of new-onset atrial fibrillation should follow CCS guidelines.
      • Skanes A.C.
      • Healey J.S.
      • Cairns J.A.
      • et al.
      Focussed 2012 Update of the Canadian Cardiovacsular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control.
      If the atrial fibrillation is considered to be secondary to the chemotherapy agent, or it complicates the successful delivery of appropriate cancer therapy, it might be reasonable to consider restoration and maintenance of sinus rhythm with elective cardioversion and/or antiarrhythmic therapy, especially if the patient remains symptomatic despite adequate rate control. Decisions to continue with the presumed offending anticancer agent will depend on the clinical situation; however, the existence of atrial fibrillation alone does not warrant discontinuation of cancer therapy.
      Use of warfarin and the novel oral anticoagulants in the setting of chemotherapy poses a unique challenge. It might be more appropriate to anticoagulate at-risk patients with alternative agents, such as low molecular weight heparin; particularly in those who might require multiple procedures or whose cancer treatments can affect the metabolic pathway of oral anticoagulants, making anticoagulant effects unpredictable.
      Drugs associated with asymptomatic bradycardias require no specific monitoring, and no specific intervention is required if identified. The elective concomitant use of heart rate-controlling drugs (ie, β-blockers or nondihydropyridine calcium channel blockers) should be avoided if bradycardia is detected.
      Initial evaluation of patients receiving QT-prolonging drugs should include a baseline electrocardiogram examination and periodic monitoring of the QTc interval should be performed during treatment with these agents. Treatment interruption and dose reduction is advised if no other reversible cause is identified. Permanent discontinuation is indicated if significant QTc prolongation recurs or is accompanied by an arrhythmia, HF, hypotension, shock, syncope, or torsade de pointes.
      • Ghatalia P.
      • Je Y.
      • Kaymakcalan M.D.
      • et al.
      QTc interval prolongation with vascular endothelial growth factor receptor tyrosine kinase inhibitors.
      • Bello C.L.
      • Mulay M.
      • Huang X.
      • et al.
      Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic-pharmacodynamic evaluation of sunitinib.
      • Priori S.G.
      • Schwartz P.J.
      • Napolitano C.
      • et al.
      Risk stratification in the long-QT syndrome.

      Ischemia

      Proposed mechanisms for the spectrum of ischemic complications attributable to anticancer treatments have been inconsistent (coronary vasospasm, thrombosis, and vascular dysfunction), making management challenging. Importantly, these pathologies have not been reliably associated with underlying CAD risk.
      • Kelly C.
      • Bhuva N.
      • Harrison M.
      • et al.
      Use of raltitrexed as an alternative to 5-fluorouracil and capecitabine in cancer patients with cardiac history.
      In the case of antimetabolites (5-fluorouracil [5-FU] and derivatives), it is important to establish the temporal relationship between drug administration and chest pain onset. If symptoms occur during 5-FU administration, the 5-FU should be stopped and an electrocardiogram, cardiac troponin levels, and cardiac monitoring should be performed until cardiac symptoms resolve.
      Acute symptoms should be treated with sublingual nitroglycerin and opioids.
      • Saif M.W.
      • Shah M.M.
      • Shah A.R.
      Fluoropyrimidine-associated cardiotoxicity: revisited.
      If cardiac enzyme levels are found to be elevated, management per American College of Cardiology/American Heart Association acute coronary syndrome (ACS) guidelines should be initiated.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/American College of Cardiology/American Heart Association guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
      Treating physicians should be mindful of issues such as thrombocytopenia and need for future cancer surgery when choosing a revascularization strategy, if needed. In the non-ACS setting, elective assessment for the presence of underlying CAD might be warranted.
      When a diagnosis of myocardial ischemia due to cancer therapy is made (eg, 5-FU), an alternate antineoplastic treatment should be considered. Rechallenge of the offending agent might be considered if no alternate treatment is available. However, this is not routinely recommended, and must be approached with caution because of the frequent recurrence of symptoms
      • Manojlovic N.
      • Babic D.
      • Stojanovic S.
      • et al.
      Capecitabine cardiotoxicity-case reports and literature review.
      • Cianci G.
      • Morelli M.F.
      • Cannita K.
      • et al.
      Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity.
      and should be performed in a controlled setting with close cardiac monitoring and with safer administration regimens (ie, bolus 5-FU instead of infusion, dose reduction).
      • Cianci G.
      • Morelli M.F.
      • Cannita K.
      • et al.
      Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity.
      Prophylactic therapy with nitrates and calcium channel blockers does not appear to be universally effective, but are the only available options.
      • Cianci G.
      • Morelli M.F.
      • Cannita K.
      • et al.
      Prophylactic options in patients with 5-fluorouracil-associated cardiotoxicity.
      For other classes of chemotherapy drugs associated with myocardial ischemia, there are insufficient data to propose management strategies. If ischemia is confirmed, the cancer therapy should be stopped and alternate options should be considered.
      RIHD is an important cause of ischemia in patients treated with radiation to the chest.
      • Mast M.E.
      • van Kempen-Harteveld L.
      • Heijenbrok M.W.
      • et al.
      Left-sided breast cancer radiotherapy with and without breath-hold: does IMRT reduce the cardiac dose even further?.
      It is important to manage cardiac risk factors before, during, and after radiation therapy. Coronary manifestations of RIHD are typically seen several years after completion of treatment and present similarly to other causes of ischemic heart disease.
      • Vermorken J.B.
      • Remenar E.
      • van Herpen C.
      • et al.
      Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer.
      Patients with stable angina should be assessed and managed in the same manner as patients with stable angina from atherosclerotic CAD,
      • Mancini G.B.
      • Gosselin G.
      • Chow B.
      • et al.
      Canadian Cardiovascular Society guidelines for the diagnosis and management of stable ischemic heart disease.
      and those with unstable symptoms managed as per existing ACS guidelines.
      • Amsterdam E.A.
      • Wenger N.K.
      • Brindis R.G.
      • et al.
      2014 AHA/American College of Cardiology/American Heart Association guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
      • Welsh R.C.
      • Travers A.
      • Huynh T.
      • Cantor W.J.
      Canadian Cardiovascular Society Working Group: providing a perspective on the 2007 focused update of the American College of Cardiology and American Heart Association 2004 guidelines for the management of ST elevation myocardial infarction.
      Patients with RIHD might also have mediastinal fibrosis, aortic calcification, valvular heart disease, pericardial disease, and cardiomyopathy.
      • Lancellotti P.
      • Nkomo V.T.
      • Badano L.P.
      • et al.
      Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      Careful review of cardiac imaging is necessary to assess these concomitant lesions, because they have an important effect on the choice of coronary intervention, if needed.

      HF and LV dysfunction

      We now recognize the dose dependency of LV systolic dysfunction with anthracyclines and the potential reversible decline in LVEF seen with trastuzumab, but evidence-based guidelines for management of HF before, during, and after chemotherapy are still elusive in the literature. In cancer patients who develop clinical HF or an asymptomatic decline in LVEF during or after treatment, investigations and management should follow current CCS HF guidelines.
      • Arnold J.M.
      • Liu P.
      • Demers C.
      • et al.
      Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: diagnosis and management.
      Other causes of LV dysfunction should be excluded.
      Cardiac function should be optimized with standard guideline-driven pharmacotherapy for HF. Treatment interruption and avoidance of agents known to cause LV dysfunction (particularly anthracyclines) is appropriate and alternative agents should be used where possible. Daily exercise should be encouraged among all patients before, during, and after chemotherapy as evidence mounts regarding the beneficial effects of exercise in attenuating the risk of cardiotoxicity.
      • Smuder A.J.
      • Kavazis A.N.
      • Min K.
      • Powers S.K.
      Exercise protects against doxorubicin-induced oxidative stress and proteolysis in skeletal muscle.

      Jones L, Dolinsky VW, Haykowsky MJ, et al. Effects of aerobic training to improve cardiovascular function and prevent cardiac remodeling after cytotoxic therapy in early breast cancer. Presented at: 102nd Annual Meeting of the American Association of Cancer Research, April 2-6, 2011; Orlando, FL.

      Trastuzumab presents a unique challenge to the clinician in that LV dysfunction is generally assumed to be transient. Management of patients who experience a reduction in LVEF during trastuzumab therapy have largely followed protocols from large clinical trials in the adjuvant breast cancer setting. It should be noted, however, that the schedule of cardiac assessment and criteria for withholding therapy vary across different trastuzumab studies. In general, patients in these trials with > 10 % reduction in LVEF or to below institutional lower limit of normal using similar imaging modalities of LV function, had therapy held for one cycle, cardiac assessment repeated, and therapy restarted if cardiac function normalized. If not, further therapy was held. There is emerging evidence that early initiation of ACE inhibitor therapy and/or β-blockers can reverse the effects of trastuzumab on LV dysfunction.
      • Seicean S.
      • Seicean A.
      • Alan N.
      • et al.
      Cardioprotective effect of β-adrenoreceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure.
      • Cardinale D.
      • Colombo A.
      • Sandri M.T.
      • et al.
      Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition.
      Aside from trastuzumab adjuvant trials, there are very few studies on the effect of holding or rechallenging patients with these agents. In general, if the risk of LV dysfunction or HF during treatment with the agent exceeds the risk of cancer recurrence without the agent, the agent should be discontinued. This prioritization might shift in the metastatic setting or other scenarios where there might be significant benefit in continuing cancer treatment. Initiating evidence-based LV enhancement therapies, continuing cancer treatment, and close clinical monitoring might be appropriate strategies in this setting.
      • 8.
        We recommend that for patients with preexisting hypertension or for those who experience hypertension related to their cancer therapy, it is important to start, maintain, or augment antihypertensive therapy as per the Canadian Hypertension Education Program guidelines. A target BP of < 140/90 mm Hg should be established for all patients except those with diabetes in whom the goal should be adjusted to < 130/80 mm Hg (Strong Recommendation, High-Quality Evidence).
      • 9.
        We suggest in patients who receive QTc-prolonging agents, a baseline electrocardiogram examination before cancer treatment and periodic monitoring of the QTc during treatment. If the QTc interval exceeds 500 ms during treatment, metabolic and electrolyte disturbances should be identified and corrected, and the use of concomitant QT-prolonging drugs be minimized where possible (Weak Recommendation, Moderate-Quality Evidence).
      • 10.
        We recommend that in cancer patients who develop clinical HF or an asymptomatic decline in LVEF (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) during or after treatment, investigations, and management follow current CCS guidelines. Other causes of LV dysfunction should be excluded (Strong Recommendation, High-Quality Evidence).
      • 11.
        We suggest that alternate antineoplastic treatments be considered if patients experience myocardial ischemia due to their cancer therapy (Suggestion, Low-Quality Evidence).
      Values and Preferences.
      • i.
        Treatment targets (eg, hypertension) should be tailored on the basis of goals of care (eg, curative vs palliative) and by assessing the overall risks and benefits of cancer therapies within this context.
      • ii.
        We suggest cautious use of drugs metabolized by the cytochrome P450 system (eg, diltiazem or verapamil) for hypertension management in patients who receive tyrosine kinase inhibitors because of potential drug-drug interactions.
      • iii.
        Although the CCS guidelines recommend institution of ACE inhibitors/angiotensin receptor blockers, and β-blockers in patients with an LVEF < 40%, in clinical practice, the combination of LV enhancement therapy might be considered in patients with an asymptomatic decline in LVEF (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) during cancer therapy.
      • iv.
        In the setting of trastuzumab-related LV dysfunction, we recommend following the algorithm proposed by Jones et al.,
        • Jones A.L.
        • Barlow M.
        • Barrett-Lee P.J.
        • et al.
        Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.
        recognizing there might be clinical scenarios in which continuing trastuzumab alongside initiation of evidence-based HF therapies might be considered.

      Recommendations for a Multidisciplinary Approach to Cardio-oncology

      Cardio-oncology is a collaborative medical discipline with focused expertise in the prevention, diagnosis, and treatment of cardiovascular disease in cancer patients.
      • Yeh E.T.
      Onco-cardiology: the time has come.
      Historically, cancer patients at high risk of treatment-related cardiotoxicity were referred to cardiology services outside of a formalized program resulting in variability in cardiac assessment, delays in diagnosis, and treatment of cardiac disease, as well as the risk of stopping a potential life-saving cancer treatment. Improved collaboration between oncology and cardiology is needed to address the clinical care gaps experienced by this at-risk patient population, thus leading to the evolution of cardio-oncology as a distinct, inter- and multidisciplinary patient-centred clinical specialty.
      There are currently no established benchmarks to guide clinicians with regard to timely access and assessment of patients who experience cancer-related cardiotoxicity. For cancer patients, wait times to be assessed in a cardio-oncology clinic need to be balanced with the urgency of impending cancer treatments. The CCS HF Companion
      • Howlett J.G.
      • Chan M.
      • Ezekowitz J.A.
      • et al.
      The Canadian Cardiovascular Society Heart Failure Companion: bridging guidelines to your practice.
      provides wait-time benchmarks for HF patients to be seen in a specialty clinic. The patient receiving active treatment will generally require more urgent access (1-2 weeks), and it might be appropriate for patients not receiving active therapy (eg, surveillance) to be seen in a less timely fashion (weeks to months). We believe this framework might also be applicable in the cardio-oncology setting.
      It is important to acknowledge the potential for late cardiac complications in long-term cancer survivors. Although beyond the scope of this document, health care providers caring for adult survivors of pediatric cancer should refer to the Children's Oncology Group long-term follow-up guidelines at: http://www.survivorshipguidelines.org/pdf/LTFUGuidelines_40.pdf.

      A Call to Action

      In clinical practice, the cardiovascular surveillance of cancer patients is inconsistent and there is a lack of evidence to guide therapies. The European Society of Medical Oncology have published guidelines for the cardiovascular surveillance of cancer patients who receive anthracyclines (with or without trastuzumab) and have recommended assessment of heart function (LVEF) with serial echocardiograms, and troponin levels (with each cycle of anthracycline-based therapy).
      • Curigliano G.
      • Cardinale D.
      • Suter T.
      • et al.
      Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines.
      However, the feasibility and cost effectiveness of this multimodality approach is not defined and has not yet been evaluated in the cancer community at large. Furthermore, it is unclear if early detection strategies decrease the burden of cardiovascular disease and ultimately improve the outcome of cancer survivors. Further complicating the clinical management of cardiotoxicity is the lack of high-quality evidence for effective primary and secondary prevention strategies.
      Thus, we believe that there is an urgent need for collaborative studies to help guide patient management. Large prospective registries will enable the development of risk models for predicting cardiovascular events among cancer survivors as well as evaluate the downstream effect of surveillance strategies for cardiac toxicity prevention. Multicentre randomized controlled trials are also needed to test traditional and novel pharmacotherapy as primary and secondary interventions. Effective knowledge translation strategies as well as education of trainees will be required to increase awareness and provide guidance on the management of these patients. Organizations such as the CCS, Canadian Cardiac Oncology Network (www.cardiaconcology.ca) and the International CardiOncology Society (www.icosna.org) will continue to play an important role in promoting the development of clinical care models, development of educational structures, and promotion of evidence-based research.
      • 12.
        We suggest that patients at high risk of cancer therapy-related cardiovascular disease or patients who develop cardiovascular complications during cancer therapy (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) be referred to a cardio-oncology clinic or practitioner skilled in the management of this patient population, for optimization of cardiac function and consideration of primary or secondary prevention strategies (Suggestion, Low-Quality Evidence).

      Supplementary Material

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