- Email: [email protected]
Rehabilitation Needs in Cancer Treatment-Related Cardiotoxicity
ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2020) 150986
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Rehabilitation Needs in Cancer Treatment-Related Cardiotoxicity Edith Pituskin, PhD, MN (NP), RNa,*, Amy A. Kirkham, PhD, P.Kin, ATTHb, Nanette Cox-Kennett, MN, RN (NP)c, Rebecca Dimitry, MN, RN (NP)c, John Dimitry, MD, FRCPCc, Ian Paterson, MD, FRCPCd, Gabor T. Gyenes, MD, PhDe a
Faculty of Nursing, Edmonton Clinic Health Academy (ECHA), Edmonton, AB, Canada Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada c Medical Oncology, Alberta Health Services, Edmonton, AB, Canada d Division of Cardiology, University of Alberta, Edmonton, AB, Canada e Cardiac Rehabilitation, Division of Cardiology, University of Alberta, Edmonton, AB, Canada b
A R T I C L E
I N F O
Key Words: survivorship rehabilitation cardiotoxicity cardiovascular chemotherapy radiation therapy tyrosine kinase inhibitor
Objectives: To examine and summarize current international guidelines regarding cardiovascular risk reduction before and during cancer therapy, and to discuss the emerging role of cardio-oncology as a subspecialty in cancer care and the role of cardio-oncology rehabilitation. Data Sources: Published articles and guidelines. Conclusion: With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number of individuals now survive a cancer diagnosis. However, for some the cost is high — many survivors are now at higher risk of death from cardiovascular disease than from recurrent cancer. Cardiovascular morbidity and mortality are common and associated with common cancer therapies serially administered in adult oncology care. Implications for Nursing Practice: Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and support the patient within the family and community. © 2020 Elsevier Inc. All rights reserved.
At some point in their lives more than half of all North Americans will be diagnosed with cancer, with 1,762,450 new cases estimated to occur in the United States in 2019.1,2 With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number now survive a cancer diagnosis, projecting to exceed 20 million individuals by 2026.3 In fact, the number of cancer survivors is increasing at twice the rate of new cancer diagnoses.4 But for some the cost is high — many survivors are now at higher risk of death from cardiovascular disease (CVD) than from recurrent cancer.5 The majority of chemotherapeutic agents, thoracic radiation, and other anticancer systemic medications (including monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies) can have deleterious effects on the cardiovascular system. Subclinical signs of cardiovascular damage can occur early in active treatment and often before the development of symptoms. Symptoms of cardiovascular dysfunction may not be manifested for several years after the completion of treatment. This review will address cardiovascular morbidities associated with curative cancer treatment in adult oncology, the emerging
* Address correspondence to: Edith Pituskin PhD, MN (NP), RN, Faculty of Nursing, 3-141 Edmonton Clinic Health Academy (ECHA), 11405 87 Ave., Edmonton, AB Canada T6G 1C9. E-mail address: [email protected] (E. Pituskin). https://doi.org/10.1016/j.soncn.2020.150986 0749-2081/© 2020 Elsevier Inc. All rights reserved.
role of cardio-oncology as a subspecialty in cancer care, and the role of cardiac rehabilitation (CR) in this population. Systemic Therapies Cardiotoxicity was recognized as a consequence of cancer therapy as early as the 1960s. Adult leukemia survivors who received multidrug chemotherapy regimens that included anthracyclines experienced arrhythmias, heart failure and sudden cardiac-related deaths.6 However, cardio-oncology was not recognized as a necessary field of study or medicine until the early 2000,s with overwhelming evidence of heart failure in patients with breast cancer resulting from antihuman epidermal growth factor 2 (HER2+) targeted antibody (trastuzumab).7 Other classes of cancer drugs, such as alkylating agents, microtubule agents, estrogen agents, and others, are also recognized for cardiac complications. However, associated declines in heart function are less common.7 The modern definition of cardiotoxicity is a drop in left ventricular ejection fraction (LVEF) by >10 points to a value of <53%, preferably assessed by echocardiography.8 However, cardiotoxicity actually represents a much broader spectrum of cardiac injury, including tissue inflammation, edema and fibrotic changes, electrophysiologic instability, changes in blood pressure control, valvular dysfunction, myocardial ischemia, and thrombogenesis.7 The predominant therapies associated with cardiotoxicity are
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those involving anthracyclines, radiation therapy to the chest and/or mediastinum, and monoclonal antibody-based or ‘targeted’ kinase therapies. As sequential or multi-drug treatment protocols are the standard of care for many types of cancers, patients treated with such protocols are considered to be at particularly high risk.9 Anthracyclines remain a widely used and active class of drugs for many cancer types, including breast, lymphoma, leukemia, and gynecologic.10 An “acceptable ceiling” of doxorubicin dose is thought to be in the 400 to 450 mg/m2 range, allowing for an estimated 5% risk of developing overt heart failure. However, cardiotoxicity is not reliably related to cumulative anthracycline dose. In 135 consecutive patients with lymphoma treated with standard-dose regimen of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with anthracycline doses >200 mg/m2, early onset cardiac toxicity was identified clinically in 27 (20%) at 1 year, with those >50 years of age at higher risk.11 Among these, 14 patients had clinical signs of heart failure directly attributable to the anti-cancer therapy, and three patients died from cardiac causes. Hequet et al12 assessed outcomes in 141 patients with lymphoma 5 years post-chemotherapy, demonstrating a drop in LV function among 39 (27.6%) of patients using echocardiography. Importantly, only eight of the 39 patients had received a doxorubicin dose >300 mg/m2, indicating that even conservative doxorubicin dosing conveys long-term cardiac effects. Such findings would imply a looming health issue for the >60,000 patients per year exposed to anthracyclines in the United States alone.13 The development of tyrosine kinase inhibitors and monoclonal antibodies, driven by advances in molecular biology, have dramatically changed the landscape of oncology care. In multivariate analysis of randomized clinical trials studying trastuzumab (n = 9,117 HER2+ early patients with breast cancer) the treatment arms were associated with a 30% reduction in mortality (pooled odds ratio, 0.52).14 Unfortunately, this same study found a 2.45-fold higher (95% confidence interval 1.89 3.16) likelihood of cardiotoxicity in the trastuzumab arms. The Cochrane review of trastuzumab randomized controlled trials (11,191 patients in eight trials) identified a 5-fold increase in the relative risk of heart failure and nearly doubled risk of LVEF decline.15 The anti-cancer activities of HER2 inhibition, including promotion of angiogenesis, cell apoptosis, and inhibition of metastases, are the same vital pathways in the heart that influence cell survival in the setting of stress, ischemia, hypertension, or aging. Of note, some authors have suggested that trastuzumab-related cardiotoxicity may be ‘reversible.’ However, this remains controversial. In 36 of 152 (22%) patients that stopped trastuzumab because of LV systolic dysfunction, even with optimal treatment in expert hands 14 of 36 (40%) showed no improvement or worsening of LVEF over time.16,17 In >45,000 women in the US, adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 heart failure or cardiomyopathy occurrence per 100 patients over 1, 2, and 3 years of follow-up, respectively.17 Taken together, these data debunk the notion that trastuzumab does not contribute to increased risk of cardiomyopathy over time. Recently, attention has focused on ibrutinib, an oral Bruton’s tyrosine kinase inhibitor and a highly effective treatment against many lymphoid malignancies. Arrhythmias have been known to develop in approximately 20% of patients taking ibrutinib, and significant hypertension has also been reported. In patients assessed at a median 30 months, nearly 80% had new or worsening hypertension (increase >10mmHg systolic) contributing to atrial fibrillation, heart failure, and other major adverse cardiac events.18 Taken together, as these targeted therapies are developed and utilized, oncology nurses must be vigilant for off-target and other unexpected effects to organ systems.
exposure and dose delivered to the myocardium.19 These effects are primarily related to radiation-induced fibrosis and scarring of cardiac tissues, with microvascular damage affecting the coronary vasculature, accelerating age-related atherosclerosis, and the development of obstructive coronary artery disease. Ten percent to 30% of breast cancer survivors experience symptomatic heart disease 5 to 10 years posttreatment, and up to 88% are found to have asymptomatic abnormalities of the heart muscle, valves, pericardium, conduction abnormalities, and vasculature.20 In a retrospective analysis of 2,168 patients with breast cancer, cardiac events increased linearly by 7.4% with each Gray directed to the heart, with no apparent threshold.19 Patients with lymphoma who present with bulky lymph node masses or have evidence of isolated residual mediastinal disease routinely receive radiation therapy after completing induction chemotherapy. In long-term follow-up, a 3- to 5-fold increased incidence of CVD (myocardial infarction, angina, and heart failure) compared with the general population is observed.21 While approaches aiming to limit dose to left ventricle and coronary vessels are now being employed (3-D planning, breath hold techniques, and patient positioning), data evaluating contemporary cardiovascular risk using these approaches are lacking. How Big of an Issue is Cardiotoxicity, and What Can Be Done? Some survivors are now at higher risk of death from cardiovascular causes than from recurrent cancer.5 A population-based study showed that people with breast cancer who received chemotherapy had admission rates for heart failure 3-fold that of age-matched controls, within only 3 years of treatment completion.22 Heart failure has no cure and the mortality rate is 50% within 5 years of heart failure diagnosis. The American Heart Association estimates costs for heart failure the US are $30.7 billion annually, not including individual costs to patient and family from symptom management, loss of independence or work, or loss of life. The American Society of Clinical Oncology published a Practice Guideline for prevention and monitoring of cardiac dysfunction in adult cancer patients,9 as have other clinical organizations.23,24 In addition to reviewing the aforementioned cancer treatment modalities, guidelines recommend identification and management of cardiovascular risk factors, the focus of the remainder of this paper. Interventions Before Treatment The oncology nurse should undertake a careful baseline evaluation of cardiovascular risk factors as the initial step to identify patients at increased risk for cardiotoxicity (Table 1).9,24 These risk factors are not an exclusive list, and clinicians should comprehensively assess all potential issues. Key factors well-established to contribute to cardiotoxicity to date have not been studied in cancer patients. However, preliminary evidence in women with breast cancer suggests that women who present with hypertension, diabetes, hypercholesterolemia, or CVD prior to or at the time of diagnosis have an elevated risk of CVD-related mortality.5,25 Whether or not this is related to the breast cancer diagnosis, careful assessment and management of cardiovascular risk factors appears prudent in cancer populations. Another under-addressed area is the effect of psychosocial stressors on development of CVD in cancer patients. In women with breast cancer and no prior CVD, anxiety conveys 48% increased hazard for
Table 1 Baseline risk factors for cardiotoxicity.
Local Therapy
Non-modifiable
Cardiotoxicity associated with radiotherapy to the thorax is a wellestablished phenomenon increasing in prevalence with time from
Modifiable
Age > 60, pre-existing cardiovascular diseases, dyslipidemia, hypertension, borderline LV function (50%-55%) Smoking, high alcohol consumption, obesity, sedentary behavior, psychosocial stress
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subsequent CVD.26 Patient-reported mental and physical symptoms should be documented and investigated at each visit. Physical examination should include careful assessment of blood pressure, auscultation of lung fields, complete cardiac examination including assessment of jugular venous pressure and inspection for peripheral and central edema. These assessments should be performed at each clinical visit. Interventions During Treatment: Cardio-Oncology Rehabilitation During treatment, guidelines advocate management of modifiable cardiovascular risk factors in all patients receiving potentially cardiotoxic therapies.9,24 This represents an entirely new approach to supportive care during the cancer trajectory. Major centers have established cardio-oncology programs for both primary and secondary prevention, engaging multiple health disciplines to address patients’ complex needs (including nursing, physicians, pharmacists, nutritionists, psychologists, and exercise therapists).27,28 Such programs are remarkably similar to the model of CR, which for decades has proven to be an effective approach in the holistic care of people with heart disease.29 Indeed, given that CR centers are widely available in the community, this presents an ideal opportunity for an established team of experts to provide rehabilitation care to high treatment-risk cancer patients. In a pilot project, we referred patients with relapsed lymphoma undergoing stem cell transplantation to an established CR program.30 Functional testing was performed before stem cell collection and after discharge from hospital, with the CR program commencing thereafter. No adverse events occurred, and we showed that adherence to exercise was good (57%), exceeding that of traditional CR populations. Moreover, functional tests performed after the 8-week program including 6-minute walk test and grip strength not only met but exceeded baseline measurements. Accordingly, we have shown proof-of-principle that this collaboration with a CR center with cancer patients receiving high-risk treatment is safe and feasible. Other groups have reported that a CR program customized to patients with breast cancer improved cardiorespiratory fitness, quality of life, and depression symptoms.31 A diverse range of care models are possible, from tertiary centers of excellence with on-site services to community-based networks of resources, local experts, and outreach programs such as telehealth,32 also established approaches in successful CR care delivery.33 The core components of CR include physical activity counseling, nutrition counseling, psychosocial support, weight management,
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smoking cessation, and management of hypertension, diabetes, and dyslipidemia. Exercise is the cornerstone of CR and has also been embraced by the oncology research and clinical community9,33,34 as a critical component of supportive care. Exercise has been studied in oncology populations since the late 1980s as a therapeutic intervention both during and after cancer treatment.35 Multiple health benefits have been described, including most commonly improved physical function and exercise capacity (ie, cardiorespiratory fitness), muscular strength, and quality of life. Weight loss and improved body composition (loss of fat mass) also result from exercise training and nutritional advice in oncology populations. Oncology nurses can help patients navigate self-directed lifestyle behavior improvement or direct patients to available resources and facilities, based on patient abilities and local availability of expertise (Fig. 1). Currently, oncology exercise recommendations are generic, suggesting 150 minutes of moderate-intensity aerobic exercise per week, similar to recommendations for the general adult population.36 However, it has been suggested that a more personalized approach is needed, customizing the exercise program to the individual based on maximal cardiopulmonary exercise testing as well as assessment of baseline risks and the prescribed treatment regimens.37,38 Additionally, functional impairments resulting from tumor-related effects or surgery should be addressed by physiotherapy and/or occupational therapy expertise, with exercise customized accordingly. Moreover, while substantial evidence demonstrates the beneficial effects of exercise on cardiorespiratory fitness, limited evidence currently exists for its use as a treatment for cancer therapy-related cardiotoxicity.39 Management of smoking cessation, hypertension, diabetes, and dyslipidemia are also key areas where the oncology nurse can provide important support. Medication compliance can be aided with conversations regarding timing of medications and management of side effects. Again, regular symptom review to evaluate fatigue, shortness of breath, or other potentially concerning symptoms should be performed regularly, with careful attention to any changes. Given the wide variability of cardio-oncology expertise and support, the oncology nurse may be the primary cardio-oncology care provider. Armed with knowledge of available resources and facilities, oncology nurses can navigate patients according to individual needs and local expertise. Oncology nurses can also contribute to cardiovascular health and treatment safety across multiple disease populations. In patients referred for bone marrow transplantation, we have shown when systematic pre-transplant screening is performed by
Fig. 1. Recommended cardio-oncology rehabilitation approach.
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skilled oncology nurse practitioner, 20% required cardio-oncology assessment and treatment, with 100% successfully proceeding to transplantation.40 Future Directions Currently, the greatest challenge faced by clinicians is determining which individual patients will develop cardiotoxicity, and when. We recommend large collaborative and prospective registries with exhaustive metrics, including comprehensive cardiovascular history, oncologic treatments, relative dose intensities, and patient-reported outcomes to develop personalized risk algorithms. With this information in hand, point-of-care tools could be developed to aid end-users, wherever they may be. Providers will be able to make evidencebased decisions regarding preventive measures and treatment strategies. Survivors will better understand their individual risks and receive personalized supports. Ultimately, people will live longer and live better after cancer treatment. Future directions in cardio-oncology research should aim to quantify the benefit of rehabilitation and work toward adopting feasible and effective models of CR in oncology populations. CR has repeatedly demonstrated benefits for mortality reduction, symptom relief, reduction in smoking, and improved exercise tolerance, risk factors modification, and the overall psychosocial well-being in patients with multiple cardiac conditions including ischemic heart disease, heart failure, and post heart surgery.29 Whether similar benefits can be afforded to oncology populations remains to be seen. CR providers will need extensive education regarding common issues experienced by cancer patients that would potentially affect exercise capacity or ability, including pancytopenia, intravenous access devices, and radiation dermatitis or desquamation. Issues of referral, enrollment, and retention to CR will be an important future consideration. Participation rates in CR in cardiac populations in the US are poor, ranging from 20% to 30% because of inadequate referral rates, enrollment of inappropriate individuals, and suboptimal adherence.41 Compelling evidence and concerted educational efforts will be required in the oncology setting. We have completed recruitment to TITAN, a randomized clinical trial studying the effect of intensive multidisciplinary care including exercise, nutrition, and cardio-oncology supervision to usual care, with our primary outcome LVEF at 1 year.42 The intervention, based on a CR model, will be an initial step in determining the utility of such approaches in cardio-oncology populations. Implications for Oncology Nursing The number of cancer diagnoses and cancer survivors are increasing exponentially. With advances in traditional and targeted therapies, an entirely new and rapidly growing population requiring supportive care from cardiovascular effects of necessary treatment is emerging. Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and to support the patient within the family and community. Future work should focus on developing personalized risk profiles and holistic interventions. References 1. Canadian Cancer Statistics Advisory Committee. Canadian cancer statistics 2019. Toronto, ON: Canadian Cancer Society; 2019. Available at: cancer.ca/CanadianCancer-Statistics-2019-EN. Accessed 30 September 2019. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7– 34. 3. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–289.
4. de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers Prev. 2013;22:561–570. 5. Patnaik JL, Byers T, DiGuiseppi C, Dabelea D, Denberg TD. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res. 2011;13: R64. 6. Malpas JS, Scott RB. Rubidomycin in acute leukaemia in adults. Br Med J. 1968;3:227–229. 7. Truong J, Yan AT, Cramarossa G, Chan KKW. Chemotherapy-induced cardiotoxicity: detection, prevention, and management. Can J Cardiol. 2014;30:869–878. 8. Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality 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. Eur Heart J Cardiovasc Imaging. 2014;15:1063–1093. 9. Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2017;35:893–911. 10. Smith LA, Cornelius VR, Plummer CJ, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337. 11. Limat S, Demesmay K, Voillat L, et al. Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2003;14:277–281. 12. Hequet O, Le QH, Moullet I, et al. Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol. 2004;22:1864–1871. 13. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55:213–220. 14. Viani GA, Afonso SL, Stefano EJ, De Fendi LI, Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153. 15. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4: CD006243. 16. Wadhwa D, Fallah-Rad N, Grenier D, et al. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat. 2009;117:357–364. 17. Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol. 2012;60:2504–2512. 18. Dickerson T, Wiczer T, Waller A, et al. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019;134:1919–1928. 19. Darby SC, Ewertz M, Hall P. Ischemic heart disease after breast cancer radiotherapy. N Engl J Med. 2013;368:2527. 20. Cutter DJ, Darby SC, Yusuf SW. Risks of heart disease after radiotherapy. Tex Heart Inst J. 2011;38:257–258. 21. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood. 2007;109:1878–1886. 22. La Rosa E, Consoli SM, Le Clesiau H, Birouste J, Joubert M, Soufi K. [Psychosocial distress and its moderating factors in patients living in precarious socioeconomic conditions consulting in a preventive health and social work center]. Rev Epidemiol Sante Publique. 2000;48:351–362. [Article in French]. 23. Virani SA, Dent S, Brezden-Masley C, et al. Canadian Cardiovascular Society Guidelines for evaluation and management of cardiovascular complications of cancer therapy. Can J Cardiol. 2016;32:831–841. 24. Zamorano JL, Lancellotti P, Rodriguez Munoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur J Heart Fail. 2017;19:9–42. 25. Simon MS, Beebe-Dimmer JL, Hastert TA, et al. Cardiometabolic risk factors and survival after breast cancer in the Women's Health Initiative. Cancer. 2018;124: 1798–1807. 26. Schoormans D, van de Poll-Franse L, Vissers P, et al. Pharmaceutically treated anxiety but not depression prior to cancer diagnosis predicts the onset of cardiovascular disease among breast cancer survivors. Breast Cancer Res Treat. 2017;166:259–266. 27. Parent S, Pituskin E, Paterson DI. The Cardio-oncology Program: a multidisciplinary approach to the care of cancer patients with cardiovascular disease. Can J Cardiol. 2016;32:847–851. 28. Dittus KL, Lakoski SG, Savage PD, et al. Exercise-based oncology rehabilitation: leveraging the cardiac rehabilitation model. J cardiopulm Rehabil Prev. 2015;35: 130–139. 29. Mampuya WM. Cardiac rehabilitation past, present and future: an overview. Cardiovasc Diagn Ther. 2012;2:38–49. 30. Rothe D, Cox-Kennett N, Buijs DM, et al. Cardiac rehabilitation in patients with lymphoma undergoing autologous hematopoietic stem cell transplantation: A cardiooncology pilot project. Can J Cardiol. 2018;34:S263–S269. https://doi.org/10.1016/j. cjca.2018.07.001. 31. Dolan LB, Barry D, Petrella T, et al. The Cardiac Rehabilitation Model improves fitness, quality of life, and depression in breast cancer survivors. J Cardiopulm Rehabil Prev. 2018;38:246–252. 32. McLean LD, Clark AM. Telehealth interventions versus center-based cardiac rehabilitation: it's time to strengthen the evidence. Eur J Prev Cardiol. 2016;23:21–22. 33. Segal R, Zwaal C, Green E, Tomasone JR, Loblaw A, Petrella T, Exercise for People with Cancer Guideline Development Group. Exercise for people with cancer: a clinical practice guideline. Curr Oncol. 2017;24:40–46.
ARTICLE IN PRESS E. Pituskin et al. / Seminars in Oncology Nursing 00 (2020) 150986 34. Hayes SC, Newton RU, Spence RR, Galvao DA. The Exercise and Sports Science Australia position statement: exercise medicine in cancer management. J Sci Med Sport. 2019;22:1175–1199. 35. Winningham ML, MacVicar MG, Burke CA. Exercise for cancer patients: guidelines and precautions. Phys Sportsmed. 1986;14:125–134. 36. Wolin KY, Schwartz AL, Matthews CE, Courneya KS, Schmitz KH. Implementing the exercise guidelines for cancer survivors. J Support Oncol. 2012;10:171–177. 37. Scott JM, Zabor EC, Schwitzer E, et al. Efficacy of exercise therapy on cardiorespiratory fitness in patients with cancer: a systematic review and meta-analysis. J Clin Oncol. 2018;36:2297–2305. 38. Gilchrist SC, Barac A, Ades PA, et al. Cardio-oncology rehabilitation to manage cardiovascular outcomes in cancer patients and survivors: a scientific statement from the American Heart Association. Circulation. 2019;139:e997–e1012.
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39. Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ. Curing breast cancer and killing the heart: a novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer. Prog Cardiovasc Dis. 2019;62:116–126. 40. Pituskin E, Cox-Kennett N, Becher H, et al. Cardio-oncology interventions in outpatients referred for autologous bone marrow transplantation. J Clin Oncol. 2016;34:137. 41. Ades PA, Keteyian SJ, Wright JS, et al. Increasing cardiac rehabilitation participation from 20% to 70%: a road map from the Million Hearts Cardiac Rehabilitation Collaborative. Mayo Clin Proc. 2017;92:234–242. 42. Pituskin E, Haykowsky M, McNeely M, Mackey J, Chua N, Paterson I. Rationale and design of the multidisciplinary team IntervenTion in cArdio-oNcology study (TITAN). BMC Cancer. 2016;16:733.
Contents lists available at ScienceDirect
Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing
Rehabilitation Needs in Cancer Treatment-Related Cardiotoxicity Edith Pituskin, PhD, MN (NP), RNa,*, Amy A. Kirkham, PhD, P.Kin, ATTHb, Nanette Cox-Kennett, MN, RN (NP)c, Rebecca Dimitry, MN, RN (NP)c, John Dimitry, MD, FRCPCc, Ian Paterson, MD, FRCPCd, Gabor T. Gyenes, MD, PhDe a
Faculty of Nursing, Edmonton Clinic Health Academy (ECHA), Edmonton, AB, Canada Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada c Medical Oncology, Alberta Health Services, Edmonton, AB, Canada d Division of Cardiology, University of Alberta, Edmonton, AB, Canada e Cardiac Rehabilitation, Division of Cardiology, University of Alberta, Edmonton, AB, Canada b
A R T I C L E
I N F O
Key Words: survivorship rehabilitation cardiotoxicity cardiovascular chemotherapy radiation therapy tyrosine kinase inhibitor
Objectives: To examine and summarize current international guidelines regarding cardiovascular risk reduction before and during cancer therapy, and to discuss the emerging role of cardio-oncology as a subspecialty in cancer care and the role of cardio-oncology rehabilitation. Data Sources: Published articles and guidelines. Conclusion: With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number of individuals now survive a cancer diagnosis. However, for some the cost is high — many survivors are now at higher risk of death from cardiovascular disease than from recurrent cancer. Cardiovascular morbidity and mortality are common and associated with common cancer therapies serially administered in adult oncology care. Implications for Nursing Practice: Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and support the patient within the family and community. © 2020 Elsevier Inc. All rights reserved.
At some point in their lives more than half of all North Americans will be diagnosed with cancer, with 1,762,450 new cases estimated to occur in the United States in 2019.1,2 With improvements in cancer detection and the use of novel adjuvant therapies, an increasing number now survive a cancer diagnosis, projecting to exceed 20 million individuals by 2026.3 In fact, the number of cancer survivors is increasing at twice the rate of new cancer diagnoses.4 But for some the cost is high — many survivors are now at higher risk of death from cardiovascular disease (CVD) than from recurrent cancer.5 The majority of chemotherapeutic agents, thoracic radiation, and other anticancer systemic medications (including monoclonal antibodies, tyrosine kinase inhibitors, and immunotherapies) can have deleterious effects on the cardiovascular system. Subclinical signs of cardiovascular damage can occur early in active treatment and often before the development of symptoms. Symptoms of cardiovascular dysfunction may not be manifested for several years after the completion of treatment. This review will address cardiovascular morbidities associated with curative cancer treatment in adult oncology, the emerging
* Address correspondence to: Edith Pituskin PhD, MN (NP), RN, Faculty of Nursing, 3-141 Edmonton Clinic Health Academy (ECHA), 11405 87 Ave., Edmonton, AB Canada T6G 1C9. E-mail address: [email protected] (E. Pituskin). https://doi.org/10.1016/j.soncn.2020.150986 0749-2081/© 2020 Elsevier Inc. All rights reserved.
role of cardio-oncology as a subspecialty in cancer care, and the role of cardiac rehabilitation (CR) in this population. Systemic Therapies Cardiotoxicity was recognized as a consequence of cancer therapy as early as the 1960s. Adult leukemia survivors who received multidrug chemotherapy regimens that included anthracyclines experienced arrhythmias, heart failure and sudden cardiac-related deaths.6 However, cardio-oncology was not recognized as a necessary field of study or medicine until the early 2000,s with overwhelming evidence of heart failure in patients with breast cancer resulting from antihuman epidermal growth factor 2 (HER2+) targeted antibody (trastuzumab).7 Other classes of cancer drugs, such as alkylating agents, microtubule agents, estrogen agents, and others, are also recognized for cardiac complications. However, associated declines in heart function are less common.7 The modern definition of cardiotoxicity is a drop in left ventricular ejection fraction (LVEF) by >10 points to a value of <53%, preferably assessed by echocardiography.8 However, cardiotoxicity actually represents a much broader spectrum of cardiac injury, including tissue inflammation, edema and fibrotic changes, electrophysiologic instability, changes in blood pressure control, valvular dysfunction, myocardial ischemia, and thrombogenesis.7 The predominant therapies associated with cardiotoxicity are
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those involving anthracyclines, radiation therapy to the chest and/or mediastinum, and monoclonal antibody-based or ‘targeted’ kinase therapies. As sequential or multi-drug treatment protocols are the standard of care for many types of cancers, patients treated with such protocols are considered to be at particularly high risk.9 Anthracyclines remain a widely used and active class of drugs for many cancer types, including breast, lymphoma, leukemia, and gynecologic.10 An “acceptable ceiling” of doxorubicin dose is thought to be in the 400 to 450 mg/m2 range, allowing for an estimated 5% risk of developing overt heart failure. However, cardiotoxicity is not reliably related to cumulative anthracycline dose. In 135 consecutive patients with lymphoma treated with standard-dose regimen of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with anthracycline doses >200 mg/m2, early onset cardiac toxicity was identified clinically in 27 (20%) at 1 year, with those >50 years of age at higher risk.11 Among these, 14 patients had clinical signs of heart failure directly attributable to the anti-cancer therapy, and three patients died from cardiac causes. Hequet et al12 assessed outcomes in 141 patients with lymphoma 5 years post-chemotherapy, demonstrating a drop in LV function among 39 (27.6%) of patients using echocardiography. Importantly, only eight of the 39 patients had received a doxorubicin dose >300 mg/m2, indicating that even conservative doxorubicin dosing conveys long-term cardiac effects. Such findings would imply a looming health issue for the >60,000 patients per year exposed to anthracyclines in the United States alone.13 The development of tyrosine kinase inhibitors and monoclonal antibodies, driven by advances in molecular biology, have dramatically changed the landscape of oncology care. In multivariate analysis of randomized clinical trials studying trastuzumab (n = 9,117 HER2+ early patients with breast cancer) the treatment arms were associated with a 30% reduction in mortality (pooled odds ratio, 0.52).14 Unfortunately, this same study found a 2.45-fold higher (95% confidence interval 1.89 3.16) likelihood of cardiotoxicity in the trastuzumab arms. The Cochrane review of trastuzumab randomized controlled trials (11,191 patients in eight trials) identified a 5-fold increase in the relative risk of heart failure and nearly doubled risk of LVEF decline.15 The anti-cancer activities of HER2 inhibition, including promotion of angiogenesis, cell apoptosis, and inhibition of metastases, are the same vital pathways in the heart that influence cell survival in the setting of stress, ischemia, hypertension, or aging. Of note, some authors have suggested that trastuzumab-related cardiotoxicity may be ‘reversible.’ However, this remains controversial. In 36 of 152 (22%) patients that stopped trastuzumab because of LV systolic dysfunction, even with optimal treatment in expert hands 14 of 36 (40%) showed no improvement or worsening of LVEF over time.16,17 In >45,000 women in the US, adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 heart failure or cardiomyopathy occurrence per 100 patients over 1, 2, and 3 years of follow-up, respectively.17 Taken together, these data debunk the notion that trastuzumab does not contribute to increased risk of cardiomyopathy over time. Recently, attention has focused on ibrutinib, an oral Bruton’s tyrosine kinase inhibitor and a highly effective treatment against many lymphoid malignancies. Arrhythmias have been known to develop in approximately 20% of patients taking ibrutinib, and significant hypertension has also been reported. In patients assessed at a median 30 months, nearly 80% had new or worsening hypertension (increase >10mmHg systolic) contributing to atrial fibrillation, heart failure, and other major adverse cardiac events.18 Taken together, as these targeted therapies are developed and utilized, oncology nurses must be vigilant for off-target and other unexpected effects to organ systems.
exposure and dose delivered to the myocardium.19 These effects are primarily related to radiation-induced fibrosis and scarring of cardiac tissues, with microvascular damage affecting the coronary vasculature, accelerating age-related atherosclerosis, and the development of obstructive coronary artery disease. Ten percent to 30% of breast cancer survivors experience symptomatic heart disease 5 to 10 years posttreatment, and up to 88% are found to have asymptomatic abnormalities of the heart muscle, valves, pericardium, conduction abnormalities, and vasculature.20 In a retrospective analysis of 2,168 patients with breast cancer, cardiac events increased linearly by 7.4% with each Gray directed to the heart, with no apparent threshold.19 Patients with lymphoma who present with bulky lymph node masses or have evidence of isolated residual mediastinal disease routinely receive radiation therapy after completing induction chemotherapy. In long-term follow-up, a 3- to 5-fold increased incidence of CVD (myocardial infarction, angina, and heart failure) compared with the general population is observed.21 While approaches aiming to limit dose to left ventricle and coronary vessels are now being employed (3-D planning, breath hold techniques, and patient positioning), data evaluating contemporary cardiovascular risk using these approaches are lacking. How Big of an Issue is Cardiotoxicity, and What Can Be Done? Some survivors are now at higher risk of death from cardiovascular causes than from recurrent cancer.5 A population-based study showed that people with breast cancer who received chemotherapy had admission rates for heart failure 3-fold that of age-matched controls, within only 3 years of treatment completion.22 Heart failure has no cure and the mortality rate is 50% within 5 years of heart failure diagnosis. The American Heart Association estimates costs for heart failure the US are $30.7 billion annually, not including individual costs to patient and family from symptom management, loss of independence or work, or loss of life. The American Society of Clinical Oncology published a Practice Guideline for prevention and monitoring of cardiac dysfunction in adult cancer patients,9 as have other clinical organizations.23,24 In addition to reviewing the aforementioned cancer treatment modalities, guidelines recommend identification and management of cardiovascular risk factors, the focus of the remainder of this paper. Interventions Before Treatment The oncology nurse should undertake a careful baseline evaluation of cardiovascular risk factors as the initial step to identify patients at increased risk for cardiotoxicity (Table 1).9,24 These risk factors are not an exclusive list, and clinicians should comprehensively assess all potential issues. Key factors well-established to contribute to cardiotoxicity to date have not been studied in cancer patients. However, preliminary evidence in women with breast cancer suggests that women who present with hypertension, diabetes, hypercholesterolemia, or CVD prior to or at the time of diagnosis have an elevated risk of CVD-related mortality.5,25 Whether or not this is related to the breast cancer diagnosis, careful assessment and management of cardiovascular risk factors appears prudent in cancer populations. Another under-addressed area is the effect of psychosocial stressors on development of CVD in cancer patients. In women with breast cancer and no prior CVD, anxiety conveys 48% increased hazard for
Table 1 Baseline risk factors for cardiotoxicity.
Local Therapy
Non-modifiable
Cardiotoxicity associated with radiotherapy to the thorax is a wellestablished phenomenon increasing in prevalence with time from
Modifiable
Age > 60, pre-existing cardiovascular diseases, dyslipidemia, hypertension, borderline LV function (50%-55%) Smoking, high alcohol consumption, obesity, sedentary behavior, psychosocial stress
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subsequent CVD.26 Patient-reported mental and physical symptoms should be documented and investigated at each visit. Physical examination should include careful assessment of blood pressure, auscultation of lung fields, complete cardiac examination including assessment of jugular venous pressure and inspection for peripheral and central edema. These assessments should be performed at each clinical visit. Interventions During Treatment: Cardio-Oncology Rehabilitation During treatment, guidelines advocate management of modifiable cardiovascular risk factors in all patients receiving potentially cardiotoxic therapies.9,24 This represents an entirely new approach to supportive care during the cancer trajectory. Major centers have established cardio-oncology programs for both primary and secondary prevention, engaging multiple health disciplines to address patients’ complex needs (including nursing, physicians, pharmacists, nutritionists, psychologists, and exercise therapists).27,28 Such programs are remarkably similar to the model of CR, which for decades has proven to be an effective approach in the holistic care of people with heart disease.29 Indeed, given that CR centers are widely available in the community, this presents an ideal opportunity for an established team of experts to provide rehabilitation care to high treatment-risk cancer patients. In a pilot project, we referred patients with relapsed lymphoma undergoing stem cell transplantation to an established CR program.30 Functional testing was performed before stem cell collection and after discharge from hospital, with the CR program commencing thereafter. No adverse events occurred, and we showed that adherence to exercise was good (57%), exceeding that of traditional CR populations. Moreover, functional tests performed after the 8-week program including 6-minute walk test and grip strength not only met but exceeded baseline measurements. Accordingly, we have shown proof-of-principle that this collaboration with a CR center with cancer patients receiving high-risk treatment is safe and feasible. Other groups have reported that a CR program customized to patients with breast cancer improved cardiorespiratory fitness, quality of life, and depression symptoms.31 A diverse range of care models are possible, from tertiary centers of excellence with on-site services to community-based networks of resources, local experts, and outreach programs such as telehealth,32 also established approaches in successful CR care delivery.33 The core components of CR include physical activity counseling, nutrition counseling, psychosocial support, weight management,
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smoking cessation, and management of hypertension, diabetes, and dyslipidemia. Exercise is the cornerstone of CR and has also been embraced by the oncology research and clinical community9,33,34 as a critical component of supportive care. Exercise has been studied in oncology populations since the late 1980s as a therapeutic intervention both during and after cancer treatment.35 Multiple health benefits have been described, including most commonly improved physical function and exercise capacity (ie, cardiorespiratory fitness), muscular strength, and quality of life. Weight loss and improved body composition (loss of fat mass) also result from exercise training and nutritional advice in oncology populations. Oncology nurses can help patients navigate self-directed lifestyle behavior improvement or direct patients to available resources and facilities, based on patient abilities and local availability of expertise (Fig. 1). Currently, oncology exercise recommendations are generic, suggesting 150 minutes of moderate-intensity aerobic exercise per week, similar to recommendations for the general adult population.36 However, it has been suggested that a more personalized approach is needed, customizing the exercise program to the individual based on maximal cardiopulmonary exercise testing as well as assessment of baseline risks and the prescribed treatment regimens.37,38 Additionally, functional impairments resulting from tumor-related effects or surgery should be addressed by physiotherapy and/or occupational therapy expertise, with exercise customized accordingly. Moreover, while substantial evidence demonstrates the beneficial effects of exercise on cardiorespiratory fitness, limited evidence currently exists for its use as a treatment for cancer therapy-related cardiotoxicity.39 Management of smoking cessation, hypertension, diabetes, and dyslipidemia are also key areas where the oncology nurse can provide important support. Medication compliance can be aided with conversations regarding timing of medications and management of side effects. Again, regular symptom review to evaluate fatigue, shortness of breath, or other potentially concerning symptoms should be performed regularly, with careful attention to any changes. Given the wide variability of cardio-oncology expertise and support, the oncology nurse may be the primary cardio-oncology care provider. Armed with knowledge of available resources and facilities, oncology nurses can navigate patients according to individual needs and local expertise. Oncology nurses can also contribute to cardiovascular health and treatment safety across multiple disease populations. In patients referred for bone marrow transplantation, we have shown when systematic pre-transplant screening is performed by
Fig. 1. Recommended cardio-oncology rehabilitation approach.
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skilled oncology nurse practitioner, 20% required cardio-oncology assessment and treatment, with 100% successfully proceeding to transplantation.40 Future Directions Currently, the greatest challenge faced by clinicians is determining which individual patients will develop cardiotoxicity, and when. We recommend large collaborative and prospective registries with exhaustive metrics, including comprehensive cardiovascular history, oncologic treatments, relative dose intensities, and patient-reported outcomes to develop personalized risk algorithms. With this information in hand, point-of-care tools could be developed to aid end-users, wherever they may be. Providers will be able to make evidencebased decisions regarding preventive measures and treatment strategies. Survivors will better understand their individual risks and receive personalized supports. Ultimately, people will live longer and live better after cancer treatment. Future directions in cardio-oncology research should aim to quantify the benefit of rehabilitation and work toward adopting feasible and effective models of CR in oncology populations. CR has repeatedly demonstrated benefits for mortality reduction, symptom relief, reduction in smoking, and improved exercise tolerance, risk factors modification, and the overall psychosocial well-being in patients with multiple cardiac conditions including ischemic heart disease, heart failure, and post heart surgery.29 Whether similar benefits can be afforded to oncology populations remains to be seen. CR providers will need extensive education regarding common issues experienced by cancer patients that would potentially affect exercise capacity or ability, including pancytopenia, intravenous access devices, and radiation dermatitis or desquamation. Issues of referral, enrollment, and retention to CR will be an important future consideration. Participation rates in CR in cardiac populations in the US are poor, ranging from 20% to 30% because of inadequate referral rates, enrollment of inappropriate individuals, and suboptimal adherence.41 Compelling evidence and concerted educational efforts will be required in the oncology setting. We have completed recruitment to TITAN, a randomized clinical trial studying the effect of intensive multidisciplinary care including exercise, nutrition, and cardio-oncology supervision to usual care, with our primary outcome LVEF at 1 year.42 The intervention, based on a CR model, will be an initial step in determining the utility of such approaches in cardio-oncology populations. Implications for Oncology Nursing The number of cancer diagnoses and cancer survivors are increasing exponentially. With advances in traditional and targeted therapies, an entirely new and rapidly growing population requiring supportive care from cardiovascular effects of necessary treatment is emerging. Timely risk-reduction interventions hold promise in reducing cardiovascular morbidity and mortality. Oncology nurses are the key providers to identify baseline risks, perform necessary referrals, provide individualized teaching, and to support the patient within the family and community. Future work should focus on developing personalized risk profiles and holistic interventions. References 1. Canadian Cancer Statistics Advisory Committee. Canadian cancer statistics 2019. Toronto, ON: Canadian Cancer Society; 2019. Available at: cancer.ca/CanadianCancer-Statistics-2019-EN. Accessed 30 September 2019. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7– 34. 3. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66:271–289.
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Zamorano JL, Lancellotti P, Rodriguez Munoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur J Heart Fail. 2017;19:9–42. 25. Simon MS, Beebe-Dimmer JL, Hastert TA, et al. Cardiometabolic risk factors and survival after breast cancer in the Women's Health Initiative. Cancer. 2018;124: 1798–1807. 26. Schoormans D, van de Poll-Franse L, Vissers P, et al. Pharmaceutically treated anxiety but not depression prior to cancer diagnosis predicts the onset of cardiovascular disease among breast cancer survivors. Breast Cancer Res Treat. 2017;166:259–266. 27. Parent S, Pituskin E, Paterson DI. The Cardio-oncology Program: a multidisciplinary approach to the care of cancer patients with cardiovascular disease. Can J Cardiol. 2016;32:847–851. 28. Dittus KL, Lakoski SG, Savage PD, et al. Exercise-based oncology rehabilitation: leveraging the cardiac rehabilitation model. J cardiopulm Rehabil Prev. 2015;35: 130–139. 29. Mampuya WM. Cardiac rehabilitation past, present and future: an overview. Cardiovasc Diagn Ther. 2012;2:38–49. 30. Rothe D, Cox-Kennett N, Buijs DM, et al. Cardiac rehabilitation in patients with lymphoma undergoing autologous hematopoietic stem cell transplantation: A cardiooncology pilot project. Can J Cardiol. 2018;34:S263–S269. https://doi.org/10.1016/j. cjca.2018.07.001. 31. Dolan LB, Barry D, Petrella T, et al. The Cardiac Rehabilitation Model improves fitness, quality of life, and depression in breast cancer survivors. J Cardiopulm Rehabil Prev. 2018;38:246–252. 32. McLean LD, Clark AM. Telehealth interventions versus center-based cardiac rehabilitation: it's time to strengthen the evidence. Eur J Prev Cardiol. 2016;23:21–22. 33. 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39. Kirkham AA, Beaudry RI, Paterson DI, Mackey JR, Haykowsky MJ. Curing breast cancer and killing the heart: a novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer. Prog Cardiovasc Dis. 2019;62:116–126. 40. Pituskin E, Cox-Kennett N, Becher H, et al. Cardio-oncology interventions in outpatients referred for autologous bone marrow transplantation. J Clin Oncol. 2016;34:137. 41. Ades PA, Keteyian SJ, Wright JS, et al. Increasing cardiac rehabilitation participation from 20% to 70%: a road map from the Million Hearts Cardiac Rehabilitation Collaborative. Mayo Clin Proc. 2017;92:234–242. 42. Pituskin E, Haykowsky M, McNeely M, Mackey J, Chua N, Paterson I. Rationale and design of the multidisciplinary team IntervenTion in cArdio-oNcology study (TITAN). BMC Cancer. 2016;16:733.