the interconnection between cancer inside this issue and ... · therapy. j am coll cardiol. 2010;...

Current Issues & Trends in Cardiovascular Disease Prevention and Rehabilitation (CV Edge) | October 2019

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Inside this Issue

The Interconnection between Cancer and Heart Disease PAGE 1 — 2

Exercice et cardiotoxicité des traitements contre un cancer PAGE 3 — 5

CACPR Committees PAGE 5

Don’t Go Breakin’ My Heart PAGE 6 — 7

Social Media and Modules PAGE 7

Review and References PAGE 8 — 9

Webinars PAGE 8

Case Study PAGE 10 — 11

Program Profile PAGE 12

A Message from the Editor PAGE 12

The Interconnection between Cancer

and Heart Disease Michele A. Turek, MD FRCPC Faculty of Medicine, University of Ottawa

Non-communicable diseases such as cancer and cardiovascular disease result in substantial mortality and disability worldwide. As shown in the most recent systematic analysis of data from 2017 [published in 2019], cardiovascular disease and cancer are ranked first and second respectively with respect to disability–adjusted life years with a marked change compared to 2007 (1). Nevertheless there have been significant gains in overall survival in the last decade. Cardiovascular disease (CVD) mortality has decreased 6.7 %/year. Breast cancer mortality, for example, has decreased 1.8 %/year. 90% of breast cancer patients survive at least 5 years post diagnosis. Older women [more than 65 years old] are more likely to die of CVD rather than breast cancer with early-stage disease. However in breast cancer survivors, there is an increased risk of CVD approximately 7 years after breast cancer diagnosis (2).Therefore, there is a window of opportunity for early recognition and treatment of cardiovascular risk factors particularly in this patient population, although older patients with other cancers have similar rates of cardiac disease and CVD risk factors. Similar data has been shown in our Ottawa Hospital Cardio–Oncology clinic (3).

There are shared risk factors for both cardiac disease and cancers (4). These include advanced age, diet, obesity, physical activity and smoking. For example, there is an inverse relationship between physical activity and breast cancer events and death. The relationship between obesity and breast cancer is complex with increased weight not necessarily carrying added risk [although short-term weight gain particularly before menopause may be deleterious]. Being physically active may decrease cancer incidence for many cancers, including breast cancer. Consuming a heart healthy diet [so-called Mediterranean diet] not only reduces heart disease risk but also has been shown to reduce the incidence of invasive breast cancer. Putting this altogether, ideal cardiovascular health has been shown to be inversely associated with breast, lung and colorectal cancers, thus further interrelating these shared risk factors (5) Cancer care can result in cardiovascular toxicities that influence ongoing cancer treatments. There are latent effects of cardiovascular disease from such cancer treatments that can modify cancer survivorship. Cardiac toxicity associ-ated with cancer treatments is not a new concept. We have known about the


cardiotoxic effect of anthracycline chemotherapy for many years. What has changed in the last decade is that novel and targeted cancer therapies can now result in cure or substantial disease free survival. Since such cardiotoxicity can be noted early in treatment, ongoing surveillance for overt as well as subclinical/asymptomatic cardiac dysfunction is now the norm with recognition for risk factors that include cardiovascular comorbidities. As well, management strategies include standard cardiovascular treatments and medications, with early initiation indicated in those patients who are deemed to be higher risk (6). Higher risk can be signaled by assessment of previous cardiac disease, standard cardiac risk factors such as diabetes and hypertension, as well as combination chemotherapy/targeted therapy/radiation therapy. There are pathways that regulate both cancer and cardiovascular hemostasis and which are used in cancer treatment [trastuzumab, pertuzumab, tyrosine kinase inhibitors]. These inhibitors [targeted therapies] have effects on the heart that can result in both reversible and irreversible cardiac dysfunction (7).

Prevention includes monitoring and mitigating risk associated with cancer treatments as well as treatment of cardiovascular disease in cancer patients. This has been shown best in breast cancer patients, whereby an understanding of the direct effects of cancer treatments as well as the indirect effects of [mostly] cardiovascular risk factors has resulted in dedicated cardio–oncology programs and directed surveillance strategies. Strategies for surveillance in patients deemed to be at higher risk include cardiac biomarkers and imaging modalities such as echocardiography. Utilizing novel techniques, these strategies can be used to identify subclinical disease [before overt congestive heart failure or coronary events] which can result in an adjustment of cancer treatments or initiation of cardioprotective medications. More recently, we have shown that coronary artery calcium detected on chest CT in breast cancer patients can predict cardiac events (8). This information can then be leveraged to adjust medical therapy, such as introducing statin therapy. As well, initiating a dedicated cardiac rehabilitation program for such patients may be useful to optimize cardiovascular health and improve cancer outcomes. Integrating a model that includes a cardio–oncology program that encompasses an understanding of cardiac risk factors, preventive strategies, the benefits of early detection of cardiac problems has been shown to ensure a higher rate of cancer therapy completion (9).

Cancer outcomes are influenced by cardiovascular health and cardiovascular health influences treatment decisions for cancer care. Because cancer and cardiovascular disease share risk factors, shared screening for cancer as well as cardiovascular disease is warranted. Prevention for cardiovascular disease and cancer should incorporate and message these shared risk factors.

References

1) Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncology 2019. Published online September 27, 2019

2) Patnaik J et al. 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(3)

3) Sulpher J et al. Clinical experience of patients referred to a multidisciplinary cardiac oncology clinic: an observational study. Journal of Oncology vol 2015. Article ID 671232.

4) Johnson CB et al. Shared risk factors for cardiovascular disease and cancer: implications for preventive health and clinical care in oncology patients. Can J Cardiol 2016; 32 (7).

5) Rasmussin-Torvik LJ et al. Ideal Cardiovascular Health Is Inversely Associated With Incident Cancer. Circulation 2013 Volume: 127, Issue: 12, Pages: 1270-1275.

6) Cardinale D et al. Anthracycline- induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010; 55:213-220

7) Bellinger AM et al. Cardio-Oncology: how targeted cancer therapies and precision medicine can inform cardiovascular discovery. Circulation 2015. 132(23)

8) Phillips WJ et al. Comparison of Framingham risk score and chest-CT identified coronary artery calcification in breast cancer patients to predict cardiovascular events. International Journal of Cardiology 2019. Vol 289. 138-143.

9) Dent S et al. The experience of a multidisciplinary clinic in the management of early-stage breast cancer patients receiving trastuzumab therapy: an observational study. Cardiology Research and Practice 2012. Article ID 135819.


Exercice et cardiotoxicité des traitements contre un cancer : une avenue de collaboration prometteuse entre professionnels de l’exercice et

cardio-oncologues

Hugo Parent-Roberge1,2, Adeline Fontvieille2, Eléonor Riesco1,2, Warner Mampuya3,4 1 Faculté des sciences de l’activité physique, Université de Sherbrooke, Sherbrooke, Qc, Canada 2 Centre de recherche sur le vieillissement du CIUSSS de l’Estrie – CHUS, Sherbrooke, Qc, Canada 3 Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Qc, Canada 4 Centre de recherche du CHUS, Sherbrooke, Qc, Canada

Introduction

Les progrès des dernières décennies dans le dépistage et le traitement du cancer ont permis une impressionnante hausse du taux de survie pour de nombreux types de cancer. Cependant, plusieurs traitements sont également associés à des effets secondaires importants, pouvant perdurer plusieurs années après la fin de ces derniers. Parmi ceux-ci, la cardiotoxicité liée à de nombreuses classes de chimiothérapie (principalement les anthracyclines), à la radiothérapie thoracique et à certains inhibiteurs de tyrosine kinase telles que le Trastuzumab est un phénomène bien démontré1. La combinaison de ces traitements augmente le risque de complications cardiovasculaires liées au cancer du sein2, ce qui représente la première cause de mortalité chez cette population, devant la mortalité spécifique au cancer3. De plus, malgré les avancées impressionnantes des traitements par inhibition des points de contrôles immunitaires (Immune Checkpoint Inhibitors, ICI) dans le traitement de plusieurs cancers avancés, le risque de myocardite associé est aussi de mieux en mieux documenté4.

L’exercice aérobie semble intuitivement prometteur dans ce contexte, dans la mesure où ses effets cardioprotecteurs en contexte d’insuffisance cardiaque et de maladies coronariennes sont établis5. En contexte de traitements contre un cancer, l’entrainement d’intensité progressive est bien toléré6 et plusieurs des bénéfices associés suggèrent qu’il puisse s’agir d’un pilier dans la prévention et le traitement des complications cardiovasculaires. Dans ce contexte, l’objectif de cet article est 1) de synthétiser l’état des connaissances concernant les bénéfices liés à la prévention des complications cardiovasculaires chez le patient atteint d’un cancer et 2) souligner l’importance de la collaboration entre les professionnels de l’activité physique et le domaine de la cardio-oncologie.

Entrainement durant les traitements : effet sur la condition physique et la fatigue liée au cancer

Au-delà des effets cardiotoxiques directs de plusieurs types de thérapies, d’autres mécanismes peuvent expliquer le risque de complications cardiovasculaires chez les patients et survivants d’un cancer. L’âge7, l’inactivité physique8 et la faible capacité cardiorespiratoire9 sont des facteurs de risque importants de nombreux types de cancers, ce qui prédispose cette clientèle aux maladies cardiovasculaires (MCV). Plus encore, la majorité des patients et jusqu’au tiers des survivants sont atteints de fatigue liée au cancer (FLC) durant ou après les traitements anti-cancer6. Ces patients et survivants fatigués tendent à réduire leur niveau d’activité physique durant les traitements10, ce qui exacerbe évidemment le déconditionnement cardiorespiratoire et le risque de MCV. Or, le maintien de la capacité cardiorespiratoire et la réduction de la FLC6,11 font partie des bénéfices les mieux documentés chez cette population 6,11.

Concernant la capacité cardiorespiratoire, une méta-analyse a rapporté une augmentation moyenne du VO2 pic de 1,21 mLO2/kg/min avec l’entrainement lorsqu’il est réalisé en cours de traitements adjuvants, en comparaison d’un déclin moyen de 1,02 mLO2/ kg/min sans exercice12. D’autre part, une amélioration moyenne de 3,36 mLO2/kg/min fut observée chez les survivants après 8 à 24 semaines d’entrainement12. Une réduction de la pression artérielle systolique et diastolique, de la fréquence cardiaque de repos, une amélioration de capacité vitale forcée (CVF) et du volume expiratoire maximal en une seconde (VEMS) ont aussi été rapportées13. Les améliorations de la condition physique chez les survivants ayant complétés leurs traitements sont comparables aux effets chez les populations du même âge en santé, suggérant un effet surtout protecteur en cours de traitements12,13.

Concernant la réduction de la FLC, il s’agit probablement du bénéfice le mieux documenté en cours de traitements6. Bien que cette idée soit contre-intuitive pour plusieurs patients, l’exercice représente la modalité de réduction de la FLC la plus efficace, en comparaison d’approches pharmacologiques et psychothérapeutiques14. Cet effet permet à terme de lutter contre la spirale du déconditionnement physique et évidemment d’améliorer la qualité de vie des patients et des survivants aux prises avec une fatigue persistante. . .

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Finalement, un autre bénéfice de l’exercice pouvant possiblement permettre de réduire le risque de maladies cardiovasculaires est son effet anti-inflammatoire chez les survivants (post-traitements) aux prises avec une inflammation silencieuse persistante. Une méta-analyse récente rapporte ainsi une faible réduction de la concentration sanguine en protéine C-réactive chez les survivants d’un cancer du sein ou de la prostate après un programme d’entrainement aérobie, et une réduction modérée avec l’entrainement combiné (aérobie et musculaire)15. Cette amélioration du profil inflammatoire pourrait donc participer à réduire le risque de maladies cardiovasculaires à long terme, que l’on sait accru chez les survivants de plusieurs types de cancers1.

L’exercice et la cardiotoxicité liée aux traitements contre un cancer

L’effet direct de l’exercice sur les mécanismes de cardiotoxicité liée aux traitements est étudié depuis moins longtemps, mais plusieurs modèles animaux offrent des résultats prometteurs à ce sujet. En effet, une réduction de plusieurs marqueurs d’apoptose myocardique, une réduction du stress oxydatif et une amélioration de la fonction ventriculaire gauche ont été rapporté lorsque l’entrainement aérobie est réalisé pendant un traitement par anthracyclines5.

Chez l’humain, cependant, les effets spécifiques de l’exercice sur ces mécanismes de cardiotoxicité demeurent peu documentés. Une étude préclinique a montré une préservation de plusieurs paramètres hémodynamiques (débit cardiaque, fréquence cardiaque de repos, résistance vasculaire périphérique) avec des séances d’exercice aérobie d’intensité vigoureuse exécutées 24h avant chaque traitement de doxorubicine. Toutefois, une autre étude n’a pas observée d’effet protecteur de l’entrainement aérobie continu d’intensité modérée sur le remodelage ventriculaire et la réduction de la fraction d’éjection induits par la prise de Trastuzumab16. Fait intéressant, une étude clinique à plus large échelle, actuellement en cours, vise à évaluer les effets de l’entrainement combiné (aérobie et musculaire) en cours de traitement par anthracyclines sur plusieurs marqueurs de cardiotoxicité (fraction d’éjection, NT-proBNP, fréquence cardiaque et pression artérielle systolique de repos, d’effort et de récupération, indices de variabilité de la fréquence cardiaque)17.

Par ailleurs, l’entrainement par intervalles à haute intensité (HIIT) pourrait également représenter une avenue prometteuse selon certains modèles animaux18. Il semble naturel de douter de la faisabilité de l’entrainement de type HIIT chez des patients en cours de traitements. Ceci dit, de plus en plus d’études tendent à en démontrer la faisabilité, la sécurité et les bénéfices sur la capacité cardiorespiratoire et ce, pour divers types de cancers19. Évidemment, davantage de recherche demeure nécessaire pour évaluer les effets spécifiques de l’exercice en prévention et traitement d’autres types de cardiopathies dont l’étiologie diffère, par exemple les myocardites liées aux ICI.

L’importance de l’encadrement de la pratique d’exercice chez les patients traités contre un cancer

Pour de nombreux patients en cours de traitements et survivants en rémission d’un cancer, il est contre-intuitif de penser augmenter le niveau d’activité physique, voire même débuter un programme d’entrainement. Bien que l’exercice demeure l’une des façons les mieux documentées de lutter contre la FLC et préserver la capacité physique, la fatigue représente paradoxalement l’une des principales barrières à l’exercice chez les patients traités contre un cancer10. Le manque d’information et de supervision représentent aussi deux des barrières principalement rapportées10. Il est d’ailleurs bien documenté que la supervision de l’exercice par des professionnels de l’activité physique est le premier déterminant de l’adhérence à la prescription d’exercice ainsi que des bénéfices associés durant la phase de traitements6,11.

Conclusion

Il est de plus en plus souvent suggéré que des programmes d’exercices adaptés, spécifiques aux patients et survivants récents d’un cancer, fassent partie intégrante du continuum de soins offert aux patients. Au Canada, plusieurs programmes en milieux hospitaliers ou communautaires sont déjà sur pied20, et l’efficacité de certains sur la réduction de la FLC et l’amélioration de la capacité cardiorespiratoire a été documentée21. Considérant les retombées potentielles de ces programmes adaptés sur la prévention et le traitement des complications cardiovasculaires, il sera donc tout aussi important d’évaluer leurs effets cardioprotecteurs, pour éventuellement les intégrer dans la prise en charge de la cardiotoxicité liée au cancer.

Rèfèrences

1) Han, X., Zhou, Y. & Liu, W. Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. npj P recis. Oncol. 1, 1–10 (2017).

2) Seidman, A. et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20, 1215–1221 (2002).

3) 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. Breast Cancer Res. 13, R64 (2011).

4) Segal, R. et al. Exercise for people with cancer: a systematic review. Curr. Oncol. 24, e290–e315 (2017). . . .


5) Canadian Cancer Statistics Advisory Committee. Canadian Cancer Statistics 2019. Canadian Cancer Society (2019).

6) Moore, S. C. et al. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern. Med. 176, 816 (2016).

7) Pozuelo-Carrascosa, D. P. et al. Cardiorespiratory fitness and site-specific risk of cancer in men: A systematic review and meta-analysis. Eur. J. Cancer 113, 58–68 (2019).

8) Clifford, B. K. et al. Barriers and facilitators of exercise experienced by cancer survivors: a mixed methods systematic review. Support. Care Cancer 26, 685–700 (2018).

9) Buffart, L. M. et al. Targeting Exercise Interventions to Patients With Cancer in Need: An Individual Patient Data Meta-Analysis. JNCI J. Natl. Cancer Inst. 110, 1190–1200 (2018).

10) Jones, L. W. et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist 16, 112–120 (2011).

11) Schneider, C. M., Hsieh, C. C., Sprod, L. K., Carter, S. D. & Hayward, R. Effects of supervised exercise training on cardiopulmonary function and fatigue in breast cancer survivors during and after treatment. Cancer 110, 918–925 (2007).

12) Mustian, K. M. et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: A meta-analysis. JAMA Oncol. 3, 961–968 (2017).

13) Khosravi, N., Stoner, L., Farajivafa, V. & Hanson, E. D. Exercise Training, Circulating Cytokine Levels and Immune Function in Cancer Survivors: A Meta-Analysis. Brain. Behav. Immun. 0–1 (2019). doi:10.1016/j.bbi.2019.08.187

14) Haykowsky, M. J., Mackey, J. R., Thompson, R. B., Jones, L. W. & Paterson, D. I. Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin. Cancer Res. 15, 4963–4967 (2009).

15) Antunes, P. et al. Impact of exercise training on cardiotoxicity and cardiac health outcomes in women with breast cancer anthracycline chemotherapy: a study protocol for a randomized controlled trial. Trials 20, 1–11 (2019).

16) Alihemmati, A. et al. Effects of high-intensity interval training on the expression of microRNA-499 and pro- and anti-apoptotic genes in doxorubicin-cardiotoxicity in rats. J. Electrocardiol. 55, 9–15 (2019).

17) Mugele, H. et al. High-intensity interval training in the therapy and aftercare of cancer patients: a systematic review with meta-analysis. J. Cancer Surviv. (2019). doi:10.1007/s11764-019-00743-3

18) Mina, D. S. et al. Connecting people with cancer to physical activity and exercise programs: A pathway to create accessibility and engagement. Curr. Oncol. 25, 149–162 (2018).

19) Santa Mina, D. et al. Effects of the community-based wellspring cancer exercise program on functional and psychosocial outcomes in cancer survivors. Curr. Oncol. 24, 284–294 (2017).

CACPR Committees The Canadian Association of Cardiovascular Prevention and Rehabilitation (CACPR) is a national body comprised of interdisciplinary health professionals. Our focus is enhancing knowledge and clinical care, as well as enabling research for those who work in cardiovascular prevention and rehabilitation.

Looking to be more involved in the CACPR community? You can join one of our committees!

Membership Committee

Knowledge Transfer Committee

CV Edge Publication Committee

Research Committee

Marketing Committee

For more information, visit our website or email the CACPR Office!

https://cacpr.wildapricot.org/Committees

mailto:[email protected]


Don’t Go Breakin’ My Heart: Exploring the emerging evidence of

the mechanisms of cardiotoxicity from radiation therapy Jennifer Edgecombe, BSc (HK), ACSM CCEP & CET University of British Columbia, Masters Student Rehabilitation Sciences Exercise Physiologist, Kamloops, British Columbia

According to the Canadian Cancer Society, 1 in 2 Canadians will receive a diagnosis of Cancer in their lifetime2. Thanks to advances in medical technology, more people are surviving cancer than ever before. The 5-year survival rate of a Canadian with cancer in 2019 is 63% compared to 55% in 19992. Life-saving cancer therapies have the consequence of lifetime side effects including toxicities to the heart and vascular system. Due to the curative approach to cancer care, resultant heart disease, vascular disease and elevated risk profiles are often not addressed with the individual. The oncology population has a risk for heart disease that is four times that of their age-matched, non-cancer counterparts7. By definition, cardiovascular disease prevention is a series of actions at the individual or population level aimed at minimizing or removing the impact of cardiovascular disease risk factors6. The oncologic population represents a demographic for whom the promotion of healthy lifestyle behaviors is not yet established as a standard of care8.

Chemotherapy include classes of drugs that target fast dividing cells in the body and do not differentiate between cancer cells and healthy tissue. Knowledge about the cardio-toxicity of some chemotherapy agents is on the rise amongst clinicians. The stress on the heart results in damages to the myocytes and the endothelial tissue4. A common example is seen in the breast cancer population receiving anthracycline chemotherapies and trastuzumab-based therapy as increased risk for hypertension, heart attack, non-ischemic cardiomyopathy and cardiac dysfunction. These side effects may occur at the beginning of therapy or years later 7. Another tumor type often affected by an increased cardiac risk profile is lymphoma. As many as 42% of lymphoma survivors were found to have signs of heart failure and cardiac dysfunction at 2 – 10 years following treatment cessation7. Increased knowledge about this risk has resulted in recommendations by cardiology and oncology agencies to assess cardiac function prior to exposure to known cardiotoxic agents in high risk patients8. In most Canadian centers, the gap exists at the transition following therapy cessation as these cardiovascular side effects of chemotherapy can present following therapy cessation when the patient is discharged from active surveillance by the cancer clinic.

External beam radiation is a common oncology therapy in some tumor types. It is often received as an outpatient with a daily radiation treatment plan. The DNA of the cancer cell is damaged by the repeat radiation exposure and as a result, the tumor stops growing, shrinks or is completely destroyed2.

Radiation exposure also impacts the DNA of neighboring, healthy tissue. The extent of the damage to the heart and vascular system by radiation therapy is still being realized. Mid-sternal radiation in tumor types such as breast cancer or types of lymphoma can damage lung and heart tissue by direct irradiation. The main cause of late mortality and morbidity amongst the population who have received mid-sternal radiation is cardiac disease4. Heart valves exposed to radiation therapy undergo thickening, fibrosis and calcification resulting in valvular stenosis or regurgitation. The surgical risk to the patient is underestimated when calculated by the traditional risk scores by as much as 18%4. Exposure of the heart structure to radiation causes microvascular fibrosis, diastolic dysfunction, conduction abnormalities, pericardial thickening and calcification4. This damage does not resolve following therapy cessation. New techniques such as deep inspiration breath hold are being employed to move the target tissue out of the way of organs. This technique has been shown to reduce heart disease by 35%3. There is emerging evidence to suggest that radiation therapy causes vascular endothelial cell inflammation inducing pro-thrombotic changes which may accelerate atherosclerosis1,5. The mechanism is not yet fully understood and there is no established dose-response relationship. The cardiovascular risks of radiation therapy are traditionally underestimated resulting in insufficient risk factor management for the individual.

Canada is seeing more cancer survivors than ever before. This group has an increased risk for cardiovascular disease risk due three main factors: 1) pre-existing modifiable and non-modifiable risk factors within the individual, 2) direct cardiotoxic consequences resulting from therapy (chemotherapy and radiation therapy discussed here) and 3) indirect cardiac consequences of sedentary behavior, increased stress and poor nutrition habits resulting from oncology therapy side effects8. This elevated risk profile can be addressed by positive lifestyle behavior strategies in addition to pharmacologic approaches7. Exercise is not yet a standard of care within the oncology population. There is an opportunity to retain cardiovascular function during cancer therapy with exercise training. Additionally, the long term cardiovascular risk factors of the cancer population must be addressed and supported through engagement in positive lifestyle behavior throughout the cancer treatment and survivorship trajectory. . .

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References

1) Baselet, B., Belmans, N., Coninx, E., Lowe, D., Janssen, A., Michaux, A., . . . Aerts, A. (2017). Functional gene analysis reveals cell cycle changes and inflammation in endothelial cells irradiated with a single X-ray dose. Frontiers in Pharmacology, 8, 213-213. doi:10.3389/fphar.2017.00213)

2) Canadian Cancer Society (2019). Canadian cancer statistics 2019. Retrieved from https://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2019-EN.pdf?la=en

3) Corradini, S., Simonetto, C., Eidemüller, M., Gaasch, A., Pazos, M., Schönecker, S., . . . Belka, C. (2018). Does deep inspiration breath hold prolong life? individual risk estimates of ischemic heart disease after breast cancer

radiation therapy. International Journal of Radiation Oncology, Biology, Physics, 102(3), e598-e599. doi:10.1016/j.ijrobp.2018.07.1645

4) Ghoneim, A., MD, Bouhout, I., MD, Perrault, Louis P., MD, PhD, Bouchard, Denis, MD, PhD, Pellerin, M., MD, Lamarche, Y., MD, . . . El-Hamamsy, Ismail, MD, PhD. (2017). Reexamining the role of surgical aortic valve replacement after mediastinal radiation therapy. Annals of Thoracic Surgery, 104(2), 485-492. doi:10.1016/j.athoracsur.2017.01.097

5) Jacob, S., Pathak, A., Franck, D., Latorzeff, I., Jimenez, G., Fondard, O., . . . Bernier, M. (2016). Early detection and prediction of cardiotoxicity after radiation therapy for breast cancer: The BACCARAT prospective cohort study. Radiation Oncology, 11(1), 54-54. doi:10.1186/s13014-016-0627-5

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Advanced Training Modules CACPR will soon be introducing Advanced Training Modules on numerous topics surrounding cardiovascular prevention and rehabilitation, with the first module being released after the 2019 Fall Conference!

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Warner Mampuya MD/PhD FRCPC Faculté de médecine et des sciences de la santé, Université de Sherbrooke, Sherbrooke, Qc, Canada

The Exercise and Sports Science Australia position statement: Exercise medicine in cancer management

Sandra C. Hayes, Robert U. Newton, Rosalind R. Spence, Daniel A. Galvao Journal of Science and Medicine in Sport 22 (2019) 1175–1199

In 2009, Exercise & Sports Science Australia (ESSA) published the first ever position statement on exercise guidelines for cancer patients in the world. Since then, there has been exponential growth in research evaluating the role of exercise before, during and after cancer treatment.

An update on this position statement has been recently released. This position statement presents contemporary evidence of the benefits of exercise following a cancer diagnosis, and the recommended process for targeted, exercise prescription for cancer patients.

The position statement reports that the optimal exercise prescription is to be determined by individual patient assessment, identification and consideration of general and cancer-specific health issues and their contribution to quality of life, and subsequent patient-driven goals.

An exercise prescription framework is proposed to take into account cancer-specific considerations for individualization, specificity, safety, feasibility and progression of exercise for these patients. The document also presents practical implications for exercise prescription in cancer patients.

Clinical Oncology Society of Australia position statement on exercise in cancer care

Prue Cormie, Morgan Atkinson, Lucy Bucci, Anne Cust, Elizabeth Eakin, Sandra Hayes, Sandie McCarthy, Andrew Murnane, Sharni Patchell, Diana Adams, Med J Aust. 2018 Aug 20;209(4):184-187.

Exercise as an additional therapy for patients undergoing cancer treatment has been well-studied and associated with many benefits. This article summarizes the position of the Clinical Oncology Society of Australia (COSA) on the role of exercise in cancer care, considering the strengths and limitations of the evidence base. It provides guidance for all health professionals involved in the care of people with cancer about integrating exercise into routine cancer care. COSA is very clear on the directive. Its recommendations are:

Exercise should be embedded as part of standard practice in cancer care and viewed as an adjunct therapy that helps counteract the adverse effects of cancer and its treatment;

All members of the multidisciplinary cancer team should promote physical activity and recommend patients with cancer adhere to exercise guidelines;

Best practice cancer care should include referral to an accredited exercise physiologist or physiotherapist with experience in cancer care.

CAPCR Webinars CACPR is pleased to announce the launch

of the first Education Webinar!

On October 9, 2019, Simon Bacon hosted the first Education Webinar:

Mental Health and Exercise

Be on the lookout for the next one! Members get discounted rates!

References & Reviews

https://zoom.us/recording/play/WLudY7po-B1zkRzfsYNomr2WbUp2gZ04fY2UU2RN67PkgJVhrN9KDU1T1tNZ_nRF?startTime=1570632248000


References & Reviews A new specialty, a new journal, JACC: CardioOncology!

The ACC Publications Committee has launched a new journal, JACC: CardioOncology. The goal of JACC: CardioOncology is to publish the best original research and review articles pertaining in this rapidly emerging field.

The first issue of this new journal was published on September 24th, 2019. The journal is very interesting for those dealing with cardiovascular complications of cancer therapies. In the journal, one will find original articles related to basic, clinical and translational investigation in CardioOncology. Topics of interest include molecular mechanisms and biomarkers of cardiotoxicity; early diagnosis of cardiotoxicity; risk stratification and prevention of cardiotoxicity; oncologic treatment for patients with cardiovascular disease; and cardiovascular care for cancer survivors.

Here are a few original research papers of interest published in this first issue of JACC: CardioOncology:

Increase in Blood Pressure Associated With Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Sarah Waliany, MD, MS,a Kristin L. Sainani, PHD,b Lesley S. Park, PHD, MPH,c Chiyuan Amy Zhang, MPH,d Sandy Srinivas, MD,e,* Ronald M. Witteles, MDf,* JACC CardioOncology , Volume 1, Issue 1, September 2019: Pages 24–36 Pre-Diagnosis Exercise and Cardiovascular Events in Primary Breast Cancer Women’s Health Initiative Tochi M. Okwuosa, DO, Roberta M. Ray, MS, Andres Palomo, MD, Randi E. Foraker, PHD, MA, Lisa Johnson, MS, Electra D. Paskett, PHD, Bette Caan, DRPH, Lee W. Jones, PHD JACC CardioOncology, Volume 1, Issue 1, September 2019, Pages 51-53 Efficacy of Neurohormonal Therapies in Preventing Cardiotoxicity in Patients With Cancer Undergoing Chemotherapy Muthiah Vaduganathan, MD, MPH, Sameer A. Hirji, MD, MPH, Arman Qamar, MD, Navkaranbir Bajaj, MD, MPH, Ankur Gupta, MD, PHD, Vlad G. Zaha, MD, Alvin Chandra, MD, Mark Haykowsky, PHD, Bonnie Ky, MD, MSCE, Javid Moslehi, MD,h Anju Nohria, MD, Javed Butler, MD, MPH, MBA,i Ambarish Pandey, MD, MSCS JACC CardioOncology, Volume 1, Issue 1, September 2019, Pages 66-67

Nouvelles recommandations d’activité physique pour les survivants du cancer

Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable Kristin L. Campbell, Kerri M. Winters-Stone, Joachim Wiskemann, Anne M. May, Anna L. Schwartz, Kerry S. Courneya, David S. Zucker, Charles E. Matthews, Jennifer A. Ligibel, Lynn H. Gerber, G. Stephen Morris, Alpa V. Patel, Trisha F. Hue, Frank M. Perna, Kathryn H. Schmitz. Medicine & Science in Sports & Exercise, 2019; 51 (11): 2375

Ce récent article publié par un groupe international d’experts dirigé par des chercheurs de l’Université de la Colombie-Britannique recommande que les survivants d’un cancer devraient faire une séance d’environ 30 minutes d’activité physique trois fois par semaine.

Ce travail vient nous rappeler le fait que l’activité physique reste importante dans cette population même si l’on sait qu’elle est plus difficile atteindre chez les survivants d’un cancer en raison des effets secondaire et des séquelles potentielles de leur maladie. Cependant ces recommandations se démarquent de celles prônées depuis une dizaine d’années et qui préconisaient la même quantité d’activité physique chez les survivants de cancer comme dans la population générale, soit de faire 150 minutes d’activité physique par semaine.

On recommande maintenant plutôt aux survivants de cancer trois séances de 30 minutes d’activités aérobiques ou de résistance, par semaine.

Cet article rappelle le rôle important de l’activité physique tant dans le traitement que dans la prévention des cancers qu’on pourrait résumer en trois points:

Aide à soulager des effets secondaires courants des traitements du cancer, comme l’anxiété, la dépression et la fatigue; Prévention du cancer en réduisant notamment les risques de cancer du sein, de l’œsophage, de l’estomac, du côlon, de

l’endomètre, du rein et de la vessie. Contribue à l’amélioration de la survie de certains cancer tels que les cancers du sein, du côlon et de la prostate.


. . .

Immune Checkpoint Inhibitor Associated Myocarditis Carolyn Baer, MD, FRCPC Horizon Health Moncton, NB

BACKGROUND

Approximately 40% of Canadians will be diagnosed with cancer in their lifetime (1). Although survival from cancer is increasing, follow up studies are reporting increasing deaths from cardiac causes (1). In a recent population cohort study in the UK, smoking, hypertension, prior history of cardiovascular and chronic kidney disease were more prevalent in cancer survivors (3). There were more cases of thromboembolism, heart failure, cardiomyopathy, arrhythmia, pericarditis, coronary heart disease and valvular heart disease compared to the general population (3).

Immune checkpoint inhibitors (ICIs) are increasingly being used for treatment of many immune sensitive malignancies, including metastatic melanoma. These drug classes target activated T-cells at different stages of immune surveillance to improve anti-cancer immune responses. As a consequence to prolonged T-cell activation, ICIs can cause a spectrum of autoimmune like adverse effects which can affect any organ system, including myocarditis, known as immune related adverse events (irAEs).

We present here a case of ICIs induced myocarditis.

CASE PRESENTATION

A 68-year-old male with a past medical history of Type II Diabetes and hypertension presents with metastatic, BRAF V600E mutation positive melanoma. His initial ECOG status is 1. He is treated with 1st line combination ipilimumab plus nivolumab. After his third cycle he develops chest pain, shortness of breath, and peripheral edema. His initial lab investigations reveal elevations of CPK –MB (>20x ULN) and troponin. The ECG shows diffuse T wave abnormalities. An echocardiogram shows global hypokinesis with an ejection fraction (EF) of 25%. He undergoes a cardiac catheterization, which shows no significant abnormalities. A subsequent endomyocardial biopsy is consistent with immune mediated myocarditis. He is treated with methylprednisolone 2mg/kg IV, perindopril 8mg daily, bisoprolol 5mg daily and diuretics. His infectious work up all comes back as negative. With treatment his EF increases to 30% in 10 days and 40% at 3 months.

DISCUSSION

Ipilimumab is a monoclonal antibody that inhibits activation of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) receptor and nivolumab is an antibody that inhibits activation of programmed death (PD-1) receptors on T-cells. Both of these ICIs are used as both mono- and combination therapy in metastatic melanoma. Five year survival with combination of ipilimumab and nivolumab in metastatic melanoma is higher than either agent alone (6). In a recent follow up study, treatment related adverse events and discontinuation rates were higher with the combination treatment, however, overall and progression free survival in patients who had to stop treatment due to adverse events was similar to the overall population (6).

The incidence of myocarditis from initial studies is quoted at 1 in 2000 for nivolumab alone and 1 in 300 for combination with ipilimumab (4). However these data may underestimate the true incidence due to underreporting bias (4).

Mortality from myocarditis has been reported to be as high as 46% (5). The likelihood of developing myocarditis appears to be higher with combination treatment and in patients with diabetes (5). Registry data indicates that diabetes and sleep apnea were more common in patients with myocarditis but this has not been replicated in other case series (2) and there are no screening protocols or reliable predictors available to date. In one systematic review, 45% of cardiac irAEs presented as myocarditis (4). Other reported cardiac adverse effects included heart failure, cardiomyopathy, conduction abnormalities and pericardial disease (4).

Case Study


antithymocyte globulin (ATG) and abatacept, and plasmapheresis (4,7). The overall case fatality rate is reported to be approximately 35% based on a recent systematic review (4). Recommended strategies for follow up in all patients receiving ICIs include a baseline ECG, troponin with follow up ECG, and troponin weekly for 4 weeks, or if symptoms of cardiotoxicity are suspected. Other protocols include monitoring BNP in addition to the aforementioned monitoring parameters if symptoms arise. If myocarditis is suspected, ischemia should be ruled out and the patient placed in a cardio-oncology unit for specialized monitoring and intervention. An echocardiogram should be done to assess left ventricular (LV) function. If myocarditis is diagnosed by PET, MRI or biopsy, the ICI(s) should be permanently discontinued and immune suppression with corticosteroids should be initiated. Treatment of heart failure should follow usual guidelines (8,9).

CONCLUSION

ICIs can cause cardiac irAEs and the true incidence is unknown but is likely to be rare (<1%). The current treatment is discontinuation of the ICI(s) and high dose intravenous corticosteroids. Other immunosuppressants have been challenged in case series and future research is needed to determine the optimal approach to therapy. There are no good predictors of my ocarditis or other cardiac irAEs, although diabetes and hypertension may be predisposing factors. There is lack of established guidelines focused on screening for myocarditis, however, an assessment of LV function prior to initiation may be useful. Vigilance is important when using these agents for treatment of malignancy, especially when used in combination.

REFERENCES

1) Virani,SA et al. Canadian Cardiovascular Society Guidelines for Evaluation and Management of Cardiovascular Complications of Cancer Therapy, Society Guidelines; Canadian Journal of Cardiology 32 (2016) 831-841.

2) Mahmood,S et al ;Myocarditis in Patients Treated With Immune Checkpoint Inhibitors; JACC 71(16),2018:1755-64

3) Strongman,H et al Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases ; Lancet 2019; 394: 1041–54

4) Mir,H et al Systematic Review/Meta-analysis ;Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area; Canadian Journal of Cardiology 34 (2018) 1059e1068

5) Guha,A et al Update on cardio-oncology: Novel cancer therapeutics and associated cardiotoxicities, Trends in Cardiovascular Medicine 29 (2019) 29–39

6) Larkin,J et al ; Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma NEJM,2019 DOI: 10.1056/NEJMoa1910836

7) Salem, JE, Abatacept for Severe Immune Checkpoint Inhibitor–Associated Myocarditis ;NEJM 380;24:2377-2379

8) Totzeck,M et al ; Cardio-oncology - strategies for management of cancer-therapy related cardiovascular disease; International Journal of Cardiology 280 (2019) 163–175

9) Brahmer,J et al; Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 36(17) 2018:1714-1768.

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https://www.ottawaheart.ca/clinic/cardiology-oncology-clinic

Canadian Guidelines for Cardiac Rehabilitation and Cardiovascular

Disease Prevention: Translating Knowledge into Action

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A Message from the Editor

Program Profile Ottawa Cardio-Oncology Program

Dr Michele Turek, MD Faculty of Medicine University of Ottawa

The Cardio–Oncology program was inaugurated in 2008. The Cardio Oncology clinic was the first dedicated cardio oncology clinic in Canada at its inception and is truly multi-disciplinary. We are in close proximity to the Cancer Center at the Ottawa Hospital which facilitates communication between providers and minimizes a silo approach to care. The program involves cardiologists, oncologists, malignant hematologists, pharmacists and nurses. Our cardiologists have extensive imaging experience which is helpful for surveillance as well as an affinity for non-cardiac diseases. Trainees [physicians and nurses] also attend the clinic and there have been monthly joint cardiology/oncology rounds at which time complex cases can be discussed by everyone. Cardiologists see patients during the twice monthly clinic with referrals from their colleagues in oncology and malignant hematology. In addition, there has been a robust research program with presentations at dedicated Cardio-Oncology conferences as well as links to other national and international programs. In recent years, there has been more awareness of the role of rehabilitation in patients who have received potentially cardiotoxic therapy for their cancers.

http://thinkottawamedicine.ca/clinical-care/the-cardiac-oncology-

program/

https://www.ottawaheart.ca/clinic/cardiology-oncology-clinic

Cardiovascular disease (CVD) and cancer are the 2 leading causes of death worldwide. There are various similarities and interactions between these two conditions, both in terms of some risk factors (diabetes mellitus, obesity) involved and their pathogenesis which has chronic inflammation as an indispensable feature. Although therapeutic advances in the cancer therapy have improved longevity, they have also increased the overlap between these diseases, putting many cancer survivors at risk of developing CVD. Hence, cardiac risk factors have a major impact on subsequent chemotherapy or radiotherapy-related cardiotoxicity. In this CV Edge edition, we explore the interconnection between Cancer and Heart Disease, and some of the ways a multidisciplinary collaboration can help improve the care of cancer patients. One of the major changes in this new format is that, the articles are published in the language in which they are submitted, French or English.

Nous espérons vous apprécierez cette nouvelle formule qui encourage le bilinguisme dont le Canada est si fière.

N’hésitez pas à nous soumettre vos commentaires pour qu’ensemble nous puissions travailler à améliorer la prise en charge globale des patients atteints de cancer et de maladies cardiovasculaires

We decided to publish this edition around the CACPR fall conference in Montreal as a way of encouraging your participation and contribution to the advancement of cardiac rehabilitation and prevention through your CACPR membership!

Together we can achieve great things!

Sincerely,

Warner Mampuya

CV Edge Chief Editor


CACPR Publication Editor and Associate Editors

Warner Mampuya, Chief Editor Carolyn Baer, Associate Editor John Buckley, Associate Editor Andrew Jeklin, Associate Editor Tasuku Terada, Associate Editor

Danielle Smith — CACPR Secretariat, Formatting Editor

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Disclaimer: The materials contained in this publication are the views/findings of the author(s) and do not represent the views/findings of CACPR. The information is of a

general nature and should not be used for any purpose other than to provide readers with current research in the area.

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