Cardiovascular Disease in Survivors of Cancer

Cardiovascular disease (CVD) and cancer are the leading causes of death in the United States.¹ As a result of advances in cancer prevention, early detection, and treatment, the cancer death rate has decreased by 23% since 1991,¹ and it is projected that the number of long-term cancer survivors will be 18 million people by 2022.² An unanticipated consequence of improved cancer-specific mortality is that cancer survivors are at increased risk for CVD-related morbidity and mortality.^2-4 Indeed, 5- and 8-year overall survival is significantly lower among survivors of cancer who developed CVD compared with survivors of cancer without CVD.⁵

In accordance with the "multiple hit" hypothesis, increased CVD mortality in cancer survivors is related to underlying CVD risk factors coupled with the direct effects of anti-cancer therapies (arrhythmias, cardiomyocyte damage, hypertension, and myocardial and vascular ischemia) and indirect effects of an unhealthy lifestyle (decreased physical activity and increased body mass) that result in reduced cardiovascular reserve.⁶ Accordingly, an important goal across the cancer survivorship continuum is to maintain optimal cardiovascular health.

Reduced Cardiorespiratory Fitness in Patients With Cancer and Survivors

Cardiorespiratory fitness is a major independent predictor of mortality in healthy persons with or without CVD.^7,8 As shown in Figure 1, cardiorespiratory fitness, measured objectively as peak oxygen uptake (peak VO₂), has been shown to be 25% lower (11-36%) in cancer survivors compared with age- and sex-matched sedentary individuals without a history of cancer.^9-13 The relatively few studies published to date suggest that the magnitude of the decline in peak VO₂ may be related to the type of cancer, with lowest and highest reported values found in survivors of lung and prostate cancer, respectively (Figure 1). Importantly, peak VO₂ in survivors of lung and breast cancer is below the cut point value (i.e., 18 ml/kg/min) distinguishing between high and low physical function (Figure 1).¹⁴ A consequence of the reduced peak VO₂ is that it is a predictor of survival in survivors of lung and breast cancer.^9,10

Figure 1: Peak Oxygen Uptake in Cancer Survivors

Currently, there is a paucity of studies that have examined the mechanisms of exercise intolerance in cancer survivors. Our research group compared peak VO₂ and its determinants during cycle exercise in 47 female survivors of breast cancer (mean age was 59 years; mean time post-chemotherapy completion was 34 months) and 11 age-matched women.¹⁵ In accordance with the Fick principle (VO₂ = stroke volume [SV] x heart rate x arterial VO₂ content difference), the significantly lower peak VO₂ (19%) in survivors of breast cancer versus healthy controls was due to a lower peak exercise SV and cardiac output (CO) because heart rate and arterial VO₂ content difference were not significantly different between groups (Figure 2).¹⁵ In turn, the reduced peak SV may be due to increased ventricular afterload and/or reduced myocardial contractility during exercise.¹⁵ Finally, given that oxygen extraction is directly proportionate to muscle oxygen-diffusing capacity (i.e., transport of oxygen from hemoglobin to muscle mitochondria) and inversely related to CO,¹⁶ our finding that peak exercise arterial VO₂ content difference is not different between survivors of breast cancer and healthy, age-matched controls despite a significantly lower CO (and a longer transit time for muscle oxygen extraction) suggests that abnormalities in microvascular function or skeletal muscle morphology (i.e., decreased capillarity, oxidative muscle fibers, and enzymes) may limit peak VO₂ in survivors of breast cancer. Future studies are required to examine the mechanisms of exercise intolerance in multiple cancer populations, including early and latent effects from anti-cancer therapy.

Figure 2: Determinants of Oxygen Uptake During Peak Cycle Exercise in Breast Cancer Survivors

Role of Exercise Training to Improve Health Outcomes in Survivors of Cancer

A meta-analysis by McNeely et al. demonstrated that exercise training resulted in significant improvements in peak VO₂, physical functioning, quality of life, and reduced symptoms of fatigue in survivors of breast cancer.¹⁷ A more recent meta-analysis by Jones et al.¹⁸ and Beaudry et al.¹⁹ extend these findings by demonstrating that endurance exercise performed alone or with supplemental strength training significantly increased peak VO₂ (Jones et al. weighted mean change was 2.90 ml/kg/min¹⁸; Beaudry et al. weighted mean change was 3.13 ml/kg/min¹⁹) in survivors of lymphoma and breast, colon, liver, and prostate cancer with early or advanced disease. Importantly, Beaudry et al. reported that a threshold workload of 600 intensity-minutes (i.e., a 10-week exercise program of 90 minutes per week at 70% peak VO₂) was the threshold level required to obtain a clinically significant improvement (i.e., effect size > 1.0) in peak VO₂. Currently, the physiological mechanisms responsible for the exercise-training-mediated improvement in peak VO₂ in survivors of cancer have not been studied. Moreover, it is also unknown if the favorable change in peak VO₂ with training is associated with increased survival.

Summary

Due to advances in cancer prevention, early detection, and treatment, cancer mortality rate has decreased by 23% in the past 25 years. Long-term survivors of cancer have been shown to be at increased risk for CVD-related mortality^2-4 that may be due to the direct effects of anti-cancer therapies and indirect effects of an unhealthy lifestyle.⁶ Evidence to date suggests that decreased peak VO₂ is an independent predictor of survival in lung cancer and advanced breast cancer.^9,10 Regular exercise training is a safe and effective therapy to improve peak VO₂ in cancer survivors.^17-19 Despite this benefit, the mechanisms responsible for this favorable adaptation and its relationship to improved cancer survival remain unknown.

References

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4. Bradshaw PT, Stevens J, Khankari N, Teitelbaum SL, Neugut AI, Gammon MD. Cardiovascular Disease Mortality Among Breast Cancer Survivors. Epidemiology 2016;27:6-13.
5. Armenian SH, Xu L, Ky B, et al. Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study. J Clin Oncol 2016;34:1122-30.
6. Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007;50:1435-41.
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9. Jones LW, Watson D, Herndon JE 2nd, et al. Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer. Cancer 2010;116:4825-32.
10. Jones LW, Courneya KS, Mackey JR, et al. Cardiopulmonary function and age-related decline across the breast cancer survivorship continuum. J Clin Oncol 2012;30:2530-7.
11. Kelsey CR, Scott JM, Lane A, et al. Cardiopulmonary exercise testing prior to myeloablative allo-SCT: a feasibility study. Bone Marrow Transplant 2014;49:1330-6.
12. Cramer L, Hildebrandt B, Kung T, et al. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer. J Am Coll Cardiol 2014;64:1310-9.
13. Scott JM, Hornsby WE, Lane A, Kenjale AA, Eves ND, Jones LW. Reliability of maximal cardiopulmonary exercise testing in men with prostate cancer. Med Sci Sports Exerc 2015;47:27-32.
14. Morey MC, Pieper CF, Cornoni-Huntley J. Is there a threshold between peak oxygen uptake and self-reported physical functioning in older adults? Med Sci Sports Exerc 1998;30:1223-9.
15. Jones LW, Haykowsky M, Pituskin EN, et al. Cardiovascular reserve and risk profile of postmenopausal women after chemoendocrine therapy for hormone receptor--positive operable breast cancer. Oncologist 2007;12:1156-64.
16. Haykowsky MJ, Tomczak CR, Scott JM, Paterson DI, Kitzman DW. Determinants of exercise intolerance in patients with heart failure and reduced or preserved ejection fraction. J Appl Physiol (1985). 2015;119:739-44.
17. McNeely ML, Campbell KL, Rowe BH, Klassen TP, Mackey JR, Courneya KS. Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis. CMAJ 2006;175:34-41.
18. Jones LW, Liang Y, Pituskin EN, et al. Effect of exercise training on peak oxygen consumption in patients with cancer: a meta-analysis. Oncologist 2011;16:112-20.
19. Beaudry R, Kruger C, Liang Y, Parliament M, Haykowsky M, McNeely ML. Effect of supervised exercise on aerobic capacity in cancer survivors: Adherence and workload predict variance in effect. World J Meta-Anal 2015;3:43-53.

Keywords: Arrhythmias, Cardiac, Breast Neoplasms, Capillary Action, Cardiovascular Diseases, Colon, Heart Rate, Hemoglobins, Hypertension, Liver, Lymphoma, Mitochondria, Muscle, Muscle, Skeletal, Myocytes, Cardiac, Prostatic Neoplasms, Quality of Life, Risk Factors, Stroke Volume, Stroke Volume, Survival Rate, Cardiotoxicity

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