February 2020 Issue

Cancer & Cardiovascular Care
By Karen Collins, MS, RDN, CDN, FAND
Today’s Dietitian
Vol. 22, No. 2, P. 20

An Overview of This Emerging Practice Area

Cardiology and oncology often are considered separate medical fields, yet they frequently intertwine. Cardiovascular health before a cancer diagnosis and cardiovascular effects of cancer treatments both influence health outcomes in cancer survivors.

This article explores the growing field of cardio-oncology and potential opportunities for dietitians to play a valuable role. Although cardiovascular risk factors increase in many cancer survivors, discussion of modifying these risk factors during and after cancer treatment, especially through lifestyle, may not be addressed as recommended. Statements from cardiovascular and oncology professional organizations now emphasize the need to promote heart-healthy lifestyles for cancer survivors.1,2

Growth of Cardio-Oncology
Currently, more than 16.9 million people in the United States have a history of cancer. The number of US cancer survivors is predicted to increase further—to more than 22.1 million by 2030—based only on the growth and aging of the population.3

Almost two-thirds of cancer survivors are aged 65 or older.3 And people living at least five years beyond a cancer diagnosis have significant increases in CVD risk factors and a 1.3- to 3.6-fold greater risk of death from CVD compared with age-matched counterparts with no history of cancer.2 CVD may become even more prevalent among oncology patients; the population of aging adults is growing, and continued improvements in success of cancer treatment bring potential for late effects that can emerge months or even years after completion of cancer treatment.2,3 As a result, cardio-oncology (sometimes called onco-cardiology) programs are growing, dedicated to the prevention and treatment of CVD in patients with cancer.4

Cancer Treatment and CVD Risk
Increased risk of CVD in cancer survivors can reflect combined effects of several factors. These include common age-related changes, direct consequences of cancer treatment, and indirect results of cancer and its treatment (including cardio-respiratory deconditioning and weight gain), acting across multiple body systems.2 Some side effects can occur during cancer treatment, although late effects may go unseen until months or decades after treatment.

Efforts to address cardiovascular risk related to cancer therapy often have focused on the early detection and prevention of congestive heart failure. Yet cancer treatments can cause a variety of cardiovascular toxicities, including cardiac arrhythmias, hypertension, thromboembolism, valvular disease, accelerated atherosclerosis and ischemic heart disease, and peripheral vascular disease and stroke.2,5-7

To prevent or minimize these effects, work is in progress to identify ways to adjust treatment choice, dose, and timing, or provide additional cardio-protective treatments. Risk identified in cohort studies often reflects older protocols and doesn’t account for advances in methods to reduce cardiotoxicity. Still, although these side effects occur in a minority of patients, the health impact is significant when they do. And survivors with past exposures to cardiotoxic therapies should continue to be considered at increased risk for developing cardiac dysfunction.1

Heart failure is a progressive disorder that can develop during or after cancer treatment. During treatment, it can cause interruption or discontinuation of cancer-directed therapy, potentially reducing the chance for long-term survival.1,3 It may result as a side effect of anthracycline chemotherapy (eg, doxorubicin), HER2-targeted therapy, or radiation therapy with the heart in the field of treatment.6,7 These treatments commonly are used for breast cancer and certain leukemias and lymphomas, including those that are among the most common cancers in children and adolescents. Risk of heart failure is greatest in people with two or more CVD risk factors, and blood pressure management is an important strategy in its prevention.1

Ischemia already may be present in many adults, and it can be enhanced by some cancer treatments, including a variety of chemotherapy agents and radiation therapy.7 This may occur through changes in lipid metabolism and inflammation-mediated acceleration of atherosclerosis. Hypertension, smoking, dyslipidemia, and insulin resistance all seem to trigger atherosclerosis by promoting endothelial cells’ expression of adhesion molecules and enabling leukocyte attachment to blood vessel walls.8

People at greatest risk of adverse cardiovascular side effects of cancer treatment are those with older age, a history of myocardial infarction or other heart disease, or two or more major risk factors (eg, smoking, hypertension, diabetes, dyslipidemia, obesity).1 Survivors of childhood cancer also are at increased risk of cardiovascular late effects. Current clinical practice guidelines state that clinicians should screen for and actively manage the aforementioned major modifiable CVD risk factors in all patients receiving or previously treated with potentially cardiotoxic treatments. These guidelines also say that a heart-healthy lifestyle, including the role of a healthful diet and exercise, should be discussed as part of their long-term follow-up care.1,9

Dietitians, therefore, can be valuable members of the cardio-oncology health care team with skills to address side effects of cancer treatment that affect the ability to eat and nourish the body, promote dietary choices that affect CVD risk factors, and help set priorities among those choices on an individual basis. The American Society of Clinical Oncology clinical practice guidelines state that patients need to be advised that cardiac dysfunction can be a progressive disorder that initially may be asymptomatic. Therefore, “a heart-healthy lifestyle, including the role of diet and exercise, should be discussed with all patients with cancer before and after completion of their cancer therapy.”1

Mutual Risk Factors
Both cancer risk and CVD risk are associated with various risk factors, some that can’t be modified (such as family history of the disease) and some that can (through lifestyle choices and/or medical care). One reason for the frequent overlap of cancer and CVD is that age is a steady independent risk factor for both. Although a few cancers (such as neuroblastoma, nephroblastoma, and certain sarcomas) strike predominantly in childhood, 78% of the new cancer diagnoses in developed countries occurs in those aged 55 and older. However, it’s important to remember that associations between age and onset of both cancer and CVD can be highly influenced by modifiable risk factors, including diet, physical activity, BMI, and smoking.8

Tobacco Smoking
Tobacco smoking contributes to all stages of atherosclerosis by decreasing levels of nitric oxide and causing vasomotor dysfunction, while the multiple carcinogens it contains significantly increase cancer risk. Tobacco promotes both CVD and cancer by causing oxidative stress that leads to endothelial and DNA damage and by increasing inflammation.8

Diabetes
Both type 1 and type 2 diabetes increase risk of CVD and cancer. Risk from type 2 diabetes involves inflammation, hyperglycemia, hyperinsulinemia, and elevated levels of insulinlike growth factor (IGF).8 Elevated triglyceride-rich lipoproteins commonly seen in type 2 diabetes increase risk of myocardial infarction and stroke through inflammation and enhanced formation of foam cells that lead to atherosclerosis.10 Chronic hyperinsulinemia and resulting elevated IGF enhance cancer development by promoting cell proliferation and inhibiting apoptosis (self-destruction of abnormal cells).11-13 Elevated insulin levels also decrease liver production of sex hormone–binding globulin, thus increasing bioavailable estrogen and testosterone, increasing risk of hormone-sensitive cancers.12 In type 1 diabetes, oxidative stress stemming from chronic elevated blood glucose is considered the primary link to CVD, possibly amplified by a dysfunctional immune response.14,15 Type 1 diabetes has been associated with increased risk of some cancers, but the link is less well understood at this time.11

Some chemotherapeutic agents can worsen blood glucose control, and radiation therapy can increase risk of developing diabetes. Thus, dietitians’ skills in helping people modify eating habits for better blood sugar levels can be valuable.

Hyperlipidemia
Hyperlipidemia is a well-established risk factor for CVD. LDL cholesterol traditionally has been the primary target for risk reduction, but VLDL, intermediate-density lipoprotein, and other non-HDL cholesterol fractions also are atherogenic.10,16 Evidence is inconclusive about any association of serum cholesterol and cancer risk. Current evidence suggests that the inverse association between levels of LDL and cancer incidence seen in some studies may be a result of the malignancy.8

Hypertension
Hypertension is another major established CVD risk factor. It causes structural changes in blood vessels and the heart, which can lead to heart failure, and induces oxidative stress that promotes atherosclerosis. Increased oxidative stress also contributes to increased cancer risk, and, by increasing vascular endothelial growth factor (VEGF), it may potentiate development or progression of cancer.8

VEGF signaling pathway inhibitor treatments are used for a variety of advanced or metastasized cancers. They block angiogenesis (growth of blood vessels) that supports tumor growth but also can cause or increase hypertension, which indicates success in targeting cancer-blocking effects in blood vessels.6 However, these elevations in blood pressure, whether new or from destabilization of previously controlled hypertension, can lead to heart failure and other forms of CVD, so current reviews emphasize maintaining blood pressure control.6,7

Obesity
Obesity increases CVD risk by acting through major risk factors (eg, type 2 diabetes and hypertension) and possibly through atherogenic dyslipidemia and emerging risk factors such as insulin resistance, a proinflammatory state, a prothrombotic state, and sleep apnea commonly found in people with obesity. Obesity also increases metabolic demands of cardiac output, requiring increased stroke volume, which can lead to increased left ventricular filling pressure and volume overload.8 Cancer risk due to excess adiposity seems related to many of the same conditions, such as inflammation and insulin resistance, as well as increased estrogen production in postmenopausal women.17 Although most research on body fat’s link to chronic disease has used BMI as a marker of overweight and obesity, this doesn’t address the complexity of body composition or adipose tissue. Dysfunctional adipose tissue, which is characteristic of most, but not all, people with overweight and obesity, is centrally involved in development of the metabolic disturbances that promote CVD and obesity-related cancers and obesity-associated increased mortality rates.18,19

Alcohol Drinking
Alcohol in moderation has been associated with reduced CVD risk in observational studies, although without data from randomized controlled trials.8 However, this occurs in a well-documented “J-shaped dose-effect curve,” with excessive alcohol leading to elevated triglycerides, hypertension, cardiomyopathy, increased cardiovascular events, and all-cause mortality.5,8,20 Evidence shows a causal relationship between alcohol and risk of several cancers.5,8,21 This may involve the genotoxic effect of acetaldehyde (the primary metabolite of alcohol), oxidative stress, increased estrogen levels, effects on folate metabolism (needed for healthy DNA), and alcohol’s ability to serve as a solvent for carcinogens. Increase in cancer risk is most substantial when consumption is beyond moderation (defined as up to one standard drink per day for women and two per day for men). However, even light drinking of up to one drink per day poses some increase in women’s risk of breast cancer and in risk of esophageal and oropharyngeal cancers.21 (See “Alcohol Consumption and Cancer Risk — The Other Side of a Health Halo,” in the April 2018 issue of Today’s Dietitian.)

Although alcohol is a well-established risk factor for the development of certain cancers, it’s unclear how postdiagnosis alcohol use affects cancer treatment and long-term survival. One systematic review and meta-analysis shows increased cancer recurrence, but no association with overall mortality.22 As for prevention, cancer survivors are advised to limit alcohol to no more than one drink per day for women or two per day for men.9,23 The National Comprehensive Cancer Network clinical practice guidelines recommend survivors of liver, esophageal, kidney, and head and neck cancers abstain from alcohol.9

Cardio-Oncology Rehabilitation
Cardiac rehabilitation (CR) programs aim to increase cardiorespiratory fitness, decrease anginal symptoms, improve psychosocial well-being, and reduce CVD-related morbidity, recurrent hospitalizations, and mortality. These multidisciplinary efforts provide medical evaluation, prescriptive exercise, education, and counseling and behavioral interventions to modify CVD risk factors. CR has been demonstrated to reduce CVD mortality and improve health-related quality of life, and referral to CR is a recognized recommendation for people with acute coronary syndromes. In 2019, the American Heart Association issued a scientific statement proposing a cardio-oncology rehabilitation (CORE) model to adapt the multimodality approach of CR (with exercise, nutrition counseling, tobacco cessation interventions, and risk factor assessment) to decrease CVD events in cancer survivors at highest CVD risk. The scientific statement emphasizes that for CORE program effectiveness, CR program staff must be equipped to address both CVD- and cancer-related concerns, including nutrition.2

Exercise Training
Exercise training is the cornerstone of CR and is proven to improve cardiorespiratory fitness and reduce CVD symptoms in people with established CVD. Although more research is needed, controlled intervention trials in a variety of cancer populations show that exercise after cancer treatment is generally safe and may lessen typical declines in cardiorespiratory fitness and muscle strength; reduce fatigue, anxiety, depressive symptoms, and sleep disturbances; and improve health-related quality of life.2,24 Exercise’s potential benefits for treatment-related cardiotoxicity, peripheral neuropathy, and cognitive functioning remain uncertain.24 In addition to its potential for reducing risk of several forms of cancer,21 moderate evidence supports postdiagnosis physical activity to improve cancer-specific and all-cause survival following breast, colorectal, and prostate cancer.25

Health professionals need to recognize unique exercise-related needs of some cancer survivors. For example, anemia, compromised immune function, neuropathy, balance problems, an ostomy or indwelling catheter, bone metastases, presence of or risk factors for breast cancer–related lymphedema, and decreased bone density as a result of hormonal treatments may require modifying the type or amount of exercise.24 A 2018 international roundtable of experts developed guidelines for assessing the needs of people during and after cancer therapy, and referring them to appropriate options to support physical activity.24,26

Nutrition
Nutrition is a core component of primary and secondary prevention of CVD, reducing cancer risk, and lifestyle recommendations for cancer survivors. The American Institute for Cancer Research (AICR) recommends that after the acute stage of cancer treatment, people should follow the AICR recommendations for cancer prevention, unless otherwise advised by their health professional.21 As cancer survivors increasingly live longer, they’re at risk of developing new primary cancers as well as other chronic diseases, and these recommendations are appropriate for overall health as well as cancer-specific risk.

Guidelines from national organizations specifically for cancer survivors recommend a dietary pattern that’s high in vegetables, fruits, and whole grains; limits red meat and refined sugars; minimizes alcohol; and provides heart-healthy sources of dietary fat.9,23 This pattern is consistent with the AICR recommendations for prevention. For breast cancer survivors, limited evidence suggests foods providing dietary fiber and foods containing soy (in moderation) may reduce all-cause mortality.21

During cancer treatment, and if ability to consume or metabolize food has been impaired by treatment, people may have special nutritional needs. Dietitians can help address taste changes or other side effects.

Nutrition is also vital in combination with exercise to help cancer survivors achieve and maintain a healthy weight and body composition, as advised by current recommendations.2,9 Weight alone doesn’t adequately reflect changes in lean body mass, which can dramatically decrease with aging and during cancer treatment. Low lean body mass, whether reflecting unhealthy weight loss or as part of sarcopenic obesity, is associated with poor health outcomes. Androgen deprivation therapy for prostate cancer can cause rapid development of sarcopenic obesity, so preventive attention is appropriate for care.27

Many survivors today have overweight or obesity at the time of their diagnosis, and this often continues or increases following treatment.9 Prediagnosis obesity increases the risk of cancer recurrence, cancer mortality, and all-cause mortality. These associations are most strongly documented for breast cancer, though overweight, obesity, and unintended weight gain also are associated with a worse prognosis for other cancer survivors.2,9,21

Research is still unclear about the benefits of promoting weight loss in cancer survivors. Evidence does show reduction in comorbidities and in biomarkers linked with cancer risk and prognosis.28 Some clinical guidelines for cancer survivors encourage those with overweight or obesity to achieve and maintain a weight that’s healthy for them.9,23 Identified components for CORE include addressing the spectrum of weight management issues.2

Through their content knowledge and behavior change promotion skills, dietitians can play a valuable role in the growing field of cardio-oncology, whether in specific CORE programs or as part of the overall health care system.

— Karen Collins, MS, RDN, CDN, FAND, is a nutrition consultant specializing in cancer prevention and cardiometabolic health, and nutrition advisor to the American Institute for Cancer Research.

References
1. 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(8):893-911.

2. 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(21):e997-e1012.

3. Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363-385.

4. Barac A, Murtagh G, Carver JR, et al. Cardiovascular health of patients with cancer and cancer survivors: a roadmap to the next level. J Am Coll Cardiol. 2015;65(25):2739-2746.

5. Mehta LS, Watson KE, Barac A, et al. Cardiovascular disease and breast cancer: where these entities intersect: a scientific statement from the American Heart Association. Circulation. 2018;137(8):e30-e66.

6. Chang HM, Moudgil R, Scarabelli T, Okwuosa TM, Yeh ETH. Cardiovascular complications of cancer therapy: best practices in diagnosis, prevention, and management: part 1. J Am Coll Cardiol. 2017;70(20):2536-2551.

7. Zamorano JL, Lancellotti P, Rodriguez Muñoz 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 Heart J. 2016;37(36):2768-2801.

8. Koene RJ, Prizment AE, Blaes A, Konety SH. Shared risk factors in cardiovascular disease and cancer. Circulation. 2016;133(11):1104-1114.

9. NCCN guidelines: survivorship. National Comprehensive Cancer Network website. https://www.nccn.org/professionals/physician_gls/default.aspx#survivorship. Accessed November 21, 2019.

10. Nordestgaard BG. Should we target triglycerides for ASCVD risk reduction? Paper presented at: American Heart Association Scientific Sessions 2019; November 17, 2019; Philadelphia, PA.

11. Zelenko Z, Gallagher EJ. Diabetes and cancer. Endocrinol Metab Clin North Am. 2014;43(1):167-185.

12. Gallagher EJ, LeRoith D. Epidemiology and molecular mechanisms tying obesity, diabetes, and the metabolic syndrome with cancer. Diabetes Care. 2013;36 Suppl 2:S233-S239.

13. Hursting SD, Hursting MJ. Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer. Arterioscler Thromb Vasc Biol. 2012;32(8):1766-1770.

14. Bebu I, Braffett BH, Pop-Busui R, et al. The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study. Diabetologia. 2017;60(10):2084-2091.

15. Sousa GR, Pober D, Galderisi A, et al. Glycemic control, cardiac autoimmunity, and long-term risk of cardiovascular disease in type 1 diabetes mellitus. Circulation. 2019;139(6):730-743.

16. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1 — full report. J Clin Lipidol. 2015;9(2):129-169.

17. World Cancer Research Fund; American Institute for Cancer Research. Continuous Update Project Expert Report 2018: body fatness and weight gain and the risk of cancer. https://www.wcrf.org/sites/default/files/Body-fatness-and-weight-gain_0.pdf. Published 2018.

18. Goyal A, Nimmakayala KR, Zonszein J. Is there a paradox in obesity? Cardiol Rev. 2014;22(4):163-170.

19. Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29(24):2959-2971.

20. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ. 2011;342:d671.

21. World Cancer Research Fund; American Institute for Cancer Research. Diet, nutrition, physical activity and cancer: a global perspective: the third expert report. https://www.wcrf.org/dietandcancer. Published 2018.

22. Schwedhelm C, Boeing H, Hoffmann G, Aleksandrova K, Schwingshackl L. Effect of diet on mortality and cancer recurrence among cancer survivors: a systematic review and meta-analysis of cohort studies. Nutr Rev. 2016;74(12):737-748.

23. Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62(4):243-274.

24. Campbell KL, Winters-Stone KM, Wiskemann J, et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med Sci Sports Exerc. 2019;51(11):2375-2390.

25. Patel AV, Friedenreich CM, Moore SC, et al. American College of Sports Medicine roundtable report on physical activity, sedentary behavior, and cancer prevention and control. Med Sci Sports Exerc. 2019;51(11):2391-2402.

26. Schmitz KH, Campbell AM, Stuiver MM, et al. Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA Cancer J Clin. 2019;69(6):468-484.

27. Bonn SE, Wiklund F, Sjölander A, et al. Body mass index and weight change in men with prostate cancer: progression and mortality. Cancer Causes Control. 2014;25(8):933-943.

28. Ligibel JA, Alfano CM, Courneya KS, et al. American Society of Clinical Oncology position statement on obesity and cancer. J Clin Oncol. 2014;32(31):3568-3574.