- Email: [email protected]
Shared Risk Factors for Cardiovascular Disease and Cancer: Implications for Preventive Health and Clinical Care in Oncology Patients
Accepted Manuscript Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients Christopher B. Johnson, MD, FRCP, Dr. Margot K. Davis, MD, FRCP, Dr. Angeline Law, MD, FRCP, Dr. Jeffrey Sulpher, MD, FRCP PII:
S0828-282X(16)30052-6
DOI:
10.1016/j.cjca.2016.04.008
Reference:
CJCA 2095
To appear in:
Canadian Journal of Cardiology
Received Date: 16 February 2016 Revised Date:
19 April 2016
Accepted Date: 20 April 2016
Please cite this article as: Johnson CB, Davis MK, Law A, Sulpher J, Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients
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Christopher B Johnson, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Dr. Margot K Davis, MD, FRCP. Assistant Professor of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Dr. Angeline Law, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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Dr. Jeffrey Sulpher, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Corresponding Author:
Dr. Christopher B Johnson, MD, FRCP. Assistant Professor of Medicine, University of Ottawa,
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[email protected]
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Ottawa, Ontario, Canada. 501 Smyth Road, Ottawa, Ontario, Canada. K1H8L6. 613-737-8582.
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Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients
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Dr. CB Johnson, Dr. M. Davis, Dr. A. Law, Dr. J. Sulpher.
Brief Summary:
Risk factors associated with cardiovascular disease also increase the risk of cancer. We review
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the evidence linking smoking, obesity, poor diet, and inactivity to both heart disease and cancer. The importance of cardiac co-morbidity and risk factors in adversely affecting oncological
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outcomes is discussed. Awareness of shared risk factors is important for prevention at the population level, and has clinical implications in evaluating cardiotoxicity risk and optimizing cardiac health in patients who require cancer treatment.
Abstract:
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Cardiovascular toxicity of cancer therapy has raised awareness of the importance of heart disease in cancer care among oncologists and cardiologists leading to the new interdisciplinary field of cardio-oncology. Evidence is accumulating to suggest that risk factors associated with
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cardiovascular disease are also related to increased incidence of cancer and excess cancer mortality. We review the epidemiological evidence that smoking, obesity, poor diet, and inactivity
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can cause both heart disease and cancer. The importance of cardiovascular disease and cardiovascular risk factors in adversely affecting oncological outcomes leading to increased cancer mortality is discussed. Cardiotoxicity prediction tools that incorporate cardiac disease and risk factors are described. Raising awareness of shared risk factors for cancer and heart disease may result in more effective advocacy to promote healthy lifestyle changes through the combined efforts of the historically separate specialties of cardiology and oncology.
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Introduction:
Together, heart disease and cancer account for half of all deaths in Canada and the United 1
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States. A growing body of evidence suggests that heart disease and cancer share many risk factors related to unhealthy lifestyle. In 2004, the American Diabetes Association, American
Cancer Society, and American Heart Association published a scientific statement calling for more 2
effective preventive health targeting shared risk factors for these three important diseases . The
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more recent Canadian C-CHANGE endeavor aims to harmonize risk factors to prevent cardiovascular disease, stroke, and diabetes, without specifically focusing on cancer 3,4
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prevention . Such statements are important for preventive health since strategies that can successfully improve shared lifestyle risk factors for cancer and cardiovascular disease have the potential to prevent these 2 leading causes of death. In addition to health prevention, increased awareness of shared risk factors has patient care implications as clinicians consider the cardiac health of oncology patients whose cancer therapy may be cardiotoxic. Cancer treatment may require modification, interruption, or even cessation due to cardiac co-morbidity, with important
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consequences for oncological outcomes (figure 1). Rather than review cardiotoxicity associated with specific cancer therapy such as anthracyclines or chest radiation, the focus of this paper is risk factors and cardiac co-morbidity in cancer patients. The first part of this review summarizes
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the evidence supporting shared lifestyle-related risk factors for cancer and cardiac disease. The second part reviews the influence of cardiac disease and risk factors on oncology treatment and
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how this affects cancer outcomes, and discusses tailored cardiotoxicity risk assessment based on risk factors.
Section 1: Shared Lifestyle Risk Factors For Cancer and Cardiovascular Disease.
Smoking as a Shared Risk Factor for Cancer and Cardiovascular Disease:
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Smoking is a well known shared risk factor for cancer and cardiovascular disease. Cancer and heart disease account for most of the 2-3 fold increased risk of death in smokers compared to 5
non-smokers. Worldwide, smoking causes approximately one third of first myocardial 6
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infarctions. In addition to coronary disease, smoking increases the risk of stroke, aortic aneurysm, hypertensive heart disease, and intestinal ischemia. Smoking increases the risk of
cancer at 14 different sites, including new evidence linking smoking to both breast and prostate 5
cancer. In North America, smoking rates have declined since the 1960s, with recent data 7
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reporting that 18% of Canadians are smokers, which is the lowest rate since 2001. American 8
data reports a 33% decrease in total cigarette consumption over the last decade. It takes
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approximately three decades for a reduction in smoking to cause an associated decline in lung cancer, but such trends are now apparent among male smokers in North America and Northern 9
Europe . In spite of falling cigarette consumption, the incidence of heart disease and malignancies other than lung cancer has increased in the US and Canada due to rising rates of obesity, poor diet, and sedentary behavior. As smoking rates decline in Canada and the United States, the cigarette industry is targeting countries such as China and Africa leading to rising
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global consumption of cigarettes with serious implications for future global rates of cardiac disease and cancer, particularly lung cancer.
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Obesity As a Shared Risk Factor For Cardiovascular Disease and Cancer:
As of 2013, over one third of the world’s adults are obese, 12% of children worldwide are obese,
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obesity rates have increased in every single country, and in 7 countries half of all adult females are obese.11 In Canada, one in five adults and one in 8 children are obese, and it is projected that by 2031, one third of the Canadian population will be obese.
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Both total obesity, measured by
body mass index, and central obesity, measured as waste circumference or waste to hip ratio, are associated with an increased risk of cardiovascular death.
6,11,13,14,15
In addition to
cardiovascular disease, obesity appears to increase cancer incidence and mortality. Long term cohort studies suggest that obesity is a risk factor for cancer death, with a population attributable risk as high as 14% in men and 20% in women.
13,16,17
The higher attributable risk in women may
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relate to increased estradiol production in obese women leading to increased mortality from estrogen sensitive cancers of the breast and ovaries.
16
In Canada, obesity is responsible for at
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least 8% of incident cancers. Obesity increases the risk of cancer at 9 different sites in men, 11 2
21%.
19,20
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different sites in women, and each 1kg/m of excess weight increases the risk of cancer by Weight change as an adult has been linked to cancer risk. Each 5 KG of weight gained
during adulthood increases breast cancer risk by 5%, while dramatic weight loss from gastric bypass surgery reduces cancer mortality by as much as 60%.
21,22,23,24
This suggests that
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promoting healthy weight change in adults can have important health benefits.
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The metabolic syndrome, commonly associated with obesity, may account for the increased risk of cancer in obese subjects. Metabolic risk factors such as high BMI, hyperglycemia, and dyslipidemia are associated with increased cancer incidence and mortality.
25
Pro-inflammatory
cytokines from adipose tissue that increase cardiovascular risk also stimulate tumor growth and promote tumor invasion.
26,27
Several adipokines have been linked to increased cancer incidence
and poor oncological outcomes. Several reviews of the literature discussing biochemical
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mechanisms linking obesity, metabolic syndrome and cancer have recently been published, and potential biological mediators are summarized in table 1.
28-31
In addition to biochemical
mechanisms linking obesity to cancer mortality, it is worth considering that obesity may increase
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cancer mortality indirectly via the cardiovascular system. Obese patients are at risk for cardiac disease and may have reduced cardiac reserve making them more susceptible to cardiotoxicity
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from cancer therapy. If cardiotoxicity compromises cancer therapy in obese subjects, cancer mortality may increase (figure 1).
Diet as a Shared Risk Factor For Cardiovascular Disease and Cancer:
It is estimated that only 5% of US adults have an ideal diet, and globally 78% of the population consume less than recommended fruit and vegetable intake.
32,33
Strong associations between
diet and health outcomes are evident when dietary patterns are evaluated, rather than specific
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food ingredients, and this reflects the complicated socioeconomic factors that influence what we eat.
2,32
Increased cardiac risk has been established for a non-prudent diet, which is common in
western countries, and is characterized by a high content of saturated fat, red meat, and sugar, 34-37
Dietary patterns such as
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including fructose based sugars commonly used in processed food.
the Mediterranean diet and DASH diet are high in fruits and vegetables, whole grains, and
unsaturated fat and are associated with improved cardiovascular outcomes.34-41 Randomized primary and secondary prevention trials confirm that the Mediterranean diet reduces cardiac 42,43,44
In addition to favorable cardiovascular outcomes,
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events by approximately one third.
prudent dietary patterns like the Mediterranean diet are associated with a lower incidence of
overall cancer incidence.
36,40,45,46
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specific malignancies such as colorectal and gastric cancer, and are associated with a lower Long-term follow up of randomized primary and secondary
cardiac prevention trials have observed that the Mediterranean diet reduces the incidence of cancer.
47,48
In addition to reduced cancer incidence, meta analysis of cohort studies suggests that
the Mediterranean diet is associated with a 10% reduction in cancer mortality.
49
The mechanism
of reduced cancer incidence and mortality with prudent dietary patterns remains to be fully
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explained, but likely relates to a reduction in obesity and metabolic syndrome with favorable effects on cytokines and adipokines. Effective strategies to replace the western diet with more prudent dietary patterns should be a major priority given the potential to prevent both heart
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disease and cancer.
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Sedentary Behavior as a Shared Risk Factor For Cardiovascular Disease and Cancer:
Even at a healthy body weight, sedentary behavior assessed using self report surveys is associated with increased cardiac mortality.17,50, 51 Meta analysis suggests a dose response relationship for the protective effects of exercise on reducing coronary mortality. Compared to being sedentary, 150 minutes of weekly moderate activity reduces mortality by 14%, 300 minutes of weekly activity reduces mortality by 20%, and women benefit more than men from regular physical activity.
52
A similar dose response relationship has been established for exercise in the
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prevention of heart failure, with the highest levels of physical activity reducing heart failure risk by 30%.
53
The protective effect of exercise on heart failure is relevant to cardio-oncology given that
some cancer therapies cause left ventricular dysfunction leading to heart failure. Measuring
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fitness on an exercise treadmill test is a powerful cardiac prognosticator. Each MET of increased maximal exercise capacity is associated with a 15% reduction in cardiovascular mortality, and
cardiac patients have a good prognosis if they can achieve at least 8 METs.54,55 High levels of fitness measured by treadmill testing may attenuate or even eliminate the excess cardiac
17,50,56
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if they are also fit.
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mortality associated with obesity, and lean subjects appear to have a good cardiac prognosis only
In addition to cardiovascular protection, exercise results in a modest reduction in the incidence of 17
cancer. While obese, inactive subjects are at highest risk for both cardiac disease and cancer, even subjects with a healthy body weight are at increased risk for cancer if they are inactive.
17
Modest associations between physical inactivity and several specific cancers have been reported (table 2)57-62. There appears to be a dose response relationship between increased exercise and
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reduced incidence of breast and endometrial cancer.
62,66
For example, a sedentary female who
adopts the recommended 150 minutes of weekly activity could reduce her breast cancer risk by 6 %.
54
In addition to reducing cancer incidence, exercise reduces cancer mortality, with a 1%
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reduction in cancer mortality for each 15 minute increment of daily physical activity.
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Compared
to being sedentary, small amounts of moderate exercise, or longer duration low intensity exercise 64,65
The mechanism
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such as walking several hours per week, can reduce mortality from cancer.
linking exercise to lower cancer incidence and mortality likely relates at least in part to reductions in obesity and metabolic syndrome. However, reduced cancer mortality in fit patients who exercise may also relate to better cardiovascular health, greater cardiac reserve, and a lower likelihood that cardiotoxicity will compromise cancer therapy.
A number of wearable devices have recently been developed to measure physical activity. A recent survey using such technology among Canadians reveals that 69% of waking time is spent
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sedentary, only 15% of Canadians meet the minimum 150 minutes of weekly activity, and Canadians over-estimate their physical activity using self report instruments.
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Devices that
directly measure physical activity may help us develop, evaluate and implement strategies to
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increase exercise in order optimize cardiac health and prevent cancer.
Section 2: Effect of Cardiovascular Disease and Risk Factors On Oncological Outcomes
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Prevalence of Risk Factors & Cardiovascular Disease Among Cancer Patients:
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Given the shared risk factors for cancer and cardiac disease, it is not surprising that the prevalence of cardiovascular disease and many cardiovascular risk factors are higher in cancer populations compared to controls. In a study of over 1500 survivors of breast, prostate, colorectal, and gynecologic cancers, cardiovascular risk factors such as obesity, physical inactivity, hypercholesterolemia, hypertension, and diabetes were more common among survivors than age-matched controls.67 The most common risk factors were overweight / obesity (62%),
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hypertension (55%), and diabetes (21%). The Childhood Cancer Survivor Study demonstrates that adult survivors of childhood cancer are more likely than their siblings to be on medications for hypertension, dyslipidemia, or diabetes, and those who receive chest radiation are at risk for 68,69
Compared to post-menopausal controls, breast cancer survivors
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premature coronary disease.
are more likely to have an atherogenic profile characterized by obesity, elevated serum levels of
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glucose, LDL cholesterol, and hsCRP, and many survivors meet criteria for metabolic syndrome.
70
Recently, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort has demonstrated
that cancer survivors are more likely to have new coronary artery calcification over 10 year followup.71 Cancer survivors are a population with a high burden of cardiac risk factors who develop cardiovascular disease earlier than expected and are at high cardiovascular risk.
While much of the increased cardiovascular morbidity and mortality in cancer survivors relates to effects of cardiotoxic cancer therapy, cancer patients also have an increased prevalence of heart
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disease at the time of cancer diagnosis, before they receive treatment. A study of Dutch breast cancer patients demonstrates that coronary artery calcium scores were higher in cancer patients than in age-matched controls from the MESA cohort, suggesting that cancer patients have a 72
Men referred for androgen deprivation
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higher rate of subclinical coronary disease than controls.
therapy (ADT) for high-risk prostate cancer have a higher burden of risk factors and established cardiac disease than the general population, including hypertension (58%), dyslipidemia (51%), diabetes or impaired glucose tolerance (24%), and established cardiac disease (25%).
73
Higher
74,75
cancer cohorts
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rates of metabolic syndrome in cancer patients versus controls has been reported in several
Shared risk factors for both cancer and cardiac disease likely accounts for the
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increased incidence of cardiac disease in cancer patients at the time of diagnosis.
Influence of Cardiovascular Co-Morbidity on Cancer Outcomes:
There is evidence that cardiovascular comorbidity has an effect on cancer outcomes. The role of risk factors and the metabolic syndrome in directly worsening oncological outcomes has already 28-31,71,72
In addition, it is important to consider the possibility that patients with
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been discussed.
cardiac disease and cardiac risk factors who have cancer may receive less aggressive cancer treatment, often driven by concerns about cardiotoxicity (figure 1). In a prospective study of over
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17,000 patients treated for a variety of cancers, severity of comorbidity influenced cancer survival in a dose-dependent fashion, and comorbidity was shown to affect prognosis regardless of 76
Comorbidities that affect cancer survival include hypertension and diabetes, in
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cancer stage.
addition to conditions identified in comorbidity coding systems such as the Charlson and Elixhauser. Among older prostate cancer patients, comorbidity burden was a significant predictor of not receiving treatment, and of receiving hormonal therapy rather than surgery or radiation.77 Elderly patients with Hodgkins lymphoma and comorbidities such as cardiovascular disease, hypertension, and diabetes received 50% less chemotherapy than elderly Hodgkins lymphoma patients without comorbidity.
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It is clear that cancer specialists modify cancer therapy in the face
of cardiovascular co-morbidity, and this likely results in sub-optimal cancer outcomes. What is
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less clear is to what extent cancer patients have their cardiovascular condition optimized by cardiologists familiar with oncology issues, and whether such optimization can permit more 79,80
.
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aggressive cancer treatment with better long term outcomes for cardiac patients with cancer
Cardiovascular disease and risk factors are important predictors of cardiotoxicity associated with cancer therapy. Coronary artery disease (CAD), hypertension, and diabetes are among the strongest predictors of left ventricular dysfunction among patients receiving anthracycline
breast cancer patients receiving trastuzumab.
81,82
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chemotherapy, while CAD, hypertension, and obesity increase the risk of LV dysfunction among Pre-existing hypertension is the single
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strongest predictor of severe hypertension requiring interruption of cancer therapy in patents receiving anti-angiogenic targeted agents for a variety of malignancies.
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CAD increases the risk
of coronary artery vasospasm in patients receiving 5-fluorouracil or capecitabine for 84
gastrointestinal cancers. As each of these adverse effects may limit the ability to provide full cancer treatment, it follows that uncontrolled cardiovascular disease or cardiovascular risk factors may predispose to less aggressive cancer therapy and inferior cancer outcomes (figure 1).
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Cardiologists and oncologists must understand the type of cardiac toxicity associated with a given cancer therapy, especially in patients with risk factors and established cardiac disease. Optimization of cardiac disease and risk factors combined with appropriate monitoring, routinely
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performed in a cardio-oncology clinic, can ensure that cardiac patients receive the cancer therapy 79
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they need at acceptable risk .
Predicting Cardiotoxicity From Cancer Therapy:
The ability to stratify patient risk for cardiotoxicity before initiation of cancer therapy allows clinicians to individualize preventative therapy and intensify cardiac monitoring in order to reduce the acute and chronic effects of cancer therapy on cardiovascular health. Accurate identification of patients at low risk of cardiac complications may reduce unnecessary cardiac monitoring in this population, improving quality of life for patients and allowing health care resources to be re-
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directed to higher risk individuals. Mathematical modeling incorporating patient-specific factors to derive individualized cardiac risk scores has been used to predict cardiotoxicity risk from cancer therapy. Most of this work has focused on breast cancer patients treated with anthracycline
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chemotherapy and targeted agents such as trastuzumab, both of which can cause left ventricular dysfunction. An early mathematical model identified several risk factors for cardiac toxicity, including age over 50, initial weight over 70 kilograms, cumulative baseline anthracycline
exposure >100mg/m2, Eastern Cooperative Oncology Group (ECOG) Performance Status score 93
This has been applied to
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greater or equal to 1, and number of cycles of current therapy.
patients at the Ottawa Hospital (TOH), receiving both adjuvant anthracycline chemotherapy and 94
Higher risk patients were more likely to
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trastuzumab in HER2/neu positive breast cancer.
experience decline in LVEF, heart failure, or referral to specialized cardiac oncology services with a sensitivity and specificity of 41.9% and 85.4%, respectively.
94,95
Two additional models have
used risk factors to predict cardiotoxicity in patients receiving trastuzumab-based therapy for breast cancer.
96
The Romond model incorporates patient age and baseline LVEF to predict for
subsequent cardiac events at 5 years.96 The Ezaz model incorporates baseline chemotherapy,
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age, history of coronary artery disease, atrial fibrillation/flutter, renal failure, diabetes, and 97
hypertension to predict for cardiac events at 3 years . While these models have been derived and evaluated in breast cancer patients, many other cancer populations are at increased risk of
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cardiac toxicity from cancer therapy, in particular from targeted agents. Risk prediction models specific to other cancers and their targeted therapies may permit tailored patient monitoring and
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risk factor intervention, resulting in improved cardiac and cancer outcomes while optimizing health care resource use.
Conclusion:
Established cancer therapies such as anthracyclines and chest radiation have well known short and long term cardiovascular toxicity. Targeted therapies in contemporary cancer care improve cancer outcomes, but have been associated with a variety of cardiovascular toxicities. In addition
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to the clinical consequences of cardiac events, cardiotoxicity limits cancer therapy with serious consequences for cancer patients. Optimal treatment of today’s cancer patient requires consideration of shared risk factors, recognition of worse oncological outcomes in the setting of
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heart disease and risk factors, and identifying heart disease and risk factors in order to predict cardiotoxicity from cancer therapy. Cardio-oncology clinics play an important role in optimizing cardiac health to permit the most effective cancer therapy in patients with cardiac disease and
cardiac risk factors. For the cancer survivor, awareness of the importance of exercise, prudent
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diet, smoking cessation and maintaining a healthy body weight should be part of a survivorship care plan. We know what causes cancer and heart disease, but what we don’t know is how to
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effectively reduce smoking, optimize nutrition, increase physical activity and contain the global obesity epidemic. In 2010, the American Heart Association set national goals to reduce the burden of cardiovascular disease by 2020 through improved cardiovascular risk factors. In addition to optimizing the cardiac health of patients facing cancer therapy, the emerging discipline of cardio-oncology is well placed to co-ordinate population health advocacy efforts to promote
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healthy lifestyle behavior that can prevent heart disease and cancer.
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54. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H. Cardiorespiratory Fitness as a Quantitative Predictor of AllCause Mortality and Cardiovascular Events in Healthy Men and Women. A Meta-Analysis. JAMA. 2009;301: 2024-2035. 55. Meyers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise Capacity and Mortality Among Men Referred For Exercise Testing. N Engl J Med. 2002;346: 793-801. 56. Sui X, LaMonte MJ, Laditka JN, Hardin JW, Chase N, Hooker SP, Blair SN. Cardiorespiratory Fitness and Adiposity as Mortality Predictors in Older Adults. JAMA 2007;298(21):2507-2516. 57. Liu Y, Hu F, Li D, et al. "Does Physical Activity Reduce the Risk of Prostate Cancer? A Systematic Review and Meta-analysis." European Urology, 2011;60: 1029-1043. 58. Wu Y, Zhang D, Kang S. "Physical activity and risk of breast cancer: a meta-analysis of prospective studies." Breast Cancer Res Treat, 2013;137: 869–882.
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59. Kiemling M, Behrens G, Schmid D, Leitzmann MF. The Association Between Physical Activity and Bladder Cancer: Systematic Review and Meta-Analysis. Br J Cancer, 2014;110:1862-1870. 60. Behrens G, Leitzmann MF. The Association Between Physical Activity and Renal Cancer: Systematic Review and Meta-Analysis. Br J Cancer. 2013;108: 798-811.
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61. Behrens G, Jochem C, Keimling M, Ricci C, Schmid D, Leitzmann MF. The Association Between Physical Activity and Gastroesophageal Cancer: Systematic Review and Meta-Analysis. Eur J Epidemiol. 2014;29: 151-170. 62. Keum NN, Ju W, Lee DH, et al. Leisure-time physical activity and endometrial cancer risk: Dose–response meta-analysis of epidemiological studies. International Journal of Cancer, 2014;135: 682–694.
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63. Wen CP, Pui Man Wai J, Tsai MK, et al. "Minimum amount of physical activity for reduced mortality and extended life expectancy: a prospective cohort study." Lancet, 2011: 1-10.
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64. Zhong S, Jiang T, Ma T, Zhang X, Tang J, Chen W, Lv M, Zhao J. Association Between Physical Activity and Mortality in Breast Cancer: A Meta-Analysis of Cohort Studies. Eur J Epidemiol 2014;29: 391-404. 65. Holmes MD, Chen WY, Feskanich D, et al. "Physical Activity and Survival After Breast Cancer Diagnosis." JAMA, 2005;293(20): 2479-2486. 66. Colley RC, Garriguet D, Janssen I, Craig CL, Clarke J, Tremblay MS. Physical Activity of Canadian Adults: Accelerometer Results From the 2007 to 2009 Canadian Health Measures Survey. Health Reports (Statistics Canada, Catalogue 82-003) 2011;22:7-14.
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69. Rademaker, J. et al. Coronary artery disease after radiation therapy for Hodgkin's lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients. AJR Am J Roentgenol 191, 32–37 (2008). 70. Buttros, D. B. et al. Risk of metabolic syndrome in postmenopausal breast cancer survivors. Menopause (2012). doi:10.1097/gme.0b013e318272bd4a 71. Whitlock, M. C. et al. Cancer and Its Association With the Development of Coronary Artery Calcification: An Assessment From the Multi-Ethnic Study of Atherosclerosis. J Am Heart Assoc 4e002533–e002533 (2015). 72. Mast, M. E. et al. Preradiotherapy calcium scores of the coronary arteries in a cohort of women with early-stage breast cancer: a comparison with a cohort of healthy women. Int. J. Radiat. Oncol. Biol. Phys. 83, 853–858 (2012). 73. Davis, M. K., Rajala, J. L., Tyldesley, S., Pickles, T. & Virani, S. A. The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada. J Oncol 2015, 820403–7 (2015).
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74. Morote, J. et al. The metabolic syndrome and its components in patients with prostate cancer on androgen deprivation therapy. J. Urol. 193, 1963–1969 (2015). 75. Healy, L. A. et al. Metabolic syndrome and leptin are associated with adverse pathological features in male colorectal cancer patients. Colorectal Dis 14, 157–165 (2012).
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78. Van Spronsen, D. J., Janssen-Heijnen, M. L., Breed, W. P. & Coebergh, J. W. Prevalence of co-morbidity and its relationship to treatment among unselected patients with Hodgkin‘s disease and non-Hodgkin’s lymphoma, 1993-1996. Ann Hematol 78, 315–319 (1999).
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79. Dent S, Hopkins S, Graham N, Johnson C, Law A, Campbell M, Crawley F, Allen K, Turek M. The Experience of a Multidisciplinary CLinic in the Management of Early-Stage Breast Cancer Patients Receiving Trastuzumab Therapy: An Observational Study. Cardiol Res Pract. 2012;2012:135819.doi:10.1155/2012/135819. 80. Barac A, Murtagh G, Carver JR, Chen MH, Freeman AM, Herrmann J, Iliescu C, Ky B, Mayer EL, Okwuosa TM, Plana JC, Ryan TD, Rzeszut AK, Douglas PS. Cardiovascular Health of Patients With Cancer and Cancer Survivors: A Roadmap to the Next Level. J Am Coll Cardiol. 2015 Jun 30;65(25):2739-46. 81. Lotrionte, M. et al. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am. J. Cardiol. 112, 1980–1984 (2013).
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82. Gunaldi, M. et al. Risk factors for developing cardiotoxicity of trastuzumab in breast cancer patients: An observational single-centre study. J Oncol Pharm Pract 1078155214567162 (2015). doi:10.1177/1078155214567162 83. Hamnvik, O.-P. R. et al. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer (2014). doi:10.1002/cncr.28972
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84. Collins, C. & Weiden, P. L. Cardiotoxicity of 5-fluorouracil. Cancer Treat Rep 71, 733–736 (1987).
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85. The Emerging Risk Factors Collaboration. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314:52-60. 86. Kenfield, S. A., Stampfer, M. J., Chan, J. M. & Giovannucci, E. Smoking and prostate cancer survival and recurrence. JAMA 305, 2548–2555 (2011). 87. Zu, K. & Giovannucci, E. Smoking and aggressive prostate cancer: a review of the epidemiologic evidence. Cancer Causes Control 20, 1799–1810 (2009). 88. Gerdtsson, A. et al. Anthropometric Measures at Multiple Times Throughout Life and Prostate Cancer Diagnosis, Metastasis, and Death. Eur. Urol. 68, 1076–1082 (2015). 89. Cao, Y. & Ma, J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res (Phila) 4, 486–501 (2011). 90. Azrad, M. & Demark-Wahnefried, W. The association between adiposity and breast cancer
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recurrence and survival: A review of the recent literature. Curr Nutr Rep 3, 9–15 (2014). 91. Sharma, A. et al. Colorectal cancer: Histopathologic differences in tumor characteristics between patients with and without diabetes. Clin Colorectal Cancer 13, 54–61 (2014). 92. Ligibel, J. Lifestyle factors in cancer survivorship. J. Clin. Oncol. 30, 3697–3704 (2012).
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93. Dranitsaris G, Rayson D, Vincent M, Chang J, Gelmon K, Sandor D, Reardon G. The Development of a Predictive Model to Estimate Cardiotoxic Risk For Patients With Metastatic Breast Cancer Receiving Anthracyclines. Breast Cancer Res Treat. 2008; 107(3) : 443-450.
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94. Sulpher J., F. Dattilo, A. Law, G. Dranitsaris, F. Crawley, M. Kovacs, N. Graham and S. Dent. 2014. Development of a predictive model to estimate cardiotoxic risk associated with anthracyclines and trastuzumab – San Antonio Breast Cancer Symposium, December 9-13, 2014. San Antonio, Texas
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95. Gauthier JM, T Nguyen, C Johnson, J Sulpher, S Dent, JR Wentzell. Validation of a Novel Trastuzumab-Induced Cardiotoxicity Prediction Scale for Breast Cancer Patients. Global Cardio-Oncology Summit, Nasville TN – October 15-16, 2015.
96. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, Rathi V, Fehrenbacher L, Brufsky A, Asar CA, Flynn PJ, Zapas JL, Polikoff J, Gross HM, Biggs DD, Atkins JN, Tan-Chiu E, Zheng P, Yothers G, Mamounas EP, Wolmark N. Seven Year Follow-up Assessment of Cardiac Function in NSABP-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab as Adjuvant Therapy For Patients With Node-Positive, Human Epidermal Growth Factor 2- Positive Breast Cancer. J Clin Oncol. 2012;30(31) :3792-3799.
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97. Ezaz G, Long JB, Gross CP, Chen J. Risk Prediction Model for Heart Failure and Cardiomyopathy After Adjuvant Trastuzumab Therapy for Breast Cancer. J Am Heart Assoc. 2014;3 :e000472 doi : 10.1161/JAHA.113.000472.
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Figure 1: Interaction Between Shared Risk Factors, Cardiac Disease & Cancer
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Given that cancer and cardiac disease share risk factors, many cancer patients have sub-clinical or clinically overt cardiac disease at the time of cancer diagnosis. In order to avoid cardiotoxicity, cancer therapy may be modified with the potential for lower efficacy. Cardiotoxicity during cancer therapy may result in interruption or cessation of cancer treatment. In this way, cardiac comorbidity due to shared risk factors compromises cancer therapy leading to worse oncological outcomes. In cancer survivors, risk factors often worsen during cancer therapy. Cardiotoxic effects of cancer treatment combined with worsening risk factors lead to late cardiotoxicity. Shared risk factors and cardiac co-morbidity increase both short-term and long term cardiac risk and cancer risk.
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Table 1: Potential Biological Mediators Linking Obesity With Cancer
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Animal and human data suggest that growth hormones, sex hormones, and the adipokines Leptin 28-31 and Adiponectin may mediate the relationship between obesity and cancer .
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Table 2: Protective Effects of Exercise on Cancer Incidence: Meta Analyses of Cohort Studies
Cancer Site
Cancer Cases (n) RR (95% CI)
Author
Year
88294
0.9 (0.84-0.95)
Liu
2011
Breast
63786
0.88 (0.85-0.91)
Wu
2012
Bladder
27784
0.85 (0.74-0.98)
Kiemling
2014
Esophageal
15745
0.79 (0.66-0.94)
Behrens
Renal
10756
0.88 (0.79-0.97)
Behrens
Endometrial
NA
0.82 (0.75-0.9)
Keum
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Prostate
2014
2013
2014
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Meta-analyses of cohort studies suggest that subjects who exercise have modest reductions in 57-62 the incidence of several common cancers .
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CANCER RISK
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Smoking Obesity Non-Prudent Diet Physical Inactivity
CANCER
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Shared Risk Factors:
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Figure 1: Interaction Between Shared Risk Factors, Cardiac Disease & Cancer
Radiation
Cancer Risk: -Less therapy offered due to CVD -Cardiotoxicity limits therapy
Targeted Therapy
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Perioperative Cardiac Events
High Long Term Risk
Cardiotoxicity From Cancer Therapy
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CARDIAC RISK
Chemotherapy
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Surgery
Cancer Survivors:
Clinical Cardiovascular Disease at Cancer Diagnosis
Sub-Clinical Cardiovascular Disease at Cancer Diagnosis
Risk Factors Persist During Cancer Treatment Risk Factors May Worsen During Cancer Treatment
Cardiac Risk: -Cardiotoxic cancer therapy -Worsening risk factors
S0828-282X(16)30052-6
DOI:
10.1016/j.cjca.2016.04.008
Reference:
CJCA 2095
To appear in:
Canadian Journal of Cardiology
Received Date: 16 February 2016 Revised Date:
19 April 2016
Accepted Date: 20 April 2016
Please cite this article as: Johnson CB, Davis MK, Law A, Sulpher J, Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.04.008. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients
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Christopher B Johnson, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Dr. Margot K Davis, MD, FRCP. Assistant Professor of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Dr. Angeline Law, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
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Dr. Jeffrey Sulpher, MD, FRCP. Assistant Professor of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Corresponding Author:
Dr. Christopher B Johnson, MD, FRCP. Assistant Professor of Medicine, University of Ottawa,
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[email protected]
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Ottawa, Ontario, Canada. 501 Smyth Road, Ottawa, Ontario, Canada. K1H8L6. 613-737-8582.
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Shared Risk Factors for Cardiovascular Disease and Cancer: Implications For Preventive Health and Clinical Care of Oncology Patients
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Dr. CB Johnson, Dr. M. Davis, Dr. A. Law, Dr. J. Sulpher.
Brief Summary:
Risk factors associated with cardiovascular disease also increase the risk of cancer. We review
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the evidence linking smoking, obesity, poor diet, and inactivity to both heart disease and cancer. The importance of cardiac co-morbidity and risk factors in adversely affecting oncological
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outcomes is discussed. Awareness of shared risk factors is important for prevention at the population level, and has clinical implications in evaluating cardiotoxicity risk and optimizing cardiac health in patients who require cancer treatment.
Abstract:
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Cardiovascular toxicity of cancer therapy has raised awareness of the importance of heart disease in cancer care among oncologists and cardiologists leading to the new interdisciplinary field of cardio-oncology. Evidence is accumulating to suggest that risk factors associated with
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cardiovascular disease are also related to increased incidence of cancer and excess cancer mortality. We review the epidemiological evidence that smoking, obesity, poor diet, and inactivity
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can cause both heart disease and cancer. The importance of cardiovascular disease and cardiovascular risk factors in adversely affecting oncological outcomes leading to increased cancer mortality is discussed. Cardiotoxicity prediction tools that incorporate cardiac disease and risk factors are described. Raising awareness of shared risk factors for cancer and heart disease may result in more effective advocacy to promote healthy lifestyle changes through the combined efforts of the historically separate specialties of cardiology and oncology.
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Introduction:
Together, heart disease and cancer account for half of all deaths in Canada and the United 1
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States. A growing body of evidence suggests that heart disease and cancer share many risk factors related to unhealthy lifestyle. In 2004, the American Diabetes Association, American
Cancer Society, and American Heart Association published a scientific statement calling for more 2
effective preventive health targeting shared risk factors for these three important diseases . The
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more recent Canadian C-CHANGE endeavor aims to harmonize risk factors to prevent cardiovascular disease, stroke, and diabetes, without specifically focusing on cancer 3,4
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prevention . Such statements are important for preventive health since strategies that can successfully improve shared lifestyle risk factors for cancer and cardiovascular disease have the potential to prevent these 2 leading causes of death. In addition to health prevention, increased awareness of shared risk factors has patient care implications as clinicians consider the cardiac health of oncology patients whose cancer therapy may be cardiotoxic. Cancer treatment may require modification, interruption, or even cessation due to cardiac co-morbidity, with important
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consequences for oncological outcomes (figure 1). Rather than review cardiotoxicity associated with specific cancer therapy such as anthracyclines or chest radiation, the focus of this paper is risk factors and cardiac co-morbidity in cancer patients. The first part of this review summarizes
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the evidence supporting shared lifestyle-related risk factors for cancer and cardiac disease. The second part reviews the influence of cardiac disease and risk factors on oncology treatment and
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how this affects cancer outcomes, and discusses tailored cardiotoxicity risk assessment based on risk factors.
Section 1: Shared Lifestyle Risk Factors For Cancer and Cardiovascular Disease.
Smoking as a Shared Risk Factor for Cancer and Cardiovascular Disease:
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Smoking is a well known shared risk factor for cancer and cardiovascular disease. Cancer and heart disease account for most of the 2-3 fold increased risk of death in smokers compared to 5
non-smokers. Worldwide, smoking causes approximately one third of first myocardial 6
5
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infarctions. In addition to coronary disease, smoking increases the risk of stroke, aortic aneurysm, hypertensive heart disease, and intestinal ischemia. Smoking increases the risk of
cancer at 14 different sites, including new evidence linking smoking to both breast and prostate 5
cancer. In North America, smoking rates have declined since the 1960s, with recent data 7
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reporting that 18% of Canadians are smokers, which is the lowest rate since 2001. American 8
data reports a 33% decrease in total cigarette consumption over the last decade. It takes
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approximately three decades for a reduction in smoking to cause an associated decline in lung cancer, but such trends are now apparent among male smokers in North America and Northern 9
Europe . In spite of falling cigarette consumption, the incidence of heart disease and malignancies other than lung cancer has increased in the US and Canada due to rising rates of obesity, poor diet, and sedentary behavior. As smoking rates decline in Canada and the United States, the cigarette industry is targeting countries such as China and Africa leading to rising
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global consumption of cigarettes with serious implications for future global rates of cardiac disease and cancer, particularly lung cancer.
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Obesity As a Shared Risk Factor For Cardiovascular Disease and Cancer:
As of 2013, over one third of the world’s adults are obese, 12% of children worldwide are obese,
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obesity rates have increased in every single country, and in 7 countries half of all adult females are obese.11 In Canada, one in five adults and one in 8 children are obese, and it is projected that by 2031, one third of the Canadian population will be obese.
12
Both total obesity, measured by
body mass index, and central obesity, measured as waste circumference or waste to hip ratio, are associated with an increased risk of cardiovascular death.
6,11,13,14,15
In addition to
cardiovascular disease, obesity appears to increase cancer incidence and mortality. Long term cohort studies suggest that obesity is a risk factor for cancer death, with a population attributable risk as high as 14% in men and 20% in women.
13,16,17
The higher attributable risk in women may
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relate to increased estradiol production in obese women leading to increased mortality from estrogen sensitive cancers of the breast and ovaries.
16
In Canada, obesity is responsible for at
18
least 8% of incident cancers. Obesity increases the risk of cancer at 9 different sites in men, 11 2
21%.
19,20
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different sites in women, and each 1kg/m of excess weight increases the risk of cancer by Weight change as an adult has been linked to cancer risk. Each 5 KG of weight gained
during adulthood increases breast cancer risk by 5%, while dramatic weight loss from gastric bypass surgery reduces cancer mortality by as much as 60%.
21,22,23,24
This suggests that
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promoting healthy weight change in adults can have important health benefits.
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The metabolic syndrome, commonly associated with obesity, may account for the increased risk of cancer in obese subjects. Metabolic risk factors such as high BMI, hyperglycemia, and dyslipidemia are associated with increased cancer incidence and mortality.
25
Pro-inflammatory
cytokines from adipose tissue that increase cardiovascular risk also stimulate tumor growth and promote tumor invasion.
26,27
Several adipokines have been linked to increased cancer incidence
and poor oncological outcomes. Several reviews of the literature discussing biochemical
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mechanisms linking obesity, metabolic syndrome and cancer have recently been published, and potential biological mediators are summarized in table 1.
28-31
In addition to biochemical
mechanisms linking obesity to cancer mortality, it is worth considering that obesity may increase
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cancer mortality indirectly via the cardiovascular system. Obese patients are at risk for cardiac disease and may have reduced cardiac reserve making them more susceptible to cardiotoxicity
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from cancer therapy. If cardiotoxicity compromises cancer therapy in obese subjects, cancer mortality may increase (figure 1).
Diet as a Shared Risk Factor For Cardiovascular Disease and Cancer:
It is estimated that only 5% of US adults have an ideal diet, and globally 78% of the population consume less than recommended fruit and vegetable intake.
32,33
Strong associations between
diet and health outcomes are evident when dietary patterns are evaluated, rather than specific
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food ingredients, and this reflects the complicated socioeconomic factors that influence what we eat.
2,32
Increased cardiac risk has been established for a non-prudent diet, which is common in
western countries, and is characterized by a high content of saturated fat, red meat, and sugar, 34-37
Dietary patterns such as
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including fructose based sugars commonly used in processed food.
the Mediterranean diet and DASH diet are high in fruits and vegetables, whole grains, and
unsaturated fat and are associated with improved cardiovascular outcomes.34-41 Randomized primary and secondary prevention trials confirm that the Mediterranean diet reduces cardiac 42,43,44
In addition to favorable cardiovascular outcomes,
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events by approximately one third.
prudent dietary patterns like the Mediterranean diet are associated with a lower incidence of
overall cancer incidence.
36,40,45,46
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specific malignancies such as colorectal and gastric cancer, and are associated with a lower Long-term follow up of randomized primary and secondary
cardiac prevention trials have observed that the Mediterranean diet reduces the incidence of cancer.
47,48
In addition to reduced cancer incidence, meta analysis of cohort studies suggests that
the Mediterranean diet is associated with a 10% reduction in cancer mortality.
49
The mechanism
of reduced cancer incidence and mortality with prudent dietary patterns remains to be fully
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explained, but likely relates to a reduction in obesity and metabolic syndrome with favorable effects on cytokines and adipokines. Effective strategies to replace the western diet with more prudent dietary patterns should be a major priority given the potential to prevent both heart
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disease and cancer.
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Sedentary Behavior as a Shared Risk Factor For Cardiovascular Disease and Cancer:
Even at a healthy body weight, sedentary behavior assessed using self report surveys is associated with increased cardiac mortality.17,50, 51 Meta analysis suggests a dose response relationship for the protective effects of exercise on reducing coronary mortality. Compared to being sedentary, 150 minutes of weekly moderate activity reduces mortality by 14%, 300 minutes of weekly activity reduces mortality by 20%, and women benefit more than men from regular physical activity.
52
A similar dose response relationship has been established for exercise in the
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prevention of heart failure, with the highest levels of physical activity reducing heart failure risk by 30%.
53
The protective effect of exercise on heart failure is relevant to cardio-oncology given that
some cancer therapies cause left ventricular dysfunction leading to heart failure. Measuring
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fitness on an exercise treadmill test is a powerful cardiac prognosticator. Each MET of increased maximal exercise capacity is associated with a 15% reduction in cardiovascular mortality, and
cardiac patients have a good prognosis if they can achieve at least 8 METs.54,55 High levels of fitness measured by treadmill testing may attenuate or even eliminate the excess cardiac
17,50,56
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if they are also fit.
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mortality associated with obesity, and lean subjects appear to have a good cardiac prognosis only
In addition to cardiovascular protection, exercise results in a modest reduction in the incidence of 17
cancer. While obese, inactive subjects are at highest risk for both cardiac disease and cancer, even subjects with a healthy body weight are at increased risk for cancer if they are inactive.
17
Modest associations between physical inactivity and several specific cancers have been reported (table 2)57-62. There appears to be a dose response relationship between increased exercise and
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reduced incidence of breast and endometrial cancer.
62,66
For example, a sedentary female who
adopts the recommended 150 minutes of weekly activity could reduce her breast cancer risk by 6 %.
54
In addition to reducing cancer incidence, exercise reduces cancer mortality, with a 1%
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reduction in cancer mortality for each 15 minute increment of daily physical activity.
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Compared
to being sedentary, small amounts of moderate exercise, or longer duration low intensity exercise 64,65
The mechanism
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such as walking several hours per week, can reduce mortality from cancer.
linking exercise to lower cancer incidence and mortality likely relates at least in part to reductions in obesity and metabolic syndrome. However, reduced cancer mortality in fit patients who exercise may also relate to better cardiovascular health, greater cardiac reserve, and a lower likelihood that cardiotoxicity will compromise cancer therapy.
A number of wearable devices have recently been developed to measure physical activity. A recent survey using such technology among Canadians reveals that 69% of waking time is spent
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sedentary, only 15% of Canadians meet the minimum 150 minutes of weekly activity, and Canadians over-estimate their physical activity using self report instruments.
66
Devices that
directly measure physical activity may help us develop, evaluate and implement strategies to
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increase exercise in order optimize cardiac health and prevent cancer.
Section 2: Effect of Cardiovascular Disease and Risk Factors On Oncological Outcomes
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Prevalence of Risk Factors & Cardiovascular Disease Among Cancer Patients:
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Given the shared risk factors for cancer and cardiac disease, it is not surprising that the prevalence of cardiovascular disease and many cardiovascular risk factors are higher in cancer populations compared to controls. In a study of over 1500 survivors of breast, prostate, colorectal, and gynecologic cancers, cardiovascular risk factors such as obesity, physical inactivity, hypercholesterolemia, hypertension, and diabetes were more common among survivors than age-matched controls.67 The most common risk factors were overweight / obesity (62%),
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hypertension (55%), and diabetes (21%). The Childhood Cancer Survivor Study demonstrates that adult survivors of childhood cancer are more likely than their siblings to be on medications for hypertension, dyslipidemia, or diabetes, and those who receive chest radiation are at risk for 68,69
Compared to post-menopausal controls, breast cancer survivors
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premature coronary disease.
are more likely to have an atherogenic profile characterized by obesity, elevated serum levels of
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glucose, LDL cholesterol, and hsCRP, and many survivors meet criteria for metabolic syndrome.
70
Recently, the Multi-Ethnic Study of Atherosclerosis (MESA) cohort has demonstrated
that cancer survivors are more likely to have new coronary artery calcification over 10 year followup.71 Cancer survivors are a population with a high burden of cardiac risk factors who develop cardiovascular disease earlier than expected and are at high cardiovascular risk.
While much of the increased cardiovascular morbidity and mortality in cancer survivors relates to effects of cardiotoxic cancer therapy, cancer patients also have an increased prevalence of heart
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disease at the time of cancer diagnosis, before they receive treatment. A study of Dutch breast cancer patients demonstrates that coronary artery calcium scores were higher in cancer patients than in age-matched controls from the MESA cohort, suggesting that cancer patients have a 72
Men referred for androgen deprivation
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higher rate of subclinical coronary disease than controls.
therapy (ADT) for high-risk prostate cancer have a higher burden of risk factors and established cardiac disease than the general population, including hypertension (58%), dyslipidemia (51%), diabetes or impaired glucose tolerance (24%), and established cardiac disease (25%).
73
Higher
74,75
cancer cohorts
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rates of metabolic syndrome in cancer patients versus controls has been reported in several
Shared risk factors for both cancer and cardiac disease likely accounts for the
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increased incidence of cardiac disease in cancer patients at the time of diagnosis.
Influence of Cardiovascular Co-Morbidity on Cancer Outcomes:
There is evidence that cardiovascular comorbidity has an effect on cancer outcomes. The role of risk factors and the metabolic syndrome in directly worsening oncological outcomes has already 28-31,71,72
In addition, it is important to consider the possibility that patients with
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been discussed.
cardiac disease and cardiac risk factors who have cancer may receive less aggressive cancer treatment, often driven by concerns about cardiotoxicity (figure 1). In a prospective study of over
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17,000 patients treated for a variety of cancers, severity of comorbidity influenced cancer survival in a dose-dependent fashion, and comorbidity was shown to affect prognosis regardless of 76
Comorbidities that affect cancer survival include hypertension and diabetes, in
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cancer stage.
addition to conditions identified in comorbidity coding systems such as the Charlson and Elixhauser. Among older prostate cancer patients, comorbidity burden was a significant predictor of not receiving treatment, and of receiving hormonal therapy rather than surgery or radiation.77 Elderly patients with Hodgkins lymphoma and comorbidities such as cardiovascular disease, hypertension, and diabetes received 50% less chemotherapy than elderly Hodgkins lymphoma patients without comorbidity.
78
It is clear that cancer specialists modify cancer therapy in the face
of cardiovascular co-morbidity, and this likely results in sub-optimal cancer outcomes. What is
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less clear is to what extent cancer patients have their cardiovascular condition optimized by cardiologists familiar with oncology issues, and whether such optimization can permit more 79,80
.
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aggressive cancer treatment with better long term outcomes for cardiac patients with cancer
Cardiovascular disease and risk factors are important predictors of cardiotoxicity associated with cancer therapy. Coronary artery disease (CAD), hypertension, and diabetes are among the strongest predictors of left ventricular dysfunction among patients receiving anthracycline
breast cancer patients receiving trastuzumab.
81,82
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chemotherapy, while CAD, hypertension, and obesity increase the risk of LV dysfunction among Pre-existing hypertension is the single
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strongest predictor of severe hypertension requiring interruption of cancer therapy in patents receiving anti-angiogenic targeted agents for a variety of malignancies.
83
CAD increases the risk
of coronary artery vasospasm in patients receiving 5-fluorouracil or capecitabine for 84
gastrointestinal cancers. As each of these adverse effects may limit the ability to provide full cancer treatment, it follows that uncontrolled cardiovascular disease or cardiovascular risk factors may predispose to less aggressive cancer therapy and inferior cancer outcomes (figure 1).
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Cardiologists and oncologists must understand the type of cardiac toxicity associated with a given cancer therapy, especially in patients with risk factors and established cardiac disease. Optimization of cardiac disease and risk factors combined with appropriate monitoring, routinely
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performed in a cardio-oncology clinic, can ensure that cardiac patients receive the cancer therapy 79
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they need at acceptable risk .
Predicting Cardiotoxicity From Cancer Therapy:
The ability to stratify patient risk for cardiotoxicity before initiation of cancer therapy allows clinicians to individualize preventative therapy and intensify cardiac monitoring in order to reduce the acute and chronic effects of cancer therapy on cardiovascular health. Accurate identification of patients at low risk of cardiac complications may reduce unnecessary cardiac monitoring in this population, improving quality of life for patients and allowing health care resources to be re-
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directed to higher risk individuals. Mathematical modeling incorporating patient-specific factors to derive individualized cardiac risk scores has been used to predict cardiotoxicity risk from cancer therapy. Most of this work has focused on breast cancer patients treated with anthracycline
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chemotherapy and targeted agents such as trastuzumab, both of which can cause left ventricular dysfunction. An early mathematical model identified several risk factors for cardiac toxicity, including age over 50, initial weight over 70 kilograms, cumulative baseline anthracycline
exposure >100mg/m2, Eastern Cooperative Oncology Group (ECOG) Performance Status score 93
This has been applied to
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greater or equal to 1, and number of cycles of current therapy.
patients at the Ottawa Hospital (TOH), receiving both adjuvant anthracycline chemotherapy and 94
Higher risk patients were more likely to
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trastuzumab in HER2/neu positive breast cancer.
experience decline in LVEF, heart failure, or referral to specialized cardiac oncology services with a sensitivity and specificity of 41.9% and 85.4%, respectively.
94,95
Two additional models have
used risk factors to predict cardiotoxicity in patients receiving trastuzumab-based therapy for breast cancer.
96
The Romond model incorporates patient age and baseline LVEF to predict for
subsequent cardiac events at 5 years.96 The Ezaz model incorporates baseline chemotherapy,
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age, history of coronary artery disease, atrial fibrillation/flutter, renal failure, diabetes, and 97
hypertension to predict for cardiac events at 3 years . While these models have been derived and evaluated in breast cancer patients, many other cancer populations are at increased risk of
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cardiac toxicity from cancer therapy, in particular from targeted agents. Risk prediction models specific to other cancers and their targeted therapies may permit tailored patient monitoring and
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risk factor intervention, resulting in improved cardiac and cancer outcomes while optimizing health care resource use.
Conclusion:
Established cancer therapies such as anthracyclines and chest radiation have well known short and long term cardiovascular toxicity. Targeted therapies in contemporary cancer care improve cancer outcomes, but have been associated with a variety of cardiovascular toxicities. In addition
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to the clinical consequences of cardiac events, cardiotoxicity limits cancer therapy with serious consequences for cancer patients. Optimal treatment of today’s cancer patient requires consideration of shared risk factors, recognition of worse oncological outcomes in the setting of
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heart disease and risk factors, and identifying heart disease and risk factors in order to predict cardiotoxicity from cancer therapy. Cardio-oncology clinics play an important role in optimizing cardiac health to permit the most effective cancer therapy in patients with cardiac disease and
cardiac risk factors. For the cancer survivor, awareness of the importance of exercise, prudent
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diet, smoking cessation and maintaining a healthy body weight should be part of a survivorship care plan. We know what causes cancer and heart disease, but what we don’t know is how to
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effectively reduce smoking, optimize nutrition, increase physical activity and contain the global obesity epidemic. In 2010, the American Heart Association set national goals to reduce the burden of cardiovascular disease by 2020 through improved cardiovascular risk factors. In addition to optimizing the cardiac health of patients facing cancer therapy, the emerging discipline of cardio-oncology is well placed to co-ordinate population health advocacy efforts to promote
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healthy lifestyle behavior that can prevent heart disease and cancer.
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96. Romond EH, Jeong JH, Rastogi P, Swain SM, Geyer CE Jr, Ewer MS, Rathi V, Fehrenbacher L, Brufsky A, Asar CA, Flynn PJ, Zapas JL, Polikoff J, Gross HM, Biggs DD, Atkins JN, Tan-Chiu E, Zheng P, Yothers G, Mamounas EP, Wolmark N. Seven Year Follow-up Assessment of Cardiac Function in NSABP-31, a Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel (ACP) With ACP Plus Trastuzumab as Adjuvant Therapy For Patients With Node-Positive, Human Epidermal Growth Factor 2- Positive Breast Cancer. J Clin Oncol. 2012;30(31) :3792-3799.
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97. Ezaz G, Long JB, Gross CP, Chen J. Risk Prediction Model for Heart Failure and Cardiomyopathy After Adjuvant Trastuzumab Therapy for Breast Cancer. J Am Heart Assoc. 2014;3 :e000472 doi : 10.1161/JAHA.113.000472.
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Figure 1: Interaction Between Shared Risk Factors, Cardiac Disease & Cancer
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Given that cancer and cardiac disease share risk factors, many cancer patients have sub-clinical or clinically overt cardiac disease at the time of cancer diagnosis. In order to avoid cardiotoxicity, cancer therapy may be modified with the potential for lower efficacy. Cardiotoxicity during cancer therapy may result in interruption or cessation of cancer treatment. In this way, cardiac comorbidity due to shared risk factors compromises cancer therapy leading to worse oncological outcomes. In cancer survivors, risk factors often worsen during cancer therapy. Cardiotoxic effects of cancer treatment combined with worsening risk factors lead to late cardiotoxicity. Shared risk factors and cardiac co-morbidity increase both short-term and long term cardiac risk and cancer risk.
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Table 1: Potential Biological Mediators Linking Obesity With Cancer
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Animal and human data suggest that growth hormones, sex hormones, and the adipokines Leptin 28-31 and Adiponectin may mediate the relationship between obesity and cancer .
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Table 2: Protective Effects of Exercise on Cancer Incidence: Meta Analyses of Cohort Studies
Cancer Site
Cancer Cases (n) RR (95% CI)
Author
Year
88294
0.9 (0.84-0.95)
Liu
2011
Breast
63786
0.88 (0.85-0.91)
Wu
2012
Bladder
27784
0.85 (0.74-0.98)
Kiemling
2014
Esophageal
15745
0.79 (0.66-0.94)
Behrens
Renal
10756
0.88 (0.79-0.97)
Behrens
Endometrial
NA
0.82 (0.75-0.9)
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Prostate
2014
2013
2014
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Meta-analyses of cohort studies suggest that subjects who exercise have modest reductions in 57-62 the incidence of several common cancers .
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CANCER RISK
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Smoking Obesity Non-Prudent Diet Physical Inactivity
CANCER
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Shared Risk Factors:
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Figure 1: Interaction Between Shared Risk Factors, Cardiac Disease & Cancer
Radiation
Cancer Risk: -Less therapy offered due to CVD -Cardiotoxicity limits therapy
Targeted Therapy
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Perioperative Cardiac Events
High Long Term Risk
Cardiotoxicity From Cancer Therapy
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CARDIAC RISK
Chemotherapy
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Surgery
Cancer Survivors:
Clinical Cardiovascular Disease at Cancer Diagnosis
Sub-Clinical Cardiovascular Disease at Cancer Diagnosis
Risk Factors Persist During Cancer Treatment Risk Factors May Worsen During Cancer Treatment
Cardiac Risk: -Cardiotoxic cancer therapy -Worsening risk factors