Introduction
The time has come for cardiovascular disease (CVD) prevention to play a more prominent
role in cardio-oncology (Figure 1A). Cardio-oncology is an emerging subspecialty within
internal medicine, and particularly cardiology, which involves the prevention and
management of cardiovascular injury from cancer therapies (4–6). A small section of
the field is dedicated to diagnosing and managing primary or secondary tumors to the
heart (7). The majority of the field focuses on cardiotoxicity from radiotherapy,
chemotherapy, and immunotherapy. While anthracyclines are the most commonly studied
drugs and are frequently associated with cardiomyopathy, a myriad of novel cardiotoxic
chemotherapeutic and immunotherapeutic drugs are continuously being developed in Oncology,
with diverse cardiovascular (CV) effects (Figure 1B). Radiation to the chest can result
in accelerated atherosclerosis, pericardial disease, valve disease, conduction abnormalities,
and cardiomyopathies (8–10). Traditional chemotherapies, endocrine therapies, and
targeted or immunotherapies can also associate with these cardiovascular toxicities
in addition to myocarditis (3, 11–18), with valve disease possibly being no exception
(19–22).
Figure 1
(A) Potential Scope of Preventive Cardio-Oncology: Preventive Cardio-Oncology can
potentially consist of prehabilitation, habilitation, and rehabilitation, with synergistic
risk assessment in cardiology and oncology screening tests, as well as optimization
of cardiometabolic risk factors (pre-existing, or consequential from cancer/therapies),
in addition to adequate cardioprotection in the setting of cancer therapy, with appropriate
screening and surveillance guided by lifetime specialty care. (B) Cardiovascular Toxic
Effects of Cancer Therapies: A wide spectrum of cancer therapeutics can injure or
aggravate a variety of components of the cardiac (top) and vascular (bottom) system,
knowledge of which can assist with vigilant monitoring, prevention if possible, and
appropriate diagnosis if present. (C) American Heart Association (AHA) Life's Simple
7: Seven different domains can guide conceptualization and realization of Ideal Cardiovascular
Health, recognizing specific factors (underlined) that underlie risk of development
of both CVD and cancer. (D) ABCDEFs of Preventive Cardio-Oncology: A proposed ABCDEF
approach to prevention of CVD and cancer in the general population and in those with
a prior history of cancer addresses all seven factors in the AHA Life's Simple 7,
as well as other characteristics that can contribute to CVD, cancer (new or recurrent),
or both (underlined), with expansion of a previously published ABCDE algorithm (1,
2) to include Family History and Genetic Factors and Formation of Cardio-Oncology
Teams to prevent or mitigate the impact of these multiple hits and risk factors relevant
to the development of CV toxicities from cancer therapies. (E) Algorithm for Synergistic
Screening in Preventive Cardio-Oncology: Patients presenting for screening or assessment
for cancer could also be considered for simultaneous or subsequent CV screening and
reporting, particularly if the initial imaging test is of the chest, with radiology
teams scheduling or reading chest x-rays or chest CTs contacting patients' ordering
clinician to consider CV assessment and reporting in tandem, or with ordering clinician
teams (primary care, oncology, cardiology, cardio-oncology, preventive cardio-oncology)
also requesting assessment and reporting of CV findings when ordering chest x-rays
or CTs for patients at low/intermediate risk for CVD, especially for patients with
any previous cancers who received radiation therapy or chemotherapy with drugs that
associate with coronary artery atherosclerosis or thrombosis. (F) Algorithm for Risk
Assessment and Follow-up: Initial assessment of patients in oncology can occur with
the oncologist in partnership with primary care, with those patients at low risk continuing
to be followed predominantly in oncology and primary care, while other patients can
be referred to (preventive) cardio-oncology for recommendations on additional screening
and preventive measures prior to, during, and after cancer therapies, recognizing
that close monitoring for symptoms, abnormal vitals, or findings on lab testing, ECG,
or Echo can help guide the need for more advanced testing related to potential cardiotoxicities;
various specific cardiotoxicities may benefit most from particular initial monitoring
methods (black arrows), e.g., myocarditis from ICIs may first manifest with symptoms
with or without changes in the ECG or troponin (which can further be assessed with
cardiac MRI), while VEGFI toxicity most commonly manifests as hypertension; high risk
determinants are adapted from (3). (G) Preventive Cardio-Oncology Paradigm Shift:
Efforts at prevention in Cardio-Oncology may need to be shifted earlier than traditionally
implemented or currently considered; in typical Preventive Cardiology, primordial
prevention targets the general population prior to development of risk factors for
CVD, such as hypertension or diabetes; primordial prevention in Preventive Cardio-Oncology,
if truly merging Preventive Cardiology and Cardio-Oncology, could benefit from maintaining
this place of primordial prevention on the prevention spectrum; as such, indeed, primordial
prevention would remain in the general population before cancer is diagnosed; at the
time of cancer diagnosis, individuals in the general population would then become
cancer survivors, with a focus on primary prevention for those with CV risk factors,
then secondary prevention following cancer therapy, especially once structural heart
disease is visible on imaging and manifested with signs or symptoms; with advanced
CVD, tertiary prevention would be in effect, in hopes to optimize quality while delaying
premature mortality. CAD, coronary artery disease; CHF, congestive heart failure;
CV, cardiovascular; CVD, cardiovascular disease; Echo, echocardiogram; ECG, electrocardiogram;
Gy, Gray; ICIs, immune checkpoint inhibitors; PAD, peripheral artery disease; RT,
radiation therapy; TIA, transient ischemic attack; VEGFI, vascular endothelial growth
factor inhibitor (a tyrosine kinase inhibitor).
Various chemotherapies and targeted or immunologic therapies can also lead to peripheral
vascular toxicities, such as systemic hypertension, pulmonary hypertension, thrombosis,
stenosis, vasospasm, or vasculitis (3, 11–18) (Figure 1B). Systemic hypertension can
further increase the risk of cardiovascular toxicity, as do all baseline CV risk factors
(e.g., diabetes) and known CVD itself (11, 17, 23). Systemic hypertension occurs in
more than one fourth of all individuals treated with vascular endothelial growth factor
inhibitors (small molecule tyrosine kinase inhibitors), while all patients experience
some increase in their blood pressure (24). These drugs also associate with cardiomyopathy,
vasculopathy, coagulopathy, and nephropathy largely due to systemic endothelial dysfunction,
reduced nitric oxide production, and destruction of the glomerular filtration barrier
resulting from alteration of the balance between angiogenic and antiangiogenic, or
vasoconstrictor and vasodilator, factors (24–26).
With all of this in mind, we should no longer direct the bulk of our efforts at intervention
toward management of cardiovascular toxicities that have already occurred. It is time
for us to swing the pendulum further in the direction of prevention of cardiovascular
toxicities. Prevention can take different forms and can be pursued in different ways,
with definition, scope, awareness, partnership, screening, surveillance, and intervention.
Further, primordial (or health promotion), primary, secondary, and tertiary prevention
may be defined somewhat differently in the traditional field of Preventive Cardiology
(27, 28), than in a more recent proposal for consideration of prevention in cardio-oncology
(20). It would be useful to reconcile these two slightly disparate paradigms, and
attempt to continue to envision the potential scope of preventive efforts in cardio-oncology.
Thus, as we advocate for moving from a traditionally reactive model to a more proactive
model for prevention of cardiovascular toxicities in response to cancer therapies,
we are entering the era of Preventive Cardio-Oncology. This concept is further introduced
here, with a suggested near-future scope for the field (Figure 1A).
Cancer Survivorship and Cardiometabolic Risk
As cancer therapies become more effective over time, the prevalence of cancer survivorship
continues to rise. For 2019, almost 2 million new cancer diagnoses and just over 600,000
new cancer deaths are estimated; as cancer incidence continues to increase for most
cancers, cancer mortality continues to decrease, leading to millions of cancer survivors
each year (29). CVD remains a leading cause of death in cancer survivors (second only
to cancer recurrence) (4, 20, 30, 31), and shares some risk factors with various cancers.
For example, CVD and breast cancer have several risk factors in common, such as unhealthy
Western diet, red or processed meat, physical inactivity or sedentary lifestyle, smoking,
early menarche, and hormone replacement therapy (20) (Figures 1C,D, underlined). Yet,
some factors affect risk differently for each disease. Premenopausal obesity and early
menopause can increase CVD, while decreasing the risk of breast cancer; light to moderate
intake of alcohol can attenuate cardiovascular risk, while increasing breast cancer
risk (20). Given this reality, individuals diagnosed with breast cancer may already
have baseline risk factors for CVD, as is also the case for individuals diagnosed
with a variety of other cancer types. Overlapping risk factors for developing CVD
or cancer (or both) (12, 16, 20, 32, 33) are underlined in Figures 1C,D.
Baseline cardiometabolic risk in individuals diagnosed with cancer can also conceivably
increase even before beginning cancer therapies, because of cardiometabolic derangements
or systemic inflammation due to the presence of the cancer itself (34, 35). Metabolic
derangements and barriers to cardiometabolic health can also occur due to cancer therapies
(4, 36–38). For example, chemotherapy can affect the vasculature and lead to initial
diagnosis of, or aggravation of pre-existing, hypertension (12, 39). Radiation to
the abdomen, brain, or whole body can affect the endocrine system resulting in abnormalities
with hypothalamus-pituitary, thyroid, or pancreatic function (36, 40, 41), as well
as hypertension, hyperlipidemia, and elevated waist circumference and levels of free
fatty acids (40). Surgery to the brain can potentially also affect endocrine function,
but appears to have very limited effect on cardiovascular risk, if any at all (42).
A greater effect is seen when radiation is combined with surgery, and even greater
so when chemotherapy also is added (42). In addition to direct physiological contributions
to cardiovascular risk, cancer therapies can also have indirect effects. Fatigue,
musculoskeletal discomfort, decrease in quality of life, or early menopause related
to cancer therapies can limit individuals' ability to continue to pursue ideal cardiovascular
health during therapy and can contribute to obesity and the metabolic syndrome (34,
36, 41). Thus, the CV impact of therapies for cancer (and potentially the presence
of cancer itself) can superimpose on pre-existing CVD risk factors to worsen CV outcomes,
which is described as the “multiple hit” hypothesis (23).
Given the co-existence of risk for cancer and CVD based on baseline factors, it has
been suggested that joint screening for cancer and CVD should perhaps be pursued (32).
This could include assessing for coronary artery calcification on chest CT scans initially
ordered to screen for or evaluate known lung cancer or for radiation treatment planning
in appropriate individuals, or following up on breast arterial calcification noted
during mammography while screening for breast cancer (32, 43–47) (Figure 1E). When
ordering chest x-rays or CTs for patients at low/intermediate risk for CVD, especially
for patients with any previous cancers who received radiation therapy or chemotherapy
with drugs that associate with coronary artery atherosclerosis or thrombosis, ordering
clinician teams (primary care, oncology, cardiology, cardio-oncology, preventive cardio-oncology)
could also request assessment and reporting of CV findings. Additionally, for patients
with appointments for chest x-rays or chest CTs, radiology team schedulers and clinicians
could contact patients' ordering clinicians to consider concurrent or subsequent CV
assessment and reporting. A clinical trial (the BRAGATSTON Study) is currently in
progress to provide low-cost automated quantification of coronary artery calcification
on radiation planning chest CTs for CV risk prediction
1
. Similar studies could be pursued for chest CTs screening for or assessing cancers
in the chest. Indeed, cardiovascular risk assessment in individuals diagnosed with
cancer can uncover cardiometabolic risk factors out of proportion to the general population.
CVD is more prevalent in individuals with cancer, compared to age-matched controls
(48), and patients with cancer who develop CVD experience worse outcomes (31). Cardiovascular
risk assessment should therefore be considered in tandem with screening for or managing
various cancers.
Risk scores can play a role. In addition to the CVD risk scores used in the general
population, such as the American Heart Association (AHA) and American College of Cardiology
(ACC) pooled cohort atherosclerotic cardiovascular disease risk equations, there are
also scores being developed for assessing CVD risk in individuals with a history of
adult or childhood cancer (49, 50). Such risk scores may become invaluable in preventive
cardio-oncology.
Risk Mitigation
To mitigate cardiovascular risk in individuals with cancer, typical cardiovascular
risk management should be pursued as in the general population with pharmacotherapy
and lifestyle modification as appropriate (17, 51, 52), while recognizing that a history
of cancer therapy increases overall cardiovascular risk and should inform the approach
to lifestyle intervention (23) (proposed ABCDEF approach, Figure 1D).
Pharmacologic Therapies and Oncologic Treatment Maneuvers in Prevention of Cardiomyopathy
Additional cardioprotective measures in the setting of cancer therapies should also
be pursued as indicated (17). These can possibly include pharmacotherapy such as dexrazoxane,
beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers,
statins, and other medications (53–55). Dose limitation or reduction for chemoradiation,
as well as drug formulation and length of infusion for pharmacological cancer therapies
can also be addressed (17, 55). Contemporary radiotherapy methods can also be adopted,
with proton beam therapy, deep inspiration breath hold, prone imaging, and CT treatment
planning, as well as dose limitation as appropriate (8–10, 55). Lifetime appropriate
screening and surveillance would also be key (3, 4, 55). Meta-analyses and systematic
reviews have suggested cardioprotective effects of beta blockers, angiotensin converting
enzyme inhibitors, angiotensin receptor blockers, statins, dexrazoxane, and continuous
infusion of a limited dose of liposomal doxorubicin, particularly for individuals
with breast cancer receiving chemotherapy with anthracyclines, trastuzumab, or both
(56–59). A single-center study determined deep inspiration breath hold as an effective
method to reduce CV toxicity in patients with breast cancer (60). A multi-center randomized
clinical trial is underway to assess benefits of proton vs. photon beam radiation
therapy for individuals with non-metastatic breast cancer (61). Accordingly, cardioprotective
pharmacotherapeutics and oncologic treatment maneuvers are currently most often used
for patients with breast cancer who will undergo treatment with anthracyclines, trastuzumab,
or both, especially those deemed to be high risk, e.g., based on chemotherapy dose,
concurrent radiation, or pre-existing CVD, or those who have developed cardiotoxicity
(17, 55) (Figure 1F). While further data needs to be obtained to strengthen recommendations
for pharmacologic cardioprotection, studies so far support the likelihood of clinical
utility in these patients.
Pharmacologic Therapies in Optimization of Hypertension
For patients treated with vascular endothelial growth factors, antihypertensives usually
provide sufficient control of blood pressure to allow for continuation of cancer therapy
(14, 18). Most commonly, ACE inhibitors, ARBs, calcium channel blockers, and diuretics
are used (18, 26, 62). ACE inhibitors have been thought to be preferred for concurrently
impacting proteinuria, as well as release of endothelial nitric oxide and expression
of plasminogen activator inhibitor-1 (63, 64). In fact, ACE inhibitors also associated
with significant improvement in overall survival of patients with metastatic renal
cell carcinoma (65). Of note, two recent retrospective studies were pursued using
robust databases, with differences in study design, patient baseline characteristics,
cancer type, and timing of use of antihypertensive therapy (26, 62). One study showed
a greater extent of blood pressure control with ACE inhibitors and ARBS, compared
to other antihypertensive drug classes (including calcium channel blockers and diuretics)
(62). Conversely, the other recent study of patients treated with VEGF inhibitors
identified blood pressure reductions most effectively associated with the use of calcium-channel
blockers and potassium-sparing diuretics, compared to ACE inhibitors, ARBs, and other
antihypertensive classes (26). Indeed, results from a preclinical study indicated
a preference for nifedipine over captopril to achieve optimal control of severe blood
pressure increases of 35–50 mm Hg (66). Thus, conclusions regarding inhibition of
the renin-angiotensin-aldosterone system as the preferred method for managing hypertension
in these patients have been divergent (67). Therefore, no clear broad recommendation
can currently confidently be made for use of one antihypertensive class of medications
over the other in all patients (64, 67). Care of the patient should continue to be
individualized, and collaborations for patient care and further research in this area
should persist (67). Nevertheless, a singular consensus remains: non-dihydropyridine
calcium channel blockers specifically should be avoided, as these drugs inhibit the
cytochrome P450 3A4 enzyme which metabolizes VEGFIs; use of non-dihydropyridine calcium
channel blockers such as diltiazem or verapamil could lead to high levels of VEGFIs,
potentially even further aggravating VEGFI-induced hypertension (18, 67, 68).
Nutrition Counseling
Nutritional counseling could be personalized and re-assessed before, during, and after
cancer therapy. Currently, dietitians have the option of training in Oncology as a
nutrition subspecialty, which is particularly helpful for patients with cancer who
develop malnutrition [estimated at 40% of all cancer patients, or >50% in patients
with gastrointestinal or head and neck cancers (69, 70)]; dietitians can also become
certified in Obesity and Weight Management
2
. Perhaps dieticians or nutritionists could be trained in preventive cardio-oncology
and opt for certification in both Oncology Nutrition and Obesity And Weight Management,
to merge philosophies from oncology and preventive cardiology in the context of individual
patient nutrition needs. Indeed, studies in nutrition oncology encourage individualization
of patients' nutritional care (71, 72), which may be a good fit as a component of
Preventive Cardio-Oncology. A multicenter study indicated that a majority of clinicians
in Oncology assessed patients for obesity and pursued weight management counseling
during and after patients' cancer treatment, but did not refer patients for continued
lifestyle intervention and support to optimize or maintain a healthy weight (73).
Of note, a recent document providing recommendations and guidelines for obesity management
in cancer highlights obesity as a risk factor for cancer development, recurrence,
or outcomes, and cautions clinicians to be aware that obesity can sometimes mask acute/subacute
malnutrition in individuals with cancer (74). Given the intricacies of obesity and
nutrition for cancer patients and survivors, the American Society of Clinical Oncology
has established a multifaceted initiative focused on education, awareness, research,
policy, and advocacy for obesity and weight management in cancer patients and survivors
(75). Perhaps partnerships among Oncology and Cardiology societies, including the
American Society for Preventive Cardiology would be key in the advancement of Preventive
Cardio-Oncology (75).
Cardio-Oncology or Cardiovascular Oncology Prehabilitation, Habilitation, Rehabilitation
Incorporation of various methodologies in typical cardiac rehabilitation could also
have utility for secondary prevention (76), and possibly also primary prevention,
of cardiovascular toxicity from a variety of cancer therapies. Some have suggested
a multidimensional system consisting of cardiovascular oncology prehabilitation (30,
77, 78), habilitation (30, 79, 80), and rehabilitation (30, 78, 81), to optimize cardiovascular
health before, during, and after cancer therapies, respectively. Prehabilitation focuses
on optimizing baseline cardiovascular health and cardiopulmonary fitness prior to
initiation of cancer therapies (30, 77, 78). Habilitation refers to ongoing optimization
of cardiovascular health and cardiopulmonary fitness while patients are undergoing
cancer therapies (30, 79, 80). Rehabilitation refers to efforts to recover cardiopulmonary
function after completion of cancer therapies (30, 78, 81).
Potential Challenges in Cardio-Oncology Prehabilitation, Habilitation, Rehabilitation
There is often little time from diagnosis of cancer to initiation of chemotherapy,
which can limit the time window for pursuing cardio-oncology prehabilitation in the
cardiology community. Nevertheless in the oncology community, timely calls to action
for developing high-quality cancer rehabilitation programs propose prospective models
that actually begin upon cancer diagnosis and continue throughout cancer therapy then
for a lifetime (82, 83), which could also be termed cancer prehabilitation (before
therapy), habilitation (during therapy), and rehabilitation (after therapy). These
multidisciplinary programs aim to optimize physical and psychosocial health and function.
The models include establishment of baseline functioning prior to cancer therapies.
This can include tests such as the 6-min walk or Get-Up-And-Go, or formal fitness
assessment as in the general population prior to exercise training (84). This can
help assure both patients and clinicians of the safety of pursuing exercise training
(84). Fitness testing as part of baseline assessment can also identify potential physical
vulnerabilities that may limit or modify exercise regimens (84). Pre-existing conditions
that may associate with high risk for cardiovascular and other toxicities can be identified
and addressed; exercise level, mobility, strength, and gait, among other parameters,
are objectively assessed. Ongoing surveillance subsequently occurs during and after
therapy, with referrals made for exercise, nutrition, and weight management. With
further collaboration between the cardiology and oncology communities, efforts could
be combined to establish and pool resources and protocols for comprehensive multidimensional
cardio-oncology programs pursued before (prehabilitation), during (habilitation),
or after (rehabilitation) cancer therapy.
Cardio-oncology habilitation can be challenging for some patients, due to physical
or psychosocial effects of cancer therapy. Studies have shown reduction in physical
activity levels in cancer patients following diagnosis and during therapy (85–87).
In fact, patients have traditionally often been advised to limit their physical activity
during therapy, particularly for those who are older or experience fatigue or side
effects of cancer therapy (82). The most frequent symptoms in cancer patients include
fatigue and peripheral neuropathy. Of note, aerobic, resistance, and strength training
have been shown to improve fatigue; strength and balance training also improve fatigue
(88).
It should be recognized that patients often maintain lower physical activity levels
even after completion of cancer therapies, and generally do not return to their pretreatment
levels of physical activity (85–87). In spite of a myriad of guidelines and recommendations
from various societies regarding the safety and efficacy of exercise (75, 89, 90)
3
, ~70% of cancer survivors do not meet recommendations for physical activity in cancer
survivors (91, 92). It should be noted too that adverse effects of cancer therapies
extend to the entire cardiovascular and skeletal muscle axis (76). As a result, cardiorespiratory
fitness (CRF) declines are in part due to impairment of components of the cardiovascular
and respiratory muscle system. Thus, survivors may have impairments in mobility and
function beyond the general population (93). For example, CRF in survivors can be
30% lower than in age-matched healthy yet sedentary control individuals (94), and
as stated often does not recover following cancer therapy (94–96). However, physical
function and cardiorespiratory fitness can both improve with structured exercise regimens
in cancer rehabilitation (85–87, 97). Additionally and importantly, post-treatment
exercise reduces the risk of mortality (98–102).
In one established program, oncology rehabilitation is modeled based on cardiac rehabilitation
and is available to all cancer survivors, with no restrictions on length of time since
diagnosis
4
(103). Evaluation by a physical therapist clears patients for safe and effective exercise
therapy. Physical activity is tailored to each patient's capabilities and limitations.
The initial focus is on brisk walking and resistance training. More than 500 individuals
have gone through the program, with significant improvements in peak oxygen consumption
and the 6-min walk test, as well as upper and lower extremity strength. Patients start
slowly and are encouraged to aim for similar recommended physical activity levels
as the general population
5
(89, 104). The system is similar to recommendations in the AHA statement on Cardio-Oncology
rehabilitation, which also includes a suggestion for “opt-out” referrals to maximize
utilization (76).
Survivors find it quite helpful to have supervised exercise in the context of social
support, encouragement, motivation, and accountability from other patients or from
oncologic/cardiac rehabilitation staff. The convenience of having cardiac rehabilitation
facilities close to and affiliated with the medical institution that hosts the cancer
center may help cancer patients and survivors embrace cardio-oncology rehabilitation
programs in the post-adjuvant period (i.e., after completion of cancer therapies).
This should also apply to cardio-oncology prehabilitation (before cancer therapies;
neoadjuvant?) and habilitation (while undergoing cancer therapies; adjuvant) programs.
Studies show that cardiovascular fitness is preserved or improved if exercise training
is initiated prior to completion of cancer therapy, rather than waiting to recover
cardiopulmonary function after completion of cancer therapy (105, 106). This provides
support for the benefit of habilitation even over rehabilitation. If programs initiate
exercise training before the first dose of cancer therapy, this points toward the
potential for prehabilitation.
In the general population, outpatient cardiac rehabilitation has low utilization rates,
although there is potential to decrease morbidity and mortality by ~25% (107). Women
in particular face a myriad of barriers in cardiac rehabilitation (108, 109), and
large numbers of women are not referred at all (108, 109). High intensity interval
training (HIIT) may be among practical solutions to meet women's needs in cardiac
rehabilitation (108). HIIT provides more effective and efficient regimens than typical
exercise programs, at all stages of prevention (104). HIIT has been shown to improve
cardiovascular health components such as fitness (110, 111), body fat percentage (111,
112), waist circumference (112), insulin resistance (111), blood glucose levels (113),
blood pressure (113), and lipids (111, 112) in the general population, as well as
those with a history of cardiac disease (114, 115) and in patients with a history
of cancer (116). Thus, HIIT should play role in Cardio-Oncology prehabilitation, habilitation,
and rehabilitation. However, HIIT will not overcome all barriers. Besides time limitations,
accessibility, education level, multiple comorbidities, language, social support,
and family responsibilities also play a role. Automated referrals or “opt-out” methods
may improve referral and participation of women, as may enrollment assistance, incentives,
and home-based exercise regimens (109). The remaining barriers of health literacy,
multiple comorbidities, language, family responsibilities, and side effects from cancer
therapy will also need to be addressed.
Outpatient cardiac rehabilitation utilization in the general population is also particularly
limited in rural communities, as well as in those with limited education, lower socioeconomic
status, or older age (107). Research is therefore needed to continue to assess the
feasibility and effectiveness of these proposed cardio-oncology prehabilitation, habilitation,
and rehabilitation programs in academic and community centers or in patients' homes
preferably with virtual exercise trainers or accountability groups. Innovative approaches
with telemedicine, mobile health, and remote monitoring are being evaluated as potentially
cost-effective means of delivery of these structured programs.
6
Cardiopulmonary Stress Testing in Prehabilitation, Habilitation, Rehabilitation
It would also be ideal for cardiopulmonary stress testing to be incorporated to assess
cardiopulmonary functional status before, during, or after cancer therapies. This
could potentially be helpful for preventive counseling and subsequent management for
any abnormalities in cardiopulmonary function, given that various cancer therapies
can injure the heart and lungs and lead to reduced cardiopulmonary function and fitness
(94, 95, 117–119), which associates with increased risk of long-term cardiovascular
toxicities, cardiopulmonary symptoms, and mortality (120, 121).
Rehabilitation Too Late?
Currently, the AHA has issued a Scientific Statement endorsing cardio-oncologic rehabilitation,
including cardiopulmonary stress testing after patients have completed cancer therapy,
particularly for those who received high doses of cardiotoxic chemotherapy or radiation
and who have known cardiopulmonary symptoms, CVD, or untreated CVD risk factors (76).
The statement is supported by various studies suggesting the benefit of structured
exercise therapy for improving cardiovascular health and cardiopulmonary or fitness
for cancer survivors (30, 81, 97, 122). In turn, cardiopulmonary fitness associates
with lower levels of short-term and long-term cardiovascular and other toxicities,
as well as a lower risk of mortality in individuals with cancer (94, 120, 121). Studies
also indicate benefits of exercise prior to initiation of or during cancer therapy
(30, 116, 123). The statement also encourages optimization of patient evaluation,
nutrition and dietary counseling, obesity management, blood pressure and lipids management,
diabetes, tobacco cessation, and management of psychosocial contributing factors (76).
Additionally, the AHA statement encourages continued research to help determine best
practices for implementation of cardio-oncology rehabilitation and determine of clinical
indication and feasibility to support reimbursement.
Perhaps once rehabilitation becomes more established, we can then also strategize
and implement cardio-oncology prehabilitation and habilitation. Yet, will it be too
late to wait? Should we primarily focus our efforts on rehabilitation after cancer
therapies, or should we turn our attention to habilitation during cancer therapies
while patients are undergoing cycles of chemotherapy and radiation before or after
surgery? In fact, should we start sooner? Should we advocate for initiating cardio-oncology
prehabilitation before patients undergo chemotherapy, radiation, or surgery? In the
overall surgical world, exercise or nutritional prehabilitation (initiated before
surgery) seems to improve outcomes and lower healthcare costs compared to waiting
for rehabilitation (initiated after surgery) alone (124–137). Clinical trials are
underway to further define the prehabilitation period (before surgical therapy) as
optimal for fitness intervention (138–140). Data for cardio-oncology prehabiltiation
is also promising. Most recently, a study suggested that long-term survivors of breast
cancer who had higher levels of physical activity (and presumably fitness) prior to
their cancer diagnosis demonstrated a graded reduction in subsequent CV outcomes (e.g.,
coronary artery disease, heart failure, peripheral artery disease, cardiovascular
death), compared to their counterparts with lower levels of physical activity pre-diagnosis
(123). Does this also provide indirect support for stronger consideration of primordial
and primary prevention in cardio-oncology (Figure 1G)? Primordial prevention focuses
on preventing development of CVD risk factors such as hypertension, hyperlipidemia,
or obesity. Primary prevention focuses on managing existing CVD risk factors such
as hypertension, hyperlipidemia, obesity, or diabetes, in efforts to prevent development
of CVD itself. If through primordial and primary prevention in the general population
we can optimize ideal cardiovascular health (e.g., based on the AHA Life's Simple
7) before cancer diagnoses occur, then perhaps when individuals from among the general
population are diagnosed with cancer and become cancer survivors, those with greater
CV health may already be ahead of the curve. The AHA Life's Simple 7 campaign encourages
optimization of seven modifiable cardiovascular risk factors, specifically diet, physical
activity, weight, smoking, hypertension, hyperlipidemia, and diabetes (141, 142) (Figure
1C).
Paradigm Shift
In Preventive Cardiology, the prevention spectrum includes primordial, primary, secondary
(and often tertiary) components. For Cardio-Oncology, a prevention timeline has been
suggested in a recent AHA Scientific Statement on the intersection of CVD and breast
cancer (20), specifically for the development of cardiovascular toxicity from cancer
therapies, regardless of the presence of baseline cardiovascular health and risk factors.
In this timeline, primordial prevention of cardiotoxicity would begin upon cancer
diagnosis before cancer therapies are administered, since administration of cancer
therapies is the key risk factor for development of cardiotoxicity from cancer therapies.
Primary prevention would then begin after receiving cancer therapies as the main risk
factor for cardiotoxicity. Secondary prevention would begin upon diagnosis of structural
heart disease, such as decline in left ventricular systolic function, thought to be
due to administration of cancer therapy. Treatment of subsequently developed CVD could
then be considered tertiary prevention in this model.
In pursuit of preventive cardio-oncology, we will need to determine how to align the
typical paradigm in preventive cardiology with the timeline proposed in the recent
scientific statement. Perhaps the two paradigms could be reconciled as follows (Figure
1G). Ideal cardiovascular health based largely on the AHA Life's Simple 7 would be
the initial baseline in the general population, from among which cancer survivors
will ultimately be diagnosed. This ideal baseline would include optimal parameters
for diet, physical activity, obesity, smoking, hypertension, hyperlipidemia, and diabetes,
as well as nontraditional cardiovascular risk factors. Primordial prevention of CVD
in the general population would limit or avoid development of CVD risk factors (e.g.,
hypertension). If baseline CVD risk factors develop (e.g., hypertension or hyperlipidemia),
then primary prevention would ensue in two different and complementary categories.
The first category would be typical primary prevention of CVD in the general population,
optimizing management of existing traditional and nontraditional cardiovascular risk
factors. The second category would add cardioprotective measures if indicated for
those who have been diagnosed with cancer and are deemed to be high risk for developing
cardiotoxicity (Figures 1F,G). Such measures may include utilization of beta blockers,
angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statins,
dexrazoxane, continuous infusion of a limited dose of liposomal doxorubicin, and potentially
proton vs. photon beam therapy, and so on.
Once cancer therapies are administered, subclinical cardiovascular injury undetected
by standard diagnostic testing may be presumed, since studies have shown microscopic
evidence of cardiovascular injury (preclinical) and development of macroscopic CVD
(clinical) with even low doses of cancer therapy (143–150). Thus, one could argue
that secondary prevention of cardiovascular injury could start following administration
of any dose of cancer therapies. However, undetected subclinical injury could be considered
Stage A akin to the corresponding ACC stage of heart failure (143), consistent with
the presence of risk factors for CVD without overt evidence of macroscopic CVD detected
on standard diagnostic tests (151, 152). Once detection of CVD on diagnostic testing
occurs, then this would be classified as Stage B, if no symptoms have yet developed,
with continuation of secondary prevention. Traditionally, change in left ventricular
ejection fraction has been most commonly used to identify cardiotoxicity, heralding
Stage B/C CVD; more recently, studies are underway (including an international multicenter
prospective randomized controlled trial) to assess the efficacy of global longitudinal
strain as a more sensitive and earlier echocardiographic marker of cardiovascular
injury in Stage B (153, 154). Once cardiovascular symptoms develop, then Stage C CVD
would be diagnosed. Tertiary prevention would be initiated at this point, to avoid
complications or further events, or progression of CVD to Stage D, or eventually premature
mortality (Figure 1G).
Partnerships for Monitoring, Surveillance, and Intervention in Prevention
It is interesting to consider who should be responsible for CV screening, monitoring,
and treatment in Preventive Cardio-Oncology, in the short-term and long-term, before,
during, and after cancer therapies. There are several excellent algorithms in literature
to guide the flow of patient care in Cardio-Oncology (3, 11, 14, 17, 18, 155–158).
Most of these algorithms focus on the relationships among the cardiologist, oncologist,
hematologist, and patient, or on steps to follow regarding surveillance for or management
of left ventricular dysfunction or other cardiovascular toxicities, or monitoring
recommendations for patients being treated with particular cancer therapies. Very
few if any of the algorithms explicitly incorporate partnership with patients' primary
care providers, and if so, where in the algorithm their input would be present. It
goes without saying that patients' primary care providers are understood to be part
of their care at all stages. Nevertheless, it may be helpful to clearly include primary
care expertise in Preventive Cardio-Oncology algorithms. In Figure 1F, for example,
baseline screening and follow-up for all patients in Cardio-Oncology traditionally
begins in Oncology (or Hematology), and this should be in partnership with our colleagues
in Primary Care. Involving Primary Care clinicians from early on may help streamline
long-term follow-up of cancer patients and survivors. A study revealed the prevalent
interest and practice of Primary Care clinicians in optimal long-term care of cancer
survivors, juxtaposed with their concerns about limited information received regarding
patients' detailed treatment plan and survivorship care recommendations (159). Primary
Care clinicians also appear to generally desire more guidance, communication, and
training to best manage shared care and delegation of responsibility for complications
that arise for cancer survivors (159).
Perhaps in Preventive Cardio-Oncology, we can establish distinct methods and training
to help guide assessment and follow-up of patients in the context of their (Preventive)
Cardio-Oncology team (in F portion of ABCDEF, Figure 1D). At baseline, asymptomatic
patients with low risk medical history and low risk treatment plans could continue
to be followed closely in Oncology and Primary Care, with a goal of optimizing CVD
risk and medications before, during, and after cancer therapy, guided by Cardiology
if needed (Figure 1F). In fact, if at any point before, during, or after cancer therapy,
patients are symptomatic or are not deemed to be at low risk based on their medical
history or treatment plan, these patients should be evaluated to determine the best
roles for prevention and management at that moment in their Cardio-Oncology care.
A role for Preventive Cardio-Oncology would include providing recommendations for
cardioprotection, screening, and surveillance, especially prior to initiation of cancer
therapy. All care decisions for patients should be guided by individualization of
care, with adherence to any available society expert consensus or scientific statements,
or guidelines for prevention, surveillance, and survivorship, as well as management
(12, 16, 18, 20, 55, 76).
Minimal surveillance prior to most if not all cancer therapies should include close
monitoring for development of symptoms, as well as vital signs and ECG, and often
echocardiogram, and troponin (Figure 1F). On subsequent testing, these modalities
could most often capture initial signs of cardiovascular toxicity. Various forms of
early toxicity may be more likely to show up on some modalities than others (black
arrows, Figure 1F). For example, most groups recommend ECG and troponin for monitoring
of early toxicity from immune checkpoint inhibitors, of course along with observation
for symptoms and assessment of vitals; with escalation to cardiac MRI if suspicion
for myocarditis persists, or endomyocardial biopsy, if indicated, in conjunction with
Cardio-Oncology consultation and management (13, 160–163). Weekly monitoring of troponin
may be pursued for the first 6 weeks, given that aggressive and often fulminant myocarditis
typically occurs at a median of 30 days from initiation of therapy (13, 164). However,
it should be recognized that troponin levels, echocardiography, or electrocardiography
can be normal in patients presenting with myocarditis (162); a high index of suspicion
is paramount for any non-specific symptoms or signs noted in patients treated with
immunotherapy. As another example, tyrosine kinase inhibitors such as vascular endothelial
growth factor inhibitors most commonly aggravate hypertension; accordingly, monitoring
and close management of vital signs is of utmost importance in patients being treated
with these drugs (165, 166). Weekly monitoring of blood pressure (goal <140/90 mm
Hg) for the first 4–6 weeks is recommended, and subsequently every 2–3 weeks until
completion of therapy, as systemic hypertension as a form of CV toxicity usually manifests
within 4 weeks (14, 18, 26, 62, 67, 167, 168). For patients receiving anthracyclines,
an echocardiogram (or cardiac MRI or MUGA if echocardiography is not available or
technically feasible) is usually pursued prior to initiation of therapy and within
6–12 months of completion of therapy particularly in high-risk patients, or sooner
if concerning CV signs or symptoms arise for any patient during therapy (17, 55).
For treatment with trastuzumab, an echocardiogram is commonly pursued at baseline
and at 3, 6, and 9 months and often indefinitely while on therapy, although the timing
of surveillance remains debatable
7
(55). Recognizing the need for differential monitoring of patients based on their
treatment regimen is critical to excellent team-based care in (Preventive) Cardio-Oncology,
particularly since some drugs are more cardiotoxic than others (Figure 1B).
Following therapy, surveillance and screening in Preventive Cardio-Oncology can be
guided by algorithms based on individual patients' treatment plans. All patients could
pursue an ABCDEF approach (Figure 1D), which expands on the established ABCDE approach
(1, 2), to optimize CV health. For asymptomatic patients with normal cardiac function
following therapy with anthracyclines or trastuzumab, while no strict recommendations
are available for frequency and duration of echocardiographic or biomarker surveillance,
management of CV risk factors should be pursued lifelong (55). Those treated with
vasotoxic drugs with persistent cardiovascular risk after therapy (e.g., cisplatin,
nilotinib) could consider imaging formal screening tests for peripheral artery disease
every 1–2 years and non-invasive stress testing every 5 years (3). Non-invasive stress
testing could also be considered every 5 years, along with a concomitant transthoracic
echocardiogram, for those who received radiation therapy (3, 158). Most recently,
a study illustrated a strong correlation between coronary artery radiation exposure
and subsequent segmental coronary artery calcification scores (169). New coronary
artery calcification was noted in some patients with breast cancer, lung cancer, lymphoma,
or myeloma at a median of 32 months after radiation therapy. Recommendations could
be developed for using coronary artery calcification for surveillance in cancer survivors
starting 2–3 years after radiation therapy, for those individuals who would otherwise
be at low/intermediate CVD risk. The current ACC/AHA prevention guidelines suggest
consideration of statin therapy for any CAC > 0 (51). Perhaps this recommendation
could also be considered for cancer survivors, who are at an even greater risk for
developing CVD than the general population. Perhaps in the future prophylactic statin
initiation may be considered for those with higher levels of mean heart dose or coronary
artery radiation exposure, even in the absence of (1) known CAC score or (2) CAC score
> 0. In the current prevention guidelines, a CAC score of 0 does not preclude statin
therapy, if individuals have a personal history of diabetes or cigarette smoking,
or a family history of premature coronary heart disease (51). Preventive Cardio-Oncology
recommendations could include a history of treatment with radiation therapy or vasotoxic
drugs with persistent risk (e.g., cisplatin, nilotinib) in this list of risk modifiers.
Discussion
We can no longer wait to intensify our focus on prevention in cardio-oncology, as
the number of survivors of childhood and adult cancers approaches 17 million in 2019
and is projected at ~22 million by 2030
8
. The presence of baseline cardiovascular risk factors raises CVD risk after cancer
therapies, but at a higher rate than in the general population due to cardiotoxic
effects of cancer therapies. Risk mitigation strategies in the general population
are also applied in cardio-oncology, while recognizing the higher risk. Cardioprotection
specific to cardio-oncology (e.g., dexrazoxane) is also potentially used, along with
appropriate screening and surveillance. A paradigm shift may be beneficial, to initiate
preventive efforts sooner than currently considered.
One in three men and women will develop cancer over the course of their lifetime
9
, and many of these individuals will become long-term cancer survivors. A greater
emphasis on encouraging and facilitating healthy behaviors, screening and surveillance,
and other methods of cardioprotection will be needed for cancer survivors, as well
as novel methods of identifying those at greatest CVD risk (170). Cardiopulmonary
function testing and cardio-oncology prehabilitation, habilitation, and rehabilitation
will likely help promote efforts at achieving and maintaining ideal cardiovascular
health characterized by optimization of Life's Simple 7, along with non-modifiable
and nontraditional risk factors. These will need to be applied for survivors of adult
and childhood cancers, with improved care transition when children and adolescents
become adults. Lifetime access to specialty care will need to continually be established,
as particularly desired by childhood cancer survivors (171, 172). Disparities in the
medically underserved and in ethnic minorities will also need to be addressed (170),
particularly as efforts in precision cardio-oncology and innovation in cardio-oncology
unfold.
Research should continue in all of these arenas, to help inform best practices for
prevention in cardio-oncology. Several clinical trials are underway to assess CV risk
factors and profiles in individuals with a variety of cancer types being treated with
a myriad of chemotherapies and endocrine therapies at various stages following diagnosis
10
. These studies are utilizing traditional or innovative (e.g., Clinical Informatics
using the electronic health records) methods to assess cardiovascular risk profiles
in the short-term or long-term for patients with breast, endometrial, prostate, testicular,
or colorectal carcinoma, or Hodgkin's or Non-Hodgkin's lymphoma, or other cancers
treated with endocrine therapies or other forms of cancer therapy. Dozens of clinical
trials are also ongoing to assess potential benefits and cost-effectiveness of preventive
efforts with pharmacotherapeutics (e.g., statins, ACE inhibitors, beta blockers) before,
during, or after cancer therapies, and nutrition and exercise initiated before, during,
or after cancer therapies (for cardio-oncology prehabilitation, habilitation, or rehabilitation)
11
. Pharmacologic cardioprotection will likely continue to be the most feasible intervention
to institute, for high risk patients prior to initiation of cancer therapies. Prehabilitation
with nutrition and exercise for those diagnosed with cancer may have a limited timeframe
for initiation. Nevertheless, it may be prudent to counsel those diagnosed with cancer
about nutrition and exercise benefits even prior to starting canscer therapies. Valuable
efforts in prehabilitation may indeed also be to partner with Preventive Cardiologists
and Primary Care clinicians to encourage health promotion and synergistic surveillance
and screening in the general population before cancer diagnoses are made. Perhaps
with a somewhat thorough approach to preventive cardio-oncology, we may be able to
prevent some injury, protect more hearts, and facilitate cancer remission or cure,
with a goal of greater quality and quantity of life.
Author Contributions
S-AB conceived of designed, wrote, revised, and approved the submitted manuscript.
Conflict of Interest
The author declares that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.