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Exercise, cancer and cardiovascular disease: what should clinicians advise?

Zimmerman, Allisona; Planek, Maria Isabel Camaraa; Chu, Catherineb; Oyenusi, Opeyemib; Paner, Agnec; Reding, Kerrynd; Skeete, Jamarioe; Clark, Briane; Okwuosa, Tochi M.e

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Cardiovascular Endocrinology & Metabolism: June 2021 - Volume 10 - Issue 2 - p 62-71
doi: 10.1097/XCE.0000000000000228
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Abstract

Introduction

The relationship between cancer therapy and cardiovascular disease (CVD) is well-recognized. This is in part due to some chemotherapeutic agents being inherently toxic to cardiac cells (cardiotoxic), a phenomenon driven by cellular injury and cardiac myocytes’s susceptibility to damage compounded by its very limited regenerative capacity. Unfortunately, this makes the cardiovascular system (CVS) particularly vulnerable to irreparable damage when exposed to certain agents used in the treatment of cancer [1]. While much of the current research on the impact of cancer therapy on the CVS focuses on changes to the heart, cancer therapy (including chemo and radiation therapy) also affect oxygen utilization by the body. Specifically, exposure to various chemotherapeutic regimens produces declines in cardiovascular function and reserve, as can be seen with findings of decreased peak oxygen consumption uptake (peak VO2) in patients post-chemotherapy [2,3]. Additionally, cardiorespiratory fitness (CRF), a global measure of cardiovascular function, declines between 5 and 26% during exposure to cancer therapy, and may remain depressed even after cessation of treatment [2,4].

Notably, there is an emerging paradigm of involvement of the cardiovascular-skeletal muscle axis in CRF in cancer patients [5]. This is corroborated by data suggesting that cancer survivors may experience decrements in skeletal muscle quality in addition to cardiovascular decrements which together contribute to CRF [6,7]. It is clear that rehabilitation focused on improving cardiovascular function has the potential to mitigate damage from cancer therapy and improve patient outcomes. However, the extent to which these programs should focus on muscle quality is yet unclear. While exercise therapy and cardiac rehabilitation are recommended and mainstay for many cardiac and pulmonary conditions, this strategy is not routinely offered to cancer patients despite a growing body of evidence that indicates these patients would likely see cardiovascular benefit from exercise [8]. Here, we review the current evidence exploring the impact of exercise on cardiovascular outcomes in adults with cancer, and propose a framework for targeted exercise prescription in this population.

Utilizing multiple approaches, several studies have been conducted to explore the impact of exercise on cardiac outcomes in subjects with cancer. These predominantly involve examining variables such as the timing of introduction of exercise, whether initiated pre- or post-cancer diagnosis/treatment, and include both animal and human subject studies.

Impact of exercise before cancer treatment on preventing future cardiovascular outcomes

As noted, certain cancer treatments may result in profound damage to the CVS. Until recently, only animal studies had examined whether exercise in the period before cancer diagnosis alters subsequent risk of cardiovascular events (CVEs) extending to the post-treatment period. Most of these studies have focused on anthracyclines, a therapeutic class of chemotherapy that is known to be cardiotoxic. One such study demonstrated the cardioprotective effects of exercise preconditioning after as little as 5 days to 3 weeks of endurance training in rodents [9]. Two other rodent studies similarly showed that doxorubicin-induced cardiovascular toxicity was attenuated by exercise training before treatment [10,11]. Additionally, both studies concluded that exercise training prevented a decline in the expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a, which has been implicated in the pathogenesis of other types of cardiomyopathies. Other cardioprotective benefits of exercise before exposure to chemotherapy include the attenuation in acute rises in cardiac troponin and markers of oxidative stress and apoptosis as well as decreases in levels of heat shock protein expression, and the extent of cardiac mitochondrial dysfunction which can be seen in the context of cardiac injury [9,12–14].

Exercise has been shown to improve cardiovascular outcomes in patients with cancer even when initiated before the diagnosis of cancer. This was demonstrated in a recent large prospective observational cohort study (the first human study of its kind) which showed that higher levels of physical activity before cancer diagnosis were associated with lower risks of CVEs in women with breast cancer [15]. Using cardiovascular endpoints such as heart failure, myocardial infarction, angina, coronary revascularization, peripheral and coronary artery disease, transient ischemic attack, stroke, and death; exercise was shown to be beneficial in this cohort. Specifically, the study demonstrated that individuals with high levels of physical activity, defined as those in the top quartile of physical activity levels before the diagnosis of cancer, had significantly lower risk of future composite CVEs [hazard ratio (HR): 0.63, 95% confidence interval (CI) 0.45–0.88, P = 0.02] as well as death secondary to coronary heart disease (HR: 0.41, 95% CI 0.21–0.78, P < 0.01) when compared to their counterparts with lower levels of physical activity before diagnosis of cancer. Not only does this study provide added incentive to encourage exercise in the general population but acts as a basis to better define whether this observed benefit is present when exercise is initiated after diagnosis of cancer in previously inactive individuals.

Taken together, these studies provide support for stronger consideration for exercise as primordial and primary prevention to mitigate cardiovascular risks associated with cancer and cancer therapy. It is therefore suggested that typical cardiovascular risk management in cancer patients should be pursued in the same manner or more aggressively as with the general population [16].

Exploring the safety and efficacy of exercise in patients undergoing cancer treatment

Several recent reviews have concluded that exercise in patients with cancer is not only safe, but also improves quality of life, improves aerobic fitness, reduces risk of cancer recurrence, and reduces risk of all-cause mortality [8,17–20]. Specifically, while results have been widely variable, exercise studies during cancer treatment suggest that overall, exercise diminishes cancer treatment-associated decline and improves cardiovascular outcomes.

The randomized controlled trials (RCTs) examining exercise during treatment are summarized in Table 1 and have variable findings, likely due to the heterogeneous nature of these studies as elaborated further.

Table 1 - Summary of randomized controlled trials for effects of exercise on cardiovascular outcomes during cancer treatment
Study (year) N Cohort, settinga Baseline CVD Cardiotoxic cancer therapies Modality, intensity, frequency (day/week), duration (weeks) Cardiovascular outcomes Protocol adherence LTF %
MacVicar et al. (1989) (25) 45 Breast cancer patients: AT, stretching, UC NR Adjuvant CT CE VO2p NR
60–85% HRR AT: 40% increase LTF: 27%
3 days/week UC: NC
10 weeks P = 0.05
Segal et al. (2001) (26) 123 Breast cancer patients: AT, self-directed AT, UC NR Previous XRT: 37% TM VO2p (estimated) NR
Most common CT regimens: Fluorouracil, doxorubicin and cyclophosphamide: 35% 50–60% VO2p Supervised: 2.4% increase LTF: 27%
3–5 days/week Self: 3.5% increase
Adriamycin and cyclophosphamide: 31% 26 weeks UC: NC
P = NS
Kim et al. (2006) (27) 41 Breast cancer patients: AT, UC None CT: 40.9% CE, TM, or walking, jogging, running on track VO2p 78.3%
XRT: 31.8% Moderate to High AT: 8.3% increase NR
Combination: 27.3% 3 days/week UC: 2.1% increase
8 weeks P < 0.001
Resting SBP
AT: t39 = 2.09
UC: NC
P < 0.05
Courneya et al. (2007) (28) 242 Breast cancer patients: AT, RT, or UC NR Taxane CT: 31% AT: CE, ET, TM VO2p AT: 93%
Non-taxane CT: 61% 60–80% VO2p AT: 0.2% increase RT: 96%
RT: 8–12 reps RT: 5% decrease LTF: 9%
60–70 RM UC: 6% decrease
3 days/week P = 0.006
17 weeks
Daley et al. (2007) (29) 108 Breast cancer patients: AT, UC None Exercise AT: 1:1 supervised therapy 8-minute TM walk test 77%
CT: 79.4% 65–85% max HR AT versus UC NR
XRT: 79.4% 3 days/week P = 0.002
Control 8 weeks
CT: 73%
XRT: 78.9%
Courneya et al. (2009) (30) 122 Lymphoma patients: AT or UC HTN 29% CT: % NR CE VO2p 95%
DLD 30% 60–100% VO2p AT: 17% increase LTF: 11%
3 days/week UC: 2% decrease
12 weeks P = 0.021
Segal et al. (2009) (31) 121 Prostate cancer: AT, RT, UC NR XRT: % NR AT: CE, ET, TM VO2p NR
ADT: 61.2% 50–75% VO2p AT: 0.1% increase LTF: 7%
RT: 8–12 reps RT: 0.5% increase
60–70% RM UC: 5% decrease
3 days/week P = 0.01
24 weeks
Courneya et al. (2013) (32) 301 Breast cancer patients: AT, high-dose AT, combined AT/RT Obese 23% Taxane: 74.1% AT: CE, ET, TM, row VO2p NR
Trastuzumab: 16.6% RT: 8–12 reps AT: 12% decrease LTF: 7%
Neither: 9.3% 60–70% RM High-dose AT: 9% decrease
3 days/week Combined: 13% decrease
16 weeks P = 0.03
Jones et al. (2013) (33) 20 Breast cancer patients: AT, UC NR Neoadjuvant CT CE VO2p 66%
55–100% VO2p AT: 13% increase LTF: 5%
3 days/week UC: 9% decrease
12 weeks P = NS
Samuel et al. (2013) (34) 48 Head and neck cancer patients: AT or RT, UC NR CT: % NR AT: walking 6-minute walk test Adherence not measured
3–5/10 perceived exertion AT/RT: 42 m increase
RT: 8–12 reps UC: 96 m decrease
5 days/week P < 0.001
6 weeks
Study (year) N Cohort, settinga Baseline CVD Cardiotoxic cancer therapies Modality, intensity, frequency (day/week), duration (weeks) Cardiovascular outcomes Protocol adherence LTF %
Hornsby et al. (2014) (35) 20 Breast cancer patients: AT, UC NR Neoadjuvant doxorubicin + cyclophosphamide CE VO2p 82%
Moderate to high intensity AT: 13.3% increase NR
3 days/week UC: 8.6% decrease
12 weeks P < 0.05
Moller et al. (2015) (36) 45 Breast and colon cancer patients: hospital or home-based intervention versus UC NR Neoadjuvant CT Home: walking with pedometer Peak VO2 decreased across study groups 12% NR
Hospital: bikes, resistance and circuit training, dance 3 days/week P = NS NR
12 weeks
Van Waart et al. (2015) (37) 230 Breast or colon cancer patients: home or supervised AT, CT, UC NR Adjuvant CT Home AT: 12–14 Borg Score Estimated exercise capacity NR
XRT: 78% 50–80% maximal workload Home: 9% decrease LTF: 11%
5 days/week Supervised: 14% decrease
NR UC: 18% decrease
P < 0.001
Gilbert et al. (2016) (38) 50 Prostate cancer: Exercise, UC Prior MI: 8% Androgen deprivation therapy CE, TM, row FMD of the brachial artery 93%
Angina: 12% 55–75% max HR P = 0.04 NR
HTN: 64% 3 days/week
HTN since ADT: 12% 12 weeks
Scott et al. (2018) (8) 65 Breast cancer patients with metastatic disease: AT, stretching (control) HTN, DLD, DM, or CAD: 34% CT: 57% 55–100% VO2p VO2p NR
3days/weeks AT and control: P = NS LTF: 3%
12weeks
Bold value indicates statistically significant of P values.
ADT, androgen deprivation therapy; AT, aerobic training; CE, cycle ergometer; CT, chemotherapy; CVD, cardiovascular disease; DLD, dyslipidemia; ET, elliptical training; FMD, flow-mediated dilatation; HR, hazard ratio; HRR, heart rate reserve; HTN, hypertension; LTF%, lost to follow-up percent; NC, no change; NR, not reported; NS, non-significant; RCT, randomized controlled trial, RM, resistance maximum; RT, resistance training; TM, treadmill; UC, usual care; VO2p, peak oxygen consumption; XRT, radiation therapy.
aSupervised unless otherwise stated.

First, there is a lack of standardization in the utilized methodologies and measured outcomes in these studies. For instance, most clinical studies examining this topic during treatment focus on changes in aspects of CRF and peak VO2, rather than clinically relevant outcomes such as reductions in functional status or mortality. Furthermore, the methods used to define CRF are not standardized throughout clinical reviews and often do not consider factors such as age, comorbidities and baseline functional status, all of which are established to have a strong impact on CRF. Similarly, there is inconsistency in exercise specific variables such as the exercise dosing regimen, VO2, and metabolic equivalent targets. To overcome these inconsistencies in methodologies, standardized guidelines by which age-specific CRF categories are defined have been recently proposed [21].

Second, there is paucity of robust clinical data on the effects of exercise during cancer treatment on CVD outcomes such as subclinical reductions in left ventricular ejection fraction (LVEF), ischemic CVD events, and cardiovascular mortality [8]. For instance, a noteworthy study by Haykowsky et al. examined the effect of aerobic training (AT) on 17 women with HER2-positive breast cancer during the first 4 months of adjuvant trastuzumab therapy. They found that despite exercise, initiation of trastuzumab was associated with LV cavity dilation and reduced LVEF (pre: 64 ± 4% versus post: 59 ± 4% P < 0.05). While the findings might suggest that the benefit of exercise might be absent in preventing changes in LVEF post-exposure to trastuzumab, this might be a premature conclusion, given the small population size and absence of a control group [22]. As such, large scale research is on-going to better assess the impact of exercise on improving cardiovascular outcomes in patients during cancer therapy.

The ongoing Multidisciplinary Team IntervenTion in Cardio-Oncology (TITAN) and Exercise to prevent AnthraCycline-base Cardio-Toxicity seek to integrate exercise into treatment plans for cancer patients [23,24]. TITAN specifically will assess cardiac remodeling with imaging and biomarkers at 6–12 months follow-up from supervised to independent exercise training with Cardiology team support in breast cancer or lymphoma patients receiving chemotherapy [24]. The Optimal Training Women with Breast Cancer Trial RCT has a longer follow up of 5 years; and via personalized exercise prescriptions, aims to compare AT and combined resistance training to usual care in breast cancer patients, with CRF as a secondary endpoint. So far, at 2-year follow-up, there has been no statistically significant difference in pre-specified outcomes between exercise and usual care control groups [39]. Nonetheless, a recent protocol has been proposed for a systematic review of the effectiveness of exercise in counteracting cardiotoxicity related to anticancer therapies in women with breast cancer. The proposed primary outcomes for this review include systolic function, diastolic function, and myocardial deformation imaging outcomes [40].

Despite the variations in baseline characteristics across the existing studies on this subject, the overall, results are promising and suggest that exercise during cancer treatment improves cardiovascular health (Table 1), and therefore act as a basis for supporting the call for structured exercise therapy for patients with cancer.

The impact of exercise initiated post-cancer treatment

There is some evidence that exercise improves CRF even when initiated after the completion of cancer therapy. Compared to clinical studies exploring the impact of exercise when started before or during cancer treatment, findings surrounding the post-treatment phase are somewhat mixed. However, while several studies suggest no difference in CRF measured by VO2 in exercise regimens after cancer treatment, the majority of studies point towards efficacy in post-treatment exercise (Table 2) [41,42].

Table 2 - Summary of randomized controlled trials after treatment
Study (year) N Cohort, settinga Baseline CVD Timing after treatments Modality, intensity, frequency, duration Cardiovascular outcomes Protocol adherence LTF %
Courneya et al. (2003) (51) 53 Breast cancer patients: AT, UC NR 14 months after CT CE VO2p NR
70–75% VO2 AT: 15% increase LTF: 6%
3 days/weeks UC: NC
15 weeks P < 0.001
Thorsen et al. (2005) (42) 139 Breast, gynecological, lymphoma, testicular cancer: unsupervised AT, UC NR 30 days after therapy TM, CE, skiing VO2p NR
13–15 Borg Score AT and UC: LTF: 20%
3 days/weeks P = NS
15 weeks
Daley et al. (2007) (29) 108 Breast cancer patients: AT, UC None Post therapy 1:1 specialized AT Aerobic fitness score AT versus UC 77%
65–85% max HR P = 0.002 NR
3 days/week
8 weeks
Courneya et al. (2013) (32) 301 Breast cancer patients: AT, high dose AT, UC None Post-treatment CE, ET, TM, row High dose AT superior to AT and UC NR
NR
55–75% VO2 P = 0.03
3 days/week
Ending 3–4 post-CT
Jones et al. (2014) (44) 90 HF patients with cancer: 3 months supervised + 4–12 months unsupervised AT, UC HTN: 94% Post-HF therapy CE, TM VO2p NR
DM: 38% 60–70% HRR AT: 4% LTF: 14%
HF: 100% 4 days/week Increase
52 weeks UC: 6% increase
P = NS
Jones et al. (2014) (52) 50 Prostate cancer patients: AT, UC HTN: 54% 75 days after therapy TM VO2p 79%
HPL: 60% 55–100% speed at VO2p AT: 9% LTF: 8%
DM: 16% 5 days/week UC: 1%
CVD: 8% 24 weeks P < 0.05
Low CRF: 100%
Rogers et al. (2015) (41) 222 Breast cancer patients: supervised or unsupervised AT, UC HTN: 11% 54 months after therapy CE, ET, TM VO2p NR
40–59% HRR AT: 12% increase LTF: 2%
3–5 days/week UC: 10% increase
12 weeks P = NS
Adams et al. (2017) (43) 63 Testicular cancer patients: supervised AT, UC Obese: 21% 8 years after therapy TM VO2p 98%
Pre-HTN: 19% 75–95% VO2p AT: 11% LTF: 3%
Metabolic syndrome: 19% 3 days/week Increase
12 weeks UC: NC
Mild carotid plaque: 57% Carotid intima-media thickness:
Moderate-severe carotid plaque: 24%
AT: 7% increase in thickness
UC: NC
Carotid distensibility:
AT: 16% increase
UC: NC
Framingham risk score:
AT: 0.5% increase
UC: NC
P < 0.01
Scott et al. (2020) (46) 174 Postmenopausal breast cancer patients: LET, NLET, AC Impaired VO2p 2.8 years after therapy VO2p Intention-to-treat analysis, regardless of adherence
LET: 0.6 ± 1.7 mLO2/kg·min
NLET: 0.8 ± 1.8mLO2/kg·min → both compared to AC
P = 0.05
Bold value indicates statistically significant of P values.
AC, attention control: Control group; AT, aerobic training; CE, cycle ergometer; CRF, cardiorespiratory fitness; CT, chemotherapy; CVD, cardiovascular disease; DM, diabetes; ET, elliptical training; HPL, hyperlipidemia; HR, hazard ratio; HRR, Heart rate reserve; HTN, hypertension; LET, linear, fixed-dose regimen; LTF, lost to follow up; NC, no change; NLET, nonlinear, variable dose regimen; NR, not reported; RCT, randomized controlled trial; RM, resistance maximum; RT, resistance training; TM, treadmill; UC, usual care; VO2p, peak oxygen consumption; XRT, radiation therapy.
aSupervised unless otherwise stated.

Similar to clinical studies focusing on exercise during treatment, there are a few notable studies that have assessed the effects of exercise when initiated after completion of cancer therapy using parameters beyond CRF/VO2. Notably, a recent RCT by Adams et al. [43] was the first to provide evidence that high-intensity AT on testicular cancer patients post-treatment improved not only CRF, but other variables such as also arterial thickness, Framingham risk score, arterial stiffness, and low-density lipoprotein (P < 0.01).

On the other hand, two recent RCTs demonstrated mixed benefit of exercise post-cancer treatment in this population. Jones et al. [33] showed that exercise produced increases in VO2 peak, which was associated with improved vascular endothelial function, with no changes in LVEF. Similarly, a recent retrospective intention-to-treat analysis of the Efficacy and Safety of Exercise Training in Patients with Chronic Heart Failure (HF-ACTION) RCT showed that in patients with cancer who have heart failure and randomized to AT had a cardiovascular mortality reduction compared to the usual care group (HR 1.94; CI 1.12–3.16; P = 0.02) [44]. It is notable that although mortality reduction was observed in this study, VO2 improvement was not, which contrasts with what is seen in the general population, in which VO2 has the strongest predictive ability for future mortality [45]. This raises the possibility that VO2 may not be a sufficiently sensitive outcome in the assessment of exercise effect on cardiovascular health in cancer patients despite being the most frequently utilized outcome measure in clinical trials as seen in Tables 1 and 2. It also speaks to the potential presence of alternate mechanisms by which exercise might confer cardiovascular benefit in this population.

Regarding the type of exercise, recently, a RCT by Scott et al. [46] examined patients with primary breast cancer patients who had completed cancer treatment. In this study, patients were randomized to linear AT, non-linear AT, or usual care. Here, linear prescription of exercise defined as having fixed-dosing (per week) and fixed intensity for all patients revealed only modest improvement in CRF independent of dosing of chemotherapy. Of note, this study reported substantial heterogeneity in the response to both linear and non-linear AT in this population of breast cancer survivors with impaired CRF. The authors concluded that exercise programs of greater amount or length, as prescribed in their non-linear programs, may be needed to produce meaningful improvements among this population of post-treatment breast cancer patients [46].

In summary, there is yet insufficient but increasing evidence to conclude that non-linear AT and better-tailored exercise post-cancer treatment improves cardiovascular health. Additional studies are needed to examine the impact of specific approaches to individually-tailored exercise interventions on a variety of outcomes in cancer survivors.

Clinical guidelines and recommendations

Based on current evidence, clinical guidelines recommend moderate-intensity exercise–both aerobic and resistance training–for patients with cancer both during and after treatment. This recommendation also applies to intense cancer treatments such as stem cell transplantation [47,48]. However, such linear exercise recommendations in cancer patients and survivors are fraught with specific problems. For example, the determination of moderate-intensity exercise recommendation may be confounded by the presence of sequela of cancer therapies, such as autonomic dysfunction due to cisplatin or external radiation therapy; or via medications used to treat cardiac complications of chemotherapy such as beta-blockers [49]. Additionally, it is important to consider that there will be significant differences in exercise tolerability due to considerable variability in baseline clinical status such as differences in treatments received, cardiovascular risk factors, and physiologic status (below or comparable to age- and sex-matched VO2peak) [50].

Additional evidence suggests that generalized exercise recommendations might not be appropriate for all patients with cancer. For example, a study by Jones et al. [44], showed that cardiovascular mortality and hospitalization was significantly higher in patients with heart failure and a history of cancer when randomized to aerobic exercise compared to the patients with heart failure and history of cancer assigned to guideline-based usual care. As such, standardized exercise prescription may not be appropriate in this population given the significant potential for patient variability. Based on this, we recommend an individualized approach to exercise recommendations in patients with cancer (Fig. 1).

Fig. 1
Fig. 1:
Suggested algorithm for exercise prescription in adult cancer patients peri- and post-cancer therapy. *Considered to be at increased cardiovascular risk by ASCO guidelines (52): Treatment with high-dose anthracycline therapy, high dose radiation therapy (when the heart is included in the treatment field), or low dose anthracycline therapy in combination with low dose radiotherapy; Treatment with low-dose anthracycline or trastuzumab alone plus the presence of two or more risk factors (smoking, hypertension, diabetes mellitus, obesity, dyslipidemia, age greater than 60 years at time of treatment, or the presence of compromised cardiac function); Treatment of low-dose anthracycline followed by trastuzumab. **In settings where CPET unavailable investigators can use maximal incremental exercise tolerance testing (ETT) to determine workload and peak exercise heart rate. CPET, cardiopulmonary exercise testing.

To determine which patients with cancer might safely tolerate exercise before, during or post-chemotherapy, exercise stress testing may be a worthwhile risk stratification tool. Specifically, exercise stress testing and can identify individuals unlikely to tolerate the recommendations for moderate-intensity exercise based on submaximal and maximal exercise reached [53,54]. For example, among deconditioned patients, standardized functional and submaximal exercise testing heart rate and blood pressure responses can be used to prescribe exercises of varying intensities independent of disease severity or baseline fitness status [55].

On the other hand, exercise prescriptions that are determined by baseline physiologic endpoints in the absence of up-to-date objective determination of exercise capacity, are at increased susceptibility of underdosing or overdosing exercise therapy. For example, in primary breast cancer patients with autonomic dysfunction and decreased heart rate reserve, the use of standardized age-predicted maximum heart rate may result in exercise overdosing [49].

To date, no organization has reached a consensus on the impact of cancer therapies on overall CVD risk. However, the American Society of Clinical Oncology has provided evidence-based guidelines regarding selected therapies that predispose cancer patients to CVD. The guideline recommends that those who should be considered at increased CVD risk include: (1) treatment with high-dose anthracycline therapy, high dose radiation therapy (when the heart is included in the treatment field), or low-dose anthracycline therapy in combination with low-dose radiation therapy; (2) treatment with low-dose anthracycline or trastuzumab alone plus the presence of two or more risk factors (smoking, hypertension, diabetes mellitus, obesity, dyslipidemia, age greater than 60 years at time of treatment, or the presence of compromised cardiac function); (3) treatment with low-dose anthracycline followed by trastuzumab [56].

Another strategy to determine exercise capacity before prescribing exercise therapy in patients with cancer is cardiopulmonary exercise testing (CPET). CPET-based metabolic and ventilatory responses allow for the generation of 3 to 5 different exercise intensity zones and provides information on the patient’s VO2peak, thus providing data for individualized tailoring of exercise training [57]. Beyond prediction of exercise tolerability, CPET can be repeated after training to objectively measure and document improvement in cardiac fitness and refine training levels. This is supported by a systematic review which found that CPET is a safe, noninvasive method to measure cardiopulmonary fitness in cancer patients both during and after treatment [58]. As discussed, VO2 may not be the most appropriate method for assessing exercise effect on cardiovascular health in cancer patients; nonetheless, it is the most constructive method currently available for assessing exercise needs. We therefore recommend formal CPET in addition to clinical risk stratification to guide moderate-intensity recommendations (Fig. 1). In settings where CPET is unavailable, investigators may use maximal incremental exercise tolerance testing as the next (although suboptimal) alternative to determine workload and peak exercise heart rate [59].

Finally, we recommend exercising in a group or supervised setting. Data suggest greater and more consistent benefit with exercise interventions that occurred in group settings compared with individual settings [44,60–62]. A supervised setting can provide more motivation for patients and lend initial educational components to ensure that professionals have the opportunity to review how to perform exercises safely with the patient. Exercise prescriptions should be delivered by the American College of Sports Medicine/American Cancer Society-certified exercise trainers. Fitness trainers should be encouraged as much as possible to learn about specific cancer diagnoses and treatments rendered. They should be included as part of the medical team, as a diagnosis of cancer can affect multiple parts of the body, and treatments are becoming increasingly customized.

Future directions

In this review of exercise in the care of cancer patients, we proposed an algorithm to risk stratify cancer patients and develop a personalized approach to exercise implementation. Transition from the research setting to widespread clinical availability presents significant challenges including lack of staff education on the complexities involved in the overall health and management of cancer patients. The effects of cancer stage, treatment type, and patient-specific risk factors should be clarified when identifying periods of greatest physical decline and recovery. Exercise programs will require infrastructures that enable them to provide services uniquely aligned with exposures and needs of cancer patients. The responsibility of identifying and referring patients with cancer at risk for cardiac dysfunction to exercise programs remains in the hands of both cardiologists and oncologists. Cardiologists have traditionally worked with oncologists to care for cancer patients after cardiac toxicity has occurred, and a proactive stance between specialties is pivotal to developing cardio-oncologic exercise-based rehabilitation.

Further work is needed to demonstrate the benefits of exercise in producing a reduction in cardiac dysfunction in the cancer population and to generate guidelines to help shape referrals and reimbursements. Reimbursement for cardiac rehabilitation was first established in 1982 for patients that experienced myocardial infarctions, coronary artery bypass graft surgery, and stable angina [48]. Unfortunately, there is currently no reimbursement strategy available in the USA that can provide patients with access to exercise-based cardiac rehabilitation programs on the bases of their malignancy and associated potentially cardiotoxic treatment. With further research and the development of formal guidelines, exercise-based cardiac rehabilitation has the potential to provide a widely accessible comprehensive program that has the potential to be significantly beneficial to cancer patients across the United States, regardless of treatment phase.

Conclusion

Persons with cancer, particularly those receiving certain chemotherapeutic agents are at heightened risk of developing cardiovascular sequela which can be measured using a number of outcomes. There is convincing evidence that exercise whether performed before, during, or following cancer treatment can mitigate these risks. As such a patient-tailored, supervised, exercise program using predictions of exercise capacity from stress testing or CPET, is likely to maximize the benefit of this approach and assist in the prevention of poor cardiovascular outcomes in patients with cancer.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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                              Keywords:

                              cancer; cardioprotection; cardiotoxicity; cardiovascular complications; cardiovascular disease prevention; exercise

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