Exercise as Medicine Could Be a Chance for Early Detection and Prevention of Cardiotoxicity in Cancer Treatments: A Narrative Review

Background: For cancer patients, cardiovascular complications as a consequence of certain oncological therapies are the leading cause of death, apart from the cancer itself. Currently, there are no uniform guidelines for detecting subclinical cardiotoxicity. Hence, the identification of cardiotoxicity arises late in the course of myocardial dysfunction after cardiac damage has occurred already. Early detection, prevention, and treatment of these cardiotoxic effects remain a challenge; therefore, supportive strategies such as physical activity gain in importance. Summary: Exercise therapy, during and after cancer therapy, is considered to be safe, feasible, and effective. While animal models show protective effects, the evidence for the benefits of physical activity on future cardiovascular outcomes in human patients caused by certain cancer treatments is still limited. Consequently, targeted exercise recommendations such as frequency, intensity, time, or type are yet unclear, and certain guidelines, specifically preventing cardiotoxicity, are nonexistent. Low cardiorespiratory fitness is strongly associated with all-cause mortality as well as cardiac dysfunction. In this context, the role of cardiorespiratory fitness as an early predictor in the detection of cardiovascular dysfunction will be discussed. Key Message: Exercise therapy during cancer treatment could have the potential to aid in both the diagnosis and treatment of cardiovascular complications. This narrative review considers the current evidence on the impact of physical activity on cardiovascular outcomes in cancer patients and proposes, according to the present knowledge, a framework for cardioprotective exercise therapies.


Introduction
Cardiotoxicity is one of many side effects that cancer therapy entails and is, especially for cancer survivors, one of the most fatal ones. Due to improved treatment regimes, the number of cancer patients who are expected to survive at least 5 years is consequently projected to increase as well, with cardiotoxic side effects increasingly impacting patient outcomes in this ever-growing patient population [1]. Cardiotoxicity refers to the direct harmful effects of cancer treatments, such as cytotoxic chemotherapy, radiotherapy, targeted inhibitors, and antibodies or immune checkpoints [2].
The European Society of Cardiology defines cardiotoxicity as the decrease in left ventricular ejection fraction (LVEF) from ≥5% to ≤55% with concomitant symptoms of heart failure or a decrease in LVEF by ≥ 10% to ≤55% without concomitant symptoms. However, these definitions are not uniform worldwide. For example, the American Society for Echocardiography defines cardiotoxicity as a drop in LVEF of 10% from baseline and an absolute value of <53% [3,4]. Another relatively novel parameter that is said to have the potential as an early marker for cardiotoxicity is the global longitudinal strain (GLS). This strain is measured using speckle tracking echocardiography, which measures left ventricular (LV) regional and global deformations in response to force as a marker of contractility and elasticity. Due to the myriad definitions and novel status of speckle tracking echocardiography, there are currently no uniform guidelines to detect subclinical cardiotoxicity, meaning that it is usually not diagnosed before it manifests. Biomarkers such as troponin and natriuretic peptides are recommended in current guidelines for monitoring cardiotoxic therapy, but validated cut-offs are missing and assessment is unfortunately not a part of the clinical routine. For optimal management of cardiovascular complications, it is recommended to determine the LVEF before and during cardiotoxic treatment, monitored by either echocardiography or other methods that provide suitable image quality [5].
Acute cardiotoxic events are characterised by arrhythmias, QT prolongation, or even sudden cardiac death [6]. Late cardiotoxic events still can occur years after cancer treatment with an incidence of cardiac dysfunction or congestive heart failure. In adult breast cancer survivors who received a medium dose of the anthracycline doxorubicin (390 mg/m 2 ) in combination with human epidermal growth factor receptor-type 2 (HER2) antibodies, 34% of survivors were diagnosed with either cardiac dysfunction or heart failure [7,8]. The monoclonal antibody trastuzumab leads to partially reversible damage of the myocardium, typically known as type-2 cardiotoxicity [9]. Up to 57% of childhood cancer survivors show late cardiotoxic effects like asymptomatic ventricular dysfunction or cardiomyopathy. Among those, cardiovascular complications are the leading cause of death, after the cancer itself [5,10].
The physiological cause of acute or late cardiovascular complications depends on different factors. For one, the type of cytotoxic agents, for example, anthracyclines, especially in combination with other cardiotoxic agents, are known to have a high risk for cardiovascular complications, such as oxidative stress, cardiac apoptosis, sinus tachycardia, or thrombosis with subsequent myocardial ischaemia [6,11]. Furthermore, immune and targeted therapeutics that inhibit the vascular endothelial growth factor pathway, like sorafenib and sunitinib, increase the risk of arterial thrombosis [8]. Furthermore, radiotherapy is associated with a higher incidence for severe atherosclerotic disease which can lead to ischaemic heart disease [9].
Because toxic effects on the cardiovascular system are often irreversible once they have manifested, preventive and rehabilitative supportive therapies are of great inter-est in this context [12]. Exercise therapy with the goal of enhancing cardiorespiratory fitness (CRF) in oncology has great potential to exert positive preventive, as well as rehabilitative, effects on the cardiovascular system by, for example, preventing cardiac cell damage and reducing oxidative stress [13][14][15]. Within the general population, improvements in CRF are associated with reduced mortality risk. Although CRF seems to constitute an important marker of cardiovascular health, it is currently not routinely assessed in the routine care of oncological patients [16]. In addition, one of the most interesting and best modifiable risk factors might be the sedentary lifestyle, which often leads to weight gain, arterial hypertension, and reduced physical capacity. Both aspects will be discussed in this overview. The following narrative review will discuss the role of CRF and its potential as an early predictor in the detection of cardiovascular dysfunction, as well as summarize current evidence on the effects of exercise therapy on cardiovascular outcomes in cancer patients and propose a framework for cardioprotective exercise therapies.

Exercise Therapy for Management of Cardiovascular Complications and Cardiotoxicity
Exercise therapy has long been established as an integral part of supportive therapy for cancer patients. In 2010, the American College of Sports Medicine published its first exercise guidelines, concluding that exercise training is safe during and after cancer therapy and results in improvements in quality of life, physical function, and cancer-related fatigue [17]. Moreover, there is consistent evidence that exercise therapy, and physical activity in general, have a compelling effect on preventing many types of cancer and on the mortality rate in cancer survivors [18]. Furthermore, it is indisputable that targeted and personalised exercise therapy is one of the important keys to the management of side effects of cancer and its therapy, such as fatigue, cachexia, and peripheral neuropathy [19]. Nevertheless, to date, the effect of exercise therapy on cardiovascular toxicity has rarely been studied. Because of the rising numbers of patients suffering from cardiovascular complications, there is a great need for future studies to focus on this side effect [4,20]. The goodquality evidence and implementation of exercise therapy in healthy people, as well as in patients with myocardial infarction after bypass surgery or symptomatic angina pectoris, give detailed indications that supportive therapy can have positive effects in cancer patients with acute and late cardiac sequelae [21][22][23]. Moreover, exercise therapy has a great positive impact on cardiovascular risk factors such as obesity, arterial hypertension, and a low physical performance status, which play an important role in the development of cardiovascular complications [24].

Role of CRF in the Early Detection of Cardiovascular Dysfunction in Cancer Patients
Despite intensified interdisciplinary efforts, as well as comprehensive diagnostic techniques, risk stratification for cardiac dysfunction following cancer therapy remains a challenge. Reductions in LVEF often occur late in the course of myocardial dysfunction, after cardiac damage has occurred already. It is widely accepted that CRF, given as peak oxygen consumption (VO 2 peak) in non-cancer [25] as well as in cancer populations [26], is strongly associated with all-cause mortality, especially cardiac dysfunction [25]. Namely, within a cohort analysis of 1,632 cancer patients who underwent exercise treadmill testing around 7 years after certain cancer diagnoses, Groake et al. [26] (2020) demonstrated that high CRF, measured as metabolic equivalent of task (MET), was associated with significant reductions in the risk of cardiovascular mortality in cancer survivors.
Another study, including 147 women with early stage HER2+ breast cancer receiving anthracyclines and trastuzumab, focused on CRF early post-cancer treatment [27]. Around 40 days after trastuzumab completion 44% of them achieved a VO 2 peak < 18mL O 2 /kg/min, which can be considered compromised functional independence and consequently an increased risk for cardiovascular diseases [28]. Furthermore, Bonsignore et al. [27] showed that an abnormal GLS of <18% as well as abnormal E/e´ (measure of diastolic filling pressures) threshold of ≥7.8 had been associated with significant reductions in VO-2 peak. These findings, confirmed by previous studies [29,30], suggest that impaired CRF in the early phase after cancer treatment may be a predictor of increased cardiovascular risk caused by cancer-related treatments. Therefore, current screening strategies in cancer patients receiving cardiotoxic therapies mainly focus on cardiac biomarkers, ECG, and echocardiographic parameters [4]. The American Heart Association (AHA) is already discussing the use of CRF as a vital sign in clinical practice, as it is seen to be important and feasible [31]. However, validated cut-offs for CRF are still missing. Thus, further research is required to identify the cut-offs that classify low, moderate, and high CRF. Moreover, prospective trials should be initiated to determine the feasibility of CRF assessments as part of clinical routine, especially in regard to the need of experienced exercise professionals, resources, and costs [31].

Cardioprotective Mechanisms of Physical Activity and Exercise Therapy
Molecular mechanisms of physical activity play, with great certainty, an important role in managing cardiotoxic effects. Animal models show protective effects of endurance exercise in mice under doxorubicin on cardiac state as well as vascular endothelial function [13]. Besides, they show that aerobic exercise can prevent cardiac cell damage, as well as systolic and diastolic dysfunction. By reducing oxidative stress, especially reactive oxygen species (ROS), pathological apoptosis can be prevented. Furthermore, as the adenosine monophosphate-activated protein kinase (AMPK) rises, the intracellular calcium content can be regulated and energy metabolism can be better economised [13][14][15].
In the face of preclinical evidence, there is only a limited number of human studies investigating the cardioprotective mechanisms underlying the link between physical activity and cardiotoxicity. Existing randomized controlled trials are heterogeneous in nature and provide variable results. Standardization in the methodologies as well as consistent results of these studies are still pending.

Effect of Exercise Therapy during Cancer Treatment on Preventing Cardiac Dysfunction
Exercise therapy during cancer treatment has been shown to be safe, feasible, and effective [32]. However, the effects of exercise therapy on future cardiovascular outcomes caused by certain cancer treatments still must be clarified.
Within an interventional trial, including 24 women with stage I-III breast cancer receiving doxorubicin-containing chemotherapy, a single vigorous-intensity aerobic exercise training was performed 24 h prior to each doxorubicin treatment, collectively four single exercise sessions per person. While this intervention did not mitigate negative changes in GLS, LV twist, and troponin, positive effects on cardiovascular haemodynamics such as cardiac output, systemic vascular resistance, and resting heart rate as well as prevention of weight gain could be shown [33].
In the context of a prospective non-randomized controlled trial, Howden et al. [34] designed a 12-week exercise therapy program incorporating aerobic and resistance training which was synchronized with each individual chemotherapy schedule. Twenty-eight women with early stage breast cancer were able to choose between exercise therapy and usual care. Neither resting LVEF and GLS nor the biomarkers troponin and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) were influenced by exercise therapy. VO 2 peak, in contrast, decreased over the course of chemotherapy in both groups. Within the exercise group, however, reductions were significantly smaller. Kirkham et al. [35] demonstrated similar results. A combination of aerobic and resistance training during anthracycline chemotherapy did not influence LV longitudinal strain, LVEF, LV mass as well as E/A ratio (marker of the function of the left ventricle of the heart) in women with breast cancer stages I-III. In spite of exercise training, VO 2 peak decreased from baseline to follow-up. Due to a lack of VO 2 peak DOI: 10.1159/000529205 data for the usual care group, drawing comparisons was impossible. Haykowsky et al. [36] also did not show significant increases of VO 2 peak after 4 months of aerobic training in HER2+ breast cancer patients. An acknowledged limitation of this study was the lack of a control group. Consequently, neither Kirkham et al. [35] nor Haykowsky et al. [36] could describe the development of VO 2 peak without exercise training. In contrast, 12 weeks of aerobic training led to significant increases in VO 2 peak in IIB-IIIC breast cancer patients, whereas the control group showed significantly reduced VO 2 peak values [37].
The surveillance of Howeden et al. [34] can be supported by Ansund et al. [38] as well. Women with breast cancer stage I-IIIA, who were scheduled to undergo chemotherapy consisting of anthracyclines and/or taxanes, were randomly allocated to one of three groups: resistance combined with high-intensity interval training, moderate aerobic combined with high-intensity interval training, or usual care. None of the exercise programs led to significant results in terms of cardiac biomarkers (i.e., troponin and NT-pro-BNP), but VO 2 peak increased significantly in the exercise groups, whereas it decreased in the control group. After 1-and 2-year follow-up analyses, patients having higher CRF before chemotherapy, exhibited marked smaller increases in cardiac biomarkers.

Impact of Exercise Therapy after Cancer Treatment
In most cases, cancer therapy is accompanied by a decline in physical functions if patients do not receive supportive care. Up to 80% of all cancer patients show significant or marked impairments of VO 2 peak [39][40][41]. A poor VO 2 peak is not only associated with a higher burden of side effects but can also result in a higher mortality rate [40,42]. Moreover, regular exercise is known to have a prophylactic effect on developing cardiovascular comorbidities such as hypertension and heart diseases. Jones et al. [43] showed via meta-analysis, that an aerobic exercise intervention during medical treatment can positively affect VO 2 peak (mean difference 1.21 [0.50-1.92]). Thus, aerobic interventions beginning after cancer treatment (e.g., operation or chemotherapy) have a significant effect (mean difference 3.36 [2.20-4.53]) on VO 2 peak, and as the results of the meta-analysis show, it is never too late to start exercising. In a narrative review, Ghignatti and colleagues [35] examined the effect of aerobic training on cardiac functionality (measured by fractional shortening [FS] in echocardiography). Overall, aerobic exercise showed a great effect on FS compared to the control groups (mean difference 7.40 [5.75-9.05]). And even though an intervention before medical therapy had a greater effect on FS, an intervention during and after medical therapy also had a significant positive effect on FS. It should be mentioned, however, that Ghignatti and colleagues also included preclinical studies in their review. In summary, they conclude that at this time, intervention is recommended as soon as possible, but no upper time limit has been identified that would preclude a beneficial effect.

Conclusion for Exercise Therapy
Oncological exercise medicine could be a beneficial tool, with regard to the diagnosis and treatment of cardiovascular complications, during cancer therapy. Prospectively, regular monitoring of VO 2 peak should be an integral part of exercise therapy practice in order to assess performance and potential impairments. Following the "Proposed Decision Support Algorithm for Cardio-Oncology and Cardiac Rehabilitation" (CORE) by Bonsignore et al. [27] (2021), a form of screening process and risk assessment should be used to determine which patients should be closely monitored and receive specialised exercise therapy (shown in Fig. 1) [19]. Ideally, the patient would be referred to a professional exercise therapist immediately after diagnosis. An initial history of the upcoming or previous therapy can identify whether this therapy may develop cardiotoxic side effects [20]. If there is no risk of cardiotoxicity, the patient can be transferred to a standard, individual training program. In case of a cardiotoxic therapy, the detailed initial diagnosis and medical history should be discussed with the referring cardiologists. Second, information about specific cardiac risk factors should be considered. If the therapist detects modifiable risk factors throughout the anamnesis (e.g., smoking, unhealthy diet, or lack of physical activity in leisure time), individual health education should be offered to the patient alongside the transfer into the specialised exercise program.
Ideally, exercise therapy should be performed after detailed performance diagnostics over the entire medical therapy period (cf. Fig. 2). After the end of therapy, the therapist should train the patient to continue physical activity independently. Besides a detailed history about possible comorbidities at the beginning and the end of the exercise program, a spiroergometry assessment should be performed if it is not contraindicated. A spiroergometry assessment provides information about cardiorespiratory deficits. Another meaningful diagnostic tool could be a strength test which could be used for training control. The specialised exercise program should mainly be compromised of endurance training, as it is currently the most promising training method. Due to the scarcity of studies, it is not yet possible to make any specific recommendations regarding the intensity of endurance training in cancer patients treated with cardiotoxic agents. However, considering studies in cardiological settings leads to the cautious assumption that cancer patients also benefit more from vigorous endurance training (defined as 64-90% of VO 2 peak, Rated Perceived Exertion (RPE) Scale 14-17) than from moderate or light training. However, in the case of vigorous endurance training, the safety aspects (shown in Table 1) should always be considered and the cardiologist treating the patient should be consulted beforehand. If vigorous training is contraindicated, a moderate intervention (46-63% of VO 2 peak, RPE 12-13) is recommended [37]. Figure 2 shows the first and global recommendations in the exercise therapeutic management of cancer patients while undergoing cardiotoxic therapy [38]. In cancer patients, the subjective sensation (RPE scale) should be used first and foremost for load control, as the heart rate often is unreliable under medical therapy. In addition to the important endurance training 2-3x/week, strength training should also be implemented 2-3x/week. The intensity should be determined individually based on the patient's previous experience and goals. Throughout the either vigorous or moderate intervention, it is very important to have regular consultations with cardiologists to discuss patient safety as well as a regular monitoring of the patient reported outcomes and symptoms (e.g., angina pectoris, shortness of breath).

Prospects for Future Studies
According to the American College of Sports Medicine, there is still insufficient evidence on the benefit of exercise on cancer-related cardiotoxicity [14]. Consequently, methodical advice for targeted exercise strategies such as frequency, intensity, time, and type is yet unclear, and therefore, targeted guidelines are missing.  Unfortunately, many questions remain regarding the management of exercise therapy with cancer patients receiving cardiotoxic treatments. First of all, early markers for detecting cardiotoxic effects must be investigated and defined. From an exercise science perspective, future studies should test the theory that cardiovascular performance (e.g., VO 2 peak), alongside medical parameters, can provide early information about cardiotoxic effects. Second, the effects of specific exercise therapy on cardiac health in cancer patients, such as an increased ejection volume, decreased ROS, and support of protein synthesis by increasing the cardiac progenitor cells, should be investigated. Due to the known promising effects of aerobic exercise in general, its impact on cardiac health should be further researched. To fill in these knowledge gaps, a strong interaction between exercise science and medicine is essential and indispensable. For the optimal and interdisciplinary treatment of a patient who is at high risk for cardiotoxic effects, close cooperation between both disciplines is required to detect early changes and to treat them accordingly. Due to the fact that cardio-oncology is a relatively novel field itself, the cooperation and integration of exercise science within it remains a challenge.
Until there is a satisfactory care for oncological patients with cardiotoxic effects much needs to be done. This is why it is recommended to begin to discuss the role and integration of exercise medicine in cardio-oncology. This way, there is a realistic chance that relevant supportive care will be taken into account from the onset and optimise cardio-oncological care for future cancer patients.