The Impact of Exercise on Cardiotoxicity in Pediatric and Adolescent Cancer Survivors: A Scoping Review

Childhood and adolescent cancer survivors are disproportionately more likely to develop cardiovascular diseases from the late effects of cardiotoxic therapies (e.g., anthracycline-based chemotherapy and chest-directed radiotherapy). Currently, dexrazoxane is the only approved drug for preventing cancer treatment-related cardiac damage. While animal models highlight the beneficial effects of exercise cancer treatment-related cardiac dysfunction, few clinical studies have been conducted. Thus, the objective of this scoping review was to explore the designs and impact of exercise-based interventions for managing cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors. Reviewers used Joanna Briggs Institute’s methodology to identify relevant literature. Then, 4616 studies were screened, and three reviewers extracted relevant data from six reports. Reviewers found that exercise interventions to prevent cancer treatment-related cardiac dysfunction in childhood and adolescent cancer survivors vary regarding frequency, intensity, time, and type of exercise intervention. Further, the review suggests that exercise promotes positive effects on managing cancer treatment-related cardiac dysfunction across numerous indices of heart health. However, the few clinical studies employing exercise interventions for childhood and adolescent cancer survivors highlight the necessity for more research in this area.


Introduction
Antineoplastics are increasingly effective at treating malignancies and minimizing damage to healthy tissues [1]. However, many standard cancer treatments exhibit cardiotoxic effects leading to the development of late or acute cardiovascular complications. Chest-directed radiotherapy and anthracycline treatments are of particular concern as they can cause severe cardiac complications [2][3][4][5][6][7][8]. The risk of cancer treatment-related cardiac dysfunction (CTRCD) is related to the dose of cardiotoxic treatment received, and specific populations are at a higher risk.
Childhood and adolescent cancer survivors (CACS) have a remarkably elevated risk of developing CTRCD. The incidence of CTRCD is widely reported in CACS [2,7,8] such that they are two times more likely to develop cardiac abnormalities and have an 11-fold higher cardiovascular disease-related mortality risk than their healthy siblings [9]. Cardiac-related diseases are also the leading cause of non-malignant deaths in CACS [4], likely because CACS often live long into remission, allowing the latent effects of their cancer treatments to manifest. CACS commonly develop left ventricular (LV) systolic dysfunction, heart (Appendix A). The search strategy aimed to identify published primary studies and reviews as well as text and opinion papers.

Inclusion and Exclusion Criteria
This review included studies whose participants were CACS diagnosed at 19 years of age or younger and received anthracycline treatment and/ or chest-directed radiation therapy. Studies were required to include an exercise intervention aimed at decreasing cardiovascular disease in CACS and needed to employ a measure of cardiac surveillance at a minimum of two different time points. Studies without an exercise intervention (i.e., physical activity recall studies) were excluded.

Information Sources
The databases searched included MEDLINE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, Scopus, PsychINFO and SportDiscus. Sources of unpublished studies and grey literature were searched using the first ten pages of Google Scholar, ProQuest Dissertations, and organizational, governmental and health care association websites, including Children's Oncology Group, PanCare, Canadian Cancer Society, American Cancer Society, National Cancer Society, Cancer Research UK, and National Health Institute (Appendix B).

Study Selection
Following the search, all identified records were collected and uploaded into Covidence [35], a citation management platform and duplicates were removed. A team of four reviewers (S.J.K., J.E.L., M.A., W.J.J.) screened all titles and abstracts against the inclusion criteria. Potentially relevant papers were retrieved in total, and their full-papers were imported into Covidence. Next, the same four reviews (S.J.K., J.E.L., M.A., W.J.J.) assessed the full text of the selected citations in detail against the inclusion criteria. Reasons for exclusion of full-text articles were recorded and reported. Any disagreements were discussed between two reviewers (S.J.K. & J.E.L.).

Data Extraction
Data were extracted by a team of 3 extractors (S.J.K., J.E.L., M.A.) with at least two extractors per paper. The extraction tool was initially piloted in five studies, in which any additional aspects were discussed to retrieve from the sources. A complete extraction tool is in Appendix C.

Data Synthesis and Analysis
All data were combined to provide a complete dataset for analysis and cleaned by one reviewer (S.J.K.). The results were presented to all authors and were discussed regarding the implications.

Study Selection
The reviewers identified 6510 records from the database search. 301, 729, 3866, 132, 160 and 611 reports were found on CINAHL, Medline, Embase, SportDiscus, PsycInfo and Scopus, respectively. All records were loaded into the review management website, Covidence. From the database search, Covidence removed 1891 duplicates, leaving 4616 articles. Two reviewers screened the title and abstract of the 4616 articles against the inclusion and exclusion criteria. Upon completion, the full text of 230 articles was assessed for eligibility, and an exclusion reason was provided for each excluded article. Reviewers identified that 64 reports focused on cardiopulmonary fitness testing, 65 did not have an exercise intervention, 28 were secondary sources, 25 did not focus on cardiotoxicity, ten did not have enough information to extract, nine were measurement validation studies, eight did not have an English full-text version, seven focused on adult cancer survivors, three focused on pharmacological treatments, three were duplicates, two assessed non-human subjects, and one did not assess cancer patients. Thus, six reports were included in the review from the database search. However, two separate papers were written based on the same study cohort and merged during the analysis [36,37]; thus, this review includes five exercise interventions.
Additionally, 80 articles were identified through other search methods, including the grey literature and citation search. A single reviewer screened these articles following the above steps. The reviewer identified that nine reports focused on cardiopulmonary fitness testing, 18 did not have an exercise intervention, five were secondary sources, 32 did not focus on cardiotoxicity, 13 focused on adult cancer survivors, and two did not assess cancer patients. Thus, one record was included in the review through the other search methods. See Figure 1 for the PRISMA flow chart detailing the number of records found at each review stage.
articles. Two reviewers screened the title and abstract of the 4616 articles against the inclusion and exclusion criteria. Upon completion, the full text of 230 articles was assessed for eligibility, and an exclusion reason was provided for each excluded article. Reviewers identified that 64 reports focused on cardiopulmonary fitness testing, 65 did not have an exercise intervention, 28 were secondary sources, 25 did not focus on cardiotoxicity, ten did not have enough information to extract, nine were measurement validation studies, eight did not have an English full-text version, seven focused on adult cancer survivors, three focused on pharmacological treatments, three were duplicates, two assessed nonhuman subjects, and one did not assess cancer patients. Thus, six reports were included in the review from the database search. However, two separate papers were written based on the same study cohort and merged during the analysis [36,37]; thus, this review includes five exercise interventions.
Additionally, 80 articles were identified through other search methods, including the grey literature and citation search. A single reviewer screened these articles following the above steps. The reviewer identified that nine reports focused on cardiopulmonary fitness testing, 18 did not have an exercise intervention, five were secondary sources, 32 did not focus on cardiotoxicity, 13 focused on adult cancer survivors, and two did not assess cancer patients. Thus, one record was included in the review through the other search methods. See Figure 1 for the PRISMA flow chart detailing the number of records found at each review stage.
Study characteristics are included in Table 1.
Study characteristics are included in Table 1.

Patient Characteristics of the Included Studies
Morales et al., 2020 was the only study that compared a control group of non-exercising CACS with an intervention group of exercising CACS and conducted a long-term followup [41]. The reports from Järvelä et al., 2013 and 2016 included a group of healthy controls to provide a baseline comparison with an exercising group of CACS, but the healthy controls were only assessed at baseline [36,37]. There was no control group in the other three studies [40,42,43].
Patient characteristics varied in the studies included in this review regarding treatment, time since diagnosis, and cancer type. In two studies, all participants were treated with anthracyclines and/ or chest-directed radiation treatment, and in the remaining three studies, most participants were treated with anthracyclines and/or radiation [40,41,43]). All study cohorts analyzed CACS, and various cancer types were included across the study cohorts. Four studies focused on survivors, and one on CACS currently undergoing treatment [41]. Finally, each study included a similar number of males and females, except the Morales et al., 2020 study, whose study sample included more males (n = 124) than females (n = 65) [41].  [36]. Methodologies as cited in [38].
Endothelial function in long-term survivors of childhood ALL: Effects of a home-based exercise program [37]; Home-based exercise training improves LV diastolic function in survivors of childhood ALL: A tissue doppler and velocity vector imaging study [36].

Finland
Case-control study Assess the effects of a home-based exercise intervention on endothelial structure in survivors of childhood ALL [37]; Determine the effects of an exercise program on anthracycline-induced cardiotoxicity as assessed by tissue doppler imaging and velocity vector imaging in long-term childhood ALL survivors [36]. Study patient characteristics are summarized in Table 2.

Exercise Intervention Characteristics of the Included Studies
All reviewed exercise interventions included resistance and aerobic exercise training [36,37,40,41,43], except Sharkey et al., 1993, which only included aerobic training [42]. The frequency of exercise in the reviewed studies varied from two to five sessions per week, with most studies asking participants to complete three exercise sessions per week but would allow for two sessions when necessary. For studies including a resistance training component, exercise intensity and time widely varied. However, aerobic training was generally 30 to 45 min of moderate to vigorous-intensity aerobic training, except for Long et al., 2018, which was shorter in duration [40]. Exercise interventions were based out of the participant's home [36,37], the hospital [41], or both [42]. Long et al., 2018 did not state the setting of the exercise intervention [40].
Study exercise intervention characteristics are summarized in Table 3.
The studies used a variety of techniques to determine CACS' heart health. Measurements included echocardiography to assess left ventricular ejection fraction (LVEF) [36,41,43] and tissue doppler imaging to measure mitral annulus valve velocity [36]. Other measurements included velocity vector imaging to assess strain [36], echocardiography using M-mode to assess fractional shortening [36,41], and cardiopulmonary exercise-based testing using a re-breathing technique to estimate cardiac index, defined as the cardiac output divided by body surface area [44], and stroke volume from cardiac output [42].
Three studies investigated the direct impact of the exercise intervention on LV function [36,41,43]. Of these three, only Morales et al., 2020 investigated the impacts of exercise on heart health during treatment in CACS and included a long-term follow-up of the patients [41]. The results of this study indicated that there was not a significant decline in LVEF or fractional shortening in CACS who exercised, while CACS who did not exercise saw a significant decline in LVEF (p < 0.001) and fractional shortening (p < 0.001). However, LVEF and fractional shortening decreased in CACS who exercised at the 1-year follow-up and after. Similarly, Smith et al., 2013 observed that LVEF markedly improved in all five participants upon completing an exercise intervention (median ∆LVEF = 38.2%, range: 7.6 to 56.9) [43]. In contrast, Järvelä et al., 2016 found that LVEF was not affected by the exercise intervention (p = 0.82) [36]. Although, other measures of LV function in this study were affected, including early diastolic mitral inflow velocity (p < 0.01) and early diastolic mitral annulus velocity (p < 0.01), indicating that the exercise intervention improved LV function. Sharkey et al., 1993 investigated the impact of the exercise intervention on heart health using cardiac index and stroke volume [42]. This study indicated that the exercise intervention did not significantly change cardiac or stroke volume indices. A summary of the findings related to heart health is presented in Table 4

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43]. A summary of the findings related to peripheral heart health is presented in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise interventions and their impact on CTRCD varied. In brief, exercise interventions included only aerobic [42] or a combination of aerobic and resistance training [36,37,40,41,43]. Most

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43]. A summary of the findings related to peripheral heart health is presented in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise interventions and their impact on CTRCD varied. In brief, exercise interventions included only aerobic [42] or a combination of aerobic and resistance training [36,37,40,41,43]. Most

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardi health. Measurements included echocardiography for the left common carotid tima-media thickness [37], ultrasound to determine flow-mediated dilation of th chial artery [37,40], and a cardiopulmonary exercise test to determine peak oxy [42].
Three studies investigated the impact of the exercise intervention on perip diovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-me ness significantly decreased (p = 0.02), and the flow-mediated dilation 40-sec point (p = 0.01) increased after the exercise intervention, although the specific fl ated dilation values were not reported [37]. Similarly, Long et al. found that in flow-mediated dilation (p = 0.008) significantly increased after the exercise int and the change in time to peak brachial diameter (p = 0.031) significantly decre Smith et al. observed that peak oxygen pulse, defined as peak oxygen consum vided by the corresponding heart rate, markedly improved in all five of their pa upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, ran 58.6) points [43].
A summary of the findings related to peripheral heart health is in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventio development of CTRCD in CACS. The review identified five published studi ports) that met this review's inclusion and exclusion criteria. Within these studie interventions and their impact on CTRCD varied. In brief, exercise interventions only aerobic [42] or a combination of aerobic and resistance training [36,37,40,41

Key findings of the included studies relating to periphera
The studies also used various techniques to assess health. Measurements included echocardiography for t tima-media thickness [37], ultrasound to determine flow chial artery [37,40], and a cardiopulmonary exercise tes [42].
Three studies investigated the impact of the exerci diovascular health [37,40,43]. Järvelä et al. found that in ness significantly decreased (p = 0.02), and the flow-m point (p = 0.01) increased after the exercise intervention ated dilation values were not reported [37]. Similarly, L flow-mediated dilation (p = 0.008) significantly increas and the change in time to peak brachial diameter (p = 0 Smith et al. observed that peak oxygen pulse, defined vided by the corresponding heart rate, markedly impro upon completing an exercise intervention (median Δ o 58.6) points [43].
A summary of the findings related to p in Table 5.

Discussion
This is the first scoping review exploring the impa development of CTRCD in CACS. The review identifi ports) that met this review's inclusion and exclusion crit interventions and their impact on CTRCD varied. In bri only aerobic [42] or a combination of aerobic and resista

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43].
A summary of the findings related to peripheral heart health is presented in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise interventions and their impact on CTRCD varied. In brief, exercise interventions included only aerobic [42]

Key findings of the included studies relating to peripheral cardiovascul
The studies also used various techniques to assess CACS' perip health. Measurements included echocardiography for the left comm tima-media thickness [37], ultrasound to determine flow-mediated d chial artery [37,40], and a cardiopulmonary exercise test to determin [42].
Three studies investigated the impact of the exercise interventi diovascular health [37,40,43]. Järvelä et al. found that in survivors, th ness significantly decreased (p = 0.02), and the flow-mediated dila point (p = 0.01) increased after the exercise intervention, although th ated dilation values were not reported [37]. Similarly, Long et al. fou flow-mediated dilation (p = 0.008) significantly increased after the and the change in time to peak brachial diameter (p = 0.031) signific Smith et al. observed that peak oxygen pulse, defined as peak oxy vided by the corresponding heart rate, markedly improved in all five upon completing an exercise intervention (median Δ oxygen pulse 58.6) points [43].
A summary of the findings related to peripheral hea in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise development of CTRCD in CACS. The review identified five publ ports) that met this review's inclusion and exclusion criteria. Within t interventions and their impact on CTRCD varied. In brief, exercise in only aerobic [42] or a combination of aerobic and resistance training

Key findings of the included studies relating
The studies also used various techniqu health. Measurements included echocardiog tima-media thickness [37], ultrasound to det chial artery [37,40], and a cardiopulmonary [42].
Three studies investigated the impact o diovascular health [37,40,43]. Järvelä et al. fou ness significantly decreased (p = 0.02), and point (p = 0.01) increased after the exercise in ated dilation values were not reported [37]. flow-mediated dilation (p = 0.008) significan and the change in time to peak brachial diam Smith et al. observed that peak oxygen pul vided by the corresponding heart rate, mark upon completing an exercise intervention (m 58.6) points [43].
A summary of the findings in Table 5.

Discussion
This is the first scoping review explorin development of CTRCD in CACS. The revi ports) that met this review's inclusion and ex interventions and their impact on CTRCD va only aerobic [42] or a combination of aerobic
Three studies investigated th diovascular health [37,40,43]. Järv ness significantly decreased (p = point (p = 0.01) increased after th ated dilation values were not rep flow-mediated dilation (p = 0.008 and the change in time to peak b Smith et al. observed that peak o vided by the corresponding heart upon completing an exercise inte 58.6) points [43].
A summary of th in Table 5.

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43].
A summary of the findings related to peripheral heart health is presented in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise interventions and their impact on CTRCD varied. In brief, exercise interventions included Curr. Oncol. 2022, 29, FOR PEER REVIEW 8

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43].
A summary of the findings related to peripheral heart health is presented in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardio health. Measurements included echocardiography for the left common carotid a tima-media thickness [37], ultrasound to determine flow-mediated dilation of the chial artery [37,40], and a cardiopulmonary exercise test to determine peak oxyg [42].
Three studies investigated the impact of the exercise intervention on periph diovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-med ness significantly decreased (p = 0.02), and the flow-mediated dilation 40-seco point (p = 0.01) increased after the exercise intervention, although the specific flo ated dilation values were not reported [37]. Similarly, Long et al. found that in s flow-mediated dilation (p = 0.008) significantly increased after the exercise inte and the change in time to peak brachial diameter (p = 0.031) significantly decrea Smith et al. observed that peak oxygen pulse, defined as peak oxygen consum vided by the corresponding heart rate, markedly improved in all five of their par upon completing an exercise intervention (median Δ oxygen pulse = 25.8%, ran 58.6) points [43].
A summary of the findings related to peripheral heart health is p in Table 5.

Discussion
This is the first scoping review exploring the impact of exercise interventio development of CTRCD in CACS. The review identified five published studie ports) that met this review's inclusion and exclusion criteria. Within these studies , significant change; LVEF, left ventricle ejection fraction; FS, fractional shortening; CI, cardiac index; SV, stroke volume; N/A, not applicable.

Key Findings of the Included Studies Relating to Peripheral Cardiovascular Health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intimamedia thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-s time point (p = 0.01) increased after the exercise intervention, although the specific flow-mediated dilation values were not reported [37]. Similarly, Long et al. found that in survivors, flow-mediated dilation (p = 0.008) significantly increased after the exercise intervention and the change in time to peak brachial diameter (p = 0.031) significantly decreased [40]. Smith et al. observed that peak oxygen pulse, defined as peak oxygen consumption divided by the corresponding heart rate, markedly improved in all five of their participants upon completing an exercise intervention (median ∆ oxygen pulse = 25.8%, range: 6.3 to 58.6) points [43]. A summary of the findings related to peripheral heart health is presented in Table 5.

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery intima-media thickness [37], ultrasound to determine flow-mediated dilation of the left brachial artery [37,40], and a cardiopulmonary exercise test to determine peak oxygen pulse [42].
Three studies investigated the impact of the exercise intervention on peripheral cardiovascular health [37,40,43]. Järvelä et al. found that in survivors, the intima-media thickness significantly decreased (p = 0.02), and the flow-mediated dilation 40-second time point (p = 0.01) increased after the exercise intervention, although the specific flow-medi-

Key findings of the included studies relating to peripheral cardiovascular hea
The studies also used various techniques to assess CACS' peripheral health. Measurements included echocardiography for the left common ca tima-media thickness [37], ultrasound to determine flow-mediated dilation chial artery [37,40], and a cardiopulmonary exercise test to determine pea [42].
Three studies investigated the impact of the exercise intervention on diovascular health [

Key findings of the included studies relating to peripheral cardiovascular hea
The studies also used various techniques to assess CACS' peripheral health. Measurements included echocardiography for the left common ca tima-media thickness [37], ultrasound to determine flow-mediated dilation chial artery [37,40], and a cardiopulmonary exercise test to determine pea [42].
Three studies investigated the impact of the exercise intervention on diovascular health [

Key findings of the included studies relating to perip
The studies also used various techniques to as health. Measurements included echocardiography tima-media thickness [37], ultrasound to determine ↑ Abbreviations: . 2022, 29, FOR PEER REVIEW 8

Key findings of the included studies relating to peripheral cardiovascular health
The studies also used various techniques to assess CACS' peripheral cardiovascular health. Measurements included echocardiography for the left common carotid artery in-, significant change IMT, intima-media thickness; FMD, flow-mediated dilation; NA, not applicable; ↑, increased; ↓, decreased.

Discussion
This is the first scoping review exploring the impact of exercise interventions on the development of CTRCD in CACS. The review identified five published studies (six reports) that met this review's inclusion and exclusion criteria. Within these studies, exercise interventions and their impact on CTRCD varied. In brief, exercise interventions included only aerobic [42] or a combination of aerobic and resistance training [36,37,40,41,43]. Most studies (4/5 = 80%) reported positive findings suggesting that exercise may help manage CTRCD in CACS [36,37,40,41,43].

Impact of Reviewed Exercise Interventions
The impact of exercise on CTRCD were assessed using various measurements across the five studies. All studies but Sharkey et al. [42] found that exercise significantly improved heart [36,41,43] and periphery cardiovascular health [36,40,43]. Such findings align with the current literature on healthy children. A recent interim report from the Cardiovascular Risk in Young Finns Study from 1994 to 2011 indicates that high amounts of physical activity are associated with improved left ventricular function in adulthood, as indicated by echocardiographic measurements [45]. Furthermore, Unnithan et al., 2018 found that child soccer players have significantly greater left ventricular end-diastolic volume than infrequently active controls [46].
Additionally, the findings align with the current literature on adults with cancer. Kirkham et al., 2018 found that a multi-modal exercise intervention administered during adjuvant chemotherapy treatment in early-stage breast cancer patients mitigated CTRCD, specifically exercise prevented increases in resting heart rate, hypotension, tachycardia, and impaired heart rate recovery [30]. Such findings indicate that exercise can prevent cardiac dysfunction by initiating physiological adaptations, including increased cardiac fibre contractility, leading to enhanced cardiac output and a healthier heart [47]. However, in CACS, the benefits of exercise regarding CTRCD are not entirely understood and exhibit inconsistencies. For example, Järvelä et al., 2016 indicated that exercise does not improve LVEF or fractional shortening in CACS [36], while Morales et al., 2020 indicated that exercise significantly maintains LVEF and fractional shortening [41].
Despite the current guidelines from the Children's Oncology Group recommending frequent echocardiograms and cardiovascular monitoring of CACS [48], such intensive screening protocols are challenging to implement because of limited access to cardiooncology services, infrastructure, interest, and educational opportunities [49]. Moreover, many survivors remain in primary care and do not have access to dedicated survivorship clinics or services. Furthermore, cardiac surveillance measures, such as LVEF, often do not indicate damage until significant and irreversible maladaptation occurs [15,50,51]. Thus, CACS may develop extensive CTRCD before the damage is detected. Additionally, cardiac imaging may not be sensitive enough to detect the positive effects of an exercise intervention on cardiac health in CACS. More in-depth cardiac profiling using biomarkers, such as high sensitivity troponin and natriuretic peptides, combined with cardiac imaging, as proposed by Cardinale et al., may better detect CTRCD and possibly exercise-induced cardiac adaptations [50].

Exercise Intervention Designs of Reviewed Studies
In this review, exercise intervention designs consisted of aerobic and resistance training, but the specifics of the exercise prescription varied. Most reports investigated CACS four to 30 years after receiving their diagnosis [36,37,40,42,43], while Morales et al., 2020 investigated children receiving treatment [41].
As many exercise guidelines for cancer survivors exist, it is worthwhile to contrast them with the studies reviewed here.  [40], suggesting the exercise intervention mitigated some CTRCD risk. Furthermore, the Morales et al., 2020 [41] report aligned with the pediatric oncology exercise guidelines that aerobic training should be completed 2 to 5 times per week at a moderate to vigorous intensity for 20 to 70 min and resistance training should be completed 2 to 3 times per week at a high intensity for 20 to 30 min [53]. None of the reviewed studies met the current guidelines for CACS exposed to cardiotoxic treatments. These guidelines indicate that adults should complete 2.5 h per week and children should complete one hour per day of aerobic exercise, and all CACS should also perform strength training twice per week. However, all reviewed reports demonstrated some benefits of exercise in mitigating CTRCD risk, except Sharkey et al., 1993 [42], suggesting that any exercise can mitigate CTRCD. CACS should be encouraged to exercise even if they cannot meet the guidelines and will still reap cardioprotective benefits.

Limitations
A drawback of this scoping review was that three of the five [40,41,43] reviewed studies did not meet the review's full inclusion and exclusion criteria, which required all participants to have received anthracycline and/or radiation therapy. The reviewers opted to include these three studies as the nature of the review was to map out the literature, and these studies met all other inclusion and exclusion criteria. Further, the few studies to review indicate the importance of more clinical research in this area.
Another limitation of this review was the different methods of the included studies. While most studies indicated that the exercise intervention improved cardiac outcomes, nine measures were used to assess cardiac health across the five included studies. Cardiac surveillance methods of the reviewed studies included measures such as LVEF [36,41,43], strain [36] and fractional shortening [36,41]. Additionally, the reviewed studies used a variety of measures regarding peripheral cardiovascular health, such as brachial artery intima-media thickness [37] and flow-mediated dilation [37,40]. Thus, evaluating the efficacy of the exercise interventions to prevent CTRCD was challenging as no standardized measurements were used.
Furthermore, the reviewed studies included a wide variety of participants. The reviewed study dates occurred within a similar time frame, except Sharkey et al., 1993 [42], published nearly 30 years before Morales et al., 2020 [41]. Compared with 30 years ago, anthracyclines are used with more awareness of cardiotoxicity and better dose limitation, and advancements in radiotherapy techniques allow for decreased exposure of healthy tissues to radiation [11]. Similarly, the studies occurred in four different countries and assessed many different cancer types. As many treatment protocols are not internationally regulated and vary across cancer types, participant heterogeneity was high. Thus, comparing all studies was challenging, and these limitations should be considered when interpreting the results.

Conclusions
This review indicates that exercise may be a viable treatment to mitigate/manage CTRCD in CACS. Further, the included studies varied widely concerning exercise intervention design, suggesting that any amount and type of exercise could help manage CTRCD. Finally, very few exercise intervention studies monitoring cardiac health have been conducted in CACS, and thus, extensive clinical research is necessary to increase the homogeneity and applicability of findings.
Notably, the results of this review highlight the importance and benefits of exercise for CACS in preventing and managing the development of CTRCD. As the reviewed exercise interventions for CACS vary, CTRCD can be managed by various forms of physical activity and movement, and CACS should engage in exercise and become more physically active to mitigate CTRCD risk.