Introduction

In 2020, breast cancer (BC) has become the most prevalent cancer in the world [51]. It is estimated that there are about 2.26 million new cases of BC worldwide, of which approximately 420,000 are in China [8, 51]. Advances in modern detection strategies and treatments have led to improved survival rates for BC [32]. Anthracyclines, such as doxorubicin and epirubicin, are one of the basic chemotherapeutic agents for BC, and anthracycline-containing regimens have been shown to reduce mortality in women with breast cancer by 38% [13]. However, patients may experience adverse cardiovascular events related to cancer treatment or exacerbation of underlying cardiovascular diseases [7]. Anthracycline-induced cardiotoxicity could significantly impact the cardiovascular system, causing damage to both the heart and vascular endothelial cells [34]. It has been reported that cardiotoxicity may cause treatment interruptions, and cardiovascular disease has become the leading cause of non-cancer-related mortality in BC survivors [3]. Therefore, it would be prudent to consider strategies to mitigate the effects of cardiotoxicity during treatment.

Cardiotoxicity begins with myocardial damage and gradually progresses to cardiac dysfunction [9, 34]. If a decline in cardiac function is detected, myocardial damage has already occurred [9]. Therefore, the detection of myocardial damage through biochemical markers, such as N-terminal brain natriuretic peptide precursor (NT-proBNP), cardiac troponin, and creatine kinase isoenzymes (CK-MB), can be an earlier sign of cardiotoxicity compared to cardiac function [29, 35, 56]. Echocardiographic indexes, such as LVEF and GLS, are also commonly used to detect cardiotoxicity [22, 55]. Furthermore, peak oxygen uptake (VO2peak), as an indicator of the cardiorespiratory fitness and cardiac reserve function, can be estimated through a graded exercise test, which could more precisely detect early cardiac injury and predict future cardiac events [26, 44]. It has been widely reported that the VO2peak can be improved by physical activity, including structured exercise, in apparently healthy populations and patients with various chronic diseases [6, 50].

Numerous strategies, including continuous infusion, dosage reduction, liposomal formulations, and cardioprotective drugs (e.g., dexrazoxane) have been utilized clinically to reduce the risk of cardiotoxicity induced by anthracyclines [12]. However, the risk of anthracyclines-induced cardiotoxicity is still high [27]. In an analysis of nearly 23,000 cancer survivors receiving anthracycline chemotherapy with a median follow-up of nine years, the rates of clinical and subclinical cardiotoxicity were 6.3% and 17.9%, respectively [33]. Anthracyclines induce cardiotoxicity through a number of pathways, with the more commonly reported mechanisms including topoisomerase II inhibition, oxidative stress, and cardiomyocyte apoptosis [53]. A growing body of evidence indicates that mitochondrial dysfunction is strongly associated with cardiotoxicity [45]. There is clear evidence to support the benefits of exercise on alleviating numerous chemotherapy side effects. Preclinical studies have shown that exercise mitigates and reverses cardiotoxicity, without compromising anthracycline’s antitumor effects [4, 41, 42, 54]. It is well known that cancer survivors should ‘avoid inactivity’ [1]. The American College of Sports Medicine (ACSM) and American Heart Association (AHA) recommend cancer survivors engage in at least 150 min of moderate-intensity exercise or 75 min of vigorous-intensity exercise, or an equal combination of both, per week [7, 18, 47].

There still needs to be more clarity among clinicians and BC patients about the effectiveness of exercise in reducing cardiotoxicity and the implemention of exercise prescriptions in clinical settings. This includes defining the type, intensity, duration, and frequency of exercise. Moreover, most BC patients cannot tolerate the recommended exercise amounts due to weakness, a common side effect of chemotherapy [24]. Several systematic reviews and two narrative reviews concluded that exercise might be an effective non-pharmacological intervention for improving aerobic capacity and reducing cardiotoxicity among BC patients. However, the conclusion was based on a limited number of randomized controlled trials (RCTs) and observational studies [27, 36, 39, 40, 52]. It is crucial to recognize the limitations of existing reviews. First, the RCTs included in these reviews contained a small number of subjects, and most of these RCTs were published before 2023, with only three relevant RCTs published since then. Second, the effects of exercise on cardiotoxicity-related indicators were inconsistent. Third, these reviews focused more on the beneficial effects of aerobic exercise than cardiotoxicity. The efficacy of different types of exercise in anthracycline-induced cardiotoxicity is still uncertain. One recent systematic review by Ma et al. [36] unveiled that while aerobic exercise increased VO2peak, it had no significant effect on biomarkers of cardiac injury. Conversely, resistance exercise can improve the function of the cardiovascular muscles [17, 27], thereby improving the aerobic system and reducing cardiotoxicity. In summary, the objectives of this review were to summarize RCTs published between 2010 and 2023 and to: (1) describe the efficacy of exercise (aerobic and/or resistance) on anthracycline-induced cardiotoxicity in clinical settings; (2) provide recommendations for clinicians and BC patients to prevent anthracycline-induced cardiotoxicity, including the timing, type (aerobic, resistance and flexibility exercise), duration, frequency, intensity and precautions of exercise interventions.

Methods

Registration and Protocol

This review protocol was registered in PROSPERO on October 2, 2022 (CRD42022364256), and the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement were followed [38].

Search Strategy

The literature search was conducted using the following six electronic databases: China National Knowledge Infrastructure, Wan Fang Data Knowledge Service Platform, VIP Chinese Journal Service Platform, Web of Science, PubMed, and the Cochrane Library. The retrieval strategy was Mesh combined Entry Terms and was determined by two researchers (LHM and LHY). The search targeted candidate studies published from January 1, 2010, to March 29, 2023. The search terms, a combination of four filters, were used to select relevant articles: (“Exercise” OR “Physical Activity” OR “Training”) AND (“Breast Neoplasms” OR “Breast Cancer” OR “Breast Tumor”) AND (“Anthracyclines” OR “Doxorubicin” OR “Epirubicin” OR “Pirarubicin”) AND (“Cardiotoxicity” OR “Cardiac Toxicity” OR “Cardiomyopathy” OR “Heart Failure” OR “Myocarditis” OR “Arrhythmia” OR “Cardiac Function”). In addition, the references of included articles were screened to identify potentially eligible studies.

Inclusion and Exclusion Criteria

Inclusion criteria based on PICOS principles involved: (1) participants: BC patients scheduled to receive anthracycline chemotherapy; (2) intervention: exercise intervention encompassing either acute (a single bout) or long-term exercise interventions (aerobic, resistance or combined); (3) comparison: usual cancer care; (4) Outcomes related to the cardiotoxicity: biochemical markers,echocardiographic index, and cardiorespiratory fitness, etc.; (5) study design: clinical RCTs.

Exclusion criteria were: (1) repeatability study; (2) Subjects were included in addition to BC patients, but also patients with other types of cancer, such as melanoma. (3) animal models or cell model research; (4) studies published as conference proceedings or reviews; (5) observation groups receiving interventions other than exercise, such as nutrition or cardioprotective drugs (e.g., dexrazoxane).

Study Selection and Data Extraction

Study selection and data extraction were independently carried out by two researchers (LHM and LHY). The following information was extracted: title, author, publication year, subjects, drug dosage, exercise intervention program details (type, intensity, session duration, time, and frequency), the timing of exercise intervention (before, during, and after chemotherapy), adherence, and outcome indicators. When two researchers (LHM and LHY) disagreed, a third researcher was consulted (SD).

Risk of Bias in Individual Studies

The risk of bias in human studies was independently assessed during data extraction using the Cochrane risk-of-bias tool by two researchers (LHM and LHY) [20]. The tool included seven items: (1) random sequence generator, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective reporting, and (7) other bias. Each item was assigned a score of ‘high’ (bias with the potential to seriously alter the results), ‘low’ (bias unlikely to seriously alter the results), or ‘unclear’ (indicating lack of information, or uncertainty over potential bias) [20].

Results

Search Results

Figure 1 provides details of the study exclusion and inclusion process. The initial search yielded 200 records from six databases, and two additional studies were identified through a reference search of eligible studies. After removing duplicates and screening the titles and abstracts, 13 full articles were retrieved and assessed for eligibility. The final number of included studies was ten (one was in Chinese and nine were in English) [2, 10, 16, 21, 25, 28, 29, 31, 35, 56].

Fig. 1
figure 1

Flow diagram for study inclusion of the systematic review

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Studies description

The quality assessment is shown in Table 1. ‘Random sequence generator’ and ‘allocation concealment’ were graded as low risk in eight studies, while the risk was unclear in two studies [35, 56]. ‘Blinding of participants and personnel’ were assessed as high risk in 10 studies due to the need for supervision during exercise interventions. Nine studies were graded as low risk for ‘blinding outcome assessment’, and one study was graded as unclear. Ten studies were rated as being at low risk of ‘incomplete outcome data’ and ‘selective reporting’, and as unclear for ‘other bias’. Across the seven domains of bias, the proportion (range) of studies rated as ‘high’ was 14.3%; ‘low’, 64.3% (28.6% to 71.4%); and ‘unclear’, 21.4% (14.3% to 57.1%).

Table 1 Studies’ quality assessment
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The experimental design of included studies is shown in Table 2. A total of 434 participants were involved in this review, consisting of stage I–IIIC BC patients scheduled to receive anthracyclines for (neo) adjuvant chemotherapy. The mean age of participants ranged from 43.5 to 52.4 years, and sample sizes ranged from 20 to 102. Anthracycline doses were reported in 7/10 studies [2, 10, 16, 21, 25, 28, 29]. One study conducted acute high-intensity aerobic exercise before chemotherapy, and the exercise adherence was 100% [29]. The remaining nine studies conducted long-term (8 weeks–12 months) continuous moderate-to-high training or high-intensity interval training (HIIT) during chemotherapy, with exercise adherence ranging from 63.2% to 98% [10, 21, 25, 28, 31, 35, 56]. Three out of then articles reported aerobic combined with resistance exercise [2, 10, 16], and the remaining seven articles reported aerobic exercise.

Table 2 Characteristics of included studies
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Discussion

This systematic review described the role of exercise in the prevention and treatment of anthracycline-induced cardiotoxicity in women with BC (I–IIIC stage). The main findings of this review were that (1) acute moderate-to-vigorous aerobic exercise could avoid elevated NT-proBNP levels; (2) long-term moderate-to-high intensity aerobic exercise (continuous or interval) or a combination of aerobic and resistance exercises could increase or maintain echocardiographic indexes and cardiorespiratory fitness in BC patients. However, the effectiveness of aerobic exercise on biochemical markers of myocardial injury was inconsistent. Owing to the lack of high-quality RCTs and the differences in training variables such as timing, intensity, duration, and adherence of aerobic exercise performed in each study, some caution is warranted in interpreting these results.

NT-proBNP is synthesized and secreted by the myocardium in response to increased hemodynamic stress, including increased left ventricular end-diastolic volume and pressure [49]. Kirkham et al. [29] found an transient increase in NT-proBNP levels between 24 and 48 hours after the scheduled starting time of participants’ first doxorubicin treatment. Aerobic exercise at 70% heart rate reserve (HRR) in the exercise intervention group prevented NT-proBNP from surpassing the threshold for acute myocardial injury (> 300 pg/mL) ([23, 29], whereas NT-proBNP elevation in the control group exceeded this acute myocardial injury threshold. Another facet of the same trial by Kirkham et al. [28] revealed a significant increase in NT-proBNP levels at 7–14 days after the final doxorubicin treatment, despite acute aerobic exercise at 70% HRR (once per cycle) was conducted prior to four cycles of chemotherapy. Studies by Zhang et al. [56] and Ma et al. [35] reported that a 16-week HIIT regimen (three times a week) at 90%–95% HRmax also prevented NT-proBNP elevations above the threshold for acute myocardial injury. Notably, the study by Kirkham et al. [28] did not continuously monitor changes in NT-proBNP, and both studies by Zhang et al. [56] and Ma et al. [35] did not report the time of blood collection and lacked follow-up, so it is unclear how long the effects of acute and long-term exercise would last. Above mentioned findings may suggest that acute exercise can mitigate myocardial injury induced by a single injection of anthracyclines, which is a stress response with a temporary beneficial effect. In contrast, acute exercise (once per cycle) prior to four chemotherapy cycles cannot offset the myocardial injury caused by prolonged accumulation of anthracyclines. Since cardiotoxicity is a chronic condition, regular long-term exercise is required to effectively mitigate anthracycline-induced myocardial damage to achieve the lifelong protective effect of exercise.

Adherence rates across the studies in this review ranged from 63.2% to 98% for sessions lasting 8 weeks ~ 12 months, and decreased with a longer duration of the intervention. It is significant to find strategies to improve adherence to long-term exercise intervention. Notably, exercise adherence, an element related to the effectiveness of exercise, was not described in two studies within this review [35, 56]. Exercise is generally deemed safe for cancer survivors during and after cancer treatment, and no adverse events were reported in the included studies of this review. However, cancer survivors often experience a variety of acute, chronic, and late side effects of cancer and its treatment, which can create barriers (i.e., side effects, co-morbid conditions and emotional changes) to exercise adherence [19]. Optimal exercise benefits are more likely to be achieved in younger patients [35, 56], because clinical experience suggests that younger patients are more willing to adopt exercise intervention during chemotherapy and have better compliance [5]. To comprehensively understand the effects of exercise on cardiotoxicity, future studies should describe more details (i.e., adherence, barriers, and adverse events) during implementation. Clinicians might play a critical role in assisting BC patients in identifying and overcoming challenges in long-term exercise adhere, thus they could have lifelong benefits. According to the clinical experience of our research team, patients should be provided with education on the benefits of exercise, regular feedback, timely progression or regression, and enhanced supervision.

Although exercise prescriptions used in the included studies are consistent with the current ACSM guideline for cancer survivors [1, 7]. The optimal timing, modality, and intensity of exercise for individuals with BC are still unclear. Regarding the timing of exercise interventions, one study implemented exercise before chemotherapy and nine studies conducted interventions during chemotherapy, which was related to the convenience of availability and adherence monitoring of patients during chemotherapy. Future studies are required to investigate how the timing of exercise (before, during, and after anthracycline exposure) might influence cardiotoxicity outcomes. All studies included in this review focused on aerobic exercise interventions, which demonstrated positive changes in LVEF and cardiorespiratory fitness. These positive changes were also found in interventions combining aerobic and resistance exercise [10]. Resistance exercise, commonly prescribed for improving neuromuscular functions such as muscle mass, strength, and endurance, has also been shown to be safe and beneficial in attenuating various treatment-related adverse effects, such as cancer-related fatigue and diminished physical functioning, and improving health-related quality of life in cancer patients [11, 14]. Traditionally, resistance exercise is prescribed to improve skeletal muscle strength and muscle mass [27, 37], which leads to the optimization of cardiac function and improvement of their daily life (e.g., stair climbing, carrying objects) for BC patients. Resistance exercise can also promote the production of factors that resist inflammation [15], which is considered to be one of the mechanisms of cardiotoxicity [57]. Furthermore, resistance exercise-induced arterial compliance may reduce arterial stiffness by effectively enhancing nitric oxide bioavailability and reducing endothelial senescence [30]. Future studies could explore the effects of resistance exercise or combined exercise in reducing cardiotoxicity.

All studies included in this review used moderate-to-vigorous intensity or HIIT exercise. However, there are certain obstacles in adhering to higher intensity exercise for vulnerable groups such as those who do not often exercise, have significant side effects of chemotherapy, or have underlying diseases. Those people should start exercise at lower intensity and gradually increase the intensity as their body adapt. Future research is needed to explore and directly compare the effects of (1) low-intensity exercise with the same volume as moderate-to-vigorous intensity exercise, and (2) different exercise intensities, in mitigating cardiotoxicity.

The variations in results among the studies in this review are related to differences in exercise prescription elements and differences between subjects across the studies. The reviewed studies encompassed BC patients of different ages (mean age 43.5–52.4 years) or stages (stage I–III). Grouping patients of diverse ages and disease stages raises concerns because potential differences in age and disease severity could influence exercise response. In addition, some studies in this review did not report the dose of anthracyclines received by BC patients, and others reported different doses of anthracyclines, which were known to be associated with cardiotoxicity [48].

For clinicians providing exercise guidance to BC patients receiving anthracycline-based chemotherapy and expressing willingness to engage in exercise training, some special considerations are as follows: (1) patients should perform a supervised moderate-to-vigorous exercise with heart rate and RPE monitored during exercise [52], (2) initiating exercise with a small volume to prevent adverse cardiovascular events at the beginning, then the frequency, intensity, and time of exercise can be incrementally increased based on tolerance. In addition, lymphedema and bone metastases require special attention. Lymph node dissection: patients have a risk of developing lymphedema in the upper limbs, shoulders, and back, and should wear appropriate compression cuffs or garments during resistance exercise [46]. Bone metastases: modalities for exercise should be chosen to avoid direct musculoskeletal loading on metastatic lesions or muscles proximal to these metastatic lesions. Careful attention on balance and safety should be given to reduce the risk of falls and injuries [43]. Patients who are not suitable candidates for resistance or endurance exercise and those with bone pain should be monitored during and after exercise [11].

To better interpret the present results, the following limitations should be acknowledged. First, the systematic review included only ten studies with small sample sizes and inherent risk of bias. Second, some studies lacked the necessary details for quality assessment. Third, the terms ‘anthracyclines’ only focused on doxorubicin, epirubicin, and pirirubicin, commonly used clinically in China, potentially excluding relevant studies. Finally, the large variability among studies (e.g., the timing of exercise interventions, duration of sessions, the dose of anthracyclines, and outcome measures) made result comparison difficult and pooling unsuitable. Therefore, a meta-analysis was not conducted (Table 3).

Table 3 Cardiotoxicity outcomes
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Conclusions

Overall, a limited number of quality-controlled studies suggest that both acute moderate-to-vigorous aerobic exercise and long-term moderate-to-high intensity aerobic exercise (continuous or interval) or a combination of aerobic and resistance exercises could protect against anthracycline-induced cardiotoxicity in BC patients. Despite these findings, the optimal timing, type, and intensity of exercise for preventing cardiotoxicity in individuals with BC remain unclear. Recruiting a large sample of BC patients is challenging in a clinical setting, so studies with well-described procedures and harmonized outcome measures may improve the quality and comparability of evidence. Future clinical studies should prioritize quality control, provide detailed intervention descriptions, coordinate outcome indicators comprehensively, and incorporate long-term follow-up to further investigate the effects of exercise on cardiotoxicity. This provides evidence for guiding clinical staff and patients in implementing exercise to prevent cardiotoxicity.