Effects of exercise interventions on cancer-related fatigue in breast cancer patients: an overview of systematic reviews

Objective This overview of systematic reviews aims to critically appraise and consolidate evidence from current systematic reviews (SRs)/meta-analyses on the effects of exercise interventions on cancer-related fatigue (CRF) in breast cancer patients. Methods SRs/meta-analyses that explored the effects of exercise interventions on CRF in breast cancer patients compared with the routine methods of treatment and care were retrieved from nine databases. The methodological quality of the included SRs was appraised using A MeaSurement Tool to Assess systematic Reviews II (AMSTAR II). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to calculate the grading of outcomes in the included SRs. The exercise type, frequency, duration, and inclusion/absence of supervision were further evaluated with subgroup analyses. The Stata 16.0 software was utilized for data analysis. Results Twenty-nine reviews were included. The overall methodological quality and level of evidence of the included reviews were unsatisfactory, with only three reviews rated as high methodological quality and no review identified as high-quality evidence. Moderate certainty evidence indicated that exercise could improve fatigue in breast cancer patients (SMD = − 0.40 [95%CI − 0.58, − 0.22]; P = 0.0001). Subgroup analysis based on the types of exercise showed that yoga (SMD = − 0.30 [95%CI − 0.56, − 0.05]; I2 = 28.7%) and aerobic exercise (SMD = − 0.29 [95%CI − 0.56, − 0.02]; I2 = 16%) had a significantly better effect on CRF in breast cancer patients; exercising for over 6 months (SMD = − 0.88 [95%CI − 1.59, − 0.17]; I2 = 42.7%; P = 0.0001), three times per week (SMD = − 0.77 [95%CI − 1.04, − 0.05]; I2 = 0%; P = 0.0001), and for 30 to 60 min per session (SMD = − 0.81 [95%CI − 1.15, − 0.47]; I2 = 42.3%; P = 0.0001) can contribute to a moderate improvement of CRF. Supervised exercise (SMD = − 0.48 [95%CI − 0.77, − 0.18]; I2 = 87%; P = 0.001) was shown to relieve CRF. Conclusion Exercise played a favorable role in alleviating CRF in breast cancer. Yoga was recommended as a promising exercise modality for CRF management in the majority of the included studies. Exercising for at least three times per week with 30 to 60 min per session could be recommended as a suitable dosage for achieving improvement in CRF. Supervised exercise was found to be more effective in alleviating CRF than unsupervised exercise. More rigorously designed clinical studies are needed to specify the exact exercise type, duration, frequency, and intensity to have an optimal effect on CRF in breast cancer patients. Trial registration ClinicalTrials.gov Identifier: CRD42020219866. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-022-07389-5.


Introduction
The Global Burden of Disease Study 2020 [1] indicated that breast cancer remains the leading cancer diagnosis among females [2]. Although survival rates of breast cancer are improving, patients still experience a series of adverse effects caused by cancer and its related treatment, such as depression, fatigue, sleep disturbance, and bone marrow suppression [3,4]. Cancer-related fatigue (CRF) is Hong-Juan Zhou and Tao Wang have contributed equally to this work and share the first authorship. one of the most familiar and often overlooked symptoms [5], referring to a general, persistent, and subjective feeling of fatigue caused by cancer or relevant treatment that cannot be improved by sleep or rest [6] and may persist for months or even years [7]. The incidence of CRF in breast cancer patients is higher than that in other types of cancers [1], among which up to 33% of patients experience fatigue five years after the end of breast cancer treatment [8]. CRF adversely affects breast cancer patients in multiple aspects [9], which severely not only affects their quality of sleep but also prolongs their length of hospital stay and can result in a reduction of physical, mental, and emotional function and poor quality of life [10].
Currently, some pharmaceutical agents such as stimulants, antidepressants, acetylcholinesterase inhibitors, and corticosteroids have been recommended for CRF management in breast cancer patients [10] However, those pharmacological approaches were reported to be associated with a range of undesirable side effects such as tumor protection [11], decreased appetite [12] and venthrombotic events [13,14]. The unclear pathophysiological mechanism of CRF also makes it difficult to develop tailored pharmacological interventions for CRF management [6]. Non-pharmacological interventions such as exercise interventions [10], mindfulness-based decompression therapy [15], and cognitive behavioral therapy [16] have been explored as adjuvant approaches to pharmacological interventions to alleviate CRF. Exercise interventions refer to a physical activity treatment that is planned, structured, and repetitive and have a final or an intermediate objective of improving or maintaining physical fitness, which includes running, aerobics, tai chi, yoga, and resistance exercise [17]. Exercise interventions have been commonly utilized and recommended as an effective intervention for the alleviation of CRF by the American Society of Clinical Oncology (ASCO) [18] and Exercise and Sports Science Australia (ESSA) [19]. In addition, the Japan Breast Cancer Society (JBCS) [20], the German Gynecological Oncology Group (AGO) [21], and a previous systematic review [22] found that exercise interventions are an effective, low-risk modality for breast cancer patients in reducing morbidity and improving body functions and quality of life. However, most of the literature on exercise interventions [18,19,21] have not clearly stated the type, frequency, and duration of exercise for practice in breast cancer patients with CRF, leading to a gap in developing personalized and evidence-based exercise intervention protocols tailored to patients' health conditions and needs.
With the rapid development of evidence-based medicine in the field of cancer supportive care, an increasing body of systematic reviews (SRs)/meta-analyses have provided much evidence on using exercise interventions for CRF management in breast cancer patients, but their conclusions were inconsistent [23,24] and the methodological quality varied across studies, which are barriers to the transformation of research evidence to practice and the application of clinical decision-making.
To our knowledge, no overviews of systematic reviews on the effects of exercise interventions on CRF in breast cancer patients have been conducted so far. Thus, the aim of this overview was to critically appraise and consolidate evidence from current SRs/meta-analyses on the effects of exercise interventions on CRF in breast cancer patients. Specifically, the study objectives were as follows: (1) to identify the effects of exercise interventions on relieving CRF in breast cancer patients; (2) to assess the methodological quality of as well as the level of evidence from current SRs/metaanalyses on the effects of exercise interventions for breast cancer patients with CRF; and (3) to identify the optimal modality, duration, and frequency of exercise interventions for CRF management in breast cancer patients.

Methods
This overview of systematic reviews was reported in accordance with the Preferred Reporting Items for OoSRs (PRIOharms) checklist and the Preferred Reporting Items for OoSRs (PRIO) checklist. The protocol has been registered with PROSPERO (CRD42020219866). A pre-print version of this manuscript is also available at https:// www. resea rchsq uare. com/ artic le/ rs-13761 71/ v1

Data sources and searches
This overview included SRs/meta-analyses that focused on the effects of exercise therapy on CRF in breast cancer patients. Relevant SRs/meta-analyses were comprehensively searched until September 2021 through the following data sources: (1) PubMed, Cochrane Library, Excerpta Medica Database (EMBASE), Web of Science, China National Knowledge Infrastructure (CNKI), China Biology Medicine Disc (CBMdisc), Wan Fang Data, and China Science and Technology Journal Database, and The Lancet; (2) references of the included SRs/metaanalyses; and (3) grey literature from the National Institute for Health Research (NIHR) Centre, such as unpublished manuscripts and published reports. The search terms included "breast neoplasms", "exercise therapies", "fatigue", "systematic review", and "meta-analysis". The search procedure in the databases above followed the text string "((Breast neoplasms) OR (Breast tumor) OR (Mammary cancer) OR (Breast cancer) OR (Carcinoma breast)) AND (Exercise OR (Physical activity) OR (Physical exercise) OR (Exercise training) OR (Exercise therapies)) AND (Fatigue OR CRF) AND ((Systematic review) OR meta-analysis)". Taking PUBMED and EMBASE as examples, a full search strategy was summarized in Supplementary file A.

Inclusion and exclusion criteria
The inclusion criteria were developed in accordance with the Population, Intervention, Comparator, Outcome, Study (PICOS) framework: (1) types of studies: SRs/ meta-analyses of randomized controlled trials (RCTs) that were published in either English or Chinese; (2) types of populations: adult breast cancer patients [5] with CRF [25], regardless of stages of cancer, age, gender, and nationality; (3) types of interventions: exercise interventions [17], such as aerobic exercise, tai chi, yoga, resistance training, dancing, and walking; (4) types of comparison: routine methods of treatment and care with no active exercise components or any other types of active treatments; and (5) types of outcomes: CRF as the primary outcome as measured by valid assessment tools, such as the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale, the Multidimensional Fatigue Inventory (MFI), or the Brief Fatigue Inventory (BFI). Exclusion criteria were the following: (1) proposals of SRs or meta-analyses; (2) study population was breast cancer mixed with other diseases or complications; (3) conference abstracts; (4) full text was not available after multiple search methods, including contacting the author.

Literature screening and data extraction
Duplications were identified and removed via reference management software (NoteExpress). The titles and abstracts of the rest of the SRs/meta-analyses were screened by two reviewers (HJZ and YZX) independently to determine the potentially eligible SRs/meta-analyses. Full texts of the potentially eligible SRs/meta-analyses were further screened and examined by the same two reviewers. If there were duplications, the latest version of the SR or meta-analysis was selected. Eligible SRs/meta-analyses were finally included after discussion between the reviewers. Any contradiction regarding study inclusion was resolved through consultation or arbitration by an experienced third reviewer (TW). Data from the included SRs/meta-analyses were extracted using a data extraction form predesigned by one reviewer (HJZ), which was verified by another reviewer (YZX). Disagreements between the two reviewers regarding data extraction were discussed by involving a third reviewer (TW). The extracted data included the author, publication year and country, number of studies and sample size of the participants, types of intervention and control, quality assessment (whether the included SRs/ meta-analyses evaluated the quality of their included studies and the tools used for the quality appraisal), measurement tools, main conclusion, and whether it included a meta-analysis. Moreover, relevant data for subgroup analysis including the exercise type, frequency, duration, and inclusion/absence of supervision were extracted and verified. The study selection process is presented in Fig. 1.

Quality appraisal of the included reviews
The methodological quality and the level of evidence of the included SRs/meta-analyses were independently assessed by two reviewers (HJZ and YZX) with two tools (see the "Methodological quality" and the "Evidence quality" sections). The final assessment results were cross-checked. Any disapprovals were discussed and decided by involving a third reviewer (JYT).

Methodological quality
A Measurement Tool to Assess systematic Reviews II (AMSTAR II) was used to comprehensively assess the methodological quality of the included SRs/meta-analyses [26], which is presently the most widely used methodological quality assessment tool [27,28]. The AMSTAR II includes 16 items (www. amstar. ca), each of which can be answered "yes" or "no", and some of the items can be answered "partially yes" [27,28]. Seven items, including items 2, 4, 7, 9, 11, 13, and 15, that are considered to critically affect the validity of the included reviews and its conclusions are generally recommended as critical items [26]. The methodological quality of the included reviews was rated using the following criteria: (1) high quality: no or only one non-critical item flaw; (2) moderate quality: more than one non-critical item flaw but no critical item flaws; (3) low quality: one critical item flaw, with or without a non-critical item flaw; and (4) critically low quality: more than one critical item flaw, with or without a non-critical item flaw [26,27,29].

Evidence quality
Two reviewers (HJZ and YZX) used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the level of evidence of the included SRs/meta-analyses in five aspects, including limitations, inconsistencies, indirectness, imprecision, and publication bias [30]. Disagreements were addressed by involving a third author (TW) until consensus was achieved. For each aspect, the evidence was graded as high, moderate, low, or extremely low. Detailed grading criteria were as follows [31]: (1) high-level evidence: not downgraded, which represents the true effect estimates; (2) moderate-level evidence: downgraded one grade, which indicates that the true value is possible to come near to the estimate but is substantially different; (3) low-level evidence: downgraded two grades, which indicates that there is a significant difference between the actual and estimated values; and (4) extremely low-level evidence: downgraded three grades, which indicates that the true value is likely to be very different from the estimated value.

Data analysis
The characteristics of the included SRs, including author, publication year and country, number of studies and sample size, types of intervention and control, and main findings (i.e., effects of the exercise on CRF), are summarized in Table 1. The overlap across the included studies (only RCTs) of the analyzed SRs/meta-analyses was estimated using the corrected covered area (CCA) [32]. A lower CCA value indicated a lower likelihood of overlaps [32]. A CCA value of 5% or below was regarded as a "slight overlap", 6-10% as a "moderate overlap", 11-15% as a "high overlap", while above 15% was regarded as a "very high overlap" [33]. For continuous variables, mean differences (MD) or standardized mean differences (SMD) with 95% confidence intervals (CI) was used for meta-analysis and effect size calculation (a P value of ≤ 0.05 was considered statistically significant). For continuous variables, the random-effects model was used to calculate the number of participants and RCTs included in the meta-analyses and to summarize the effect size [with 95% confidence intervals (CI) and P values ≤ 0.05 considered significant]. According to Cohen [33], 0.2 is considered a small effect, 0.2 to 0.8 a medium effect, and 0.8 or above a large effect. We also extracted and analyzed the data of included meta-analyses to better illustrate the effects of the duration of the interventions, exercise type, frequency, and duration of each session on CRF of breast cancer patients. Because of the lack of relevant data, direct comparisons between different interventions were impossible. I-square (I 2 ) statistics were used to measure the heterogeneity of the included SRs/meta-analyses and explain the various thresholds by effect size and direction and the P-value from Cochran's Q test [34]. An I 2 value > 50% is regarded as a substantial level of heterogeneity [34]. Sub-group analyses are planned based on exercise type, frequency, and duration, and inclusion/absence of supervision. Statistical analysis was conducted with the Stata version 16.0 software.
Adapted from: Preferred reporting items for overviews of systematic reviews [35].

Identification of the included reviews
A total of 369 records were searched, of which 135 were excluded due to duplication and 193 were screened by title or abstract and deemed irrelevant to the topic. Of the remaining 41 records, 12 were excluded after assessing the full text for eligibility. Twenty-nine SRs/meta-analyses [23,24, were finally included in the overview. The literature retrieval and selection process are shown in Fig. 1

Methodological quality
Regarding the methodological quality of the included SRs/ meta-analyses, three reviews [40,45,53] were evaluated as high quality, 21 reviews [23, 24, 36, 37, 39, 41, 43, 44, 46-48, 50-52, 54, 56-58, 60-62] were rated as low quality, and the remaining five reviews [38,42,49,55,59] were assessed as critically low quality. Specifically, the critical items that had an effect on the quality of the reviews were item 2 (only five reviews [45,46,50,55,61] were evaluated as "yes" due to registered proposals in the early stage, and the remaining reviews only provided the research methods so they were assessed as "partly yes", which means that the research methods could not be compared with the registered proposals approved by official organizations and may have caused a risk of bias), item 4 (whether to search for grey literature and counsel experts in the relevant field was not mentioned in 18 reviews [23, 24, 36, 37, 39, 43-45, 48-51, 54-57, 59, 60], suggesting that there may have been incomplete retrievals in the above, which may have led to results and conclusion errors), and item 7 (apart from three reviews [40,45,53], the list of excluded references and the causes for their exclusion were not provided and illustrated in the other reviews, which reduced the rigor of the study and the reliability of the results). In addition, non-critical item 10 also affected the methodological quality results since none of the 29 reviews reported the funding of their included RCTs, which indicated uncertainty about the possibility of commercial funding interference that might have made study results favorable to the commercial funder. All the reviews described the basic characteristics of and were able to scientifically discuss and analyze the included studies. Specific methodological quality assessment results are shown in Table 2.

Table 2
Methodological quality of the 29 SRs/meta-analyses Q1. "Did the research questions and inclusion criteria for the review include the components of PICO?"; Q2. "Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?"; Q3. "Did the review authors explain their selection of the study designs for inclusion in the review?"; Q4. "Did the review authors use a comprehensive literature search strategy?; Q5. "Did the review authors perform study selection in duplicate?"; Q6. "Did the review authors perform data extraction in duplicate?"; Q7. "Did the review authors provide a list of excluded studies and justify the exclusions?"; Q8. "Did the review authors describe the included studies in adequate detail?"; Q9. "Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?"; Q10. "Did the review authors report on the sources of funding for the studies included in the review?"; Q11.
"If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?"; Q12. "If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?"; Q13. "Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?"; Q14. "Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?"; Q15. "If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?"; Q16. "Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?" (

Data synthesis and meta-analysis
The overall effects of the exercise interventions in the 29 SRs/meta-analyses indicated that exercise had a moderate effect on the reduction of fatigue in the breast cancer patients in the intervention groups (SMD = − 0.40 [95%CI − 0.58, − 0.22]; P = 0.0001) (see Fig. 2). However, due to the high heterogeneity among the 29 reviews (I 2 = 95.4%), the overall effect size might be affected by various existing moderating variables. Therefore, the standardized mean differences of the moderating variables were further analyzed to determine the most effective intervention modalities based on the exercise type, frequency, intervention duration, and inclusion/absence of supervision in the intervention protocol. These results are shown in Table 4.

Exercise type
Seven exercise types were reported in the 29 SRs/metaanalyses, including aerobic exercise, resistance exercise, yoga, mind-body exercise (Pilates and gymnastics), combination exercise (home-based exercise and combined Table 3 Evidence quality of the 29 SRs/meta-analyses 1 The included reviews were biased in terms of randomization, allocation concealment, and blinding method; 2 the confidence intervals of different studies overlapped greatly, and the combined result of heterogeneity was large (> 80%, decreased by two grades); 3 significant benefits or harms were included in the confidence interval (RR < 0.75 or RR > 1.25 were the criteria); 4 whether gray literature and manual retrieval were included was not stated in the review; 5 the number of included reviews was small and all positive, so publication bias should be considered; 6 the invalid value (RR = 1.0) was included in the confidence interval; 7 only one study was included, so heterogeneity could not be measured; 8 most of the included studies were of moderate methodological quality; 9 incomplete reports and outcome events and selective outcome bias (including adverse reactions, negative results) were not presented or explained. The rating standard of 1 to 9 is referenced in Sects. 4

Duration of the intervention
Intervention duration among the included studies were categorized as: less than 2 months, 2 to 6 months, and more than

Frequency of exercise
The frequency of exercise included in the 29 SRs/metaanalyses can be categorized as 3 ≤ times per week and > 3 times per week, and the heterogeneity of the combined effect size between the two types was 95.3% (P = 0.0001), suggesting that the breast cancer patients' CRF was affected by the frequency of exercise.

Discussion
In this overview, we assessed the methodological and evidence quality of the included SRs/meta-analyses, and additional meta-analyses were performed for the 29 reviews to identify the effects of exercise on CRF in breast cancer patients. The intervention duration, exercise type, duration, and frequency, and whether the exercise intervention was supervised had varying degrees of influence on the effects of exercise on CRF. However, the unsatisfactory methodological quality and level of evidence of the included reviews might affect the reliability of the overview findings on the effects of exercise interventions on CRF in breast cancer survivors, which warrants a prudent interpretation of the study results. Findings from this study suggested that exercise could be introduced as an effective intervention for CRF management in breast cancer patients. The findings supported the recommendations proposed in some clinical practice guidelines [18,19,68], in which exercise was rated and recommended as a beneficial approach to alleviating CRF. However, these guidelines [18,19,68] did not mention specific exercise plans. To help further detail the recommendations in the guidelines and facilitate healthcare professionals' decision-making, subgroup analyses based on the type, frequency, duration, and intensity of exercise were conducted in this study. For exercise type, the study findings suggested that aerobic exercise and yoga were commonly recommended as promising approaches to improving CRF, which is consistent with Lin's study [69], indicating that yoga can relieve patients' tension and anxiety and help decrease their fatigue. Yoga is a convenient, easy-to-practice, and safe exercise modality that has been recommended as Grade I evidence by the U.S. National Comprehensive Cancer Network Guidelines [70]. The subgroup analyses results on the duration of exercise indicated that patients who had exercised for more than 6 months achieved the best improvement in fatigue. Our study findings showed that exercising more than three times per week for 30 to 60 min per session was beneficial for CRF alleviation, which is in line with previous research findings [71][72][73]. The included SRs/meta-analyses also indicated that patients should be encouraged to participate in supervised exercise when conditions permitted, which might lead to a better CRF outcome.
Although quantitative synthesis indicated that exercise interventions can alleviate CRF in breast cancer patients, the findings should be interpreted with caution given the unsatisfactory methodological quality (e.g., lack of reporting a list of exclusion studies and unclear funding resources) and level of evidence identified in the included reviews. For future studies, a list of excluded studies should be provided as an independent appendix to journals to facilitate readers' understanding of the data selection process and further improve the reliability of the review findings [74]. Moreover, funding sources should be clearly declared in future publications to help readers determine whether funding bias existed. To achieve a comprehensive literature search, future systematic reviews are suggested to identify potential studies by searching not only the commonly used databases but also gray literature retrieval websites to minimize publication bias, for example, Greynet International (http:// greyn et. org/), the British Library (http:// www. b1. uk), and other free grey literature sites such as PLoS. Conference abstracts, book chapters, academic theses and dissertations should also be sources of gray literature. In order to further improve the level of evidence of the included SRs, more original studies with rigorous study designs and detailed descriptions of the intervention protocols (e.g., type, frequency, intensity, and duration of the exercise) are necessary. Nevertheless, there is a need to acknowledge that the results of the unsatisfactory methodological quality of the included SRs may have been related to the selection of the quality appraisal tool. In this overview, nine of the included SRs were published before 2017, while the tool that we used for the quality appraisal (i.e., AMSTAR II) was also updated in 2017, which is an issue that needs to be considered for future overviews.

Study limitations
This overview has some limitations. Suboptimal methodological quality of some of the includes reviews (e.g., lack of registered protocols, unclear descriptions of data sources) may affect the strength of the evidence. language bias is possible given that only reviews published in Chinese and English were included. Due to the limited number of included reviews, within each current subgroup analysis, further subgroup analyses based on the intervention "dose" (e.g., intervention duration and frequency of each type of exercise intervention) were not conducted, which might, to some extent, limit the generalizability of the review findings to clinical practice.

Conclusion
Findings from this overview suggested that yoga and aerobic exercise with a long-term practice duration (over 6 months) might benefit CRF alleviation in breast cancer patients. Exercising for at least three times per week for 30 to 60 min per session might be an appropriate dose for alleviating CRF in breast cancer patients. Although existing evidence indicated that exercise interventions have a positive impact on CRF in breast cancer patients, the results should be interpreted with caution due to the limited quantity and unsatisfactory methodological quality and level of evidence of the included SRs/ meta-analyses. More rigorously designed large-scale RCTs are needed to provide more robust evidence to specify the exact exercise type, duration, frequency, and intensity to have an optimal effect on CRF in breast cancer patients.
Author contribution HJZ and TW contributed to study conception and design, data extraction, analysis and interpretation, manuscript drafting and revision. JXC and JYT contributed to study conception and design, data interpretation, and manuscript revision. YZX, LJD, YNC, and CW supported study design, data extraction and/or double check, and manuscript revision. All authors approved the submitted version.
Funding Open Access funding enabled and organized by CAUL and its Member Institutions Data availability All authors agreed that the data can be made public and used.
Code availability Not applicable.

Declarations
Ethics approval Not applicable.

Consent to participate Not applicable.
Consent for publication All authors agree that the data can be made public.

Conflict of interest The authors declare no competing interests.
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