The Effects of Martial Arts on Cancer-Related Fatigue and Quality of Life in Cancer Patients: An Up-to-Date Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

Background: To evaluate and synthesize the existing evidence of the effects of practicing martial arts by cancer patients and cancer survivors in relation to overall quality of life (QoL) and cancer-related fatigue (CRF). Methods: Randomized controlled trials (RCTs) from 1 January 2000 to 5 November 2020 investigating the impact of martial arts were compared with any control intervention for overall QoL and CRF among cancer patients and survivors. Publication quality and risk of bias were assessed using the Cochrane handbook of systematic reviews. Results: According to the electronic search, 17 RCTs were retrieved including 1103 cancer patients. Martial arts significantly improved social function, compared to that in the control group (SMD = −0.88, 95% CI: −1.36, −0.39; p = 0.0004). Moreover, martial arts significantly improved functioning, compared to the control group (SMD = 0.68, 95% CI: 0.39–0.96; p < 0.00001). Martial arts significantly reduced CRF, compared to that in the control group (SMD = −0.51, 95% CI: −0.80, −0.22; p = 0.0005, I2 > 95%). Conclusions: The results of our systematic review and meta-analysis reveal that the effects of practicing martial arts on CRF and QoL in cancer patients and survivors are inconclusive. Some potential effects were seen for social function and CRF, although the results were inconsistent across different measurement methods. There is a need for larger and more homogeneous clinical trials encompassing different cancer types and specific martial arts disciplines to make more extensive and definitive cancer- and symptom-specific recommendations.


Introduction
In 2020, 19.3 million new cancer cases were diagnosed globally, where breast, lung, and prostate were the most frequent type of malignancies [1]. Cancer is the second cause of mortality worldwide after ischemic heart disease, with 8.97 million deaths, and it is predicted to become the leading cause of death by 2060 with approximately 18.63 million deaths [2]. Improvements in diagnostics and treatments have increased the survival rate of the most prevalent cancers in developed countries [3]. As of January 2019, there were an estimated 16.9 million cancer survivors in the United States. The number of cancer survivors is projected to increase to 22.2 million by 2030 [4]. Furthermore, the burden of cancer incidence and survivors continues to increase in low-and middle-income countries as well [5].
The physical, emotional, and financial impacts of cancer diagnosis and its management, along with the side effects of treatments, normally have long-term consequences

Eligibility Criteria
Following the PICO principles (patient, intervention, control, and outcomes) [29], the inclusion criteria were: (a) randomized controlled trials (RCTs) that investigated cancer patients with the primary intervention of martial arts and compared with any comparator for QoL and fatigue; (b) original articles in peer reviewed journals; and (c) eligible studies in English. Non-randomized or any other trials rather than RCTs, non-English RCTs, trials that did not assess the QoL or CRF, non-human studies, studies with no full text, single arm studies, and reviews and secondary works were excluded from this study.

Screening of Results
Initially, two authors (D.S. and S.S.) screened all titles and abstracts using the inclusion criteria. Subsequently, they coded the abstracts as "yes" for inclusion in full text-review and "no" for excluding the abstract. If both authors coded an abstract as "yes", they were considered for full text review. If both were coded as no, they were excluded. For abstracts where there were discrepancies, the decision was made through either mutual discussion or with the help of a third reviewer (S.A). In the next stage, a full text review of all articles was performed against the inclusion criteria. Following that, the full text was read carefully for eligibility criteria.

Data Extraction
The extracted data were divided into three categories. The first one was baseline characteristics, including author name, country, sample size, age, gender, marital status, and cancer treatment (surgery, chemotherapy, and radiation, as well as author name). The second contained the key characteristics of the included studies, such as country, cancer type, the timing of intervention, duration of the intervention (sessions, frequency, and period), and outcomes. The last one was outcome measures, including: (I) quality of life by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [30], Functional Assessment of Cancer Therapy-General (FACT-G) [31], and The Short-Form 36 (SF-36) [32]; and (II) fatigue by The Brief Fatigue Inventory (BFI) [33], Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) [34], and the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) [35,36].

Quality Assessment
The quality of this meta-analysis was judged based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) guideline [37]. GRADE is a transparent and reproducible system that allows the researcher to grade the quality and certainty of the evidence. Based on the quality of the evidence, the level of confidence was assessed that an estimate of the effect could be correct. Following that, two researchers (D.S. and S.S.) evaluated each study. An overall quality score was assigned to each study, ranging from high, moderate, low, to very low grade of evidence. These grades mean the grade certainty/quality of the evidence of the studies. If there was any uncertainty between the two independent researchers, a third researcher (S.A.) evaluated the evidence to obtain the conclusion. The risk of bias of the included studies was also evaluated using the Cochrane's risk of bias tool [38]. This tool was used to evaluate the RCTs regarding randomization tools; concealment of allocation; blinding of assessors, participants, and personnel; and selective reporting, attrition, and other biases. No paper evaluated was excluded from the results because of low quality or high risk of bias.

Statistical Analysis
The data were analyzed as a standardized mean difference (SMD) and 95% confidence interval (CI) under a random-effects model using the inverse-variance method in the Review Manager Software (version 5.3, The Nordic Cochrane Centre, Copenhagen, Denmark) package. The heterogeneity was considered when I-square test (I2) and Chi-Square P were more and less than 50% and 0.1, respectively [38][39][40].

Search Results and Summary of Included Studies
Our electronic search retrieved 801 records, 744 of which underwent title and abstract screening after removal of duplicates. Out of these, 38 records progressed for full-text screening, and 21 of them were excluded from the study. Finally, 17 RCTs were included for further analysis [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Figure 1 illustrates the study selection process. These studies included a total of 1103 cancer patients who were divided into control groups (n = 546) and treatment groups with martial arts (n = 557). The mean age of the included cancer patients was 58 ± 3.1 years. The baseline characteristics and summary of the included studies are shown in Tables 1 and 2.

Description of Intervention
Most of the studies analyzed martial arts, such as Tai Chi and Qigong, in one of the comparator arms. They compared the effect of martial arts with standard care, control, psychosocial support, strength training, and even dance. Tai Chi is a traditional Chinese martial art used for defense as well as for its health benefits [58]. Tai Chi and its derivates (Tai Chi Chih, Tai Chi Chuan, Tai Chi Qi Qong, and Tai Chi Easy) are efficient complementary approaches used in improving wellbeing and fatigue [59]. Qigong is considered a form of Chinese martial arts with benefits in immune regulation, balancing the "qi", and strengthening muscles and tendons [60]. These traditional martial arts forms involved meditation, breathing techniques, coordinating the movements, and relaxation exercises [61]. Another martial art used in the clinical trials was Kyoshu Jitsu. This martial art focuses on pressure points for self-defense as well as its benefits for healing [53]. The majority of the studies analyzed for this meta-analysis focused on breast cancer. Only a small number of studies considered other tumor types, such as lymphoma, ovary, colon, lung, prostate, and nasopharyngeal cancer (Tables 1 and 2). Int. J. Environ. Res. Public Health 2021, 18, x FOR PEER REVIEW personnel; and selective reporting, attrition, and other biases. No paper excluded from the results because of low quality or high risk of bias.

Statistical Analysis
The data were analyzed as a standardized mean difference (SMD) a dence interval (CI) under a random-effects model using the inverse-varia the Review Manager Software (version 5.3, The Nordic Cochrane Centre Denmark) package. The heterogeneity was considered when I-square tes Square P were more and less than 50% and 0.1, respectively [38][39][40].

Search Results and Summary of Included Studies
Our electronic search retrieved 801 records, 744 of which underwent tit screening after removal of duplicates. Out of these, 38 records progresse screening, and 21 of them were excluded from the study. Finally, 17 RCTs for further analysis [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. Figure 1 illustrates the study selection process included a total of 1103 cancer patients who were divided into control gr and treatment groups with martial arts (n = 557). The mean age of the in patients was 58 ± 3.1 years. The baseline characteristics and summary of the ies are shown in Tables 1 and 2.    Values reflect number or mean (standard deviation); 1 median (range); 2 standard error of the mean.

Quality Assessment of the Included Studies
An overall moderate risk of bias was found in selection, reporting, and other bias. Furthermore, performance, detection, and attribution biases were judged as having a high risk of bias. Detailed risk of bias summary and graph are shown in Figures 8 and 9.

Quality Assessment of the Included Studies
An overall moderate risk of bias was found in selection, reporting, and other bias. Furthermore, performance, detection, and attribution biases were judged as having a high risk of bias. Detailed risk of bias summary and graph are shown in Figures 8 and 9.

Discussion
Cancer patients are encouraged to participate in an exercise program during and following treatment [15]; however, there are still gaps related to regimes and forms of exercise appropriate for each individual. Improvement of QoL in cancer patients and management of their CRF have gained importance in recent years to enhance the general wellbeing of cancer patients and ameliorate the side effects of cancer therapies [62]. Multiple studies have covered the role of physical activity and exercise studying their effects on QoL and CRF of cancer patients during and after standard cancer treatment [63]. In this regard, martial arts have gained popularity in western countries as a new form of physical activity. In addition, martial arts combine musculoskeletal conditioning and training in cognitive skills, together with breathing exercises, which are typically delivered in group training sessions that also provide social support for cancer patients [24]. The results of the benefits of martial arts on QoL and CRF have been reported in several studies with a limited number of participants covering limited martial arts disciplines and cancer types [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57].
This is the first systematic review and meta-analysis grouping martial arts and their effects on QoL and CRF as a primary intervention in cancer patients during and after treatment, regardless of the cancer type and treatment received. The data extracted from different studies of cancer patients practicing martial arts show a significant improvement of social function measured through SF-36 and a significant reduction of CRF measured using FACIT-F and MFSI-SF. The effects reported on social function by Campo et al. [41] and Sprod et al. [52] were positive but modest in their studied population. Social function is an important dimension for cancer patients since the disease and its treatment can affect diverse aspects, such as marital relationships, parental responsibilities, work environment, and social activities [64]. Regarding the significant reduction of CRF using the FACIT-F assessment scale, Oh et al. found a significant difference in their study of breast cancer survivors practicing Tai Chi Chuan for 60 min, 3 times per week, for 12 weeks [51]. Mustian et al. found a non-significant positive effect on fatigue measured by the same tool in breast cancer survivors practicing Tai Chi, possibly due to the small number of participants in their studies [48,49]. Considering the CRF measured through the MFSI-SF scale, Zhou et al. found a significant reduction of CRF in nasopharyngeal patients undergoing radiotherapy after practicing Tai chi for 60 min, 5 times per week, for 8 months [57]. In line with these results, another study found that lung cancer patients who followed a Tai Chi program of 60 min every other day for 12 weeks and underwent chemotherapy had a significant reduction of CRF, compared to those who were in a low-impact exercise program. This reduction was observed after 6 and 12 weeks of the program initiation [56]. Other outcomes analyzed in this meta-analysis did not reach a significant difference, even after heterogeneity was solved.
In the articles analyzed by our team, most of the patients in the trials were breast cancer patients who finished their treatment and started a program for physical activity or are undergoing chemotherapy or radiotherapy. The trials analyzed had small batches of patients enrolled and the population was too heterogeneous for us to be able to conclude about the optimal load and specifics of exercises. Furthermore, most of the martial arts sessions presented ranged from a period of 3 weeks to 24 weeks of practice, with a normal session being 40-60 min. The schedule of the sessions was from 2 weekly classes to 12 weekly classes depending on the type of martial arts. Taking into account the results of the analyzed trials, we consider that practicing martial arts is safe and recommended for patients undergoing treatment as well as for cancer survivors at the completion of their oncological therapy Other meta-analyses have reviewed the effects of martial arts in QoL and/or CRF [64,65]. Tao et al. in a study analyzed the effects of acupuncture, Tuina, Tai Chi, Qigong, and traditional Chinese music therapy on symptom management and QoL in cancer patients. According to the results, Tai Chi and Qigong had no effect on QoL or CRF in breast cancer survivors [65]. Wayne et al. also analyzed the effects of Tai Chi and Qigong in cancer survivors, finding a significant improvement in CRF, sleep difficulty, depression, and overall QoL, as well as a non-significant trend in pain control [66].
Albeit all the evidence points to the benefits of physical activity in cancer patients, these changes to increase their physical activity seem harder to implement by cancer patients [67]. Martial arts have been demonstrated in several studies to be a feasible option for cancer patients [41,53]. Moreover, they may reduce some of the negative effects of cancer and improve physical as well as psychological health [68]. This study may help healthcare professionals involved in cancer management and patients decide to choose an activity to improve QoL and reduce CRF. Martial arts offer a wide variety of disciplines with different levels of intensity that would allow cancer patients the possibility of deciding the activity that fits better with their needs.
Different guidelines covering CRF, such as NCCN (National Comprehensive Cancer Network) guidelines, focused on CRF [15], and the guidelines from the Oncology Nursing Society "Putting Evidence into Practice" [69] proposed exercise and physical activity as a first-line intervention for CRF. Other interventions, in addition to erythropoiesisstimulating agents and low-dose dexamethasone, do not offer effectiveness reducing CRF in patients with cancer [69]. The beneficial effects of martial arts in QoL of cancer patients can be due to the relaxation response and the immunomodulatory [50,70] and hormonal effects [71]. A recent meta-analysis has shown that Tai Chi has an impact on reducing cortisol levels in breast cancer survivors. The same study showed an impact on physical and mental health, improving limb-muscular function and promoted sleep [72].
There is some evidence showing that CRF and QoL are not improved only by physical exercises [73,74], supporting the concept that a more holistic approach should be considered in order to benefit these outcomes in cancer patients. Adverse effects due to martial arts practice did not exist in several studies [42,49,51].
Meta-analyses allow overcoming several limitations. First, pooling the data from different studies allows correcting the statistical limitation of the small sample data of some of the analyzed studies. Another strength is that meta-analyses allow detecting the heterogeneity existing in different studies that used martial arts as a primary intervention in cancer patients. It also helps settle the effect from conflicting results coming from different studies.
Regarding the limitations of this study, one can refer to the analysis of only studies that were published in English. This fact excludes the articles written in other languages that could represent the evidence better and make more general conclusions. Second, the diversity of the outcomes measured in the studies analyzed in this meta-analysis made the task of comparison arduous. Future studies should report outcomes in a more homogeneous way in order to be able to pool all available data. Another limitation is that the majority of the studies analyzed were performed on breast cancer survivors, limiting the conclusions drawn in this study to this group of patients. Accordingly, future studies involving the investigation of the effects on QoL and CRF of martial arts in cancer patients should cover other cancer types. In that way, it would be possible to stratify the results by cancer types and other variables, such as age or other interesting conditions, including gender or grade of disability, which could help tailor the interventions to the patients' needs. In addition, the control groups analyzed were very heterogeneous, and this could be a source of heterogeneity of this study. Another limitation comes from the fact that the analyzed studies covered broad inclusion criteria related to how fatigue was evaluated in those patients enrolled. Finally, some limitations are due to the sample size of the studies and the fact that the patients in some cases were not homogenously under cancer treatment, limitations that are intrinsic to the scarce available data in this regard.
Future studies should address the limitations existing in previous trials. Sample size was an issue in several trials, not providing enough statistical power to draw significant observations. Furthermore, martial arts should be studied in more cancer types, and patients should be stratified in order to be able to extract cancer-and population-specific conclusions. Moreover, trials should try to overcome a common issue where neither the participants nor the instructors or investigators were blinded to the condition against drug trial recommendations. Another limitation was related to the selection bias found in several of the analyzed studies. Longer intervention periods should be followed in order to see if the interventions have effects on cancer survivors.

Conclusions
The results of this systematic review and meta-analysis reveal that the effects of practicing martial arts on CRF and QoL in cancer patients and survivors are inconclusive. Although some potential effects were seen for social function and CRF, the results are inconsistent across different measurement methods. Therefore, larger and more homogeneous clinical trials encompassing different cancer types and specific martial arts disciplines are needed before definitive cancer-and symptom-specific recommendations can be made. Funding: There is no financial support for this study.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data that support the findings of this study are available on request from the corresponding author.      Figure A3. Results of SF-36 after sensitivity analysis. Figure A3. Results of SF-36 after sensitivity analysis. Figure A3. Results of SF-36 after sensitivity analysis. Figure A4. Results of BFI after sensitivity analysis. Figure A5. Results of MFSI-SF after sensitivity analysis. Figure A4. Results of BFI after sensitivity analysis. Figure A3. Results of SF-36 after sensitivity analysis. Figure A4. Results of BFI after sensitivity analysis. Figure A5. Results of MFSI-SF after sensitivity analysis. Figure A5. Results of MFSI-SF after sensitivity analysis.