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Address correspondence to: Silvia Belloni, RN, MSN, PhD, Educational and Research Unit, Humanitas Research Center–IRCCS, Via Manzoni 56, 20089 Rozzano (MI), Italy.
Health Professions Research and Development Unit, IRCCS Policlinico San Donato, San Donato Milanese, Milan, ItalyDepartment of Biomedical Sciences for Health, University of Milan, Milan, Italy
Evidence supporting complementary and integrative medicine (CIM) for improving cancer-related fatigue (CRF) is still fragmented. This study therefore critically appraised all the systematic reviews (SRs) regarding the effectiveness of CIM in mitigating CRF in adults.
Methods
A systematic review of SRs and a meta-analysis were conducted in 4 databases. The effect sizes of the included SRs were quantitatively pooled (standardized mean difference [SMD]; 95% CI) using a random-effects model. Heterogeneity was tested by using χ2 (Q) tests and I² statistics.
Findings
Twenty-two SRs met the inclusion criteria, and results from 20 SRs underwent meta-analysis. The pooled significant estimate of fatigue reduction was as follows: SMD, −0.50; 95% CI, −0.67 to −0.32; P < 0.001. The subgroup analysis based on the type of CIM intervention revealed that the approach showing higher effects in reducing fatigue thus far is acupuncture: SMD, –0.99; 95% CI = –1.37 to –0.62, P < 0.001; I2 = 84%. CIM therapies showed a significant reduction of fatigue in patients with breast cancer: SMD, –0.46; 95% CI, –0.69 to –0.23; P < 0.001; I2 = 82%.
Implications
CIM interventions showed effectiveness in reducing CRF. Subgroup analysis suggested some potential influencing, such as tumor type and specific CIM therapy factors, that require in-depth assessment in future research. Study protocol registration: PROSPERO CRD42020194254.
The use of complementary and integrative medicine (CIM) therapies among patients with cancer has increased in the last decades, and a growing number of integrative oncology centers and formal programs have been spreading worldwide.
In recent years, the integrative oncology field has arisen as a scientific discipline to gather evidence-based CIM therapies and conventional cancer treatment to address the unmet needs of cancer patients and their families.
With increasing interest in integrative cancer research, CIM therapies seem to effectively reduce side effects and improve the quality of life in patients with cancer. As a result, an average of 51% of patients with cancer commonly use CIM as supportive care to manage treatment-related side effects during the cancer trajectory.
the current specific lack of knowledge and awareness among patients, concerns for insurance coverage of CIM, and costs are the most common barriers to broader adoption of CIM among cancer survivors, particularly among patients with lower education.
Independent demographic variables are associated with CIM use, such as young age, sex (female), higher education, higher income, and previous use of CIM.
For these reasons, clinicians and the conventional care plan should consider regular consultation regarding the possibility of adopting CIM interventions to address these barriers and promote equitable access to CIM therapies.
Addressing unmet information needs: results of a clinician-led consultation service about complementary and alternative medicine for cancer patients and their relatives.
Clinical concerns regarding the safe and effective use of specific CIM interventions during conventional treatment, particularly nutritional supplements, have risen because of the necessity of knowing precisely any potential adverse events related to their simultaneous use.
Although dietary supplements containing Panax quinquefolius and acetylcarnitine reduced fatigue in 82% of patients in a palliative setting (except in those with very-low-performance status),
some CIM substances can interfere with the action of pharmacologic agents by modulating the cytochrome P450 enzyme. It is therefore reasonable to assume that nutritional supplements using the same isoenzymes in the cytochrome P450 pathway may be contraindicated for concomitant use.
However, a recent investigation reported a low interaction between anticancer treatments and the concomitant use of some biologically based CIM interventions.
Unless specific recommendations are provided, the criterion for obtaining successful outcomes and minimizing risks should be ensuring that patients receive accurate information regarding CIM usage during active cancer treatments.
Several studies about CIM interventions for reducing CRF have been performed, given that CRF is one of the most distressful cancer- and treatment-related symptoms.
Thus far, the literature encompasses several systematic reviews and meta-analyses, including different primary randomized controlled trials (RCTs), on CIM's efficacy for improving CRF. This multitude of systematic reviews portrays a complex and fragmented scenario regarding the possibility of synthetically framing the knowledge regarding the effective use of CIM in reducing CRF. In this complex scenario, breast cancer is the most examined cancer type, and acupuncture is the most investigated intervention, regardless of cancer diagnosis. Nevertheless, CIM interventions pose a challenge for health care professionals, and it is unclear which specific intervention within the framework of CIM has more substantial evidence of effectiveness in reducing CRF. Evidence supporting the use of such therapies in oncology settings remains controversial, with limited evidence to draw reliable and shared clinical recommendations.
To facilitate an understanding of this complex scenario, we sought to critically appraise the existing systematic reviews and perform a meta-analysis regarding CIM therapies and their effects on reducing CRF.
Materials and Methods
A systematic review was performed of systematic reviews by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and flowchart
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch V. Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. Cochrane; 2019. www.training.cochrane.org/handbook.
The rationale behind this study derived from a preliminary and rapid literature search that revealed several systematic reviews and meta-analyses on CIM interventions for reducing CRF. The review's protocol was registered on PROSPERO (CRD42020194254).
Data Sources and Search Strategy
A comprehensive literature search was conducted to select studies from January 2010 to June 2022. The last literature search was performed manually in June 2022. The following electronic databases were systematically searched independently by two reviewers (S.B. and R.C.): PubMed, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and the Physiotherapy Evidence Database. The search query was first structured for the PubMed database and then adequately adapted to the other databases (see Supplemental File 1). Based on recent recommendations, we combined MeSH terms and free-text words using a single-line search strategy.
The main following search terms were used: “cancer,” “neoplasm,” “fatigue,” “cancer-related fatigue,” and “systematic literature review.” Boolean operators (AND, OR, NOT, AND NOT) were used to combine the key words. To ensure a sensible search strategy, we used a general search query on CRF, and we then selected articles analyzing the efficacy of complementary and alternative medicine for reducing CRF. The search was restricted to cancer subsets and systematic reviews, with abstracts available, selecting methods-based filters (PubMed Clinical Queries) and topic-specific filters (Topic-Specific/Special Queries).
To find all relevant publications, no language restriction was initially established. The reference list was cross-referenced and hand-searched to identify additional articles,
and a manual search was conducted on the Google Scholar search engine as a complementary search.
Eligibility Criteria
This systematic review is based on the Population, Intervention, Control, Outcomes, and Study design (PICOS) framework: (P) adult patients with cancer and survivors (≥18 years); (I) complementary integrative medicine interventions; (C) usual care or no intervention or any intervention; (O) cancer-related fatigue as a primary end point; and (S) systematic reviews and meta-analysis that include RCTs or longitudinal RCTs. The inclusion criteria were as follows: (1) all scientific methodologic articles (published and unpublished) focused on the efficacy of complementary and alternative medicine interventions aimed at improving CRF, such as martial arts (Tai Chi and Qigong), yoga, massage therapy, acupressure, acupuncture, moxibustion, and nutritional/dietary supplements (excluding educational and psychosocial interventions); (2) inclusion of an abstract; (3) systematic reviews published between 2010 and 2022 to retrieve the most up-to-date evidence on this topic; (4) systematic reviews containing any type of RCT studies with an appropriate sample size (pilot studies, feasibility studies, and uncontrolled trials were excluded); and (5) systematic reviews that examined general fatigue as a primary outcome as measured through reliable psychometric instruments. The choice to select studies from 2010 to 2022 was made to identify the most recent evidence in assessing the efficacy of CIM interventions and guiding decision-makers, particularly regarding medical approaches. Given that the selected systematic reviews included primary studies published since 2000 and covering a broad period, the choice to undertake the research from 2010 to 2022 was consistent with the study's goal and methodology.
To reduce any potential language misinterpretation, articles published in languages other than English were consequently excluded during the selection of titles and abstracts unless they were highly significant for the review's purposes. Considering that likely eligible articles in languages other than English would not add different and relevant information to our synthesis, we excluded these articles during the final phase of the selection process. We excluded articles entirely focused on hematologic patients, considering the disease's variable clinical course.
What is different about patients with hematologic malignancies? A retrospective cohort study of cancer patients referred to a hospice research network.
Systematic reviews without a quantitative synthesis of the results or including only one study's effect size were ultimately excluded according to the study's aim to reach an overall quantitative estimation of the effect of CIM interventions. During the selection process, we did not consider articles without abstracts to guarantee the recommended selection process steps of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. This choice was also consistent with only including scientific methodologic articles.
Operational Definition of CIM
For our analysis, we adopted the definition of the National Center for Complementary and Integrative Medicine, which defines CIM as follows: “A group of diverse medical and healthcare interventions, practices, products, or disciplines that are not presently considered to be part of conventional medicine.”
These interventions include nutritional/dietary supplements and mind–body practices, such as Tai Chi and Qigong, yoga, acupuncture/acupressure, and massage therapy. Some of these practices are also part of traditional Chinese medicine approaches. The National Center for Complementary and Integrative Medicine incorporated psychological approaches (mindfulness and psychotherapy practices) and art therapies (art, dance, and music) into mind–body interventions. However, we did not consider psychological approaches or art therapies for our study because they target a specific dimension of fatigue that was not the focus of our investigation.
Data Selection and Extraction
Two authors (S.B. and R.C.) conducted the literature search independently by reviewing the titles and abstracts of identified papers. The authors debated the reasons for inclusion or exclusion and disagreements to ensure the process's reliability and consistency. Systematic reviews identified as eligible during abstract screening were then independently reviewed in full by the 2 authors (S.B. and R.C.) and read several times to analyze the studies’ contents accurately. Data extraction was performed by one reviewer (S.B.) and then verified by the other (R.C.) using a piloted electronic extraction form (Excel form).
The following variables were extracted from the studies: first author/year, number of studies included in the systematic reviews, number of participants, cancer diagnoses, intervention, comparison, CRF measurements, and outcome results. A consensus discussion resolved disagreements between the 2 authors during the data selection and extraction phase.
Quality Appraisal
The risk of bias in eligible systematic reviews was independently assessed by 2 authors (R.C. and S.B.) using the Cochrane Collaboration's risk of bias tool (ROBIS), which has recently been recommended for the systematic review of systematic reviews methodology.
Quality assessment versus risk of bias in systematic reviews: AMSTAR and ROBIS had similar reliability but differed in their construct and applicability.
The ROBIS tool comprised 3 evaluations: (1) relevance assessment; (2) review process evaluation; and (3) judgment of overall risk of bias. More precisely, phase two (review process evaluation) required the assessment of 4 domains: study eligibility criteria, identification and selection of studies, data collection and study appraisal, and synthesis and findings. We considered methodologically reliable and appropriate for the final synthesis only those systematic reviews that obtained a low risk of bias in all the domains. Any disagreement between the 2 authors in the quality appraisal process was addressed by discussion.
Data Analysis
We quantitatively pooled the effect size (standardized mean difference [SMD]; 95% CI) of each meta-analysis included in the selected systematic reviews to estimate the pooled magnitude of CIM effects for reducing CRF (from positive to negative) by applying the restricted maximum likelihood estimation.
In the primary studies, the SMD was calculated when different scales were used across trials to assess the outcome (CRF, with 95% CIs). The analyses were performed by using random-effects models with 95% CIs because it was plausible to have true differences in the effect sizes between the included primary studies in each systematic review; the plausible hypothesized differences were related to the expected clinical heterogeneity of the included populations and intervention with different characteristics within the area covered by the specific aim of each systematic review. If data about means, SDs, or P values in the primary studies were not reported due to the authors using median, quartiles, and/or 95% CIs, the authors of the included reviews have estimated the intervention effect by transforming the available information from the primary studies into mean and variance. The outcome (CRF) was assessed by using self-reported questionnaires at baseline and after all interventions. Observing a high clinical heterogeneity among the studies, a random-effects model was used to consider within- and between-study variances.
The Cochrane Q test (P level significance set at 0.05) and the I2 statistics estimated between-study heterogeneity. The following I2 cutoffs were considered to assess heterogeneity: 0% to 40% (unimportant heterogeneity), 30% to 60% (moderate), and higher than 50% (substantial and considerable heterogeneity). The relevance of the I2 value depends on the magnitude and direction of effects and the strength of evidence for heterogeneity (P value from the χ2 test or CI).
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch V. Cochrane Handbook for Systematic Reviews of Interventions Version 6.0. Cochrane; 2019. www.training.cochrane.org/handbook.
In case of high or moderate statistical heterogeneity, subgroup analyses were planned on the type of CIM intervention (if there were at least 2 meta-analyses for each group), considering that this factor might influence the fatigue outcome. If <10 studies were available for the outcome, we would not assess publication bias since real asymmetry could not be detected due to low test power, assuming a moderate publication bias.
In this regard, the regression-based Egger's test for small-study effects was performed to regress the effect estimate on its SE, weighted by its inverse variance. In the regression-based Egger's test, when the outcome is continuous, no association between the effect estimate and its SE (nonsignificant test) indicates a plausible absence of publication bias because the sample means should be independent of the sample variance (under the assumption of normality). According to the overall effect estimation methodology adopted, the overlap between articles was manually checked to investigate the potential overlapping of the primary studies included in the selected systematic reviews. Data analyses were performed by using STATA 16 software (StataCorp, College Station, TX, USA).
Results
The literature search process and reasons for exclusion are presented in Figure 1. Our database search yielded 1600 citations. Seven additional records were found through manual searching, 3 of which were removed because they were duplicates. None of these articles was found to be eligible for the final inclusion. After removing duplicates from the databases, 1294 articles were screened for eligibility by title and abstract, and 156 records were appropriate for inclusion. Of these 156 records, 24 systematic reviews met the inclusion criteria after full-text reading. Two
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
Effect of Chinese Traditional Wushu on cancer-related fatigue, sleep quality and upper limb dysfunction of breast cancer survivors: a systematic review and meta-analysis.
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.
Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: what intervention characteristics are related to higher efficacy?.
The effect of yoga interventions on cancer-related fatigue and quality of life for women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
by retrieving the results matching our eligibility criteria.
Figure 1Flow diagram of the selection process. CINAHL = Cumulative Index to Nursing and Allied Health Literature; PEDro = Physiotherapy Evidence Database; PICOS = Population, Intervention, Control, Outcomes, and Study; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Overall Characteristics of the Included Systematic Reviews
A summary of the included studies is presented in Table I. In total, the 22 systematic reviews comprised 90 primary studies, including adults (aged ≥18 years) affected by various cancer diagnoses and survivors (particularly breast, lung, and prostate cancer). For one systematic review,
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
it was unfeasible to know the exact number of individuals involved in the comparisons and the number of pooled studies in the selected comparison. All of the studies included in the systematic reviews were RCTs investigating the effects of different types of CIM interventions on CRF during and/or after completion of cancer treatments (after completing primary treatment or off-treatment), such as chemotherapy, radiotherapy, hormonotherapy, and surgery, compared with any interventions (eg, usual care, sham acupuncture, Chinese herbs, no treatment, waitlist, health education, psychological support, counseling, physical exercise, sham Qigong). Among the control groups, the waitlist approach implied receiving usual care and then being treated as an intervention group after the trial completion.
Table ICharacteristics of the included studies.
First Author/Year
No. of Studies
Sample
Type of Cancer
Intervention
Comparison
Measurements
Results
Acupuncture
Hsieh, 2021
9
495
Various
Acupressure 1–3 times/d, 3–27 min each session for 4–6 wk
Usual care or sham acupressure
MDASI, FACIT-F, MFI, BFI
SMD, –0.87; 95% CI, –1.19 to –0.55; P < 0.001; I2 = 75%
Li, 2021
3
308
Breast
Acupuncture for 6–8 wk (no additional information)
Usual care or waitlist
BFI, MFI-GF, PFS, EORTC QLQ-C30
SMD, –0.97; 95% CI, –1.23 to –0.72; P < 0.001; I2 = 0%
Zhang, 2021
6
590
Breast
Acupuncture 1–2 times/week, 20–30 min each session for 4–12 wk
Usual care or no intervention
BFI, MFI-GF, PFS, EORTC QLQ-C30
SMD, –0.39; 95% CI, –0.55 to –0.22; P < 0.001; I2 = 0%
Zhang, 2018
10 5
1327 809
Various Breast
Acupuncture and/or moxibustion, 1–3 times/week, 20–30 min each session for 2–8 wk Acupuncture 1–3 times/week, 20–30 min each session for 2–8 wk
Usual care or sham acupressure Usual care or sham acupressure
BFI, MFI, ESAS, FACIT-F BFI, MFI, FACIT-F, ESAS
SMD, –1.26; 95% CI, –1.80 to –0.71; P < 0.001; I2 = 94% SMD, –1.2; 95% CI, –1.82 to 0.72; P < 0.001; I2
Tai Chi and/or Qigong for 6–60 wk (no additional information)
Usual care
BFI, FSI, PFS-R
SMD, –0.73; 95% CI, –1.49 to 0.03; P < 0.001; I2 = 89%
Kuo, 2021
5
370
Various
Qigong for 8–24 wk (no additional information)
Usual care
BFI
SMD, –0.27; 95% CI, –0.42 to –0.17; P < 0.00001; I2 = 0%
Sur, 2021
3 3 3
237 268 204
Various Various Various
Tai Chi and/or Qigong, 2–5 times/week, 60 min each session for 5–10 wk Tai Chi and/or Qigong, 1–5 times/week, 60–120 min each session for 6–12 wk Tai Chi and/or Qigong, 1–3 times/week, 60–90 min each session for 8–12 wk
Usual care or waitlist Usual care or waitlist Usual care or psychosocial support
BFI MFSI-SF FACT-F
SMD, 0.01; 95% CI, –0.39 to 0.41; P = 0.96; I2 = 26% SMD, –0.51; 95% CI, –0.80 to –0.22; P < 0.001; I2 = 0% SMD, –0.68; 95% CI, –0.96 to –0.39; P < 0.001; I2 = 0%
Meng, 2021
6
401
Breast
Qigong 1–3 times/week, 15–60 min each session for 12–24 wk
Usual care
BFI, FACIT-F, PFS, SF-36, EORTC QLQ-C30
SMD, 0.32; 95% CI, –0.07 to 0.71; P = 0.11; I2 = 73%
Song, 2018
6 3 2
373 156 151
Breast, lung, and prostate Breast Lung
Tai Chi 2–5 times/week, 30–60 min each session for 4–12 wk Tai Chi 2–5 times/week, 30–60 min each session for 12 wk Tai Chi 2–5 times/week, 30–60 min each session for 4 wk
Usual care, education, waitlist, psychological support, physical exercise, sham Qigong Education, waitlist, psychological support, sham Qigong Usual care and physical exercise
Yoga 1–3 times/week, 20–30 min each session for 6–24 wk
Waitlist, health education, supportive counseling
FACT-F, FSI, BFI, POMS, FACIT-F, EORTC QLQ-C30
SMD, –0.51; 95% CI, –0.79 to –0.22; P < 0.001; I2 = 44%
Nutritional supplements
de Araujo, 2021
3
139
Breast
Guarana 15–100 mg/d for 21–90 d
Placebo
BFI, FACIT-F
SMD, –0.02; 95% CI, –1.54 to 1.50 P = 0.98; I2 = 93%
Marx, 2017
3
659
Various
Levocarnitine oral solution or acetyl-L-carnitine capsules 2–4 mg/d for 2–6 mo
Placebo
BFI, FACT-F
SMD, 0.06; 95% CI, –0.09 to 0.21; P = 0.45; I2 = 0%
BFI = Brief Fatigue Inventory; BFS = Berlin Mood Questionnaire; CFS-D = Cancer Fatigue Scale (German version); FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue; FACT-B = Functional Assessment of Cancer Therapy–Breast; FACT-F = Functional Assessment of Cancer Therapy–Fatigue; FSI = Fatigue Scale Inventory; FSMC = Fatigue Scale of Motor and Cognitive Functions; FSI-16 = 16-term Fatigue Scale Inventory; FSS = Fatigue Severity Scale; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; ESAS = Edmonton Symptom Assessment System; MDASI = MD Anderson Symptom Inventory; MFI = Multidimensional Fatigue Inventory; MFI-GF = Multidimensional Fatigue Inventory–General Fatigue; MFSI-SF = Multidimensional Fatigue Syndrome Inventory–Short Form; PFS = Piper Fatigue Scale; POMS = Profile of Mood State Questionnaire; SF-36 = 36-item Short Form Health Survey; SMD = standard mean difference; VAS = visual analog scale.
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
Effect of Chinese Traditional Wushu on cancer-related fatigue, sleep quality and upper limb dysfunction of breast cancer survivors: a systematic review and meta-analysis.
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.
Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: what intervention characteristics are related to higher efficacy?.
The effect of yoga interventions on cancer-related fatigue and quality of life for women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
Acupuncture (or electroacupuncture) sessions were performed 1 to 3 times per week, lasting for 3 to 30 minutes each, for 4 to 12 weeks. Traditional acupuncture uses thin needles to stimulate specific pressure points associated with undesirable symptoms. A single needle is used at each treatment point in traditional acupuncture, whereas electroacupuncture is a variant that uses 2 needles. During treatment, a mild electric current is passed between these needles. Acupressure involves the same acupressure technique using pressure and massage to stimulate acupoints.
in the acupuncture group as a particular technique. Massage therapy consists of arm/shoulder, posture correction, coordination, exercises for muscular strength, exercises to prevent lymphedema, soft tissue massage of the surgical scar, core stability exercises plus massage-myofascial release, stroking, kneading, pressing, stretching the neck (Swedish techniques), reflexology, and scalp massage. Massages were performed 3 times per week, 30 to 80 minutes each session, ranging from 3 to 24 weeks. Tai Chi and Qigong sessions, lasting for 15 to 120 minutes each, were undertaken 1 to 5 times per week for 1 to 60 weeks. Tai Chi and Qigong involve slow movements combined with deep and diaphragmatic breathing and meditation, which could improve bodily system function.
Yoga exercises included numerous styles and were practiced 1 to 5 times per week, for 20 to 120 minutes each session, for 3 to 26 weeks. Yoga is a mind–body exercise that combines muscular activity with an internally directed, mindful focus on self-awareness, breath, and energy.
Nutritional therapy consisted of levocarnitine oral solution or acetyl-L-carnitine capsules 2 to 4 mg per day for 2 to 6 months, and guarana 15 to 100 mg/d for 21 to 90 days. Forms of exercise interventions included supervised classes (in-hospital or outpatient clinics) and/or home-based self-practice.
Outcome and Measurements
The studies included in the selected systematic reviews assessed CRF as a primary outcome, measured throughout various multidimensional fatigue scales and subscales at different time points (short- or long-term follow-up): MD Anderson Symptom Inventory, Brief Fatigue Inventory, Multidimensional Fatigue Inventory, Functional Assessment of Chronic Illness Therapy–Fatigue, Edmonton Symptom Assessment System, Piper Fatigue Scale, Profile of Mood State Questionnaire, Berlin Mood Questionnaire, Multidimensional Fatigue Syndrome Inventory–Short Form, Fatigue Severity Scale, Fatigue Scale Inventory, Fatigue Scale of Motor and Cognitive Functions, 16-item Fatigue Scale Inventory, Functional Assessment of Cancer Therapy–Fatigue, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Cancer Fatigue Scale, visual analog scale, and the Functional Assessment of Cancer Therapy–Breast.
Risk of Bias in the Selected Systematic Reviews
The authors independently evaluated the risk of bias of the 24 included systematic reviews according to ROBIS tool guidance recommendations. We judged 22 systematic reviews at low risk of bias
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
Effect of Chinese Traditional Wushu on cancer-related fatigue, sleep quality and upper limb dysfunction of breast cancer survivors: a systematic review and meta-analysis.
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.
Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: what intervention characteristics are related to higher efficacy?.
The effect of yoga interventions on cancer-related fatigue and quality of life for women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
The lower quality was detected in the study eligibility criteria, identification, and selection phases. The lack of or incomplete description of search strategies and reasons for exclusions provided eligibility criteria. Results of the risk of bias assessment are shown in Table II and Figure 2.
Table IIRisk of bias assessment of the selected systematic reviews.
Review
Phase 2
Phase 3
Study Eligibility Criteria
Identification and Selection of Studies
Data Collection and Study Appraisal
Synthesis and Findings
Risk of Bias in the Review
Hsieh, 2021
Low
Low
Low
Low
Low
Li, 2021
Low
Low
Low
Low
Low
Zhang, 2021
Low
Low
Low
Low
Low
Jang, 2020
High
Unclear
High
Low
High
Zhang, 2018
Low
Low
Low
Low
Low
Lee, 2014
Low
Low
Low
Low
Low
Zeng, 2014
Low
Low
Low
Low
Low
He, 2013
Low
Unclear
High
Unclear
High
Pan, 2014
Low
Low
Low
Low
Low
Wu, 2019
Low
Low
Low
Low
Low
Ren, 2022
Low
Low
Low
Low
Low
Kuo, 2021
Low
Low
Low
Low
Low
Sur, 2021
Low
Low
Low
Low
Low
Meng, 2021
Low
Low
Low
Low
Low
Song, 2018
Low
Low
Low
Low
Low
Xiang, 2017
Low
Low
Low
Low
Low
Ma, 2016
Low
Low
Low
Low
Low
Haussmann, 2022
Low
Low
Low
Low
Low
O'Neill, 2020
Low
Low
Low
Low
Low
Dong, 2019
Low
Low
Low
Low
Low
Boehm, 2012
Low
Low
Low
Low
Low
Buffart, 2012
Low
Low
Low
Low
Low
de Araujo, 2021
Low
Low
Low
Low
Low
Marx, 2017
Low
Low
Low
Low
Low
Low risk of bias: The findings of the review are likely to be reliable. Phase 2 did not raise any concerns with the review process, or concerns were appropriately considered in the review conclusions. The conclusions were supported by the evidence and included consideration of the relevance of included studies. High risk of bias: One or more of the concerns raised during the Phase 2 assessment was not addressed in the review conclusions, the review conclusions were not supported by the evidence, or the conclusions did not consider the relevance of the included studies to the review question. Unclear risk of bias: There is insufficient information reported to make a judgment on risk of bias.
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
Effect of Chinese Traditional Wushu on cancer-related fatigue, sleep quality and upper limb dysfunction of breast cancer survivors: a systematic review and meta-analysis.
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.
Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: what intervention characteristics are related to higher efficacy?.
The effect of yoga interventions on cancer-related fatigue and quality of life for women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
The decision to exclude nutritional supplements from the analysis was made because these therapies differ greatly from the other interventions in terms of mechanism of action. We found two different substances within the same category (guarana and levocarnitine). The pooled significant estimate of fatigue reduction, retrieved from the 23 meta-analyses, was an SMD of −0.50 (95% CI, −0.67 to −0.32; P < 0.001) compared with the control arm. We applied a random-effects model considering the high clinical heterogeneity among the studies, which was confirmed by I2 = 92% and significant Q statistic [Q(22) =135.66; P < 0.001] (Figure 3). The heterogeneity was explored through subgroup analyses on CIM interventions. The subgroup analysis indicated a significantly higher improvement of fatigue (SMD, –0.99; 95% CI, –1.37 to –0.62; P < 0.001; I2 = 84%) after acupuncture and a lower significant effect on fatigue reduction with yoga interventions (SMD, –0.29; 95% CI, –0.39 to –0.19; P = 0.08; I2 = 50%) (Figure 4). A nonsignificant effect on fatigue improvement resulted from massage interventions: SMD, –0.58; 95% CI, –1.05 to –0.11; P = 0.60; I2 = 0%. Tai Chi and Qigong interventions have a significant moderate effect on fatigue reduction: SMD, –0.31; 95% CI, –0.52 to –0.10; P < 0.001; I2 = 79%. The variability in the included studies seemed to be higher in the Tai Chi and Qigong groups (tau = 0.039), where we found the highest statistical heterogeneity (I2 = 65%). The effect of CIM therapies (acupuncture, Tai Chi, and yoga) on specific cancer populations showed a significant reduction of fatigue score in patients with breast cancer despite a high statistical heterogeneity (SMD, –0.46; 95% CI, –0.69 to –0.23; P < 0.001; I2 = 82%) (Figure 5).
Figure 3The overall effect of complementary integrative medicine (acupuncture, massage, Tai Chi, and yoga) on cancer-related fatigue. REML = restricted maximum likelihood estimation.
Figure 4Subgroup analysis on the effect of complementary integrative medicine on cancer-related fatigue compared with any intervention. REML = restricted maximum likelihood estimation.
The funnel plot (see Supplemental File 2) showed a slight asymmetry, indicating a potential risk of publication bias. However, the contour-enhanced funnel plot (see Supplemental File 3) depicted missing studies in both the significant and nonsignificant regions, suggesting that this asymmetry may be due to other reasons such as studies’ heterogeneity and the small number of selected studies. Accordingly, funnel plots within groups (see Supplemental File 4) appeared more symmetrical for studies including acupuncture and massage, whereas they remained asymmetrical for Tai Chi/Qigong and yoga interventions, where we found the highest statistical heterogeneity in the meta-analysis results. Nevertheless, the regression-based Egger's test for small-study effects was statistically significant (P < 0.001), indicating possible evidence of publication bias or a violation of normality in the outcome distribution of the primary studies.
Overlapping Analysis of the Primary Studies Included in the Meta-Analysis of Meta-Analyses
Our meta-analysis of meta-analyses on CIM interventions (Figure 3) included 90 primary studies. Among these, we found results overlapping for 29 studies: results of 13 studies were included twice, 9 studies were included 3 times, 5 studies were included 4 times, 1 study was incorporated 5 times, and 1 study was included 6 times. For one meta-analysis (Wu et al
Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
), it was impossible to retrieve the primary studies. The meta-analysis of meta-analyses on the breast cancer population (Figure 5) included 55 primary studies. Among these, we found results overlapping for 17 studies: 11 results were included twice, 4 were included 3 times, and 2 results were included 4 times.
Discussion
A growing number of studies have examined the potential of CIM interventions to promote health and alleviate disease or treatment-related symptoms in the cancer population. The present study provides a rigorous analysis of the effects of CIM interventions on CRF in adult patients and survivors at different phases of disease and cancer treatments to facilitate the framing of a comprehensive state-of-the-art about this topic. Our pooled synthesis suggests a statistically significant beneficial effect of CIM interventions (acupuncture/acupressure, massage, Tai Chi/Qigong, and yoga) on CRF compared with the control group (any interventions) during and after the completion of cancer treatments. CIM interventions are increasingly adopted among patients with cancer, as 85% use at least one CIM intervention after cancer diagnoses.
In particular, the adoption of CIM therapies seems to decrease during active cancer treatment compared with before treatment, considering all CIM categories.
In the present study, the role of nutritional/herbal supplements was not the object of a pooled meta-analysis because we found only 2 eligible systematic reviews on this topic, including different types of substances, indicating that among CIM, the effects of nutritional/herbal supplements on CRF are less investigated. Accordingly, a recent systematic review on herbal medicine confirmed the need for further high-quality RCTs as limited evidence exists on their efficacy on CRF and safety.
The unique available synthesis in our analysis failed to show any positive effect of levocarnitine oral solution or acetyl-L-carnitine capsules (2–4 mg/d for 2–6 months) and guarana (15–100 mg/d for 21–90 days) on CRF. Our findings regarding nutritional/herbal supplements are consistent with clinical guidelines on this topic, discouraging the consumption of acetyl-L-carnitine during cancer treatments.
However, these results require further in-depth investigations if we consider that dietary supplements are the most commonly used CIM among patients with cancer during and after cancer treatments.
The subgroup analysis based on the type of CIM intervention revealed that the approach showing higher effects in reducing fatigue thus far is acupuncture, despite no direct comparisons between acupuncture and other CIM interventions being available in the pooled analyses. These findings align with a recent overview of systematic reviews and meta-analyses that suggest acupuncture is effective for treating CRF.
Massage therapy had no significant difference in CRF improvement compared with the control group; however, we included only 2 eligible studies. Tai Chi/Qigong and yoga interventions significantly reduced fatigue in patients with cancer and survivors, albeit we found a lower effect than with acupuncture.
The differences in the treatment effects should be interpreted in light of the mechanisms of action of these interventions. The mechanisms through which these exercise interventions may improve fatigue are not entirely known. Inflammation, altered immune response, and mitochondrial dysfunction are among the leading hypothesized biological mechanisms in the etiology of CRF.
Tai Chi/Qigong and yoga interventions may have a direct effect on the immune system and inflammation, as well as an indirect effect on these biological pathways by improving cardiorespiratory fitness.
Research suggests that cytokines and tumor necrosis factor signaling play a role in fatigue development; acupuncture affects inflammatory cytokines and T lymphocytes.
However, acupuncture differs greatly from Ta Tai Chi/Qigong and yoga in terms of the type of intervention, which may explain the substantial difference in the obtained treatment effect results and the similarity between the effects of Ta Tai Chi/Qigong and yoga.
We also found a statistical reduction of CRF in the subgroup of patients with breast cancer, implying that disease clusters may play a role in predicting CIM therapy responses. The adoption of CIM therapies is most common among patients with breast cancer (93%), followed by those with colorectal cancer (83%), prostate cancer (77%), and lung cancer (77%).
we could not perform subgroup analysis on this cluster as no pooled quantitative effect of more than one study was available in the results of Lau et al,
which currently represent the most up-to-date evidence regarding CIM adoption in patients with lung cancer. A study of patients with prostate cancer found that impotence and incontinence are essential factors influencing the decision to turn to CIM therapies. However, there is little evidence regarding the efficacy of CIM interventions in prostate cancer.
Overall, caution is advised when using CIM because there is a theoretical risk of adverse interactions with chemotherapy through the modulation of the cytochrome P450 enzyme system, mainly when CIM substances such as nutritional supplements are consumed during active treatment.
Given these considerations, selecting the most appropriate CIM intervention for specific cancer population clusters seems to be the most effective treatment option about the type of cancer treatment. However, additional, more targeted clinical trials are needed to foster this approach.
Nonetheless, the findings of the present study should be interpreted with caution due to the following limitations. First, our synthesis is based on the results of multiple meta-analyses, and the estimated effect sizes result from a pooled synthesis of the available knowledge. Our meta-analysis of meta-analyses could be influenced by the methodology used to estimate the overall effect. The study's findings should then be explained based on our overlapping analysis. Furthermore, the lack of assessment of the certainty in the range of an effect estimate or an association referred to the primary studies encompassed in each included systematic review is an intrinsic limit of performing a systematic review of systematic reviews, as indicated by the Grading of Recommendations Assessment, Development, and Evaluation approach. This limit was mitigated by selecting only high methodologic systematic reviews for the final synthesis throughout the ROBIS assessment, which is highly conservative and rigorous in each phase of the review process. In other words, the method of a systematic review of systematic reviews helps provide a synthesis of the available literature and effect sizes of CIM in reducing CRF; however, this method is not feasible to support a generation of graded recommendations as this research allows a general overview of the available systematic reviews, pooling their effect sizes synthetically. Second, the heterogeneity of the scales used to measure fatigue, intervention types, and characteristics, even within the same CIM interventions class, were the most significant issue that affected the results of the present study. Third, we selected articles published from January 2010 to December 2020 and did not search Chinese literature databases. This may have limited the number of potentially eligible articles. However, because this is a systematic review of reviews, the primary studies included were published after 2000. Fourth, during the article selection process, we established language restriction as an eligibility criterion to reduce any potential language misinterpretation unless they were highly significant for the review's purposes. This approach may result in language bias due to the selection of reports published in selected languages. However, this aspect was not the primary reason for the articles’ exclusion. Fifth, our analysis reflects the effect of CIM intervention on general fatigue without examining the effects of the interventions on specific fatigue dimensions. However, given the available literature data, this was unfeasible.
Conclusions
This systematic review of systematic reviews provides a comprehensive and up-to-date synthesis of CIM interventions for improving fatigue in adult cancer patients, using published systematic reviews and meta-analyses. According to our findings, CIM interventions seem to effectively reduce CRF. Mainly, acupuncture showed larger significant effect sizes compared with other CIM interventions. However, the performed subgroup analysis suggested some potential influencing factors, such as tumor type and specific CIM therapy, that can modify the beneficial effects of CIM. Furthermore, there is limited evidence for consuming nutritional supplements during cancer treatment, and higher quality studies are needed. This study also identified the main current knowledge gaps, given the lack of focus on specific cancer diseases and direct comparisons between concurrent CIM, to determine the most effective CIM intervention in reducing CRF. For this reason, we recommend more robust research to fill these gaps. In clinical practice, the most recommended approach to incorporating CIM into the cancer care pathway for reducing CRF is proper patient assessment based on clinical characteristics and individual preferences toward CIM.
Declaration of Interest
None declared.
Fundings
This research did not receive any specific grant from funding agencies in the public, commercial, or not for profit sectors.
Authorship statement
RC, SB were responsible for the conception and design of the systematic review. SB, RC conducted the database search and data collection. RC and SB were responsible for the data analysis. SB, RC, MB, CA, FD were involved in interpreting results and drafting the article. All the authors revised the manuscript critically and approved the final version.
Data availability
All data relevant to the study are included in the article or uploaded as supplemental information.
Addressing unmet information needs: results of a clinician-led consultation service about complementary and alternative medicine for cancer patients and their relatives.
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Wu C, Zheng Y, Duan Y, et al. Nonpharmacological interventions for cancer-related fatigue: a systematic review and bayesian network meta-analysis. Worldviews evidence-based Nurs. 2019;16:102-110. doi:10.1111/wvn.12352
Effect of Chinese Traditional Wushu on cancer-related fatigue, sleep quality and upper limb dysfunction of breast cancer survivors: a systematic review and meta-analysis.
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.
Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: what intervention characteristics are related to higher efficacy?.
The effect of yoga interventions on cancer-related fatigue and quality of life for women with breast cancer: a systematic review and meta-analysis of randomized controlled trials.
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