Mindfulness-Based Stress Reduction on breast cancer symptoms: systematic review and meta-analysis

ABSTRACT Mindfulness-Based Stress Reduction practices increase the capacity for concentration and attention, and these practices are particularly effective for people with breast cancer. To analyze the effects of the application of Mindfulness-Based Stress Reduction on breast cancer symptoms. Systematic review and meta-analysis were carried out. To find suitable studies, the PubMed/ MEDLINE database was searched using the keywords “breast cancer” and “Mindfulness-Based Stress Reduction”. Studies included were published between 2013 and 2017, written in English and showed methodological quality through the PEDro scale (score greater than 3). They also presented empirical evidence, had an experimental study design (randomized or non-randomized), and had full text available. For the meta-analysis, we used a random-effects model, with standardized mean differences and 95% confidence intervals. Seven studies were included, one non-randomized and containing only an intervention group of Mindfulness-Based Stress Reduction, and six randomized including samples of two or three groups. The non-randomized study showed 6 points on the PEDro scale, the randomized studies of two groups 6 to 7 points and studies with three groups showed 7 points. In the meta-analysis of the two randomized studies, the results, although not significant, revealed a moderate effect for Mindfulness-Based Stress Reduction on the outcome of fatigue, with a mean difference of −0.42 (95%CI −0.92- −0.07; p=0.09). Mindfulness-Based Stress Reduction seems to be a promising alternative for treatment of this disease's symptoms.


❚ OBJECTIVE
To analyze the effects of the practice of Mindfulness-Based Stress Reduction on symptoms as fatigue, depression, anxiety and cognitive aspects in women with breast cancer.

❚ METHODS Search strategy
Studies were identified using the US National Library of Medicine/National Institutes of Health/MEDLINE (NLM/NIH/MEDLINE) − PubMed database. The procedures related to searching the database complied with the following steps: -First step: identification of the keyword controlled by the Medical Subject Headings (MeSH) "breast cancer" and the not controlled "MBSR mindfulness-based stress reduction". These terms were searched in MEDLINE database: "breast neoplasms" OR "breast" AND "neoplasms" OR "breast neoplasms" OR "breast" AND "cancer" OR "breast cancer" AND "MBSR" AND "mindfulness" OR "mindfulness" AND "based" AND "Stress" OR "stress" AND reduction. -Second step: two reviewers independently screened the reports in two phases as proposed by Cook et al. (41) Phase one, articles that included the key terms were screened by their titles and abstracts for relevance. Then, in phase 2, the full texts of the relevant articles were retrieved to assess their eligibility.

Inclusion and exclusion criteria
Inclusion criteria for articles were: written in English from the PubMed/PMC database; directly addressed the topic breast cancer and mindfulness-based stress reduction; that demonstrated empirical evidence, with experimental study design (randomized or nonrandomized); available in full text; that obtained a score greater than 3 on the Physiotherapy Evidence Database (PEDro; http://www.pedro.org.au); and with the year of the study limited to between 2013 and 2017. Exclusion criteria were: other types of cancer different from breast cancer; other therapies (with MBSR only accepted alone or in comparison with other therapies); other symptoms that were not fatigue, depression, anxiety and cognitive aspects; and not written in English language.

Methodological quality
The methodological quality of all studies was assessed using the PEDro (42) (Table 1). It is a free database of randomized controlled trials, systematic reviews and clinical practice guidelines in physiotherapy. PEDro is based on the Delphi list and its purpose is to help its users to identify more rapidly which of the known or suspected randomized clinical trials (i.e. randomized controlled trials or RCTs) available at PEDro database are likely to be internally valid (criteria 2 to 9), and could have sufficient statistical information to make their results interpretable (criteria 10 to 11). (42)

Risk of bias assessment
Methodological quality was independently assessed by at least two reviewers using the Cochrane collaboration risk for bias tool that considered seven different domains: adequacy of sequence generation; allocation sequence concealment; blinding of participants and caregivers; blinding for outcome assessment; incomplete outcome data; selective outcome reporting; and the presence of other potential sources of bias not accounted for in the other six domains. The estimated overall risk of bias for each trial was categorized as low (if the risk of bias was low in all key domains), unclear (if there is low or unclear risk of bias for all key domains) or high (if the risk of bias was high in one or more key domains). (43)

Data analysis
Meta-analysis was conducted with two studies classified as randomized, as they had scores of fatigue as continuous data. The Stata software (version 12.0; Stata Corp., College Station, USA) was used for data synthesis and analysis. Post-intervention intergroup effect sizes were calculated using a random effects model (as this allows generalization of findings beyond the set of included studies) and variability in the estimates, with 95% confidence intervals (95%CI), and stratified by type of comparison group (MBSR versus control).
Next, Hedges' (adjusted) g was used to calculate the effect size for each study. The magnitude of Hedges' g may be interpreted using Cohen's (44) convention as small (0.2), medium (0.5), and large (0.8). To establish whether the results of the studies were consistent, tests of heterogeneity were performed, using Q and I² statistics. Q statistics calculates the probability value for the heterogeneity of studies (significant heterogeneity is indicated by a p value ≤0.05). An I² value of 0% indicates no observed heterogeneity, while values of 25%, 50%, and 75% are considered low, moderate, and high. (45) Publication bias was assessed using a funnel plot.

Search results and study characteristics
The search located 370 studies in the MEDLINE (PubMed/ PMC) database using the keywords "Mindfulness-Based Stress Reduction" AND "breast cancer". Of these, seven studies were selected for analysis because they met the inclusion criteria ( Figure 1).

Figure 1. Flow diagram of search
For a description of the studies in the tables, the following categories were taken into account: the year of publication, local where the study was conducted, the classification in PEDro scale, the scales used as measuring instruments, the periodical of publication, the sample (age and sex), the intervention (mindfulness) monitoring of the sample and the results obtained.
The countries where the studies were developed were the United States  Table 2).

Methodological quality results
PEDro ranged from 6 to 7 (mean total of all studies of 6.71; standard deviation of 0.48). Non-randomized study presented a PEDro scale score of 6 points; (50) the randomized three group studies the score was between 6 and 7 points; (47,49,51) and three group studies had 7 points. (46,48,52)
Because of the small number of trials included in this meta-analysis, we could not reliably examine funnel plots for publication bias.

Meta-analysis results
Two studies presented continuous data, for a meta-analysis the results of which, although not significant, showed a moderate effect of MBSR on the outcome of fatigue with a mean difference of -0.42 (95%CI -0.92--0.07; p=0.09). The forest plot shows the respective 95%CI for each study. It should be noted that the 95%CI of the articles and the diamond graph did not cross the line indicating statistically null results in favor of MBSR, regarding the scores of fatigue. The result of the effect size (ES) of the MBSR regarding the scores of fatigue showed small ES for both studies, with the greatest effect in the study by Reich et al., (47) (0.46; 95%CI -1.09-0.17), followed by that of Rahmani et al., (51)

❚ DISCUSSION
The results of the systematic review with meta-analysis (random effects model) and of the other studies (randomized and non-randomized studies) indicate that MBSR is likely to reduce the symptoms of breast cancer compared to other treatments (control, usual care, nutritional intervention, metacognitive treatment) by improving scores of depression, fatigue and cognitive aspects. It is assumed that, with the improvement of a breast cancer symptom, there is a tendency for the improvement of various other symptoms together. With the improvement of a breast cancer symptom, there is a tendency for the improvement of various other symptoms together. In this review, some of these symptoms and their relationships with others were highlighted, so that we could understand the treatment of individuals with breast cancer.
Four studies showed MBSR as beneficial in decreasing the symptoms of fatigue. (47,48,51) Fatigue is defined as the inability to initiate and maintain tasks  that require attention and self-motivation, (52)(53)(54) and is one of the most prevalent, severe and debilitating symptoms among cancer patients, leading to decreased physical functioning (55) and becoming a major problem during breast cancer treatment. (56) Armes et al., (57) highlighted that there is no pharmacological treatments for fatigue. However, interventions should focus on psychological, educational, social and group support therapies aiming to allow the individuals to interpret the fatigue, to respond to the symptoms with positive thinking and return to their daily activities. (57,58) The practice of meditation appears to be beneficial in the treatment of fatigue, as it is considered a psycho-educational therapy (59) that combines cognition with intensive meditation training, (38) focusing on observation and working on cognitive and affective processes in order to teach the individuals to become more aware and to relate to themselves. (60) The positive relationship between the practice of meditation and symptoms of breast cancer is consistent with several other studies. Some show reduced fatigue and increased physical vigor, such as the study of Carlson et al., (61) with 89 subjects of both genders and various types of cancer, in 6 weeks of meditation practice, and the study of Carlson et al., (62) with 63 individuals of both genders with cancer (breast cancer, ovarian, lymphoma and prostate), after 8 weeks of MBSR practice. Others show a reduction of fatigue with improved physical energy, such as the study of Carlson et al., (63) with 49 women with breast cancer and 10 men with prostate cancer, in 8 weeks of practice of MBSR, and Lengacher et al., (64) with 41 women with BC, after 6 weeks of MBSR practice.
Cognitive aspects also showed improvement with the practice of MBSR, (48,51) as well as for the metacognition group therapy. (48) Between 17% and 75% of patients with breast cancer, who perform chemotherapy, showed altered brain structure and function which suggests a pattern of diffuse brain injury that underlies the cognitive deficits that may occur during the first 6 months, followed by a recovery of 1 to 2 years and/or a period of stabilization. (65) Executive functions (e.g., working memory) and processing speed, cognitive processes largely controlled by frontally mediated brain systems, have been most prominently reported. (66) The memory has the function of storing and manipulating information for a short period of time, requiring integration of the prefrontal cortex with the other cerebral connections. (67) Attention is a key modulator of cognitive processing, enabling us to select task-relevant stimuli and inhibit irrelevant information, sustain focus on cognitive performance, divide attention, and stay vigilant when needed. (68) Chemotherapy can affect memory (verbal and visual), attention, concentration, multiple decision-making tasks, mental flexibility and speed of processing. (69) Therefore, MBSR is a promising therapy as it is associated with increased density in the regions of the brain related to attention and sensory processing, including the prefrontal cortex and right anterior insula, leading to increased brain activation involved in the processing of emotions, sense of well-being and reduction of relapse and recurrence. (70,71) A two-component model of mindfulness, involving self-regulation of attention (maintained on immediate experience) and attitudinal orientation (curiosity, openness, and acceptance). (68) The study of Schellekens et al., (72) was consistent in showing the atmosphere in the MBSR training experienced by 37 women with breast cancer as safe and provide a context in which participants could connect with and trust one another and encourage patients to fell accepted, and helped them to facilitate each other learning processes, such as acknowledge their emotions and gaining different perspectives.
The metacognition group therapy also showed promising for the improvement of cognitive aspects in breast cancer. Metacognition group therapy is similar to MBSR, as it is based on the premise that the negative evaluation of disease (i.e., negative thoughts about cancer and its consequences) instigates and maintains anguish and, therefore, uses elements of mindfulness in the pursuit of self-knowledge, and understanding of feelings and emotions, focusing on interrupting negative thoughts. (73,74) Studies have shown that MBSR improved depression and anxiety, (46,49,50,52) as well as depression for the nutritional education intervention. (46) From 22% to 50% of women with breast cancer have depression, 3% to 19% post-traumatic stress and 33% stress. (75) Huang et al., (76) highlighted that almost 60% of breast cancer patients report high levels of anxiety, while 25.6 to 58% report living with depression.
Mindfulness is important to combat these psychological symptoms, as it leads the person to accept their inner experiences without judgment, reduce the usual or automatic responses to stressful experiences and develop a view of their life events (that cannot be changed), therefore, reducing the stress and psychological symptoms. (77) Some meta-analyzes confirm that the practice of MBSR can help reduce psychological symptoms, such as mood and sleep disorders, depression and anxiety in women with breast einstein (São Paulo). 2018;16(4):1-10 cancer. (9,59,78) Other randomized studies are consistent in showing the relationship of the practice of meditation and the improvement in the symptoms of depression and anxiety, with 6 (61,64) or 8 weeks of practice. (62,63) The nutritional education intervention also showed an improvement in depression, with the use of similar elements to MBSR, in terms of group therapy held in 8 sessions with homework assignments (containing no meditation or yoga elements), but focused on nutritional education with dietary change through group meal preparation, following the principles of social cognitive theory and patient-centered counseling. (46,79) Nutritional education intervention is important, as an intervention in the lifestyle, to reduce dietary fat intake, with modest influence on body weight, and it may improve the disease-free survival of patients with breast cancer. (80) Limitations Some limitations of this meta-analysis should be considered. One is the quality of the studies, because not all achieve the maximum score on PEDro scale. In addition, some studies did not report basic data of descriptive and inferential statistics, providing only frequency values. Other limitation is attributed to the inclusion of non-randomized clinical trials without performing a meta-analysis of them. This choice was because of the need to observe in the literature articles to supply innovative results although not performed randomly. Another limit is the choice of the articles from just one database that can lead to lack of intervention studies with excellent quality available in other databases. This choice was made because this database is freely accessible and presents quality in its publications.

❚ CONCLUSION
This systematic review and meta-analysis suggests that Mindfulness-Based Stress Reduction can be considered a promising alternative for the treatment of breast cancer symptoms. The results show that Mindfulness-Based Stress Reduction, alone or integrated with other cognitive interventions (nutrition education intervention, Metacognition group therapy), is effective for main symptoms of breast cancer. These findings demonstrate the need for greater provision of alternative treatments for breast cancer symptoms, as this would reduce costs of the intervention and complement the usual treatment.
❚ AUTHORS' CONTRIBUTOR All authors (RL and FDC) contributed to the conception and design of the study.