Evidence of psychological and biological effects of structured Mindfulness‐Based Interventions for cancer patients and survivors: A meta‐review

Abstract Objective A large number of studies have been conducted exploring the effects of mindfulness programs on health outcomes, such as psychological and biological outcomes. However, there is substantial heterogeneity among studies and, consequently, in the systematic reviews/meta‐analyses. Since clinical practice is massively informed by evidence on review studies, our main objective was to summarize the reported evidence regarding the effects of structured mindfulness‐based programs on psychological, biological, and quality‐of‐life outcomes in cancer patients. Methods We conducted a meta‐review, using a literature search from inception to June 2020 in several electronic databases using a combination of keywords including MBSR, MBCT, cancer, and meta‐analysis OR “systematic review” (PROSPERO registration CRD42020186511). Results Ten studies met the eligibility criteria and were included. The main findings were beneficial small to medium effect sizes of Mindfulness‐Based Stress Reduction (MBSR)/Mindfulness‐Based Cognitive Therapy (MBCT)/Mindfulness‐Based Cancer Recovery (MBCR) on psychological health, such as anxiety, depression, stress, and quality of life. A beneficial effect was found for biological outcomes, albeit based on a reduced number of studies. Studies were moderate homogenous regarding the intervention, population, and outcomes explored. Results on long‐term follow‐up seem to indicate that the effects tend not to be maintained, namely in shorter follow‐ups (6 months). Conclusions This meta‐review brings a broad perspective on the actual evidence regarding MBSR/MBCT/MBCR. We expect to contribute to future project design, focused on developing high‐quality studies and exploring the moderating effects that might contribute to biased results, as well as exploring who might benefit more from MBSR/MBCT/MBCT interventions.


| INTRODUCTION
Research on the effects of mindfulness on health has proliferated, with the number of publications increasing exponentially since the late 1990s. 1 However, a large number of articles do not guarantee that the evidence gathered on the effectiveness of mindfulness is strong since research on mindfulness is complex, with multiple methodological issues that can compromise the quality of evidence. 2 One of the most relevant problems concerns the definition of mindfulness. Successive adaptations to better adjust to theories and psychological intervention programs and simplifications resulting from its practice in contexts not guided by science resulted in different versions of the concept. A universal technical definition of mindfulness and its underlying aspects has not yet been found. 2,3 Another problem results from the diversity of ways to carry out interventions based on mindfulness. These can range, for example, from simple guided meditation to intervention programs that include a mindfulness component, programs with different components or timelines, adaptations to standardized programs, or differences in methods of teaching and practicing mindfulness, which makes it difficult to compare them in clinical studies. The term Mindfulness-Based Interventions (MBIs) has emerged to include interventions with mindfulness components in conjunction with other interventions or theoretical approaches. Some interventions include some components of mindfulness, but the basis of the therapy is not mindfulness, such as Dialectical Behaviour Therapy (DBT) and Acceptance and Commitment Therapy (ACT), 4,5 these so-called Mindfulness-Informed Interventions. 6 Until a consensus is reached on the concept of mindfulness, research on its effectiveness would benefit from comparing standardized mindfulness intervention protocols, which could be replicated, and the resulting evidence would only apply to these programs.

Mindfulness was introduced in Medicine and Psychology by Jon
Kabat Zinn in 1979 as a standardized program to reduce stress in the Stress Reduction Clinic at The University of Massachusetts. This Mindfulness-Based Stress Reduction (MBSR) program integrates a classic view of mindfulness accordingly to its Buddhist roots. Kabat-Zinn defined mindfulness as "the awareness that emerges through paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment" (p. 145). 7 MBSR program is based on intensive training in mindfulness meditation and mindful hatha yoga and preconizes present-centered non-judgmental acceptance, awareness, and attentiveness compassion. 8 MBSR is based on four foundations: awareness of the body, feeling tone, mental states, and mental contents and is based in formal and informal practices: "mindful movement (gentle hatha yoga with an emphasis on mindful awareness of the body); the body scan (designed to systematically, region by region, cultivate awareness of the body-the first foundation of mindfulness-without the tensing and relaxing of muscle groups associated with progressive relaxation); and sitting meditation (awareness of the breath and systematic widening the field of awareness to include all four foundations of mindfulness: awareness of the body, feeling tone, mental states, and mental contents)" (p. 188). 4 The gold-standard model which is in the base of other two main MBIs have been increasingly used to improve psychological health in diverse psychological and health conditions, for example, inflammatory bowel disease. 9 In particular, MBSR and MBCT suggest being effective for improving mental health outcomes in people with vascular disease 10 and with chronic fatigue syndrome. 11 In the context of cancer, MBIs such as MBSR, MBCT, and MBCR or their modified versions are the most used standardized protocols and have been applied to reduce distress in patients across all stages of the disease. 12 MBCT was initially created to be a relapseprevention therapy for major depression disorder. 13 It modified the classic structure of MBSR to include components of cognitivebehavioral therapy. The MBCR is an adaptation of the MBSR program to make it more suitable for cancer patients. 14 Evidence supports that MBIs can improve the psychological health of individuals with cancer, 15 cancer-related fatigue, 16 and, more recently, cancer-related biomarkers. 17 Research on the communication between psychological and biological aspects of cancer has been growing over the last few years.
There is a growing interest in understanding the interconnections between biological and psychological systems, aiming to find effective ways to improve health outcomes (biological and psychological) in cancer patients and survivors. [17][18][19] Several studies and, consequently, reviews have summarized the evidence on some of these outcomes. A descriptive review on mindfulness and biomarkers in cancer patients found that participation in MBIs impacts psychological measures and biological parameters (immune function, hypothalamic-pituitary-adrenal axis regulation, and autonomic nervous system activity). 18 However, this review was not systematic, which imposes a methodological limitation. Sanada and colleagues reviewed the effects of MBIs on biomarkers in cancer and healthy groups and found some evidence of changes in cytokine levels. 17 The majority of reviews focused exclusively on physiological outcomes or only on psychological outcomes. It brought a challenge to interpret and inform health professional's decision-making, namely PEDRO ET AL.
-1837 due to the heterogeneity of participants included and incongruence in MBI definition, which might have contributed to different results.
The goal of this meta-review is to sum all evidence presented in previous reviews investigating the effect of structured MBIs on psychological outcomes (such as anxiety, depression, and stress), quality of life (QoL), as well as biological outcomes (e.g., inflammatory response), focusing on patients with cancer and cancer survivors.
Using systematic reviews as a unit of analysis allows addressing broader research questions than those examined in individual systematic reviews, and understanding the diversity present in the existing systematic review literature. 20 We hope that this work might help clarify the available evidence on the effectiveness of structured mindfulness interventions, identify specific gaps in scientific literature, guide future research, and inform health providers' decisionmaking.

| Study design
A meta-review of reviews was conducted following the PRISMA-P guidelines (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 21 and guidance from Cochrane 20 and Smith and colleagues 22 on methodology in conducting a systematic review of systematic reviews of healthcare interventions. The protocol of this meta-review was pre-registered in PROSPERO (CRD42020186511). systematic review/meta-analysis methodology.

| Search strategy
The preliminary search expression used for Medline was the following: ("Meditation intervention" OR mindfulness OR "Mindful*psychotherap*" OR meditation OR MBIs OR "Mindfulness-Based Stress Reduction" OR MBSR OR "Mindfulness-Based Cognitive Therapy" OR MBCT) AND (cancer OR "cancer survivor" OR "cancer recovery" OR "cancer survivorship") AND (meta-analysis OR "systematic review" OR review).

| Inclusion and exclusion criteria
Systematic reviews addressing the effectiveness of MBIs conducted with adult cancer patients and/or survivors were included. Following Smith 22 and Cochrane guidelines, 20 the inclusion criteria were defined so that the included systematic reviews were sufficiently homogenous regarding interventions, population, comparators, and outcome measures. The criteria for inclusion were as follows 1 : being a systematic review or meta-analysis of randomized controlled trials The exclusion criteria were as follows 1 : reviews that addressed other types of mindfulness or meditation-based techniques (e.g., complementary therapies, yoga solely, tai-chi; mind-body therapies focused only on exercise and meditation/yoga) 2 ; reviews considered of low-quality 3 ; grey literature: thesis, letters, editorials, posters, and not peer-reviewed papers 4 ; reviews presenting a significant overlap of studies included (see Table S1).

| Study screening and selection process
All entries were imported to Covidence software (www.covidence.org) This software facilitates the management of databases-selected entries, search for duplicates, and selection process conducted by independent reviewers. In the first phase, entries were inspected for duplicates. Then, titles and abstracts were screened for eligibility independently by two reviewers (JP and ES). Subsequently, a full-text evaluation was conducted on those who met the previous criteria.
Disagreements at each stage of screening and selection were solved by discussion between the two authors.

| Data extraction
One author (JP) conducted the data extraction, which was crosschecked by the last author (ES). The data extracted included the author, year, country of publication, type of review, database searched, restrictions (e.g., language, dates), interventions addressed, number of studies included, quality assessment of studies included in the review, population/sample characteristics, interventions, primary outcome, and findings. The overlap of systematic reviews based on exactly the same primary studies was resolved by selecting only one of them, being this the most recent, complete, and extensive systematic review. According to the method suggested by Pollock,20 since the main goal is not to re-systematically review the primary studies, only studies where conclusions can be extracted (based on evidence, preferably meta-analysis results) will be included.

| Assessment of review quality
AMSTAR tool 23,24 was used to assess the quality of the systematic reviews included. This tool was found to be reliable 24 and has been used in several meta-reviews. 25,26 Previous studies using AMSTAR considered scores indicating low quality (score 0-4), moderate quality (score [5][6][7][8], and high quality (9)(10)(11). 25,26 According to this criteria, only reviews with a moderate or higher score (5 or above) were included in this meta-review. The first author evaluated all the studies, and 50% of these were evaluated by the second author.

| Strategy for data analysis and synthesis
The information extracted from the included studies was summarized in tables, describing the characteristics of studies included and a summary of the main findings and conclusions. A narrative synthesis approach was used to conduct this meta-review. 27 Included studies were categorized, analyzed, and presented according to the outcomes reported (psychological, biological). In addition, results on subgroup analysis and moderators will be described, if available. Data on heterogeneity, sensitivity analysis, and other risk bias will be extracted and summarized for each study included. on title and abstract. In this phase, 331 were irrelevant. During the full-text phase, 148 studies were assessed for eligibility. One hundred and thirty-eight did not meet the inclusion criteria (see Figure 1 for details), and thus, 10 studies were included in this meta-review.

| Overlap between studies
Overlap between studies is summarized in Table S1. One review 29 included primary studies that were all present in the other reviews, so it was excluded from the present study. The majority of other reviews included presented significant overlap; however, all of them included studies that were only present once; in this sense, no other review was excluded. On average, each study was included in two reviews. The number of reviews that included the same primary study range from one to seven; only four original studies were presented in more than four reviews.

| Studies quality
Using AMSTAR tool, studies had a mean quality value of 8.6 (range 5-10), meaning that all included studies were of high quality (all studies were classified 5 or above). The rate of agreement between the first and the second authors was high (all studies were rated as 5 or above by both authors, being the maximum difference between quality rates 3 points). Table 1 shows the characteristics of the 10 included studies. Studies were published between 2012 and 2020. The studies were from China (n = 2), Germany (n = 2), Denmark (n = 2), United States (n = 1), Singapore (n = 1), and Spain (n = 1). All studies included used more than two databases for their systematic searches, with Medline,

| Psychological outcomes related to mental health
In general, most systematic reviews and meta-analyses concluded that MBSR/MBCT/MBCR had a significant and beneficial effect on anxiety symptoms, depression, stress, and general psychological outcomes.
Calero and colleagues concluded that all studies found a significant improvement in psychological symptoms, including anxiety, depression, stress, and QoL and fear of recurrence. 30

| Biological outcomes
The effects of mindfulness on immune-related biomarkers have also been reported in two studies included in this review. 30,31 In this context, MBSR/MBCT/MBCR were shown to improve Tand natural killer (NK)-cells activity, as well as an immune recovery (measured by the T helper (Th)-1/Th-2 and CD4+/CD8+ ratios) (data described, not pooled effects available). 31 In another study, increased telomere activity was associated with the implementation of structured MBI. 30

| Moderators
The studies included performed subgroup and other analyses to explore the role of moderators on the effectiveness of MBIS. Cillensen reported that larger effects on psychological distress were found in younger patients when comparing with passive control conditions, shorter follow-up times. 12

| Publication bias, heterogeneity, and quality of the evidence
The majority of studies assessed the methodological quality of studies included, assessed heterogeneity and other risks of bias relevant. In sum, the majority reported some concerns regarding quality and heterogeneity between studies was frequent. Some of the studies could not report the risk of bias and conduct sensitivity analysis due to a low number of studies included.
Cramer et al. assessed heterogeneity and concluded that age was similar among studies but found some heterogeneity regarding treatment phase (some patients were in adjuvant treatments, others finished the treatment) 31 ; sensitivity analysis and publication bias were not possible to assessed due to the small number of studies included in the meta-analysis. Cillensen reported a slightly small publication bias. 12 Haller et al. 33 used the Cochrane risk of bias tool and reported that findings were robust to methodological bias since results did not change when only studies with low risk of bias were considered; however, the number of studies was low, and the reported effects were below the criteria to be considered clinically relevant. Piet and colleagues reported a low-to-moderate heterogeneity between included studies, and no evidence of publication bias was found for short-term results; RCTs reported successful randomization (no baseline differences on characteristics); however, the results on follow-up were considered less robust. 34 Schell et al. noted that all studies included were at high risk of performance, detection, and selection bias. Even though, results on short-term and medium-term effects for anxiety were considered high-certainly evidence and for depression moderatecertainly evidence, using GRADE tool. 35 Xunlin et al. 36   mindfulness, even after people have survived the disease. FCR is highly frequent among cancer survivors, being estimated that more than half experience FCR moderate and high intensity. 40 The intensity of FCR has been linked with dysfunctional levels of worry in all-day life, affecting well-being and emotional and social functioning. 41 The studies included in this meta-review exploring this outcome were published recently. Other recent studies have conceptualized an MBCT program targeting FCR 42 and tested its effectiveness, 43,44 with results remaining 4 weeks after the intervention. 43 Thus, it could be that mindfulness programs targeting this specific concern would be of great clinical value to cancer survivors.

| Study limitations
Although numerous reviews address the effects of MBSR/MBCT/ MBCR, the evidence is based on some overlapping studies, which may bias the results found. For this reason, one review was excluded since all primary studies included were presented in other reviews.
Our overlapping analysis showed us that, on average, the same primary study was included twice. Even though the overlapping seems not to be highly significant, results should be interpreted with caution.
Importantly, although only studies that included and reported separated results for cancer patients and survivors were included, some bias might occur with the results found. The inclusion and exclusion criteria were diverse among the studies included in this meta-review. For example, some included only breast cancer patients, others included other cancer types, and some included both.
Although we only retained the studies in the reviews that met all of our criteria, the samples characteristics were slightly different across the studies that examined the effectiveness of MBSR/MBCT/MBCR.
Half of the studies focused exclusively on breast cancer, and as a consequence, female patients are overrepresented. This might contribute to biased results: on the one hand, women seem to participate more in research, and an effect of social desirability might happen; on the other hand, due to the hormonal contribution of menopause, the results might be different among those in before and after menopausal phase. 45 However, the majority of the reviews included found low heterogeneity in the sample characteristics. In general, the studies included estimated a low risk of bias, and sensitivity analysis showed robust short-term results. The majority reported moderated quality of the primary studies included. However, some also reported the impossibility of running sensitivity and risk of publication bias analysis due to the low number of studies included. 33 This meta-review highlighted the need for future studies exploring the differences between different age groups, cancer type, and treatment status as moderators of the effects of MBSR/MBCT/ MBCR.
Additionally, the methodological options of the included studies may have introduced some bias, such as the use of different control groups: "white" control groups (waitlist; no intervention) and active control groups may also contribute to the above-mentioned bias. The treatment and procedures offered as "usual" care might significantly differ between cancer hospitals or even more between different settings (hospital vs. other settings). It should be noted that studies with passive control conditions (compared with active/competing conditions) seemed to report more beneficial results. 31,33 Further studies might focus on studying the common factors between these interventions. Evidence has shown that common factors such as alliance and empathy are determinant factors for the effectiveness of different psychological interventions. 47 In this way, future studies exploring the role of these variables might contribute to a more accurate "picture" of these effects.

ACKNOWLEDGMENTS
This study is part of the MindGAP project funded by European