Impact of Exercise Training on Depressive Symptoms in Cancer Patients: A Critical Analysis

Simple Summary Cancer patients need to overcome several issues, leaving them more vulnerable to depressive symptoms. Exercise is recognised as a practice that helps to deal with depressive symptoms. This study is an umbrella review of meta-analyses about the effect of exercise on depressive symptoms among cancer patients. Six studies were included. A significant reduction in depressive symptoms was observed because of exercise. However, the studies varied in methodological terms, making a broad generalisation difficult. We can conclude that exercise is a good alternative to deal with depressive symptoms among cancer patients. Still, more studies are needed to clarify some aspects that are not answered yet. Abstract Background: Cancer patients must deal with several health challenges, including emotional distress and depressive symptoms. This study aimed to evaluate evidence from published systematic reviews and meta-analyses about the efficacy of exercise on depressive symptoms in cancer patients. Methods: We searched for previous meta-analyses of randomised controlled trials on PubMed, Web of Science and Scopus, with data inception to 30 December 2021. Two independent researchers assessed the methodological quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR2) instrument. Six meta-analyses were integrated. All included middle-aged and older adults. Five presented moderate quality, and one presented low quality. Results: Overall, a significant reduction in depressive symptoms was observed among the included studies. However, the heterogeneity between studies was high, and high-quality evidence for the efficacy of exercise on depressive symptoms was limited. Conclusions: Exercise could be a possibility in the treatment of depressive symptoms in cancer patients, especially when supervised and outside the home. The better dose of exercise needs to be clarified. More high-quality evidence is needed to better prescribe exercise to this vulnerable population.


Introduction
Cancer is a global public health issue, with 19.3 million new cases of cancer diagnosed in 2020 and 10 million individuals dying from the disease [1]. Cancer occurs mostly with older age and in the United States of America, and 90% of cancers are diagnosed in those aged >50 years [2]. Female breast cancer is the most commonly diagnosed cancer (11.7%), followed by lung (11.4%), colorectal (10.0%), prostate (7.3%), and stomach (5.6%) cancers [1]. Despite the lethality of different types of cancer, many cancer patients survive. However, cancer patients are in a vulnerable situation since they go through several health challenges, as cancer diagnosis and treatment have a serious impact on their physical and mental well-being [3]. Cancer patients experience several emotional disruptions, such as fear of death, interruption of life plans, decreased body image and self-esteem, and changes in social role and lifestyle [4]. One of the most common impacts is depression, which affects up to 20% of patients with cancer [5], however, the prevalence rate of depression among cancer patients is heterogeneous, according to clinical setting [6], the stage of the disease [5,7] and type of cancer [8], ranging between 5% and 49% [9]. Aggravating this issue, depression in cancer patients is associated with low chemotherapy compliance [10] and an increased risk of death [11]. Therefore, the treatment of depression among cancer patients should be a priority. However, there is still the notion that depression is inevitable and untreatable [12]. In addition, there is limited trial data on depressive symptoms' treatment efficacy in cancer patients [13]. Pharmacological therapy, consisting of antidepressant medications, is usually considered for the treatment of moderate to severe major depression; also, a combined modality approach, including psychosocial and pharmacologic interventions, is a feasible alternative [14].
Alongside pharmacological and psychosocial therapy, exercise can have a positive impact on depressive symptoms [15]. Several mechanisms are involved in the association between exercise and depression, from neurobiological to behavioural mechanisms [16]. One is the inflammation-related factors (IRFs) [17], where studies have shown an association between inflammatory markers and depressive symptoms, including fatigue, impaired sleep and cognitive dysfunction [18,19]. Exercise could create an anti-inflammatory environment and reduce the serum level of leptin and fibroblast growth factors (FGF) [20]. IL-10, produced by exercise, acted as an anti-inflammatory cytokine and is stimulated by the release of adrenaline and cortisol from the adrenal gland, which reduces the release of pro-inflammatory cytokines in the hippocampus [21]. Regarding behavioural mechanisms, exercise can promote several behavioural changes. Engagement in exercise programs and learning new movements skills or completing physically challenging exercises may lead to gaining a sense of mastery [22]. The activity-based perception of physical strength and flexibility is associated with increased physical self-esteem and consequently, an increase in global self-esteem [23].
Regular exercise after diagnosis increases survivorship by 50-60%, with strong evidence for breast and colorectal cancers [15]. In addition to improving depressive symptoms, exercise positively impacts other depression-and cancer-related outcomes, such as anxiety, fatigue, physical functioning, and health-related quality of life [3]. Although the efficacy of exercise interventions in reducing depressive symptoms among cancer patients was already established by previous systematic reviews and meta-analyses [24][25][26][27][28][29], previous studies substantially vary in scope, quality and methodology, which can cause considerable confusion and misdirect efforts in the implementation of exercise interventions. An umbrella review of previous research is warranted to better inform future trials needs, as well as establish a consistent message for health policies targeting this vulnerable population. The specific questions that we should answer with this study are: (1) regarding some aspects of exercise intervention, such as the type of exercise, the dose of exercise, the difference between home-based exercise and other locations, which are the most effective to deal with depressive symptoms? (2) Regarding the difference between the type of cancer, the moment of the exercise intervention, before, during or after cancer treatment, are there any differences? Therefore, this study aimed to present an umbrella review of an exercise inter-vention on depressive symptoms among cancer patients, appraising hints of uncertainty and bias in the body of literature and providing recommendations for future research.

Literature Search
The protocol of this umbrella review was registered under PROSPERO (CRD42021254843) and followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines [30]. Two researchers performed the literature search in PubMed, Web of Science, and Scopus, focusing on meta-analyses published until 30 December 2021 to investigate the efficacy of exercise in reducing depressive symptoms among cancer patients. In cases of disagreement, a third researcher was asked to arbitrate. The search terms were: ("physical activ*" OR "physical inactiv" OR exercise OR training OR sport* OR fitness OR "movement behavio*" OR walking OR running OR yoga OR jogging OR swimming OR cycl*) AND (depress* OR "mental health" OR mood OR "psychological health" OR "psychological function*" OR "mental function*" OR worries OR worry OR "depressive disorder*" OR "baby blues") AND (cancer OR neoplas* OR tumor OR chemo* OR radiat* OR malign* OR carciniom*) NOT Rats. No language limitation was established. Records previously known to the authors were also identified.

Eligibility Criteria
Included articles in the systematic review met the PICOS (participants, intervention, comparison, outcome, study design) criteria [31]. The criteria included characteristics of participants (cancer patients); intervention (any type of exercise); comparison: regular care or physical activity; outcome (depressive symptoms diagnosed using a structured clinical interview, screened for probable depression using a validated assessment, or diagnosed according to the judgement of a health professional); study design (meta-analyses of parallel designs, controlled trials. Meta-analyses were excluded if the studies involved animals.

Quality Assessment
Two authors assessed the methodological quality of the included meta-analyses using the Assessment of Multiple Systematic Reviews (AMSTAR 2) checklist. Scores range from 0 to 11, with higher scores indicating greater quality [25]. The AMSTAR checklist involves the dichotomous scoring (0 or 1) of 11 items related to the rigour of systematic reviews and meta-analyses (e.g., comprehensive search strategy, publication bias assessment). AMSTAR scores are graded as high (8)(9)(10)(11), medium (4-7), and low (0-3) quality [32]. The authors discussed grading discrepancies and reached a consensus.

Literature Search
The study selection process is summarised in Figure 1. A total of 54 records were identified in the literature search, 53 from the databases and 1 from other sources, i.e., previously known to the authors. After removing the duplicates (n = 32), two researchers reviewed the remaining 22 records' titles and abstracts. Ten records were excluded at this stage. The remaining 12 records' full text were assessed for eligibility. From this analysis, six records were excluded for the following reasons: another type of intervention (n = 1); without meta-analysis (n = 3); without data on depressive symptoms (n = 2). Therefore, six records were included in this study [24][25][26][27][28][29].

Study Characteristics
The characteristics of the meta-analyses included in this umbrella review are presented in Table 1.

Number of RCTs and Participants
The number of participants included in each meta-analysis varied according to the number of included RCTs. The Brown et al. research had the largest sample, including 37 RCTs and 2929 participants [24], while Vashistha et al. presented the smallest sample, with three RCTs and 196 participants [28]. Considering all the included meta-analyses, this study undertook 100 RCTs and 8125 participants. The overlap of single studies within the six included meta-analyses was low (27%), leading to a final number of 79 RCTs.

Participants' Characteristics
The mean age of the participants ranged between 45 [29] and 73 years [28]. The mean age of five [24][25][26][27]29] out of the six included studies is above 50 years, that is, patients of older age. Two meta-analyses only included women [27,29], the other two meta-analyses included men and women [24,26], and one meta-analysis only included men [28]. One meta-analysis did not present participants' gender information [25]. Two meta-analyses were focused on breast cancer [27,29]. In three other meta-analyses, most RCTs were focused on breast cancer (24 out of 37 [24], 60% of participants [25], and 18 out of 26 [26]). One meta-analysis was focused on prostate cancer [28].

Quality Assessment of Studies
All included meta-analyses conducted a risk of bias analysis regarding single studies. Three of them used the PEDro scale. The mean PEDro score was 7.0 ± 1.0 in Brown's study [24], representing high quality. In the Craft's study, all with the exception of three studies attained high quality [25]. Additionally, in Patsou's study, the mean PEDro score indicated high quality (6.1 ± 2.0) [27]. The other three studies used the Cochrane risk of bias tool, assessing six aspects of the trial methodology. Under each domain, studies were classified as low, high or unclear risk of bias. More details about each domain for each study analysed can be seen in the original paper [26,28,29]. Table 2 presents the results obtained with the AMSTAR 2 checklist regarding the methodological quality of the meta-analyses. All meta-analyses, except one, presented a moderate-quality review. Vashistha et al. [28] had a low-quality review, mostly because it did not account for the risk of bias in individual studies when interpreting the review results. 1. Did the research questions and inclusion criteria include the components of PICO?

Quality Assessment
Did the review report contain a statement that the review methods were established before the conduct of the review, and did the report justify significant deviations from the protocol?
10. Did the review authors report funding sources for the studies included? X X X X X X 11. If meta-analysis was performed, did the review authors use appropriate methods for the statistical combination of results?
12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?
13. Did the review authors account for RoB in individual studies when interpreting/discussing the review results?
14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the review results?
15. If they performed quantitative synthesis, did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the review results?
16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?
Note: V when it fulfills the evaluation criterion and X when it does not fulfill the evaluation criterion.

Main Results
The main results of each included meta-analysis are summarised in Table 3. Different methods were used to present aggregate effects, including Cohen's d, Hedges' g statistic, and the standardised mean difference (SMD) using a random-effects model. In four out of the six included meta-analyses, the authors observed a significant reduction in depressive symptoms favouring the exercise group. In studies from Patsou et al. [20] and Vashistha et al. [21], no statistically significant decrease in depressive symptoms for the exercise group was observed. Three meta-analyses, Brown et al. [17], Craft et al. [18] and Patsou et al. [20] observed small effect sizes, whereas two meta-analyses, Gonzalez et al. [19] and Yi et al. [22], reported moderate effect size. All the included meta-analyses presented a large or very large heterogeneity (I2 from 55% to 84%). Table 3. Results of the meta-analyses included in the study.

Sensitivity and Subgroup Analyses
Four of the six included meta-analyses presented sensitivity or subgroup analyses. Regarding the type of cancer, the Brown et al. [17] subgroup analysis revealed significant reductions in depressive symptoms among breast cancer patients (d= −0.17; 95% CI: −0.32, −0.02), but non-significant differences for prostate, leukaemia, lymphoma and colorectal cancer patients. Gonzalez et al. [19] proceeded with a subgroup analysis of only breast cancer patients and presented a significant moderate reduction in depressive symptoms favouring exercise (g = −0.41; 95% CI: −0.59, −0.23).
Regarding participants' age, only Brown et al. [17] explored this subgroup analysis and showed that exercise was the most effective when cancer patients were between 47 and 62 years (ß = −0.27, p = 0.01). Among older adults, the effect of exercise on depressive symptoms was not significant.
The Gonzalez et al. [19] sensitivity analysis showed that removing one study greatly reduced heterogeneity (I2 = 36.9%) but also reduced the effect size to the small-medium range (g = −0.41; 95% CI: −0.55, −0.28). Additionally, comparing studies that used active and inactive control interventions did not find differences; both had a significant, medium to small effect size post-intervention.

Discussion
This umbrella review included six meta-analyses that comprised 100 individual studies with little overlap that investigated the effect of exercise on depressive symptoms among cancer survivors. Overall, a small significant reduction in depressive symptoms in this vulnerable population was observed in the studies. However, high-quality evidence for the efficacy of exercise on depressive symptoms is limited. For a more detailed analysis, some points need to be considered, such as the type of cancer, the specificity of exercise prescription, the time of interventions, and during or after cancer.
In our umbrella review, participants had mainly breast cancer in the included metaanalysis and were mostly women. Only one study did not include breast cancer [27] and was with prostate cancer patients, and it was the one that did not observe a significant effect of exercise on depressive symptoms. In a subgroup analysis, Brown et al. found a significant reduction in depressive symptoms among breast cancer survivors but did not find the same in prostate, leukaemia, lymphoma and colorectal cancer [17]. The prevalence of depression among breast cancer survivors is higher than in other cancers and can achieve 32.8% [35]. Moreover, depression is more prevalent in women than men [36], and breast cancer is prevalent in women. Evidence suggests that depression in breast cancer patients decreases over time and is more common throughout the disease and in the recurrent phase of breast cancer [37]. The occurrence of depression among patients with breast cancer is due to several factors, such as treatment-related distress, worries regarding fear of death and disease recurrence, and altered body image, sexuality and attractiveness [38][39][40]. In addition, a study exposes the association between depression and tumour levels of estrogen receptors and progesterone receptors [41]. A study found that fatigue and pain are significant risk factors for developing depression among breast cancer survivors [37]. Fatigue is also a recognised barrier to exercise [42]; however, exercise can reduce fatigue among women with breast cancer [43]. The benefits of exercise can be extended to improve physical functioning and multiple aspects of quality of life among cancer patients [44]. Moreover, exercise is a feasible alternative to control symptoms burden and improve well-being among breast cancer patients [39].
Another sample characteristic that must be highlighted is that most patients were older adults (>50 years old). In the general population, the prevalence of depression symptoms rises with increasing age, 10% to 15% of older adults have clinically significant depressive symptoms [45]. Older patients with cancer often experience depression, fatigue, pain, and sleep disturbance [46]. Only one included meta-analysis directly explored the role of age in the effectiveness of exercise on depression symptoms and found that the efficacy seems to disappear among old age patients [24]. However, an RCT with older cancer patients receiving chemotherapy found that after the six-week structure exercise program, participants' anxiety and mood improved [47]. Besides the effects of exercise on mental health, physically active old age patients improve general health, such as physical fitness outcomes, quality of life and increased life expectancy [48].
When considering the effects of exercise on depressive symptoms, it is necessary to consider the characteristics of the exercise we are referring to. Many dimensions of exercise exist, which are captured in part by the principle (frequency, intensity, time and type of exercise), as well as the way of practising, whether accompanied or not and if exercise occurs indoors or outdoors. However, the included systematic meta-analyses showed great variance concerning exercise. Except for Gonzalez et al. and Yi et al. [26,29], which analysed the effects of yoga intervention, the others included meta-analyses that examined a variety of exercises, such as aerobic (e.g., walking, cycling), resistance (e.g., weight machine, resistance bands) and qigong. Only the Patsou et al. study explored the difference between the types of exercise and found that aerobic intervention yields a large significant effect on depressive symptoms. At the same time, resistance training presents a small significant effect, and combined aerobic and resistance training yielded a moderate effect [27]. This statement is in accordance with the American College of Sports Medicine (ACSM), which describes that resistance training alone does not seem effective for depression [3]. Aerobic activities are cost-effective and should be popularised in clinical practice.
Regarding yoga, both included meta-analyses that analysed only intervention found significant and medium effects on depressive symptoms [26,29]. However, in the Patsou et al. study, which included aerobic exercise, resistance exercise and yoga intervention, when a subgroup analysis proceeded and considered only yoga intervention, no significant difference in depression symptoms was observed [27]. The contradictory results found in the three studies can be explained by the fact that yoga combines breathing (pranayama) and meditative techniques during a series of postures (asanas), but different types of yoga were being practised, which made it difficult to understand the effects of this practice [49].
Two included meta-analyses found that supervised exercise is more efficient than non-supervised exercise [32,38], which also appears in the ACSM recommendation [3]. Craft et al.'s study [25] explored the effects of exercise session durations and found that more than 30 min had larger effects compared with less than 30 min of the exercise session. In Patsou et al. [27] ≤135 min/week yielded a moderate to large effect and no effect with ≥135 min/week of exercise. The ACSM describes that aerobic training performed three times per week and for at least 12 weeks or twice weekly with combined aerobic plus resistance training lasting 6 to 12 weeks, can significantly reduce depressive symptoms in cancer survivors during and after treatment. However, the exact exercise duration per week has not yet been established by the ACSM. Gonzalez et al.'s study [26] explored the frequency and found no differences between one class per week and two or more classes per week. In contrast, Patsou et al. [27] explored the exercise intervention program duration and found that exercise for up to 12 weeks yielded a moderate to large effect compared with a small effect of over 12 weeks. Aside from the efficacy of depressive symptoms, exercise has other benefits in health outcomes among cancer survivors that must be considered such as improving cardiorespiratory fitness [50], and muscle strength [51,52].
Another important aspect of the efficacy of exercise on depressive symptoms among cancer survivors is the time of intervention, before the diagnosis, during treatment or in a recovering phase. This aspect was explored, and no difference was found between patients receiving cancer treatment, following treatment or mixed treatment status [26]. On the other hand, patients under treatment yielded a moderate effect, and patients post-treatment yielded a small effect [27]. Exercise increases the chemotherapy completion rate during treatment without causing lymphedema or significant adverse events [53]. In addition, exercise appears to reduce chemotherapy-induced peripheral neuropathy symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy [54].
Concerning the methodological quality, the AMSTAR 2 scores show that the majority were of moderate methodological quality. Nevertheless, as for item #10, "Did the review authors report on the sources of funding for the studies included in the review", no study reported the source of funding which can entail a risk of bias.

Strengths and Limitation
The strength of our study is that we included two recent meta-analyses, one from 2020 [19] and one from 2021 [22], and compiled current data regarding the effectiveness of exercise in depressive symptoms among cancer patients. However, some limitations should be exposed. The prevalence of breast cancer was substantial, which prevented us from generalising the findings to other types of cancer. Two studies did not perform subgroup analysis, and those who performed subgroup analysis did not analyse the same constructs, specifically in relation to the FITT principles of exercise. Future research is required to clarify the effectiveness of different intervention modalities (frequency, intensity, time and type) for depressive symptoms among cancer survivors to allow determination of exercise dose-response. Moreover, additional studies are needed to evaluate the cost-analysis and adverse events of exercise, and there is an urgent need for innovative methods to generate high-quality evidence.

Conclusions
Our critical review contributed to the evidence of the effects of exercise on depressive symptoms among cancer patients. Four in six studies found a significant effect of exercise. Some aspects should be highlighted and should be used for future interventions. Supervised exercise is better than non-supervised. The dose of exercise seems to be important, however, the finding did not present a specific dose-response relation. Exercise outside of the home is better than home-based exercise. Aerobic exercise is the most effective type of exercise. The effect of exercise on depression seems to be more effective among breast cancer patients. Future studies should explore other types of cancer.