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

**Priscila Marconcin 1,2,\*, Adilson Marques 1,3 , Gerson Ferrari <sup>4</sup> , Élvio R. Gouveia 5,6,7 , Miguel Peralta 1,3 and Andreas Ihle 7,8,9**


**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.

**Keywords:** tumour; exercise; depression; mental health; cancer survivorship

**Citation:** Marconcin, P.; Marques, A.; Ferrari, G.; Gouveia, É.R.; Peralta, M.; Ihle, A. Impact of Exercise Training on Depressive Symptoms in Cancer Patients: A Critical Analysis. *Biology* **2022**, *11*, 614. https://doi.org/ 10.3390/biology11040614

Academic Editor: Redha Taiar

Received: 1 March 2022 Accepted: 14 April 2022 Published: 18 April 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **1. 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 [24–29], 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 intervention on depressive symptoms among cancer patients, appraising hints of uncertainty and bias in the body of literature and providing recommendations for future research.

#### **2. Materials and Methods**

#### *2.1. 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.

#### *2.2. 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.

#### *2.3. 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 (8–11), medium (4–7), and low (0–3) quality [32]. The authors discussed grading discrepancies and reached a consensus.

#### *2.4. Data Extraction*

Study characteristics were extracted from full texts, including the number of randomised controlled trials (RCTs) and participants; participants' characteristics; exercise intervention's characteristics; comparisons; and outcomes measures. Data on the standardised mean difference (SMD) and heterogeneity (I2 statistic) in meta-analytic comparisons were also extracted. The SMD was classified as trivial (<0.20), small (0.20 to 0.49), medium (0.50 to 0.79) or large (≥0.80) [33]. I2 statistic values were considered to be representative of low (0 to 25%), moderate (25 to 50%), large (50 to 75%) or a very large (>75%) inconsistency [34].

### **3. Results**

#### *3.1. 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 [24–29].

**Figure 1.** PRISMA flow diagram of study selection.

### *3.2. Study Characteristics*

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

*Biology* **2022**, *11*, 614


\* Gonzalez et al. [26] analysed 26 RCTs, but 1 was not included in the meta-analysis. \*\* Vashistha et al. [28] analysed 13 RCTs, but only 3 included measures of depressive symptoms.

\*\*\* Yi et al. [29] analysed 8 RCTs, but only data regarding the 6 that analysed depressive symptoms is presented.

### *3.3. 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.

#### *3.4. Participants' Characteristics*

The mean age of the participants ranged between 45 [29] and 73 years [28]. The mean age of five [24–27,29] 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].

#### *3.5. Exercise Intervention Characteristics*

Different types of exercise interventions were included, such as aerobic training (e.g., walking, cycling) [24,25,27,28], resistance training (e.g., weight machines, resistance bands) [24,25,27,28], yoga [24,26,27] and qigong [28]. The duration and session frequency were also different for each intervention. For instance, the mean duration of the intervention in the three meta-analyses that reported this information was 13 weeks [24], 4 to 14 weeks [25], and 9 weeks [26].

#### *3.6. Comparison of Experimental Conditions*

Exercise interventions were compared with different control conditions, including: no exercise program [24], usual care [25–29], educational print material [25], psychosocial or educational interventions [26], and stretching [27,28].

#### *3.7. Outcome Measures*

Depressive symptoms were assessed by different instruments, such as the Center for Epidemiological Studies—Depression [24,26–29], the Profile of Mood States [24,26,29], the Beck Depression Inventory [24,26,29], the Hospital Anxiety Depression Scale [24,26,27,29], the Symptoms Assessment Scale [24], the Patient Health Questionnaire [26], the Brief Symptom Inventory [28], and the Self-rating Depression Scale [29].

#### *3.8. 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].

#### *3.9. Quality Assessment*

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.



Note: V when it fulfills the evaluation criterion and X when it does not fulfill the evaluation criterion.

**Table 2.** Quality of the meta-analyses included in the study according to AMSTAR 2 criteria.
