Effects of physical exercise on the functional capacity and muscle strength of patients with gastric and esophageal cancer: a systematic review

Esophageal and gastric cancers have a significant prevalence. These patients often face a decline in functional capacity (FC) and muscle strength (MS), as consequence of neoadjuvant treatments and surgical resection; however, this decline can be minimized through appropriate exercise protocols. To assess evidence of the effects of physical exercise on HR and MS in patients with esophageal and stomach cancer. Systematic review of Randomized clinical trials with intervention based on exercises for patients with esophagogastric cancer (EGC). FC and MS were the outcomes. Searches in Medline via Pubmed, PEDro, Cochrane Library, Embase and CINAHL databases were performed. Cochrane Collaboration tool and GRADE system for risk of bias assessment. From 117 articles identified, eight studies were included, involving a total of 673 patients. In general, the approach during neoadjuvant therapy had a positive effect on the 6-minute walk test (6MWT) and on FM. Exercise performed in the preoperative period showed divergent results for inspiratory muscle strength, but improved HR assessed by the 6-minute walk test (6MWT). The postoperative exercise protocol increased the FC in 6MWT, and maximal oxygen consumption (VO2max). However, it does not improve MS. Studies also showed a moderate-to-high risk of bias. Although some studies point to positive results in favor of physical exercise in improving FC and MS in patients being treated for esophagogastric cancer, the degree of clinical recommendation is low. study evaluated the impact of exercise on functional capacity and muscle strength during neoadjuvant In this study, the intervention group (IG) was submitted to a supervised walking exercise protocol thrice a week and nutritional counseling once a week. The exercise consisted of 5 minutes of warm-up and 20 minutes of walking at the patient's pace, before and after neoadjuvant therapy (chemotherapy and radiotherapy). Functional capacity was assessed by 6MWT and peripheral muscle strength by handgrip strength (HGS). Analysis of pre-treatment and post-treatment changes indicated that the intervention group had a significantly lower decline in the 6MWT walking distance when compared to the usual care control group (CG) (18 vs. 118 m; group difference: 100, adjusted p = 0.012). Similarly, the IG had significantly lower decline in FPP when compared to the CG (1.1 vs. 4.1 kg, respectively, mean difference between groups (CI: 95%): 3.0 (1.3 – 4.9); adjusted p = 0.002). shoulder and strength for the extensors of the back, shoulders and legs, The intervention one week after and lasted until the in intensity during the period. Preoperative postoperative grip strength the dominant hand) IG CG. strength postoperatively


Introduction
Cancer is the leading cause of death and a barrier to increasing life expectancy worldwide. World statistics revealed about 19.3 million new cancer cases and nearly 10.0 million cancer deaths for the biennium 2020-2021 (Sung et al., 2021). In addition, stomach and esophagus cancer accounts for 5.6% and 3.1% of expected new cases, respectively, as well as 7.7% and 5.5% of estimated deaths, respectively (Sung et al., 2021).
The clinical approach to esophageal or gastric cancer involves a combination of treatments, including chemotherapy and/or neoadjuvant radiotherapy followed by surgical resection. Neoadjuvant therapy in esophagogastric cancer (EC) is associated with short-and long-term adverse effects, in addition to nutritional compromise (Tully et al., 2020).
Surgery, in turn, is planned for up to 80% of esophagogastric cancer patients, and is considered primordial for curative or palliative treatment (Carcas, 2014). Open resection, however, is associated with greater trauma, numerous complications, slow recovery, prolonged hospitalization, and many other problems (Sato et al., 2015). The act itself represents a stressful event that can lead to adverse effects unrelated to the objective of treatment, impairing postoperative recovery (Gonçalves & Groth, 2019). Therefore, the current best surgical practice involves the Enhanced Recovery After Surgery (ERAS) program, which aims to optimize preoperative status, reduce surgical stress and postoperative complications, and accelerate recovery through an integrated multidisciplinary approach (Guinan et al., 2017).
Despite these advances, esophagogastric surgery is still associated with undesirable outcomes, including high rates of postoperative complications and mortality (Van Adrichem et al., 2014), which add to the difficulty of these cancer patients to achieve a positive energy balance, leading to weight loss, decreased muscle mass and strength, respiratory complications, physical inactivity, reduced functional capacity, fatigue, depression, emotional stress, anxiety, and poor quality of life (Bolger et al., 2019;Lidoriki et al., 2019;Minnella et al., 2018;Van Adrichem et al., 2014). The risk of postoperative pulmonary complications after esophagectomy is generally high (27%-57%) (Feeney et al., 2010). Respiratory complications are commonly reported after esophagectomy and contribute to prolonged hospital stay and intensive care unit (ICU) stay, with increased health care costs (Ferguson et al., 2011).
The vast majority of exercise-based interventions for oncology patients have been evaluated in patients with breast cancer, prostate cancer, and hematologic neoplasms, which precludes generalizing the results to cancer types with more Research, Society andDevelopment, v. 11, n. 11, e256111133596, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i11.33596 3 complex multimodal treatment, such as EC (van Vulpen et al., 2021). However, recent studies with exercise-based interventions before and after surgery associated with nutritional support seem to be important elements for patients to withstand surgical stress and minimize postoperative morbidities (Minnella et al., 2018) for important benefits in functional capacity, muscle function and quality of life of patients with EC (Minnella et al., 2018;Van Adrichem et al., 2014). However, the effect needs to be measured together with other publications and the risk of bias of the studies evaluated.
In order that rehabilitation professionals and those involved in oncologic care can safely transpose the evidence to clinical practice, contributing to the improvement of the physical performance of gastric cancer patients (Cho et al., 2014). In addition, how much the types of exercise and the standardization of training protocols influence this outcome is not yet well defined in the literature (Bolger et al., 2019). Thus, this review aimed to evaluate the quality of evidence on the effects of physical exercise on functional capacity (FC) and muscle strength (MS) of with esophagogastric cancer patients.

Methodology
This systematic review was developed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al., 2009;Page et al., 2021) and the protocol was registered at PROSPERO under number CRD42021225201.

Data source and search strategy
The data search was performed on 06 October 2021 using the databases Medline via Pubmed, PEDro, Cochrane

Study selection and eligibility criteria
The eligibility criteria were as follows: (i) randomized clinical trials (RCT), with adult patients (≥18 years) of both sexes, with histologically diagnosed esophageal cancer, esophagogastric or gastric junction, treated with surgery (esophagectomy / gastrectomy, total or partial) and/or neoadjuvant treatment (chemotherapy and/or radiotherapy); (ii) interventions applied at different clinical times, parallel with neoadjuvant treatment, during the pre-and/or postoperative period; and (iii) studies that evaluated the effect of exercise protocols, which may be combined with other therapies or nutritional support, on functional capacity and muscle strength of these patients. Studies that evaluated the effect of exercisebased intervention through another type of methodological design (systematic review articles, meta-analysis, cohort, casecontrol, case studies, or protocols), or that did not present data on the outcomes of interest were excluded. No publication year or language restrictions were applied.
After excluding duplicate entries, the titles and abstracts were identified by two independent and geographically separate researchers and were considered for inclusion based on study design and relevance to the proposed research question.
Relevant articles were read in full to apply the eligibility criteria and studies meeting the criteria were included. Disagreements were resolved by a third researcher. Research, Society andDevelopment, v. 11, n. 11, e256111133596, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i11.33596 4 The articles included were independently reviewed by the reviewers and the data extracted using an electronic form.
The following data were extracted: publication year, authors, country, patient characteristics, intervention protocol (type of exercise, frequency, intensity, and progression), moment of intervention (during neoadjuvant treatment, pre-or post-surgical), outcome measures, results, and risk of bias.

Outcomes
The primary outcome was the functional capacity measured by peak oxygen consumption (VO2 peak), by maximal oxygen consumption (VO2max), by the 6-minute walk test (6MWT) or other validated physical evaluation. Respiratory and peripheral muscle strength were the secondary outcomes.

Risk of bias assessment
The methodological quality of the included studies was assessed using the Cochrane Collaboration tool for risk of bias (Higgins et al., 2019) using RevMan (version 5.3), which analyzes the risk of bias in seven domains: random sequence generation, allocation confidentiality, blinding of participants and professionals, blinding in outcome assessment, incomplete outcome data, selective outcome reporting and other sources of bias. The risk of bias of the selected studies was classified as low, uncertain, or high based on the tool-established criteria (Higgins et al., 2019). The degree of recommendation of the evidence was assessed by the GRADE system as very low, low, moderate, or strong (Guyatt et al., 2011) , (Brugnolli et al., 2014).

Data analysis
Inter-reviewer agreement during study selection was measured using the kappa coefficient (k), with values of 0.61-0.80 and 0.81-0.100 considered as substantial and almost perfect, respectively. (McHugh, 2012). The main characteristics of the samples and interventions, and main outcomes and results obtained in each selected study were qualitatively described and summarized in tables.

Study Selection
The article selection and inclusion processes are summarized in Figure 1. Of the 117 articles identified, 89 were screened by title and abstract, and eight articles were included at the end. The agreement between reviewers was substantial (k = 0.700).  Table 1 describes the characteristics of the selected studies. A total of 673 patients were included. Of the eight studies, four applied postoperative intervention protocols, three started the intervention preoperatively, and one started the intervention during neoadjuvant therapy. The studies varied in terms of outcome measures and exercise protocols. The intervention protocols and results are shown in Tables 2 and 3, respectively.

Characteristics of the Studies
Records identified from Databases: (3) Records removed before screening: Duplicate records removed (n = 28)

Records screened (n = 83 )
Records removed for other reasons (n =67 ) Reports sought for retrieval (n = 16) Reports not retrieved (n = 0 ) Reports assessed for eligibility (n =16 ) Reports excluded: *Another study design or did not present complete text (n = 5) *Addressed various types of cancer with no isolated outcome for gastroesophageal cancer (n = 2) *Approached another population (n = 1) Studies included in review (n = 8) Reports of included studies (n = 0 )

Effect of exercise during neoadjuvant therapy
A study evaluated the impact of exercise on functional capacity and muscle strength during neoadjuvant therapy (Xu et al., 2015). In this study, the intervention group (IG) was submitted to a supervised walking exercise protocol thrice a week and nutritional counseling once a week. The exercise consisted of 5 minutes of warm-up and 20 minutes of walking at the patient's pace, before and after neoadjuvant therapy (chemotherapy and radiotherapy).

Effect of exercise performed preoperatively
Three studies evaluated the impact of exercise performed preoperatively ( Another study also evaluated inspiratory muscle strength through Pi max (Valkenet et al., 2018). Inspiratory muscle training was performed daily, a series of 30 breaths, 2x/day, for 2 weeks or more until the date of surgery. An initial inspiratory load of 60% of the initial Pimax was used. When the perceived effort rate was below 7, the inspiratory load was increased by 5%; this evaluation was done at the end of each session. Inspiratory muscle strength was assessed at 5 moments: baseline (T0), before surgery (T1) and during hospitalization in the postoperative period on day 3 (T2), day 6 (T3) and day 9 (T4). Mean The third study selected evaluated the impact of a pre-habilitation program (Minnella et al., 2018). The functional capacity was evaluated by the 6MWT after the intervention group went through the following exercise program: moderate intensity aerobic exercise, performed for 30 minutes, 3x/week, with intensity selected by the Borg Scale of Perceived Effort (12 to 13). Strengthening activity: 30 minutes, 3 sets of 8 to 12 repetitions for 8 muscle groups, using elastic band with resistance. A statistically significant difference in the change in walking distance was observed between the groups both in the

Effect of exercise performed postoperatively
Of the included studies, four evaluated the impact of exercise in the postoperative period (Chang et al., 2020;Fagevik Olsen et al., 2017;O'Neill et al., 2018;van Vulpen et al., 2021).
In one study, the IG was submitted to an exercise program to restore lung function, range of motion in the thoracic Research, Society and Development, v. 11, n. 11, e256111133596, 2022 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v11i11.33596 spine and shoulder and strength exercises for the extensors of the back, shoulders and legs, performed daily (Fagevik Olsen et al., 2017). The intervention started one week after surgery and lasted until the third month. The program was gradually increased in intensity during the rehabilitation period. Preoperative and postoperative grip strength (of the dominant hand) was assessed in IG and CG. Both groups had significantly lower grip strength postoperatively (p < 0.05), but there were no significant differences between the groups.
Another study that was selected used the 6MWT and VO2 max to evaluate the physical capacity of patients in the postoperative period of esophagectomy (Chang et al., 2020). The IG was submitted to a home walking exercise program for 12 weeks, with moderate intensity walking, 3 to 5 days a week, for 30 minutes, totaling 150 minutes of walking per week.
The last study in question evaluated the effect of exercise, performed postoperatively, on cardiorespiratory fitness through VO2peak (van Vulpen et al., 2021). In this study it was evidenced that there was significant difference in cardiorespiratory fitness by VO2peak (0.13 l / minutes, 95% CI (0.04 to 0.22), P < 0.05, however, the effect size (ES) was small (0.26).

Risk of Bias and Quality of Evidence Analysis
The risk of bias analysis was performed by the Cochrane Collaboration tool and are summarized in Figures 2 and 3.
The studies showed moderate-to-high risk of bias, especially in the items of blinding of assessors and participants. In addition, the studies provided a poor description of the intervention, limiting the assessment of other risks of bias.
The quality of the evidence was evaluated by the GRADE system. Exercise has a low recommendation for changes in the functional capacity of patients, when evaluated by the 6MWT and VO2peak, and moderate when evaluated by VO2max.
Regarding muscle strength, the degree of evidence is low that physical exercise promotes improvements in respiratory and peripheral muscle strength.

Discussion
According to the evidence, physical exercise seems to be a tool to allow patients to support oncological treatment with less damage to their functional capacity. However, the heterogeneity of intervention protocols and clinical moments applied stands out. Moreover, the studies have important methodological issues that impose moderate-to-high risk of bias to the results found. Such limitations corroborate a previous study that found high heterogeneity between preoperative and postoperative exercises in cancer patients (Bolger et al., 2019).
Esophagogastric neoplasms offer very specific challenges in dealing with poor nutritional status and declining functional capacity, combined with an advanced age population. In addition, toxicities associated with neoadjuvant therapy can be challenging in the preoperative and postoperative periods (Christensen et al., 2019;Horowitz et al., 2015). Therefore, strategies that aim to enhance the patient's physical condition are necessary to allow better recovery to treatment. (Adamsen et al., 2009).
In this review, one study evaluated the impact of exercise on functional capacity by 6MWT and muscle strength by PGS during chemo-and radiotherapy (Xu et al., 2015). The most notable finding of this pilot randomized controlled trial is that the intervention effectively preserved functional walking ability between the initiation and completion of neoadjuvant therapy for patients with newly diagnosed, locally advanced esophageal cancer. The benefits were clinically significant. Patients who walked had 100 m less decline in walking distance. In this study, the patients received weekly nutritional orientation.
Regarding the PGS, there was a significant effect in favor of exercise. It was clear that the control group had a significant decline, both in walking distance and in handgrip strength, indicating a strong need for intervention. The benefits of this intervention seem evident for patients with esophageal cancer, but our results cannot be compared with those of other studies, as this population is poorly studied. A randomized clinical trial that evaluated the effect of walking during chemotherapy in cancer patients (breast, intestinal, hematological, and other malignant neoplasms) showed significant results, corroborating with the study included in our review (Katrin Stuecher et al., 2019).
Despite advances in surgical techniques, most patients do not recover satisfactorily. Patients submitted to major abdominal surgeries for neoplasms, for example, can benefit from pre-habilitation (Ryan et al., 2016). This is defined as the process of increasing functional and nutritional capacity to reduce the potential deleterious effects of a significant stressor, which is the surgical procedure itself (Carli & Zavorsky, 2005).
In this review, three studies evaluated the effect of exercise performed preoperatively. Two studies focused on inspiratory muscle training (IMT) as an intervention and aimed to improve inspiratory muscle strength (Van Adrichem et al, 2014;Valkenet et al, 2018). However, the included studies provided divergent results, making them inconclusive for this outcome. The effect of preoperative IMT on inspiratory muscle strength is not comparable to the results reported in another study of IMT in preoperative esophagectomy (Dettling et al., 2013).
The other study selected investigated the effect of exercise in the context of pre-habilitation, with a positive impact on the functional capacity of patients submitted to the walking program performed before surgery, when compared to the group that received usual care (Minnella et al., 2018). In this study, functional capacity was evaluated by the 6MWT, with a positive impact for the intervention group and a significant difference between the groups. Reduced functional capacity is a potential limitation for patients to resist cancer treatment interventions. Studies have shown that receiving full cancer treatment is related to good physical and nutritional status (Argudo et al., 2021;Katrin Stuecher et al., 2019), and 60%-70% of esophageal cancer patients do not receive the planned treatment (Dunphy & Schöder, 2014). By mitigating functional impairment, pre-habilitation in cancer treatment pathways can be of considerable value.
A good functional capacity is directly related to the postoperative evolution (Dronkers et al., 2013). Rehabilitation exercises performed postoperatively have shown beneficial effects on cardiorespiratory performance, physical performance, and muscle strength in oncologic patients (K Stuecher et al., 2019).
In this review, one study with postoperative intervention protocols evaluated the effect of exercise on muscle strength in patients in the postoperative period of esophageal resection of Ivor-Lewis (Fagevik Olsen et al., 2017). Although some rehabilitation treatments exist, few patients receive rehabilitation and there is little scientific evidence about its possible value in this group of patients. This trial is the first to evaluate 3 months of long-term training intervention aimed at improving chest Research, Society and Development, v. 11, n. 11, e256111133596, 2022 (CC BY 4. Another study selected in this review showed that the exercise intervention had benefits on maximal and submaximal cardiorespiratory fitness, suggesting the importance of supervised exercise after esophageal cancer treatment regarding physical recovery, since multimodal treatment of esophageal cancer causes short-and long-term decline in VO2peak (van Vulpen et al., 2021). The significant results observed at the submaximal level are relevant, since most activities of daily living are performed at a submaximal level (von Döbeln et al., 2016). Another included study evaluated cardiorespiratory fitness by VO2peak using the RESTORE intervention protocol (O'Neill et al., 2018). This clinical trial was the first to demonstrate that exercise rehabilitation significantly improves cardiorespiratory fitness levels in esophagogastric cancer survivors.
Cardiorespiratory fitness in cancer survivors is invariably 30% lower than sedentary survivors of the same age and sex in control groups (Jones et al., 2011).
Another selected study evaluated the effect of exercise performed postoperatively showed that exercise showed improvement in exercise capacity for participants in the computer-based exercise program (Chang et al., 2020). VO2max and the 6MWT significantly improved 3 months after hospital discharge for the intervention group. This results is similar to other study demonstrating improvements in exercise capacity resulting from exercise programs beginning after surgical treatment (Minnella et al., 2018).
A limitation of this review was that in some studies, the exercise program was combined with other interventions, such as nutritional counseling and educational guidelines. Thus, the effect of exercise alone cannot be isolated. However, esophagogastric cancer patients suffer nutritional deterioration and nutritional counseling is part of the surgical guidelines (Guinan et al., 2017). Another limitation was the variation in intervention protocols and their form of application.
Some protocols were unsupervised, only using computerized programs or guided through telephone calls. There was variation in the professionals who applied the intervention protocols. This variety may have impacted the adherence and results of the exercises on the outcomes measured. Due to the different outcome measures evaluated, it was not possible to group the studies and meta-analysis for a better estimate of the size of the effects found.

Conclusion
Given the above, exercise seems to bring benefits to patients with esophagogastric cancer, regardless of the therapeutic moment in which the patient is. Physical exercise should be a modality of clinical intervention for these patients, in order to provide a better physical condition to patients within their line of treatment. The available evidence the effect of physical capacity improvement on exercise patients in esophagogastric fitness cancer treatment has moderate-to-high risk of bias. Therefore, there is a low degree of recommendation for physical exercise in improving the functional capacity and muscle strength of these patients.
Thus, we highlight the importance of further studies on the implementation of exercises in patients with esophagogastric cancer. These studies must follow good practice guidelines and improve the description of intervention protocol for more reliability and incorporation in clinical practice. Then, better evidence about exercise in this context may help professionals and recovery of patients with esophageal and gastric cancer.