The impact of lifestyle interventions on therapy associated side effects in postmenopausal breast cancer survivors: systematic reviews and meta-analysis

Background: Medically Supervised Exercise (MSE) are advisable for the prevention and treatment related side effects among breast cancer survivors. Aerobic and resistance either exercise, separately or in combination, have been shown to improve physical functioning and manage some symptoms in breast cancer patients. However, the level of evidence on the effects of lifestyle interventions on therapy related adverse events and the required dose responses of exercises are not yet systematically reviewed. This review was conducted to assess the efficacy of medically supervised exercises(MSE) coupled with diet in preventing/managing aromatase inhibitors induced adverse events and improving range of motion(ROM) and heath related quality of life (HRQOL) in postmenopausal breast cancer patients following treatment. Methods: Two independent authors extracted data using PRISMA guidelines of published clinical trials. We searched the Cochrane Central Register of Controlled Trials, PubMed, MEDLINE, EMBASE, as well as clinical practice guidelines. We included only randomized controlled trials that examined exercise interventions coupled with diet interventions in postmenopausal breast cancer women. Health related quality of life (HRQOL) and range of motion were assessed as the main outcomes. Results: Random effects meta-analysis was conducted for pooling of the effect size. The age of patients varied from 50 to 60 years. The results illustrate that the mean difference (MD) in improving ROM in the MSE group versus no supervised exercises was 1.35% (95% CI: 0.63 to 2.07%, P = 0.0002; heterogeneity: Tau² = 0.71; Chi² = 112.14, df = 5 (P < 0.00001); I² = 96%). A summary of the data shows that show

Results: Random effects meta-analysis was conducted for pooling of the effect size.
The age of patients varied from 50 to 60 years. The results illustrate that the mean difference (MD) in improving ROM in the MSE group versus no supervised exercises was 1.35% (95% CI: 0.63 to 2.07%, P = 0.0002; heterogeneity: Tau² = 0.71; Chi² = 112.14, df = 5 (P < 0.00001); I² = 96%). A summary of the data shows that supervised exercises significantly improved ROM and HRQOL in postmenopausal BCS on endocrine therapy compared to no supervised exercises 3.02 (95% CI: 2.59 to 3.45, P < 0.00001). These outcomes show that lifestyle interventions (MSE +diet) have positive effects on AI-associated adverse events and likely improve ROM and HRQOL in postmenopausal BC patients.
Conclusion: The evidence was based on a body of research with moderate study quality. Moreover, further studies are recommended to assess the effect of lifestyle interventions on markers of inflammation as the predictors of treatment nonresponse and associated comorbidities.

BACKGROUND
Breast cancer (BC) is a major public health challenge globally with the greatest ramifications in low and middle-income countries [1]. GLOBACAN 2012 data indicate that 25% of women were diagnosed with BC worldwide (an estimated 1.7 million cases), and 521,900 related deaths [2]. With this devastating statistics, BC remains an ongoing clinical challenging. BC treatment is multidisciplinary, including surgery, radiation therapy, endocrine therapy and chemotherapy [1]. The two widely used endocrine therapies are aromatase inhibitors (AIs) and tamoxifen, depending to anatomical pathological classification and menopausal status. AIs are the more effective standards of care for long-term estrogen suppression and reduction of risk recurrence in postmenopausal women as compared to premenopausal women [3].
Adherences to endocrine therapy among BC patients ranges from 79.6% at 1 year to 68.3% at 5 years. Non-adherence to endocrine therapy among BC patients is well acknowledged and associated with both morbidity and mortality [4]. However, estrogen deprivation therapy accompanies various adverse events which are associated with late complications associated with poor prognosis in BCS following a number of treatment strategies [5].
A meta-analysis conducted by Dent et al., (2011) revealed that AIs increase disease free survival (DFS) and overall survivorship (OS) when sequentially administered for 2-3 years following 2-3 years of tamoxifen therapy [6]. Similarly, their use after 5 years of tamoxifen treatment also produces an increase in DFS. As for OS, a clinical and statistical difference may be obtained only when AIs are administered after 2-3 years of tamoxifen treatment. In comparison with tamoxifen, AIs reduce the incidence of thromboembolic and gynaecologic side effects, however, increases body mineral density (BMD) adverse events [6]. Although the impact of adjuvant endocrine therapy related side effects are documented to be associated with both BC recurrence and cardiovascular diseases (CVD) risk [7], medically supervised exercises (MSE) programs have been suggested to be beneficial among postmenopausal BC patients on different BC treatment strategies [8]. While multiple adjuvant therapies are used to manage endocrine related adverse events, current treatment is focused on interventions in patients who already developed symptoms (tertiary prevention) rather than primary prevention.
Diverse risk factors have an impact on Health Related Quality of Life (HRQOL) due to significant functional, psychosocial and metabolic disturbances. Obesity as one of rick factors may require interventions (healthy diet intake and MSE) programs as one of treatment strategies to improve HRQOL in postmenopausal BCS [9,10].
These exercises aim to restore upper limb function, range of motion (ROM) and muscle strength, and reduce comorbidities associated with BC surgery, radiation therapy and AIs [9]. Current clinical practice for exercises recommended by the American Cancer Society (ACS) [9] and American College of Sports Medicine (ACSM) [10], suggest that aerobic exercises of 150 minutes/week of moderate-intensity or 75 minutes/week of vigorous-intensity or an equivalent combination should be initiated for each BCS upon physician fitness examination. For muscle strength, at least moderate intensity resistance exercises (2 days/week) should be performed for each major muscle group. A review revealed that exercise may be beneficial in reducing treatment-related adverse outcomes among cancer patients [9]. Moreover, cancer type-specific exercises, clinical heterogeneity, lack of blinding in many trials, frequency and exercise mode, unknown level of evidence, and timing of exercise regimen are not yet evaluated for evidence based clinical recommendations. Understanding the role of exercise in side effect prevention in postmenopausal BC patients will assist in developing more effective therapy guidelines.
The relationship between lifestyle risk factors and BC recurrence has not been specifically studied in postmenopausal BCS using adjuvant endocrine therapy such as AIs. Given that BMI > 30 kg/m 2 is a consistent risk factor associated with various side effects among this population. The lifestyle modifications which aim at preventing disease recurrence, typically defined as a relapse event at a local, regional, or distal site, have consisted of a healthy diet, nutritional supplements, regular exercise, or some combination of these components [10]. Therefore, this systematic review and meta-analysis were conducted to assess the efficacy of current recommended lifestyle interventions (MSE + diet) in preventing AIs-induced adverse events in postmenopausal BCS subjected to different BC treatment strategies.

Ethics proclamations
No Ethics clearance is required to conduct a systematic review and meta-analysis.
The primary studies included in this review were approved by the respective national Ethics Committees. The first author performed this verification.

Search strategy and selection criteria
This meta-analysis was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [11]. We conducted a Interventions: RCT studies involving postmenopausal BC following different BC management strategies with a detailed MSE program (frequency, duration, ROM, types of exercises) coupled with diet or other BC management strategies including endocrine therapies (AIs, tamoxifen (TAM)). Studies in which mean difference (MD), relative risk, risk radio, odd ratios and HRQOL tools used to measure the level of disability were extracted and compared between intervention and control groups without years and settings restriction.

Exclusion criteria
Studies including premenopausal women, men, pharmacological interventions, and traditional medicines. Individual studies, non-randomized studies, case controls, duplicated studies, narrative reviews, grey literature, no defined exercise interventions, studies without control groups, case studies, case reports, crosssectionals and qualitative studies.

Screening and data abstraction
Two medical reviewers (JPM, JM) independently selected the study abstracts and full articles, and risk of bias was performed using standard tools. A third reviewer was consulted if there were disagreements, and such disagreements were resolved by commitment. Clinical heterogeneity was assessed by comparing the study designs, settings, sample sizes, countries of publication, methods used for diagnosis and measurement of outcomes. Random effects meta-analysis was conducted for pooling of the effect size. Statistical heterogeneity was evaluated, using chi-square test of homogeneity and I 2 statistical tests were conducted on quantitative data. Subgroup analysis was conducted for different tools used to measure the side effects associated with both postmenopausal status and AIs. Articles were classified as potentially eligible if the titles indicated an RCT on the prevention of side effects associated with BC treatment. If no judgment could be made about the eligibility of a study based on the title, the judgment was based on its title and abstract. Any disagreements about eligibility were resolved at consensus meetings. The same procedure was applied for references included in this systematic review. Review articles identified in the search were screened for relevance and reference lists were checked to identify additional potentially eligible studies. Final decisions about inclusion of all articles judged potentially eligible was based on the full texts of the published articles.

Quality assessment and personal study quality
Two reviewers independently assessed the quality of ten eligible studies ( Table 1).
Risk of bias was conducted, using the Cochrane risk of bias tool for the appraisal of RCTs, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0 [12]. The tool contains six domains and each domain was assigned a judgement related to the risk of bias (Table 2 and Figure 1). The judgement could be 'low risk', 'high risk', or 'unclear risk'. The latter judgement was assigned if the risk of bias of a characteristic in an included study was judged to be unclear, or if there was insufficient information on which to base the judgement. We compared excel datasets between two data extractors and a third reviewer was consulted to resolve discrepancy. A summary of the risk of bias is reported in ( Table 2). All analyses were performed using Review Manager Software. Figure 2 shows PRISMA guideline for reporting systematic reviews.

RESULTS
The search strategy identified 4 422 reports. After screening the articles based on inclusion criteria. A total of 109 were assessed for final screening. From these, 68 duplicates and without pre and post measurements, 5 did not describe the exercise programs, 7 did not report control groups. Fourteen were reported in narrative synthesis because of high degree of heterogeneity and 10 were considered for meta-analysis.
No adverse events were reported in the included studies.
Resistance and aerobic exercises were common among the selected studies. The authors described the mode and frequency of each component of exercises regimen as recommend by ACSM.  [19]. The above results were also confirmed in four other trials [20 -23].

Effects of diet and MSE on AIs-induced obesity in postmenopausal BCS.
Goodwin side effects prevention to counteract sarcopenic obesity [26]. were statically significant in MSE group compared to non MSE. The authors concluded that MSE should be incorporated into BC treatment and survivorship care plan because of its benefits in attenuating metabolic syndrome and risk factors for CVD [28].

Heterogeneity assessment
Our screening revealed that the methods using the RCTs were rigorous. The six domains of risk bias assessed revealed that biases were reduced in the most of included studies.
This meta-analysis included ten RCTs for which the ages of patients ranged from 50 to 60 years. The mean difference (MD) in age between supervised exercises and no in MSE program compared to no supervised exercises (Statistically significant with P=0.0002) forest plot Figure 4. However, the statistical heterogeneity between RCTs was high. The pooled summary of data on the efficacy of MSE in improving HRQOL has shown moderate evidence that MSE Improved HRQOL compared to no supervised exercises by up to 3.02 (95% CI: 2.59 to 3.45, P <0.00001), as illustrated by the forest plot in Figure 4. The results were statistically significant.
Heterogeneities were assessed in three forest plots (Figures 2-4) Obesity is a known shared risk factor between postmenopausal BC status and NCDs, such as CVD. Inflammation is considered as a major unifying risk factor in sharing the same biological pathways of both CVD and BC [39]. Evidence revealed that lifestyle strategies that target weight loss may decrease perilymphatic inflammatory markers (cells), improve lymphatic function, and reverse pathological mechanisms in gene expression in lymphatic endothelial cells [40].  [43]. The most known side effects related to surgery and radiation therapy are upper limb edema/inflammation and pain with an incidence rate of about 40% within 5 years following treatment, depending on types of therapy within 5 years following treatment [44]. Given that postmenopausal BC status shares the same risk factors with metabolic syndromes, such as CVD, dyslipidaemia and diabetics, tailored exercise interventions are suggested to reduce BP, and psychosocial and neurological adverse events associated with adjuvant therapy [39]. The present meta-analysis confirmed with moderate evidence that all types of exercises are effective in improving metabolic function, homeostatic, lymphatic systems function and likely to improve BCS survivorship. The generalizability of these findings to other populations with severe stage of BC associated comorbidities should be established with a sufficient level of evidence.

Limitations
Finally, further meta-analysis with high-quality RCTs should also explore the correlation between the ACSM and ACS exercise regimens in assessing the doseresponse relationship between different types of exercises and survival outcomes stratified by BC subtypes.

Further perspective
A review on the effects of exercises on cancer related fatigue suggested that exercises may be used in the rehabilitation of cancer and associated comorbidities to reduce inflammatory markers and fatigue [45]. Evidence from rigorous high-quality studies to recommend the impact of different types of exercises, exercise intensity, and weight loss on inflammatory markers is still lacking in the literature.
A narrative synthesis evaluating the effects of exercises on markers of inflammation among BCS and a healthy population revealed that the effects were similar in reducing inflammatory markers in both populations. However, research gaps were identified in literature; good understanding of the relationship between exercises and inflammation, as well as, the underlying biological mechanisms that are responsible for these changes in postmenopausal breast cancer patients on endocrine therapy needs further investigations as recommended in previous review [46]. Our review briefly outlined the effects on lifestyle interventions on common averse associated with endocrine therapy; specifically, with AIs and optimal exercise protocols developed to mitigate these comorbidities. Consequently, we   *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.