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

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/m² 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.

METHODS

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 review of the literature in PubMed/Medline, Embase and the Cochrane Breast cancer registry. The study included only randomised controlled trials (RCTs) investigating the efficacy of MSE programs describing mode of exercises, frequency, length of follow up, and HRQOL scores were computed for meta-analysis. Only English and French published RCTs on the effects of MSE based on ACS and ACSM for cancer survivors were included in the present study. We used the search term: (Breast cancer treatment side effects [MESH] OR BC [MESH]) AND (supervised exercise program OR mentored exercise program) AND (quality of life [tw] OR QOL [tw] endocrine therapy [tw]).

Eligibility criteria were established using the participants, interventions, comparator and outcomes (PICO) framework:

Participants: All randomised controlled trials (RCTs) conducted to assess the effects of lifestyles interventions, which include diet and MSE based on ACSM or ACS guidelines including postmenopausal BCS. The most common adverse events associated with endocrine therapy, surgery, radiation therapy and the study authors of each primary study defined chemotherapies. We excluded animal and in vitro studies.

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.

Comparators: Studies involving standard exercises initiated to mitigate AIs side effects reported in the literature without medical supervision or other conventional recommended unstructured rehabilitative strategies in postmenopausal BCS or self-reported QOL questionnaires.

Outcome measures

Primary outcomes: Prevention and management of symptoms of AIs-associated adverse events/ TAM commonly reported in the literature; such as limited ROM, inflammation and grip‐strength.

Secondary outcomes included improved in HRQOL measured with a validated and standardized HRQOL questionnaire which including three dimensions: physical function, psychosocial wellbeing and emotional factors. These may include international classification of functionality (ICF) questionnaire.

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, cross-sectionals 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 I² 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.

NARRATIVE SYNTHESIS

Effects of MSE on arthralgia and bone mineral density in postmenopausal BCS on AIs-associated adverse events

Arem et al., (2016) conducted a study to assess the effects of MSE (150 minutes/week of moderate-intensity aerobic exercise and twice-weekly MSE) on arthralgia, or joint pain in postmenopausal BCS taking AIs. Authors concluded that the patients are able to initiate and maintain a yearlong MSE exercise program, regardless of other factors that influence activity levels. This is because MSE have shown to improve AI-associated arthralgia [13]. Nyrop et al., (2017) confirmed the similar results [14]. According to Fields et al.,(2016) nordic walking as a structured exercise program should be used to reduce pain associated with AIs-induced arthralgia in postmenopausal BCS in AIs [15]. Knobf et al., (2016) evaluated the effects of a 12-month MSE program (3 times/week) compared to a home-based physical activity group on BMD and biomarkers of bone turnover in postmenopausal BCS taking AIs coupled with vitamin D and calcium [16]. No significant difference in BMD was observed for MSE group vs home-based group. However, patients on TAM or no endocrine therapy did not significantly lose BMD, with the exception of the femoral neck [16]. In contrast, patients on AIs had significant BMD loss at different levels. The majority of BCS had sufficient serum level of Vitamin D (>20 ng/mL) but there was significantly less bone loss in BCS in the 20-29 ng/mL range at the LS (p = 0.01), hip (p = 0.03), and GT (p = 0.008) compared to lower or higher levels [16].

In a study conducted by Peppone et.al (2015) demonstrated that among BCS on endocrine ([AIs] or tamoxifen [TAM] on yoga exercises that there are greater reductions in musculoskeletal symptoms such as general pain, muscle aches and total physical discomfort from pre- to post-intervention than the control group (all p ≤ 0.05). The severity of musculoskeletal symptoms was higher for AI users compared to TAM users. The authors concluded that the community-based yoga program significantly reduced general pain, muscle aches, and HRQO [17]. DeNysschen et al. (2014) who assessed the effects of MSE program in reducing joint pain and improving HRQOL identified similar results. In addition, MSE reduced joints pain, depressive symptoms, and upper limb mobility and improved in HRQOL among BCS on AIs. However, no significant difference changes in cardiovascular endurance or in anthropometric measures were not observed between two groups [18].

Thomas et al, (2017) identified that MSE group relative to the usual care group had a significant increase in lean body mass (0.32 vs. -0.88 kg, p = 0.04), a decrease in percent body fat (-1.4% vs. 0.48%, p = 0.03), and a decrease in BMI (-0.73 vs. 0.17 kg/m², p = 0.03). Change in BMI was not different between two groups (0.001 vs. -0.006 g/cm², p= 0.38) [8]. Winters-Stone et al. (2011) identified that the survivors on MSE program preserved BMD at the lumbar spine (0.48 vs. -2.14%; p = 0.002) comparing to usual care (p= 0.01) [19]. Lifestyle interventions, which include exercises and healthy diet intake, reduced risk factors for osteoporosis (obesity, BMD) among postmenopausal BCS and may be particularly beneficial for BCS on AIs because of the effects of MSE on muscle mass that may reduce CVD risk factors and join pain [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 et al., (2014) evaluated the effects of lifestyles interventions (telephone based dietary education) to reduce obesity-induced AIs averse event. The authors found that MSE coupled with dietary interventions significantly reduced weight gain (p < .001) greater in intervention group versus the usual care (4.3 v 0.6 kg or 5.3% v 0.7% at 6 months and 3.1 v 0.3 kg or 3.6% v 0.4% at 24 months) and occurred consistently across strata (BMI 24 to < 30 v ≥ 30 kg/m (2); prior v no prior adjuvant chemotherapy). The authors concluded that telephone-based lifestyle interventions were effective in reducing weight loss, HRQOL in postmenopausal BCS on AIs [24]. In addition, Zanardi et al., (2012) found that lipid profile was significantly improved by AP vs. diet: 1.8% decrease in total cholesterol on diet and a further 15.3% decrease with AP vs. diet (P<0.001); a 3.1% decrease in LDL cholesterol after diet and an 18.9% decrease after AP treatment vs diet alone (P<0.01) [25]. A 1year follow-up study on postmenopausal BCS taking endocrine therapy have shown that both home diet based on food naturally high in proteins, calcium, probiotics and prebiotics (D), or this diet and 4' isometric exercises (D+MSE) significantly reduced BMI and fat loss. D patients lost 3.3 kg, 3.2% BF and 1% visceral fat. D+MSE patients lost 6.5 kg, 3.3% body fat 2%, visceral fat. The authors therefore concluded dietary and MSE interventions are effective for ER+/PR±/HER2- BCS on antiestrogenic therapies. Adjunctive MSE program also can be used for anti-drug side effects prevention to counteract sarcopenic obesity [26].

Effects of exercises on treatment induced side effects among postmenopausal BCS with metabolic syndrome

Two RCTs evaluated the effects of exercises on treatment-induced side effects among postmenopausal BCS with CVD related risk factors. The first study after 15 weeks follow up revealed exercise programs may improve metabolic syndrome profiles in postmenopausal women treated with that adjuvant endocrine therapy improved metabolic profiles(peak oxygen uptake (Vo2peak), rest heart rate (RHR), systolic blood pressure (SBP), BMI and WHR, waist to hip ratio (WHR), SBP, fasting insulin and glucose, HDL-C and TG) between experimental and control groups [27]. Additionally, Dieli-Conwright et al (2018) identified that metabolic syndrome z-score was significantly improved in MSE versus no MSE (MD -4.5; 95% CI: - 5.8 to – 2.8; p < 0.0010). Clinical phenotypes of obesity (appendicular bone mass index, p =0 .001; BMI , P= 0.001) and markers of inflammation, insulin (p = 0.001), insulin-like growth factor-1 (IFF-1) (P =0.001 ), leptin (P= 0 .001), and adiposity (P = 0 .001), 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].

Meta-analysis of the impact of MSE on ROM and HRQOL in postmenopausal BCS

About nine studies were included in meta-analysis [29-37]. The ROM and degree of inflammation were measured using bioimpedence spectrometry and the standardized European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 questionnaire [38], as well as Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire was used to measure the ROM and HRQOL respectively.

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 supervised exercises groups was -0.34 (95% CI: -1.23 to 0.56) as presented in the forest plot in Figure 3. The difference was not statistically significant, with p-value of 0.46. The pooled on the effects of MSE versus no supervised exercises on ROM (Figure 3). The MD between intervention group versus control group was 1.35 (95% CI: 0.63 to 2.07; P= 0.002); heterogeneity: Tau² = 0.71; Chi² = 112.14, df = 5 (P < 0.00001); I² = 96%. These results have shown that ROM was improved (SMD =35%) 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). The overall clinical heterogeneity was high in all meta-analysis. Bias assessment revealed that the random allocation of patients in all RCTs was adequate. Confounding was minimized. Other risk of bias was likely and the final report was graded as moderate.

DISCUSSION

This review summarized the current level of evidence on the effects of lifestyle interventions on AIs-associated adverse events and the HRQOL in postmenopausal BCS survivors. The gaps identified in literature are discussed for further investigations. The review identified that AIs-associated adverse events such as arthralgias, osteoporosis, obesity, metabolic syndrome, CVD risk factors, join pain and fatigue were significantly reduced by implementing lifestyle interventions (healthy diet + MSE) in postmenopausal BCS following different treatment strategies. Improvements in potential side effects with MSE were seen across the board regardless of age, disease stages, molecular subtypes of cancer treatment (chemotherapy, radiation, surgery, TAM), and duration of AIs therapy. Dose-response effects were also observed, with subjects who participated at least 81% of the MSE regimens having about 24% reduced in worst pain scores, whereas BCS who attended less than 81% of the MSE regimens having about 14% decrease [21]. In addition, cardio -respiratory fitness was correlated with pain scores, BMI, body fat reduction. The findings from our meta-analysis revealed that MSE, combined with usual care, are more effective in improving ROM (MD: 1.35; 95% CI: 0.63 to 2.07, P = 0.002; heterogeneity: Tau² = 0.71; Chi² = 112.14, df = 5, P < 0.00001, I² = 96%) than no supervised exercises or usual care alone. The pooled MD of HRQOL scores in intervention group compared to the control group was 3.02 (95% CI: 2.59 to 3.45, P < 0.00001). Subgroup analysis for exercises mode, types, and intensity was not conducted for regimen heterogeneity throughout the studies. The mean intervention duration was between 3 and 6 months. Studies evaluating the effect of supervised exercises versus no supervised exercises on treatment adverse events postmenopausal BCS, based on our inclusion criteria, are scarce. Further systematic reviews and meta-regressions/regressions can be conducted to identify biomedical pathways that may be influencing the effects of MSE on AI-associated adverse effects, such as AIs-associated obesity, mediators of inflammation, genetic risk factors, muscular strength, as well as the time of onset of pain improvement with MSE programs.

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]. A Cochrane review conducted by McNeely et al. (2010) confirmed that exercise programs in the postoperative period significantly improved HRQOL as defined by short term physical, psychosocial, and emotional wellbeing. No evidence based result was found on the relationship between obesity induced by lymphatic dysfunction and exercise intervention [41]. This discrepancy related to the effects of exercises on HRQOL observed in our review should be explained by the fact that, our meta-analysis included only postmenopausal BCS who were subjected to ACSM and ACS guidelines for lifestyle interventions. In addition, MSE programs play an important role in the effects of exercise interventions in chronically ill patients. The value of supervision has been attributed to improvements in adherence and exercise intensity, perhaps because of greater encouragement or confidence to exercise when the help of a healthcare provider is at hand. A sports physician or therapist may also help to individualise the exercise regimen to the specific condition of the person, such as the complex sequelae of cancers and its treatment. These MSE effects are evidence based, and the findings from our review and meta-analysis are statistically significant compared to other exercise strategies. Moreover, the studies included in our meta-analysis were only those with a specified medically supervised programs, for which the components included exercise types, frequency, mode, HR, 1-RM, duration of follow-up, and tailored based on patient comorbidities. This may be one of the reasons that our findings were more significant than other reviews included all types of exercises without considering evidence based guidelines for exercise prescription [10, 42].

Review by Zaidi et al ., (2017) classified BC treatment side effects based on types treatment strategies, molecular subtypes, metabolic profiles/comorbidities and environmental factors[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.

Limitations

Outcomes on the correlation of the effects of exercises with BC subtypes, and subgroup based analysis focused on tools used to measure the efficacy of exercises across intervention and control arms were not reported. The meta-analyses of the above limitations were not conducted because of significant heterogeneity within the studies, and these results were reported narratively. Additionally, the results did not consider exercises in patients on other types of unestablished conservative therapies for BC such as yoga, acupuncture, Chinese medicine, and African traditional medicine. Moreover, the findings of this meta-analysis should be considered in light of small sample sizes and few studies evaluating MSE versus no supervised exercises in preventing side effects associated with BC treatment. About half of the studies included in this review were graded low quality of evidence for primary outcomes and moderate quality for secondary outcomes. The exercise modes, frequencies, and duration varied according to setting and author’s flexibility, suggesting threat to internal validity. Study samples included females with initially stable conditions who were fit for physical activity. Since many subjects were used to routine standardized exercises, the adherence should be maximized by the fact that safety and feasibility were generally compromised before participating into the trials. As such, the effectiveness, relevance, adherence, side effects, and safety of exercises among those patients with severe comorbidities could not be assessed in this study, and work of this nature could be considered for further assessment. Other bias should be introduced by the lack blinding of patients and assessors of outcomes in many studies. While blinding is not always possible in exercise intervention studies; potential bias may be introduced by objective assessment of ROM for primary outcome. Publication bias was not addressed with a funnel plot because the number of studies was less than ten, and the review included only peer-reviewed articles. It is likely that the omission of unpublished studies and other well conducted observational studies resulted in publication bias. This is because studies with negative results are less likely to be published and the inclusion of these types of studies may reduce the threats to internal validity. However, to mitigate this potential selection bias, the authors performed risk of bias independently using the Cochrane risk of bias tool. This approach assesses the quality of selected studies, and is a reliable and valid measure of methodological quality of RCTs (http://training.cochrane.org/handbook). The generalizability of these findings to other populations with severe stage of BC associated comorbidities should be established with a sufficient level of evidence. Finally, further meta-analysis with high-quality RCTs should also explore the correlation between the ACSM and ACS exercise regimens in assessing the dose-response 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 emphasised on the level of evidence and the role of exercise in post-primary treatment in BCS in improving HRQOL. The intent is to encourage healthcare providers and BCS to implement lifestyle interventions as part of the path to prolong survivorship. To remedy physical and psychosocial compromises of these patients, personalized patient-oriented lifestyle programs that embrace the needs, strength and specialized healthcare providers should design preferences of BCS.

References

[1] Runowicz CD, Leach CR, Henry NL, Henry KS, Mackey HT, Cowens-Alvarado RL, Cannady RS, Pratt-Chapman ML, Edge SB, Jacobs LA, Hurria A, Marks LB, LaMonte SJ, Warner E, Lyman GH, Ganz PA. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. CA Cancer J Clin 2016; 66(1):43-73.

[2] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136(5): E359-86.

[3] Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2015). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet;386: 1341–52

[4] Huiart L, Ferdynus C, Giorgi R. A meta-regression analysis of the available data on adherence to adjuvant hormonal therapy in breast cancer: Summarizing the data for clinicians. Breast Cancer Res Treat 2013138: 325–328.

[5] Ewertz M & Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation. Acta Oncologica 2011; 50:2, 187-193

[6] Dent SF, Gaspo R, Kissner M, Pritchard KI. Aromatase inhibitor therapy: Toxicities and management strategies in the treatment of postmenopausal women with hormone-sensitive early breast cancer. Breast Cancer Res and Treat 2011; 126(2): 295–310.

[7] Rubió JG, Cortés F, Ferrer JR. A meta-analysis of the effectiveness of aromatase inhibitors as adjuvant treatment for postmenopausal patients with breast cancer. Farmacia Hospitalaria 2007; 31(1):5-16.

[8] Thomas GA, Cartmel B, Harrigan M, Fiellin M, Capozza S, Zhou Y, Ercolano E, Gross CP, Hershman D, Ligibel J, Schmitz K, Li FY, Sanft T, Irwin ML. The effect of exercise on body composition and bone mineral density in breast cancer survivors taking aromatase inhibitors. Obesity (Silver Spring) 2017; 25(2):346-351.

[9] Segal R, Zwaal C, Green E, Tomasone JR, Loblaw A, Petrella T; Exercise for People with Cancer Guideline Development Group. Exercise for people with cancer: a systematic review. Curr Oncol. 2017; 24(4): e290-e315

[10] Doyle C, Kushi LH, Byers T, Courneya KS, Demark-Wahnefried W, Grant B, McTiernan A, Rock CL, Thompson C, Gansler T, Andrews KS. Nutrition and physical activity during and after cancer treatment: An American Cancer Society guide for informed choices. CA Cancer J Clin 2006; 56(6):323-53.

[11] Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009 21;6(7): e1000097.

[12] Higgins JPT & Green S. Editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 (2011). The Cochrane Collaboration. Available from www.cochrane-handbook.org

[13] Arem H, Sorkin M, Cartmel B, Fiellin M, Capozza S, Harrigan M, Ercolano E, Zhou Y, Sanft T, Gross C, Schmitz K, Neogi T, Hershman D, Ligibel J, Irwin ML. Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: The Hormones and Physical Exercise (HOPE) study. J Cancer Surviv. 2016; 10(4):654-62.

[14] Nyrop KA, Callahan LF, Cleveland RJ, Arbeeva LL, Hackney BS, Muss HB. Randomized Controlled Trial of a Home-Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor-Associated Arthralgia in Breast Cancer Survivors. Oncologist. 2017;22(10):1238-1249.

[15] Fields J, Richardson A, Hopkinson J, Fenlon D. Nordic Walking as an Exercise Intervention to Reduce Pain in Women with Aromatase Inhibitor-Associated Arthralgia: A Feasibility Study. J Pain Symptom Manage. 2016;52(4):548-559.

[16] Knobf MT, Jeon S, Smith B, Harris L, Kerstetter J, Thompson AS, Insogna K 7. Effect of a randomized controlled exercise trial on bone outcomes: influence of adjuvant endocrine therapy. Breast Cancer Res Treat 2016.; 155(3):491-500.

[17] Peppone LJ, Janelsins MC, Kamen C, Mohile SG, Sprod LK, Gewandter JS, Kirshner JJ, Gaur R, Ruzich J, Esparaz BT, Mustian KM. The effect of YOCAS©® yoga for musculoskeletal symptoms among breast cancer survivors on hormonal therapy. Breast Cancer Res Treat. 2015; 150(3):597-604.

[18] DeNysschen, C, Burton, H, Ademuyiwa, F, Levine E, Tetewsky, S. and O'Connor, T. Exercise intervention in cancer patients: pilot study. Eur J Cancer Care 2014; 23: 493-501.

[19] Winters-Stone KM, Dobek J, Nail L, Bennett JA, Leo MC, Naik A, Schwartz A. Strength training stops bone loss and builds muscle in postmenopausal breast cancer survivors: a randomized, controlled trial. Breast Cancer Res Treat 2011; 127(2):447-56.

[20] Li C, Zhou C, Li R. Can Exercise Ameliorate Aromatase Inhibitor-Induced Cognitive Decline in Breast Cancer Patients? Mol Neurobiol 2016; 53(6):4238-4246.

[21] Irwin ML, Cartmel B, Gross CP, Ercolano E, Li F, Yao X, Fiellin M, Capozza S, Rothbard M, Zhou Y, Harrigan M, Sanft T, Schmitz K, Neogi T, Hershman D, Ligibel J. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015; 33(10):1104-11.

[22] Waltman NL, Twiss JJ, Ott CD, Gross GJ, Lindsey AM, Moore TE, Berg K, Kupzyk K.The effect of weight training on bone mineral density and bone turnover in postmenopausal breast cancer survivors with bone loss: a 24-month randomized controlled trial. Osteoporos Int. 2010; 21(8):1361-9

[23] Bošković L, Gašparić M, Petković M, Gugić D, Lovasić IB, Soldić Ž, Miše BP, Dabelić N, Vazdar L, Vrdoljak Bone health and adherence to vitamin D and calcium therapy in early breast cancer patients on endocrine therapy with aromatase inhibitors. Breast. 2017; 31:16-19

[24] Goodwin PJ, Segal RJ, Vallis M, Ligibel JA, Pond GR, Robidoux A, Blackburn GL, Findlay B, Gralow JR, Mukherjee S, Levine M, Pritchard KI. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: the LISA trial. J Clin Oncol 2014; 32(21):2231-9

[25] Zanardi M, Quirico E, Benvenuti C, Pezzana A. Use of a lipid-lowering food supplement in patients on hormone therapy following breast cancer. Minerva Ginecol 2012; 64(5):431-5.

[26] Artene DV, Bordea CI, Blidaru A. Results of 1-year Diet and Exercise Interventions for ER+/PR±/HER2- Breast Cancer Patients Correlated with Treatment Type. Chirurgia (Bucur) 2017 ;112(4):457-468.

[27] Nuri R, Kordi MR, Moghaddasi M, Rahnama N, Damirchi A, Rahmani-Nia F, Emami H. Effect of combination exercise training on metabolic syndrome parameters in postmenopausal women with breast cancer. J Cancer Res Ther 2012 ;8(2):238-42

[28] Dieli-Conwright CM, Courneya KS, Demark-Wahnefried W, Sami N, Lee K, Buchanan TA, Spicer DV, Tripathy D, Bernstein L, Mortimer JE. Effects of Aerobic and Resistance Exercise on Metabolic Syndrome, Sarcopenic Obesity, and Circulating Biomarkers in Overweight or Obese Survivors of Breast Cancer: A Randomized Controlled Trial. J Clin Oncol 2018 ;36(9):875-883.

[29] Buragadda S, Alhusaini AA, Melam GR, Arora N. Effect of complete decongestive therapy and a home program for patients with post mastectomy lymphedema. J Phys Ther Sci 2015;27(9):2743-8.

[30] Melam GR, Buragadda S, Alhusaini AA, Arora N. Effect of complete decongestive therapy and home program on health- related quality of life in post mastectomy lymphedema patients. BMC Womens Health 2016; 16:23.

[31] Hayes SC, Reul-Hirche H, Turner J. Exercise and secondary lymphedema: safety, potential benefits, and research issues. Med Sci in Sports and Exerc 2009; 41(3):483-9.

[32] McClure MK, McClure RJ, Day R, Brufsky AM. Randomized controlled trial of the Breast Cancer Recovery Program for women with breast cancer-related lymphedema. Am J Occup Ther 2010 ;64(1):59-72

[33] Buchan J, Janda M, Box R, Schmitz K, Hayes S. A Randomized Trial on the Effect of Exercise Mode on Breast Cancer-Related Lymphedema. Med Sci in Sports and Exerc 2016; 48(10):1866-74.

[34] Kim DS, Sim YJ, Jeong HJ, Kim GC. Effect of active resistive exercise on breast cancer-related lymphedema: a randomized controlled trial. Arch Phys Med Rehabil 2010;91(12):1844-8.

[35] Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvão DA, Pinto BM, Irwin ML, Wolin KY, Segal RJ, Lucia A, Schneider CM, von Gruenigen VE, Schwartz AL American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010; 42(7):1409-26. American College of Sports Medicine.

[36] Irdesel J & Çeliktaş SK. Effectiveness of Exercise and Compression Garments in the Treatment of Breast Cancer Related Lymphedema. Turk J Phys Med &Rehab 2007; 53 (1),16

[37] Şener HÖ, Malkoç M, Ergin G, Karadibak D, Yavuzşen T. Effects of Clinical Pilates Exercises on Patients Developing Lymphedema after Breast Cancer Treatment: A Randomized Clinical Trial. J Breast Health 2017; 13(1):16-22.

[38] Aaronson NK, Ahmedzai S, Bergman B Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, Stein Kaasa, Marianne Klee, David Osoba, Darius Razavi, Peter B. Rofe, Simon Schraub, Kommer Sneeuw, Marianne Sullivan, Fumikazu Takeda. The European Organization for Research and Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical Trials in Oncology, JNCI 1993;(85)5: 365–376.

[39] Koene RJ, Prizment AE, Blaes A, Konety SH. Shared Risk Factors in Cardiovascular Disease and Cancer. Circulation 2016; 133(11):1104-14.

[40] Nitti MD, Hespe GE, Kataru RP, García Nores GD, Savetsky IL, Torrisi JS, Gardenier JC, Dannenberg AJ, Mehrara BJ. Obesity-induced lymphatic dysfunction is reversible with weight loss. J Physiol. 2016 Dec 1;594(23):7073-7087. doi: 10.1113/JP273061. Epub 2016 Oct 9. PubMed PMID: 27619475; PubMed Central PMCID: PMC5134379.

[41] McNeely ML, Campbell K, Ospina M, Rowe BH, Dabbs K, Klassen TP, Mackey J, Courneya K. Exercise interventions for upper-limb dysfunction due to breast cancer treatment. Cochrane Database Syst Rev 2010: (6):CD005211

[42] Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvão DA, Pinto BM, Irwin ML, Wolin KY, Segal RJ, Lucia A, Schneider CM, von Gruenigen VE, Schwartz AL American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010; 42(7):1409-26. American College of Sports Medicine.

[43] Zaidi S, Hussain S, Verma S, Veqar Z, Khan A, Nazir SU, Singh N, Moiz JA, Tanwar P, Srivastava A, Rath GK, Mehrotra R. Efficacy of Complementary Therapies in the Quality of Life of Breast Cancer Survivors. Front Oncol. 2018; 7:326.

[44] Casla S, Hojman P, Márquez-Rodas I, López-Tarruella S, Jerez Y , Barakat R , Martín M, Running away from side effects: physical exercise as a complementary intervention for breast cancer patients. Clinical and Translational Oncology 2010; 17(3):180–96.

[45] Meneses-Echávez JF, González-Jiménez E, Ramírez-Vélez R. Effects of supervised exercise on cancer-related fatigue in breast cancer survivors: a systematic review and meta-analysis. BMC Cancer 2015; 15:77.

[46] Mills RC 3rd. Breast Cancer Survivors, Common Markers of Inflammation, and Exercise: A Narrative Review. Breast Cancer (Auckl) 2017; 24; 11:117822341774397

Tables

Table 1: List of included studies in meta-analysis

Authors/years

Country

Mean age/samples

Interventions/ control

Outcomes

Buragadda et al., (2015) India, [39]

N=60(n=30, n=30)

MSD = 56.3(3.5)

MSE, mixed AR, 50 min/d or 3-5times/wk,5x weeks/12 weeks versus conventional no SE.

ROM,QOL

Melam et al.,(2016) India,[40]

N= 60 (n=30, n=30)

MSD = 56.3(3.5)

MSE, mixed AR, 50 min/d or 3-5times/wk,5x weeks/12 weeks versus conventional no SE.

EORTC QLQ C30 and EORTC QLQ-BR23

Hayes et al.

2009, [41]. Australia

N=32(n=16, n=16)

MSD=60(10)

MSE versus no, AE, 30-5/3 times daily/12weeks, versus no SE

ROM

McClure et al. 2010, [42]

Australia

N=32(n=16, n=16), MSD=(59.7 ± 2.1)

MSE: 60 min/d, twice weekly, /17 weeks (N= 16, N=16) each group. versus no SE

ROM, QRQOL

Bushan et al. (2016), [43]

Australia

N=41(n=21, n=20)

MSD=58.5 (95%CI:54.2–62.8)

MSE: AE, 150 weekly, 3-5times/12 weeks. versus no SE

ROM, HRQOL

Kim et al. (2010) [44]

Korea

N=40(n=20, n=20)

MSD = 50.50(10.58)

MSE: Resistance, 15min/d, 5 days, 8 weeks. versus no SE

ROM, HRQOL

Irdelsel et al.(2007) [45] Tyrkey

N=19(n=9, n=20)

MSD=51.6(8.8)

MSE: AR,3 to 6 months, 3 times daily, versus no SE

ROM, QOL

Schmitz et al. (2009), [46]SA

N=142(n=71, n=70)

MSD=(58±10)

MSE: 90 min twice weekly, 12 weeks. versus no SE

ROM,QRQOL

Sener et al. 2017, [47]

Turkey

N=60(n=30, n=30)

MSD= 53.2±7.7

MSE: 5-8 persons 3 times a week/8 weeks. versus no SE

ROM, HRQOL

Legends: AE= aerobic and resistance, n= sample by group allocation, RCTs= randomised controlled trials, MSE: medically supervised exercises, HRQOL= Health related quality of life, MSD= mean standard deviation, N= sample,

Table 2: Risk of bias assessment

Patient or population: Postmenopausal BCS on adjuvant endocrine therapy Settings: Australia, USA, Turkey Intervention: Lifestyle interventions (medically supervised programs+ diet)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Assumed risk	Corresponding risk	Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Control
Improved ROM		The mean ULV reduction in the intervention groups was 1.35 higher (0.63 to 2.07 higher)		371 (6 studies)	⊕⊕⊝⊝ low^1,2
Improved HRQOL		The mean improved QOL in the intervention groups was 3.02 higher (2.59 to 3.45 higher)		201 (4 studies)	⊕⊕⊕⊝ moderate³
Mean age of BCS		The mean age of BCS in the intervention groups was 0.34 lower (1.23 lower to 0.56 higher)		483 (10 studies)	⊕⊕⊕⊝ moderate³
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.
¹ Other bias were more than 75% ² Heterogeneity was more than 75%

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

Abstract

BACKGROUND

METHODS

RESULTS

DISCUSSION

CONCLUSION

List of Abbreviations

Declarations

References

Tables