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Meta-Analysis
. 2020 Jan 29;1(1):CD012988.
doi: 10.1002/14651858.CD012988.pub2.

Exercise therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer

Kate E Roberts  1   2 , Kirsty Rickett  3 , Sophie Feng  4 , Dimitrios Vagenas  5 , Natasha E Woodward  2   4
Affiliations
Meta-Analysis

Exercise therapies for preventing or treating aromatase inhibitor-induced musculoskeletal symptoms in early breast cancer

Kate E Roberts et al. Cochrane Database Syst Rev. .

Abstract

Background: Survival for stage I to III, hormone receptor-positive, breast cancer has substantially improved over time due to advances in screening, surgery and adjuvant therapy. However many adjuvant therapies have significant treatment-related toxicities, which worsen quality of life for breast cancer survivors. Postmenopausal women with hormone receptor-positive breast cancer are now prescribed aromatase inhibitors (AI) as standard, with longer durations of therapy, up to 10 years, being considered for certain women. AI treatment is associated with a high incidence of AI-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS reduces compliance with AI therapy in up to one half of women undergoing adjuvant AI therapy, potentially compromising breast cancer outcomes. Exercise has been investigated for the prevention and treatment of AIMSS but the effect of this intervention remains unclear.

Objectives: To assess the effects of exercise therapies on the prevention or management of aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) in women with stage I to III hormone receptor-positive breast cancer.

Search methods: We searched Cochrane Breast Cancer's Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases up to 13 December 2018. We also searched two conference proceedings portals and two clinical trials registries for ongoing studies or unpublished trials, or both, in August 2019. We also reviewed reference lists of the included studies.

Selection criteria: We included randomised controlled trials that compared exercise versus a comparator arm. We did not impose any restriction on the comparator arm, which could include an alternative type of exercise, no exercise or a waiting list control. Both published and non-peer-reviewed studies were eligible.

Data collection and analysis: Two review authors independently extracted data, assessed risk of bias and certainty of the evidence using the GRADE approach. The outcomes investigated were pain, joint stiffness, grip strength, health-related quality of life, cancer-specific quality of life, adherence to AI therapy, adverse events, incidence of AIMSS, breast cancer-specific survival and overall survival. For continuous outcomes that were assessed with the same instrument, we used the mean difference (MD); for those outcomes that used different instruments, we used the standardised mean difference (SMD) for the analysis. For dichotomous outcomes, we reported outcomes as an odds ratio (OR).

Main results: We included seven studies with 400 randomised participants; one study assessed exercise for preventing AIMSS and six studies assessed treating AIMSS. For preventing AIMSS, the single study reported no difference in pain scores, grip strength or compliance to taking AI medication between groups. Data values were not provided in the study and no other outcomes were reported. For managing AIMSS, we found that the evidence for the effect of exercise therapies on overall change in worst pain scores was very uncertain (SMD -0.23, 95% confidence interval (CI) -0.78 to 0.32; 4 studies, 284 women; very low-certainty evidence). The evidence suggested that exercise therapies result in little to no difference in overall change in stiffness scores (Western Ontario McMasters Universities Osteoarthritis Index (WOMAC) stiffness score MD -0.76, 95% CI -1.67 to 0.15 and Visual Analogues Scale (VAS) stiffness score MD -0.42, 95% CI -2.10 to 1.26; 1 study, 53 women; low-certainty evidence). The evidence was very uncertain for the outcomes of overall change in grip strength (MD 0.30, 95% CI -0.55 to 1.15; 1 study, 83 women; very low-certainty evidence); overall change in health-related quality of life (subscales of SF-36 tool ranged from least benefit of MD 1.88, 95% CI -2.69 to 6.45 to most benefit of MD 9.70, 95% CI 1.67 to 17.73; 2 studies, 123 women, very low-certainty evidence); overall change in cancer-specific quality of life (MD 4.58, 95% CI -0.61 to 9.78; 2 studies, 136 women; very low-certainty evidence); and adherence to aromatase inhibitors (OR 2.43, 95% CI 0.41 to 14.63; 2 studies, 224 women; very low-certainty evidence). There were no adverse events identified across four studies in either arm (0 events reported; 4 studies; 331 participants; low-certainty evidence). There were no data reported on incidence of AIMSS, breast cancer-specific survival or overall survival.

Authors' conclusions: Given the wide-ranging benefits of exercise for people affected by cancer, it was surprising that this review provided no clear evidence of benefit for exercise therapies in women with early breast cancer with AIMSS. This review only yielded seven eligible studies with 400 participants, which is likely to have underpowered the findings. The meta-analysis was challenging due to the considerable heterogeneity amongst the trials, with a wide range of exercise regimens and follow-up periods. Despite these inconclusive findings, exercise needs to be part of routine care for women with breast cancer due to its wide-ranging benefits. Future research in this area would be enhanced with further understanding of the mechanism of AIMSS, a single clear definition of the condition, and phase III randomised controlled trials that are adequately powered to test targeted exercise interventions on the key clinical outcomes in this condition.

PubMed Disclaimer

Conflict of interest statement

KER: received sponsorship from Roche, Amgen & BMS for accommodation, travel and registration to educational meetings. This financial support is unrelated to the topic under review. KR: none to declare DV: none to declare SF: travel/accommodation by Eisai. This financial support is unrelated to the topic under review. NW: consultancy fees from Roche, Novartis; grants from Medivation; expert panel review for Roche and Pfizer; travel/accommodation/meeting expenses for Roche, Novartis; stock in CSL. While both Pfizer and Novartis do market aromatase inhibitors (and these medicines are now off patent), this review focuses on managing side effects rather than assessing their efficacy. Relationship with Roche is not relevant to a review of managing aromatase inhibitor side effects.

Figures

1
1
Study flow diagram
2
2
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
3
3
Forest plot of comparison 1. Primary outcomes, outcome 1.1: overall change in worst pain, using WOMAC pain subscale for Nyrop 2017
4
4
Funnel plot of comparison 1. Primary outcomes, outcome 1.1: overall change in worst pain, using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale for Nyrop 2017
5
5
Forest plot of comparison 2. Secondary outcomes, outcome 2.2: health‐related quality of life
6
6
Forest plot of comparison 2. Secondary outcomes, outcome 2.3: cancer‐specific quality of life
1.1
1.1. Analysis
Comparison 1 Primary outcomes, Outcome 1 Overall change in worst pain, using WOMAC pain subscale for Nyrop 2017.
1.2
1.2. Analysis
Comparison 1 Primary outcomes, Outcome 2 Overall change in worst pain with VAS scale for Nyrop 2017.
1.3
1.3. Analysis
Comparison 1 Primary outcomes, Outcome 3 Overall change in worst pain using final values standard deviations for Irwin 2015.
1.4
1.4. Analysis
Comparison 1 Primary outcomes, Outcome 4 Overall change in stiffness scores.
1.5
1.5. Analysis
Comparison 1 Primary outcomes, Outcome 5 Overall change in grip strength.
2.1
2.1. Analysis
Comparison 2 Secondary outcomes, Outcome 1 Persistence and compliance with aromatase inhibitors.
2.2
2.2. Analysis
Comparison 2 Secondary outcomes, Outcome 2 Health‐related quality of life.
2.3
2.3. Analysis
Comparison 2 Secondary outcomes, Outcome 3 Cancer‐specific quality of life.
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References

References to studies included in this review

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