What was the aim of this review?
Hormonal therapy with aromatase inhibitors is used to treat a type of early breast cancer (hormone-receptor positive) in women after the menopause. AI cause side effects including joint and muscle pains and stiffness (aromatase inhibitors musculoskeletal symptoms, or so-called AIMSS), which may cause some women to stop taking their aromatase inhibitors, and potentially worsen survival. The aim of this Cochrane Review was to examine whether systemic therapies (treatments that reach cells throughout the body by travelling through the bloodstream) can prevent or treat AIMSS. The authors collected and analysed all relevant studies to answer this question.
It is very unclear if systemic therapies improve, worsen or make no difference to pain or quality of life for women taking aromatase inhibitors. Most of the evidence was of very low quality. It was very unclear if systemic therapies for AIMSS were safe.
What did the review study?
We looked at research studies of systemic therapies, which included medicines, vitamins, and complementary and alternative medicines, to see if these could prevent or treat the joint and muscle pains and stiffness of women taking aromatase inhibitors. We included trials of systemic therapies compared to placebo (dummy treatment), or to standard treatments. Women treated with aromatase inhibitors for early-stage hormone receptor-positive breast cancer were included. Most studies were for treatment of AIMSS.
Outcomes that were studied included changes in pain, stiffness, hand strength (grip strength), safety and side effects of the study treatments, number of women continuing to take their aromatase inhibitors, quality of life for women, how many women developed muscle and joint aches from their aromatase inhibitors, and survival.
What were the main results of this review?
After collecting and analysing all the relevant studies, we found 17 studies with 2034 women included. Different numbers of women were involved in these studies, ranging from 37 to 299. Four studies looked at systemic therapies to prevent the joint and muscle pains from aromatase inhibitors; 13 studies investigated systemic therapies to treat these symptoms. Ten studies were carried out in the USA, three in China, two in Australia, one in Italy and one in Brazil. Many of the studies had low numbers of women and this may have made it difficult to find small differences. There were problems with some studies being at risk of bias. Other problems were because several studies had not fully published information about their treatment ingredients or their results, so that some data were not available for review or analysis. In addition, studies used many different types of treatment, and it was not appropriate to combine their results in analysis.
AIMSS prevention studies
It is unclear whether any of these studies found a positive or negative effect on pain, and on the number of women who developed AIMSS because of the very low quality evidence. Systemic therapies may have little to no effect on grip strength, quality of life or on women continuing to take their aromatase inhibitors (low-quality evidence). None of the studies looked at stiffness.
AIMSS treatment studies
It is unclear whether any of these studies found a positive or negative effect on pain, stiffness and quality of life of women because of the very low-quality evidence. Systemic therapies likely result in little to no change on grip strength in women with AIMSS (low-quality evidence). None of the studies looked at the number of women continuing to take aromatase inhibitors or who developed AIMSS, or their survival.
We do not know if systemic therapies for AIMSS are safe as the evidence is very uncertain. There were no serious side effects. One treatment, duloxetine, resulted in an increase in side effects for women, and one treatment, etoricoxib, had a safety alert during the trial. Length of monitoring of women for many studies was short. Safety data should be interpreted with caution.
How up-to-date is this review?
The last search for studies (published and ongoing) in this review was in September 2020 within the specified databases and in March 2021 in the Cochrane Breast Cancer's Specialised Register.
AIMSS are chronic and complex symptoms with a significant impact on women with early breast cancer taking AI. To date, evidence for safe and effective systemic therapies for prevention or treatment of AIMSS has been minimal. Although this review identified 17 studies with 2034 randomised participants, the review was challenging due to the heterogeneous systemic therapy interventions and study methodologies, and the unavailability of certain trial data. Meta-analysis was thus limited and findings of the review were inconclusive. Further research is recommended into systemic therapy for AIMSS, including high-quality adequately powered RCT, comprehensive descriptions of the intervention/placebo, and robust definitions of the condition and the outcomes being studied.
Adjuvant aromatase inhibitors (AI) improve survival compared to tamoxifen in postmenopausal women with hormone receptor-positive stage I to III breast cancer. In approximately half of these women, AI are associated with aromatase inhibitor-induced musculoskeletal symptoms (AIMSS), often described as symmetrical pain and soreness in the joints, musculoskeletal pain and joint stiffness. AIMSS may have significant and prolonged impact on women's quality of life. AIMSS reduces adherence to AI therapy in up to a half of women, potentially compromising breast cancer outcomes. Differing systemic therapies have been investigated for the prevention and treatment of AIMSS, but the effectiveness of these therapies remains unclear.
To assess the effects of systemic therapies on the prevention or management of AIMSS in women with stage I to III hormone receptor-positive breast cancer.
We searched CENTRAL, MEDLINE, Embase, WHO International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov registries to September 2020 and the Cochrane Breast Cancer Group (CBCG) Specialised Register to March 2021.
We included all randomised controlled trials that compared systemic therapies to a comparator arm. Systemic therapy interventions included all pharmacological therapies, dietary supplements, and complementary and alternative medicines (CAM). All comparator arms were allowed including placebo or standard of care (or both) with analgesia alone. Published and non-peer-reviewed studies were eligible.
Two review authors independently screened studies, extracted data, and assessed risk of bias and certainty of the evidence using the GRADE approach. Outcomes assessed were pain, stiffness, grip strength, safety data, discontinuation of AI, health-related quality of life (HRQoL), breast cancer-specific quality of life (BCS-QoL), incidence of AIMSS, breast cancer-specific survival (BCSS) and overall survival (OS). For continuous outcomes, we used vote-counting by reporting how many studies reported a clinically significant benefit within the confidence intervals (CI) of the mean difference (MD) between treatment arms, as determined by the minimal clinically importance difference (MCID) for that outcome scale. For dichotomous outcomes, we reported outcomes as a risk ratio (RR) with 95% CI.
We included 17 studies with 2034 randomised participants. Four studies assessed systemic therapies for the prevention of AIMSS and 13 studies investigated treatment of AIMSS. Due to the variation in systemic therapy studies, including pharmacological, and CAM, or unavailable data, meta-analysis was limited, and only two trials were combined for meta-analysis. The certainty of evidence for all outcomes was either low or very low certainty.
The evidence is very uncertain about the effect of systemic therapies on pain (from baseline to the end of the intervention; 2 studies, 183 women). The two studies, investigating vitamin D and omega-3 fatty acids, showed a treatment effect with 95% CIs that did not include an MCID for pain. Systemic therapies may have little to no effect on grip strength (RR 1.08, 95% CI 0.37 to 3.17; 1 study, 137 women) or on women continuing to take their AI (RR 0.16, 95% 0.01 to 2.99; 1 study, 147 women). The evidence suggests little to no effect on HRQoL and BCS-QoL from baseline to the end of intervention (the same single study; 44 women, both quality of life outcomes showed a treatment effect with 95% CIs that did include an MCID).
The evidence is very uncertain for outcomes assessing incidence of AIMSS (RR 0.82, 95% CI 0.63 to 1.06; 2 studies, 240 women) and the safety of systemic therapies (4 studies, 344 women; very low-certainty evidence). One study had a US Food and Drug Administration alert issued for the intervention (cyclo-oxygenase-2 inhibitor) during the study, but there were no serious adverse events in this or any study.
There were no data on stiffness, BCSS or OS.
The evidence is very uncertain about the effect of systemic therapies on pain from baseline to the end of intervention in the treatment of AIMSS (10 studies, 1099 women). Four studies showed an MCID in pain scores which fell within the 95% CI of the measured effect (vitamin D, bionic tiger bone, Yi Shen Jian Gu granules, calcitonin). Six studies showed a treatment effect with 95% CI that did not include an MCID (vitamin D, testosterone, omega-3 fatty acids, duloxetine, emu oil, cat's claw).
The evidence was very uncertain for the outcomes of change in stiffness (4 studies, 295 women), HRQoL (3 studies, 208 women) and BCS-QoL (2 studies, 147 women) from baseline to the end of intervention. The evidence suggests systemic therapies may have little to no effect on grip strength (1 study, 107 women). The evidence is very uncertain about the safety of systemic therapies (10 studies, 1250 women). There were no grade four/five adverse events reported in any of the studies. The study of duloxetine reported more all-grade adverse events in this treatment group than comparator group.
There were no data on the incidence of AIMSS, the number of women continuing to take AI, BCCS or OS from the treatment studies.