Strengths and Weaknesses of the Evidence

There are limitations within the evidence base of the Primary Systematic Review and the Supplementary Evidence Review [SR2] that was used to inform the recommendations in women with a history of breast cancer. For some interventions, RCTs that specifically assessed menopausal symptoms in the population of women with a history of breast cancer were not identified. Across many of the studies identified, the clinical importance of the magnitude of observed effects was difficult to interpret and this has limited the strength of the conclusions that can be drawn.

Overall, the Primary Systematic Review undertaken for this guideline provides level II evidence for the treatment of vasomotor symptoms (hot flushes and night sweats) in women previously treated for breast cancer. Improvement in vasomotor symptoms was the primary outcome investigated by the majority of the studies, with improvement in other symptoms typically assessed as secondary outcomes. As such, studies were generally powered for detecting changes in vasomotor symptoms only and were insufficiently powered to detect a difference in secondary outcomes. Further, treatment doses were specifically chosen for efficacy in treating vasomotor symptoms and not for the secondary outcomes; thus, drug dosage and duration of treatment may not have been sufficient to elicit a significant effect for outcomes other than vasomotor symptoms. Some interventions were supported only by a single study. Further studies with larger study samples and greater methodological rigour are needed to assess treatments for sleep disturbance, sexual function, psychological wellbeing and global quality of life.

A key limitation of the literature assessed in the Supplementary Evidence Review undertaken for this guideline is the varying ways that treatment was administered and outcomes were measured in the studies included in the systematic reviews. This prevented synthesis of the findings, and several analyses were based on a small number of studies.  Additionally, the systematic reviews pooled the effects of the treatments of interest with other treatments, such as escitalopram with other SSRIs, and testosterone with oestrogen, making it difficult to identify the individual treatment effects.  Conversely, the Supplementary Evidence Review on compounded hormones only investigated one form of treatment, compounded progesterone cream, when compounded oestrogen and compounded androgens may also be used to treat menopausal symptoms.

For many of the therapies included in these guidelines there is little or no evidence for their long-term safety in peri- and postmenopausal women. In particular, the use of testosterone, SERMs and compounded hormones in this population is not informed by long-term studies. Tibolone may be associated with an increased risk of breast cancer, although the evidence is drawn from a limited number of trials and there is some inconsistency in the effects observed. In addition, all of the therapies included in these guidelines, both pharmacological and non-pharmacological, have specific contraindications and adverse event profiles that should inform the consideration of their benefits and harms for individual women.