Hormone replacement therapy is an effective treatment for HFNS, but is generally contraindicated for patients with breast cancer because it can increase the risk of breast cancer recurrence, and HFNS can return in women who discontinue hormone replacement therapy.⁸ A Cochrane review of non-hormonal medical treatments concluded that clonidine (an antihypertensive drug), gabapentin (an anticonvulsant that works through an unknown mechanism), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) showed a mild to moderate effect on the frequency of HFNS in women with a history of breast cancer (reductions of between 15% and 58%; average 37%).⁹ Three trials done since the review was undertaken recorded similar reductions.^10–12 Various side-effects of medical treatments were reported—eg, dry mouth, sleep problems, and nausea—and short follow-up limited conclusions about long-term outcomes.⁹ Some SSRIs (paroxetine and fluoxetine), but not all, might reduce the effectiveness of endocrine treatments.¹³ Evidence of improvements to quality of life is mixed; six of 12 studies of non-hormonal drugs reported no effect.^10–12,14 Moreover, many breast cancer survivors prefer to use non-medical treatments.³ For non-pharmacological therapies—eg, vitamins, magnetic devices, or acupuncture—the Cochrane review concluded that outcomes were either inconsistent or not statistically significant.⁹ Consequently, a need exists for safe, acceptable, and effective non-hormonal treatments that are free from side-effects to help these women to manage HFNS.^15,16

An intervention based on cognitive behavioural therapy (CBT) has been developed,¹⁷ including psychoeducation, paced breathing and relaxation, and CBT to help women to manage HFNS. This intervention has been shown to be acceptable to women and has shown promise in exploratory trials of one-to-one and group CBT.^17,18 The treatment is based on a model of the hypothesised causal mechanisms and maintaining factors of HFNS, which include anxiety, stress, embarrassment, negative beliefs, catastrophic thoughts, and avoidance behaviours.^19,20 In a pilot, uncontrolled trial of group CBT, 17 women who had been treated for breast cancer reported an average 49% reduction in HFNS problem rating and a 38% reduction in self-reported HFNS frequency.¹⁸

Problem rating scores at 9 weeks and 26 weeks were lower in the CBT group than they were in the usual care group (table 2). There was a significant difference between groups in the primary outcome—HFNS problem rating at 9 weeks following randomisation (adjusted mean difference of −1·67, 95% CI −2·43 to −0·91; p<0·0001) with a greater reduction from baseline in problem rating in the CBT group compared to the usual care group. At 9 weeks, the change in problem rating from baseline was −3·05 (SD 2·3) in the CBT group, compared with −1·06 (SD 1·7) in usual care group, equating to a 46% reduction in the CBT group and a 19% reduction in the usual care group. At 26 weeks, the problem rating had decreased from baseline by 52% (mean change −3·39, SD 2·3) in the CBT group and by 25% (mean change −1·26, SD 2·2) in the usual care group (table 2; figure 2).

We recorded no significant difference between groups in HFNS frequency, or in the hot flush frequency and night sweat frequency subscales when analysed separately, at 9 weeks or 26 weeks (table 3 and appendix). Compared with baseline, both groups reported non-significantly fewer HFNS at 9 weeks (21% in the CBT group and 24% in the usual care group) and 26 weeks (38% in both groups). We recorded little change in 24-h rate of HFNS at 9 weeks, measured either by sternal skin conductance or participant-reported event markers; all frequency measures showed large variability in response (table 3).

Women in the CBT group reported less depressed mood and fewer sleep problems at week 9 and week 26 compared with those in the usual care group (table 3 and appendix). Women receiving CBT also reported less anxiety than did women in the usual care group at 9 weeks, but this difference was not statistically significant at 26 weeks (table 3). We recorded small improvements in memory and concentration of participants in the CBT group compared with those in the usual care group, but no statistically significant differences in somatic symptoms (table 3). At 26 weeks, women in the CBT group reported significantly better social functioning, physical functioning, and improved general health (at both 9 weeks and 26 weeks) than did women in the usual care group, according to the SF-36 assessments (table 3). Compared with women in the usual care group, women in the CBT group reported better mental health at 9 weeks and less bodily pain at 26 weeks (table 3). We recorded no significant differences between the groups in emotional role functioning or vitality subscales (table 3).

Although we did not record a mean two-point difference between treatment groups (figure 3), a greater percentage of individuals had reached this two-point threshold in the CBT group than in the usual care group at both 9 weeks (65% [95% CI 50–78] vs 38% [25–52]) and 26 weeks (78% [62–88] vs 33% [20–48]). This exploratory analysis suggests that improvement from baseline was clinically better in the CBT group than it was in the usual care group (figure 3).

In the 10% of sessions assessed for quality assurance, CBT was delivered according to the treatment manual, with 98–100% adherence. Training and clinical supervision were provided by a consultant clinical psychologist (MSH) throughout the study. Participant adherence to treatment was good; 39 (91%) of 43 participants who received CBT attended at least four of six sessions, and relaxation or paced breathing was practised, on average, 29 times each week (SD 26·93).

Individuals taking prescribed drugs for HFNS tended to continue them throughout the trial. Exceptions were one participant who stopped taking fluoxetine (CBT group), and one woman who stopped taking clonidine (usual care group). Three women started homoeopathy or herbal remedies (one in the CBT group, two in the usual care group), and one woman in the usual care group started acupuncture. When the adjusted primary analyses were repeated excluding these five participants, the estimates and CIs remained within the same margins (week 9 hot flush problem rating, CBT vs usual care mean difference −1·58, 95% CI −2·38 to −0·79; p<0·0001; week 26 hot flush problem rating, CBT vs usual care mean difference −1·77, −2·59 to −0·95; p<0·0001).

Additionally, group CBT provided sustained benefits to depressed mood and sleep and some improvements in dimensions of quality of life. At baseline, on average, participants had higher scores for sleep problems, somatic symptoms, and memory and concentration (WHQ) compared with norms for healthy women (table 3 and data not shown).²⁷ According the the SF-36 scale, they had lower scores (lower quality of life) than did healthy women, especially for physical role functioning, general health, vitality, and bodily pain. The significant improvements in mood and sleep, as well as memory and concentration, after CBT are clinically important because difficulties with mood sleep and cognitive functions are commonly reported by patients with breast cancer, particularly by those with HFNS.³⁰ Moreover, the improvement in social functioning after CBT is relevant because women report finding hot flushes especially difficult to deal with at work and in other social situations.¹⁸ Although randomised controlled trials of non-hormonal drugs for HFNS have shown moderate reductions in HFNS frequency, they have recorded little evidence of improved quality of life.⁹ Similarly, some studies show only weak relations between frequency of HFNS and quality of life.^21,22

The results of our study are very similar to the preliminary findings of a parallel trial of CBT for HFNS in a sample of healthy women (MENOS2).³¹ This consistent pattern of results suggests that the CBT might work by affecting symptom perception and cognitive appraisal of HFNS and possibly mood, rather than physiological mechanisms of HFNS, such as temperature regulation or the thermoneutral zone in the hypothalamus.¹⁹ Further analyses of moderators and mediators of HFNS are planned to clarify this issue through identification of the underlying causal pathways to improvement on the hot flush problem rating scale.²⁰ For example, changes in sleep after treatment might partly mediate the improvements in mood and quality of life. We postulate that hot-flush beliefs and behaviours, as well as mood and sleep, will act as potential mediators. For the moderator analysis, baseline clinical and demographical characteristics, such as anxiety and depression, will be considered alongside factors such as drug use and health behaviours. Further studies should examine particular components of the intervention to test these analyses experimentally.

We postulated that CBT would reduce HFNS frequency to a greater extent than would usual care, especially because paced breathing has been shown to reduce HFNS frequency measured both physiologically and subjectively.³² Women receiving CBT reported practising paced breathing daily. Paced breathing, once learnt, is practised for 2–5 min throughout the day and at the onset of a hot flush, so an average of 29 times per week is a realistic rate at which to practise. However, participants in both groups reported improvements in HFNS frequency. Women in the usual care group did receive psychoeducation, advice (which included paced breathing), and nursing support, which could have led to reductions in the usual care group, although we did not record paced breathing or other techniques done by these women. CBT treatment effects could have been attributable to the placebo effect of additional attention in the group CBT. However, we controlled for usual care and assessment effects and we should gain some insight into the placebo effects of usual care through the planned mediator and moderator analysis.²⁰ Further research could compare different types of control conditions with differing levels of information, advice, and support. The group CBT programme should be generalisable to other breast cancer settings because it is delivered in a hospital setting, is done by use of easily transferable guidelines (the treatment manual), and adherence to the guidelines was high. Drop-out rates were low, and the preliminary results of qualitative interviews done at the end of the trial suggest that the CBT was highly acceptable. The cost of delivering the treatment needs to be assessed, with a need for comparison with non-hormonal drugs. The most cost-effective method of delivering the group CBT would probably be to include it as part of survivorship support programme, delivered by trained and supervised breast-care nurses.

To date, the best available treatments have been non-hormonal drugs including SSRI and SNRIs, clonidine, and gabapentin.⁹ These treatments have produced moderate reductions in HFNS frequency (averaging 37% across trials⁹), but have had little effect on quality-of-life measures. By contrast our findings suggest that both CBT and usual care resulted in a 38% reduction in frequency, and compared with the usual care group, those who received CBT showed statistically significant and lasting reductions in problem rating and improvements in quality of life. CBT could, therefore, be an important alternative or additional treatment option for patients with breast cancer (panel 2).

Limitations of this study include the frequency measures, which had high variability. The main subjective measure (hot flush rating scale) is retrospective—daily diary measures might be more reliable. However, findings from another study show evidence of the validity of this scale compared with daily diary measures.²⁴ Estimation of the frequency of night sweats with the hot flush rating scale can be more difficult because women do not report night sweats that they sleep through, but this limitation is common to all self-report measures. The physiological measure was used for 24 h at baseline and at 9 weeks after randomisation; in view of the variability of this measure, future studies might include a longer time of SSC monitoring and also include this measure at follow-up assessments. Additionally, we did not control for all potential confounding factors that could have an effect on menopausal symptoms, such as the use of drugs to manage HFNS and the use of adjuvant hormone therapy. Health behaviours might also have affected HFNS and other secondary outcomes, but were not controlled for in the analyses (eg, caffeine intake). Finally, we do not know whether HFNS were caused by breast cancer treatments or whether women were naturally menopausal when they had breast cancer. However, treatment options are still restricted for these women, so a need still exists for non-hormonal interventions.