Duijits 2012.

Methods	Study design: multi‐centre RCT Number randomised: 422; 109 to cognitive‐behavioural therapy (CBT); 104 to physical exercise; 106 to CBT and physical exercise combined; 103 to control group Study start: January 2008; recruitment stop date: December 2009 Length of intervention: 12 weeks Length of follow‐up: at 6 months (at 3 months post intervention) Country: Netherlands
Participants	Age, years (mean SD): CBT: 48.2 (5.7) Exercise: 47.7 (5.6) CBT + Exercise: 49.0 (4.9) Control: 47.8 (6.0) Stage: Stages: T1‐4, N0‐1, and M0 (i.e. stage I‐IIIC) Inclusion criteria: • Primary breast cancer (stages T1‐4, N0‐1, and M0) • Younger than 50 years and premenopausal at diagnosis • Had received adjuvant chemotherapy and/or hormonal therapy • Disease‐free at study entry • Reported at least a minimal level of menopausal symptoms • Chemotherapy had to be completed at least 4 months before but not more than 5 years before study entry (hormonal therapy could still be ongoing) Exclusion criteria: • Lack of basic proficiency in Dutch • Serious cognitive or psychiatric problems • Serious physical comorbidity • Obesity (body mass index > 35), because exercise may be contraindicated as a treatment for hot flashes in obese women • Participating in concurrent studies targeted at menopausal symptoms or involving similar interventions
Interventions	109, 104, and 106 participants were assigned to CBT, exercise and CBT, and exercise 12‐week intervention, respectively: CBT consisted of 6 weekly group sessions of 90 minutes each and 1 booster session 6 weeks post completion, including relaxation exercises. The primary focus of CBT was on hot flashes and night sweats, but other symptoms (e.g. vaginal dryness) and problem areas (such as body image, sexuality, and mood disturbance) were also addressed. The aerobic exercise programme was an individually tailored, home‐based, self‐directed exercise programme of 2.5 to 3 hours per week. During the intake session, the physiotherapist assisted each woman in selecting an appropriate form of exercise (e.g. swimming, running, cycling). Each woman was provided with a heart rate monitor and was instructed in its use to achieve a target heart rate (60% to 80% Karvonen). During weeks 4 and 8, women had telephone interviews with the physiotherapist to discuss their experiences and possible need to adjust the programme. During the last week, women visited the clinic for a final session, during which they received advice on how best to maintain their desired level of physical activity. Women in the combined intervention group underwent CBT and exercise programmes concurrently. Adherence: Fifty‐eight per cent of the CBT group, 64% of the PE group, and 70% of the CBT and exercise group did not meet criteria for compliance (i.e. at least 4 of 6 CBT sessions and/or minimum of 24 PE training sessions, with an average of 3 kCals/kg or 6.45 METs per session). 103 participants assigned to control: Wait‐list control: On completion of the study, control group participants could choose to undergo the CBT or PE programme.
Outcomes	Primary outcomes: Endocrine symptoms assessed by the 18‐item endocrine subscale of the Functional Assessment of Cancer Therapy questionnaire (FACT‐ES) Hot flashes and night sweats (HF/NS) assessed by the Hot Flush Rating Scale. The Hot Flush Rating Scale comprised 2 items measuring frequency of hot flashes and night sweats (HF/NS frequency rating) and 3 items measuring the extent to which these symptoms were perceived to be problematic and interfered with daily life (HF/NS–problem rating). Secondary outcomes: Sexual functioning assessed by the Sexual Activity Questionnaire (SAQ) Urinary symptoms assessed by the 5‐item incontinence scale of the Bristol Female Lower Urinary Tract Symptoms Questionnaire (BFLUTS) Body image assessed by the 4‐item QLQ‐BR23 subscale Psychological distress assessed by the 14‐item Hospital Anxiety and Depression Scale (HADS) Generic HRQoL assessed by the MOS SF‐36, which includes 8 subscales as well as physical and mental component scores Program compliance assessed via session attendance records for CBT participants and number and intensity of training sessions, as recorded by the heart rate monitor, for PE participants. Participants were considered to be compliant if they attended at least 4 of 6 CBT sessions and/or had a minimum of 24 PE training sessions, with an average of 3 kCals/kg per session (or 6.45 METs). Numbers of participants assessed: CBT: baseline, 109; at 12 weeks, 86; at 6 months, 88 Exercise: baseline, 104; at 12 weeks, 87; at 6 months, 79 CBT + Exercise: baseline, 106; at 12 weeks, 90; at 6 months, 89 Control: baseline, 103; at 12 weeks, 89; at 6 months, 84 Adverse events: not reported
Notes	Trial registration link: https://clinicaltrials.gov/ct2/show/NCT00582244 Trial authors contacted: no Intention‐to‐treat analysis: no Funding: supported by grant No. NKI 2006‐3470 from the Dutch Cancer Society; the Integral Cancer Center, Amsterdam; the Pink Ribbon Foundation; and Polar Electro Nederland
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Computerized block randomization”
Allocation concealment (selection bias)	Unclear risk	Whether treatment assignment was concealed from study personnel and participants was not described. Centralised randomisation was not mentioned.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Owing to the nature of the intervention, it was not possible to conceal allocation to the intervention from participants.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No mention of whether study personnel and outcome assessors were masked or blinded to study interventions
Incomplete outcome data (attrition bias) All outcomes	High risk	“Missing values were replaced by the average score of the completed items in the same scale for each individual, provided that at least 50% of the items in that scale had been completed”.
Selective reporting (reporting bias)	Low risk	No selective reporting of outcomes is apparent.
Other bias	Low risk	Trial appears to be free of other problems that could put it at high risk of bias.