Internet-based Cognitive Behavioral Therapy for Breast Cancer Patients With Climacteric Symptoms
Condition: Climacteric Symptoms; Breast Cancer Survivors
MeSH terms: Breast Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      The current study will evaluate systematically the efficacy and cost-effectiveness of two
      internet-based CBT/relaxation programs (one guided, the other self-managed) in reducing the
      severity of menopausal symptoms and improving copings skills with regard to hot flushes and
      night sweats as well as improving sexual functioning, improving quality of sleep, reducing
      emotional distress and improving quality of life in younger breast cancer patients who
      experience treatment-induced menopause.
    

Detailed description: 
      Background: Breast cancer is the most common cancer among women in the Netherlands, with
      approximately 14.000 new cases reported in 2011 (1). Nearly 30% of all women with breast
      cancer are premenopausal at the time of diagnosis (2). Ovarian damage is a major long-term
      sequela of chemotherapy in premenopausal women (3,4). Ovarian failure induced by chemotherapy
      and/or endocrine treatment leads to an earlier onset of menopause, with age and duration of
      treatment being its strongest predictors (5).

      Premature menopause is a major concern of younger women undergoing (adjuvant/preventive)
      therapy for cancer (6). Primary menopausal symptoms include hot flushes, night sweats,
      vaginal dryness, decreased libido, dysuria and urinary incontinence. Secondary symptoms
      include insomnia due to night sweats, dyspareunia because of vaginal dryness, weight gain,
      and psychological distress (3,7,8). Previous studies have indicated that the severity of hot
      flushes is increased in women who experience transition into menopause during cancer
      treatment or after PBSO, compared to women going through natural menopause (9,10,11).

      Among menopausal symptoms, hot flushes are considered to be the most disruptive, with
      prevalence rates between 63% and 80% in breast cancer patients (7,12-15). Moreover, vasomotor
      symptoms are an important reason why some women discontinue tamoxifen treatment (16,17).
      Hormonal replacement therapy (HRT) is highly effective in alleviating vasomotor symptoms
      associated with menopause (18). However, HRT is contraindicated in women with a history of
      breast cancer (19), even after prophylactic bilateral salpingo oophorectomy (PBSO) (20).

      There is increasing evidence that behavioral interventions have a positive impact on symptoms
      in women with naturally occurring and treatment-induced menopause (21-27). A cognitive
      behavioral therapy (CBT) intervention including information about symptoms, monitoring and
      modifying precipitants, relaxation and stress management, cognitive restructuring of
      unhelpful assumptions and automatic thoughts, and encouraging helpful behavioral strategies
      has been found to be beneficial in the alleviation of menopausal symptoms in women with
      breast cancer (25,26), but compliance with face-to-face CBT programs can be problematic (26).
      A promising approach is to make this form of CBT more accessible and feasible for
      participants by having it available via the internet. Although the efficacy of CBT for this
      patient population has been demonstrated in the form of face-to-face group therapy, its
      efficacy has not been investigated when delivered via an internet platform in an individual
      setting.

      Design. For this trial patients will be recruited from several hospitals in the Netherlands
      (predominantly Amsterdam region). Participants will be randomly allocated to either the
      guided intervention group, the self-management group or the control group (N = 83 per group).
      Upon completion of the study, the patients assigned to the control group will be given the
      opportunity to undergo the internet-based cognitive behavioral therapy program.

      Women in the two intervention and control group will be asked to complete a battery of
      questionnaires prior to randomization (TO), at 10 weeks (T1) and at 6 months (T2).

      Study measures. The primary outcomes are menopausal complaints, as assessed with a menopausal
      complaints questionnaire, the Functional Assessment of Cancer Therapy - Endocrine Symptoms
      (FACT-ES), and hot flushes and night sweats as assessed by the Hot Flushes Rating Scale
      (HFRS). The secondary study outcomes are sexuality problems (the Sexual Activity
      Questionnaire (SAQ)); sleep quality (The Groningen Sleep Quality Score (GSQS)); psychological
      distress (The Hospital Anxiety and Depression Scale (HADS)) and health related quality of
      life (The Medical Outcome Study 36-Item Short Form-36 Health Survey (SF-36)).

      Patients' evaluation of the intervention program. The women in both intervention groups will
      be asked to provide their opinion of the internet-based CBT program at the 10 week evaluation
      point. All these women will be asked to complete a short questionnaire about the perceived
      efficacy of and satisfaction with the intervention program, whether they would suggest any
      changes to the program, and if they would recommend it to other women experiencing symptoms
      of premature menopause. In addition, telephone interviews (30 minutes) will be held with
      women who: (1) stated in the questionnaire that the intervention did not have the desired
      effect; and/or (2) gave the intervention a low rating (<6) and/or (3) would not recommend the
      program to others.

      Cost effectiveness. The cost-effectiveness of the internet-based guided CBT versus the
      internet-based self-management CBT versus usual care will be expressed as: (1) cost per
      patient with a clinically relevant significant reduction on the HFRS and (2) cost per quality
      adjusted life year (QALY) gained.

      Sample size and statistical power calculations: In total, 248 women will be recruited into
      the study, to allow for an attrition rate of approximately 20% (i.e., women who discontinue
      participation in the study entirely, including failure to complete all follow-up
      questionnaires; those women who discontinue participation in one of the groups but complete
      the follow-up assessments will be included in the analysis). Thus, a minimum of 130 women
      will be available for the primary intention-to-treat analysis. With a total sample of 130
      women (65 per group), the study will have 80% power to detect an effect size of 0.5 with a p
      value of 0.05 (28).

      Statistical analyses: Analyses will first be performed to evaluate the comparability of the
      intervention groups (guided versus self-management) and control group at baseline in terms of
      sociodemographic and clinical characteristics. ANOVA tests or appropriate non-parametric
      statistics will be used, depending on the level of measurement. If, despite the stratified
      randomization procedures, the groups are found not to be comparable on one more background
      variables, those variables will be employed routinely as covariates in subsequent analyses.

      We will evaluate between-group differences over time in self-reported endocrine symptoms,
      sexual functioning, psychological distress, sleep quality and HRQOL. Scores for the FACT-ES,
      the HFRS, the SAQ, the HADS, the GSQS, and the SF-36 and the utility version of the SF-36,
      the SF-6D will be calculated according to published scoring algorithms.We will compare both
      intervention groups with the control group over time using multilevel procedures with
      repeated measures, using a restricted maximum likelihood (REML) solution to model specific
      contrasts between groups and follow-up assessment (29). Within each multilevel model the
      control group will be the reference category. Differences in mean change scores over time
      between the intervention groups and the control group will be accompanied by effect sizes
      (ES). As indicated previously, the FACT-ES and the HFRS will be used as the primary study
      endpoints, and the remaining measures will be considered as secondary endpoints. The p-value
      for overall model effects will be set at 0.05, and for specific contrasts at 0.01, lowering
      the risk of Type errors due to multiple testing.

      All analyses will be conducted on an intention-to-treat (ITT) basis. In addition,
      per-protocol (PP) analyses will be performed on patients who met criteria for minimal
      compliance with the intervention(s). Supplementary analyses will be carried out in which data
      relating to compliance with the program elements is taken into account. Specifically, we will
      determine whether the level of compliance (based on completed homework assignments and
      self-report data) is associated significantly with the changes over time in symptom relief,
      sexuality, psychological distress, sleep quality, and cost-effectiveness. In addition the
      potential mediating effect of hot flush beliefs and behaviors will be examined through
      mediator analysis.

      A cost-effectiveness analysis (CEA) will be performed using a validated health economic model
      as developed for use in the EVA-Trial (30). The analysis will consider the societal
      perspectives, the third-party payer perspective and the healthcare system perspective in
      comparing the effectiveness and costs of web-based CBT for alleviating treatment-induced
      menopausal symptoms versus waiting list control. Effectiveness data as gathered from the
      trial will be combined with the cost data from the cost-diary and hospital administration
      data.
    

Intervention name(s): EVA-Online
Intervention type(s): Behavioral
Intervention description(s): Internet-based cognitive behavioral therapy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Climacteric symptoms; Menopause; Breast Cancer Survivors; Internet-based; Cognitive behavioral therapy; Psychosocial intervention