To achieve study aims, we will carry out a randomized, interventional, prospective study. Patients will be recruited at Dijon cancer center (Georges François Leclerc-Unicancer center) in France. This center is specialized in cancer management, therefore clinicians are experienced in patient’s HRQoL evaluation and are accustomed to take this criterion into consideration in the routine patient management.
Women aged 18 and over, with non-metastatic hormone receptor positive BC will be included in this study. These women will have to be at the end of primary treatment, have an indication for endocrine therapy treatment during 5 to 10 years, be affiliated to a French social security scheme or beneficiary of such a scheme and have agreed to participate by signing a written consent. Patients who participate in another clinical trial where HRQoL is assessed will not be included, as well as women for whom HRQoL evaluation is not possible (cognitive disorders, psychiatric disorders, people who do not speak French, etc.).
Inclusion procedure
The study will be proposed to eligible patients by their doctors (oncologists, surgeons, radiation oncologists). Patients will be included at the time of the first prescription of ET (at the end of the treatments by surgery +/- chemotherapy +/- radiotherapy). Once included, patient will be randomized into one of the two study arms (interventional arm or control arm). Patients will then be referred to the clinical research associates, whose role will be to collect patient data (clinical and sociodemographic) in both study arms and to instruct patients in the interventional arm on how to use the CHES software [26]. For patients who wish to access the platform from home, a username and password will also be provided. If needed, clinical research associates will also assist patients to complete HRQoL questionnaires. This information will be collected in the case report form, to take into account the social desirability bias.
Randomization
Eligible patients who agree to participate will be randomized into two parallel arms (ratio 1:1) by the minimization technique with stratification by age, stage, presence or absence of comorbidities and type of ET prescribed.
Intervention arm
Assessment of HRQoL
The intervention will consist in an electronic measurement of patient HRQoL before each consultation with delivery scores to clinicians, who can discuss it with patients and couple it with therapeutic information. Patients will complete the EORTC-QLQ-C30 and the EORTC-QLQ-BR23 questionnaires before their consultation, via a touch pad or from their home via a secure web portal. Patients will complete the questionnaires via the CHES software [26]. The CHES software was developed by ESD (Evaluation Software Development) in collaboration with the EORTC Quality of Life Group to facilitate the inclusion of HRQoL measurement instruments in research projects and daily clinical practice. This mode of collection provides clinicians with real-time results, and generates alerts in the event of clinically significant deterioration of patients' HRQoL scores, allowing them to tailor treatment in a personalized manner. The scores will then be generated and provided to patients and clinicians in a graphic form, describing scores course. Access to CHES web portal will also be open to patients outside consultation time points, to enable them to monitor HRQoL if necessary. If minimal HRQoL impairment is observed (decrease lower than 20 points) [27], self-help tools can be generated, providing patients with indications on how to deal with certain adverse effects. Moreover, if a significant deterioration in HRQoL (decrease higher than 20 points) [27], the clinical research assistant will receive an alert and, if necessary, will forward the information to the medical team for appropriate care.
Therapeutic information
Therapeutic information will consist on workshops on various themes and will be coordinated by a pharmacist in charge of therapeutic education in Dijon cancer center. This healthcare professional will be responsible for the organization and implementation of these workshops. Workshops will be performed by pharmacists, nurses or dieticians. Only attendance Workshop 1 will be required, other workshops will be optional.
Workshop 1, will deal with “understanding the prescription”. The aim is to inform patients about their ET and treatment benefits. It also helps patients to recognize and react to the occurrence of possible adverse effects, and anticipate their occurrence through appropriate preventive means. This workshop will be held within 2 months after the first prescription of ET. This workshop will be performed by pharmacists with training in therapeutic education.
Two additional optional workshops on nutrition (Workshop 2) and fatigue (Workshop 3) will be offered. This workshops will be collective and performed by a dieticians and nurses, respectively. Workshop 2, on Nutrition, will focus on the benefits of exercise and the need to adopt an appropriate diet. Patients will have the opportunity to express their representations and experiences related to their diet and the consequences of disease and treatments on diet. Workshop 3, on fatigue, will address the recognition of fatigue and early management of this symptom. Patients can describe their experiences of fatigue and how their life is affected by it. Moreover, they can identify possible causes and finally discuss solutions to better this symptom.
Every month, a letter encouraging patients to regularly take their medication will be sent. This letter, derived from Hadji’s work [10], will also include some tips on how to deal with some particular side effects of endocrine therapy.
Control Arm
Patients in the control arm will receive standard care. They will not undergo digital HRQoL collection, and therapeutic information workshops will not be proposed. This information will be taken into account when performing statistical analyses.
For both arms, HRQoL will be evaluated at baseline using the FACT-G questionnaire to ensure the comparability of groups concerning HRQoL at inclusion, and again at 12 months. This HRQoL assessment will be performed using a traditional paper questionnaire and scores will not be provided to clinicians. Anxiety and depression, social support and patient satisfaction with care will also be assessed in both arms at baseline and 12 months after.
Endpoints
Primary endpoint
The primary endpoint of this study is 12-month compliance with ET, as evaluated using the Morisky Green Levine scale (MGL). Patients will be considered as compliant if they have a high adherence in MGL scale.
Secondary endpoints
The secondary endpoints will be anxiety and depression assessed by the HADS questionnaire, social support assessed by Sarason’s SSQ6 questionnaire and HRQoL assessed by the FACT-G questionnaire.
HRQoL data using FACT-G questionnaire will be assessed at inclusion in both arms to ensure comparability between groups and at 12 months, to assess the predictive value of HRQoL on compliance to ET.
Patient satisfaction with care will be assessed by the EORTC-SAT-C33 and EORTC-OUT-PATSAT-7 questionnaires.
Physician perception regarding the utility of systematic HRQoL evaluation will be assessed using an ad hoc questionnaire derived from the work of Velikova, including the perceived utility and satisfaction of routine assessment HRQoL, reasons for use/non-use and the intention to adopt this assessment in routine care.
Sample size
A total of 342 patients with non-metastatic BC are required, based on the following assumptions: an estimated compliance rate of 59% [5] in patients with non-metastatic breast cancer one year after the first prescription of ET, a bilateral risk alpha of 5%, a statistical power of 80%, to show a 15% difference in compliance between patients in the intervention arm and those in the control arm 1 year after the first prescription, it is necessary to include 155 patients per arm (bilateral chi-square test). Taking into account a loss to follow-up rate of 10%, a total of 171 patients will be included in each arm (nQuery Advisor V7).
Data collected
Sociodemographic characteristics (age, sex, level of education, family situation, socio-professional category ...), medical and surgical history, date of tumor diagnosis, tumor characteristics, previous treatments, patient clinical characteristics at inclusion and at each follow-up visit (weight, height, overall patient condition), concomitant treatment, type of ET received, HRQoL data (FACT-G ), anxiety and depression (HADS), social support (SSQ6), treatment modification (change in the type of ET), treatment-related toxicities and their grade will be collected. Patient satisfaction with provided care will be measured using the EORTC-SAT-C33 and the EORTC-OUT-PATSAT-7. Clinicians' perceptions of systematic health-related quality of life assessment (utility and perceived satisfaction, reasons for use or non-use, and the intention to adopt it in practice) will be collected via an ad hoc questionnaire. Sociodemographic data and reasons for refusing to participate will also be documented for patients who refuse to participate. Data on patients’ withdrawal or death will be documented in the case report form. Reasons for study withdrawal should also be documented. All data from this study will be transcribed in an electronic case report form (Clinsight).
Questionnaires and tools
EORTC-QLQ-C30 and EORTC-QLQ-BR23 questionnaires
The cancer-specific EORTC-QLQ-C30 questionnaire and its breast cancer-specific QLQ-BR 23 module are available in French and are validated tools to assess HRQoL in cancer and more specifically in BC [28]. The EORTC-QLQ-C30 questionnaire renders possible to assess one dimension of HRQoL / overall health, five functional dimensions (physical, current activities, cognitive, emotional and social), eight dimensions of symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation and diarrhea) and a scale of financial difficulties. The EORTC-QLQ-BR23 consists of 23 questions which assess four functional dimensions (body image, sexual activity, sexual pleasure and future perspectives) and four dimensions of symptoms (side effects of systemic therapy, breast symptoms, symptoms at the arm and upset by hair loss). Scores are generated per dimension in accordance with the EORTC [29] scoring rules. These scores vary from 0 (worst) to 100 (best) for the functional and global health parameters and from 0 (best) to 100 (worst) for symptom parameters.
MGL questionnaire
The 4-item Morisky Green Levine Medication Adherence Scale (MGL) was developed to measure adherence to treatment by Morisky et al [30]. It has a range of 0 to 4, where 0 is very low and 4 is highest. Patients are categorized according to three levels of adherence: high (score equal to 4), moderate (score equal to 2 or 3) and low (score equal to 0 or 1).
HADS questionnaire
The Hospital Anxiety and Depression Scale (HADS) is an instrument for detecting anxiety and depressive disorders. It was validated and adapted in French in 1989 by Lepine et al [31]. This scale has 14 items rated from 0 to 3 and covers 2 dimensions. Seven questions related to the anxiety dimension and seven other related to the depressive dimension, yielding 2 scores, A (Anxiety) and D (Depression). The maximum score for each dimension is 21. A score of 11 or higher indicates the probable presence of the disorder.
FACT-G questionnaire
The FACT-G (Functional Assessment of Cancer Therapy-General) is a 27-question tool validated in cancer patients and has four subscales to assess wellbeing. The FACT-G instrument assesses 4 HRQoL domains: physical well-being (7 items); social and/or family well-being (7 items); emotional well-being (6 items); and functional well-being (7 items). Respondents use a 5-point Likert-type scale which rates the relevant domain from 0 (not at all) to 4 (very much). From these subscales a global score is obtained [32, 33]. The FACT-G total score vary from 0 to 108. The higher the score, the better the HRQoL.
EORTC PATSAT-C33 and EORTC-OUT-PATSAT-7 questionnaires
The EORTC-PATSAT-C33 questionnaire and its EORTC-OUT-PATSAT7 ambulatory context-specific supplementary module were developed to assess perceptions of cancer patients regarding the quality of care received [34]. They consist of 33 and 7 items, respectively. The EORTC-PATSAT-C33 questionnaire includes three sections on the perceived quality of care provided by physicians, radiotherapy nurses / technicians and services / care organization. The clinician section includes three dimensions that address technical skills (3 items), quality and quantity of information exchanged (3 items) and behavior (4 items). The radiotherapy nurses / technicians section has two dimensions: information provision and reactivity (3 items) and affective behavior (4 items). The service and organization of care section has three dimensions: coordination (4 items), interaction with the healthcare team (7 items) and five single items.
The complementary EORTC-OUT-PATSAT7 includes two dimensions dealing with convenience of care (3 items) and transition (3 items) and a single item on continuity of care. The instructions invite patients to evaluate the most recent care experience and to specify the cancer care setting. The score vary from 0 to 100. A higher score indicates higher level of satisfaction.
SSQ6 questionnaire
Social support will be evaluated by Sarason’s six-item Social Support questionnaire (SSQ6), validated and adapted in French by Rascle et al. in 2005 [35]. This questionnaire reflects the support available in patients’ environment. Social support is measured across 2 dimensions: support availability, through the number of contacts that the patient can count on (0 to 9 people) and quality of support, through patient satisfaction with support received.
Each item represents a situation in which the patient may need support. Patient is asked to cite the number of people that she could count on in that particular situation. Concerning the second item, the patient is asked to assess satisfaction with the support provided. The scores are generated according to Sarason's recommendations. A score is calculated for each dimension. Support availability score is calculated as the sum of the number of people available for the 6 items, this score ranges from 0 to 54, with 54 representing the highest availability. The social support satisfaction score is calculated by the sum of the satisfaction of the 6 items. This score ranges from 6 to 36, with 36 representing the highest level of satisfaction [36].
Ad hoc questionnaire
This ad-hoc questionnaire derived from the work of Velikova [19, 37] will assess the perception of doctors concerning the interest of systematic HRQoL evaluation. It evaluates the following criteria: usefulness of the systematic evaluation of HRQoL, perceived satisfaction with systematic evaluation of HRQoL, reasons to use it or not in current clinical practice and whether or not to adopt it routinely.
CHES
For this study, a French version of the CHES web-based solution will be available. Each patient will be represented by an identifier, to guarantee the data confidentiality and anonymous exploitation of database for statistical purposes. CHES offers a cross-sectional presentation (presentation of scores for each dimension) and a presentation of the longitudinal course of HRQoL for each dimension of the questionnaires. CHES also minimizes input errors, reduces the number of missing data related to data collection, and avoids ambiguities in the responses. This software also allows remote access via a platform that will allow patients, who desire (outside the consultations) to give an input on their HRQoL, in the event of a deterioration or improvement perceived at the clinical level.
Follow up
Patients treated with adjuvant ET will attend a consultation every 6 months, HRQoL assessment will be performed at each visit. As the aim of this project is to integrate this intervention in daily clinical practice, it will be performed in agreement with patients’ routine follow-up. Patients will complete the questionnaires prior to each consultation, either at home via access to the web portal within 24 hours before consultation, or at the time of consultation. During consultation physician will have access to the results immediately, via the secure web portal, and will be able to discuss them with the patient.
Statistical analyses
Descriptive analysis
A descriptive analysis of patients’ clinical and socio-demographic characteristics at inclusion will be performed for each arm. Data will be expressed as number and percentage for categorical variables, and as mean ± standard deviation (SD), or median and interquartile range [IQR] for continuous variables, as appropriate. The number of missing data will be specified. The number of patients with available data will also be specified for quantitative variables. Normality will be tested using the Shapiro-Wilk test. According to data distribution, independent Student t tests or non-parametric Mann-Whitney tests will be used to compare results between groups. The basic categorical characteristics will be compared using tests of Chi square or Freeman Halton according to the number of the variable categories. Continuous variables can be transformed into categorical variables according to thresholds defined by literature or according to the median.
HRQoL analysis
All HRQoL scores will be calculated according to FACT-G guidelines and described according to the arm (interventional arm or control arm). A logistic regression model will be used to assess the capacity of HRQoL to predict 12-month compliance with endocrine therapy. The modulatory potential of social support on compliance will be assessed using an interaction term between the availability / satisfaction of social support that patients receive and HRQoL in a logistic regression model. The modulatory potential of psychological distress on compliance will be assessed using an interaction term between patient anxiety / depression and HRQoL in a logistic regression model.
An analysis of missing HRQoL data profiles will also be performed. If a Missing Not At Random (MNAR) profile is demonstrated / suspected, multiple imputation of missing data can be performed in sensitivity analysis, taking into account the variables associated with the occurrence of missing data.
The significance level for the statistical analyses is fixed at p < 0.05 and all tests will be bilateral. The data analysis will be performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
Sensitivity analysis
Contamination-based intent-to-treat analysis will be conducted to account for potential cross-contamination between the arms.
Ethical considerations
As a specific research intervention is carried out, the protocol falls within the scope of interventional biomedical research and was authorized by the French Health Agency (ANSM- Agence Nationale de la Sécurité du Médicaments et des produits de santé”, IDRCB number: 2019-A01323-54) in June 2019 and by the French Ethical Research Committee (CPP- “Comité de Protection des Personnes”) in October 2019. The clinical trial has been registered at ClinicalTrials.gov with the identifier NCT04176809.
This study will be done in accordance with the ethical principles of the Helsinki Declaration and the Good Clinical Practice of the International Harmonization Conference. Participants must provide informed consent. Subjects will be informed of the objectives of the project and the risks and benefits of the explorations to be carried out. Confidentiality of participant data will be guaranteed at all times in agreement with the CNIL MR01 reference methodology registered for CGFL (1878714v0, 30/07/2015).