Evaluating Optimal Timing of Endocrine Therapy and Radiation Therapy in Early-stage Breast Cancer (REaCT-RETT)

Study Overview
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Brief Summary
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REaCT-RETT will demonstrate the non-inferiority of concurrent compared to sequential endocrine therapy in patients receiving post-operative radiotherapy for early stage breast cancer.

Detailed Description
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Clinical equipoise exists around the optimal time to start adjuvant endocrine therapy in patients who will receive post-operative radiotherapy for breast cancer. Patients receive either concurrent or sequential endocrine and radiation therapy, where concurrent therapy consists of endocrine therapy started before, with or during radiotherapy, while sequential treatment is defined as endocrine therapy starting after the completion of radiotherapy. A recent survey of Canadian oncologists showed that the main reason for prescribing sequential endocrine therapy was a concern that concurrent endocrine therapy and radiotherapy would worsen the toxicity of endocrine treatment. This is despite the absence of any clinical trial evidence to support this. Indeed, a recent systematic review by our group was unable to confirm or refute whether increased toxicities, related to the timing of endocrine therapy and radiotherapy actually exist in clinical practice. The investigators are therefore proposing a pragmatic randomised trial to assess whether or not concurrent endocrine therapy and radiotherapy worsens endocrine treatment-related symptoms in an era of modern endocrine and radiation therapy.

Official Title
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A Pragmatic Randomised, Multicentre Trial Evaluating Optimal Timing of Endocrine Therapy and Radiation Therapy in Early-stage Breast Cancer (REaCT-RETT)

Conditions
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Early-stage Breast Cancer

Intervention / Treatment
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* Combination Product: Endocrine Therapy and Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with newly diagnosed early stage, hormone receptor positive breast cancer Planned to receive both endocrine therapy and post-operative radiotherapy Able to provide verbal consent Exclusion Criteria: Previous endocrine therapy for invasive breast cancer Previous radiotherapy for breast cancer in the same breast

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Concurrent Endocrine Therapy and Radiotherapy<br>Concurrent endocrine therapy and radiotherapy. Concurrent endocrine therapy will be defined as, the commencement of endocrine therapy around 2 weeks before (a minimum of 1 week before to a maximum of 4 weeks) commencement of radiotherapy and continued throughout radiotherapy. | Combination Product: Endocrine Therapy and Radiotherapy<br>* Endocrine therapy and radiotherapy administered either concurrently or sequentially<br>* Other names: Exemestane;|
| Active Comparator: Sequential Endocrine Therapy after Radiotherapy<br>Sequential endocrine therapy after radiotherapy. Using the pragmatic definition sequential endocrine therapy should commence around 2 weeks (minimum 1 week, maximum 4 weeks) after the last fraction of radiotherapy. | Combination Product: Endocrine Therapy and Radiotherapy<br>* Endocrine therapy and radiotherapy administered either concurrently or sequentially<br>* Other names: Exemestane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endocrine toxicity | To measure endocrine toxicity. The Functional Assessment of Cancer Therapy - Endocrine Sub-scale (FACT-ES) is a questionnaire specific to patients with endocrine symptoms and measures the side effects and putative benefits of hormonal treatments given (endocrine therapy) in breast cancer. The FACT-ES questionnaire is comprised of 5 sections; physical well-being (7 questions), social/family well-being (7 questions), emotional well-being (6 questions), functional well-being (7 questions) and additional concerns (19 questions). A total of 46 questions are asked that all contain an answer on a scale range of 0-4, with 0 representing the answer 'not at all' and 4 representing the answer 'very much'. Of the 46 questions asked 31/46 have 'very much' representing the worst answer and the remaining 15/46 have 'very much' representing the best answer. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiotherapy toxicity | To evaluate the acute and early-moderate late toxicities of radiotherapy in terms of skin toxicity, pneumonitis, and breast pain. This will be recorded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with breast cosmesis recorded as per the European Organisation for Research and Treatment of Cancer (EORTC) cosmetic rating system for breast cancer. These standardized criteria have been used in a recent Canadian breast radiation randomized trial, RAPID, and the investigators will use a similar template to record any radiation toxicities at different points of time. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 
| Rates of starting endocrine therapy and compliance | Rates of starting endocrine therapy, compliance rates, discontinuation rates, along with the reasons for discontinuation. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 
| Direct Estimation of Health Utility Values | To measure the patient quality of life using the validated FACT-B questionnaire. The Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) is a questionnaire that measures multidimensional quality of life in patients with breast cancer. The FACT-B questionnaire is comprised of 5 sections; physical well-being (7 questions), social/family well-being (7 questions), emotional well-being (6 questions), functional well-being (7 questions) and additional concerns (10 questions). A total of 37 questions are asked that all contain an answer on a scale range of 0-4, with 0 representing the answer 'not at all' and 4 representing the answer 'very much'. Of the 46 questions asked 20/37 have 'very much' representing the worst answer and the remaining 17/37 have 'very much' representing the best answer. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 
| Incremental cost-effectiveness ratios | Incremental cost-effectiveness ratios (cost per one quality-adjusted life year (QALY) gained and cost per one endocrine toxicity case averted) will be measured using the EQ-5D-5L questionnaire. The EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire consists of two sections; the descriptive system and the visual analogue scale. The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and has 5 levels associated with it (no problems, slight problems, moderate problems, severe problems and extreme problems). The scale range of 1-5 is used for the 5 dimensions where 1 is the best outcome and 5 is the worst outcome. The Visual Analogue scale records the respondent's self-rated health on a vertical, visual scale with endpoints labelled the best health you can imagine at the top and the worst health you can imagine at the bottom. This ranges 0-100 with 0 being the worst outcome and 100 being the best outcome. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 
| Exploratory analyses on evaluating radiotherapy toxicity | Exploratory analyses will be performed evaluating toxicity in patients receiving different types of radiotherapy (i.e. local versus regional radiotherapy). This will be evaluated using data collected on breast volume, seroma size, dose heterogeneity and the time of stimulation and planning. | 12 months (+/- 2 weeks) post final fraction of radiotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiation Therapy, Endocrine Therapy