Hypofractionated LocoRegional Radiotherapy in Breast Cancer

Study Overview
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Brief Summary
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The primary objective of this study is to determine if hypofractionated RT delivered over 1 week to the breast or chest wall and regional nodes (26Gy in 5 daily fractions) following BCS or mastectomy, is non-inferior to conventional fractionation to the breast or chest wall and regional nodes delivered over 3 weeks (40Gy in 15 daily fractions) in patients with node-positive breast cancer.

Detailed Description
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A multi-centre, randomized, non-inferior, phase III study comparing two radiation treatment modalities, conventional fractionation with hypofractionation for locoregional RT. Eligible, consenting patients with newly diagnosed and histologically confirmed invasive carcinoma of the breast without evidence of metastatic disease; treated with definitive surgery [BCS or mastectomy with nodal staging using sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)] will be randomized in a 1:1 fashion to either conventional locoregional RT (control group) or hypofractionated locoregional RT (experimental group). Stratification factors include: body mass index, the performance of ALND, type of surgery (BCS or mastectomy) and clinical centre. Study participants will be assessed for lymphedema, the primary outcome, by measuring arm volume. Arm mobility will be assessed by measuring arm movement. Study participants will be assessed for acute and late radiation toxicities, during and post RT. Study participants will be followed and assessed annually for breast cancer recurrence (BCR), new second cancers, quality of life (QOL) and overall survival. Cost effectiveness and cost utility will also be determined. The planned sample size is 588 study participants. The study will be conducted at clinical centres throughout Canada.

Official Title
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Randomized Trial of Hypofractionated LocoRegional Radiotherapy in Breast Cancer and Lymphedema (RHEAL)

Conditions
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Breast Neoplasms, Radiotherapy, Lymphedema

Intervention / Treatment
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* Radiation: Locoregional radiation treatment - Conventional fractionation
* Radiation: Locoregional radiation treatment - Hypofractionation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed invasive carcinoma of the breast. Treated with definitive surgery (BCS or mastectomy with nodal staging using SLNB or ALND) with clear margins of excision.* Note: *Patients with limited positive posterior margin where disease is resected to chest wall or limited positive anterior margin where disease is resected to dermis are eligible. Candidate for locoregional radiotherapy: breast cancer stage after definitive surgery: Neoadjuvant chemotherapy was not administered: pathologic stage T3N0,T1-3 N1-2** ** patients with nodal micromets (N1mi) are eligible Neoadjuvant chemotherapy was administered: clinical stage T3N0, T1-3, N1-2 and pathologic stage T0-3, N0-2† Patients who are clinically N1-2 prior to chemotherapy should be confirmed histologically unless it is clear that they are node positive. Patients who are deemed node negative prior to chemotherapy but are node positive following chemotherapy are eligible. Patients who are node positive prior to chemotherapy and who have complete response in the lymph nodes are also eligible. No evidence of metastatic disease. Exclusion Criteria: Age < 18 years. Clinical stages T4 and/or N3. Clinical lymphedema in the ipsilateral arm or breast/chest wall. Any prior history, not including index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated with radiation therapy. (Patients with previous ipsilateral DCIS or LCIS not treated with radiation are eligible.) Synchronous or previous contralateral breast cancer.(Patients with previous contralateral DCIS or LCIS not treated with radiation are eligible.) History of non-breast malignancy within the last 5 years other than non-melanoma skin cancer or treated in-situ carcinoma. Neoadjuvant endocrine therapy. (Extended neoadjuvant endocrine therapy is not permitted. Endocrine therapy exposure for 12 weeks or less prior to surgery is acceptable.) Breast reconstruction. Presence of known medical conditions that would preclude follow-up for 5 years. Previous radiotherapy to the ipsilateral breast or chest wall or serious non-malignant disease e.g. scleroderma, severe lung or heart disease that would preclude radiotherapy. Known pregnancy or currently lactating. Geographic inaccessibility for follow-up. Inability to provide informed consent.

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: Control<br>Conventional fractionation for locoregional radiotherapy | Radiation: Locoregional radiation treatment - Conventional fractionation<br>* 40 Gray in 15 daily fractions over 3 weeks<br>|
| Experimental: Experimental<br>Hypofractionation for locoregional radiotherapy | Radiation: Locoregional radiation treatment - Hypofractionation<br>* 26 Gray in 5 daily fractions over 1 week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lymphedema | Lymphedema defined as relative volume change (RVC) >10% | 3 years post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast cancer recurrence | Both locoregional and distant recurrence and second cancers | Annually for 5 years post randomization | 
| Mortality | Survival | Annually for 5 years post randomization | 
| Radiation toxicity | Acute and late radiation toxicity | During last week of radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization | 
| Arm mobility | Assessed by measuring the straight lateral abduction of both the ipsilateral and contralateral arm | 1 and 3 years post randomization | 
| Patient Quality of Life with respect to daily health and activities | Impact on quality of life will be assessed with the European Organization for Research in Treatment of Cancer and the Breast Cancer Specific Module 23. The scale is 1 to 4 where a higher score means a worse outcome. | During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization | 
| Perception of lymphedema | Impact of lymphedema on quality of life will be assessed with the National Surgical Adjuvant Breast and Bowel Project questionnaire. The scale is 1 to 5 where a higher score means a worse outcome. | During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization | 
| Perception of breast cosmesis | Patient-reported breast cosmesis using a Breast Cosmesis Questionnaire to study the late effects of radiation. | 1 and 3 years post randomization | 
| Health Care Resource Utilization | Health Care Resource Utilization will be estimated using dates and duration of radiotherapy treatment and emergency department visits and hospitalizations. | During radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization | 
| Patient Costs | Patient costs will be assessed using a Time Off Work Questionnaire to study the financial impact of breast cancer and its treatment | During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphedema, Hypofractionated, Locoregional, Breast Cancer