Trial Comparing 3 Schedules of Hypofractionated Whole Breast Irradiation in Females With Early Stage Breast Cancer

Study Overview
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Brief Summary
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The establishment of conservative breast surgery (CBS) and whole breast irradiation (WBI) as an alternative to mastectomy was a process that occurred over two to three decades. Based on the available evidence, hypofractionated WBI may be safely offered to most women with ductal carcinoma insitu (DCIS) or early-stage invasive breast cancer after CBS. This prospective randomized clinical trial aims to evaluate the outcomes of one-week and once weekly schedules of WBI against the investigator's standard hypofractionated WBI ( 40 Gy /15 fraction /3 weeks) in females with early stage breast cancer after CBS.

Detailed Description
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Radiotherapy Timing If the patient is not receiving chemotherapy, WBI is to be initiated within 9 weeks following lumpectomy or re-excision of margins. For patients receiving chemotherapy, WBI is to begin no fewer than 2 weeks and no more than 8 weeks after the last cycle of chemotherapy. Randomization: 138 patients will be randomized using permuted blocks randomization to 3 equal comparable arms. - Dose Prescriptions Arm 1: One week WBI: 27Gy/5 fractions /1 week. 5.4 Gy/fraction ± boost to tumor bed 5.4 Gy/ 1 fraction, 2 days after the end of WBI. Arm 2: Once weekly WBI: 28.5 Gy/ 5 fractions/ 5 weeks. 5.7 Gy/fraction ± boost to tumor bed 5.7 Gy/ 1 fraction, one week after the end of WBI. WBI is given on the same day each week. Arm 3: Hypofractionated WBI 40 Gy/ 15 fractions/ 3 weeks. 2.67 Gy/ fraction ± boost to tumor bed 10 Gy/ 4 fraction / 4 days after the end of WBI. 3-Tumor bed boost A tumor bed boost is recommended to high-risk patients [Age < 50 years, high grade] according to the National Comprehensive Cancer Network (NCCN) guidelines. 4-Radiotherapy simulation, Localization and Outlining: The guidelines for contouring will conform to the policies set by the Radiation Therapy Oncology Group (RTOG) Breast cancer Atlas. www.rtog.org/CoreLab/ContouringAtlases/BreastCancerAtlas.aspx Megavoltage ( MV) photon beams with energies ≥ 6 MV are required. Radiotherapy Planning: Computed tomography based conformal radiotherapy (CT-based 3D-CRT) planning with tissue inhomogeneity correction is required . 5- Systemic Therapy Chemotherapy Adjuvant chemotherapy may be given at the discretion of the patient's medical oncologist. The use of chemotherapeutic agents during radiation therapy is not allowed. The use of neoadjuvant chemotherapy is not allowed. Hormonal therapy Patients with ER-positive and/or PR-positive tumors should be treated with hormonal therapy for a minimum of 5 years. The use of hormonal therapy during radiation therapy is allowed. Trastuzumab Trastuzumab is given to HER2 positive patients. The use of Trastuzumab during radiation therapy is allowed. 6-Surgical Treatment: All patients will undergo CBS, axillary staging and/or dissection with negative surgical margins (sm). Negative surgical margin (Curigliano, 2017) Invasive breast cancer: no ink on tumor DCIS: 2mm Surgical clips will be used to define the tumor bed borders Breast reconstruction and cosmetic breast implants are not allowed 7-Follow-up. Schedule of Follow up: History and physical exam for all randomized patients will occur every 3 months in the first 2 years after the date of end of radiotherapy treatment Monitor and refer for lymphedema management. Mammography will be requested annually

Official Title
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Randomized Trial Comparing 3 Schedules of Hypofractionated Whole Breast Irradiation in Females With Early Stage Breast Cancer

Conditions
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Breast Cancer Female

Intervention / Treatment
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* Other: Whole Breast Irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tis, pT1-2, pN0-1, M0 disease Invasive carcinoma of the breast or ductal carcinoma insitu [DCIS] CBS (reconstruction is not allowed) Negative surgical margin Axillary staging &/or dissection Exclusion Criteria: pT3-4, pN2-3 breast cancer Inadequate axillary lymph node dissection Neoadjuvant chemotherapy Non-epithelial breast malignancies such as sarcoma or lymphoma Synchronous bilateral invasive or non-invasive breast cancer History of invasive breast cancer or DCIS (Patients with a history of lobular carcinoma in situ (LCIS) treated by surgery alone are eligible.) Past history of malignancy except Basal cell skin cancer CIN cervix uteri Cosmetic breast implants (Patients who have had implants removed are eligible.) Prior breast or thoracic RT for any condition Collagen vascular disease, specifically systemic lupus, or scleroderma Pregnancy or lactation at the time of radiotherapy. Women of reproductive potential must agree to use an effective non-hormonal method of contraception during therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: One week Whole Breast Irradiation<br>WBI: 27 Gy/5 fractions/1 week. 5.4 Gy /fraction ± boost to tumor bed 5.4 Gy/ 1 fraction, 2 days after the end of WBI. | Other: Whole Breast Irradiation<br>* Whole Breast Irradiation after CBS in females with DCIS and early stage breast cancer<br>|
| Experimental: Once weekly Whole Breast Irradiation<br>WBI: 28.5 Gy/ 5 fractions/ 5 weeks. 5.7 Gy/fraction ± boost to tumor bed 5.7 Gy/ 1 fraction, one week after the end of WBI. WBI is given on the same day each week. | Other: Whole Breast Irradiation<br>* Whole Breast Irradiation after CBS in females with DCIS and early stage breast cancer<br>|
| Active Comparator: 3 weeks Whole Breast Irradiation<br>WBI: 40.05 Gy/ 15 fractions/ 3 weeks. 2.67 Gy/ fraction ± boost to tumor bed 10 Gy/ 4 fraction / 4 days after the end of WBI | Other: Whole Breast Irradiation<br>* Whole Breast Irradiation after CBS in females with DCIS and early stage breast cancer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute toxicity | The proportion of patients with grade ≥3 toxicity according to The Radiation Therapy Oncology Group (RTOG) morbidity scoring criteria. | 3 months from the start of whole breast irradiation | 
| Cosmetic outcome | measured by The European Organisation for Research and Treatment of Cancer (EORTC) breast cosmetic rating system (observer rating) | Annually after the end of whole breast irradiation for 5 years | 
| Ibsilateral locoregional tumor control | must be confirmed by cytological/ histological assessment | Annually after the end of whole breast irradiation for 5 years. | 
| patient-reported outcome measures (PROMs) | measured by The European Organisation for Research and Treatment of Cancer, EORTC Quality of Life questionnaire for breast cancer patients ( EORTC QLQ-BR 23). | Annually after the end of whole breast irradiation for 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| late toxicity | Late toxicity according to The Radiation Therapy Oncology Group/ The European Organisation for Research and Treatment of Cancer (RTOG/EORTC) late radiation morbidity scoring schema | Annually after the end of whole breast irradiation for 5 years. | 
| Distant disease-free survival | Defined as the time from initial diagnosis of breast cancer to first diagnosis of distant disease, regardless of the occurrence of any intervening local or regional failure, contralateral breast cancer, or non-breast second primary cancer. | 5 years from the initial diagnosis of breast cancer | 
| Overall survival | Defined as the time from initial diagnosis of breast cancer to date of death or last follow up. | 5 years from the initial diagnosis of breast cancer |