A Randomized Trial of Five Fraction Partial Breast Irradiation

Study Overview
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Brief Summary
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The primary objective of this study is to determine in women with node negative BC ≤3cm in size, if PBI compared to WBI, both given once-a-day over 1 week following BCS, is non-inferior for LR and reduces adverse cosmesis. The primary outcomes are LR and patient-assessed cosmesis at 3 years post randomization.

Detailed Description
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This is a randomized, two-arm, single blinded trial comparing two radiation treatment modalities, PBI and WBI. Following BCS or on the completion of additional adjuvant chemotherapy, eligible and consenting patients with newly diagnosed and histologically confirmed invasive carcinoma of the breast (without evidence of metastatic disease); with microscopically clear resection margins of 1mm (or no residual disease on re-excision) and negative axillary node involvement will be randomized in a 1:1 fashion to receive either PBI (experimental group) or WBI (control group). Study participants will receive 26Gy in 5 fractions in both treatment arms, treated once per day, for a period of 5-7 days. Study participants will not be made aware of treatment allocation to prevent any potential bias in their assessment of cosmesis. Stratification factors include tumour size, estrogen receptor (ER) status, and clinical centre.

Official Title
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A Randomized Trial of Five-Fraction Partial Breast Irradiation (RAPID2)

Conditions
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Breast Neoplasm Female, Radiotherapy, Cosmetic Outcome

Intervention / Treatment
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* Radiation: Whole Breast Irradiation (WBI)
* Radiation: Partial Breast Irradiation (PBI)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For inclusion in this study, patients must fulfill all of the following criteria: Female with a new histological diagnosis of invasive carcinoma of the breast with no evidence of metastatic disease.(AJCC TNM Cancer Staging). Treated by BCS with microscopically clear resection margins ≥ 1mm for invasive and non-invasive disease or no residual disease on re-excision. Negative axillary node involvement as determined by either sentinel lymph node biopsy or axillary node dissection. Exclusion Criteria: Patients who satisfy any of the following exclusion criteria are NOT eligible for this study: Age less than 50 years. Known to be BRCA 1 and/or BRCA 2 positive. Tumour size >3cm in greatest diameter on pathological examination. Lobular carcinoma only. More than one primary tumour in different quadrants of the same breast (patients with multifocal breast cancer are eligible). Synchronous or previous contralateral breast cancer (patients with contralateral DCIS or LCIS are eligible). History of non-breast malignancy within the last 5 years other than treated non-melanoma skin cancer or treated in-situ carcinoma. Known pregnancy or currently lactating. Inability to localize tumour bed on CT planning (no evidence of surgical clips or seroma). Inability to plan the patient for the experimental technique.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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Female

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Whole Breast Irradiation (WBI)<br>26 Gy in 5 fractions to the whole breast | Radiation: Whole Breast Irradiation (WBI)<br>* The dose fractionation and prescription is 26Gy in 5 fractions to the PTV once per day over 5-7 days (due to holiday weekends up to 8 days will be acceptable).<br>|
| Experimental: Partial Breast Irradiation (PBI)<br>26 Gy in 5 fractions to the tumour bed with a margin of normal tissue | Radiation: Partial Breast Irradiation (PBI)<br>* The dose fractionation and prescription is 26Gy in 5 fractions to the PTV prescribed at the isocentre of the treatment fields treated once per day over 5-7 days (due to holiday weekends up to 8 days will be acceptable).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local Recurrence | Time from randomization to any evidence of tumour recurrence (invasive and non-invasive) in the treated breast. | Annually for 5 years post-randomization | 
| Patient Assessment Cosmesis at 3 years | Cosmesis will be assessed by the patient using the Breast Cosmesis Questionnaire which incorporates the Modified EORTC Breast Cosmetic Rating System and the UK Patient Reported Outcomes Questions following BCS. | 3 and 5 years post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distant Disease Free Survival (DDSF) | Time from randomization to evidence of metastasis involving distant sites (e.g. bone, liver, lung, or brain). | Annually for 5 years post-randomization. | 
| Disease Free Survival (DFS) | Time from randomization to local recurrence, regional or distant recurrence, contralateral breast cancer, other second cancer, or death. | Annually for 5 years post-randomization. | 
| Overall Survival | Time from randomization to death of any cause. | 3 years post-randomizaton. | 
| Radiation Toxicity | Acute (2 weeks and up to 3 months after completing RT) and late toxicity (beyond the 3 months after completing RT) will be assessed by clinical centre personnel using the NCI CTCAE version 5.0. | 2 weeks and 3 months post-radiation treatment, then annually for 5 years post-randomization. | 
| Nurse/Clinical Research Associate assessed cosmesis at 3 and 5 years. | A nurse/Clinical Research Associate (CRA) assessment of cosmesis using the EORTC Breast Cosmetic Rating System. Nurses and CRAs will be training in assessing cosmesis using training slides and guide previously developed for other trials. | 3 and 5 years post-randomization. | 
| Patient Assessed Cosmesis at 5 years. | Cosmesis will be assessed by the patient using the Breast Cosmesis Questionnaire which incorporates the Modified EORTC Breast Cosmetic Rating System13,27,42 and the UK Patient Reported Outcomes Questions following BCS. | 5 years post-randomization. | 
| Patient Reported Quality of Life | Patients will complete the EORTC Breast Cancer Quality of life questionnaire | 2 weeks post-radiation treatment, then at 3 and 5 years post-randomization. |