Standard or Hypofractionated Radiotherapy Versus Accelerated Partial Breast Irradiation (APBI) for Breast Cancer

Study Overview
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Brief Summary
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The standard treatment for localized breast cancer is based on conservative surgery (when possible) followed by radiation therapy (RT) delivered to the whole breast. The recommended total RT dose is 45 to 50 Gy delivered in 4.5 to 5 weeks followed by a 10 to 16 Gy boost to the tumor bed for 1 to 1.5 weeks. The rationale for the development of APBI was based on the difficulty for many patients to reach RT centers to receive standard whole breast irradiation (WBI) after conservative surgery. APBI offers decreased overall treatment time and several theoretical advantages over WBI, including a decrease in dose delivered to uninvolved portions of the breast and adjacent organs. If equivalence between the two treatments can be shown, then APBI will be considered as a historic evolution in breast cancer management. In this phase III trial, designed in postmenopausal women >50 years of age, the objective is to compare the effectiveness and safety of APBI compared with whole breast irradiation. This study is also designed to ensure high quality criteria for surgery, pathology and RT techniques in the 3 arms and will allow to provide data on economics and costs.

Detailed Description
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Following breast conservative surgery, patients will be stratified according to the following prognostic factors using a minimisation technique: age (<70 vs ≥70), HER2 status (HER2+ vs HER2-), hormonal receptor status (RH+ vs RH-) and lymph node invasion (pN0 vs pN0i+). Patients will be allocated to receive either standard treatment, hypofractionated treatment or APBI. Radiation therapy should be started between 4 and 12 weeks after the last surgery. Patients treated with standard whole breast irradiation will receive a total dose of 50 Gy in 25 fractions, 2 Gy per day, 5 days a week. The boost of 16 Gy will be delivered in 8 fractions for all patients after completion of the 50 Gy, without interruption. All patients will receive one fraction per day, 5 fractions a week. Patients treated with hypofractionated irradiation will receive a total dose of either 40 Gy (in 15 fractions, 2.66 Gy per day) or 42.5 Gy (in 16 fractions, 2.65 Gy per day) 5 days a week. Patients treated with APBI will receive a total dose of 40 Gy in 10 fractions, delivered twice a day over a time period of 5-7 days. Each daily dose must be separated by 6 hours. Patients will be followed at 3 and 6 month after the last dose of irradiation, at 12 months after the date of last surgery and then on a yearly basis during 10 years.

Official Title
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Phase III Multicentric Trial Comparing Accelerated Partial Breast Irradiation (APBI) Versus Standard or Hypofractionated Whole Breast Irradiation in Low Risk of Local Recurrence of Breast Cancer

Conditions
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Breast Cancer, Lumpectomy

Intervention / Treatment
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* Radiation: Whole Breast Irradiation + Boost or Hypofractionated irradiation
* Radiation: Accelerated partial breast irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged ≥50 years Menopausal status confirmed Pathology confirmation of invasive carcinoma (all types) Complete tumor removal and conservative surgery Pathologic tumor size of invasive carcinoma ≤2 cm (including the in situ component) pT1 All histopathologic grades Clear lateral margins for the invasive and in situ disease (>2 mm) pN0 or pN(i+) No metastasis Radiotherapy should be started more than 4 weeks and less than 12 weeks after last surgery Surgical clips (4 to 5 clips in the tumor bed) No prior breast or mediastinal radiotherapy Eastern Cooperative Oncology Group (ECOG) 0-1 Information to the patient and signed informed consent Exclusion Criteria: Multifocal invasive ductal carcinoma defined as the presence of at least two distinct tumors that are separated by normal tissue or when the distance between the two lesions does not permit conservative surgery Bilateral breast cancer No or less than 4 surgical clips in the tumor bed Nodal involvement : pN1 (including micrometastasis, mi+), pN2, pN3 Metastatic disease internal mammary node involvement or supraclavicular lymph node involvement Indication of chemotherapy or trastuzumab Involved or close lateral margins for the invasive and /or in situ components (<2 mm) AND impossibility to re-operate or impossible to perform another conservative surgery Patients with known BRCA1 or BRCA2 mutations Previous mammoplasty Previous homolateral breast and/or mediastinal irradiation Previous invasive cancer (except basocellular epithelioma or in situ carcinoma of the cervix) No geographical, social or psychologic reasons that would prevent study follow

Ages Eligible for Study
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Minimum Age: 50 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard or Hypofractionated radiotherapy<br>Whole breast RT, 50 Gy + boost 16 Gy. Whole breast hypofractionated RT without boost, either 40 Gy or 42.5 Gy | Radiation: Whole Breast Irradiation + Boost or Hypofractionated irradiation<br>* Whole Breast Irradiation 50 Gy + Boost 16 Gy or Whole breast, either 40 Gy in 15 fractions in 3 weeks or 42.5 Gy in 16 fractions in 3 weeks<br>* Other names: Standard radiation;|
| Experimental: Accelerated Partial Breast Irradiation (APBI)<br>APBI using 3D CRT technique, in 5 days, 38.5 Gy to the tumor bed | Radiation: Accelerated partial breast irradiation<br>* Tumor bed 40 Gy in 10 fractions, 2 fractions of 4 Gy per day in 5 to 7 days.<br>* Other names: APBI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of local recurrence | To estimate and compare the rate of local recurrence between the experimental and control arms. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ipsilateral breast recurrence-free survival | To evaluate Ipsilateral breast recurrence-free survival | 10 years | 
| Nodal regional recurrence-free survival | To evaluate nodal regional recurrence-free survival | 10 years | 
| Distant recurrence-free survival | To evaluate distant recurrence-free survival | 10 years | 
| Disease-specific survival | To evaluate disease-specific survival | 10 years | 
| Overall survival | To evaluate the overall survival | 10 years | 
| Toxicities: Measurement of the rate and type of toxicity (acute and late toxic effects) | To evaluate rates and type of acute and late toxicities | 10 years | 
| Cosmetic: comparison of the cosmetic result (according to both the physician and the patient) | To evaluate Cosmetic results (Patient and Physician evaluations) | 10 years | 
| Quality of Life and Satisfaction | To evaluate the patient quality of life and patient satisfaction | 10 years | 
| Medico-economic study | To evaluate the cost of APBI compared with Standard and Hypofractionated irradiation | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, Accelerated Partial Breast Irradiation, invasive cancer, Hypofractionated Irradiation, Lumpectomy