Whole Breast Irradiation vs Twice Daily vs. Once Daily Accelerated Partial Breast Irradiation

Study Overview
=================
Brief Summary
-----------------
This is a randomized phase III trial in women with invasive carcinoma of the breast with negative axillary nodes treated by Breast Conserving Surgery (BCS). Eligible, patients will be randomly allocated to receive radiotherapy of 3 Dimensional Conformal Radiation Therapy (3DCRT) Whole Breast Irradiation (WBI) 50 Gray (Gy) in 25 daily fractions over 5 weeks or Accelerated Partial Breast Irradiation (APBI) 38.5 Gy in 10 daily fractions of 3.85Gy over two weeks or 38.5 Gy in 10 twice daily fractions of 3.85Gy over one week. Patients will be followed at 6, 12, 18 and 24 months post randomization. Cosmetic outcome will be measured using photographs and evaluated by a panel of trained radiation oncologists. Radiation toxicity will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).

Detailed Description
-----------------
Women with invasive carcinoma of the breast less than 3 cm with negative axillary nodes , following BCS, who meet the inclusion criteria will be approached for potential study enrollment. Eligible, consenting patients will be randomly allocated to receive radiotherapy of 3DCRT WBI 50 Gy in 25 fractions over 5 weeks or APBI 38.5 Gy in 10 once daily fractions of 3.85Gy over two weeks or 38.5 Gy in 10 twice daily fractions of 3.85 Gy over one week. Patients will be followed at 6, 12, 18 and 24 months post randomization. Cosmetic outcome will be measured using photographs and evaluated by a panel of trained radiation oncologists using the EORTC Breast Cosmetic Rating System. Radiation toxicity will be assessed using the NCI CTCAE version 4.0. The primary outcome is to compare the acute, late toxicities and adverse cosmetic outcomes at 6, 12 and 18 months among the three groups.

Official Title
-----------------
Phase III Randomized Study of Adjuvant Whole Breast Versus Partial Breast Irradiation Using Once Daily or Twice Daily Fractionation Scheme in Women With Stage I or II Breast Cancer

Conditions
-----------------
Breast Cancer, Radiation Toxicity

Intervention / Treatment
-----------------
* Radiation: Once Daily APBI
* Radiation: Twice Daily APBI
* Radiation: Whole Breast Irradiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Tumor characteristics Histologically confirmed invasive adenocarcinoma of the breast Tumors must be ≤ 3 cm. Gross disease must be unifocal. Negative lymph nodes Hormone receptor status: Estrogen receptor (ER) status known Progesterone status known if ER analysis is negative Marginal or borderline results are considered positive Surgery Tumor removed with conservative breast surgery with adequate margin Re-excision of surgical margins allowed No prior breast implants Prior axillary staging required for patients including 1 of the following: Sentinel node biopsy alone (if sentinel node is negative) Sentinel node biopsy followed by axillary dissection if sentinel node is positive) Axillary dissection alone with ≥ 6 axillary nodes Target lumpectomy cavity clearly delineated AND target lumpectomy/whole breast reference volume ≤ 30% based on postoperative pre-randomization CT scan Final surgery (i.e., lumpectomy, re-excision of margins, or axillary staging procedure) within the past 42 days No prior biologic therapy for this malignancy Chemotherapy No prior chemotherapy for this malignancy No concurrent chemotherapy during study radiotherapy Endocrine therapy No prior hormonal therapy for this malignancy Concurrent hormonal therapy allowed provided it is not administered during chemotherapy No concurrent raloxifene, tamoxifen, or other selective estrogen receptor modulating drugs No concurrent hormone replacement therapy Radiotherapy No prior radiotherapy for this malignancy No prior breast or thoracic radiotherapy No concurrent regional nodal irradiation Other No other concurrent anticancer therapy Menopausal status Premenopausal or postmenopausal Performance status WHO 0-1 Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective non-hormonal contraception Exclusion Criteria: Multicentric carcinoma in more than 1 quadrant or separated by ≥ 4 cm. Non-epithelial breast malignancies (e.g., sarcoma or lymphoma). Positive axillary nodes. Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes unless there is histologic confirmation that these nodes are negative for tumor. Suspicious microcalcifications, densities, or palpable abnormalities in the ipsilateral or contralateral breast unless biopsied and found to be benign Paget's disease of the nipple Previous history of invasive breast cancer or DCIS. Synchronous bilateral invasive or non-invasive breast cancer Collagen vascular disease (e.g., systemic lupus erythematosus or scleroderma), specifically dermatomyositis with a CPK level above normal, or active skin rash Psychiatric or addictive disorder that would preclude study therapy

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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<br>Adjuvant 3D Conformal Radiation Therapy to a dose of 50 Gy in 25 fractions over 5 weeks. Boost is given as 10 Gy in 5 fractions over one week to patients with high grade tumors or age younger than 50 years | Radiation: Whole Breast Irradiation<br>* Adjuvant 3D Conformal Radiation Therapy to a dose of 50 Gy in 25 fractions over 5 weeks. Boost is given as 10 Gy in 5 fractions over one week to patients with high grade tumors or age younger than 50 years<br>|
| Experimental: Once Daily APBI<br>Adjuvant 3D Conformal Accelerated Partial Breast Irradiation to a dose of 38.5 Gy in 10 once daily fractions given over 2 weeks | Radiation: Once Daily APBI<br>* Adjuvant 3D Conformal Accelerated Partial Breast Irradiation to a dose of 38.5 Gy in 10 once daily fractions given over 2 weeks<br>|
| Experimental: Twice Daily APBI<br>Adjuvant 3D Conformal Accelerated Partial Breast Irradiation to a dose of 38.5 Gy in 10 twice daily fractions given over 1 week | Radiation: Twice Daily APBI<br>* Adjuvant 3D Conformal Accelerated Partial Breast Irradiation to a dose of 38.5 Gy in 10 twice daily fractions given over 1 week<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Adverse cosmetic outcome using the EORTC Breast Cosmetic Rating System | The primary outcome is the change in the adverse cosmesis assessed prior to radiation, 6, 12 and 18 months after end of radiation. The cosmetic outcome will be assessed by a radiation oncologist who is unaware of treatment allocation, using the EORTC Breast Cosmetic Rating System. | prior to radiation, 6,12 and 18 months after radiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ipsilateral Breast Tumor Recurrence (IBTR) | defined as recurrent invasive or in situ cancer in the ipsilateral breast. Histological evidence of local recurrence will be required. | throughout the study up to 5 years | 
| Disease Free Survival | defined as the time from randomization to the time of documented recurrent disease in the ipsilateral breast or regional nodes (supraclavicular, axillary or internal mammary) or distant sites (e.g. bone, liver, lung or brain). | throughout the study up to 5 years | 
| Overall Survival | defined as the time from randomization to death from any cause | From date of randomization until the date of death up to 5 years | 
| Radiation Induced Early and late toxicities | using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0 | during radiation and at 6, 12 and 18 months after radiation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast Cancer, Accelerated partial Breast Irradiation, Breast cosmesis, radiation Toxicity