Intraoperative Radiotherapy After Local Recurrence in Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The investigators propose a prospective, multicenter, single arm Phase II design to evaluate the feasibility of repeated breast-conserving surgery combined with re- irradiation using IORT after local recurrence of breast carcinoma.

Detailed Description
-----------------
Currently, the rate of ipsilateral breast tumor recurrence (IBTR) after breast- conserving surgery and radiotherapy remains at 10% at 10 years to 15% at 20 years, respectively. IBTR is an independent predictor of poor survival with a 3 to 4.6 increased risk of cancer-related death. In a heterogeneous population, local control remains a major therapeutic challenge for these relapses, especially those considered of better prognosis, namely occurring late and of low histological grade. Therapeutic de-escalation is possible for these relapses to avoid a mutilating and often traumatic mastectomy. However, this second conservative surgery has a high rate of second local relapse (19 to 50% at 5 years) due to the absence of a re-irradiation, rendered impossible by the problem of tolerance of previously irradiated tissues. Retrospective or prospective studies on partial breast irradiation (PBI) in adjuvant setting report promising results, both in terms of tolerance (saving healthy tissue) and local control (74% to 100% at 5 years). Used techniques include brachytherapy, external beam radiotherapy and intraoperative radiotherapy (IORT). IORT is now the subject of renewed interest in breast cancer. It has the advantages of high-precision ballistics on the operated area and of preservation of healthy tissue. To date, no prospective data, however, have been published in the indication of ipsilateral breast recurrence. A prospective, multicenter, single arm Phase II design will evaluate the feasibility of repeated breast-conserving surgery combined with re- irradiation using IORT after local recurrence of breast carcinoma.

Official Title
-----------------
Feasibility Clinical Trial of Intraoperative Radiotherapy (IORT) and Second Breast-conserving-surgery After Local Recurrence of Breast Carcinoma

Conditions
-----------------
Breast Carcinoma

Intervention / Treatment
-----------------
* Procedure: tumorectomy
* Radiation: Intra Operative Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven non-lobular invasive breast recurrence Time from whole breast radiation following the initial lumpectomy >5 years Unifocal tumor Recurrent tumor size ≤ 2 cm Adequate breast size for a second breast-conserving surgery with acceptable cosmetic result Bilateral breast mammogram within 90 days prior to study entry Breast MRI within 90 days prior to study entry Histological grade I-II Estrogen-receptor-positive tumor (ER+) Cerb2-negative tumor N0 M0 Prior radiotherapy delivered within a standard fractionation schedule Performance status (ECOG) 0-1 Women ≥ 50 years -Absence of any psychological, familial, sociological, or geographical conditions with a potential to hamper compliance with the study and follow- up schedule Affiliated to the French Health Insurance regimen Written and signed informed consent form. Exclusion Criteria: Multifocal and/or multicenter recurrence Lobular carcinoma Estrogen-receptor-negative tumor (ER-) Cerb2 (her2) overexpressed - breast cancer Extensive intraductal component (EIC) on biopsy Lymph vessel invasion on biopsy N1-3 status: Regional cytological or histologically proven node recurrence M1 status: Metastatic disease cT4 (Skin or muscle involvement) or Paget's disease of the nipple Prior radiotherapy delivered within an accelerated or hypo-fraction schedule Prior malignancy other than non-melanoma skin cancer unless the patient has been disease free for at least 5 years Patients with a small breast volume, technically unsatisfactory for a second conservative surgery or intraoperative breast irradiation. Preoperative chemotherapy or hormone therapy for local relapse Connective tissue disease or scleroderma, contraindicating radiotherapy Known BRCA1/2 gene mutation (genetic testing is not required)

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

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

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

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

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: surgery and Intra Operative Radiotherapy<br>Surgery : Tumorectomy will be performed according to the current standards, obtaining clear margins. The axillary lymph node control will depend on the initial management (clinical and ultrasound) of these N0 patients, chosen by the teams. Intra Operative Radiotherapy (IORT): After the excision of the tumor, IORT will be delivered. A single dose of 20 Gy by 50 kV photons (Intrabeam™) will be administered in tumor bed. The addition of IORT does not modify the surgical procedure. | Procedure: tumorectomy<br>* Tumorectomy will be performed according to the current standards, obtaining clear margins. The axillary lymph node control will depend on the initial management (clinical and ultrasound) of these N0 patients, chosen by the teams.<br>Radiation: Intra Operative Radiotherapy<br>* After the excision of the tumor, IORT will be delivered. A single dose of 20 Gy by 50 kV photons (Intrabeam™) will be administered in tumor bed. The addition of IORT does not modify the surgical procedure<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The tolerance of RIOP (Intra Operative Radiotherapy) in patients with delayed local recurrences, after a second conservative treatment of breast cancer | Fibrosis rate of RIOP grade 2 at 12 months of IORT (Intra Operative Radiotherapy) according to NCI CTCAE v4.0 classification | Up ti 12 months post radiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cosmetic outcome evaluated by photography | A esthetic evaluation (photographs) | before treatment, at 15 days, at 3, 6, 12 and 24 months | 
| Rate of early and late toxicities | Rate of Early toxicities (Hematoma, Lymphorrhea, Breast infection) Late toxicities (telangiectasia, breast pain, skin hyperpigmentation, skin ulceration, skin atrophy) | from the baseline to 5 years after treatment | 
| Local relapse-free survival | Time from baseline to the apparition of local relapse | from the baseline to 5 years after treatment | 
| Metastasis relapse-free survival | Time from baseline to the apparition of metastatic relapse | from the baseline to 5 years after treatment | 
| Disease-free survival. | Time without relapse | from the baseline to 5 years after treatment | 
| Overall survival | Time from baseline to the apparition of relapse | from the baseline to 5 years after treatment | 
| Free interval without mastectomy. | Time from baseline to the mastectomy | from the baseline to 5 years after treatment |