Trial of Superiority of Stereotactic Body Radiation Therapy in Patients With Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The previous reported phase I study allows us to prospectively define the optimal total dose in different metastatic locations (88). However, several questions are still unanswered such as the adequate timing of the stereotactic body radiation therapy (SBRT) in oligometastatic disease. Indeed, there are two different oligometastatic states: de novo, i.e. occurring at first metastatic presentation without any previous systemic therapy; and secondary, defined as residual disease after systemic treatment. The investigators wish to prospectively study the role of metastases SBRT with curative intent in de novo oligometastatic disease. This clinical trial would be the first randomized study studying SBRT at onset of the metastatic disease. If this trial shows a PFS improvement, it will definitively change the standard of treatment and it will highlight SBRT as a key treatment of metastatic disease. It will confirm the oligometastasis hypothesis as well as the Simon Norton hypothesis (92).

Official Title
-----------------
Multicentric Phase III Trial of Superiority of Stereotactic Body Radiation Therapy in Patients With Metastatic Breast Cancer in First-line Treatment

Conditions
-----------------
Breast Cancer

Intervention / Treatment
-----------------
* Radiation: stereotactic body radiation therapy
* Radiation: Systemic treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Biopsy proven breast cancer stage IV AJCC TNM Age >18 years WHO status</=2 Hormonal receptors positive breast cancer (IHC) 6. The primary tumor has to have been treated with curative intent (surgery and /or radiotherapy) 7. No prior treatment for metastatic relapse It will be accpeted patients which would have begun a treatment in the case where: Hormonotherapy </= 1 month Chemotherapy </= 1 cycle 8. a. Metastatic lesions out of previous radiation field 8. b. Equal or less than 5 metastatic lesions (measurable or not) 8. c. In case of measurable lesions, each </=10 cm or </=500 mL 9. For liver mets: adequate liver function (liver enzyme <3N, bilirubin<30mg/dl, albumin>2.5g/dl) no underlying cirrhosis or hepatitis liver metastase size </=7cm diameter not adjacent to stomach or small bowel 10. For abdominal mets: Adequate renal function with a creatinine clearance (Cockroft formula) > 60ml/min 11. Absence of any psychological, familial, sociological or geographical condition with a potential to hamper compliance with the study protocol and follow-up schedule 12. Life expectancy > 3 months 13. Affiliated to Health Insurance regimen 14. Written and signed consent form Exclusion Criteria: 1. Triple negative breast cancer 3. Prior systemic treatment in metastatic setting (endocrine therapy, chemotherapy, targeted therapies, radionuclide) 4. Brain metastases 5. In spinal cord mets: More than 3 consecutive and contagious spinal segments involved by tumor Neurological examination prior randomization > 1 week Inability to tolerate treatment (unable to lie flat) Treated with radionuclide/systemic chemotherapy within 30 days before SBRT Significant or progressive neurological deficit More than 25% spinal canal compromise Malignant epidural spinal cord compression or cauda equina syndrome Spine instability or neurological deficit resulting from bony compression of neural structures 6. Scleroderma or connective tissue disease as a contraindication to radiotherapy 7. Pregnancy or breast feeding period

Ages Eligible for Study
-----------------
Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: stereotactic body radiation therapy<br>The SBRT of all metastases should start in maximum 4 weeks after randomization. Beginning of systemic treatment will take place before 2 and 7 days after SBRT completion. All metastases lesions should be treated every 48h. | Radiation: stereotactic body radiation therapy<br> <br> Radiation: Systemic treatment<br> <br> |
| Active Comparator: no specific treatment<br>no specific treatment to the oligometastatic sites except for palliation (pain, compression, hemorrhage) | Radiation: Systemic treatment<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | events: local recurrence, distant progression of the target metastases, any new metastasis, death of any cause The definition of progression is based on RECIST1.1 criteria. Progression is assessed locally, in any metastasis present at the time of randomization or in any newly diagnosed metastasis. | evaluated with a minimal follow-up of 3 years in all patients | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative rate of local failure | assessed with RECIST1.1 criteria | evaluated with a minimum follow-up of 3 years in all patients. | 
| Overall survival |  | evaluated with a minimum follow-up of 3 years in all patients |