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

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

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).

Inclusion Criteria:

1. Biopsy proven breast cancer stage IV AJCC TNM

2. Age >18 years

3. WHO status≤2

4. Hormonal receptors positive breast cancer (IHC)

5. The primary tumor was treated or will be treated with curative intent (surgery and/or radiotherapy)"

6. No new treatment for metastatic relapse Prior history of adjuvant hormonotherapy or relapse under adjuvant hormonotherapy are not exclusion criteria.

   It will be accepted patients which would have begun new line of systemic treatment in the case where:

   1. Hormonotherapy or CDK4/6 inhibitors ≤ 3 months.
   2. Chemotherapy or immunotherapy ≤ 2 cycles. If SBRT arm: The treatment (except hormonotherapy by aromatase inhibitor and/or LHRH agonist) must be interrupted during the completion of radiotherapy.

a. Metastatic lesions out of previous radiation field b. Equal or less than 5 metastatic lesions (measurable or not) c. In case of measurable lesions, each ≤10 cm or ≤500 mL 8. For liver mets:

1. adequate liver function (liver enzyme <3N, bilirubin<30mg/dl, albumin>2.5g/dl),
2. no underlying cirrhosis or hepatitis
3. liver metastase size ≤7cm diameter
4. not adjacent to stomach or small bowel 9. For abdominal mets:

a. Adequate renal function with a creatinine clearance (Cockroft formula) > 60ml/min 10. Absence of any psychological, familial, sociological or geographical condition with a potential to hamper compliance with the study protocol and follow-up schedule 11. Life expectancy > 3 months 12. Affiliated to Health Insurance regimen 13. Written and signed consent form

Non-inclusion Criteria:

1. Triple negative breast cancer

2. Prior systemic treatment in metastatic setting (endocrine therapy, chemotherapy, targeted therapies, radionuclide)

3. Brain metastases

4. In spinal cord mets:

   1. More than 3 consecutive and contiguous spinal segments involved by tumor
   2. Neurological examination prior randomization >1 week
   3. Inability to tolerate treatment (unable to lie flat)
   4. Treated with radionuclide/systemic chemotherapy within 30 days before SBRT
   5. Significant or progressive neurological deficit
   6. More than 25% spinal canal compromise
   7. Malignant epidural spinal cord compression or cauda equina syndrome
   8. Spine instabilityor neurological deficit resulting from bony compression of neural structures

5. Scleroderma or connective tissue disease as a contraindication to radiotherapy

6. Pregnancy or breast feeding period