Metastases Directed Therapy for Oligometastatic Breast Cancer

Objectives:

Primary objectives:

• Assessment of the outcome (progression free survival) of patients with extracranial oligometastatic breast cancer receiving standard of care systemic treatment compared to patients receiving ablative radiotherapy in addition to systemic treatment

Secondary objectives:

* Improving quality of life of patients with oligometastatic breast cancer (OMBC) * Ensuring a safe toxicity profile among the patients receiving SBRT to the metastatic sites in addition to SOC treatment vs patients who receive SOC treatment alone.

Study Methodology:

1. Study Design: Randomized Controlled Trial. 2. Study population \& disease Condition: Adult female patients, with pathologically and radiologically proven Oligometastatic breast cancer presenting to National Cancer Institute, Cairo University. 3. Background and Demographic characteristics:

Adult (\>18 years old), Egyptian female patients, who present for treatment in the National Cancer Institute, Cairo University. A detailed informed consent will be signed, proper contraception is a must during systemic and radiotherapy treatment. 4. Inclusion criteria:

i) Female patients aged 18 to 70 years. ii) Pathological evidence of breast cancer, any grade, any T stage. iii) Radiological (at least) evidence of metastatic activity with maximum number of 5 extracranial lesions.

iv) Performance status ≤ 2 v) No pre-existing conditions that may prohibit radiotherapy. e) Exclusion criteria i) Pregnant and lactating women. ii) Prior radiotherapy to affected site(s) in less than a year. iii) Active Connective tissue diseases (e.g Rheumatoid Arthritis). iv) Progression to widespread metastatic disease. v) Cases with brain metastasis

f) Interventions (in details):

Pre-treatment evaluation:

Laboratory studies:

CBC, Liver and Kidney functions and Tumor markers (CA15-3, CEA and CA-125)

Imaging Studies:

Initial Sono-mammography for assessment of local disease (MRI breast to be done whenever indicated, e.g., young patients with dense breast tissue: ACR C\&D).

Metastatic workup for establishing oligometastatic status: CT chest, abdomen and pelvis with contrast with Bone scan or PET/CT, more sophisticated imaging techniques to be done in case of failure of modalities to establish the metastatic status (e.g., Dynamic MRI of liver in cases which conventional imaging fails to confirm the nature of a suspected hepatic focal lesion).

Pathological diagnosis: Tru-Cut, core-cut or excisional biopsy from suspicious primary breast mass, also core biopsy from suspected metastatic site whenever indicated.

Treatment plan:

Patients will be randomized into 2 arms: (FIG.A) i) Arm A (interventional) ii) Arm B (control)

* The interventional arm will receive Metastasis Directed Therapy (MDT) using Stereotactic body radiotherapy (SBRT) to oligometastatic lesions initially along with standard of care systemic treatment (SOC) according to discretion of multi-disciplinary team decision. * The control arm will receive SOC alone. * Locoregional control to the primary will be done in cases with regressive disease or complete response according to RECIST 1.1 criteria.

The radiation schedule in Arm A will be as follows:

SBRT is recommended to be completed within no more than 3 weeks since the start of the first session. Not all metastases need to receive radiotherapy in the same day, IGRT assisted treatment is a must, PTV expansion will be decided separately for each site treated.

Patients will receive single fraction, 3 fractions or 5 fractions of SBRT according to treated site as follows (Data from NRG BR-002 protocol and ASTRO 2022 conference):

Bone (Peripheral and spine): 18-24Gy/S.S or 30Gy/3fx or 35Gy/5fx Liver: 45-60Gy/3fx or 40-60Gy/5fx Lung: 50-60Gy/3fx (rib tolerance must be met) or 50-60Gy/5fx Others (e.g Adrenals and lymph nodes): according to risk organ tolerances, usually 30Gy/3Fx or 40-60Gy/5fx

Treatment Setup and simulation:

All patients will undergo CT-based treatment planning in with proper immobilization and comfortable setup position. High resolution CT scans should be obtained with uniform slice thickness of ≤ 3mm. When treating multiple metastases such as a lung and extremities, varying the treatment position may be necessary (i.e., simulation with arms up and arms to the side. The use of IV contrast will be required for liver and nodal metastases. For other metastases (central \& peripheral lung, cervical/mediastinal, abdominal-pelvic, and spinal/paraspinal), the use of IV contrast is encouraged but will be left to the discretion of the treating physician. As an SBRT protocol, this study requires the use of IGRT, cone-beam CT (CBCT) using a specially mounted kV imaging will be the routine verification method.

Delineation of target volume and organs at risk (OARs):

It will be done using the RTOG contouring guidelines, a maximum intensity projection (MIP) volume will be created in lesion situated in organs with remarkable internal motion (e.g lung lesions), fusion with diagnostic imaging such as PET/CT will be done when delineation of gross lesions is infeasible.

Treatment planning:

General guidelines include the following:

* Multiple coplanar or non-coplanar beam arrangements are acceptable. * A minimum field dimension of 3 cm should be observed while treating small metastases. * Doses higher than the prescription isodose (i.e., hotspots) should be manipulated to occur within the target.

Planning SBRT Near Prior Radiotherapy Volumes with toxicity of delivering SBRT to multiple metastases in close proximity to previously irradiated volumes is a bit challenging. A multicenter analysis by German Society of Radiation Oncology (DEGRO) was done in 2021, included patients with primary and secondary pulmonary tumors that has been subject to reirradiation using SBRT to same or near target volumes. It showed feasibility of reirradiation and safe toxicity profile, close adherence to dose constraints made by AAPM TG-101 report will be ensured. Re-irradiated volumes will be delineated with the best possible simulation setup and reproducibility, plans of previous treatment will be fused with overlapping volumes to be minimized as much as possible.

Contouring of Normal Tissue Structures In order to verify each of these limits:

The organs must be contoured such that appropriate volume histograms can be generated.

Dose Tolerance to OARs: will be followed as the SABR consortium guidelines published in 2019.

Data Collection:

Demographic data: Age, family history, comorbidity, grade, stage

Pretreatment Evaluation:

Laboratory, Radiological and pathological data as previously mentioned.