Ablative SBRT in Elderly BC Patients

SBRT will be performed using appropriate LINACs (Truebeam®, Varian, Palo Alto, US or Cyberknife®, Accuray, Morges, Switzerland) with a volumetric arc technique (VMAT), or non-coplanal technique, depending on the treating device. The medical devices have a CE certification and will be used in the trial as stated in the CE-marked instructions for use.

The gross tumor volume (GTV), as visualized on computed tomography (CT) within clips/fiducials, when present, with a 1mm (Cyberknife®)- 3mm (TrueBeam®) isotropic margin will be treated with an adaptive fractionation, depending on its total volume within 1,3 or 5 fractions. An elective volume of 2 cm around the GTV (clinical target volume (CTV)), plus a 1mm (Cyberknife®)- 3mm (TrueBeam®) isotropic margin will be treated at constant doses by fractionation cohort. These planning target volumes (PTVs) will be cropped at 5mm to skin and chest wall. The principle of irradiating an "elective volume" around the GTV will be used in this study, as done by Vasmel et al. [3]. This is decided because uncertainties do exist concerning true micro- and macrometastatic extension around the tumor, as visualized in the CT and delineation of the tumor on injected CT scans is not expected to be sufficient for coverage of macro and micrometastatic disease. Breast MRI is concordant to tumor size, as evaluated in pathology, within 0.5 cm for 53% of patients [4]. Organs at risk will be defined according to international guidelines [5].

Enrolment will be performed within 1-8 weeks after discussion in the HUG Breast Cancer Multidisciplinary Tumor Board (MTB).

All patients diagnosed with BC in our Institution, presenting the aforementioned characteristics, are candidates for screening for participation in the study, and will be offered clip placement, when feasible, during diagnostic biopsy by the specialized radiologist. Screening criteria will be assessed by the radiologist and radiation oncologist at the time of diagnostic biopsy.

Pre-screened patients will be discussed at the Institutional BC MTB. Eligible patients will be considered for the study.

Treatment procedures Treatment planning: Treatment planning will be performed using appropriate TPS (Eclipse®, (Varian, Palo Alto, US) or Accuray Precision®), with relevant techniques of SBRT in order to provide dose-delivery optimizations respecting predefined criteria for target coverage and normal-tissue constraints.

Accuracy issues: Accuracy of target volume delineation and dose delivery are of outmost importance for both tumor control and toxicity avoidance, given the limited number of fractions delivered. Accuracy issues are further detailed in the protocol section 3.4.1.

Quality assurance: A quality assurance (QA) program accompanies this trial, consisting of review of treatment plans by the trial medical physicist and the coordinating investigator.

SBRT fractionation will be adapted to PTV-GTV and PTV-CTV final volumes. With increasing volumes, more fractions will be used, according to the algorithm presented below, representing the dose-adapted fractionation regimens. SBRT will be delivered with isoeffective doses: a single fraction of 21, 23, or 25 Gy on day 1 or in three fractions of 11, 13 or 14 Gy/fraction on days 1, 3 and 5 or in five fractions of 8 or 9 or 10 Gy/fraction on days 1, 3, 5, 7 and 9. Dose per adaptive regimen will be escalated every three patients if no DLT appears.

In addition, patients will undergo physical exams at each study visit and (Serious) Adverse Events ((S)AE)s will be recorded. Questionnaires will be given to patients at selected study visits to assess Quality of Life (QoL). Other study procedures include measure of vital signs, ECOG performance status and record of concomitant treatments and procedures at each study visit.

Inclusion criteria

• Age over 70 years
• Histologically confirmed diagnosis of BC, any time before study enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3.
• Patient considered inoperable in multidisciplinary board decision or refusing surgery. Main criteria determining inoperability are inability to receive general anesthesia after anesthetics and/or surgical evaluation. Criteria described in the statement of American Society of Anesthesiologists (ASA) {, #4699} and American College of Surgeons Surgical risk calculators {, #4695} are usually addressed in the multidisciplinary discussion (Appendix ).
• Presence of measurable disease in the breast, defined as a lesion that can be accurately measured in at least one dimension with imaging (ultrasound, CT or MRI). Disease in the axilla or internal mammary chain is allowed and will be treated at the discretion of the radiation oncologist. Regional disease is not considered in measurements of local response.
• Primary tumor accessible to SBRT, as defined by treating radiation oncologist.
• Neo-adjuvant systemic therapy is allowed.
• Tumor size in planning computed tomography (CT) permitting SBRT delivery. SBRT appropriateness is defined by the treating radiation oncologist.
• Multifocality (over two tumor foci within the same breast quadrant) is allowed, as long as the total treatment volumes remain suitable for SBRT, as defined by the treating radiation oncologist.
• Total tumor treatment volume/ whole breast volume ratio not exceeding 30%.
• Previous treatment for BC to the contralateral breast is allowed. Previous treatment to the same breast for other reason than BC is allowed.
• Capacity of patient to collaborate for SBRT delivery.
• Capacity of patient to understand and sign a written informed consent according to International Council for Harmonization (ICH)/Good Clinical Practice (GCP) regulations before registration.

Exclusion criteria

• Prior surgery for the current diagnosis.
• Prior whole or partial breast irradiation to the involved breast.
• Absolute contraindication to RT, such as Li-Fraumeni syndrome.
• Current participation and receipt of study therapy or previous participation in a study of an investigational agent and receipt of study therapy or used an investigation device within 4 weeks of the first day of treatment.
• Not able to communicate meaningfully with investigator and site staff and/or incapable of discernment.
• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

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