Study Design
This single-arm prospective trial will be conducted at the radiation oncology department of Austin Health, Melbourne, Australia. The purpose of this study is to evaluate the feasibility of delivering a single fraction of preoperative accelerated partial breast irradiation using an MR linac. The primary endpoint of the study is the successful administration of a single fraction of preoperative breast radiation therapy under the guidance of an MR linac.
The secondary objective is to evaluate the relationship between preradiotherapy MRI and post-radiotherapy MRI with respect to histopathological findings.
Patient Recruitment and Selection
Prospective participants for the study will be identified through two main channels: multidisciplinary meetings and direct referrals from external specialists to the Radiation Oncology Department.
Table 1 presents an overview of the inclusion and exclusion criteria, which align with the guidelines for accelerated partial breast irradiation set forth by ASTRO and ESTRO [18, 34]
Table 1: Overview inclusion and exclusion criteria RICE trial.
Inclusion
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Exclusion
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Age≥ 60 years
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Previous Radiotherapy to same breast
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Unifocal
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Suspicious diffuse microcalcifications
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Tumor Visible on pre-treatment imaging
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Invasive lobular carcinoma on core biopsy
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Tumor size on pre-treatment imaging ≤ 2cm
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Lymphovascular invasion on core biopsy
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Grade 1-2 on pre-treatment core biopsy
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Any clinical nodal or metastatic disease
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Oestrogen receptor (ER) and Progesterone (PR) positive (>10%)
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Human epidermal growth factor receptor 2 (HER2) positive
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Clinically node negative
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Prior non-hormonal therapy
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Breast primary tumor visible on MR radiation oncology imaging (with or without IV contrast) for treatment localization
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Skin or chest wall involvement
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Collagen vascular disease (e.g. lupus, scleroderma)
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Pregnant or lactating
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Absolute contraindications to MRI (e.g. incompatible implants, unable to tolerate duration)
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Informed Consent
If a subject is considered eligible based on this preliminary screening, the surgeon will provide detailed information about the clinical study. Patients interested will receive additional information from the Radiation Oncology trial coordinator. Furthermore, patients will be referred to the Radiation Oncologist at Olivia Newton John cancer center for preoperative consultation and to receive further information about the radiation therapy.
Procedure
An overview of the study procedures for the trial is illustrated in Figure 1.
Upon entering the trial, patients will first undergo a clinical examination and core biopsy. This will be followed by treatment planning, which involves MRI and CT simulation. For the purpose of radiotherapy planning and diagnostic workup, [18F] FDG PET/CT and [18F] FES PET/CT images of both breasts will be acquired.
Six weeks after receiving radiotherapy treatment, patients will undergo wide local excision along with sentinel lymph node biopsy.
Pre-Treatment Surveillance Imaging
The baseline assessment of treatment response will be conducted on an MRI simulator system (Phillips Ingenia Ambition 1.5T MRI) utilizing the department's 1.5 T system. The MRI is equipped with a dStream 7 Channel dedicated breast coil from Phillips Healthcare (Best, Netherlands). For this assessment, patients will assume a prone position.
MR Linac and Radiotherapy for breast sites
The Elekta Unity MR-linac (Elekta, Stockholm, Sweden) is a combination of a modified Philips Ingenia 1.5 T MRI with a split-coil superconducting magnet and a linear accelerator. The beam generation system produces a single 7 Megavoltage flattening filter-free x-ray source and is mounted on an annular gantry that freely rotates around a cylindrical cryostat containing the static-field MR coils. The Unity radiation field is shaped by a multi-leaf collimator, ranging from 0.8 cm x 0.5 cm to 57.4 cm x 22.0 cm at the isocentre. The patient positioning system is capable of only longitudinal movement, making it impossible to move the treatment couch laterally or vertically. The isocentre is 14.0 cm above the patient positioning system and 143.5 cm from the source.
The challenges particularly associated with breast treatment on the MR-linac include geometric accuracy due to gradient non-linearities combined with lateral target volumes, the electron return effect, and the electron stream effect. These issues have been described and addressed by earlier studies [35] and procedures are included in the protocol for this study to minimize their impact on treatment for RICE patients. These procedures include the use of distortion correction software for geometric accuracy, carefully chosen beam angles, and organs at risk margins to minimize the effects of electron stream effect, as well as the use of bolus material to shield any predicted electron stream effect from treatment planning simulation. Strategies for online plan adaptation compensate for the fixed couch position, and online motion monitoring allows for gating (beam pause) when the target moves out of the planned high-dose volume.
Radiotherapy Planning
In this study, radiotherapy planning will involve both MRI and CT simulation, conducted with the patient in either the supine or prone position. MRI simulation will occur prior to CT to ensure that the lesion is visible on the imaging sequences that are available on the integrated MRI-Linac, to support treatment verification and delivery. It will also be used to determine whether the patient would benefit from treatment in the supine or prone position without additional exposure to ionizing radiation. The gross tumor volume (GTV) will be contoured as the visible tumor on the CT and MRI scans. The clinical target volume (CTV) will be defined by uniformly expanding the GTV by 15 mm. This expansion will be limited posteriorly by the pectoralis muscles and an anterolateral margin of 5 mm from the skin. The volume will not extend across the midline. The PTV will be created from a 3 mm margin expansion of the CTV, to account for minor inter and intra-fraction variations in patient positioning.
Treatment planning will be completed using Monaco Treatment Planning System (Elekta Stockholm, Sweden) using step and shoot Intensity Modulated Radiation Therapy, with multiple beams positioned at angles optimized for target coverage and organ at risk sparing within the current MRI-Linac capabilities.
For the dose prescription, the plan is to ensure that 95% of the CTV receives the full prescribed single dose of 21 Gy. Additionally, 95% of the PTV is intended to receive at least 95% of the prescribed dose, while a maximum of 2% of the PTV is intended to be exposed to 107% of the prescribed dose. Dose criteria for this study was determined based on conservative consideration of available literature for similar dose prescriptions for this clinical indication [6, 29, 30]
Radiotherapy Delivery
Following planning, a single 21 Gy fraction will be delivered within 10 days of the simulation. Treatment will be administered via an MR linac (Elekta Unity Sweden). The patient will be positioned according to the radiotherapy planning position and a verification image will be acquired. The image will be assessed, anatomical contours adjusted, and the treatment plan adapted to match the patient’s anatomy. Treatment will be delivered with real-time cine MRI monitoring to ensure safe and accurate delivery of the dose to the PTV.
Post-Treatment Surveillance Imaging
Post-treatment assessment of the response will be conducted 5 weeks after treatment using the MRI simulator. The same patient positioning and protocol as established in the pre-treatment surveillance imaging step will be used; this consistency will ensure comparability between the pre- and post-treatment images, allowing for accurate evaluation of the effectiveness of treatment.
Breast-Conserving Surgery
Six weeks after completing radiotherapy treatment, the patients will undergo breast conservation surgery, which consists of wide local excision for removing the tumor, along with sentinel lymph node biopsy to assess for the potential spread of cancer to the lymph nodes. In cases where the sentinel lymph node is found to be positive, indicating potential cancer spread, patients will be counseled regarding the possibility of axillary clearance. The decision for this additional procedure will be made based on the discretion of the treating surgeon, considering the individual patient's condition and treatment needs.
Histopathological assessment of the excised tissue will be performed by a pathologist with a sub-specialization in breast cancer. Tumor cells will be evaluated using hematoxylin and eosin staining and cytokeratin antibody activity. The response to treatment will be graded using the Miller and Payne Reporting Criteria [36].
Tumor samples will be securely stored within the Pathology Health biobank, and blood samples will be stored in the pathology freezer.
Follow-Up
Several clinical assessments, cosmetic photographs and formal acute toxicity scoring will be conducted by the treating Radiation Oncologist at key time points throughout the study. A baseline assessment will be performed prior to the commencement of treatment; then, follow-up assessments will be performed at 2 weeks, 6 months, and 12 months posttreatment.
The acute toxicity and cosmetic outcome scores will adhere to the standards set by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 [37].
All adverse events resulting from radiation treatment experienced by the participants will be documented in the case report form. Importantly, adverse events that could be influenced by the study interventions will be considered outcomes of the study.
Patient-Reported Outcomes
Patients will be asked to complete quality of life questionnaires (QLQ-C30 and QLQ-BR23) [38] at four key time points: upon study enrollment, on the day of radiotherapy treatment, two weeks postsurgery, and at the 12-month follow-up. Additionally, patient-based cosmetic evaluations will also be reported on the questionnaires.
Sample Size
Based on the eligibility criteria, 30 patients are expected to provide consent and be recruited over the 2-year study period. This number of patients will provide an estimated 95% confidence limit of feasibility consisting of a lower bound of 74.4% and an upper bound of 96.5% (based on the Wilson score interval approximation), if a feasibility proportion of 90% is achieved.
Statistical Methods
Descriptive summary statistics will be determined to summarize the patient clinical characteristics, responses to patient-reported outcome questionnaires and rates of adverse events at each follow-up timepoint. The primary outcome will be reported as the proportion of patients who can be feasibly treated with MRI-guided single-fraction accelerated partial breast irradiation. Success of this outcome will be defined as meeting this criterion for at least 90% of patients. For the secondary outcome assessment, univariate analysis will be performed to investigate the association between MRI parameters and the tumor response rate. Categorical variables (i.e., Clavien–Dindo grade) will be presented as counts and percentage frequencies, while continuous variables (i.e., quality of life or patient-reported outcome measures) will be presented as the mean ± standard deviation if they are normally distributed or the median (interquartile range) if their distribution is skewed.
Pearson or Spearman’s rank correlation coefficients will be used to assess correlations for normally and non-normally distributed continuous variables, respectively. Appropriate parametric or nonparametric tests will be applied to assess associations between the MRI data and histopathological features of the patients. Additionally, the MRI results will be compared between good responders to treatment and poor responders to treatment. Receiver operating characteristic (ROC) curve analysis may be employed to determine cut-off points for evaluating associations between continuous variables and binary outcomes, such as the tumor response rate.
All the statistical analyses will be carried out using Stata version 18.0 (StataCorp, College Station, Texas, USA), and a p value less than 0.05 will be used to indicate statistical significance.