Study setting {9}
Study participants will be recruited and treated at the Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
Eligibility criteria {10}
Inclusion – Patients
- Left-sided breast cancer patients (invasive and in situ)
- To be treated in the supine position
- Ability to perform a ≥ 20s breath hold
- > 18 years old
- Female
- An ECOG score from 0 to 2
- Able to read and complete questionnaires in English
- Able to give written informed consent and willingness to participate and comply with the study
Exclusion - Patients
- No regional lymph nodes involved or at risk
- No pregnant / lactating women
Who will take informed consent? {26a}
Potential participants will be identified by their consulting clinician who will explain the study, including risks and benefits and give the opportunity for informed discussion. They will receive a copy of the informed consent form to carefully read and take home for further analysis if necessary. Trained clinical trials staff at Royal North Shore Hospital will obtain informed consent from patients prior to their CT simulation appointment.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Not applicable.
Interventions
Explanation for the choice of comparators {6b}
The choice was made to compare the novel Breathe Well device to RPM/RGSC as an existing widely adopted commercial system in clinical use for breath hold management.
Intervention description {11a}
Training and simulation: The patients will be trained to perform DIBH with the assigned system and assessed for ability to perform a 20 second breath hold (at 80-90% of the maximal lung capacity). Based on this screening the patient will be deemed suitable for DIBH. For patients suitable for DIBH the breath hold AV guidance while acquiring the planning CT scan will be provided by the assigned system. The unallocated system will be set up to passively record motion, not interfering with simulation in any way. The reference breath hold depth will be recorded for both systems.
Treatment delivery: For treatment, similarly to simulation, both systems will be set up to monitor breathing motion. The patient will be guided with AV biofeedback from the assigned system depending which arm of the trial they have been randomised to. The unallocated system will passively acquire data but not interfere with treatment in any way. Prior tests showed that no interferences and difficulties are anticipated when operating the ‘Breathe Well’ system and the RPM/RGSC system at the same time. If any treatment fraction cannot be delivered due to a failure of the Breathe Well device, this will be recorded. The treatment will continue at the physician’s discretion either (1) using the RPM system, (2) the fraction will be rescheduled or (3) delivered using free breathing.
Criteria for discontinuing or modifying allocated interventions {11b}
If the patient is not suitable for DIBH, the standard clinical workflow for free breathing (FB) is followed. The patient will complete the patient experience questionnaire and progress to treatment with free breathing using no breath hold management system and with no further study interventions.
Strategies to improve adherence to interventions {11c}
Not applicable. Assessment of ease of use of treatment with the Breathe Well device is the aim of this trial, so non-adherence to the intervention should be recorded. Inability to carry out DIBH will result in free-breathing treatment as per current standard of care.
Relevant concomitant care permitted or prohibited during the trial {11d}
No restrictions on concomitant care being offered as per standard hospital practice.
Provisions for post-trial care {30}
Participants will receive post-treatment care as per standard hospital procedure. Compensation could be available through sponsor insurance.
Outcomes {12}
The primary outcome of this study is a comparison of the accuracy of the novel device Breathe Well compared to existing clinical standard RPM/RGSC, with data to be analysed after completion of treatment.
Participant timeline {13}
Table 1 shows the schedule of enrolment, interventions, and assessments. Initial toxicity baseline will be taken at enrolment, and again at post-treatment follow up at 6 weeks and every 6 months for three visits.
Table 1: schedule of enrolment, interventions, and assessments
|
STUDY PERIOD
|
|
Enrolment
|
Allocation
|
Post-allocation
|
Follow up
|
TIMEPOINT
|
Initial consult
|
CT appoint.
|
Prior to Treatment
|
First treatment
|
Last treatment
|
6w then every 6m
|
ENROLMENT:
|
Eligibility screen
|
X
|
|
|
|
|
|
Informed consent
|
|
x
|
|
|
|
|
Allocation
|
|
X
|
|
|
|
|
INTERVENTION:
|
DIBH training and assessment
|
|
x
|
|
|
|
|
CT scan
|
|
x
|
|
|
|
|
Radiotherapy planning
|
|
|
x
|
|
|
|
Radiotherapy treatment with Breathe Well, RPM/RGSC or free breathing
|
|
|
|
|
|
|
ASSESSMENTS:
|
History & physical exam Toxicity will be assessed at each scheduled history and physical exam visit
|
x
|
|
|
|
|
x
|
Ease of use questionnaires
|
|
X
|
|
X
|
X
|
|
Sample size {14}
The sample size was estimated by assuming that the systematic error in treatment accuracy, Σ, will be smaller for patients on the experimental (Breathe Well) arm than the control (RPM) arm. Previously published data for a different surface monitoring system (AlignRT: VisionRT, London, UK) is given by Kanphet et al. [18] who found a systematic error of 0.46 mm in the vertical direction. For comparison, Lutz et al. [19] found a systematic error of 1.33 mm with RPM. Assuming this study will give similar results, and using an F-test for equality of two variances, 36 patients will be needed for statistical significance with a power of 0.8 and alpha error probability of 0.05. The sample size for this study was set at 40 to account for an estimated 10% drop out rate for patients who cannot maintain a breath hold and are treated with free breathing.
Recruitment {15}
Recruitment rate is expected to be relatively high due to the non-invasive nature of the intervention proposed, the fact that no extra appointments are required and no extra radiation dose will be delivered, and the number of eligible patients treated at the site.
Assignment of interventions: allocation
Sequence generation {16a}
A total of 40 patients will be recruited. After an eligibility assessment and informed consent, participants will be assigned to the experimental arm or control arm with allocation ratio 1:1. The randomisation sequence and grouping will be generated by one researcher who will not be involved directly in patient screening, enrolment or assessment, and uploaded to Research Electronic Data Capture (REDCap). No stratification will be utilised. The randomisation tables were set up using permuted blocks with random varying block sizes of 4 and 6.
Concealment mechanism {16b}
The BRAVEHeart trial is randomised but not blinded. As the trial is to use one device versus another, the arm a patient is assigned to cannot be concealed to the patient or the treatment team.
Implementation {16c}
Randomisation is performed at the site electronically by the hospital clinical trials staff using REDCap. The allocation sequence is locked down within the REDCap database and is not accessible to anyone.
Assignment of interventions: Blinding
Who will be blinded {17a}
No blinding will be used in this trial.
Procedure for unblinding if needed {17b}
Not applicable.
Data collection and management
Plans for assessment and collection of outcomes {18a}
Collection of data during treatment will be initiated by the radiation therapists delivering the treatment. Clinical trials staff will administer the ease of use questionnaires (see Additional Files 2 and 3) with the results entered in REDCap. Clinicians will administer baseline and toxicity questionnaires, with the results entered in REDCap.
Plans to promote participant retention and complete follow-up {18b}
Participants are only required to attend treatment and follow-up appointments as normally required for their treatment and no drop out is expected. Clinicians and radiotherapy staff will be trained to answer any participant questions or concerns about the trial.
Data management {19}
Respiratory data (‘Breathe Well’ and RPM/RGSC), CT images, MV frames from during the irradiation, and demographic information will be collected from the subjects. At the randomisation stage of the study, patients will receive a trial ID. The data saved for the trial will be under this de-identified trial ID. A separate key of the subject study number and their medical record number will be securely stored by the chief investigator to allow re-identification if necessary. This master list for re-identification will remain at the Royal North Shore Hospital. Only the principal investigator will have the ability to re-identify subjects. Questionnaire and toxicity information will be entered in REDCap and collated information transferred to the same secure drive at the University of Sydney for storage.The data will be stored for 15 years as per clinical trial guidelines. Data sent from the Northern Sydney Cancer Centre, Royal North Shore Hospital in accordance with the study site’s ethics and security allowances and protocols to the study site University of Sydney will be anonymised but re-identifiable. Patient data could be made re-identifiable to obtain additional clinical information for the data analysis stage of the project, but only by the principal investigator. The de-identified data will be stored at the University of Sydney on a secure, password protected backed up database that will be created, much the same as what we have designed for previous University of Sydney studies.
Confidentiality {27}
At the hospital, copies of questionnaires will be stored in a locked cabinet. Digital information will be stored on the secure local network. Data will be anonymised before leaving the hospital and being transferred to the University of Sydney for storage on a secure, password-protected drive accessible by authorised researchers only. The anonymisation table will remain at Royal North Shore Hospital.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Not applicable.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
A continuous series of images from the megavoltage (MV) treatment beam itself will be captured from the electronic portal imaging device (EPID) on the linac. Following the method of Jensen et al. [15], the chest wall position during treatment will be extracted from these images in postprocessing with no additional dose to the patient and no prolongation of treatment time. The planned chest wall position will be extracted from the digitally reconstructed radiograph (DRR). The chest wall displacement for each EPID frame taken during treatment is then defined as the difference of the extracted chest wall position from the planned position.
Deriving an average chest wall displacement per patient we can calculate the systematic error in treatment accuracy, Σ, as the standard deviation of these values across all patients, as described by Bland and Altman [16]. For each patient the collected respiratory data from both Breathe Well and RPM/RGSC will be recorded, analysed and compared to the ground truth chest wall motion extracted from the cine MV images.
For the secondary aims for the trial, the following data analyses will be carried out. Setup times will be gathered using timepoints recorded in the Aria patient management system and compared for the two trial arms. Questionnaires for patients and staff will be collated and average scores compared for the two systems. Assessment of the dose delivered to patients in each arm will be carried out following the approach of Doebrich et al. [17].
Interim analyses {21b}
Not applicable.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Not applicable.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Sample size estimation includes an estimation of patients who will be unable to perform DIBH.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
Only non-identifiable data may be available for other scientific research, e.g., non-identifiable data placed on a well-controlled university site, upon request. The data sharing platform is a secure on-line storage solution ("CloudStor") provided through University of Sydney. The data will be stored as a password-protected, encrypted Zip-file. In order to download / decompress the data, participating researchers agree to the terms of use for the data, including: (I) that the data is not to be published or otherwise redistributed without the express consent of the original investigator(s) and (ii) that the data is forbidden to be used for any commercial purpose.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Our steering committee (investigators and sub investigators including consumer representatives) will meet monthly to monitor the conduct of the study and assess progress. In addition, the chief and majority of sub investigators will maintain weekly contact via email and face-face or teleconference meetings in order to facilitate implementation of the study and provide quality assurance to all aspects of the study. The chief investigator will be on-site to personally conduct, oversee, and supervise all of the activities
Composition of the data monitoring committee, its role and reporting structure {21a}
The imaging modalities that are used in this study are approved for clinical practice, therefore this study we will not nominate a separate Data and Safety Monitoring Board.
Adverse event reporting and harms {22}
The principal investigator and sub investigators will report adverse events to the Radiation Safety Officer on site and to the Human Research Ethics Committee and the Research Governance Officer within 72 hours of the event occurring unless immediate notification is required.
Frequency and plans for auditing trial conduct {23}
Auditing will only be conducted if required by the funder or Human Research Ethics Committee.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any amendments to the protocol will be reviewed and approved by the Human Research Ethics Committee and communicated to all relevant parties by the lead investigator.
Dissemination plans {31a}
The results of this study will be published in internationally recognised peer-reviewed journals and presented at international/national conferences. Non-identifiable data may be available for other scientific research on application to the lead investigator.