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Trial registered on ANZCTR


Registration number
ACTRN12618001691235p
Ethics application status
Not yet submitted
Date submitted
2/10/2018
Date registered
12/10/2018
Date last updated
12/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Breath-Hold in Abdominal & Lung Cancer Radiotherapy - Tumour Reproducibility, Tumour Stability & Patient Experience

Scientific title
Optimal Breath-hold technique for Upper-abdominal & thoracic Radiotherapy in patients with liver, pancreas, kidney, adrenal gland & lung cancer – Deep-inhale, Inhale or Exhale? Investigating stability, reproducibility, patient experience & treatment efficiency (BURDIE)
Secondary ID [1] 296225 0
None
Universal Trial Number (UTN)
U1111-1221-5423
Trial acronym
BURDIE
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Lung Cancer 309863 0
Liver Cancer 309979 0
Kidney Cancer 309980 0
Pancreatic Cancer 309981 0
Adrenal Gland Cancer 309982 0
Condition category
Condition code
Cancer 308655 308655 0 0
Lung - Non small cell
Cancer 308656 308656 0 0
Kidney
Cancer 308657 308657 0 0
Pancreatic
Cancer 308658 308658 0 0
Liver
Cancer 308751 308751 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1. Breathing Assessment:
It is our department policy to deliver SABR and some standard fractionated radiotherapy to upper abdominal tumours in EBH using the Elekta ABC device. DIBH may be used if a patient is unable to comply with EBH requirements. It is our department policy to deliver SABR to lung tumours in DIBH using the ABC device, for select patients. Standard pre-treatment management in our department for patients assessed as suitable for a breath-hold technique is to undergo a breathing assessment to confirm eligibility. The breathing assessment involves a training session to confirm the patient is able to perform breath-hold with the ABC device, for a minimum time of 15 seconds. The breathing assessment also involves a 4DCT (lung) or 4D- CBCT (upper abdominal) to confirm a breath-hold technique is required.
For this study, all consenting patients planned for radiotherapy to liver, pancreas, adrenal and kidney cancers will be assessed for eligibility for each of EBH, DIBH and IBH techniques. Patients planned for radiotherapy to lung cancer will only be assessed for DIBH technique (i.e. no change to usual care).
Two radiation therapists perform the breathing assessment. At the breathing assessment, patients are determined to be eligible for proceeding with a breath-hold technique if they are able to comply with all ABC requirements (use mouth-piece, nose-peg and operate control switch) and breath-hold in at least one technique (of IBH, DIBH and/or EBH) for greater than 15 seconds. With the exception of patients planned for radiotherapy to the lung, patients will be screened for eligibility in all three techniques (IBH, DIBH & EBH).
During the breathing assessment, the patient’s maximum tolerable breath-hold time in each technique will be determined. This is the maximum amount of time, measured in seconds that the patient is able to hold their breath comfortably, and repeatedly. This time will be recorded for each technique (IBH, DIBH & EBH). The patient’s recovery time between consecutive breath holds will also be recorded. Recovery is determined by the patient as the time from completing one breath hold to the patient indicating they are ready to perform the next breath hold. Patients indicate when they are ready by depressing the ABC control switch.
2. Stability & Reproducibility Assessment:
To assess the stability and reproducibility of the tumour position during each breath-hold, and between consecutive breath holds, a series of kV x-ray fluoroscopy images will be acquired.
It is our department policy for patients undergoing lung SABR to perform three breath-holds whilst kV fluoroscopy images are acquired. For this study, all consenting patients undergoing lung SABR will perform five breath-holds, under kV fluoroscopy imaging in DIBH. There is an additional two kV images acquired, compared to usual care of lung SABR patients in this study.
It is our department policy for patients undergoing upper abdominal SABR to perform three breath-hold kV fluoroscopy images are acquired in either EBH or DIBH. For this study, all consenting patients undergoing upper abdominal radiotherapy will perform five breath-holds, under kV fluoroscopy imaging for each eligible technique (EBH, IBH, DIBH). This is up to twelve additional kV fluoroscopy images for patients in this study, compared to usual care.
The kV fluoroscopy is performed on an Elekta™ linear accelerator, using the XVI™ software “MotionView” function. The position of the tumour will be tracked under kV fluoroscopy by assessment of the tumour (if directly visible) or via an appropriate tumour surrogate (diaphragm or fiducial marker) position. Each kV fluoroscopy image is acquired as an Antero-Posterior (AP) image, with the x-ray tube located anterior to the patient. The order in which the breath-hold techniques (EBH, IBH, & DIBH) will be assessed will be randomized for each patient, to reduce risk of bias.
Stability: The stability of the breath-hold is defined as the range of cranio-caudal motion, of the tumour, or its surrogate, during a breath-hold.
Reproducibility: The reproducibility is defined as the cranio-caudal displacement of the tumour/surrogate position between consecutive breath-holds.
Patient Experience Questionnaire:
Immediately following this assessment, patients will be asked to complete a questionnaire to assess their experience of each technique. The questionnaire will ask patients to rate their experience of each of the attempted breath-hold methods. Patients who were assessed for all three breath-hold methods will also be asked to rank the breath-hold methods in order of their preference. The order of the questions provided to the patient will match the order in which the breathing assessment was randomized.
This questionnaire has been developed specifically for this study, as no validated questionnaire tools were able to be identified. Statistical advice was sought in the development of this questionnaire. As required, a staff member involved in the breathing and/or reproducibility & stability assessment will conduct a semi-structured interview with the patient to elicit responses to all applicable questions.
3. Determination of Treatment Technique:
Following the Breathing Assessment and Stability & Reproducibility Assessment, selection of a breath-hold technique will be made, which will be used for the patient’s radiotherapy treatment.
For upper abdominal patients who were deemed eligible for more than one technique, selection of treatment technique is made by prioritizing:
a. Reproducibility assessment: Selection of the most reproducible technique should be prioritized highest. If two or more techniques have the same reproducibility, then;
b. Stability assessment: Selection of the most stable technique should be prioritized second. If two or more techniques have the same reproducibility and stability, then;
c. Breath-hold time: Selection of the technique with the longest maximum tolerable breath-hold time should be prioritized third.
For lung patients, the selection of the DIBH is indicated if:
a) Tumour motion exceeds 10mm on free-breathing radiotherapy planning 4DCT
OR
b) If otherwise deemed to require DIBH based on Radiation Oncologist assessment. Reasons may include: previous radiotherapy in the area; organ at risk in close proximity to tumour.
4. Radiotherapy Planning
Patients will have all subsequent planning and treatment imaging performed using the chosen breath-hold technique. There is no change to usual care for radiotherapy planning procedures.
The Gross Tumour Volume (GTV) will be delineated on each planning CT by the treating Radiation Oncologist. The tumour surrogates will be delineated on each planning CT by a Radiation Therapist or Radiation Oncologist.
The inter-breath hold displacement of the tumour or tumour surrogate will be measured as change in GTV centroid location in three planes. The measurements will be recorded in the patient’s Mosaiq electronic record.
5. Radiotherapy Treatment – Inter-fraction & Intra-fraction reproducibility
Usual care radiotherapy treatment will be delivered for all patients. There is no change to standard patient management.
For all treatment fractions, Cone Beam Computed Tomography (CBCT) images are acquired before radiotherapy treatment delivery. For patients undergoing Stereotactic Ablative Radiotherapy (SABR), images may also be acquired during and after treatment delivery. At each treatment fraction, a minimum of one breath-hold CBCT will be acquired as per standard practice. Each CBCT will be acquired over several breath-holds. The displacement of the tumour or its surrogate will be measured and used to assess the intra-fraction and inter-fraction reproducibility.
Each CBCT will be automatically fused to the planning CT using a two-step registration. Step one, a bone algorithm fusion is used to correct any gross patient misalignment. Step two, a tumour or tumour surrogate (grey value) or fiducial marker (seed) fusion is used to correct any misalignment of the tumour position. For this study, the tumour displacement will be measured as the correction applied from step one to step two. The measurements will be recorded in the patient’s Mosaiq electronic record.
6. Radiotherapy Treatment – Efficiency
Total treatment time (measured as total “beam on” time, in seconds, including “beam-hold” recovery time, where patient is between consecutive breath-holds but excluding time to reposition gantry between treatment beams), breath-hold time, and number of breath-holds required to deliver treatment will be recorded for the first three fractions for all patients. From this, an estimate of treatment efficiency will be determined as:
(breath hold time (sec) x number of breath holds)/total treatment time (sec)
e.g. 17 seconds x 12 breath-holds / 540 seconds total = 17 x 12 / 540 = 0.378

The measurements will be recorded in the patient’s Mosaiq electronic record.
Intervention code [1] 312553 0
Treatment: Other
Comparator / control treatment
Please see description of interventions/exposure above.

Each patient will act as their own control.

Upper Abdominal Cohort: Patients will attempt all three breath hold methods (IBH, EBH, DIBH). The optimal technique will be selected (as described) and used for all subsequent procedures.

Lung Cohort: Patients will attempts DIBH only if required. The optimal technique (DIBH or Free-Breathing) will be selected (as described) and used for all subsequent procedures.
Control group
Active

Outcomes
Primary outcome [1] 307613 0
1. To measure the reproducibility of tumour position (or its surrogate) between each breath hold in inhale, deep-inhale and exhale, measured using kV fluoroscopy.
Timepoint [1] 307613 0
At time of test
Primary outcome [2] 307614 0
2. To measure the stability of tumour position (or its surrogate) during each breath hold in inhale, deep-inhale and exhale breath-hold, measured using kV fluoroscopy.
Timepoint [2] 307614 0
At time of test
Primary outcome [3] 307615 0
3. To measure the inter-fraction and intra-fraction reproducibility of tumour position at treatment delivery, measured on Cone Beam Computed Tomography (CBCT)
Timepoint [3] 307615 0
At time of test
Secondary outcome [1] 352425 0
1. Overall treatment efficiency of inhale, deep-inhale and exhale breath-hold.

The following measurements will be recorded for the first three fractions for all patients:
Total treatment time - measured as total “beam on” time (measured with stopwatch), in seconds, including “beam-hold” recovery time, where patient is between consecutive breath-holds but excluding time to reposition gantry between treatment beams);
Breath-hold time (pre-determined before treatment); and
Number of breath-holds required (counted directly at each treatment fraction) to deliver treatment.

From this, an estimate of treatment efficiency will be determined as:
(breath hold time (sec) x number of breath holds)/ total treatment time (sec). The average treatment efficiency measurement will be determined from the first three treatment fractions.

This is a composite secondary outcome.
Timepoint [1] 352425 0
At time of test
Secondary outcome [2] 352426 0
2. Patient-reported experience of each breath-hold technique (inhale, deep-inhale and exhale)
Immediately following this assessment, patients will be asked to complete a questionnaire to assess their experience of each technique. The questionnaire will ask patients to rate their experience of each of the attempted breath-hold methods. Patients who were assessed for all three breath-hold methods will also be asked to rank the breath-hold methods in order of their preference. The order of the questions provided to the patient will match the order in which the breathing assessment was randomized.
This questionnaire has been developed specifically for this study, as no validated questionnaire tools were able to be identified. As required, a staff member involved in the breathing and/or reproducibility & stability assessment will conduct a semi-structured interview with the patient to elicit responses to all applicable questions.

Timepoint [2] 352426 0
At time of test

Eligibility
Key inclusion criteria
1. Eligible for standard fractionated or SABR treatment to liver, kidney, adrenal, pancreas or lung (SABR only) per standard departmental policy
2. Informed consent
3. Aged >18 years
4. English speaking, or able to follow instructions in English
5. Eligible for breath-hold technique based on radiation oncologist assessment. Considerations may include but are not limited to:
a) Patient able to voluntarily hold their breath for greater than 15 seconds when comfortably seated
b) Patient of good performance status, ECOG 0-2
c) Patient able to lay in treatment position for greater than 45 minutes
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Unable to consent/withdrawal of consent/decline consent
2. Non-English Speaking or unable to follow spoken English instructions
3. Ineligible for any breath-hold technique based on radiation oncologist assessment & criteria outlined in study methods

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is not a randomized controlled trial
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Upper Abdominal Cohort (Liver, Pancreas, Adrenal Gland, Kidney): Patients will attempt all three methods (IBH, EBH, DIBH).

Lung Cohort: Patients will undergo a 4D CT. Based on assessment of images, patients will attempt DIBH as required.

For all patients, the optimal technique will be selected for all subsequent procedures
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The sample size is dictated by the number of patients able to be recruited over the 12-month study period, and thus no power calculations are able to be conducted.
The stability and reproducibility measurements taken within and between the three breath-holding techniques will be assessed using intra and inter class correlation coefficients, with 95% confidence intervals estimated for each value. For non lung-cancer patients, the order of the EBH, IBH and DIBH techniques will be randomly assigned to each patient, with the order recorded.
For stability and reproducibility measurements a two-way intra-class correlation (ICC) model with absolute agreement definition of concordance is likely to be used, to account for the order of the measurements taken. A one-way model may be utilized if there is no evidence of systematic variation over the 3 measurements (i.e. repeated measures).
The same modeling design and process will be used to test the inter-fraction and intra-fraction reproducibility for the radiotherapy treatment using the CBCT image data acquired before, during and/or after delivery of treatment. The analysis within a breath-hold technique group may be limited if only a few patients are assigned to the group as the optimal breath-hold technique.
Questionnaire results will be interpreted by comparison of proportions. Chi Squared and Fischers Exact tests may be used if appropriate for statistical analysis.
Descriptive analysis will be undertaken with categorical data presented as counts and frequencies, and/or means and standard deviations (for normally distributed data) or median and inter-quartile ranges (for non-normally distributed data). Data will be collected in Microsoft Excel with statistical analysis conducted using Stata version 15.0 (StataCorp, College Station, Texas, USA), with a p-value of <0.05 used to indicated statistical significance.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12050 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 24207 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 300824 0
Hospital
Name [1] 300824 0
Austin Health
Address [1] 300824 0
145 Studley Rd Heidelberg VIC 3084
Country [1] 300824 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Rd Heidelberg VIC 3084
Country
Australia
Secondary sponsor category [1] 300370 0
None
Name [1] 300370 0
Address [1] 300370 0
Country [1] 300370 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 301592 0
Austin Health Human Research Ethics Committee
Ethics committee address [1] 301592 0
145 Studley Rd Heidelberg VIC 3084
Ethics committee country [1] 301592 0
Australia
Date submitted for ethics approval [1] 301592 0
03/10/2018
Approval date [1] 301592 0
Ethics approval number [1] 301592 0

Summary
Brief summary
This aim of this study is to compare three breath hold techniques for radiotherapy in patients with liver, kidney, adrenal, pancreatic or lung tumours.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and are eligible for radiotherapy treatment to the liver, kidney, adrenal gland, pancreas or lung.

Study details
Non-lung cancer participants will undergo three breath hold techniques in a random order: exhale breath-hold (EBH); inhale breath-hold (IBH) and deep-inhale breath-hold (DIBH). Participants with lung cancer will undertake the DIBH technique only. The patient breathes through an Active Breathing Coordinator machine, which automatically stops air flow when the correct volume of air is measured. Exhale Breath Hold requires the patient to breathe out and hold their breath. Inhale Breath Hold requires the patient to breathe in and hold their breath. Deep Inhale Breath Hold requires the patient to take a deep breath in and hold their breath.

X-Ray images will be taken while the patient holds their breath, to measure the stability and reproducibility of their tumour. Patients will also be asked to complete a questionnaire to assess their experience of the breath-hold technique(s). It is hoped that we can determine the best techniques to enable delivery of high dose radiation to the tumour, while minimising the radiation dose to healthy organs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87494 0
Dr Richard Khor
Address 87494 0
Austin Health
145 Studley Rd Heidelberg VIC 3084
Country 87494 0
Australia
Phone 87494 0
+61 394962800
Fax 87494 0
Email 87494 0
richard.khor@austin.org.au
Contact person for public queries
Name 87495 0
Ms Briana Welsh
Address 87495 0
Austin Health
145 Studley Rd Heidelberg VIC 3084
Country 87495 0
Australia
Phone 87495 0
+61 394962800
Fax 87495 0
Email 87495 0
briana.welsh@austin.org.au
Contact person for scientific queries
Name 87496 0
Dr Richard Khor
Address 87496 0
Austin Health
145 Studley Rd Heidelberg VIC 3084
Country 87496 0
Australia
Phone 87496 0
+61 394962800
Fax 87496 0
Email 87496 0
richard.khor@austin.org.au

No data has been provided for results reporting
Summary results
Not applicable