Evaluation of a Cone-beam CT Scanner for Image Guided Radiotherapy (CONFIGURE)
Phase: NA
Conditions: Head and Neck Cancer, Lung Cancer, Breast Cancer, Abdominal Cancer, Pelvic Cancer
Sponsor: Varian, a Siemens Healthineers Company

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Evaluation of a Cone-beam CT scanner for 
Image Guided Radiotherapy (CONFIGURE) 
 
 
 
 
 

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Evaluation of a cone-beam CT scanner for image-guided radiotherapy (CONFIGURE) 
Protocol ID 
VAR-2022-04 
Short title 
CONFIGURE 
EudraCT number  
N/A 
Version 
1.3 
Date 
6 March 2023 
Coordinating 
investigator/project leader 
 
Dr. ir. Wouter van Elmpt 
Dr Tanslaan 12, NL-6229 ET Maastricht 
wouter.vanelmpt@maastro.nl 
Principal investigator 
Dr. Ir. Wouter van Elmpt  
Maastro (Maastricht, The Netherlands)  
Writing committee 
Dr. Marta Bogowicz  
Dr. ir. Richard Canters 
Dr. Colien Hazelaar 
Dr. Vicki Trier Taasti 
Dr. ir. Rik Hansen 
Prof. Dr. Dirk De Ruysscher 
Dr. Karolien Verhoeven 
Drs. Frederik Wesseling 
Dr. Evert Van Limbergen 
Dr. Maaike Berbee 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Varian Medical Systems 
3100 Hansen Way 
Palo Alto, CA 94304 USA 
Subsidising party 
Varian Medical Systems 
Independent expert 
Dr. Danielle Eekers 
Dr Tanslaan 12, NL-6229 ET Maastricht 
danielle.eekers@maastro.nl 
Laboratory sites <if applicable> 
N/A 
Pharmacy <if applicable> 
N/A 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Sean Davidson 
Senior Clinical Research Manager  
Varian, a Siemens Healthineers Company 
 
 
 
Principal Investigator: 
Dr. Ir. Wouter van Elmpt 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ................................................................................. 8 
2. 
OBJECTIVES .................................................................................................................. 10 
3. 
STUDY DESIGN ............................................................................................................. 10 
4. 
STUDY POPULATION .................................................................................................... 10 
4.1 
Population (base) ..................................................................................................... 10 
4.2 
Inclusion criteria ....................................................................................................... 10 
4.3 
Exclusion criteria ...................................................................................................... 11 
4.4 
Sample size calculation ........................................................................................... 11 
5. 
TREATMENT OF SUBJECTS ........................................................................................ 11 
5.1 
Investigational product/treatment ............................................................................. 11 
6. 
INVESTIGATIONAL PRODUCT ..................................................................................... 12 
6.1 
Name and description of investigational product(s) ................................................. 12 
6.2 
Summary of findings from non-clinical studies ......................................................... 12 
6.3 
Summary of findings from clinical studies ................................................................ 12 
6.4 
Summary of known and potential risks and benefits ................................................ 12 
6.5 
Description and justification of route of administration and dosage ......................... 12 
6.6 
Dosages, dosage modifications and method of administration ................................ 12 
6.7 
Preparation and labelling of Investigational Medicinal Product ................................ 12 
6.8 
Drug accountability .................................................................................................. 12 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................ 12 
8. 
METHODS ...................................................................................................................... 12 
8.1 
Study parameters/endpoints .................................................................................... 12 
8.1.1 
Main study parameter/endpoint ........................................................................ 12 
8.1.2 
Secondary study parameters/endpoints ........................................................... 13 
8.1.3 
Other study parameters (if applicable) .............................................................. 14 
8.2 
Randomisation, blinding and treatment allocation ................................................... 14 
8.3 
Study procedures ..................................................................................................... 14 
8.4 
Withdrawal of individual subjects ............................................................................. 15 
8.4.1 
Specific criteria for withdrawal (if applicable) .................................................... 15 
8.5 
Replacement of individual subjects after withdrawal ............................................... 15 
8.6 
Follow-up of subjects withdrawn from treatment ...................................................... 15 
8.7 
Premature termination of the study .......................................................................... 15 
9. 
SAFETY REPORTING .................................................................................................... 16 
9.1 
Temporary halt for reasons of subject safety ........................................................... 16 
9.2 
AEs, SAEs and SUSARs ......................................................................................... 16 
9.2.1 
Adverse events (AEs) ....................................................................................... 16 
9.2.2 
Serious adverse events (SAEs) ........................................................................ 16 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .......................... 17 
9.3 
Annual safety report ................................................................................................. 17 
9.4 
Follow-up of adverse events .................................................................................... 17 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee .................................... 18 

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10. STATISTICAL ANALYSIS ............................................................................................... 18 
10.1 
Primary study parameter(s) ..................................................................................... 18 
10.2 
Secondary study parameters ................................................................................... 18 
10.3 
Other study parameters ........................................................................................... 20 
10.4 
Interim analysis (if applicable) .................................................................................. 20 
11. ETHICAL CONSIDERATIONS ........................................................................................ 20 
11.1 
Regulation statement ............................................................................................... 20 
11.2 
Recruitment and consent ......................................................................................... 20 
11.3 
Objection by minors or incapacitated subjects (if applicable) .................................. 21 
11.4 
Benefits and risks assessment, group relatedness .................................................. 21 
11.5 
Compensation for injury ........................................................................................... 21 
11.6 
Incentives (if applicable) .......................................................................................... 22 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ............................. 22 
12.1 
Handling and storage of data and documents ......................................................... 22 
12.2 
Monitoring and Quality Assurance ........................................................................... 24 
12.3 
Amendments ............................................................................................................ 24 
12.4 
Annual progress report ............................................................................................ 24 
12.5 
Temporary halt and (prematurely) end of study report ............................................ 25 
12.6 
Public disclosure and publication policy ................................................................... 25 
13. STRUCTURED RISK ANALYSIS ................................................................................... 25 
13.1 
Potential issues of concern ...................................................................................... 25 
13.2 
Synthesis ................................................................................................................. 26 
14. REFERENCES ................................................................................................................ 27 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
2D 
Two Dimensional 
ABR 
General Assessment and Registration form (ABR form), the application 
form that is required for submission to the accredited Ethics Committee; 
in Dutch: Algemeen Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
CBCT 
Cone-Beam Computed Tomography 
CNR 
Contrast-to-Noise Ratio 
CT 
Computed Tomography 
DVH 
Dose-Volume Histogram 
DSMB 
Data Safety Monitoring Board 
FOV 
Field Of View 
HU 
Hounsfield Units 
IB 
Investigator’s Brochure 
IMDD 
Investigational Medicinal Product Dossier 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
RT 
Radiation Therapy 
(N)SCLC (Non-)Small Cell Lung Cancer 
(S)AE 
(Serious) Adverse Event  
Sponsor The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A 
party that provides funding for a study but does not commission it is not 
regarded as the sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
1 
Rationale: A novel cone-beam computerized tomography (CT) imaging system has been 
2 
developed for image-guided radiotherapy. This new system can acquire cone-beam CT 
3 
(CBCT) images faster than previous systems. Furthermore, the new system has demonstrated 
4 
increased image quality, resolution and Hounsfield Unit (HU) accuracy in phantom images 
5 
compared to previous cone-beam CT systems. This CBCT system opens new possibilities for 
6 
use of CBCT images in various radiotherapy tasks for which previous CBCT images were not 
7 
optimal. Specifically, the use of CBCT images for delineation of anatomical structures, 
8 
radiotherapy treatment planning and radiation treatment dose calculation is limited with current 
9 
on-board imaging technology. The improved image quality of the new system will be evaluated 
10 
in a broad clinical setting and patient population with respect to its suitability for tumour and 
11 
organ delineation, image-guided radiotherapy and radiation dosimetry for patients receiving 
12 
external beam photon radiotherapy. 
13 
Objective: The main objective of this study is to evaluate the image quality of a new cone-
14 
beam CT imaging system that will be used to acquire images of a wide selection of anatomical 
15 
locations in patients receiving radiotherapy for cancer. 
16 
Study design: Single arm, non-randomized prospective study. 
17 
Study population: Patients treated with external beam photon radiotherapy at Maastro. Six 
18 
treatment/tumour sites will be investigated: head-and-neck, lung (stage I), lung (stage II-IV), 
19 
left breast, pelvis, and (upper) abdomen. A total of 40 subjects distributed over the various 
20 
anatomical sites will be enrolled with at least 5 subjects per treatment site. 
21 
Intervention: One additional imaging session with 1-2 additional CBCT image acquisitions will 
22 
be performed using the novel cone-beam CT imaging device. The acquired images will not be 
23 
used in any way to change the patient’s treatment. 
24 
Main study parameters/endpoints: Primary objective: Qualitative comparison of the image 
25 
quality of the novel cone-beam CT imaging system to standard cone-beam CT imaging and 
26 
conventional fan beam CT imaging used for radiotherapy planning purposes. 
27 
Secondary objectives: Evaluation of the suitability of the novel CBCT images for radiation 
28 
treatment planning and dose calculation. Qualitative assessments of novel CBCT vs. standard 
29 
(cone-beam) CT images. 
30 
Nature and extent of the burden and risks associated with participation, benefit and 
31 
group relatedness: There is no direct benefit expected for the individual patients who 
32 
participate in this study. Additional imaging is performed on the novel cone-beam CT imaging 
33 
device using x-rays. Additional radiation exposure resulting from the two additional CBCT 
34 
images acquired for this study is a small fraction (<0.1%) of the radiation received during a 
35 
subject’s standard radiotherapy treatment. Collected data will not be used for clinical decision 
36 
making.  
37 
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1. INTRODUCTION AND RATIONALE 
39 
Radiotherapy is administered to 40-50% of patients receiving treatment for cancer making it a 
40 
standard treatment modality for a large number of patients. The radiation can be administered 
41 
with high precision to the tumour while minimizing dose to the surrounding healthy tissue. 
42 
Patient-specific radiation dosimetry plans are generated for patients receiving radiotherapy. A 
43 
treatment planning fan-beam computed tomography (CT) scan is acquired using dedicated 
44 
equipment (e.g., flat tabletop, laser-alignment based patient positioning, and dedicated CT 
45 
scan protocols calibrated for radiotherapy purposes). Both the target (tumour) and the 
46 
surrounding normal organs and tissues (so-called organs at risk) are delineated on the 
47 
treatment planning CT, which forms the basis of an individualized treatment plan for each 
48 
patient. Calibration of the treatment planning CT allows radiation doses to be calculated based 
49 
on the CT Hounsfield numbers.  
50 
 
51 
Radiation therapy is typically delivered in 25-35 daily treatments, or “fractions”, over the course 
52 
of 5-7 weeks. Before every fraction of radiation treatment, images are acquired with the patient 
53 
on the treatment table to ensure correct patient positioning and set-up (i.e., alignment with the 
54 
patient position and set-up on the treatment planning CT). Daily images are acquired using 
55 
imaging systems integrated with the treatment device (linear accelerator) [Jaffray 2012]. 
56 
Typical on-board imaging systems produce either orthogonal 2D x-ray images or cone-beam 
57 
CT (CBCT) images, the quality of which has historically been less than that of the treatment 
58 
planning CT. 
59 
 
60 
A novel cone-beam CT imaging system has recently been developed specifically for image-
61 
guided radiotherapy (Halcyon 4.0, developed by Varian, a Siemens Healthineers company). 
62 
The new CBCT imaging system has the potential to optimize the image guidance workflow and 
63 
increase the efficiency of the radiotherapy workflow. This new imaging system can acquire 
64 
cone-beam CT images faster (i.e., by a factor of 3-6) than conventional CBCT systems and 
65 
has a larger imaging panel resulting in an increased field-of-view (FOV). Image quality and 
66 
Hounsfield Unit accuracy have increased compared to previous cone-beam CT image guided 
67 
systems, as determined by evaluation of images acquired of phantoms. Furthermore, 
68 
improvements have been made to the reconstruction algorithms used to convert the x-ray 
69 
projections collected at multiple rotation angles around the patient into a 3D image volume. 
70 
The updated algorithms may reduce artefacts due to both motion and due to the presence of 
71 
metal implants. 
72 
 
73 
The improved image quality of the new CBCT imaging system may allow the use of CBCT 
74 
images for radiotherapy purposes for which standard CBCT images are not appropriate. 
75 
Specifically, the use of high-quality CBCT images may enable the anatomic contouring 
76 
required for radiotherapy treatment planning and the Hounsfield unit accuracy for radiation 
77 
treatment dose calculation [Giacometti 2020]. This would represent a considerable advance 
78 
over the CBCT technology currently integrated with treatment machines. High-quality CBCT 
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images would open possibilities for adaptive radiotherapy and streamlined palliative treatment 
80 
workflows [Glide-Hurst 2021]. The quality of the CBCT images from this new system will be 
81 
evaluated in a clinical setting. 
82 
 
83 
This study will evaluate the image quality and Hounsfield Unit accuracy of the new CBCT 
84 
images, which is necessary to determine the accuracy of radiation dose calculation based on 
85 
those images. Images of tumours at multiple anatomical locations (head-and-neck, lung (stage 
86 
I), lung (stage II-IV), left breast, pelvis, and (upper) abdomen) will be acquired and analysed. 
87 
In addition to the quantitative metrics, images from each anatomical location will be evaluated 
88 
using different qualitative metrics since higher quality CBCT images may offer different 
89 
advantages for different anatomical locations. 
90 
 
91 
For head-and-neck images, the expected improvement in visualisation of soft tissue contrast 
92 
between the tumour, lymph nodes and various organs-at-risk (possibly combined with the 
93 
reduction of image artefacts caused by metal, e.g., dental implants), together with an extended 
94 
field of view in both axial and cranial-caudal directions, could allow for the omission of a repeat 
95 
CT scan that is regularly needed in this patient population for mid-treatment replanning to 
96 
account for significant changes in the patient anatomy. A CBCT could be captured for 
97 
treatment replanning purposes without the patient leaving the treatment room and without 
98 
requiring an additional patient visit.  
99 
 
100 
For images of the thorax, visualisation of small lesions, such as stage I (non-)small cell lung 
101 
cancer ((N)SCLC), is sometimes difficult in current clinical practice because of the presence 
102 
of motion artifacts due to breathing. The faster image acquisition of the novel CBCT system 
103 
(approx. 6 seconds) should allow imaging in a single breath hold for most patients, which 
104 
should reduce motion artifacts and improve image quality. Also, for lower lobe tumours close 
105 
to the diaphragm (where diaphragmatic motion compromises image quality), the new CBCT 
106 
images may provide better visualisation than in current technology for image-guidance. 
107 
 
108 
For advanced stage lung cancer (Stage II-IV), a poor contrast-to-noise ratio (CNR) in the 
109 
mediastinal region currently hampers proper identification of anatomical structures of interest 
110 
(e.g., heart, lymph nodes). Improved image quality with improved CNR properties may improve 
111 
image-guidance procedures for thoracic tumours. 
112 
 
113 
For breast cancer patients, who may have large (nodal) areas that need to be treated, the 
114 
visualisation of these (nodal) areas on current CBCT systems is hampered by (residual) 
115 
breathing motion during a breath hold. Also, metal hardware (e.g., surgical clips, expanders) 
116 
introduce artifacts in the standard CBCT images. The increased FOV, faster image acquisition 
117 
and newer metal artifact reduction strategies of the novel CBCT system may overcome these 
118 
problems and improve visualisation. 
119 
 
120 
For the pelvic and (upper) abdominal regions, various tumour sites may be eligible (e.g., 
121 
bladder, liver, stomach, cervical, prostate, anal and rectal cancer) for inclusion in this study. In 
122 

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all these tumour sites, artifacts may occur with standard CBCT imaging systems due to long 
123 
(e.g., 30-60 seconds) CBCT imaging acquisition times. Regions with air-tissue interfaces such 
124 
as the stomach, intestines, and rectum are known to cause image artifacts with standard CBCT 
125 
systems. Faster image acquisition with the novel CBCT system (approx. 6 seconds) reduces 
126 
the likelihood of (residual) motion during the scan. Improved soft-tissue characterisation may 
127 
improve visualization of individual structures in this anatomical region. Furthermore, metal 
128 
artifact reduction strategies of the novel CBCT system may improve visualization of structures 
129 
in the pelvis in patients with hip implants, which lead to severely decreased image quality in 
130 
standard CBCT images. 
131 
 
132 
2. OBJECTIVES 
133 
Primary Objective:  
134 
• 
Describe the differences in quality of CBCT images acquired with the novel cone-beam 
135 
CT imaging system to the quality of standard cone-beam CT images used for image-
136 
guidance and to that of conventional CT images used for radiotherapy planning 
137 
purposes. 
138 
 
139 
Secondary Objectives:  
140 
• 
Evaluate the suitability of the novel CBCT images for radiation dose calculation. 
141 
• 
Obtain qualitative assessments of novel CBCT vs. standard cone-beam CT images (if 
142 
available) from the perspectives of radiation oncologists and radiation therapists for the 
143 
use of the CBCT images in image guidance and planning. 
144 
• 
Obtain qualitative assessments of breath hold CBCT vs. free breathing cone-beam CT 
145 
images (for patients receiving a breath hold and a free breathing CBCT) or of fast CBCT 
146 
acquisition vs. slow CBCT acquisition (for patients receiving a 6-second and a 60-
147 
second CBCT) for the use of the CBCT images in image guidance and planning. 
148 
 
149 
3. STUDY DESIGN 
150 
Single arm, non-randomized, prospective study.  
151 
 
152 
4. STUDY POPULATION 
153 
 
154 
4.1 Population (base)  
155 
The population being investigated are patients referred to Maastro for external beam 
156 
photon radiation treatment. 
157 
 
158 
4.2 Inclusion criteria 
159 
In order to be eligible to participate in this study, a subject must meet all of the following 
160 
criteria: 
161 
- 
The patient will be treated with external beam photon radiotherapy at Maastro for head-
162 
and-neck cancer, stage I lung cancer, stage II-IV lung cancer, left breast cancer, or 
163 
tumours in the abdominal or pelvic region. 
164 
- 
Age ≥ 18 years 
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- 
Ability to understand the requirements of the study and to give written informed consent, 
166 
as determined by the treating physician 
167 
- 
Provision of written informed consent 
168 
 
169 
4.3 Exclusion criteria 
170 
A potential subject who meets any of the following criteria will be excluded from 
171 
participation in this study: 
172 
- 
Patient is pregnant 
173 
 
174 
4.4 Sample size calculation 
175 
This study is being performed to generate initial quality and suitability assessments for a 
176 
novel cone beam CT imaging system. The study design does not involve any intervention 
177 
in the subject’s cancer care. 
178 
 
179 
Endpoints are based on the comparison of image quality produced by the novel cone-beam 
180 
CT imaging system to that of standard cone-beam CT imaging and to conventional CT 
181 
images used for radiotherapy planning purposes. Image quality is determined from 
182 
Contrast-to-Noise Ratio (CNR) for a Region of Interest (ROI) and a Reference (REF). The 
183 
specific ROI and REF depend on the tumour site that is scanned (see Chapter 10.1). 
184 
Therefore, the expected mean difference and variation for CNR are unclear up front and 
185 
no single assumption for a minimum difference and standard error can be selected. The 
186 
sample size calculation will be based on effect size of the CNR for a paired samples T-
187 
Test. With this method, no assumptions have to be made on the exact difference and 
188 
variation. 40 subjects will be enrolled with a minimum of 5 patients per each of the six target 
189 
anatomical locations (head-and-neck, stage I lung cancer, stage II-IV lung cancer, left 
190 
breast, pelvic and abdomen), which will provide sufficient data for initial assessments to be 
191 
performed in each anatomical location. A sample of 40 patients is sufficient to  determine 
192 
differences between means for related samples with an effect size of 0.45. This is between 
193 
a small and medium effect size [Cohen 1988]. In order to attain sufficient variability in 
194 
patient shape, size and distribution of anatomical structures, a minimum of 5 patients per 
195 
each of the six target areas (head-and-neck, stage I lung cancer, stage II-IV lung cancer, 
196 
left breast, pelvic and abdomen) will be included in the study. 
197 
 
198 
5. TREATMENT OF SUBJECTS 
199 
Not applicable as no treatment of patients will be delivered on the new Halcyon 4.0 system. 
200 
Patients will receive regular treatment in Maastro using the standard clinical equipment and 
201 
procedures. 
202 
 
203 
5.1 Investigational product/treatment 
204 
An investigational product is used (see Chapter 6), no treatments are performed using the 
205 
investigational product. 
 
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6. INVESTIGATIONAL PRODUCT  
207 
 
208 
6.1 Name and description of investigational product(s) 
209 
Halcyon 4.0 
210 
 
211 
6.2 Summary of findings from non-clinical studies 
212 
No pre-clinical (animal) testing of the novel CBCT imaging system was performed because 
213 
it is standard practice to verify dose and image quality using head and body phantoms. 
214 
Information about the pre-clinical testing for safety and conformity is presented in Section 
215 
6 (Product verification and validation) of the Investigational Medicinal Product Dossier 
216 
(IMDD) checklist, which is attached to this clinical trial protocol. 
217 
 
218 
6.3 Summary of findings from clinical studies 
219 
There are no results or findings from clinical studies currently available. 
220 
 
221 
6.4 Summary of known and potential risks and benefits 
222 
Information about the benefit-risk analysis and the risk management for the novel CBCT 
223 
imaging system is provided in Section 5 (Benefit-risk analysis and risk management) of the 
224 
Investigational Medicinal Product Dossier (IMDD) checklist, which is attached to this clinical 
225 
trial protocol. 
226 
 
227 
6.5 Description and justification of route of administration and dosage 
228 
Not Applicable. 
229 
 
230 
6.6 Dosages, dosage modifications and method of administration 
231 
Not applicable. 
232 
 
233 
6.7 Preparation and labelling of Investigational Medicinal Product 
234 
Not Applicable. 
235 
 
236 
6.8 Drug accountability 
237 
Not applicable. 
238 
 
239 
7. NON-INVESTIGATIONAL PRODUCT 
240 
Not applicable.  
241 
 
242 
8. METHODS 
243 
 
244 
8.1 Study parameters/endpoints 
245 
 
246 
8.1.1 Main study parameter/endpoint 
247 
Primary objective: Describe the differences in  image quality produced by the novel 
248 
cone-beam CT imaging system to the quality of standard cone-beam CT imaging and 
249 
to that of conventional CT images used for radiotherapy planning purposes. For this 
250 

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objective, the image contrast-to-noise ratio (CNR) will be evaluated. CNR is frequently 
251 
used to measure image quality.  
252 
 
253 
8.1.2 Secondary study parameters/endpoints 
254 
Secondary objective: Evaluate the suitability of the novel CBCT images for radiation 
255 
dose calculation. 
256 
For this objective, targets and organs at risk will be delineated on the novel CBCT 
257 
images acquired for each subject. The treatment plan created for the patient on the 
258 
planning CT scan will be registered to the novel cone-beam CT dataset, the dose will 
259 
be recalculated on the standard CBCT (if available) as well as the novel cone-beam 
260 
CT. The delineations of target and OARs will either be copied, deformed or manually 
261 
delineated on the CBCT images, the radiotherapy dose metrics for specific structures 
262 
relevant for the anatomical site that is imaged will be compared to dose metrics from 
263 
the original treatment plan. 
264 
 
265 
Secondary objective: Qualitative assessment of novel CBCT vs. standard cone-beam 
266 
CT imaging system by radiation oncologists and therapists. 
267 
Qualitative assessment of the novel CBCT images will be obtained by presenting 
268 
individual novel CBCT images as well as head-to-head comparisons of novel and 
269 
standard CBCT images from the same patient. At least 2 radiation oncologists and 2 
270 
radiation therapists will be asked to rank the suitability of the images for image guided 
271 
radiotherapy and for treatment planning on a 5-point Likert scale, with specific 
272 
assessments for each of the anatomical locations included in the study: 
273 
- 
Head and neck: contrast between tumour and organs at risk; sufficiency of 
274 
imaging volume, reduction in metal artifacts (where applicable)  
275 
- 
Lung cancer (stage I): Identification and delineation of the tumour 
276 
- 
Lung cancer (stage II-IV): Identification of structures of interest in the 
277 
mediastinal region (organs-at-risk, primary tumour and possible involved lymph 
278 
nodes). 
279 
- 
Left breast cancer: Identification and delineation of structures of interest; 
280 
sufficiency of imaging volume; reduction in metal artifacts (where applicable). 
281 
- 
Abdominal cancers: Identification and delineation of structures of interest; 
282 
reduction in air/tissue interface artifacts. 
283 
- 
Pelvic cancers: Identification and delineation of structures of interest; reduction 
284 
in air/tissue interface artifacts; reduction in metal artifacts (where applicable). 
285 
Secondary objective: Qualitative assessment will be performed for the patient 
286 
categories receiving 2 different novel CBCT imaging modes. Stage II-IV lung cancer 
287 
patients stage (II-IV) receive a 60 seconds free breathing CBCT acquisition and a 6 
288 
seconds breath hold CBCT acquisition. Breast, stage I lung cancer stage I and 
289 
abdominal cancer patients receive a 6 seconds breath hold and a 6 seconds free-
290 
breathing CBCT acquisition. A head-to-head comparison of image quality between 
291 
the 2 modes of novel CBCT image acquisition will also be performed. At least 2 
292 
radiation oncologists and 2 radiation therapists will be asked to rank the suitability of 
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the images for RT image guidance and for treatment planning on a 5-point Likert 
294 
scale, with specific assessments for each of the anatomical locations included in the 
295 
study (as defined in previous secondary endpoint). 
296 
 
297 
In all analyses where a novel CBCT is compared to a standard CBCT, the standard 
298 
CBCT will be taken from the subject’s radiation treatment fraction that was delivered 
299 
on the same day as the novel CBCT image acquisition. Therefore, the only additional 
300 
imaging is the novel CBCT. 
301 
 
302 
8.1.3 Other study parameters (if applicable) 
303 
 
Not applicable 
304 
 
305 
8.2 Randomisation, blinding and treatment allocation 
306 
 
No randomisation will be performed. 
307 
 
308 
8.3 Study procedures 
309 
Patients will be recruited from the standard radiotherapy population. Patients will be asked 
310 
to undergo an additional imaging session on the novel cone-beam CT imaging system 
311 
during which 1 or 2 additional CBCT images will be acquired. The additional imaging 
312 
session will be performed on one of the subject’s standard treatment days to limit additional 
313 
travel and burden on the patients. 
314 
 
315 
The exact technical details of the additional imaging session depend on the anatomical 
316 
region to be investigated, as described below. 
317 
 
318 
For head-and-neck patients: one additional extended cone-beam CT scan will be 
319 
performed. The extended CBCT consists of (typically 2) sequential cone-beam CT scans 
320 
that are automatically stitched together to create a full field-of-view of the treated region. 
321 
 
322 
For stage I lung cancer patients: two additional cone-beam CT scans will be acquired. The 
323 
first cone-beam CT scan will be performed under conditions of free-breathing. An additional 
324 
cone-beam CT scan will be acquired with the subject performing a breath hold. 
325 
 
326 
For stage II-IV lung cancer patients: two additional cone-beam CT scans will be acquired. 
327 
Both cone-beam CT scans will be performed under conditions of free-breathing. The first 
328 
cone-beam CT will be a fast (6 second) cone-beam CT. The second CBCT will be a slow 
329 
scan (approximately 60 seconds in duration) that will be used to evaluate novel motion 
330 
compensation algorithms. 
331 
 
332 
For left breast cancer patients: one additional breath hold cone-beam CT scan will be 
333 
acquired. 
334 
 
335 

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For pelvic cancer patients: one additional cone-beam CT scan will be acquired under 
336 
conditions of free breathing. 
337 
 
338 
For abdominal cancer patients: two additional cone-beam CT scans will be acquired. The 
339 
first cone-beam CT scan will be performed under conditions of free-breathing. An additional 
340 
cone-beam CT scan will be acquired with the subject performing a breath hold. 
341 
 
342 
All cone-beam CT scans will be acquired using the vendor-supplied default imaging mode 
343 
for the anatomical region being imaged. 
344 
 
345 
8.4 Withdrawal of individual subjects 
346 
Subjects can withdraw from the study at any time for any reason if they wish to do so. The 
347 
decision to withdraw from the study will not result in any consequences for the subject. The 
348 
investigator can decide to withdraw a subject from the study if the investigator decides that 
349 
continuation in the study may be harmful to the subject. Data collected until the time of 
350 
withdrawal will be used for analysis, unless the patient requests that the data is destroyed. 
351 
 
352 
8.4.1 
Specific criteria for withdrawal (if applicable) 
353 
Not applicable 
354 
 
355 
8.5 Replacement of individual subjects after withdrawal 
356 
Subjects who withdraw before their novel CBCT imaging session has occurred will be 
357 
replaced by new subjects as long as the inclusion numbers are not exceeded. 
358 
 
359 
8.6 Follow-up of subjects withdrawn from treatment 
360 
No follow-up is foreseen after withdrawal.  
361 
 
362 
8.7 Premature termination of the study 
363 
Premature termination of the study will occur if: 
364 
- 
The approval of the competent medical ethics review committee that assessed the 
365 
research is irrevocably withdrawn; 
366 
- 
It appears that the continuation of the research cannot serve a scientific purpose, and 
367 
this is confirmed by the medical ethics review committee that had given a positive 
368 
assessment of the research; 
369 
- 
The principal investigator is no longer able to perform the duties of the principal 
370 
investigator, and no substitute can be found by mutual consent. 
371 
- 
The Sponsor decides to end the study early. 
372 
- 
It can be reasonably concluded that the study must be terminated in the interests of the 
373 
health of the study subjects. 
374 
- 
The Sponsor and/or the Institution become or are declared insolvent or a petition in 
375 
bankruptcy has been filed against one of them or if one of them is dissolved 
376 
- 
Circumstances beyond a party’s control occur that render continuation of the study 
377 
unreasonable. 
378 

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- 
One of the parties fails to comply with the obligations arising from the CTA and, if 
379 
capable of remedy, is not remedied within 30 days after receipt of written notice from 
380 
the other party specifying the non-compliance and requiring its remedy, unless failure 
381 
to comply is not in reasonable proportion to the premature termination of the study. 
382 
 
383 
9. SAFETY REPORTING 
384 
 
385 
9.1 Temporary halt for reasons of subject safety 
386 
In accordance with section 10, subsection 4, of the WMO, the sponsor will suspend the 
387 
study if there is sufficient grounds to believe that continuation of the study will jeopardise 
388 
subject health or safety. The sponsor will notify the accredited METC without undue delay 
389 
of a temporary halt, including the reason for such an action. The study will be suspended 
390 
pending a further positive decision by the accredited METC. The investigator will ensure 
391 
that all subjects are kept informed.  
392 
 
393 
9.2 AEs, SAEs and SUSARs 
394 
 
395 
9.2.1 
Adverse events (AEs) 
396 
An adverse event, per ISO 14155:2020, is any untoward medical occurrence, 
397 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
398 
findings) in subjects, users or other persons, whether or not related to the 
399 
investigational medical device and whether anticipated or unanticipated. 
400 
 
401 
All adverse events that are reported spontaneously by the subject or observed by the 
402 
investigator or his staff, and that the investigator judges to be possibly, probably or 
403 
definitely related to the acquisition of the novel CBCT images will be recorded in the 
404 
study database. 
405 
 
406 
9.2.2 
Serious adverse events (SAEs) 
407 
A serious adverse event, per the CCMO, is any untoward medical occurrence or effect 
408 
that results in:  
409 
a) death; 
410 
b) serious deterioration in the health of the subject, users, or other persons as 
411 
defined by one or more of the following: 
412 
1) a life-threatening illness or injury (at the time of the event), or  
413 
2) a permanent impairment of a body structure or a body function including 
414 
chronic diseases, or  
415 
3) in-patient or prolonged hospitalization, or  
416 
4) medical or surgical intervention to prevent life-threatening illness or injury, 
417 
or permanent impairment to a body structure or a body function,  
418 
c) foetal distress, foetal death, a congenital abnormality, or birth defect including 
419 
physical or mental impairment. 
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d) any other important medical event that did not result in any of the outcomes listed 
421 
above due to medical or surgical intervention but could have been based upon 
422 
appropriate judgement by the investigator. 
423 
 
424 
Items a), b), and c) are aligned with the ISO 14155:2020 definition of a Serious 
425 
Adverse Event. 
426 
 
427 
Note that planned hospitalization for a pre-existing condition, or a procedure required 
428 
by this protocol without serious deterioration in health, is not considered a serious 
429 
adverse event. 
430 
 
431 
Study staff are required to notify the Principal Investigator of any serious adverse 
432 
event (SAE) experienced by a subject while that subject is enrolled in the study.    
433 
SAEs that the investigator judges as possibly, probably or definitely related to the 
434 
acquisition of a novel CBCT image must be reported to the study sponsor within 24 
435 
hours of becoming aware of the event.   
436 
 
437 
Sponsor contact for AE reporting: 
438 
Sean Davidson  
439 
Phone: +1 (437) 991-8294 
440 
Email: sean.davidson@varian.com 
441 
 
442 
The local principal investigator or an authorized delegate will report the SAE to the 
443 
sponsor within 24 hours delay after obtaining knowledge of the event. The local 
444 
principal investigator or an authorized delegate will report the SAEs through the web 
445 
portal ToetsingOnline to the accredited METC that approved the protocol. An initial 
446 
notification of SAEs that result in death or are life threatening will be made within 7 
447 
days of first learning about the SAE, with a complete preliminary report submitted 
448 
within at most an additional 8 days. All other SAEs will be reported within a period of 
449 
at most 15 days after the local investigator has first knowledge of the serious adverse 
450 
events. 
451 
 
452 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
453 
Not applicable 
454 
 
455 
9.3 Annual safety report 
456 
The sponsor will submit, once a year throughout the clinical trial, or as part of the final report 
457 
if the trial takes less than a year to complete, a safety report to the accredited METC. 
458 
 
459 
9.4 Follow-up of adverse events 
460 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
461 
Depending on the event, follow up may require additional tests or medical procedures as 
462 
indicated, and/or referral to the general physician or a medical specialist. Recording of AEs 
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is required during the period that a subject participates in the study. A subject’s participation 
464 
ends with the additional novel CBCT acquisitions.  
465 
 
466 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
467 
A DSMB or safety committee is not deemed applicable for this study. 
468 
 
469 
10. STATISTICAL ANALYSIS 
470 
 
471 
Analysis will include all patients that provided informed consent and completed the novel cone 
472 
beam CT imaging. In general, analyses will depend upon the type of data. Categorical data 
473 
will be described using proportions and 95% confidence interval and differences will be tested 
474 
using Chi-square analyses. Means, standard deviations and 95% confidence interval will be 
475 
calculated for continuous parameters which are normally distributed and differences will be 
476 
analysed using T-tests or analysis of variance. In case variables violate the normality 
477 
distribution, medians, interquartile range, minimum and maximum will be reported and the 
478 
appropriate non-parametric alternative for T-tests and analysis of variance will be used. 
479 
 
480 
10.1 Primary study parameter(s) 
481 
Primary objective: Describe the differences in image quality produced by the novel cone-
482 
beam CT imaging system to the quality of standard cone-beam CT imaging and to that of 
483 
conventional CT images used for radiotherapy planning purposes. To quantify image 
484 
contrast-to-noise ratio (CNR) every image acquired for each subject will be analysed. 
485 
Contrast-to-noise ratio (CNR) will be quantified using the following equation: 
486 
 
487 
 
CNR = (|<HUROI> - <HUREF>|) / (SDROI2+ SDREF2)0.5  
488 
 
489 
where <HUROI> and <HUREF> are the mean Hounsfield Units (HU) in a region of interest 
490 
and referenced (background) region, respectively, with SDROI and SDREF the corresponding 
491 
standard deviations of the HU values in those regions.  
492 
The ROI and REF are defined for every tumour site individually. For the head-and-neck 
493 
cohort this will be the tumour region (ROI) and a proximal muscle tissue for reference 
494 
(REF). For lung cancer (both stage I and II-IV), the gross tumor volume will be defined as 
495 
ROI, and a proximal muscle or fat tissue will serve as the reference (REF). For the left-
496 
sided breast cancer, the breast tissue is the ROI, with a proximal muscle or fat tissue as 
497 
the reference. For abdominal and pelvic case, the tumour volume is the ROI, with a 
498 
proximal muscle or fat tissue  
499 
Difference in CNR will be tested using a paired samples T-Test for which the hypothesis is 
500 
that there is a difference in CNR between the novel  CBCT imaging system and standard 
501 
cone-beam CT/conventional planning CT imaging. A p-value lower than 0.05 (Bonferroni 
502 
corrected p-value lower than 0.025) will be assumed to be statistically significant. 
503 
 
504 
10.2 Secondary study parameters  
505 
Secondary objective: Evaluate the suitability of the novel CBCT images for radiation dose 
506 
calculation. For this objective, targets and organs at risk will be delineated or propagated 
507 

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from the planning CT scan on the standard CBCT and novel CBCT images acquired for 
508 
each subject. The treatment plan created for the patient on the planning CT scan will be 
509 
registered to both the CBCT acquired during the standard treatment of the patient (if 
510 
available) and the novel cone-beam CT dataset. The dose will be recalculated on the 
511 
standard CBCT and the novel cone-beam CT and the radiotherapy dose metrics for specific 
512 
structures relevant for the imaged tumour location will be compared to dose metrics from 
513 
the original treatment plan. The standard CBCT will be taken from the patients’ radiation 
514 
treatment fraction delivered on the same day (if available) as the novel CBCT image 
515 
acquisition. Dose Volume Histogram (DVH) parameters will be extracted using the 
516 
commercially available treatment planning system (Varian Eclipse). 
517 
 
518 
Secondary objective: Qualitative assessment of novel CBCT vs. standard cone-beam CT 
519 
imaging system from radiation oncologists and therapists. Qualitative assessment of the 
520 
novel CBCT images will be obtained by presenting individual novel CBCT images as well 
521 
as head-to-head comparisons of novel and standard CBCT images from the same patient 
522 
(if available). At least 2 radiation oncologists and 2 radiation therapists will be asked to rank 
523 
the suitability of the images for RT image guidance and for treatment planning on a 5-point 
524 
Likert scale, with specific assessments for each of the anatomical locations included in the 
525 
study. 
526 
 
527 
Besides a rating of the image quality in terms of overall quality impression, specific 
528 
questions will be tailored for the different anatomical areas: 
529 
- 
Head and neck: contrast between tumour and organs at risk; sufficiency of imaging 
530 
volume; reduction of artifacts (e.g., due to dental fillings), where applicable. 
531 
- 
Lung cancer (stage I): Identification and delineation of the tumour 
532 
- 
Lung cancer (stage II-IV): Identification of structures of interest in the mediastinal region 
533 
(organs-at-risk, primary tumour and possible involved lymph nodes).  
534 
- 
Left breast cancer: Identification and delineation of structures of interest; sufficiency of 
535 
imaging volume; reduction in metal artifacts (where applicable). 
536 
- 
Abdominal cancers: Identification and delineation of structures of interest; reduction in 
537 
air/tissue interface artifacts. 
538 
- 
Pelvic cancers: Identification and delineation of structures of interest; reduction in 
539 
air/tissue interface artifacts; reduction in metal artifacts (where applicable). 
540 
 
541 
Secondary objective: Qualitative assessment will be performed for the patient categories 
542 
receiving 2 different novel CBCT imaging modes. Stage II-IV lung cancer patients stage 
543 
receive a 60 seconds free breathing and a 6 seconds breath hold CBCT acquisition. Breast, 
544 
stage I lung cancer and abdominal cancer patients receive a 6 seconds breath hold and 6 
545 
seconds free-breathing CBCT acquisition. A head-to-head comparison of image quality 
546 
between the 2 modes of novel CBCT image acquisition will also be performed. At least 2 
547 
radiation oncologists and 2 radiation therapists will be asked to rank the suitability of the 
548 
images for RT image guidance and for treatment planning on a 5-point Likert scale, with 
549 
specific assessments for each of the anatomical locations included in the study (as defined 
550 

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in previous secondary endpoint).No statistical tests are planned for these secondary 
551 
endpoints. Comparisons will be based on descriptive statistics and calculation of 95% 
552 
confidence intervals.  
553 
 
554 
10.3 Other study parameters 
555 
Not applicable. 
556 
 
557 
10.4 Interim analysis (if applicable) 
558 
Not applicable. 
559 
 
560 
11. ETHICAL CONSIDERATIONS 
561 
 
562 
11.1 Regulation statement 
563 
The study will be conducted according to the principles of the Declaration of Helsinki 
564 
(version date 19th October 2013), in accordance with the Medical Research Involving 
565 
Human Subjects Act (WMO) and in accordance with the Medical Device Regulation (EU) 
566 
2017/745 (MDR, article 82).  
567 
 
568 
11.2 Recruitment and consent 
569 
Potential participants will be identified by the Trial Physician Assistant (TPA), a process 
570 
that is embedded in the standard clinical patient workflow at Maastro. When a patient is 
571 
identified as a potential participant and meets all inclusion and exclusion criteria, the 
572 
treating physician will inform the patient about the study and will provide the patient with 
573 
the written patient information and informed consent that has been prepared and approved 
574 
for the study. The treating physician will give the patient a brief explanation of the study ask 
575 
the patient for permission to contact them about the study. 
576 
 
577 
Informed Consent procedure will be conducted conforming Article 63 of the MDR. If the 
578 
patient agrees to be contacted about the study, the TPA will provide the patient with 
579 
additional information about the clinical trial and will answer any questions the patient may 
580 
have. If the patient will not visit Maastro before the start of the study, the TPA will provide 
581 
the patient with all the information and will answer questions the patient may have by 
582 
phone. If, after reading the written patient information and informed consent, the patient 
583 
has additional questions, the patient can contact the TPA who informed the patient about 
584 
the study. The patient can also contact the independent physician for this study with their 
585 
questions. The contact details for all these persons are included in the informed consent 
586 
document that is provided to the patient.  
587 
 
588 
The recruitment will take place at Maastro. The patient will have at least 3 days of time to 
589 
consider participation in the trial, however a period much longer than 3 days will interfere 
590 
with normal clinical workflows and risk delaying urgently needed treatment. Therefore, the 
591 
subject will be contacted after 3 days by the TPA. The TPA will ensure that the patient 
592 
understands the content of the study, that all the patient’s questions are answered, and the 
593 
patient is willing to participate in the study. The TPA will verify whether the patient 
594 

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understands what participation in the trial entails by asking them to repeat in their own 
595 
words what the participation means. If the patient decides to participate in the trial, they will 
596 
give verbal consent to plan the additional scan. Prior to this scan, an appointment will be 
597 
planned for the patient and TPA to discuss any questions of the patients regarding the trial 
598 
and to sign the Informed Consent form. The participant must personally sign and date the 
599 
latest approved version of the Informed Consent form before any trial specific procedures 
600 
are performed. 
601 
 
602 
The written and verbal versions of the Participant Information and Informed Consent that 
603 
are presented to the participants will detail no less than: the exact nature of the trial; what 
604 
participation in the trial will involve for the participant; the implications and constraints of 
605 
the protocol and any risks involved in taking part. It will be clearly stated that the participant 
606 
is free to withdraw from the trial at any time for any reason without prejudice to future care, 
607 
and with no obligation to give the reason for withdrawal. 
608 
 
609 
Written Informed Consent will then be obtained by means of a dated participant signature 
610 
and a dated signature of the person who presented and obtained the Informed Consent. 
611 
The TPA will, together with the clinical trial coordinator, ensure that the informed consent 
612 
is correctly and fully signed and dated by the participant and included in the study 
613 
documentation at the research department of Maastro before any study-related procedures 
614 
take place. The person who obtains the consent must be suitably qualified and experienced 
615 
and have been authorized to do so by the Principal Investigator. The participant will also 
616 
receive an original of the signed informed consent form. The signed form will be retained 
617 
at the trial site.  
618 
 
619 
11.3 Objection by minors or incapacitated subjects (if applicable) 
620 
Not applicable. 
621 
 
622 
11.4 Benefits and risks assessment, group relatedness 
623 
Additional imaging is performed on the novel cone-beam CT imaging device using x-rays. 
624 
There is no direct benefit for the individual patients. Additional radiation exposure is only a 
625 
small fraction (<0.1%) of the radiation received during their standard radiotherapy 
626 
treatment. Collected data will not be used for clinical decision making. If the novel CBCT 
627 
images provide new information that may lead to improved treatment, the findings will be 
628 
communicated to the treating physician but need verification using standard imaging 
629 
procedures. 
630 
 
631 
11.5 Compensation for injury 
632 
The sponsor has a liability insurance which is in accordance with article 7 of the WMO. The 
633 
sponsor (also) has a clinical trial insurance which is in accordance with the legal 
634 
requirements in the Netherlands (Article 7 WMO). This insurance provides coverage for 
635 
damage to research subjects through injury or death caused by participation in the study. 
636 
The insurance applies to the damage that becomes apparent during the study or within 4 
637 
years after the end of the study.  
638 

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639 
11.6 Incentives (if applicable) 
640 
Not applicable. 
641 
 
642 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
643 
Data processing Varian-Maastro is described within the CTA; various precautions 
644 
regarding the protection of patient privacy are included in; only deidentified 
645 
(pseudonomyzed) information will be shared with Varian and legal arrangements are in 
646 
place using Standard Contractual Clauses for GDPR describing the details of the data 
647 
processing, transfer and storage of data using encryption methods, rules and roles of 
648 
MAASTRO and Varian personnel handling the data including user authentication and 
649 
training, logging and auditing of access. 
650 
 
651 
12.1 Handling and storage of data and documents 
652 
A study ID will be attributed to each patient registered in the trial consisting of a sequential 
653 
inclusion number (i.e. H4GN-MAAS-###). This code will identify the patient and must be 
654 
included on all case report forms. All data in the study database will be linked to a study 
655 
ID. Information that could directly identify a patient will not be entered in the database. The 
656 
study ID will be attributed by Clinical Trial Office (CTO) Maastro. The link between the 
657 
participant study IDs and their name, unique patient identifier, or other identifying 
658 
information will be accessible only to delegated Maastro clinical site personnel and will be 
659 
stored in a secure location at Maastro with limited access. Any paper documents (e.g., 
660 
worksheets) used in the collection of study data will also be securely stored at the site. 
661 
Study data will be stored for 15 years on a protected server at Maastro and Varian. The 
662 
IGJ (Inspectie Gezondheidszorg en Jeugd) and monitors have permission to check all data 
663 
documents, which will be obtained by CTO Maastro based on the codes for the included 
664 
patients. 
665 
 
666 
When the participant has signed the informed consent, the participant has given permission 
667 
that the collected data can be used to answer the research questions of this trial. The patient 
668 
will be asked to give additional permission for storing and using the data for 15 years for 
669 
future research projects that are related to CT imaging in cancer patients. 
670 
 
671 
Patient data will be used in accordance with the EU General Data Protection Regulation 
672 
and the Dutch Act on Implementation of the General Data Protection Regulation, for transfor 
673 
to Varian (USA based company) dedicated Standard Contractual Clauses ensuring 
674 
compliance with the EU 2016/679 regulations. Patient data and/or patient material can only 
675 
leave Maastro in coded form. 
676 
 
677 
Data collected for this study will consist of: 
678 
• 
Case report form data. 
679 
• 
Image data and radiation planning data (target and organ at risk contours, treatment 
680 
plans, calculated radiation dose distributions). 
681 
 
682 

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Case report form data 
683 
 
684 
Case report form data will include 
685 
• 
Basic demographic data (age at consent, sex) 
686 
• 
Information about the anatomical region and type of cancer being imaged 
687 
• 
Medical information relevant to the interpretation of medical images (e.g., the 
688 
presence of metal implants) 
689 
• 
Information about the acquisition of the images (date, time, imaging parameters) 
690 
that are collected for the study 
691 
• 
Information about any adverse events or device issues related to the study 
692 
 
693 
Case report form data will be stored in an electronic database provided by a third-party 
694 
vendor that is contracted by the Sponsor. The database vendor (Cloudbyz) has built their 
695 
system on top of the Salesforce platform. Study data will be stored in a secure Salesforce 
696 
data centre located in the United States. All data are encrypted in transit and any data value 
697 
that can potentially contain personal participant information will be encrypted at rest. 
698 
 
699 
Maastro site personnel who have been delegated responsibility for study data management 
700 
will be specified on the delegation log and trained by Varian on the study database prior to 
701 
receiving access to it. Maastro site personnel will access study data via a secure web portal 
702 
(Cloudbyz Investigator Portal). Individual login credentials (username and password) are 
703 
provided to each person who will be responsible for data entry. All access and all changes 
704 
to study data are recorded in an audit log. 
705 
 
706 
Sponsor personnel with responsibilities related to the study will have read-only access to 
707 
study data. Sponsor access is also linked to individual credentials and requires two-factor 
708 
authentication. All access to the study database (clinical site and sponsor) is role-based, 
709 
with permissions defined by a user’s role. 
710 
 
711 
Imaging and radiation planning data 
712 
The image files collected for the study analyses (novel CBCTs, standard CBCTs and 
713 
standard CTs used for radiation treatment planning) and the radiation treatment plan data 
714 
(dose, plan and structure set files) used for the dosimetry analyses, will be exported from 
715 
the system(s) where they are generated and de-identified. All identifying information will be 
716 
removed from the image file headers and the patient ID will be replaced with the study ID 
717 
so that the images can be linked to the correct case report form data and so that images 
718 
from the same participant can be compared. 
719 
 
720 
Maastro site personnel will upload the de-identified image and radiation treatment plan data 
721 
generated in this study to a Varian-hosted SharePoint that is physically located in the 
722 
United States. Access to the SharePoint will be provided via unique web links that are tied 
723 
to an individual’s institutional email address and verified through access codes sent to that 
724 
email address. Access to the SharePoint will be granted only to site personnel who have 
725 

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been delegated authorization by the Principal Investigator to manage study data and who 
726 
have received specific training on SharePoint uploads. Only sponsor personnel with 
727 
responsibilities related to the study will have access to the de-identified data once it has 
728 
been uploaded. Sponsor personnel will perform periodic checks of the data that have been 
729 
uploaded to ensure that it does not contain any identifying information. 
730 
 
731 
Varian personnel will upload de-identified image data from Varian’s SharePoint to MeVis 
732 
Online Academy to conduct the qualitative image assessments specified in this protocol. 
733 
The MeVis software will be configured to present individual CBCTs or head-to-head 
734 
comparisons of CBCTs from the same participant to observers (radiation oncologists and 
735 
radiation therapists). Observers access MeVis Online Academy using individual login 
736 
credentials and can only see imaging “cases” that are assigned to their account. Sponsor 
737 
personnel are responsible for managing observer accounts and assigning “cases”. The 
738 
observers will be able to rank the suitability of CBCTs for image guidance and dosimetry 
739 
planning by answering questions presented by the MeVis software. Only image data will be 
740 
presented to the observers via MeVis Online Academy (no header information is displayed). 
741 
Image data will be stored in the MeVis database (physically located in Germany) only long 
742 
enough for all observers to perform their assessments; image data will be deleted from the 
743 
MeVis database once the qualitative assessments specified in the protocol are complete. 
744 
 
745 
12.2 Monitoring and Quality Assurance  
746 
Regular reviews of case report form data will be performed by the Sponsor Clinical 
747 
Research Manager or Clinical Data Manager. Data queries will be issued directly from 
748 
within the study database by sponsor personnel. Maastro clinical site personnel can 
749 
respond to those queries via the Investigator Portal to the study database. 
750 
 
751 
Monitoring of the study data will be performed onsite on behalf of the sponsor by qualified 
752 
Maastro monitoring personnel from the Maastro Clinical Trial Office. Maastro monitors will 
753 
be individuals who are not directly involved in conducting the study. The focus of monitoring 
754 
activities will be to ensure the rights of the participants are respected, to ensure the study 
755 
is conducted according to Good Clinical Practice and according to this protocol, and to 
756 
ensure accurate data collection. Further details will be provided by a Monitoring Plan 
757 
drafted by the Sponsor. 
758 
 
759 
12.3 Amendments  
760 
Amendments are changes that are made to the research after a favourable opinion by the 
761 
accredited METC has been given. All amendments will be communicated to the METC that 
762 
provided the favourable opinion of the research. 
763 
 
764 
12.4 Annual progress report 
765 
The sponsor will submit a summary of the progress of the trial to the accredited METC once 
766 
a year. Information will be provided on the date of inclusion of the first subject, numbers of 
767 
subjects included and numbers of subjects that have completed the trial, serious adverse 
768 
events/serious adverse reactions, other problems, and amendments.  
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770 
12.5 Temporary halt and (prematurely) end of study report 
771 
The sponsor will notify the accredited METC within eight weeks of the end of the study, 
772 
which is defined as the last participant’s novel CBCT imaging session. The sponsor will 
773 
notify the METC immediately of a temporary halt of the study, including the reason of such 
774 
an action. In case the study is ended prematurely, the sponsor will notify the accredited 
775 
METC within 15 days, including the reasons for the premature termination. 
776 
 
777 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
778 
report with the results of the study, including any publications/abstracts of the study, to the 
779 
accredited METC. 
780 
 
781 
12.6 Public disclosure and publication policy 
782 
The results of the study, whatever they may be, will be presented at international scientific 
783 
conference(s) and published in peer-reviewed scientific journals by either the clinical site 
784 
or the sponsor. This will be done in accordance with the CCMO guidelines with regard to 
785 
publication of research results.  
786 
 
787 
Agreements made in the research contract (Chapter 11) with regard to the ‘publication 
788 
conditions’ prevail over the statement(s) made in the research protocol. However, Maastro 
789 
and Varian have agreed on a policy concerning publication. The publishing party will 
790 
provide the reviewing party with a proposed publication. The reviewing party will respond 
791 
within 30 days. When reviewing a proposed publication submitted by the clinical site, Varian 
792 
may comment on the scientific content of the publication, may make suggestions to improve 
793 
the clarity of the publication, may request the removal of Varian’s confidential information 
794 
and may request a postponement of publication to allow time to protect proprietary 
795 
information. 
796 
 
797 
13. STRUCTURED RISK ANALYSIS  
798 
 
799 
13.1 Potential issues of concern 
800 
A full risk analysis of the novel CBCT imaging system has been performed and information 
801 
about the residual risks can be found in Section 5 of the IMDD checklist. 
802 
 
803 
The additional risks to study participants related to their participation in the study include 
804 
the small amount of additional ionizing radiation received from the extra 1-2 novel CBCT 
805 
images acquired during this study. As mentioned previously in this document, the amount 
806 
of additional radiation is very small compared to the radiation doses these participants are 
807 
receiving for their cancer treatment. The additional dose received from acquisition of a 
808 
novel CBCT is equivalent to the dose received from a standard CBCT acquisition, which is 
809 
performed at least once every treatment fraction in standard care. The additional dose from 
810 
the novel CBCT is unlikely to result in additional harm to the participants. 
811 
 
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Participation in the trial also includes additional risk of a privacy breach created by the 
813 
collection of data for the study. This risk will be minimized by collecting only the minimum 
814 
amount of data required to conduct the analyses specified in this study, by linking study 
815 
data to study IDs and removing any information that could directly identify the subject, and 
816 
by restricting access to the study data to those individuals with defined responsibilities in 
817 
conducting the study. 
818 
 
819 
The mechanism of action of CBCT imaging is well understood and there are no adverse 
820 
effects expected from 1-2 additional CBCT images. A search of international medical 
821 
device databases shows no recalls or serious adverse events within the last four years that 
822 
are related to previous versions of the CBCT imaging system and radiation treatment 
823 
platform, indicating that the system has a strong safety record. The new imaging system 
824 
has been characterized as much as possible through the use of standardized phantoms. 
825 
The purpose of this study is to evaluate the suitability of the images in a clinical setting, 
826 
which requires acquiring images of human patients who are being treated with radiation 
827 
therapy. 
828 
 
829 
13.2 Synthesis 
830 
The results from this study have the potential to benefit future patients undergoing radiation 
831 
treatment for cancer or other malignant conditions. Participation in the study is not expected 
832 
to result in direct benefits to the participants. The higher image quality that is anticipated in 
833 
the novel CBCT imaging system may result in findings that may improve a participant’s 
834 
treatment but such findings must be confirmed by conventional imaging; no clinical 
835 
decisions will be made from the novel CBCTs acquired during this study. 
836 
 
837 
The residual risks from the novel imaging system and the risks from participation in the 
838 
study are low and have been reduced as low as reasonably achievable. On balance, the 
839 
benefits from the study outweigh the risks. 
 
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14. REFERENCES 
841 
 
842 
[Jaffray 2012] Jaffray D. Image-guided radiotherapy: from current concept to future 
843 
perspectives. Nat Rev Clin Oncol 2012 Dec;9(12):688-99. 
844 
 
845 
 [Glide-Hurst 2021] Glide-Hurst CK, Lee P, Yock AD, Olsen JR, Cao M, Siddiqui F, Parker W, 
846 
Doemer A, Rong Y, Kishan AU, Benedict SH, Li XA, Erickson BA, Sohn JW, Xiao Y, Wuthrick 
847 
E. Adaptive Radiation Therapy (ART) Strategies and Technical Considerations: A 
848 
State of the ART Review From NRG Oncology. Int J Radiat Oncol Biol Phys. 2021; Mar 
849 
15;109(4):1054-1075. 
850 
 
851 
[Giacometti 2020] Giacometti V, Hounsell AR, McGarry CK. A review of dose calculation 
852 
approaches with cone beam CT in photon and proton therapy, Phys Med 2020 Aug;76:243-
853 
276. 
854 
 
855 
[Cohen 1998] Cohen, Jacob. Statistical Power Analysis for the Behavioral Sciences. Lawrence 
856 
Erlbaum Associates. 1988. Hillsdale, New Jersey 
857