Masks Against Surface-Scanning for Radiation Therapy Immobilisation in Head and Neck Cancer (MASSC Study)
Phase: NA
Conditions: Head and Neck Neoplasm
Sponsor: Cancer Research Antwerp

 
1 
GZA vzw 
 
Clinical Protocol 
 
Masks Against Surface-Scanning for radiation therapy 
immobilisation in head and neck cancer (MASSC study) 
 
Study number: 
CTOR20051GZA 
Clinical Phase: 
0 
Protocol version and date: 
Version 1.0.1; August 2021 
EudraCT/BUN number: 
/ 
Sponsor: 
GasthuisZusters Antwerpen vzw 
Oosterveldlaan 22 
2610 Wilrijk 
 
 
 
This study will be conducted in compliance with the protocol, the current International Conference on 
Harmonization and the guidelines for Good Clinical Practices (ICH-GCP), the principles of the Declaration of 
Helsinki (version 2002) and any applicable regulatory requirements. 
 
Confidentiality Statement 
This document and its contents are the property of and confidential to GZA vzw. Any unauthorized copying or use of this 
document is prohibited. 
 
 
 
 
 

2 
SIGNATURE PAGE 
 
Protocol title: “Masks Against Surface-Scanning for radiotherapy immobilisation in head and neck cancer.” 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Sponsor approval: 
Signature: 
 
Date: 
 
Name: 
Willeke Dijkhoffz   
 
 
General Director of GZA Hospitals 
GZA Hospitals, Oosterveldlaan 22 
2610 Wilrijk (Antwerp) 
Phone: +32(0)34433990 
Fax: +32(0)34433129 
www.gza.be 
 
 
 
Study responsible physician:  
Signature: 
 
Date: 
 
 
Name:  Dr. Daan Nevens 
Iridium Netwerk 
Phone: +32(0)34433737 
Fax: +32(0)4433009 
E-mail: daan.nevens@gza.be  
 
 
 
 
 
 
 

3 
Investigator agreement 
Protocol title: “Masks Against Surface-Scanning for radiotherapy immobilisation in head and neck cancer.” 
 
I confirm that I have read this protocol, I understand it and I shall work according to this protocol and to the 
ethical principles stated in version of 2002 of the Declaration of Helsinki, the current International Conference 
on Harmonization (ICH) and the guidelines for good clinical practices (GCP) or the applicable laws and 
regulations of the country of the study site, for which I am responsible, whichever provides the greater 
protection of the individual. 
 
I am aware of my responsibilities as an Investigator/Representative under the good clinical practices, national 
regulations and trial protocol. I agree to appropriately direct and assist the staff under my control, who will be 
involved in this clinical trial. This is documented in a training log. 
 
 
Signature: 
 
Date: 
 
Name: 
 
 
 
 
 
 

4 
TABLE OF CONTENTS 
Signature page ............................................................................................................................................... 2 
Table of Contents ........................................................................................................................................... 4 
Abbreviations ................................................................................................................................................. 6 
Study synopsis ............................................................................................................................................... 7 
Administrative structure ................................................................................................................................ 9 
1. Introduction ............................................................................................................................................. 11 
1.1 Background & rationale .............................................................................................................................. 11 
1.2 Risks and benefits ....................................................................................................................................... 13 
2. Overall study design ................................................................................................................................. 14 
2.1 Study period ............................................................................................................................................... 14 
2.2 Study duration ............................................................................................................................................ 14 
2.3 Study termination ....................................................................................................................................... 15 
3. Study objectives and endpoints ................................................................................................................ 15 
3.1 Primary objective ........................................................................................................................................ 15 
3.2 Primary endpoint ........................................................................................................................................ 15 
3.3 Secondary objective ................................................................................................................................... 15 
3.4 Secondary endpoints .................................................................................................................................. 15 
4. Study population ...................................................................................................................................... 16 
4.1 Subject inclusion criteria ............................................................................................................................ 16 
4.2 Subject exclusion criteria ............................................................................................................................ 16 
4.3 Subject withdrawal criteria and procedures .............................................................................................. 16 
5. Treatment allocation ................................................................................................................................ 17 
5.1 Assignment of participant numbers ........................................................................................................... 17 
6. Treatments ............................................................................................................................................... 18 
6.1 Details of study treatment .......................................................................................................................... 18 
6.2 Prior and concomitant medications ........................................................................................................... 21 
7. Study assessment ..................................................................................................................................... 21 
7.1 Time and events schedule .......................................................................................................................... 21 
7.2 Study procedures ........................................................................................................................................ 21 
8. Safety monitoring and reporting ............................................................................................................... 22 
8.1 Adverse event definitions and classifications ............................................................................................. 22 
8.2 Reporting procedures ................................................................................................................................. 23 
9. Data management .................................................................................................................................... 25 
9.1 Data collection ............................................................................................................................................ 25 
10. Statistical considerations ........................................................................................................................ 25 
10.1 Justification of sample size ....................................................................................................................... 25 
10.2 Statistical plan .......................................................................................................................................... 25 
10.3 Protocol deviations ................................................................................................................................... 25 
10.4 Safety analyses ......................................................................................................................................... 25 
10.5 Interim analyses ....................................................................................................................................... 26 
11. Study management ................................................................................................................................ 26 
11.1 Ethics and consent .................................................................................................................................... 26 

5 
11.2 Insurance and indemnification ................................................................................................................. 26 
11.3 Informed consent ..................................................................................................................................... 26 
11.4 Data protection ........................................................................................................................................ 27 
11.5 Discontinuation of the study by the sponsor ........................................................................................... 27 
11.6 Data management and quality control ..................................................................................................... 27 
11.7 Use of information and publication .......................................................................................................... 28 
References ................................................................................................................................................... 29 
Appendices .................................................................................................................................................. 30 
 
 
 
 

6 
Abbreviations 
 
AE 
 
Adverse Event 
CBCT 
 
Cone Beam Computed Tomography 
CRF 
 
Case Report Form 
EC 
 
Ethics Committee 
ECOG  
Eastern Cooperative Oncology Group 
EOS 
 
End Of Study 
GCP 
 
Good Clinical Practice 
HNC 
 
Head and Neck Cancer 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonisation 
IEC 
 
Independent Ethics Committee  
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse Events 
PICO 
 
Patient Intervention Comparison Outcome 
RT 
 
Radiotherapy 
SAE 
 
Serious Adverse Event 
SS 
 
Surface Scanning 
 
 
 

7 
STUDY SYNOPSIS 
Protocol title: 
Masks Against Surface-Scanning for radiation therapy immobilisation 
in head and neck cancer. 
Alias: 
MASSC study 
Protocol number: 
CTOR20051GZA 
EudraCT/BUN number: 
 
Sponsor: 
GZA vzw 
Oosterveldlaan 22, 2610 Wilrijk, Belgium 
Principal Investigator: 
Dr. Daan Nevens 
Iridium Kankernetwerk 
Phone: +32(0)3443, Fax: +32(0)3443 
Daan.nevens@gza.be  
Investigator(s)/study 
center(s): 
GZA Sint-Augustinus 
Study objectives and 
endpoints: 
Primary objective 
To compare the accuracy and reproducibility of radiation therapy (RT) 
with open face masks and surface-scanning (SS), and with SS alone 
without masks to irradiation with a full thermoplastic mask, for 
patients with head and neck cancer. 
 
Primary endpoint 
Set-up and treatment accuracy, determined by in-vivo dosimetry using 
PerFRACTION, and by the evaluation of intrafractional motion by 
comparing a CBCT before and at the end of treatment in patients 
receiving RT with an open mask, without a mask and using a closed 
thermoplastic mask. 
Secondary objectives 
1) to demonstrate that irradiation with open face masks and SS or no 
face masks and SS for patients with head and neck cancer reduces 
the patients’ levels of distress when compared to irradiation with 
full thermoplastic masks. 
2) to demonstrate that irradiation with open face masks and SS or no 
face masks and SS is feasible for the treating RTT’s. 
 
Secondary endpoints 
1) Level of distress of patients, determined by using the subjective 
units of distress scale (scale of 0-100). 
2) Preferred delivery technique as evaluated by treating RTT’s 
involved in this study. 
Study design: 
Non randomised clinical interventional study 
Planned sample size: 
In total, 24 patients will be enrolled into this study. 

8 
Medical condition or 
disease under 
investigation: 
Adult HNC patients receiving radiation therapy as their primary 
treatment 
Participant selection 
criteria: 
Each potential subject must satisfy all of the following criteria to be 
enrolled in the study. 
- 
Patients ≥ 18 years old  
- 
Histologically confirmed head and neck cancer. 
- 
Patients treated with RT as primary treatment.  
- 
An Eastern Cooperative Oncology Group (ECOG) Performance 
Status grade of 0-1. 
- 
Each subject must sign an informed consent form (ICF) 
indicating that he understands the purpose of and procedures 
required for the study and is willing to participate in the study. 
- 
Patients must be willing to comply with treatment plan and 
other study procedures. 
Each potential subject must NOT have any of the following criteria to 
be enrolled in the study. 
- 
Patients with significantly altered mental status or with 
psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study. 
- 
Individual deprived of liberty or placed under guardianship. 
- 
Patients who cannot stay still during fraction because of a 
disorder (e.g. Parkinson’s disease) 
Treatment: 
The treatment of every patient will be divided into different phases: 
-patients will be irradiated with an open face mask and SS 
-patients will be irradiated with SS without a mask 
-patients will be irradiated with a full thermoplastic mask 
 
The delivery technique will change for every patient each 5 fractions. 
The first 8 patients included in the study will have the following 
schedule: full mask-open mask-no mask-full mask-… 
The 9th till 16th patient included in the study will have the following 
schedule: open mask-no mask-full mask-open mask-… 
The 17th till 24th patient included in the study will have the following 
schedule: no mask-full mask-open mask-no mask-… 
Duration of study: 
12 months 
Accuracy: 
- 
In-vivo dosimetry using PerFRACTION 
- 
Evaluation of intrafractional motion by comparing a CBCT 
before and at the end of treatment 
Statistical methods: 
A sample size of 24 patients is estimated to provide 95% power in 
order to rule out an mean displacement in excess of 2 mm, assuming a 
significance level of 0.05 (1-sided as testing for non-inferiority).  

9 
 
Mean displacements and standard deviations will be compared for the 
different delivery techniques for each patient. Using the method 
described by van Herck, population mean displacement (MD), 
systematic (R) and random (r) errors were estimated.  
CBCT registration results will be analysed in 3-dimensions for each 
patient; population MD, R and r will be calculated. Paired t- tests will 
be used to compare the parameters listed above, and timing data (CT 
and treatment session times).  
Patient comfort and acceptability questionnaires will be summarised 
as patient comfort scores ranging from 0 (most comfortable) to 100 
(least comfortable).  
RTT satisfaction questionnaires will be summarised as scores ranging 
from 0 (most satisfactory) to 100 (least satisfactory).   
Statistical analyses will be performed using SPSS Statistics.  
 
Trial registration: 
This study will be registered on www.clinicaltrials.gov 
 
Funding Source:  PENDING 
KOM OP TEGEN KANKER, PSYCHOSOCIALE COMMISSIE 
ADMINISTRATIVE STRUCTURE 
Study responsible physician 
Daan Nevens 
Radiotherapeut-oncoloog 
Iridium 
Kankernetwerk, 
gastprofessor 
Universiteit 
Antwerpen 
Phone: +32(0)34433737, Fax: +32(0)4433009 
daan.nevens@gza.be 
Investigator(s) 
Melanie Machiels 
Radiotherapeut-oncoloog Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009  
melanie.machiels@gza.be 
Hilde Verstraete 
Radiotherapeut-oncoloog Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009  
Hilde.verstraete@gza.be  
Yasmyne Geussens 
Radiotherapeut-oncoloog Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009  
Yasmyne.geussens@gza.be  
Nathalie Meireson 
Radiotherapeut-oncoloog Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009  

10 
Nathalie.meireson@gza.be  
 
Philip Poortmans 
Radiotherapeut-oncoloog Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009  
Philip.poortmans@gza.be  
 
Sofie Proost 
Medical student, University of Antwerp 
Maxim Van den Kieboom 
Medical student, University of Antwerp 
Jonathan Michielsen 
Medical student, University of Antwerp 
Ann Vermylen 
RTT, hoofdverpleegster 
Ann.vermylen@gza.be 
Wim Vingerhoed 
RTT 
Wim.vingerhoed@gza.be 
Dirk Verellen 
Physicist, Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009 
dirk.verellen@gza.be 
An Sprangers 
Physicist, Iridium Kankernetwerk 
Phone: +32(0)34433737, Fax: +32(0)4433009 
an.sprangers@gza.be 
Yawo Atsu Constantino Fiaga  
PhD student 
Michaël Claessens 
PhD student 
Michael.claessens@uantwerpen.be 
 
Data center 
CTO GZA 

11 
Sponsor 
GZA vzw, Oosterveldlaan 22, 2610 Wilrijk (Antwerp) 
Phone: +32(0)34433990, Fax: +32(0)34433129 
www.gza.be 
1. Introduction 
1.1 Background & rationale 
Head and neck cancer (HNC) is a broad term that encompasses a large number of tumour entities 
originating from different subsites, such as the nasal cavity, nasopharynx, oral cavity, oropharynx, 
larynx, hypopharynx and salivary glands.  
In Belgium, in the year 2016 (latest data Belgian Cancer Registry), more than 2500 patients were 
diagnosed with head and neck cancer. (1) In the United States, for the year 2014, there was an 
estimate of 55.070 new cases of HNC (2). Approximately 60% to 80% of HNC patients present with 
loco-regionally advanced disease at time of diagnosis. The main treatment options for loco-regionally 
advanced HNC are (chemo-) radiotherapy (RT) and surgery (often followed by RT).  During each RT 
course, patients are immobilised using a thermoplastic mask (Figure 1 a.) to limit the possibility to 
move during the treatment. Furthermore, this mask enables correct positioning before the start of 
each RT session.  
 
a.                                                                    
   b.                
Figure 1. Full thermoplastic mask (a.) and open thermoplastic mask (b.). 
 
The use of these masks results in the following disadvantages: 
▪ 
They can cause claustrophobia and anxiety. (3, 4, 6) 
▪ 
Intrafractional surface monitoring is not possible with closed masks. (3) 
▪ 
Full-face masks can be very uncomfortable and cause pain by pressure. (5, 6, 7) 
▪ 
The masks don’t adapt to weight loss or edema that can occur during radiotherapy. 
 
Lately, to reduce these side effects, there is an interest in using open face masks (Figure 1 b.) in 
combination with surface scanning (SS). SS is a system which tracks a patient’s position before and 
during RT, to aid in setup and treatment accuracy. Using 3D stereo camera units, the SS tracks the 
skin surface, and compares it to the ideal position. (4) The combination of an SS and an open face 
mask therefore enables us to monitor intrafractional movement. (8) This system can then 
automatically signal the treatment delivery system to pause radiation if the patient moves out of the 
desired position.  

12 
The use of SS together with open face masks for HNC has been studied. An overview of the relevant 
literature review can be found in Table 1. 
 
 
 
 
Article 
Number 
of 
participants 
Hypothesis 
Conclusion 
A prospective evaluation of 
open 
face masks for head and neck 
radiation therapy. 
Wiant D, Squire S, Liu H, 
Maurer J, Lane Hayes T, Sintay 
B. 
50 
To investigate if open 
mask radiotherapy can 
be implemented as the 
new standard for the 
treatment of HNC. 
Immobilization with an open 
mask works as well as with a 
closed mask and offers the 
possibility of real-time 
monitoring with surface 
scans. 
Migration from full-head mask 
to “open-face” mask for 
immobilization of patients with 
head and neck cancer. 
Li G, Lovelock DM, Mechalakos 
J, 
Rao S, Della-Biancia C, Amols H, 
et al. 
15 
To quantitatively 
characterize the 
immobilization 
performance of the 
open-face mask. 
Open-face masks offer 
advantages in patient comfort 
and can be used in the 
treatment of head and neck 
cancer. 
Minimal mask immobilization 
with optical surface guidance 
for head and neck radiotherapy. 
Zhao B, Maquilan G, Jiang S, 
Schwartz DL. 
20 
To investigate the 
feasibility and setup 
accuracy of minimal face 
and neck mask 
immobilization with 
optical surface guidance. 
Minimal mask immobilization 
offers a streamlined clinical 
workflow with surface 
guidance during set-up and 
treatment. On-board 
radiographic imaging remains 
the recommended standard. 
 
Table 1. Relevant literature concerning the use of open-face masks and OSMS 
Until now, 3 studies have investigated the use of open face masks in combination with SS. Although 
the results of these studies are promising, even open masks can be problematic for claustrophobic 
patients or patients with edema or weight loss during RT. Theoretically, it should be possible to 
combine a less-rigid immobilization with continuous patient motion monitoring to minimize patient 
discomfort, without losing precision of the treatment (9).  Therefore, we want to test the feasibility 
of irradiating head and neck cancer patients without a mask using SS and compare this technique 
with open face masks and full thermoplastic masks. The results of this study could possibly help us 
find a proper alternative for patients who have difficulties with full and open masks.  Until now, 
maskless irradiation has only been investigated in one study with whole brain irradiation (6), so more 
research is definitely necessary.  
In the future, the knowledge we gather with this study regarding SS and maskless irradiation in head 
and neck cancer patients, will help us to set up new studies eg. the introduction of precise 
stereotactic radiotherapy for head and neck cancer patients. 
 
 

13 
1.2 Risks and benefits 
- 
Possible risk: 
 
A longer treatment time in the open face mask or mask-less phase 
 
 
- 
Possible benefit: 
      
           -Possibly less claustrophobia in the open face mask or mask-less phase 
 
 
        
 
 

14 
2. Overall study design 
The study is designed to evaluate whether irradiating head and neck cancer patients without a mask 
or with open face masks using SS is comparable to irradiation with full thermoplastic masks in terms 
of set-up and treatment accuracy and average treatment time. 
In total, 24 patients will participate in the study. They are treated with radiotherapy for 35 fractions. 
The treatment of every patient will be divided into different phases: 
-patients will be irradiated with an open face mask and SS 
-patients will be irradiated without a mask but with SS 
-patients will be irradiated with a full thermoplastic mask 
 
The delivery technique will change for every patient each 5 fractions.  
• 
The first 8 patients included in the study will have the following schedule:  
full mask-open mask-no mask- full mask-open mask-no mask-full mask 
• 
The 9th till 16th patient included in the study will have the following schedule:  
open mask-no mask-full mask-open mask-no mask-full mask-open mask 
• 
The 17th till 24th patient included in the study will have the following schedule:  
no mask-full mask-open mask- no mask- full mask-open mask-no mask 
We chose the number of patients for each group based on the published literature and the power 
calculation (Table 1). 
2.1 Study period 
For each participant, the study starts once written consent is provided and is composed by 2 study 
phases.  
Screening phase 
Eligibility of patients will be determined according to the inclusion/exclusion criteria as detailed in 
section 8. Patients are asked complete the validated Dutch claustrophobia questionnaire before start 
of treatment (see Section 12 and appendix 1).  
Treatment phase 
Once enrolled, fully eligible patients will start the intended RT according to the standard of care. The 
RT dose prescription is left to the discretion of the treating radiation oncologist and is the current 
standard treatment. Patients are asked about their distress level by the treating physician on a 
weekly basis (see Section 12 and appendix 2). A score of 0-100 is given by using the Subjective Units 
of Distress Scale.  
The set-up and treatment accuracy will be determined by in-vivo dosimetry using PerFRACTION and 
by the evaluation of intrafractional motion by comparing a CBCT before and at the end of treatment. 
The average treatment time will be measured for all treatment fractions. 
2.2 Study duration 
The start of the study is defined as the first visit for the first participant providing informed consent. 
Similarly, the end of study (EOS) is defined as the last visit or scheduled procedure shown in the 

15 
schedule of assessments for the last participant. Primary study completion is defined as the final date 
on which data for the primary endpoint are expected to be collected. The study duration is expected 
to be around 12 months, subject to change on an ongoing basis.  
2.3 Study termination  
The sponsor reserves the right to terminate any portion of the study at any time. Possible reasons for 
termination include:  
- 
Safety reasons  
- 
New scientific knowledge becomes known that makes the objectives of the study no longer 
feasible/valid.  
- 
Unsatisfactory enrolment of participants.  
In terminating the study, the sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 
3. Study objectives and endpoints 
3.1 Primary objective 
We would like to investigate whether irradiation with open face masks and SS, and without masks 
and SS, for patients with head and neck cancer is at least as good as irradiation with a full 
thermoplastic mask in terms of set-up and treatment accuracy. 
3.2 Primary endpoint 
 
1) Set-up and treatment accuracy, determined by in-vivo dosimetry using PerFRACTION, and by the 
evaluation of intrafractional motion by comparing a CBCT before and at the end of treatment in 
patients receiving RT with an open mask, without a mask and using a closed thermoplastic mask. 
2) Average treatment time for the different deliveries (full mask, open mask, without a mask) 
3.3 Secondary objective 
Our secondary objective is: 
3) to demonstrate that irradiation with open face masks and SS or no face masks and SS for patients 
with head and neck cancer reduces the patients’ levels of distress when compared to irradiation 
with full thermoplastic masks. 
4) to demonstrate that irradiation with open face masks and SS or no face masks and SS is feasible 
for the treating RTT’s. 
3.4 Secondary endpoints 
3) Level of distress of patients, determined by using the subjective units of distress scale (scale of 0-
100). 
4) Preferred delivery technique as evaluated by treating RTT’s involved in this study. 
 

16 
Our hypothesis for this trial can be best described by the PICO (Patient Intervention Comparison 
Outcome): 
● Patient: patients who are in need of primary treatment with radiotherapy for a histologically 
confirmed HNC 
● Intervention: irradiation with SS and an open face mask; irradiation with SS but without a 
thermoplastic mask  
● Comparison: standard of care treatment, irradiation with a full thermoplastic mask 
● Outcome: accuracy of the irradiation (in-vivo dosimetry, intra-fractional motion during 
radiotherapy); duration of the irradiation in the different groups; results of claustrophobia 
questionnaires; results of RTT satisfaction questionnaires 
4. Study population 
4.1 Subject inclusion criteria 
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
• 
Patients ≥ 18 years old  
• 
Histologically confirmed head and neck cancer. 
• 
Patients treated with RT as primary treatment.  
• 
An Eastern Cooperative Oncology Group (ECOG) Performance Status grade of 0-1 as defined in 
Appendix 3. 
• 
Each subject must sign an informed consent form (ICF) indicating that he understands the 
purpose of and procedures required for the study and is willing to participate in the study. 
• 
Patients must be willing to comply with treatment plan and other study procedures. 
4.2 Subject exclusion criteria 
Each potential subject must NOT satisfy any of the following criteria to be enrolled in the study. 
● Patients with significantly altered mental status or with psychological, familial, sociological or 
geographical condition potentially hampering compliance with the study. 
● Patients who cannot stay still during fraction because of a disorder (e.g. Parkinson’s disease) 
4.3 Subject withdrawal criteria and procedures 
● The general condition of the patient is too bad to continue the RT 
● The patient can withdraw from the study at any moment for any reason  
The patients who withdraw will not be replaced.  
Specific aftercare for this therapeutic strategy is no different from the current standard of care. 

17 
5. Treatment allocation 
Patients will be assigned to a study group based on their date of enrolment.  
The treatment of every patient will be divided into different phases: 
-patients will be irradiated with an open face mask and SS 
-patients will be irradiated without a mask but with SS 
-patients will be irradiated with a full thermoplastic mask 
 
The delivery technique will change for every patient each 5 fractions.  
• 
The first 8 patients included in the study will have the following schedule:  
full mask-open mask-no mask- full mask-open mask-no mask-full mask 
• 
The 9th till 16th patient included in the study will have the following schedule:  
open mask-no mask-full mask-open mask-no mask-full mask-open mask 
• 
The 17th till 24th patient included in the study will have the following schedule:  
no mask-full mask-open mask- no mask- full mask-open mask-no mask 
 
5.1 Assignment of participant numbers 
To manage study enrolment, each participant will be allocated a -character participant number 
comprised of a -digit study site number (01, 02, etc.) and a -digit number incremental per center 
representing the sequential order in which they are screened (01-001, 01-002, etc.). The -digit 
participant number will be used to identify the participant throughout the study. 

 
 
18 
Positioning of 
the patient 
using mask
CBCT pre
Radiotherapy
CBCT post (at 
first 3 
sessions of 
every 
thermoplastic 
mask phase)
6. Treatments 
6.1 Details of study treatment and different phases 
 
 
 
 

19 
InstallatIon 
using SS
Positioning of 
the open 
mask
CBCTpre
Radiotherapy
CBCT post
(at first 3 
sessions of 
every open 
mask phase)
 
 
 
 
 
 

20 
InstallatIon 
using SS
CBCTpre
Radiotherapy
CBCT post (at 
first 3 
sessions of 
every 
thermoplastic 
mask phase)
 
 
 
 
 
 

 
 
21 
6.2 Prior and concomitant medications 
Before and during the period of radiotherapy administration there are no specific medications that 
are prohibited. We would ask the subject to mention if they took any anxiolytics the day of a session 
of radiotherapy because this could influence our results. This should be recorded in the CRF. 
7. Study assessment  
7.1 Time and events schedule  
The procedures and assessment to be performed throughout the study are outlined in the time and 
events schedule.  
Table 2. Time and events schedule for all participants  
Procedure or assessment 
Screening 
During treatment 
Informed consent 
procedure 
 
x 
 
Eligibility criteria 
assessment 
 
x 
 
ECOG Performance Status 
 
x 
 
RTT appreciation 0-100 
 
 
Q1wk 
Dutch Claustrophobia 
questionnaire 
Appendix 1 
x 
 
Level of distress 
Appendix 2 
 
Q1wk 
Treatment time 
 
 
Every treatment session 
In vivo dosimetry 
 
 
Every first 3 sessions of every phase 
Evaluation of the 
intrafractional motion 
 
 
Every first 3 sessions of every phase 
Abbreviations: Q1wk: weekly 
7.2 Study procedures 
The study procedures are described in subsequent sections 
Patient demographics and other screening characteristics 
The data that will be collected at screening include: 
- 
Demography (date of birth) 
- 
ECOG performance status (Appendix 3) 
- 
Patient questionnaire: the Dutch Claustrophobia questionnaire 
- 
Use of anxyolitic medication 
Accuracy assessments 
       -using PerFRACTION (in vivo dosimetry) 
      - using the intrafractional motion determined by the change in position between the CBCT pre 
and post treatment 
Assessment of patients’ distress level 

22 
    -Weekly using the level of distress (see appendix) 
Assessment of treatment time 
    -Will be done automatically using the radiotherapy delivery software 
Assessment of RTT preference 
- 
Using score of 0-100 
8. Safety monitoring and reporting 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events/reactions in clinical trials. These procedures 
are described in this section of the protocol. 
8.1 Adverse event definitions and classifications 
Definitions in Law of May 7, 2004 concerning experiments on the human person: 
Adverse event (AE): 
An adverse event is any untoward medical occurrence in a patient or clinical investigation subject 
which does not necessarily have a causal relationship with treatment.  
Serious adverse event (SAE): 
An SAE is any untoward medical occurrence that: 
- 
results in death  
- 
is life-threatening 
- 
requires inpatient hospitalisation or prolongation of existing hospitalisation  
- 
results in persistent or significant disability or incapacity 
- 
is a congenital anomaly or birth defect 
- 
is medically important (medical and scientific judgement should be exercised in deciding 
whether expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalisation but 
may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above). 
Relationship of AEs to the intervention under investigation is assessed using the following scale: 
related (that is, it resulted from any of the research procedures)/unrelated. 
Unexpected AE are events that are not listed in the protocol as an expected occurrence. 
Severity criteria: the NCI-CTCAE (version 5.0 or later) will be used to grade the severity of adverse 
events.  
The assignment of the relationship/severity should be made by the investigator responsible for the 
care of the participant. The sponsor of the study has delegated the assessment of expectedness to 
the study responsible physician or his delegate. The expectedness assessment will be performed and 
compared to known complications for this type of radiotherapy.  

23 
8.2 Reporting procedures 
Period of observation  
Table 2: Reporting period for AEs and SAEs 
Period 
AEs (non-serious) 
SAEs 
From: Main ICF signature 
To: Day 1 of the intervention 
under investigation 
Only if related to trial 
participation 
All (regardless of relationship) 
From: Day 1 of the intervention 
under investigation 
To: 30 days after last treatment 
All (regardless of relationship) 
All (regardless of relationship) 
 
Reporting 
All AEs must be recorded using medical terminology in the source document and the eCRF. 
Whenever possible, diagnoses should be given when signs and symptoms are due to a common 
etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as 
"upper respiratory infection"). Investigators must record in the eCRF their opinion concerning the 
relationship of the adverse event to treatment. 
The investigator shall report all serious adverse events immediately (<24h), after first knowledge, to 
the sponsor. Information regarding SAEs will be transmitted to the sponsor using the SAE form, 
which must be completed and signed by a physician from the study site and transmitted to the 
sponsor (safetycto@gza.be) within 24 hours.  
All SAEs that have not resolved by the end of the study or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the following 
occurs: 
- 
the event resolves 
- 
the event stabilizes 
- 
the event returns to baseline, if a baseline value/status is available 
- 
the event can be attributed to agents other than the treatment or to factors unrelated to 
study conduct 
- 
it becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts) 
The immediate and follow-up SAE reports shall identify subjects by patient specific study numbers.  
The following situations do not need to be reported as SAEs: 
• 
Elective hospitalization for pre-existing conditions that have not been exacerbated by the 
treatment; 
• 
A hospitalization which was planned before the patient consented for study participation and 
where admission did not take longer than anticipated; 
• 
A hospitalization planned for protocol-related treatment or protocol-related procedure as per 
institutional standard timelines; 
• 
Social and/or convenience admission to a hospital; 
• 
Medical or surgical procedure, e.g., endoscopy, appendectomy; unless the condition that leads to 
the procedure is an (S)AE. 

24 
• 
Situations where an untoward medical occurrence did not occur (palliative care, rehabilitation, 
overdose without occurrence of an AE); 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
For reported death of a subject, the investigator shall supply the sponsor and the accredited ethics 
committee with any additional information requested. 
The sponsor shall keep detailed records of all adverse events which are reported to him by the 
investigators. These records shall be submitted to the minister if the experiment is being conducted 
in Belgium, if he so requests. 
Notification of serious adverse events 
The sponsor shall ensure that all relevant information about related unexpected serious adverse 
events that are fatal or life-threatening is recorded and reported as soon as possible to the 
competent ethics committee, and in any case no later than seven days after knowledge by the 
sponsor of such a case, and that relevant follow-up information is subsequently communicated 
within an additional eight days.  
All other suspected unexpected serious adverse reactions shall be reported to the ethics committee 
concerned as soon as possible but within a maximum of fifteen days of first knowledge by the 
sponsor. The sponsor shall also inform the other investigators. 
Once a year throughout the experiment, the sponsor shall provide the ethics committee with an 
annual safety report, listing all suspected serious adverse reactions which have occurred over this 
period and a report of the subjects' safety (development safety update report). Regarding those 
adverse events and serious adverse reactions the Study responsible physician will take all reasonable 
measures, in consultation with Sponsor, to protect subjects at risk following the occurrence of such 
events. 
 
!
 

25 
9. Data management 
9.1 Data collection 
Data required by the protocol will be entered in an Excel based database. The PI and Sofie Proost 
, Maxim Van den Kieboom and Jonathan Michielsen will have acces to this database. 
These patients will be numbered and anonymised according to the moment of inclusion. Database 
will be excel-based and Access-based.  
10. Statistical considerations 
10.1 Justification of sample size 
A sample size of 24 patients was estimated to provide 95% power in order to rule out an excess of 2 
mm in mean displacement, assuming a significance level of 0.05 (1-sided as testing for non-
inferiority).  
10.2 Statistical plan 
A sample size of 24 patients was estimated to provide 95% power in order to rule out an excess of 2 
mm in mean displacement, assuming a significance level of 0.05 (1-sided as testing for non-
inferiority).  
 
Mean displacements and standard deviations will be compared for the different delivery techniques 
for each patient. Using the method described by van Herk, population mean displacement (MD), 
systematic (R) and random (r) errors were estimated.  
CBCT registration results will be analysed in 3-dimensions for each patient; population MD, R and r 
will be calculated. Paired t- tests will be used to compare the parameters listed above, and timing 
data (CT and treatment session times).  
Patient comfort and acceptability questionnaires will be summarised as patient comfort scores 
ranging from 0 (most comfortable) to 100 (least comfortable).  
RTT satisfaction questionnaires will be summarised as scores ranging from 0 (most satisfactory) to 
100 (least satisfactory).   
Statistical analyses will be performed using SPSS Statistics.  
10.3 Protocol deviations 
All protocol deviations will be assessed and documented on a case-by-case basis before database 
lock. Important protocol deviations related to study inclusion or exclusion criteria, conduct of the 
study, non-compliance, participant management, or participant assessment should be described. 
Protocol deviations will be listed, and significant protocol deviations will be reported to the Ethics 
Committees (EC). 
10.4 Safety analyses  
No separate safety analyses are planned.  

26 
10.5 Interim analyses  
No interim analyses are scheduled.  
11. Study management 
11.1 Ethics and consent 
Regulations and guidelines 
The study will be conducted in compliance with this protocol, the principles of the Declaration of 
Helsinki (64th WMA General Assembly, Fortaleza, Brazil, October 2013), the principles of GCP and all 
of the applicable regulatory requirements.  
Independent Ethics Committees (IEC) 
A favourable opinion from the relevant IEC(s) will be obtained before the start of the study.  
The IEC will be notified about the EOS and a report summarizing the study results will be sent to the 
IEC within 1 year after the EOS. If the study is terminated early, the IEC will be notified within 15 
days.  
Favourable opinion is required for the study protocol, protocol amendments, ICFs, participant 
information sheets, and advertising materials if any.  
11.2 Insurance and indemnification 
In accordance with the Belgian law relating to experiments on human persons dated May 7, 2004, 
the sponsor shall assume, even without fault, the responsibility of any damages incurred by a study 
patient and linked directly or indirectly to the participation to the study, and shall provide 
compensation therefore through its insurance. 
11.3 Informed consent 
For each study participant, informed consent will be obtained in writing before any protocol-related 
activities commence. As part of this procedure, the investigator or a designated representative must 
explain orally and in writing, by means of the ICF, the nature, duration, the purpose of the study, the 
number of visits, the assessments, procedures to undergo, and the action of the treatment in such a 
manner that the participant is aware of the potential risks, inconveniences, or adverse effects that 
may occur. Participants should be informed that they may withdraw from the study at any time 
without any resulting disadvantage and prejudice to their standard treatment care. They will receive 
all information that is required by national regulations and ICH guidelines.  
The participant and the investigator will sign the ICF. A copy will be provided to the participant. The 
originally signed ICF will remain at the study center and filed in the participant’s medical records.  
All participants will be insured against injury caused by their participation in the study according to 
the legal requirements. They will be informed about the insurance and the resulting obligations on 
their part.  

27 
11.4 Data protection 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to fulfil the objectives of the study. 
These data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. Appropriate technical and 
organizational measures to protect the personal data against unauthorized disclosures or access, 
accidental or unlawful destruction, or accidental loss or alteration must be put in place. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity of 
subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and regulatory 
inspection. 
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps will 
be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations. 
11.5 Discontinuation of the study by the sponsor 
The sponsor reserves the right to discontinue the study at 1 center or at multiple centers for safety 
or administrative reasons at any time. In particular, a center that does not recruit at a reasonable 
rate may be discontinued. Should the study be terminated, and/or the center closed for whatever 
reason, all documentation pertaining to the study must be returned to the sponsor or its 
representative. 
11.6 Data management and quality control 
Electronic case report forms 
The investigator should maintain adequate and accurate source documents and study records that 
include all pertinent observations on each of the center’s study participants. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete.  
All clinical data will be captured via electronic data capture using a web-based tool in compliance 
with all legislation relevant to electronic data capture (FDA 21 CFR Part 11, Good Clinical Practice).  
The investigator’s study center staff will enter and edit the data via a secure network, with secure 
access features (username and password). A complete electronic audit trail will be maintained. The 
investigator will approve the data using an electronic signature (FDA 21 CFR Part 11), and this 
approval is used to confirm the accuracy of the data recorded. Electronic CRFs will be used for all 
participants. The investigator’s data will be accessible from the investigator’s site throughout the 
study. The eCRF must be kept current to reflect participant status at each part during the course of 
the study. The eCRF will not capture personalized data. The investigator must make a separate 
confidential record of personalized details (name and initials) on the participant identification and 
enrollment log. All changes to data are done by the investigator or designated site personnel through 
the electronic data capture system.  

28 
It is the responsibility of the principal investigator of the respective center to ensure that all 
participant discontinuations or changes in treatment entered on the participant’s eCRF are also made 
on the participant’s medical records. The eCRFs for any participant leaving the study should be 
completed at the time of the final visit or shortly thereafter. 
Study monitoring and quality assurance 
The sponsor will implement a system to manage quality throughout the design, conduct, recording, 
evaluation, reporting and archiving of the study with a focus on study activities essential to ensuring 
protection of participants and the reliability of study results. The quality management system will use 
a risk-based approach.  
This study will be monitored for quality assurance at all stages of its development by the clinical 
research personnel of the sponsor. Monitoring will be based on a systematic approach and will 
include site visits and telephone communication to assure that the investigation is conducted 
according to the protocol, standard operating procedures, Good Clinical Practice guidelines, and 
applicable regulatory requirements. Quality control procedures will be applied to each stage of data 
handling to ensure that all data are reliable and have been processed correctly. On-site review of 
eCRFs will include a review of forms for completeness and clarity, and consistency with source 
documents available for each participant. Note that a variety of original documents, data, and 
records will be considered as source documents in this study.  
The eCRF itself is not to be used as a source document under any circumstances. The study may be 
audited by the sponsor or by regulatory authorities. If such an audit occurs, the investigator must 
agree to allow access to required participant records. By signing this protocol, the investigator grants 
permission to personnel from the sponsor, its representatives, and appropriate regulatory authorities, 
for on-site monitoring of all appropriate study documentation, as well as on-site review of the 
procedures employed in eCRF generation, where clinically appropriate. Relevant data (concomitant 
medication, and AEs) will be transcribed by the center personnel into the eCRF. The eCRFs for any 
participant leaving the study should be completed at the time of the final visit or shortly thereafter. 
Record retention 
The investigator must arrange for retention of study records at the center. The nature of the records and  the  
duration  of  the  retention  period  must  meet  the  requirements  of  the  relevant regulatory authority. The  
investigator  should  take  measures  to  prevent accidental or premature destruction of these documents. 
To meet regulatory requirements, the CRF data will be electronically stored at the data center. The eCRF and 
audit trail data will be created and provided to the centers in PDF files. 
11.7 Use of information and publication 
Publications will be coordinated by the study responsible physician. Authorship to publications will 
be determined in accordance with the requirements published by the International Committee of 
Medical Journal Editors and in accordance with the requirements of the respective medical journal.  
!
 

29 
References 
1. 
Belgian Cancer Registry. Belgian Cancer Registry- Cijfers 2016 [Available from: 
http://kankerregister.org/Statistieken_cijfers. 
2. 
Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29. 
3. 
Wiant D, Squire S, Liu H, Maurer J, Lane Hayes T, Sintay B. A prospective evaluation of open 
face masks for head and neck radiation therapy. Pract Radiat Oncol. 2016;6(6):e259-e67. 
4. 
Li G, Lovelock DM, Mechalakos J, Rao S, Della-Biancia C, Amols H, et al. Migration from full-
head mask to “open-face” mask for immobilization of patients with head and neck cancer. Journal of 
Applied Clinical Medical Physics. 2013;14(5):243-54. 
5. 
Zhao B, Maquilan G, Jiang S, Schwartz DL. Minimal mask immobilization with optical surface 
guidance for head and neck radiotherapy. Journal of Applied Clinical Medical Physics. 2018;19(1):17-
24. 
6. 
Dekker J, Rozema T, Böing-Messing F, Garcia M, Washington D, De Kruijf W. Whole-brain 
radiation therapy without a thermoplastic mask. Physics and Imaging in Radiation Oncology. 
2019;11:27-9. 
7. 
Ali I, Matthiesen C, Algan O, Thompson S, Bogardus C, Herman T, et al. Quantitative 
evaluation of increase in surface dose by immobilization thermoplastic masks and superficial 
dosimetry using Gafchromic EBT film and Monte Carlo calculations. J Xray Sci Technol. 
2010;18(3):319-26. 
8. 
Stieler F, Wenz F, Shi M, Lohr F. A novel surface imaging system for patient positioning and 
surveillance during radiotherapy. A phantom study and clinical evaluation. Strahlenther Onkol. 
2013;189(11):938-44. 
9. 
Cervino LI, Pawlicki T, Lawson JD, Jiang SB. Frame-less and mask-less cranial stereotactic 
radiosurgery: a feasibility study. Phys Med Biol. 2010;55(7):1863-73. 
 
 
 

30 
Appendices 
Appendix 1: Dutch Claustrophobia questionnaire (English translation) 
 
 
Name:………………. 
 
 
 
 
 
Date………………… 
 
How anxious would you feel in the following situations? 
 
A= Not anxious B= a bit anxious   C=Fairly anxious 
  D= very anxious 
 E= Extramely anxious 
 
1. Being restrained in a straight jacket for 15 minutes. 
2. Being tied to an immoveable chair. 
3. Being tied up with your hands behind your back for 15 minutes.  
4. Being handcuffed for 15 minutes 
5. Being locked up in a small dark room during 15 minutes 
6. Laying in a small sleeping bag which fits tightly around your arms and legs and which 
is tied at the level of your neck. 
7. Laying in the trunk of a car during 15 minutes with sufficient oxygen supply. 
8. Wearing clothes that are to small and not being able to remove them. 
9. Laying in a closed sleeping bag with your head at the end where your feet should be 
and not being able to get out. 
10. Being locked op in a lit room without windows for 15 minutes. 
11. Being in an overcrowded train, stopped between two stations. 
12. Noticing the door is jammed on a public toilet. 
13. Swimming with a nose clip on. 
14. Working underneath the sink for 15 minutes. 
15. Standing in an elevator on the ground floor with the doors shut. 
16. Trying to catch your breath during heavy exercise. 
17. Having trouble breathing through your nose during a bad cold. 
18. Snorkeling in a safe practice tank for 15 minutes. 
19. Using an oxygen mask. 
20. Lying at the bottom of a bunk bed  
21. Standing on the third row at a sold-out concert and realizing you won’t be able to 
leave the room before the end of the show. 
22. Sitting in the middle of a full row at the movie theater. 
23. Working beneath a car for 15 minutes. 
24. Standing still during an excursion within an underground mine at the furthest point 
from the exit. 
25. Lying inside a sauna for 15 minutes. 
26. Waiting inside of an airplane which stands on the ground while the doors are closed. 

31 
 
Appendix 2: Subjective Units of Distress Scale 
 
 
 

32 
 
Appendix 3: ECOG Performance Status Grade 
Developed by the Eastern Cooperative Oncology Group  (Oken M, Creech R, Tormey D, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655) 
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead.