Pilot Study for the Development and Implementation of a Virtual Reality-based Radiation Therapy Education and Anxiety Mitigation Program
Phase: NA
Conditions: Anxiety, Stress, Satisfaction, Patient, Preparedness, Information Needs
Sponsor: Medical College of Wisconsin

Document Cover Page 
Official Title of the Study:  
Pilot Study for the Development and Implementation of a Virtual Reality-based Radiation Therapy 
Education and Anxiety Mitigation Program  
NCT Number: NCT04029961 
Date of Document: June 14, 2019 
 
 

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Protocol Title: Pilot study for the development and implementation of a virtual reality-based 
radiation therapy education and anxiety mitigation program 
 
MCW Protocol No.: PRO00032593 
Patients will be enrolled at the following site(s): Community Memorial Hospital, St. Joseph’s 
Hospital, Froedtert Hospital 
 
Co-Principal Investigator: 
Carmen Bergom, MD, PhD 
Associate Professor 
Medical College of Wisconsin 
9200 W. Wisconsin Avenue 
Department of Radiation Oncology 
Milwaukee, WI 53226 
XXX.XXX.XXXX 
xxxxxxx@xx.xxx  
Co-Principal Investigator 
John LaDisa Jr., PhD 
Associate Prof. of Biomedical Engineering 
Marquette University & Medical College of 
Wisconsin 
1637 West Wisconsin Avenue, room 311 
Milwaukee, WI 53233 
414-288-6739 
John.LaDisa@marquette.edu 
Co-Investigator: 
Sophia Shanahan, B.S. 
Graduate Student 
Biomedical Engineering 
Marquette University 
xxx.xxxxxxxx@mu.edu  
Co-Investigator: 
Melinda Stolley, PhD 
Health Psychologist 
Professor 
Medical College of Wisconsin 
8701 Watertown Plank Rd. 
Milwaukee, WI 53226 
xxxxxxxx@mcw.edu  
Co-Investigator: 
Monica Shukla, MD 
Assistant Professor 
Associate Director, Radiation Oncology 
Residency Program 
Medical College of Wisconsin 
Department of Radiation Oncology 
8701 Watertown Plank Rd. 
Milwaukee, WI 53226 
XXX.XXX.XXXX 
xxxxxxx@xx.xxx 
Biostatistician: 
Anjishnu Banerjee, PhD 
Assistant Professor 
Division of Biostatistics 
Institute for Health and Society 
8701 Watertown Plank Rd. 
Medical Education Building 
(MEB): M2460 
Milwaukee, WI 53226 
     XXX.XXX.XXXX 
xxxxxxx@xx.xxx 
 
Sponsor/funding: 
Xxxxx xxxxxxxxxx xxxx xxxx xx xxx,xxx 

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Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1: Study schema 
 
 
1. Questionnaire Group 1: 
• STAI, INS, and “Questionnaire 1” (see Appendix 4) 
 
 
2. Questionnaire Group 2: 
• STAI, INS, and “Questionnaire 2” (see Appendix 4) 
 
 
3. Questionnaire Group 3: 
• STAI, INS and “Questionnaire 3” (see Appendix 4) 

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Study Calendar 
 
Period/ 
Procedure 
Study Day/Visit Day 
Screening 
Period in 
Preparation for 
Provider Visit 
Breast Cancer 
Provider Visit 
Education  
First 
Radiation 
Treatment 
Eligibility screening1 
X 
Informed consent2 
X 
Randomization3 
X 
Questionnaire Group 14 
X 
Education Intervention5 
X 
Questionnaire Group 26 
X 
Questionnaire Group 37 
X 
Adverse Event Monitoring: 
Protocol SpecificAE; AN 
         X 
X 
 
1 If a patient meets initial eligibility criteria, they will be introduced to the study at a provider visit 
through a verbal description of the study. 
2 Patients will be provided an informed consent form at the breast cancer provider visit where they are first 
introduced to the study; if interested, patients can choose to sign the consent form at that visit, or take the 
consent form home and sign it at a future visit. 
3 Patients will be randomized to either the experimental (VR education) or control (standard education) with 
approximately 18 patients / group after being consented. 
4 Questionnaire Group 1 consists of the STAI, INS and “Questionnaire 1” and is provided before any education or 
RT. 
5 The education intervention consists of a VR education program for the experimental group and 
standard patient education for the control group (ASTRO video). 
 
 
6  Questionnaire Group 2 consists of the STAI, INS and “Questionnaire 2” and is provided immediately after the 
education intervention. 
7 Questionnaire Group 3 consists of the STAI, INS and “Questionnaire 3” and is provided immediately 
after the first fraction of treatment. Half of “Questionnaire 3” will only be completed by experimental group 
patients as it relates to improvements that could be made to the VR program. 
AE ONLY complete AE form for AE’s as described by the protocol. Add as an additional procedure to a visit. 
ANAs Needed 

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Table of Contents 
Study Schema ................................................................................................................................. 2 
Study Calendar ............................................................................................................................... 3 
List of Abbreviations........................................................................................................................ 5 
1.0 BACKGROUND ....................................................................................................................... 6 
2.0 OBJECTIVES ........................................................................................................................... 8 
3.0 SUBJECT ELIGIBILITY .......................................................................................................... 10 
3.1 Inclusion criteria .................................................................................................... 10 
3.2 Exclusion criteria .................................................................................................... 10 
4.0 ACCRUAL GOAL AND STUDY DURATION .......................................................................... 11 
5.0 SUBJECT REGISTRATION ................................................................................................... 11 
6.0 STUDY DESIGN ..................................................................................................................... 11 
6.1 Education ............................................................................................................... 11 
6.2 Baseline Visit .......................................................................................................... 12 
6.3 Randomization ....................................................................................................... 12 
6.4 Intervention............................................................................................................. 12 
7.0 SUBJECT WITHDRAWAL CRITERIA .................................................................................... 14 
8.0 ADVERSE EVENT REPORTING ........................................................................................... 15 
9.0 STATISTICS ........................................................................................................................... 16 
10.0 DATA MANAGEMENT.......................................................................................................... 17 
11.0 RISKS AND BENEFITS ........................................................................................................ 18 
11.1 Risks… .............................................................................................................................. 18 
11.2 Benefits… .......................................................................................................................... 19 
12.0 REFERENCES ..................................................................................................................... 20 
Appendix 1. VR Education Script .................................................................................................. 22 
Appendix 2. INS ............................................................................................................................. 26 
Appendix 3. STAI ........................................................................................................................... 27 
Appendix 4. Questionnaires… ....................................................................................................... 30 

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List of Abbreviations 
 
 
AE 
adverse event 
CRA 
clinical research assistant 
CRC 
clinical research coordinator 
CRF 
case report form 
CTO 
clinical trials office 
CTCAE 
Common Terminology Criteria for Adverse Events 
ET 
exposure therapy 
HMD 
head-mounted display 
ICF 
informed consent form 
INS 
informational needs scale 
IVET 
in vivo exposure therapy 
LINAC 
linear accelerator 
RCT 
randomized controlled trial 
RT 
radiation therapy 
SAE 
serious adverse event 
STAI 
state-trait anxiety inventory 
UPIRSO 
Unanticipated Problems Involving Risks to Subjects or Others 
VAS 
visual analogue scale 
VR 
virtual reality 
VRET 
virtual reality exposure therapy 

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Figure 1. Examples of VR-based head- 
mounted displays including the Microsoft 
HoloLens, Oculus Rift and Samsung Gear VR. 
Each device permits 3D rendering and 
interaction in a virtual environment. The patient-
specific content shown above was created in 
MARVL. 
1.0 BACKGROUND 
 
Importance of the problem. 350,000 is the lower bound for the number of patients that receive 
radiation therapy (RT) for cancer treatment each year. Previous studies found that 60% of cancer 
patients endorse substantial anxiety in the preoperative stage of treatment and 80% of patients 
suffer from anxiety in the postoperative stage1. A standard of care for management of early 
stage breast cancer is a partial mastectomy, otherwise known as lumpectomy, followed by 
postoperative radiation therapy. The current study proposal is aimed at breast cancer patient 
education; 45% of breast cancer patients, specifically, suffer from anxiety2. The first conceptual 
framework for anxiety in surgical patients was provided by Janis et al in 1958, where 
preoperative anxiety was proposed as a predictive component of surgical outcome/success1. 
More recent studies published in medical and psychology journals have corroborated this 
finding by comparing the former with the latter in patients undergoing various types of 
surgery3,4,5,6. 
In 2012, Halkett et al published a study regarding the informational needs of breast 
cancer patients at different time points as they proceed through the radiotherapy treatment 
process. The study discusses the importance of addressing patients’ informational needs through 
sensory and procedural information as a mechanism of anxiety reduction. The novel virtual 
reality (VR) approach proposed in this study aims to reduce anxiety levels and increase patient 
understanding by targeting what Halkett et al proposes as the cause of increased anxiety: a lack 
of treatment-related information2. Through an immersive audiovisual experience, the VR 
education module proposed in this study will sequentially guide the patient through the 
treatment procedure with accompanying sensory information (sights and sounds). 
 
Critical barriers to mitigating the problem. Improved education about radiation-related treatments 
may help to reduce anxiety related to RT in cancer patients. Critical examination of the types of 
communication strategies used by the radiation team at the time 
of the radiation planning session did not demonstrate that 
communication differences could account for patient anxiety 
levels7. However, currently is it unknown whether immersive 
experiences that have the potential to better replicate treatment 
processes and educate patients about RT are feasible, can 
decrease anxiety, and/or can lead to improved patient 
satisfaction with their RT treatment experience. 
VR provides a computer-generated depiction of a real or an 
imagined environment8. For example, VR can be used to move 
through simulated buildings that do not yet exist, show blood 
flow through an artery in vivid 3D9, or 
simulate health care procedures with no danger to a user. The use of VR-based audiovisual output 
devices allows human operators to experience the environment as if they were part of that world. 
VR worlds are ideally suited to training experiences, such as that proposed here. As mentioned 
above, immersion refers to the technical capability of the VR system to deliver a surrounding 
environment within which a patient can interact, and convincingly create a sense of presence within 
this virtual environment. This can be accomplished in an affordable and straightforward 

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manner with head-mounted displays (HMDs) that place a user into a virtual world through the use 
of an integrated optical system that is placed in front of the user’s eyes (Figure 1). Another key feature of 
the VR experience is the ability to interact with the virtual environment in real-time. This interaction 
typically occurs through the use of external input devices ranging from a Bluetooth controller to preset 
actions that respond to the user’s real physical motions exerted while exploring the VR world. Perhaps 
most importantly, the added value of VR for education is the possibility for the user to learn through first- 
person experience8 and for that learning to be monitored and assessed through analytics from the user’s 
interactions. 
 
Building from exposure therapy. Studies show exposing an individual to a feared event or 
environment in a non-threatening setting can lead to positive treatment results10. Exposure therapy 
(ET) has served as the gold standard for many psychological conditions, including anxiety11. ET is 
usually conducted via in vivo mechanisms involving the physical world (e.g. patient with fear of 
elevators guided in riding one), but limitations include situational control, access to stimuli, 
financial and time constraints, and difficulty recreating a specific situation or fear11. More recent 
VR exposure therapy (VRET) avoids these limitations by creating the exposure though a realistic 
virtual reconstruction of a feared stimulus within a safe and controlled environment. VRET also 
allows for customizable and repeat sessions without additional cost or resources11. To test the 
clinical applicability of VRET, a recent study pulled 11 VRET randomized controlled trials (RCT) 
from major medical, health, and psychological literature and analyzed their effectiveness with 
various phobias and psychological disorders, including different types of anxiety. The study 
concluded VRET is an innovative application with serious potential towards treating psychological 
conditions12. Further, one meta-analysis published in the Journal of Anxiety Disorders compared 
VRET to in vivo exposure therapy (IVET) and control conditions in 13 cases and found VRET to 
be highly effective at treating various phobias and slightly but significantly more effective than 
IVET13 while another meta-analysis comparing VRET with classical evidence-based interventions 
(i.e., cognitive-behavioral therapy with no VR exposure or behavioral therapy with no VR 
exposure) published in Depression and Anxiety found therapy involving VRET to be just as 
effective as classical evidence-based mechanisms14. While pre-treatment anxiety is not typically 
considered a clinical phobia, Andersen et al found 60-80% of patients receiving RT treatment to 
experience significant anxiety levels1. The effectiveness of VRET in post-traumatic stress, phobias, 
and anxiety disorders provides strong evidence for future success in treating anxiety in the current 
work. 
 
Related Studies. The virtual environment for radiotherapy training (VERT) system was originally 
created as an RT training instrument for medical students studying to be radiation therapists. 
However, a recent study performed in Australia leveraged the impressive visual capabilities of the 
VERT system to present complex RT treatment concepts to 19 breast cancer patients as a form of 
preoperative education. The VERT education session consisted of an introduction to the VERT 
system in addition to educational information on the following RT treatment components: 
immobilization, simulation, and planning and treatment. Study measures included a demographic 
questionnaire and a 21-statement questionnaire that asked patients to rate their level of agreement 
regarding various features of the VERT system (i.e., structure, content, venue) on a 5-point Likert 
scale. Open-ended questions were also included to glean insight into aspects of the program that 
patients found most and least useful. The results of the second study measure showed high ratings 
towards the program content and delivery, with particular acknowledgement of the 3D visuals. The 

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authors found the results encouraging and supportive of the use of VERT in patient education. The 
conclusion of the study pressed for further utilization of the 3D visual capabilities of the VERT 
system in patient education to promote patient engagement and effectively transfer knowledge 
from clinicians to patients15. 
 
Another study measured patient anxiety and comprehension levels after providing preoperative 
patient education via the VERT system to twenty-two prostate cancer patients scheduled to 
undergo RT. The patients attended a classroom-based VR session, modeled as a linear accelerator 
flight simulator. The experience included complete immersion in a standard radiotherapy treatment 
room, a presentation of treatment-based objectives, and a digital anthropomorphic phantom for 
visualization of linear accelerator movement and laser beam positioning about the patient. Two 
questionnaires, one anxiety-focused and one comprehension-focused, were given to each patient 
both prior to and subsequent to the VR education program. Statistical analysis of the questionnaires 
found substantial results proving the authors’ hypothesis that patient education in the form of a VR 
module decreases preoperative anxiety and increases treatment comprehension for patients16. 
 
A third study using VR patient education conducted an RCT in which 127 patients were assigned in a 1:1 
ratio to either a standard or immersive preoperative education experience prior to a neurologic operation. 
The study objective was to make patients feel more comfortable in the treatment environment through 
information and VR preoperative treatment exposure. The VR demonstration consisted of a five-minute 
audiovisual VR video that presented the preoperative and postoperative experience through Oculus VR 
goggles. Patients were then given the opportunity to ask questions about the demo. This study used two 
scales: the Evaluation du Vecu de l’ Anesthesie Generale (EVAN-G) score and the Amsterdam 
Preoperative Anxiety and Information (APAIS) score. The study concluded that patients subject to VR 
preoperative education had improved satisfaction following the surgical procedure17. 
 
 
 
2.0 OBJECTIVES 
It is challenging to explain a complex topic such as radiotherapy to patients15, but this education is 
critical as it has an impact on the quality of care provided from the patient’s perspective7. 
Moreover, the quality of patient education is variable from practice to practice. Hence, there is a 
need to create and disseminate an interactive platform that improves the patient education 
experience and facilitates an increased level of patient understanding. The potential of VR is 
intriguing in this regard. VR uses rendered data, audiovisual cues, 3D viewing and motion 
response to replicate experiences from the physical world. Within the context of VR, the term 
immersive specifically refers to experiences that facilitate motion of a participant and a field-of- 
view that covers a user’s gaze up to the level of peripheral vision (i.e., >180-degrees). Prior 
research on the use of VR for patient education demonstrates that a VR-based preoperative 
treatment exposure session can improve patient satisfaction ratings more definitively than 
prevalent pharmacologic and standard education anxiety-relieving interventions17. Unfortunately, 
there is a paucity of tools (content, software, specific protocols) and associated studies supporting 
the use of VR with breast cancer patients. 

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The objective of this pilot study is to create an immersive VR-based education program allowing 
breast cancer patients to experience the procedure and emotions associated with radiation therapy 
administered via a linear accelerator (LINAC) machine, before physical treatment occurs. The 
team assembled has the expertise to complete the proposed work, which was built from related 
information available in the literature. For example, studies suggest clinically relevant anxiety is 
associated with emotion-focused coping, difficulty communicating with the treating team, and a 
perceived lack of support from RT team members, but the subsequent inability of these factors to 
predict patient outcome underscores a need for additional tools such as those proposed in the 
current work. While a recent RCT using immersive VR for patients revealed improvements in 
preoperative patient anxiety, as well as perioperative patient experience and satisfaction, this work 
was performed in individuals undergoing elective neurosurgeries17. Based on this data, our central 
hypothesis is that developing and incorporating VR content into the current RT patient 
education model will reduce anxiety levels and lead to better patient understanding of the 
treatment plan. The central aim below will provide the foundation for a novel tool to reduce 
anxiety during an RT session, which represents a critical unmet need for patients facing RT 
treatment. 
Central Aim. Assess patient anxiety and satisfaction after incorporating VR-based content into 
the current patient education model. Following consultation with the Clinical Trials Office, and 
consistent with current approaches for related patient research, the team has designed a protocol to 
assess patient anxiety, satisfaction and knowledge of the RT protocol. After noting any prior VR 
experience and education, groups of patients (approximately 18/group) will be exposed to VR-based 
content (Appendix 1) or a control audiovisual experience. A patient-reported outcome questionnaire 
consisting of the Informational Needs Scale (INS; Appendix 2), State-Trait Anxiety Inventory (STAI; 
Appendix 3), and Visual Analogue Scales (VAS; Appendix 4) for stress, preparedness, and 
satisfaction will serve as the primary study endpoints scrutinizing patient anxiety levels, treatment 
comprehension, and the VR content and experience. The second study endpoint involves 
improvements that could be made to the VR education program for future studies/use based on 
patient feedback. This post-interventional questionnaire will only be given to patients in the 
experimental group. 

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3.0 SUBJECT ELIGIBILITY 
3.1 Inclusion criteria 
(Y)  
Patient is 18 years of age or older 
(Y)  
Patient is female 
(Y)  
  Patient has been diagnosed with breast cancer 
(Y)  
Patient will be receiving whole breast radiation therapy without supraclavicular nodal irradiation 
(Y)  
Patient is scheduled for an outpatient radiation oncology visit 
(Y)  
Patient has the ability to understand a written informed consent document, and the 
willingness to sign it 
(Y)  
Patient has the ability to complete a series of self-reported questionnaires 
 
 
3.2 Exclusion criteria 
(N)  
Non-English-speaking patients (as the VR education program includes English narration) 
(N)  
Patients with visual defects that affect their ability to watch a movie 
(N)  
Patients with auditory defects that affect their ability to listen with headphones 
(N)  
Patients who have worked in the field of radiation oncology as they would have previously 
undergone treatment-related education 
(N)  
Patients who have been treated previously with radiation oncology as they would have 
previously undergone treatment-related education 
(N)  
Patients that have been diagnosed with epilepsy, conditions causing seizures, or have 
any previous history of seizures because a very minute number of head-mounted 
display (HMD) users have experienced a seizure as a result of using the device 
(N)  
Patients with a reported history of cognitive disability as their ability to understand 
educational content may be impaired 
(N)  
Patients with a history of severe motion sickness because a side effect of using a HMD in a 
very small number of users is motion sickness symptoms 
(N)  
Patients with a pacemaker, hearing aid(s), and/or defibrillator, while patients with other types 
of electronic medical devices / implants will be assessed for eligibility on a case-by-case basis 
because there could be potential interference with the HMD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physician’s Signature  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Coordinator’s Signature 
 
 
 
 
Date 

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4.0 ACCRUAL GOAL AND STUDY DURATION 
 
Data from approximately 36 patients is needed to meet study objectives. Patients will be 
randomized to an immersive VR intervention versus standard patient education session regarding 
the process of receiving radiation therapy. The approximate study duration will be 9 months to 
obtain data from approximately 36 patients. The study team has a high enrollment estimate of 60 
patients to obtain data from approximately 36 patients.  
 
 
5.0 SUBJECT REGISTRATION 
 
After being introduced to the study and provided study details at a breast cancer provider 
appointment, interested patients will complete an informed consent form prior to enrollment in the 
trial. Patients will be consented by one of the radiation oncologists listed on the study team, Ms. 
Shanahan, a nurse or a clinical research assistant/clinical research coordinator(CRA/CRC) in the 
Clinical Trials Office of the Froedtert & Medical College of Wisconsin Cancer Center (please see 
eBridge form section 2 for study team members) depending on schedule availability. 
 
All patients who are consented will be registered in OnCore®, the MCW Cancer Center 
Clinical Trial Management System. The system is password protected and meets HIPAA 
requirements. Cancer stage and related diagnosis information for each patient will be collected 
from Epic. 
 
Please call Carmen Bergom, MD, PhD, at xxx-xxx-xxxx or Monica Shukla, MD at XXX.XXX.XXXX 
 if there are any questions regarding registration or eligibility. 
 
 
6.0 STUDY DESIGN 
 
The proposed study is a multi-site RCT. The study protocol will be conducted at three different RT 
treatment sites: Froedtert Hospital (Milwaukee, WI), Community Memorial Hospital (Menomonee Falls, 
WI), and St. Joseph’s Hospital (West Bend, WI). 
 
6.1 Education 
 
6.1.1 Control Group Education 
 
The control group will receive education in the form of an educational video created by the American 
Society for Radiation Oncology (ASTRO) (https://www.astro.org/Patient-Care-and- Research/Patient-
Education/Patient-Videos). The ASTRO Radiation Therapy (RT) video provides audiovisual education for 
patients on RT. The ASTRO RT video is considered standard education at Community Memorial Hospital 
(CMH) and St. Joseph’s Hospital. The video will be started for the patient by one of the radiation 

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oncologists listed on the study team, Ms. Shanahan, a nurse, or a CRA/CRC in the Clinical Trials Office of 
the Froedtert & Medical College of Wisconsin Cancer Center depending on schedule availability. 
 
                 6.1.2 Experimental Group Education 
 
The experimental group will receive education in the form of an immersive VR education program delivered 
via a HMD, similar in duration to the control group education. Patients will have the opportunity to be 
immersed in a CT simulation room, a dosimetry room, and an RT treatment room while a virtual model of a 
clinician delivers verbal educational content (please see the VR education script in Appendix 1). Patients 
will also have the opportunity to virtually undergo the RT treatment process through camera movements and 
animations that have been programmed into the VR program. 
 
6.2 Baseline Visit 
 
The baseline visit is the provider visit where eligible patients are introduced to/recruited for the 
study. Study objectives and the patient’s potential role in the study will be discussed, and the 
patient will have plenty of time to pose questions to the research team. At this visit, interested 
subjects will be provided an informed consent form. No trial procedures will be conducted prior to 
a subject being consented. 
 
 
6.3 Randomization 
 
Approximately 36 patients (depending on withdraw rate) will be randomized into the control 
group and experimental group (approximately 18/group) via the randomization feature 
within the OnCore® system, and stratified by receipt of chemotherapy, if possible. 
 
6.4 Intervention 
 
A copy of the signed informed consent form (ICF) will be given to the subject and a copy will be filed in 
the medical record. The original will be kept on file with the study records. 
 
Patients will be given Questionnaire Group 1; Questionnaire Group 1 consists of the STAI, INS and 
“Questionnaire 1” (see Appendix 4) and is provided before any education or RT. 
 
The administration of the questionnaires will be conducted by one of the radiation oncologists 
listed on the study team, Ms. Shanahan, a nurse, or a CRA/CRC in the Clinical Trials Office of the 
Froedtert & Medical College of Wisconsin Cancer Center depending on schedule availability. 
 
Subjects will then be briefed on the education intervention they are about to receive. Subjects in the control 
group will undergo a standard, non-immersive patient education experience. Subjects 

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in the experimental group will be taught how to use the VR HMD and undergo education in the 
immersive environment. The HMD instruction will be provided by either one of the radiation 
oncologists listed on the study team, Ms. Shanahan, a nurse, or a CRA/CRC in the Clinical 
Trials Office of the Froedtert & Medical College of Wisconsin Cancer Center, depending on 
schedule availability. 
 
At the end of the education intervention, patients will complete Questionnaire Group 2; 
Questionnaire Group 2 consists of the STAI, INS and “Questionnaire 2” (see Appendix 4) and is 
provided immediately after the education intervention. The completion of the two groups of 
questionnaires, with the education intervention is expected to take less than 60 minutes in total. 
Patients will have time to ask questions regarding the education and/or any concerns they may 
have to their treatment team. 
After the first fraction of RT, patients will be given Questionnaire Group 3; Questionnaire Group 
3 consists of the STAI, INS and “Questionnaire 3” (see Appendix 4) and is provided immediately 
after the first fraction of treatment. The second page of “Questionnaire 3” in this group is used to 
improve the VR content and its delivery via input from patients, and therefore is only completed by 
members of the experimental group. Iterative adjustments to the VR program will be implemented 
after completion of the current proposed study based on rankings of importance and frequency. In 
this manner, future studies using VRET with radiation oncology will benefit from the use of this 
human-centered design approach. 
Patients may withdraw from this study at any time, and experimental group patients will be 
instructed that they should remove the VR HMD if they feel any discomfort while wearing it. If a 
patient withdraws from the study, no further information will be collected on that patient and 
another eligible and interested patient will be consented to meet the study accrual goal, as budget 
permits. 
There will be no long-term follow-up for subjects in this study.

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Table 1: Estimated completion times for individual questionnaires, the education intervention, and 
questionnaire groups 
 
Activity 
Time (min) 
Questionnaire Group Total (min) 
STAI 
10 
INS 
10 
Questionnaire 1 
2 
Group 1: 22 
Education Intervention 
20 
STAI 
8 
INS 
8 
Questionnaire 2 
2 
Group 2: 18 
STAI 
8 
INS 
8 
Questionnaire 3 
2 
Group 3: 18 
 
 
7.0 SUBJECT WITHDRAWAL CRITERIA 
 
In the absence of treatment delays, educational study may be completed unless: 
 
• Disease progression 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further questions in the investigator’s judgement 
• Inter-current illness that prevents further involvement in the study 
• Patient decides to withdraw from the study 
• Significant patient non-compliance with protocol 
• Unacceptable adverse event(s) 
Patient-Initiated Withdrawal: A patient may decide to withdraw from the study at any time and 
experimental group patients will be instructed that they should remove their VR HMD if they 
feel any discomfort while wearing it. 
 
Investigator-Initiated Withdrawal: The Investigator will withdraw a patient whenever continued 
participation is no longer in the patient’s best interests. Reasons for withdrawing a patient 
include, but are not limited to, disease progression, the occurrence of an adverse event or a 
concurrent illness, a patient’s request to end participation, a patient’s noncompliance or simply 
significant uncertainty on the part of the Investigator that continued participation is prudent. 
There may also be administrative reasons to terminate participation, such as concern about a 
patient’s compliance with the prescribed treatment regimen. 

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Subjects may call Dr. Carmen Bergom at XXX.XXX.XXXX or the study’s Clinical Research Coordinator/nurse to be 
withdrawn from the study. No further data will be collected from a subject who has withdrawn from the study. Information 
collected prior to subject withdraw is required  to be kept. As budget permits, the next RT patient that meets the eligibility 
criteria and expresses interest in the study will be enrolled to meet the study accrual goal. 
8.0 ADVERSE EVENT REPORTING 
 
Table 2: Description of adverse events that will be reported in this study 
Adverse Event 
Study Arm Affected 
Reportable Timeframe 
Key linking subjects to their 
alpha-numeric identifier is 
subject to unauthorized 
access or lost 
Control and Experimental 
At any point throughout the 
duration of this study 
Blackout / loss of awareness18 Experimental 
While the subject is 
undergoing VR education 
Seizure18 
Experimental 
Within 12 hours of using the 
head-mounted display 
(HMD) 
- 
Nausea18 
- 
Disorientation18 
- 
Dizziness18 
- 
Eye strain18 
- 
Impaired balance18 
- 
Visual abnormalities18 
(i.e. blurred or double 
vision) 
- 
Discomfort or pain in 
the head or eyes18 
Experimental 
Reported if symptom is 
described by patient as being 
severe, mild cases do not 
resolve within 30 minutes of 
removing the HMD, or 
symptom presents post-use 
within 12 hours of using the 
HMD 
Onset of a contagious 
condition that could have 
spread through transfer of the 
HMD18 such as pink eye or a 
cold 
Experimental 
Within 48 hours of using the 
HMD 
Skin irritation18 that could 
have resulted from wearing 
the HMD or using the hand 
controller 
Experimental 
Within 12 hours of using the 
HMD 
This team will follow the Medical College of Wisconsin policies related to adverse event 
reporting. This information may be found on the Human Research Protection Program website. 
 
The investigator and his or her team will follow the Medical College of Wisconsin policies related to 
unanticipated problems involving risks to subjects or others (UPIRSO). This information may be found 

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on the Human Research Protection Program website. 
 
 
9.0 STATISTICS 
A prior study17 reported effect sizes of approximately 0.97 standard deviations (the standard 
deviation estimated from the reported confidence interval) when using a VR based intervention for 
anxiety scores (abbreviated as APAIS scores in the referenced study). Using these numbers, with 
about 18 patients in control and test (i.e., VR experience) groups, we will be able to detect 
statistically significant effect sizes of 0.97 or larger for differences in means in pre-post changes 
of measures between the groups, with at least 80% power, at the 0.05 type I error level, with two 
sided tests. Block sizes of 6 will be used for the randomization. These are estimates for our pilot study, 
meant to guide sample size and statistical design for larger studies. Calculations are based on 
Cohen’s method using the “pwr” package in R software. 
The study team estimates an enrollment number of 60 patients will guarantee that data is obtained 
from approximately 36 patients. This is a high estimate to be on the safe side when creating the 
OnCore® build. 
 
Descriptive and exploratory analysis will include one-sample paired t-test(difference pre vs post), 
Cohen’s d, Wilcoxon signed-ranked test, sensitivity analysis, in addition to tabulations of the 
number of patients, mean score, standard deviation vs confidence intervals, age, race, and other 
related covariates including education, occupation, receipt of chemotherapy, diagnosis/cancer 
stage, previous VR experience, and sources of support. 
 
 
The principal hypothesis of interest is whether measure score changes between different time 
points vary between the test and control groups. To measure the difference in measures in patients, 
we will use a mixed multivariate regression model. This model will account for multiple 
measurements from the same patient (e.g., measurements of VAS scores at 3 time points) through 
a random effects term accounting for individual patient variations. Multiplicity corrections 
wherever needed will be done using the Holm-Sidak method. All statistical analysis will be 
conducted on SAS and/or R software. 
 
The STAI will be analyzed as an individual questionnaire as the patient-reported values for each 
measure are summed for an overall questionnaire score, while each item on the other 
questionnaires will be analyzed individually as we are looking to see if changes exist for each 
patient between the three different data collection time points. The questionnaire results will be 
reported in aggregate. 
 
All patients will be instructed to fill out each item on each questionnaire. Regression models named 
above can typically accommodate missing data (for example, responses for all time points from a 
patient are not recorded), imputation will therefore not be considered. Missingness will be 
investigated to explore evidence for informative missingness, if any; appropriate adjustments such 
as inverse probability weighting will be used to adjust for any informative missingness. 

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10.0 DATA MANAGEMENT 
 
Study questionnaires will be completed by the patient in hard-copy format and entered into 
OnCore® via standardized case report forms (CRFs), in accordance with the study calendar, using 
single data entry with a secure access account. If desired for analysis purposes, data may also be 
entered into a password-protected Excel sheet. Data will be entered by a member of the study team 
or a member of the Clinical Trials Office (CTO). The original hard copies of data will be locked 
within a secure-access building and a secure access office and/or cabinet. Data that is transported 
between sites involved in this multi-site study (i.e., from CMH to Marquette University) will be 
transported on an encrypted flash key and then stored on a private, network-attached share drive. 
 
Further, upon enrollment in the study, all patients will be assigned a unique alpha-numeric code to 
be used as identification on all hard-copy study questionnaires in place of their name, thereby 
minimizing the risk associated with the unlikely but potential risk of unauthorized questionnaire 
access. The key linking patient’s name to unique identifier will be locked within a secure-access 
building or on a password-protected file/system. 
 
All source documentation and data will be available for review/monitoring by regulatory agencies. 

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11.0 Risks and Benefits 
 
11.1 Risks 
 
Table 3: Includes risks and mitigation tactics associated with this low-risk study 
 
Risk 
Risk Mitigation 
HMD could have side effects including but 
not limited to motion sickness, nausea, 
disorientation, and dizziness18 (please see 8.0: 
Adverse Events Table for more information) 
Slow camera movements and fade-in/fade out 
between scenes were a part of the VR education 
module design to minimize triggering of any of 
these symptoms. Patients will be informed that 
they should remove the HMD if they feel any 
discomfort. 
The goal of this study is to provide a novel 
source of patient education by developing an 
immersive VR program that realistically 
replicates the treatment experience and enables 
patients to feel a strong sense of presence in the 
virtual treatment room. A potential risk 
associated with this goal is if patients are 
incredibly anxious about the radiotherapy 
treatment process, the VR experience may also 
induce anxiety. 
Patients will be informed that they should 
remove the HMD if they feel any discomfort. 
Patients should talk to their radiation oncologist 
if they feel anxiety regarding their treatment. 
Contagious conditions, such as those in the 
eyes, nose, or scalp, may transfer between 
different users of the device18. 
Patients with a known infection/contagious 
condition will not undergo the VR experience 
if they are considered to be contagious. 
Further, the HMD will be cleaned between 
each use with germicidal 
wipes (i.e. Purell). 
Patient responses to surveys could potentially 
be leaked/ subject to unauthorized access and 
be used in a way that could embarrass the 
subject. Further, someone could find out a 
patient is in this study. 
Hard-copies of patient-completed questionnaires 
will remain locked inside of a cabinet in a secure- 
access building. Responses from these hard- 
copies will also be entered into OnCore® and 
potentially stored in a password- protected format 
on private, network-attached shared drive. 
Transportation of data, if necessary, will occur on 
an encrypted flash key. Further, upon enrollment 
in the study, patients will be assigned a unique 
alphanumeric identifier, so their name will not be 
attached to hard- 
copies of the study questionnaires. The study 
will be discussed with the patient in a private 
setting. 

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The VR HMD blocks view of the outside 
world. Patients could potentially bump into 
something or fall because they cannot see what 
is around them at the time of use. 
Patients will sit down while experiencing the 
VR education program. Pre-determined 
movement about the virtual treatment room has 
been implemented by moving the camera in the 
scene, so patients will not need to conduct any 
physical navigation 
 
If a complaint is received by anyone on the study staff, it will be discussed with the study staff and will 
be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints will be 
reported to the IRB if indicated. 
 
If the subject has questions about his or her rights as a study subject, wants to report any problems or 
complaints, obtain information about the study or offer input, the subject can call the Medical College 
of Wisconsin/Froedtert Hospital research subject advocate at 414-955-8844. This information is 
provided to the subject in their consent. 
 
11.4 Benefits 
Table 4: Benefits of Study 
 
Potential Direct Benefit to Subject 
Benefit to Science 
The goal of the current study is to lessen the 
burden that pre-treatment anxiety 
unfortunately places on many breast cancer 
patients' lives. Through familiarizing patients 
with the sights and sounds of radiotherapy by 
presenting a VR program designed to give 
patients a strong sense of presence in a virtual 
treatment room, and increasing 
comprehension with educational narration and 
interactive mechanisms designed to promote 
patient-engagement, we believe that patients 
in the experimental group may be less 
anxious about their treatment in the time 
period leading up to the first fraction of 
treatment, and during treatment. 
If the hypothesis of this study is met (i.e., VR 
patient education is shown to provide 
increased comprehension of upcoming 
treatment procedures and decreased anxiety 
levels), then VR education programs may be 
become more widespread and used in 
accompaniment to standard education 
interventions when those interventions alone 
are not enough to explain to patients the 
complex nature of a given treatment. We are 
also not limited to breast cancer treatment, 
but if this study proves successful (as the 
limited number of related studies have) then 
over time, a multitude of treatments may 
have their own accompanying VR patient 
education programs, thereby decreasing 
anxiety and increasing comprehension for all 
types of patients at a national, and potentially 
global level. 

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12.0 REFERENCES 
 
 
 
1Andersen, B. and Tewfik, H. (1985). Psychological reactions to radiation therapy: 
Reconsideration of the adaptive aspects of anxiety. Journal of Personality and Social Psychology, 
48(4), pp.1024-1032. 
2Halkett, G., Kristjanson, L., Lobb, E., Little, J., Shaw, T., Taylor, M. and Spry, N. (2012). 
Information needs and preferences of women as they proceed through radiotherapy for breast 
cancer. Patient Education and Counseling, 86(3), pp.396-404. 
 
3Auer, C., Glombiewski, J., Doering, B., Winkler, A., Laferton, J., Broadbent, E. and Rief, W. 
(2015). Patients’ Expectations Predict Surgery Outcomes: A Meta-Analysis. International 
Journal of Behavioral Medicine, 23(1), pp.49-62. 
 
4Sieberg, C., Manganella, J., Manalo, G., Simons, L. and Hreski, M. (2017). Predicting 
Postsurgical Satisfaction in Adolescents with Idiopathic Scoliosis. Journal of Pediatric 
Orthopaedics, 37(8), pp.e548- e551. 
 
5Hamilton, D., Lane, J., Gaston, P., Patton, J., MacDonald, D., Simpson, A. and Howie, C. 
(2013). What determines patient satisfaction with surgery? A prospective cohort study of 4709 
patients following total joint replacement. BMJ Open, 3(4), p.e002525. 
 
6Kiyak, H., Vitaliano, P. and Crinean, J. (1998). Patients’ expectations as predictors of 
orthognathic surgery outcomes. Health Psychology, 7(3), pp.251-268. 
 
7Lewis F, Merckaert I, Liénard A, Libert Y, Etienne A-M, Reynaert C, Slachmuylder J-L, Scalliet 
P, Van Houtte P, Coucke P, Salamon E, Razavi D. Anxiety at the first radiotherapy session for 
non-metastatic breast cancer: 
Key communication and communication-related predictors. Radiotherapy and Oncology. 2015;114:35-41 
 
8Sanchez-Vives MV, Slater M. From presence to consciousness through virtual reality. 
Nature Reviews Neuroscience. 2005;6:332 
 
9Quam DJ, Gundert TJ, Ellwein L, Larkee CE, Hayden P, Migrino RQ, Otake H, LaDisa JF, 
Jr. Immersive visualization for enhanced computational fluid dynamics analysis. J Biomech 
Eng. 2015;137 
 
10Association AP. What is exposure therapy? 2018 
 
11Mishkind MC, Norr AM, Katz AC, Reger GM. Review of virtual reality treatment in psychiatry: 

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Evidence versus current diffusion and use. Curr Psychiatry Rep. 2017;19:80 
 
12Botella C, Fernandez-Alvarez J, Guillen V, Garcia-Palacios A, Banos R. Recent progress 
in virtual reality exposure therapy for phobias: A systematic review. Curr Psychiatry Rep. 
2017;19:42 
 
13Powers, M., & Emmelkamp, P. (2008). Virtual reality exposure therapy for anxiety disorders: A meta- 
analysis. Journal Of Anxiety Disorders, 22(3), 561-569. doi: 10.1016/j.janxdis.2007.04.006 
 
14Opriş, D., Pintea, S., García-Palacios, A., Botella, C., Szamosközi, Ş., & David, D. (2011). Virtual 
reality exposure therapy in anxiety disorders: a quantitative meta-analysis. Depression And Anxiety, 29(2), 
85-93. doi: 10.1002/da.20910 
 
15Jimenez YA, Wang W, Stuart K, Cumming S, Thwaites D, Lewis S. Breast cancer patients' 
perceptions of a virtual learning environment for pretreatment education. J Cancer Educ. 2017 
 
16Marquess, M., Johnston, S., Williams, N., Giordano, C., Leiby, B., Hurwitz, M., Dicker, A. 
and Den, R. (2017). A pilot study to determine if the use of a virtual reality education module 
reduces anxiety and increases comprehension in patients receiving radiation therapy. Journal of 
Radiation Oncology, 6(3), pp.317-322. L; 
 
17 Bekelis K, Calnan D, Simmons N, MacKenzie TA, Kakoulides G. Effect of an immersive 
preoperative virtual reality experience on patient reported outcomes: A randomized controlled 
trial. Ann Surg. 2017;265:1068-1073 
 
18 "Oculus", Oculus.com. [Online]. Available: https://www.oculus.com/legal/health-and-safety-warnings/. 
[Accessed: 15- Mar- 2019]. 

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Appendix 1: VR Education Script - Excluded for Copyright reasons 
 
 

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Appendix 2: INS - Excluded for Copyright reasons 

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Appendix 3: STAI - Excluded for Copyright reasons

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Appendix 4: Questionnaires - Excluded for Copyright reasons