Pilot Study of a Novel Optical Surface Image Guidance System for Beam-Gated Online Adaptive SBRT Delivery in Mobile Lower Lung and Upper Abdominal Malignancies
Phase: NA
Conditions: Any Solid Malignancies of Any Tissue Origin (Except for Small Cell Lung Cancer) Involving the Upper Abdomen and Thorax
Sponsor: Washington University School of Medicine

Protocol Version: 10/14/2022 
 
Page 1 of 39 
 
 
 
Pilot Study of a Novel Optical Surface Image Guidance System for Beam-Gated Online 
Adaptive SBRT Delivery in Mobile Lower Lung and Upper Abdominal Malignancies 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol #: 202107198 
Version Date: 14 October 2022 
 
Principal Investigator: 
 
Pamela Samson, M.D., M.P.H.S 
Phone: (314) 747-1786 
E-mail:  psamson@wustl.edu  
 
 
Co-Investigators: 
 
 
 
Alex Price, MS 
Taeho Kim, PhD 
Eric Laugeman, MS 
Nels Knutson, PhD 
James Kavanaugh, PhD 
 
Study Device: 
ETHOS 
NCT#: 
NCT05030454 
 
Funded by: 
Varian Medical Systems 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Pilot Study of a Novel Optical Surface Image Guidance System for Beam-Gated Online 
Adaptive SBRT Delivery in Mobile Lower Lung and Upper Abdominal Malignancies 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
07/27/2021 
Amendment #1 Version 
 
 
 
 
 
 
10/14/2022 
 
 
 

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Page 3 of 39 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
 
 

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Table of Contents 
 
PROTOCOL SUMMARY .............................................................................................................. 6 
Synopsis ..................................................................................... Error! Bookmark not defined. 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 9 
1.1 
SBRT for tumor ablation .................................................................................................. 9 
1.2 
SBRT Considerations for Mobile Tumors ....................................................................... 9 
1.3 
Inter-fraction Motion Management ................................................................................ 10 
1.4 
Intra-fraction Motion Management ................................................................................ 11 
1.5 
Varian ETHOS system ................................................................................................... 12 
1.6 
Identify Surface Guidance system .................................................................................. 13 
1.7 
Study Rationale .............................................................................................................. 13 
2.0 
OBJECTIVES .................................................................................................................... 14 
2.1 
Primary Objective .......................................................................................................... 14 
2.2 
Exploratory Objectives ................................................................................................... 14 
3.0 
PATIENT SELECTION .................................................................................................... 14 
3.1 
Inclusion Criteria ............................................................................................................ 14 
3.2 
Exclusion Criteria ........................................................................................................... 15 
3.3 
Inclusion of Women and Minorities ............................................................................... 15 
4.0 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Confirmation of Patient Eligibility ................................................................................. 16 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 16 
4.3 
Assignment of UPN ....................................................................................................... 16 
4.4 
Screen Failures ............................................................................................................... 16 
5.0 
TREATMENT PLAN AND DELIVERY ......................................................................... 16 
5.1 
Radiation Therapy Guidelines ........................................................................................ 16 
5.2 
Evaluability Guidelines .................................................................................................. 18 
5.3 
General Concomitant Medication and Supportive Care Guidelines .............................. 19 
5.4 
Women of Childbearing Potential .................................................................................. 19 
5.5 
Duration of Therapy ....................................................................................................... 19 
5.6 
Duration of Follow-up .................................................................................................... 20 
5.7 
Lost to Follow-Up .......................................................................................................... 20 
6.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 20 
6.1 
WU PI Reporting Requirements .................................................................................... 21 
6.2 
Exceptions to Expedited Reporting ................................................................................ 21 
7.0 
STUDY CALENDAR ....................................................................................................... 22 
8.0 
DATA SUBMISSION SCHEDULE ................................................................................. 22 
8.1 
Adverse Event Collection in the Case Report Forms ..................................................... 22 
9.0 
MEASUREMENT OF EFFECT........................................................................................ 23 
9.1 
Antitumor Effect – Solid Tumors ................................................................................... 23 
9.2 
Disease Parameters ......................................................................................................... 23 
9.3 
Methods for Evaluation of Measurable Disease ............................................................ 24 
9.4 
Response Criteria ........................................................................................................... 26 
10.0 DATA AND SAFETY MONITORING ............................................................................ 29 
11.0 STATISTICAL CONSIDERATIONS............................................................................... 30 
11.1 Stopping Criteria ............................................................................................................ 30 

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11.2 Sample Size .................................................................................................................... 30 
11.3 Primary Objective .......................................................................................................... 30 
11.4 Exploratory Objectives ................................................................................................... 31 
11.5 Statistical Analysis Plan ................................................................................................. 31 
12.0 REFERENCES .................................................................................................................. 32 
APPENDIX A: Karnofsky Performance Scale ............................................................................. 35 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 36 
APPENDIX C: Reporting Timelines ............................................................................................ 38 
 
 

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PROTOCOL SUMMARY 
 
Title: 
Pilot Study of a Novel Optical Surface Image Guidance System for 
Beam-Gated Online Adaptive SBRT Delivery in Mobile Lower 
Lung and Upper Abdominal Malignancies 
Study Description: 
Motion during radiation therapy can be categorized as inter-fraction 
(changes in anatomy that occur between treatment days) and intra-
fraction (changes that occur during the “beam on” window of 
treatment delivery).  Inter-fraction motion is managed by adaptive 
radiotherapy (ART), the process of making changes in the treatment 
plan while the patient remains on the treatment table. This is now a 
standard-of-care therapy within our clinic. Intra-fraction motion is 
managed by gated and non-gated delivery techniques.  Varian 
Medical Systems has integrated the necessary components into a CT-
guided radiotherapy device (ETHOS).  In the ETHOS, Varian has 
built a device that integrates on-board cone beam CT imaging 
capable of delineating target and organ-at-risk positions and a 
dedicated artificial intelligence-driven treatment planning system for 
inter-fraction motion management as well as a paired optical surface 
image guidance system for intra-fraction motion management. 
Although online ART is a standard-of-care practice in our clinic and 
has previously been shown to be feasible, use of surface-guidance 
for intra-fraction gating of abdominal and thoracic SBRT on ETHOS 
is novel. 
 
Therefore, in this study, we propose to evaluate the feasibility and 
safety of using a novel surface guidance beam-gating system, 
incorporated with a CBCT-guided adaptive radiotherapy platform, to 
manage respiratory motion during delivery of CT-guided stereotactic 
radiotherapy.  To best assess the utility of this technology to manage 
respiratory motion, we will focus on disease sites that are highly 
affected by respiratory motion: upper abdominal or lower thoracic 
malignancies. 
Objectives: 
Primary Objective: 
To demonstrate that surface guided, breath-hold respiratory gated 
delivery of CT-guided stereotactic adaptive radiotherapy (CT-
STAR) is feasible in the abdomen and lower thorax by confirming 
that gated treatment can be delivered successfully in more than 75% 
of scheduled treatment fractions using a novel surface guidance 
system. 
 
Exploratory Objectives: 
1. Determine 
geometric 
agreement 
between 
breath-hold 
positioning as determined by a novel surface guidance system 
vs. concomitant breath-hold CBCT image sets. 

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2. Evaluate the compatibility of a standard-of-care respiratory 
gating system and the novel surface-guidance system for 
concomitant use. 
3. Determine the minimum safe planning target volume and 
planning organ-at-risk volumes to be subsequently utilized 
with the novel surface guidance system. 
4. Determine the local, in-field control rate at three months post-
treatment. 
5. Determine acute toxicity rates at three months post-treatment. 
6. Identify patient and or treatment factors that maximize the 
potential efficacy of surface guided breath-hold respiratory 
gating. 
Endpoints: 
Primary Endpoint: 
Percentage of scheduled treatment fractions delivered successfully 
using the surface guidance system. Success will be defined as 
delivery of a given treatment fraction in one on-table attempt, 
without requiring use of a secondary (backup) motion management 
system, or alternative treatment machine. Unsuccessful delivery of a 
fraction will be defined as multiple attempts for gating without 
reproducible positioning, breath-hold, and/or surface guidance 
feedback, such that the fraction is abandoned. 
 
Exploratory Endpoints: 
1. Geometric agreement between breath-hold positioning as 
determined by a novel surface guidance system compared 
with standard of care concomitant breath-hold CBCT image 
sets, as evaluated by average symmetric surface distance 
(ASSD), modified Hausdorff distance (MHD), and Dice 
similarity coefficient measurements. 
2. Qualitative evaluation of the compatibility of a standard-of-
care respiratory gating system and the novel surface-
guidance system for concomitant use. 
3. Quantitative and qualitative measurement of minimum 
planning target volume (PTV) margins and planning organ-
at-risk volumes to be subsequently utilized with the novel 
surface guidance system as determined through measurement 
evaluations in exploratory endpoint 1. 
4. Local, in-field control rate at three months post-treatment 
will be determined as part of standard-of-care clinical 
evaluation by the treating physicians, using RECIST criteria. 
5. Qualitative description of acute (within 90 days) Grade 3 or 
higher non-hematologic toxicity events related to radiation 
therapy at three months post-treatment. 
6. Qualitative description of patient and treatment site factors, 
such as unique patient surface topography or skin tone, that 

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might impact surface imaging tracking at the region of 
interest.  
Participant Population 
Ten adult patients with upper abdominal or lower thoracic 
malignancies who will be treated with CT-guided stereotactic 
radiotherapy with optional online adaptation and surface-guided 
beam-gating. 
Phase: 
N/A (device feasibility) 
Description of Sites / 
Facilities Enrolling: 
This study will be open at the Siteman Cancer Center at Washington 
University School of Medicine. 
Description 
of 
Study 
Intervention: 
The Varian ETHOS is a ring-gantry CT-guided radiotherapy unit.  It 
pairs a linear accelerator within a ring-gantry imaging unit.  It has an 
on-board cone beam CT imaging unit capable of delineating target 
and organ-at-risk position and a dedicated AI-driven treatment 
planning system to enable online adaptive radiotherapy. Recently,  it 
has also been paired with an optical surface image guidance system 
(the Identify OSIG) which relies upon a time-of-flight, ceiling 
mounted, stereo camera system and a random pattern projector. A 
random light pattern is projected onto the patient’s surface, the 
reflection of which is captured by the stereoscopic cameras with 
subsequent calculation of a 3D point cloud based on corresponding 
points identified across the camera set.  A surface region of interest 
is selected and then monitored for motion or deformation. This has 
been utilized previously for surface-based radiation delivery, such as 
for breast cancer, but has not previously been utilized to guided 
stereotactic body radiotherapy (SBRT) for internal thoracic or 
abdominal targets as part of the Varian ETHOS treatment platform. 
In this pilot/Phase I study, the feasibility and safety of using the 
Identify OSIG system to guide delivery of thoracic and abdominal 
SBRT will be evaluated. 
 
Consenting and eligible patients will be treated using SBRT in five 
fractions over one to two weeks.  For patients undergoing optional 
plan adaptation, adaptation will be based on daily anatomic changes 
as per standard of care.  For both adaptive and non-adaptive patients, 
the prescription dose will be determined based on normal tissue 
constraints and capped at 12 Gy per fraction, as per standard 
institutional practice. 
Study Duration: 
12 months (enrollment) + 2 weeks (treatment) + 3 months (follow-
up) + 12 months (analysis) = 28 months 
Participant Duration: 
4 months 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
SBRT for tumor ablation 
 
Within the realm of radiation therapy, stereotactic body radiotherapy (SBRT) has emerged 
as a means to focally target and ablate both primary and metastatic cancers 1. This technique 
involves delivery of numerous, individually weak radiation beams to converge on a focal 
target for delivery of a highly precise, conformal, and ablative dose in five or fewer 
treatment fractions. The dose per fraction is substantially higher than that used in 
conventionally fractionated radiotherapy, where treatment fields tend to be larger, may 
overlap with normal tissues, and are treated in small amounts of radiation per day over 
multiple (usually 5 or more) weeks of therapy. The high dose per day used for SBRT--
unthinkable in the prior era—is enabled by progressive advancement in treatment delivery 
and image-guidance technology that allows safe, accurate, and precise treatment delivery. 
Compared to conventionally fractionated radiotherapy, SBRT has been shown to improve 
overall survival outcomes in early stage non-small cell lung cancer2 and is associated with 
improved overall survival in upper abdominal cancers like pancreatic cancer 3,4. Similarly, 
when compared to standard systemic therapies or conventional care, focal disease ablation 
with SBRT also improves overall survival in oligometastatic cancers of multiple 
histologies 5-7.  
 
The efficacy of SBRT in producing durable disease control and survival benefit is 
predicated on delivery of sufficiently ablative dose. Dose escalation, particularly to dose 
thresholds achieving a biologically effective dose (BED) of 100Gy or more, has been 
demonstrated to improve local control and survival outcomes across histologies 8-10. 
Delivery of such high dose treatment depends on focal target delineation and rapid 
radiation dose fall off to avoid excess dose to surrounding normal tissues. Excess dose to 
adjacent critical structures erodes the therapeutic gain of SBRT over conventional 
fractionation and can result in high grade toxicity and even mortality risk 11. Thus, precise 
SBRT delivery and minimized dose to surrounding organs-at-risk (OARs) is critical. This 
balance of the therapeutic index is particularly challenging in treatment sites subject to 
motion, especially when critical structures are proximal to the tumor. Indeeed, in such 
cases, adequate treatment of the tumor with necessary margins to account for its possible 
locations in a four-dimensional (4D) space can then compete with the space occupied by 
adjacent OARs and their similar motion. 
 
1.2 
SBRT Considerations for Mobile Tumors 
 
Motion during radiation therapy can be broadly categorized as being inter-fraction or intra-
fraction. Inter-fraction motion comprises less-predictable changes in anatomy that occur in 
between treatment days, such as normal organ motion from peristalsis (e.g., bowel 
peristalsis) or organ filling (bladder, stomach, rectum), or changes like tumor shrinking 
response to treatment. Intra-fraction motion refers to the motion occurring during the 
“beam on” window of treatment delivery. Predictable motion from the respiratory cycle is 
a dominant contributor to intra-fraction motion during SBRT to thoracic and abdominal 

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tumor sites and is a common focus of intra-fraction motion management. In order to 
maximize the therapeutic index for SBRT delivery, one ideally considers and manages both 
types of motion. 
 
1.3 
Inter-fraction Motion Management 
 
Until recently, inter-fraction motion management options to adjust for changes in tumor 
and organ-at-risk geometry in between treatment days have been limited. This motion is 
often unpredictable, such as with peristalsis, or difficult to control even with explicit 
instructions to patients, such as bladder filling. It can also be due to more permanent 
changes in patient anatomy, like reduction in tumor size during treatment or patient weight 
loss. Management of such semi-permanent inter-fraction changes has relied inconsistently 
on offline adaptation, or changes made to the radiation treatment plan in the hours between 
deliveries, while the patient is off of the treatment table. Offline ART is most commonly 
utilized in head and neck cancer radiotherapy for tumor response and patient weight loss 
12. In contrast, a plan library approach attempts to address more dynamic (but still 
predictable) motion like organ filling. It involves creation of several plan choices for a 
single patient, so that depending on the “anatomy of the day”, the best-matching plan is 
crudely selected for delivery. This is best described in pelvic radiotherapy to mitigate the 
impact of bladder filling changes on target coverage and OAR sparing 13,14. However, 
neither offline nor plan library adaptive approaches permit flexible real-time adjustment of 
treatment plans and neither accounts for unpredictable motions, like peristalsis. 
 
Online ART is well-suited to account for both unpredictable and predictable types of inter-
fraction motion. Online ART defined as the process of making daily changes in the 
radiation therapy treatment plan in response to observed changes in daily anatomy, while 
the patient remains on the treatment table. Our institution was the first in the world to 
clinically implement this technique for SBRT in 2014, using advanced image-guidance 
with magnetic resonance imaging 15,16. In the setting of SBRT, this allows the treating 
physician to account for and respond to inter-fraction organ motion and tumor changes to 
maximize tumor dose while minimizing dose to normal tissue. This improves the precision 
and accuracy of SBRT delivery and widens the therapeutic index. Specifically, our 
institution and others have shown improvement in the dosimetric therapeutic index of 
SBRT using online ART for upper abdominal 16, thoracic 17, and pelvic disease sites 18. 
This has translated into prospectively and retrospectively validated reduction in treatment-
related toxicities and is associated with improvement in local control and survival 
outcomes 4,18,19.  
 
Efficient delivery of online ART requires three key components: 1. on-table imaging 
sufficient to delineate the target and organs-at-risk, 2. a dedicated treatment planning 
system (TPS) for rapid on-table treatment plan generation and comparison, and 3. real-time 
quality assurance of adaptive plans prior to treatment delivery 20. While online ART can 
be achieved by existing integrated magnetic-resonance image-guided systems 21 as well as 
patched-together systems using CT-on-rails and rapid plan exportation outside of a 
dedicated TPS, these components have now also been successfully integrated into a CT-
guided radiotherapy device (ETHOS, Varian Medical Systems, Palo Alto, CA) on a widely 

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available commercial platform. This CT-guided device received CE MARK and FDA 
clearance in late 2019 and early 2020 respectively, and has been clinically implemented 
both at our institution and in Europe. Improved access to the online adaptive planning 
techniques through this high-through-put, integrated, and commercially available CT-
guided radiotherapy system is likely to further advance the use of online ART for inter-
fraction motion management in the global clinic. 
 
1.4 
Intra-fraction Motion Management 
 
Unlike inter-fraction motion, which can be addressed at a single daily pre-treatment time 
point using online ART, intra-fraction motion management requires continual management 
of motion actively occurring throughout the beam-on time of daily treatments. The 
dominant contributor to intra-fraction motion in affected sites like the thorax and abdomen 
is the predictable motion of the respiratory cycle 22. 
 
1.4.1 Non-gated delivery techniques 
 
In some mobile sites, where respiratory motion amplitude is smaller and occurs 
away from organs-at-risk, the full positional range of the tumor (the “internal target 
volume”, or ITV) can be determined using 4-dimensional CT planning images. In 
this common approach for upper and middle lung lesions, 4DCT at time of 
simulation simultaneously acquires spatial and temporal information on mobility 
and shape of a tumor. From this, reconstructed imaging data can be binned 
according to respiratory phase and used to generate the ITV according to imaging 
reconstructions like the maximum intensity projection (MIP) or average intensity 
projection (AIP), with further editing to ensure the tumor is fully encompassed by 
the ITV in all phases of breathing 23,24. Physical interventions like use of abdominal 
compression plates can be complementarily used to limit ITV size by limiting the 
amplitude of respiratory excursion and have been shown to reduce motion in the SI 
plane by up to 50% 25. Nevertheless, in such sites, one still accepts that the ITV 
motion envelope expands the ablation target into low-risk normal tissues, like 
normal surrounding lung parenchyma, in order to capture the full extent of tumor 
location during delivery. 
 
1.4.2 Gated Delivery Techniques 
 
In sites where respiratory motion amplitude is larger, such as in the lower lobes of 
the lung or the upper abdomen, gated treatment delivery may be utilized instead in 
order to avoid excessive intentional treatment of normal tissues. Respiratory beam-
gating comprises turning the treatment beam on and off as the tumor moves in and 
out of the radiation beam path with respiration during treatment delivery. This may 
be phase (e.g. end-exhale breath-hold) or amplitude based or be triggered based on 
implanted internal fiducial marker tracking. In lung patients, the typical threshold 
to trigger gated delivery as opposed to using an ITV approach is a measured tumor 
respiratory motion amplitude of >1cm despite adequate abdominal compression at 
the time of simulation image acquisition (PACIFIC-4 protocol) TG 101. In the 

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abdomen, where surrounding tissues are at higher injury risk, e.g., the duodenum 
relative to the pancreas 26, and/or the 4D motion envelope of a tumor may have ill-
defined margins, gated delivery of SBRT is a common approach 27-29. 
  
Gated delivery of SBRT requires real-time monitoring of respiratory motion, most 
often using surrogates for the tumor motion. This can be accomplished using 
several technologies. One standard technique is real-time position management 
(RPM), with an infrared camera system mounted in the treatment room that 
monitors the movement of a reflective surrogate external marker block placed on 
the patient’s abdomen or chest 30. A respiratory trace is generated based off of 
tracked surrogate motion and the beam can be gated on and off at desired phases or 
amplitude ranges of the respiratory cycle. However, use of a single external marker 
box alone to capture motion in a single plane may not robustly account for 
respiratory motion of an internal target and can result in errors in target localization 
of ~5mm in the SI plane31. RPM can be used in combination with periodic triggered 
intra-fraction imaging visualization of the tumor or internally placed fiducial 
markers to verify consistent correlation between the tumor and surrogate motion 
and improve accuracy, although an additional 2-3mm of uncertainty may remain 
31,32. While more robust, fiducial placement and monitoring or even fiducial 
tracking-based deliveries are expensive, require an invasive procedure for fiducial 
implantation, lead to delays in initiation of treatment for marker placement and 
settling before simulation 28, and expose the patient to protracted treatment times 33 
as well as additional imaging dose during delivery 34. 
 
An alternative and emerging technique is the use of optical surface image 
monitoring for continuous, non-invasive, and non-radiographic patient localization 
and respiratory tracking for SBRT. Surface guided radiotherapy can enable both 
breath-hold and amplitude phase-based gating, using a combination of light 
projectors to project a pattern of light onto the patient’s surface and 2-3 optical 
cameras to generate and then track the motion of a 3-dimensional map of patient 
topography. Compared with techniques like RPM, monitoring of multiple surface 
points instead of a single surrogate marker improves accuracy of motion monitoring 
35. Surface guidance motion monitoring has been shown to be accurate to 1mm 
motion/1degree of rotation in the delivery of intracranial stereotactic radiosurgery 
36. It is also used to enable deep inspiratory breath hold (DIBH) gating in focal 
radiotherapy treatments like accelerate partial breast radiotherapy (APBI) to within 
2mm of setup accuracy 37. Recently, it has been implemented for monitoring of 
internal target motion for lung and upper abdomen SBRT, and shown to accurately 
reflect internal anatomic shifts of 2mm or more compared to repeat cone beam CT 
alignment 25 38.  
 
1.5 
Varian ETHOS system 
 
Ideally, to maximize the therapeutic index of SBRT, both inter- and intra-fraction motion 
management strategies would be combined within a single treatment platform. This 
combination is now possible using a novel CT-guided radiotherapy device. Varian Medical 

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Systems (Palo Alto, CA) has produced a unique ring-gantry CT-guided radiotherapy unit, 
pairing a linear accelerator within a ring-gantry imaging unit. In addition to housing an on-
board cone beam CT (CBCT) imaging unit capable of delineating target and OAR positions 
39 and dedicated artificial-intelligence (AI)-driven TPS to enable online adaptive 
radiotherapy, this system also has a paired optical surface image guidance system for intra-
fraction motion management. Our institution is among the first in the world to use this 
device for standard of care patient treatment, having completed commissioning and testing 
of treatment planning software, dose delivery, and imaging technology. Its online adaptive 
radiotherapy capabilities (for inter-fraction motion management) have already been 
established in non-mobile sites. Similarly, the paired Identify OSIG system has been 
evaluated for conventionally fractionated radiotherapy treatment. However, the OSIG 
system has yet to be prospectively evaluated for beam-gating specifically during SBRT. 
 
1.6 
Identify Surface Guidance system 
 
The Identify system relies upon a time-of-flight, ceiling mounted, stereo camera system 
and a random pattern projector. A random light pattern is projected onto the patient’s 
surface (e.g., abdominal or thoracic wall), the reflection of which is then captured by the 
stereoscopic cameras with subsequent calculation of a 3D point cloud based on 
corresponding points identified across the camera set. A surface region of interest (ROI) is 
selected and then monitored for motion or deformation. Motion of the respiratory cycle can 
be tracked in this manner and used to derive a phase-based respiratory trace for on-off 
gating of the radiation beam at particular respiratory phases, such as DIBH and end-exhale. 
 
A recorded surface can be calculated at time of patient planning simulation and used for 
initial patient alignment on days of treatment, with subsequent updating of both the 
reference surface and patient alignment based on the initial daily setup verification CBCT 
acquired in room. This new daily surface ROI can then be monitored for intra-fraction 
respiratory motion management through beam-gating, with SGRT software calculation of 
differences in the patients’ actual surface vs. the daily reference surface. The respiratory 
trace is utilized by the treatment team to gate the beam on and off, with available use of 
visual feedback of the respiratory trace to the patient (through an institutional in-room 
display monitor or patient goggles) for respiratory coaching. The patient can then be treated 
in a series of end-exhale or DIBH breath-holds, with optional CBCT verification of patient 
position at pre-set intervals during treatment. 
 
1.7 
Study Rationale 
 
In light of this new motion management technology, we propose to evaluate the feasibility 
and safety of using a novel surface guidance beam-gating system, incorporated with a 
CBCT-guided adaptive radiotherapy platform, to manage respiratory motion during 
delivery of CT-guided stereotactic radiotherapy. To best assess the utility of this 
technology to manage respiratory motion, we will focus on disease sites that are highly 
affected by respiratory motion. Specifically, we will enroll patients with upper abdominal 
or lower thoracic malignancies to receive CT- guided stereotactic radiotherapy with 
optional online adaptation and surface-guided beam-gating. Patients will be treated in five 

Protocol Version: 10/14/2022 
 
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fractions over one to two weeks. For patients undergoing optional plan adaptation, 
adaptation will be based on daily anatomic changes as per our clinical standard of care. For 
both adaptive and non-adaptive patients, the prescription dose will be determined based on 
normal tissue constraints, and capped at 12 Gy per fraction. By adhering to standard 
institutional normal tissue constraints and gating window parameters, expected toxicity 
will be within the current standard of care. Feasibility of using the Identify optical surface 
guidance system to gate stereotactic treatment of the upper abdomen and lower thorax has 
never previously been reported and will be the primary goal of the present study. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
Demonstrate that surface guided, breath-hold respiratory gated delivery of CT-guided 
stereotactic adaptive radiotherapy (CT-STAR) is feasible in the abdomen and lower thorax by 
confirming that gated treatment can be delivered successfully in more than 75% of scheduled 
treatment fractions using a novel surface guidance system. Success will be defined as delivery 
of a given treatment fraction in one on-table attempt, without requiring use of a secondary 
(backup) motion management system, or alternative treatment machine. Unsuccessful delivery 
of a fraction will be defined as multiple attempts for gating without reproducible positioning, 
breath-hold, and/or surface guidance feedback, such that the fraction is abandoned. 
 
 
2.2 
Exploratory Objectives 
 
1. Determine geometric agreement between breath-hold positioning as determined by a 
novel surface guidance system vs. concomitant breath-hold CBCT image sets. 
2. Evaluate the compatibility of a standard-of-care respiratory gating system and the novel 
surface-guidance system for concomitant use. 
3. Determine the minimum safe planning target volume and planning organ-at-risk 
volumes to be subsequently utilized with the novel surface guidance system. 
4. Determine the local, in-field control rate at three months post-treatment. 
5. Determine acute toxicity rates at three months post-treatment. 
6. Identify patient and or treatment factors that maximize the potential efficacy of surface 
guided breath-hold respiratory gating, such as differences in surface topography and 
skin tone. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Primary or metastatic disease of the abdomen or lower thorax, with biopsy-proven or 
radiographically diagnosed disease histology of solid tumor categorization, with the 
exception of small cell cancers. 

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2. Must be medically fit for SBRT as determined by the treating physician, with at least 
one disease site to be deemed suitable for treatment with CT-guided stereotactic 
radiation to the abdomen or thorax as per radiation oncologist evaluation. 
 
3. At least 18 years of age. 
 
4. Karnofsky performance status > 60 (see Appendix A) 
 
5. Capable of single deep inspiratory breath-hold or end-exhale breath-hold of at least 17 
seconds in duration and of repeated end-exhale or deep inspiratory breath-hold of at 
least 10 seconds in duration upon verbal instruction. 
 
6. Must have completed any systemic therapy at least one week prior to planned start of 
SBRT (two weeks preferred), and must have no plans to initiate systemic therapy for 
at least one week following end of SBRT (two weeks preferred). 
 
7. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
3.2 
Exclusion Criteria 
 
1. Past history of radiotherapy within the projected treatment field of any of the disease 
sites to be treated by CT-guided SBRT. 
 
2. Currently receiving any investigational agents. 
 
3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
4. Pregnant and/or breastfeeding.  Patient must have a negative pregnancy test within 14 
days of study entry. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 

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The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form 
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All data 
will be recorded with this identification number on the appropriate CRFs. 
 
4.4 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not subsequently entered in the study.  A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (if applicable).   
 
 
5.0 
TREATMENT PLAN AND DELIVERY 
 
5.1 
Radiation Therapy Guidelines 
 
5.1.1 Dose, Fractionation 
 
Radiotherapy will consist of stereotactic body therapy, to be given over five 
fractions, delivered once daily or once every other day for a period of one to two 
weeks, for a total of five treatments.  Of note, safety of treatment well be kept within 
established guidelines based on standard institutional constraints applied to normal 

Protocol Version: 10/14/2022 
 
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tissues. Patients will be planned for a minimum dose of 35 Gy in five fractions to 
the PTV, with optional dose adaptation based on safety constraints that are already 
approved of, up to a maximum allowed total dose of 60 Gy in five fractions to the 
PTV. The maximum allowable prescription dose to the PTV on any day with 
adaptive planning will be constrained to 12 Gy, subject to coverage goals below. 
 
5.1.2 Simulation Procedures/Patient Positioning 
 
All patients will undergo both CT and CBCT simulation in positioning appropriate 
for the specific treatment site. When medically feasible and applicable, patients will 
be simulated with IV and small bowel contrast (for non-thorax cases). 
  
5.1.3 Clinical Target Volume (CTV) and Planning Target Volume (PTV) 
Definitions 
 
The treatment target will be defined based on the gross tumor volume (GTV) only. 
No CTV expansion will be utilized, as per standard-of-care procedures in the setting 
of SBRT. Additionally, no ITV expansion will be utilized, as gated delivery is 
planned. The PTV will be generated at the discretion of the treating physician but 
should range between 3 mm and 7 mm. 
  
5.1.4 Initial Treatment Planning 
 
All patients will be initially planned to at least 35 Gy in 5 fractions, subject to hard 
constraints based on the treatment site. Dose volume histogram (DVH) information 
for the target volumes and surrounding critical structures is mandatory. This is to 
assist in interpreting outcome, including morbidity. Coverage goal will be for 95% 
of the volume to be covered by 95% of the dose, although in situations where a 
critical structure is violated, reduction of dose will be allowed in areas of overlap. 
   
5.1.5 SBRT Dose Constraints 
 
Standard institutional 5-fraction organ-at-risk dose constraints will be used, at the 
discretion of the treating physician, and in concordance with the treated (abdomen 
vs. thorax) site. For those patients undergoing optional plan adaptation, on 
treatment days where all constraints are met, the prescription dose for that day’s 
treatment may be escalated up to a maximum dose of 12 Gy, if all constraints are 
met. Adaptive plans will be evaluated under the assumption that the delivered 
adaptive plan would meet all hard constraints for 5 fractions with stable anatomy. 
For example, on a given day, the maximum cord dose (to 0.5cc) will be 5 Gy 
(extrapolate to maximum dose 25 Gy over 5 fractions).  
 
5.1.6 Adaptive Treatment Planning 
 
When patients present for their first SBRT treatment session, patients planned for 
optional adaptation will be evaluated by the treating physician to determine if 

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adaptive planning is indicated. Treatment plan re-optimization will be performed 
for dose adaptation if it is determined that the patient’s anatomy allows for dose 
adaptation with acceptable sparing of normal structures (i.e., not violating the 
predetermined hard constraints based on safety constraints that are already 
approved of for routine, clinical use). Dose adaptation can also be done in cases 
where on the volumetric imaging attained, there is noted to be violation of 
previously met hard constraints. If there are no violations of any hard constraint, 
the maximum dose delivered will be capped at 12 Gy per treatment fraction.  
 
5.1.7 Quality Assurance of Adaptive Plans 
 
Patient specific QA will be performed at each fraction prior to delivery of the 
adaptive treatment plan for any patients undergoing optional dose adaptation. 
Given that dose measurements will not be possible with the patient on the table, 
this will be achieved by performing an independent secondary QA check using 
Mobius. The independent QA will be compared to the dose distribution exported 
from the ETHOS system, looking at dose volume histograms and 3D gamma 
analysis of all voxels within the patient. After completion of the automated checks, 
a final review by physics will be required prior to proceeding to treatment delivery.   
 
5.1.8 Surface-Guided Gated Delivery 
 
At time of CT and CBCT simulation, a baseline reference surface region of interest 
will be determined. The region of interest (ROI) will be selected on an individual 
basis for the most sensitivity to detect respiratory motion. At time of first treatment, 
the patient will be set up to marks and the reference surface. Breath-hold CBCT 
daily alignment image will be acquired and a new reference surface ROI will be 
established based on the daily anatomy. The reference surface will be monitored 
using the Identify system and a respiratory trace will be generated and displayed to 
the treatment team for breath-hold respiratory gating of treatment delivery. A visual 
feedback system will be displayed to the patient to aid in respiratory coaching for 
breath-hold. After treatment alignment and optional adaptation, a repeat breath-
hold CBCT will be obtained to evaluate for any patient motion. Shifts can be 
applied as needed prior to initiation of delivery. CBCT can be repeated in the 
breath-hold position at set time points, e.g., after each arc in VMAT plans, and at 
the end of treatment delivery. A recommended maximum of 10 images will be 
taken per fraction. This will be used for intrafraction patient monitoring as well as 
subsequent evaluation of concordance between geometric patient position as 
identified by the Identify system vs. CBCT. 
 
5.2 
Evaluability Guidelines 
 
All patients who receive any radiation therapy are evaluable for the primary objective 
(feasibility of delivering CT-guided SBRT with surface-guidance for gated delivery). 
 
Patients who receive at least one fraction of radiation therapy are evaluable for the 

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exploratory objectives relating to tumor response/control rate and toxicity. 
 
Success will be defined as delivery of a given treatment fraction in one on-table attempt, 
without requiring use of a secondary (backup) motion management system, or alternative 
treatment machine. Unsuccessful delivery of a fraction will be defined as multiple attempts 
for gating without reproducible positioning, breath-hold, and/or surface guidance feedback, 
such that the fraction is abandoned. 
 
Should respiratory gating using the Identify optical surface guidance system not be feasible 
for any given fraction or patient, the treatment fraction will be delivered using an 
alternative, backup motion management device and/or an alternative linear accelerator as 
per standard-of-care therapy. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients are not permitted to receive systemic therapy beginning one week prior to start of 
SBRT and continuing through SBRT and one week post-completion of SBRT.  (It is 
preferred that patients do not receive systemic therapy within 2 weeks of starting and 
ending SBRT, but that is left to the discretion of the treating physician.) 
 
5.4 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 
amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the start of SBRT.   
 
If a patient is suspected to be pregnant, SBRT should be immediately discontinued.  In 
addition a positive urine test must be confirmed by a serum pregnancy test.  If it is 
confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy, 
the investigator must be notified in order to facilitate outcome follow-up. 
 
5.5 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation documented 
in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue for up to 
5 fractions (5 days of SBRT) or until one of the following criteria applies: 
 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 

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permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious noncompliance with the study protocol 
• Lost to follow-up 
• Patient withdraws consent 
• Investigator removes the patient from study 
• The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will be followed for 3 months following the completion of SBRT or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse events will 
be followed until resolution or stabilization of the adverse event.  Follow-up will consist 
of routine volumetric imaging at 3 months post-completion of SBRT to evaluate treatment 
response, and evaluation of toxicity 3 months post-completion of SBRT.  Any additional 
follow-up and imaging will be obtained off-study as per routine clinical policies of the 
treating physician. 
 
5.7 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 3 
consecutive scheduled visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within three weeks of the missed encounter and counsel the participant on the 
importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
6.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 

Protocol Version: 10/14/2022 
 
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outlined below.  Please refer to Appendix B for definitions and Appendix C for a grid of reporting 
timelines. 
 
Adverse events will be tracked from start of treatment through 3 months following the last day of 
SBRT.  All adverse events must be recorded on the toxicity tracking case report form (CRF) with 
the exception of: 
• Baseline adverse events, which shall be recorded on the medical history CRF 
• Grade 1 adverse events 
 
Refer to the data submission schedule in Section 8 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for the Washington University study team may be found in Section 6.1. 
 
6.1 
WU PI Reporting Requirements 
 
6.1.1 Reporting to the Human Research Protection Office (HRPO) at 
Washington University 
 
Reporting will be conducted in accordance with Washington University IRB 
Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to implementing the 
change. 
 
6.1.2 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI (or designee) is required to notify the QASMC of any unanticipated 
problems involving risks to participants or others occurring at WU or any BJH or 
SLCH institution that has been reported to and acknowledged by HRPO.  
(Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via 
email to qasmc@wustl.edu.  Submission to QASMC must include the myIRB form 
and any supporting documentation sent with the form. 
 
6.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 6.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 

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Events that do not require expedited reporting must still be captured in the EDC. 
 
 
7.0 
STUDY CALENDAR 
 
  
Screening 
D1 
D2 
D3 
D4 
D5 
3 mos post-
SBRT4 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Volumetric imaging1 
X 
 
 
 
 
 
X 
CBC 
X 
 
 
 
 
 
 
CMP 
X 
 
 
 
 
 
 
Pregnancy test2 
X 
 
 
 
 
 
 
Adaptive SBRT3 
 
X 
X 
X 
X 
X 
 
Adverse events assessment5 
 
X 
X 
X 
X 
X 
X 
Treatment summary form6 
 
 
 
 
 
X 
 
 
1. CT, MRI, or PET are acceptable as per routine clinical evaluation at the discretion of the treating physician 
2. Women of childbearing potential only 
3. Adaptation of daily SBRT plans is optional 
4. Window is 2-4 months post-completion of SBRT 
5. Assessment during treatment will be through standard care and standard, weekly on-treatment visits  
6. To be completed by the clinical research coordinator 
 
 
8.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
3 months after end of SBRT 
Tumor Response Form 
Baseline, 3 months after end of SBRT 
Progression Form 
Time of disease progression 
Death Form 
Time of death 
 
8.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 6.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 

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Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
9.0 
MEASUREMENT OF EFFECT 
 
9.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response at 3 months 
post-completion of SBRT. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
RECIST evaluations will be performed by study physicians, not IRAC. 
 
9.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since 

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they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements.  
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
9.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 

Protocol Version: 10/14/2022 
 
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scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then 
the CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 

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ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may 
be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
9.4 
Response Criteria 
 
9.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 

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target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
9.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
9.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    

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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
9.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 

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(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that progressive disease is objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline 
measurements.  
 
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual and study-wide actual accrual 
• Protocol activation date 
• Average rate of accrual observed in year 1, year 2, and subsequent years 
• Expected accrual end date 
• Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
• Measures of efficacy 
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities 
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 

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Page 30 of 39 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Stopping Criteria 
 
If at any point in trial enrollment, >2 out of the first 5 patients experience symptoms of G3 
or greater toxicity that is probably or definitely attributable to and did not pre-date SBRT, 
the trial will be suspended. Symptoms that pre-dated SBRT will not be count towards 
stopping criteria (example: central thorax patients requiring oxygen prior to and after 
SBRT will not be scored as G3 toxicity, however a new O2 requirement after RT would 
count towards stopping criteria). If at any time a grade 5 toxicity (death) is observed that 
is probably or definitely attributable to treatment, accrual will be suspended and the event 
will be reviewed by the principal investigator.  Since some patients accruing to the trial 
may have metastatic disease, it is anticipated that deaths unrelated to the trial may be 
observed. Death that is felt either due to disease progression or patient comorbidity will 
not result in trial suspension.  
 
11.2 
Sample Size 
 
The primary endpoint of this study is to assess the feasibility of surface-guided, respiratory 
gated delivery of CT-guided stereotactic radiotherapy for upper abdomen and lower thorax 
malignancies by confirming that gated treatment can be delivered successfully in more than 
75% of scheduled treatment fractions using a novel surface guidance system. A total of 10 
evaluable patients (as defined in Section 5.2) will be included, with five treatment fractions 
each, for a total of n = 50 evaluable fractions. In order to assess the feasibility of the gating 
methodology on the novel surface guidance system, we conducted a one-sample reliability 
demonstration test based on the binomial distribution. The study will be powered based on 
an expected success rate of 95% and a minimum accepted rate of 75%. With 10 patients 
and 5 fractions per patient, 50 total fractions (n=50) would be assessed. In-patient 
correlation is anticipated, as surface-guided delivery is in part patient-surface dependent, 
with an anticipated value of 0.2. With a one-sided alpha of 0.25 and n=50 fractions across 
10 unique patients, we would have a minimum of 92% power to detect feasibility of 
successful gated delivery.  
       
11.3 
Primary Objective 
 
Demonstrate that surface guided, respiratory gated delivery of CT-guided stereotactic 
adaptive radiotherapy (CT-STAR) is feasible in the abdomen and lower thorax by 
confirming that gated treatment can be delivered successfully in more than 75% of 
scheduled treatment fractions using a novel surface guidance system. Success will be 
defined as delivery of a given treatment fraction in one on-table attempt, without requiring 
use of a secondary (backup) motion management system, or alternative treatment machine. 
Unsuccessful delivery of a fraction will be defined as multiple attempts for gating without 
reproducible positioning, breath-hold, and/or surface guidance feedback, such that the 
fraction is abandoned. 

Protocol Version: 10/14/2022 
 
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11.4 
Exploratory Objectives 
 
• Determine geometric agreement between breath-hold positions as determined by a 
novel surface guidance system vs. concomitant breath-hold CBCT image sets.  
Geometric agreement will be evaluated by average symmetric surface distance 
(ASSD), modified Hausdorff distance (MHD), and Dice similarity coefficient 
measurements. 
• Evaluate the compatibility of a standard-of-care respiratory gating system and the novel 
surface-guidance system for concomitant use.  This will be evaluated qualitatively. 
• Determine the minimum safe planning target volume (PTV) and planning organ-at-risk 
volumes (PRV) to be subsequently utilized with the novel surface guidance system.  
This will be determined through measurement evaluations in the first exploratory 
endpoint. 
• Determine the local, in-field control rate at three months post-treatment.  This will be 
determined by the treating physicians using RECIST criteria. 
• Determine acute toxicity rates at three months post-treatment.  This will be assessed by 
a qualitative description of grade 3 or higher non-hematologic toxicity events related 
to radiation therapy at three months post-treatment. 
• Identify patient and or treatment factors that maximize the potential efficacy of surface 
guided breath-hold respiratory gating. These include factors such as surface topography 
features as well as skin tone.  This will be evaluated qualitatively. 
  
11.5 
Statistical Analysis Plan 
 
Our principal objective in this trial will be to determine the feasibility of surface guided, 
respiratory gated delivery of CT-guided stereotactic adaptive radiotherapy (CT-STAR) in 
the abdomen and lower thorax using a novel surface-guidance system. Given that no prior 
data exists for thoracic or abdominal SBRT using this surface guidance system for 
respiratory gating, we will also report descriptive statistics for treatment adaptation, 
dosimetry, geometric and phase agreement between the novel surface guidance system and 
CBCT, acute toxicity, in-field control rates, and minimum acceptable PTV and PRV 
expansions for treatment planning. As a pilot study we will establish these baseline 
parameters.  
 
 

Protocol Version: 10/14/2022 
 
Page 32 of 39 
 
12.0 
REFERENCES 
 
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33 Whyte RI, Crownover R, Murphy MJ, et al. Stereotactic radiosurgery for lung tumors: 
preliminary report of a phase I trial. Ann Thorac Surg 2003; 75: 1097–101. 
34 Stelczer G, Tatai-Szabó D, Major T, et al. Measurement of dose exposure of image guidance 
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38 Naumann P, Batista V, Farnia B, et al. Feasibility of Optical Surface-Guidance for Position 
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39 Cai B, Laugeman E, Mazur TR, et al. Characterization of a prototype rapid kilovoltage x-ray 
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1355–70. 
 
 

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APPENDIX A: Karnofsky Performance Scale 
 
Able to carry on normal activity and to work; no 
special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease.  
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
 
 

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APPENDIX B: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for all toxicity reporting.  A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 
o A life-threatening adverse event 

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o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 
 

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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
Unanticipated problem 
involving risk to 
participants or others 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
Report via email after IRB 
acknowledgment 
Major deviation 
Report within 10 working days.  If the event 
results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day. 
 
A series of minor 
deviations that are being 
reported as a continuing 
noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to 
implementing the change 
 
Complaints 
If the complaint reveals an unanticipated 
problem involving risks to participants or 
others OR noncompliance, report within 10 
working days.  If the event results in the death 
of a participant enrolled at WU/BJH/SLCH, 
report within 1 working day.  Otherwise, 
report at the time of continuing review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 
If withdrawing the participant does not 
represent a safety issue and the patient will be 
withdrawn, report at continuing review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 
which is typically due 
every 6 months. 
Minor deviation 
Report summary information at the time of 
continuing review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If 
the event results in the death of a participant 
enrolled at WU/BJH/SLCH, report within 1 
working day.  Otherwise, report at the time of 
continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety 
issue, report within 10 working days.   
 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, 
report at continuing review.