Pilot Study of Same-session MR-only Simulation and Treatment With Stereotactic MRI-guided Adaptive Radiotherapy (SMART) for Oligometastases of the Spine
Phase: NA
Conditions: Oligometastases of the Spine
Sponsor: Washington University School of Medicine

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Pilot Study of Same-session MR-only Simulation and Treatment with 
Stereotactic MRI-guided Adaptive Radiotherapy (SMART) for 
Oligometastases of the Spine 
 
 
Washington University School of Medicine 
Department of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
  
Protocol #: 201903023 
Version Date: 02/27/2023 
  
Principal Investigator: 
Clifford Robinson, M.D. 
Phone: (314) 362-8567 
E-mail:  clifford.robinson@wustl.edu 
  
Sub-Investigators:   
 
 
 
 
 
Pamela Samson, MD 
 
 
 
 
Shahed Badiyan, MD 
 
 
 
 
Greg Vlacich, MD, PhD 
 
 
 
 
Eric Morris, PhD 
 
 
 
 
 
  
  
Study Device: 
MRIdian Linac System from ViewRay (0.35T MRI combined with 
a linear accelerator (MR-linac)) 
NCT #:        
 
 
NCT03878485 
Funded by: 
 
 
Departmental of Radiation Oncology (seed grant) 
  
 
 
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 Same-session MR-only Simulation and Treatment with Stereotactic MRI-
guided Adaptive Radiotherapy (SMART) for Oligometastases of the Spine 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
03/04/2019 
Amendment #1 Version 
 
 
 
 
 
 
11/04/2019 
Amendment #2 Version 
 
 
 
 
 
 
11/02/2020 
Amendment #3 Version 
 
 
 
 
 
 
05/16/2022 
Amendment #4 Version 
 
 
 
 
 
 
09/20/2022 
Amendment #5 Version 
 
 
 
 
 
 
11/23/2022 
Amendment #6 Version 
 
 
 
 
 
 
02/27/2023 
 
 

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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 ...................................................................................................................................... 6 
1 
BACKGROUND ..................................................................................................................... 7 
1.1 
Spinal Metastases ............................................................................................................. 7 
1.2 
Stereotactic Body Radiation Therapy for Metastatic Disease .......................................... 7 
1.3 
Magnetic Resonance Image-guided Radiotherapy ........................................................... 8 
1.4 
Same-Day Radiotherapy Treatment Planning .................................................................. 9 
1.5 
Rationale ......................................................................................................................... 11 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 12 
3 
STUDY POPULATION ........................................................................................................ 13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 13 
3.3 
Inclusion of Women and Minorities ............................................................................... 13 
4 
REGISTRATION PROCEDURES ....................................................................................... 14 
4.1 
Confirmation of Patient Eligibility ................................................................................. 14 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 14 
4.3 
Assignment of UPN ....................................................................................................... 14 
4.4 
Screen Failures ............................................................................................................... 14 
4.5 
Strategies for Recruitment and Retention ...................................................................... 14 
5 
TREATMENT PLAN............................................................................................................ 15 
5.1 
Study Intervention Description and Administration ...................................................... 15 
5.2 
Collection of AEs ........................................................................................................... 20 
5.3 
Definitions of Evaluability ............................................................................................. 20 
5.4 
Women of Childbearing Potential .................................................................................. 20 
5.5 
Duration of Therapy ....................................................................................................... 21 
5.6 
Duration of Follow-up .................................................................................................... 21 
5.7 
Lost to Follow-Up .......................................................................................................... 21 
6 
DOSE DELAYS / DOSE MODIFICATIONS ...................................................................... 22 
7 
REGULATORY AND REPORTING REQUIREMENTS ................................................... 22 
7.1 
WU PI Reporting Requirements .................................................................................... 22 
7.2 
Exceptions to Expedited Reporting ................................................................................ 23 
8 
STUDY CALENDAR ........................................................................................................... 23 
9 
DATA SUBMISSION SCHEDULE ..................................................................................... 24 
9.1 
Adverse Event Collection in the Case Report Forms ..................................................... 24 
10 
MEASUREMENT OF EFFECT........................................................................................ 24 
10.1 Antitumor Effect – Solid Tumors ................................................................................... 24 
10.2 Disease Parameters ......................................................................................................... 24 
10.3 Methods for Evaluation of Measurable Disease ............................................................ 25 
10.4 Response Criteria ........................................................................................................... 28 
11 
DATA AND SAFETY MONITORING ............................................................................ 30 
12 
STATISTICAL CONSIDERATIONS............................................................................... 31 

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12.1 Stopping Criteria ............................................................................................................ 31 
12.2 Sample Size Calculation ................................................................................................. 31 
12.3 Statistical Analysis Plan ................................................................................................. 31 
13 
REFERENCES .................................................................................................................. 33 
APPENDIX A: Supplementary Data ............................................................................................ 36 
APPENDIX B: Karnofsky Performance Scale ............................................................................. 42 
 
 
 

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PROTOCOL SUMMARY  
 
Synopsis 
 
Title: 
Pilot Study of Same-session MR-only Simulation and Treatment 
with Stereotactic MRI-guided Adaptive Radiotherapy (SMART) for 
Oligometastases of the Spine 
Study Description: 
This is a pilot study evaluating the ability to treat patients with 
metastatic disease to the spine with same-session MRI-only 
simulation and treatment with MRI-guided radiotherapy. 
Objectives: 
Demonstrate that same-session MRI-only simulation and treatment 
with stereotactic MRI-guided radiotherapy (SMART) for spinal 
oligometastases is feasible. 
Endpoints: 
Primary Endpoint(s): Feasibility will be defined as delivery of the 
first fraction of same-session MRI-only simulation and treatment 
with SMART in the first on-table attempt for at least 70% of patients. 
Secondary Endpoints: None 
Study Population: 
Patients with at least one disease site deemed to be suitable for 
treatment with spine SBRT as per radiation oncology evaluation. 
Phase: 
Not applicable. 
Description of 
Sites/Facilities 
Enrolling: 
This is a single center study enrolling at Siteman Cancer Center at 
Washington University School of Medicine. 
Description of Study 
Intervention: 
Consenting and eligible patients will receive MRI-only simulation 
and stereotactic MRI-guided radiotherapy (2 or 5 fractions). 
Study Duration: 
48 months for accrual + 4 months of participant duration (screening, 
treatment, and follow-up) + 12 months for data analysis = 64 months 
Participant Duration: 
Maximum of 4 months per patient (screening, 2 or 5 fractions of 
radiotherapy, 3-month follow-up). 
 
 
 
 
 
 
 

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1 
BACKGROUND 
  
1.1 
Spinal Metastases 
 
Despite advances in cancer therapy, metastatic disease is an eventual reality for 
innumerable oncology patients. With advances in systemic therapies, the life expectancy 
of cancer patients increases, concomitantly increasing the global burden of metastatic 
disease (1). As patients live longer with metastases, the role of local therapy to ablate 
individually symptomatic and threatening tumor foci is increasingly important. Spinal 
metastases, in particular, are considered critical disease foci for local treatment due to the 
substantial morbidity and mortality of disease progression in sites proximal to the spinal 
cord and nerve roots (2). 
 
1.2 
Stereotactic Body Radiation Therapy for Metastatic Disease 
 
Within radiation oncology, stereotactic body radiation therapy (SBRT) is a favored 
modality for local ablation of metastatic disease. SBRT, defined as delivery of high-dose 
radiation in five or fewer fractions, offers sharp dose gradients that allow physicians to 
ablate such disease while sparing immediately adjacent critical structures. In-field control 
rates of metastases treated with SBRT are roughly 80% up to four years after therapy, even 
in series examining heterogeneous histologies, sites, and dose (3-5). SBRT is particularly 
favored for oligometastatic disease, a phase in oncogenic progression where malignant 
clones have not yet achieved widespread malignant potential, often defined as three or 
fewer progressive sites of disease. Ablation of metastases, particularly oligometastases, 
may improve not only patient functional status through local control but has also recently 
been shown to improve overall survival in solid tumor histologies (6-8). Although a 
majority of patients who undergo SBRT for oligometastatic disease will experience relapse 
with distant metastases, approximately 20% of patients with in-field control remain 
disease-free at 2-4 years of follow-up (3, 4, 6). In a randomized prospective study by Palma 
et al., delivery of SBRT for oligometastases of broad histologic types (five or fewer sites) 
improved median overall survival from 28 to 41 months compared to palliative standard of 
care treatments such as chemotherapy (7). Of  patients treated with SBRT or other 
metastectomy who experience recurrence, as many as 60% have very limited metastatic 
progression that could be amenable to further intervention such as repeated SBRT (8). 
Epidemiologic data suggests that patients undergoing such repetitive metastectomy have a 
survival benefit that is comparable to those undergoing their first procedure (9). 
 
Regarding spine metastases in particular, spine SBRT is a proven treatment modality and 
is often preferred over conventionally fractionated radiation for patients who have good 
performance status, potentially long projected life spans, and/or radioresistant tumors (10). 
However, given the proximity of the spinal cord, the clinical standard of care requires 
magnetic resonance imaging (MRI) or computed tomography (CT) myelography imaging 
in the process of radiation planning, in order to visualize the spinal cord itself as an organ-
at-risk (OAR).  
 
Typically, the spine SBRT treatment-planning paradigm is initiated through a simulation 
(planning) CT and a simulation MRI (or fusion of previously obtained diagnostic MR 

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image sets). Simulation typically takes place within several business days of the clinical 
consult appointment, and an additional 1-2 weeks are needed from the time of simulation 
before a treatment plan is prepared and verified for delivery. Therefore, a patient may not 
start treatment until two weeks after their consult appointment. This workflow prolongs 
patient discomfort from painful osseous and nerve pain and increases the opportunity for 
further threatening of neurologic functions like ambulation and continence as tumors 
progress. Ideally, this workflow could be substantially compressed through advances in 
technology and treatment planning processes. 
 
1.3 
Magnetic Resonance Image-guided Radiotherapy 
 
One such advance within radiation oncology is the emergence of magnetic resonance 
image-guided radiotherapy (MRgRT) over the past five years. MRgRT, which involves RT 
delivery using an integrated MRI, radiotherapy device, and dedicated treatment planning 
system, has become a staple at our institution since we became the first to clinically 
implement it in 2014 (11). Currently, two MRgRT devices are widely used: the original 
0.35 Tesla imaging unit integrated with a tri-Cobalt-60 radiotherapy device and the newer 
device comprising a 0.35T MRI combined with a linear accelerator (MR-linac) (11, 12). 
Although analyses have demonstrated that complex radiation plans created for the tri-
Cobalt-60 source are acceptable (13), plans for small target volumes such as for SBRT are 
less conformal using a tri-Co-60 device compared to a traditional linear accelerator (14). 
Until now, this has limited some uses of MRgRT for SBRT, such as for the spine where 
rapid dose fall-off and conformality adjacent to the spinal cord is critical. However, we 
have recently completed commissioning of the newer MR-linac device and our institutional 
analyses indicate that plan quality with the MR-linac is equivalent to CT-based linac plans, 
like those widely used for spine SBRT (unpublished internal data). 
 
Importantly, these MRgRT devices offer both daily imaging that is sufficient for treatment 
planning and plan modification “online” (while the patient lies on the treatment table) (15, 
16). These daily plans, typically created in response to changes in daily anatomy, are 
termed “adaptive radiotherapy” (ART). Stereotactic, MRI-guided ART (SMART) has 
become common at our institution and we have delivered 1060 adaptive treatment fractions 
in 190 unique treatment courses since 2014 (17, 18). Our primary use of SMART is for 
abdominal malignancies, for which daily planning while the patient lies on the treatment 
machine is a useful way to respond to inter-fraction bowel motion (17). However, the 
SMART treatment planning process could theoretically also be used to generate the 
original plan, rather than to simply adapt existing plans. For sites like the spine, where 
treatment is urgent and the anatomy is more predictable, the SMART paradigm might allow 
creation of spine SBRT plans on the day of treatment, bypassing the need for simulation. 
Indeed, the SMART treatment planning process already comprises nearly all components 
of traditional treatment planning, including volumetric imaging, target volume and organ-
at-risk delineation by the physician, treatment plan generation, and quality assurance with 
an independent, Monte Carlo-based dose verification (15, 18).   
 

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1.4 
Same-Day Radiotherapy Treatment Planning 
 
However, the current treatment planning workflow for SMART has two key characteristics 
that have precluded same-day original plan generation until this point. One is that SMART 
is still based on the use of a pre-treatment simulation session, allowing time (1-2 weeks) 
for careful selection of optimal beam angles and robust planning to target a particular 
disease site (18, 19). Additionally, the simulation process also includes a CT image that is 
used to provide geometric information and tissue relative electron densities (and therefore 
dose) information (13). Ideally, to expedite treatment for spine SBRT, treatment planning 
could rely on same-day MR imaging alone to create a same-session MR-only simulation 
and treatment SMART plan-of-the-day.  
 
The first of these obstacles can be sufficiently overcome for same-session MR-only 
simulation and treatment spine SBRT through simple pre-planning. Spinal anatomy and 
target volumes are fairly predictable in comparison to other disease sites and follow a pre-
determined set of consensus volumes (20). Use of physics pre-planning based upon typical 
spinal anatomy to create a standard initial set of beam angles could mitigate some of the 
same-session simulation and on-table planning time requirements. Additionally, spine 
tumor patients almost uniformly have volumetric diagnostic spine imaging prior to 
radiation consult, typically with MRI. These image sets can be used in the time between 
treatment consult and the first treatment day to adjust the standard set of beam angles to 
individually optimize the tentative pre-plan before the patient is on the treatment table for 
clinical treatment planning. This use of pre-planning will improve the feasibility of creating 
the clinical plan in a time frame that is acceptable and tolerable for the patient to be on the 
treatment table. 
 
Regarding CT-free treatment planning for MRgRT, some progress has been made towards 
this goal at other institutions, but in a limited setting of very simple radiation treatments 
that lack the complexity of SBRT. Investigators at the University of Wisconsin have used 
their MRgRT device for same-session simulation and treatment planning and delivery of 
the first fraction of 2D and 3D-conformal palliative spine radiation treatments (21). 
However, following the first treatment fraction, patients then underwent traditional CT 
simulation and treatment planning; ART was used only to expedite the first fraction. In 
their treatment planning, bulk density overrides were used to assign electron densities 
based on typical values for basic tissue types (bone, fat, lung, soft tissue) (21). Bulk density 
overrides are the only current FDA-approved mechanism for dose extrapolation in MRgRT 
radiation planning, and can overcome the absence of CT density information (22). Such 
overrides carry an anticipated dose uncertainty of <3%, which is considered acceptable 
(23). For reference, the International Commission of Radiation Units and Measurements 
(ICRU) mandates that dosimetry systems be capable of delivering dose to an accuracy of 
5% (24). Other techniques using MR image processing to infer more precise (voxel by 
voxel) density information are emerging within the field and may be useful in the future 
for improving the precision of dosimetry in MRI-only planning. However, these techniques 
are not yet FDA-approved (25). Prospective evaluation of such techniques would be useful 
to inform further MRI-only treatment planning. 
 

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1.4.1 Preliminary Studies 
 
Given that bulk-density override planning is the only FDA-approved method 
available to use for this study, it is important to preliminarily establish the 
dosimetric safety of bulk density override MR-only planning for spine SBRT. To 
this end, we recently completed an in silico evaluation of dosimetric accuracy of 
this method specifically for spine SBRT. Five patients previously treated with 
MRgRT were identified and their 0.35-T MRI and CT datasets were used to create 
spine SBRT plans on the MR-linac treatment planning system (TPS). Patients were 
selected on the basis of availability of spinal imaging and with intent to represent 
anatomy of both sexes and varying body habitus. Patient demographics and 
characteristics are listed in Table 1 below. Six clinical target volume (CTV) and 
planning target volume (PTV) contours were created on each patient’s MRI dataset, 
to represent the six possible contour target volumes endorsed by the International 
Spine Radiosurgery Consortium guidelines, described in the next section. Three 
sets of unique treatment plans were then created for each of the six target volumes 
on all five patients and were subjected to the planning constraints identified for use 
in this protocol.  
 
Table 1. Planning analysis patient demographics 
Patient # 
Gender 
Age 
Habitus 
1 
Male 
62 
Normal 
2 
Male 
67 
Obese 
3 
Female 
66 
Underweight 
4 
Female 
60 
Obese 
5 
Female 
70 
Overweight 
 
The first set of treatment plans (6 plans per each of 5 patients, 30 total plans) were 
made using bulk density override MR-only planning. Specifically, the bony 
anatomy, as contoured by study physicians (vertebral body and adjacent ribs), as 
well as adjacent soft tissues and lung, were assigned standard bulk relative electron 
density values by tissue type: bone (1.12 g/cc), soft tissue (1.01 g/cc), lung (0.25 
g/cc).   
 
After creating the bulk-density override plans, a second set of 30 corresponding 
plans were created by reassigning the relative electron density values based on the 
co-registered CT dataset, and a comparison of plan dosimetric characteristics was 
made, detailed in Supplementary Table 1. For comparison of PTV coverage, two 
metrics were used: coverage by 100% of the prescribed dose (35 Gy) and coverage 
by 95% of the prescribed dose (33.25 Gy). As the dose fall-off for PTV can be 
steep, these two metrics were used to adequately describe the differences when a 
small difference in coverage appears as a large difference in dose.  The maximum 
dose to the spinal cord, as well as doses to circumferential volumes expanded 1, 3, 
5, 7, and 10 mm outward from the cord, were compared to ensure the geometric 
robustness of plans calculated with bulk density overrides. Last, when appropriate, 
the dose received by a small portion of the esophagus (when it was adjacent to the 

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vertebral body) was compared, as well. The dosimetric differences observed 
between the plans with bulk density overrides and those recalculated using CT-
based relative electron densities, as delineated in Table 1 in the Supplementary Data 
Section below, are clinically acceptable and were on average within the 5% dose 
uncertainty recommended by the ICRU.  
 
More specifically, bulk density override MR-only planning is also projected to be 
safe in terms of dose to the spinal cord, which is the key safety consideration for 
spine SBRT. The average dose discrepancy for the maximum point was well within 
the 5% threshold recommended by the ICRU, ranging between 0.2 and 1.8% 
(Suppl. Table 1). Importantly, these dose discrepancies did not result in spinal cord 
constraint dose violation in any of the 30 plan comparisons. The projected dose 
discrepancy identified also met more stringent national guidelines set by the 
American Association of Physicists in Medicine (AAPM). Per AAPM Task Group 
(TG) 71, monitor unit (dose) calculations for external photon beam radiation should 
display 2-3% agreement between an initial calculation method and a second 
redundant check (26). Similarly, per AAPM TG-142’s specific recommendations 
for stereotactic radiation delivery, the prescribed versus delivered monitor units 
(dose) discrepancy should be within a 2% threshold (27). Therefore, bulk density 
override MR-only planning results in a dose projection that not only meets ICRU 
requirements but also meets more stringent national consensus guidelines in terms 
of projected dose to the spinal cord. This indicates that bulk density override 
MR-only planning is safe for spine SBRT. 
 
Use of MRI-simulation alone has also been limited by concern over geometric 
distortions of MR and the complexities of determining of electron density 
information without CT. These historical obstacles have been all but eliminated by 
modern advancements. Nyholm et al. found that after standard corrections, 
uncertainty from MR geometric distortions translated to a maximum error of only 
1mm. In fact, by eliminating the need for CT and MRI registration, treatment 
planning directly on MR images actually reduced spatial uncertainty when 
compared to CT-based radiotherapy (28). Indeed, based upon our preliminary in 
silico planning analysis above, the any geometric uncertainties present did not 
meaningfully impact dose projected to serial volumetric expansions of the spinal 
cord, which is the principle planning concern for safety in SBRT. 
 
1.5 
Rationale 
 
In light of our increasing experience with MRgRT and adaptive planning and advances in 
MR-only planning, we propose here to evaluate the feasibility and safety of same-session 
MR-only simulation and treatment with SMART for spinal metastases. Although spine 
SBRT is a standard-of-care treatment modality, this expedited same-session MR-only 
simulation and treatment with SMART workflow is novel. Previously, delivery of spine 
SBRT has typically required several days from time of consultation to simulation and then 
1-2 weeks from simulation to the initiation of treatment. On this proposed study, patients 
will not undergo CT simulation and will instead have same-session MR-only simulation 

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and treatment planning, on-table, using SMART. In this manner, patients would initiate 
treatment within just several days from the consult. Feasibility of the workflow will be 
defined as successful delivery of the first fraction of same-session MRI-only simulation 
and treatment with SMART on the first on-table attempt for at least 70% of patients. 
Patients will be treated in either a two or five fraction course over 1-2 weeks. Although our 
long-term goal will be to achieve a significantly shortened time from consult to treatment 
as compared to traditional SBRT using simulation, the present study will be driven by 
short-term goals of workflow feasibility and safety.  
 
 
2 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for 
Endpoints 
Primary 
Demonstrate that same-session MRI-only 
simulation and treatment with stereotactic 
MRI-guided radiotherapy (SMART) for 
spinal oligometastases is feasible by 
confirming that the first fraction of same-
session MRI-only simulation and 
treatment with SMART can be delivered 
on the first on-table attempt for at least 
70% of patients. 
Delivery of the first 
fraction of same-session 
MRI-only simulation and 
treatment with SMART 
within the first on-table 
attempt for at least 70% of 
patients. 
Clinically relevant  
Exploratory 
1. Determine the average time (days) 
from patient consult appointment to 
successful delivery of the first 
treatment fraction. 
Average time (days) from 
patient consult 
appointment to successful 
delivery of the first 
treatment fraction. 
Clinically relevant 
2. Determine the local, in-field tumor 
response and control rates at three 
months. 
Local control rate 
 
Local in-field tumor 
response 
Clinically relevant  
3. Demonstrate that same-session MR-
only simulation and treatment with 
SMART for treatment of spinal 
metastases will lead to comparable 
toxicities compared with historically 
reported rates using standard, CT-
based SBRT assessed prospectively at 
three months post-treatment and 
retrospectively for later time-points. 
CTCAE version 5, 
treatment related Grade 3 
or higher toxicities 
Clinically relevant  
4. Determine the projected dosimetric 
differences between the study method 
of MRI-only planning using standard 
Dosimetric differences 
between MRI-only planning 
using standard bulk density 
Generation of 
preliminary data for 

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bulk density override dose calculations 
(which will be clinically used for all 
patients) and an exploratory alternative 
method of a novel voxel-by-voxel 
MRI-based dose calculation using an 
institutionally developed machine 
learning algorithm (which will be 
simulated for comparison but not used 
in clinical treatment planning). 
override dose calculations 
and voxel-by-voxel MRI-
based dose calculation using 
MLA  
  
future radiation 
planning techniques. 
5. Determine the on-table time required 
for same-session MR-only simulation 
and treatment with plan generation for 
the initial treatment fraction and for 
subsequent treatment fractions. 
On-table time required for 
initial treatment fraction and 
subsequent treatment 
fractions  
Clinically relevant 
 
 
3 
STUDY POPULATION 
 
3.1 
Inclusion Criteria 
 
1. At least one disease sit e deemed to be suitable for treatment with spine SBRT as per 
radiation oncology evaluation. 
2. Karnofsky Performance Status (KPS) ≥ 60. 
3. Deemed medically fit for SBRT by treating physician 
4. Diagnostic CT with images through the projected treatment area within six months 
prior to enrollment.  
5. At least 18 years of age. 
6. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
3.2 
Exclusion Criteria 
 
1. Past history of radiotherapy within the projected treatment field to be treated by MRI-
guided SBRT 
2. Medical contraindication to undergoing MR imaging. 
3. Spine metastasis resulting in symptomatic spinal cord compression. 
4. Any other condition that, in the opinion of the treating radiation oncologist, renders the 
patient unfit for SBRT. 
5. Pregnant and/or breastfeeding.  Women of childbearing potential 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.   
 
 

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4 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
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 database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
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).   
 
4.5 
Strategies for Recruitment and Retention 
 
Patients will be accrued on basis of presentation to the radiation oncology clinic with spinal 
metastasis amenable to SBRT. Potential participants will be identified in the inpatient and 
outpatient radiation oncology clinic setting, as well as from the multidisciplinary spine 
tumor board. Patients will be approached regarding participation at or around the time of 

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their radiation oncology consultation visit. Patients will be treated at a single facility, at the 
Siteman Cancer Center’s Center for Advanced Medicine clinic, as the technology required 
for this study is confined to this center. We anticipate an accrual rate of approximately 15 
patients per year, or an estimated study accrual period of 8-12 months. There will be no 
compensation or incentives offered for study participation.  
 
 
5 
TREATMENT PLAN 
 
5.1 
Study Intervention Description and Administration 
 
Radiotherapy will consist of stereotactic body therapy to the spine, to be given over two or 
five fractions, delivered once daily or once every other day for a period of one to two 
weeks, for a total of two or five treatments. 
 
5.1.1 Dose, Fractionation 
 
Radiotherapy will consist of stereotactic body therapy, to be given over either a two 
or five fraction course, delivered once daily or once every other day for a period of 
one to two weeks, for a total of two or five treatments (depending on whether a 2 
or 5 fraction course is selected). Patients will be planned for an initial prescription 
dose at the discretion of the treating physician, delivered in two or five total 
fractions to the PTV, with dose adaptation based on safety constraints that are 
already approved of to prevent OAR injury. Suggested dose prescriptions are 24 
Gy in 2 fractions or 35 Gy in 5 fractions. 
  
5.1.2 Patient Positioning 
 
All patients will undergo volumetric MR imaging on treatment days in positioning 
appropriate for the specific treatment site.  
 
5.1.3 Clinical Target Volume (CTV) and Planning Target Volume (PTV) 
Definitions 
 
The treatment target will be defined based on the clinical target volume (CTV) only, 
based on International Spine Radiosurgery Consortium (ISRC) consensus 
guidelines. The PTV will be generated at the discretion of the treating physician 
but will generally range between 3 mm and 7 mm. 
 
Vertebral bodies are divided into 6 sectors as illustrated below from the ISRC 
consensus guidelines:  

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CTV definitions are listed below and use the previously defined sectors to delineate 
volumes:  
 
Tumor involvement 
ISRC bony CTV 
recommendation 
CTV description 
Any portion of the vertebral 
body 
1 
Include the entire vertebral 
body 
Lateralized within the 
vertebral body 
1, 2 
Include the entire vertebral 
body and the ipsilateral 
pedicle/transverse process 
Diffusely involves the 
vertebral body 
1, 2, 6 
Include the entire vertebral 
body and the bilateral 
pedicles/transverse processes 
Tumor involves vertebral 
body and unilateral pedicle 
1, 2, 3 
Include entire vertebral body, 
pedicle, ipsilateral transverse 
process, and ipsilateral lamina 
Tumor involves vertebral 
body and bilateral 
pedicles/transverse 
processes 
2, 3, 4 
Include entire vertebral body, 
bilateral pedicles/transverse 
processes, and bilateral 
laminae 
Tumor involves unilateral 
pedicle 
2, 3 ± 1 
Include pedicle, ipsilateral 
transverse process, and 
ipsilateral lamina, ± vertebral 
body 

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Tumor involves unilateral 
lamina 
2, 3, 4 
Include lamina, ipsilateral 
pedicle/transverse process, and 
spinous process 
Tumor involves spinous 
process 
3, 4, 5 
Include entire spinous process 
and bilateral laminae 
 
5.1.4 Same-session MR-only Simulation and Fraction 1 Adaptive 
Treatment Planning 
 
All patients will be planned for a two or  five fraction treatment course. Prescription 
dose will be at the discretion of the treating physician but will be 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 situation where a 
critical structure is violated, reduction of dose will be allowed in areas of overlap. 
For specific hard constraints and optimization parameters, see Section 5.1.5.  
 
Prior to day of first fraction and creation of the clinical plan, each patient will be 
tentatively pre-planned based on their diagnostic MRI volumetric image set 
obtained prior to study enrollment.  A bulk density override method will be used to 
manually assign relative electron density values to the diagnostic dataset for the 
purpose of dose calculation and setting up initial plan parameters.  For example, 
voxels representing the patient’s bones will be assigned an average bone density, 
voxels representing fat will have a different density assignment, etc.   This “pre-
plan” will allow for efficient same-session simulation and clinical planning on the 
day of treatment.  On treatment day one, another volumetric MRI image will be 
obtained on the treatment machine itself, and the plan will be adjusted based on 
anatomy and patient habitus of the day.  Previously assigned density values will be 
reviewed and adjusted if needed, after which the final clinical treatment plan will 
be created.   
 
In tandem with the clinical planning process above, a novel exploratory non-clinical 
density override method will be used for comparative dosimetry. In this method, 
the density values are assigned on a voxel-by-voxel basis automatically, rather than 
as a manual bulk override as clinically used, via a machine-learning 
algorithm.  This will not be used for clinical decision making or affect treatment 
planning.  The data gathered will be used to improve the MRI-only planning 
process in the future. 
 
5.1.5 SMART Dose Constraints 
 
These shall function as hard constraints in treatment planning, and coverage will be 
sacrificed to meet these constraints. All listed constraints are for 2 fraction 
treatment (Table A) or 5 fraction treatment (Table B), which are both acceptable 

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course fractionations for this study. Adaptive plans will be evaluated under the 
assumption that the delivered adaptive plan would meet all hard constraints for 2 
or 5 fractions with stable anatomy. For example, on a given day, in a 5-fraction 
course, the maximum cord dose (to 0.5 cc) will be 5 Gy (extrapolate to maximum 
dose 25 Gy over 5 fractions). 
 
Table A 
 
Organ-at-Risk 
Volume Constraint (Gy) 
Other 
PRV spinal cord subvolume (thecal sac or 2mm) <0.03cc 
17 
- 
PRV Cauda Equina 
<0.03cc 
17 
- 
Sacral Nerve S1-5 
<0.03cc 
26 
- 
Esophagus 
<0.03cc 
20 
- 
Pharynx/Larynx 
<0.03cc 
20 
Mean < 9Gy 
Brachial Plexus 
<0.03cc 
21.5 
- 
Parotid 
- 
- 
Mean < 7Gy 
Rectum 
<0.03cc 
20 
- 
Trachea 
<0.03cc 
20 
- 
Rib 
<5cc 
45 
57 
Skin 
<10cc 
20 
- 
Stomach 
<0.03cc 
20 
- 
Duodenum 
<0.03cc 
20 
- 
Small Bowel 
<0.03cc 
20 
- 
Large Bowel 
<0.03cc 
20 
- 
Kidneys 
<0.03cc 
26 
Mean < 6Gy 
Lungs (combined) 
         - 
- 
V10Gy <10% 
- 
- 
V5Gy < 35% 
Liver 
- 
- 
Mean < 8Gy 
 
 
Table B 
Organ-at-Risk 
Volume 
Max Dose to 
Volume (Gy) 
Max Point 
Dose* (Gy) 
Brainstem (not medulla) 
<0.5cc 
23 
31 
Spinal Cord and medulla 
<0.35cc 
22 
28 
  
<1.2cc 
15.6 
- 
Spinal Cord Sub-volume (5-6mm 
above and below level treated) 
<10% of sub-
volume 
22 
28 
Cauda Equina 
<5cc 
30 
31.5 
Sacral Plexus 
<5cc 
30 
32 
Esophagus 
<5cc 
19.5 
35 
Brachial Plexus 
<3cc 
27 
32.5 
Heart/Pericardium 
<15cc 
32 
38 

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Great Vessels 
<10cc 
47 
53 
Trachea and Large Bronchi 
<5cc 
32 
40 
Rib 
<5cc 
45 
57 
Skin 
<10cc 
36.5 
38.5 
Stomach 
<5cc 
26.5 
35 
Duodenum 
<5cc 
18.5 
26 
Small Bowel 
<30cc 
20 
32 
Large Bowel 
<20cc 
28.5 
40 
Rectum 
<35.cc 
50 
55 
<20cc 
32.5 
- 
Ureter 
- 
- 
45 
Bladder Wall 
<15cc 
20 
38 
Penile Bulb 
<3cc 
30 
- 
Femoral Heads 
<10cc 
30 
- 
Kidneys 
mean 
18 
- 
Lungs (combined) 
1500cc 
12.5 
- 
1000cc 
13.5 
- 
Liver 
700cc 
21 
- 
*Max point dose defined as dose to ≤ 0.035 cc. 
 
5.1.6 Adaptive Treatment Planning at Subsequent Fractions 
 
After delivery of the first treatment fraction using a same-session MR-only 
simulation and treatment with SMART, the treating physician will evaluate the 
patient’s individual anatomy at subsequent treatment fractions to determine if 
further daily adaptive planning is indicated. Treatment plan re-optimization will be 
performed for dose adaptation if it is determined that the patient’s anatomy 
necessitates dose adaptation with the goal of 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).    
 
5.1.7 Quality Assurance of the Adaptive Plan 
 
Patient specific QA will be performed at each fraction prior to delivery of the 
adaptive treatment plan. Given that dose measurements will not be possible with 
the patient on the table, this will be achieved by performing our standard process 
of an independent Monte Carlo dose calculation on the image of the day, using the 
exported beam parameters, and mapped electron density. The independently 
calculated dose distribution will be compared to the dose distribution exported from 
the MRIgRT system, looking at dose volume histograms and 3D gamma analysis 
of all voxels within the patient. In addition, in-house plan integrity verification 
software will be utilized to evaluate plan quality and integrity via plan parameters 
including contours, beam angles, segments, and monitor units. After completion of 
the automated checks, a final review by physics will be required prior to proceeding 
to treatment delivery.  
 

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5.2 
Collection of AEs 
 
For all patients, neurologic toxicities of concern include (but are not limited to) treatment-
related spinal injury resulting in sensory alteration, muscle weakness, or neuropathic pain 
limiting self-care in activities of daily living. For patients receiving treatment to lower 
thoracic and lumbar spine sites, toxicities of concern also include (but are not limited to) 
gastrointestinal toxicities such as: severe pain, severe nausea or diarrhea, severe 
constipation, and/or gastrointestinal hemorrhage, stenosis, ulceration, fistula, perforation, 
etc. Patients undergoing treatment for thoracic metastases will additionally be assessed 
using the CTCAE v5.0 criteria for lung, esophageal (eg esophagitis), and cardiovascular 
toxicity. Regardless of treatment site, skin toxicity will be tabulated according to the 
CTCAE v5.0 criteria. 
 
5.3 
Definitions of Evaluability 
 
Endpoint 
In order to be evaluable for this endpoint, a 
patient must have… 
Primary: Feasibility 
Received simulation 
Exploratory: Time from consult to delivery 
of first fraction 
Had a consult and received at least 1 fraction of 
RT 
Exploratory: Local, in-field tumor 
response rates at 3 mos 
Received any study treatment and undergone 
volumetric imaging at 3 mos 
Exploratory: Local, in-field tumor control 
rate at 3 mos 
Exploratory: Grade 3 or higher toxicity 
Received any study treatment 
Exploratory: Dosimetric differences 
between MRI-only planning using 
standard bulk density override dose 
calculations and voxel-by-voxel MRI-
based dose calculation using MLA 
Received MRI and dose calculated using bulk 
density vs voxel-by-voxel 
Exploratory: On-table time required for 
initial treatment fraction and subsequent 
treatment fractions 
Received at least 1 fraction of RT 
 
 
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 first fraction of SBRT.   
 
Female patients are required to use two forms of acceptable contraception, including one 
barrier method, during the course of study treatment.  
 
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. 

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If a female 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 a total 
of 2 or 5 fractions of SBRT or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 
• Death 
• Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• General or specific changes in the patient’s condition render the patient unable to 
receive further treatment in the judgment of the investigator 
• Suspected pregnancy 
• Serious non-compliance 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 still be followed as 
indicated in the study calendar. 
 
5.6 
Duration of Follow-up 
 
Patients will have a single follow-up visit at 3 months post-end of treatment.  
 
5.7 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for the 
scheduled three-month follow up visit 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 3 days 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. 

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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 
DOSE DELAYS / DOSE MODIFICATIONS 
 
There will be no dose delays or modifications permitted. 
 
 
7 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
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 treatmenthrough the 3-month post-treatment follow-
up visit.  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 1-2 AEs regardless of relatedness 
• Grade 3-4 AEs that predate SBRT 
• Grade 3-4 AEs that are not at least probably attributable to treatment 
 
Refer to the data submission schedule in Section 9 for instructions on the collection of AEs in the 
EDC. 
 
Reporting requirements for Washington University study team may be found in Section 7.1.  
  
7.1 
WU PI Reporting Requirements 
 
7.1.1  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. 
 
 

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7.1.2 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. 
 
 
7.2 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 1.1 include: 
• planned hospitalizations 
• hospitalizations < 24 hours 
• respite care 
• events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
8 
STUDY CALENDAR  
 
  
Screening 
Pre-
Treatment 
D1 D2 D3 D4 D5 
3 mos post-
SBRT1 
Informed consent 
X 
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
Volumetric imaging 
X5 
  
  
  
  
  
  
X 
Pregnancy test2 
X 
 
  
  
  
  
  
  
Adaptive SBRT 
  
  
X 
X 
X3 
X3 
X3 
  
Adverse events 
assessment 
  
 X 
 X ------------------------------------X 
1. Window is 10-14 weeks post-completion of SBRT 
2. Women of childbearing potential only; within 14 days of start of treatment 
3. Treatment days 3,4,5 are for a 5-fraction course of treatment only. If a 2-fraction course is selected, then there would 
be only two treatment days. 
5. Collection of a standard of care diagnostic CT scan completed in the past 6 months  
 

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9 
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 
Prior to starting treatment 
Treatment Summary Form 
End of treatment 
Toxicity Form 
During treatment and at 3-mo f/u 
Follow Up Form 
3-mo f/u 
 
9.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment (minus exceptions defined 
in Section 7.0) must be captured in the Toxicity Form.  Baseline AEs should be captured 
on the Medical History Form. 
 
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. 
 
 
10 
MEASUREMENT OF EFFECT 
 
10.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response at the 3-month 
follow-up visit. 
 
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. 
 
10.2 
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). 
 

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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 
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.  
 
10.3 
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. 
 

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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 
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 

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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 
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 

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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. 
 
10.4 
Response Criteria 
 
10.4.1 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 
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. 
 
10.4.2 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 

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progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
10.4.3 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. 
    
 
 
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. 
 
 
 
 
 
 

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                                      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 
 
 
10.4.4 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 
(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.  
 
 
11 
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 five patients have been enrolled) or one 
year after accrual has opened (if fewer than five 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 

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• 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. 
  
 
12 
STATISTICAL CONSIDERATIONS 
 
12.1 
Stopping Criteria 
 
If at any point in trial enrollment, >2 out of the first 5 patients, or >4 out of the first 10 
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: thoracic spine 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 
patients accruing to the trial 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 be scored as grade 5 toxicity and will not result in trial suspension. 
 
12.2 
Sample Size Calculation 
  
As a pilot study, the sample size is determined based on clinical considerations rather than 
statistical power. For our primary objective, our goal will be to report the description of 
same-session MR-only simulation and treatment with SMART treatment workflows, 
adaptation, and the time to delivery of first treatment fraction. Goal accrual will be 10 
evaluable patients. For the secondary objectives, sample size is also based on clinical 
considerations rather than statistical power.  
 
12.3 
Statistical Analysis Plan 
 

Protocol Version: 02/27/2023 
 
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Regarding toxicity, we will report descriptive statistics for acute toxicity at a three-month 
time point. Toxicity rates are anticipated to be identical to those of other linear accelerator 
based SBRT treatments. Because spine SBRT is a standard-of-care treatment that is not in 
and of itself investigational, further prospective toxicity assessments are not indicated. 
Given that no prior data exists for same-session MR-only simulation and treatment with 
SMART for spinal metastases, we will report descriptive statistics. As a pilot study we will 
establish these baseline parameters. 
  
The primary objective is to demonstrate that same-session MRI-only simulation and 
treatment with stereotactic MRI-guided radiotherapy (SMART) for spinal oligometastases 
is feasible by confirming that the first fraction of same-session MRI-only simulation and 
treatment with SMART can be delivered on the first on-table attempt for at least 70% of 
patients. 
 
Our principle objectives in this trial will be to determine the feasibility and safety of for 
same-session MR-only simulation and treatment with stereotactic MR-guided online-
adaptive radiotherapy (SMART) for treatment of spinal oligometastatic disease. If we can 
successfully deliver the first treatment fraction at time of the first on-table treatment 
attempt in 70% of patients, while maintaining the safety and efficacy profile of standard 
spine SBRT, we will consider this study as having provided sufficient pilot data to support 
more widespread study of same-session SMART paradigm. The long-term goals will be to 
improve patient outcomes and care by reducing time to treatment, through an expedited 
radiotherapy delivery workflow for spinal SBRT.   
 
All exploratory aims will be analyzed at the end of the study.   
 
  
 
 
 

Protocol Version: 02/27/2023 
 
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13 
REFERENCES 
 
1. Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015. 
National Cancer Institute. 2018:1–4. 
2. Kim JM, Losina E, Bono CM, et al. Clinical Outcome of Metastatic Spinal Cord Compression 
Treated With Surgical Excision ± Radiation Versus Radiation Therapy Alone. Spine. 
2012;37:78–84. 
3. Milano MT, Katz AW, Muhs AG, et al. A prospective pilot study of curative-intent 
stereotactic body radiation therapy in patients with 5 or fewer oligometastatic lesions. Cancer. 
2008;112:650–658. 
4. Salama JK, Hasselle MD, Chmura SJ, et al. Stereotactic body radiotherapy for multisite 
extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of 
metastatic disease. Cancer. 2012;118:2962–2970. 
5. Inoue T, Katoh N, Aoyama H, et al. Clinical outcomes of stereotactic brain and/or body 
radiotherapy for patients with oligometastatic lesions. Jpn. J. Clin. Oncol. 2010;40:788–794. 
6. Kang J-K, Kim M-S, Kim JH, et al. Oligometastases confined one organ from colorectal 
cancer treated by SBRT. Clin. Exp. Metastasis. 2010;27:273–278. 
7. Palma DA, Olson RA, Harrow S, et al. Stereotactic Ablative Radiation Therapy for the 
Comprehensive Treatment of Oligometastatic Tumors (SABR-COMET): Results of a 
Randomized Trial. Int. J. Radiat. Oncol. Biol. Phys. 2018;102:S3–S4. 
8. Salama JK, Chmura SJ, Mehta N, et al. An initial report of a radiation dose-escalation trial in 
patients with one to five sites of metastatic disease. Clin. Cancer Res. 2008;14:5255–5259. 
9. Casiraghi M, De Pas T, Maisonneuve P, et al. A 10-year single-center experience on 708 lung 
metastasectomies: the evidence of the "international registry of lung metastases". J Thorac 
Oncol. 2011;6:1373–1378. 
10. Ryu S, Pugh SL, Gerszten PC, et al. RTOG 0631 phase 2/3 study of image guided 
stereotactic radiosurgery for localized (1-3) spine metastases: Phase 2 results. Practical 
Radiation Oncology. 2014;4:76–81. 
11. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-guided and controlled 
radiotherapy. Semin Radiat Oncol. 2014;24:196–199. 
12. Mutic S, Low D, Chmielewski T, et al. The Design and Implementation of a Novel Compact 
Linear Accelerator-Based Magnetic Resonance Imaging-Guided Radiation Therapy (MR-IGRT) 
System. Radiation Oncology Biology. 2016;96:E641. 
13. Wooten HO, Green O, Yang M, et al. Quality of Intensity Modulated Radiation Therapy 
Treatment Plans Using a ⁶⁰Co Magnetic Resonance Image Guidance Radiation Therapy System. 
Int. J. Radiat. Oncol. Biol. Phys. 2015;92:771–778. 

Protocol Version: 02/27/2023 
 
Page 34 of 48 
 
14. Park JM, Park SY, Kim HJ, et al. A comparative planning study for lung SABR between tri-
Co-60 magnetic resonance image guided radiation therapy system and volumetric modulated arc 
therapy. Radiotherapy and Oncology. 2016;120:279–285. 
15. Acharya S, Fischer-Valuck BW, Kashani R, et al. Online Magnetic Resonance Image Guided 
Adaptive Radiation Therapy: First Clinical Applications. Int. J. Radiat. Oncol. Biol. Phys. 
2016;94:394–403. 
16. Noel CE, Parikh PJ, Spencer CR, et al. Comparison of onboard low-field magnetic resonance 
imaging versus onboard computed tomography for anatomy visualization in radiotherapy. Acta 
Oncol. 2015:1–9. 
17. Henke L, Contreras J, Green OL. Magnetic Resonance Image-Guided Radiotherapy 
(MRIgRT): A 4.5-Year Clinical Experience. Clinical Oncology. 2018. Epub ahead of print: 
https://www.clinicaloncologyonline.net/article/S0936-6555(18)30419-9/fulltext 
18. Henke L, Kashani R, Robinson C, et al. Phase I trial of stereotactic MR-guided online 
adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary 
malignancies of the abdomen. Radiotherapy and Oncology. 2018;126:519–526. 
19. Bohoudi O, Bruynzeel AME, Senan S, et al. Fast and robust online adaptive planning in 
stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer. Radiother 
Oncol. 2017;125:439–444. 
20. Cox BW, Spratt DE, Lovelock M, et al. International Spine Radiosurgery Consortium 
consensus guidelines for target volume definition in spinal stereotactic radiosurgery. In: Vol 83. 
2012:e597–605. 
21. De Costa AMA, Mittauer KE, Ko HC, et al. Rapid Access Palliative Radiation Workflow 
Using MRI-Guided Single-Session Simulation, Online Adaptation, and Treatment. Int. J. Radiat. 
Oncol. Biol. Phys.  2017;99:S126. 
22. Karotki A, Mah K, Meijer G, et al. Comparison of bulk electron density and voxel‐based 
electron density treatment planning. J Appl Clin Med Phys. 2011;12:97–104. 
23. Jonsson JH, Karlsson MG, Karlsson M, et al. Treatment planning using MRI data: an 
analysis of the dose calculation accuracy for different treatment regions. Radiat Oncol. 
2010;5:62. 
24. International Commission on Radiation Units and Measurements, “Determination of 
absorbed dose in a patient irradiated by beams of X or gamma rays in radiotherapy procedures,” 
ICRU Report No. 24 (International Commission on Radiation Units and Measurements, 
Washington, 1976). 
25. Kemppainen R, Suilamo S, Tuokkola T, et al. Magnetic resonance-only simulation and dose 
calculation in external beam radiation therapy: a feasibility study for pelvic cancers. Acta 
Oncologica. 2017;56:792–798. 

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26. Gibbons JP, Antolak JA, Followill DS, et al. Monitor unit calculations for external photon 
and electron beams: Report of the AAPM Therapy Physics Committee Task Group No. 71. Med 
Phys. 2014;41:031501–34. 
27. Klein EE, Hanley J, Bayouth J, et al. Task Group 142 report: Quality assurance of medical 
acceleratorsa). Med Phys. 2009;36:4197–4212. 
28. Nyholm T, Nyberg M, Karlsson MG, et al. Systematisation of spatial uncertainties for 
comparison between a MR and a CT-based radiotherapy workflow for prostate treatments. 
Radiat Oncol. 2009;4:54. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: Supplementary Data 
 
Table 1. Difference in projected dosimetry for MR-only bulk density override planning versus 
CT-based plans (Calculated as bulk density - CT-based).  
PTV1: Vertebral Body 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-0.63 
-0.64 
1.01 
-0.7% 
1.1% 
Difference in PTV coverage 
by 95% Rx 
% 
-0.18 
-0.21 
0.25 
-0.2% 
0.3% 
Difference in spinal cord 
maximum dose 
Gy 
0.08 
0.11 
0.44 
0.6% 
2.8% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
0.00 
0 
0.01 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
0.00 
0 
0.05 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.03 
-0.05 
0.1 
  
  
Difference in volume of 
cord+10mm receiving 28 Gy 
cc 
-0.05 
-0.05 
0.14 
  
  
Difference in percent 
conformity index 
% 
-2% 
-2% 
6% 
  
  
Difference in percent 
gradient index 
% 
-3% 
-1% 
6% 
  
  
Difference in volume of 
esophagus receiving 19.5 
Gy 
cc 
-0.03 
-0.05 
0.1 
  
  
 
 
 
 
 

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PTV2: Vertebral Body and Unilateral Pedicle 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-1.18 
-0.91 
3.33 
-1.3% 
3.7% 
Difference in PTV coverage 
by 95% Rx 
% 
-0.21 
-0.14 
0.53 
-0.2% 
0.5% 
Difference in spinal cord 
maximum dose 
Gy 
0.15 
0.06 
0.43 
0.7% 
1.9% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
0.00 
0 
0.03 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
-0.04 
-0.03 
0.09 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.08 
-0.06 
0.16 
  
  
Difference in volume of 
cord+10mm receiving 28 Gy 
cc 
-0.10 
-0.11 
0.15 
  
  
Difference in percent 
conformity index 
% 
-4% 
-2% 
11% 
  
  
Difference in percent 
gradient index 
% 
-3% 
-4% 
6% 
  
  
Difference in volume of 
esophagus receiving 19.5 
Gy 
cc 
-0.14 
-0.03 
0.38 
  
  
 
 
 

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PTV3: Vertebral Body and Bilateral Pedicles 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-0.63 
-0.48 
1.49 
-0.7% 
1.6% 
Difference in PTV coverage 
by 95% Rx 
% 
-0.24 
-0.18 
0.48 
-0.3% 
0.5% 
Difference in spinal cord 
maximum dose 
Gy 
-0.05 
-0.08 
0.26 
-0.2% 
1.7% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
0.00 
0 
0.01 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
-0.02 
-0.02 
0.08 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.06 
-0.05 
0.17 
  
  
Difference in volume of 
cord+10mm receiving 28 Gy 
cc 
-0.09 
-0.09 
0.27 
  
  
Difference in percent 
conformity index 
% 
-3% 
-2% 
9% 
  
  
Difference in percent 
gradient index 
% 
-2% 
-1% 
4% 
  
  
Difference in volume of 
esophagus receiving 19.5 
Gy 
cc 
0.00 
0 
0.23 
  
  
 
 
 

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PTV4: Vertebral Body and Unilateral Pedicle and Lamina 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-1.44 
-0.54 
3.35 
-1.7% 
3.9% 
Difference in PTV coverage 
by 95% Rx 
% 
-0.37 
-0.2 
1.14 
-0.4% 
1.2% 
Difference in spinal cord 
maximum dose 
Gy 
-0.36 
-0.37 
0.83 
-1.8% 
3.9% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
-0.01 
-0.01 
0.05 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
-0.05 
-0.02 
0.22 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.08 
-0.03 
0.37 
  
  
Difference in volume of 
cord+10mm receiving 28 Gy 
cc 
-0.14 
-0.02 
0.64 
  
  
Difference in percent 
conformity index 
% 
-6% 
-4% 
18% 
  
  
Difference in percent 
gradient index 
% 
-1% 
-1% 
5% 
  
  
Difference in volume of 
esophagus receiving 19.5 
Gy 
cc 
-0.18 
-0.175 
0.34 
  
  
 
 
 
 
 

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PTV5: Unilateral Pedicle and Lamina, and Spinous Process 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-2.08 
-2.22 
3.54 
-2.6% 
5.0% 
Differnce PTV coverage by 
95% Rx 
% 
-0.50 
-0.26 
1.22 
-0.5% 
1.3% 
Difference in spinal cord 
maximum dose 
Gy 
0.00 
0.03 
0.3 
0.1% 
1.9% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
0.00 
0 
0.01 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
-0.01 
-0.01 
0.05 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.07 
-0.06 
0.12 
  
  
Difference in volume of 
cord+10mm receiving 28 Gy 
cc 
-0.09 
-0.08 
0.14 
  
  
Difference in percent 
conformity index 
% 
-4% 
-2% 
10% 
  
  
Difference in percent 
gradient index 
% 
-2% 
0% 
13% 
  
  
Difference in volume of 
esophagus receiving 19.5 
Gy 
cc 
-0.29 
-0.29 
0.29 
  
  
 
 
 

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 PTV6: Spinous Process and Bilateral Lamina 
Metric 
Unit 
Average 
Median 
Max 
Ave. difference (% of 
original projected by 
bulk density plan) 
Max difference (% of 
original projected by 
bulk density plan) 
Difference in PTV coverage 
by 100% Rx 
% 
-3.00 
-1.54 
6.52 
-4.1% 
9.0% 
Difference in PTV coverage 
by 95% Rx 
% 
-0.65 
-0.32 
1.63 
-0.7% 
1.8% 
Difference in spinal cord 
maximum dose 
Gy 
0.25 
0.26 
1.04 
1.3% 
5.6% 
Difference in volume of 
cord+3mm receiving 28 Gy 
cc 
0.00 
0 
0.02 
  
  
Difference in volume of 
cord+5mm receiving 28 Gy 
cc 
-0.02 
-0.03 
0.06 
  
  
Difference in volume of 
cord+7mm receiving 28 Gy 
cc 
-0.07 
-0.04 
0.22 
  
  
Difference in volume of 
cord +10mm receiving 28 
Gy 
cc 
-0.10 
-0.08 
0.39 
  
  
Difference in percent 
conformity index 
% 
-8% 
-8% 
14% 
  
  
Difference in percent 
gradient index 
% 
1% 
-1% 
9% 
  
  
 
 
 
 

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APPENDIX B: 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 C: 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. 
 
A. 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. 
 
B.  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 
o Inpatient hospitalization or prolongation of existing hospitalization 

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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 
 
C. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
D. 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 D: Reporting Timelines 
 
Event 
HRPO 
QASMC 
Serious AND 
unexpected suspected 
adverse reaction 
 
 
Unexpected fatal or 
life-threatening 
suspected adverse 
reaction 
 
 
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 
 
Clinically important 
increase in the rate of 
a serious suspected 
adverse reaction of 
that list in the protocol 
or IB 
 
 
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.   
 

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

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APPENDIX E: Study-Specific DSM Tables 
 
Protocol Objectives and Subject Evaluability 
Objective 
# of patients 
evaluable for this 
endpoint to date 
Primary 
Demonstrate that same-session MRI-only simulation and treatment with 
stereotactic 
MRI-guided 
radiotherapy 
(SMART) 
for 
spinal 
oligometastases is feasible by confirming that the first fraction of same-
session MRI-only simulation and treatment with SMART can be delivered 
on the first on-table attempt for at least 70% of patients. 
 
Exploratory 
Determine the average time (days) from patient consult appointment to 
successful delivery of the first treatment fraction. 
 
Determine the local, in-field tumor response and control rates at three 
months. 
Local in-field 
tumor response =  
Local in-field 
control rate =  
Demonstrate that same-session MR-only simulation and treatment with 
SMART for treatment of spinal metastases will lead to comparable 
toxicities compared with historically reported rates using standard, CT-
based SBRT assessed prospectively at three months post-treatment and 
retrospectively for later time-points. 
 
Determine the projected dosimetric differences between the study method 
of MRI-only planning using standard bulk density override dose 
calculations (which will be clinically used for all patients) and an 
exploratory alternative method of a novel voxel-by-voxel MRI-based dose 
calculation using an institutionally developed machine learning algorithm 
(which will be simulated for comparison but not used in clinical treatment 
planning). 
 
Determine the on-table time required for same-session MR-only 
simulation and treatment with plan generation for the initial treatment 
fraction and for subsequent treatment fractions. 
 
 
 
Interim Analysis and Early Stopping Rules 
Does the study design include an interim toxicity analysis? 
No 
Does the study design include an interim futility analysis? 
No 
Are there early stopping rules that outline circumstances under which the study must be 
suspended or closed? 
No 

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Response 
UPN 
On tx date 
1st fx delivered at 1st 
on table attempt? 
(Y/N) 
Response 
at 3 mos 
Pt 
replaced? 
(Y/N) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Discontinuation and Survival 
UPN 
Date off tx 
Reason off tx 
Vital status 
If dead, cause