A Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT) for Patients With Sarcoma, Thoracic, Abdominal, and Pelvic Cancers
Phase: NA
Conditions: Sarcoma, Thoracic Cancer, Abdominal Cancer, Pelvic Cancer
Sponsor: Washington University School of Medicine

Protocol Version Date: 06/09/2023 
 
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A  Trial of Palliative Lattice Stereotactic Body Radiotherapy (SBRT) for Patients with 
Sarcoma, Thoracic, Abdominal, and Pelvic Cancers 
 
Washington University School of Medicine 
Division of Radiation Oncology 
660 South Euclid Avenue, Campus Box 8224 
St. Louis, MO  63110 
 
Protocol #: 202009022 
Version Date: 09 June 2023 
 
Principal Investigator: 
Pamela Samson, M.D. 
Phone: (314) 747-1786 
E-mail:  psamson@wustl.edu    
 
Sub-Investigators:     
James Kavanaugh, M.S. 
 
 
 
 
Phone: (314) 286-2640 
 
 
 
 
E-mail: jkavanaugh@wustl.edu 
 
Sai Duriseti, M.D., Ph.D. 
 
 
 
 
 
Phone: (314) 565-3032 
 
 
 
 
 
E-mail: durisetiks@wustl.edu 
 
Sub-Investigators 
 
 
 
Modality 
Clifford Robinson, M.D. 
 
 
Radiation Oncology 
Jeff Michalski, M.D. 
 
 
 
Radiation Oncology 
Dennis Hallahan, M.D.  
 
 
Radiation Oncology 
 
Stephanie Markovina, M.D., Ph.D. 
 
Radiation Oncology 
Hyun Kim, M.D. 
 
 
 
Radiation Oncology 
Brian Van Tine, M.D., Ph.D. 
 
 
Medical Oncology 
Aadel Chaudhuri, M.D., Ph.D.  
 
Radiation Oncology 
Jeff Szymanski, M.D., Ph.D. 
 
 
Radiation Oncology 
Dinesh Thotala, Ph.D.  
 
 
Radiation Oncology  
Sreekrishna Goddu, Ph.D. 
 
 
Radiation Oncology  
Nels Knutson, Ph.D. 
 
 
 
Radiation Oncology  
Christopher Abraham, M.D. 
 
 
Radiation Oncology 
Yi Huang, M.S.  
 
 
 
Biostatistics 
 
NCT#: 
  
 
NCT04553471 
Funded by: 
Goldman Sachs Philanthropy Fund (Emerson 
Collective) 

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A Trial Palliative Lattice Stereotactic Body Radiotherapy (SBRT) for Patients with 
Sarcoma, Thoracic, Abdominal, and Pelvic Cancers 
 
Protocol Revision History 
 
 
Initial Approval Version 
 
 
 
 
 
09/02/2020 
Amendment #1 
 
 
 
 
 
 
09/08/2020 
Amendment #2 
 
 
 
 
 
 
11/09/2020 (not submitted) 
Amendment #3 
 
 
 
 
 
 
12/07/2020 
Amendment #4 
 
 
 
 
 
 
01/11/2021 
Amendment #5 
03/29/2021 (submitted, not 
approved) 
Amendment #5 
05/21/2021 
Amendment #6 
09/01/2021 
Amendment #7 
07/05/2022 
Amendment #8  
04/11/2023 
Amendment #9 
06/09/2023 
 
 

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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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Glossary of Abbreviations  
 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ATC 
Advanced Technology Consortium  
BJH 
Barnes Jewish Hospital 
CBC 
Complete blood count 
CD4+ 
Cluster of differentiation 4+ 
CFR 
Code of Federal Regulations 
CMP 
Comprehensive metabolic panel 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CYP3A4 
Cytochrome P450 3A4 
DHHS 
Department of Health and Human Services 
DNA 
deoxyribonucleic acid 
DOB 
Date of birth 
DSM 
Data and Safety Monitoring  
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FWA 
Federal wide assurance 
GCP 
Good Clinical Practice 
GTV 
Gross Tumor Volume 
HHS 
Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
ICH 
International Council for Harmonisation 
IGRT 
Image-guided radiation therapy 
IMRT 
Intensity modulated radiotherapy 
IL 
Interleukins  
IRB 
Institutional Review Board 
MRI 
Magnetic resonance imaging 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NRS 
Numeric Rating Scale  
NSCLC 
Non-small cell lung cancer 
OAR 
Organs at risk  
OHRP 
Office of Human Research Protections  
PD-L1 
Programmed death ligand 1 

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PI 
Principal investigator 
PRO-CTCAE 
Patient Reported Outcomes-Common Terminology Criteria for Adverse Events 
PTV 
Planning Target Volume  
QASMC 
Quality Assurance and Safety Monitoring Committee 
QoL 
Quality of Life  
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SBRT 
Stereotactic body radiation 
SFRT 
Spatially fractionated radiotherapy 
Lattice SBRT 
Spatially-fractionated stereotactic body radiation 
SIB 
Simultaneous integrated boost 
SLCH 
St. Louis Children’s Hospital  
TEAE 
Treatment emergent severe adverse events 
TNF 
Tumor necrosis factor 
TPCF 
Tissue Procurement Core Facility  
UPN 
Unique patient number 
VMAT 
Volumetric modulated arc therapy 
WU 
Washington University 
 
 

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Table of Contents 
PROTOCOL SUMMARY .............................................................................................................. 8 
SCHEMA ...................................................................................................................................... 10 
SCHEDULE OF ACTIVITIES ................................................................................................. 11 
1.0 
INTRODUCTION ............................................................................................................. 12 
 
Metastatic or Unresectable Tumors ................................................................................ 12 
 
Radiotherapy for Tumors Needing Palliation ................................................................ 12 
 
Spatially Fractionated Radiotherapy (SFRT) ................................................................. 12 
 
Correlative Studies Background..................................................................................... 13 
 
Rationale for treatment approach ................................................................................... 13 
 
Study Design .................................................................................................................. 13 
 
Risk/Benefit Assessment ................................................................................................ 15 
2.0 
OBJECTIVES AND ENDPOINTS ................................................................................... 15 
3.0 
STUDY POPULATION .................................................................................................... 16 
 
Inclusion Criteria ............................................................................................................ 16 
 
Exclusion Criteria ........................................................................................................... 17 
 
Inclusion of Women and Minorities ............................................................................... 18 
4.0 
REGISTRATION PROCEDURES ................................................................................... 18 
 
Confirmation of Patient Eligibility ................................................................................. 18 
 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 18 
 
Assignment of UPN ....................................................................................................... 18 
 
Screen Failures ............................................................................................................... 18 
 
Strategies for Recruitment and Retention ...................................................................... 19 
5.0 
TREATMENT PLAN ........................................................................................................ 19 
 
Study Intervention Description ...................................................................................... 19 
 
Risk Designation for Tumor Lysis Syndrome (TLS) ..................................................... 19 
 
Monitoring for TLS ........................................................................................................ 20 
 
Pre-Radiation Evaluation ............................................................................................... 20 
 
Radiation Therapy .......................................................................................................... 20 
 
Patient-Reported Quality of Life Outcome and Toxicity Measures .............................. 24 
 
Acquisition of Blood for Research ................................................................................. 24 
 
Definitions of Evaluability ............................................................................................. 25 
 
Concomitant Therapy and Supportive Care Guidelines ................................................. 25 
 Women of Childbearing Potential .................................................................................. 25 
 Duration of Therapy ....................................................................................................... 25 
 Follow-up Specifications................................................................................................ 26 
 Lost to Follow-Up .......................................................................................................... 26 
6.0 
RADIATION THERAPY DOSE/DELAYS MODIFICATIONS ..................................... 27 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 27 
 
WU PI Reporting Requirements .................................................................................... 27 
 
Exceptions to Expedited Reporting ................................................................................ 28 
8.0 
CORRELATIVE STUDIES .............................................................................................. 28 
 
Blood Sample Collection and Processing ...................................................................... 28 
9.0 
DATA SUBMISSION SCHEDULE ................................................................................. 29 
 
Adverse Event Collection in the Case Report Forms ..................................................... 29 
10.0 DATA AND SAFETY MONITORING ............................................................................ 30 

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11.0 STATISTICAL CONSIDERATIONS............................................................................... 31 
 Study Design .................................................................................................................. 31 
 Study Endpoints ............................................................................................................. 31 
 Data Analysis ................................................................................................................. 33 
 Power Analysis and Sample Size ................................................................................... 33 
 Accrual ........................................................................................................................... 33 
 Continuous Toxicity Monitoring using Pocock-type boundary ..................................... 33 
12.0 REFERENCES .................................................................................................................. 35 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 39 
APPENDIX B: Definitions for Adverse Event Reporting ............................................................ 40 
APPENDIX C: Reporting Timelines ............................................................................................ 42 
APPENDIX D: PRO-CTCAE Inventories.................................................................................... 44 
APPENDIX E: MEASUREMENT OF EFFECT (RECIST 1.1) .................................................. 46 
 
 

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PROTOCOL SUMMARY 
 
Title: 
A Trial of Palliative Lattice Stereotactic Body Radiotherapy 
(SBRT) for Patients with Sarcoma, Thoracic, Abdominal, and 
Pelvic Cancers 
Study Description: 
Lattice SBRT will be used to deliver palliative radiotherapy to large 
(≥4.5 cm) tumors for patients with soft tissue sarcomas, thoracic 
cancers (including esophageal), abdominal, and pelvic cancers. The 
safety and efficacy of this approach will be assessed. 
Objectives: 
Primary Objective:  
1. To evaluate the efficacy and safety of 5-fraction palliative 
Lattice SBRT in patients with large lesions (≥4.5 cm) who 
are planning to undergo palliative radiotherapy. This will be 
assessed with the co-primary endpoints of target lesion 
control at 6 months and rate of treatment-related severe 
toxicity within 6 months.  
 
Secondary Objectives: 
1. To assess the rate of treatment-related severe toxicity within 
12 months of completion of treatment (i.e. late toxicity) 
2. To assess patient reported toxicity with PRO-CTCAE 
3. To assess patient-reported QoL with PROMIS 
4. To assess patient-reported pain 
 
Exploratory Objectives: 
5. To evaluate blood for immune- and tumor damage-associated 
response with Lattice SBRT 
Endpoints: 
Primary:  
1. Rate of local control by RECIST at 6 months 
2. Proportion of patients with treatment-related grade 3+ 
CTCAE v5.0 toxicity assessed within 6 months of 
completion of treatment 
 
Secondary:  
1. Proportion of patients with treatment-related grade 3+ 
CTCAE v5.0 toxicity at 12 months. 
2. PRO-CTCAE assessment at baseline, post-treatment, 30 
days, 3 months, 6 months, and 12 months.  
3. PROMIS physical function, global health, anxiety, and 
depression assessment at baseline, post-treatment, 30 days, 3 
months, 6 months, and 12 months.  
4. Numeric Pain Scale at baseline, post-treatment, 30 days, 3 
months, 6 months, and 12 months. 
 
Exploratory: Peripheral blood immune-related biomarkers. 

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Study Population: 
67 adult patients will be enrolled and treated, (with a goal of 47 
evaluable patients), ≥ 18 years of age with ECOG ≤ 2. At least 10 
patients will be enrolled in each cohort (soft tissue sarcomas, thoracic 
cancers (including esophageal), abdominal, and pelvic cancers). All 
genders and races will be included.  
Any participants who do not receive treatment will be replaced. 
Phase: 
N/A 
Description of Sites / 
Facilities Enrolling: 
This is a single-institutional study conducted at Washington 
University School of Medicine 
Description of Study 
Intervention: 
5-fraction Lattice SBRT delivered to 20 Gy with a simultaneous 
integrated boost (SIB) to 66.7 Gy. 
Study Duration: 
16 months plus 2 weeks for treatment and 12 months follow up 
Participant Duration: 
2 weeks of treatment plus 12 months follow up. 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Plan 
Pre-treatment imaging and blood sample collection. 
QOL surveys completed prior to treatment. 
SF- SBRT to 20 Gy with a SIB to 66.7 Gy in 5 
fractions. 
Immediate post-treatment blood sample collection. 
Eligible Patients 
Patients ≥ 18 years of age with histologically confirmed cancer with a 
lesion ≥ 4.5 cm in any dimension and planning to undergo palliative 
radiotherapy  
Follow Up 
Post-treatment blood sample collection and QOL 
surveys at 14 and 30 days, and imaging at 3, 6, and 
12 months. Continued disease, symptom, and 
toxicity monitoring for 12 months. 

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SCHEDULE OF ACTIVITIES 
Procedures 
Screening 
Pre-Tx / 
Baseline 
Fractions 1-5 
EOT (2 Weeks 
Post-Tx)5 
30 Days 
Post-Tx6 
Follow-
Up9 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
ECOG PS 
X 
 
 
 
 
 
Physical exam (including ht/wt) 
X 
 
X3 
 
X 
 
Medical history 
X 
 
 
 
 
 
Pregnancy test4 
X 
 
 
 
 
 
TLS risk designation 
 
X 
 
 
 
 
Hematology and metabolic function 
X 
X14 
X14 
X14 
 
 
Staging of the chest, abdomen, and pelvis8 
 
X7 
 
 
 
X 
Peripheral blood collection 
 
X12 
X13 
X 
X 
 
Questionnaires10 
 
X2 
 
X 
X 
X 
Lattice SBRT1 
 
 
X 
 
 
 
AE review and evaluation 
 
X 
X3 
 
X 
X11 
Notes: 
1. Treatment is given every other day. 
2. Completed at least 2 weeks prior to treatment with Lattice SBRT. 
3. Every patient will be required to have 1 on-treatment visit per standard clinical practice. 
4. For women of child-bearing potential only, and within 20 days prior to study entry. 
5. +/- 1 week. 
6. +/- 2 weeks 
7. Within the past 4 months 
8. Imaging will be performed per care team. CT, MRI, or PET/CT are acceptable modalities, but it is recommended that the same method be used at all imaging 
timepoints.  
9. Follow up will take place at 90 days, 180 days, and 360 days, +/- 4 weeks. 
10. PROMIS and PRO-CTCAE will be utilized at these timepoints. 
11. AEs will be tracked through 360 days post treatment. 
12. Peripheral blood for immune monitoring can be collected up to 2 weeks prior to first day of treatment, but no later than 1st day of treatment. 
13. Peripheral blood for immune monitoring will be collected at fraction 5 only. 
14. For all patients, assessments of hematologic and metabolic function will be collected no more than 1 week before treatment (including on the day of 
treatment), immediately after radiotherapy completion (Fraction 5), at 48-72 hours after radiotherapy completion, and 7 days (+/- 1 day) after radiotherapy 
completion.  This must include assessments of uric acid, potassium, phosphorus, and calcium. 

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1.0 
INTRODUCTION 
 
 
Metastatic or Unresectable Tumors 
 
In 2018, it is estimated that the US cancer prevalence was about 14.5 million Americans, 
and this is expected to balloon to approximately 19 million Americans by 2024 (American 
Cancer Society 2019). Metastatic or unresectable disease is the cause of cancer-related 
morbidity and mortality for about 90% of cancer patients (Chaffer and Weinberg 2011). 
Clinical presentation of disease can vary widely depending on the site of the tumor, but 
pain is frequently a presenting symptom (Hamilton et al. 2015). 
 
 
Radiotherapy for Tumors Needing Palliation  
 
While radiotherapy paradigms evolve, symptomatic palliation is at the forefront of 
treatment intent (Spencer et al. 2018; Jones and Simone II 2014). As such, appropriate 
modality, dose, and fractionation continue to be investigated. Ongoing studies suggest 
hypofractionated approaches are favorable for this population with regimens  based on 
principles of cancer radiobiology, such as the Spanos Regimen and the QUAD SHOT, 
having variable success in specific disease sites (Carrascosa et al. 2007; Corry et al. 2005). 
 
Recent data demonstrates that SBRT offers improvements over conventionally fractionated 
radiotherapy for palliative treatment (Sprave et al. 2018; Nguyen et al. 2019). Three issues 
limit the utility of SBRT. First, dose escalation can be difficult given the proximity to 
surrounding OARs (Hartsell et al. 2005; Shiue et al. 2018). Second, it may be unsafe to 
treat large tumors with SBRT. Retrospective data and secondary analyses from SBRT trials 
for NSCLC suggest that 5 cm should be the upper limit for which SBRT may be employed 
(Allibhai et al. 2013; Videtic et al. 2017). Third, SBRT may not be as effective for larger 
lesions as it is for smaller lesions. Prior studies support this limitation. (Ricco et al. 2017; 
Masucci 2018) 
 
 
Spatially Fractionated Radiotherapy (SFRT) 
 
SFRT may address these limitations of traditional SBRT. SFRT relies on beam collimation 
to create high-dose “peaks,” organized throughout a target volume with intervening low-
dose “valleys” (Billena and Khan 2019). SFRT as a 2-dimensional technique is being 
evaluated in soft tissue sarcoma in a prospective setting (M. Mohiuddin et al. 2009; 
Mohammed Mohiuddin et al. 2014). In these studies, a single dose of 2-dimensional SFRT 
was used either alone or in combination with further conventionally fractionated radiation 
with or without chemotherapy with1-2 year LC greater than 90% and limited Grade 2-3 
skin toxicities.  
 
Lattice radiotherapy is a form of SFRT that uses a 3-dimensional beam arrangement to 
target high-dose spherical volumes which allows for a more flexible beam arrangement, 
better normal tissue optimization, and lower exit beam skin dose (X et al. 2010). 
Classically, SFRT had been planned to achieve a dose fall off to 20-30% of the “peak” 
dose (Meigooni et al. 2006). Tested approaches for Lattice designate spheres 1-2 cm spaced 

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2-3 cm apart (center to center) (Amendola et al. 2018; E et al. 2010). Prior studies show 
that Lattice SFRT can be delivered using IMRT or VMAT (Gholami et al. 2016; Billena 
and Khan 2019). 
 
 
Correlative Studies Background 
 
In animal models, extreme hypo-fractionation was found to induce infiltration of T-cells 
(Lugade et al. 2005). Also, SBRT has been shown to alter levels of soluble PD-L1, IFN 
α/β/γ, TNFα, and various interleukins (Trovo et al. 2016; Ellsworth et al. 2017; Walle et 
al. 2018; Song et al. 2019). 
 
It is hypothesized that SFRT spares interspersed small volumes of normal tissue allowing 
it to tolerate higher doses of radiotherapy while immune-mediated bystander effects allow 
for cell kill of areas of tumor receiving a lower dose. This hypothesis is supported by the 
finding SFRT is associated with increased serum TNFα and that higher levels of TNFα are 
associated with complete tumor response (Sathishkumar et al. 2002). 
 
SFRT has been shown to elicit a local effect by the “bystander effect” (i.e. effects to tumor 
cells in the valleys) via secretion of cytokines, induction of cellular repair pathways, and 
induction of apoptosis (Sathishkumar et al. 2016; Najafi et al. 2014; Asur et al. 2012). 
 
While SBRT and SFRT are both felt to elicit robust immune responses, the immunogenic 
effects of Lattice SBRT have not been studied.  
 
 
Rationale for treatment approach 
 
Standard palliative radiotherapy regimens may provide limited durability of response in 
large tumors. Thus, there is a clinical need for a new approach. A standard palliative 
radiotherapy regimen is 20 Gy in 5 fractions, and therefore it is reasonable to assume that 
this should be the minimum dose delivered for adequate tumor coverage in an Lattice 
SBRT plan. Assuming that this represents the 30% isodose (i.e. the “valley”), this would 
allow appropriate dose escalation in the “peak” to 66.7 Gy (i.e. the 100% isodose). The 
Lattice SBRT approach may improve symptom response, LC, and better prime the tumor 
microenvironment for immune response (Ko, Benjamin, and Formenti 2018; Walle et al. 
2018; Krombach et al. 2019) compared with canonical palliative radiotherapy doses with 
the added benefit of less toxicity than a traditional homogenous SBRT plan.  
 
 
Study Design 
 
 Overall Design 
 
This is a study evaluating the safety and efficacy of Lattice SBRT for patients with 
large tumors (≥ 4.5 cm) planning to undergo palliative radiotherapy. Patients will 
be enrolled into 1 of 4 cohorts based on their cancer histology (each at least N=10): 
sarcoma, thoracic cancers (including esophageal), upper abdominal (including 
hepatobiliary), or pelvic cancers (including gynecologic and lower GI cancers). 

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Eligible patients will undergo radiotherapy using Lattice SBRT. Lattice SBRT will 
be prescribed to 20 Gy in 5 fractions delivered every other day with a Lattice SIB 
to 66.7 Gy in 5 fractions. Patients will be followed for 12 months after the 
completion of all therapy for efficacy and treatment-related toxicity assessment.    
 
Secondary outcomes will include patient-reported quality of life outcomes. In 
addition, we will analyze blood-based markers of treatment response, so blood will 
be drawn prior to and after completion of radiotherapy. 
 
 Scientific Rationale for Study Design 
 
Tumor burden incurs significant morbidity in terms of symptomatology, including 
pain, dyspnea, hemoptysis, and mass effect on surrounding organs. Palliative 
hypofractionated radiotherapy is known to be a useful modality for control and/or 
amelioration of such symptoms. However, large tumors are difficult to treat with 
traditional palliative methods. Hypofractionated radiotherapy may offer 
insufficient control and SBRT may be associated with a high rate of toxicity. 
 
Dose escalation using SFRT may offer improved local control, symptom relief, and 
reduced toxicity compared with traditional radiotherapy methods. Also, SFRT has 
been associated with significant activation of systemic anti-tumor cytokines and 
chemokines.  
 
Our initial pilot study of SBRT has been successful thus far, demonstrating that 
Lattice SBRT is safe and effective treatment for large tumors. However, the pilot 
study has thus far demonstrated significant heterogeneity in the patient population. 
Patients are enrolled for different indications and tumor types have varied (i.e. 
treatment of oligoprogressive disease, palliation of pain, palliation of lung cancer 
for dyspnea, palliation of sarcoma for bleeing). Further, Lattice SBRT has been 
followed with varied treatments (i.e. medical therapies, surgery), and sometimes no 
treatment. Given this heterogeneity, objectively determining the effect of Lattice 
SBRT both on tumor control and patient QoL is difficult. 
 
This trial of Lattice SBRT will attempt to define efficacy and safety using dual 
primary endpoints for all patients: local tumor control at 6 months and rate of 
treatment related grade 3+ CTCAE v5.0 toxicity. Secondary endpoints will then 
evaluate patient reported QoL in 4 pre-specified sub-groups: sarcomas, thoracic 
malignancies, gastrointestinal malignancies, and pelvic cancers.   
 
 Justification for Dose 
 
One standard regimen for palliative radiotherapy is 20 Gy in 5 fractions. In SFRT, 
the traditional dose gradient between minimum tumor dose and maximum tumor 
dose is 30% to 100%, respectively. Using 20 Gy in 5 fractions as traditional 
coverage for lesions needing palliation (i.e. 30% “valley” tumor coverage), the 
“peak” 100% dose is 66.7 Gy in 5 fractions. 

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Risk/Benefit Assessment 
 
 Known Potential Risks 
 
High-dose radiation has been known to cause toxicity to normal tissue. This is 
manifested variably depending on the area of the body treated. While the potential 
toxicities can be serious and include death, these toxicities are rare when high-
quality, high-dose radiation is delivered within established normal tissue dose 
constraints using appropriate immobilization, image guidance, and institutional 
experience.  
 
We have successfully tested Lattice SBRT plans prescribed to 66.7 Gy in 5 
fractions using institutional quality assurance protocols similar to conventional 
SBRT and have implemented this treatment approach in the LITE SABR M1 pilot 
study with few treatment related toxicities. At the time of this writing, LITE SABR 
M1 has accrued 15 patients. A review of the first 8 patients and a data safety 
monitoring report was completed on 4/29/2020. This passed review and found no 
protocol SAEs. Since that time, we have had one potentially treatment-related grade 
3+ toxicity.  
 
Given this experience, we continue to expect that the toxicity risks associated with 
Lattice SBRT plans to be similar or better than conventional SBRT for large tumors 
if the required established dose constraints are met. Blood collection prior to and 
after radiotherapy poses a small risk of pain and bleeding. 
 
 
2.0 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Justification for Endpoints 
Primary 
To evaluate the efficacy of 5-
fraction palliative Lattice 
SBRT in patients with with 
large lesions who are 
planning to undergo 
palliative radiotherapy (≥4.5 
cm).  
Rate of target lesion local 
control at 6 months per 
RECIST 1.1 
RECIST 1.1 is a standard 
measure of local control. 
To evaluate the acute and 
sub-acute toxicity of 5-
fraction palliative Lattice 
SBRT in patients with large 
lesions who are planning to 
undergo palliative 
radiotherapy (≥4.5 cm).  
Rate treatment-related, non-
hematologic CTCAE v5.0 
Grade ≥ 3  toxicity at 6 months 
SBRT to large tumors is 
traditionally associated with 
high dose to OARs, with 
sequelae of radiation-induced 
toxicities. As these patients 
have no effective treatment 
options, evaluation of the 
safety of this method of dose-

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escalation with SBRT is 
warranted. CTCAE v5.0 is a 
widely accepted standardized 
measure of treatment-related 
toxicity. 
Secondary 
To assess pain response to 
Lattice SBRT 
For patients that have pain, 
their pain level will be 
assessed with the pain 
Numeric Rating Scale (NRS) 
The NRS is an 11-point scale 
for patient self-reporting of 
pain. This is selected because 
it is a reliable and clinically 
meaningful measure of pain 
that is extensively used in 
research and clinical practice.  
To assess patient-reported 
toxicity outcomes 
For patients that do not have 
pain, patient-reported symptom 
response will be assessed with 
PRO-CTCAE. A treatment site 
specific package of PRO-
CTCAE measures will be 
defined for each treatment 
location (thorax, abdomen, 
pelvis, extremity) 
PRO-CTCAE is a 
standardized inventory to 
collected patient reported 
symptomatic adverse events 
in clinical trials.  
To assess patient reported 
quality of life outcomes 
 
Patient reported quality of life 
and functional outcomes will 
be measured before treatment, 
after treatment, and at each 
follow up with the PROMIS 
Global, Physical Function, 
Pain Interference, Anxiety, and 
Depression system 
This patient reported outcome 
inventory was selected 
because it is a reliable and 
clinically meaningful measure 
of patient reported toxicities 
and functional outcomes. 
Exploratory 
 
 
To evaluate blood for 
immune- and tumor damage-
associated response with 
Lattice SBRT 
Whole blood will be collected 
at baseline and after Lattice 
SBRT for exploratory studies 
of immune and tumor damage 
associated-response 
The response of immune-
related markers will be 
assessed before and after 
Lattice SBRT to better 
understand the immunogenic 
effects of treatment on tumor. 
 
 
3.0 
STUDY POPULATION 
 
 
Inclusion Criteria 
 
1. Histologically or cytologically confirmed sarcoma (including extremity), thoracic 
cancer (including esophageal), abdominal cancer, or pelvic cancer. 
 

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2. Planning to undergo palliative radiotherapy to a lesion ≥ 4.5 cm as measured with 
radiographic imaging or with calipers by clinical exam. 
 
3. ECOG performance status ≤ 2 
 
4. At least 18 years of age. 
 
5. Radiotherapy is known to be teratogenic.  For this reason, women of childbearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control, abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she must inform her treating physician immediately.  Men 
treated or enrolled on this protocol must also agree to use adequate contraception prior 
to the study, for the duration of the study, and 6 months after completion of the study 
 
6. Ability to understand and willingness to sign an IRB approved written informed 
consent document. 
 
 
Exclusion Criteria 
 
1. Prior high-dose radiotherapy that overlaps with any planned site of protocol 
radiotherapy. Patients where the Lattice SBRT fields may overlap with the low dose 
(<10 Gy) region of prior radiotherapy treatments are eligible and may be treated if 
this is determined to be safe by the treating physician.  
 
2. Patients with tumors in need of urgent surgical intervention, such as life-threatening 
bleeding or those at high risk for pathologic fracture. 
 
3. Currently receiving any cytotoxic cancer therapy regimens or VEGF inhibitors that 
will overlap with the Lattice SBRT administration. 
a. Cytotoxic chemotherapy and VEGF inhibitors prior to radiotherapy or planned 
after radiotherapy delivery are allowed at the discretion of the treating radiation 
oncologist. This includes continuing a treatment plan which was initiated prior to the 
start of radiotherapy. A 2-week washout is recommended, but not required.  
 
4. Pregnant.  Women of childbearing potential must have a negative pregnancy test within 
20 days of study entry. 
 
5. Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or 
they have a history of AIDS-defining opportunistic infection within the 12 months prior 
to registration.  Concurrent treatment with effective ART according to DHHS treatment 
guidelines is recommended.  Recommend exclusion of specific ART agents based on 
predicted drug-drug interactions (i.e. for sensitive CYP3A4 substrates, concurrent 
strong CYP3A4 inhibitors (ritonavir and cobicistat) or inducers (efavirenz) should be 
contraindicated). 
 

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Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
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) 
 
 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. The 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 
 
 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
 
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. 
 
 
Screen Failures 
 
Screen failures are defined as participants who consent to participate in the clinical trial 
but are not 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).   
 

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Strategies for Recruitment and Retention 
 
Our institution sees a high volume of patients that are referred for palliative radiotherapy.  
 
The primary source of patients who are eligible for this study will be radiation oncologists 
within our department. The most likely service lines to see patients with large tumors in 
need of palliative radiotherapy are sarcoma, thorax (i.e. lung cancer), gastrointestinal, 
gynecologic (pelvic), and palliative. Dr. Samson (sarcoma, thorax, gastrointestinal) is the 
PI, and the other service line chiefs are enthusiastic about this trial and are listed as co-
investigators: Dr. Clifford Robinson (Thorax), Dr. Hyun Kim (Gastrointestinal), Dr. 
Stephanie Markovina (Gynecologic), Dr. Chris Abraham (Palliative). Additionally, a full-
time research coordinator will be assigned to this study who will assist in screening patients 
who are referred to our department for palliative radiotherapy for a large tumor.   
 
With the current rate of patients in need of palliative radiotherapy presenting to our 
department, we anticipate approximately 100 patients per year will be eligible for this 
protocol. A conservative estimate is that 50% of these patients will consent to participate 
in this study. This yields an estimated accrual of 50 patients per year. We anticipate that 
we will enroll 67 patients of all genders, races, and ethnicities. Given the hypofractionated 
course of therapy, 95% of patients should be able to complete therapy. We anticipate that 
we will accrue approximately 4 patients per month, therefore completing accrual in 15 
months. Patients will be accrued from the outpatient clinics and inpatient hospitals of one 
U.S. site. Potential participants will be identified by our multidisciplinary team physicians 
and discussed in tumor board.  
 
 
5.0 
TREATMENT PLAN 
 
 
Study Intervention Description 
 
Consenting and eligible patients will undergo Lattice SBRT prescribed to a dose of 20 Gy 
in 5 fractions with a simultaneous integrated boost of 66.7 Gy in 5 fractions. As long as 
radiotherapy fields do not overlap, treatment of up to 4 other tumor sites are allowed. 
Lattice SBRT is required for all tumor sites ≥ 4.5 cm. Lattice SBRT fractions will be 
delivered every other day. For sites < 4.5 cm, other planning techniques may be used (i.e. 
3D conformal or SBRT). Following radiotherapy, patients will be evaluated for toxicity at 
30 days, 3 months, 6 months, and 12 months. 
 
 
Risk Designation for Tumor Lysis Syndrome (TLS) 
 
While it is rare with solid tumor malignancies, the risk of tumor lysis syndrome (TLS) may 
be elevated with spatially fractionated radiotherapy. Patients at high-risk for or 
complications from TLS are those meeting ANY of the following criteria: 
 
o Radiosensitive histologies including lymphoma, breast cancer, small cell 
carcinoma, neuroblastoma, germ cell tumors, medulloblastoma, myxoid 

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liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma, synovial 
sarcoma, and squamous cell carcinomas of the head and neck, skin, or 
gynecological cancers (i.e. cervix, ovary) 
o Patients who have received or plan to receive systemic therapy within 2 weeks or 
less of starting or finishing Lattice SBRT 
o Patients with a history of CKD stage III based on MDRD eGFR calculation, a 
history of cardiac arrhythemias, or seizures. 
o Patients with LDH, uric acid, or potassium above the normal limit on pre-radiation 
evaluation. 
 
 
Monitoring for TLS 
 
For all patients, assessments of hematologic and metabolic function such as a CBC and 
renal function panel (required to include assessments of uric acid, potassium, phosphorus, 
and calcium) will be collected at the following time points: 
• No more than 1 week before treatment (including on the day of treatment) 
• Immediately after radiotherapy completion (Fraction 5, day 0) 
• At 48-72 hours after radiotherapy completion 
• At 7 days (+/- 1 day) after radiotherapy completion 
 
 
Pre-Radiation Evaluation 
 
• History and physical exam by team radiation oncologist 
• Assessment of hematologic and metabolic function such as a CBC and renal 
function panel. This must include assessments of uric acid, potassium, phosphorus, 
and calcium. 
• CT, PET/CT, or MRI of the chest, abdomen, and pelvis 
• Completion of baseline NRS pain score (if applicable), PRO-CTCAE, PROMIS 
Global, Physical Function, Pain Interference, Anxiety, and Depression 
questionnaires 
• Peripheral blood collection. 
 
 
Radiation Therapy 
 
Lattice SBRT must be used for at least one lesion 4.5 cm or greater. The prescription dose 
for Lattice SBRT is 20 Gy in 5 fractions with a SIB to 66.7 Gy in 5 fractions. For Lattice 
SBRT, patients must be treated with intensity modulated radiotherapy (IMRT) or 
volumetric modulated arc therapy (VMAT). Intensity modulated proton therapy (IMPT) is 
allowed. 
 
For Lattice SBRT, each lesion should be treated no more frequently than every other day, 
but treatment of each lesion may be staggered so that the patient has radiotherapy daily. 
No more than 3 lesions should be treated on the same day. 
 
For other lesions, a standard palliative regimen of 5 fractions or less is encouraged but not 
required, and lesions amenable to conventional SBRT may be treated as such as well. 

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Multiple Lattice radiotherapy plans delivered during the trial period may not overlap. 
Reirradiation of prior irradiated sites is not allowed.  
 
 Localization, Simulation, and Immobilization 
 
Simulation and treatment position will be determined by the treating radiation 
oncologist and team. Patients should be optimally positioned for stereotactic body 
radiation therapy with alpha cradles, aquaplast masks, or other methods of 
immobilization. The use of devices to alter dose distributions, such as bolus or lead 
shields, are allowed. Use of techniques to control and/or accommodate tumor 
motion may also be employed in constructing the planning target volume (PTV). 
 
A treatment planning CT scan or MRI in the treatment position will be required to 
define the PTV. The extent of the CT scan will be determined at the discretion of 
the treating physician. A CT scan slice thickness of ≤ 5 mm should be employed.  
 
 Treatment Planning/Target Volumes 
 
The definitions for the GTV, PTV and normal structures used in this protocol 
generally conform to the 1993 ICRU report #50 titled Prescribing, Recording and 
Reporting Photon Beam Therapy.  
 
5.5.2.1 Target Volumes and Normal Structures  
 
Target Volumes 
Gross Tumor Volume (GTV): Contour using all available clinical and 
radiographic information. Fusion of other diagnostic imaging to delineate 
the GTV is allowed. Construction of an iGTV using 4DCT imaging is 
allowed. For boney lesions of the spine, the entire involved vertebral body 
may be included in the GTV.  
 
Planning Target Volume 2000 cGy (PTV_2000): Represents a geometric 
expansion of the GTV (or iGTV) of up to 1.0 cm. The PTV should be 
reduced as not to extend beyond the patient (i.e. in to air) and may be 
reduced as to not extend into skin (i.e. external contour contracted by 3-5 
mm). 
 
GTV-5: Represents a geometric contraction of 0.5 cm from the GTV, and is 
used for generation of the subsequent high-dose target. 
 
Planning Target Volume 6670 cGy (PTV_6670): Spheres with diameter 1.5 
cm should be placed 6 cm apart as measured from center to center inside 
the GTV. The spheres should be placed to maximize the number of whole 
spheres within the GTV. There should be 3 cm between axial slices in which 
spheres are placed. Spheres extending outside of the GTV-5 structure will 

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be cropped, and the resultant spherical volume will represent the high-dose 
target of the PTV_6670. 
 
 
A) Geometric representation of sphere placement. Yellow dots represent the 1.5 cm diameter 
PTV_6670 target vertices, and dotted line vertices represent the transposed target vertices from 
adjacent planes. Axial planes where vertices are placed are separated by 3 cm in-plane. Within a 
plan, vertices are separated by 6 cm center to center (4.5 cm edge to edge) in orthogonal axes, 
and 3√2 cm along the diagonal. B) Axial CT slices of a pelvic tumor with the yellow outlined target 
vertices (PTV_6670) in each plane, red GTV_2000, and green PTV_2000. Magenta arrows denote 
cropped vertices in PTV_6670 that extend outside of the GTV_2000. C) Dose distribution after 
VMAT planning for the pelvic tumor with accompanying dose color wash legend. 
 
Normal structures: Relevant normal structures and their dose constraints are 
described in the table below. Each normal structure should be contoured in 
its entirety.  
 
5.5.2.2 Radiation Treatment Planning 
 
CT-based planning with tissue inhomogeneity correction is required. Daily 
IGRT is required. Motion management strategies such as breath holding, 
respiratory gating, fluoroscopy, and MR-guided daily adaptive therapy are 
allowed.  
 
5.5.2.3 Planning Objectives and Normal Tissue Constraints 
 
The normal tissues in the table below are to be contoured in their entirety 
when present on the CT simulation scan.  
 
The following organs and doses are guidelines for the radiation treatment 
plan. Organ at risk tolerance levels cannot be exceeded. Under coverage 
of PTV targets in order to meet OAR constraints is allowed. 
 

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• PTV_2000: at least 95% should be covered by 20 Gy. Keeping Dmax 
within the PTV_2000 and outside the PTV_6670 to less than 24 Gy 
is recommended but not required. 
• PTV_6670: at least 95% should be covered by 66.7 Gy. A Dmin of at 
least 60 Gy within vPTV is recommended. 
 
Serial Tissue 
Max point* 
dose (Gy) 
Optic pathway 
25 
Cochlea 
22 
Brainstem (excluding medulla) 
31 
Spinal cord and medulla 
28 
Cauda equina 
31.5 
Sacral plexus 
32 
Esophagus 
35 
Brachial plexus 
32.5 
Heart/pericardium 
38 
Great vessels 
53 
Trachea and large bronchus 
40 
Bronchi 
33 
Skin 
38.5 
Stomach 
35 
Bile duct 
41 
Duodenum 
26 
Jejunum/ileum 
32 
Colon 
40 
Rectum 
55 
Ureter 
45 
Bladder wall 
38 
*A point is defined as volume ≤ 0.035 cc) 
 
 
Parallel Tissue 
Critical 
Dose (Gy) 
Critical 
Volume 
Lungs - GTV 
12.5 
< 1500 cc 
13.5 
< 1000 cc 
< 37% 
Liver 
21 
< 700 cc 
Renal cortex (bilateral) 
28 
< 200 cc 
Renal cortex (single kidney) 
14.5 
< 130 cc 
Femoral Heads (Right & Left) 30 
<10 cc 
 
 Dose Specifications 

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For Lattice SBRT, the daily prescription dose will be 20 Gy to be delivered to the 
PTV_2000 with a SIB of 66.7 Gy to be delivered to the PTV_6670 over 5 fractions 
(4 Gy and 13.34 Gy to the PTV_2000 and PTV_6670 per day, respectively). All 
doses will be prescribed to the periphery of the PTVs. In general, the prescription 
isodose line (generally 93-98%) chosen should encompass at least 95% of the PTV. 
Under coverage of the PTV to meet dose constraints is allowed.  
 
The maximum point dose, minimum point dose, and the mean dose to the PTV will 
also be reported. 
 
 Technical Factors 
 
The guidelines for VMAT in this trial will conform to the policies set by the 
Advanced Technology Consortium (ATC) and the National Cancer Institute (NCI).  
Each of the target volumes and normal structures listed below must be delineated 
on each slice from the 3D planning CT in which that structure exists.  
 
 Radiation Quality Assurance 
 
Radiation quality assurance will be evaluated by a Medical Physics team. Prior to 
treatment, plan quality will be assessed with an ion chamber and film-based 
dosimeters. 
 
 
Patient-Reported Quality of Life Outcome and Toxicity Measures 
 
Symptom response and patient-reported quality of life will be measured using the pain 
numeric rating scale, PRO-CTCAE (abridged as indicated in Appendix D), PROMIS 
Global, Physical Function, Pain Interference, Anxiety, and Depression questionnaire at the 
following time points: 
 
1. Within 2 weeks prior to the start of radiotherapy 
2. Within 3 weeks after completion of radiotherapy 
3. At 30 days after radiotherapy   
4. At 90 days after radiotherapy 
5. At 180 days after radiotherapy 
6. At 360 days after radiotherapy 
 
The patient reported outcomes measures will be conducted using a computer-assisted 
interview program and may be done in person before/after a routine office visit or over the 
phone at the preference of the study participant. Patient reported outcomes may also be 
collected online. 
 
 
Acquisition of Blood for Research 
 
Refer to Section 8.0. 

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Definitions of Evaluability 
 
All patients enrolled on the study are evaluable for toxicity if they have received at least 
one fraction of radiation.  Patients are evaluated from first receiving study treatment until 
90 days after the conclusion of treatment or death.  Participants who are consented but do 
not receive study treatment will be replaced. 
 
 
Concomitant Therapy and Supportive Care Guidelines 
 
Patients may not receive any concurrent systemic therapy with radiation. The interval from 
last receipt of systemic therapy to the initiation (or re-initiation) of systemic therapy will 
be at physician discretion. Supportive care will be consistent with standards for palliative 
radiotherapy, directed by the treating physician.  
 
 
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 serum/urine pregnancy test within 20 days prior to the first dose of 
radiation. 
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study 
and for 6 months following the last dose of radiation.  
 
If a patient is suspected to be pregnant, radiation 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 therapy. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy or 
within 6 months after the last dose of radiation, the investigator must be notified in order 
to facilitate outcome follow-up. 
 
 
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 
maximum of 2 weeks or until one of the following criteria applies: 
 
• Documented and confirmed disease progression 

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• 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. 
 
 
Follow-up Specifications 
 
Patients will be followed at 14, 30, 90, 180, and 360 days after completion of radiotherapy. 
Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event.  Patients may be followed in-person during 
visits, medical records review, phone calls, office visits, and assessment of any other 
clinically relevant materials after completion of therapy. 
 
 
Lost to Follow-Up 
 
A participant will be considered lost to follow-up if he or she fails to return for 90 days 
scheduled visits and is unable to be contacted by the study team. 
 
The following actions must be taken if the participant fails to return to clinic for a required 
study visit: 
o The study team will attempt to contact the participant and reschedule the missed 
visit within 1-2 weeks and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain if the participant wishes to and/or should 
continue in the study. 
o Before a participant is deemed lost to follow-up, the investigator or designee will 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address).  These contact attempts should be documented in the participant’s medical 
record or study file. 
o Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 
 
 

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6.0 
RADIATION THERAPY DOSE/DELAYS MODIFICATIONS 
 
The planned course of radiation therapy is five fractions delivered every other day to each lesion. 
For plans unable to meet dose constraints to OARs, under coverage of the PTV in order to meet 
the constraints is recommended. Patients with delayed treatment starts of any duration may be 
treated using existing or new plans at physician discretion. Continuance of treatment for delays 
while on-treatment will be at the discretion of the treating physician.  
 
 
7.0 
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 treatment through 360 days following the completion 
of radiotherapy.  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 
• AEs that do not fall under the following categories 
o Gastrointestinal 
o Hepatobiliary 
o Immune system 
o Metabolic 
o Nervous system 
o Renal and urinary 
o Respiratory 
o Skin disorders 
• AEs that are grade 1 
 
Refer to the data submission schedule in Section 9.1 for instructions on the collection of AEs in 
the EDC. 
 
 
WU PI Reporting Requirements 
 
 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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 Reporting to the Quality Assurance and Safety Monitoring 
Committee (QASMC) at Washington University 
 
The PI 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. 
 
 
Exceptions to Expedited Reporting 
 
Events that do not require expedited reporting as described in Section 7.1 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. 
 
 
8.0 
CORRELATIVE STUDIES 
 
 
Blood Sample Collection and Processing 
 
Patients will be have up to 30 mL of anticoagulated blood collected in up to 3 EDTA purple 
top tubes at the following time points: 
• Baseline 
• immediately after radiotherapy completion (Fraction 5) 
• 14 days after radiotherapy 
• 30-days follow-up 
 
All samples will be marked with the patient’s study number, initials, and date of sampling 
with the use of an indelible marker. 
 
Blood and tissue samples will be stored in Dr. Aadel Chaudhuri’s lab in the Cancer Biology 
Division of the Department of Radiation Oncology.  
 
 Plasma and Whole Blood 
 
Each sample will be labeled with a unique de-identified specimen ID number, and 
stored in Dr. Chaudhuri’s lab until analysis. Specifically, blood samples (up to 30 
mL) will be collected in 3 EDTA (10 mL each) purple top tubes at baseline, post-

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treatment (i.e. immediately following fraction 5), 14 days after treatment, and at 30 
days follow-up. EDTA whole blood samples will be spun at 1200 g and processed 
for platelet depleted plasma and peripheral white blood cells. Nucleated white 
blood cells will be isolated using Ficoll or Lymphoprep extraction using Sepmate 
tubes, washed in phosphate buffered saline, then divided into approximately 10 x 
106 cells/aliquot, and cryopreserved at -80° C for 24-72 hours, then moved for 
longer term storage in a LN2 tank. All plasma and aliquots of platelet-depleted 
whole blood will also be stored at -80° C.  
 
All samples should be sent to: 
 
Aadel Chaudhuri, M.D., Ph.D. 
Peter Harris, Ph.D. (Lab Manager) 
4511 Forest Park Avenue 
Phone: 314-273-9040, 269-598-2212 (cell)  
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
On-Study Form 
Medical History Form 
Prior to starting treatment 
Specimen Collection Form 
Screening, immediately after radiotherapy completion 
(Fraction 5), 14 days after radiotherapy, and 30 days after 
radiotherapy  
Questionnaires  
Baseline, after radiation at 2 weeks, 1 month, 3 months, 6 
months, and 1 year 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
RECIST Form 
Baseline, then 3 months, 6 months, and 1 year post 
treatment 
Follow Up Form 
After radiation at 2 weeks, 1 month, 3 months, 6 months, 
and 1 year 
Death Form 
At time of death (if applicable) 
 
 
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. 
 

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Participant death due to disease progression should be reported on the Toxicity Form as 
grade 5 disease progression.  If death is due to an AE (e.g. cardiac disorders: cardiac arrest), 
report as a grade 5 event under that AE.  Participant death must also be recorded on the 
Death Form. 
 
 
10.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the 
Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington 
University Quality Assurance and Safety Monitoring Committee (QASMC) semi-annually 
beginning six months after accrual has opened (if at least one patient has been enrolled) or one 
year after accrual has opened (if no patients have been enrolled at the six-month mark). 
 
The Principal Investigator will review all patient data at least every six months, and provide a 
semi-annual report to the QASMC. This report will include: 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
• Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of study 
• History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol exceptions, 
error, or breach of confidentiality including start/stop dates and reason 
• Study-wide target accrual 
• 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 (phase I studies only if efficacy is objective of the protocol) 
• Measures of efficacy  
• Early stopping rules with supporting data and list the number of participants who have 
met the early stopping rules 
• Summary of toxicities  
• Abstract submissions/publications 
• Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC according 
to institutional guidelines. 
 
 

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11.0 
STATISTICAL CONSIDERATIONS 
 
 
Study Design  
 
This is a single arm study where 67 eligible patients with non-hematologic malignancies 
patients with large tumors (≥ 4.5 cm) will undergo radiotherapy using Lattice SBRT. 
Lattice SBRT will be prescribed to 20 Gy in 5 fractions delivered every other day with a 
LATTICE simultaneous integrated boost (SIB) to 66.7 Gy in 5 fractions. Patients will be 
followed for 12 months after the completion of radiotherapy for treatment effect and 
treatment-related toxicity assessment.  An exploratory study will analyze blood-based 
markers of treatment response, so blood will be drawn prior to and after completion of 
radiotherapy. 
 
 
Study Endpoints  
 
The co-primary endpoints are rate of local control of the treated (i.e. target) lesion at 6 
months, and proportion of patients with treatment related grade 3+ CTCAE v5.0 toxicity. 
Local control will be determined by RECIST 1.1 analysis of baseline compared with 
imaging at 6 months. Imaging may include CT scan, PET/CT, or MRI. It is strongly 
suggested that the same imaging modality is used between baseline and at every follow-up 
timepoint for staging of disease.  
 
Importantly, there are limited available data to determine expected local control of large 
tumors after SBRT. Almost all studies have focused on tumors with average maximal 
diameter of only 5.5 cm corresponding to a tumor volume of approximately 87 cc. In such 
studies, local control rates are approximately 70-85%. In the pilot study of Lattice SBRT 
at Washington University, the median treated tumor volume was 435 cc (N=14). Likewise, 
these few studies of SBRT for large tumors report a grade 3+ toxicity rate of 5-25%, 
varying based on tumor location.  
 
Due to the lack of a reliable historical comparison, the enrollment target was defined by 
clinical considerations as opposed to power calculations for comparison with a historical 
control. This study instead seeks to establish the expected local control rate at 6 months for 
patients with such large tumors treated with Lattice SBRT. After discussing with internal 
and external stakeholders, we determined that a clinically reasonable bound on local 
control at 6 months would be 15%. Approximately 47 patients would be required to 
determine local control with a 95% confidence interval of +/- 15%; 67 patients will be 
enrolled to get 47 evaluable patients.  We anticipate that up to 30% of patients may not be 
evaluable for local control at 6 months and are accounting for this potential drop-out rate 
by enrolling 67 patients.  This is because patients with very large tumors needing palliative 
radiotherapy often have short survival. 
 
Likewise, the study seeks to establish the expected grade 3+ treatment related toxicity rate 
for treatment of large tumors with lattice SBRT. The treatment will be considered safe if 
the grade 3+ treatment related toxicity rate is less than 20%, which is in line with prior 
studies of SBRT of large tumors.  
 

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As secondary endpoints, this study will evaluate patient reported outcomes through 12 
months follow up. Comparisons of patient-reported outcomes such as pain in patients 
undergoing palliative radiotherapy are notoriously difficult. These can be impacted by the 
initial indication for palliative radiation (i.e. oligoprogression versus uncontrolled 
symptom), presence or absence of other tumors outside the target(s), subsequent therapies 
after treatment, and co-morbidities. This study will attempt to reduce this heterogeneity by 
studying the secondary endpoints within pre-specified subgroups. Additionally, this study 
will evaluate PROs using the reliable change index, which allows evaluation of the change 
of individual patient PROs of comparison to their own baseline.  
 
The RCI utilizes the known retest reliability and standard deviation of a test to calculate 
the standard error of measurement and standard error of the difference between scores 
[Jacobson, 1992]. This value represents the level of change associated with statistically 
significant change from baseline. RCI is calculated as follows: 
𝑅𝑅𝑅𝑅𝑅𝑅= 𝑥𝑥2 − 𝑥𝑥1
𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
 
Where x2 – x1 represents an individual’s change between timepoints. This can also be 
reported as a difference in population mean. Sdiff, the standard error of the difference 
between the two scores accounting for reliability of the test, is calculated as: 
𝑆𝑆𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑= ඥ2(𝑆𝑆𝐸𝐸)2 
𝑆𝑆𝐸𝐸= 𝑠𝑠1ඥ1 −𝑟𝑟𝑥𝑥𝑥𝑥 
Where SE is the standard error of measurement of the test, s1 is the standard deviation of 
the test results at the initial time point, and rxx is the test-retest reliability of the measure. 
The test-retest reliabilities of PROMIS domains used in this study have been previously 
evaluated in patients with musculoskeletal conditions and range from 0.85-0.92 [Deyo, 
2016].  
 
The RCI will be calculated for each individual patient for pain score, PRO-CTCAE, and 
each PROMIS domain between baseline and the 3, 6, and 12 month time points. In order 
for a change to be deemed statistically reliable at a 90% confidence interval, the Z-score of 
the RCI must be greater than 1.645. The 90% confidence interval is standard use in the 
literature when calculating RCI because it increases the sensitivity in detecting reliable 
change and defines a change which occurs in only 5% of healthy individuals in either 
direction [Stein, Gray, Schmitt, Hensel]. Changes that exceed this threshold in either 
direction are likely due to actual change rather than due to chance. Individual changes are 
reported as either significant increase, significant decrease, or no change.  
 
Mean RCI for each time-point and domain will be calculated to determine significant 
change on a population level for each sub-group. The Sdiff for each domain will be used to 
calculate a minimum important change at each time-point based on a 90% confidence 
interval. Lastly, the proportion of individuals in each histology cohort group whose RCI 
indicated significant increase, significant decrease, or no change in PRO scores will be 
reported.  
 

Protocol Version Date: 06/09/2023 
 
Page 33 of 50 
 
 
Data Analysis  
 
Demographic and clinical characteristics including treatment toxicity will be summarized 
using descriptive statistics. RECIST 1.1 will be used to determine local control per the 
protocol described in Appendix E. The RCI will be used to compare the QoL scores 
between before and after treatment with Lattice SBRT.  
 
 
Power Analysis and Sample Size  
 
Approximately 67 evaluable patients will be enrolled. The proposed sample size was 
chosen based on clinical considerations, to allow for establishment of an expected 6-month 
local control rate and treatment related grade 3+ CTCAE toxicity rate for treatment of very 
large tumors.  
 
After discussing with internal and external stakeholders, we determined that a clinically 
reasonable bound on local control at 6 months would be 15%. Approximately 47 patients 
would be required to determine local control with a 95% confidence interval of +/- 15%. 
However, patients with large tumors needing Lattice SBRT are expected to have a short 
median survival. Based on our prior experience, we expect 20-30% of patients will 
complete Lattice SBRT but may be unevaluable for the primary endpoint. Enrolling 67 
patients with an up to 30% drop out rate would ensure at least 47 evaluable patients to 
create our clinically acceptable 95% CI estimate for local control at 6 months. 
 
 
Accrual  
 
The rate of accrual for the study is expected to be about 4 patients per month. It is estimated 
67 eligible patients will be enrolled in 12 months.  
 
 
Continuous Toxicity Monitoring using Pocock-type boundary 
 
The toxicities will be reviewed and monitored on a continuous basis. Early stopping of this 
trial will be based on the excessive Lattice SBRT treatment emergent severe adverse events 
(TSAE) of grade 3 or higher non-hematological rate. We assume the TSAE rate is expected 
~30% or less and a toxicity rate of 40% or more is not desired. Sequential boundaries will 
be used to monitor dose-limiting toxicity rate after three patients are enrolled and evaluable 
for toxicity. The accrual will be halted if excessive numbers of TSAE are seen, that is, if 
the number of TSAE is equal to or exceeds bn out of n patients with full follow-up (see 
table below). This is a Pocock-type stopping boundary that yields the probability of 
crossing the boundary at most 0.3 when the rate of TSAE is equal to the acceptable rate of 
0.3 (Ivanova, Qaqish, and Schell 2005).  
 
 

Protocol Version Date: 06/09/2023 
 
Page 34 of 50 
 
 
 
 
Thus, based on the continuous monitoring algorithm for toxicity using Pocock-type 
boundary, the study will halt if excessive Lattice SBRT -related adverse events occur in 
the 3 of the first 3 patients, or 4 of the first 6, or 5 of the first 9, or 5 of the 10 patients has 
completed the trial. 
 
The operating characteristics including early stopping probability, expected number of 
TSAEs and associated with the calculated boundaries are listed below. 
 
TEAE 
rate 
Early 
stopping 
(hitting the 
boundary) 
probability 
Expected 
number 
of TEAEs 
Standard 
deviation 
on number 
of TEAEs 
Expected 
number of 
patients 
enrolled  
Standard 
deviation 
of number 
of patinets 
enrolled  
Expected 
TEAE 
rate 
Standard 
deviation 
on TEAE 
rate 
0.30 
0.3980 
14.08 
6.93 
46.94 
26.85 
0.41 
0.23 
0.40 
0.8648 
9.76 
7.27 
24.38 
22.99 
0.56 
0.22 
0.50 
0.9950 
5.63 
4.22 
11.26 
11.69 
0.66 
0.22 
0.60 
1.0000 
3.85 
2.24 
6.41 
5.76 
0.75 
0.21 
0.70 
1.0000 
3.03 
1.36 
4.32 
3.28 
0.82 
0.19 
0.80 
1.0000 
2.56 
0.88 
3.20 
1.98 
0.89 
0.15 
0.90 
1.0000 
2.24 
0.53 
2.49 
1.11 
0.95 
0.11 
1.00 
1.0000 
2.00 
0.00 
2.00 
0.00 
1.00 
0.00 
 
 
 
 
 
number of patients  
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
Boundary (bn) 
3 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
7 
8 
9 
9 
9 
9 
10 
10 
number of patients  
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
Boundary (bn) 
10 
11 
11 
11 
12 
12 
12 
13 
13 
13 
14 
14 
14 
15 
15 
15 
16 
16 
17 
17 
number of patients  
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
55 
56 
57 
58 
59 
60 
61 
62 
Boundary (bn) 
17 
18 
18 
18 
19 
19 
19 
20 
20 
20 
21 
21 
21 
22 
22 
22 
23 
23 
23 
24 
number of patients  
63 
64 
65 
66 
67 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Boundary (bn) 
24 
24 
25 
25 
25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Version Date: 06/09/2023 
 
Page 35 of 50 
 
 
12.0 
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We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials Core 
which provided protocol development services. The Siteman Cancer Center is supported in part 
by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 

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

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

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APPENDIX C: Reporting Timelines 
 
Expedited Reporting Timelines 
Event 
HRPO 
QASMC 
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.   
 
If withdrawing the participant does not 
represent a safety issue and the patient 
will be withdrawn, report at continuing 
review. 
 
 
Routine Reporting Timelines 
Event 
HRPO 
QASMC 
Adverse event or SAE 
that does not require 
expedited reporting 
If they do not meet the definition of an 
unanticipated problem involving risks to 
participants or others, report summary 
information at the time of continuing review 
Adverse events will be 
reported in the toxicity 
table in the DSM report 

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Routine Reporting Timelines 
Event 
HRPO 
QASMC 
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 D: PRO-CTCAE Inventories 
 
All patients will complete the following PRO-CTCAE inventories: 
• Rash 
• Numbness/tingling 
• Dizziness 
• Concentration 
• Memory 
• General pain 
• Fatigue 
• Insomnia 
• Anxious 
• Discouraged 
• Sad 
 
Patients with GI cancers (including esophagus, lower GI, and retroperitoneal sarcoma) will 
complete the following additional PRO-CTCAE inventories: 
• Decreased appetite 
• Nausea 
• Vomiting 
• Heartburn 
• Gas 
• Bloating 
• Hiccups 
• Constipation 
• Diarrhea 
• Abdominal pain 
• Fecal incontinence 
 
Patients with thoracic cancers (including esophagus, lung, and chest wall) will complete the 
following additional PRO-CTCAE inventories: 
• Decreased appetite 
• Nausea 
• Vomiting 
• Heartburn 
• Gas 
• Bloating 
• Hiccups 
• Shortness of breath 
• Wheezing 
• Voice changes 
• Hoarseness 
 

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Patients with pelvic cancers (including prostate, gynecologic, sarcomas, rectum, anus) will 
complete the following additional PRO-CTCAE inventories: 
• Vaginal discharge 
• Vaginal dryness 
• Painful urination 
• Urinary urgency 
• Urinary frequency 
• Change in urine color 
• Urinary incontinence 
• Erection 
• Ejaculation 
• Libido 
• Delayed orgasm 
• Unable to have orgasm 
• Pain with intercourse 
 
Patients with head and neck cancers will complete the following additional PRO-CTCAE 
inventories: 
• Dry mouth 
• Swallowing 
• Mouth sores 
• Cheilitis 
• Voice changes 
• Hoarseness  
 
 
 
 

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APPENDIX E: MEASUREMENT OF EFFECT (RECIST 1.1) 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria.   
 
RECIST 1.1 
 
Target lesions:  The treated lesions (i.e. those defined as treatment targets by the radiation 
oncologist, GTVs) should be identified as target lesions and recorded and measured at baseline.  
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. 
 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter 
as assessed using calipers (e.g., skin nodules).  In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung.  However, CT is 
preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions 
on CT 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).   
 

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Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables involved 
in MRI, which greatly impact image quality, lesion conspicuity, and measurement.  
Furthermore, the availability of MRI is variable globally.  As with CT, if an MRI 
is performed, the technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and 
the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.  Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as 
closely as possible to prior scans.  Body scans should be performed with breath-
hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT performed 
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or 
serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not 
be used as a method of measurement.  Ultrasound examinations cannot be 
reproduced in their entirety for independent review at a later date and, because they 
are operator dependent, it cannot be guaranteed that the same technique and 
measurements will be taken from one assessment to the next.  If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is 
advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained or to determine relapse 
in trials where recurrence following complete response (CR) or surgical resection 
is an endpoint. 
 
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:  
 

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• Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
• No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT scans 
are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, 
this is not PD. 
• FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to 
represent fibrosis or scarring.  The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be 
acknowledged that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image. 
 
Response Criteria 
 
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. 
 
 

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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. 
                           
    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 
 
 

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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.