A Pilot Study to Assess Feasibility of Hypofractionation and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma Patients Awaiting Liver Transplantation
Phase: NA
Conditions: Hepatocellular Carcinoma
Sponsor: OHSU Knight Cancer Institute

 
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Study Title: 
A Pilot Study to Assess Feasibility of Hypofractionation and 
Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma 
Patients Awaiting Liver Transplantation 
Protocol Number:  18810 
ClinicalTrials.gov ID:  NCT03812289 
Investigational modality: Hypofractionation and Stereotactic Body Radiation Therapy 
Version Number:  1.4 
Version Date: 07 March 2024 
Replaces: v1.3 
IND/IDE Status: Not Applicable 
Principal Investigator: Nima Nabavizadeh, MD 
 
Department of Radiation Medicine 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503-418-3685 
Email: nabaviza@ohsu.edu 
Sub-Investigators: 
 
Ramtin Rahmani 
Department of Radiation Medicine 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KPV4  
Portland, OR 97239  
Phone: 503-418-3685 
Email: rahmani@ohsu.edu 
 
Alice Fung, MD 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road 
Portland, OR 97239 
Phone: 503-494-1438 
funga@ohsu.edu 
 
 
Statisticians: 
 
Jessica Minnier, PhD  
Biostatistics Shared Resource  
Oregon Health & Science University 
3181 SW Sam Jackson Park Road 
Portland, OR 97239  
Email: minnier@ohsu.edu 

 
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Andy Kaempf, MS 
Biostatistics Shared Resource  
Oregon Health & Science University 
3181 SW Sam Jackson Park Road 
Portland, OR 97239  
Email: kaempf@ohsu.edu 
 

 
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SUMMARY OF CHANGES 
 
# 
Section 
Page(s) 
Change 
Justification 
1. 1.2.1 
16 
Corrected sentence 
Previously incomplete 
2. 4.5 
24 
Screening period changed from 
10 days to 28 days 
Clarified to reflect schedule of 
events 
3. 5.3.1 
28 
Clarified required duration of 
contraception after treatment 
Inconsistency between 
exclusion criteria and 
description in 5.3.1 
4. 6.2.2 
32 
Removed LDH and magnesium 
from biochemistry panels 
These are not part of normal lab 
panels and are not routinely 
collected 
5. 6.8 
34 
Updated schedule of events per 
standard of care 
Labs and time points were not 
represented accurately 
6. Title 
Page 
1 
Updated list of investigators and 
statistician 
Include only investigators who 
are participating in the study and 
have received 
training/delegation from PI 
 
 

 
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SYNOPSIS 
 
Study Title 
A pilot study to assess feasibility of stereotactic body radiation 
therapy for hepatocellular carcinoma patients awaiting liver 
transplantation 
Protocol # 18810 
Study Center OHSU, single-site   
Clinical Phase Pilot  
 
Investigational
Component(s) Radiation Therapy  
Interventional Study Type Single-arm 
Précis 
 
Liver transplantation (LTX) is the best treatment for patients with 
hepatocellular carcinoma (HCC) and Child-Pugh (CP) B or C 
cirrhosis, as both conditions can be very effectively treated at once.  
As liver transplantation wait-lists can be many months, liver directed 
therapies (LDTs) are essential as oncologic temporizing measures to 
bridge patients to transplantation. However, due to the fear of further 
hepatic decompensation, many patients with advanced cirrhosis are 
excluded from receiving LDTs. This study hypothesizes that liver 
stereotactic body radiation therapy (SBRT) can be of safe and 
practical use in this fragile patient population and may result in the 
reduction of transplantation drop-out rates. The overall goal of this 
pilot proposal is to evaluate the feasibility of bridge-to-transplantation 
liver SBRT in hepatocellular carcinoma patients with Child-Pugh B8 
or higher cirrhosis.  
 
Primary Objectives 
Assess the use of SBRT in HCC patients with advanced liver 
cirrhosis as a feasible approach to providing localized disease control 
that adequately suffices liver transplant eligibility criteria.   
Secondary Objectives Assess preliminary efficacy and toxicity in HCC patients with 
advanced cirrhosis following liver SBRT 
Exploratory Objectives 
Assess quality of life (QoL) in HCC patients with advanced cirrhosis 
following liver SBRT 
Examine SBRT-related histopathologic changes in explanted livers of 
patients with advanced cirrhosis. 
Primary Endpoints 1. Proportion of participants that are transplant eligible 1 year 
following SBRT 
Secondary Endpoints 
1. Incidence of progressive disease within or at the planned tumor 
volume (PTV) margin (i.e. local control) 
2. Incidence of progressive disease within any section of the liver, 
including the PTV (e.g. intrahepatic disease free survival) 
3. Incidence of progressive disease outside of the liver (e.g. 
extrahepatic disease free survival) 
4. Overall Survival 
5. Proportion of participants that proceed to transplantation 
6. Incidence of non-classical radiation-induced liver disease (RILD), 
defined as grade 4 aspartate aminotransferase or alanine 
aminotransferase elevation, or an increase in CP score of ≥ 2 
within 1 week to 3 months after completing SBRT.  

 
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7. Incidence of liver toxicity per CTCAE v5.0 within 1 week to 3 
months after completing SBRT. 
Exploratory Endpoints 
1. QoL scores for EORTC QLQ-C30 questionnaire 
2. QoL scores for Functional Assessment of Cancer Therapy-
Hepatobiliary (FACT-Hep) questionnaire 
3. At time of transplantation, histopathologic changes in irradiated 
tumor sites relative to uninvolved liver tissue will be assessed 
 
Number of Participants 15 
Duration of Therapy SBRT will be administered as 5 fractions every other day (~10 day) 
Duration of Follow Up Time of progression, or transplantation, or 2-years after last SBRT 
dose, whichever occurs first 
Key Inclusion Criteria 
1. Participants aged ≥18 years 
2. Patient diagnosed with HCC and recommended for LTX 
3. Meets clinical criteria for eligibility for SBRT to the target lesion  
4. Childs-Pugh Class B8 or higher 
5. Eastern Clinical Oncology Group performance status ≤2 
6. Safe radiation treatment planning parameters that adhere to all 
organs at risk constraints per section 5.1 of the protocol. If normal 
organs at risk constraints (including at least 700cc of uninvolved 
liver) are unable to be met at the lowest dose modification (30 Gy 
in 5 fractions), the patient is deemed ineligible for SBRT and 
deemed a screen failure. 
Key Exclusion Criteria 
1. Prior radiotherapy to the upper abdomen or radioembolization of 
the liver 
2. Prior SBRT to the target lesion, RFA, or LTX 
3. Active GI bleed within 2 weeks of study enrollment 
4. Contraindication to receiving SBRT 
5. Contraindication to both contrast enhanced MRI and contrast 
enhanced CT (i.e. unable to undergo follow-up imaging or SBRT 
treatment planning) 
6. Women who are pregnant 
 
Investigational Product SBRT 
 
Statistical 
Considerations 
This is a pilot study with no formal hypothesis test but to assess a 
preliminary estimate of feasibility.  A sample size of 15 patients will 
ensure that at least on 1 SBRT ineligible participant is encountered 
(at a 95% confidence interval).  

 
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SCHEMATIC OF STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 3 
SYNOPSIS ................................................................................................................................. 4 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 7 
LIST OF TABLES ..................................................................................................................... 13 
LIST OF ABBREVIATIONS ...................................................................................................... 14 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 16 
 
Overview of Hepatocellular Carcinoma ..................................................................... 16 
 
Liver Directed THerapies .......................................................................................... 16 
1.2.1 Stereotactic Body Radiotherapy of LIver in Setting of Advanced Cirrhosis ........... 16 
 
Rationale .................................................................................................................. 17 
 
Potential Risks and Benefits ..................................................................................... 18 
1.4.1 Known Potential Risks .......................................................................................... 18 
1.4.2 Known Potential Benefits ..................................................................................... 18 
2. OBJECTIVES ...................................................................................................................... 19 
 
Primary Objectives .................................................................................................... 19 
 
Secondary Objectives ............................................................................................... 19 
 
Exploratory Objectives .............................................................................................. 19 
3. STUDY DESIGN AND ENDPOINTS .................................................................................... 20 
 
Description of the Study Design ................................................................................ 20 
 
Study Endpoints ........................................................................................................ 20 
3.2.1 Primary Endpoint .................................................................................................. 20 
3.2.2 Secondary Endpoints ........................................................................................... 20 
3.2.3 Exploratory Endpoint ............................................................................................ 21 
4. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 22 
 
Participant Inclusion Criteria ..................................................................................... 22 
 
Participant Exclusion Criteria .................................................................................... 22 
 
Strategies for Recruitment and Retention ................................................................. 23 
4.3.1 Accrual Estimates ................................................................................................ 23 
4.3.2 Inclusion of Children ............................................................................................. 24 
 
Registration Procedures ........................................................................................... 24 
4.4.1 OHSU Registration ............................................................................................... 24 
 
Participant Screening and Enrollment ....................................................................... 25 

 
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Participant Withdrawal or Discontinuation ................................................................. 25 
4.6.1 Handling Participant Withdrawal and Discontinuation ........................................... 25 
 
Off-Study Criteria ...................................................................................................... 25 
4.7.1 Screen Failures .................................................................................................... 26 
 
Study Discontinuation ............................................................................................... 26 
5. TREATMENT PLAN............................................................................................................. 27 
 
Dosage and Administration ....................................................................................... 27 
5.1.1 Simulation ............................................................................................................ 27 
5.1.2 Target and Normal Structure Contouring .............................................................. 27 
5.1.3 Radiation Therapy ................................................................................................ 27 
5.1.4 Planning Constraints ............................................................................................ 28 
 
Dosing Delays and Modifications .............................................................................. 28 
 
Concomitant Medication and Supportive Care Guidelines ........................................ 29 
5.3.1 Contraception ....................................................................................................... 29 
5.3.2 Use in Pregnancy ................................................................................................. 30 
 
Prohibited Medications, Treatments, and Procedures ............................................... 30 
6. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE ................................................ 31 
 
Study Specific Procedures ........................................................................................ 31 
6.1.1 Medical history ..................................................................................................... 31 
6.1.2 Disease Assessment ............................................................................................ 31 
6.1.3 Medication history ................................................................................................ 31 
6.1.4 Physical examination ............................................................................................ 31 
6.1.4.1 
Vital signs ............................................................................................ 31 
6.1.4.2 
Height and weight ................................................................................ 31 
6.1.4.3 
Performance status .............................................................................. 31 
6.1.5 Radiographic or other imaging assessments ........................................................ 32 
6.1.6 Adverse event evaluation ..................................................................................... 32 
6.1.6.1 
Radiation-induced liver toxicity ............................................................. 32 
6.1.7 Fiducial Marker Placement ................................................................................... 32 
6.1.8 Assessment of participant-reported outcomes ...................................................... 32 
 
Laboratory Procedures and Evaluations ................................................................... 33 
6.2.1 Hematology .......................................................................................................... 33 
6.2.2 Biochemistry ........................................................................................................ 33 
6.2.3 Coagulation panel ................................................................................................ 33 
6.2.4 Echocardiogram ................................................................................................... 33 

 
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6.2.5 Pregnancy test ..................................................................................................... 33 
 
Screening Assessments ........................................................................................... 33 
6.3.1 Screen Failures .................................................................................................... 33 
 
Assessments During Treatment ................................................................................ 34 
 
Follow-up .................................................................................................................. 34 
 
Early Termination Visit .............................................................................................. 34 
 
Unscheduled Visits ................................................................................................... 34 
 
Schedule of Events ................................................................................................... 35 
7. EFFICACY MEASURES ...................................................................................................... 36 
 
Definition of Efficacy Measures ................................................................................. 36 
7.1.1 Disease Parameters ............................................................................................. 36 
 
Disease Evaluation ................................................................................................... 36 
 
Efficacy Criteria for Tumor Response ....................................................................... 37 
7.3.1 Evaluation of Target Lesion .................................................................................. 37 
7.3.2 Evaluation of Non-Target Lesion .......................................................................... 37 
7.3.2.1 
Evaluation of New Lesions ................................................................... 37 
7.3.3 local Control Rate ................................................................................................. 37 
7.3.4 Intrahepatic progression-free survival ................................................................... 38 
7.3.5 Overall Survival .................................................................................................... 38 
 
Response Review ..................................................................................................... 38 
 
Milan Criteria............................................................................................................. 38 
8. SAFETY ............................................................................................................................... 39 
 
Specification Of Safety Parameters .......................................................................... 39 
 
Definitions ................................................................................................................. 39 
8.2.1 Adverse Event (AE) .............................................................................................. 39 
8.2.2 Serious Adverse Event (SAE) .............................................................................. 39 
8.2.3 Unanticipated Problems (UP) ............................................................................... 40 
8.2.4 Severity of Event .................................................................................................. 40 
8.2.5 Assessment of Causality Relationship To Study Agent ........................................ 40 
 
Expectedness ........................................................................................................... 40 
 
Adverse Event List(s) ................................................................................................ 41 
8.4.1 Adverse Event List for SBRT ................................................................................ 41 
 
Adverse Event Assessment and Follow-Up .............................................................. 41 
 
Reporting Procedures ............................................................................................... 41 
8.6.1 OHSU IRB Reporting of Unanticipated Problems and Adverse Events ................ 41 

 
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8.6.2 MedWatch Reporting ............................................................................................ 42 
8.6.3 Reporting Of Pregnancy ....................................................................................... 42 
 
Study Stopping Rules ............................................................................................... 42 
9. STATISTICAL CONSIDERATIONS ..................................................................................... 43 
 
Analysis Populations ................................................................................................. 43 
 
Description of Statistical Methods ............................................................................. 43 
9.2.1 General Approach ................................................................................................ 43 
9.2.2 Analysis of Primary Endpoint ................................................................................ 43 
9.2.3 Analysis Of The Secondary Endpoints ................................................................. 43 
9.2.4 Analysis Of The Exploratory Endpoint .................................................................. 43 
 
Sample Size, Power, Accrual Rate and Study Duration ............................................ 44 
9.3.1 Sample size and Power ........................................................................................ 44 
 
Handling of Missing Data .......................................................................................... 44 
10. CLINICAL MONITORING .................................................................................................. 45 
 OHSU Knight Cancer Institute Data & Safety Monitoring Plan .................................. 45 
 Clinical Data & Safety Monitoring .............................................................................. 45 
 Quality Assurance & Quality Control ......................................................................... 46 
11. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ........................................ 47 
 Source Data/Documents ........................................................................................... 47 
 Participant & Data Confidentiality .............................................................................. 47 
 Data Collection & Storage: Privacy, Confidentiality & Security .................................. 47 
 Maintenance of Records ........................................................................................... 48 
 Publication and Data Sharing Policy ......................................................................... 49 
12. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 50 
 Ethical Standard ....................................................................................................... 50 
 Institutional Review Board......................................................................................... 50 
 Informed Consent ..................................................................................................... 50 
12.3.1 
Consent Procedures and Documentation ........................................................ 50 
 Protocol Review ........................................................................................................ 50 
 Changes to Protocol ................................................................................................. 51 
13. REFERENCES .................................................................................................................. 52 
APPENDIX A: CHILD-TURCOTTE PUGH SCORE .................................................................. 54 
APPENDIX B: PERFORMANCE STATUS ............................................................................... 55 

 
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APPENDIX C: CONTRACEPTION ........................................................................................... 56 
 
 
 
 
 

 
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LIST OF TABLES 
 
Table 1. Projected accrual for present study based on Oregon population demographics .........24 
Table 2. SBRT – Dose Modification ..........................................................................................28 
Table 3. Dose Constraints .........................................................................................................28 
Table 4. Supportive care guidelines for radiation therapy ..........................................................29 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CHO 
Community Hematology & Oncology 
CFR 
United States Code of Federal Regulations  
CP 
Child-Pugh criteria 
CR 
Complete response 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CSF 
Cerebral spinal fluid 
CT 
Computerized tomography 
CTEP 
Cancer Therapy Evaluation Program 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LDT 
Liver directed therapy 
LFT 
Liver function test 
LTX 
Liver transplantation 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
N/A 
Not applicable 
NCI 
National Cancer Institute 
OHRP 
Office for Human Research Protections 

 
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OHSU 
Oregon Health & Science University 
PD 
Progressive Disease 
PET 
Positron emission tomography 
PI 
Principle Investigator 
PR 
Partial response 
QOL 
Quality of Life 
RBC 
Red blood cell (count) 
RILD 
Radiation-induced liver disease 
RNI 
Reportable new information 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SBRT 
Stereotactic body radiotherapy 
SD 
Stable disease 
SD 
Standard deviation 
TAE/TACE 
Transarterial embolization / transarterial chemoembolization 
TSMP 
Trial Specific Monitoring Plan 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
WBC 
White blood cell (count) 
 
 
 
 
 

 
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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
 
OVERVIEW OF HEPATOCELLULAR CARCINOMA 
 
Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers worldwide, with an 
approximately 782,000 new cases and 746,000 deaths expected in 2012.1  In the United States 
alone, HCC is attributed to nearly 30,000 deaths annually.2,3 The age-adjusted worldwide 
incidence of HCC is 10.1 cases per 100 000 person-years, and this number is expected to 
continue rising as the number of hepatitis C virus (HCV) carriers increases.4 
 
Partial hepatectomy or LTX are the only available curative treatments; however, >80% of 
patients with HCC have chronic liver disease, and mandatory hepatic reserve requirements 
often exclude many patients with advanced cirrhosis from liver resection.  In patients with early 
to intermediate-stage HCC and advanced liver disease, LTX confers superior disease-free 
survival compared to resection.5  Whether a patient is eligible for LTX is largely based on the 
Milan selection criteria established by Mazzaferro et al6, which demonstrated that LTX recipients 
with early HCC (as defined by having either a single lesion no > 5 cm or ≤ 3 lesions each ≤ 3 
cm) can achieve favorable long term patient survival.  Unfortunately, prolonged wait times pose 
a major disadvantage to patients awaiting suitable livers.7,8  Rather, using these criteria, 20-30% 
of listed patients will have oncologic progression outside of the Milan criteria during this waiting 
period.9  To minimize the risks of disease progression, a bridge-to-LTX using LDT is often 
recommended.10  Whereas ideal candidates for LDT have preserved liver functions with  Child-
Turcotte-Pugh (CP) scores of B7 or better11, many LTX candidates with advanced cirrhosis (CP-
B8 or higher) are excluded from treatment as they lack sufficient hepatic reserve.  
 
 
LIVER DIRECTED THERAPIES  
 
Alternative therapeutic approaches to LTX for patients with unresectable HCC include, partial 
hepatectomy, radiofrequency ablation, transarterial embolization/chemoembolization 
(TAE/TACE), and radioembolization, among others.12  Unfortunately, many of these approaches 
are associated with procedural complications that can cause significant morbidity. 
 
TACE with the transcatheter delivery of a mixture of chemotherapy and embolic agents is 
considered standard of care for early and intermediate stage unresectable HCC patients with 
preserved liver function.12  This approach is associated with a strong response rate (OR: 5.95; 
95%CI: 2.96–11.99), and is significant survival benefit over best supportive therapy (HR: 0.76; 
95%CI: 0.64–0.91).13  However, major complications associated with this approach include (but 
are not limit to): hepatic failure, liver abscess, liver rupture, biliary tract injury, renal failure, 
necrotizing pancreatitis, cerebral lipiodol embolism, and hepatic encephalopathy.14-16  Aside 
from complications, use of TACE is also limited by cases of excessive tumor burden (i.e., <50% 
of liver) and minimum tumor size (i.e., >5 cm) requirements, as well as limitations of vascular 
invasion, biliary obstruction, and anatomical localization (e.g., infradiaphragmatic or adjacent to 
large vessels).  Moreover, TACE, is generally not performed for patients having Child-Pugh 
classification C (or late B); further highlighting the limited treatment option for patients with 
severely compromised liver function. 
 
1.2.1 STEREOTACTIC BODY RADIOTHERAPY OF LIVER IN SETTING OF ADVANCED 
CIRRHOSIS 
 
Guidelines have historically omitted external beam radiation therapy for the management of 
HCC because of the high incidence of radiation-induced liver disease (RILD).  Modern 
advances to computer and imaging technologies have greatly improved methods of conformal 

 
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liver irradiation, which are associated with RILD ≤ 5%.17  SBRT involves the use of a few (≤10) 
potent doses of highly conformal radiation therapy with high geometric precision and accuracy.18 
These advances have renewed interest in SBRT as an approach to managing HCC, with data 
from several studies supporting its safety and efficacy in patients with the greatest degree of 
hepatic reserve.19-22   
 
Bujold et al19 reported on the outcomes of a prospective trials consisting of 102 evaluable 
patients with HCC (CP-A) that were treated with SBRT.  The underlying liver disease among 
patients consisted of hepatitis B (38%), hepatitis C (38%), alcohol related (25%), other disease 
(14%), and no disease (7%).  The authors evaluated patients 1-year after receiving SBRT (dose 
range: 24 to 54 Gy in six fractions), and observed local control of 87%, and a median overall 
survival of 17 months.  Toxicity ≥ grade 3 was reported in 30% of patients. Importantly, no RILD 
was observed.  
 
Lasley et al20 conducted a phase 1-2 trial to examine variables influencing liver toxicity in 
patients receiving SBRT for hepatocellular carcinoma. In this study, 38 CP-A (39 lesions) and 
21 CP-B (26 lesions) patients were followed for ≥6 months following SBRT.  The authors 
observed that local control at 6 months was 92% for CP-A and 93% for CP-B. Two- and 3-year 
estimates with local control was 91% for CP-A and 82% for CP-B (P = .61). The median overall 
survival was 44.8 months and 17.0 months for CP-A and CP-B. Assessment of safety among 
CP-A and CP-B patients revealed 4 (11%) and 8 (38%) patients that experienced grade III/IV 
liver toxicity, respectively.  The authors further reported that the risk of death was 4.6 times 
greater for CP-A patients with ≥grade III liver toxicity compared to those without toxicity. In 
contrast, no such correlation was seen for CP-B patients. Notably, CP-B patients experiencing 
grade III/IV liver toxicity had significantly higher mean liver dose, higher dose to one-third 
normal liver, and larger volumes of liver receiving doses <2.5 to 15 Gy in 2.5-Gy increments. 
This finding suggests that for CP-B patients, careful consideration should be given to low-dose 
volumes that could potentially result in increased liver toxicity. Overall, the authors concluded 
that SBRT is safe for therapy of patients with HCC.  
 
In a recent retrospective study, Nabavizadeh et al22 reported on their single institution 
experience using SBRT or hypofractionated radiation therapy (AHRT) to treat 146 HCC patients 
with varying degrees of cirrhosis. The cohort included 51 patients with CP-B8 or higher cirrhosis 
(34% of entire cohort). Within this cohort, only a third of all patients experienced toxicity, defined 
as a CP elevation of 2 or more within 6 months of RT. These findings are comparable with other 
reports.20,21  Notably, the authors did not identify a statistically significant difference between 
rates of toxicity when comparing patients with CP-B8 or higher baseline cirrhosis to those with 
CP-A or B7 cirrhosis. Thirteen patients in the cohort with CP-B8 or higher cirrhosis eventually 
underwent LTX; suggesting that radiotherapy affords localized disease control for these patients 
awaiting transplantation. In this regard, the authors further observed that the 1- and 2-year local 
control (LC) rates were greater significantly better among patients receiving SBRT compared to 
those given AHRT (1-year LC 97% vs 72%, P <.0001; 2-year LC 94% vs 65%, P <.0001).  
 
 
RATIONALE 
 
Liver transplantation (LTx) is the best treatment for patients with hepatocellular carcinoma HCC 
and CP-B or C cirrhosis, as both conditions can be very effectively treated at once.  As LTX 
wait-lists can be many months, LDTs are essential as oncologic temporizing measures to bridge 
patients to LTX.  However, due to the fear of further hepatic decompensation, many patients 
with advanced cirrhosis are excluded from receiving LDT.  Rather, recent studies suggest that 
SBRT can be of safe and practical use in this fragile patient population, and thereby reduce the 
rate of transplantation drop-out.22,23  
 

 
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In this pilot study of HCC patients with severe cirrhosis, the feasibility of utilizing SBRT will be 
evaluated as a stopgap method to provide localized disease control until time of transplantation. 
By achieving the study endpoints listed in Section 3.2, this pilot trial will contribute to the 
development of a larger-scaled multi-institutional clinical trial of SBRT in HCC patients with 
advanced hepatic decompensation by sharpening our hypothesis, identifying barriers to 
subsequent study participation and estimating bridging efficacy relative to historical controls. 
 
 
POTENTIAL RISKS AND BENEFITS 
 
1.4.1 KNOWN POTENTIAL RISKS  
 
The use of SBRT is associated with increased risk for radiation-induced liver disease and 
further decompensation of liver function. At Oregon Health and Science University, the 
treatment of patient with severely compromised liver function is associated with a 31% increase 
in liver toxicity, as determined by an increase CP score of ≥ 2 within 6 months after SBRT.22  
Only 11 of 146 patients (7.5%) were observed to have a Grade 4 toxicities (per Common 
Terminology Criteria for Adverse Event [CTCAE] criteria) within 6 months of RT.  These grade 4 
AEs consisted of 1 gall bladder perforation, 4 cases of thrombocytopenia, 2 cases of 
hyperbilirubinemia, 2 cases of upper gastrointestinal bleeding, and 2 cases of encephalopathy; 
however, no definitive treatment-related deaths were seen.  In comparison, authors of a 
separate institutional study observed that 26% of 101 patients with baseline CP-A cirrhosis and 
7 of 13 (53%) of patients with CP-B7 cirrhosis experienced CP ≥ 2 toxicity within 3 months of 
6-fraction SBRT.24  However, it is very challenging to discern treatment-related hepatic toxicity 
from natural decline of hepatic functionality secondary to advanced cirrhosis.  For example, the 
SHARP trial, a randomization of placebo versus sorafenib for advanced HCC, identified that the 
placebo arm had a 52% rate of adverse events likely due to cirrhosis or HCC progression.25 
Refer to Section 8.4 for additional information.  
 
1.4.2 KNOWN POTENTIAL BENEFITS 
 
There are a minimal number of approaches currently available to help bridge the time to 
transplantation in patients with severely compromised liver function.  The current study using 
SBRT may provide access to a new treatment approach not previously available.  It cannot, 
however, be guaranteed that participants in this study will directly benefit from treatment during 
participation, as the clinical trial is designed to provide information about the safety and 
effectiveness of the investigational approach. 
 

 
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2. OBJECTIVES 
 
 
PRIMARY OBJECTIVES 
 
Assess the use of SBRT in HCC patients with advanced liver cirrhosis as a feasible approach to 
providing localized disease control that adequately suffices liver transplant eligibility criteria.   
 
 
SECONDARY OBJECTIVES 
 
Assess preliminary efficacy and toxicity in HCC patients with advanced cirrhosis following liver 
SBRT.  
 
 
EXPLORATORY OBJECTIVES 
 
Assess qualify of life in HCC patients with advanced cirrhosis following liver SBRT.  Examine 
SBRT-related histopathologic changes in explanted livers of patients with advanced cirrhosis. 

 
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3. STUDY DESIGN AND ENDPOINTS 
 
 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 9, Statistical Considerations, for additional information regarding statistical 
methods used in this study. 
 
This is pilot study to assess the feasibility of bridge-to-transplantation SBRT for patients with 
severe liver disease.  Participants must meet the inclusion criteria, have none of the exclusion 
criteria, and have provided written informed consent before the conduct of any screening tests 
not performed routinely in their treatment. 
 
In general, patients with CP-B8 or higher cirrhosis and non-metastatic HCC who have been 
listed or recommended to be listed for liver transplantation will be eligible for participation in this 
study.  Eligible participants will undergo SBRT consisting of 40 Gy to be given in 5 fractions 
every other day provided that criteria for normal organ constraints are met (i.e., ≥700 cc of 
uninvolved liver).  In cases where normal organ constraints are not met, the dose will be 
iteratively de-escalated to two dose levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions).  If 
normal organ constraints are unable to be met at 30 Gy in 5 fractions, the participant will be 
considered ineligible for SBRT and considered a screen failure. 
 
Following SBRT, the rate of radiation-induced liver disease (non-classical RILD) and associated 
toxicities will be evaluated, along with treatment response and an assessment of quality of life 
associated with SBRT.  The proportion of participants that are successfully bridged to liver 
transplantation, and times to liver transplantation following SBRT will be recorded for each 
participant.  Additional exploratory studies will assess SBRT-related histopathologic changes in 
explanted livers of participants with advanced cirrhosis.  In these studies, pathologic treatment 
response in explanted livers will be evaluated, and regions of uninvolved liver both near and 
remote to the irradiated volume will be assessed for histopathologic changes consistent with 
RILD (e.g., obliteration of central veins, increased perisinusoidal reticulin network and 
hepatocyte necrosis). 
 
This study aims to enroll 15 participants at OHSU.  Participant data for primary, secondary, and 
exploratory endpoints will be collected by the site providing clinical care.  The analyses of the 
data collected will take place at OHSU.   
 
 
STUDY ENDPOINTS 
 
3.2.1 PRIMARY ENDPOINT 
 
Endpoint 
Start  
End  
Proportion of participants who are transplanted or 
with localized disease control that meets Milan 
criteria (Section 7.5) within 1 year 
Start of SBRT 
Time of progression, or 
transplantation, or 1-
years after last SBRT 
dose, whichever occurs 
first 
 
3.2.2 SECONDARY ENDPOINTS 
 

 
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Endpoint 
Start  
End  
1. Localized control rate: Incidence of progressive 
disease within or at the planned tumor volume 
(PTV) margin 
First dose of 
SBRT  
Time of progression, 
transplantation, death 
or 2-years after last 
SBRT dose, whichever 
occurs first. 
2. Incidence of intrahepatic progressive disease  
3. Incidence of extrahepatic progressive disease 
4. Proportion of participants that proceed to 
transplantation   
5. Overall Survival 
Time of death or 2-
years after last SBRT 
dose 
6. Incidence of non-classic RILD, defined as 
grade 4 aspartate aminotransferase or alanine 
aminotransferase elevation, or an increase in 
CP score of ≥ 2 within 1 week to 3 months after 
completing SBRT (Appendix A) 
3 months after last 
SBRT dose 
 
3.2.3 EXPLORATORY ENDPOINT 
 
Endpoint 
Start  
End  
QoL scores for QLQ-C30 questionnaire 
Screening 
Death or 2-years after 
last SBRT dose, 
whichever occurs first 
QoL scores for Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-Hep) questionnaire 
Proportion of histopathologic changes in irradiated 
tumor sites relative to uninvolved liver tissue 
Transplantation Transplantation 
 

 
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4. STUDY ENROLLMENT AND WITHDRAWAL 
 
 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Age ≥18 years at time of informed consent.  All people regardless of biologic sex and 
members of all races and ethnic groups will be included. 
3. Must be listed or recommended to be listed for orthotopic liver transplantation at the 
participating institution  
4. Have a CP score ≥ B8, as defined in Appendix A 
5. Eastern Clinical Oncology Group (ECOG) performance status ≤ 2, or Karnofsky 
Performance Scale >60 (refer to Appendix B) 
6. Must have a life expectancy > 12 weeks 
7. Safe radiation treatment planning parameters that adhere to all organs at risk constraints 
per section 5.1 of the protocol. If normal organs at risk constraints (including at least 700cc 
of uninvolved liver) are unable to be met at the lowest dose modification (30 Gy in 5 
fractions), the patient is deemed ineligible for SBRT and deemed a screen failure. 
8. Except for prior radiotherapy or radioembolization, other prior therapies to previously treated 
lesions, are permitted. 
9. People of childbearing potential must have a negative urine or serum pregnancy test within 
72 hours prior to receiving the first dose of SBRT. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
Participants of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for >1 year without an alternative medical cause.  
Note: Abstinence is acceptable if this is the preferred contraception for the participant. 
10. No other prior invasive malignancy is allowed except for the following: adequately treated 
basal (or squamous cell) skin cancer, in situ breast or cervical cancer. Stage I or II invasive 
cancer treated with a curative intent without evidence of disease recurrence for at least five 
years. 
 
 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Participants have any one of the following liver tumor characteristics: 
a. have > 5 liver tumors, or  
b. maximal diameter > 5 cm 
2. Complete obstruction of portal venous flow to the segment of liver that includes the target 
lesion  
3. Prior radiotherapy to the upper abdomen or radioembolization of the liver, or prior thermal 

 
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ablation to the target lesion.   
4. For fiducial marker placement:  
a. Have a gold allergy,  
b. Any coagulopathy preventing safe fiducial placement 
5. Contraindication to both contrast enhanced MRI and contrast enhanced CT (i.e. unable to 
undergo follow-up imaging or SBRT treatment planning)  
6. Participation in another concurrent treatment protocol  
7. Participant is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
8. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions 
associated with diarrhea, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs or compromise the ability 
of the patient to give written informed consent 
 
 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants for this study will primarily be recruited from hematology and oncology practices 
within OHSU and its affiliated community hematology and oncology (CHO) practices.  
Participants may also be identified and referred to this study by their primary treating physician 
from within OHSU, CHO, VAPORHCS, or from the outside community.  Participants may be 
identified by a member of the patient’s treatment team, the PI, research team, or medical and 
surgical oncology clinics part of OHSU, CHO, or VAPORHCS.  As a member of the treatment 
team, the investigator(s) will screen their patient’s medical records for suitable research study 
participants and discuss the study and their potential for enrolling in the research study, which 
may include discussion of patient at a multidisciplinary liver tumor board meeting.  In these 
meetings, a participant’s medical history will be presented at a multidisciplinary comprised of 
hepatobiliary surgical oncologists, medical oncologists, radiologist, radiation oncologists, and 
hepatologists.  In this conference, patient imaging and pathology may be reviewed by the group 
for consensus that the prospective participant satisfies all inclusion and exclusion criteria.  
Referral of potential participants to investigator(s) of this study is made as part of standard of 
care, with the referring physician seeking advice on the diagnosis, evaluation, and/or treatment 
of the patient’s malignancy.   
 
The investigators(s) may also screen the medical records of potential participants with whom 
the investigator does not have a treatment relationship.  This will be done for the limited purpose 
of identifying patients who would be eligible to enroll in the study and to record appropriate 
contact information in order to approach these potential individuals regarding the possibility of 
participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
4.3.1 ACCRUAL ESTIMATES 
 
The number of participants to be accrued is driven by the study primary objective. An estimated 
15 participants over a 12 month period.   

 
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This study will not focus on any particular gender, racial or ethnic subset. No participant will be 
excluded from the study on the basis of gender, racial or ethnic origin. Gender-nonconforming 
and gender-fluid individuals as members of the general population will also be recruited.  Male, 
female and minority volunteers will be recruited for this study from the general population.  The 
incidence of male HCC is disproportionately higher than females; at a rate of approximately 2:1 
across studies reported.4  The projected gender, racial, and ethnic composition of the study, 
adjusted for the approximate 2:1 disproportion in male to females, will otherwise represent that 
of the state of Oregon (Table 1). 
 
Table 1. Projected accrual for present study based on Oregon population demographics 
Ethnic Category [OR] 
Sex/Gender 
Females 
Males 
Total 
  
n 
% 
n 
% 
n 
% 
Hispanic or Latino 
0-1 
6.5 
1-2 
6.3 
2 
12.8 
Not Hispanic or Latino 
3 
44.0 
9 
43.2 
12 
87.2 
Ethnic Category: Total of all participants* 
4 
  
11 
  
15 
100* 
  
Racial Category 
  
American Indian or Alaskan Native 
0 
0.9 
0 
0.9 
0 
1.8 
Asian 
0 
2.3 
0-1 
2.2 
1 
4.5 
Black or African American 
0 
1.1 
0 
1.0 
0 
2.1 
Native Hawaiian or other Pacific Islander 
0 
0.2 
0 
0.2 
0 
0.4 
White 
3 
44.1 
9 
43.3 
12 
87.4 
Two or more races 
0 
1.9 
0-1 
1.9 
1 
3.8 
  
Racial Category: Total of all participants* 
4 
50.5 
11 
49.5 
15 
100 
Source: Adapted from U.S. Census Bureau, 2017. 
*Totals may not equal 100 due to rounding. 
 
4.3.2 INCLUSION OF CHILDREN 
 
This protocol does not include children as the number of children with this type of cancer is 
limited. 
 
 
REGISTRATION PROCEDURES 
 
There is no randomization for treatment in this study. Participants will be required to give written 
informed consent to participate in the study before any screening tests or evaluations are 
conducted that are not part of standard care. 
 
4.4.1 OHSU REGISTRATION 
 
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS).  The OHSU coordinating center team will 
verify completeness of documents, enter registration information into the CRMS, and assign a 
study number/identifier.  At a minimum, registration of OHSU participants will include signed 
copies of the most recently IRB-approved, informed consent form and HIPAA authorization.   

 
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PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant or the participant's legally acceptable representative. The current Institutional Review 
Board (IRB) approved informed consent must be signed and dated by each participant prior to 
undergoing any study procedures or before any prohibited medications are withheld from the 
participant in order to participate in this study.  
 
Screening will begin once the participant has provided written informed consent to participate in 
the study and ends on Day 1 of the study. All screening and baseline evaluations will be 
performed during the screening phase (i.e., up to 28 days before on-study treatment is initiated). 
Day 1 of the clinical trial will be when participants are administered first dose of SBRT.  Total 
accrual of all participants is anticipated to take a total of 12 month. 
 
 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment. If a participant no longer wants to receive 
investigational product, but is willing to come for follow-up appointments, the participant’s 
request should be honored, if possible. The following are examples demonstrating why a 
participant’s treatment might be discontinued. 
• 
Toxicity precludes further study treatment.  
• 
There is a need for any treatment not allowed by the protocol.  
• 
The participant fails to meet the criteria for study treatment.  
• 
Pregnancy or intent to become pregnant. 
• 
Disease recurrence or progression. 
• 
Investigator’s discretion.  
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study. Information about the reason(s) for discontinuation and collection of 
any new or ongoing adverse events (AEs) should be collected at the time the participant 
withdraws consent.  
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 6.8. 
 
4.6.1 HANDLING PARTICIPANT WITHDRAWAL AND DISCONTINUATION 
 
Participants enrolled in this study that withdraw prior to initiating on-study treatment will be 
replaced.  
 
 
OFF-STUDY CRITERIA 
 
Criteria that can take a participant off-study include: 
• 
Participant requests to be withdrawn from study without further follow-up, 
• 
Completed study follow-up period, 
• 
Progression of disease, 
• 
Death, 
• 
Screen failure, 
• 
Investigator’s discretion 

 
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4.7.1 SCREEN FAILURES 
 
Any participant that has signed the consent form (for either screening or study participation) but 
does not meet the study eligibility criteria, or meets study eligibility criteria but terminates their 
participation prior to receiving study treatment, will be considered a screen failure.  The reason 
for screen failure should be captured in the database for each participant failing to meet the 
eligibility criteria.  
 
 
STUDY DISCONTINUATION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to IRB and other regulatory 
authorities (as applicable).  If the study is prematurely terminated or suspended, the Investigator 
will promptly inform the IRB and will provide the reason(s) for the termination or suspension. 
 
Reasons for terminating the study may include the following: 
• 
Incidence or severity of adverse events, in this or other studies, indicates a potential 
health hazard to participants. 
• 
Data that are not sufficiently complete and/or evaluable. 
• 
Investigator(s) do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to regulatory authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.    
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor, IRB and/or other regulatory authority (e.g. FDA). 
 
 

 
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5. TREATMENT PLAN 
 
 
DOSAGE AND ADMINISTRATION 
 
On-study treatment will be administered on an out-patient basis. Reported adverse events and 
potential risks are described in Section 8.4.  Appropriate dose modifications are described in 
Section 5.2, Dose modifications.  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant's 
malignancy. 
 
5.1.1 SIMULATION 
 
All imaging for radiation planning will be performed according to institutional guidelines.  If 
deemed necessary by the treating radiation oncologist for targeting purposes, eligible 
participants will undergo placement of intrahepatic fiducial markers prior to simulation (refer to 
Section 6.1.7).  Imaging for radiation planning will include triple-phase contrast-enhanced 
simulation with immobilization.  Participants will be immobilized with standard motion 
management techniques. The simulation should be performed with the participant in treatment 
position (i.e., supine, with arms above head).   
 
5.1.2 TARGET AND NORMAL STRUCTURE CONTOURING 
 
Diagnostic CT scans and MRIs (if available) will be fused to the CT simulation for contouring 
purposes to help guide contouring of target and normal structures, which will be recorded on the 
CT images.  Normal structures to be contoured include spinal cord, esophagus, heart, chest 
wall, body, stomach, duodenum, small bowel, large bowel, lung, liver, and kidneys.   
 
The gross tumor volume (GTV) (or internal target volume (ITV) if 4-dimensional CT is utilized) 
will be contoured using all available images, and the planning target volume (PTV) will be 
constructed using a 5 mm circumferential margin.  All participants must have a critical volume of 
liver minus GTV (or ITV) of at least 700 cm3.  
 
If tumor motion is greater than 3 mm, participants will be simulated and treated with a 
breathhold technique.  In breathhold technique, the participant is treated in a specific inspiratory 
phase of the respiratory cycle.  If appropriate and at the discretion of the treating physician, 
participants may also undergo a MRI simulation in the treatment position to assist in the 
contouring of tumor and normal structure. If performed, MRI should be done with contrast. 
 
5.1.3 RADIATION THERAPY 
 
A total of 40 Gy will be administered to the PTV in 5 fractions given every other day, provided 
that normal organ constraints are met (i.e., uninvolved liver volume of ≥700 cc).   
 
If normal organ constraints are not met, the dose will be iteratively de-escalated to two dose 
levels (35 Gy in 5 fractions, then 30 Gy in 5 fractions)(Table 2).  If normal organ constraints are 
unable to be met at 30 Gy in 5 fractions, the patient is deemed ineligible for SBRT and is 
considered a screen failure. Cone-beam CT will be obtained prior to each fraction delivered. 
 
 
 

 
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5.1.4 PLANNING CONSTRAINTS 
 
Dose constraints for normal organs at risk including spinal cord, esophagus, heart, chest wall, 
skin, stomach, duodenum, small bowel, large bowel, lung, liver, and kidneys will be according to 
institutional standards for liver SBRT (Table 3). 
 
Table 3. Dose Constraints 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy)** 
CORD 
0.1cc 
<0.35 cc 
<1.2 cc 
25 Gy 
23 Gy (4.6 Gy/fx) 
14.5 Gy (2.9 Gy/fx) 
30 Gy (6 Gy/fx) 
Esophagus* 
<5 cc 
19.5 Gy (3.9 Gy/fx) 
35 Gy (7 Gy/fx) 
Heart/Pericardium <15 cc 
32 Gy (6.4 Gy/fx) 
38 Gy (7.6 Gy/fx) 
Chest wall/Rib 
<30 cc 
35 Gy (7 Gy/fx) 
43 Gy (8.6 Gy/fx) 
Skin 
<10 cc 
36.5 Gy (7.3 Gy/fx) 
39.5 Gy (7.9 Gy/fx) 
Stomach 
0.1cc 
<10 cc 
27.5 Gy 
18 Gy (3.6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
Duodenum* 
0.1cc 
<5 cc 
<10 cc 
30 Gy 
18 Gy (3.6 Gy/fx) 
12.5 (2.5 Gy/fx) 
32 Gy (6.4 Gy/fx) 
Small bowel* 
<5 cc 
19.5 Gy (3.9 Gy/fx) 
35 Gy (7 Gy/fx) 
Large Bowel* 
<20 cc 
25 Gy (5 Gy/fx) 
38 Gy (7.6 Gy/fx) 
 
 
 
 
Parallel Tissue 
Critical Volume (cc) 
Critical Volume Dose 
Max (Gy) 
 
LungTotal 
1500 cc 
12.5 Gy (2.5 Gy/fx) 
 
LungTotal 
1000 cc 
13.5 Gy (2.7 Gy/fx) 
 
LiverGTV 
700 cc 
15 Gy (3 Gy/fx) 
21 Gy (major dev) 
KidneyTotal 
200 cc 
17.5 Gy (3.5 Gy/fx) 
 
*Avoid circumferential irradiation 
** “point” defined as 0.035cc or less 
 
The PI will perform RT Quality Assurance Reviews of all plans within 10 days of patients starting 
the treatment. 
 
 
DOSING DELAYS AND MODIFICATIONS 
 
SBRT will be delivered in a total of 5 fractions over two weeks, with treatments delivered every 
other day between Monday and Friday.  SBRT will not occur on Saturdays, Sundays or 
holidays.  There should be no more than a 14 day interruption between the planned 
administration of each fraction.  Dosing interruptions lasting longer than 14 days between each 
fraction, for any reason, are considered an unacceptable and participants will be removed from 
Table 2. SBRT – Dose Modification 
Dose Level Liver-directed SBRT  
0* 
40 Gy in 5 fractions 
-1 
35 Gy in 5 fractions  
-2 
30 Gy in 5 fractions 
*Dose level -1 and -2 are treatment doses for patients requiring a dose reduction from the starting dose level (0).  

 
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study and replaced with another participant.  Participants removed from study will be treated per 
institutional standards or offered participation in another clinical trial if one is available.  All 
dosing interruptions should be recorded in CRF. 
 
 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Supportive measures for optimal medical care are to be given throughout the study as indicated 
by the treating physician’s assessment of the participant’s medical need and institutional and 
general medical guidelines for the care of participants undergoing treatment of HCC.  
Supportive care guidelines for radiation therapy are described in Table 4.  Additional supportive 
care procedures and any premedications, according to institutional guidelines, include 
hydration, pain management, anti-emetics, and treatment interruption in case of severe 
radiation-related symptoms. 
 
Table 4. Supportive care guidelines for radiation therapy 
Adverse effect 
Support Treatment 
Psychological 
Depression: 
Selective serotonin reuptake inhibitors effective for depression 
but not for fatigue 
Fatigue: 
Exercise; sleep hygiene, stress reduction, cognitive and 
relaxation therapies 
Skin 
Dermatitis: Moisturizing creams; routine skin care with mild, unscented 
soap 
Radiation recall: Same as dermatitis 
Cardiovascular and pulmonary 
Cardiovascular disease: Cardiovascular monitoring (ECG) 
Gastrointestinal 
Diarrhea Loperamide 
Genitourinary 
Urinary obstruction Tamsulosin (for males) administered according to institutional 
guidelines 
Cystitis: Pyridium (both males and females) administered according to 
institutional guidelines  
Infertility / teratogenicity: Egg and sperm preservation; ovarian transposition 
 
5.3.1 CONTRACEPTION 
 
SBRT may have adverse effects on a fetus in utero, and may have adverse effects on the 
composition of sperm.  People may be enrolled if they are willing to use methods of birth control 
or are considered highly unlikely to conceive. Highly unlikely to conceive people are defined as: 
1) surgically sterilized or biologically absent reproductive organs, or 2) postmenopausal (a 
woman who is ≥ 45 years of age and has not had menses for more than 1 year), or 3) not 
heterosexually active for the duration of the study.  Birth control methods can either be two 
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Participants 
should start using birth control from study visit 1 throughout the study period up to 120 days 
after the last dose of study therapy.  
 

 
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5.3.2 USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while receiving SBRT, the participant will 
immediately be removed from the study.  The site will contact the participant at least monthly 
and document the participant’s status until the pregnancy has been completed or terminated. 
The site will report the outcome of the pregnancy to Sponsor without delay and within 24 hours 
if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn).The pregnancy will be 
recorded on the CRF and reported by the Investigator to the IRB.   Refer to Section 8.6. 
 
 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Herbal supplements will be allowed on study and noted on CRF.  For patients with contrast 
allergy, steroids will be allowed for CT scans.  
 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
 
• 
Anti-cancer systemic chemotherapy or biological therapy. 
• 
Chemotherapy not specified in this protocol. 
• 
Investigational agents other than those described in this protocol. 
• 
No radiation therapy other than what is allowed in this study. 
Participants who require the use of any of the aforementioned treatments for clinical 
management may, at the discretion of the investigator, be removed from the trial.  Participants 
may receive other medications that the investigator deems to be medically necessary. 
 
Participant exclusion criteria (Section 4.2) describes other medications prohibited in this trial. 
 

 
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6. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
 
STUDY SPECIFIC PROCEDURES 
 
6.1.1 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any prior conditions that are considered to be clinically significant by the PI. Details regarding 
the participant’s cancer will be recorded separately and not listed as medical history. 
 
6.1.2 DISEASE ASSESSMENT 
 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s cancer. 
 
6.1.3 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history. Concomitant 
prescription, over-the-counter medications and any supplements or herbals should be captured 
prior to start of SBRT.   
 
6.1.4 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits 
and per institutional standards.  The physical examination to be conducted will include an 
evaluation of: general appearance; head, ears, eyes, nose, and throat; neck; skin; 
cardiovascular system; respiratory system; gastrointestinal system; lymphatic system, 
musculoskeletal system, and nervous system.  All other physical exams after baseline will 
include an evaluation of any AEs, or any previously reported symptoms, or prior physical 
examination findings.  All physical examinations will also include: 
 
6.1.4.1 
Vital signs  
 
Vitals to be collected include BP, HR, temperature, and oxygen saturation by pulse oximetry. As 
part of screening/baseline visit, vitals should be obtained within 14 days prior to first dose of 
SBRT. Vitals will also be obtained during treatment.  
 
Significant findings that were present prior to the signing of the informed consent must be 
included in the Medical History CRF.  Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event CRF.  
 
6.1.4.2 
Height and weight  
 
Height, weight, body surface, will be collected at initial radiation oncology consultation.  
 
6.1.4.3 
Performance status  
 

 
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Performance status will be determined for all participants at screening and at select times during 
treatment as per assessment schedule in Section 6.8.  Refer to Appendix B for performance 
criteria. 
 
6.1.5 RADIOGRAPHIC OR OTHER IMAGING ASSESSMENTS  
 
All imaging for radiation planning and subsequent follow-up will be in accordance with 
institutional standards, and include (but are not limited to): multiphasic CT (4D-CT), CT, MRI, X-
ray, Fluorodeoxyglucose (FDG) Positron emission tomography (PET), and ultrasound.  Cone-
beam CT will be obtained prior to each fraction delivered. Imaging procedures will occur 
according to Section 6.8, Schedule of Events, but may occur more frequently if clinically 
indicated. 
 
6.1.6 ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the CTCAE v5.0 and 
quantifying current Child-Pugh score to assess risk of RILD.  Adverse events will be monitored 
from the time the participant signs the Consent Form up until 3 months following SBRT. 
Participants will be instructed to report all AEs during the study and will be assessed for the 
occurrence of AEs up until 3 months following radiation therapy. All AEs (serious and non-
serious) must be recorded on the source documents and CRFs regardless of the assumption of 
a causal relationship with the study therapy.    
 
For details on AE collection and reporting, refer to Section 8.6.  
 
6.1.6.1 Radiation-induced liver toxicity 
 
Radiation-induced liver disease (RILD) is defined as either classical or non-classical RILD.  
Classical RILD (typically occurring in patients without background liver dysfunction or cirrhosis) 
is characterized as the presence of nonmalignant ascites and anicteric elevation of alkaline 
phosphatase level twice the upper level of normal or baseline value occurring between 2 weeks 
and 3 months after the completion of irradiation. Non-classical RILD (typically occurring in 
patients with baseline liver dysfunction or cirrhosis), occurs is defined as grade 4 AST and/or 
ALT elevations, or an increase in CP score of ≥ 2 within 1 week to 3 months after completing 
SBRT.26  
 
6.1.7 FIDUCIAL MARKER PLACEMENT 
 
The type of fiducial along with method implantation will be according to institutional standards 
and at the discretion of the treating radiation oncologist, as some tumors may be targetable 
without fiducial guidance.  Participants should discontinue antiplatelet medications 
approximately 7 days before the fiducial implantation.  In general, warfarin should be 
discontinued 5 days before insertion, and heparin and related products discontinued 
approximately 12-24 hours prior to the procedure.  Absent any complications, these treatments 
may be approximately restarted 24-48 hours following the procedure. 
 
6.1.8 ASSESSMENT OF PARTICIPANT-REPORTED OUTCOMES 
 
Quality of life (QoL) care metrics using the will be assessed using the EORTC QLQ-C30 and 
FACT-Hep questionnaires at time points shown in Section 6.8, Schedule of Events.  The 
questionnaire will each take <45 minutes to complete.  

 
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LABORATORY PROCEDURES AND EVALUATIONS 
 
6.2.1 HEMATOLOGY 
 
Hematologic profiling will be collected per institutional standards, and should include evaluation 
of hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. 
 
6.2.2 BIOCHEMISTRY  
 
Blood chemistry will be collected per institutional standards and should include the following: 
Liver function test (LFT), including: Total Protein, Albumin, Total Bilirubin, Alkaline Phosphatase, 
AST, ALT serum creatinine, blood urea nitrogen, calcium, potassium, and alpha-fetoprotein 
tumor marker (AFP).   
 
6.2.3 COAGULATION PANEL 
 
INR will be collected for calculation of CP score 
 
6.2.4 ECHOCARDIOGRAM 
 
As clinically indicated.  
 
6.2.5 PREGNANCY TEST  
 
A serum or urine pregnancy test is required during screening for all persons of childbearing 
potential. The pregnancy test is required within 72 hours prior to study intervention and results 
must be available prior to administration of SBRT. If the urine pregnancy test is positive, a 
serum pregnancy test must be performed per institutional standards.  
 
 
SCREENING ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care.  If a participant is eligible 
for the study after review of key inclusion/exclusion criteria, additional screening visits will be 
scheduled while staff members are requesting insurance authorization to participate in a clinical 
trial. 
 
The following will be reviewed at screening visit:  
• 
Clinical history and physical exam (per standard of care) 
• 
Informed consent obtained and documented 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis.  Consent 
must be obtained before initiation of any clinical screening procedure that is performed solely for 
the purpose of determining eligibility for this research study.  Evaluations performed as part of 
routine care before informed consent can be utilized as screening evaluations if done within the 
defined time period.  
 
6.3.1 SCREEN FAILURES 
 

 
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A participant who signed an informed consent form but does not initiate planned SBRT, for any 
reason, will be considered a screen failure.  Those found not to be eligible after signing the 
study consent will be considered screening failures, and data will be handled in the same 
manner.  The demographic information, informed consent, and inclusion/exclusion pages must 
also be completed for screen failures.  No other data except reason for screen failure will be 
entered into the clinical database for individuals who are screen failures. 
 
 
ASSESSMENTS DURING TREATMENT 
 
Participants will be assessed once during the course of 5 fraction SBRT.  Specific on-study 
assessments are listed in the Section 6.8, Schedule of Events.  Under certain circumstances 
(e.g., clinic holiday, inclement weather) scheduled visits may be delayed by no more than 7 
days between each visit. 
 
 
FOLLOW-UP 
 
Participants will be followed and disease assessments will take place 6 weeks following 
completion of SBRT, then every 3 months up until enrollment on hospice or death, or 2 years 
from time of last SBRT dose, whichever occurs first.  Follow-up visits will be consistent with 
standard of care, and assessments are listed in Section 6.8.  Any participants removed from 
protocol therapy for unacceptable AE(s) will be followed until resolution or stabilization of the 
AE.  
 
 
EARLY TERMINATION OR END OF TREATMENT VISIT  
 
Any participant that discontinues treatment earlier than planned must be evaluated within 30 
days after termination or prior to the initiation of any other off-study interventional therapy, if not 
performed within the last 30 days.  On-treatment Day 9 study visit and associated assessments 
(i.e., radiographic imaging and AE assessments) will serve as the end of treatment visit (Section 
6.8, Schedule of Events).  These assessments also pertain to participants that discontinue study 
intervention.  
 
 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (e.g., laboratory or clinical assessments) at those visits should be recorded in the 
CRF. 
 

 
35 
 
 
SCHEDULE OF EVENTS  
 
Visit Days  
Screening 
Treatment 
Follow-UpB 
(±4 weeks) 
Days 
-28 to -1 
Days† (+7 days) 
1 
3 
5 
7 
9* 
SBRTA 
 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
XB 
Prior/concomitant medications 
X 
 
 
 
 
 
XB 
Physical ExaminationC 
X 
 
 
 
 
 
XB 
Radiographic Imaging 
X 
XD 
XD 
XD 
XD 
XD 
XE 
HematologyF 
X 
 
 
 
 
 
XB 
BiochemistryG 
X 
 
 
 
 
 
XB 
Coagulation 
X 
 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
 
Fiducial placement (if needed) 
X 
 
 
 
 
 
 
AE assessment 
X 
X 
X  
EORTC QLQ-30 
X 
 
 
 
 
 
XB 
FACT-Hep 
X 
 
 
 
 
 
XB 
† Starting on day 1, SBRT dose fractions are given every other day (i.e., Monday-Friday), but not administered on Saturdays, Sundays, or holidays. Dosing 
interruptions because of weekends and holidays will be recorded in CRF. 
*Day 9 study assessments of radiographic imaging and AE collection will serve as Early Termination and/or End of Treatment Visit.  
A Scheduled SBRT visits may be delayed by no more than 7 days between each visit, or may occur earlier than scheduled by no more than 3 days. 
B Follow-up assessment to occur 6 weeks following completion of SBRT then every 3 months up to 2 years post SBRT therapy 
C  All physical exams will include assessing weight, vital signs, and ECOG performance status. Height will be measured at screening visit only. 
DCone-beam CT will be obtained prior to each SBRT fraction. 
E Participants will undergo surveillance imaging (e.g., CT scan) 6 weeks following completion of SBRT and then every 3 months for the first 2 years. 
F Hemoglobin, platelets and white cell count with differential white count 
G Biochemistry to include renal (creatinine, urea, sodium, potassium) and liver function (AST, ALT, bilirubin) 
HAEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0 as well as definition of radiation-induced liver disease (Child-Pugh 
elevation of 2 or more). All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. Record all AEs and SAEs occurring from the 
time of consent signing to 3 months following the completion of SBRT. 
 
 

 
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7. EFFICACY MEASURES 
 
Where applicable, tumor response will be determined per the investigators’ assessment, 
according to modified Response Evaluation Criteria in Solid Tumors (mRECIST).27,28 
 
 
DEFINITION OF EFFICACY MEASURES 
 
Evaluable for response. The analysis population to assess efficacy endpoints (e.g., local control 
rate, intrahepatic disease free survival, and overall survival), will include only participants who 
have received at least 85% of the prescribed SBRT dose (i.e., 85% Level 0 = 34 Gy; 85% Level 
-1 = 30 Gy; 85% Level -2 = 25.5 Gy).  Participants that experience more than 14 days of dose 
interruption, after having received ≥ 85% of the prescribed SBRT dose will be included for 
analysis.  
 
7.1.1 DISEASE PARAMETERS 
 
Measurable disease. The lesion is considered as a RECIST measurable so long as the lesion 
can be accurately measured in at least one dimension as 1 cm or more. 
 
HCC Target lesions.  Measured in two perpendicular axes = longest diameter (long axis) and 
their longest perpendicular (short axis).  The sum of the products of the diameters is defined (Σ 
long-axis diameter × short-axis diameter in mm2).  Up to 6 lesions/patient, representing the 
largest possible number of anatomical sites, with a preference for the largest lesions and 
mediastinal and retroperitoneal sites.  
 
Consider the following for cases in which lesions show partial internal necrosis: 
 
• 
The measurement of the viable tumor should be performed on CT or MRI obtained in the 
arterial phase, when the contrast between viable vascularized tumor tissue and non-
enhancing necrotic tissue is the highest. 
• 
The longest diameter of the viable tumor is not necessarily located in the same scan 
plane in which the baseline diameter was measured: a thorough careful evaluation of the 
CT or MRI scans is required. 
• 
The measurement of the viable tumor diameter should not include any major intervening 
areas of necrosis. 
 
HCC Non-target lesions. Measurable lesions not selected as targets and non-measurable 
lesions. Lesion too small (< 10 mm), infiltrating or atypical enhancement (non-arterial). 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node longest diameter must be > 15 mm or short axis >10 mm.  
 
 
 
DISEASE EVALUATION 
 
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 

 
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preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Conventional CT and MRI: Participants should be followed with either contrast-enhanced spiral 
computed tomography (CT) – preferably with use of multi-slice scanners – or contrast enhanced 
dynamic magnetic resonance imaging (MRI). The administration of intravenous contrast is 
recommended for all CT or MRI studies if not medically contraindicated.  For multidetector CT 
scanners that are capable of acquiring very thin slices, it is necessary to keep in mind that it is 
mandatory to use contiguous slices for image read and interpretation, to avoid missing small 
lesions. The analysis of contiguous slices with traditional 5 mm thickness and 5 mm 
reconstruction interval is acceptable; however, the analysis of 2.5 mm thickness slices at 5 mm 
intervals is not acceptable.   
 
 
EFFICACY CRITERIA FOR TUMOR RESPONSE 
 
7.3.1 EVALUATION OF TARGET LESION 
 
Progressive Disease (PD): An increase of at least 20% in the sum of the diameters of 
viable (enhancing) target lesions, taking as reference the 
smallest sum of the diameters of viable (enhancing) target 
lesions recorded since treatment started 
Non-Progressive Disease  
Any cases that do not qualify for progressive disease 
 
7.3.2 EVALUATION OF NON-TARGET LESION 
 
Non-Progressive Disease 
Any cases that do not qualify for progressive disease 
Progressive Disease (PD): Appearance of one or more new lesions. See 7.3.2.1    
 
Although a clear progression of non-target lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed 
at a later time by the principal investigator. 
 
7.3.2.1 
Evaluation of New Lesions 
 
A new liver nodule is classified as HCC, and will therefore be declared as a progression, when 
its longest diameter is ≥ 10 mm and it presents the typical enhancement of HCC on dynamic 
imaging, i.e. contrast uptake during the arterial phase with portal vein/delayed phase washout. 
Liver lesions ≥ 10 mm, which do not exhibit typical enhancement dynamics may be diagnosed 
as HCC if they increase of ≥ 10 mm on subsequent scans. In this latter case, the date of 
progression used a posteriori will be the date of first detection of the lesion. 
 
7.3.3 LOCAL CONTROL RATE 
 
Local control is defined as the absence of progressive disease (per Section 7.3.1) within the 
PTV or at the PTV margin, measured from time of first SBRT dose to time of progression or 
transplantation, or 2 years from last SBRT dose, whichever occurs first.  

 
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7.3.4 INTRAHEPATIC PROGRESSION-FREE SURVIVAL 
 
Intrahepatic progression-free survival (PFS) is defined as the development of intrahepatic 
recurrent or new disease within any section of the liver, including the PTV.  The consideration of 
whether a lesion is within or adjacent to the PTV is determined by the individual site 
investigator.  Intrahepatic PFS is measured from time of first SBRT dose to time of progression 
or transplantation, or 2 years from last SBRT dose, whichever occurs first. 
 
7.3.5 OVERALL SURVIVAL  
 
OS is defined as the time after having completed at least 85% of the prescribed SBRT dose up 
time of death, or 2 years from last SBRT dose, whichever occurs first.  
 
 
RESPONSE REVIEW 
 
Response assessment will be determined by the investigator. 
 
 
MILAN CRITERIA 
 
Participant eligibility for transplantation will be based on guidelines reported by Mazzaferro et 
al.6  To be considered eligible for liver transplantation, participants with HCC must have disease 
as follows: 
• 
Single tumor with diameter ≤5 cm OR up to 3 tumors, each with diameter ≤3 cm, AND 
• 
No major vessel or extra-hepatic involvement. 
 

 
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8. SAFETY 
 
 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. Safety assessments will be based on medical review of adverse events and the results of 
safety evaluations at specified time points as described in Section 6.8, Schedule of Events. Any 
clinically significant adverse events persisting at the end of treatment visit will be followed by the 
Investigator until resolution/stabilization or death, whichever comes first. 
 
 
DEFINITIONS 
 
8.2.1 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether or not considered intervention-related (21 
CFR 312.32 (a)). In general, this includes signs or symptoms experienced by the participant 
from the time of signing the informed consent to completion of the study.   
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 
treatment.  
 
8.2.2 SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator, it results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and/or participant may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include: 
 
• 
Allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
• 
Blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 

 
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• 
The development of drug dependency or drug abuse.  
 
8.2.3 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
8.2.4 SEVERITY OF EVENT 
 
The Investigator will grade the severity of each AE using, when applicable, the current version 
of the CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
• Mild (grade 1) – An event that is usually transient in nature and generally not interfering with 
normal activities 
• Moderate (grade 2) – An event that is sufficiently discomforting to interfere with normal 
activities 
• Severe (grade 3) – An event that is incapacitating with inability to work or do usual activity, 
or inability to work or perform normal daily activity 
• Life-threatening/debilitating (grade 4) – An event that puts the participant at immediate or 
potential risk of death, requires hospitalization, or which drastically impacts a participant’s 
well-being 
• Fatal (grade 5) 
 
8.2.5 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY AGENT  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated –The AE is clearly NOT related to the study treatment. 
 
 
EXPECTEDNESS 
 

 
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The investigator will be responsible for determining whether an AE is expected or unexpected. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. 
 
 
ADVERSE EVENT LIST(S)  
 
8.4.1 ADVERSE EVENT LIST FOR SBRT 
 
Rates of non-classical RILD (defined as a CP elevation of 2 or more within 3 months after 
radiation) are reported to be in the range of 20-30%. 
 
Rates of Grade CTCAE 1-2 toxicities are reported to range from 0-27% and Grade 3-4 toxicities 
are observed in around 5%. The most commonly reported toxicities are fatigue, right upper 
quadrant pain, low-grade pyrexia, and elevation in transaminase.  Minor pain, fever and chills 
(Grade 1) is observed in 14% of patients. Gastric ulceration and esophagitis occurred at rates of 
7% (Grade 2) and 3% (Grade 3), respectively.  
 
 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate CRF. Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, seriousness, expectedness, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and 
date of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
 
AEs will be evaluated using the current version of the CTCAE v5.0 from the time the participant 
signs the consent form to 3 months following SBRT. 
  
 
REPORTING PROCEDURES 
 
8.6.1 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 

 
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Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801). At a minimum, events 
requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IND safety reports 
that require a change to the protocol or consent,  
• 
New FDA black box warning,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
8.6.2 MEDWATCH REPORTING  
 
The Investigator is required to report AEs to the FDA through the MedWatch reporting program, 
even if the trial involves a commercially available agent. Adverse events to be reported include 
any UPs (i.e., not listed in the package insert) and any SAEs with a suspected association to the 
investigational product. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified in the 
investigational new drug/biologic regulations using Form FDA 3500, the MedWatch Voluntary 
Reporting form (available here), or completed online. A copy of Form FDA 3500 and supporting 
materials will be kept on file in the study regulatory binder.  
 
8.6.3 REPORTING OF PREGNANCY 
 
To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence.  The pregnancy should be followed to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the 
presence or absence of any birth defects, congenital abnormalities, or any pregnancy- or 
childbirth-related and/or newborn complications. 
 
The pregnancy should be recorded on the CRF and reported by the Investigator to the IRB. 
Pregnancy follow-up should be reported using the same form.  Any SAE experienced during 
pregnancy must be reported. 
  
If while on study treatment a participant’s sexual partner becomes pregnant, the pregnancy and 
pregnancy outcomes must also be reported as described above.  Consent to report information 
regarding the pregnancy should be obtained from the pregnant individual. 
 
 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected 
• 
Death suspected to be related to SBRT 

 
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9. STATISTICAL CONSIDERATIONS 
 
Refer to Section 3.1, Description of the Study Design for a detailed description of the study 
design and endpoints.   
 
 
ANALYSIS POPULATIONS  
 
Safety analysis set: All participants will be evaluable for toxicity from the time of their first 
fraction of SBRT. 
 
Efficacy analysis set: The analysis population to assess transplantation eligibility (i.e., Milan 
criteria) and efficacy endpoints (e.g., localized control rate, intrahepatic progression, 
extrahepatic progression and overall survival), will include only participants who have received 
at least 85% of the prescribed SBRT dose (i.e., 85% Level 0 = 34 Gy; 85% Level -1 = 30 Gy; 
85% Level -2 = 25.5 Gy). 
 
 
DESCRIPTION OF STATISTICAL METHODS 
 
9.2.1 GENERAL APPROACH 
 
This is a pilot study to assess the feasibility of bridge-to-transplantation using SBRT for patients 
with severe liver disease. 
 
9.2.2 ANALYSIS OF PRIMARY ENDPOINT 
 
Using the efficacy analysis set, the proportion of transplant eligible participants at 1 year (per 
Milan criteria, Section 7.5) will be measured from time of first SBRT dose, reported with 95% 
exact confidence interval (CI). 
 
9.2.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
 
Using the efficacy analysis set, the estimate of local control rate, intrahepatic progression free 
survival, and overall survival, will be plotted using Kaplan-Meier curve and reported with median 
survival and 95% CI if available. Using the same efficacy analysis set, the proportion of 
participants that proceed to transplantation, will be measured and reported with 95% CI. 
 
Non-classic RILD, liver toxicity defined as a ≥ 2 increase in CP score (Appendix A), and liver 
toxicity per CTCAE v5.0, will be estimated along with an exact CI using the safety analysis set.   
 
9.2.4 ANALYSIS OF THE EXPLORATORY ENDPOINT 
 
The QoL scores will be recorded over time (See Sections 6.1.8 and 6.8) using the EORTC 
QLQ-C30 and FACT-Hep questionnaires.  Summary of QoLs and its change over time will be 
presented graphically using box plot and spaghetti plot, in addition to a summary table of QoL 
over time. No hypothesis testing is planned for QoL. 
 
Descriptive statistical analysis, utilizing the efficacy analysis set, will be used to measure the 
proportion of histopathologic changes in irradiated tumor sites relative to uninvolved liver tissue 
will be measured.  
 

 
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SAMPLE SIZE, POWER, ACCRUAL RATE AND STUDY DURATION 
 
9.3.1 SAMPLE SIZE AND POWER 
 
The primary goal of this pilot study is to help identify unforeseen problems with a subsequent 
larger-scale clinical trial. We predict that there is a 20% probability that a particular patient’s 
treatment plan will fail to meet all dosimetric constraints29, most notably the 700 cc critical 
volume constraint for the liver minus GTV since many cirrhotic patients have small total liver 
volumes, rendering them ineligible for SBRT. A sample size of 15 patients will ensure that we 
will encounter at least one incidence of SBRT ineligibility at a 95% CI.30 
 
 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points as described in the primary 
and secondary endpoints. For time points that have no data, we will evaluate whether or not the 
other time points can be used to fulfill the primary and secondary data.  If the data are not 
sufficient to analyze specific endpoints, the participant’s data may be excluded entirely or 
partially, depending on the specific endpoints in question and in consultation with the 
biostatistician. No missing data will be imputed. Whenever possible, all available data will be 
included in the analysis. A sample size for each analysis will be clearly stated along with the 
reason for exclusion, if any participant is excluded from the analysis due to missing data. 
 

 
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10. CLINICAL MONITORING 
 
 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN 
 
This study is under the oversight of the Knight Cancer Institute’s DSMC as described in the 
Knight institutional DSMP. The Knight DSMP outlines the elements required to ensure the 
safety of clinical trial participants, the accuracy and integrity of the data and the appropriate 
modification of cancer-related clinical trials for which significant benefits or risks have been 
discovered or when the clinical trial cannot be successfully concluded. The Knight DSMP also 
describes the methods and procedures for ensuring adequate oversight of cancer-related 
research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The Knight DSMC will review and monitor study progress, toxicity, safety and other data from 
this study. Information that raises any questions about participant safety or protocol 
performance will be addressed by the Investigator, statistician and study team. Should any 
major concerns arise, the Knight DSMC may recommend corrective action and determine 
whether or not to suspend the study. 
 
The Knight DSMC will review each protocol every 6 months, but may occur more often, if 
required, to review toxicity and accrual data (please refer to Knight DSMP for additional details 
on audit frequency). The Knight DSMC will review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMC may include: participant accrual; treatment 
regimen information; AEs and SAEs reported by category; summary of any deaths on study; 
audit results; and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request.  
 
 
CLINICAL DATA & SAFETY MONITORING 
 
The OHSU Investigator is ultimately, singularly responsible for overseeing every aspect of the 
investigation, including design, governing conduct at all participating sites, and final analysis of 
study data.  
 
In the absence of a formal monitoring plan, the Investigator may work with his/her study team to 
conduct and document internal monitoring of the study to verify protection of human 
participants, quality of data, and/or ongoing compliance with the protocol and applicable 
regulatory requirements. 
 
If at any time Investigator noncompliance is discovered at OHSU, the Investigator shall promptly 
either secure compliance. 
 
Independent audits will be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
and that evidence of ongoing investigator oversight is present. 
 

 
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QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
Quality assurance (QA) auditing activities will occur as detailed in the Knight DSMP. All 
discrepancies, queries, deviations, observations, and findings will be compiled into a final audit 
report along with a Corrective and Preventative Action Plan. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 

 
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11. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The Investigator will maintain adequate case 
histories of study participants, including accurate CRFs, and source documentation. 
 
 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
Upon enrollment, participants will be assigned a code that will be used instead of their name, 
medical record number or other personally identifying information. Electronic files for data 
analysis will contain only the participant code. Codes will not contain any part of the 18 HIPAA 
identifiers (e.g., initials, DOB, MRN). The key associating the codes and the participants’ 
personally identifying information will be restricted to the Investigator and study staff. The key 
will be kept secure on a restricted OHSU network drive a in a limited access folder. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives. Individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives. At the end of the study, all study 
databases will be de-identified and archived within the Knight Cancer Institute. 
 
 
DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 

 
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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique 
coded identifier consisting of numbers. This identifier will be associated with the participant 
throughout the duration of their participation in the trial. The coded identifier will also be used to 
identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon. Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC), REDCap, system on OHSU secure servers, which facilitates information 
being stored in a unified format and location. To further preserve confidentiality, PHI in the EDC 
system will be limited to just birth date and visit dates. The web-accessible EDC system is 
password protected and encrypted with role-based security, and administered by designated 
informatics staff within OHSU or Knight Cancer Institute. All users of the database are assigned 
a unique ID, username, and password and must complete training appropriate to their role 
before they are authorized to enter, access, and store data in the database.  
 
Data from correlative studies will be entered into the EDC system by study personnel at OHSU. 
All other electronic data extracts will be stored only on OHSU computers and restricted drives, 
limited only to study investigators and staff with authorization to access the data. Quality 
assurance will be conducted as outlined in Section 10.3, Quality Assurance & Quality Control. 
 
 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified.  It is the responsibility of the sponsor to inform the Investigator when these 
documents no longer need to be retained. 
 
If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution or another investigator at 
OHSU. Records must be maintained according to institutional or FDA requirements.  
 

 
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PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  
 

 
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12. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, and/or the ICH E6. 
 
 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the 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.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50.  Documentation of the consent process and a copy of the signed 
consent shall be maintained in the participant’s medical record.  
 
12.3.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate.  Consent forms will be IRB-approved and the participant will be asked to read 
and review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate.  The participant will sign the informed consent 
document prior to any procedures being done specifically for the study.  The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records.  The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study.   
 

 
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CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
other regulatory bodies, as applicable) within 5 business days after the implementation.  
 

 
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13. REFERENCES 
 
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Center MM, Jemal A. International trends in liver cancer incidence rates. Cancer 
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L. SR, D. MK, Ahmedin J. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 
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El-Serag HB. Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma. 
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Iwatsuki S, Starzl TE, Sheahan DG, et al. Hepatic resection versus transplantation for 
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Mazzaferro V, Regalia E, Doci R, et al. Liver Transplantation for the Treatment of Small 
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Palmer WC, Lee D, Burns J, et al. Liver Transplantation for Hepatocellular Carcinoma: 
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Salvalaggio PR, Felga G, Axelrod DA, Della Guardia B, Almeida MD, Rezende MB. List 
and Liver Transplant Survival According to Waiting Time in Patients With Hepatocellular 
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Freeman RB, Edwards EB, Harper AM. Waiting List Removal Rates Among Patients 
with Chronic and Malignant Liver Diseases. American Journal of Transplantation. 
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K. HJ, M. KL, S. FR, et al. AASLD guidelines for the treatment of hepatocellular 
carcinoma. Hepatology. 2018;67(1):358-380. 
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Granito A, Bolondi L. Non-transplant therapies for patients with hepatocellular carcinoma 
and Child-Pugh-Turcotte class B cirrhosis. The Lancet Oncology. 2017;18(2):e101-e112. 
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Cabrera R, Nelson D R. Review article: the management of hepatocellular carcinoma. 
Alimentary Pharmacology & Therapeutics. 2010;31(4):461-476. 
13. 
Katsanos K, Kitrou P, Spiliopoulos S, Maroulis I, Petsas T, Karnabatidis D. Comparative 
effectiveness of different transarterial embolization therapies alone or in combination 
with local ablative or adjuvant systemic treatments for unresectable hepatocellular 
carcinoma: A network meta-analysis of randomized controlled trials. PLoS ONE. 
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14. 
Brown DB, Nikolic B, Covey AM, et al. Quality Improvement Guidelines for Transhepatic 
Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic 
Malignancy. Journal of Vascular and Interventional Radiology. 2012;23(3):287-294. 
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Jia Z, Tian F, Jiang G. Ruptured hepatic carcinoma after transcatheter arterial 
chemoembolization. Current therapeutic research, clinical and experimental. 
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Lv WF, Lu D, He YS, Xiao JK, Zhou CZ, Cheng DL. Liver Abscess Formation Following 
Transarterial Chemoembolization: Clinical Features, Risk Factors, Bacteria Spectrum, 
and Percutaneous Catheter Drainage. Medicine. 2016;95(17):e3503. 
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Feng M, Ben-Josef E. Radiation Therapy for Hepatocellular Carcinoma. Seminars in 
Radiation Oncology. 2011;21(4):271-277. 
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Guckenberger M, Andratschke N, Alheit H, et al. Definition of stereotactic body 
radiotherapy. Strahlentherapie und Onkologie. 2014;190(1):26-33. 
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Bujold A, Massey CA, Kim JJ, et al. Sequential phase I and II trials of stereotactic body 

 
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radiotherapy for locally advanced hepatocellular carcinoma. Journal of Clinical 
Oncology. 2013;31(13):1631-1639. 
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Lasley FD, Mannina EM, Johnson CS, et al. Treatment variables related to liver toxicity 
in patients with hepatocellular carcinoma, Child-Pugh class A and B enrolled in a phase 
1-2 trial of stereotactic body radiation therapy. Practical radiation oncology. 
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Culleton S, Jiang H, Haddad CR, et al. Outcomes following definitive stereotactic body 
radiotherapy for patients with Child-Pugh B or C hepatocellular carcinoma. Radiotherapy 
and Oncology. 2014;111(3):412-417. 
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Nabavizadeh N, Waller JG, Fain R, et al. Safety and Efficacy of Accelerated 
Hypofractionation and Stereotactic Body Radiotherapy for Hepatocellular Carcinoma 
Patients with Varying Degrees of Hepatic Impairment. International Journal of Radiation 
Oncology* Biology* Physics. 2017. 
23. 
Nugent FW, Gunturu K, Stuart KE, et al. A randomized phase II study of individualized 
stereotactic body radiation therapy (SBRT) versus transarterial chemoembolization 
(TACE) as a bridge to transplant in hepatocellular carcinoma (HCC). American Society 
of Clinical Oncology; 2017. 
24. 
Velec M, Haddad CR, Craig T, et al. Predictors of Liver Toxicity Following Stereotactic 
Body Radiation Therapy for Hepatocellular Carcinoma. International Journal of Radiation 
Oncology*Biology*Physics. 2017;97(5):939-946. 
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Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. 
The New England journal of medicine. 2008;359(4):378-390. 
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Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-Associated Liver Injury. 
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27. 
Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and Endpoints of Clinical Trials in 
Hepatocellular Carcinoma. JNCI: Journal of the National Cancer Institute. 
2008;100(10):698-711. 
28. 
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Paper presented at: Seminars in liver disease2010. 
29. 
Pollom EL, Chin AL, Diehn M, Loo BW, Chang DT. Normal Tissue Constraints for 
Abdominal and Thoracic Stereotactic Body Radiotherapy. Seminars in Radiation 
Oncology. 2017;27(3):197-208. 
30. 
Viechtbauer W, Smits L, Kotz D, et al. A simple formula for the calculation of sample size 
in pilot studies. Journal of Clinical Epidemiology. 2015;68(11):1375-1379. 
 

 
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APPENDIX A: CHILD-TURCOTTE PUGH SCORE 
 
The Child-Turcotte-Pugh (CP) scoring system utilizes the serum bilirubin, serum albumin, 
prothromin time (PT)/ international normalized ratio (INR), degree of ascites and degree of 
hepatic encephalopathy and assigns 1–3 points for each variable. Patients are divided into three 
classes based on total points with ≤6, 7–9, and ≥10 points representing Child’s class A, B, and 
C, respectively. 
 
Child-Pugh-Turcotte Score 
 
Variable score 1 
Variable score 2 
Variable score 3 
Serum albumin (g/dL) >3·5 
2·8–3·5 
<2·8 
Ascites 
Absent 
Mild to moderate 
(diuretic controlled) 
Severe (diuretic 
refractory) 
Prothrombin time (INR) <1·7 
1·7–2·3 
>2·3 
Encephalopathy 
Absent 
Mild to moderate 
(grade 1–2) 
Severe (grade 3–4) 
Total bilirubin (mg/dL) <2 
2–3 
>3 
 
 
 
 
Interpretation -Points Class 
 
 
5-6 
A 
 
 
7-9 
B 
 
 
10-15 
C 
 
 
 
 
 
 
 
 

 
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APPENDIX B: PERFORMANCE STATUS 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
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). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 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. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 

 
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APPENDIX C: CONTRACEPTION 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner or 
partners of male participantmust use 2 highly effective method of contraception. These include: 
levonorgestrel-releasing intrauterine system (e.g., Mirena®), copper intrauterine device, and 
hormonal methods. Appropriate hormonal contraceptives include:  Etonogestrel-releasing 
implants (e.g. Implanon® or Norplant®), ethinylestradiol/etonogestrel-releasing intravaginal 
devices (e.g. NuvaRing®), medroxyprogesterone injection (e.g., Depo-Provera®), normal and 
low dose combined oral contraceptive pill, norelgestromin/ethinylestradiol-releasing transdermal 
system (e.g. Ortho Evra®), progesterone based oral contraceptive pill using desogestrel (NB, 
Cerazette® is currently the only highly effective progesterone-based)  
 
Non-sterilized male participants, or partners of female participant, must use male condom plus 
spermicide throughout this period.  Cessation of birth control after this point should be 
discussed with a responsible physician.  Abstaining from sexual activity for the total duration of 
the drug treatment and the drug washout period is an acceptable practice for both female and 
male participants; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control. Female participant should also refrain from 
breastfeeding throughout this period.