International Randomized Study of Transarterial Chemoembolization (TACE) Versus Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual or Recurrent Hepatocellular Carcinoma After Initial TACE
Phase: PHASE3
Conditions: Child-Pugh Class A, Child-Pugh Class B, Recurrent Hepatocellular Carcinoma
Sponsor: Stanford University

 
 
 
 
 
International Randomized Study of Transarterial Chemoembolization 
(TACE) Versus Stereotactic Body Radiotherapy (SBRT) / Stereotactic 
Ablative Radiotherapy (SABR) for Residual or Recurrent Hepatocellular 
Carcinoma After Initial TACE 
Study Protocol and Statistical Analysis Plan 
NCT02762266 
September 21, 2022 

Confidential                                                   Page 1 of 87                         
 
International Randomized Study of Transarterial 
Chemoembolization (TACE) versus Stereotactic Body Radiotherapy 
(SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual 
or Recurrent Hepatocellular Carcinoma after Initial TACE 
 
 
Protocol Number:  IRB-35937 
 
 
COORDINATING CENTER:  
Stanford Comprehensive Cancer Center 
 
 
 
 
875 Blake Wilbur Drive  
 
 
 
 
Stanford, CA 94305 
 
PRINCIPAL INVESTIGATOR:                      Erqi Pollom, MD, MS 
 
 
                                    Department of Radiation Oncology 
 
 
 
                        875 Blake Wilbur Drive 
                                                                              Stanford, CA 94305 
                                                                              Phone: 650-498-0484 
                                                                              Fax: 650-725-8231 
                                                                              Email: erqiliu@stanford.edu 
 
 
 
 
CO-PRINCIPAL INVESTIGATORS:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nishita Kothary, M.D. 
 
 
 
 
Stanford University Medical Center 
 
 
 
 
Division of Interventional Radiology 
 
 
 
 
300 Pasteur Drive, 
  
 
 
 
 
Stanford, CA  94305-
 
 
 
 
 
Phone: 
 
 
 
 
 
Fax: 650-725-0533 
 
 
 
 
Email: nkothary@stanfordmed.org 
 
 
 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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 CO-INVESTIGATORS: 
 
 
 
 
Stanford University 
 
 
 
 
 
 
 
 
 
Daniel Sze, MD 
 
 
 
 
Stanford University Medical Center 
 
 
 
 
Department of Radiology 
 
 
 
 
Division of Interventional Radiology 
 
 
 
 
300 Pasteur Drive, 
 
 
 
 
 
Stanford, CA  94305-
 
 
 
 
 
Phone: 
 
 
 
 
 
Fax: 650-725-0533 
 
 
 
 
Email: dansze@stanford.edu  
 
David Wang, MD 
Stanford University Medical Center 
Department of Radiology 
Division of Interventional Radiology 
Stanford, CA  94305 
Phone: 
 
Fax: 650-723-0533 
 
 
 
Email: 
 
 
Aya Kamaya, MD 
Stanford University Medical Center 
Department of Diagnostic Radiology 
Stanford, CA  94305 
Phone: 
 
Fax: 650-723-1909 
Email: 
 
 
 
 
 
 
 
 
 
Hokkaido University 
 
 
 
 
 
Principal Investigator 
Hiroki Shirato, M.D., Ph.D. 
Department of Radiation Medicine 
Hokkaido University 
Graduate School of Medicine 
, Sapporo, Hokkaido 
 JAPAN 
Tel 
  
Fax 
 
 
 
Co- Principal Investigator 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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Norio Katoh, M.D.Ph.D 
Department of Radiation Medicine 
Hokkaido University 
Graduate School of Medicine 
, Sapporo, Hokkaido 
, JAPAN 
Tel 
 
Fax 
 
Email: 
 
 
 
Daisuke Abo MD, PhD. 
Department of Diagnostic and Interventional 
Radiology,  
Hokkaido University Hospital 
 Sapporo, 
 
Tel: 
 
Fax:+
 
Email: 
                                                      
 
Takeshi Soyama MD., PhD. 
Dept of Diagnostic & Interventional Radiology 
Hokkaido University Hospital 
 Sapporo, JAPAN 
 
Tel 
 
Fax 
 
Email: 
 
 
Akira (Ryo) Morita MD 
Dept of Diagnostic & Interventional Radiology 
Hokkaido University Hospital 
 Sapporo, JAPAN 060-8648 
Tel 
 
Fax 
 
Email: 
 
 
Yusuke Uchinami MD 
Department of Radiation Medicine 
Hokkaido University 
Graduate School of Medicine 
 Sapporo, Hokkaido 
, JAPAN 
Tel: 
 
Email: 
 
 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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National Taiwan University Hospital  
 
 
 
 
Principal Investigator 
Jason Cheng, M.D., M.S., Ph.D. 
Division of Radiation Medicine 
Department of Oncology, National Taiwan 
University Hospital Graduate Institute of 
Oncology National Taiwan University College 
of Medicine No. 7 Chung-Shan South Road, 
Taipei 100, Taiwan 
TEL: 
 
FAX: 
  
Email: 
 
 
Eugenia (Chiao-Ling) Tsai M.D.  
Division of Radiation Medicine 
Department of Oncology, National Taiwan 
University Hospital Graduate Institute of 
Oncology National Taiwan University College 
of Medicine No. 7 Chung-Shan South Road, 
Taipei 100, Taiwan 
TEL: 
 
FAX: 
  
Email: 
 
 
 
Stritch School of Medicine, Loyola University 
Chicago 
Tarita Thomas, MD, PhD, Principal Investigator 
Department of Radiation Oncology  
Cardinal Bernardin Cancer Center 
2160 S 1st Ave 
 
Maywood, IL 60153 
Phone: 
 
Email: 
 
 
*Biostatistician: 
 
 
 
 
 
 
 
 
 
 
 
Department of Radiation Oncology  
 
 
 
875 Blake Wilbur Drive 
 
 
 
 
 
Stanford, CA  94305-
 
 
Phone:  
 
 
Email: 
 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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Study Coordinators: 
 
 
Clinical Research Coordinator 
 
Department of Radiation Oncology  
800 Welch Rd 
  
Palo Alto, California 94304   
Phone: 
  
 
Email: 
  
 
 
 
 
 
 
Ms. Yuriko Takemura 
Research Fellow 
Global Station for Quantum Medical Science 
and Engineering 
Hokkaido University 
, Sapporo, Hokkaido 
 JAPAN 
Phone: 
 
Email: 
 
 
 
Hokkaido University Hospital 
Clinical Research and Medical Innovation 
Center 
 Sapporo, Hokkaido, 
, Japan 
TEL 
 
FAX 
 
 
 
Hokkaido University Hospital 
Clinical Research and Medical Innovation 
Center 
, Sapporo, Hokkaido, 
, Japan 
TEL 
 
FAX 
 
 
   
 
 
 
 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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, RN 
Research Nurse 
Loyola University Medical Center 
Radiation Oncology Department 
 
2160 S. First Avenue 
Maywood, IL 60153 
Phone: 
 
Fax:     
 
Email: 
 
 
 
 
 
Contract: 
 
 
Clinical Trial Contract Officer 
Stanford University - RMG 
3172 Porter Drive 
 
Palo Alto, CA 94304-
 
Phone: 
 
Email:   
 
 
 
 
 
 
V11 Final Protocol / Version Date: 21 September 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB-35937 / Protocol Version 11, 21 September 2022
Page 7 of 87 
Protocol Signature Page
INTERNATIONAL RANDOMIZED STUDY OF TRANSARTERIAL
CHEMOEMBOLIZATION (TACE) VERSUS STEREOTACTIC BODY 
RADIOTHERAPY (SBRT)/STEREOTACTIC ABLATIVE RADIOTHERAPY 
(SABR) FOR RESIDUAL OR RECURRENT HEPATOCELLULAR 
CARCINOMA AFTER INITIAL TACE
I have read this protocol and agree to adhere to the requirements. I will provide copies of 
this protocol and all pertinent information to the study personnel under my supervision. I 
will discuss this material with them and ensure they are fully informed regarding the conduct 
of the study according to the protocol and in strict accordance with all applicable U.S. Food 
and Drug Administration (“FDA”) regulations and guidelines applicable to the Study, 
including without limitation the regulations set forth in Parts 50, 54, 56 and 812 of 21 C.F.R., 
and all other applicable federal, state, or local laws, guidelines, rules, and regulations of any 
type.  
__________________________ 
 
Clinical Site  
Signature, Principal Investigator  
 
 
 
 
Date
Printed Name, Principal Investigator  
 
 
Contents
SCHEMA ..................................................................................................................................... 15
OBJECTIVES .................................................................................................................. 17

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1.1
Primary Objectives
17
1.2
Secondary Objectives
17
BACKGROUND AND RATIONALE ........................................................................... 17
2.1
Study Disease
17
2.2
Trans Chemoembolization
18
2.3
Stereotactic Ablative Radiotherapy for Liver Tumors
19
2.4
Rationale for Study
21
PRE-TREATMENT AND PATIENT SELECTION.................................................... 22
3.1
Patient Eligibility
22
3.2
Pretreatment Studies
23
3.3
Informed Consent Process
23
3.4
Planning quality assurance
24
STUDY ENROLLMENT AND REGISTRATION ...................................................... 25
4.1
Registration and Enrollment
25
4.2
Online Registration
26
4.3
Randomization procedures
26
TREATMENT PLANNING AND DELIVERY............................................................ 27
5.1
Study Design and Schedule
27
5.2
Transarterial Chemoembolization (TACE)
27
5.3
Radiation Treatment Planning Technique
29
5.4
Follow Up
32
5.5
Duration of Follow-Up
33
5.6
Criteria for Removal from Study
33
5.7
Alternatives
33
5.8
Compensation
33
ADVERSE EVENTS AND REPORTING REQUIREMENTS................................... 33

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6.1
Serious Adverse Events (SAEs), Unanticipated Problems (UPs), and Adverse Events 
(AEs) 33
6.2
Review and Reporting of Minor Deviations
37
6.3
Correcting Protocol Deviations
38
6.4
Potential Adverse Events
38
6.5
Site Compliance
39
STUDY CALENDAR ...................................................................................................... 40
CORRELATIVE STUDIES............................................................................................ 41
8.1
Tumor Marker Evaluation
41
MEASUREMENT OF EFFECT .................................................................................... 41
9.1
Evaluation Criteria
41
9.2
Evaluation of Response
42
Response Review.............................................................................................................. 42
10.1
Progression Free Survival
43
10.2
Overall Survival
43
DATA REPORTING AND REGULATORY CONSIDERATIONS .......................... 43
11.1
Monitoring Plan
43  
11.2
Electronic Monitoring
44
STATISTICAL CONSIDERATIONS ........................................................................... 47
12.1
Stopping rules
47
12.2
Data Management
47
12.3
Data security and confidentiality
48
12.4
Endpoints
48
12.5
Sample Size
49
12.6
Plan of Analysis
50
MULTI-SITE STUDY GUIDELINES........................................................................... 51
13.1
Study documents
51

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13.2
Site Activation
52
13.3
Communication with the Institutional Review Board (IRB)
52
13.4
Site Communication
52
CITED REFERENCES................................................................................................... 54
Appendix I ................................................................................................................................... 57
Appendix II.................................................................................................................................. 58
Appendix III ................................................................................................................................ 59
Supporting Documentation*...................................................................................................... 59
Supporting Documentation*...................................................................................................... 60
Appendix IV ................................................................................................................................ 62
Appendix V.................................................................................................................................. 80
Appendix VI ................................................................................................................................ 84

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PROTOCOL SYNOPSIS 
 
Title 
International Randomized Study of Transarterial 
Chemoembolization (TACE) versus Stereotactic Body 
Radiotherapy (SBRT)/Stereotactic Ablative Radiotherapy 
(SABR) for Residual or Recurrent Hepatocellular Carcinoma 
after Initial TACE 
Phase  
III 
Indication 
Hepatocellular carcinoma (HCC) is the third most deadly cancer in 
the world.  It is primarily seen in areas where hepatitis is endemic, 
such as Asia, but other risk factors include alcoholic cirrhosis. 
 
Surgical resection and/or transplantation remain the only potentially 
curative options.  However, more than 80% of patients present with 
unresectable disease.  For these patients with unresectable tumors, a 
variety of treatment options are available, including transarterial 
chemoembolization (TACE), radiofrequency ablation (RFA), 
yttrium-90 radioembolization, microwave coagulation, laser-induced 
thermotherapy, and percutaneous alcohol injection, each of which 
have limitations.  Stereotactic body radiotherapy (SBRT) or 
stereotactic ablative radiotherapy (SABR) for unresectable HCC is a 
relatively new treatment option made available because of significant 
improvements in diagnostic imaging and radiation delivery 
techniques.  Although follow-up is limited, pilot study results show 
encouraging local control rates.  Some investigators have combined 
TACE with fractionated conventional radiotherapy as a means of 
intensifying local therapy, with evidence of enhanced efficacy.  
 
TACE remains the dominant mode of local therapy for unresectable 
HCC.  However, recurrence rates are high and residual disease is 
noted in approximately 1/3 of patients.  Because SBRT/SABR is 
rapidly becoming an accepted local therapy for hepatic lesions, its 
role in treating HCC needs to be more precisely defined.  Moreover, 
once patients are found to have residual disease after initial TACE, it 
is unclear if additional TACE will be as effective or if another mode 
of local therapy such as SBRT/SABR would be preferable.   
 
We propose to conduct a multicenter randomized study comparing 
TACE vs SABR for residual or recurrent HCC after initial therapy 
with TACE.  Residual or recurrent HCC will include lesions that 
persist, progress, or recur following completion of all planned TACE 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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therapy.  
Primary Objective(s) 
To determine the freedom from local progression (FFLP) of TACE vs 
SABR in patients with persistent HCC after TACE. 
Secondary Objective(s) 1) To determine the overall survival of TACE vs SABR for residual 
or recurrent HCC.   
2) To determine the progression-free survival of TACE vs SABR for 
residual or recurrent HCC.   
3) To determine the toxicities associated with TACE or SABR in the 
treatment of HCC. 
Hypothesis 
SABR is more effective than repeat TACE in the treatment of 
patients with residual or recurrent HCC after initial TACE. 
Study Design 
Patients with residual or recurrent disease after initial TACE will be 
randomized to receive either repeat TACE or SABR.  Residual or 
recurrent disease after initial TACE will be determined by CT or 
MRI.  
 
TACE 
• TACE study treatment must start within 3 months of eligibility 
confirmation/randomization date.  If these dates are not the same 
treatment should start within 3 months of randomization. 
Treatment may be delivered in up to 3 staged procedures 
depending on the architecture of the tumor vasculature, 6-8 weeks 
apart.   
 
SABR 
• Patients will undergo a 4-dimensional CT scan and contrast CT 
scan for radiation treatment planning and target delineation. 
• SABR will be delivered using a respiratory compensatory method 
or using a margin inclusive of respiratory motion.  
• Image-guidance during SABR will be achieved with either 
implanted fiducials, surgical clips, or using the residual radio-
opaque material (lipiodol) from the initial TACE. 
• Treatment will be delivered in 3 or 5 fractions, within 1-2 weeks 
(and at least 2 fractions per week), at the discretion of the 
investigator. 
• Dose will be administered according to the following 
recommended schedule: 
o Independent of tumor size, 15 Gy x 3 fractions should be 
utilized as long as the normal tissue constraints can be met.  If 
the normal tissue constraints cannot be met, then it is allowable 
to treat tumors with 8-10 Gy x 5 fractions as long as the tissue 
constraints are met. 
o Results will be analyzed according to tumor size and radiation 
dose. 
• The following dose constraints are required to be met: 
o Liver (excluding tumor):  700 cc of the normal liver volume 
should be limited to <12 Gy (3 fractions) or <15 Gy (5 
fractions) 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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o Kidney:  Combined volume for both should have 75% <12 Gy 
o Adjacent bowel and stomach (within 2.5cm):  Dmax < 40 Gy, 
V33Gy<1cc, V30Gy<10cc, V20<30cc  
o Spinal Cord max:  no more than 1cc > 8 Gy 
o Esophagus max: no more than 1cc > 27 Gy 
Primary and 
Secondary Endpoints 
 
Primary Endpoint 
Freedom from local progression (FFLP) at 12 months as defined in 
Section 9.  (Sample size is powered for 12-month endpoint.) 
Secondary Endpoints 
• Comparison of median progression free survival (PFS)  and 
progression free survival at 12 months for individuals treated with 
SBRT and individuals treated with TACE  
• Progression free survival (PFS). 
• Overall survival (OS). 
• Serum AFP levels. 
• FFLP at 18 months. 
Sample size by 
treatment group 
The target accrual is 80 patients per arm for a total of 160 patients 
from all sites worldwide.  Anticipated enrollment at Stanford is 15-30 
patients over 3 years. 
Summary of Eligibility 
Criteria 
• Confirmed HCC by one of the following: 
o Histopathology 
o One radiographic technique that confirms a lesion >1cm with 
arterial hypervascularization with washout on delayed phase 
• Radiographic evidence of persistent, progressive or recurrent 
disease following completion of all planned TACE therapy.  
• Subject is within one year of initial TACE 
• Subject has had 3 or less TACE interventions. 
 
• Multi-specialty evaluation which should include: 
o Liver CT or MR with IV contrast within 6 weeks of date of 
eligibility.   
o AFP within 4 weeks of date of eligibility (recommended but not 
required).   
• Unifocal liver tumors < 7.5cm in greatest axial dimension. 
Multifocal lesions will be restricted to lesions that can be treated 
within a single target volume within the same liver segment, to an 
aggregate of 10cm, and dose constraints to normal tissue must be 
met.  
• ECOG 0, 1 or 2  
• Child Pugh class A or B, Score < 9 
Intervention and Mode 
of Delivery 
• Transarterial Chemoembolization – direct intravascular--- 
administration of chemotherapy and embolization material under 
general anesthesia/sedation, conscious sedation and/or local 
anesthesia. 
• SABR – Stereotactic ablative radiotherapy (outpatient procedure). 

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Duration of 
Intervention and 
Evaluation 
The duration of intervention will be 1 to 16 weeks. The follow-up 
period will be 18 months following completion of treatment; and 3 
years for survival only. 
Statistical 
Considerations 
56 informative subjects are required in order to have a 90% chance of 
detecting a 30% difference between the 2 arms.  Eighty patients in 
each arm, for a total sample size of 160 patients, will be enrolled to 
account for patients who may be taken off the study (prior to the 
primary endpoint of FFLP) due to progression or declining 
performance status that would preclude necessary study follow-up.  A 
30% attrition rate in this patient population is a reasonable 
assumption. 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEMA
Crossover between arms allowed at progression 
(Patients followed on-study after crossover)
Randomize
(stratified by tumor size ≤ 3 cm vs > 3 cm)
Residual or recurrent HCC disease following TACE 
160 Total Subjects
Treatment
80 Subjects
TACE
Treatment
80 Subjects
SABR
15 Gy x 3 = 45 Gy or
6-10 Gy x 5 = 30-50 Gy with tissue 
constraints met, see Section 5.3.4
Follow-Up
Follow up for 18 months 
Follow up for 3 years for survival only

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ABBREVIATIONS  
 
AFP 
Alpha-fetoprotein 
AE 
Adverse events 
CBC 
Complete blood count 
CMP 
Complete metabolic panel 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTV 
Clinical target volume 
DLT 
Dose limiting toxicity 
DVH 
Dose volume histogram 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FFLP 
Freedom from local progression 
GI 
Gastrointestinal 
GIB 
Gastrointestinal bleeding  
GTV 
HCC 
Gross tumor volume 
Hepatocellular Carcinoma 
IMRT 
Intensity-modulated radiotherapy  
INR 
International normalized ratio 
ITV 
Internal target volume 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
OS 
Overall Survival 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PTV 
Planned treatment volume 
RFA 
Radiofrequency ablation 
RILD 
Radiation induced liver disease 
RTOG 
Radiation Therapy Oncology Group 
SABR 
Stereotactic ablative radiotherapy 
SAE 
Serious adverse events 
SUV 
Standardized uptake value 
TACE 
Transarterial chemoembolization 
 
 
 
 
 

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OBJECTIVES
1.1
Primary Objectives
To determine the freedom from local progression (FFLP) of TACE vs SABR in patients with 
persistent HCC after initial TACE.
1.2
Secondary Objectives
1.2.1
To determine the progression-free survival (PFS) of TACE vs SABR in patients with 
persistent HCC after initial TACE.
1.2.2
To determine the overall survival (OS) of TACE vs SABR for persistent HCC.
1.2.3
To determine the toxicities associated with TACE or SABR for persistent HCC.
BACKGROUND AND RATIONALE
2.1
Study Disease
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and represents 
more than 5% of all cancers, while accounting for 80-90% of all liver cancers. Approximately 
500,000 cases of HCC are diagnosed each year, and it is the third leading cause of cancer-
related deaths worldwide (1). There are wide geographical variations in the incidence of the 
disease, with the highest rates in the developing countries of Asia and Africa. However, the 
incidence of HCC is increasing in North America and Europe (2, 3). HCC occurs more often 
in males than females and is more common in people aged 50 to 60 years.
HCC most commonly appears in patients with chronic viral hepatitis, alcoholism, and cirrhosis. 
In particular, cirrhosis is the strongest predisposing risk factor for HCC; exposure to aflatoxin, 
hemochromatosis, certain autoimmune diseases of the liver, and other diseases that instigate 
chronic inflammation of the liver are also risk factors.
The reported prognosis of HCC used to be poor, and most patients died within 1 year 
regardless of the treatment they received (4). However, with the introduction of screening 
programs for high risk patients, 30-40% of patients are diagnosed at the early stages when 
curative treatments are possible (5). Very early HCC patients have the best survival rates, 
reporting a 5-year survival rate of 89-93% following resection, and 71% following 
percutaneous treatment (5).
Early stage patients are also less prone to recurrence after curative treatments. In contrast, 
prognosis for patients with endstage HCC remains poor. Life expectancy is less than 6 months 
with no survival benefit from any treatment (6, 7). In general, early detection offers the only 
possibility for cure. Unlike other cancers, prognosis of HCC does not solely depend on tumor 
stage, but is also determined by cancer related symptoms (i.e. performance status), and degree 
of liver function compromise. The usual TNM cancer staging system is not a useful indicator 
for prognosis. The Barcelona group has worked out a staging system, called the Barcelona 
Clinic Liver Cancer (BCLC) Classification, incorporating the three main prognostic factors and 
linking the classification with a treatment approach and prognosis (8).

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The American Association for the Study of the Liver Diseases has published a guideline on the 
treatment of hepatocellular carcinomas (9).  Surgical resection, liver transplantation and 
percutaneous treatments are considered to be highly effective, even curative if the patients have 
only mild cirrhosis (Child-Pugh A), only 1 nodule that is smaller than 5 cm or less than 4 
nodules smaller than 3 cm.  In fact, hepatic resection is the treatment of choice, certainly in 
non-cirrhotic patients where it can be performed with low rates of life-threatening 
complications (10).  Surveillance programs for HCC have increased the proportion of patients 
diagnosed at an early stage.  Nevertheless, half of all patients are still diagnosed at an 
intermediate-advanced tumor stage.  This stratum is composed of patients who do not qualify 
for curative options, but who have not reached a terminal stage as reflected by heavily 
impaired liver function with intense physical deterioration (11). 
 
2.2 
Transarterial Chemoembolization 
Patients who are classified as intermediate stage according to the BCLC Classification and 
present with a larger nodule or multiple nodules, have well-preserved liver function (Child-
Pugh A), but no extrahepatic invasion or symptoms benefit most from embolization of the 
arterial network supplying the tumor.  A comparative survey of 310 patients found that patients 
with larger tumors treated by TACE had a significant better survival than when treated with 
percutaneous acetic acid injection (12).  Both transarterial embolization (TAE) and TACE 
induce tumor necrosis in more than 50% of the patients. Meta-analysis showed survival 
benefits for TACE, but not for TAE (13).  This outcome was confirmed in two randomized 
controlled trials (14, 15) and is now recommended as standard practice in the specified subset 
of patients by the American Association for the Study of the Liver Diseases. 
 
As for the chemotherapy used in TACE procedures, cisplatin, doxorubicin, and mitomycin are 
the most frequently used in the United States, usually given as a single agent or combination of 
agents emulsified with lipiodol (ethiodized fatty acids of poppyseed oil).  Solid embolic 
material may be mixed with the chemotherapy and lipiodol, or may be administered separately 
after completion of chemotherapy administration.  These materials may include gelatin sponge, 
polyvinyl alcohol particles, or embolic beads.  Methods using lipiodol are referred to as 
conventional TACE, or cTACE. No direct comparative data are available to conclude which 
chemotherapeutic agents, dosage, or treatment schedule is most effective. From the few 
randomized controlled trials and published protocols, the standard of practice is to perform 
multiple treatment sessions initially every 6-12 weeks until technical success is achieved (all 
visible tumor tissue treated, requiring 1-4 treatments), with follow-up diagnostic imaging 
approximately quarterly with retreatment dictated by imaging findings for the duration of the 
patient’s life (13).   
 
With the drug shortages prevalent in the past decade, protocols for TACE have evolved to 
exploit available materials.  For cTACE, single agent treatment using doxorubicin has become 
most common, although alternatives including epirubicin, oxaliplatin, and gemcitabine may be 
substituted or added.  In the Western world, using ion-exchange resin microspheres rather than 
lipiodol as the carrier has become the dominant method. These microspheres are calibrated to 
match arteriolar lumen diameters, and can be loaded with chemotherapeutics with cationic 
moieties such as doxorubicin or irinotecan.  After intra-arterial delivery, these microspheres 
lodge downstream in the arterioral bed, causing ischemia, and elute the chemotherapeutic agent 
over a period of weeks. This method, sometimes referred to as drug-eluting bead TACE or 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 19 of 87 
DEB-TACE, has been shown to have lower hepatic and systemic toxicity, and efficacy at least 
equivalent to that of cTACE (16) 
 
TACE procedures can derive efficacy by two related mechanisms.  One is that the infusion of 
chemotherapeutic with a viscous material that impedes flow in the tumor microvasculature 
(e.g. lipiodol) along with macroscopic embolization of the blood vessel with particles or 
spherical embolic agents will interrupt the arterial blood supply to the tumor, causing infarction 
and necrosis of the tumor.  Secondly, focused administration of the chemotherapeutic agents 
allows a higher drug concentration to be delivered to the tumor with reduced systemic 
exposure, which is the dose-limiting factor in most systemic chemotherapy.  This effect is 
further enhanced by arterial embolization which prevents the chemotherapeutic agents from 
being washed out of the tumor bed.  TACE has a tumor necrosis rate on histopathology of 
56%–100% depending on tumor size, location, and morphology (17-19). Jang and colleagues 
found that subsequent TACE did not reduce tumor recurrence or improve survival when 
complete necrosis had been achieved in the first TACE procedure (20). 
 
Liver transplantation provides the highest possibility of cure for HCC.  Survival at 4 years has 
been reported to be 75% in patients with single tumors < 5cm or up to 3 tumors < 3 cm (21).   
However, this treatment option is limited by the strict eligibility criteria and the availability of 
donor livers.  Even after satisfying the criteria and being listed for transplantation, many 
patients drop out of eligibility before receiving a transplant, with a rate of >40% at 2 years.  
Drop out can be due to comorbidities or change of social support status, but is commonly due 
to progression of intrahepatic malignancy or development of extrahepatic metastases.   
 
TACE is the established standard initial therapy for a subgroup of HCC patients with adequate 
hepatic function, no extrahepatic disease, and who are not eligible for other potentially curative 
treatment options.  Unfortunately, the 3-year overall survival is only 20%-40% (22).  
Recurrence of HCC following initial remission occurs after 27 months on average (23). A 
meta-analysis has shown that adjuvant therapy with TACE may increase survival (24).  
However, TACE alone may not be sufficient, especially for larger tumors. Numerous pilot 
studies suggest that combination therapy of TACE plus radiofrequency ablation (RFA) or other 
locoregional therapies may reduce the incidence of recurrence, and may extend patient 
survival. 
 
 
2.3 
Stereotactic Ablative Radiotherapy for Liver Tumors 
For selected patients, aggressive focal radiation can deliver tumoricidal doses using 3-
dimensional treatment planning techniques, including intensity modulated radiotherapy 
(IMRT).  Experience with 3-dimensional treatment planning has allowed the safe irradiation of 
two thirds of the normal liver to 48-52.8 Gy and one third of the liver to 66-72.6 Gy (fraction 
size 1.5-1.65 Gy administered twice per day) (25-28). Further dose escalation with 
conventional radiation therapy techniques risks injury to adjacent abdominal organs.   
 
Stereotactic Body Radiation Therapy (SBRT) or Stereotactic Ablative Radiotherapy (SABR) 
has emerged as a novel approach for the local ablation of liver tumors.  SABR provides a 
conformal isodose distribution with a steep radiation dose gradient allowing much higher doses 
of radiation than conventional radiation therapy and conformal radiotherapy techniques to be 

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delivered safely with high precision to focal liver tumors while minimizing the radiation dose 
to normal liver and adjacent organs (44,45).   
 
The first published SBRT/SABR results were a phase I/II study by Herfarth and colleagues. 
This study delivered single-dose stereotactic radiation therapy to 60 liver tumors (29).  The 
dose was escalated from 14 to 26 Gy (reference point), with the 80% isodose surrounding the 
planning target volume.  Median tumor size was 10cm3 (range, 1 to 132cm3).  All patients 
tolerated the treatment well without any major side effects.  Eleven patients experienced 
intermittent loss of appetite or mild nausea for 1-3 weeks after treatment.  None of the treated 
patients developed clinically detectable radiation-induced liver disease (weight gain, ascites, 
newly developed increase of alkaline phosphatase concentration).  The overall actuarial local 
tumor control rates were 75%, 71%, and 67% at 6 months, 12 months, and 18 months of 
follow-up, respectively.  There was a statistically significant difference in Kaplan-Meier 
estimates of local tumor control between tumors treated with 14-20 Gy vs. 22-26 Gy but the 
local control may have also influenced a “learning” phase.  The investigators noted that the 
local control was improved in patients treated later in the study after establishing the proper 
margin expansion.  In the patients treated after this phase, the actuarial local tumor control rate 
was 81% at 18 months.  Stratification by size did not reveal a statistically significant difference 
in the local control rate for larger lesions (>15cm3) compared with smaller one (<15cm3) in the 
22-26 Gy range.   
 
Wada et al delivered 45 Gy in 3 fractions to 11 primary and secondary liver tumors (treatment 
of lung lesions was also reported in this study) (30).  Local control of liver lesions was 
approximately 85% at 6 months and 71% at 18 months.  Local control was enhanced for 
smaller lesions (95% at 18 months for lesions less than 3cm diameter [liver and lung lesions 
combined] versus 58% for lesions over 3cm).  No serious adverse events were reported. 
Mendez-Romero et al utilized 12.5 Gy in 3 fractions or 5 Gy in 5 fractions for patients with 
primary and secondary liver lesions (31). One-year and two-year local control rates were 94% 
and 82% for all patients and 100% and 86% for patients with metastases.  Survival ranged from 
92% overall at 6 months to 70% overall at 18 months.  They noted 3 instances of acute grade 3 
or higher toxicity, including a Childs B patient that died secondary to liver decompensation, 
esophageal bleeding, and infection 2 weeks post-radiosurgery.  More recently Tse et al 
delivered 24-54 Gy in 6 fractions to 41 patients with primary liver tumors in a dose escalation 
study (32).  Local control was 65% at 1 year, with 50% of patients surviving at 1 year.  Grade 3 
changes in liver function indexes and platelet count were noted in 12 patients within 3 months 
of radiosurgery.  Two late GI toxicities, one leading to death, were also reported. 
 
More recently, Hoyer et al reported a phase II study in which patients with colorectal hepatic 
metastases were treated with 15 Gy in 3 fractions.  They demonstrated a 2-year local control 
rate of 86% and a 38% overall 2-year survival rate (33).  This treatment was well tolerated.  In 
another phase I study for liver metastases, Schefter et al dose escalated to 20 Gy in 3 fractions 
without reaching maximum tolerated dose (MTD).  These investigators limited 700cc of 
normal liver to less than 15 Gy and included tumors up to 6cm in maximum dimension (34).   
 
Lee et al reported a phase I study using SBRT/SABR for liver metastases in 68 patients (35).  
They used a 6-fraction schedule based on the risk of liver toxicity.  With a median dose of 41.4 
Gy (range: 27.7-60 Gy), they reported a 1-year local control rate of 71% and 10% rate of grade 
≥3 toxicity.  No cases of radiation induced liver disease were noted. 

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Rusthoven et a. reported results from a multi-institutional phase I/II study using SBRT/SABR 
for liver metastases using a 3-fraction regimen escalated to a total dose of 60 Gy (36).  Forty-
seven patients were enrolled, and the 1-year and 2-year local control rates were 95% and 92%, 
respectively.  One case of grade 3 toxicity was noted. 
 
Examination of these and other studies (34, 37-41) suggests that hypofractionated treatment of 
liver with doses in the range of 20-60 Gy delivered in 1-5 fractions can control tumor growth in 
about 90-100% of tumors in the first 6 months post-treatment, and about 70-90% of tumors at 
18 months post-treatment. Survival in this relatively heterogeneous group of patients ranges 
from about 80-95% at 6 months to 40-70% at 18 months.  Very few serious acute or late 
toxicities have been reported; many of the toxicities noted are related to the dose received by 
adjacent organs (31, 32, 40).  Some studies limited the size of lesions treated to 5 or 6cm or 
less (29, 30, 40).  Outcomes are likely improved when smaller lesions are treated (30) but 
studies addressing this issue specifically have not been conducted.  Although patients in these 
studies often receive chemotherapy before or after radiosurgery, this variable is usually not 
uniformly controlled and its contribution to local control, survival, and toxicity is difficult to 
gauge. 
 
Very little data exists for radiation to primary liver tumors.  Tse et al conducted a phase I study 
demonstrating the feasibility and safety of SBRT/SABR for HCC and intrahepatic 
cholangiocarcinoma using a 6-fraction regimen (32).  In addition, Takeda et al reported on 14 
patients treated with TACE and SBRT/SABR with a 5-7 fraction regimen, reporting 1 local 
recurrence and no serious adverse toxicity (42). 
 
Stanford University has recently completed a Phase I dose escalation trial using SBRT/SABR 
for unresectable liver tumors (43). In this single institution study, patients were treated with a 
single fraction of 18 Gy, 22 Gy, 26 Gy, and 30 Gy.  In these patients, 3 to 5 gold fiducial seeds 
were implanted percutaneously for tumor tracking, and 4D CT and FDG-PET CT scans were 
utilized for treatment planning.  These investigators demonstrated that treating patients in this 
manner was feasible and that SBRT/SABR could be applied with minimal toxicity even at the 
highest dose.  
 
 
2.4 
Rationale for Study 
 TACE remains the dominant mode of local therapy for unresectable HCC.  Recurrence rates 
after TACE are high (60-70% at one year).  Because SABR is a rapidly emerging local therapy 
for hepatic lesions with encouraging results (local control 70-100% of liver tumors in the first 
12 months post-treatment), its role in treating HCC patients should be further defined.   
 
Because of the association of hepatitis liver disease and alcoholic cirrhosis, many patients with 
HCC have compromised liver function.  Precise ablation of the tumor with SABR and 
continuous tumor and respiratory tracking have the potential to reduce the radiation to normal 
liver and adjacent organs with minimal toxicity even for patients with large tumors or 
compromised liver function (47). 
 
While safety data is known in patients receiving TACE, fractionated radiation and combination 
TACE and fractionated radiotherapy, no efficacy and toxicity data exists on SABR after 
TACE.  

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The present study will investigate the efficacy, survival and toxicity of TACE vs. SABR for 
persistent or recurrent HCC in a multi-institutional setting. SABR has the potential of 
significantly improving tumor control of HCC, even for large tumors or tumors close to critical 
organs, which could translate into more effective palliation, less toxicity, better quality of life, 
and longer patient survival. 
PRE-TREATMENT AND PATIENT SELECTION  
3.1
Patient Eligibility
3.1.1
Inclusion Criteria (to be verified with source documents, See Appendix III). 
-
Confirmed hepatocellular carcinoma (HCC) by one of the following:  
•
Histopathology 
•
One radiographic technique that confirms a lesion > 1cm with arterial 
hypervascularization with washout on delayed phase 
-
Radiographic evidence of persistent, progressive, or recurrent disease following 
completion of all planned TACE therapy. 
-
The subject is within one year of initial TACE.
-
The subject has had 3 or less TACE interventions.  
-
Unifocal liver tumors not to exceed 7.5 cm in greatest axial dimension. Multifocal 
lesions will be restricted to lesions that can be treated within a single target volume 
within the same liver segment and to an aggregate of 10 cm as long as the dose 
constraints to normal tissue can be met 
-
ECOG PS (Eastern Clinical Oncology Group) performance status 0, 1 or 2 (Appendix 
I)
-
Patients with liver disease classified as Child Pugh class A or B, with score < 9 
(within 4 weeks of treatment)
-
Life expectancy > 6 months 
-
Age > 18 years old 
-
Ability of the research subject or authorized legal representative to understand and 
have the willingness to sign a written informed consent document 
3.1.2
Exclusion Criteria (to be verified with source documents, See Appendix III).
-
Prior radiotherapy to the upper abdomen 
-
Prior radioembolization to the liver

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- 
Prior RFA to index lesion 
 
- 
Liver transplant 
 
- 
Active gastrointestinal bleed within 2 weeks of study enrollment  
 
- 
Ascites refractory to medical therapy (mild to moderate ascites is allowed) 
 
- 
Women who are pregnant or breastfeeding 
 
- 
Administration of chemotherapy within the last 1 month 
 
- 
Extrahepatic metastases 
 
- 
Participation in another concurrent treatment protocol 
 
- 
Prior history of malignancy other than HCC, dermatologic basal cell or squamous cell 
carcinoma. 
 
3.2 
Pretreatment Studies 
Pretreatment tests required for eligibility should be performed within specified timeframes as 
follows: 
 
• CT of the liver with IV contrast within 6 weeks of enrollment showing residual or 
recurrent disease after initial TACE.  If the patient is unable to have CT contrast, a 
liver MRI may be done.   
• Labs including CBC with differential, coagulation labs (PT or INR, PTT), and CMP 
(comprehensive metabolic panel or chemistry panel with liver function tests [LFTs]).  
Other labs as needed may be ordered by treating physician.  Labs should be done 
within 4 weeks of treatment to determine the Child Pugh Score. 
• Serum AFP levels is not required within 4 weeks of enrollment, but recommended. 
 
3.2.1 
Additional Pre-treatment Instructions: 
 
• 
Subjects should have a multi-specialty evaluation whereby the residual or 
recurrent liver lesion is deemed amenable to treatment by either modality, by both 
the attending radiation oncologist and interventional radiologist.  This should be 
documented in a note signed by the physician, or included in the consultation note 
of each physician. 
 
3.3 
 Informed Consent Process 
 
• The Principal Investigator (PI) is responsible for ensuring that proper informed consent 
has been obtained from the subject before any study/research activity is conducted. The 
PI can designate authorized members of the research team to obtain the informed consent.   
• The protocol and Informed Consent Form must have Stanford and local institution’s IRB 
approval prior to research activity.  The PI at each participating center is responsible for 

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ensuring that proper consent process is performed and the most current study-specific 
IRB-approved consent form is signed properly by participant and research staff.  
• The PI at each participating center is ultimately responsible for determining whether a 
subject has the capacity to consent.  If the subject is lacking such capacity, whether due to 
cognitive impairment or other causes, the PI/designee may obtain consent from a legally 
authorized representative.   
• As part of the consent process, the subject’s or his/her representative’s questions must be 
answered prior to consent being given and throughout the study.  The subject or his/her 
representative should be asked if there are any questions prior to consent being obtained. 
• When giving consent, the subject or an authorized legal representative needs to verbalize 
understanding and sign and date the appropriate page(s) of the Consent Form along with 
the investigator or designated research staff member.  
• Consent forms will be maintained according to the standards of Stanford University as 
well as each collaborating center's regulations.  This includes, but is not limited to, 
providing the subject or his/her authorized representative a copy of the consent form; 
keeping a copy in the patient's study chart and medical record; and keeping the original 
consent form in a secured appropriate place for the required period set forth by Stanford's 
IRB.  
• The written consent document should embody, in a language understandable to the 
participant, all the elements necessary for legally informed consent.  For research 
conducted in a language other than English, consent forms must be translated accurately. 
• The sponsor may audit any or all consent forms at participating sites during monitoring 
site visits to determine whether the informed consent process has been appropriately 
completed and documented. 
 
Remote consenting may be conducted during the COVID outbreak to limit exposure risk.  
 
3.4 
Planning quality assurance 
 
3.4.1 
Benchmark (Dry run) case review 
All sub-sites shall receive, prior to patient enrollment, an anonymous electronic patient 
data set including diagnostic images.  The sub-site will develop a treatment plan for 
review by a Stanford PI or designated Stanford Co-Investigator.  Completion of a 
satisfactory dry run case review for each site and verification by a Stanford Co-
Investigator is required prior to opening the site for patient enrollment.   
 
3.4.2 
Treatment Plan Review (pre-treatment)  
The treatment plan for each patient enrolled at each site must be reviewed and approved 
by a Stanford PI or designated Co-Investigator prior to beginning SBRT.  The Principal 
Investigators (or qualified co-investigator designated by the PIs) shall be notified at the 
time of enrollment for each patient, and of the proposed treatment date, to assure a PI’s 
availability for review.  After planning is complete, the treating site will submit the 
following information to the Stanford research team for a PI review:  
1)  
De-identified copy of the treatment planning data sets (including fused primary and 
secondary imaging studies, contour sets, and isodose distributions/DVHs), and  
2)  
Treatment Plan QA form.   
 

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The review will be completed within 3 working days of receipt; treatment will only begin 
after all necessary corrections are implemented and the final plan is approved from 
Stanford.  Evaluation of the plans will be based on the dose constraints described in 
Section 5.3.4.  Criteria for allowed major and minor protocol modifications are also 
described in Section 5.3.4.
3.4.3
Patient post-treatment review
In addition, a post-SBRT treatment plan (treatment summary) and treatment delivery 
records of the first protocol patient from each participating site, as developed by the site’s 
radiation oncologists and physicists, shall be reviewed by a Stanford PI or designated Co-
Investigator.  Additionally, treatment plans and treatment delivery records of three 
additional randomly chosen cases from each site per year, may be reviewed.  If warranted 
by the outcomes of the above QA reviews, a PI may request additional cases to be 
submitted for review prior to further patient treatments. 
STUDY ENROLLMENT AND REGISTRATION 
4.1
Registration and Enrollment 
Prior to enrollment of study participants, each sub-site must have completed all requirements 
for site activation and a site initiation visit, as detailed in Section 12 of the protocol. All 
research staff involved in this study at the sub-sites will have completed Good Clinical Practice 
and Human Subjects Protection training, and have been documented on the site specific 
delegations log, signed off by the site-PI.   
The PI at each sub-site will ensure that all requisite procedures and tests have been performed 
and complete an Eligibility Checklist (See Appendix III) to submit to Stanford research staff 
for review with applicable source documents and/or records. Records to be used for source 
documentation will be translated into English by the sub-site’s university translation center and 
sent with the records in the original language. When patient's eligibility is confirmed by the
Stanford research staff, the patient will be assigned a unique study identifier and the sub-site 
will be notified of approval of patient’s study participation.  Participating sites must obtain 
Stanford approval prior to study activities taking place. 
Documents to be provided in this order, from sub-sites, required for eligibility confirmation:
•
Most recent version of signed ICF approved by EC (in local language)
•
Completed Eligibility Checklist (Appendix III) (completed in English)
•
Source documentation (translated into English):
o
History and Physical note by treating physician
o
Pathology Report confirming diagnosis or one radiographic technique 
that confirms a lesion >1cm with arterial hypervascularization with 
washout on delayed phase.
The sub-site will then register subjects according to their institutional guidelines, as well as 
enter patient data into OnCore, Stanford’s clinical trials management system. Required data in 
OnCore includes but is not limited to:  demographics, on-study information, consent date, 
eligibility verification, deviations (if any), and Serious Adverse Events (SAEs).  Remaining 

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Page 26 of 87 
information, including data for outcomes and final analysis, will be entered into Stanford’s 
secure study patient database.  
 
Each center must also begin a patient paper study chart to collect and maintain subjects’ 
records and study-related documents.  Patient study charts will be reviewed by Stanford 
research team and the Stanford DSMC to ensure data validity, integrity, and safety of subjects 
throughout the trial (Section 11). 
 
Shared data will be de-identified and unique identifiers will be assigned to ensure patient 
confidentiality.  Unique identification numbers for each subject will be assigned by Stanford at 
randomization. 
 
Participating sites must also have a designated research staff person to serve as main contact 
for questions, issues, and communications. 
 
4.2 
Online Registration 
Patient registration will be done via OnCore, Stanford’s clinical trials management system.  
Data may also be entered and maintained in Stanford's secure study patient database.  Access 
to these systems will be created once the collaborating institution has obtained all regulatory 
approvals and becomes a participating center in the study.   
 
Patients may be registered only after all eligibility criteria are met and verified, (see Inclusion 
and Exclusion Criteria in Section 3.1); and after the patient signs and dates the IRB-authorized 
consent form which includes an authorization for the release of protected personal health 
information (“Authorization To Use Your Health Information For Research Purposes”).  The 
authorization that each institution obtains to use and disclose protected health information must 
include the Stanford research team or entities with which they may share data.  Participating 
sites should register the patient in OnCore within 5 days of enrollment.  
 
Subjects' unique ID numbers assigned by Stanford should be used in patient registration, as 
well as to identify patients in Case Report Forms; Notes to File; patient-related notes or 
records; and reports of patients' events or deviations.     
 
4.3 
Randomization procedures 
Registered patients will be stratified according to tumor size; ≤ 3 cm and > 3 cm, and 
randomized to receive TACE or SABR.  Freedom from local progression, progression free 
survival, overall survival and toxicities will be analyzed and compared between the two 
modalities.  Subset analysis for efficacy endpoints will be done based on tumor size (≤ or > 3 
cm).   
 
Randomization will be provided by Stanford.  Participating centers will have a certified local 
agency translate the source documentation in both the local language as well as the translation 
to accompany the eligibility checklist and the informed consent form of the patient in a secure 
electronic mail message to the PI (Dr. Daniel Chang) and Study Coordinator (Rachel Freiberg 
or Samantha Wong) with subject line:  “SECURE:  HCC STUDY PATIENT FOR 
RANDOMIZATION”.  Once verification is completed, the research staff will ask the study 
coordinator to randomize the subject by participating site and within the next business day, 

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research staff will send an electronic message to the PI and Research Coordinator from the 
participating center with the outcome and instructed treatment plan.  
Randomization will be done with a randomized block design software.  It will be performed by 
the Stanford study coordinator who will maintain a password-protected list and assign patients 
to the treatment arms as each patient is enrolled at each institution.
TREATMENT PLANNING AND DELIVERY
5.1
Study Design and Schedule
Assessment of response after TACE will occur at least 12 weeks after the initial procedure and 
patients will be eligible for enrollment if there is radiographic evidence of residual or recurrent 
disease within one year.  If initial TACE is delivered in stages, the 12 week assessment of 
response should be determined from the date of the last TACE treatment.
If patients are randomized to the SABR arm, radiotherapy will be delivered using image-
guidance and respiratory compensation techniques. Tumor location may be determined by 
imaging either the residual radio-opaque material (lipiodol) from the initial TACE or implanted 
fiducial seeds or clips. Treatment will be delivered in 3 fractions within a 7-day window, or 5 
fractions within a 2-week window (minimum 2 fractions per week). 
Subjects will be followed with consultations with physical exams, routine blood tests, serum 
AFP, and CT/MRI scans according to the calendar in Section 8.
If a patient develops unmanageable toxicity deemed related to treatment before the completion 
of TACE or SABR, no further protocol therapy will be administered and the patient will be 
removed from the protocol and monitored only for survival. Further treatment may be 
continued off study and will be at the treating physician’s discretion.
If a subject shows evidence of disease progression, s/he will be removed from the protocol and 
followed for survival only; continued treatment will be as per local standard of care and may 
include TACE or further radiation therapy.   
Patients will be followed for 18 months after the completion of protocol therapy and thereafter 
up to 3 years for survival.
5.1.1 Study Treatment Start Date Parameters
Study treatment must start within 3 months of eligibility confirmation/randomization date. If 
these dates are not the same, treatment should start within 3 months of randomization.
5.2
Transarterial Chemoembolization (TACE)
5.2.1
Pre-TACE Evaluation
Patients must be evaluated prior to TACE to determine if they are suitable to undergo the 
procedure. One or more of the following factors may prompt the investigator to cancel 
the TACE procedure:

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• Bilirubin > 3mg/dL 
• Encephalopathy 
• Gross ascites not controllable with medication 
• Serum creatinine > 2.0 mg/dL 
 
5.2.2 
Pre-TACE Procedure(s) 
Patients may be admitted to hospital 1 day prior to the TACE procedure or as according 
to hospital standards.  Patients will be adequately hydrated, pre-medicated with 
prophylactic broad-spectrum antibiotics, and medicated as needed with anti-emetics 
and/or analgesics.  No oral intake will be allowed from 6 hours prior to the procedure or 
as per hospital protocol.   
 
 
Within 4 weeks prior to the TACE, the below laboratory studies below must be done; 
baseline labs obtained for eligibility may be used if they are within 4 weeks of the TACE 
procedure.  
• Complete Blood Count with differential (CBCD) 
• Coagulation studies (PT or INR, PTT) 
• Comprehensive Metabolic Panel (must include Liver Function Tests and Renal 
Test [Cr or eGFR]) 
• AFP (tumor marker). 
 
On the day of the TACE procedure, the following should be performed and/or noted: 
• Vital signs  
• Pertinant physical examination (PE) as determined by physician.  
• Pre-treatment medications 
This information is to be noted in the Case Report Form (CRF) in Appendix IV and sent 
to the Stanford Research Team. 
 
5.2.3 
TACE Procedure 
TACE will be performed by transfemoral artery approach with selective cannulation of 
the hepatic artery.  Diagnostic visceral arteriography will be carried out to delineate 
anatomic anomalies (found in ~50% of patients), to determine hepatic arterial supply to 
the tumors, to identify extrahepatic parasitized arteries supplying tumors, and to assess 
patency of the portal vein.  Subselective catheterization or superselective 
microcatheterization of branch arteries directly supplying tumor(s) should be performed.  
Once the patient’s arterial anatomy is determined, single or combination of accepted 
chemotherapeutic agents for cTACE (Appendix II) with or without accepted contrast 
agents (Appendix II) will be infused intra-arterially into the branches of the hepatic artery 
feeding the tumor(s).  After injection of the mixture, accepted embolization agents 
(Appendix II) may be injected to complete the embolization, as deemed appropriate by 
the interventional radiologist. For DEB-TACE, doxorubicin loaded onto LC Beads or 
Quadraspheres may be substituted.  DEB-TACE allowed as per institutional protocol.  
 
Catheter selection will be by the radiologist’s preference.  Vasodilators may be used if a 
spasm is detected during the procedure and estimated required in the judgment of the 
investigator/interventional radiologist. 
 

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The entire TACE procedure is performed under fluoroscopic guidance to avoid 
inadvertent reflux into non-target vessels.  The dose and composition of the 
chemotherapeutic mixture is injected based on tumor and vessel size and rate of flow.  
The endpoint for the procedure is administration of the entire chemoembolic mixture or 
stagnation of flow in the branches of vasculature-feeding tumor(s).  In patients with more 
extensive disease, the procedure may be performed in a segmental or lobar territory of 
treatment.  In these cases, the endpoint of TACE will be administration of 100% of the 
chemotherapeutic cocktail or “pruning” of the arterial vascular tree without complete 
occlusion of the main or lobar hepatic artery. 
 
The exact position of the embolization will be determined by the interventional 
radiologist.  At the end of the procedure, hemostasis can be achieved by manual 
compression or with a percutaneous closure device.  The patient may be discharged after 
recovery, or can be admitted for overnight observation, according to the hospital standard 
medical monitoring system for post-TACE HCC patients. 
 
TACE procedure information must be documented in the Case Report Form (CRF) found 
in Appendix IV.  The CRF information will include: 
• vessels embolized,  
• amount of embolization agents used,  
• pre-medications and medications used during the procedure (including 
analgesics, sedatives, antiemetics, chemotherapeutic agents and contrast 
medium). 
• time of commencement and termination of the TACE procedure,  
• hospital discharge date, and 
• medications prescribed at discharge (proton pump inhibitor, antiemetics, and 
analgesics)  
 
The TACE procedure note by the treating Interventional Radiologist should be submitted 
to Stanford with the CRF. 
 
Patients may be admitted for overnight observation with analgesics for pain and 
antiemetics for nausea/vomiting.  Patients should be discharged within 6–24 hours after 
the procedure with a prescription for a suitable oral narcotic medication for pain and oral 
antiemetic for nausea. 
 
Any serious adverse event described in Section 5.2.1 (Pre-TACE Evaluation) must result 
in premature cessation of TACE procedures.  Pre- and post-TACE arteriography images 
will be reviewed centrally.  Participating sites will be expected to provide these images to 
Stanford in a secure and HIPAA-compliant manner.    
 
5.3 
Radiation Treatment Planning Technique 
 
5.3.1 
Tumor Tracking 
Whenever possible, the residual radio-opaque material (lipiodol) from the initial TACE 
should be used for image-guidance during SABR.  Occasionally, the diaphragm may also 
be used for image guidance, particularly for tumors in the dome of the liver.  Clips or 

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gold markers (seeds) may be implanted for image guidance during SABR.  Traditional 
fiducial markers used in target tracking are 2.5mm gold (99.9% pure) seeds that are 
placed through a needle into and/or around the area of the primary tumor.  This provides 
better localization of the target, allowing for reduced margin expansion to account for 
uncertainty due to set-up variation and respiratory motion.  The markers may be placed 
percutaneously, into or around the tumor under CT or ultrasound guidance.  In order to 
minimize streak artifact from the gold, recommended seeds should be 1mm in diameter 
and 2.5mm in length.  Seeds should be placed in multiple planes within 3cm of the tumor 
edge.  In conjunction with the imaging system, fiducials will serve to identify the precise 
location of the liver tumor relative to these markers during SABR.  It is expected that 
fiducial seed placement will be done on an outpatient basis.   
 
Fiducials will not be implanted unless patients are enrolled onto this study and 
randomized to the SABR arm of this study.   
 
5.3.2 
Set-up Technique 
Biphasic CT scans are required for set up.  MRI may be substituted for biphasic CT scan 
in situations where a biphasic CT scan is contraindicated or cannot be obtained.  Patients 
will be simulated in the supine position using an Alpha Cradle or equivalent 
immobilization device which will be custom made for each patient.  The biphasic CT 
scan will be obtained to visualize the entire abdominal cavity, using 0.75-1.5mm thick 
slices, with the tumor centered within the scanning range.  A minimum scanned region of 
3cm must be obtained inferior and superior to the liver.  The contrast phase should be 
obtained during expiration breath-hold.  In addition, a 4D CT scan is strongly 
recommended for optimal target volume definition. FDG PET-CT scan is optional. 
 
5.3.3 
Target Definitions 
The biphasic CT scan will be used to define the GTV.  A 4D CT scan is strongly 
recommended to define the internal target volume (ITV) to account for tumor 
deformation and respiratory motion.  Representative CT slices during inspiration, mid-
inspiration, and expiration should be used.  FDG PET-CT is optional. 
 
If a 4D CT scan is used, PTV margin expansion around the ITV should be 3mm.  Non-
uniform margin expansion is allowable if this expansion results in excessive radiation 
dose to an adjacent organ at risk (OAR). 
 
If 4D CT scan is not utilized, then the ITV will be defined as GTV+5 mm.  The PTV 
expansion will remain 3 mm.  Non-uniform margin expansion is allowable if this 
expansion results in excessive radiation dose to an adjacent organ at risk (OAR).  An 
individualized treatment plan will be developed based on tumor geometry and location. 
 
5.3.4 
Dose Prescription and Constraints 
The prescription dose will be dependent on the tumor size and Child Pugh score 
according to the following guidelines: 
 
 
 
 

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5.3.4.1.1.1 Child Pugh A 
Dose 
# of Fractions 
45 Gy at 15 Gy/fraction 
3 
50 Gy at 10 Gy/fraction 
5 
45 Gy at 9 Gy/fraction 
5 
40 Gy at 8 Gy/fraction 
5 
35 Gy at 7 Gy/fraction 
5 
30 Gy at 6 Gy/fraction 
5 
 
Child Pugh B 
Dose 
# of Fractions 
40 Gy at 8 Gy/fraction 
5 
35 Gy at 7 Gy/fraction 
5 
30 Gy at 6 Gy/fraction 
5 
 
 
The dose will be prescribed to the maximum isodose volume (typically >80% isodose 
line) which covers 95% of the PTV.  All tumors should receive the higher dose unless the 
normal tissue constraints cannot be met.  
 
The requirements for dose constraints are as follows: 
• Liver (excluding tumor):  700 cc of the normal liver volume should be limited 
to <12 Gy (3 fractions) or <15 Gy (5 fractions), or mean liver dose < 15 Gy for 
Child Pugh A and 12 Gy for Child Pugh B 
• Kidney:  Combined volume for both should have 75% < 12 Gy 
• Bowel and stomach:  Dmax < 40 Gy, V33Gy<1cc, V30Gy<10cc, V20<30cc 
• Spinal Cord max:  no more than 1cc > 8 Gy 
• Esophagus max:  no more than 1cc > 27Gy 
 
These requirements are recommended but not required; 
• Central hepatobiliary tree (portal vein from porto-splenic confluence to the 
bifurcation of the right and left main portal vein + 1.5 cm): 5-fraction: 
V40<21 cc, 3-fraction: V33.8<24 cc 
• Chest Wall: V30Gy <30cc 
 
If the normal tissue constraints as defined above cannot be met even with the lowest 
prescription dose, the participating site may re-evaluate the patient’s participation on-

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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study.  Deviations for normal tissue or tumor prescription dose (periphery of tumor) 
which are less than or equal to 5% are deemed a minor protocol deviation, and a request 
for deviation may be submitted to Stanford PI or Co-PI for review and approval.  If the 
treatment plan is not accepted by Stanford or if the deviations for normal tissue are 
greater than 5%, then the patient should be withdrawn from the study and treated 
according to the local standard of care.   
 
Study PIs will evaluate treatment plans as described in Section 3.4. 
 
5.3.5 
SABR Treatment Procedure 
• Patients should be treated within 2 weeks of the radiation set-up scan and within 
4 weeks of fiducial seed implantation (if applicable).   
• Treatment planning scans must be acquired at least 5 days after fiducial seed 
implantation (if applicable).   
• Patients will be treated in the supine position.   
• Respiratory compensation system should be used, and typically will be 
respiratory gating.  If not, an ITV must include all motion due to respiration as 
visualized on a 4D CT. 
• 3 fractions should be delivered within a 1-week time period; 5 fractions should 
be delivered within 2 weeks with at least 2 fractions per week.   
 
5.3.6 
Supportive Care 
• Antiemetics should be administered prior to each radiation treatment and for up 
to 5 days as needed following SABR or as deemed needed by the treating 
physician. 
• Proton pump inhibitors (PPIs) must be started by the first day of SABR and 
should be continued for 6 months, particularly if significant radiation to 
adjacent duodenum or stomach is anticipated.  This will be at the discretion of 
the treating radiation oncologist.  
• Treatment-related diarrhea should be managed with loperamide.  The 
recommended dose of loperamide is 2-4 mg initially (two tablets) then 2 mg 
after each loose stool, not to exceed 16 mg (eight tablets) daily, but prescription 
is at the discretion of the treating physician. 
• Platelet transfusions should be considered for thrombocytopenia. 
 
5.4 
Follow Up 
Subsequent to study treatment, patients will be monitored clinically and radiographically 
according to the schedule below.  Patients may have visits, labs, or scans sooner if deemed 
necessary by treating physician for clinical evaluation and surveillance.  Additionally, study 
visits may be conducted via video (i.e., MyHealth video, telehealth, telemedicine) or phone to 
minimize exposure risk.  
 
• At 1 month* which is optional, a phone call post-treatment or consultation with 
physical examination, labs (CBC, CMP, and tumor marker or AFP), and toxicity 
evaluation will be done.  Toxicity will be scored according to the Common 
Terminology Criteria for Adverse Events Version 4.0 (NCI CTCAE v 4.0, 
available at http://ctep.cancer.gov/reporting/ctc.html).  

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•
At 3 months*, 6 months*, 12 months*, and 18 months* a consultation with 
physical examination, labs, Child-Pugh score, optional QOL (3,6,12 months 
only) and scans will be done as specified in Section 7 - Study Calendar.  Scans 
should include triphasic CT or MRI; FDG PET-CT scans may be obtained in 
addition to either CT or MRI scans at intervals noted in the Study Calendar 
(Section 7).  Toxicity at each visit will be scored according to the Common 
Terminology Criteria for Adverse Events version 4.0, available at 
http://ctep.cancer.gov/reporting/ctc.html.
•
The 18 month visit will conclude the toxicity and local control efficacy 
endpoints of the study, though patients will be followed thereafter up to 3 years 
for survival only. 
*2 weeks before or after each follow-up period will be permitted, e.g., for optional 1 month follow 
up - visit, labs, and scans can be done at 2-6 weeks; 3 months follow-up can be done at 10-14 
weeks, etc.
5.5
Duration of Follow-Up
Subjects will be followed clinically and radiographically for 18 months as per Study Calendar 
in Section 7, and up to 3 years for survival.  
5.6
Criteria for Removal from Study
Patients may be removed at any time from the study at their request.  Additionally, patients 
will be withdrawn if they do not complete protocol therapy, develop disease progression, 
receive systemic chemotherapy or any treatment not as per protocol, or undergo a liver 
transplant. If patients are removed from the study prior to receiving protocol therapy, they will 
be replaced to achieve target accrual. For patients who are taken off study for disease 
progression, they will continued to be followed for survival.
5.7
Alternatives
Standard therapies for liver tumors include TACE alone, TACE with RFA, RFA alone, 
radioembolization, surgery, palliative radiotherapy with conventional fractionation, systemic 
chemotherapy, other ablative procedures, and supportive care only.  Patients enrolled in this 
study will not be candidates for surgical resection.  Therefore, the alternative therapy would 
include TACE alone, RFA, systemic chemotherapy, or supportive care.   
5.8
Compensation 
Patients will not be paid.  Patients and/or their insurance companies will be responsible for the 
cost of all procedures and treatments under this protocol.  Some data management, salary 
support and supplies will be provided to the sites by Varian Inc., Palo Alto, CA (project 
sponsor). 
ADVERSE EVENTS AND REPORTING REQUIREMENTS 
6.1
Serious Adverse Events (SAEs), Unanticipated Problems (UPs), and Adverse Events 
(AEs) 
As Coordinating Center, we will follow guidelines from Stanford’s Research Compliance 
Office for defining, identifying, and reporting events, as defined below.   

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Page 34 of 87 
6.1.1 
Serious Adverse Events (SAEs)  
A Serious Adverse Event is defined as: Any adverse event that meets any of the 
following criteria: 
• Fatal (i.e., the adverse event actually causes or leads to death) 
• Life threatening (i.e., the adverse event, in the view of the investigator, places 
the patient at immediate risk of death).  This does not include any adverse event 
that had it occurred in a more severe form or was allowed to continue might 
have caused death 
• Requires or prolongs inpatient hospitalization 
• Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug  
• Significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical/surgical intervention to prevent one of the 
outcomes listed above).(28) 
 
6.1.1.1 Reporting SAEs 
SAEs that require reporting to Stanford within 24 hours include:   
 Grade 5 (fatal) events 
 Any unexpected and/or treatment-related gastrointestinal Grade 4 event 
 Grade 4 hematological event if within Complete Blood Count (CBC) or Liver 
Function Test (LFT) results 
 
The Stanford issued CCTO SAE case report form (CRF), completed with narrative is 
required to be reported to Stanford within 24 hours upon learning of the SAE. Translated 
or English source documents for the SAE are not required within the 24 hour reporting 
timeframe to give sub-sites time to obtain translation, however must be sent as soon as 
possible. All further enrollment for the sub-site will be held until English source 
documents have been received by the Stanford main site.  
 
All other SAEs not required to be reported within 24 hours must be reported within 3 
calendar days to Stanford.  
 
SAEs should be graded according to the NCI Common Terminology Criteria for Adverse 
Events, Version 4.0, available at http://ctep.cancer.gov/reporting/ctc.html. 
 
CTCAE toxicity grades will also be used for toxicity monitoring and study analyses.   
 
The SAE should be documented on the Case Report Form in Appendix IV and sent to Dr. 
Erqi Pollom and the Study Coordinator (Samantha Wong) via email within 24 hours of 
learning of the event with the subject line:  “SECURE:  INTERNATIONAL HCC 
STUDY CRF” and the CRF attached.  If email is not available, the form can be faxed as 
long as the participating center contacts a member of Stanford’s research team to notify it 
is being sent by fax and to which secured Stanford fax number.  Participating sites are 
encouraged to confirm receipt of the CRF by Stanford.    

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Page 35 of 87 
 
Case Report Forms must be provided in English; accompanying source documents must 
also be provided in English.  Additional time needed for translations may be requested 
from the Stanford PI or Study Coordinator.  Any source document requiring English 
translation is the responsibility of the reporting site.  
 
Case Report Forms of SAEs received by Stanford's study staff member will be submitted 
to Stanford Cancer Center Trials Office (CCTO) within 5 days of receipt, and CCTO or 
study research staff will submit the information to Stanford regulatory boards and 
committees as required.  
 
Participating sites should also: 
- Keep 2 copies of the CRF:  1 for the patient’s study chart and 1 in the regulatory 
binder (electronic regulatory binder is allowed). 
- Follow patient and provide update to Stanford until any of the below:  
• Resolution of event 
• Resolution of event with sequelae 
• Death of patient 
 
The site Principal Investigator will also report AEs and SAEs to their individual 
Institutional Review Board (IRB) and/or Institutional Ethics Committee (IEC) as per 
local IRB and facility standards. 
 
6.1.2 
Identifying Protocol Deviations 
Stanford Protocol Director (PD) will monitor research activities on an ongoing basis for 
adherence to the research protocol.  If a protocol deviation has been identified in a 
Stanford subject or in a subject at a participating facility, the PD will ascertain whether 
the event has resulted in harm to participants or affects the study’s progress and will 
ensure that all proper documentation and reporting of the deviation has been completed. 
 
The following constitute protocol deviations: 
• Non-adherence to exclusion and inclusion criteria 
• Failure to comply with SABR dosing as described in protocol 
• Test requirements not followed per protocol -- either tests not done, incorrect 
tests done, or not done on schedule 
• Study visits not completed, or not completed at intervals specified in the 
protocol. 
 
6.1.3 
Unanticipated Problems (UPs) and Major Deviations 
Per Stanford IRB, UPs are events involving risks to participants or others and must meet 
the following 3 criteria: 
1.  Unexpected - in terms of nature, severity, or frequency  
 
 AND 
2.  Related or possibly related to participation in the research  
     AND 
 
3.  Harmful - or that the research places subjects or others at a greater risk of 
harm than was previously known or recognized. 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 36 of 87 
 
UPs generally will warrant consideration of substantive changes in the research protocol 
or informed consent process/document, or other corrective actions, in order to protect 
the safety, welfare, or rights of subjects or others.(27)  Due to this, UPs will be reported 
promptly to Stanford IRB following the below guidelines. 
 
6.1.3.1 
Reporting Unanticipated Problems (UPs) and Major Deviations 
 
UPs which are also SAEs should be reported as an SAE following the guidelines 
in 6.1.1.1, Reporting SAEs. 
 
UPs that are deviations qualify as a major deviation and should be reported to 
Stanford PI and Study Coordinators within 24 hours of learning of the event, via 
an email sent to Dr. Erqi Pollom and the Study Coordinator (Samantha Wong) 
with the subject line:  “SECURE:  INTERNATIONAL HCC STUDY MAJOR 
DEVIATION”, and the email should contain basic information about the event.  
If the deviation has been entered into OnCore, a pdf or saved c opy of the report is 
acceptable.  Stanford research staff will notify Stanford IRB or other regulatory 
bodies of the UP/deviation as is required.   
 
Participating sites should: 
• 
Enter the Deviation into OnCore within 5 days of learning of the 
event.   
• 
Record the deviation in the patient’s study chart and in the regulatory 
binder (a report from OnCore is acceptable). 
• 
Follow patient and provide update to Stanford until 1 of the below:  
-  
Resolution of event 
-  
Resolution of event with sequelae 
-  
Death of patient 
 
Case Report Forms must be provided in English; accompanying source documents 
must also be provided in English.  Additional time needed for translations may be 
requested from the Stanford PI or Study Coordinator.  Any source document 
requiring English translation is the responsibility of the reporting site.  
 
Protocol Directors or their designee must document in Oncore any deviation that 
could affect the safety of participants (e.g. eligibility criteria, toxicity monitoring, 
errors in the administration of investigational agents), or impact study endpoints 
(e.g. tests needed for response assessment).  The DSMC will review all protocol 
deviations documented in Oncore at their monthly meeting.  Deviations will also be 
reviewed at the study’s monitoring sessions. Failure to properly document 
deviations may result in DSMC and IRB corrective action such as temporary hold 
on enrollment, or study closure. 
 
6.1.4 
Adverse Events (AEs) and AE Monitoring 
 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
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An AE is defined as any untoward medical occurrence in a clinical investigation subject, 
regardless of causal attribution.   
 
PIs at each participating institution will assess adverse events in consultations, and more 
frequently as needed, and grade each event according to the NCI Common Terminology 
Criteria for Adverse Events, Version 4.0, available at: 
 
 http://ctep.cancer.gov/reporting/ctc.html.   
 
Grade 3 unexpected and/or treatment-related gastrointestinal AEs should be reported to 
Stanford within 72 hours of learning of the event, using the Case Report Form (CRF) in 
Appendix IV.  Remaining AEs could be recorded and reported quarterly and/or as per 
request by Stanford.   
 
 
Overall, all AEs should be:   
- 
Recorded in the Adverse Event log (Appendix IV) and reported to Stanford 
as per guideline within this protocol, or upon request 
- 
Noted in the patient study chart   
- 
Entered into the study's secure patient database   
- 
Reported to the participating center’s IRB as per their institutional 
guidelines.  
 
The site Principal Investigator ensures appropriate recording and reporting of all AEs and 
SAEs.  Source documentation should be supplied when appropriate.  Also, any source 
documents requiring English translation is the responsibility of the reporting site.  All 
AEs should be followed until resolution.   
 
The site Principal Investigator is responsible for ensuring proper reporting of AEs and 
SAEs to their individual Institutional Review Board (IRB) and/or Institutional Ethics 
Committee (IEC) as per local IRB and facility standards. 
 
The Adverse Event Log should be kept current and be available upon request from 
Stanford for study renewal applications, monitoring committee audits, reports, analyses 
or other submissions requested by Stanford IRB, Scientific Review Committee (SRC), or 
Data Safety Monitoring Committee (DSMC).   
 
Discussion of AEs will take place in conference calls performed quarterly by a study 
monitoring group consisting of representative PIs and/or Research Coordinators from 
each participating site.  AEs may be reviewed by members of the study monitoring group 
in meetings, audits, and/or site visits.   
 
Updates and outcomes of AEs, SAEs, UPs, and deviations will take place during regular 
conference call discussions or more frequently as needed. 
 
6.2 
Review and Reporting of Minor Deviations 
All deviations will be recorded and reported to Stanford by the participating center’s Principal 
Investigator or research staff member using the Case Report Form (CRF) in Appendix IV.  
Protocol deviations regarding the consent process and those that could affect safety or 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 38 of 87 
measurement of study endpoints will be reported to Stanford PI or research staff member 
within 48 hours, and will then be reported to the Stanford Cancer Center CCTO and IRB as per 
Stanford regulatory guidelines.  
 
Discussions of updates and outcomes of all deviations will take place during regular 
conference call discussions or more frequently as needed. 
 
6.3 
Correcting Protocol Deviations 
DSMC and IRB representatives will notify the PD of any necessary corrective action.  
Research staff should place all DSMC and IRB communication in the regulatory binder.  
Investigators must review and implement all corrective action, and the DSMC may conduct 
additional monitoring to verify that the deviation has been resolved. 
 
6.4 
Potential Adverse Events 
 
6.4.1 
Anticipated Mild and Moderate Adverse Events 
 
TACE 
 SBRT 
- Post embolization syndrome - triad of 
local RUQ pain, nausea and low-grade 
fever lasting no more than 7 days 
- Fatigue lasting < 2 weeks 
- Elevated liver enzymes (AST, ALT) 
lasting < 4 weeks 
- Hair loss 
- Fatigue 
- Nausea 
- Diarrhea 
- Mild abdominal discomfort lasting < 30 
days 
- Elevated liver enzymes (ALT, AST) 
- Any grade thrombocytopenia 
- Any grade anemia 
- Any grade neutropenia 
- Grade 1 - 2 GI bleeding 
- Skin erythema 
- Fever 
- Grade 1 - 2 bowel or gastric ulcer 
- Grade 1 - 2 bowel obstruction 
 
 
6.4.2 
Anticipated Serious Adverse Events 
 
TACE 
SBRT 
- New ascites 
- Encephalopathy (new onset) 
- Abscess formation or infection 
- Death due to toxicity 
- Contrast-induced renal failure 
- Hepatic artery thrombosis 
- Vascular complications related 
to procedure 
- Grade 4 GI toxicity 
- New ascites 
- Encephalopathy (new onset) 
- Grade 3 - 4 bleeding 
- Grade 3 - 4 fistula 
- Grade 3 - 4 bowel obstruction 
- Grade 3 - 4 bowel or gastric 
ulcer/perforation 
- Renal failure requiring dialysis 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 39 of 87 
- Any Grade 4 toxicity possibly or 
likely due to treatment 
- Death due to toxicity 
- Rib fracture 
 
 
 
6.5 
Site Compliance 
It is the Site Principal Investigator’s responsibility to comply with the Monitoring Plan and site 
specific Monitoring Reports.  Any discrepancies or complaints regarding the clinical 
monitoring or the Monitoring Report should be communicated directly to the Stanford PI in 
writing. 
 
 
 

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STUDY CALENDAR 
Activity
Screenin
g / Pre-
Study
Study 
Enrollment
&
Registratio
n
Treatment -
Randomized 
SBRT or 
TACE
Follow-Up (in Time From Completion of 
Study Treatment)
1- 2 
Wks
l
1
Mos
l
3 
Mos
^
6
Mos*
^
12 
Mos*
^
18 
Mos*
^
Q 6 
mos up 
to 3 yrs
SBRT
-
3 -14
days
TACE-
to 16 
wkse
Eligibility 
Confirmation
X
Informed consent
X
Randomization
X
Consult/Physical 
Exam
X
X
X
X
X
X
ECOG PS
X
X+
Xf
Xf
X
X
X
X
X
Child-Pugh Score
Xj
Xj
Xj
Xj
Xj
Xj
QOLk
X
X
X
X
X
Labs 
  - Liver Functiona
X
X+
Xf
Xi
X
X
X
X
X
  - Renal Functionb
X
X+
Xf
Xi
X
X
X
X
X
  - Chemistry Panelc
X
X+
Xf
Xi
X
X
X
X
X
  - CBC w/ diff
X
X+
Xf
Xi
X
X
X
X
X
  - Coags (PT or INR,  
     PTT)
X
X+
Xf
Xi
X
X
X
X
X
  - AFPm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
- Pregnancy Testd
X
CT (or MRI)
X
Xg
X
X
X
X
FDG PET/CT-
Optionalh
X
X
X
X
X
Phone call post-
treatment-Optional
X
X
AE evaluation
X----------------------------------------
X
*Freedom from local progression to be determined. 
^2 weeks before or after each follow-up period will be permitted, e.g., for optional 1 month follow up 
- visit, labs, and scans can be done at 2-6 weeks; 3 months follow-up can be done at 10-14 weeks, 
etc.
+Baseline values may be used if they are within 4 weeks of treatment.
aLiver Function Panel: as per institution; Required: Albumin, ALK P'TASE, ALT (SGPT), AST 
(SGOT),Total Bilirubin
bRenal function panel: as per institution; Required: Urea nitrogen, Creatinine

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cChemistry Panel: as per institution; Required: Glucose, Sodium, Potassium, Chloride
dWomen of childbearing potential, urine or serum allowed. 
eUp to 3 procedures if needed, 6-8 weeks apart, total possible time of procedures up to 16 weeks.
fRepeat if most recent was more than 4 weeks from first treatment, or as per MD.
gCT for Study Enrollment/Registration should be w/in 6 weeks of date of eligibility; may be repeated
if it will be >6 weeks from date of first treatment of TACE or SBRT, or if needed per MD.
hPET/CTs are optional and deemed as needed per treating MD.
iRepeat if most recent are more than 4 weeks from TACE, or if needed per MD.
jChild Pugh score at study entry and every 3 months from study treatment. 
kQOL is optional.  Collected as indicated by agreement on IC document.
lOptional
mRecommended but not required
CORRELATIVE STUDIES
8.1
Tumor Marker Evaluation
Tumor marker evaluation is a secondary endpoint for this study.  Serum AFP levels will be 
drawn at every consultation.  For patients with elevated AFP at study enrollment, both the 
initial AFP and the response in AFP levels following therapy will be correlated with tumor 
response and disease progression.  Two definitions of AFP response will be used for the 
analysis: 1) AFP nadir and 2) percent decrease in AFP from the initial.
Increasing AFP levels following previously decreasing AFP levels or stable AFP levels over 2 
separate measurements will be defined as AFP progression.  However, in the absence of 
clinical or radiographic evidence of disease recurrence, this will not be considered disease 
progression.  However, AFP progression will be correlated with disease progression and 
survival.
For patients whose AFP was not elevated at the time of study enrollment, AFP will not be used 
as a correlative marker.  Additional plasma for subjects may be obtained and analyzed for 
additional biomarkers as part of an ongoing biomarker identification effort at Stanford 
University.
MEASUREMENT OF EFFECT
9.1
Evaluation Criteria
9.1.1
Definition of Local Progression
Local control will be defined as lack of progressive disease at the site of the treated 
lesion. Radiographic response of the treated lesion will be defined by either contrast 
enhanced arterial phase CT or MRI according to EASL criteria (9,11,49):
•
Complete response (CR) = complete disappearance of any arterial intratumoral 
enhancement of target lesion(s)
•
Partial response (PR) = at least 30% decrease in the sum of diameters of viable 
(arterial enhancing) target lesion(s)

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•
Progressive disease (PD) = more than 20% increase in sum of the viable (arterial 
enhancing) target lesion(s), taking as reference the smallest sum of the diameters 
of viable (arterial enhancing) target lesion(s) recorded since the treatment started 
•
Stable disease (SD) = does not meet criteria for PR or PD
Additionally, any new enhancing lesion seen within 2 mm of the prescription isodose 
curve will be defined as local progression.
9.1.2
Definition of Freedom from Local Progression
Freedom from local progression at time T is defined as lack of local progression in the 
treated liver lesion in the set of patients alive and on study at time T and without distant 
progression up to time T.  The rate will be determined at 6, 12, and 18 months.  
Patients will be removed from the study and considered inevaluable for further 
assessment of local progression of the treated lesion if, within time T, they receive 
systemic chemotherapy (without documented progression), receive a liver transplant, or 
have extrahepatic progression, at which point they will be censored.
9.1.3
Definition of Progression-Free Survival
Progression-free survival is defined as the time from randomization until death or any 
progression including local, regional or distant progression. For progression free survival 
a patient will also be considered as having progression if the patient receives systemic 
chemotherapy or a liver transplant.  The rate will be determined at 6, 12 and 18 months.
9.1.4
Definition of Overall Survival
Overall survival will be determined as a measure of time from randomization until death 
from any cause.  The rate will be determined up to three years following therapy.
9.1.5
Serum AFP levels
Serum AFP levels will be measured at specific points during the study.  The 2 endpoints 
to be analyzed are:
- Initial AFP levels
- AFP response - the percent decrease in serum AFP levels from the initial result to 
the eventual nadir after therapy
These endpoints will be correlated to the clinical endpoints (freedom from local 
progression, progression free-survival, and overall survival).
9.2
Evaluation of Response
Response to treatment will be monitored with CT or MRI scanning as well as physical exam 
and serum AFP levels.  Physical exams and serum AFP levels will be done at 3 months, 6 
months, 12 months and 18 months. Imaging scans will be done at 3 months, 6 months, 12 
months and 18 months. 
Response Review
All imaging scans will be determined by a central review at Stanford Cancer Center to assess response.  
Participating institutions will be responsible for uploading DICOM imaging datasets to the electronic
database using their unique usernames and passwords.  Scans will be de-identified and labeled with the 

IRB-35937 / Protocol Version 11, 21 September 2022
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corresponding study identification number and date of scan.  Diagnostic images including CT, MRI and 
PET/CT (optional) must be uploaded and stored in the electronic database within 1 week post 
treatment.  Follow up images are due at 3, 6, 12 and 18 months post treatment according to the study 
calendar, Section 7.  Imaging scans will be assessed at least quarterly for response and the reviewing 
radiologists will be blinded to the treatment arm
The treating radiation oncologist will perform routine physical exams to assess for clinical signs of 
progression. 
10.1
Progression Free Survival
Progression free survival at  12 months and median progression free survival are secondary 
endpoints to this study.  Evaluation of progression will be done at the previously established 
schedule. 
10.2
Overall Survival
Overall survival at 6, 12, 18 months and up to 3 years is a secondary endpoint to this study.  
DATA REPORTING AND REGULATORY CONSIDERATIONS
11.1
Monitoring Plan
With Stanford University as the Coordinating Center, the Stanford PI is responsible for 
ensuring all participating site investigators and their study personnel are trained on the conduct 
of the protocol including HIPAA and confidentiality standards; study procedures, activities, 
and schedules; AE/SAE, deviation and CRF documentation and reporting; and proper data 
collection.
The Stanford coordinator will send a delegation log to each site, to be filled out with the 
names, signatures, and roles of all personnel working on the study. Once complete, the 
delegation logs will be emailed back to the Stanford coordinator. 
The site PI is responsible for providing written summaries of the status of the study to the local 
IRB / EC annually or more frequently in accordance with the policies and procedures 
established by the institution's IRB / EC. The site PI is also responsible for ensuring requests 
for study data, forms, document or records will be submitted appropriately and in a timely 
manner and in the timelines set forth in this protocol.  Each participating center will create and 
maintain a study regulatory binder, electronic or paper, and will also maintain a patient study 
chart for each subject, as detailed in Section 12.
Any time an amendment is made to the protocol, the Stanford coordinator will communicate 
the change to all sites via email or video/phone conference session if needed. The sites will 
then have the amended protocol approved by the local IRB.
Overall study audits of all sites will be performed by Stanford DSMC, three patients at 
Stanford and one patient per sub-site will be chosen at random for audit review at a minimum 
of once per year; more frequent monitoring will occur as needed. All of the source 
documentation required for consent, eligibility, treatment and follow-up will be translated into 
English by a local certified translation center associated with University and sent for audit 

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 44 of 87 
review to Stanford University upon request. Preliminary reviews may take place by Stanford 
research staff participating centers, prior to Stanford DSMC audits.  
 
Additionally, an independent monitoring committee (MC) consisting of a radiation oncologist 
and a research coordinator not on the study protocol will be set-up to review cumulative AEs, 
SAEs, and accrual. The MC will meet twice a year annually, and more often as needed.    
 
Research staff at each center will enter subject information into OnCore after access has been 
coordinated by Stanford research and OnCore personnel.  Clinical and other data may be 
entered into another designated secure study database such as Redcap. The Stanford 
coordinator will either hold a training session in person during site initiation visits or will 
create a video/phone conference training session on how to register patients in OnCore and fill 
out case report forms (eCRFs). The training session will be held before each site starts 
enrolling patients on the study. All sites will fill out the forms in English. Important: When 
the local coordinator is working in OnCore or Redcap, he or she will only be able to see local 
data, not Stanford data or data from the other international sites.  
 
Participating centers will supply radiation treatment plan data upon request by uploading scan 
images and information.  If uploading is not possible, images and reports may be supplied 
electronically or on encrypted and/or password-protected discs or drives.  Further data may be 
requested from each institution for study analyses.   
 
All tools, computers, and systems used for monitoring and analyses will be secure, password-
protected, and HIPAA compliant.  Shared data will be de-identified and unique identifiers will 
be assigned to ensure patient confidentiality. 
 
11.2 
Electronic Monitoring 
Electronic monitoring will be performed when possible.  Participating institutions will be 
advised what records will be needed for electronic review and information will be transmitted 
via a secure electronic mail or study database.  At a minimum, eligibility checklists (with 
necessary source documents) will be verified via electronic exchange and after Stanford review 
and approval a participating center's patient may be enrolled to the study.  The exchange of 
subject information will be done in a secure manner and transferred through Stanford's secure 
electronic or study data management systems.  Unique identifiers assigned by Stanford at the 
time of patient registration will be used on subject records and any documents containing 
subjects' personal health information (PHI).   Additional monitoring of participating center's 
study data will be accomplished through formal PI reviews as scheduled and needed.   
 
Unanticipated Problems (UPs) and Significant Adverse Events (SAEs) will be and reported 
according to the guidelines described in Section 6.   
 
Questions related to eligibility, response and toxicity may be communicated to the PIs on an 
ongoing process through secure email communications. 
 
All tools, computers, and systems used for monitoring and analyses will be secure, password-
protected, and HIPAA compliant.  Shared data will be de-identified and unique identifiers will 
be assigned to ensure patient confidentiality. 
 

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All records must be provided or translated into English.  Individual participating sites are 
responsible for all necessary translations. 
 
11.2.1 
Sub-Site Clinical Monitoring 
Due to the distance of the sub-site locations and budgeting and language constraints, 
monitoring of the sites will be conducted as follows: 
 
- 
After confirmation of Site Activation, every subject enrolled by the sub-sites must 
submitted to Stanford for central review of eligibility 
- Site Activation includes submittal of all regulatory documents required for 
enrollment detailed in Section 11.2.2.  
- 
Initial Review: Each of the sub-sites must submit source documents (English 
translated) for review at each of the following time points for at least the first  
subject enrolled, with the ability to review subsequent subjects if errors are 
identified: 
- Baseline (eligibility source documents, baseline imaging and labs, treatment 
plans) 
- End of Treatment (treatment summary) 
- After the 1st Follow Up Visit  
- 
Annual Review: Each sub-site will be required to submit one complete study 
binder (English translated) of one patient chosen at random for review by the 
Stanford DSMB, per institutional requirements. This will accompany the 3 random 
subjects reviewed at Stanford annually.  
- 
An Independent Monitoring Committee (MC) consisting at least of a radiology 
oncologist and research coordinator not on study protocol will monitor the 
cumulative AEs (reported in RedCap), SAEs, and accrual for the overall study and 
each individual site, on a bi-annual basis, or more often as needed 
-  The MC monitor will complete a Monitoring Report which describes the 
findings and conclusions, noted in the visit. Additional information may be 
documented in the monitoring report such as number of subjects screened, 
enrolled, withdrawn, and treatments completed.  The regulatory binder, new 
adverse events or serious adverse events, staff changes and protocol violations 
and deviations will also be properly documented. 
 
-  A copy of the report will be sent to the participating sub-site’s investigators and 
staff after the visit.   Sites will have 60 days to make corrections and respond to 
this report.  If serious deficiencies are found during the visit, the Stanford PI 
may require the institution to submit copies of documentation to satisfy 
information gaps or queries, or require other appropriate remedies.  The 
Stanford PI may also suspend the sub-site’s patient enrollment privileges if 
warranted until the site’s issues are addressed and resolved. 
 
- 
 These clinical study reports will also serve as feedback for adequate adjustments of 
the monitoring plan to ensure quality control and patient safety throughout the 
study.  Appropriate documentation of regular communication and meetings with all 
participating sites will be collected by Stanford and filed in the study binder. 
 

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-  A Conference Call with all sub-sites will be conducted upon eligibility of the first 
patient to be enrolled to discuss questions regarding eligibility, treatment, or 
adverse events once the first patient is enrolled. Thereafter we will have a 
mandatory quarterly call if the first 3 patients pass Initial Review and there are no 
outstanding safety concerns. Other issues from sub-sites will be addressed directly 
with the Stanford investigators.   
 
   
11.2.2 
Regulatory Binder 
The Stanford research team may visit the institution and review the study regulatory 
binders and examine the institutional records for study participants.  Source documents 
will be reviewed to verify eligibility, treatment compliance, treatment toxicity, response 
assessment and overall record-keeping.  Source documentation should be independently 
verifiable. The sub-site will be given a minimum of 60 days notice for this possible visit.   
 
Records and source documents in binders should include but are not limited to: 
- Documentation of IRB approval and renewal letters and relevant 
correspondence with local site’s IRB 
- Protocol signed by the investigator (with amendments and subsequent 
versions including the final version approved by local IRB) 
- IRB-approved Consent Form and all amendments 
- Study personnel CVs and  Medical Licenses 
- Laboratory Licenses and information; and copies of normal range values for 
each lab 
- Study Subject Log including patient name or identifier, Consent Date, 
Treatment Dates, and Off-Study date with reason 
- Site Signature/Delegation log 
- SRC approval and correspondence 
- DSMC Correspondence 
- Any other pertinent reports or records 
 
Records and study-related documents in patient study charts include but are not 
limited to: 
- Completed Eligibility Checklists accompanied by all related source materials 
- Pre-study reports, scans, labs and notes 
- Signed Informed Consent Forms  
- Radiation treatment records 
- Treating physician’s notes  
- Consultation or visit notes, medical oncology records (as applicable), 
interventional radiology notes and procedure reports  
- Laboratory results 
- Scan or radiology reports 
- Follow-up records 
- Notes to file 
- Deviation records or notes with source documents 
- SAE, AE, and toxicity reports with source documents 
 

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Prior to leaving the facility, the monitor(s) may discuss with the investigator(s) and staff
any discrepancies or problems identified during the visit. If significant noncompliance or 
suspected data fabrication/falsification are identified during the audit, the monitors will 
immediately notify the Stanford PIs and the Stanford Clinical Trials Office for further 
actions.
Records requested for review must be translated into English.  Individual sites are 
responsible for any necessary translations.
11.2.3
Study oversight committees
11.2.3.1 Data and Safety Monitoring Board (DSMB)
Stanford’s DSMB will also conduct study audits to review each participating 
centers’ regulatory binders and patient study charts.  These audits will ensure 
guidelines set forth in this protocol are followed for all aspects of the study 
including but not limited to regulatory approvals and renewals; patient eligibility, 
enrollment, treatment, and follow-up; proper documentation and record-keeping; 
and adverse event reporting.  Audits will be performed yearly by Stanford DSMC; 
more frequent monitoring will occur as needed. 
Preliminary reviews will take place by Stanford research staff prior to audits. 
STATISTICAL CONSIDERATIONS
12.1
Stopping rules
If, after the first 40 patients, the incidence of grade 4 or greater toxicity attributable to SABR
exceeds 10% the DSMB will be informed.  A decision will be made to either continue the 
study or to amend the protocol to reduce the radiation dose or further limit the dose to adjacent 
critical organs. 
12.2
Data Management  
The procedures for data collection, data management and data security and confidentiality used 
in the clinical study are described below. These procedures comply with the principles of good 
clinical practice, and Stanford Cancer Center Multi-Site trials SOP.
12.2.1
Data is managed via three components:
I.
OnCore
Patients are registered and reported to the NCI through OnCore, a web-based 
database application. Patients are registered in OnCore within 5 days after signing the 
consent form. Patients are numbered consecutively. Each sub-site will have their 
study ID’s assigned to their enrollees after eligibility confirmation by Stanford 
through the process described in Section 4.1.
II. Redcap
Case report forms (CRFs) are filled and stored electronically in Redcap, a web-based 
database application. Patients are numbered consecutively using the same numbers as 

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in OnCore. The CRFs include a Baseline Evaluation Form, Registration Form, 
Treatment Summary Form, and Follow-Up Form. One Follow-Up Form is filled out 
for each patient follow-up visit, so several Follow-Up Forms are filled out for each 
patient over the course of the study. The Follow-Up Form records local, regional, and 
distant control provided by the protocol treatment. It also records any adverse events 
experienced by the patient. Common adverse events are recorded using radio buttons. 
Other adverse events can be typed into a Comments box.  
III.Document binders
Study binders/patient binders must contain records of all data pertaining to the study. 
This includes all primary data for the items listed in the calendar, signed/dated 
informed consent, documentation of consent and all data listed in section 11.2.2 
above. Binders should have the following sections/tabs: 
Informed Consent – Copy of the signed/dated informed consent and 
documentation of the consent process. 
Eligibility – The eligibility checklist document from appendix III with each 
section filled out preferably electronically, printed out and signed.  Following 
the checklist each supporting document should be included, in order (to the 
extent possible) as well as all pretreatment studies and documentation of multi-
specialty evaluation. 
Randomization – Documentation of Arm patient is randomized to (an email 
from the Stanford site) 
Treatment Plan – De-identified copy of treatment planning data sets and 
treatment plan QA form. 
TACE – Documentation of all data required in section 5.2.2, TACE CRF, and 
primary documentation of the TACE procedure from the medical record, 
treatment summary written by the treating physician, including adverse events. 
QOL – Quality of Life EQ-5D-3L and FACT-Hep (if subject consents to 
questionnaires. 
Follow up – Documentation of all follow up procedures/H&P/labs/and imaging 
as detailed in the Study Calendar (section 7).
SAE/AE and Deviations – AE logs, SAE reports with source documentation 
and deviation reports.
12.3
Data security and confidentiality
•
Data used for the clinical study is confidential. Unique identification numbers will be 
assigned and used for each subject on eCRFs.
•
Electronic data will be stored on devices that are back-upped in a secure and timely 
manner. Protocol data for this study will be stored in the secure database systems OnCore 
and REDCap
•
The Stanford PI shall retain all records and reports for up to 10 years after the date of the 
last patient care activity as per Stanford Multi-Site trial SOP.
12.4
Endpoints

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12.4.1 
Primary Endpoints 
To compare the freedom from local progression (FFLP) at 12 months.  
 
12.4.2 
Secondary Endpoints 
• To compare the freedom from extra hepatic progression between individuals treated 
with SBRT and individuals treated with TACE  
• To compare the progression free survival (PFS) between individuals treated with 
SBRT and individuals treated with TACE  
• To compare the overall survival between individuals treated with SBRT and 
individuals treated with TACE  
• To determine the median FFLP, progression free survival, extra hepatic progression 
free survival and overall survival for patients with tumors smaller than 3 cm per 
treatment group and for patients with tumors greater than 3 cm per treatment group 
• To evaluate AFP levels as a predictor for FFLP, PFS, extra hepatic progression free 
survival and OS 
 
 
12.5 
Sample Size 
 
12.5.1 
Accrual Estimates 
This is a multi-center, randomized study, designed to compare the 12-month freedom 
from local progression (FFLP) rate of TACE vs. SBRT in the initial management of 
patients with recurrent HCC after initial TACE. 
 
After completion of an initial application, we will open this study at various institutions 
in the United States and in Asia and Canada with SABR capabilities.  Since many of 
these centers will be in Asia where HCC is much more prevalent than in the U.S., we 
anticipate that the majority of patients enrolled onto this study will come from Asia.   
 
Accrual will occur over 3 years with a total enrollment of 160 patients, 80 patients in 
each arm.  Expected enrollment at Stanford is 15-30 patients over 3 years, or 
approximately 5-10 patients per year.  As the incidence of HCC at the 3 other sub-sites 
are higher, we expected total accrual from each of the sites to be 40-45, with annual 
accrual of approximately 10-15 patients per year.  
 
In 2007, 200 TACE procedures were performed at Stanford Hospital. From 2002 – 2006, 
436 newly diagnosed patients with HCC were evaluated at Stanford Cancer Center, 
which is a yearly average of 87 new patients per year over that time period.  Based on the 
number of TACE procedures performed per year, we estimate that 1 patient per 2 months 
can reasonably be expected to accrue onto this study.   
 
12.5.2 
Sample Size Justification 
A sample size of 56 informative subjects per arm will provide at least 90% power in a 
two-sided log rank test of detecting a 30% difference in the 12 month of the two groups 
with alpha level of 0.05 given an accrual period of 36 months and a total follow up period 
of 36 months.  The survival curves of both groups are assumed to follow an exponential 

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distribution and the 12 month FFLP for the TACE group is assumed to be 30% and the 
expected 12 month FFLP for the SBRT group is 60%. 
 
We propose enrolling 160 patients onto this study to account for patients who may be 
taken off of the study prior to reaching the primary endpoint of local progression-free 
survival (FFLP) at 12 months because of progression elsewhere in the liver or declining 
performance status that may preclude follow-up scans at required intervals.  We estimate 
that up to 30% of this patient population will not be evaluable for local progression (as 
defined in section 9.1.1).  Starting with 80 patients per arm we expect to have 
approximately 56 patients evaluable for local progression at 12 months. 
 
12.5.3 
Analysis populations 
In general analysis will follow the intent-to-treat principle.   However, for FFLP, patients 
must be evaluable for FFLP as defined in section 9.1.2 (treatment will be analyzed as 
randomized) 
 
Analysis for all other endpoints will be carried out for all evaluable patients with intent to 
treat. 
 
Additional subset analysis for efficacy endpoints will be done based on tumor size (<= 3 
cm or > 3 cm). 
 
12.6 
Plan of Analysis 
 
12.6.1 
Evaluable patients 
 All patients are considered evaluable except as noted in Section 9.1.2 for FFLP.  
Treatment is as randomized.    
 
12.6.2 
Design 
This is a two-arm randomized trial.  Patients will be randomly assigned to receive TACE 
or SABR.  At progression, crossover between the 2 arms of the study will be allowed; the 
crossover is not mandatory and will not be analyzed statistically. 
 
12.6.3 
Freedom from local progression 
Analysis will be carried out on the subset of patients evaluable for local progression (See 
Section 9.1.2).   Freedom from local progression at time T is defined as lack of local 
progression in the treated liver lesion in the set of patients alive and on study at time T 
and without distant progression up to time T.  The rate will be determined at 6, 12, and 18 
months.  Freedom from extra hepatic progression is defined as time from randomization 
until regional or distant progression.  For both FFLP and freedom from extra hepatic 
progression, individuals who are lost to follow up will be censored at the date of the last 
progression evaluation.  Individuals who were given systemic chemotherapy or received 
a liver transplant will be censored at the data of the medical intervention.  The time to 
freedom from local progression will be estimated by competing risk models with death 
and regional or distant progression as competing risks.  The time to freedom from extra 
hepatic progression will be estimated by competing risk models with death as a 
competing risk.  For both models, risk factors such as tumor size and institution will be 
tested in a multivariate Cox regression model adjusting for the competing risks. 

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12.6.4
Progression free and overall survival
Progression-free survival is defined as the time from randomization until death or any 
progression including local, regional or distant progression.  For progression free survival 
a patient will also be considered as having progression if the patient receives systemic 
chemotherapy or a liver transplant.  Overall survival is defined as the time from 
randomization until death from any cause.  Overall and progression free survival will be
summarized using Kaplan-Meier curves and medians with 95% confidence intervals 
calculated using Greenwood’s formula.  Log rank tests will be used to compare treatment 
groups.  Cox proportional hazard models will be used to estimate hazard ratios between 
treatment groups and to assess other risk factors, in particular the effect of tumor size and 
the impact of the different institutions.  
12.6.5
Subgroup analysis
Patients will be divided into two subgroups depending on whether the size of their tumor 
is less than or greater than 3 cm.  Within each subgroup the progression free survival and 
overall survival will be summarized using Kaplan-Meier curves and medians with 95% 
confidence intervals calculated using Greenwood’s formula. Freedom from local 
progression and freedom from extra hepatic progression within each subgroup will be 
summarized by cumulative incidence function estimators adjusted for the competing risk 
of death or regional or distant progression. 
12.6.6
AFP / Alpha fetoprotein analysis
The impact of elevated AFP level on time to event endpoints: FFLP, PFS, extra hepatic 
progression free survival and OS will be evaluated both in terms of the initial AFP level 
and on-study levels in a Cox proportional hazards model. 
MULTI-SITE STUDY GUIDELINES
13.1
Study documents
An application and investigator packet (including the protocol, informed consent form and 
relevant supporting information) will be sent by Stanford to each prospective site for their 
Institution Review Board (IRB) or Institutional Ethics Committee (IEC) review.  Each site is 
asked to return the completed application which includes a list of regulatory requirements 
according to the Stanford PI and research team. 
The regulatory requirements include:
•
IRB/IEC letter of approval, IRB/IEC-approved study protocol, and any other pertinent 
IRB/IEC documents or communications
•
IRB/IEC-approved Informed Consent Form
•
IRB/IEC panel members
•
CVs and Medical licenses for site PI’s and Co-investigators 
•
Financial Disclosure from participating site PI and each sub-investigator
•
International participating sites must meet local country requirements.
If any additional sites were to be added in the future, a committee consisting of Stanford PIs
will review each application and jointly determine site eligibility for this study.  All required 

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Page 52 of 87 
regulatory documents and site communications will be filed with the Sponsor and in the central 
regulatory binder as well as the site investigator’s regulatory binder.  
 
13.2 
Site Activation 
Each sub-site will be required to complete all of the following before they can begin research 
related activities for this protocol: 
- 
Provide confirmation of study documents detailed in Section 13.1 
o Stanford will then submit the local ICF and Ethics Committee approval from 
sub-site to Stanford IRB for approval  
- 
Certification of GCP and HSP training for all sub-site research staff 
- 
Delegation of Duty Log 
- 
Site Initiation Visit (via conference or video call with Stanford University) 
o Review of Study Design and Eligibility Criteria 
o Review registration process onto secure Oncore database 
o Review SAE Reporting requirements 
o Review Data and Safety Monitoring Plan 
- 
Submit a Benchmark (Dry Run) case review (Section 3.4) to the Stanford PIs 
 
At the completion of the aforementioned items, Stanford will issue the sub-site an activation 
letter indicating that the site is ready to enroll.  
 
13.3 
Communication with the Institutional Review Board (IRB) 
This protocol, the Informed Consent Form, and relevant supporting information must be 
submitted to the local IRB or Ethics Committee (EC) by the Site PI for review and approval, 
the approved ICF and approval letter must then be submitted to Stanford IRB for approval 
before the study is initiated. The consent will be back translated into English from the local 
language for confirmation.  In addition, any advertising materials must be approved by the 
local IRB.  The study will be conducted in accordance with U.S. FDA, applicable national and 
local health authority, and IRB requirements.   
 
There will be one protocol document and each participating institution will utilize that 
document.  It is the responsibility of the Stanford PI to ensure that the participating sites use 
the correct version of the protocol as well as subsequent amendments.  The site PI is 
responsible for ensuring that their study team members have the current version of the protocol 
and informed consent documents.  Site PIs are also responsible for promptly informing the 
local IRB or EC of any protocol changes or amendments.  
 
The Site PI is responsible for providing written summaries of the status of the study to the local 
IRB at least annually and more frequently in accordance with the policies and procedures 
established by their local IRB.  The site PI reports AEs and SAEs to their individual 
Institutional Review Board (IRB) and/or Institutional Ethics Committee (IEC) as required and 
of all unanticipated problems involving risk to human patients or others. 
 
13.4 
Site Communication 
The Stanford PIs will document regular communication with all participating sites.  Once a site 
has completed activation and enrollment has begun, a quarterly conference call will be 
scheduled with each sub-site to address any eligibility, treatment, adverse events, and 
miscellaneous issues regarding the protocol.  The sub-site may contact the research team at 

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Page 53 of 87 
Stanford at any time with questions regarding the protocol or request a conference or video call 
to review or re-educate any members of the sub-site research team. Communication may 
include site visits or additional conference calls to update and inform all participating sites 
about the progress of the study and discuss adverse events and deviations.  The minutes and 
reports from these site visits will be recorded by Stanford; and meetings and conference calls 
records will be filed in the Regulatory Binder and adequately stored and retained by the 
sponsor. 
 
 
 

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CITED REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J 
Cancer. 2001;94(2):153-6.
2. Nair S, Shiv Kumar K, Thuluvath PJ. Mortality from hepatocellular and biliary cancers: changing 
epidemiological trends. Am J Gastroenterol. 2002;97(1):167-71.
3. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J 
Med. 1999;340(10):745-50.
4. Okuda K, Ohtsuki T, Obata H, Tomimatsu M, Okazaki N, Hasegawa H, et al. Natural history of 
hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer. 
1985;56(4):918-28.
5. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. 
Hepatology. 2002;35(3):519-24.
6. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. 
Semin Liver Dis. 1999;19(3):329-38.
7. Villa E, Moles A, Ferretti I, Buttafoco P, Grottola A, Del Buono M, et al. Natural history of inoperable 
hepatocellular carcinoma: estrogen receptors' status in the tumor is the strongest prognostic factor for 
survival. Hepatology. 2000;32(2):233-8.
8. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907-17.
9. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208-36.
10. Bismuth H, Majno PE. Hepatobiliary surgery. J Hepatol. 2000;32(1 Suppl):208-24.
11. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management 
of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European 
Association for the Study of the Liver. J Hepatol. 2001;35(3):421-30.
12. Huo T, Huang YH, Wu JC, Chiang JH, Lee PC, Chang FY, et al. Comparison of transarterial 
chemoembolization and percutaneous acetic acid injection as the primary loco-regional therapy for 
unresectable hepatocellular carcinoma: a prospective survey. Aliment Pharmacol Ther. 
2004;19(12):1301-8.
13. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: 
Chemoembolization improves survival. Hepatology. 2003;37(2):429-42.
14. Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, et al. Arterial embolisation or 
chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular 
carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734-9.
15. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of 
transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 
2002;35(5):1164-71.
16. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study 
of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the 
PRECISION V study. Cardiovascular and interventional radiology. 2010;33(1):41-52.
17. Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, et al. 
Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumor 
progression while on the waiting list and leads to excellent outcome. Liver Transpl. 2003;9(6):557-63.
18. Wong LL, Tanaka K, Lau L, Komura S. Pre-transplant treatment of hepatocellular carcinoma: 
assessment of tumor necrosis in explanted livers. Clin Transplant. 2004;18(3):227-34.
19. Kamel IR, Bluemke DA, Ramsey D, Abusedera M, Torbenson M, Eng J, et al. Role of diffusion-
weighted imaging in estimating tumor necrosis after chemoembolization of hepatocellular carcinoma. 
AJR Am J Roentgenol. 2003;181(3):708-10.

IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Page 55 of 87 
20. Jang MK, Lee HC, Kim IS, Lim YS, Chung YH, Lee YS, et al. Role of additional angiography and 
chemoembolization in patients with hepatocellular carcinoma who achieved complete necrosis following 
transarterial chemoembolization. J Gastroenterol Hepatol. 2004;19(9):1074-80. 
21. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for 
the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 
1996;334(11):693-9. 
22. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005;40(3):225-
35. 
23. Lee JK, Chung YH, Song BC, Shin JW, Choi WB, Yang SH, et al. Recurrences of hepatocellular 
carcinoma following initial remission by transcatheter arterial chemoembolization. J Gastroenterol 
Hepatol. 2002;17(1):52-8. 
24. Marelli L, Stigliano R, Triantos C, Senzolo M, Cholongitas E, Davies N, et al. Treatment outcomes for 
hepatocellular carcinoma using chemoembolization in combination with other therapies. Cancer Treat 
Rev. 2006;32(8):594-606. 
25. Borgelt BB, Gelber R, Brady LW, Griffin T, Hendrickson FR. The palliation of hepatic metastases: 
results of the Radiation Therapy Oncology Group pilot study. Int J Radiat Oncol Biol Phys. 
1981;7(5):587-91. 
26. Leibel SA, Pajak TF, Massullo V, Order SE, Komaki RU, Chang CH, et al. A comparison of 
misonidazole sensitized radiation therapy to radiation therapy alone for the palliation of hepatic 
metastases: results of a Radiation Therapy Oncology Group randomized prospective trial. Int J Radiat 
Oncol Biol Phys. 1987;13(7):1057-64. 
27. Lawrence TS, Ten Haken RK, Kessler ML, Robertson JM, Lyman JT, Lavigne ML, et al. The use of 3-
D dose volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys. 1992;23(4):781-8. 
28. Jackson A, Ten Haken RK, Robertson JM, Kessler ML, Kutcher GJ, Lawrence TS. Analysis of clinical 
complication data for radiation hepatitis using a parallel architecture model. Int J Radiat Oncol Biol 
Phys. 1995;31(4):883-91. 
29. Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, et al. Stereotactic single-dose radiation 
therapy of liver tumors: results of a phase I/II trial. J Clin Oncol. 2001;19(1):164-70. 
30. Wada H, Takai Y, Nemoto K, Yamada S. Univariate analysis of factors correlated with tumor control 
probability of three-dimensional conformal hypofractionated high-dose radiotherapy for small 
pulmonary or hepatic tumors. Int J Radiat Oncol Biol Phys. 2004;58(4):1114-20. 
31. Mendez Romero A, Wunderink W, Hussain SM, De Pooter JA, Heijmen BJ, Nowak PC, et al. 
Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-
ii study. Acta Oncol. 2006;45(7):831-7. 
32. Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, et al. Phase I study of individualized 
stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin 
Oncol. 2008;26(4):657-64. 
33. Hoyer M, Roed H, Traberg Hansen A, Ohlhuis L, Petersen J, Nellemann H, et al. Phase II study on 
stereotactic body radiotherapy of colorectal metastases. Acta Oncol. 2006;45(7):823-30. 
34. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of 
stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys. 
2005;62(5):1371-8. 
35. Lee MT, Kim JJ, Dinniwell R, Brierley J, Lockwood G, Wong R, et al. Phase I study of individualized 
stereotactic body radiotherapy of liver metastases. J Clin Oncol. 2009;27(10):1585-91. 
36. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, et al. Multi-
institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 
2009;27(10):1572-8. 

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37. Fuss M, Thomas CR, Jr. Stereotactic body radiation therapy: an ablative treatment option for primary 
and secondary liver tumors. Ann Surg Oncol. 2004;11(2):130-8. 
38. Herfarth KK, Hof H, Bahner ML, Lohr F, Hoss A, van Kaick G, et al. Assessment of focal liver reaction 
by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors. Int J Radiat Oncol Biol 
Phys. 2003;57(2):444-51. 
39. Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P. Hypofractionated 
stereotactic body radiation therapy (SBRT) for limited hepatic metastases. Int J Radiat Oncol Biol Phys. 
2007;67(3):793-8. 
40. Kavanagh BD, Scheftera TE, Wersall PJ. Liver, renal, and retroperitoneal tumors: stereotactic 
radiotherapy. Front Radiat Ther Oncol. 2007;40:415-26. 
41. Schefter TE, Welsh J, Gaspar LE, Kavanagh B, editors. Normal Liver V30% and Mean Liver Dose 
Predicts the Maximum Normal Liver Volume Reduction After Stereotactic Body Radiation Therapy 
(SBRT). ASTRO 2007; 2007; Los Angeles: American Society for Therapeutic Radiation Oncology. 
42. Takeda A, Takahashi M, Kunieda E, Takeda T, Sanuki N, Koike Y, et al. Hypofractionated stereotactic 
radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not 
eligible for other ablation therapies: Preliminary results for efficacy and toxicity. Hepatol Res. 
2008;38(1):60-9. 
43. Goodman KA, Wiegner EA, Maturen KE, Zhang Z, Mo Q, Yang G, et al. Dose-escalation study of 
single-fraction stereotactic body radiotherapy for liver malignancies. International journal of radiation 
oncology, biology, physics. 2010;78(2):486-93. 
 
 
 

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Appendix I 
 
ECOG Performance Status 
 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office 
work 
2 
Ambulatory and capable of all selfcare but unable 
to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed 
or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 
 
 
 
 
 

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Appendix II 
 
Acceptable TACE Agents 
 
  
1. Acceptable embolic agents include: 
• 
Gelatin sponge (gelfoam) 
• 
Polyvinyl alcohol (PVA) particles  
• 
Microspheres / Embolic beads 
 
 
2. Acceptable chemotherapeutic agents include (excluding drug eluting beads): 
• 
Doxorubicin 
• 
Epirubicin 
• 
5-fluorouracil  
• 
Mitomycin C 
• 
Gemcitabine 
• 
Cisplatin 
• 
SMANCS (styrene maleic acid neocarzinostatin) 
 
3. Acceptable contrast agents include: 
• 
Lipiodol 
 
4.  Acceptable drug-eluting bead formulations, based on provider preference and size of 
tumor, include : 
 
 
LC Beads, 100-300 micron and/or 300-500 microron microspheres, loaded with 
doxorubicin 
 
 
Quadraspheres, 30-60 micron or 50-100 micron, loaded with doxorubicin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix III 
 
Eligibility Checklist  
 
Protocol Information 
Title 
International Randomized Study of Transarterial 
Chemoembolization (TACE) versus Stereotactic Body Radiotherapy 
(SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual 
or Recurrent Hepatocellular Carcinoma after Initial TACE 
Protocol Number 
35937 
Principal 
Investigator 
Daniel Chang 
 
Subject Information 
Subject Name: ______________________________________________ 
Study ID: ___________________________________        Gender:   
 Male     
 Female 
 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria  
Yes No 
Supporting Documentation* 
1. Confirmed hepatocellular carcinoma (HCC) by one of 
the following:  
• Histopathology 
• One radiographic technique that confirms a lesion > 
1cm with arterial hypervascularization with washout 
on delayed phase 
 
 
 
2.  Radiographic evidence of persistent, progressive or 
recurrent disease in an area previously treated with 
TACE; This evaluation should be within 6 weeks of 
study eligibility.  
 
 
 
3.  Unifocal liver tumors not to exceed 7.5cm in greatest 
axial dimension. Multifocal lesions will be restricted 
to lesions that can be treated within a single target 
volume within the same liver segment and to an 
aggregate of 10cm as long as the dose constraints to 
normal tissue can be met. 
 
 
 
4.  ECOG (Eastern Clinical Oncology Group 
Performance Status) 0, 1, or 2 (Appendix I) 
 
 
5.  Patients with liver disease classified as Child Pugh 
class A or B, with score < 9 (within 4 weeks of 
treatment) 
 
 
 
 
 
 

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a. Albumin (1, 2, 3) _________________ 
b. Total bilirubin (1, 2, 3) ____________ 
c. INR (1, 2, 3) ____________________ 
d. Encephalopathy (1, 2, 3) ___________ 
e. Ascites (1, 2, 3) __________________ 
 
CP score total: (5-15) _______________ 
CP class: (A, B, or C) _________________ 
 
6.  Life expectancy ≥ 6 months 
 
 
7.  Age > 18 years old 
 
 
8.  Ability of the research subject or authorized legal 
representative to understand and have the 
willingness to sign a written informed consent 
document 
 
 
 
 
Exclusion Criteria  
Yes No 
Supporting Documentation* 
1.  Prior radiotherapy to the upper abdomen 
 
 
 
2.  Prior radioembolization to the liver 
 
 
 
3.  Prior RFA to index lesion 
 
 
 
4.  Liver transplant 
 
 
 
5.  Active gastrointestinal bleed within 2 weeks of study 
enrollment  
 
 
 
6.   Ascites refractory to medical therapy (mild to 
moderate ascites is allowed) 
 
 
7.  Women who are pregnant or breastfeeding 
 
 
 
8.  Administration of chemotherapy within the last 1 
month 
 
 
 
9.  Extrahepatic metastases 
 
 
 
10.  Participation in another concurrent treatment protocol 
 
 
 
10.   Prior history of malignancy other than HCC, 
dermatologic basal cell or squamous cell carcinoma. 
 
 
 
*Supporting documentation is required to confirm subject eligibility and can include but is not 
limited to:  clinic or consultation notes, lab results, pathology results, radiology reports, subject 
self-report, or MD documentation.   
 
 
Statement of Eligibility 
 
By signing this form of this trial I verify that this subject is [
eligible / 
ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific Review 
Committee, the Stanford IRB, and has finalized financial and contractual agreements as required by 
Stanford School of Medicine’s Research Management Group. 
 

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Study Coordinator Signature: 
Date: 
Printed Name: 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
Treating Physician Signature: 
Date: 
Printed Name: 
 
 
 

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Appendix IV 
 
 
Case Report Form and Patient Logs: 
 
 
1. Case Report Form for TACE Procedure 
 
2. Subject Log 
 
3. Deviation Log 
 
4. Adverse Event Log 
 
5. Adverse Event Tracking form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Page 63 of 87
 
 
 
Protocol Title:  International Randomized Study of Transarterial Chemoembolization (TACE) 
versus Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) 
for Residual or Recurrent Hepatocellular Carcinoma after Initial TACE
Stanford eprotocol #: IRB-35937  
 
OnCore #: HEP0052
Case Report Form for TACE Procedure
Fill in each item below.  Return the completed form, with the final report/note of the TACE 
procedure, to Stanford Research staff. Keep a copy of all CRFs in patient's study chart and as 
needed per your institution in the patient's medical record.   
PRE-TREATMENT:
Vital Signs
Temp 
oC______    oF______    
Check if Oral, or if other, 
define:_______________
Pulse
BP
________  /________
RR
PE Findings
General
WNL    
Abnormal, specify: ___________________________
Not 
Done
HEENT
WNL    
Abnormal, specify: ___________________________      
Not 
Done
Neuro
WNL    
Abnormal, specify: ___________________________      
Not 
Done
Cardio
WNL    
Abnormal, specify: ___________________________      
Not 
Done
Pulmonary 
WNL    
Abnormal, specify: ___________________________      
Not 
Done
GI
WNL    
Abnormal, specify: ___________________________      
Not 
Done
Edema
WNL    
Abnormal, specify: ___________________________      
Not 
Done
GU
WNL    
Abnormal, specify: ___________________________      
Not 
Done
TACE date: ________________________ 

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 Skin 
WNL    
Abnormal, specify: ___________________________      
Not 
Done 
 Mobility 
(musculoskeletal) 
WNL    
Abnormal, specify: ___________________________      
Not 
Done 
   
 
 
 
Medications 
 
(pre-TACE 
 
 only) 
 
 
 
 
 
 
 
 
 
 
 
 
Continued on next page… 
Complete below regarding TACE and post-TACE information: 
 
1. Vessels embolized: 
 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
 
2. Amount of embolization agents used:  
 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
_____________________________________________________________________________ 
 
3. Medications used during the procedure (include chemotherapeutic agents, contrast medium, 
and agents not otherwise noted):  
 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 

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_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
 
4. Time of termination of the TACE procedure:  _______________________________ 
 
5. Hospital discharge date: _______________________________ 
 
6. Medications prescribed at discharge (antiemetics and oral narcotic medication for pain, 
include dose, frequency, and duration):   
 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 
_______________________________________________________________________ 

Confidential                                                   Page 66 of 87                         
 
SERIOUS ADVERSE EVENT Addendum Form  (Complete along with Stanford CCTO SAE Form)    
 
1. Check if event was:    
 Serious Adverse Event (SAE)  or    
 Adverse Event (AE) 
 
 
Indicate Grade*: _____   
 
*According to CTCAE, Version 4 or greater, available at http://ctep.cancer.gov/reporting/ctc.html.  
 
2. Was this also an Unanticipated Problem (UP)?    
 Yes 
 No 
 
If Yes, check that it meets UP criteria for:    
Unexpected  
 
 
 
 
Related  
 
 
 
 
Harmful  
 
 
3. Check the box of which therapy the event was related or possibly related to:    
 
 TACE  
 
 SBRT      
 Other, indicate: __________________________  
    
4. Indicate how much treatment the subject received up to the event: 
 
- For TACE, agents administered:________________________________________ 
 
- For SBRT, fractions______  and cGy_______ 
 
5. Provide a brief description of the event, including (attach additional sheets as needed): 
• symptoms reported and when (dates) 
• results of scans, labs, or other procedures or tests 
• if hospital ED visit or admission, give dates and length of hospitalization 
• If Grade 5, indicate date of death, primary cause, if death certificate obtained, and if 
autopsy performed  
 
__________________________________________________________________________________ 
 
__________________________________________________________________________________ 
 
__________________________________________________________________________________ 
 
__________________________________________________________________________________ 
 
6. Following the event:   
• Was therapy discontinued?     
 No   
Yes 
N/A 
• Was dose modified?   
 
No        
Yes     
N/A 
 
If Yes, note modified dose(s): _____________________________________________________ 
 
__________________________________________________________________________________ 
 
7. Define the action plan and follow-up, including: 

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• Next visit and follow-up schedule if not per protocol 
• Referrals for tests, procedures, specialty or other clinics 
• Other pertinent information: 
__________________________________________________________________________________ 
__________________________________________________________________________________ 
__________________________________________________________________________________

Confidential                                                   Page 68 of 87                         
 
 
Protocol:   International Randomized Study of Transarterial Chemoembolization (TACE) versus 
Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual or 
Recurrent Hepatocellular Carcinoma after Initial TACE 
 
 
 
 
   Stanford eProtocol #: IRB-35937  
 
           OnCore #: HEP0052 
 
 
 
Participating Center: ___________________________________________      
 
Subject Log 
  # 
Subject Name 
Subject 
Initials 
Subject ID 
or OnCore # 
Date On-
Study (Date of 
Randomizatio
n) 
Treatment 
Arm 
Treatment 
Start Date 
(Day 1) 
Date  
Off-Study 
Reason Off-Study 
1  
 
  
 
 TACE 
 SBRT 
 
  
  
2 
 
 
 
  
 TACE 
 SBRT 
 
  
  
3   
 
  
  
 TACE 
 SBRT 
 
  
  
4   
 
  
  
 TACE 
 SBRT 
 
  
  
5   
 
  
  
 TACE 
 SBRT 
 
  
  
6 
  
 
  
  
 TACE 
 SBRT 
 
  
  
7   
 
  
  
 TACE 
 SBRT 
 
  
  
8   
 
  
  
 TACE 
 SBRT 
 
  
  
9   
 
  
  
 TACE 
 SBRT 
 
  
  
10   
 
  
  
 TACE 
 SBRT 
 
  
  

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11  
 
 
 
 TACE 
 SBRT 
 
 
 
12  
 
 
 
 TACE 
 SBRT 
 
 
 
 
Protocol:   International Randomized Study of Transarterial Chemoembolization (TACE) versus 
Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual or 
Recurrent Hepatocellular Carcinoma after Initial TACE 
 
 
   Stanford eProtocol #: IRB-35937  
 
OnCore #: HEP0052  
 
 
 
 Participating Center: ___________________________________________      
 
Protocol Deviation Log 
# 
Subject 
Initials 
Subject ID or  
OnCore # 
Date of 
Deviation 
Category 
(see next 
page) 
Code 
(see next 
page) 
Brief Description 
Date IRB 
notified, if 
applicable 
Corrective or Action Plan 
1  
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 

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10 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
 
 
Deviation Categories   
 
A.  Safety  
B.  Informed Consent   
C.  Eligibility 
D.  Protocol Implementation   
E.  Other, specify in log 
 
 
Deviation Codes (associated with Deviation categories) 
 
 
Safety (Category A) 
1. Not reporting SAE within 24 hours 
2. Laboratory tests not done 
3. AE/SAE not reported to IRB 
4. Other, specify on log 
 
 
Informed Consent  (Category B) 
 
Eligibility (Category C) 
12. Participant did not meet eligibility criteria 
13. Randomization of an ineligible patient 
14. Participant randomized prior to Baseline Assessment 
15. Randomization or treatment of a patient prior to IRB 
approval of protocol 
16. other, specify in log 
 
Protocol Implementation (category D) 

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5. Failure to obtain informed consent 
6. Consent form used was not current IRB approved 
version 
7. Consent form does not include updates or 
information required by IRB 
8. Consent form missing 
9. Consent form not signed and dated by participant 
10. Consent form does not contain all required 
signatures 
11. Other, specify in log 
 
17. Failure to keep IRB approval up to date 
18. Participant receives wrong treatment 
19. Participant seen outside of window visit 
20. Use of unallowable concomitant treatments 
21. Prescribed dosing outside of protocol guidelines 
22. Missed Assessment 
23. Missed Visit 
24. Other, specify in log 
 
 

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Protocol:   International Randomized Study of Transarterial Chemoembolization (TACE) versus 
Stereotactic Body Radiotherapy (SBRT) / Stereotactic Ablative Radiotherapy (SABR) for Residual or 
Recurrent Hepatocellular Carcinoma after Initial TACE 
 
 
Stanford eProtocol #:  IRB-35937                    OnCore #: HEP0052 
 
Participating Center: ___________________________________________      
Adverse Event (AE) Log 
# 
 
Subject 
Initials 
Subject ID or 
OnCore # 
Date of 
Event 
Expected 
(Yes or 
No) 
Category (Per 
CTCAE  
v 4) 
Grade (Per 
CTCAE  
v 4) 
Description if needed 
Date 
Reported 
to IRB, if 
applicable 
Action Taken 
or Follow-up 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 

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12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix V 
 
FACT-Hep 
Version 4 
 
 
 

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Appendix VI 
 
 
QOL – Quality of Life 
EQ-5D 
 
 
 

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Health Questionnaire 
 
(English version for the US) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© EuroQoL Group 1990 

© EuroQoL Group 1990 
2 
IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
By placing  a checkmark  in one box in each group below, please indicate  which 
statements best describe your own health state today. 
 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
 
Self-Care 
I have no problems with self-care 
 
I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
 
Usual Activities (e.g. work, study, housework, family or leisure 
activities) 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 

© EuroQoL Group 1990 
3 
IRB-35937 / Protocol Version 11, 21 September 2022 
 
 
Best 
imaginable 
health state 
 
 
 
To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the worst 
state you can imagine is marked 0. 
 
 
We would like you to indicate on this scale how good 
or  bad  your  own  health  is  today,  in  your  opinion. 
Please do this by drawing a line from the box below to 
whichever point on the scale indicates how good or bad 
your health state is today. 
 
 
 
 
 
 
 
 
Your own 
health state 
today 
100 
 
 
 
 
 
9 0 
 
 
 
 
8 
0 
 
 
 
 
7 
0 
 
 
 
 
6 
0 
 
 
 
 
5 
0 
 
 
 
 
4 
0 
 
 
 
 
3 
0 
 
 
 
 
2 0 
 
 
 
 
1 
0 
 
 
 
 
 
0 
 
Worst 
imaginable 
health state