Yttrium-90 Radiation Segmentectomy Versus Stereotactic Body Radiation Therapy (SBRT) for the Treatment of Early Stage Hepatocellular Carcinoma (HCC): A Pilot Study
Phase: NA
Conditions: Hepatocellular Carcinoma (HCC)
Sponsor: Indiana University

 
Protocol Version: 15DEC2021  
 
1 
 
 
 
 
 
Study Title 
Yttrium-90 Radiation Segmentectomy versus Stereotactic Body Radiation 
Therapy (SBRT) for the Treatment of Early Stage Hepatocellular 
Carcinoma (HCC): A Pilot Study 
 
Protocol Number: 
RADY-IUSCC-0725 
 
Principal Investigator: 
Paul Haste, MD  
Indiana University   
550 N University Blvd Indianapolis, IN 46202 
317 944 5005 
phaste@iupui.edu 
 
Co-Investigators:  
Ryan Rhome, MD PhD  
Mark Tann, MD 
Matthew Johnson, MD  
Maximillian Pyko, DO 
 
Study Statistician: 
Yong Zang, PhD 
 
Protocol Version: 
15 DEC 2021 
 
 

 
Protocol Version: 15DEC2021  
 
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TABLE OF CONTENTS 
 
1.0 
PROTOCOL SUMMARY ......................................................................................................... 5 
1.1 
Synopsis ................................................................................................................. 5 
1.2 
Schema .................................................................................................................. 7 
1.3 
Schedule of Events ................................................................................................ 8 
2.0 
BACKGROUND AND RATIONALE ......................................................................................... 10 
2.1 
Study Rationale ................................................................................................... 10 
2.2 
Background ......................................................................................................... 10 
2.3 
Risk/Benefit Assessment ..................................................................................... 10 
3.0 
STUDY DESIGN .................................................................................................................... 11 
4.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................. 11 
4.1 
Primary Objective ................................................................................................ 11 
4.2 
Secondary Objectives (SO)/ Secondary Endpoints (SE) ....................................... 11 
5.0 
STUDY POPULATION ........................................................................................................... 14 
5.1 
Inclusion Criteria ................................................................................................. 14 
5.2 
Exclusion Criteria ................................................................................................. 14 
5.3 
Strategies for Recruitment .................................................................................. 14 
6.0 
PATIENT REGISTRATION ..................................................................................................... 14 
7.0 
STUDY INTERVENTION ........................................................................................................ 15 
7.1 
Study Interventions ............................................................................................. 15 
 
Selective transarterial radioembolization (RS): ............................................ 15 
 
Stereotactic Body Radiation Therapy (SBRT): ............................................... 15 
7.2 
Measures to Minimize Bias: Randomization and Blinding .................................. 15 
7.3 
Concomitant Therapy .......................................................................................... 15 
8.0 
STUDY EFFICACY AND SAFETY ASSESSMENTS .................................................................... 15 
8.1 
Efficacy Assessments ........................................................................................... 15 
8.2 
Safety and Other Assessments ............................................................................ 16 
9.0 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ............................................................. 16 
9.1 
Study Intervention Not or Incompletely Performed ........................................... 17 
9.2 
Participant Discontinuation/Withdrawal from the Study ................................... 17 
9.3 
Lost to Follow-Up ................................................................................................ 17 
10.0 
STATISTICAL CONSIDERATIONS .......................................................................................... 17 
10.1 
Executive Summary ........................................................................................... 17 
10.2 
Statistical Hypotheses ....................................................................................... 17 

 
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Primary Objectives/Endpoints .................................................................... 17 
 
Secondary Objectives/Endpoints ................................................................ 18 
10.3 
Sample Size Projections .................................................................................... 19 
10.4 
Populations for Analyses ................................................................................... 19 
10.5 
Statistical Analyses ............................................................................................ 19 
 
General Approach ....................................................................................... 19 
 
Analysis of the Primary Endpoint(s) ............................................................ 20 
 
Analysis of the Secondary Endpoint(s) ........................................................ 20 
 
Safety Analyses ............................................................................................ 21 
11.0 
DATA SUBMISSION AND FORMS ........................................................................................ 21 
12.0 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ................................ 21 
12.1 
Informed Consent Process ................................................................................ 21 
 
Consent Procedures and Documentation ................................................... 21 
12.2 
Study Discontinuation and Closure ................................................................... 21 
12.3 
Confidentiality and Privacy ............................................................................... 22 
13.0 
ADVERSE EVENTS ............................................................................................................... 22 
13.1 
Definition of Adverse Events ............................................................................. 22 
 
Adverse Event (AE) ...................................................................................... 22 
 
Definition of Serious Adverse Events (SAE) ................................................. 23 
 
Determining Attribution to the Intervention(s) .......................................... 23 
13.2 
Expectedness ..................................................................................................... 23 
13.3 
Time Period and Frequency for Event Assessment and Follow-Up .................. 24 
13.4 
Reporting Adverse Events ................................................................................. 24 
 
Reporting to the IRB .................................................................................... 24 
 
Reporting the IUSCC Data Safety Monitoring Committee .......................... 25 
14.0 
DATA SAFETY MONITORING PLAN ..................................................................................... 26 
14.1 
Data and Safety Monitoring Committee ........................................................... 26 
14.2 
Study Auditing and Monitoring ......................................................................... 26 
14.3 
Data Management/ Oncore Reporting Requirements...................................... 26 
14.4 
Study Accrual Oversight .................................................................................... 27 
14.5 
Oncore Safety Reporting ................................................................................... 27 
14.6 
Protocol Deviation Reporting ............................................................................ 27 
15.0 
REFERENCES ....................................................................................................................... 28 
16.0 
Appendices ......................................................................................................................... 29 
16.1 
Appendix I Protocol Amendment History ......................................................... 30 

 
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16.2 
Appendix II COST FACIT Version 1 ..................................................................... 31 
16.3 
Appendix III FACT-G Version 4 .......................................................................... 34 
16.4 
Appendix IV Modified (mRECIST) ...................................................................... 39 
16.5 
Appendix V CTCAE Version 5.0 .......................................................................... 40 
16.6 
Appendix VI Screen Fail Form ........................................................................... 41 
16.7 
Appendix VII: SBRT Constraints ......................................................................... 42 
 

 
Protocol Version: 15DEC2021  
 
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1.0 PROTOCOL SUMMARY 
 
 Synopsis 
 
TITLE: 
Yttrium-90 Radiation Segmentectomy versus Stereotactic Body Radiation 
Therapy (SBRT) for the Treatment of Early Stage Hepatocellular Carcinoma 
(HCC): A Pilot Study 
STUDY 
DESCRIPTION: 
The proposed study is a single site, prospective, randomized pilot study to assess 
the feasibility of recruitment of patients into a trial evaluating the efficacy and 
tolerability of selective transarterial Y90 radioembolization (radiation 
segmentectomy) versus stereotactic body radiation therapy (SBRT) for solitary 
early stage (≤ 3cm) hepatocellular carcinoma (HCC). 
OBJECTIVES: 
Primary Objective: 
1. To assess feasibility as measured by screen failures and rate of 
recruitment into a randomized trial comparing RS and SBRT 
 
Secondary Objectives: 
1. To evaluate the proportion of patients with any toxicities (≥ grade 4) using 
CTCAE between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
2. To evaluate the mean change in hepatobiliary function, as measured 3 
months after treatment using a functional HIDA scan, between RS and SBRT for 
patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
3. To evaluate the mean change in patient-reported outcomes from baseline, at 
1, 3 and 6 months, between RS and SBRT, for patients with small (≤3 cm) 
solitary hepatocellular carcinoma (HCC), using the Functional Assessment of 
Cancer Therapy- General (FACT-G) and COST FACIT questionnaires. 
4. To evaluate the disease-free survival (DFS) rates of RS and SBRT at 2 years 
using mRECIST on CT or MR for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
5. To evaluate time-to-secondary treatment (TTST) between RS and SBRT for 
patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC) up to 2 
years after initial treatment. 
6. To measure the objective response rate (ORR) of radiation segmentectomy 
(RS) and stereotactic body radiation therapy (SBRT) as measured at 6 months 
using mRECIST (appendix IV) for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC) to better allow for an appropriately powered 
trial evaluating the efficacy of these treatments 

 
Protocol Version: 15DEC2021  
 
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ENDPOINTS: 
Primary Endpoint: Recruitment rates measured at 6 and 12 months 
and screen failures assessed by the detailed screen failure form at the 
time patients are approached for enrollment to ascertain specific 
reasons why patients may choose not to enroll 
Secondary Endpoints: 
1. Laboratory (CBC, CMP, INR)/clinical toxicities measured using CTCAE version 
5.0 
2. Change in % radiotracer extraction from baseline, on functional HIDA 
scan, 3 months after treatment 
3. Change in FACT-G and COST FACIT from baseline at 1, 3, and 6 months 
4. ORR at 6 months after completion of treatment using mRECIST on multiphase 
CT or MR. 
STUDY 
POPULATION: 
20 (up to 10 enrolled per arm) male or female patients with small (≤3 
cm) solitary hepatocellular carcinoma with relatively preserved liver 
function (CPS ≤ 7) 
PHASE: 
N/A 
DESCRIPTION OF 
STUDY 
INTERVENTION: 
The SBRT arm of the trial will involve standard SBRT delivered over 3-5 fractions 
as tolerated with dose/total therapy adjusted as needed for safety. 
The RS arm of the trial will involve a planning arteriogram followed by selective 
transarterial delivery of Yttrium-90 into the segmental (≤2) artery supplying the 
tumor. Administered activity will be an amount prescribed to deliver a dose 
≥200 Gy to the perfused tissue. 
STUDY DURATION: Estimated 12 months for accrual with another 24 months needed to 
complete secondary endpoints. 6 more months for data analysis. Total: 
66 months 
PARTICIPANT 
DURATION: 
24 months from therapy completion. (approximately 26 months from 
randomization) 

 
Protocol Version: 15DEC2021  
 
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 Schema 
 
 
 
 
 
 
 
 
Recruitment 
Screen potential participants by inclusion/exclusion criteria and tumor board consensus 
that either treatment arm is viable. If deemed a candidate for the trial, patient will be 
seen by IR/Rad Onc and then approached for potential enrollment. 
Radiation 
(RS) 
Stereotactic body 
Radiation therapy 
(SBRT) 
1 month 
(after treatment completion) 
Clinical and laboratory assessments (cbc, cmp, INR, afp). Repeat PROM obtained. 
Randomize 
RS vs. SBRT treatment 
Pre-treatment 
Treatment planning and nuclear medicine 
hepatobiliary scan. 
Screen Fail 
(captured on 
screen fail form) 
Baseline/Enrollment 
Baseline assessments performed by IR/Rad Onc at clinic visit as standard of care. 
PROM obtained using FACT-G and COST. 
3 months 
(after treatment completion) 
Clinical and laboratory assessments (cbc, cmp, INR afp). Repeat PROMs obtained. Follow up 
multiphase CT or MRI of Abdomen and nuclear medicine hepatobiliary scan. 
6 months 
(after treatment completion) 
Clinical and laboratory assessments (cbc, cmp, INR afp). Repeat PROM obtained. Follow up 
multiphase CT or MRI of Abdomen 
9-24 months 
(after treatment completion) 
Clinical and laboratory assessments (cbc, cmp, INR, afp). Follow up multiphase CT or MRI of 
Abdomen. Secondary endpoint measures obtained. Standard of care retreatment driven by 
imaging 

Protocol Version  24APR2020 
 
 
 
 Schedule of Events 
 
Procedures 
Enrollment
/ Baseline 
Pre-Treatment 
Intervention 
/Treatment 
1 month  
visit 
3 month  
visit 
6 month  
visit 
9 month  
visit  
12 month 
 visit 
15 month 
 visit 
18 month 
visit 
21 month 
 visit 
24 month 
 visit 
Within 30 
days from 
enrollment 
Within 45 days of 
pre- treatment 
visit procedures 
30 days 
 from end of 
treatment 
 (+/- 15 days) 
90 days  
from end of  
treatment 
 (+/- 30 days) 
180 days 
 from end of 
treatment 
(+/- 30 days) 
270 days 
from end of 
treatment 
(+/- 30 days) 
360 days 
from end of 
treatment 
(+/- 30 days) 
450 days  
from end of  
treatment  
(+/- 30 days) 
540 days 
from end of 
treatment 
(+/- 30 days) 
630 days 
 from end of 
treatment 
 (+/- 30 days) 
720 days 
 from end of 
treatment 
 (+/- 30 days) 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Randomization 
X 
Pregnancy Test 
(urine or 
serum)G 
X 
Planning/mappin
g arteriogramF 
X 
CT simulationE 
X 
Administer 
Study 
interventionc 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lab testsA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
event review 
and 
evaluationH 
X 
X 
X 
X 
X 
X 
Radiologic/Imagin
g assessmentD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete 
Case Report 
Forms (CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
            Protocol Version: 15DEC2021 
 
Functional 
Hepatobiliary 
Scan 
XB 
X 
Patient Reported 
Outcome 
Measures (FACT-
G, COST FACIT) 
X 
X 
X 
X 
A Complete Blood Count (CBC), Comprehensive Metabolic Profile (CMP), International normalized ratio (INR), and Alpha Fetoprotein (AFP). AFP will only continue to be drawn after baseline if initially elevated (>10 ng/mL) 
B Baseline functional hepatobiliary scan should be completed after enrollment, but prior to start of treatment. 
C SBRT Arm: Child Pugh A patients will receive a prescription dose of either 5000cGy in 5 fractions delivered every other day or 4800cGy in 3 fractions delivered twice weekly. Child Pugh B patients will receive a prescription dose of 4000cGy in 5 fractions 
delivered every other day. Patients will be seen at least once per week by a clinician to grade toxicities, with on-treatment labs (CBC, CMP, INR) each week. RS Arm: After planning arteriogram, subjects will return within 30 days to receive a single administration 
of Yttrium-90 into the segmental (≤2) artery supplying the tumor. Administered activity will be an amount prescribed to deliver a dose ≥200 Gy to the perfused tissue. 
D Multi-phase contrast enhanced CT or MR of the abdomen. Baseline imaging should be obtained within 3 months of enrollment 
E To be performed in patients receiving SBRT only prior to treatment 
F To be performed in patients receiving RS only prior to treatment 
G Required only in women of child bearing potential 
H Adverse events will be reviewed and collected from the time of informed consent until 30 days after the 6 month visit. See section 12.4 for details 
I SBRT arm only: Patients will be seen at least once per week by a clinician to grade toxicities during treatment, with on-treatment labs (CBC, CMP, INR) each week. 

 
Protocol Version 15DEC2021 
 
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2.0 BACKGROUND AND RATIONALE 
 
 Study Rationale 
Primary liver cancer is one of the five the most frequently diagnosed cancers in the world and is the second 
leading cause of cancer death worldwide. Early stage HCC (≤3 cm) is often treated by surgical resection 
with curative intent. Patients are often not candidates for surgery and there are multiple locoregional 
therapy options that exist as second line therapy options. Two of these options focus on directed radiation 
delivery to the tumors, either externally via SBRT or internally via transarterial radioembolization. There 
are currently limited data on differences in efficacy and safety between these modalities. At our 
institution, both of these treatments are offered as comparable first line options for unresectable HCC. A 
direct comparison of these two-radiation based locoregional therapies is therefore felt to be valuable. 
Unfortunately, the majority of published data with these treatments are retrospective, single institution 
studies. A direct comparison of the published results is made more difficult by the fact that most literature 
for radioembolization reports response rates using specific imaging response criteria (i.e. RECIST, 
mRECISCT, EASL) while most studies on SBRT report efficacy in terms of disease control rate. Given these 
limited data, with response rates reported using different criteria, a pilot study measuring ORR using the 
modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma criteria is proposed to better 
estimate the true ORR to help aid in the power calculation for a full trial. 
 
 Background 
Primary surgical resection remains the first-line treatment for small HCC (<3 cm) in patients with preserved 
liver function. Child-Pugh class A patients with small HCC have shown a 5-year overall survival rate around 
70% following surgical resection. Unfortunately, many patients are not eligible for surgical resection either 
secondary to tumor location, underlying portal hypertension or co-morbidities. The NCCN guidelines 
recommend surgical resection when possible, with locoregional therapy being recommended for patients 
who are not candidates for resection (recommending ablation, arterial directed therapies, and external 
beam radiation therapy as category 2B recommendations). 
 
There are no data directly comparing stereotactic body radiotherapy (SBRT) to high-dose segmental 
radioembolization (radiation segmentectomy). Both of these treatment approaches have relatively small 
published data sets demonstrating efficacy and relative safety, but a head-to-head comparison has yet to 
be performed. In addition to efficacy and toxicity, patient-reported outcomes (PROs) such as quality of life 
(QoL) and patient out-of-pocket cost of care should play a role in the choice of treatment of these patients. 
The majority of patients with HCC have chronic liver disease which may already affect their QoL. Many 
patients, particularly at our institution, also travel multiple hours for their treatments and the difference 
between the number of visits required for radioembolization and SBRT may affect their treatment choice 
and PROs. 
 
 Risk/Benefit Assessment 
There is very minimal risk outside the standard of care as both treatment options are currently utilized 
and have category 2B recommendations from the NCCN. Expected toxicities of both treatment arms 
include fatigue and potential worsening of liver function. 
 
The only added non-standard of care risk would be for RS patents surrounding their functional HIDA scan. 
The risks involved in a HIDA scan are minimal. They include the following: 

 
Protocol Version 15DEC2021 
 
11 
 
1. Radiation exposure; a very small amount of radioactive material is used and the radiation 
exposure is well below the level that causes adverse effects. 
2. Allergic reactions to the radioactive material; however, this is extremely rare, without 
documented cases. 
3. Discomfort, bruising or rash at the injection site or discomfort while lying on the table for the 
required amount of time for the scan. 
 
3.0 STUDY DESIGN 
The proposed study is a single site, prospective, randomized pilot study to assess the feasibility of 
recruitment of patients into a trial evaluating the efficacy and tolerability of selective transarterial Y90 
radioembolization (radiation segmentectomy) versus stereotactic body radiation therapy (SBRT) for solitary 
early stage (≤ 3cm) hepatocellular carcinoma (HCC). 
 
4.0 STUDY OBJECTIVES AND ENDPOINTS 
 
 Primary Objective 
To assess feasibility as measured by screen failures and rate of recruitment into a randomized trial 
comparing RS and SBRT 
 
Primary Endpoint: Recruitment rates measured at 6 and 12 months and screen failures assessed by the 
screen failure form at the time patients are approached for enrollment to ascertain specific reasons why 
patients may choose not to enroll 
 
 Secondary Objectives (SO)/ Secondary Endpoints (SE) 
 
1. SO: To compare the proportion of patients with toxicities (≥ grade 4) using CTCAE version 5.0 between 
RS and SBRT for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). Only those 
toxicities at least possibly related to treatment will be considered. 
SE: Laboratory (CBC, CMP, INR)/clinical toxicities measured using CTCAE version 5.0 up to 6 months 
post treatment. 
 
2. SO: To compare the mean change in hepatobiliary function, as measured 3 months after treatment 
using a functional HIDA scan, between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). SE: Change in % radiotracer extraction from baseline, on functional 
HIDA scan, 3 months after treatment 
 
3. SO: To compare the mean change in patient-reported outcomes (PROs) from baseline, at 1, 3 and 6 
months, between RS and SBRT, for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC), 
using FACT -G and COST FACIT questionnaires. SE: Change in FACT-G and COST FACIT from baseline 
at 1, 3 and 6 months 
 
4. SO: To compare the disease-free survival (DFS) rates of RS and SBRT at 2 years using mRECIST on CT or 
MR for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC).SE: DFS at 2 years after 
treatment completion as measured with mRECIST on CT or MR 
 
5. SO: To compare time-to-secondary treatment (TTST) between RS and SBRT for patients with small 
(≤3 cm) solitary hepatocellular carcinoma (HCC) up to 2 years after initial treatment. SE: TTST for 
target tumor up to 2 years following treatment. 

 
Protocol Version 15DEC2021 
 
6. SO: To measure the objective response rate (ORR) of radiation segmentectomy (RS) and stereotactic 
body radiation therapy (SBRT) as measured at 6 months using mRECIST (appendix IV) for patients 
with small (≤3 cm) solitary hepatocellular carcinoma (HCC) to better allow for an appropriately 
powered trial evaluating the efficacy of these treatments. SE: ORR at 6 months after completion of 
treatment using mRECIST on multiphase CT or MR.   
 
 
  Table 1: Justification for Endpoints 
OBJECTIVES 
ENDPOINTS 
JUSTIFCATION FOR ENDPOINTS 
Primary  
1. To assess feasibility as 
measured by screen failures 
and rate of recruitment into 
a randomized trial 
comparing RS and SBRT 
  
  
a. Recruitment rates measured at 
6 and 12 months 
 
b. Screen failure form 
 
 
a. Given the technical differences 
between the two modalities, 
recruitment may prove difficult so 
analyzing recruitment rates at 6 and 12 
months may reveal futility.  
b. Screen failure form will help PI assess 
feasibility for a larger scale study.   
  
Secondary   
1. To compare the proportion 
of toxicities (≥ grade 4) 
using CTCAE between RS 
and SBRT for patients with 
small (≤3 cm) solitary 
hepatocellular carcinoma 
(HCC). 
 
Laboratory (CBC, CMP, INR)/clinical 
toxicities measured using CTCAE 
Provide a measure of each treatment’s 
potentially deleterious effect on the 
surrounding liver parenchyma.   
2. To compare the change in 
hepatobiliary function, as 
measured 3 months after 
treatment using a 
functional HIDA scan, 
between RS and SBRT for 
patients with small (≤3 cm) 
solitary hepatocellular 
carcinoma (HCC).  
 
Change in % radiotracer extraction 
from baseline, on functional HIDA 
scan, 3 months after treatment  
 
Provide a measure of each treatment’s 
potentially deleterious effect on the 
surrounding liver parenchyma.   
3. To compare the change in 
patients reported outcomes 
from baseline, at 1, 3 and 6 
months, between RS and 
SBRT, for patients with 
small (≤3 cm) solitary 
hepatocellular carcinoma 
(HCC), using FACT-G and 
COST FACIT.  
 
 
Change in FACT-G and COST FACIT 
from baseline at 1, 3 and 6 months  
 
Provide insight into whether or not one 
treatment is more deleterious to a patient’s 
quality of life overall, as measured by the 
patient themselves. 

 
Protocol Version 15DEC2021 
4. To compare the disease-
free survival (DFS) rates of 
RS and SBRT at 2 years 
using mRECIST on CT or MR 
for patients with small (≤3 
cm)  
DFS at 2 years after treatment 
completion as measured with 
mRECIST on CT or MR  
DFS at 2 years will allow for assessment of 
both target and non-target recurrence in 
this population who are often prone to 
have new tumors secondary to cirrhosis.  
  
5. To compare time-to-
secondary treatment (TTST) 
between RS and SBRT for 
patients with small (≤3 cm) 
solitary hepatocellular 
carcinoma (HCC) up to 2 
years after initial 
treatment.   
TTST for target tumor up to 2 years 
following treatment.   
TTST will allow for some measure of the 
long term efficacy of the treatment as 
these tumors are often treated multiple 
times. 
6. To measure the objective 
response rate (ORR) of 
radiation segmentectomy 
(RS) and stereotactic body 
radiation therapy (SBRT) as 
measured at 6 months 
using mRECIST for patients 
with small (≤3 cm) solitary 
hepatocellular carcinoma 
(HCC).   
ORR at 6 months after completion of 
treatment using mRECIST on 
multiphase CT or MR.   
  
ORR is a common endpoint for the measure 
of efficacy of liver directed therapy. This 
may also help provide an estimate which 
will be used for the sample size calculation 
for the following large scale study  
   

 
Protocol Version 15DEC2021 
5.0 STUDY POPULATION 
 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to provide written informed consent and HIPAA authorization 
2. Stated willingness to comply with all study procedures and availability for the duration of 
the study 
3. Male or female, aged ≥ 18 years at time of informed consent 
4. Solitary HCC (≤3 cm) diagnosed by imaging (LI-RADS 4-5) or histology 
5. Childs-Pugh score ≤ 7 
6. ECOG performance status 0-1 
7. Tumor location/characteristics eligible for either SBRT or Y90 therapy as deemed by local 
tumor board 
8. Adequate organ function defined as: 
a. serum bilirubin < 4.0 mg/dL 
b. albumin > 2 g/dL 
 
 Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Any prior locoregional therapy to the target tumor 
2. Any prior radiation therapy to the liver 
3. Pregnancy or lactation: Women of childbearing potential must have a negative pregnancy 
test within 14 days of protocol registration. Women are considered to have childbearing 
potential (regardless of sexual orientation, having undergone a tubal ligation, or remaining 
celibate by choice) unless they meet one of the following criteria: 
i. Has undergone a hysterectomy or bilateral oophorectomy; or 
ii. Has been naturally amenorrheic for at least 24 consecutive months 
4. Known severe allergic reaction (anaphylaxis) to iodinated contrast 
5. Coagulopathy (platelets < 50 K/mm3 and/or INR > 2) not correctable by transfusion 
6. Macrovascular invasion or extrahepatic HCC 
 
 Strategies for Recruitment 
The majority of patients will be initially evaluated through the local liver tumor board. Currently, 1-2 
patients who fit criteria are presented most weeks. It is estimated that around 50-60 patients in a year’s 
time would be eligible. These patients will be set up to come to a multi-disciplinary clinic where they will 
have back-to-back clinic visits with both Interventional Radiology and Radiation Oncology on the same 
day. After both clinic visits are performed, a research coordinator (or if not available, an investigator) will 
approach eligible subjects and explain the trial and attempt enrollment. Direct referrals to either clinic 
who are eligible will also be seen by both specialties, and approached for the study, although this group 
will likely be much smaller than those discussed in tumor board. 
 
6.0 PATIENT REGISTRATION 
Patients who appear to be eligible for this trial will undergo the Informed Consent Process and be screened for 
eligibility utilizing the eligibility criteria. Eligible patients who complete the Informed Consent Process will be 
registered in the OnCore® database and assigned a patient ID number. Regulatory files will be maintained by 
the Department of Radiology. Applicable regulatory documents must be completed and on file prior to 
registration of any patients. 
 

 
Protocol Version 15DEC2021 
7.0 STUDY INTERVENTION 
 
 Study Interventions 
There are two comparative intervention arms, both of which are currently standard-of-care. 
 
Selective transarterial radioembolization (Radiation Segmentectomy (RS)): 
This therapy arm involves two separate steps, a planning/mapping arteriogram and a therapy delivery. 
The planning arteriogram will be performed to confirm arterial anatomy is acceptable for RS (≤2 
segment delivery) and that lung shunting is not too high to preclude treatment with RS. Once 
confirmed, patients will return for RS (within 45 days of mapping). Dose will be calculated based off the 
desired treatment volume using pre-treatment cross-sectional imaging. The desired segmental dose 
will be calculated to be ≥ 200Gy. RS will be performed by one of three separate interventional 
radiologists with experience in radioembolization. Actual administered activity and location of dose 
administration will be recorded. 
 
Stereotactic Body Radiation Therapy (SBRT): 
SBRT will be delivered with linear accelerator-based photon beams with either fixed angle non- 
coplanar fields or dynamic arcs. For treatment planning, CT simulation with triple phase IV contrast 
would be performed in the treatment position (supine, arms up). Tumor motion management would be 
assessed with 4D CT through the breathing cycle. Abdominal compression or breath-hold may be used 
at physician discretion for diaphragmatic excursion of 1cm or more. Available pre-treatment diagnostic 
imaging will be fused with the planning CT by deformable registration to assist in target and normal 
tissue delineation. An internal target volume (ITV) will be generated to account for tumor movement 
during breathing cycle. Finally, a planning target volume (PTV) will be an expansion of 3- 5mm from the 
ITV. For Child Pugh A patients, prescription dose will either be 5000cGy in 5 fractions delivered every 
other day or 4800cGy in 3 fractions delivered twice weekly. For Child Pugh B patients, prescription dose 
of 4000cGy in 5 fractions delivered every other day. Inverse planning will be used. 95% of the PTV or 
more will receive at least 100% of the prescription dose. Normal tissue dose constraints for each dose 
level will be respected with acceptable deviations permitted as outlined in appendix VII. Patients will 
be seen at least once per week by a clinician to grade toxicities, with on- treatment labs (CBC, CMP, 
INR) each week. 
 
 Measures to Minimize Bias: Randomization and Blinding 
Patients enrolling in trial will undergo permuted block randomization in groups of 4 at the time of 
enrollment. This will happen at the time of randomization using simple randomized opaque envelopes. 
Overall blinding is not feasible for this trial given that each arm features a different therapy administered 
in different departments of the hospital. Given that the primary endpoint is ORR at 6 months, a diagnostic 
radiologist reviewing for response (and DFS) will be blinded to the therapy arm. 
 
 Concomitant Therapy 
No active systemic therapy for the treatment of HCC will be allowed from the time of enrollment to the 
time of primary outcome assessment. Expected supportive medication generally given as standard of care 
with either therapy arm will be allowed. 
 
8.0 STUDY EFFICACY AND SAFETY ASSESSMENTS 
 
 Efficacy Assessments 
Patients will initially be flagged as potential candidates for the trial following a local tumor board 
discussion that the location and overall clinical picture would allow for either treatment as a viable option. 
Once tumor board agreement has been obtained, patients will be scheduled for a multi- disciplinary clinic 
visit where they will have a complete clinic visit with interventional radiology and radiation oncology back-

 
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to-back. If after these visits patients fulfill inclusion/exclusion criteria, they will immediately thereafter be 
approached by a research coordinator and enrollment will be attempted. 
 
If patients decline participation, a detailed screen fail form will be filled out to try and best ascertain 
reasons for declined participation. If the patient agrees to participate, they will be enrolled and 
randomized (as described above) at that time. 
 
A virtual/telehealth provision will be permitted for all follow-up visits. Since the virtual visit does not allow 
for effective physical exam of all body systems and vitals are unable to be obtained virtually, these 
elements will not be required during virtual visits. Labs will be obtained, however, as well as required 
imaging. If questionnaires are required during a virtual/telehealth visit, they may be administered via 
REDCap survey. 
 
Baseline: Labs, medical history/physical exam and PROs questionnaires will be obtained during the initial 
clinic visit prior to randomization. Subjects will be required to have an MRI or CT of the abdomen within 3 
months of enrollment. 
 
Pre-Treatment: Patients will return for functional hepatobiliary scan and treatment planning procedures 
prior to treatment (≤ 30 days from enrollment) 
 
Treatment: Patients will undergo treatment as described above in Section 7.1. 
 
Follow Up Visits: 
 
One month (± 15 days) after treatment completion patients will return for a clinic visit with labs (CBC, CMP, 
INR, AFP (if elevated at baseline)), physical exam, and PROs using FACT-G and COST FACIT. 
 
Three months after treatment completion (± 30 days) patients will return for a clinic visit with labs (CBC, 
CMP, INR, AFP (if elevated at baseline)), physical exam, and PROs using FACT-G and COST FACIT. Patients 
will also undergo multi-phase contrast enhanced CT or MR of the abdomen and functional hepatobiliary 
scan. 
 
Six months after treatment completion (± 30 days) patients will return for a clinic visit with labs (CBC, 
CMP, INR, AFP (if elevated at baseline)), physical exam, and PROs using COST FACIT and FACT-G. Patients 
will also undergo multi-phase contrast enhanced CT or MR of the abdomen and ORR will be measured by 
two separate abdominal radiologists, using mRECIST, who will have been blinded to the treatment 
received. 
 
9-24 months: Patients will continue to be followed every three months in clinic with labs, physical exam, 
and imaging per standard of care. Further intervention will be performed (if needed) as standard of care 
and DFS and TTST will be recorded up to 2 years from the completion of treatment. 
 
 
 Safety and Other Assessments 
Both treatment arms are currently being performed as standard of care. The PI will ultimately monitor 
safety with direct monitoring for AEs collected by research personnel with discussion with the PI as 
needed. Comparison of toxicities (≥ grade 4) will be performed as a secondary endpoint. The most 
common expected toxicities are fatigue and liver toxicity. 
 
9.0 PARTICIPANT DISCONTINUATION/WITHDRAWAL 

 
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Participants may withdraw voluntarily from the study, the PI may discontinue a participant from the study, 
or patients may be lost to follow-up. The overall estimation of total unanalyzable accruals is 10%. 
 
 Study Intervention Not or Incompletely Performed 
Study intervention arms both include a single treatment of the tumor, rather than an ongoing treatment. 
There is essentially one foreseeable area for necessary discontinuance in each arm. 
 
Patients in the RS arm could potentially be found to have arterial anatomy precluding RS (3 or more 
segmental arteries supplying tumor or high lung shunt). While this is felt unlikely, it would preclude them 
from RS and they will be unanalyzable and removed from study to receive off-protocol treatment. 
 
Patients in the SBRT arm will be monitored weekly for toxicities while on-treatment. While it is unexpected 
for patients to demonstrate toxicities that would preclude completion of the therapy cycle, if this were to 
occur, patients would be evaluated in the SBRT treatment arm, but designated to have had incomplete 
treatment. 
 
 Participant Discontinuation/Withdrawal from the Study 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may discontinue or withdraw a participant from the study for the following reasons: 
 
1. Pregnancy 
2. Significant study intervention non-compliance 
3. If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
4. The study is terminated (see section 12.1.2) 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). 
 
 Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she fails to return for 2 sequential scheduled 
visits and is unable to be contacted by the study site staff. 
 
10.0  STATISTICAL CONSIDERATIONS 
 
 Executive Summary 
The proposed study is a randomized pilot study evaluating feasibility as measured by screen failures and 
recruitment rate into a randomized trial comparing RS and SBRT. Secondary objectives will involve 
comparison of toxicities, effect on liver function, effect on patient reported outcomes and measurement 
of ORR of RS and SBRT to better allow for an appropriately powered trial evaluating the efficacy of these 
treatments.  DFS and TTST will also be measured up to 2 years after completion of initial treatment.   
 
 Statistical Analysis 
 Primary Objectives/Endpoints 
 
1. Primary Endpoint: Recruitment rates measured at 6 and 12 months and screen failures assessed by 
the detailed screen failure form at the time patients are approached for enrollment to ascertain specific 
reasons why patients may choose not to enroll 
 

 
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Primary Objective: To assess feasibility as measured by screen failures and rate of recruitment into a randomized 
trial comparing RS and SBRT for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
 
 Secondary Objectives/Endpoints 
 
1. SE: Laboratory (CBC, CMP, INR)/clinical toxicities measured using CTCAE version 5.0 
 
SO: To compare the proportion of any toxicities (≥ grade 4) using CTCAE version 5.0 between RS 
and SBRT for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC) up to 6 months 
after treatment. 
 
NH: The proportion of any toxicities (≥ grade 4), using CTCAE version 5.0, between RS and SBRT for 
patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC) are equal. 
 
AH: The proportion of any toxicities (≥ grade 4), using CTCAE version 5.0, between RS and SBRT for 
patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC) are not equal. 
 
2. SE: Change in % radiotracer extraction from baseline, on functional HIDA scan, 3 months after 
treatment 
 
SO: To compare the mean change in hepatobiliary function, as measured 3 months after treatment 
using a functional HIDA scan, between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
 
NH: The mean change in hepatobiliary function, as measured 3 months after treatment using a 
functional HIDA scan, will be equal between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
 
AH: The mean change in hepatobiliary function, as measured 3 months after treatment using a 
functional HIDA scan, will not be equal between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
 
3. SE: Change in FACT-G and COST FACIT from baseline at 3 and 6 months 
 
SO: To compare the mean change in patient-reported outcomes from baseline, at 3 and 6 months, 
between RS and SBRT, for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC), using 
FACT-G and COST FACIT. 
 
NH: The mean change in patient-reported outcomes from baseline, at 1, 3 and 6 months, will be 
equal between RS and SBRT, for patients with small (≤3 cm) solitary hepatocellular carcinoma 
(HCC), using FACT-G and COST FACIT. 
 
AH: The mean change in patient-reported outcomes from baseline, at 1, 3 and 6 months, will not 
be equal between RS and SBRT, for patients with small (≤3 cm) solitary hepatocellular carcinoma 
(HCC), using FACT-G and COST FACIT. 
 
4. SE: DFS at 2 years after treatment completion as measured with mRECIST on CT or MR 
 
SO: To compare the disease-free survival (DFS) rates of RS and SBRT at 2 years using mRECIST on 
CT or MR for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 

 
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NH: The disease-free survival (DFS) rates will be equal between RS and SBRT at 2 years using 
mRECIST on CT or MR for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
 
AH: The disease-free survival (DFS) rates will not be equal between RS and SBRT at 2 years using 
mRECIST on CT or MR for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
 
5. SE: TTST for target tumor up to 2 years following treatment. 
 
SO: To compare time-to-secondary treatment (TTST) between RS and SBRT for patients with 
small (≤3 cm) solitary hepatocellular carcinoma (HCC) up to 2 years after initial treatment. 
 
NH: The time-to-secondary treatment (TTST) between RS and SBRT for patients with small (≤3 
cm) solitary hepatocellular carcinoma (HCC) up to 2 years after initial treatment will be equal. 
 
AH: The time-to-secondary treatment (TTST) between RS and SBRT for patients with small (≤3 cm) 
solitary hepatocellular carcinoma (HCC) up to 2 years after initial treatment will not be equal. 
 
6. SE:  ORR at 6 months after completion of treatment using mRECIST on multiphase CT or MR.   
 
SO: To evaluate the objective response rate (ORR) of radiation segmentectomy (RS) and stereotactic 
body radiation therapy (SBRT) as measured at 6 months using mRECIST for patients with small (≤3 
cm) solitary hepatocellular carcinoma (HCC).   
  
NH: The objective response rates (ORR) of radiation segmentectomy (RS) and stereotactic body 
radiation therapy (SBRT) are equal, as measured at 6 months using mRECIST for patients with small 
(≤3 cm) solitary hepatocellular carcinoma (HCC).  
  
AH: The objective response rates (ORR) of radiation segmentectomy (RS) and stereotactic body 
radiation therapy (SBRT) are not equal, as measured at 6 months using mRECIST for patients with 
small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
 
 Sample Size Projections 
The primary objective of the pilot study will be to access feasibility. 20 patients in total will be enrolled, 
with up to 10 patients per arm (depending on the amount of screen fails). These numbers should be 
sufficient for the assessment of feasibility. 
 
 Populations for Analyses 
The study will be performed as a modified Intention-to-treat analysis. Patients who were randomized to 
the radiation segmentectomy arm, but were later found to be to ineligible for RS based on the planning 
arteriogram findings, will be considered unanalyzable as they will have not received any protocol therapy 
and will proceed to other standard of care therapy. If this were to occur, a replacement patient will be 
added into the RS arm to help ensure a total of 10 patients in each arm. 
 
 Statistical Analyses 
 General Approach 
The general approach to the statistical analysis will involve the use of Fisher’s exact test, with 
corresponding 95% CIs, to present comparative outcomes between the two arms. A two-sample t- test 
will be used to analyze outcomes comparing mean changes in liver function and Kaplan-Meier estimates 
with a log rank analysis used for survival comparison. The descriptive statistics such as mean, median, 

 
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standard deviation and exact confidence interval for the primary endpoint (e.g., recruitment rate and 
screen failures) will be provided. 
 
A planned interim analysis looking at feasibility will be performed at 6 months after the study is open to 
enrollment. A similar analysis will also be performed at 12 months. The purpose of these analyses will 
be to evaluate the endpoint for all subjects who have reached it, and to evaluate general recruitment 
rates to assess feasibility/futility. 
 
 Analysis of the Primary Endpoint(s) 
The primary research question to be addressed is to measure feasibility in terms of recruitment rate 
and screen failures. Recruitment rate will be measured at 6 and 12 months and screen failures assessed 
by the detailed screen failure form at the time patients are approached for enrollment to ascertain 
specific reasons why patients may choose not to enroll. Of note, analysis of the screen fail forms will 
serve as an instructive tool for the investigators as to feasibility for a larger scale study. The granular 
data collected from the screen fail forms is not intended for publication.  
 
 Analysis of the Secondary Endpoint(s) 
The secondary research questions to be addressed are as follows: 
 
1. To compare the proportion of any toxicities (≥ grade 4) using CTCAE between RS and SBRT for 
patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC). 
 
The proportion of patients with toxicities will be provided along with corresponding 95% 
confidence intervals. Toxicity rates will be compared using a Fisher’s Exact Test. 
 
2. To compare the mean change in hepatobiliary function, as measured 3 months after treatment 
using a functional HIDA scan, between RS and SBRT for patients with small (≤3 cm) solitary 
hepatocellular carcinoma (HCC). 
 
A two-sample t-test will be used to analyze mean changes in liver function as measured by 
functional HIDA scan. 
 
3. To compare the mean change in patient-reported outcomes from baseline, at 3 and 6 months, 
between RS and SBRT, for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC), using 
FACT-G and COST FACIT. 
 
A two-sample t-test will be used to analyze mean changes in patient reported outcomes as 
measured using FACT-G and COST FACIT. 
 
4. To compare the disease-free survival (DFS) rates of RS and SBRT at 2 years using mRECIST on CT or 
MR for patients with small (≤3 cm) solitary hepatocellular carcinoma (HCC).  
 
DFS rates will be compared using Kaplan-Meier estimates with a log rank analysis. 
 
5. To compare time-to-secondary treatment (TTST) between RS and SBRT for patients with small (≤3 
cm) solitary hepatocellular carcinoma (HCC) up to 2 years after initial treatment.  
 
TTST rates will be compared using Kaplan-Meier estimates with a log rank analysis. 
 

 
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6. The proportion of patients with ORR at 6 months will be provided along with corresponding 95% 
confidence intervals. ORR rates will be compared using a Fisher’s Exact Test. 
 
 Safety Analyses 
Toxicity will be measured as a secondary outcome using CTCAE version 5.0. Adverse event 
monitoring will occur throughout the duration of the study and will be performed by research 
coordinators and investigators. 
 
11.0 DATA SUBMISSION AND FORMS 
REDCap (Research Electronic Data Capture) database system will be implemented to collect data for this 
study. The servers hosting REDCap are administered and supported by Indiana University’s University 
Information Technology Services (UITS) and are physically located in IU’s secured and environmentally 
structured data center on the IU Bloomington campus. To comply with HIPAA guidelines, physical, 
administrative, and technical safeguards and on ongoing risk management framework have been 
implemented and documented (NIST 800-53) to ensure the security and protection of the study data within 
the data center, the servers, and the database. REDCap is a software toolset developed by Vanderbilt 
University, with collaboration from a consortium of institutional partners, for electronic collection and 
management of research and clinical trial data. Indiana University has joined thisconsortium and has 
implemented REDCap within the Indiana University’s central Information Technology Services (UITS) technical 
environment to enable rapid development and deployment of electronic data capture and reporting to 
support specific clinical and translational research projects. Access to the password-protected database will 
be limited to the investigators of this study, and any data that is distributed will be either de-identified or 
authorized by written permission from participants. All source documents are to remain in the patient’s clinic 
file. All documents should be kept according to applicable federal guidelines. Clinical trial data in REDCap will 
be periodically monitored by the IU Simon Cancer Center Data Safety Monitoring Committee.  
 
12.0 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 Informed Consent Process 
 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator or research personnel will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the participant’s 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written consent form 
and ask questions prior to signing. The participants should have the opportunity to discuss the study 
with their family or surrogates or think about it prior to agreeing to participate. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the study 
at any time, without prejudice. A copy of the informed consent document will be given to the participants 
for their records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 
 Study Discontinuation and Closure 

 
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This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. 
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform 
study participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of changes 
to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
● Determination of unexpected, significant, or unacceptable risk to participants 
● Demonstration of efficacy that would warrant stopping 
● Insufficient compliance to protocol requirements 
● Data that are not sufficiently complete and/or evaluable 
● Determination that the primary endpoint has been met 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and/or IRB. 
 
 Confidentiality and Privacy 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third 
party without prior written approval of the investigator. 
 
Each subject in the database will be assigned a unique study identification (ID) number. Patient- derived 
material will be linked to patient clinical information through this study ID number. Data from the 
participant’s medical record will be manually entered into the participant’s de-identified study database 
and never stored in its original form, ensuring that the data cannot be traced back the actual participant 
in the event of a data breach. Data will be stored on the University’s approved, encrypted back-up servers. 
The data will be maintained in the database for at least ten (10) years after collection. Records and/or 
data extracted from the database will be identified by the subject study ID number only and without any 
accompanying individually identifiable patient information. Thus, the code to the study identification 
numbers will be accessible only to the PI and authorized study personnel. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored in a secure database. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by the 
unique study identification number. The study data entry and study management systems will be secured 
and password protected. At the end of the study, all study databases will be de-identified and archived. 
 
All paper study materials will be stored in a locked cabinet that will only be accessed by IRB approved staff. 
Only IRB approved staff will have access to data from the participant’s medical records. All research 
activities will be conducted in as private a setting as possible. 
 
The study monitor, principal investigator, study team, representatives of the Institutional Review Board 
(IRB), and regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. 
 
13.0 ADVERSE EVENTS 
 
 Definition of Adverse Events 
 Adverse Event (AE) 

 
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An adverse event is defined as an untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention related. An adverse event can be ANY 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporarily associated with the use of an intervention, whether or not considered related to the 
intervention (attribution of ‘unrelated’, ‘unlikely’, ‘possible’, ‘probable’, or ‘definite’). Adverse events will 
be graded according to CTCAE version 5.0 
 
 Definition of Serious Adverse Events (SAE) 
A serious adverse event is any untoward medical occurrence resulting in one or more of the following: 
 
1. Results in death or ANY death occurring within 30 days of treatment 
2. Is life-threatening (defined as an event in which the patient was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
3. Requires inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
NOTE: Hospitalizations that are not considered SAEs are: 
 
Hospitalization planned prior to biopsy procedure 
 
Hospitalization < 24 hours in duration 
 
Hospitalization for elective treatment of a pre-existing condition unrelated to 
biopsy procedure. 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly or birth defect 
6. Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above). Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions not resulting in 
hospitalization; or the development of drug dependency or drug abuse. 
 
  Determining Attribution to the Intervention(s) 
Attribution is an assessment of the relationship between the AE and the medical intervention. CTCAE 
does not define an AE as necessarily “caused by a therapeutic intervention”. After naming and grading the 
event, the clinical investigator must assign an attribution to the AE using the attribution categories in 
Table 2 below. 
 
Table 2: Determining Attribution 
Relationship 
Attribution 
Description 
Unrelated to investigational 
intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related 
to 
investigational 
intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 
     Expectedness 

 
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The principal investigator will be responsible for determining whether an adverse event (AE) is expected 
or unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the study intervention. 
 
  Time Period and Frequency for Event Assessment and Follow-Up 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care or 
upon review of the medical record. 
 
Adverse events will be recorded with start dates occurring any time after informed consent is obtained until 
7 (for non-serious AEs) or up to 30 days (for SAEs) after the 6 month visit. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for 
outcome information until adequate resolution or stabilization. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, relationship to study product (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
 REPORTING ADVERSE EVENTS 
Adverse events will be recorded from the time of informed consent and for 30 days after the 6 month visit 
regardless of whether or not the event(s) are considered related to the study procedure. All AEs 
considered related to study procedures will be followed until resolution, return to baseline, or deemed 
clinically insignificant, even if this is after the 6 month visit Any death occurring within 30 days after 
intervention must be reported as an SAE regardless of attribution. 
 Reporting to the IRB 
Unanticipated problems involving risks to subjects or others will be reported promptly to the IRB if they: 
 
1. are unexpected; 
2. are related or possibly related to participation in the research; and 
3. suggest that the research places subjects or others at a greater risk of harm than was 
previously known or recognized. 
 
If the serious adverse event does not meet all three (3) criteria listed above, the event does not have to 
be promptly reported to the Indiana University IRB. However, it should be reported at the time of 
continuing review. 
 
Prompt reporting of unanticipated problems to the IRB is defined as within 5 days from becoming aware 
of the event. 

 
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 Reporting the IUSCC Data Safety Monitoring Committee 

 
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Regardless of study sponsorship, the study team must enter all initial and follow-up SAE, expedited, and 
noncompliance reports into OnCore® for review by the DSMC chair and/or coordinator. Expedited reports 
may include IRB Prompt Report Forms and additional SAE forms as required by the sponsor. When follow-
up information is received, a follow-up report should also be created in OnCore®. This DSMC reporting 
requirement is in addition to any other regulatory bodies to be notified (i.e. IRB, FDA, pharmaceutical 
company, etc.). The DSMC chair and/or coordinator will review all SAE, expedited, and noncompliance 
reports monthly and findings will be reported to the full DSMC quarterly. See section 14.5 for additional 
details 
 
14.0 DATA SAFETY MONITORING PLAN 
This study will be conducted in accordance with the IU Simon Cancer Center Institutional DSMP for  
Moderate Risk Trials. 
 
Investigators will conduct continuous review of data and subject safety. Monthly review meetings for 
moderate risk trials are required and will include the principal investigator, clinical research 
specialist/coordinator and/or research nurse (other members per principal investigator’s discretion). 
Monthly meeting summaries should include review of data, the number of subjects, significant toxicities as 
described in the protocol, and responses observed. Study teams should maintain meeting minutes and 
attendance for submission to the DSMC upon request. 
 
 Data and Safety Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of subject safety, 
regulatory compliance, and data integrity for this trial. The DSMC will review this study annually to review 
overall trial progress, toxicity, compliance, data integrity, and accrual per the Institutional DSMP. 
 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), deviations, 
reportable events, and any other outstanding business. Major issues may require further DSMC review or 
action. 
 
For any increase in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the principal investigator will notify the DSMC Chair immediately. 
The notification will include the incidence of study adverse events, grades, and attributions, as well as 
investigator statements regarding comparison with risks per the IB/ package insert. 
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or benefits) 
to the subject warrant early closure of the study, the DSMC Chair and Compliance Officer must be notified 
within 1 business day via email, and the IRB must be notified within 5 business days. Alternatively, the 
DSMC may initiate suspension or early closure of the study based on its review. 
 
 Study Auditing and Monitoring 
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the Institutional DSMP. 
Reports will be reviewed by the full DSMC at the time of study review. 
 
 Data Management/ Oncore Reporting Requirements 

 
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The DSMC will review data and study progress directly from Oncore and REDCap; therefore, timely data 
entry and status updates are vital. Study data must be entered promptly, no later than one week from 
study visit occurrence. Subject status in Oncore will be updated in real time, as this may affect overall trial 
enrollment status. Global SAEs and deviations will be reviewed on a monthly basis by the DSMC Chair 
directly from Oncore. 
 
 Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol Progress 
Committee (PPC) reviews study accrual twice per year, while the PPC coordinator reviews accrual 
quarterly. 
 
 Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events (SAEs) will be 
captured in the Oncore system within 1 business day of notification. Initial SAE reporting will include as 
much detail as available, with follow-up to provide complete information. Attributions will be assessed to 
study drugs, procedures, study disease, and other alternate etiology. 
 
 Protocol Deviation Reporting 
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the DSMC Chair 
on a monthly basis. Findings will be reported to the full DSMC at the time of study review. For serious or 
repetitive protocol deviations, additional action may be required by the DSMC.

 
Protocol Version 15DEC2021 
 
 
15.0 REFERENCES 
 
1. 
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012: 
Global Cancer Statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87–108. 
 
2. 
www.cancer.org (2017). 
 
3 
Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. 
Semin. Liver Dis. 1999;19 (03): 329-38. 
 
4. 
Poon RT-P, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after 
resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a 
strategy of salvage transplantation. Ann Surg. 2002;235(3):373–382. 
 
5. 
D.L. Andolino, C.S. Johnson, M. Maluccio, et al. Stereotactic body radiotherapy for primary 
hepatocellular carcinoma. Int J Radiat Oncol Biol Phys, 81 (2011), pp. e447-e453 
 
6. 
N Sanuki, A Takeda, Y Oku et al. Stereotactic body radiotherapy for small hepatocellular 
carcinoma: A retrospective outcome analysis in 185 patients, Acta Oncologica, 53:3, 399-404. 
 
7. 
A. Riaz, V.L. Gates, B. Atassi, et al. Radiation segmentectomy: a novel approach to increase 
safety and efficacy of radioembolization. Int J Radiat Oncol Biol Phys, 79 (2011), pp. 163-171 
 
8. 
M. Vouche, A. Habib, T.J. Ward, et al. Unresectable solitary hepatocellular carcinoma not 
amenable to radiofrequency ablation: multicenter radiology-pathology correlation and survival of 
radiation segmentectomy. Hepatology, 60 (2014), pp. 192-201 

 
Protocol Version 15DEC2021 
16.0 Appendices 
16.1 Appendix I Protocol Amendment History 
16.2 Appendix II COST FACIT Questionnaire 
16.3 Appendix III FACT-G Questionnaire 
16.4 Appendix IV mRECIST Criteria 
16.5 Appendix V CTCAE Version 5.0 Criteria 
16.6Appendix VI Screen Fail Form 
16.7 Appendix VII SBRT Constraints

 
Protocol Version 15DEC2021 
 Appendix I Protocol Amendment History 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page. 
 
Version 
Date 
Description of Change 
Brief Rationale 

 
Protocol Version 15DEC2021 
 Appendix II COST FACIT Version 1 

 
Confidential 
 
COST FACIT Version 1 
 
y90 vs sbrt 
Page 1 of 1 
 
 
 
 
Study ID 
 
 
 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
I know that I have enough 
                           
                                    
                        
                               
                                                                                                                money in savings, retirement, or 
assets to cover the costs of my 
treatment 
 
My out-of-pocket medical 
                           
                                    
                        
                               
                                                                                                             expenses are more than I 
thought they would be 
 
I worry about the financial 
                           
                                    
                        
                               
 problems I will have in the future 
as a result of my illness or 
treatment 
 
I feel I have no choice about the 
                           
                                    
                        
                               
                                                                                                     amount of money I spend on 
care 
 
I am frustrated that I cannot 
                           
                                    
                        
                               
 work or contribute as much as I 
usually do 
 
I am satisfied with my current 
                           
                                    
                        
                               
                                                                                                   financial situation 
I am able to meet my monthly 
                           
                                    
                        
                               
                                                                                                 expenses 
I feel financially stressed 
                           
                                    
                        
                               
 
I am concerned about keeping 
                           
                                    
                        
                               
                                                                                                               my job and income, including 
work at home 
 
My cancer or treatment has 
                           
                                    
                        
                               
                                                                                                           reduced my satisfaction with my 
present financial situation 
 
I feel in control of my financial 
                           
                                    
                        
                               
 situation 
 
 
 
 
 
 
English (Universal) Copyright 2014, FACIT and The University of Chicago 
 
 
 
 
 
 
 
Below is a list of statements that other people with your illness have said are important. 
Please mark one answer per line to indicate your response as it applies to the past 7 days. 

 
 
 
11/08/2019 9:18am 
projectredcap.org 

 
 Appendix III FACT-G Version 4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version 24APR2020 

11/08/2019 9:18am 
projectredcap.org 
 
 
Confidential 
 
FACT-G (Version 4) 
 
y90 vs sbrt 
Page 1 of 4 
 
 
 
 
Study ID 
 
 
 
 
I have a lack of energy 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I have nausea 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
Because of my physical condition, I have trouble 
0 - Not at all 
meeting the needs of my family 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I have pain 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am bothered by side effects of treatment 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I feel ill 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am forced to spend time in bed 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
Below is a list of statements that other people with your illness have said are important. 
Please choose one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 

 
 
Confidential 
 
Page 2 of 4 
 
 
 
I feel close to my friends 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I get emotional support from my family 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I get support from my friends 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
My family has accepted my illness 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am satisfied with family communication about my 
0 - Not at all 
illness 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I feel close to my partner (or the person who is my 
0 - Not at all 
main support) 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
Regardless of your current level of sexual activity, 
 I prefer not to answer 
please answer the following question. 
 
I am satisfied with my sex life 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
 
 
I feel sad 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
SOCIAL/FAMILY WELL-BEING 
Please choose one number per line to indicate your response as it applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 

 
 
Confidential 
 
Page 3 of 4 
 
 
I am satisfied with how I am coping with  my illness 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am losing hope in the fight against my illness 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I feel nervous 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I worry about dying 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I worry that my condition will get worse 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
 
 
I am able to work (include work at home) 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
My work (include work at home) is fulfilling 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am able to enjoy life 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I have accepted my illness 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
FUNCTIONAL WELL-BEING 

 
 
Confidential 
 
Page 4 of 4 
 
 
I am sleeping well 
0 - Not at all 
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am enjoying the things I usually do for fun 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
I am content with the quality of my life right now 
0 - Not at all  
1 - A little bit 
2 - Somewhat 
3 - Quite a bit 
4 - Very much 
 
 
 
 
 
 
Copyright © 2010 FACIT.org 

Protocol Version24APR2020  
 
 
 Appendix IV Modified (mRECIST) Criteria Assessment for Hepatocellular Carcinoma 
 
An electronic copy of the mRECIST critieria can be found at the following website: 
https://imaging.cancer.gov/clinical_trials/docs/mRECIST%20for%20HCC%202010.pdf 

 
Version 24 APR 2020 
 Appendix V CTCAE Version 5.0 
 
An electronic copy of the CTCAE version 5.0 is available on the CTEP web site at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 

 
Version 24 APR 2020 
 Appendix VI Screen Fail Form 
 
 
SCREEN FAIL FORM 
 
Date:   
 
 
Initials of person completing form:   
 
 
 
If subject refuses consent, please select a reason why and provide available details: 
 
 
 
□ Not Interested (prefers not to be on a research trial, prefers one treatment to another etc.) 
 
 
 
 
 
□ Does not have time (i.e. lives too far away, work schedule, etc.) 
 
 
 
 
 
□ Prefers not to answer 
 
□ Other 
 
 
 
 
 
 
 
 
 
 
 

 
Version 24 APR 2020 
 Appendix VII: SBRT Constraints 
 
Desired SBRT Constraints: 
Structure 
Volume 
Dose / Constraint 
PTV 
>95% 
Rx 
GTV 
>98% 
>110% Rx 
Liver – GTV 
700cc or 
V10 Gy 
<1500cGy or 
<70% 
1/3 uninvolved 
<1000cGy (CTP-A), 
<1800cGy (CTP-B7) 
500cc uninvolved 
<700cGy (CTP-A), 
<1200cGy (CTP-B7) 
Duodenum 
0.5 cc 
2400 cGy (3 fraction) 
3000 cGy (5 fraction) 
<5 cc 
1650 cGy (3 fraction) 
1800 cGy (5 fraction) 
<10 cc 
1140 cGy (3 fraction) 
1250 cGy (5 fraction) 
Stomach 
0.5 cc 
2250 cGy (3 fraction) 
3000 cGy (5 fraction) 
Esophagus 
0.5 cc 
32 Gy (5 fx) 
Spinal Cord 
100% 
<600cGy/fraction 
Chest Wall 
100% 
<5000cGy 
<5cc 
4000cGy 
<30cc 
3000cGy 
R Kidney 
2/3 
<2000cGy 
L kidney 
1/3 
<1500cGy 
Heart 
0.5 cc 
3000 cGy (3 fraction) 
5250 cGy (5 fraction) 
 
 
Variation acceptable Constraints (per RTOG 1112) 
Structure 
Variation acceptable 
Deviation unacceptable 
Esophagus max (0.5 cc) 
>32 but ≤34 Gy 
>34 Gy 
Stomach max (0.5 cc) 
>30 but ≤32 Gy 
>32 Gy 
Duodenum max (0.5 cc) 
>30 but ≤32 Gy 
>32 Gy 
Small bowel max (0.5 cc) 
>30 but ≤32 Gy 
>32 Gy 
Large bowel max (0.5 cc) 
>32 but ≤34 Gy 
>34 Gy 
Spinal cord + 5 mm max (0.5 cc) 
>25 but ≤28 Gy 
>28 Gy 
Kidneys: bilateral mean 
>10 but ≤12 Gy 
>12 Gy