The Impact of 90Yttrium (Y90) Radiation Segmentectomy on Hepatocellular Carcinoma and Cirrhosis
Phase: NA
Conditions: Hepatocellular Carcinoma
Sponsor: Icahn School of Medicine at Mount Sinai

The Impact of 90Yttrium (Y90) Radiation Segmentectomy on Hepatocellular 
Carcinoma and Cirrhosis
PI: Aaron M Fischman, MD
NCT03248375
Document Date: 9/5/2017

 
 
 
 
 
 
 
 
 
 
Study title: 
   
 
 
The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
Carcinoma 
  
 
Investigators:  
  
 
 
Edward Kim MD, PI 
Aaron Fischman, MD 
Scott Nowakowski, MD 
Rahul Patel, MD 
Robert Lookstein, MD 
Sherif Heiba, MD 
Josef Machac, MD 
Karin Knesaurek, PhD 
Myron Schwartz, MD 
Marcelo Facciuto, MD 
Bachir Taouli MD 
Gene Im, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
Carcinoma  
 
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Contact information: 
 
Edward Kim 
Assistant Professor of Radiology and Surgery 
Department of Vascular and Interventional Radiology 
Icahn School of Medicine at Mount Sinai 
(212)241-7409 
Edward.Kim@mountsinai.org

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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PROTOCOL SYNOPSIS 
 
Protocol Title:  The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable 
Hepatocellular Carcinoma  
 
Type of Protocol:   Phase I protocol to collect efficacy 
 
Protocol Design:  Prospective, open-label, single arm study. 
 
Study Objective:  The aim of this pilot study is to assess the efficacy of radiation 
segmentectomy with Theraspheres in patients with unresectable hepatocellular carcinoma 
that would qualify for thermal ablation as per the BCLC guidelines, but are unable to 
receive thermal ablation due to unfavorable location of target lesions. 
 
Primary Endpoint:  Efficacy of 90Yttrium (Y90) Radiation Segmentectomy on 
Unresectable Hepatocellular Carcinoma as measured by tumor response according to 
mRECIST based on investigator evaluations. 
 
Secondary Endpoints:   
 Time to Progression (TTP):  The length of time from radiation segmentectomy 
until progression of disease based on mRECIST based on investigator 
evaluations. 
 Assess toxicity resulting from Radiation Segmentectomy with Theraspheres 
 
Trial Population:  Patients diagnosed with Hepatocellular Carcinoma as per AASLD 
guidelines and not eligible for surgical resection or thermal ablation. 
 
Number of Patients: 30 
 
Study Duration: 2 years accrual and 2 years follow-up for a total of 4 years duration. 
 
Eligibility Criteria:  
 
1. Age greater than 18 years, regardless of race or gender 
2. Hepatocellular Carcinoma confirmed by histology for non-cirrhotic patients or non-
invasive criteria according to AASLD for cirrhotic patients. 
3. Child-Pugh class A or B7 without ascites 
4. Single tumor nodule ≤ 3 cm with a maximum distance of 5 mm from either portal 
vein, hepatic vein, inferior vena cava, diaphragm, heart, stomach, bowel, liver 
capsule, gallbladder, bile duct. 
5. No prior locoregional treatment or external beam therapy of current HCC (recurrent 
HCC after resection may be included) 
6. No confirmed extrahepatic metastases 
7. No evidence of macrovascular invasion 
8. ECOG 0 
9. Albumin > 3.0 g/dL 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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10. PLT ≥ 40 x103/μL 
11. WBC ≥ 1.5 x103/μL 
12. AST/ALT ≤ 5 times the upper limit of normal (U/L) 
13. Creatinine ≤ 2.0 mg /dL 
14. No indication for any possible curative treatment after multidisciplinary assessment 
(surgery, ablation) 
15. No contraindication to angiography or selective visceral catheterization 
16. No history of severe allergy or intolerance to contrast agents, narcotics, sedatives. 
17. Negative serum pregnancy test 
18. Signed informed consent form 
 
Imaging Requirements 
 
• MRI scans abdomen/pelvis; To assess disease extension and to 
determine liver volume measurement and identify hepatic vascular anatomy. 
• Spiral CT Chest –performed with cuts of 10 mm or less in slice thickness 
contiguously in the axial plane. To assess extra‐hepatic lesions according to the 
RECIST v 1.1. 
• Hepatic angiography and 99mTC‐MAA – selective celiac and superior mesenteric 
arteriograms are needed to evaluate the hepatic arterial anatomy for the whole 
liver, as well as evaluation of potential sources of extra‐hepatic blood supply to 
tumors. Repeat 99mTC‐MAA may be needed to estimate cumulative lung shunt or 
re‐asses GI flow. 
• SPECT imaging may be performed according to standard of care practices for 
clinical management but is not a study requirement. 
• PET/CT for quantification of dose to target lesion, as well as dose to non-target liver. 
 
Sample Size Calculation and Statistical Plan 
 
 
This is a pilot study seeking to determine the efficacy of radiation segmentectomy on 
very early to early unresectable HCC, not amenable to thermal ablation. 
 
Current reported complete response rates of approximately 50% for BCLC A patients 
utilizing selective chemoembolization have been promising. (31,32,33) Radiofrequency 
ablation has been reported to have >80% complete response for lesions < 3 cm. (30) 
 
Based on the assumption that a recent study reporting radiation segmentectomy rates 
similar to ablation, the goal is 80% complete response, compared to 50% complete 
response rate of TACE.  
 
Numeric Results for testing H0: P=P0 versus H1: P<>P0 
 
Test Statistic: Z Test using S (P0) 
 
 
 
 
Proportion 
Proportion 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Given H0 
Given H1 
 
   Reject H0 If 
Power  
N 
(P0) 
 
(P1) 
 
Alpha    Beta If [Z]> Then 
 
0.9108  
30 
0.5000  
0.8000  
0.0500    0.0892 
1.9600 
 
A sample size of 30 achieves 91% power to detect a difference (P1-P0) of 0.3000 using a 
two-sided Z test that uses S(P0) to estimate the standard deviation.  The target 
significance level is 0.0500. These results assume that the population proportion under 
the null hypothesis is 0.5000. 
 
Safety Analysis: 
 
All patients will undergo safety analysis at the interval study visits outlined below in the 
study visits section. All adverse events will be reported according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events v 4.03 (CTCAE). The 
incidence of adverse events will be summarized according to the primary system‐organ 
class and within the category defined in the CTCAE v 4.03. The summaries will be 
overall (severity grades 1‐4) and for grade ≥3 events and will also report the actions taken 
in terms of treatment discontinuation. Serious adverse events (SAE) will be tabulated by 
treatment. Laboratory values will be summarized by treatment group over time and 
overall. 
 
Screening:  
 
• Informed Consent 
• Demographics 
• Physical examination 
• Medical history 
• Child‐Pugh assessment of chronic liver disease 
• ECOG Performance Status assessment 
• Abdomen/pelvis MRI to assess liver tumor presentation, calculate liver volume. 
• Chest CT to rule out extra‐hepatic metastases 
• Required laboratory blood work plus alfaphetoprotein (AFP) 
The date of screening is the date all screening procedures are completed. 
 
Treatment: 
 
Radiation segmentectomy protocol: 
 
a. MAA mapping:   
 Patients will undergo pretreatment angiography under transfemoral or 
transradial access with conebeam CT to:  
 
(1) determine vascular anatomy of the region 
(2) determine vascular supply of tumor 
(3) prophylactically embolize vessels that may lead to aberrant deposition of 
radioembolic microspheres 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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(4) perform technetium-99 m macroaggregated albumin (99mTc-MAA) scans 
to determine lung shunt fraction (LSF) and splanchnic shunting.  
(5) Patients will not be eligible for TheraSphere infusion if the potential 
radiation dose to the lungs exceeds 30 Gy for a single treatment or cumulative 
50 Gy or embolization cannot be performed to effectively block GI blood flow 
from the hepatic arterial system.  
 
 In all patients, the vessel feeding the segment(s) being targeted for treatment 
will be identified and catheterized using standard angiographic techniques and 
conebeam CT. 
 
b. Dosimetry: 
 Based on the pretreatment angiography and conebeam CT, the volume of the 
perfused liver will be calculated on either the pretreatment CT or MRI, which 
will not be > 6 weeks from time of MAA mapping.   
 Assuming uniform distribution and complete 90Y decay in situ, radioactivity 
required for desired dose delivery to the injected tissue can be calculated using 
the pretreatment dose-planning formula A = (D x M)/50, where A is the 
administered activity (activity of the vial that is to be infused) in 
gigabecquerels, D is the desired treatment dose in grays, and M is the mass of 
the tissue perfused by the microspheres in kilograms. M is determined after 
converting the volume of that tissue to kilograms using the conversion factor 
of 1.03 x10-3kg/cm-3. 
 Target dose will be >205 Gy, assuming that is the threshold for tumor 
destruction (29). 
 After treatment, actual dose delivered to the tissue is determined after 
correcting for fraction of activity remaining in the vial (R) and LSF, using the 
formula for the posttreatment dose delivered: D = 50 (A) (1 - LSF) (1 - R)/M. 
c.  Delivery of Y90:  
 Radiation segmentectomy will be performed with Yttrium-90, whereby a high 
radiation dose is delivered to the tumor via radioactive microspheres infused 
through the hepatic artery. The radioactive microsphere delivery device used 
will be glass-based (TheraSphere; BTG, Ottawa, Ontario, Canada), in which 
90Y is an integral constituent of the biocompatible glass matrix.  
 Patients will be subsequently imaged the same day with PET-CT to calculate 
dose to target tissue, as well as dose to the non-target liver.  This will be 
performed on a PET-CT system (Siemens).   
 
 
Patients who consent to the procedure, but cannot proceed with treatment due to dose 
resulting in >30 Gy to the lungs or inability to target feeding vessels ≤ 2 Couinaud 
segments will be regarded as treatment failures. 
 
 
Study Visits and Follow-up 
 
Screening:   

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Images and test results obtained for clinical patient management and before signing of 
informed consent do not need to be repeated and may be used for screening 
assessment provided images were taken within 28 days. These evaluations will be the 
baseline values for patients in the trial. 
 
Follow-up:  
 
Patients will be followed within 6 weeks after treatment, 12 weeks after treatment and 3 
months thereafter for a period of 2 years.  Follow-up will be within 7 days of scheduled 
times post-treatment. 
 
 
Visits include assessment of: 
o ECOG1 Performance Status assessment 
o Standard laboratory blood draw for CBC, differential, electrolytes, BUN, 
glucose, liver function test, coagulation panel, and α‐fetoprotein biomarker 
o Adverse event reporting 
o Abdomen/pelvis MRI (6 weeks after treatment, 12 weeks after treatment and 3 months 
thereafter for a period of 2 years.  Imaging will be performed within 7 days of scheduled 
visits.) 
o Chest CT scan (6 weeks after treatment, 12 weeks after treatment and 3 months 
thereafter for a period of 2 years.  Imaging will be performed within 7 days of scheduled 
visits) 
 
Progression:  
 
Definition of tumor progression is defined as: 
• Radiological progression as defined by mRECIST  
• Development of extra‐hepatic disease beyond the limits defined in the eligibility criteria 
• ECOG Performance Status ≥2 
 
1ECOG Performance Status 
Score Characteristics 
0 Asymptomatic and fully active 
1 Symptomatic; fully ambulatory; restricted in physically strenuous activity 
2 Symptomatic; ambulatory; capable of self‐care; more than 50% of waking hours 
are spent out of bed. 
3 Symptomatic; limited self‐care; more than 50% of waking hours are spent in bed 
4 Completely disabled; no self‐care; bedridden. 
 
 
STUDY RATIONALE  
 
The aim of this pilot study is to assess the efficacy of radiation segmentectomy with 
Theraspheres in patients with unresectable hepatocellular carcinoma that would qualify 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
Carcinoma  
 
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for thermal ablation as per the BCLC guidelines, but are unable to receive thermal 
ablation due to unfavorable location of target lesions. 
 
BACKGROUND  
 
There is an increasing incidence of HCC in the United States over the last twenty years, 
largely due to the hepatitis C epidemic but increasingly related as well to nonalcoholic 
fatty liver disease(1,2). 
 
For patients with single HCC and compensated liver disease (normal liver function and 
without portal hypertension), partial liver resection (LR) is the preferred treatment. 
Unfortunately, only 5-10% of these patients are resectable due to a variety of factors, 
which may include portal hypertension, total bilirubin > 1.0 mg/dL and platelets less than 
100,000/mm3.  For patients with HCC who are Barcelona Clinic Liver Cancer (BCLC) 
Guidelines Class A (1 lesion < 5cm, or 2-3 lesions all < 3cm) who are not candidates for 
LR, liver transplantation (LT) is the treatment of choice. The current median waiting time 
in New York, however, is greater than 12 months, creating the risk of dropout due to 
tumor progression (currently estimated to be around 20-25%).  In order to mitigate this 
risk, patients listed for LT typically undergo locoregional therapy with TACE and/or 
thermal ablation (TA) as a bridge or downstage to LT (3,4).   
 
Patients with BCLC A HCC who due to age, medical, or psychosocial issues are not 
candidates for LR are typically treated with TA. Thermal ablation is effective in lesions 
that can have precise placement of ablation probes and are accessible from a 
percutaneous approach. Local Time to Progression in patients, who have received TA has 
been demonstrated to be 10% at 3 years by studies from Lee at el. (36) 
However, some of these lesions have demonstrated incomplete ablation cavities on 
follow-up due to adjacent heat sinks.  Serious adverse events from thermal ablation, 
although small, have been well documented and associated with unfavorable locations, 
such as adjacent to heart, bowel, gallbladder and diaphragm. As a result, some thermal 
ablations have resulted in abscesses, bowel perforation, hemothorax, cardiac tamponade, 
hematoma from superficial lesions near the liver capsule, gallbladder perforation, as well 
as seeding from the ablation tract. (37-41) 
 
Transarterial chemoembolization (TACE) has demonstrated a survival benefit in BCLC 
B, or intermediate stage, patients.  Recent studies have also demonstrated an 
approximately 50% complete response rate for single lesions, when sub-selective 
catheterization is utilized.  (31, 32, 33) However, tumors treated with TACE have 
demonstrated viable components on explanted livers by pathology.   
 
Studies with transarterial radioembolization with Yttrium 90 (Y90) have offered a 
potential benefit compared to TACE in BCLC B patients with a longer time to 
progression (TTP).  This may provide a benefit for patients awaiting transplantation. 
 
TheraSphere consists of insoluble glass microspheres in which yttrium‐90 is an integral 
component of the glass. The sphere diameter ranges from 20 to 30 μm with 22,000 to 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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73,000 microspheres per milligram.  TheraSphere is available in dose sizes ranging from 
3 GBq to 20 GBq, each supplied in 0.6 mL of sterile, pyrogen‐free water contained in a 
1.0 mL vial secured within a clear acrylic vial shield. A pre‐assembled single‐use 
TheraSphere Administration Set is provided for each dose. Each user site is provided 
with a reuseable TheraSphere Administration Accessory Kit that provides both radiation 
protection for the user and physical support of the dose vial and Administration Set 
during administration of the product.  Yttrium‐90 is a pure beta emitter which decays to 
stable zirconium‐90 with a physical half‐life of 64.1 hours.  The average energy of the 
beta emissions from yttrium‐90 is 0.9367 MeV with mean tissue penetration of 
approximately 2.5 mm. 
 
TheraSphere is administered through the hepatic artery which supplies blood to tumor 
tissue (the portal vein supplies blood to the normal hepatic tissue). The microspheres are 
trapped in the vasculature of the tumor due to arteriolar capillary blockage where they 
exert a local radiotherapeutic effect. In clinical use, the glass microspheres remain 
permanently trapped in the vasculature where the isotope decays to infinity leaving 
background radiation with no therapeutic value. 
 
Salem et al demonstrated the tolerability of TheraSphere in treatment of patients with 
HCC and branch PVT and patients with unresectable HCC. Salem et al recently 
published their long‐term experience of TheraSphere in the treatment of patients with 
HCC. In this report, patients with HCC (n=291) were treated with TheraSphere as part of 
a single‐center, prospective, longitudinal cohort study. Toxicities were recorded using the 
Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) 
were determined using World Health Organization (WHO) and European Association for 
the Study of the Liver (EASL) guidelines. Survival by stage was assessed.  
 
Univariate/multivariate analyses were performed. A total of 526 treatments were 
administered (mean, 1.8; range, 1‐5). Toxicities included fatigue (57%), pain (23%), and 
nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30‐day mortality 
rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, 
respectively. The overall TTP was 7.9 months (95% confidence interval, 6‐10.3). 
Survival times differed between patients with Child‐Pugh A and B disease (A, 17.2 
months; B, 7.7 months; P = .002). Patients with Child‐Pugh B disease who had portal 
vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5‐6.7). Baseline 
age; gender; performance status; presence of portal hypertension; tumor distribution; 
levels of bilirubin, albumin, and alpha‐fetoprotein; and WHO/EASL response rate 
predicted survival. These investigators concluded that patients with Child‐Pugh A 
disease, with or without PVT, benefited most from treatment. Patients with Child‐Pugh B 
disease who had PVT had poor outcomes. TTP and overall survival varied by patient 
stage at baseline. 
 
The clinical experience of Salem et al and a recent meta‐analysis of yttrium‐90 
microsphere radioembolization13 indicates that TheraSphere is very well tolerated when 
appropriate patient selection criteria are used. Early reports of serious adverse events 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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possibly associated with the use of TheraSphere, as described in the package labeling 
documents in Appendix 1, included death, hepatorenal failure, liver abscess, hepatic 
encephalopathy, hepatic decompensation, radiation hepatitis, radiation pneumonitis, 
duodenal ulcer, gastrointestinal bleeding and cholecystitis. These more severe events are 
now uncommon as patients with the high risk factors associated with the occurrence of 
these events are typically excluded from treatment with TheraSphere. Patients in whom 
TheraSphere should be used with caution include those with infiltrative tumor type, bulk 
disease (tumor volume >70% or nodules too numerous to count), AST or ALT > five 
times the upper limit of normal, bilirubin > 2 mg/dL, tumor volume >50% in the presence 
of an albumin < 3 g/dL, and those in whom extra‐hepatic shunting to the lungs or 
gastrointestinal tract cannot be managed through standard angiographic techniques. 
 
More recently, the technique of radiation segmentectomy utilizing TheraSphere has been 
described by Riaz et al. with treatment along an arterial anatomic plane confined to  2 
Couinaud segments (>190Gy), resulting in complete pathological necrosis of targeted 
segments while limiting radiation exposure of non-targeted tissue. 
 
In a prospective study, eighty-four patients with hepatocellular carcinoma confirmed by 
biopsy or radiographic evidence as defined by the European Association for the Study of 
the Liver (EASL) and American Association for the Study of Liver Disease (AASLD) 
criteria were treated with TheraSphere utilizing a segmental approach (Riaz A, et al).   
The objective of the study was to define radiation segmentectomy by calculating the dose 
delivered to the segment in addition to assessing safety and efficacy.   
 
The patient cohort was vastly male (58) with a median age of 68 years (range 43-90 
years) and in good performance status 0 (61) and 1 (25).  Hepatitis C virus (HCV) was 
the etiology of  their liver disease (34) and the majority of tumors were staged as T2 (32) 
and T3 (25) according to UNOS stage.  There was similarity among Barcelona Clinic 
Liver Cancer stage (A = 27; B = 25 and C = 31) and all patients were Child-Pugh A (41) 
and B (42) with the exception of one Child-Pugh class C patient.  All tumors were 
angiographically isolatable, specifically located in two or fewer Couinaud segments that 
have the capability to be perfused at the intended catheter position.   
 
Each patient underwent pretreatment angiography and 99Tc-MAA injection for shunt 
detection.  Standard dosimetry was calculated based on catheterizing the lobar branch and 
exposing the lobe with a target of 120Gy.  Following treatment, the actual dose delivered 
was calculated by assuming uniform and non-uniform microsphere distribution within the 
treatment volume.  All 84 patients received infusion at the level of the segmental artery.   
 
Response rate was determined utilizing the World Health Organization (WHO) and 
necrosis (EASL) guidelines and the time to progression (TTP) and survival analyses are 
captured in Table 3.   
 
Table 3.  Time to Progression and Survival Analyses 
 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Efficacy 
Parameter 
Time 
(Months) 
One Year 
Rates (%) 
Two Year 
Rates (%) 
Three Year 
Rates (%) 
Overall 
Survival 
(Median) 
26.9 months 
 
56 
23 
12 
Time to 
Progression 
(Median)  
13.6 months 
74 
55 
27 
 
It was demonstrated that a median segmental dose of 521 Gy assuming uniform 
microsphere distribution translated to a traditional lobar dose of 97 Gy which was further 
comparable to a whole liver dose of 35.5 Gy.  Furthermore, given the hypervascular 
nature of HCC and assuming that hepatic arterial blood flow is preferentially directed to 
the tumor, the median dose estimated to be delivered to the tumor was even greater (1657 
Gy).   Thus, the high response rates presented in this study may be due to the higher 
radiation doses selectively delivered to the tumor.    
 
The most common clinical toxicities reported were fatigue (44), abdominal pain (15), and 
nausea/vomiting (11) and grade 3/4 laboratory abnormalities reported were bilirubin (5) 
and albumin/alkaline phosphatase (2).  Twenty-nine patients experienced no adverse 
reactions.  Both clinical toxicities and laboratory abnormalities following a segmental 
approach were lower than that described following a typical lobar infusion method which 
further supports the decrease in radiation exposure to normal hepatic parenchyma and the 
utility of this methodology.   Refer to Table 4 for adverse reactions experienced in this 
patient cohort.   
 
Table 4.  Toxicities 
 
Toxicity 
n (%) 
Clinical Toxicities (All Grades) 
 
Fatigue 
44 (52) 
Abdominal pain 
15 (18) 
Nausea/Vomiting 
11 (13) 
Anorexia 
7 (8) 
Diarrhea 
1 (1) 
Fever/chills 
4 (5) 
Weight loss 
3 (4) 
None 
29 (35) 
Laboratory Abnormalities 
 
Bilirubin 
5 (6) 
Albumin 
2 (2) 
ALT 
0 
AST 
1 (1) 
Alkaline phosphatase  
2 (2) 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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A retrospective, multi-center study was also conducted in which 102 treatment-naïve 
patients with unresectable HCC ≤5cm according to AASLD (American Association for 
the Study of Liver Diseases) guidelines and the absence of portal vein thrombosis (PVT) 
were treated with TheraSphere in a segmental fashion (Vouche M, et al).  The objective 
of the study was to assess the efficacy including response rates, overall survival, and 
pathologic analysis.   
 
Radiation segmentectomy is achieved by prospectively determining lobar volumes and 
prescribing an intended lobar dose of 120-150Gy.  The activity vial(s) is then injected 
within the segmental feeding vessel which will minimize radiation to the normal 
parenchyma and increase safety to the patient.  As a result, segmental doses are higher 
than the prescribed dose by the ratio of lobar to segmental volumes.   
 
The amount of radioactivity required to deliver the desired dose to the liver may be 
calculated using the following formula: 
 
Activity Required (GBq) = [Desired Dose (Gy)] [Liver Mass (kg)] 
50 
 
The actual dose delivered to the perfused tissue can be assessed by utilizing cone-beam 
CT, the perfused volume and mass can now be measured during mapping angiography, 
resulting in real-time dosimetry in planning for radiation segmentectomy.  This method 
of utilizing cone-beam CT has resulted in a radiation segmentectomy typically being 
performed with a 3,5,7, or 10 GBq vial, depending on the vascular capacitance of the 
segmental vessel (s).   
 
Demographic and baseline characteristics revealed 59 males and 43 females with a 
median age of 64 years (range 58-75 years).   Although lesions were classified as small, 
forty percent of the patients were greater than an ECOG performance status 0 (41/102) 
and 61 BCLC A and 41 BCLC C.  Additionally, two patients had a Child-Pugh C score 
>9.   The majority of lesions were not amendable to radiofrequency ablation due to 
location in the dome of the liver specific to segments 4, 7, and 8 and T2 (82 tumors) 
according to the UNOS stage.   The median size of the tumor was 2.6cm (range 2.1-
3.6cm).   
 
Slightly greater than half of the patients experienced adverse reactions and none required 
admission.  The most common clinical toxicities according to the Common Terminology 
Criteria for Adverse Events v4 were fatigue (46), abdominal pain (10), nausea (8), fever 
(3), appetite loss (2), dyspnea (1), vomiting (1), and weight loss (1).   The first four 
adverse events were all mild in nature.  The most common grade 3/4 laboratory toxicities 
were lymphopenia, platelets, bilirubin, AST and ALT, hence many of these were present 
at baseline and not altered over a period of 24 months as demonstrated in Table 5 below. 
 
Table 5  Laboratory Abnormalities 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Laboratory 
Value 
Baseline 
1-3 
months 
p 
value 
3-6 
months 
p 
value 
6-12 
months 
12-24 
months 
AST 
2/102 
1/94 
0.99 
0/53 
0.77 
2/31 
0/19 
ALT 
4/102 
4/94 
0.72 
0/53 
.0.34 
0/31 
0/19 
Bilirubin 
3/102 
6/94 
0.17 
7/53 
0.27 
3/31 
0/19 
Albumin 
5/102 
7/94 
0.77 
3/53 
0.87 
0/31 
4/19 
INR 
14/102 
15/94 
1.0 
3/53 
0.06 
2/31 
1/19 
Absolute 
Lymphocyte 
16/102 
18/94 
0.86 
12/53 
0.67 
5/31 
2/19 
 
 
Response rates were assessed on 99 evaluable patients according to modified RECIST 
(mRECIST).  The  time-to-progression was 33.1 months for 27/102 patients, hence 16/27 
patients developed new intrahepatic lesions.  The median time to development of a new 
lesion was 6.2 months.   Refer to Table 6 for response rates.   
 
Table 6.  Efficacy Outcomes 
 
Complete Response 
47/99 
Partial Response 
39/99 
Stable Disease 
12/99 
 
 
 
Median overall survival was 53.4 months with a median follow-up of 27.1 months .   
Upon exclusion of those patients transplanted, survival was 34.5 months.  For the  thirty-
three transplanted, the mean survival was 56.5 months.   
 
Of importance, 33/102 patients were transplanted in a mean time frame of 6.3 months and 
pathologic analysis revealed 17/33 patients had a complete pathologic necrosis and 16/33 
patients had a partial pathologic necrosis.   Complete necrosis was evident when the 
radiation dose exceeded 190Gy to the treatment area which was statistically significant 
(p=0.03).   Refer to Table 7 for pathologic and dose delivered correlation.   
 
Table  7.  Pathologic Analysis and Dose Correlation  
 
Radiation Dosage 
Complete Necrosis 
Partial Necrosis 
Total 
<190Gy 
3 
9 
12 
>190Gy 
14 
7 
21 
Total 
17 
16 
33 
 
A univariate analyses revealed patients with ECOG Performance Status 0 had a survival 
benefit and in a multivariate analyses, patients with age <65, ECOG ), and Child-Pugh A 
were also associated with longer survival.   
 
In comparison to a lobar infusion, radiation segmentectomy has a comparable efficacy 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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outcomes and a lower toxicity and adverse event rate due to the limited radiation dose 
administered to the normal hepatic parenchyma.  
 
 
The assessment of treatment response after TACE and TA is currently based on loss of 
internal vascularity on contrast-enhanced imaging as outlined in the mRECIST. The 
response to Y90, however, may not be as accurately assessed by mRECIST.  Diffusion-
weighted imaging (DWI) and uptake by hepatocytes of liver-specific contrast (Gd-EOB-
DTPA) are potentially complementary methods to assess hepatocyte damage.  The use of 
DWI has been reported in the diagnosis of liver tumors and for the evaluation of 
treatment response in liver metastases (treated with systemic chemotherapy) and HCC 
(treated with TACE) (19-25).  Diffusion MRI (or dMRI) is a magnetic resonance 
imaging (MRI) method which came into existence in the mid-1980s.  It allows the 
mapping of the diffusion process of molecules, mainly water, in biological tissues, in 
vivo and non-invasively. Molecular diffusion in tissues is not free, but reflects 
interactions with many obstacles, such as macromolecules, fibers,membranes, etc. Water 
molecule diffusion patterns can therefore reveal microscopic details about tissue 
architecture, either normal or in a diseased state. In diffusion weighted imaging (DWI), 
the intensity of each image element (voxel) reflects the best estimate of the rate of water 
diffusion at that location. Because the mobility of water is driven by thermal agitation 
and highly dependent on its cellular environment, the hypothesis behind DWI is that 
findings may indicate (early) pathologic change.  The apparent diffusion coefficient 
(ADC) measures the magnitude of diffusion (of water molecules) within tissue.  Most 
studies have observed an early rise in ADC values concomitant with devascularization, 
with subsequent decrease in ADC values in HCC (19).  The extent of tissue cellularity 
and the presence of intact cell membrane help determine the impedance of water 
molecule diffusion. This impedance of water molecules diffusion can be quantitatively 
assessed using the apparent diffusion coefficient (ADC) value. This assessment can be 
done using different b values via changing gradient amplitude.  
            
We propose to test the following hypothesis: 
 
Radiation segmentectomy will provide a high response rate in patients that qualify for 
radiofrequency ablation as per the BCLC guidelines, but are deemed ineligible. 
  
STUDY OBJECTIVES 
 
The goal of this proposal is to assess the efficacy of radiation segmentectomy in patients 
with very early and early HCC as per BCLC, who cannot undergo thermal ablation.  
Towards this goal, we will also explore 1) Time to Progression  2) Quantifying dose to 
target lesion  3) Safety and 4) Toxicity.  
 
 
 
Primary end point: 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Tumor response: Assess tumor response according to mRECIST 
 
Secondary end points:  
1. Time to Progression: The length of time from radiation segmentectomy until 
progression of disease based on mRECIST. 
2. Assess toxicity resulting from Radiation Segmentectomy with Theraspheres 
 
Response assessment:  
Response assessment will be performed with mRECIST 6 weeks post-radiation 
segmentectomy, 12 weeks post-radiation segmentectomy and every 3 months thereafter 
for a period of 2 years to correlate with data collection.  Imaging will be performed 
within 7 days of scheduled visits. 
 
 
 DATA and METHODOLOGY 
 
This is a prospective, single arm study. Segmentectomy within the context of this 
protocol will be offered to patients with a single site of HCC ≤ 3 cm diameter who are not 
eligible for thermal ablation. Patients may, if otherwise qualified either before or after 
treatment, be included on the waiting list for LT. 
 
Diagnosis 
 
The diagnosis of HCC will be established using updated AASLD criteria based on CT or 
MRI. Histological confirmation will be obtained in non-cirrhotic patients.  
 
Inclusion Criteria: 
 
1. Age greater than 18 years, regardless of race or gender 
2. Hepatocellular Carcinoma confirmed by histology for non-cirrhotic patients or non-
invasive criteria according to AASLD for cirrhotic patients. 
3. Child-Pugh class A or B7 without ascites 
4. Single tumor nodule ≤ 3 cm with a maximum distance of 5 mm from either portal 
vein, hepatic vein, inferior vena cava, diaphragm, heart, stomach, bowel, liver 
capsule, gallbladder, bile duct. 
5. No prior locoregional treatment or external beam therapy of current HCC (recurrent 
HCC after resection may be included) 
6. No confirmed extrahepatic metastases 
7. No evidence of macrovascular invasion 
8. ECOG 0 
9. Albumin > 3.0 g/dL 
10. PLT ≥ 40 x103/μL 
11. WBC ≥ 1.5 x103/μL 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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12. AST/ALT ≤ 5 times the upper limit of normal (U/L) 
13. Creatinine ≤ 2.0 mg /dL 
14. No indication for any possible curative treatment after multidisciplinary assessment 
(surgery, ablation).  Unresectable parameters include platelets<100 x103/μL, portal 
hypertension, Total Bilirubin > 1.0 mg/dL, and comorbidities which exclude surgery 
agreed upon during the multidisciplinary meeting. 
15. No contraindication to angiography or selective visceral catheterization 
16. No history of severe allergy or intolerance to contrast agents, narcotics, sedatives. 
17. Negative serum pregnancy test 
18. Signed informed consent form 
 
Exclusion Criteria: 
 
1. Inability to provide informed consent 
2. Pregnancy 
3. Metastatic disease outside of the liver 
4. Macrovascular invasion 
5. Child-Pugh class > B7  
6. Total Bilirubin > 2.0 mg/dL 
7. Platelets < 40 × 103 per mm3 
8. Encephalopathy* (Defined below) 
9. Refractory ascites 
10. Greater than a single nodule > 3 cm 
 
Study Visits and Follow-up 
 
Screening:   
 
Images and test results obtained for clinical patient management and before signing of 
informed consent do not need to be repeated and may be used for screening 
assessment provided images were taken within 28 days. These evaluations will be the 
baseline values for patients in the trial. 
 
Follow-up:  
 
Patients will be followed within 6 weeks after treatment, 12 weeks after treatment and 3 
months thereafter for a period of 2 years.  Visits will occur within 7 days of scheduled 
appointments. 
 
Visits include assessment of: 
o ECOG1 Performance Status assessment 
o Standard laboratory blood draw for CBC, differential, electrolytes, BUN, 
glucose, liver function test, coagulation panel, and α‐fetoprotein biomarker 
o Adverse event reporting 
o Abdomen/pelvis MRI (6 weeks after treatment, 12 weeks after treatment and 3 months 
thereafter for a period of 2 years) 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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o Chest CT scan (12 months after treatment and 24 months after treatment) 
 
Progression:  
 
Definition of tumor progression is defined as: 
• Radiological progression as defined by mRECIST  
• Development of extra‐hepatic disease beyond the limits defined in the eligibility criteria 
• ECOG Performance Status ≥2 
 
1ECOG Performance Status 
Score Characteristics 
0 Asymptomatic and fully active 
1 Symptomatic; fully ambulatory; restricted in physically strenuous activity 
2 Symptomatic; ambulatory; capable of self‐care; more than 50% of waking hours 
are spent out of bed. 
3 Symptomatic; limited self‐care; more than 50% of waking hours are spent in bed 
4 Completely disabled; no self‐care; bedridden 
 
Data Collection 
 
Patients will be interviewed and clinical information will be obtained at baseline, 6 weeks 
after treatment, 12 weeks after treatment and 3 months thereafter for a period of 2 years.  
Visits will occur within 7 days of scheduled appointments. 
 
  
Baseline data shall include: 
1. Demographics: age, sex, etiology of liver disease 
2. Liver and renal function tests: bilirubin, AST, ALT, albumin, alkaline phosphatase, 
GGTP, BUN, creatinine, Na, INR, platelet count 
3. Presence or absence of clinical ascites and encephalopathy*     
4. Serum alpha fetoprotein   
5. MRI abdomen/pelvis 
6. Chest CT 
7. Performance status according to ECOG 
 
Follow up data shall include: 
 
o ECOG1 Performance Status assessment 
o Standard laboratory blood draw for CBC, differential, electrolytes, BUN, liver function 
test, coagulation panel, and α‐fetoprotein biomarker 
o Adverse event reporting 
o Abdomen/pelvis MRI (6 weeks after treatment, 12 weeks after treatment and 3 months 
thereafter for a period of 2 years) 
o Chest CT scan (6 weeks after treatment, 12 weeks after treatment and 3 months 
thereafter for a period of 2 years) 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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Progression:  
 
Definition of tumor progression is defined as: 
• Radiological progression as defined by mRECIST  
• Development of extra‐hepatic disease beyond the limits defined in the eligibility criteria 
• ECOG Performance Status ≥2 
 
1ECOG Performance Status 
 
Score Characteristics 
0 Asymptomatic and fully active 
1 Symptomatic; fully ambulatory; restricted in physically strenuous activity 
2 Symptomatic; ambulatory; capable of self‐care; more than 50% of waking hours 
are spent out of bed. 
3 Symptomatic; limited self‐care; more than 50% of waking hours are spent in bed 
4 Completely disabled; no self‐care; bedridden 
 
* Grades of Encephalopathy 
 
Grade 1  
Inverted sleep pattern; forgetfulness, agitation, irritability, apraxia 
Grade 2   
Lethargy; Disorientation for time or place, Subtle personality change; 
Asterixis, ataxia 
Grade 3   
Somnolence but rousability; Disorientation as regards place; Asterixis, 
hyperactive reflexes, Babinski signs, muscle rigidity 
Grade 4   
Coma (unresponsive to verbal or noxious stimuli) 
 
 
 
MRI protocol:  
 
Precontrast sequences (T1 in- and out-of-phase, T2 fat saturated, T2 HASTE, diffusion 
using 3 b-values: 50-400-800, T2*) and dynamic pre- and postcontrast 3D T1-weighted 
imaging using Gadoxetic acid contrast (Eovist, Bayer) at the arterial, portal venous, late 
venous, and hepatobiliary phases. GFR will be measured prior to examination.   
 
In addition to mRECIST, radiological parameters to be measured will include: 
 
1. Maximum tumor diameter 
2. Signal intensity enhancement in tumors at the arterial and portal venous phases.  
3. Degree of tumor necrosis using image subtraction (27) 
4. Tumor ADC: in whole tumor and viable tumor components, we will measure mean ADC 
+/- SD.  
5. Liver uptake: we will measure contrast uptake on the hepatobiliary phase 20 min post 
contrast injection in the peritumoral area to assess for hepatocyte damage. 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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6. Liver ADC will also be measured in the peritumoral liver area.   
 
 
 
Brief Summary of mRECIST 
 
mRECIST for HCC 
CR = Disappearance of any intratumoral arterial enhancement in all target lesions 
PR =  At least a 30% decrease in the sum of diameters of viable (enhancement in the 
arterial phase) target lesions, taking as reference the baseline sum of the diameters 
of target lesions 
SD =  Any cases that do not qualify for either partial response or progressive disease 
PD =  An increase of at least 20% in the sum of the diameters of viable (enhancing) 
target lesions, taking as reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since treatment started 
 
Radiation segmentectomy protocol: 
 
c. MAA mapping:   
 Patients will undergo pretreatment angiography under transfemoral or 
transradial access with conebeam CT to:  
 
(1) determine vascular anatomy of the region (≤ 2 Couinaud Segments) 
(2) determine vascular supply of tumor 
(3) prophylactically embolize vessels that may lead to aberrant deposition of 
radioembolic microspheres 
(4) perform technetium-99 m macroaggregated albumin (99mTc-MAA) scans 
to determine lung shunt fraction (LSF) and splanchnic shunting.  
 
 In all patients, the vessel feeding the segment(s) being targeted for treatment 
will be identified and catheterized using standard angiographic techniques and 
conebeam CT. 
 
d. Dosimetry: 
 Based on the pretreatment angiography and conebeam CT, the volume of the 
perfused liver will be calculated on either the pretreatment CT or MRI, which 
will not be > 6 weeks from time of MAA mapping.   
 Assuming uniform distribution and complete 90Y decay in situ, radioactivity 
required for desired dose delivery to the injected tissue can be calculated using 
the pretreatment dose-planning formula: 
 A = (D x M)/50,  
where A is the administered activity (activity of the vial that is to be infused) 
in gigabecquerels,  
D is the desired treatment dose in grays,  

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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and M is the mass of the tissue perfused by the microspheres in kilograms. M 
is determined after converting the volume of that tissue to kilograms using the 
conversion factor of 1.03 x10-3kg/cm-3. 
 Target dose will be >205 Gy, assuming that is the threshold for tumor 
destruction based on the referenced paper from Garin et al, which 
demonstrated response to Y90 at target doses > 205 Gy (29). 
 After treatment, actual dose delivered to the tissue is determined after 
correcting for fraction of activity remaining in the vial (R) and LSF, using the 
formula for the posttreatment dose delivered: D = 50 (A) (1 - LSF) (1 - R)/M. 
c.  Delivery of Y90:  
 Radiation segmentectomy will be performed with Yttrium-90, whereby a high 
radiation dose is delivered to the tumor via radioactive microspheres infused 
through the hepatic artery. The radioactive microsphere delivery device used 
will be glass-based (TheraSphere; BTG, Ottawa, Ontario, Canada), in which 
90Y is an integral constituent of the biocompatible glass matrix.  
 Patients will be subsequently imaged the same day with PET-CT to quantify 
dose to target tissue, as well as dose to the non-target liver.  This will be 
performed on a PET-CT system (Siemens).   
 
 
Patients who consent to the procedure, but cannot proceed with treatment due to dose 
resulting in >30 Gy to the lungs or inability to target feeding vessels ≤ 2 Couinaud 
segments will be regarded as treatment failures. 
 
Termination of Participation in Study to include those subjects who did not pass Y90 
mapping test, as well as those who have clinical deterioration of concurrent medical 
conditions and those who decide to terminate participation. 
 
Patients will undergo routine clinical surveillance at 6 weeks post-Y90, 12 weeks post-
Y90, and at 3 month intervals post-Y90 for 2 years post Y-90 during which time they will 
be evaluated by the physician assistant/nurse practitioner and attending physicians, with 
assessment of their clinical performance, active medical issues, and any toxicities, as 
graded by the NCI CTCAE version 4.03. Follow-up will be within 7 days of scheduled 
times post-treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Mapping 
Y90 
Treatment 
6 wks 
post 
12 wks 
post 
6 mo 
post 
9 mo 
12 mo 
15 mo 
18 mo 
24 mo 
End of 
Study 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Child Pugh 
X 
 
 
 
 
 
 
 
 
 
 
 
AFP 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior 
Treatment Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
Carcinoma  
 
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Coagulation 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry 
Panel, LFTs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum 
Pregnancy 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Liver 
Volume/Tumor 
Mass 
 
X 
 
 
 
 
 
 
 
 
 
 
Review 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatic Angio, 
MAA scan, 
Dose 
Calculation 
 
X 
 
 
 
 
 
 
 
 
 
 
Quantify dose 
on PET/CT 
 
 
X 
 
 
 
 
 
 
 
 
 
MRI 
abd/pelvis 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CT of chest 
X 
 
 
 
 
 
 
X 
 
 
X 
 
Assess/Report 
Adverse 
Events 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Record 
Study 
Treatment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Final Efficacy 
documentation 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Data from this trial will be captured on case reporting forms (CRFs). An audit trail will 
be maintained to document all data changes in the database. 
Procedures will be followed to ensure the validity and accuracy of the clinical database. 
The investigator will sign and date all indicated places on the CRFs. This signature will 
indicate that thorough inspection of the data has been made and will certify that the Site 
Investigator has reviewed and approved the data contained on the forms. 
 
DATA MANAGEMENT 
 
The investigator will ensure that trial data quality is maintained to current standards of 
Good Clinical Practice and that data are submitted in a timely manner as outlined in the 
protocol and supporting documentation. The investigator must sign an affirmation 
statement verifying the content of all subjects' CRFs. Errors must be corrected in 
accordance with EDC data entry guidelines. 
 
ADVERSE EVENTS 
Adverse experience will be considered synonymous with the term adverse event and vice 
versa. 
 
DEFINITIONS OF AE/SAE FOR DRUGS 
Adverse Device Effect (ADE) 
An adverse device effect is an adverse event (AE – previously defined) related to a 
medical device and includes any event resulting from insufficiencies or inadequacies in 
the instructions for use or the deployment, implantation, installation or malfunction of the 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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device; any event that is the result of user error; or any potential adverse device effect 
which might have occurred if suitable action had not been taken or intervention had not 
been made or if circumstances had been less fortunate. 
Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of 
the consequences characteristic of a serious adverse event (SAE – previously defined) or 
might have led to any of these consequences if suitable action had not been taken; 
intervention had not been made or circumstances had been less fortunate.  This is 
classified as Grade 3-4 as per the NCI CTCAE v4.03.  If 5 Serious Adverse Events are 
recorded, the study will be discontinued. 
 
 
Unanticipated Adverse Device Event (UADE) 
An unanticipated adverse device effect is any serious adverse effect which by its nature, 
incidence, severity and outcome has not been identified in the risk assessment, the 
informed consent form as well as the protocol. 
 
RECORDING ADVERSE EVENTS 
In this study, patients should be encouraged to report adverse events spontaneously or in 
response to general, non‐directed questions. At any time during the study, the patient may 
volunteer information that resembles an adverse event. Once it is determined that an 
adverse event has occurred, the Investigator should obtain all the information required to 
complete the adverse event form. Any medical management of an event and the date of 
resolution of the event must be recorded in the source document and on the 
appropriate case reports form(s). 
 
For each AE, the following information will be recorded: 
• Adverse event 
• Serious/non‐Serious 
• Severity (Toxicity Grade) 
• Action taken 
• Relationship to study treatment 
• Expected/Unexpected 
• Date and time of onset 
• Date and time of resolution 
 
An expected adverse event is any AE, the nature or severity of which is identified in the 
relevant Package Insert.  Any AE experienced by a subject will be followed until the AE 
has resolved to the investigator's or physician sub‐investigator's satisfaction. If a problem 
still exists, then the investigator or physician sub‐investigator at his/her discretion will 
ask the subject to come back to the clinic for further evaluation. Any serious adverse 
events should be managed as discussed. 
Once the subject has been discharged from the study, the investigator has no obligation to 
seek further follow‐up with the subject in order to identify new AEs. AEs ongoing at 
study exit will be followed to resolution. However, if the investigator becomes aware of 
an SAE that has occurred following the subject's discharge from the study and the 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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investigator considers the SAE possibly, probably, or definitely related to a study drug or 
device, then the investigator should report the SAE as described in the protocol. 
 
CAUSALITY (RELATIONSHIP TO MEDICAL DEVICE) ASSESSMENT 
The investigator or physician sub‐investigator must indicate whether he/she believes the 
AE is not related, unlikely related, possibly related (reasonable possibility that the 
medical device caused the AE), probably related, or definitely related to the medical 
device. An adverse event becomes an adverse device effect when the adverse event is 
considered associated with the use of the test device if the attribution is Possibly, 
Probably or Definitely Related.  
 
PERIODIC SAFETY REPORTING 
Adverse events will be recorded on the AE form and coded using NCI CTCAE v 4.03. 
The investigator or physician sub‐investigator will judge the severity of each AE and 
whether or not it is treatment‐related. All AEs that occur after the initiation of trial 
treatment, including events likely to be related to the underlying disease or likely to 
represent concurrent illness, will be reported, including events present at Baseline which 
worsened during the trial. 
 
EXPECTED ADVERSE EVENTS 
THERASPHERE ADVERSE EVENT PROFILE 
TheraSphere has been approved for the treatment of HCC since 1999. Adverse events 
known to be related to the device or the procedure listed in the current package insert 
(Appendix 1). Those adverse events identified in clinical trials investigating treatment 
with TheraSphere of liver lesions metastatic to non‐HCC primary cancers are listed 
below in decreasing order of frequency.  
 
Frequency  
 
Description of Adverse Event (per NCI‐CTCAE 4.03) 
Common ‐ >10%  
 
Fatigue, pain, nausea, vomiting, anorexia and laboratory 
value abnormalities 
including increased alkaline phosphatase, AST, ALT, bilirubin and 
decrease albumin 
Infrequent ‐ <10%  
Lymphopenia with no clinical sequellae; constipation, heartburn, 
weight loss, fever, ascites, muscle weakness, variations in 
hemoglobin, neutrophils and leukocytes, GI ulcer, dyspnea, 
arrhythmia, diarrhea, liver dysfunction, hypotension, insomia, 
rigors/chills, sweating, distension, GI obstruction, hematoma, GI 
hemorrhage, pleural effusion,  
Rare – < 1%  
Alopecia, bruising, pruritis, rash, hot flashes, dehydration, taste 
alteration, 
hemorrhage, infection, dizziness, mood alteration, sensory 
neuropathy, somnolence, cough, urine color change, intraoperative 
injury, flu‐like symptoms, tumor lysis syndrome, thrombosis, 
metabolic/laboratory abnormalities – creatinine, hypercalcemia, 
hyperglycemia, hyperkalemia, hypermagnesemia, lipase  
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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In addition, the following events, which may or may not be related to the use of 
TheraSphere or the administration procedure, have been reported in clinical trials of 
treatment of primary or secondary liver cancer: 
 
Abdominal pain, dyspnoea, abdominal distention, anxiety, blurred vision, chills, hot 
flashes, bladder infection, lower extremity edema, gastrointestinal stoma complication 
including mild pain, hepatic encephalopathy, hepatorenal failure, edema, malaise, hepatic 
decompensation, hepatitis, duodenal ulcer, hypertension, hypertension, aspiration 
pneumonia, fall, gastrointestinal bleeding, elevated AFP, elevated LDH, elevated 
prothrombin time, elevated BUN, bacterial sepsis, hypoglycemia, abnormal platelets and 
electrolyte disturbances including hypercalcemia, hyperkalemia, hypomagnesemia, 
hyponatremia, low serum bicarbonate and low serum chloride. 
 
STUDY MONITORING 
The study will be monitored by qualified personnel, Dr. Gene Im, MD.  
During the course of the trial, a study monitor or other authorized representatives of the 
sponsor will conduct remote monitoring and visit the investigator at suitable intervals. 
The purpose of these visits will be to verify adherence to the protocol, ensure correct 
completion of the CRFs. In order to perform his role effectively, the study monitor must 
be given access to source documentation (eg, clinic charts, original laboratory records), 
which support data on the CRF, and informed consent forms. The monitor must be able 
to verify data appearing in the CRFs against data in the subject's clinic chart (eg, chart 
notes) or in printout forms (eg, laboratory results). 
 
STATISTICAL ANALYSIS  
 
Sample size / Power Calculations  
 
This is a pilot study seeking to determine the safety and efficacy of radiation 
segmentectomy on very early to early HCC, not amenable to thermal ablation. 
 
Current reported complete response rates of approximately 50% for BCLC A patients 
utilizing selective chemoembolization have been promising. (31,32,33) Radiofrequency 
ablation has been reported to have >80% complete response for lesions < 3 cm. (30) 
 
Based on the assumption that a recent study reporting radiation segmentectomy rates 
similar to ablation, the goal is 80% complete response, compared to 50% complete 
response rate of TACE.  
 
Numeric Results for testing H0: P=P0 versus H1: P<>P0 
 
Test Statistic: Z Test using S (P0) 
 
 
 
 
Proportion 
Proportion 
 
 
 
 
Given H0 
Given H1 
 
   Reject H0 If 
Power  
N 
(P0) 
 
(P1) 
 
Alpha    Beta If [Z]> Then 
 

The Impact of  90Yttrium (Y90) Radiation Segmentectomy on Unresectable Hepatocellular 
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0.9108  
30 
0.5000  
0.8000  
0.0500    0.0892 
1.9600 
 
A sample size of 30 achieves 91% power to detect a difference (P1-P0) of 0.3000 using a 
two-sided Z test that uses S(P0) to estimate the standard deviation.  The target 
significance level is 0.0500. These results assume that the population proportion under 
the null hypothesis is 0.5000. 
 
 
 
 
 
 
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