Conditions: Hepatocellular Carcinoma HCC
Keywords: Hepatocellular Carcinoma (HCC) Liver transplant Bridge to transplant Stereotactic body radiation therapy (SBRT) Trans-arterial chemoembolization (TACE)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 9
Healthy volunteers: no

Brief summary:
This study will compare stereotactic body radiation therapy (SBRT) to trans-arterial chemoembolization (TACE) as a bridging strategy for patients with HCC undergoing liver transplantation. We propose that SBRT will be associated with longer time intervals between initial treatment and the need for retreatment, compared to TACE, as a "bridge" to liver transplantation in subjects with HCC.

Detailed description:
For patients with hepatocellular carcinoma (HCC) who are waiting for a liver transplant, local treatment of their disease has become the standard of care in an effort to decrease dropout rates and as a means of reducing tumor recurrence after transplantation. For patients undergoing local regional therapy as a bridge to transplantation, trans-arterial chemoembolization (TACE) is the most commonly utilized treatment. However, the best modality for patients undergoing treatment as a bridge to transplantation is unclear. A newer strategy for the treatment of HCC is stereotactic body radiation therapy (SBRT). This study will compare SBRT to TACE as a bridging strategy for patients with HCC undergoing liver transplantation.

Arms:
arm 1: Radiation Therapy arm 2: Procedure/Surgery - Chemoembolization Drug: Doxorubin

Interventions: intervention 1: Stereotactic Body Radiation Therapy (SBRT) intervention 2: Trans-Arterial Chemoembolization (TACE) intervention 3: Doxorubin
Intervention descriptions: intervention 1: SBRT will be delivered in five total fractions, with at a minimum of one day between any two treatments. The entire treatment must be delivered within 15 total days. intervention 2: First day will be administered and a second TACE will be administered after 4 weeks and subsequently if imaging is showing disease progression. Following each TACE procedure all patients will remain in hospital for observation intervention 3: This procedure will be completed with 2 vials of drug eluting beads each loaded with 50 mg of Doxorubin.

Protocol document:
Prot_SAP_001.pdf: 
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Confidential Information 
The information contained in this protocol is confidential.  It is the property of Lahey Hospital & Medical 
Center and should not be copied by or distributed to persons not involved. 
 
 
A Randomized Multi-Center Phase III Study of Individualized Stereotactic Body Radiation Therapy 
(SBRT) versus Trans-Arterial Chemoembolization (TACE) as a Bridge to Transplant in Hepatocellular 
Carcinoma. 
 
Principal Investigator:   Corrine Zarwan, MD 
 
Co-Investigators:            
Klaudia Hunter, MD 
Sebastian Flacke, MD 
Keith Stuart, MD 
Fredric Gordon, MD 
Christopher Molgaard, MD 
Qamar Amir, MD 
Chris Scheirey, MD 
Christopher Hallemeier, MD 
Julie Heimbach, MD 
Dayssy A Diaz Pardo, MD 
Nick Shaheen, MD 
Chi Lin, MD, PhD 
Samuel Galgano, MD 
Aisling Barry, MD 
Laura A. Dawson, MD 
Toshi Clark, MD 
 
 
 
     
NCT #:            NCT03960008 
 
Protocol #: 
LHMC 20193013 
 


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Protocol Signature Page 
 
Title: A Randomized Multi-Center Phase III Study of Individualized Stereotactic Body Radiation Therapy 
(SBRT) versus Trans-Arterial Chemoembolization (TACE) as a Bridge to Transplant in Hepatocellular 
Carcinoma 
 
 
 
 
__________________________________________    
 
_______________ 
 
 
 
 
Signature, Site Principal Investigator  
 
 
             Date 
 
Printed Name: ______________________________ 
 
Institution: _________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Personnel Contact List 
 
Sponsor: 
Lahey Hospital & Medical Center 
41 Mall Rd. 
Burlington, MA 01805 
 
Coordinating Investigator: 
Corrine Zarwan 
Office: (781) 744-8400 
Fax: (781) 744-5192 
Email: Corrine.Zarwan@lahey.org 
 
Statistics:  
Walter Kremers, PhD 
Mayo Clinic, Rochestser, MN           
 
Quality of Life: 
Angie Mae Rodday, PhD 
Tufts Medical Center, Boston, MA      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Synopsis 
 
Title 
A Randomized Multicenter Phase III Study of Individualized Stereotactic Body 
Radiation Therapy (SBRT) versus Trans-Arterial Chemoembolization (TACE) as a 
Bridge to Transplant in Hepatocellular Carcinoma. 
Objective 
Primary:  
 To compare the duration of disease control in treated lesions when utilizing 
SBRT versus TACE as a bridging strategy for patients with HCC eligible for 
liver transplantation.   
 
Secondary: 
 To determine health related quality of life (HRQL) for both treatment arms 
 To compare toxicity  
 To compare number of further interventions 
 To compare pathologic response of treated lesion(s). 
 To compare radiologic response of treated lesion(s). 
 To assess 60 day Post-transplant morbidity and mortality 
Study Design 
A multicenter prospective randomized phase III trial  
Sample Size 
196 subjects will be enrolled 
Eligibility 
Inclusion Criteria 
1. Subjects with HCC are eligible for this trial.  HCC is defined as having at least 
one of the following: 
 Biopsy proven HCC or: 
 A discrete hepatic tumor(s) as defined by the Barcelona (29) criteria for 
cirrhotic subjects, ≥2cm with arterial hyper vascularity and venous or 
delayed phase washout on CT or MRI. 
2. Subjects are liver transplant candidates (actively awaiting organ transplant per 
transplant services in documentation), or, potential liver transplant candidates 
(at the discretion of the liver team and/or Principal Investigator) advised by 
liver transplant services as needing local treatment prior to liver transplant 
evaluation.  
3. Subjects must be within UCSF criteria (one solitary tumor smaller than 6.5 cm, 
or patients having 3 or fewer nodules, with the largest lesion being smaller than 
4.5 cm or having a total tumor diameter less than 8.5 cm without vascular 
invasion) and eligible for potential liver transplant. 
4. Subjects must be eligible for TACE and SBRT procedures. 
5. Subjects must have a life expectancy of at least 12 weeks. 
6. Subjects must be 18 years of age or older. Adult subjects of all ages, both sexes 
and all races will be included in this study.  
7. Subjects must sign an informed consent form approved for this purpose by the 
Institutional Review Board (IRB) of record. 
8. Subjects must have a Child-Turcotte-Pugh (CTP) score ≤8. 
9. Patients must have adequate organ function within 2 weeks of enrollment. 


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 Bone marrow: Platelets ≥30,000/mm3 
 Renal: BUN ≤40 mg/dl; creatinine ≤2.0 mg/dl 
 Hepatic: INR ≤ 1.5 or correctable by Vitamin K, unless anti-coagulated for 
another medical reason 
 Bilirubin < 3.0 mg/dl (in the absence of obstruction or pre-existing disease 
of the biliary tract, e.g. primary sclerosing cholangitis). 
10. Patients’ uninvolved liver volume will be estimated and must be > 700ml. 
11. Patients must have a Zubrod performance status of ≤2. 
12. Patients who are sexually active must agree to the use of contraception 
throughout the duration of the study. 
 
Exclusion Criteria 
1. Subjects in a “special category” as designated by FDA and  the Canadian 
Institutes of Health or Canadian Panel on Research Ethics , Including subjects 
younger than 18, pregnant women, and prisoners. 
2. Refractory ascites that requires paracentesis for management. 
3. Known allergy to intravenous iodinated contrast agents unresponsive to 
prednisone pre-treatment.  
4. History of prior radiation to the liver. 
5. Evidence of metastatic disease. 
6. Presence of a Trans-jugular intra-hepatic porto-systemic shunt (TIPS). 
7. Untreated varices at high risk of bleeding 
8. Bile duct occlusion or a prior diagnosis of an incompetent papilla 
9. Acute infection.  
10. Uncorrectable bleeding disorder.  
11. leukopenia, ANC <1000/ul 
12. hepatic encephalopathy  
13. portal vein thrombosis  
Intervention 
Stereotactic Body Radiation Therapy (SBRT) versus Trans-Arterial 
Chemoembolization (TACE) 
Assessments 
Physician Exam, Abdominal MRI or CT, Chest CT or X-ray, MELD-Na, ALBI score, 
CTP score, Labs, HRQL 
 
 
 
 


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Table of Contents 
 
A.  
ABSTRACT ................................................................................................................................................. 7 
B.  
SPECIFIC AIMS .......................................................................................................................................... 7 
1.0 Primary endpoint: ................................................................................................................................... 7 
2.0 Secondary endpoints: ............................................................................................................................. 7 
C.  
BACKGROUND AND SIGNIFICANCE ................................................................................................... 7 
D.  
RESEARCH DESIGN AND METHODS ................................................................................................. 10 
1.0 Eligibility .............................................................................................................................................. 10 
2.0 Pretreatment Evaluation ....................................................................................................................... 11 
3.0 Randomization Plan ............................................................................................................................. 11 
4.0 Treatment Plan for SBRT ..................................................................................................................... 12 
5.0 Treatment Plan for TACE .................................................................................................................... 14 
6.0 Health Related Quality of Life (HRQL) ............................................................................................... 16 
7.0 Study Calendars .................................................................................................................................... 16 
8.0 Treatment Modifications ...................................................................................................................... 19 
9.0 SBRT Dost Adjustment ........................................................................................................................ 19 
10.0 Toxicity Considerations ..................................................................................................................... 19 
11.0 Assessment of Radiologic Response .................................................................................................. 20 
12.0 Criteria for Discontinuation of Protocol Treatment ........................................................................... 27 
13.0 Efficacy Variables .............................................................................................................................. 28 
14.0 Safety Variables ................................................................................................................................. 29 
15.0 Statistical Considerations ................................................................................................................... 29 
16.0 Sample Size ........................................................................................................................................ 29 
17.0 Statistical Analysis ............................................................................................................................. 30 
18.0 Project Management, Data Management, and Site Monitoring ......................................................... 31 
19.0 Human Subjects .................................................................................................................................. 33 
E.  
REFERENCES ........................................................................................................................................... 34 
F.  
APPENDICES ............................................................................................................................................ 37 
Appendix A: Model for End-Stage Liver Disease (MELD-Na) and Child-Turcotte-Pugh (CTP) ............ 37 
Appendix B: mRECIST for HCCA ............................................................................................................. 38 
Appendix C: TACE Quadrasphere® Microspheres ................................................................................... 39 
Appendix D: FACT-Hep (Version 4) ......................................................................................................... 40 


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A.  
ABSTRACT 
 For patients with hepatocellular carcinoma (HCC) awaiting liver transplantation, local regional 
treatment of their disease has become the standard of care in an effort to decrease dropout rates and as a 
means of reducing tumor recurrence after transplantation (1).  Retrospective single institution data 
suggests a survival benefit for patients undergoing bridging therapy prior to liver transplantation and a 
recent meta-analysis noted a non-significant trend toward reduced waitlist dropout and improved post-
transplant outcomes, while acknowledging the absence of prospective randomized data (2). Additionally, 
there is no standard of care regarding appropriate bridging strategies, although TACE is the most 
commonly performed bridging procedure in The United States (3). Recently, newer bridging modalities 
other than TACE have shown similar rates of local regional control for patients with unresectable HCC. 
One such treatment modality is SBRT.  SBRT has been shown to afford good local control and 
acceptable safety when utilized in patients with HCC. We propose to conduct a multi-center prospective 
randomized Phase III trial to compare SBRT to TACE as a bridging strategy for patients with HCC 
undergoing liver transplantation.   
 
B.  
SPECIFIC AIMS 
Hypothesis: SBRT will be associated with longer time intervals between initial treatment and the need 
for retreatment, compared to TACE, when used as a “bridge” to liver transplantation in subjects with 
HCC. 
 
 1.0 Primary endpoint: 
Time from randomization to date of progression or residual disease of previously treated lesions as 
determined by the date of the radiologic imaging.   
 
 2.0 Secondary endpoints: 
 Health related quality of life (HRQL) for both treatment arms 
 Toxicity 
 Number of further interventions  
 Pathologic response of treated lesion(s) 
 Radiologic response of treated lesion(s) 
 60 day Post-transplant morbidity and mortality 
 
C.  
BACKGROUND AND SIGNIFICANCE 
HCC is the sixth most common cancer with an increasing incidence worldwide, and is the third leading 
cause of cancer-related death (4-5). Given that people who develop HCC typically have concomitant 
cirrhosis, the best opportunity for cure for most patients is liver transplantation.  Because organ donors 
are scarce, patients who are eligible for liver transplantation may wait many months before receiving a 
liver.  Recently, local regional interventions have been utilized as a temporizing strategy to "bridge" 
individuals with HCC who are awaiting transplantation.  The aims of bridging treatments include: 
decreasing the waiting list dropout rate for transplantation due to HCC progression beyond acceptable 
criteria; reducing recurrent HCC after transplantation; and improving post-transplant overall survival 
(6). For patients undergoing local regional therapy as a bridge to transplantation, TACE is the most 
commonly utilized treatment (7). 
 


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TACE is a therapy that combines the local delivery of chemotherapy with the induction of tumor 
ischemia through obstruction of the feeding vessels. Two randomized controlled trials (RCTs), 
conducted in Europe and Asia, showed an increased survival for subjects treated by embolization with 
an emulsion of a chemotherapy agent and iodized oil when compared to conservative treatment. Llovet 
et al. reported 1-year and 2-year survival of 82% and 63%, respectively. Lo et al. found significant 
improvement in survival for Asian HCC subjects treated by chemoembolization (8,9). Drug-Eluting 
Beads (DEB) such as Quadraspheres® (of which there are several on the market) are an agent for 
chemoembolization with the ability to load doxorubicin. In vitro data has shown a slow release of 
doxorubicin over time with a decreased systemic blood serum levels and increased tumor tissue levels of 
the chemotherapeutic agent (10-13).  
 
Several pilot studies have evaluated the safety and efficacy of DEB-TACE. Poon et al showed good 
tumor response and limited toxicity in subjects with incurable HCC and Child-Pugh class A cirrhosis. 
No dose-limiting toxicity was observed for up to 150 mg doxorubicin. The pharmacokinetic study 
showed a low peak plasma doxorubicin concentration and no systemic toxicity was observed. The 
treatment-related complication rate was 11.4%. There was no treatment-related death. Among 30 
subjects who completed 2 courses of DEB-TACE, the partial response rate and the complete response 
rates were 50 and 0%, respectively, by response evaluation criteria in solid tumors (RECIST) criteria at 
computerized tomography scan 1 month after the second DEB-TACE. By modified RECIST criteria, 
taking into account the extent of tumor necrosis, 19 (63.3%) subjects had a partial response and 2 (6.7%) 
had a complete response (14). Varela et al evaluated the safety, pharmacokinetics and efficacy of TACE 
using drug eluting beads. DEB-TACE was well tolerated with an acceptable safety profile. Two cases 
developed liver abscess, one leading to death. Response rate was 75% (66.6% on intention-to-treat). 
Doxorubicin Cmax and AUC were significantly lower in DEB-TACE subjects than in conventional 
TACE. After a median follow-up of 27.6 months, 1- and 2-year survival is 92.5 and 88.9%, respectively 
(15). 
 
Malagari et al conducted an open-label, single-center, single-arm study of DEB-TACE in 62 cirrhotic 
subjects with documented solitary unresectable HCCs. Mean tumor diameter was 5.6 cm (range, 3-9 cm) 
classified as Okuda stages 1 (n=53) and 2 (n=9). Subjects received repeat embolizations with 
doxorubicin-loaded beads every 3 months (maximum of three treatments). The maximum doxorubicin 
dose was 150 mg per embolization, loaded in DC Beads® of 100-300 or 300-500 μm. Post-treatment, an 
objective response according to the European Association for the Study of the Liver (EASL) criteria was 
observed in 59.6%, 81.8%, and 70.8% across three treatments. At 9 months a complete response was 
seen in 12.2% of subjects. Severe procedure-related complications were seen in 3.2% (cholecystitis, 
n=1; liver abscess, n=1). Post-embolization syndrome was observed in all subjects (16). Several studies 
have since shown that DEB-TACE not only is favorable compared to conventional TACE regarding side 
effects but may elicit a better overall outcome. Song demonstrated in the Asian population a better 
treatment response and delayed tumor progression with DEB-TACE (17). 
 
In a multicenter study including 201 European subjects (PRECISION V), use of DC Beads® resulted in 
a clinically and statistically significant reduction in liver toxicity and drug-related adverse events 
compared with conventional TACE with lipiodoland doxorubicin (18, 19). Two other trials reported 
higher rates of tumor response and longer time to progression for the loaded DC Bead as compared to a 
bland embolic microsphere with similar characteristics (20, 21).  As a result of these investigations, 
DEB-TACE has been increasingly used as therapy for bridging treatment in subjects awaiting 
transplantation with HCC, although embolic beads without chemotherapy are also widely used (22). 
 


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Despite its increased utilization, DEB-TACE (or any strategy) as a bridge to liver transplantation 
remains of uncertain benefit. To date, multiple retrospective analyses suggest a benefit of pre-operative 
treatment for subjects with HCC awaiting liver transplantation, but no data from prospective randomized 
trials are available establishing DEB-TACE as an effective strategy to reduce the risk of recurrent HCC 
following transplantation or to improve survival (22).  Furthermore, there is conflicting data regarding 
whether TACE should be performed with chemotherapy or as a “bland” particle and whether one or 
more procedures ought to be performed. Additionally, there has been no attempt to compare TACE, 
radiofrequency ablation (RFA), resection, or other treatment strategies utilized to bridge subjects to liver 
transplantation. In the absence of a standardized approach, there is no definitive standard-of-care either 
within a given treatment strategy or between different treatment approaches and hence, different 
preoperative treatments using varied protocols are employed by different institutions for different 
individual subjects awaiting transplant.  
 
A newer strategy for the treatment of HCC is SBRT.  Historically, external beam radiation lacked 
adequate precision and was considered too toxic to be utilized to ablate tumors within the liver.  With 
large volume irradiation, the risk of radiation-induced liver disease (RILD) is prohibitive (23-27).  
However, over the past two decades, advances in computer and imaging technologies have improved 
conformal radiation such that it has become a feasible and safe technique for focal treatment to the liver 
with RILD rates of less than 10% in early stage patients.  SBRT uses a small number of high dose 
fractions of highly conformal radiation therapy, delivered with high geometric precision and accuracy.  
SBRT offers some theoretical advantages compared to other local regional strategies for the treatment of 
HCC.  First, a uniform dose of radiation is delivered to the entire tumor. There is no necessity of 
uniform blood flow which can be an issue with treatments such as TACE directed through liver 
vasculature.  Second, no direct manipulation of the primary tumor is necessary.  Hence, any concerns for 
HCC spread through needle tract dissemination such as can occur in radiofrequency ablation or other 
percutaneous interventions are absent.  Third, given that no direct manipulation of hepatic vasculature is 
necessary, potential damage to vascular structures is of no concern.  Fourth, it may be more cost 
effective than other treatment strategies as there is no requirement for hospitalization in comparison with 
subjects undergoing TACE.  
 
Retrospective studies and two prospective studies suggest that SBRT to the liver can be used safely for 
the treatment of metastatic cancer with local control rates of 75% to 100% at 1 to 2 years (28).  Data 
from Bujold et.al., utilizing SBRT for locally HCC, showed good effect and acceptable toxicity when 
compared to historical data regarding TACE or other equivalent strategies. The one year tumor control 
rate was 87% (29). A retrospective comparison by Sapir et.al. compared HCC patients with similar 
disease burdens treated with either SBRT or TACE and found SBRT to be safe for 1 to 2 tumors while 
providing better local control (30). Furthermore, a recent comparison of SBRT to TACE or RFA by 
Sapisochin et.al. found that SBRT can be safely utilized as a bridge to transplant in HCC patients as an 
alternative to conventional bridging strategies (31). 
 
Given these potential advantages, in September 2014 Lahey Hospital and Medical Center initiated a 
randomized feasibility trial prospectively comparing SBRT to DEB-TACE in the treatment of HCC as a 
bridge to liver transplantation. With an expected enrollment of 60 patients, we have presently enrolled 
45 patients with 31 eligible for evaluation. These data were presented as an Oral Abstract at the 
American Society of Clinical Oncology Gastrointestinal Cancer Symposium in January 2017. While 
preliminary, our data indicate that SBRT appears at least as effective as DEB-TACE at controlling 
tumors prior to transplant, may engender less toxicity, may better preserve quality of life, and may cost 
less (32-33). 


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In the current study, we propose to compare individualized SBRT to TACE as a bridge to liver 
 
transplantation in patients with HCC.  
 
D.  
RESEARCH DESIGN AND METHODS  
1.0 Eligibility 
1.1 Inclusion Criteria 
 Subjects with HCC are eligible for this trial. HCC is defined as having at least one of the 
following: 
 Biopsy proven HCC or: 
 A discrete hepatic tumor(s) as defined by the Barcelona (29) criteria for cirrhotic subjects, ≥
2cm with arterial hypervascularity and venous or delayed phase washout on CT or MRI. 
 Subjects are liver transplant candidates (actively awaiting organ transplant per transplant services 
in documentation), or, potential liver transplant candidates (at the discretion of the liver team 
and/or Principal Investigator) advised by liver transplant services as needing local treatment prior 
to liver transplant evaluation.  
 Subjects must be within UCSF criteria (one solitary tumor smaller than 6.5 cm, or patients 
having 3 or fewer nodules, with the largest lesion being smaller than 4.5 cm or having a total 
tumor diameter less than 8.5 cm without vascular invasion) and eligible for potential liver 
transplant. 
 Subjects must be eligible for standard TACE and SBRT procedures. 
 Subjects must have a life expectancy of at least 12 weeks. 
 Subjects must be 18 years of age or older. Adult subjects of all ages, both sexes and all races will 
be included in this study.  
 Subjects must sign an informed consent form approved for this purpose by the Institutional 
Review Board (IRB) of record. 
 Subjects must have a Child-Turcotte-Pugh (CTP) score ≤8. 
 Patients must have adequate organ function within 2 weeks of enrollment. 
 Bone marrow: Platelets ≥30,000/mm3 
 Renal: BUN ≤40 mg/dl; creatinine ≤2.0 mg/dl 
 Hepatic: INR ≤ 1.5 or correctable by Vitamin K, unless anti-coagulated for another medical 
reason 
 Bilirubin < 3.0 mg/dl (in the absence of obstruction or pre-existing disease of the biliary 
tract, e.g. primary sclerosing cholangitis). 
 Patients’ uninvolved liver volume will be estimated and must be > 700ml. 
 Patients must have a Zubrod performance status of ≤2. 
 Patients who are sexually active must agree to the use of contraception throughout the duration 
of the study. 
 
          
            1.2 Exclusion Criteria 
 Subjects in a “special category” designated by the Public Health Service, Including subjects 
younger than 18, pregnant women, and prisoners. 


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 Refractory ascites that requires paracentesis for management. 
 Known allergy to intravenous iodinated contrast agents unresponsive to prednisone pre-
treatment.  
 History of prior radiation to the liver. 
 Evidence of metastatic disease. 
 Presence of a Trans-jugular intra-hepatic porto-systemic shunt (TIPS). 
 Untreated varices at high risk of bleeding 
 Bile duct occlusion or a prior diagnosis of an incompetent papilla 
 Acute infection.  
 Uncorrectable bleeding disorder.  
 leukopenia, ANC <1000/ul 
 hepatic encephalopathy  
 portal vein thrombosis 
 
2.0 Pretreatment Evaluation 
Subjects will be consented for the study prior to starting treatment. 
 
2.1 Subjects will undergo a comprehensive liver evaluation per the treating physician’s discretion, 
including a complete history of viral status (Hep. C, Hep. B or No) and physical examination, baseline 
assessments of organ function and documentation of measurable disease (contrast-enhanced CT or MRI) 
parameters chest CT or Chest X-ray), weight, and health related Quality of Life measures.   
 
2.2 Laboratory evaluation.  
 
2.3 Assessment of clinical measures of severity of liver disease: The Model for End-Stage Liver Disease 
(30) (MELD-Na) and the CTP classification are models used for the clinical assessment of subjects with 
liver dysfunction (Appendix A). Subjects with CTP classification Grade A versus Grade B appear to 
have increased sensitivity to radiation. Additionally, in a study of subjects treated with SBRT for HCC 
or intrahepatic cholangiocarcinoma, 17% experienced progression from CTP Grade A to Grade B within 
3 months after radiation therapy (31, 32), suggesting that CTP may be a useful assessment of worsening 
liver function. MELD may perform even better than CTP at evaluating liver function (33). We propose 
to record these clinical measures (MELD-Na and CTP, and Albumin-Bilirubin (ALBI)) score, and 
assess their potential contribution to individualize our assessment of liver injury that could be used to 
adjust liver dose. 
 
2.4 Assessment can be performed by any medical provider in the liver transplant team including 
hepatology/gastroenterology, medical oncology, radiation oncology, interventional radiology and 
transplant surgery or as medically necessary per standard treatment 
 
3.0 Randomization Plan  
All consented subjects will receive a Study Identification Number (SID) in the EDC system. The SID 
number will be a 4 digit number. The first two digits are site number. Site number will be assigned by 
the Coordinating Center at Lahey and it will start with 01 with 1 increment for each site (that is 01, 02, 
03, etc.). The last two digits are the patient screening order starting from 01. Eligible subjects will be 
randomized after eligibility is confirmed by the provider, as soon as practical to the baseline tumor scan. 
Randomization will be performed using randomly selected block sizes of 2, 4 and 6 and stratified by the 


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following factors identified at screening: CTP score (either A or B) and disease etiology (with or without 
Hepatitis C). The randomization ID will be a 5 digit number in the form of ABCDE where, AB denote 
the site number, C indexes the four strata used for the randomization and DE index the order of 
screening at that site. C will be one of the numbers from 1 to 4. DE is the patient screening order starting 
from 01.Each study site will receive randomization list from the Coordinating Center at Lahey and 
randomize the eligible subjects individually. Site staff involved in randomizing subjects will not be 
aware of the randomization sequence before randomization. Randomization will be documented on both 
source document and EDC indicating assignment. If a patient is lost from the study because they are 
unable to receive their randomized treatment then an additional patient will be enrolled.(i.e., unable to 
meet SBRT dose constraints or achieve an acceptable respiratory motion strategy for SBRT). Individual 
randomization codes will be not be reused.   
 
4.0 Treatment Plan for SBRT 
4.1 Once randomized, subjects will be consented per the site’s standard for SBRT or TACE prior to 
      starting treatment.  
 
4.2 Placement of Fiducial Markers 
Fiducial markers are highly encouraged but not mandatory. This will be decided by the treating 
radiation oncologist based on clinical information and treatment delivery capabilities. If used, 
fiducials will be placed percutaneously within the liver in close proximity of the target tumor. At 
least 3 fiducial markers are recommended when used.  
 
4.3 Stereotactic Body Radiotherapy   
4.3.1 Conformal treatment planning will be used for all subjects, based on a simulation CT scan.  
Either 3D Conformal Radiation Therapy, Intensity Modulated Radiation Therapy, or Arc Rotational 
Therapy may be used as appropriate.   
4.3.2 Energy: Treatment will be delivered with 6 - 18 MV photons 
4.3.3 Localization, simulation, and immobilization: All subjects must undergo CT simulation prior to 
treatment.  A patient will be simulated using an immobilization device that allows for reproducible 
treatment setup using an Alpha Cradle, Vac-Lok, or other commercially available SBRT 
immobilization system. Patients will be simulated supine with both arms up if tolerated. IV and oral 
contrast will be used at the discretion of the treating radiation oncologist. CT images should be 
obtained from at least 2cm above the dome of the diaphragm to the bottom of the kidneys. 1-2mm 
cuts should be performed for high resolution delineation of the tumor and surrounding structures.   
 
A motion management strategy is strongly encouraged to minimize liver motion. Acceptable motion 
management strategies include active breathing control (ABC) or similar breath hold device, 
respiratory gating, tumor tracking using Cyberknife synchrony system, or abdominal compression 
using an abdominal belt or paddle. Patients who cannot be treated using one of these techniques may 
be treated free breathing with a tumor-specific internal target volume (ITV) if tumor motion is ≤10 
mm in maximal extent in any one direction and treatment planning dose constraints can be met. 
4DCT scan is required when a tumor-specific internal target volume (ITV) is being used. 
 
Prior to each SBRT treatment, the liver will be imaged. For patients with fiducial markers within the 
liver, the tumor may be localized using fluoroscopy, orthogonal kV images, or cone-beam CT scans 
using the fiducials as surrogate markers for the liver tumor. For patients without fiducial markers, 
cone-beam CT or other types of volumetric image guided radiation therapy (IGRT) available (e.g. 


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MR guidance) will be used to image the tumor and/or portion of the liver where the tumor lies as and 
soft tissue surrogates for the tumor for positioning prior to treatment. 
 
Documentation of CT-based simulation including setup, use of IV contrast, type of motion 
management, and image-guidance used for treatment delivered is required.   
 
4.3.4 Radiation target volumes: The gross tumor volume (GTV) will be defined using the planning 
CT scan with the aid of a diagnostic imaging (contrast-enhanced CT or MRI). GTV is defined as all 
parenchymal HCC. No clinical target volume (CTV) will be used in this study.  The PTV expansion 
will be determined based upon the immobilization device(s) used. Minimum PTV margin will be 0.5 
cm circumferentially.  
 
4.4 SBRT Planning Guidelines - Radiation Doses: 
4.4.1 PTV Target Doses 
4.4.1.1 The highest allowable doses to the target volumes that maintain normal tissue 
constraints should be used. The prescription isodose surface covers at least 95% of PTV. A 
goal is that 100% of the GTV is encompassed by the prescription dose.  Prescription dose 
should not extend beyond the PTV. 
4.4.1.2 Variations 
 Minor variation is defined as minimum PTV dose falling between 85% and 94.9% of   
the prescription isodose line 
 Major variation (unacceptable) is defined as minimum PTV dose < 85% of the 
prescription isodose line. 
4.4.1.3 Maximum doses are defined at 1 cc of volume. Maximum dose should be within the 
PTV <150% of the prescribed dose. 
4.4.2 Critical Normal Tissue Constraints 
Mandatory dose constraints: 
Liver minus GTV’s: volume >700cc  
Liver minus GTV’s: Mean <18 Gy 
Spinal Cord: max dose to 0.5cc is 25Gy 
Stomach:  max dose to 0.5cc 30Gy 
Duodenum: max dose to 0.5cc is 30Gy 
Small Bowel: max dose to 0.5cc is 30Gy 
Large Bowel: max dose to 0.5cc is 32Gy 
Esophagus: max dose to 0.5cc is 32Gy 
Kidneys bilateral mean dose <10Gy, or if there is only one kidney V10Gy<10% (or constraint 
for contralateral kidney, if mean dose is >10Gy to combined both kidneys) 
Heart max 0.5cc <105% PTV prescription dose 
 
Optional Dose Constraint: 
Liver minus GTV’s:  V10Gy <70% 
Common bile duct: max dose to 0.5cc <50Gy 
Skin external: max 0.5cc<32 Gy 
4.4.3 Radiation Schedule 
4.4.3.1 SBRT will be delivered in five total fractions. The entire treatment must be delivered 
within 15 total days.   


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4.4.3.2 Three dimensional treatment planning will be used for all subjects. Volumes of tumor 
and normal liver will be determined, and DVH based treatment planning will be carried out, 
targeted to the tumor only. 
4.4.3.3 Radiation Prescription Dose: The goal is to use the highest allowable prescription dose 
to the primary target while respecting normal tissue constraints. Dose prescription is based on 
the volume of normal tissues irradiated (correlated with mean liver dose) as well as proximity 
of stomach, duodenum, small and large bowel (GI luminal structures) to the target volumes. In 
the absence of adjacent GI luminal structures that may limit dose, the PTV dose prescription 
should be based on mean liver dose (MLD is the mean dose to the liver minus GTV’s). See 
table below. 
 
The dose to multiple PTVs within the same subject may vary. Conformality of the prescription 
dose and the 30Gy isodose lines are planning goals.  
For CTP A: 27.5 Gy - 50 Gy in 5 fractions  
For CTP B: 27.5 Gy - 40 Gy in 5 fractions. 
 
Table 1: Priority Constraint - Mean Liver Dose (Gy) [liver-GTV’s] 
GTV 
Prescription Dose If max MLD exceeded 
<15.0 
50 Gy 
15.0 
40 Gy 
15.5 
35 Gy 
16.0 
30 Gy 
17.0 
27.5 Gy 
 
5.0 Treatment Plan for TACE 
Subjects will be consented to TACE with Quadrasphere® Microspheres either with or without 
doxorubicin as per standard of care at the treating institution. 
 
5.1 Unilateral femoral approach 
Selective catheterization of the hepatic artery will be performed. Vascular access is obtained via the 
common femoral artery and a guide-wire advanced under fluoroscopy. A 5/6 F sheath is then 
inserted over a guide-wire. The superior mesenteric artery is selected and an angiogram performed to 
identify any aberrant arterial anatomy and verify antegrade portal vein flow. The celiac axis is then 
selected and an angiogram completed. The catheter and guide-wire are used to select proper hepatic 
artery and a limited angiogram performed to identify branches of the hepatic artery. The right and 
left hepatic is selected distal to the cystic artery if visualized, depending of the lesion to be treated 
using the appropriate catheter. 
 
5.2 Super-selective chemoembolization  
5.2.1 Once vascular supply of the tumor is identified super-selective chemoembolization of the 
tumor supplying artery is performed with catheter positioned in second or third order side branches. 
If the anatomy is sufficiently visualized with fluoroscopy, and a cone-beam CT is available, a cone-
beam CT will be performed to assess appropriate segmental contrast distribution covering the target.  
5.2.2 TACE will be performed with (see Appendix C). Two vials of beads will be prepared with, per 
the discretion of the treating physician, 50mg of Doxorubicin. Iodine contrast will be mixed 


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according to manufacturer guidelines and used to guide the delivery. Bead size will be at the 
discretion of the treating physician. 
5.2.3 TACE without doxorubicin will be performed in an identical manner. Bead size will be at the 
discretion of the treating physician. 
5.2.3 Target area will be embolized until segmental arterial stasis is achieved. In the presence of 
multifocal disease selective catheter positioning will be repeated for each lesion. 
5.2.4 If available, final cone-beam CT will be performed to document distribution of the embolic 
material. 
 
5.3 Following the TACE procedure all subjects will remain in hospital per standard of care for extended 
recovery. 
 
5.4 If stasis of arterial flow to the tumor(s) was not achieved, additional TACE treatments will be 
administered, each approximately 4-6 weeks after the prior TACE procedure was performed until 
stasis is achieved with a maximum of three TACEs administered as initial therapy. After the first 
TACE, any additional treatments will be performed per the discretion of the treating Interventional 
Radiology Team.   
 
Completed treatment will be defined by the date of the final TACE procedure considered as 
part of initial therapy (up to 3 TACE treatments).   
 
5.5 Progression of disease will be confirmed with imaging done greater than 8 weeks from last treatment 
date.  Images collected per transplant protocol within the 8 weeks of treatment will be repeated, as 
per study schematic, to confirm response to treatment or progression.  
 
If there is a radiological discrepancy regarding findings of residual, recurrent or progressive disease, 
the site must submit the subject’s de-identified images to the centralized radiology panel overseen at 
LHMC. The panel will make the final determination and notify the site investigator.  Any additional 
ablative treatment, be it to repeat TACE or SBRT or other therapy will be determined at that time. 
All treatment will be individualized by subject at the discretion of the transplant team. 
 
5.6 Additional local treatment to the target lesion(s) in the assigned treatment arm:   
Group 1: SBRT (Arm A), subjects with residual disease or local recurrence in the previously treated 
lesion(s) on radiologic imaging at any point in follow up will be considered as having met the 
primary endpoint of the trial and they are off the study. Patients may be considered candidates for 
additional local regional therapy to the treated lesion of any kind per the discretion of the treating.   
 
Group 2: TACE (Arm B), subjects with residual disease or local recurrence in the previously treated 
lesion(s) on radiologic imaging at any point in follow up will be considered as having met the 
primary endpoint of the trial and they are off the study. Patients may be considered candidates for 
additional local regional therapy to the treated lesion(s) of any kind per the discretion of the treating 
providers.   
 
5.7 Patients in either group who develop new intrahepatic lesion(s) at any point in follow up will not 
have met the primary endpoint as they have not progressed at the site of previous treatment. They 
may be considered candidates for additional local regional therapy to the new site of disease of any 
kind per the discretion of the treating providers and will be followed per Table 4 thereafter. 
 


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5.8 If patients have no evidence of progression or residual disease in the treated lesion(s) but develop 
new tumors outside the previously treated field and, per the discretion of the treating providers, 
require treatment with systemic therapy, the patient will be censored from the data analysis for the 
primary endpoint and will be discontinued from the study. 
 
6.0 Health Related Quality of Life (HRQL) 
To assess HRQL, subjects with be assessed using the Functional Assessment of Cancer Therapy–
Hepatobiliary (FACT-Hep) Questionnaire (Appendix D). This 45-item self-report instrument is designed 
to measure HRQL in patients with hepatobiliary cancers and is one of the most widely-used instruments 
in this clinical area. The FACT-Hep consists of the 27-item FACT-G, which assesses generic HRQL, 
and the 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues such as pain, 
appetite, and cramping.3,4 The FACT-G is divided into four HRQL domains: physical well-being (7 
items), social/family well-being (7 items), emotional well-being (6 items), and functional well-being (7 
items). All items have a 7-day reference period and are scored from 0-4 (“not at all” to “very much”), 
with higher scores indicating better HRQL. Score ranges are 0-28 for physical well-being, 0-28 for 
social/family well-being, 0-24 for emotional well-being, 0-28 for functional well-being, and 0-72 for 
HS. All subscale scores from the FACT-G and HS can be summed together to create a total FACT-Hep 
score, with a possible range of 0-180. The FACT-Hep takes approximately 10 minutes to complete.5  
 
Subjects assigned to the SBRT arm will complete the FACT-Hep at baseline/screening, at the time of 
the second fraction of the SBRT treatment (post treatment prior to discharge), on the last day of 
treatment (post treatment prior to discharge), 2 weeks after treatment, and at the time of follow-up scans 
at 3, 6, 9, 12, 15, 18, 21 and 24 months from randomization or until liver transplantation. 
 
Subjects assigned to the TACE arm will complete the FACT-Hep at baseline/screening, TACE treatment 
#1(post treatment prior to discharge), 2 weeks after treatment #1, at TACE treatment #2 (post treatment 
prior to discharge), 2 weeks after treatment #2, at TACE treatment #3(post treatment prior to discharge), 
and 2 weeks after treatment #3. The number of TACE treatments will vary from 1 to 3, so not all HRQL 
assessments will be collected for all subjects. The HRQL assessment at the time of the last TACE will 
serve as the HRQL assessment on the last day of treatment, while the HRQL assessment done 2 weeks 
after the last TACE assessment will serve as the 2 weeks after treatment assessment. HRQL will then 
continue to be collected at the time of follow up scans at 3, 6, 9, 12, 15, 18, 21 and 24 months from 
randomization or until transplantation. 
 
7.0 Study Calendars 
Table 2: Study Calendar for SBRT (Arm A) 
Active Treatment-SBRT 
Pre-Rx 
Eval1 
(screening) 
SBRT 
fractions (5 
in 2 week 
period)7 
Last fraction 
of treatment 
(prior to 
discharge) 
2 Week Follow 
up post 
treatment (+/- 3 
days) 
History and Physical Exam 
X 
 
 
X 
Weight 
X 
 
 
X 
CBC with differential 
X2 
 
 
X 
AST, ALT, Alk Phos, Total 
Bilirubin, Albumin  
X2 
 
 
X 
Na, BUN/Creatinine 
X2 
 
 
X 
INR 
X2 
 
 
X 


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AFP (for HCC) 
X2 
 
 
 
Toxicity Notation 
X 
 
X 
X 
Multiphasic MRI or CT of 
the abdomen within 4-6 
weeks prior to enrollment 
X 
 
 
 
Chest CT or Chest x-ray 
within 1 year prior to 
enrollment 
X 
 
 
 
MELD-Na, ALBI, and CTP 
assessment 
X3 
 
 
X 
HRQL4 
X 
X 7 
X 
X 
Randomization5 
X  
 
 
 
Simulation 
X 
 
 
 
Treatment: SBRT6 
 
X (over a 
two week 
period) 
 
 
1 Within 2 weeks prior to randomization unless otherwise specified   
2 If multiple lab results are available within the screening period, use the most recent results before randomization.   
³ If calculations are performed multiple times, use the most recent value before randomization 
4 HRQL questionnaire: FACT-Hep 
5 Randomization may occur after all screening procedures are complete and eligibility has been met.  See section 3.0 for more 
details. 
6Initial treatment should be scheduled within 3 weeks of randomization.  
7See section 6.0 for details on HRQL administration timelines.           
 
Table 3: Study Calendar for TACE (Arm B) 
 
 
 
Active Treatment – TACE 
 
 
Pre-Rx 
Eval1 
(screening) 
Initial 
TACE 
 
2 week Follow up 
post initial TACE 
(+/- 3 days) 
Second and 
Following 
TACE 
treatments  
2 week 
Follow up 
post TACE 
(+/-3 days) 
History and  
Physical Exam 
X 
X 
X (per MD SOC 
only) 
X 
X (per MD 
SOC only) 
Weight 
X 
X 
X 
X 
X 
CBC with 
differential 
X2 
X7 
X 
X7 
X 
AST, ALT, Alk 
Phos, Bilirubin, 
Albumin 
X2 
X7 
X 
X7 
X 
Na, BUN/Creatinine 
X2 
X7 
X 
X7 
X 
INR 
X2 
X7 
X 
X7 
X 
AFP (for HCC) 
X2 
X7 
 
X7 
 
Toxicity Notation 
X 
X 
X 
X 
X 
MRI or CT of the 
abdomen within 4-6 
weeks prior to 
enrollment 
X 
 
 
 
 


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Chest CT or chest x-
ray within 1 year 
prior to enrollment 
X 
 
 
 
 
MELD-Na ALBI, 
and CTP assessment 
X³ 
 
X 
 
X 
HRQL4, 5 
X 
X5 
X 
X5 
X 
Randomization6 
X 
 
 
 
 
Treatment:TACE6 
 
X 
 
X 
  
1 Within 2 weeks prior to randomization unless otherwise specified. 
2 If multiple lab results are available within the screening period, use the most recent results before randomization.   
³ If calculations are performed multiple times, use the most recent value before randomization. 
4 HRQL questionnaire: FACT-Hep 
5 See section 6.0 for details on HRQL administration timelines. 
6 Randomization may occur after all screening procedures are complete and eligibility has been met.  Initial treatment should 
begin within 3 weeks of randomization. See section 3.0 for details on randomization.             
7 If required labs were performed within 3 days of a TACE procedure, they do not have to be repeated unless requested by 
treating physician. 
 
Table 4: Study Calendar for FOLLOW-UP (Both Arm A and Arm B) 
Follow-up After Initial Treatment Phase 
 
 
3 months 
(+/- 4 weeks) 
post 
randomization 
6 months 
(+/- 4 weeks) 
post 
Randomization 
Q 3 months to 
24 months post-
randomization 
(+/- 4 weeks) 
60 days post-
transplantation 
(+/- 2 weeks) 
History and Physical Exam  
X 
X 
X 
 
Weight 
X 
X 
X 
 
CBC with differential 
X 
X 
X 
 
AST, ALT, Alk Phos, 
Bilirubin 
X 
X 
X 
 
Na, BUN/Creatinine 
X 
X 
X 
 
INR 
X 
X 
X 
 
AFP (for HCC) 
X 
X 
X 
 
Toxicity Notation  
X 
X 
X 
 
Survival Status 
X 
X 
X 
X 
MRI or CT of the abdomen1 
(mRECIST for HCC) 
X 
X 
X 
 
Chest CT or X-ray1  
X 
X 
X 
 
MELD-Na CP ALBI 
assessment  
X 
X 
X 
 
Assessment of disease 
progression, recurrence and 
transplantation status  
X 
X 
X 
 
HRQL2 
X 
X 
X 
 
Mortality and Morbidity 
 
 
 
X 
1 Scans will be obtained in accordance to liver transplantation protocols and timeframes and may not occur within the 
allotted time frame noted above. This will not be considered a protocol deviation as long as they are performed per 
United Network for Organ Sharing (UNOS) guidelines. 
2 HRQL questionnaire: FACT-Hep  
 


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8.0 Treatment Modifications 
8.1 Hepatic Toxicity: Subjects will be evaluated for symptoms and signs of RILD or other toxicity. 
 
It is expected that a proportion of subjects will have transient elevation of liver enzymes during 
treatment. Repeat of all Grade 4 LFTs is required within 5-10 days following the first abnormal lab 
value to determine if the Grade 4 levels are transient (defined here as <10 days) or persistent. 
Subjects exhibiting hepatic toxicity ≥ 5-20x baseline LFT’s will be evaluated with radiological 
imaging procedures to assess whether change in LFTs are due to tumor progression or treatment 
toxicity. Subjects whose progressive liver function abnormalities while under treatment are deemed 
due to tumor progression will stop all protocol treatment and will be managed and followed per 
physician standard of care. Subjects with treatment induced hepatic toxicity of greater than 20x 
baseline elevation will not receive further protocol treatment unless and until liver function tests 
have returned to less than 5x subjects baseline value. Subjects will be evaluated for symptoms and 
signs of RILD or other toxicity per the schedule described in the protocol or more frequently 
depending on the clinical judgment of the treating team.  If recovery of hepatic function requires an 
interruption of treatment of more than 30 days, patients will be withdrawn from the study. 
8.2 Other Toxicity 
The occurrence of treatment-related Grade 4 adverse events in any organ system will prompt 
discontinuance of protocol therapy while appropriate physical examination, laboratory, and imaging 
assessments are undertaken per each institution’s standard of care. Protocol treatment will not be 
resumed in the absence of recovery from adverse events of this magnitude. Once recovery to ≤grade 2 
has occurred, treatment may continue at the discretion of the treating physician. 
 
8.3 Exceptions that will not require discontinuation of therapy 
 Grade 3 or 4 asymptomatic hypo-albuminemia or decreased lymphocytes.  
 Transient (< 48 hours) asymptomatic grade 3 fasting hyperglycemia in type II diabetics. 
 
9.0 SBRT Dost Adjustment 
 
There will be no dose adjustments for SBRT treatment.  
 
10.0 Toxicity Considerations 
The criterion used for the grading of toxicities is the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0.  
10.1 Expected Toxicities after TACE: 
 Abdominal pain 
 Nausea 
 Vomiting 
 Fatigue 
 
10.2 Expected Acute Toxicities after SBRT: 
 Fatigue 
 Weight loss 
 Nausea, vomiting, or anorexia.  
 Abdominal discomfort. 
 Skin irritation 
 Increased frequency of bowel movements or change in stool consistency 
10.3 Possible long term toxicities after SBRT: 


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 Gastric or Bowel injury (ulceration, bleeding, perforation, fistula formation, or obstruction) 
 Biliary obstruction due to inflammation or sclerosis 
 Liver abscess 
 Hepatic subcapsular injury 
 Decreased renal function. 
 Rib fracture 
 Myositis 
 Radiation-induced liver disease (RILD) including potentially fatal liver injury.   
 In subjects who have Grade 4 elevation of liver enzymes levels and/or in subjects with early 
nonspecific signs or symptoms of liver injury, close follow-up is recommended with repeat blood 
work. If no tumor progression is documented in these subjects, liver injury will be presumed to 
be treatment related. 
 
 
Only grade ≥2 toxicities will be considered in the statistical analysis. The following toxicities will 
require subjects to be removed from protocol treatment if the protocol treatment has not yet been 
completed.  Patients will be followed per physician standard of care. 
 Grade ≥4 hepatic toxicity for changes in AST, ALT, alkaline phosphatase, or platelet counts 
attributed to treatment and not attributable to disease progression. Transient grade 4 (less than 10 
days) hepatic toxicities are acceptable.  
 Grade ≥4 Upper GI bleeding (attributed to treatment, and not attributable to disease 
progression). 
 Death due to any cause.   
 
 
11.0 Assessment of Radiologic Response  
11.1 Imaging Acquisition  
Participating centers will need to comply with minimum technical requirements for CT and MR as 
shown in Tables 5 and 6.  
11.1.1 Importance of High-Quality, Carefully Timed Multiphasic Contrast-Enhanced Imaging  
It is well known in the imaging community that optimal detection of liver nodules with predominant 
arterial vascular supply (such as HCC) on cross-sectional imaging (CT or MRI) requires careful 
timing of image acquisition to take place during late arterial phase of contrast enhancement. At that 
point in time there is maximal signal-to background contrast between capillary enhancement in the 
lesion and surrounding hepatic parenchyma. In most patients, early arterial phase imaging does not 
improve tumor conspicuity by either quantitative or subjective analysis. 
 
There is a relatively small time window for acquisition of the late arterial phase, which persists for 
approximately 10 seconds in most patients and explains the need for careful timing.  
 
While also important for diagnostic purposes, the time window of opportunity to acquire images of 
the hepatic parenchyma during portal vein and equilibrium (delayed) phase is much wider. Therefore 
it is permissible to use fixed-time delays (approximately 60 to 75 seconds post injection preferred) of 
the liver which must be obtained in a single breath hold helical acquisition. HCC has a range of 
presentations on CT. The most diagnostic images are the properly timed multi-phase contrast-
enhanced images. The following section covers the key elements necessary to achieve optimal 
diagnostic sensitivity and specificity, as well as an optional pre-contrast imaging sequence 
recommended especially after ablative therapy.  


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11.1.2 Guidelines for Multiphasic Contrast-Enhanced CT Imaging 
11.1.2.1 Pre-contrast: Recommended but not required  
Non-contrast imaging through the liver prior to contrast-enhanced imaging is optional and not 
required for the purpose of this protocol.  
  
11.1.2.2 Late arterial phase  
Imaging characteristics include the following:  
 Fully enhanced hepatic artery and branches;  
 Early contrast enhancement of portal vein;  
 Lack of enhancement of the hepatic venous system.  
 
Time to peak enhancement in abdominal aorta at celiac axis level can be determined either by timing 
bolus injection or through the use of triggering facility provided on newer scanners. Some scanners 
have an auto triggering feature that commences the scan when a pre-defined threshold (typically 100 
HU) is reached in the target area; some scanners will display a time-density curve at the pre-defined 
anatomic location to the technologist and require a manual start of the exam. Either mechanism 
optimizes timing of the scan to the cardiac output and circulatory time of the individual participant 
and is strongly preferred over a fixed-time delay exam. Late arterial phase scanning should typically 
commence 5 to 10 seconds after peak enhancement in the upper abdominal aorta at the level of the 
celiac axis. In the unlikely event that fixed time delay needs to be used, an empirical delay of 25 to 
30 seconds may work for most participants.  
 
11.1.2.3 Portal vein phase  
Imaging characteristics include the following:  
 Fully enhanced portal vein;  
 Peak liver parenchymal enhancement;  
 Early contrast enhancement of hepatic veins.  
 
The time window of opportunity to acquire images of the hepatic parenchyma during portal vein and 
equilibrium (delayed) phase is relatively wide. Portal vein phase images should typically be acquired 
35 to 55 seconds after initiation of late arterial phase.  
 
11.1.2.4 Equilibrium/Delayed phase  
Imaging characteristics include the following:  
 Variable appearance;  
  >120 to <180 seconds after initial injection of contrast.  
 
The time window of opportunity to acquire images of the hepatic parenchyma during portal vein and 
equilibrium (delayed) phase is relatively wide. Equilibrium phase images should typically be 
acquired 120 to 180 seconds post initial contrast injection.  
 
Table 5: Minimum technical specifications for multiphasic contrast-enhanced CT of the liver 
Feature 
Specification 
Comment 
Scanner type 
Multidetector row scanner 
 
Detector type 
Minimum of 8 detector rows 
Need to be able to image entire liver 


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during brief late arterial phase time 
window 
Reconstructed 
slice thickness 
Maximum of 5 mm 
reconstructed slice thickness 
Thinner slices are preferable, 
especially if multiplanar 
reconstructions are performed 
Injector 
Power injector, preferably dual 
chamber injector with saline 
flush 
Bolus tracking desirable 
 
 
Dynamic phases 
on contrast 
enhanced 
MDCT 
(comments 
describe typical 
hallmark image 
features) 
 
0) OPTIONAL: Pre-contrast 
 
 
 
1) MANDATORY: 
Late arterial phase 
1) Artery fully enhanced, beginning 
contrast enhancement of portal vein 
2) MANDATORY: 
Portal venous phase 
2) Portal vein enhanced, peak liver 
parenchymal enhancement, beginning 
contrast enhancement of hepatic veins 
3) MANDATORY: 
Equilibrium/Delayed phase 
3) Variable appearance, >120 sec after 
initial injection of contrast 
Dynamic phases 
(timing) 
Bolus tracking preferred over timing bolus for accurate timing 
 
11.1.3 MR Imaging  
11.1.3.1 General MRI parameters are outlined in the table and text below.  
 Field strength of 1.5 Tesla or greater.  
 Imaging must be performed with a specialized torso array coil or other local coil combinations 
appropriate for body imaging. Body coil for signal reception is not acceptable.  
 Image slice thickness should be ≤ 10 mm.  
 Field of view (FOV) as appropriate for given patient body habitus.  
 Matrix for T1 and T2 weighted images should be no less than 256 (frequency) x 128 (phase).  
 Diffusion-weighted imaging may be used by sites per institutional protocol but is not required by 
this trial protocol. If sites perform this type of imaging, the use of lower resolution matrices is 
acceptable.  
 For axial imaging, phase encoding should be anterior–posterior.  
 For contrast-enhanced scanning, standard extracellular gadolinium chelates that do not have 
dominant hepatobiliary excretion should be used at a dose of 0.1 mmol/kg to a maximum of 20 
mL.  
 Injection rate should be 2 cc/sec, and all injections must be followed by a saline flush of 30 cc. 
Peripheral IV access is preferred.  
 
11.1.3.2 Abdominal MRI  
Contrast-enhanced imaging with a standard extracellular gadolinium chelate that does not have 
dominant hepatobiliary excretion is required for MRI. Scanning protocol should be per institutional 
standards, but should include at a minimum: pre-contrast (mandatory) and dynamic post-extracellular-
gadolinium T1-weighted (T1W) gradient echo sequence (3D preferable), T2W (with and without FAT 


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SAT), T1W in and out of phase imaging. The inclusion of other imaging techniques/planes is acceptable 
per institutional/imaging center‘s standard.  
 
11.1.3.3 Guidelines for Multiphasic Contrast-Enhanced MR Imaging  
HCC has a range of presentations on MRI. The most common is a circumscribed mass that may be 
inconspicuous on pre-contrast T2W and T1W imaging. The strongest diagnostic images are the multiple 
contrast-enhanced timed T1W images. The key elements necessary to achieve optimal diagnostic 
sensitivity and specificity are the following:  
 3D Gradient Echo (GRE) fat-suppressed acquisitions acquired with identical parameters 
throughout the pre- and post-contrast series. 3D volumetric imaging is preferred, but multiplanar 
2D imaging is acceptable. 
 Pre-contrast T1W images:  
 2D or 3D in- and opposed-GRE;  
 3D GRE (depending on scanner platform used: Vibe; Lava-xv; Thrive) with fat suppression.  
 Parameters identical to the post-contrast 3D GRE sequence:  
 Avoid misinterpreting a nodule intrinsically with high T1W signal as an enhancing mass, as 
can be seen in regenerating nodules or dysplasia. Comparison must always be made between 
the pre-contrast and arterial phase images. Use of subtraction images is strongly 
recommended.  
 Examine the in/out-of-phase images for fat. Occasionally the T1 signal may be lower than 
adjacent liver on fat-suppressed 3D GRE due to lipid, < 10% incidence.  
 
11.1.3.3.1 Pre-contrast: Mandatory  
Non-contrast imaging through the liver prior to contrast-enhanced imaging is mandatory.  
 
11.1.3.3.2 Arterial phase  
 Imaging characteristics include the following:  
 Fully enhanced hepatic artery and branches;  
 Early contrast enhancement of portal vein;  
 Lack of enhancement of the hepatic venous system.  
 Acquisition of a properly timed late arterial phase is the most technically challenging and 
diagnostically critical element of the dynamic liver examination.  
 Using set (empirical) timing delays from the start of the injection will be associated with a large 
range of contrast arrival times (from < 12 to > 30 seconds range timed from the start of the 
contrast injection to the arrival in the hepatic artery) and will not provide the most optimized 
method.  
 HCC will transiently enhance over a period of 5 to 10 seconds above the adjacent liver 
parenchyma signal, therefore the timing is critical and is optimized if:  
 The gadolinium bolus is injected in as short a time as possible;  
 Peak HCC enhancement must be aligned in time with the time during the 3D GRE acquisition 
that accumulates low k-space frequencies (e.g., linear order = align at middle of breath hold; 
low to high ordering = align at beginning of breath hold, which means adding a longer delay 
time to account for this). 
 The following is required for optimized timing in order to achieve an arterial-phase breath hold 
liver examination (ABLE):  
 Dual chamber power injector;  


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 Injection of contrast at 2 cc/sec (measured to the recommended dose by weight; standard 
extracellular gadolinium chelates that do not have dominant hepatobiliary excretion should be 
used at a dose of 0.1 mmol/kg to a maximum of 20 mL);  
 Chase with saline at 2 to 3 cc/sec x 30 cc;  
 Start a real-time reconstruction high–speed, low-quality coronal (suggested) GRE (e.g., care-
bolus) at the start of the infusion for bolus monitoring;  
 Field of view on coronal set to allow visualization of the heart, mediastinum, and centered on 
the diaphragm to visualize the celiac axis;  
 Technologist trained to recognize filling of the right side of heart, pulmonary artery, left heart, 
aorta, in preparation for recognizing bolus arrival;  
 Stop the bolus imaging and start timing when the contrast arrives at the celiac axis 
(diaphragm);  
 Count 8 sec if using a linear ordered 16 to 18 sec breath hold acquisition time 3D GRE (based 
on data looking at perfusion kinetics of arterial enhancing tumors);  
 During this time give the breathing commands and train the technologists to provide adequate 
time for the participant to complete the breath hold maneuver 2 to 3 sec prior to initiation of 
the sequence to allow the participant to complete following the command and stop all 
voluntary movements;  
 Start the arterial phase acquisition.  
 An approximate guide to show that an ideal acquisition was obtained usually shows the hepatic 
artery fully enhanced and the portal veins centrally just enhancing to well enhanced; hepatic 
veins show no enhancement.  
 
11.1.3.3.3 Portal venous phase (AKA venous and blood pool phase)  
 Imaging characteristics include the following:  
 Fully enhanced portal vein;  
 Peak liver parenchymal enhancement;  
 Early contrast enhancement of hepatic veins.  
 Images captured just after the hepatic veins have filled with contrast. Timing is less critical and 
can be acquired (35 to 55 sec after initiation of late arterial phase scan). Typically the portal 
venous phase is started one or two breathing cycles after completion of late arterial phase.  
 This provides adequate time for the participant to regain their breath before being asked to 
perform the next breath hold and reduce motion effects from poor breath holding due to rushing 
this second enhanced acquisition.  
 This acquisition provides optimal visualization for portal or superior mesenteric vein (SMV) 
thrombosis and varices.  
 
11.1.3.3.4 Equilibrium phase (AKA extracellular, interstitial, or delayed phase)  
 Imaging characteristics include the following:  
 Variable appearance;  
 >120 to <180 seconds after initial injection of contrast.  
 Timing less critical and can be acquired at 120 to 180 sec post injection as a third breath hold. 
This provides adequate time to visualize HCC ―wash-out.  
 The signal in the HCC is lower in this phase due to a combination of lower vascular volume and 
interstitial uptake than in the adjacent liver.  
 The margins of the HCC enhance, forming an apparent thin pseudocapsule.  
 


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Table 6: Technical specifications for multiphase contrast-enhanced MRI of the liver  
Feature 
Specification 
Comment 
Scanner type 
1.5 T or greater magnetic field strength 
Low-field magnets not 
suitable 
Coil type 
Phased-array multichannel torso coil 
Unless patient-related factors 
preclude use (e.g., body 
habitus) 
Gradient type 
Current generation high speed gradients 
(providing sufficient coverage) 
 
Slice thickness 
5 mm or less for dynamic series; 
8 mm or less for other imaging 
 
Injector 
Dual chamber power injector 
recommended 
Bolus tracking desirable 
Contrast 
injection rate 
2–3 mL/sec of extracellular gadolinium 
chelate that does not have dominant 
hepatobiliary excretion 
Preferably resulting in vendor 
recommended 
total dose 
Required non-
dynamic 
sequences 
T1W in and out of phase imaging 
T2W (per institutional standard, not 
STIR) 
Optional diffusion imaging 
Dynamic 
phases on 
contrast-
enhanced 
MRI 
(comments 
describe typical 
hallmark 
imaging 
features 
0) MANDATORY: 
Pre-contrast T1W 
0) Do not change scan parameters for 
post contrast imaging 
1) MANDATORY: 
 Late arterial phase 
1) Artery fully enhanced, beginning 
contrast enhancement of portal vein 
2) MANDATORY: 
Portal venous phase 
2) Portal vein enhanced, peak liver 
parenchymal enhancement, beginning 
contrast enhancement of hepatic veins 
3) MANDATORY: 
Equilibrium/delayed phase 
3) Variable appearance, > 120 sec 
after initial injection of contrast 
 
Dynamic 
phases 
(timing) 
The use of a bolus tracking method for 
timing contrast arrival for late arterial 
phase imaging is preferable. Portal 
venous phase (35–55 sec after initiation 
of late arterial phase scan ), 
equilibrium/delayed phase (120–180 sec 
after initial contrast injection) 
 
Breath holding 
Max length of series requiring breath 
hold should be about 20 sec with a 
minimum matrix of 128 x 256 
Compliance with breath hold 
instructions very important, 
technologists need to 
understand the importance of 
participant instruction 
before and during scan 
 
11.1.3.4 Serial imaging  
Participants who are listed for liver transplant will undergo serial imaging scheduled in accordance with 
the 90-day intervals required for cyclical update of the HCC-exception points with UNOS. These images 
will be used to measure outcomes. For patients not on the transplant list, radiologic imaging will occur 


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four months (± 4 weeks) after randomization and then every three months thereafter until the primary 
endpoint is met. 
 
11.1.4 Ablative Therapy and Post-ablation imaging  
If multiple TACEs are planned, participants need to first complete the entire treatment scheme per 
institutional SOC before undergoing response assessment. In some participants, the post-ablation 
imaging time point may occur closer than 90 days to the next serial imaging time point required for liver 
transplant waitlist updates. Sets of post-ablation imaging studies that are less than 90 days old at the time 
of the next scheduled UNOS HCC-exception point update (serial) images do not have to (but may) be 
repeated at the time of exception point update and may count towards the serial imaging time point for 
the purpose of the trial. For the remainder of the trial, these participants continue to be imaged according 
to the OPTN/UNOS schedule for updating HCC-exception points. Should another round of ablative 
treatment become necessary, the above rules apply for all post-ablation imaging sets and subsequent 
serial time points. 
 
Serial MR or CT imaging will be performed at distinct time points as dictated by OPTN/UNOS until 
transplantation. Timing of serial SOC imaging in waitlisted patients is dictated by OPTN/UNOS HCC-
exception point update requirements (90 day intervals). Waitlisted patients are defined as those eligible 
for/scheduled to undergo LDALT as well as those waiting for livers from deceased donors to become 
available. Postablation imaging studies that are less than 90 days old at the time of the next scheduled 
UNOS HCC exception point update (serial) images do not have to (but may) be repeated at the time of 
exception point update and may count towards the serial imaging time point for the purpose of the trial.  
 
11.2  Local intrahepatic tumor: The status of each treated tumor/target lesion will be assessed by MRI or 
CT scan and classified as progression if there is tumor growth (excluding growth due to biloma or 
abscess formation), residual or new enhancement of the ablated tumor (excluding benign peri-ablational 
enhancement), or contiguous viable tumor. Each treated intrahepatic lesion will be evaluated utilizing 
mRECIST Criteria for HCC (Appendix B). All imaging will be assessed at the treating institution. If 
concern for residual or progressive disease is raised, imaging will be reviewed a second time at the 
individual institutions’ multi-disciplinary conference review.  
 
If there is a discrepancy between the two interpretations, imaging will be de-identified (responsibility of 
the site sending) and transferred to Ambra, to be shared in a group. The panel of radiologists who will be 
providing the consensus opinion will access the images through Ambra. To accomplish this, the treating 
institution will pull the data out of PACS, de-identify the data using LB Compass (or similar software, 
depending on the institution preference) and then will visually inspect the data to confirm de-
identification. Further tracking of the data will be done by the individual patients' assigned tracking 
number, by the treating institution. The treating institution will upload the data to Ambra for the 
radiology panel (only users internal /external that are pre-configured will have access). The treating site 
will add the assigned tracking number to a Google sheet that will track the pre and post PHI. The 
treating institution will email Dr. Zarwan (or designated individual) notifying that the data/images are 
available in Ambra for review. An email will then be sent to the panel of three independent radiologists 
so that a final radiologic consensus assessment can be made. The committee’s judgment will be final. 
The treating institution will be notified of the result and the data will be uploaded to the EDS by the 
treating institution subsequently.   
 


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11.3 Disease-Specific Mortality: For this study, disease-specific mortality will be defined as death due to 
the subject’s disease, or death due to treatment for the subject’s disease. Time zero will be defined the 
day of the last treatment. 
 
12.0 Criteria for Discontinuation of Protocol Treatment  
12.1     Off-Treatment Conditions 
 Unacceptable toxicity as defined in section 10. 
 Therapy may be discontinued prematurely at any time by subject request without prejudice to 
subsequent care.  
 Subjects may be removed from the treatment at any time per investigator discretion. 
                                          
12.2 Off Study Conditions 
 Subjects will be removed if they are unable to receive either SBRT or TACE due to 
decompensation prior to initial therapy. 
 Subjects may be removed from the study at any time by subject request. 
 Subjects who go on to receive additional non-radiation therapy (i.e., treatment that is not TACE 
or SBRT related) will be followed for progression within the treated lesion(s). They will no 
longer receive protocol-directed treatment or testing.  
 Subjects who develop extra-hepatic tumor will not be followed and will be censored from the 
data analysis. 
 Subjects who undergo a liver transplant will be considered off study and will not be followed 
from that time point (except to determine 60-day post transplantation survival status).  
 Subjects permanently removed from Liver Transplant list and will not be followed. 
 
12.3 Adverse Event Guidelines 
12.3.1 Adverse Event definitions 
 An Adverse Event is any untoward medical event that occurs in a subject who has received an 
investigational treatment, and does not necessarily have a causal relationship with the 
investigational treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational treatment, whether or not related to the treatment. 
 Pre-existing diseases or symptoms or abnormal laboratory values present upon recruitment are 
not considered an AE even when observed during the further course of the study. However, 
every worsening of a pre-existing condition is considered an adverse event. 
 All AEs ≥ grade 3 will be collected and attributed either as possibly, probably or definitely 
related to protocol treatment or not related to protocol treatment. Additional AE’s collected are, 
any grade ≥2 abdominal pain, nausea, vomiting, and fatigue. The NCI Common Terminology 
Criteria for Adverse Events Version 5.0 (CTCAE) will be utilized to grade AE’s for AE 
reporting. 
12.3. 2 Adverse Event Reporting 
During the course of an adverse event, severity and/or causality and/or seriousness may change. For 
CRF documentation this adverse event represents one entity from onset to resolution and the worst of 
the observed categories shall be attributed. When event reoccurs after it disappeared, it should be 
handled as a new AE. However, AEs that occur intermittently can be recorded as one AE. Adverse 


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events will no longer be reported if the subject has another liver - directed therapy or starts 
chemotherapy. 
 
12.4 SAE Guidelines 
12.4.1 A serious adverse event (SAE) shall be defined as an adverse event which fulfills one or more of 
the following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-subject hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above  
 Any events or hospitalizations that are unequivocally due to progression of disease should 
not be reported as an SAE.  
 The causality of SAEs (i.e., their relationship to study treatment) will be assessed by the site 
investigators and will be labeled as either related to treatment, or not related to treatment. 
 
12.4.2 Only adverse events deemed serious AND related will be reported to the IRB within 10 days 
of awareness of the event, or per institutional Policy. All other events will be noted in the subjects’ 
medical record. 
 
12.4.3 The following types of hospitalizations do not constitute SAEs: 
 Hospitalization or Emergency room visits secondary to expected cancer morbidity. 
 Admission for palliative care or pain management. 
 Planned hospitalizations for surgical procedures either related or unrelated to the subject’s 
cancer. 
 
12.4.4 SAE Reporting 
All serious adverse events (SAE) (including death and hospitalization), premature withdrawal, and 
emergency treatment disclosures must be reported to the Project Manager at the Lahey Hospital & 
Medical Center within one working day. Applicable SAE forms should be completed in the electronic 
data capture system (EDC) within 10 days of their occurrence and updated as new information becomes 
available.   
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization, but may jeopardize the subject or may require 
intervention. All deaths occurring on study must be reported to the Lahey Hospital & Medical Center. 
These include deaths within 30 days of the end of study visits.   
 
13.0 Efficacy Variables 
Primary and secondary efficacy variables are described below. 
13.1 Primary Variable 
Time to residual/recurrent disease is defined as the time from the date of randomization until the date of 
residual/recurrent disease within the treated lesion(s).  Any subject not known to have had 
residual/recurrent disease before transplant will be censored based on the last recorded date on which the 


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subject was still on study. The percentage of subjects who had residual/recurrent disease will also be 
derived. 
 
13.2 Secondary Variable 
 
 
To assess HRQL, subjects with be assessed using the Functional Assessment of Cancer Therapy–
Hepatobiliary (FACT-Hep) Questionnaire (Appendix D). This 45-item self-report instrument is designed 
to measure HRQL in patients with hepatobiliary cancers and is one of the most widely-used instruments 
in this clinical area. The FACT-Hep consists of the 27-item FACT-G, which assesses generic HRQL, 
and the 18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues such as pain, 
appetite, and cramping.3,4 The FACT-G is divided into four HRQL domains: physical well-being (7 
items), social/family well-being (7 items), emotional well-being (6 items), and functional well-being (7 
items). All items have a 7-day reference period and are scored from 0-4 (“not at all” to “very much”), 
with higher scores indicating better HRQL. Score ranges are 0-28 for physical well-being, 0-28 for 
social/family well-being, 0-24 for emotional well-being, 0-28 for functional well-being, and 0-72 for 
HS. All subscale scores from the FACT-G and HS can be summed together to create a total FACT-Hep 
score, with a possible range of 0-180. The FACT-Hep takes approximately 10 minutes to complete.5  
 
Subjects assigned to the SBRT arm will complete the FACT-Hep at baseline, at the time of the second 
fraction of the SBRT treatment , on the last day of treatment, 2 weeks after treatment, and at the time of 
follow-up scans at 3, 6, 9, 12, 15, 18, 21 and 24 months from randomization or until liver 
transplantation. 
 
Subjects assigned to the TACE arm will complete the FACT-Hep at baseline, TACE treatment #1, 2 
weeks after treatment #1, at TACE treatment #2, 2 weeks after treatment #2, at TACE treatment #3, and 
2 weeks after treatment #3. The number of TACE treatments will vary from 1 to 3, so not all HRQL 
assessments will be collected for all subjects. The HRQL assessment at the time of the last TACE will 
serve as the HRQL assessment on the last day of treatment, while the HRQL assessment done 2 weeks 
after the last TACE assessment will serve as the 2 weeks after treatment assessment. HRQL will then 
continue to be collected at the time of follow up scans at 3, 6, 9, 12, 15, 18, 21 and 24 months from 
randomization or until transplantation. 
 
14.0 Safety Variables 
Adverse events will be captured throughout the study along with, physical exams and standard 
laboratory tests.   
 
15.0 Statistical Considerations 
This is a randomized, non-blinded, Phase III trial to characterize the safety and efficacy of 
individualized SBRT, compared to TACE, for subjects who have primary HCC. The trial endpoints are 
time to progression or residual disease in the treated lesion(s), number of retreatments, radiologic 
response, pathologic response, toxicity, and HRQL, overall survival, and 60 day post-transplant 
morbidity and mortality. 
 
16.0 Sample Size 
This study is sized for hypotheses testing of improved time to residual or recurrent disease within the 
previously treated lesion(s) due to SBRT versus TACE treatment arms in the overall population of 
patients who are eligible for liver transplant and are on the waiting list.  It is believed that more than 
50% of patients will receive a transplant within 2 years of listing, but that far fewer patients will receive 


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a transplant within 1 year of study begin.  Therefore we base power calculations on one year follow up 
and a drop rate of 15%.  Based on initial data, we estimate a median time to residual or recurrent disease 
of 134 days in the TACE group.  Based upon these numbers and a hazard ratio of 0.6 for the SBRT 
relative to the TACE group, a two-sided test controlling the overall type 1 error to 5% requires a total of 
161 events (i.e. residual/recurrent disease) and about 131 patients per treatment arm to achieve a power 
of 90%. To achieve a power of 80%, a total of 120 events and about 98 patients per treatment arm are 
required.  These calculations are made accounting for follow-up on patients once every three months 
where the calculated HR of 0.6 for this discrete model corresponds roughly to a HR of 0.54 if recurrent 
disease could be measured on the continuous time scale (days).    
 
Table 7 Sample Size Calculation 
HR 
Median time1 
TACE (days) 
Median Time1 
SBRT (days) 
Power (%) 
Nb of Events 
Nb of patients 
per arm 
0.6 
134 
223 
90 
161 
131 
0.6 
134 
223 
80 
120 
98 
1 Median time is the median time to residual or recurrent disease. 
 
Recruitment period of 365 days, duration of study of 2 years, yearly dropout rate of 15% (following 
exponential distribution), alpha=5%, two-sided test. 
 
17.0 Statistical Analysis 
Baseline as well as post treatment measures will be summarized by descriptive statistics as appropriate 
such as mean, median, standard deviation, range and interquartile range.  Comparison between treatment 
groups at baseline as well as changes from baseline will be made as appropriate using t-tests, Wilcoxon, 
chi-square and McNemar’s tests as appropriate. 
 
17.1 Primary endpoint 
The primary analysis of the primary endpoint of time from randomization to residual or recurrent 
disease will be based upon the Kaplan-Meier estimates of time to event for the two groups where the 
two groups are compared using the log-rank test.  Patients will be censored at time of transplantation or 
two years, whichever comes first.  The primary analysis will treat patient death as residual or recurrent 
disease (effectively the compound endpoint of residual or recurrent disease or death). During the time 
frame of two years mortality should be low, but treatment of death as residual or recurrent disease is 
conservative. Secondary analyses using the Cox regression model will explore predictors of recurrence 
beyond group assignment, and also explore interactions between treatment and these other factors.  We 
will also explore sex and treatment center differences.  Secondary analyses will also censor for deaths 
unrelated to treatment. Statistical tests will be made at the two-sided 5% level.17.2.1 HRQL analyses 
 
17.2 Secondary Endpoints Analysis 
17.2.1 Analysis of Long term HRQL outcomes 
The main HRQL outcome will be of the overall FACT sum score (FACT-G + FACT-Hep).  The main 
analysis will be a random effects (repeated measures) analysis of the HRQL measures obtained using 
data taken at baseline, end of treatment, 2 weeks after treatment completion, and every 3 months 
thereafter (until 24 months). Depending on the amount of missing data at later time points, including for 
those patients who experience the primary outcome, are transplanted, or are loss to follow-up, the HRQL 
analysis may be truncated before 24 months (e.g., 12m months). For each patient the model will fit a 
random intercept and slope term.  We will center time to the assessment time point nearest the center of 


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the time points of the data.  Data will be inspected for linearity in time as well as constancy of variances.  
If the data show deviations from these linearity or constancy of variables we will attempt to remedy this 
through addition of nonlinearity terms or transformations.     
 
The specific domains of HRQL that are impacted by the different treatments will be analyzed as 
secondary variables using the same analysis plan as the overall FACT score.  
 
Additionally we will analyze both the primary (overall FACT score) and secondary (domain scores) 
long term HRQL measures in a descriptive manner both numerically (e.g. means, medians, standard 
deviations, ranges and interquartile ranges) comparing the groups, testing using analysis of covariance 
(ANCOVA accounting for baseline values) and graphically by plotting measures using jit plots, 
spaghetti plots (plots through time where individual patients data from multiple time points are 
connected with lines) and plots of the means or difference from baseline as estimated from the 
ANCOVA, or similar plots as suggested by the data. We will examine missing data for systematic bias.        
 
17.2.2 Analysis of Short Term HRQL Outcomes 
We will use descriptive statistics (e.g., mean, standard deviation, median, ranges and interquartile 
ranges) to describe the overall FACT sum score and each domain score by treatment arm at each 
assessment period from baseline through the end of treatment. We will graph the data over the 
appropriate time frame similar to the analysis of the long term HRQL measures. This will inform us 
about the HRQL trajectories during treatment by treatment arm.  If the data suggest it is reasonable we 
will calculate HRQL life years from areas under the curves and compare the treatment arms using 
ANCOVA or Wilcoxon test, as indicated by the data.  We will examine missing data for systematic bias.  
 
17.2.3 Other Secondary Endpoints 
Quantitative outcomes like number of retreatments and number of toxicities will be described by mean, 
standard deviations, median, minimum and maximum by treatment group and treatment group will be 
compared using a t-test. Categorical outcomes like any retreatment, any toxicity, radiologic response, 
pathologic response will be described by counts, percent and groups compared using the chi-square test. 
Overall survival, and 60 day post-transplant morbidity and mortality will be described by Kaplan-Meier 
estimates, and groups compared using the log-rank test and Cox model as for the primary outcome. 
Note, with 98 patients per arm, each arm will have 99% and 95% probabilities of observing at least one 
event of toxicity when the true probabilities per patient are 0.05 and 0.03. Further, when estimating 
proportion of patients to have a particular toxicity, the 95% confidence intervals will have precision of 
10% or tighter, for each treatment group. 
We will analyze secondary endpoints relating to time to event analogously to time to recurrence, and 
quantitative outcomes analogously to the analysis the HRQL endpoints.        
Safety Measures 
Lab measures will be described and groups compared as described using t-tests or Wilcoxon tests as 
appropriate.    
 
Adverse events 
Adverse events will be described by body system and severity, on a per patient basis as well as a number 
per patient basis, and groups compared using chi-square and t-tests as appropriate.      
  
18.0 Project Management, Data Management, and Site Monitoring 


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Lahey Hospital & Medical Center (i.e., Sponsor) staff will accomplish all the tasks necessary for 
preparation and implementation of the project, including the drafting and refinement of the study 
protocol, development of the model consent document, assisting the PI in communications, developing 
project timelines, compiling required documents, preparing the detailed operations manual that outlines 
all the tasks required for study implementation at the sites, overseeing the distribution of documents, 
updating the protocol and operations manual as needed, updating regulatory files for the study overall, 
supervising the timely renewals of IRB approvals at the sites, and overseeing enrollment.  
 
18.1 Records to Be Kept 
Each participating site will maintain appropriate medical and research records related to this trial in 
compliance with regulatory and institutional guidelines for the protection of subject confidentiality. 
 
Source data are all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Examples of these original 
documents and data records include, but are not limited to hospital records, clinical and office records, 
laboratory notes, subjects’ HRQL data, radiology records, and treatment related records. 
18.2 Role of Data Management 
Lahey Hospital & Medical Center in conjunction with Quartesian will design and distribute source 
worksheets and the electronic data capturing system that will maintain all data collected as part of the 
protocol.  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
Principal Investigator. Collected study data must be promptly entered into the EDC system used by the 
Sponsor.  Source worksheets should be used as the primary data collection instrument for the study, 
when possible.  The investigator should ensure the accuracy, completeness, and timeliness of the data 
reported in the EDC and all other required reports. Data reported in the EDC, that are derived from 
source documents, should be consistent with the source documents and any discrepancies should be 
explained. Any missing data must also be explained. An audit trail will be maintained by the EDC 
system.  
 
Sites are required to provide the Sponsor with de-identified source documents supporting the data 
entered into the EDC system within 1 week of each completed visit.  Data must be shared via a Dropbox 
account approved by Lahey. If a site is unable to provide data via Dropbox, then an alternate method of 
data sharing maybe employed. Approved methods include mailing and faxing documents or through 
secure email. 
 
All serious adverse events (SAE) (including death and hospitalization), premature withdrawal, and 
emergency treatment disclosures must be reported to the project program manager and Dr. Zarwarn at 
the Lahey Hospital & Medical Center within one working day of site becoming aware of the event.  
Sites will notify Dr. Zarwan and the project program manager by emailing li.zhang@lahey.org.  Please 
include Site Name, Patient study ID, SAE event term, grade and pertinent de-identified source 
documents.  Applicable SAE forms should be completed in the electronic data capture system (EDC) 
within one week of their occurrence and updated as new information becomes available.  
 
A data monitoring committee comprised of Dr. Zarwan along with two Co-Investigators from Lahey 
Hospital will review all Adverse Events on a quarterly basis.  All Serious Adverse Events will be 
reviewed as they occur in real time. 


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18.3 Data Verification & Quality Assurance 
The site monitoring, regulatory review, adverse event reporting and quality assurance issues will be 
overseen by Lahey Hospital & Medical Center.  Each site will permit authorized representatives of the 
sponsor and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress.  The Coordinating Center at Lahey will review and track Adverse Events, Serious Adverse 
Events, and Unanticipated Problems. 
 
Centralized remote monitoring will be carried out by Coordinating Center at Lahey Hospital & Medical 
Center. Monitoring will occur through periodic review of submitted source data and data in the EDC 
system.  A sample of enrolled patients may be randomly selected for a focused comprehensive audit of 
all data.  Depending on enrollment progress, the goal will be to audit a 10% sample of enrolled patients 
from each site involved.  The audit will be performed by comparing data submitted through the EDC 
against source documentation submitted by the site.  If a greater than 10% error rate is discovered, an 
additional 10% sample will be selected to audit. Additional auditing may be initiated per the Sponsor’s 
discretion. 
 
19.0 Human Subjects 
19.1 Institutional Review Board (IRB) Review and Informed Consent 
Informed consent must be obtained prior to performing any study specific procedures. The consent form 
will describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation.  A copy of the consent form will be given to the subject or legal guardian, and this fact 
will be documented in the subject’s record. 
 
This protocol and corresponding informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB responsible for oversight of the study.  A signed consent form will be 
obtained from each subject prior to any study intervention.   For subjects who cannot consent for 
themselves, a legal guardian, or person with power of attorney, must sign the consent form in 
accordance with institutional policies and state laws; additionally, the subject's assent must also be 
obtained if he or she is able to understand the nature, significance, and risks associated with the study.   
19.2 Subject Confidentiality 
All laboratory specimens, source documents case report forms, and other records that leave the site will 
be identified only by the SID to maintain subject confidentiality.  All computer entry and networking 
programs will be done using SIDs only.  Identifiable clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by the study monitor, IRB, the 
sponsor, or the sponsor’s designee.           
19.3 Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the sponsor or IRB as part of their duties to 
ensure that research subjects are protected. 
 
 
 
 
 
 


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E.  
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18. Vogl TJ, Lammer J, Lencioni R et al. (2011) Liver, gastrointestinal, and cardiac toxicity in intermediate 
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F.  
APPENDICES 
 
Appendix A: Model for End-Stage Liver Disease (MELD-Na) and Child-Turcotte-Pugh (CTP) 
 
The MELD-Na score includes serum sodium level.  Sodium has been added to the formulation (as of 
January 2016) and is calculated using a relatively simple formula that relies on four readily available 
objective variables: 
 Serum creatinine (Scr; mg/dL) 
 Total bilirubin (Tbil; mg/dL) 
 INR (international normalized ratio) 
 Serum sodium (mmol/L) 
 
MELD-Na Score, UNOS modified 
The MELD score will be calculated to incorporate serum sodium for candidates with a MELD score 
greater than or equal to12. These candidates’ MELD scores will be calculated according to the initial 
MELD formula, and the MELD-Na score will be derived using the initial MELD score and the serum 
sodium value as follows:    
= MELD(i) + 1.32 x (137-Na) – [0.033 x MELD(i)*(137-Na)]  
 
Sodium values less than 125 mmol/L will be set to 125, and values greater than 137 mmol/L will be 
set to 137.  
 
This does not apply to candidates with a MELD score less than 12. 
The following rules must be observed when using this formula: 
 1 is the minimum acceptable value for any of the four variables. 
 The maximum acceptable value for serum creatinine is 4, to avoid higher MELD-Na 
 scores in subjects with concomitant intrinsic renal disease 
 The maximum value for the MELD-Na score is 40. 
 
Child-Turcotte-Pugh (CTP) 
 
Points 
 
1 
2 
3 
Encephalopathy 
None 
Grade 1-2  
(or precipitant-inducted) 
Grade 3-4  
(or chronic) 
Ascites 
None 
Mild/Moderate  
(diuretic-responsive) 
Severe  
(diuretic-refractory) 
Bilirubin (mg/dL) 
<2 
2-3 
>3 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
PT (sec prolonged) 
or INR 
<4 
<1.7 
4-6 
1.7-2.3 
> 6 
>2.3 
 
CTP score is obtained by adding the score for each of the 5 parameters. 
 
CTP class: A = 5-6 points            B = 7-9 points                    C = 10-15 points 


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Appendix B: mRECIST for HCCA 
 
 
Response 
Longest viable tumor diameterB 
Complete Response (CR) 
Disappearance of any 
intratumoral arterial 
enhancement in all target 
lesions 
 
Partial Response (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 
 
Stable Disease (SD) 
Any cases that do not qualify 
for either partial response or 
progressive disease 
 
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 
 
SEMINARS IN LIVER DISEASE/VOLUME 30, NUMBER 1 2010 
                                     Downloaded by: Universidad de Barcelona. Copyrighted material. 
 
A. Target tumor response measurements on arterial-phase computed tomography (CT) or MRI scans.  
B. Measurement of longest viable tumor diameter according to mRECIST for HCC. 
 


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Appendix C: TACE Quadrasphere® Microspheres 
 
   
 
 
 
 
 
 
 
 
 
 


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Appendix D: FACT-Hep (Version 4) 
Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line 
to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of 
energy
 
 
0 
1 
2 
3 
4 
GP2 
I have 
nausea
 
 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my 
family
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have 
pain  
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of 
treatment
 
 
0 
1 
2 
3 
4 
GP6 
I feel 
ill 
 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in 
bed  
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my 
friends
 
 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my 
family
 
 
0 
1 
2 
3 
4 


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GS3 
I get support from my 
friends
 
 
0 
1 
2 
3 
4 
GS4 
My family has accepted my 
illness
 
 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my main 
support)
 
 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer it, 
please mark this box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex 
life  
0 
1 
2 
3 
4 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 44 of 3 


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FACT-Hep (Version 4) 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel 
sad  
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my 
illness
 
 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my 
illness
 
 
0 
1 
2 
3 
4 
GE4 
I feel 
nervous
 
 
0 
1 
2 
3 
4 
GE5 
I worry about 
dying
 
 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse
 
 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at 
home)
 
 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is 
fulfilling
 
 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy 
life  
0 
1 
2 
3 
4 


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GF4 
I have accepted my 
illness
 
 
0 
1 
2 
3 
4 
GF5 
I am sleeping 
well  
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for 
fun  
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now  
0 
1 
2 
3 
4 
 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 45 of 3 


__________________________________________________________________________________________ 
Version 5: August 20, 2021                                                44 
 
 
FACT-Hep (Version 4) 
 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 
days. 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
 
C1 
I have swelling or cramps in my stomach 
area  
0 
1 
2 
3 
4 
C2 
I am losing 
weight
 
 
0 
1 
2 
3 
4 
C3 
I have control of my 
bowels
 
 
0 
1 
2 
3 
4 
C4 
I can digest my food 
well  
0 
1 
2 
3 
4 
C5 
I have diarrhea 
(diarrhoea)
 
 
0 
1 
2 
3 
4 
C6 
I have a good 
appetite
 
 
0 
1 
2 
3 
4 
Hep
1 
I am unhappy about a change in my 
appearance
 
 
0 
1 
2 
3 
4 
CNS
7 
I have pain in my 
back 
0 
1 
2 
3 
4 
Cx6 
I am bothered by 
constipation
 
 
0 
1 
2 
3 
4 
H17 
I feel 
fatigued
 
 
0 
1 
2 
3 
4 
An7 
I am able to do my usual 
activities
 
 
0 
1 
2 
3 
4 


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Version 5: August 20, 2021                                                45 
 
 
Hep
2 
I am bothered by jaundice or yellow color to my 
skin  
0 
1 
2 
3 
4 
Hep 
3 
I have had fevers (episodes of high body 
temperature)
 
 
0 
1 
2 
3 
4 
Hep 
4 
I have had 
itching
 
 
0 
1 
2 
3 
4 
Hep 
5 
I have had a change in the way food 
tastes
 
 
0 
1 
2 
3 
4 
Hep 
6 
I have had 
chills
 
 
0 
1 
2 
3 
4 
HN 
2 
My mouth is 
dry  
0 
1 
2 
3 
4 
Hep 
8 
I have discomfort or pain in my stomach 
area  
0 
1 
2 
3 
4 
 
 
English (Universal) 
 
16 November 2007 
Copyright  1987, 1997 
 
Page 46 of 3