Clinical trial NCT02182687
Conditions: Hepatocellular Carcinoma HCC
Keywords: Hepatocellular carcinoma (HCC) Orthotopic liver transplant Bridge to transplant stereotactic body radiation therapy (SBRT) trans-arterial chemoembolization (TACE)
Sponsor: Lahey Clinic
Start date: 2014-06-01; Completion date: 2021-10-01
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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 orthotopic 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 orthotopic liver transplantation.

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. However, the best modality for patients undergoing treatment as a bridge to transplantation is unclear. This study will compare stereotactic body radiation therapy (SBRT) to trans-arterial chemoembolization (TACE) as a bridging strategy for patients with HCC undergoing orthotopic 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 orthotopic liver transplantation.

Arms: arm 1: Stereotactic Body Radiation Therapy (SBRT) arm 2: Trans-Arterial Chemoembolization (TACE) 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 documents:
Prot_SAP_000.pdf: 
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A Randomized Phase II Study of Individualized Stereotactic Body Radiation Therapy 
(SBRT) versus Trans-Arterial Chemoembolization (TACE) with DEBDOX Beads as a 
Bridge to Transplant in Hepatocellular Carcinoma. 
 
Principal Investigator:    Francis Nugent, MD 
 
Co-Investigators:            Klaudia Hunter, MD 
                                        Sebastian Flacke, MD 
                                        Keith Stuart, MD 
    Fredric  Gordon, MD 
                                        Christopher Molgaard, MD 
                                        Shams Iqbal, MD 
                                        Qamar Amir, MD 
 
 
 
    Amy Tien, MD 
 
 
 
    Gene Wong, MD 
                                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table of Contents 
 
A. Abstract                         
B. Specific Aims  
C. Background and Significance  
D. Research Design and Methods  
E. References  
F. Appendices  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A.  
ABSTRACT 
For subjects with 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.  However, the best modality for 
subjects undergoing treatment as a bridge to transplantation is unclear.  The most 
commonly utilized treatment in this setting is TACE.  Retrospective single institution 
data suggests a survival benefit for subjects undergoing TACE as a bridge to liver 
transplantation, but there remains no prospective data showing improved outcomes.  
Most recently, other modalities have shown similar rates of local regional control for 
subjects with unresectable hepatocellular carcinoma.  One such treatment modality is 
stereotactic body irradiation (SBRT).  SBRT has been shown to afford good local control 
and acceptable safety when utilized in subjects with locally advanced hepatocellular 
carcinoma.  We propose to conduct a pilot study to prospectively compare SBRT to 
TACE as a bridging strategy for subjects with hepatocellular carcinoma undergoing 
orthotopic liver transplantation.  The preliminary data obtained from this trial will help 
inform the design and sample size calculations for subsequent, multi-site trials. 
 
B.  
SPECIFIC AIMS 
Hypothesis: SBRT will be associated with longer time intervals between initial treatment 
and the need for retreatment, compared to TACE, as a “bridge” to orthotopic liver 
transplantation in subjects with hepatocellular carcinoma. 
 
1.0 Primary endpoint: 
Time from first treatment to date of progression of  previously treated lesions as 
determined by the date of the radiologic imaging 
 
2.0 Secondary endpoints: 
2.1 Toxicity 
2.2 Number of further interventions  
2.3 Pathologic response of treated lesion(s). 
2.4 Radiologic response of treated lesion(s). 
2.5 Quality of life. 
 
C.  
BACKGROUND AND SIGNIFICANCE 
Hepatocellular carcinoma (HCC) is the sixth most common cancer with an increasing 
incidence worldwide, and is the third leading cause of cancer-related death (1-5). Given 
that most people who develop hepatocellular carcinoma have concomitant cirrhosis, the 
best opportunity for cure for many remains liver transplantation.  Because cadaveric liver 
transplants are in short supply in the United States, subjects who are eligible for liver 
transplantation frequently can wait a year or longer before a transplantation.  Recently, 
local regional interventions have been utilized as a temporizing strategy to "bridge" 
individuals waiting for transplantation.  The aims of bridging treatments include; 
decreasing the waiting list drop out rate for transplantation; reducing recurrent 
hepatocellular carcinoma after transplantation; and improving post transplant overall 


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survival (6). For subjects undergoing local regional therapy as a bridge to transplantation, 
(TACE) is the most commonly utilized treatment (7). 
 
TACE is a therapy that combines the local delivery of chemotherapy with the induction 
of tumor ischemia through obstruction of the feeding vessels. Recently 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 and 2 year survival 
probabilities of 82 and 63%, respectively. Lo et al. found significant improvement in 
survival for Asian HCC subjects treated by chemoembolization (8,9). The Drug-Eluting 
Bead (DEB) is a novel agent for chemoembolization with a unique availability to load 
doxorubicin. In vitro data has shown a slow release of doxorubicin over time with a 
decreased systemic blood serum level and an increased tumor tissue level of the 
chemotherapeutic agent (10-13).  
 
Several pilot studies have evaluated the safety and efficacy of DEBTACE. 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 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 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). 
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 including 62 
cirrhotic subjects with documented single unresectable HCC. 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). The maximum doxorubicin dose was 150 mg per embolization, loaded in DC 
Beads of 100-300 or 300-500 m. 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 
compare to conventional TACE with regards to side effects but also has a better overall 


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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 marked and statistically significant reduction in liver toxicity and 
drug-related adverse events compared with conventional TACE with lipiodol and 
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).  As a result of these investigations, DEBDOX has been 
increasingly used as the treatment of choice is local regional therapy as preoperative 
treatment in subjects awaiting transplantation with HCC (21). 
 
Despite its increased utilization, TACE 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 TACE as an effective 
strategy to reduce the risk of recurrent hepatocellular carcinoma following transplantation 
or to improve survival (22).  In the absence of clear benefit, there is no definitive standard 
of care and different preoperative treatment strategies are employed at different 
institutions for different individual subjects. Additionally, there has been no attempt to 
compare TACE, radiofrequency ablation, resection, or other strategies when utilized to 
bridge subjects to liver transplantation. 
 
A new strategy for the treatment of both cancers metastatic to the liver and primary 
hepatocellular carcinoma is SBRT.  Historically, external beam radiation lacked adequate 
precision and was considered too toxic for radiation therapy to be utilized to target 
lesions within the liver.  When attempted, external beam radiation engendered radiation-
induced liver disease (RILD) at sufficient rates as to render treatment untenable (23-26).  
However, over the past 2 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 or equal to 5% in experienced 
hands.  SBRT uses a small number of high dose fractions of highly conformal radiation 
therapy with high geometric precision and accuracy.  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 (27).  Recently 
published data from Bujold et.al., utilizing SBRT for locally advanced hepatocellular 
carcinoma, shows good effect and acceptable toxicity when compared to historical data 
regarding TACE or other equivalent strategies. The one year tumor control rate was 87% 
(28). While not a direct comparison, SBRT may be as equally efficacious.  
 
SBRT offers some theoretical advantages compared to other local regional strategies for 
the treatment of primary hepatocellular carcinoma.  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 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 


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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 then other treatment strategies as there is no 
requirement for hospitalization in comparison with subjects undergoing TACE.  
 
In the current study, we propose to compare individualized stereotactic body radiation 
therapy (SBRT) to TACE as a bridge to liver transplantation in subjects with 
hepatocellular carcinoma.  
 
D.  
RESEARCH DESIGN AND METHODS 
 
1.0 Eligibility 
1.1 Inclusion Criteria 
1.1.1 Subjects with hepatocellular carcinoma are eligible for this trial.  
         Hepatocellular carcinoma is defined as having at least one of the following: 
 Biopsy proven hepatocellular carcinoma (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. 
1.1.2 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.  
1.1.3  Subjects should be eligible per standard of care for either TACE or SBRT 
procedures. 
1.1.4 Subjects must have a life expectancy of at least 12 weeks. 
1.1.5 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.  
1.1.6 Subjects must sign an informed consent form approved for this purpose by 
the Institutional Review Board (IRB) of the Lahey Hospital & Medical Center  
indicating that they are aware of the investigational aspects of the treatment and 
the potential risks. 
 
       
 
1.2 Exclusion Criteria 
       
 
1.2.1 Subjects in a “special category” designated the Public Health Service,  
         Including subjects younger than 18, pregnant women, and prisoners. 
       
 
1.2.2 Refractory ascites or ascites that requires paracentesis for management. 
        
 
1.2.3 Subjects with a solitary lesion greater than 5.0 cm in size or more than 2  
         discrete lesions the largest greater than 3.0 cm in size. 
1.2.4 Known allergy to intravenous iodinated contrast agents unresponsive to  
         prednisone pre-treatment. 
 
2.0 PRETREATMENT EVALUATION 
Subjects will be consented for the study prior to starting treatment. 
 
2.1 Subjects will undergo evaluation, including a complete history and physical  


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examination, baseline assessments of organ function and documentation of 
measurable disease (CT or MRI) parameters chest CT or Chest X-ray ), 
weight, and  Quality of Life Questionnaires   
2.2 Laboratory evaluation per Study Calendar 
2.3 Assessment of clinical measures of severity of liver disease: The Model for  
End-Stage Liver Disease (30) (MELD) 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 RT (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 and CTP), and assess 
their potential contribution to individualize our assessment of liver injury that 
could be used to adjust liver dose. 
 
3.0 RANDOMIZATION PLAN 
Eligible subjects will be randomized after eligibility is confirmed by provider. No stratification 
will be used. Randomization will be performed using randomly selected block sizes of 4 and 8, 
provided by Tufts CTSI prior to the start of the study. Staff members involved in randomizing 
subjects will not be aware of the randomization sequence. Randomization will be documented  
indicating assignment.  
 
4. 0 TREATMENT PLAN for SBRT 
4.1 Subjects will be consented as per standard of care for SBRT prior to starting 
treatment. 
4.2 Placement of Fiducial Markers 
4.2.1 If deemed clinically necessary, fiducial markers may be placed  
percutaneously within close proximity of the target tumor. Placement 
of markers is considered standard of care. These will be used for 
target localization. 
4.3 Stereotactic Body Radiotherapy   
4.3.1 Three dimensional treatment planning will be used for all subjects,  
          based on a simulation CT scan. 
4.3.2 Energy: Treatment will be delivered with 6 - 16 MV photons 
4.3.3 Localization, simulation, and immobilization: All subjects must  
undergo CT simulation prior to treatment, with IV and oral 
contrast if clinically appropriate. Subjects will be immobilized 
with a body cast. Liver motion will be minimized with the use of 
either breath-hold technology or respiratory-gaiting technology 
(respiratory phase-based 4D gated technique). Subjects that are 
unable to tolerate either breath-hold or respiratory-gaiting will be 
treated free-breathing using a 4D internal target volume (ITV). 
Free breathing may also be used if tumor motion is <5 mm. Prior 
to each SBRT treatment, the liver tumor will be imaged and 


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localized using either an on-board imaging orthogonal pair, using 
implanted fiducial markers, or a cone-beam CT scan. 
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 when clinically 
indicated (contrast-enhanced CT or MRI must be fused with the 
planning CT if IV contrast is not given at the time of the planning 
CT scan). GTV is defined as all parenchymal and vascular HCC 
(excluding bland thrombus). No prophylactic nodal RT is allowed.  
The CTV will be defined as the GTV for the majority of cases.  
However, CTV expansions to include regions at high risk for 
microscopic disease including non-tumor vascular thrombi, prior 
TACE sites, or adjacent RFA sites are permitted if these are 
clinically felt to be at risk. These CTV’s may be treated to a 
microscopic dose (27.5 Gy) or as high as the prescription dose as 
determined by the physician’s discretion. The PTV around the 
GTV/CTV will be determined based upon the immobilization 
device(s) used. If breath-hold or respiratory-gaiting technology is 
used (with daily localization), then the total PTV margin will be 
approximately 0.5 cm in all directions. If the subject is treated free 
breathing, then an ITV will be created based on tumor motion on the 
4D planning CT with the addition of 0.5 cm in all directions for PTV 
margin.  
4.4 SBRT Planning Guidelines - Radiation Doses: 
4.4.1 PTV Target Doses 
4.4.1.1 Doses will be prescribed to a peripheral covering isodose  
covering the PTV. Prescription isodose surface covers 95% 
of PTV with 90% of the prescription isodose line covering 
99% of the PTV. The highest allowable doses to the target 
volumes that maintain normal tissue constraints should be 
used. A goal is that 100% of the CTV is encompassed by the 
prescription dose. Any dose > 110% must be within the PTV 
(except for adjacent tumors, in which the maximum dose 
outside the PTV must be < 115%). 
4.4.1.2 Variations 
4.4.1.2.1 Minor variation is defined as minimum PTV dose  
falling between 85% and 90% (of the required 
100% isodose prescription). 
4.4.1.2.2 Major variation (unacceptable) is defined as  
minimum PTV dose < 85% (for the required 100% 
isodose prescription). 
4.4.1.3 Maximum doses are defined at 1 cc of volume.  
Maximum dose within the PTV <150% of the 
prescribed dose. 
4.4.1.4 Minimum dose to the PTV is defined as minimum  
dose to 99.0% of the PTV. 


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4.4.2 Critical Normal Tissue Constraints 
 
Mandatory dose constraints: 
Spinal Cord+5mm: 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) 
 
Recommended but not mandatory dose constraints: 
Liver minus GTV’s: >700cc and V10Gy <70% 
Stomach: goal <25Gy to 5cc 
Duodenum: goal <25Gy to 5cc 
Small Bowel: goal <25Gy to 5cc 
Lung ALARA 
Heart: 30cc <30Gy 
Great vessel max 0.5cc <60Gy 
Skin external max 0.5cc <32Gy 
Chest wall max 0.5cc <50Gy 
Gallbladder max 0.5cc <55Gy 
Common bile duct max 0.5cc <50Gy 
 
4.4.3 Radiation Schedule 
4.4.3.1 SBRT will be delivered in five total fractions treated 2-3  
weeks, with at a minimum of one day between any two 
treatments.  The entire treatment must be delivered within 
15 total days.   
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: 27.5 Gy-50Gy in 5 fractions  
based on normal tissue constraints. The goal is to use the 
highest allowable prescription dose to the primary target 
while respecting normal tissue constraints. The minimal 
planned prescription dose to the PTV is 27.5Gy (total dose 
of 50Gy, 45Gy, 40Gy, 35Gy, 30Gy, or 27.5Gy in 5 
fractions is allowed). The dose to multiple PTV’s within 
the same subject may vary. Conformality of the 
prescription dose and the 30Gy isodose lines are planning 
goals.  
 


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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 as high as 
possible based on mean liver dose (MLD is the mean dose 
to the liver minus GTV’s) and the use of effective liver 
volume (Veff) with 6 potential dose levels. If there are 
discrepancies in the Veff and MLD for the prescription 
dose allocation, MLD has priority.  
  
 
Priority Constraint- 
Mean Liver Dose (Gy) 
Optional Constraint- 
Liver Veff 
Prescription Dose 
Planned Prescription Dose/If max MLD exceeded 
13.0 
<25% 
50Gy 
Reduce to 45Gy 
15.0 
25-29% 
45Gy 
Reduce to 40Gy 
15.0 
30-34% 
40Gy 
Reduce to 35Gy 
15.5 
35-44% 
35Gy 
Reduce to 30Gy 
16.0 
45-54% 
30Gy 
Reduce to 27.5Gy 
17.0 
55-64% 
27.5Gy 
Ineligible 
 
 
5.0 TREATMENT PLAN for DEB-TACE: 
Subjects will consent to DEB-TACE as per standard of care 
5.1Unilateral femoral approach 
5.1.1 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 


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left hepatic is selected distal to the cystic artery if visualized, 
depending of the lesion to be treated using 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 a cone-beam CT 
is performed to assess appropriate segmental contrast distribution 
covering the target.  
5.2.2 DEB-TACE will be performed with two vials of drug eluting beads 
of the size 75-150 m or 100-300 m each loaded with 50 mg 
Doxorubin. Iodine contrast will be mixed according to manufacturer 
guidelines and used to guide the delivery.  
5.2.3 Target area will be embolized until segmental arterial stasis is 
reached. In the presence of multifocal disease selective catheter 
positioning will be repeated for each lesion. 
5.2.4 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 observation. 
5.4 The second TACE will be administered approximately 4 weeks after the first 
TACE procedure and per physician discretion.   
 
If subject is unable to complete second TACE, they will be followed on study 
schedule from the time point of the first TACE.   
 
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. 
 
5.6 Crossover patients and additional treatment in the assigned treatment 
arm:  Group  2 TACE (“Arm B”), subjects with residual disease, local 
recurrence or new lesions on radiologic imaging at the three month follow up, 
or subsequent follow ups, may be considered candidates for additional 
treatments with TACE or crossover to SBRT at the discretion of the provider. 
These subjects will be followed in accordance with the SBRT study calendar 
from that time point onward.  
 
For subjects treated with TACE, additional treatments (beyond the protocol 
directed two treatments) may be administered.  SBRT subjects may be 
eligible, under provider discretion, to also have additional SBRT treatment 
done.  Refer to section 12.2 for “off study guidelines” for these subjects.  
 
 
 
6.0 QUALITY OF LIFE  


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6.1 The PIQ-6 Pain Impact Questionnaire measures how a subject’s pain affects 
every day activities. The SF-36v2 Health Survey measures functional health 
and well-being from the subject’s point of view.   Each questionnaires takes 
approximately 5-10 minutes to complete.  
 
6.2  Subjects assigned to SBRT arm will complete the questionnaires at baseline, 
during the first week of treatment, on the last day of treatment, 2 weeks after 
treatment, at the 3 month follow up, and  every 3 months up to 24 months 
 
6.3 Subjects assigned to the TACE arm will complete questionnaires at baseline, 
TACE treatment #1 (pre and post/prior to discharge), 2 weeks after treatment # 1, 
at TACE treatment # 2 (pre and post/prior to discharge), 2 weeks after that 
treatment, at the 3 month follow up and then every 3 months up to 24 months 
 


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7.0 STUDY CALENDARS 
 
7.1 Study Calendar for SBRT (Arm A) 
 
Active Treatment-SBRT 
Pre-Rx 
Eval1 
(screening) 
 
During first 
week of 5 
SBRT 
fractions 
 
 On last day of 
treatment (after 
last treatment 
before discharge 
home) 
History and Physical Exam 
X 
 
 
Weight 
X 
 
 
CBC  
X 
 
 
AST, ALT, Alk Phos, 
Bilirubin 
X 
 
 
Na, BUN/Creatinine 
X 
 
 
INR 
X 
 
 
AFP (for HCC) 
X 
 
 
Toxicity Notation 
X 
 
X 
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 and CTP 
assessment 
X 
 
 
QOL2 
X 
X (first 
week) 
X 
Simulation  
X 
 
 
Treatment: SBRT 
 
Over two 
weeks  
 
 
 1 Within 2 weeks prior to randomization unless otherwise specified   
       
 
 2Quality of Life questionnaires include PIQ-6 and SF-36v2 Health Survey  
 
 
 
 
 
 
 
 
 
 
 


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Amendment  18 September 2017 version 7.0 
 
7.2 Study Calendar for TACE (Arm B) 
 
 
 
 
 
 
Active Treatment – TACE 
 
Pre-Rx 
Eval1 
(screening) 
 
Initial TACE 
 
FOLLOW-UP  
VISIT (2 weeks) 
SECOND 
TACE 
History and Physical 
Exam, 
 
X 
X 
X (per MD SOC 
only) 
X 
Weight 
X 
X 
X 
X 
CBC  
X 
X4 
X 
X4 
AST, ALT, Alk Phos, 
Bilirubin 
X 
X4 
X 
X4 
Na, BUN/Creatinine 
X 
X4 
X 
X4 
INR 
X 
X4 
X 
X4 
AFP (for HCC) 
X 
X4 
 
X4 
Toxicity Notation 
X 
X 
X 
X 
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 and CTP 
assessment 
X 
 
 
 
QOL2,3 
X 
X2 
X 
X 
Treatment:  TACE  
 
X 
 
X 
1 Within 2 weeks prior to randomization  unless otherwise specified   
2 Quality of Life questionnaires include PIQ-6, and SF-36v2 Health Survey  
3If Quality of Life questionnaires were completed within 7 days of initial TACE visit, they do not have to be 
completed again.  Questionnaires will be done pre TACE and post TACE, preferably prior to subject discharge.   
4If required labs were performed within 3 days of either TACE procedure, they do not have to be repeated unless 
requested by treating physician 
 
 
 
 
 
 
 
 
 
 


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Amendment  18 September 2017 version 7.0 
 
7.3 Study Calendar for FOLLOW-UP (Both Arm A and Arm B) 
 
 
Follow-up After Treatment Concluded 
 
Post-Treatment 
Evaluation Period 
Approximately 2 
Weeks1,4 
 
3 months 
(+/- 4 
weeks)3 
 
6 months 
(+/- 4 
weeks)3 
 
Q 3 months to 24 
months post-
treatment (+/- 4 
weeks)3 
 
History and Physical Exam,  
X per MD SOC 
X 
X 
X 
Weight 
X 
X 
X 
X 
CBC  
X 
X 
X 
X 
AST, ALT, Alk Phos, 
Bilirubin 
X 
X 
X 
X 
Na, BUN/Creatinine 
X 
X 
X 
X 
INR 
X 
X 
X 
X 
AFP (for HCC) 
X 
X 
X 
X 
Toxicity Notation  
X 
X 
X 
X 
MRI or CT of the abdomen 
(mRECIST for HCC) 
 
X 
X 
X 
Chest CT or X-ray  
 
X 
X 
X 
MELD-Na and CTP 
assessment  
X 
X 
X 
X 
QOL2 
X 
X 
X 
X 
 
1Approximately 2 weeks after second TACE or 5th SBRT fraction (or after 3rd fraction if 4th & 5th fractions will be 
not given). 
2Quality of Life questionnaires include PIQ-6 and SF-36v2 Health Survey 
3 Scans  will be obtained in accordance to liver transplantation protocols and timeframes and may not occur within 
the allotted timeframe noted above. This will not be considered a protocol deviation.   
 
 
 
 
 
 
 
8.0 TREATMENT MODIFICATIONS 
8.1 Hepatic Toxicity: Subjects will be evaluated for symptoms and signs of RILD  
or other toxicity. 
8.1.1 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 


16 
Amendment  18 September 2017 version 7.0 
 
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. 
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. 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 be reported to IRB or require discontinuation of 
therapy: Grade 3 or 4 asymptomatic hypoalbuminemia or decreased 
lymphocytes. Transient (< 48 hours) asymptomatic grade 3 fasting 
hyperglycemia in type II diabetics. 
 
9.0 SBRT DOSE ADJUSTMENT 
 
There will be no dose adjustments for SBRT treatment.  
 
10.0 TOXICITY CONSIDERATIONS 
10.1 The criteria used for the grading of toxicities is  the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.3  
 Toxicity of all grades ≥2 measuring only the following conditions will be 
collected in the database: Gastritis, hepatic pain, vomiting and fatigue. 
 
10.2 The following toxicities will require subjects to be removed from protocol 
treatment and followed per physician standard of care: 
10.2.1 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.  
10.2.2 Grade ≥4 Upper GI bleeding (attributed to treatment, and not  
   attributable to disease progression) 
 
 
 
10.2.3 Any complications or death due to disease progression 
 
10.3 Items that will not be considered unacceptable toxicities: 
 
 
 
10.3.1 Any complications (i.e. infection) resulting from a PTC tube 
 
 
 
10.3.2 Grade 4 elevation in bilirubin during the course of therapy 
10.4 Expected Toxicities 
10.4.1 Radiation Therapy (SBRT): 
  Nausea or vomiting.  
 Gastric or duodenal ulceration 


17 
Amendment  18 September 2017 version 7.0 
 
 Skin irritation, fatigue, and decreased blood counts 
  
10.5 Liver Toxicity 
10.5.1 Radiation-induced liver disease (RILD) (veno-occlusive disease), 
including the possibility of damage severe enough to result in liver 
failure which could lead to death. In some subjects it is not possible 
to avoid kidney irradiation which could produce a decrease in renal 
function  RILD is a clinical syndrome of anicteric ascites, 
hepatomegaly and elevation of alkaline phosphatase (ALP) relative 
to other transaminases that may occur 2 weeks to 4 months following 
radiation to the liver.  
 ALP must be at least 2-fold increased above the baseline  
               ALP. 
 If ascites develops at any time within 3 months following 
treatment, an abdominal CT and paracentesis with pathological 
evaluation of the ascitic fluid is recommended. If the ascitic 
fluid does not reveal malignancy and there is no evidence of 
disease progression in the liver or abdomen, it will be assumed 
that RILD has occurred 
 If disease progression in the liver or abdomen has occurred, no 
diagnosis of RILD can be made.  
 In subjects who have elevation of liver enzymes near Grade 4 
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. 
10.6 GI Toxicity 
10.6.1 Subjects will be followed for GI toxicity at each follow up visit.  
 
. 
 
11.0 RESPONSE CRITERIA 
11.1 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) 
11.2 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 
fraction. 
 
12.0 CRITERIA FOR DISCONTINUATION OF PROTOCOL TREATMENT   


18 
Amendment  18 September 2017 version 7.0 
 
12.1 Off-Treatment Conditions 
12.1.1 Unacceptable toxicity as defined in section 10. 
12.1.2 Therapy may be discontinued prematurely at any time by subject  
request without prejudice to subsequent care. 
12.1.3 Subjects may be removed from the treatment at any time per  
investigator discretion. 
12.2 Off Study Conditions 
12.2.1 Subjects will be removed if they are unable to receive SBRT   
treatments. 
12.2.2 Subjects may be removed from study at any time by subject  
request. 
12.2.3 Subjects who enroll in subsequent radiation therapeutic trials will 
be followed for survival only and for progression in the treated 
lesion(s). To further clarify, subjects who are followed for survival 
only will no longer receive protocol-directed treatment or testing.  
12.2.4 Subjects who go on to receive additional non-radiation therapy(i.e. 
treatment that is not TACE or SBRT related) will be followed for 
survival only. To further clarify, subjects who are followed for 
survival only will no longer receive protocol-directed treatment or 
testing. They will also be followed for progression within the 
treated lesion(s).  
12.2.5 Subjects who undergo a liver transplant will be considered off 
study and will not be followed from that timepoint 
12.2.6 Subjects with progression of disease as per mRECIST for HCC will 
be followed for survival only. To further clarify, subjects who are 
followed for survival only will no longer receive protocol-directed 
treatment or testing. They will also be followed for progression 
within the treated lesion(s). 
12.2.7  Subjects permenantly removed from Liver Transplant list. 
 
12.3 Adverse Event Reporting 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 as an adverse event. 


19 
Amendment  18 September 2017 version 7.0 
 
 All AEs ≥ grade 3 will be collected and attributed either as 
related to protocol treatment or not related to protocol 
treatment.  Additional AE’s collected are:  
Any grade ≥2 gastritis, hepatic pain, vomiting, and 
fatigue.  
 The NCI Common Terminology Criteria for Adverse Events 
4.03 (CTCAE) will be utilized to grade AE’s for AE 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. 
 A serious adverse event (SAE) shall be defined as an  
adverse advent 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 investigators and will be 
labeled as either  related to treatment, or not related to 
treatment. 
12.3.2 Only adverse events deemed serious AND related will be  
reported to the IRB and the PI within 10 days of awareness of 
the event. All other events will be noted in the subjects’ 
medical record. 
12.3.3 Adverse events will no longer be reported if the subject has another  
           liver-directed therapy or starts chemotherapy. 
12.3.4 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  


20 
Amendment  18 September 2017 version 7.0 
 
              related or unrelated to the subject’s cancer. 
12.4 Data and Safety Monitoring 
This trial will be monitored in accordance with the Lahey Hospital and 
Medical Center Data and Safety Monitoring Plan. The study specific Data 
and Safety Monitoring Committee (DSMC), consisting of the protocol 
investigators, other health care professionals not affiliated with this study, 
the study data manager or designee, , will meet annualy. The discussion will 
include matters related to the safety of study participants (SAE/UaP 
reporting), At the regular DSMC meetings, the protocol specific Data and 
Safety Monitoring Report form will be completed. The report will be signed 
by the Principal Investigator or by one of the co‐investigators. Data and 
Safety Monitoring Reports will be submitted to the DSMC. on an annual 
basis for independent Review. 
 
13.0 STATISTICAL CONSIDERATIONS 
This is a randomized, non-blinded, pilot Phase II trial to characterize the safety and 
efficacy of individualized SRBT, compared to TACE, for subjects who have primary 
HCC. The trial endpoints are time to progression, number of retreatments, 
radiologic response, pathologic response, toxicity, and quality-of-life.. The planned 
accrual is sixty (60) subjects at Lahey Hospital & Medical Center over two years, an 
estimate which is based on the expected number of eligible subjects seen at Lahey. While 
this sample size will not provide adequate statistical power to test for significant 
differences in treatment groups, it will provide effect estimates that will be used to inform 
the design of future, larger trials. 
 
 
 
13.1 Analysis Plan 
The primary analytic approach will use intent-to-treat comparisons.  Reasons 
for any loss to follow-up will be recorded and every effort will be made to 
learn the outcomes for these subjects. For the secondary objectives, 
subjects will be divided into those who receive transplant by one year, 
and those who do not (estimated at 50%), and stratified analyses will be 
performed. If differential loss to follow-up occurs between groups, analyses 
may include per-protocol and as-treated groups. All estimates (e.g., 
proportions and means) will include 95% confidence intervals. Descriptive 
statistics of the sample will be performed to assess the balance of subject 
characteristics between groups, specifically age, gender, and Meld-Na score. 
The reasons why any enrolled subjects become ineligible for further 
treatment or for transplant will be evaluated.  
13.1.1 Primary Objective: Subjects undergoing treatment will be imaged  
by MRI or triphasic CT every three months following therapy 
using mRECIST for HCC criteria. Any target lesions meeting 
radiologic criteria for residual tumor or tumor progression will 
undergo repeat treatment with either the modality first utilized 
unless such treatment is not possible, or physician discretion. The 
time to progression will be measured and compared between 


21 
Amendment  18 September 2017 version 7.0 
 
treatment arms using cumulative incidence curves to account for 
the competing risks of transplant, death, and stop of treatment 
before re-treatment.  
13.1.2 Secondary Objectives 
 Toxicities will be summarized with frequency tables and  
will be tabulated by CTCAE grade and relatedness to 
treatment (as assessed by the investigator or PI). The 
proportion of subjects who receive any therapy that 
experience unacceptable toxicity will be estimated and 
compared. 
 The rate of retreatments before transplantation will be 
compared between treatment groups, measured as the number 
of retreatments per subject-year of follow-up. 
 Among subjects who undergo transplantation (estimated to be 
50% of total sample, or n=30), Pathologic Response will be 
measured in the ex-plant liver. 
 Radiologic Response to treatment of the target lesion utilizing 
modified RECIST (mRECIST) for HCC at three months 
following completion of treatment will be assessed as a 
dichotomous variable in subjects who complete therapy. The 
proportion of subjects achieving lesion control in each group at 
two months will be estimated. 
 Quality of Life will be determined by PIQ-6, and the SF- 
36v2 Health Survey (35) questionnaires at baseline,  
during treatment and follow-up. Analysis will be 
completed using the QM Certified Scoring (Insight) 
program obtained from qualitymetric.com. Mean quality-
of-life and PIQ scores will be compared between groups. 
 
E.  
REFERENCES 
1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United 
States. N Engl J Med 1999;340:745–750. 
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 
2000. Int J Cancer 2001;94:153–156.  
3. Okuda K. Hepatocellular carcinoma--history, current status and perspectives. Dig 
Liver Dis 2002; 34:613-616. 
4. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. 
Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-
2000 EASL conference. European Association for the Study of the Liver. J Hepatol 
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5. Okuda K. Natural history of hepatocellular carcinoma including fibrolamellar and 
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6. Pompili M, Francica G, Ponziani F et. Al. Bridging and downstaging treatments for 
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World Journal of Gastroenterology 2013;19(43):7515-30.  


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7. Luna W, Sze D, Ahmed A. Transarterial Chemoinfusion for Hepatocellular 
Carcinoma as Downstaging Therapy and a Bridge toward Liver Transplatation. 
American Journal of Transplantation 2009 9:1158-68. 
8. Llovet JM, Real MI, Montana X, et al. Arterial embolization or chemoembolisation 
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a randomised controlled trial. Lancet 2002; 359:1734-1739. 
9. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol 
chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 
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10. Johnson P, Kalayci C, Dobbs N, et al. Pharmacokinetics and toxicity of intraarterial 
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11. Lewis AL, Gonzalez MV, Lloyd AW, et al. DC bead: in vitro characterization of a 
drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006; 
17:335-342. 13. Hong K, Khwaja A, Liapi E, Torbenson MS, Georgiades CS, 
Geschwind JF. New intra-arterial drug delivery system for the treatment of liver 
cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 
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12. Lewis AL, Taylor RR, Hall B, Gonzalez MV, Willis SL, Stratford PW. 
Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of 
hepatic arterial embolization. J Vasc Interv Radiol 2006; 17:1335-1343. 
13. Brown DB, Cardella JF, Sacks D, et al. Quality improvement guidelines for 
transhepatic arterial chemoembolization, embolization, and chemotherapeutic 
infusion for hepatic malignancy. J Vasc Interv Radiol 2006; 17:225-232. 
14. Poon RT et al. A phase I/II trial of chemoembolization for HCC using a novel intra-
arterial drug-eluting bead. Clin Gastroenterol Hepatol. 2007;5:1100-8 
15. Varela M et al. Chemoembolization of hepatocellular carcinoma with drug eluting 
beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46:474-81. 
16. Malagari K et al. Transarterial chemoembolization of unresectable HCC with drug 
eluting beads: results of an open-label study of 62 subjects. Cardiovasc Intervent 
Radiol.2008;31:269-80. 
17. Song MJ, Chun HJ, Seon D et al Comparative study between doxorubicin-eluting 
beads and conventional transarterial chemoembolization for treatment of 
hepatocellular carcinoma. Journal of Hepatology 2012 vol. 57; 1244–1250 
18. Lammer J, Malagari K, Vogl T et al (2010) Prospective randomized study of 
doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: 
results of the PRECISION V study. Cardiovasc Intervent Radiol 33:41–52  
19. Vogl TJ, Lammer J, Lencioni R et al (2011) Liver, gastrointestinal, and cardiac 
toxicity in intermediate hepatocellular carcinoma treated with Precision TACE with 
drug-eluting beads: results from the PRECISION V randomized trial. AJR Am J 
Roentgenol 197:W562–W570 
20. Malagari K, Pomoni M, Kelekis A et al Prospective randomized comparison of 
chemoembolization with doxorubicineluting beads and bland embolization with 
Beadblock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2010:33:541–
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21. Nicolini A, Martinetti L, Crespi S, Maggioni M, Sangiovanni A Transarterial 
chemoembolization with epirubicin-eluting beads versus transarterial embolization 
before liver transplantation for hepatocellular carcinoma. J Vasc Interv Radiol 2010 
21: 327–332. 
22. Porrett P, Peterman H, Rosen M, et. Al. Lack of Benefit of Pretansplant Locoregional 
Hepatic Therapy for Hepatocellular Cancer in the Current MELD. Liver 
Transplantation 12:665-73. 
23. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic 
irradiation. Int J Radiat Oncol Biol Phys 1991;21:109-122. 
24. Lawrence TS, Robertson JM, Anscher MS, et al. Hepatic toxicity resulting from 
cancer treatment. Int J Radiat Oncol Biol Phys 1995;31:1237-1248. 
25. Ingold JA, Reed GB, Kaplan HS, et al. Radiation Hepatitis. Am J Roentgenol Radium 
Ther Nucl Med 1965;93:200-208. 
26. Russell AH, Clyde C, Wasserman TH, et al. Accelerated hyperfractionated hepatic 
irradiation in the management of subjects with liver metastases: results of the RTOG 
dose escalating protocol. Int J Radiat Oncol Biol Phys 1993;27:117-123. 
27. Schacter L, Crum E, Spitzer T, et al. Fatal radiation hepatitis: a case report and 
review of the literature. Gynecol Oncol 1986;24:373-380. 
28. Bujold A, Massey C, Kim J, et. Al. Sequential Phase I and II Trials of Stereotactic 
Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma. Journal of 
Clinical Oncology 2013 31(13):1631-39. 
29. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. 
Hepatology 2011;53:1020-1022 
30. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in subjects 
with endstage liver disease. Hepatology 2001;33:464-470. 
31. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic 
body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. 
J Clin Oncol 2008;26:657-664. 
32. Mendez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation 
therapy for primary and metastatic liver tumors: A single institution phase i-ii study. 
Acta Oncol 2006;45:831-837. 
33. Limquiaco JL, Wong GL, Wong VW, et al. Evaluation of model for end stage liver 
disease (MELD)-based systems as prognostic index for hepatocellular carcinoma. J 
Gastroenterol Hepatol 2009;24:63-69. 
34. Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-
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35. Ware JE, Kosinski M, Dewey J. How to score version 2 of the SF36 health survey. 
Lincoln, RI: QualityMetric Incorporated, 2000.  
 
 
 
 
 
 
 
 


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F.  
APPENDICES 
 
Appendix A 
Model for End-Stage Liver Disease (MELD-Na) 
 
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 11. 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 


25 
Amendment  18 September 2017 version 7.0 
 
 
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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Amendment  18 September 2017 version 7.0 
 
Appendix B 
 
mRECIST for HCCA 
 
 
Response 
Longest overall tumor 
diameterB 
Longest viable tumor 
diameterC 
Complete Response (CR) 
Disappearance of all target 
lesions 
 
Disappearance of any 
intratumoral arterial 
enhancement in all target 
lesions 
 
Partial Response (PR) 
At least a 30% decrease in the 
sum of diameters of target 
lesions, taking as reference the 
baseline sum of the diameters of 
target lesions 
 
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 
 
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 
target lesions, taking as 
reference the smallest sum of 
the diameters of target lesions 
recorded since treatment started 
 
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) scans.  
B. Measurement of longest overall tumor diameter according to conventional RECIST 
C. Measurement of longest viable tumor diameter according to mRECIST for HCC.