Feasibility of Hypofractionated Stereotactic Radiotherapy in Patients With Hepatocellular Carcinoma
Phase: NA
Conditions: Liver Cancer
Sponsor: University of Nebraska

IRB # 337-07 
NCT00607828 
 
 
Feasibility of Hypofractionated Stereotactic Radiotherapy in 
Patients with Hepatocellular Carcinoma 
 
 
Principal Investigator: 
Chi Lin, MD, PhD, Radiation Oncology 
 
Secondary Investigators: 
Fedja Rochling, MB BCh 
Margaret Kessinger, MD 
Charles Enke, M.D 
 
Participating Physicians/Healthcare Personnel: 
Jean Grem, MD 
Jue Wang, MD 
Weining (Ken) Zhen, MD  
Robert Thompson, MD 
Andrew Wahl, M.D. 
Aaron Sasson, MD 
Quan P. Ly, MD 
Chandrakanth Are, MD 
Jean Botha, MB BS 
Daniel Schafer, MD  
Timothy McCashland, MD  
Mark Mailliard, MD  
Sandeep Mukherjee, MB BCH MPH  
Michael Sorrell, MD  
 
 
 
Research Coordinator:  
Mary Mailliard, RN, BSN, OCN 
 
 
 
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2
 
Index 
 
Abstract 
 
 
 
 
 
 
Page  
 
3 
 
Section 1.0 Objectives 
 
 
 
 
Page   
 
4 
 
 
Section 2.0 Introduction  
 
 
 
Page  
 
4 
 
Section 3.0 Eligibility Criteria 
 
 
 
Page  
 
10 
 
 
Section 4.0 Registration Procedures 
 
 
Page  
 
12 
 
Section 5.0 Research Design 
 
 
 
Page  
 
12 
 
Section 6.0 Measurement of Effect 
 
 
Page  
 
16 
 
Section 7.0  Study Parameters  
 
 
Page  
 
18 
 
Section 8.0 Drug Formulation and Procurement 
Page  
 
19 
 
Section 9.0 Toxicity Reporting Guidelines 
 
Page  
 
19 
 
Section 10.0 Statistical Considerations  
 
Page  
 
22 
 
Section 11.0 Record keeping 
 
 
 
Page  
 
24 
 
Section 12.0 Patient Consent Form Statement  
Page  
 
24 
 
Section 13.0  References  
 
 
 
Page  
 
24 
 
Appendix I (Child Pugh Classification) 
 
 
Page  
 
28 
 
Appendix II (Schedule of Activity)  
 
 
Page  
 
29 
 
Appendix III (Response Evaluation Criteria in Solid  
Tumors (RECIST) Quick Reference) 
Page  
 
30 
 
Appendix IV (Pain Assessment)  
 
 
Page  
 
33 
 
Appendix V (Karnofsky Performance) 
 
 
Page  
 
34 
 
Appendix VI (Eligibility checklist)  
 
 
Page  
 
35 
 
 

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ABSTRACT 
 
Purpose: 
This is a phase I study to establish safety data of hypofractionated stereotactic 
radiotherapy (SRT) in patients with hepatocellular carcinoma. 
   
Eligibility criteria: Patients must have pathologically confirmed hepatocellular carcinoma with 
at least one tumor with a maximum diameter of ≤ 8 cm and must have Karnofsky performance 
status ≥ 60% and a life expectancy of at least 12 weeks.  Patients must be ≥ 19 years of age 
and able to give written informed consent prior to initiating treatment.  Previous systemic 
chemotherapy or non-radiation local therapy (such as surgery, hepatic arterial therapy, 
chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) is 
allowed.   
 
Interventions: All patients who have had successful implantation of a liver marker will undergo 
a 4D CT scan for planning SRT.  Following transfer to the treatment planning system, the CT 
scan may be correlated by imaging fusion with MRI for contouring integrated tumor volume 
(ITV).  The planning target volume (PTV) will be defined as ITV plus individualized margins 
which are determined by a 4D CT scan.  Novalis with 6MV photons will be used for imaging 
guided SRT.  Cohorts of 3-6 patients will receive SRT at daily doses of 8, 10, 12, 14 Gy within 
2 weeks.  The starting daily dose level will be 10 Gy.  The marker will be localized by 
orthogonal X-ray to ensure reproducibility.  A continuous respiratory gating will be 
accomplished with ExacTrac Adaptive Gating system if the required planning target margin is 
larger than 1 cm based on the 4D CT data. 
 
Evaluation:  
1) Liver, right kidney and small bowel toxicity will be evaluated according to CTCAEv3.0 
2) Tumor response will be accessed by tumor marker (AFP), CT and MRI scans 
 
Follow-up: As part of standard of care, all patients will have a follow-up visit 1 month after 
SRT and every 3 months for 1 year and every 3 to 6 months indefinitely.   The study follow-up 
will coincide with these visits.  The last study follow-up visit will be 4 months after the 
completion of radiation therapy.  
 
 
 
 
 
 
 
 
 
 
 
 

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4
 
 
Section 1.0 Objectives 
 
1.1 
Primary Objective:  
1.1.1 
The safety of hypofractionated stereotactic radiotherapy in patients with 
advanced hepatocellular carcinoma. 
1.1.1.1 
Record SRT related liver, right kidney, small bowel toxicity 
according CTCAEv3.0 
1.2 
Secondary Objective:  
1.2.1 
The maximum tolerable SRT dose. 
1.2.2 
Objective tumor response rate. 
1.2.2.1 
Report the percentage of tumor size change on CT 
1.2.2.2 
Report the percentage of intensity change on MRI 
1.2.2.3 
Report the percentage of change in AFP  
1.2.3 
The value of 4D CT in liver cancer planning 
1.2.3.1 
Report extent of liver motion three dimensionally 
1.2.3.2 
Report the percentage of patients requiring breath gating 
because of the amplitude of organ motion exceeding 1 cm in 
any dimension. 
1.2.4 
The value of breath gating in liver cancer SRT 
1.2.4.1 
Report the success rate of breath gating 
1.2.4.2 
Report the percentage of treatment time prolongation 
secondary to the gating. 
 
Section 2.0 Introduction 
 
Hepatocellular Carcinoma and Cirrhosis - Review of Epidemiology 
 
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and the third most 
common cause of cancer-related death. Although there are more than 500,000 cases per year 
worldwide, there is a large geographical variation in both risk factors and incidence. Cirrhosis, 
most often due to viral and alcohol hepatitis, is the dominant risk factor for HCC. Geographical 
differences of tumor incidence are largely due to epidemiological variations in hepatitis B and 
C infection. In the United States, the incidence rate, which is approximately 3 per 100,000 
persons, is increasing, mostly related to increasing rates of hepatitis C infection (HCV), with 
additional cases associated with cirrhosis due to alcohol, hemochromatosis and nonalcoholic 
fatty liver disease.  
 
Hepatic function is an important parameter affecting the selection of therapy for HCC. The 
Child-Pugh score is widely used to assess risk in cirrhotic patients for surgical and other 
therapies. The score includes clinical manifestations of cirrhosis including encephalopathy and 
presence of ascites, as well as laboratory parameters reflecting hepatic synthetic, metabolic 
and cell function (albumin, prothrombin time [PT], and bilirubin) 1, 8. 
 

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5
 
Hepatocellular Carcinoma: Surgical Treatment Options 
Surgical resection is considered a potentially curative modality for HCC. Five-year survival 
rates for patients with resectable lesions are 60-80%. Unfortunately, only about 15% of 
patients have resectable disease at initial diagnosis.   
 
Localized HCC may still be unresectable due to tumor location or concomitant decompensate 
cirrhosis. Patients in this group may be considered candidates for liver transplantation. Post-
transplant survival in several series has been reported as 60-75%. However, liver 
transplantation is an option only for patients who meet the Milan criteria 2. Milan criteria are 
defined as the presence of a single lesion no larger than 5 cm in diameter or the presence of 
up to three lesions no larger than 3 cm with no extrahepatic disease. The model for end-stage 
liver disease (MELD) based organ allocation system in the United States provides for 
additional MELD score points for lesions size 2-5 cm in diameter. 
 
Hepatocellular Carcinoma: Locoregional Treatment 
 
Locoregional ablation therapy is the best treatment option for patients with early stage HCC 
who are not suitable for resection or transplantation.  Destruction of tumor cells can be 
achieved by the injection of chemical substances (ethanol, acetic acid, and boiling saline) or by 
modifying the temperature (radiofrequency, microwave, laser, and cryotherapy).  The results 
with ethanol injection show that it is highly effective for small HCC and has a low rate of 
adverse effects. Ethanol injection achieves necrosis rate of 90%-100% of the HCC smaller 
than 2 cm, but the necrosis rate is reduced to 70% in tumors between 2 and 3 cm and to 50% 
in HCC between 3 and 5 cm.3  The best results obtained in series of HCC patients treated by 
percutaneous ethanol injection provide 5-year survival rates of 40-50%.  The results for 
radiofrequency ablation (RFA) show that the efficacy of RFA in tumors <2 cm is similar to that 
of ethanol but requires fewer treatment sessions. The efficacy in tumors >2 cm is better than 
that of ethanol. Randomized controlled trials (RCT) have shown that RFA provides better local 
disease control. 4, 5 6 7  However, significant survival advantages have not been proved yet for 
RFA. 
 
Transcatheter arterial chemoembolization (TACE) is widely used, since the majority of patients 
diagnosed in the West present with tumors at intermediate-advanced stages, when above 
percutaneous treatment options cannot be applied.  There is a contraindication to TACE which 
is the presence of portal vein thrombosis.  TACE has been shown to significantly delay tumor 
progression and vascular invasion. Overall modest survival benefits were identified in two 
RCTS9, 10 and a metaanalysis11. However, it is currently the mainstay of treatment in only 10% 
of the HCC population.  New trials are needed to refine the selection of target population and 
to establish the best chemotherapeutic agent and the optimal treatment schedule.   
 
Hepatocellular Carcinoma: Systemic Therapy 
 
Systemic Therapy with Doxorubicin is the most widely used, and is associated with at best an 
11-15% response rate.12 However, the recently published guidelines for HCC in Hepatology 

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6
discourage the use of doxorubicin in HCC 3.  There are multiple other treatment modalities 
such as octreotide, interferon, tamoxifen, or antiandrogenic therapy, but none have been 
shown to improve survival 3 . 
 
Sorafenib (Sor) is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase 
inhibitory activity, with clinical activity in a phase II HCC trial. Recently, a  large, multicenter, 
randomized, placebo-controlled phase III trial13 evaluated the efficacy and safety of Sor vs 
placebo (P) in 602 patients with advanced measurable HCC who had no prior systemic 
treatment, ECOG PS 0-2 and Child-Pugh status A. Median OS was 10.7 vs 7.9 mos (Sor vs 
P). Incidence of serious adverse events was similar for Sor vs P (52% vs 54%). It was 
concluded that Sorafenib was well tolerated and is the first agent to demonstrate a statistically 
significant improvement in OS for pts with advanced HCC. This effect is clinically meaningful 
and establishes sorafenib as first-line treatment for these patients.   
 
Hepatocellular Carcinoma: Radiation Therapy 
 
External beam radiotherapy has historically played a minor role in the primary treatment of 
hepatocellular carcinoma. Although there is evidence for tumor response to external beam 
radiotherapy and a radiation dose-response relationship has been established, the limited 
radiation tolerance of the adjacent normal liver has prohibited wider use of radiation therapy in 
this disease21, 22. In addition the adjacent liver may not be histological “normal” – i.e. cirrhotic 
as it is in more than 80% of cases of HCC in humans.  Previous studies have shown that 
radiation-induced liver disease (RILD, defined as grade 3 or higher hepatic toxicity according 
to CTCAE v3.015) is seen in 5-10% patients that receive 30-35 Gray to the entire liver and in 
50% of patients who receive 40-50 Gray.14  A recent study by Fox and Enke at UNMC 
(unpublished data) has shown that radiation treatment to the entire liver to a dose of 40 Gray 
or higher in 8 Gy or greater fractions over 5 days does not produce liver failure, but generates 
a cytokine syndrome. A second course of similar radiation treatment to the entire liver is also 
well tolerated, if given more than 6 months after the first course of radiation treatment.  It can 
be concluded that focused radiation to a liver tumor with relatively small amounts of radiation 
dose to the remaining liver is extremely unlikely to generate significant loss of liver function.   
Robertson et al. from University of Michigan presented their experience with conformal 
radiotherapy in treating 11 patients with HCC and 11 with bile duct cancer, with concurrent 
intraarterial FdUrd infusion for radiation sensitization. They showed that overall progression-
free survival within the liver was 50% in 2 years and the 4-year actuarial survival rate was 
20%. No late hepatic toxicity was observed 23.  
 
Treatment with Conformal Radiotherapy (CRT) and Intensity Modulated Radiotherapy (IMRT) 
 
Intensity-modulated radiation therapy, image-guided radiation therapy, and stereotactic body 
radiation therapy are recent technological and conceptual developments in the field of radiation 
therapy, which have the potential to improve radiation treatments by conforming the delivered 
radiation dose distribution tightly to the tumor or target volume outline while sparing normal 
liver tissue from high-dose radiation. Image guidance allows for a reduction of added (tumor 
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7
variability. Stereotactic targeting will further reduce residual target setup uncertainty. 
Combining improvements in tumor targeting with normal tissue sparing, radiation dose delivery 
will enable clinically effective and safe radiation delivery for liver tumors such as hepatocellular 
carcinoma14.   
 
The clinical paradigm underscoring the potential success of such an approach proposed is that 
of stereotactic radiosurgery (SRS). When small beams of radiation are directed from many 
angles, a highly focal distribution of radiation dose is created which decreases rapidly within 
millimeters from the intended target.  The resultant sparing of surrounding dose-limiting 
structures enables a higher dose of radiation to be safely delivered to the target, in turn 
increasing the probability of tumor control and ultimately cure.  Stereotactic radiosurgery has 
been used for over a decade in the focal treatment of cranial neoplasms; SRS has become the 
standard of care in the treatment of brain metastases. The success of radiosurgery has given 
rise to speculation by a number of authors, however, that similar success of a highly focused 
single fraction or hypo-fractionated approach may be possible in extra-cranial solid tumors 16-
20.  
 
Early studies from the international arena 16 19 24 demonstrated that a high probability of local 
tumor control and a low likelihood of late normal tissue toxicity can be accomplished using 
focused radiotherapy techniques. More recently, Schefter et al have presented results from a 
phase I study of stereotactic body radiotherapy for the treatment of liver metastases 25. The 
dose was escalated from 36 to 60 Gy delivered in three fractions, with three patients in each 
dose regimen. Dose-volume constraints were specified such that a minimum of 700 ml of 
unaffected liver could receive no more than 15 Gy (over three fractions). Additional dosimetric 
constraints were placed on the total kidney volume (no more than 5 Gy per fraction to no less 
than 35% of the total volume), and on the spinal cord, stomach, and small intestine (maximum 
doses of 18 Gy, 30 Gy and 30 Gy respectively). No dose-limiting toxicity was observed at any 
dose level. 
 
Following the methodology of Schefter  et al 25, one can apply the linear-quadratic formalism 
for radiation cell killing to “equate” schemes that vary the dose/fraction and number of 
fractions. This concept of biologically equivalent dose (BED) says that the total effect is given 
by: 
 





+
β
α
d
nd
1
)
(
 
 
where n is the # of fractions and d is the dose/fraction. The “alpha-beta ratio” characterizes the 
radiation response of a particular tissue; a higher value is indicative of a tissue that responds 
acutely to the effects of radiation. Due to their highly proliferative nature, most tumors fall into 
this category. Because prolonging the treatment time introduces a sparing (repair) effect in 
acutely responding tissues, there is significant motivation to deliver radiation in larger fractions 
over a shorter time.  

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8
 
While the dose-fractionation scheme employed by Schefter et al resulted in no significant 
morbidity, we propose a slightly more conservative dose escalation study as follows: 
 
Dose  
Level 
# Patients 
# Fractions 
Dose/fraction 
Total Dose 
Equivalent dose in 
2 Gy/fractions 
I 
3-6 
5 
8 Gy 
40 Gy 
60.0 Gy 
II* 
3-6 
5 
10 Gy 
50 Gy 
83.3 Gy 
III 
3-6 
5 
12 Gy 
60 Gy 
110.0 Gy 
IV 
3-6 
5 
14 Gy 
70 Gy 
140.0 Gy 
 
*Starting dose level is Dose Level II. 
 
For comparison, the 3 x 12 Gy arm in the Schefter study is equivalent to a total dose of 66 Gy 
in 2 Gy fractions, while the 3 x 20 Gy arm is equivalent to 150 Gy. All calculations assume an 
alpha/beta ratio of 10.  
 
Likewise, this study will follow the dose-volume constraints used by Schefter et al 25. Using the 
Novalis to deliver radiation, and excluding patients with a maximum tumor diameter of ≥ 8 cm, 
these criteria are easily achievable. 
 
Data 26-30  have shown that radiological response rates to modern partial external radiotherapy 
of HCC are of the order of 50-70%. Single center studies show a strong dose-response 
relationship when doses >50 Gray are given 26-31.  
 
An autopsy series of patients who received 50-70 Gray showed evidence of tumor regression, 
but not eradication of HCC 32  It suggests that higher dose is required to eradicate HCC.  
 
Recently, a study50 (the abstract is published in the July volume of the 2007 ASCO annual 
meeting) evaluated the effect of Cyberknife stereotactic radiosurgery (SRS) for both small 
primary non-resectable HCC (23 lesions in 22 patients), and advanced HCC with portal vein 
tumor thrombosis (PVTT) (9 lesions in 9 patients).  The total SRS doses treated were 30-39 
Gy (median, 36 Gy) to the 70-85%, 3 fractions and the target volume was of 3.6-57.3 cc 
(median, 25.2 cc).  After median follow up of 10.5 months, a complete response (CR) was 
achieved in 10 lesions, a partial response (PR) in 13 lesions (CR+PR was 71.9%), stable 
disease in 6 lesions, and disease progression in 3 lesions. The level of serum alpha-
fetoprotein after the treatment was decreased significantly in 17 patients (54.8%) 
Complications greater than grade 3 were observed in two patients. These results suggest that 
Cyberknife SRS could be considered as an effective and safe treatment for primary HCC. For 
PVTT, Cyberknife SRS as the only curative tool, and produced acceptable local control in this 
study. 
 
The issue of respiratory motion has long been recognized as a major limitation in the 
management of radiotherapy patients. The limitations are manifest both in conventional 

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imaging for target localization, and in the delivery of radiotherapy itself.  Respiratory motion 
during computed tomography (CT) scanning causes artifacts that distort the size, shape, and 
density of objects within in the image, and introduce uncertainty in their location  33-36. Larger 
radiation fields are therefore required to ensure adequate coverage of the target anatomy. As a 
consequence, greater volumes of normal tissue are irradiated, which subsequently limits the 
therapeutic dose that can be delivered.  
 
Minimizing the impact of respiratory motion is essential in order to achieve further gains in the 
treatment of hepatic disease. In this study, we will apply advanced imaging and delivery 
technology to provide added confidence in imaging and targeting. First, all patients will 
undergo a planning CT that uses a respiratory correlation technique 37-42 43. Briefly, patients’ 
respiration will be monitored using a commercial strain gauge (ANZAI Medical Co. Ltd., Tokyo, 
Japan) device placed inside an elastic belt and positioned about the patient’s abdomen. 
Patients will subsequently undergo a low pitch, over-sampled CT scan. By retrospectively 
correlating the CT data with the respiration signal obtained using the ANZAI device, CT images 
will be reconstructed into four bins as a function of respiratory phase: end exhale, mid exhale, 
mid inhale and full inhale. End exhale images will be used for planning purposes, as this has 
been shown to be the most reproducible phase of respiration and that with the longest 
duration.  
 
The Novalis accelerator (BrainLAB AG, Heimstetten, Germany) incorporates stereotactic x-ray 
capabilities for verifying target position.  This consists of two floor mounted x-ray tubes and two 
opposing amorphous silicon (aSi) flat panel detectors mounted to the ceiling.  Each x-ray 
tube/detector pair is configured to image through the linac isocenter with a coronal field of view 
of approximately 18cm in both the superior-inferior (S-I) and left-right (L-R) directions at 
isocenter. For soft tissue targets the system is designed to be used with radio-opaque fiducial 
markers implanted near the target.  These markers are implanted prior to CT imaging and 
treatment planning, and should be placed close enough to the target anatomy so that they can 
be observed within the field of view of the x-ray localization system at the time of treatment.  
 
Markers are placed by introducing a small coil (VISICOILTM, RadioMed Corp., Tyngsboro, MA) 
percutaneously through a coaxial needle (18 to 22 gauge) in or near the target. This is 
performed under fluoroscopic guidance in a manner analogous to a biopsy or radiofrequency 
ablation. The extended and coiled-wire structure of the VISICOIL is designed to minimize 
migration and movement, providing stability of the marker in tissue. VISICOIL needles are 
delivered with preloaded coils of an appropriate length and sterilized ready for use. The use of 
implanted makers for radiotherapy localization has been described for a number of tumor sites, 
including prostate44 45, liver46, and lung47, 48. An excellent primer on the percutaneous 
placement of helical coils in lung tumors has been presented by de Mey et al 48.  
 
Based on specific patient motion characteristics determined during 4D CT, an appropriate 
course of radiotherapy will be determined.  This may include the use of gated deliver, which is, 
turning the beam on only at a specified phase of respiration.  This “freezes” target motion and 
allows reduction of beam margins, thereby reducing the amount of irradiated normal tissue (in 
this case, normal liver).  The Novalis system is well suited to gated delivery and has been 

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10
evaluated extensively by Tenn et al 49.  The following is a brief procedural summary from that 
work which will be incorporated into this study: 
 
The patient is set up in the treatment room and IR reflective markers with adhesive bases are 
attached to their anterior surface so that breathing motion can be monitored. A second set of 
IR reflective markers is rigidly attached to the treatment couch and used as a reference against 
which the movement of patient markers is measured. These rigidly mounted reflectors are also 
used to track couch location during the patient positioning process. The 3D movement of the 
patient’s anterior surface is tracked via the IR markers and the anterior-posterior (A-P) 
component of this trajectory is used to monitor breathing motion. The system plots breathing 
motion versus time and a reference level is specified on this breathing trace. This designates 
the point in the breathing trace at which the verification x-ray images will be triggered. The two 
images are obtained sequentially at the instant the breathing trace crosses this level during 
exhale phase. Because the patient is localized based on these images, the gating level is set 
at the same phase in the breathing cycle at which the planning CT data was obtained. Within 
each image the user locates the positions of the implanted markers. From these positions the 
system reconstructs the 3D geometry of the implanted markers and determines the shifts 
necessary to bring them into alignment with the planning CT. The patient is subsequently 
positioned according to the calculated shifts. Finally, a gating window (beam-on region) during 
which the linac beam will be delivered is selected about the reference level. The system can 
gate the beam in both inhale and exhale phases of the breathing cycle. Subsequent x-ray 
images verifying the location of the implanted markers locations are obtained at the gating 
level continuously during treatment. If marker positions remain within tolerance limits the target 
position may also be assumed to be correctly positioned. If they are outside the limit the newly 
obtained images can be used to reposition the patient and maintain treatment accuracy. 
 
In summary, for the majority of HCC patients, surgery is precluded.  Percutaneous ethanol 
injection and RFA showed relative good results for early stage HCC only. TACE has shown to 
provide modest survival advantages and is currently the mainstay of treatment in only 10% of 
the whole HCC population.  Systemic chemotherapy is ineffective for HCC patients. Although 
targeted therapy has been shown survival advantage, it is only on HCC patients with Child-
Pugh status A.   The effectiveness of high dose radiation therapy on both early and advanced 
HCC without dose limiting toxicity suggested the importance of the further investigation of 
newer conformal radiation technology, i.e. IMRT, IGRT, SRT, for treatment of HCC. 
 
Section 3.0 Eligibility Criteria 
 
3.1 Inclusion Criteria: 
Patients must meet all the following criteria 
3.1.1 Male or female patients ≥ 19 years of age 
3.1.2 A life expectancy of at least 12 weeks with a Karnofsky performance status ≥ 
60% (Appendix V) 
3.1.3 Histologically or cytologically documented HCC 
3.1.4 The target lesion can be accurately measured in at least one dimension 
according to RECIST and must have a maximum tumor diameter of ≤ 8 cm 

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11
3.1.5 Previous systemic chemotherapy or non-radiation local therapy (such as surgery, 
hepatic arterial therapy, chemoembolization, radiofrequency ablation, 
percutaneous ethanol injection or cryoablation) is allowed.  Local therapy must 
be completed at least 6 weeks prior to the baseline scan.  
3.1.6 Cirrhotic status of Child-Pugh class A and B (Appendix I) 
3.1.7 Platelet count ≥ 60 x 109/L, Hemoglobin ≥ 8.5 g/dL, WBC ≥ 2000/μL 
3.1.8 International normalized ratio (INR) must be ≤ 2.3.  Patients who are being 
therapeutically anticoagulated with an agent such as Coumadin or heparin will be 
allowed to participate provided that no prior evidence of underlying abnormality in 
these parameters (PT, PTT,INR) exists. 
3.1.9 Must be aware of the neoplastic nature of his/her disease and willingly provide 
written, informed consent after being informed of the procedure to be followed, 
the experimental nature of the therapy, alternatives, potential benefits, side-
effects, risks and discomforts.   
 
3.2 Exclusion Criteria: 
 
3.2.1  Previous (within 3 years) or concurrent cancer that is distinct in its primary 
site or histology from HCC, EXCEPT cervical carcinoma in situ, treated 
basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any 
cancer curatively treated > 3 years prior to entry is permitted.  
3.2.2 Renal failure requiring hemo- or peritoneal dialysis 
3.2.3 Uncontrolled inter-current illness including, but not limited to ongoing or 
active infection (> grade 2 National Cancer Institute [NCI]-Common 
Terminology Criteria for Adverse Events [CTCAE] version 3.0), congestive 
heart failure (> New York Heart Association (NYHA) class 2), active 
coronary artery disease (CAD), cardiac arrhythmias requiring anti-
arrhythmic therapy other than beta blockers or digoxin), uncontrolled 
hypertension and any condition which could jeopardize the safety of the 
patient and his/her compliance in the study . Myocardial infarction more 
than 6 months prior to study entry is permitted.  
3.2.4 Known Central Nervous System tumors including metastatic brain disease  
3.2.5 A history of variceal bleeding where the varices have not been eradicated 
or decompressed by shunt placement. 
3.2.6 Any conditions that would prevent the patient from undergoing maker 
implantation. 
3.2.7 Substance abuse, medical, psychological or social conditions that may interfere 
with the patient’s participation in the study or evaluation of the study results  
3.2.8 Pregnant or breast-feeding patients are excluded from this study because 
abdominal radiation therapy has potential for teratogenic or abortifacient effects. 
3.2.9   Prior radiotherapy to the liver. 
 

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12
Section 4.0 Registration Procedures 
 
4.1 Eligible patients will be identified from our institutional patient base or referred from 
community oncologists. All patients with HCC or suspicious HCC referred to the UNMC 
are evaluated in a multidisciplinary team conference. On initial presentation, a history 
and physical examination are performed, laboratory data obtained, and performance 
status is assessed. Imaging studies obtained include a high-resolution multi-detector 
computed tomography (CT) of the abdomen and pelvis as well as a chest radiograph 
(two views). Further imaging studies will be obtained as clinically indicated. Any 
pathologic specimens obtained at referring institutions are reviewed for accuracy. 
Patients with suspicious HCC will require liver biopsy for confirmation of malignancy. 
  
4.2 Patient’s cirrhotic status will be evaluated according to Childs-Pugh scale (Appendix I) 
 
4.3 Assessment of medication intake 
 
4.4 Patients will be consented once eligibility has been confirmed by participating 
hepatologists, medical oncologists and radiation oncologists. Eligible patients will be 
counseled about the study with special emphasis on the risks involved in a trial.  
Patients and their families who are interested in pursuing experimental therapy can be 
counseled in a group by the principal investigator.  After an appropriate waiting time, a 
second opportunity for conference will be offered to answer remaining questions.  
Informed consent will be obtained from all patients.  
 
4.5  The standard of care outside a clinical trials setting for patients with locally advanced 
HCC is localregional ablative therapy including percutaneous ethanol injection and RFA, 
TACE, palliative chemotherapy with or without palliative radiation therapy.   Targeted 
therapy may be offered in the future. 
 
4.6  Study schedule of activity (Appendix II) 
 
Section 5.0 Research Design 
 
5.1 Liver marker implantation: Under CT or ultrasound guidance, a marker will be implanted 
into the liver tumor in a fashion similar to liver tumor biopsy and a stent placement.  
Prophylactic antibiotics will be given to prevent infection.  The marker position and 
geometry will be documented on the simulation CT scan for planning SRT. 
 
5.2 SRT: 
 
5.2.1 Machine:  Novalis with 6 MV photons will be used for imaging guided SRT.   
5.2.2 Doses:  Doses of 40, 50, 60 or 70 Gy (daily doses of 8, 10, 12 or 14 Gy in 2 
weeks) will be prescribed to 90% isodose line.  The prescription isodose volume 
should encompass the entire PTV.  The subjects will be divided into groups of 5 

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13
to receive escalating doses of the SRT.  The first group will receive a daily dose 
of 10Gy (Dose Level II).  The next group will be enrolled only after the first group 
has been observed for 4 weeks following the SRT to document any side effects.   
The observation period will be used for every increase in dose level.  Each 
subject will only receive one dose level of the SRT. 
5.2.3 Localization, Immobilization and Simulation:  A body-fix bag will be used for 
treatment simulation and delivery.  Infrared markers will be attached to the 
patient’s chest and abdomen in suitable positions to yield a good breathing 
signal.  A 4D CT scan of abdomen will be performed for treatment planning.    
Treatment Planning:  Following transfer to the treatment planning system, the CT 
scan may be correlated by imaging fusion with a MRI scan for contouring tumor 
volume.  Integrated tumor volume (ITV) will be generated.  The planning target 
volume (PTV) is defined as ITV plus individualized margins, which will be 
determined by a 4D CT scan.  The uniformity requirement will be +10% -5% of 
the total dose at the prescription point within the tumor volume. The IMRT may 
be used if there is a benefit of decreasing tissue complications. The dose to the 
kidney will require careful monitoring and kidney volumes must be defined on 
simulation fields. The percent of total kidney volume (defined as the sum of the 
left and right kidney volume) receiving 15 Gy (3 Gy per fraction) should be 
required to be less than 35% of the total kidney volume.  The maximum dose to 
any point within the spinal cord should not exceed 15 Gy (3 Gy per fraction).  At 
least 700 ml or 35% of normal liver (entire liver minus cumulative GTV) should 
receive at total dose less than 15 Gy (3 Gy per fraction).  The maximum point 
dose to the stomach or small bowel except duodenum should not exceed 80% of 
prescription dose.  An isodose distribution of the treatment at the central axis 
indicating the position of kidneys, liver and spinal cord is required. The treatment 
plans should be optimized using dose volume histograms of any irradiated vital 
organ.   
5.2.4 Treatment Delivery:  The planning data containing the coordinates of tumor 
isocenter, the external infrared markers, and the implanted marker are 
transferred to the ExacTrac Adaptive Gating platform.  The daily initial positioning 
will be performed using lasers and skin marks.  The target isocenter will be 
verified on daily x-rays.  If the patient meets the criteria of breath gating, 
treatment delivery is accomplished using the ExacTrac Adaptive Gating in 
combination with Novalis.  External infrared markers attached to the patient’s 
skin are used to determine the breathing pattern.  The respiratory moving target 
is positioned, under infrared and x-ray guidance to a defined point within the 
patients’ end expiratory breathing cycle.  The gating reference level will be 
defined to evaluate target motion due to respiration.  The size of beam-on 
window will be determined based on the target motion as detected by the 4D CT 
scan.     
 
 
5.3 The study follow-up will coincide with the standard of care follow-up visits which will be 
1 and 3 months after the completion of SRT.   None of the tests or procedures is 

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14
performed more frequently than would be considered clinically standard.  No 
procedures would be done exclusively for research purposes. 
 
 
 
5.4 Toxicity: 
 
5.4.1 Implantation of a liver marker: The side effects of implantation will be similar to 
the needle biopsy of liver tumor and the stent placement including but not limited 
to tumor seeding, foreign body, infection, bleeding, pain at local area, and 
dislocation of the marker.   
 
5.4.2 SRT: Short term side effects include but not limited to skin reaction, local hair 
loss, fatigue, abdominal pain, nausea, vomiting, diarrhea, increasing liver 
function abnormality, GI bleeding or perforation which may require surgical 
intervention.  Long term side effects are less likely to occur but if they do occur 
are more likely to be permanent.  They include local hair loss, liver function 
abnormality, diarrhea, small bowel obstruction which may require surgical 
intervention, spinal cord injury which could result in paralysis, kidney function 
abnormality.   
 
5.5 Dose Modifications: 
 
Radiation therapy will be held if the AGC is < 500/μL and/or the platelets are < 
50,000/μL. Upon recovery of the AGC to ≥ 500/μL and platelets to > 50,000/μL, 
radiation therapy will resume at the full planned daily dose. 
 
5.5 Supportive Care: 
 
5.5.1 Prophylactic Anti-Emetic Premedication: 1 hr prior to radiation 
 
Granisetron 2 mg PO  
prochlorperazine 10 mg PO  
promethazine 12.5 mg PO 
or equivalent 
 
5.5.2 Diarrhea 
Patients will be instructed to begin taking loperamide after the first poorly formed 
or loose stool or first episode of 2 or more bowel movements in one day.   
 
Loperamide should be taken in the following manner:  4 mg at the first onset of 
diarrhea, then, 2 mg after every episode of diarrhea until reaching the daily 
maximum dose. 
 

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15
Loperamide should not be taken prophylactically. 
  
Patients must notify the research team as to when they initiated loperamide 
therapy. If diarrhea persists despite loperamide therapy, then the patient should 
be evaluated for the need for IV fluid & electrolyte replacement. 
 
Alternative medications 
Somatostatin analog (Octreotide7) 100 - 500 mcg SC/IV tid; maximum daily dose 
= 1500 mcg/day; Alternatively, somatostatin analog may be given at 25-50 
mcg/hour as a continuous IV infusion. 
 
Atropine/diphenoxylate which is available as either a 0.025/2.5 tab, or 0.025/2.5 
per 5 mL liquid. Patients should take 1-2 tabs PO tid or qid or 5-10 mL PO tid/qid. 
 
Atropine/difenoxin (Motofen7) 0.025/1 tab; 2 tabs PO x 1, then 1 tab PO q 2-4 hr 
(max 8 tabs per day) 
 
Paregoric: (an antidiarrheal opiate): 5 - 10 mL ORALLY 1-4 times daily: 
maximum 40 mL/day 
 
OTC meds: bismuth subsalicylate 262 mg tabs: 2 tabs PO q 1 hr prn; maximum 
4200 mg/24 hr 
 
5.5.3 Treatment of Fever & Neutropenia  
Subjects developing a fever of 100.5º C or higher will have a CBC with WBC 
differential obtained along with a history & physical examination to look for signs 
of infection. 
 
If the ANC is < 500/μL, the patient will be treated with empiric antibiotic therapy 
as an inpatient & undergo appropriate radiographic & laboratory investigation for 
sources of infection, & development of a specific treatment plan. Fever & 
neutropenia occurring during a treatment cycle will require interruption of 
chemotherapy. The patient may resume chemotherapy at the start of the next 
scheduled cycle if therapy for infection has been completed & the patient meets 
other criteria for starting a new cycle 
 
If the ANC is between 500-1000/μL, antibiotic therapy will be instituted if there is 
clinical suspicion of an infection. Daily CBCs with differentials will be obtained if 
the patient remains febrile. 
 
If the ANC is > 1000/μL, & there is no clinical evidence of an infection, then 
therapy may resume. 
 

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16
 
 
5.5.4 Blood Products 
Blood product support will utilize packed red blood cells or platelets if clinically 
indicated 
 
5.5.5 Nutritional Supplementation 
Patients will be encouraged to drink specialized cancer supplement between 
meals. 
 
5.6 Criteria for removal of patients from study 
 
5.6.1 Disease progression 
5.6.2 Study closure 
5.6.3 Any dose limiting toxicity (defined at section 10.1) 
5.6.4 Patient decision to withdraw from the study, or 
In the judgment of the investigator, further treatment would not be in the best 
interest of the patient.  
 
Section 6.0 Measurement of Effect 
 
6.1 Toxicity criteria 
The NCI Common Toxicity Criteria Adverse Events version 3 will be used to grade 
toxicity; it is available at the following internet site:  
http://ctep.cancer.gov/forms/CTCAEv3.pdf. 
 
6.2 Clinical Benefit Response 
Clinical benefit response is a measure of clinical improvement based on analgesic 
consumption, pain intensity, performance status and weight change.  
 
A patient is considered a clinical benefit responder if either: 
6.2.1 The patient shows a ≥50% reduction in pain intensity or analgesic consumption 
(Appendix IV: Pain assessment) 
OR 
6.2.2 Improvement in performance status (Appendix V) of ≥20 points  for a period of at 
least four consecutive weeks, without showing any sustained worsening in any of the 
other parameters (sustained worsening was defined as four consecutive weeks with 
either any increase in pain intensity or analgesic consumption or a ≥20 point decline in 
performance status) 
OR 
6.2.3 The patient is stable on all of the aforementioned parameters, and shows a 
marked, sustained weight gain (≥7% increase maintained for ≥ 4 weeks) not due to fluid 
accumulation 

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17
 
6.3 Tumor Response   
 
6.3.1 Measurable Disease Response: CTEP’s RECIST guidelines will be followed. A 
quick reference to the RECIST guidelines can be downloaded at the following URL:  
http://ctep.info.nih.gov/Policies/WordDocs/RCSTF.PH2TEMPF.doc.  (Appendix III) 
 
Patients enrolled in this study must have a measurable HCC which is defined as lesions 
that can be accurately measured in at least one dimension: [longest diameter to be 
recorded] on the CT scan or MRI scan. 
 
The same method of assessment & the same technique should be used to characterize 
each identified & reported lesion at baseline & during follow-up. 
 
 
 
Parameters to Measure  
Response Outcome: 
  
1 
  
Clinical examination 
  
2 
  
CT scan 
  
3 
  
MRI scan 
  
4 
  
AFP 
 
6.3.2  Response criteria 
 
6.3.2.1 Taking into account the measurement of the longest diameter only for 
those lesions with size response, response criteria are defined as: 
 
Complete Response (CR):  the disappearance of a lesion. 
 
Near Complete Response (NCR):  at least an 80% decrease in the longest 
diameter of a lesion, taking as reference the longest diameter recorded since the 
treatment started. 
 
Partial Response (PR):  at least a 30% decrease in the longest diameter of a 
lesion, taking as reference the longest diameter recorded since the treatment 
started. 
 

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18
Progressive Disease (PD):  at least a 25% increase in the longest diameter of a 
lesion, taking as reference the longest diameter recorded since the treatment 
started. 
 
Stable Disease (SD):  neither sufficient shrinkage to qualify for partial response 
nor sufficient increase to qualify for progressive disease, taking as reference the 
longest diameter since the treatment started. 
 
6.3.2.2 The criteria used to determine the objective tumor response for those 
lesions without size response: 
 
Complete Response (CR):  the normalization of AFP level. 
 
Partial Response (PR):  at least a 25% decrease in the AFP level. 
 
Progressive Disease (PD):  the maintenance of AFP level above the normal limits  
 
In some circumstances, it may be difficult to distinguish residual disease from the 
radiation induced necrotic tissue. When the evaluation of complete response 
depends on the normalization of AFP level, it is recommended that the residual 
lesion be investigated (fine-needle aspiration/biopsy) before confirming the 
complete response status.)  
 
Section 7.0 Study Parameters 
7.1 Laboratory/imaging Studies: 
 
 
Parameter 
 
 
Baseline 
 
 
Pre- and 
post-SRT 
therapy 
 
Post- 
Treatment  
Follow-up 
History 
X 
X b 
a 
Physical examination 
X 
X b 
a 
Weight 
X 
X  
a 
Vital signs 
X 
X 
a 
Performance status 
(Karnofsky) 
X 
X 
a 
CBC, differential, platelet 
count 
X 
X 
Post- SRT 
a 
Comprehensive metabolic 
panel (including bilirubin, alk 
phos, AST, ALT, ) 
X 
X 
Post- SRT 
a 

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19
Fill out pain assessment 
card 
X 
X  
Post-SRT 
a 
AFP 
X 
X  
post-SRT 
a 
PT, PTT, INR 
X 
X 
Post-SRT 
a 
CT 
X 
X 
simulation 
 
MRI 
X 
X 
Post-SRT 
a 
Serum pregnancy test 
prn 
 
 
 
a - will be done at one month and 3 months after the completion of SRT 
b – A brief physical exam and history will be performed 
 
7.2 Monitoring of peri- and post-marker implantation morbidity 
The liver marker position and geometry will be documented on simulation CT 
images. Information regarding the development of infectious complications, bleeding, 
and any implantation associated adverse events will be recorded.  
 
Section 8.0 Drug Formulation and Procurement 
 
No drugs are used in this study. 
 
Section 9.0 Toxicity Reporting Guidelines 
 
9.1 Adverse Events that will be reported to UNMC’s IRB  
 
9.1.1 Unexpected serious adverse events  
9.1.2 Any death, which occurs while the subject is being treated on protocol or occurs 
within 30 days of completing research related interventions 
9.1.3 Toxic deaths will be reported to the UNMC IRB within 24 hours following PI 
knowledge of the event via e-mail notification to irbora@unmc.edu 
 
The IRB only requires submission of internal AE reports when the event is unexpected. 
Internal adverse events occurring on a study which satisfy this criterion must be 
submitted to the IRB within two business days following the time it becomes known. Any 
death must be reported immediately. One original of the Internal AE Report form (or 
Internal Fatal Event form), and one copy of the current IRB approved consent form must 
be submitted, along with any other relevant information, to the IRB:   
 

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20
The contact information is:  Institutional Review Board, University of Nebraska Medical 
Center, 987830 Nebraska Medical Center, Omaha, NE 68198-7830; Tel: 559-6463;  
FAX:  559-3300;  e-mail: irbora@unmc.edu 
 
9.2 Reporting of Adverse Events to the Scientific Review Committee of the UNMC Eppley 
Cancer Center 
 
The SRC defines an adverse event as any undesirable experience associated with the 
use of the protocol treatment in a patient. The event is considered to be SERIOUS and 
should be reported when the patient outcome is: 
 
9.2.1 Death: Report if the patient's death is suspected as being a direct outcome of the 
adverse event. 
9.2.2 Life-threatening:  Report if the patient was at substantial risk of dying at the time 
of the adverse event or it is suspected that the use of the SRT would result in the 
patient's death. 
9.2.3 Hospitalization (initial or prolonged):  Report if the patient requires admission to 
the hospital for 24 hours or more or prolongation of a hospital stay results 
because of the adverse event. 
9.2.4 Disability. Report if the adverse event resulted in a significant, persistent, or 
permanent change, impairment, damage or disruption in the patient's body 
function/structure, physical activities or quality of life.  
9.2.5 Requires intervention to prevent permanent impairment or damage. Report if you 
suspect that the use of the protocol treatment may result in a condition which 
required medical or surgical intervention to preclude permanent impairment or 
damage to a patient. 
 
Copies of the adverse event report will be submitted to the IRB (when required), 
to the UNMC Eppley Cancer Data and Safety Monitoring Committee (DSMC). 
 
9.3 Data and Safety Monitoring Plan 
This protocol will comply with monitoring and adverse event reporting requirements of 
the UNMC/Eppley Cancer Center Data Monitoring Plan. All research data will be stored 
in the case report forms in a locked file cabinet. These forms are available only to the 
investigators, his/her designee (i.e., the study coordinator), the UNMC Eppley Cancer 
Center Scientific Review Committee (SRC), and representatives of the Institutional 
Review Board at the University of Nebraska Medical Center. Any information obtained 
during this study which could identify the subject will be kept strictly confidential and will 
be identified by code numbers rather than the patient's name. The data safety plan also 
includes: Weekly review of all patients on study by the investigators. All adverse events 
will be reported to the PRMS Internal Audit Committee for audit by a clinician not 
involved with the clinical trial. 
 

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21
All patients will be closely followed for toxicity. Toxicity will be assessed using the 
revised NCI Common Toxicity Criteria (version 3.0) retrieved from the National Cancer 
Institute, Cancer Therapy Evaluation Program web site: 
(ctepcancer.gov/forms/CTCAEv3.pdf). Therapy will be discontinued at any time due to 
the development of unacceptable toxicity.  If a Grade 1 or 2 or 3 toxicity develops, the 
investigator may elect to continue the treatment with careful monitoring. Any grade 4 or 
greater toxicity according to CTCAE v3 will constitute a DLT.  1) SRT dose escalation 
will be stopped if 2 patients at a given dose level experience a DLT.  If one patient has a 
DLT, then an additional five patients will be evaluated at the same dose level.  2) 
Implantation of a liver marker will be stopped if 2 patients experience implant-related-
adverse events which do not response to medical or surgical management. 
 
Therapy will be discontinued at any time due to the development of unacceptable 
toxicity.   If, at any time, the data suggest a significant hazard to further dose escalation, 
regardless of whether the formal stopping rules are satisfied, dose escalation will be 
halted pending a review of all data. There will be a four week waiting period after the 
last patient in each cohort completes radiation therapy for toxicity evaluation between 
dose levels. 
 
Adverse events will be assessed by reports from patients of any adverse events to their 
physician-investigators and by physical examinations.  The following information will be 
recorded for all adverse events: date of onset, date of resolution, severity, action taken, 
relationship to study medication and patient outcome.  The worsening of a concurrent 
disease or the development of a new concurrent disease will be regarded as an adverse 
event and information regarding the event will be added to the adverse event page of 
the case record book.  
 
The plan also includes the following: the status of all patients participating in this 
protocol will be reviewed by the principal investigator with the research nurse on the 
weekly visit during the SRT and on each follow-up visit. During this meeting, the clinical 
toxicities experienced by the patients will be discussed, and plans will be made for any 
modification, and whether any changes need to be made to the protocol through an 
amendment. Any logistical or social issues for the patients will also be addressed at this 
meeting. The research nurse will be in contact with each patient by either telephone or 
e-mail.  Laboratory studies done at outside facilities are faxed to the research nurse on 
a real-time basis. Any abnormalities are brought to the attention of the principal 
investigator or designee. 
 
Patients may continue on concurrent medications for symptom relief on an as needed 
basis.  The need for additional or more potent concurrent medication after the start of 
the study may constitute an adverse event, and information regarding such an 
experience will be added to the appropriate page of the case record form.  The details 
of all concurrent medications, including vitamins, blood and blood products, will be 
recorded on the case record forms. 

Version 6: 12/02/2008 
 
22
 
Section 10.0 Statistical considerations  
 
10.1 Trial Design 
This phase I trial will determine safety, dose-limiting toxicities (DLT) and maximum 
tolerable dose (MTD) of SRT for HCC. Although unacceptable toxicity is unlikely, four 
dose levels (40, 50, 60, 70 Gy in 5 fractions) will be evaluated in a cohort escalation 
design of 3-6 patients. At the MTD, 10 additional patients will be enrolled to generate 
pilot data on radiologic response and to evaluate further toxicity. Patients will start at 
dose level II (50 Gy at 5 fractions).   
Endpoints 
Toxicity will be graded by NCI Common Toxicity Criteria (CTC Version 3.0). Due to 
delayed toxicities attributable to radiotherapy, all toxicities observed within 1 month 
after SRT will be scored. DLT is defined as any of following toxicities, that is possibly, 
probably or definitely related to SRT occurring within 30 days from the start of 
treatment:  
a) grade 4 or 5 hepatic  
b) grade 4 or 5 gastrointestinal  
c) grade 4 or 5 thrombocytopenia  
d) grade 4 hepatic liver enzyme elevations persisting for ≥ 5 days  
e) any adverse event requiring interruption of therapy by ≥ 2 weeks (14 calendar days). 
This does not include patient desire to discontinue therapy. It does include failure for 
thrombocytopenia to improve to a level of 80 requiring interruption of therapy.  
f) Any grade 5 treatment-related adverse event  
 
The MTD of SRT is defined as the highest dose level at which no greater than 2 DLT is 
observed in 6 patients.  
Dose-escalation Rules 
A standard cohort escalation design will be employed to evaluate 3 dose levels of 
SRT. Three patients will initially be treated at each dose level. A minimum of 1 month 
of observation after surgery is required in all 3 patients before escalation is initiated. 
 
At the second dose level, 3 patients are entered. If: 
0/3 have DLT 
then the third dose level is investigated. 
2/3 have DLT 
then the MTD is exceeded at the second dose level. De-escalation of SRT to 
the first dose level will be considered. 
1/3 have DLT 
then 3 additional patients are entered. If none of the additional patients develop 
DLT, then the third dose will be investigated. Otherwise, the MTD is exceeded 
at the second dose level. De-escalation of SRT will be considered.  
 

Version 6: 12/02/2008 
 
23
 
At the third dose level, 3 patients are entered. If: 
0/3 have DLT 
then the fourth dose level is investigated. 
2/3 have DLT 
then the MTD is exceeded at the third dose level. The second dose level will be 
expanded to a total of 6 patients (if only 3 patients had been treated). 
1/3 have DLT 
then 3 additional patients are entered. If none of the additional patients develop 
DLT, then the fourth dose will be investigated. Otherwise, the MTD is exceeded 
at the third dose level.  
 
At the fourth dose level, 3 patients are entered. If: 
0-1/3 have DLT 
then 3 additional patients are entered. If at most 1 of 6 patients develops DLT, 
then the fourth dose will be declared the MTD. Otherwise, the MTD is exceeded 
and the third dose level will be expanded to a total of 6 patients (if only 3 
patients had been treated). 
2/3 have DLT 
then the MTD is exceeded and the third dose level will be expanded to a total of 
6 patients (if only 3 patients had been treated). 
10.2 Plans for Expansion at the MTD 
Once the MTD has been defined, 10 additional patients will be enrolled, to provide 
preliminary efficacy data.  One month of observation after SRT will not be required 
between groups of patients during the expansion phase, but monitoring DLT will be 
performed, as described in the next section. 
10.3 Monitoring Dose-Limiting Toxicity 
With 6 evaluable patients, the probability of not escalating when the true DLT rate is 
35% or higher is at least 68%. If the true DLT rate is 20%, the probability that the dose 
will be escalated is 66%.  
 
10.4 Plans for Data Analysis 
Toxicity will be graded and tabled by dose level. At the MTD, the rates of radiological 
complete and partial responses and 90% exact binomial confidence intervals will be 
calculated.  
10.5 Sample Size 
The number of evaluable patients that will be needed depends on the number of times 
the dose is escalated or possibly de-escalated. If the escalation continues up through 
Dose Level IV, 18 evaluable patients will be required. If the dose is de-escalated after 
Dose Level II, then a maximum of 12 evaluable patients will be required.  Since 10 
additional patients will be enrolled once the MTD has been defined, a maximum of 28 
patients will be enrolled on the trial. 

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24
   
Section 11.0 Records to be kept 
 
Information regarding the actual treatments, adverse effects, radiographic and 
laboratory information, and pathology are to be recorded on appropriate forms.  Serious 
adverse events, when noted, will be recorded on site via the standard serious adverse 
effects form. 
 
Section 12.0 Patient consent form statement 
 
See attached consent form. 
 
Section 13.0 References 
 
REFERENCES 
1. 
Pugh RN, Murray-Lyon IM, Dawson JL, Petron MC, Williams R. Transaction of the 
esophagus for bleeding esophageal varices. Vd. J Sur 1973; 60:646-9. 
2. 
Masadero V, Regalía E, Doce R, et al. Liver transplantation for the treatment of small 
hepatocellular carcinomas in patients with cirrhosis. N Engle J Med 1996; 334:693-9. 
3. 
Bruit J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 
42:1208-36. 
4. 
Laragia T, Goldberg SN, Nazarene S, Melon F, Sublimate L, Gazelle GS. Small 
hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol 
injection. Radiology 1999; 210:655-61. 
5. 
Lancing RA, Allayer HP, Coin D, et al. Small hepatocellular carcinoma in cirrhosis: 
randomized comparison of radio-frequency thermal ablation versus percutaneous 
ethanol injection. Radiology 2003; 228:235-40. 
6. 
Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves 
prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm. 
Gastroenterology 2004; 127:1714-23. 
7. 
Shiina S, Teratani T, Obi S, et al. A randomized controlled trial of radiofrequency 
ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 
2005; 129:122-30. 
8. 
Kudos M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma 
(CLIP score): its value and limitations, and a proposal for a new staging system, the 
Japan Integrated Staging Score (JIS score). J Gastroenterol 2003; 38:207-15. 
9. 
Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation 
versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a 
randomised controlled trial. Lancet 2002; 359:1734-9. 
10. 
Lo CM NH, Tso WK, Liu CL, Lam CM, Poon RT. Randomized controlled trial of 
transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. 
Hepatology 2002; 35:1164-1171. 
11. 
Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. 
Gastroenterology 2004; 127:S179-88. 

Version 6: 12/02/2008 
 
25
12. 
Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in 
inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 
62:479-83. 
13. 
Llovet J, Ricci S, Mazzaferro V, J Clin Oncol 2007 ASCO Ann Meet Proc Part I. 2007; 
25: No. 18S (June 20 Supplement), LBA1 
14. 
Fuss M, Salter BJ, Herman TS, Thomas CR, Jr. External beam radiation therapy for 
hepatocellular carcinoma: potential of intensity-modulated and image-guided radiation 
therapy. Gastroenterology 2004; 127:S206-17. 
15. 
Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive 
grading system for the adverse effects of cancer treatment. 
Semin Radiat Oncol. 2003 Jul;13(3):176-81. Review. 
16. 
Blomgren H. Radiosurgery for tumors in the body:clinical experience using a new 
method. J Radiosurgery 1998; 1:63-74. 
17. 
Bo X. Dose-volume analysis of sterotactic irradiation for lung tumors. J Radiosurgery 
1999; 2:239-245. 
18. 
Lax I. Extracranial sterotactic radiosurgery of localized targets. J Radiosurgery 1998; 
1:135-148. 
19. 
Sato M. Feasibility of frameless stereotactic high-dose radiation therapy for primary and 
metastatic liver cancer. J Radiosurgery 1998; 1:233-240. 
20. 
Uematsu M, Shioda A, Tahara K, et al. Focal, high dose, and fractionated modified 
stereotactic radiation therapy for lung carcinoma patients: a preliminary experience. 
Cancer 1998; 82:1062-70. 
21. 
Reed GB, Jr., Cox AJ, Jr. The human liver after radiation injury. A form of veno-
occlusive disease. Am J Pathol 1966; 48:597-611. 
22. 
Lawrence TS, Robertson JM, Anscher MS, Jirtle RL, Ensminger WD, Fajardo LF. 
Hepatic toxicity resulting from cancer treatment. Int J Radiat Oncol Biol Phys 1995; 
31:1237-48. 
23. 
Robertson JM, Lawrence TS, Andrews JC, Walker S, Kessler ML, Ensminger WD. 
Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy 
for primary hepatobiliary cancers. Int J Radiat Oncol Biol Phys 1997; 37:325-30. 
24. 
Cheng JC, Chuang VP, Cheng SH, et al. Local radiotherapy with or without 
transcatheter arterial chemoembolization for patients with unresectable hepatocellular 
carcinoma. Int J Radiat Oncol Biol Phys 2000; 47:435-42. 
25. 
Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A 
phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J 
Radiat Oncol Biol Phys 2005; 62:1371-8. 
26. 
Tokuuye K, Sumi M, Kagami Y, et al. Radiotherapy for hepatocellular carcinoma. 
Strahlenther Onkol 2000; 176:406-10. 
27. 
Seong J, Keum KC, Han KH, et al. Combined transcatheter arterial chemoembolization 
and local radiotherapy of unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol 
Phys 1999; 43:393-7. 
28. 
Seong J, Park HC, Han KH, et al. Clinical results of 3-dimensional conformal 
radiotherapy combined with transarterial chemoembolization for hepatocellular 
carcinoma in the cirrhotic patients. Hepatol Res 2003; 27:30-35. 

Version 6: 12/02/2008 
 
26
29. 
Guo WJ, Yu EX, Liu LM, et al. Comparison between chemoembolization combined with 
radiotherapy and chemoembolization alone for large hepatocellular carcinoma. World J 
Gastroenterol 2003; 9:1697-701. 
30. 
Cheng SH, Lin YM, Chuang VP, et al. A pilot study of three-dimensional conformal 
radiotherapy in unresectable hepatocellular carcinoma. J Gastroenterol Hepatol 1999; 
14:1025-33. 
31. 
Dawson LA, McGinn CJ, Normolle D, et al. Escalated focal liver radiation and 
concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. 
J Clin Oncol 2000; 18:2210-8. 
32. 
Aoki K, Okazaki N, Okada S, et al. Radiotherapy for hepatocellular carcinoma: 
clinicopathological study of seven autopsy cases. Hepatogastroenterology 1994; 
41:427-31. 
33. 
Allen AM, Siracuse KM, Hayman JA, Balter JM. Evaluation of the influence of breathing 
on the movement and modeling of lung tumors. Int J Radiat Oncol Biol Phys 2004; 
58:1251-7. 
34. 
Aruga T, Itami J, Aruga M, et al. Target volume definition for upper abdominal irradiation 
using CT scans obtained during inhale and exhale phases. Int J Radiat Oncol Biol Phys 
2000; 48:465-9. 
35. 
Ekberg L, Holmberg O, Wittgren L, Bjelkengren G, Landberg T. What margins should be 
added to the clinical target volume in radiotherapy treatment planning for lung cancer? 
Radiother Oncol 1998; 48:71-7. 
36. 
Gagne IM, Robinson DM. The impact of tumor motion upon CT image integrity and 
target delineation. Med Phys 2004; 31:3378-92. 
37. 
Keall P. 4-dimensional computed tomography imaging and treatment planning. Semin 
Radiat Oncol 2004; 14:81-90. 
38. 
Ford EC, Mageras GS, Yorke E, Ling CC. Respiration-correlated spiral CT: a method of 
measuring respiratory-induced anatomic motion for radiation treatment planning. Med 
Phys 2003; 30:88-97. 
39. 
Low DA, Nystrom M, Kalinin E, et al. A method for the reconstruction of four-
dimensional synchronized CT scans acquired during free breathing. Med Phys 2003; 
30:1254-63. 
40. 
Pan T, Lee TY, Rietzel E, Chen GT. 4D-CT imaging of a volume influenced by 
respiratory motion on multi-slice CT. Med Phys 2004; 31:333-40. 
41. 
Rietzel E, Pan T, Chen GT. Four-dimensional computed tomography: image formation 
and clinical protocol. Med Phys 2005; 32:874-89. 
42. 
Vedam SS, Keall PJ, Kini VR, Mostafavi H, Shukla HP, Mohan R. Acquiring a four-
dimensional computed tomography dataset using an external respiratory signal. Phys 
Med Biol 2003; 48:45-62. 
43. 
Wink NM. Phase versus amplitude sorting of 4D-CT data. J Appl Clin Med Phys 2006; 
in press. 
44. 
Litzenberg DW, Balter JM, Lam KL, Sandler HM, Ten Haken RK. Retrospective analysis 
of prostate cancer patients with implanted gold markers using off-line and adaptive 
therapy protocols. Int J Radiat Oncol Biol Phys 2005; 63:123-33. 

Version 6: 12/02/2008 
 
27
45. 
Kupelian PA, Willoughby TR, Meeks SL, et al. Intraprostatic fiducials for localization of 
the prostate gland: monitoring intermarker distances during radiation therapy to test for 
marker stability. Int J Radiat Oncol Biol Phys 2005; 62:1291-6. 
46. 
Kitamura K, Shirato H, Shimizu S, et al. Registration accuracy and possible migration of 
internal fiducial gold marker implanted in prostate and liver treated with real-time tumor-
tracking radiation therapy (RTRT). Radiother Oncol 2002; 62:275-81. 
47. 
Imura M, Yamazaki K, Shirato H, et al. Insertion and fixation of fiducial markers for 
setup and tracking of lung tumors in radiotherapy. Int J Radiat Oncol Biol Phys 2005; 
63:1442-7. 
48. 
de Mey J, Van de Steene J, Vandenbroucke F, et al. Percutaneous placement of 
marking coils before stereotactic radiation therapy of malignant lung lesions. J Vasc 
Interv Radiol 2005; 16:51-6. 
49. 
Tenn SE, Solberg TD, Medin PM. Targeting accuracy of an image guided gating system 
for stereotactic body radiotherapy. Phys Med Biol 2005; 50:5443-62. 
50. 
Kang K, Choi B, Jang H, et al. J Clin Oncol 2007 ASCO Ann Meet Proc Part I. 2007; 25: 
18S (June 20 Supplement), 4645 
 
 
 
  
 
 
 
 
 
 
 

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28
 
Appendix I 
Criteria for Child-Pugh Classification 
Score 
Grade A = 5-6       Grade B = 7-9       Grade C = 10-15 
Clinical and Biochemical  
Measurements  
Points Scored for 
Increasing 
Abnormality  
  
1  
2  
3  
  
Hepatic encephalopathy 
(grade)*  
1 
2 
3  
None  1 and 2  3 and 4  
Ascites  
1 
2 
3  
Absent 
Mild  
Moderate 
Total bilirubin (mg/dl)  
1 
2 
3  
< 2.0  2.0 - 3.0 
> 3.0  
Serum albumin (g/dl)  
1 
2 
3  
> 3.5  2.8 - 3.5 
< 2.8  
Prothrombin time (sec. 
prolonged) 
or 
Prothrombin time INR**  
1 
2 
3  
< 4 
or 
< 1.7  
4 - 6 
or 
1.7 - 2.3 
> 6 
or 
>2.3  
*According to grading of Trey, Burns, and Saunders (1996).  

Version 6: 12/02/2008 
 
29
 
Appendix II 
 
Schedule of Activity 
 
Screening/Baseline 
Liver 
Marker 
Implant 
Procedure 
1-7 
Days  
Post 
Implant 
SRT 
planning,   
Start 
SRT  
End 
SRT 
1 
month 
Post 
SRT 
3 
Months 
Post 
SRT 
History & Physical 
x 
  
x 
x 
x 
x 
x 
x 
CT abdomen/pelvis 
x 
x  
 
x 
  
  
  
  
MRI abdomen/pelvis 
x 
  
  
x 
  
  
  
x 
biopsy 
x 
  
  
  
  
  
  
  
Inclusion/Exclusion 
x 
  
  
  
  
  
  
  
Informed consent 
x 
  
  
  
  
  
  
  
CT or U/S guided marker 
implant 
  
x 
  
  
  
  
  
  
AFP 
x 
  
  
x 
  
  
x 
x 
CBC with diff 
x 
  
x 
x 
  
  
x 
x 
INR 
x 
  
  
  
  
  
  
  
complete chemistry pannel 
x 
  
x 
x 
  
  
x 
x 
Chest X-ray or Chest CT 
x 
  
  
  
  
  
  
  
Record adverse events 
  
x 
x 
x 
x 
x 
x 
x 

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30
Appendix III 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference: 
 
Eligibility 
• 
Only patients with measurable disease at baseline should be included in protocols where objective tumor 
response is the primary endpoint.  
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
Measurable lesions - lesions that can be accurately measured in at least one dimension with longest 
diameter  ≥20 mm using conventional techniques or ≥10 mm with spiral CT scan. 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic 
lesions, and also abdominal masses that are not confirmed and followed by imaging techniques; and. 
• 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment.  
• 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up.  
• 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and 
palpable lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.  
 
Methods of Measurement –  
• 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected 
for response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  
This applies to tumors of the chest, abdomen and pelvis. Head and neck tumors and those of extremities 
usually require specific protocols. 
• 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
• 
When the primary endpoint of the study is objective response evaluation, ultrasound (US) should not be 
used to measure tumor lesions. It is, however, a possible alternative to clinical measurements of superficial 
palpable lymph nodes, subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical examination. 
• 
The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet been fully and 
widely validated. Their uses in this specific context require sophisticated equipment and a high level of 
expertise that may only be available in some centers. Therefore, the utilization of such techniques for 
objective tumor response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are obtained. 
• 
Tumor markers alone cannot be used to assess response.  If markers are initially above the upper normal 
limit, they must normalize for a patient to be considered in complete clinical response when all lesions have 
disappeared. 
• 
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after 
treatment to differentiate between residual benign lesions and residual malignant lesions in tumor types such 
as germ cell tumors). 
 
 
Baseline documentation of “Target” and “Non-Target” lesions 
• 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, representative 
of all involved organs should be identified as target lesions and  recorded and measured at baseline.  

Version 6: 12/02/2008 
 
31
• 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically).  
• 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline 
sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor. 
• 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up.  
 
Response Criteria 
Evaluation of target lesions 
* Complete Response 
(CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
* Progressive Disease 
(PD): 
At least a 20% increase in the sum of the LD of target lesions, 
taking as reference the smallest sum LD recorded since the 
treatment started or the appearance of one or more new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started 
Evaluation of non-target lesions 
* Complete Response 
(CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level 
* Incomplete 
Response/          
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) or/and maintenance of tumor 
marker level above the normal limits 
* Progressive Disease 
(PD): 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria  
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
• 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be classified as having “symptomatic deterioration”. 
Every effort should be made to document the objective progression even after discontinuation of treatment.  

Version 6: 12/02/2008 
 
32
• 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
Confirmation 
• 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed.  In cases where confirmation of response is not feasible, it should be made clear when reporting 
the outcome of such studies that the responses are not confirmed. 
• 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met. 
Longer intervals as determined by the study protocol may also be appropriate.  
• 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry 
at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol  
Duration of overall response 
• 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking 
as reference for PD the smallest measurements recorded since the treatment started. 
Duration of stable disease 
• 
SD is measured from the start of the treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started.  
• 
The clinical relevance of the duration of SD varies for different tumor types and grades. Therefore, it is 
highly recommended that the protocol specify the minimal time interval required between two measurements 
for determination of SD. This time interval should take into account the expected clinical benefit that such a 
status may bring to the population under study.  
Response review 
• 
For trials where the response rate is the primary endpoint it is strongly recommended that all responses 
be reviewed by an expert(s) independent of the study at the study’s completion.  Simultaneous review of the 
patients’ files and radiological images is the best approach.  
Reporting of results 
• 
All patients included in the study must be assessed for response to treatment, even if there are major 
protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of the following 
categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early 
death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) 
unknown (not assessable, insufficient data). 
• 
All of the patients who met the eligibility criteria should be included in the main analysis of the response 
rate.  Patients in response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
• 
All conclusions should be based on all eligible patients. 
• 
Subanalyses may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses may not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis 
should be clearly reported.   
• 
The 95% confidence intervals should be provided. 

Version 6: 12/02/2008 
 
33
 
Appendix IV 
 
Pain Intensity Assessment 
 
UNMC IRB 
protocol # 
 
 
Date:  
 
200 
Day 
Month 
year 
Subject Initials:  
 
 
 
 
 
Subject ID:  
Visit: 
 
Baseline (prior to study treatment) 
 
 
End of treatment 
 
 
 
 
1-month follow up 
 
 
 
 
3-month follow up 
 
 
 
This form is to be completed by study subject. 
Please make a mark on the pain scale line with a black-ink pen. 
 
 
 
 
0 
 
least 
possible  
pain 
 
 
 
 
10 
 
worst 
possible 
pain 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Initials 

Version 6: 12/02/2008 
 
34
 
Appendix V 
 
KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA 
Able to carry on normal activity and to work; no 
special care needed. 
  100   Normal no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Normal activity with effort; some signs 
or symptoms of disease.  
Unable to work; able to live at home and care 
for most personal needs; varying amount of 
assistance needed. 
70 
Cares for self; unable to carry on 
normal activity or to do active work. 
60 
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission 
is indicated although death not 
imminent. 
20 
Very sick; hospital admission 
necessary; active supportive 
treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 

Version 6: 12/02/2008 
 
35
Appendix VI 
Eligibility Checklist 
 
IRB# ________________ 
 
MR# ________________ 
 
SEX Male  
female 
 
AGE ________,    ≥ 19 years of age 
 
 
 
YES  
NO 
 
 
 
 
life expectancy of at least 12 weeks  
 
 
 
YES  
NO 
 
Karnofsky performance status ≥ 60%  
 
 
 
YES  
NO 
 
Histologically or cytologically documented HCC  
 
YES  
NO 
 
The target lesion can be accurately measured in  
at least one dimension according to RECIST   
 
YES  
NO 
 
Maximum tumor diameter of ≤ 8 cm 
 
 
 
YES  
NO 
 
No prior radiotherapy to the liver  
 
 
 
YES  
NO 
 
Local therapy was completed  
at least 6 weeks prior to the baseline scan 
 
 
YES  
NO 
 
Cirrhotic status of Child-Pugh class A and B  
 
 
YES  
NO 
 
Platelet count ≥ 60 x 109/L  
 
 
 
 
YES  
NO 
 
Hemoglobin ≥ 8.5 g/DL 
 
 
 
 
 
YES  
NO 
 
WBC ≥ 2000/Μl 
 
 
 
 
 
 
YES  
NO 
 
International normalized ratio (INR) ≤ 2.3 
 
 
YES  
NO 
 
Informed consent signed  
 
 
 
 
YES 
 
NO 
 
 
Liver marker implanted  
 
 
 
 
 
YES  
NO 
AFP tested  
 
 
 
 
 
 
YES  
NO 
 
CT/MRI scans available 
 
 
 
 
 
YES  
NO 
 

Version 6: 12/02/2008 
 
36
Complete chemistry panel, PT,PTT,INR  
 
 
YES  
NO 
 
For patient with history of cancer:  
 
 
 
 
 
 
 
It is cervical carcinoma in situ or  
treated basal cell carcinoma or 
superficial bladder tumors (Ta, Tis & T1) or 
Any cancer curatively treated > 3 years  
 
 
YES  
NO  
 
Renal failure requiring hemo- or peritoneal dialysis 
 
YES  
NO 
 
Uncontrolled inter-current illness  
 
 
 
YES  
NO 
  
Central Nervous System tumors   
 
 
 
YES  
NO 
  
Varices NOT eradicated or decompressed  
by shunt placement  
 
 
 
 
 
YES 
 
NO 
 
Substance abuse or 
medical, psychological or social conditions 
that may interfere with the patient’s participation  
in the study or evaluation of the study results   
 
YES  
NO 
 
Pregnant or breast-feeding  
 
 
 
 
YES  
NO