Phase II Study of Proton Beam Irradiation for the Treatment of Unresectable Hepatocellular Cancer and Cholangiocarcinoma
Phase: NA
Conditions: Liver Cancer
Sponsor: Massachusetts General Hospital

Title: Phase II Study of Proton Beam Irradiation for the 
Treatment of Unresectable Hepatocellular Cancer and 
Cholangiocarcinoma 
PROTOCOL: 09-131 
NCT00976898
Protocol Version No./ Date: 11.16.15

Phase II Study of Protons for Liver Cancer 
11.16.15 
Protocol Version Date:   Version 11.16.15 
DFCI Protocol #: 09-131.  
Title:  Phase II Study of Proton Beam Irradiation for the Treatment of Unresectable Hepatocellular Cancer 
and Cholangiocarcinoma 
Principal Investigator:.  
Theodore S. Hong M.D. 
Massachusetts General Hospital (MGH) 
(617-726-6050) 
Coordinating Center: 
 MGH will be the coordinating center for this multi-center study.  All patients from all participating sites will be 
registered with QACT before beginning treatment.  Data will be coordinated by the MGH Biostatistics Center. 
MGH Co-Investigators:  
Co-Investigators 
Radiation Oncology Physics 
George Chen, Ph.D. 
Andrzej Niemierko, Ph.D. 
Thomas Bortfeld, Ph.D. 
Gabriel Duda, Ph.D 
Medical Oncology 
Andrew X. Zhu, M.D., Ph.D. 
Jeffrey Clark, M.D. 
Charles Fuchs, M.D. 
Matthew Kulke, M.D. 
Robert Mayer, M.D. 
David Ryan, M.D. 
Lawrence Blaszkowsky, M.D. 
Lipika Goyal, MD 

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Surgical Oncology 
Kenneth Tanabe, M.D. 
Radiation Oncology 
Thomas F. DeLaney, MD 
Harvey Mamon, M.D., Ph.D. 
Jennifer Wo, MD  
Rakesh Jain, Ph.D 
Jonathan Schoenfeld, MD 
Lorraine Drapek, NP 
Interventional Radiology 
Ronald Arellano, M.D. 
Radiology  
Peter F. Hahn, M.D., Ph.D 
Participating Site Investigators: MD Anderson Cancer Center (MDACC) 
Site PI: Christopher Crane, MD 
Sam Beddar 
Prajnan Das, MD 
Marc Delclos, MD 
Milid Javle, MD 
Chris Garrett, MD 
Ahmed Kaseb, MD 
Sunil Krishnan, MD 
Kanwal Raghav, MD 
Rachna Schroff, MD 
Participating Site Investigators: University of Pennsylvania Roberts Proton Facility (UPenn) 
Site PI:  Edgar Ben-Josef, MD 
John Plastaras, MD, PhD 
Zelig Tochner, MD 
Stefan Both, PhD 
Weijing Sun, MD 
Nevena Damjanov, MD 
Maarouf Hoteit, MD 

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Douglas Fraker, MD 
Michael Soulen, MD 
Statistician:  
Beow Yeap, ScD. 
Multi-Center Program Manager:  
 
Study Coordinator: 
 
Responsible Data Manager:  
  
Funding:  
Thomas F. DeLaney, M.D., Principal Investigator; For correlative studies (at MGH only): Federal Share of program 
income earned by Massachusetts General Hospital on C06 CA059267, Proton Therapy Research and Treatment 
Center 
Agent(s):  –Proton Beam Irradiation (no IND) 

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Protocol Summary 
Principal/Overall Investigator 
Theodore S. Hong M.D. 
Protocol Title 
A Phase II Study of Proton Beam Irradiation of Unresectable Primary Liver Tumors 
Funding 
For correlative studies (at MGH only): Federal Share of program income earned by Massachusetts General Hospital 
on C06 CA059267, Proton Therapy Research and Treatment Center 
Specific Objective 
To determine the local control of proton beam radiation for unresectable primary hepatoma (hepatocellular 
carcinoma or intrahepatic cholangiocarcinoma) 
Background and Significance 
The efficacy of the current treatment (chemotherapy, arterial embolization) of unresectable hepatocellular cancer, 
and intrahepatic cholangiocarcinoma is poor. A recent study from Japan demonstrated impressive local control and 
survival rates for 122 unresectable hepatocellular cancer patients treated with proton beam irradiation.   
Protons are a charged form of radiation. Their biology is similar to x-rays, resulting in similar cell killing effects. 
The advantage of protons lies in their physical dose distribution. Because of the defined range of protons (i.e. the 
Bragg peak), dose distributions can be designed that conform more closely to the tumor volume. This results in a 
much greater ability to reduce radiation dose to non-target normal tissues, especially liver, and allows greater dose to 
be delivered to the tumor. 
With protons, high dose irradiation of hepatic lesions is feasible because of the marked reduction in normal hepatic 
irradiation. 
Recruitment 
Patients will be recruited from the surgical, medical and radiation oncology practices at Massachusetts General 
Hospital, Brigham and Women's Hospital, Dana Farber Cancer Institute, MD Anderson Cancer Center and 
University of Pennsylvania. Patients will not be paid for participating in this study. We expect to recruit 
approximately 90 patients over a 2-year period. Because DFCI/BWH does not have a proton center, patients from 
these institutions will be referred to MGH. 
Research Design and Methods 

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This is a phase II research protocol designed to determine the local control with proton beam radiation therapy in the 
treatment of hepatocellular cancer and intrahepatic cholangiocarcinoma.   
 
Risks and Discomforts 
 
Proton Beam Radiation Therapy  
 
Very likely: These symptoms usually recover in the first few weeks following completion of 
radiation therapy 
• Irritation, redness and discoloration of the skin in the radiation area. 
• Fatigue (tiredness) 
 
Likely 
 
Decreased blood counts 
 
 Low platelet count 
 
Elevated LFTs 
 
Abdominal pain or cramps 
 
Nausea 
 
Less likely 
 
Diarrhea 
 
Decreased/ loss of appetite 
 
Vomiting 
 
Slow wound healing 
 
Weight loss 
 
Indigestion 
 
Gastritis 
 
Radiation Esophagitis 
 
Rib microfracture 
 
Rare 
 
Damage to the liver which could result in inflammation and scarring of the liver. This could 
lead to jaundice and possibly cirrhosis. Efforts to prevent excessive liver irradiation will be 
made to minimize the chance of these side effects 
 
While radiation can cause mucosal ulceration, other tissues may be damaged which may 
require surgery and may be life-threatening. 

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 
Stomach and bowel are protected well from excessive dose of radiation. However, overdosing 
the stomach or bowel can lead to ulceration or perforation. 
 
Pain, inflammation or scarring of your kidneys, stomach and bowel. These organs are 
protected well from excessive dose of radiation.  Therefore, it is unlikely that patients will 
experience symptoms of injury to these organs  
 
Nerve damage 
 
Development of a new cancer resulting from treatment may happen many years after 
completing treatment 
 
Spinal cord injury 
MRIs use powerful magnets to make images. Therefore, persons with metal implants, such as surgical clips or 
pacemakers should not have an MRI. However, there are no known health risks associated with this exposure. 
People who feel uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the narrow cylinder. 
The MRI makes loud banging noises as it takes images. Earplugs can be used to reduce the noises. The MRI can be 
stopped at any time at the request of the patient.  
CT Scans: The radiation associated with these diagnostic radioactive drug and diagnostic x-ray studies will not 
adversely affect the treatment of the patient’s disease. 
Reproductive risks: Because the treatment in this study can affect an unborn baby, female patients should not 
become pregnant while on this study.  Female patients should also not nurse a baby while on this study.    
 
Potential benefits 
The potential benefits of this treatment include shrinkage of the tumor, greater control of tumor growth, and possibly 
longer life. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA 
 
1.   REGISTER. 
 
 
2.  TREATMENT: Proton Beam Irradiation in 15 fractions.  Acute toxicity evaluation weekly during 
study treatment, and at 3 month follow up.  
 
 
3.  FOLLOW-UP: Evaluation for Tumor Response using RECIST Criteria.  Evaluation for acute and late 
toxicity per CTCAE v. 3.0 
 
Eligibility Criteria: 
1. 
Patients must have a biopsy proven  unresectable or locally recurrent cholangiocarcinoma, or a diagnosis of 
an unresectable or locally recurrent hepatocellular cancer using either pathology of the liver tumor or 
radiologic imaging and an elevated AFP.  For patients with a single tumor, lesion may be up to 12 cm in 

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size.  For patients with two lesions, no lesion may be greater than 10 cm in size.  For patients with three 
lesions, no lesion may be greater than 6cm in size. 
2. 
Patients may have single or multinodular tumors (up to 3). 
3. 
No prior liver directed radiation therapy. 
4. 
Patients are not candidates for surgery on the basis of tumor extent or medical condition. 
5. 
Patients must be 18 years or age older. 
6. 
Patients must have ECOG PS 0-2. 
7. 
If patient has underlying cirrhosis, only Child’s classification Group A or Group B patients should be 
included in this study. 
8. 
Patient must have adequate renal function; serum creatinine </=2 mg / dl. 
9. 
Expected survival must be greater than three months. 
10. 
Signed Informed Consent. 
 

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TABLE OF CONTENTS 
Page 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
vi 
 
1:  OBJECTIVES   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
1.1 
Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
1.2 
Primary Objectives  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
1.3 
Secondary Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
 
2: BACKGROUND 
2.1  Proton Beam Therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
2.2  Study Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
2.3  Rationale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
2.4  Correlative Studies Background  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
 
3: PARTICIPANT SELECTION 
3.1  Eligibility Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6 
3.2  Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 
3.3  Inclusion of Women, Minorities and Other Underrepresented Populations  
 
 
 
 
9 
 
4: REGISTRATION PROCEDURES 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
 
 
 
 
 
 
 
 
9 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions  
 
 
 
 
 
 
 
 
10 
4.3 
General Guidelines for Other Participating Institutions  
 
 
 
 
 
 
 
 
 
11 
4.4 
Registration Process for Other Participating Institutions  
 
 
 
 
 
 
 
 
 
11 
 
5:  TREATMENT PLAN 
 
5.1   Treatment Program  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
 
5.2  Pre-Treatment Criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13 
 
5.3  Proton Beam Delivery 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13 
 
5.4  General Concomitant Medication and Supportive Care Guidelines  
 
 
 
 
 
 
14 
 
5.5  Duration of Therapy  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
5.6  Duration of Follow Up  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
5.7  Criteria for Removal from Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 

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6: EXPECTED TOXICITIES AND DOSING DELAY/DOSE MODIFICATIONS 
 
6.1  Potential Toxicities  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
6.2  Anticipated Toxicities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
6.3  Toxicity Management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
6.4  Dose Modifications/Delays  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
 
7: DRUG FORMULATION AND ADMINISTRATION  
 
 
 
 
 
 
 
 
 
 
 
17 
8: CORRELATIVE/SPECIAL STUDIES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
8.1 Circulating Biomarkers  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 
8.2 Genotype Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
9: STUDY CALENDAR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 
10: MEASUREMENT OF EFFECT 
10.1 
Toxicity and Complications  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
10.2 
Tumor Response – RECIST Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
10.3 
Local Failure  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
10.4 
Marginal Failure  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
10.5 
Nodal Failure  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
10.6 
Distant Failure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
10.7 
Overall Survival  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
 
11: ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 
General 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
22 
11.2 
Definitions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 
11.3 
Recording Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 
11.4 
Reporting Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 
11.5 
Coordinating Center Notification by Investigator  
 
 
 
 
 
 
 
 
 
 
 
25 
11.6 
Institutional Review Board (IRB) Notification by Investigator 
 
 
 
 
 
 
 
 
26 
11.7 
Hospital Risk Management Notification by Investigator  
 
 
 
 
 
 
 
 
 
26 
 
12: DATA AND SAFETY MONITORING 
12.1 
Data Reporting  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27 
12.2 
Safety Meetings  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
27 
12.3 
Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
  
13: REGULATORY CONSIDERATION 
13.1 
Declaration of Helsinki  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
13.2 
Patient Confidentiality  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 

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13.3 
Protocol Review and Amendments  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 
13.4 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      29 
13.5 
Ethics and Good Clinical Practice (GCP)  
 
 
 
 
 
 
 
 
 
 
 
 
     29 
13.6 
Study Documentation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
30 
13.7 
Records Retention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     30 
13.8 
Multi-center Guidelines  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      30 
 
14: STATISTICAL CONSIDERATION 
 
14.1  Study Design/Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
31 
 
14.2  Sample Size/Accrual Rate  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
31 
14.3  Stratification Factors  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
32 
14.4  Analysis of Secondary Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
32 
14.5  Reporting and Exclusions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
32 
 
15: PUBLICATION PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
32 
16. REFERENCES  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
33 
17: APPENDICES 
Appendix I  
Performance Status Criteria  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
35 
Appendix II 
Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
36

Phase II Study of Protons for Liver Cancer 
 
 
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1 
1. OBJECTIVES 
1.1    
Study Design 
This is a phase II research protocol designed to determine the local control with proton beam radiation 
therapy in the treatment of unresectable primary hepatocellular carcinoma or intrahepatic 
cholangiocarcinoma. 
1.2 
Primary Objectives 
To demonstrate 2 yr LC of >80% with proton beam irradiation for unresectable  hepatocellular cancer.  
This will be benchmarked against 2 yr LC of ~55% for tumors > 3cm in size with radiofrequency ablation. 
1.3 
Secondary Objectives 
1.3.1 To determine safety and tolerance of this treatment program. 
1.3.2  To evaluate tumor response, patterns of failure, and survival in patients with hepatocellular      
cancer undergoing proton beam irradiation. 
 1.3.3 To evaluate 5 yr overall survival and local control in patients with hepatocellular cancer 
undergoing proton beam irradiation. 
1.3.4 To describe the tumor response, patterns of failure, local control and 5 year overall survival in 
patients with cholangiocarcinoma undergoing proton beam irradiation. 
 
2. BACKGROUND 
2.1 
Proton Beam Therapy 
 
There have been unprecedented efforts in radiation oncology to develop and use sophisticated, conformal 
photon techniques in order to improve the outcome for cancer patients. The aim of these new techniques is 
to concentrate the radiation dose distribution more completely on the disease target, thereby sparing critical 
normal tissues and increasing the target dose. Toward this end, many advances have been made and 
examples of new developments include Tomotherapy and intensity modulated photon therapy. At the same 
time, heavy, charged-particle programs, particularly those for proton therapy, have been developed. Proton 
therapy dose distributions are superior to those of photon therapy and this provides the potential to further 
improve clinical outcomes. Several institutions have committed to build dedicated proton therapy centers 
such as the Francis H. Burr Proton Therapy Center (FHBPTC) at the Massachusetts General Hospital 
(MGH), the MD Anderson Proton Treatment Center,   the Loma Linda University Medical Center proton 
therapy facility, and others. Several more proton therapy centers are in the final planning stage. 

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Figure O-1. Proton (Bragg peak and modulated 
Peak) and 10 MV depth dose curves. 
X-RAYS
PROTONS
MEDULLOBLASTOMA
  
Figure O-2. Posterior, single-beam treatment of the spinal 
axis.
2.1.1 The Advantages of Protons for Delivery of Conformal Therapy 
Characteristics of Proton Beams 
The basis for the advantages of proton 
beams lies in the physical laws that 
determine the absorption of energy in 
tissues exposed to photon or proton beams. 
In a specific tissue, photons are absorbed 
exponentially whereas protons have a finite 
range dependent upon the initial proton 
energy. Therefore, the depth dose 
characteristics of the two beams are 
qualitatively different (see Figure O-1). 
Protons lose their energy in tissue mostly 
by coulombic interactions with electrons in 
the constituent atoms; however, a small 
fraction of energy is transferred through 
nuclear collisions. The energy loss per unit 
path length is relatively small and constant 
as the proton traverses the tissue until near the end of the proton range where the residual energy is lost over a 
short distance (approximately 0.7 cm in width at 80% of the maximum dose) and the proton comes to rest, 
resulting in a distinctive sharp rise in the tissue absorbed dose (energy absorbed per unit mass) - known as the 
Bragg peak (see the curve labeled "unmodulated proton beam" in Figure O-1). In physical terms, the magnitude 
of the transfer of energy to tissue per 
unit path length traversed by the 
protons is inversely proportional to the 
square of the proton velocity. The low 
dose region between the entrance and 
the Bragg peak is called the plateau of 
the dose distribution and the dose there 
is 30-40 percent of the maximum dose. 
 
The Bragg peak is too narrow in 
extent to irradiate any but the 
smallest of targets, ablation of the 
pituitary gland for example. For the 
irradiation of larger targets/tumors 
the beam energy is modulated - 

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several beams of closely spaced energies (ranges) are superimposed to create a region of uniform dose over 
the depth of the target. These extended regions of uniform dose are called "spread-out Bragg peaks" 
(SOBP). This is shown in Figure O-1 as the “modulated proton beam”. For comparison, Figure O -1 also 
shows the depth-dose curve for a 10 MV x-ray beam, an x-ray energy commonly used to treat deep seated 
tumors.  
 
Note that the x-ray beam dose rises to a maximum value at relatively shallow depths, then falls off 
exponentially to lower doses at the treatment depth.  A clinical comparison of single-beam proton and 
photon beams is shown in Figure O-2 where a single posterior beam is used for the treatment of the spinal 
axis in the treatment of medulloblastoma. Note that, for the photon treatment, the heart, mediastinum, 
esophagus, lung and spinal cord are irradiated by the treatment beam whereas for the proton treatment, the 
beam stops abruptly distal to the target volume and there is no irradiation of the tissues and organs distal to 
the target volume.   
In the usual clinical situation, more than one radiation beam is used in both x-ray and proton treatments.  
However, the advantage shown for protons using single beams is present for each and every beam used. 
Therefore, one cannot overcome the physical disadvantage of x-rays by the use of multiple beams or 
complex beam arrangements. In modern proton therapy facilities, which have isocentric gantries and 
sophisticated beam delivery and control systems, proton therapy capabilities are equivalent to those for 
state-of-the-art, conformal therapy using x-rays with respect to numbers of beams, beam directions and 
complex delivery techniques such as intensity modulation.  
2.2 
Study Disease 
Hepatocellular carcinoma is the most common primary cancer of the liver. The disease has a dismal 
five-year survival rate of less than 5%. Hepatocellular carcinoma is an infrequent cancer in developed 
countries. However, its incidence has substantially increased in Japan during the past three decades and 
slight increases have been reported in the United Kingdom and France. In the United States, an increase in 
the number of cases from 1.4 per 100,000 to 2.4 per 100,000 has occurred over the past two decades [1]. 
The age-specific incidence of this cancer has progressively shifted toward younger patients. 
Cholangiocarcinomas are an uncommon malignancy, with an incidence of 1 to 2 cases per 100,000 
population in the United States and constituting approximately 2% of all reported cancers [2].  Untreated 
bile duct cancers are rapidly fatal diseases and majority of patients will die within 6 months to a year of 
diagnosis.  Death usually results from liver failure or biliary sepsis [2].  Long-term survival is highly 
dependent on the effectiveness of surgical therapy but many patients are not candidates for resection 
because of the local extent of disease [2]. 

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2.3 
Rationale 
Unfortunately, many patients with primary hepatobiliary cancer are not surgical candidates due to anatomic 
location or size of the tumor, concurrent cirrhosis or medical inoperability.  Therefore, an important role 
exists for a treatment that can provide the equivalent of tumor excision, but with minimal morbidity. 
 
The treatment of unresectable hepatocellular or locally recurrent hepatocellular cancer and 
cholangiocarcinoma has been palliative. Standard treatment modalities have included transarterial 
chemoarterial embolization (TACE), radiofrequency ablation, or systemic chemotherapy/targeted therapy 
with few long-term survivors. TACE is useful in patients with multiple lesions, but is not considered an 
ablative approach.  Similarly, systemic therapy is does not produce more than anecdotal complete 
responses.   
 
Most published data combines hepatocellular cancer and cholangiocarcinoma, including reporting of 
disease control and survival outcomes for both histologies together.  However, emerging data for HCC 
reported by Bujold and colleagues suggest a difference in overall survival and local control from the 
combined historical data for this histology14.  Thus, this study will further investigate outcomes for HCC, 
while describing the same outcomes for cholangiocarcinoma separately, informing future trials. 
 
Radiofrequency ablation (RFA) is the most commonly employed ablative technique for non-surgical 
candidates at many institutions.  Radiofrequency ablation refers to a method of tumor ablation by which 
local application of radiofrequency achieves thermal ablation of targeted tissues.  Generally, a 14-gauge 
electrode is placed into the tumor.  Delivery of electromagnetic energy in the form of high-frequency (~400 
MHz) alternating current causes ionic agitation and the generation of heat due to friction. Coagulative 
necrosis of hepatic tissue is achieved when temperatures greater than 55 degrees Celsius are maintained for 
a minimum of 6 minutes.  RFA can be performed percutaneously, laparoscopically, endoscopically, or at 
the time of laporotomy. The exact approach is frequently dictated by the location of the tumor. In spite of 
these multiple approaches, the use of RFA can be limited by location. An adjacent large vessel can act as a 
heat sink and limit the efficacy of therapy.  Treatment of dome lesions near the diaphragm carries the risk 
of diaphragmatic perforation and treatment of deep lesions near bowel loops may be associated with bowel 
perforation. Radiofrequency ablation can be highly effective for small lesions, with local control of 75% or 
greater. However this local control falls off steeply beyond 3-5 cm in maximum diameter. In one study by 
Solbiati et al, colorectal metastases less than 2.5 cm had a recurrence risk of 21.6% [4].  This risk increased 
to 52.8% if the tumor was 2.6-4.0 cm and as high as 68.1% for tumors > 4 cm.  Local control for RFA at 2 
years was 55%. 2 year overall survival for both groups is. 50%.  For radiofrequency ablation to more 
clearly impact survival, this local control will need to improve.  Recurrences after RFA are frequently 
marginal. 

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Because of the limited tolerance of the liver to external beam irradiation when the whole liver is irradiated, 
experience with this modality has been limited. However, several studies have demonstrated that the 
tolerance of liver significantly increases when smaller volumes of the liver are irradiated. A study from the 
University of Michigan reported the results of 22 patients with unresectable hepatocellular carcinoma and 
cholangiocarcinoma treated by high dose irradiation employing conformal 3D techniques using 10 MV X-
rays and hepatic artery fluorodeoxyuridine. These patients were observed to have a 4-year survival of 20% 
and no late hepatic toxicity [5]. Total radiation doses were determined by the fraction of normal liver 
treated to 50% of the isocenter dose. If 33% of the normal liver received 50% of the dose, the patient was 
treated to 66 Gy, if 33% to 66% of the liver received 50% of the dose the patient received 48 Gy and if 
66% of the liver received 50% of the dose the patient received 36 Gy. Treatment was given daily at 1.8 Gy 
per fraction five days per week. Several subsequent reports from the University of Michigan group 
provided more quantitative information regarding both dose-response of liver cancer and dose-volume 
sparing effects of normal liver tissue[5-9]. They estimated using maximum likelihood analysis that for 
b.i.d. fractionation with 1.5Gy per fraction the TD50 dose for radiation-induced liver disease for primary 
hepatobiliary cancer is about 40Gy when the whole liver is irradiated. When half of the liver is irradiated 
the TD50 increases to 80Gy, and when less than 1/4 of the liver is irradiated no liver toxicity is predicted 
regardless of dose level. The tumor response exhibits strong dose dependence with the response rate for 
tumor doses above 60Gy twice as high as for tumor doses below 50Gy. Similarly encouraging results of 
dose escalations studies using three-dimensional conformal radiotherapy have recently been reported by 
groups from Korea (183 patients) and Taiwan (93 patients)[10-12]. These studies demonstrated that the 
overall median survival could also be significantly improved with higher doses. The chief cause of 
mortality was progression of underlying severe cirrhosis and not tumor or treatment related causes.  
 
Given these promising results in otherwise incurable malignancies, the MGH group undertook a Phase I 
study to evaluate the use of high dose conformal proton beam irradiation for selected patients with 
hepatocellular cancer, cholangiocarcinoma and hepatic metastases.  The dose escalation was based on a 
model based on the amount of radiation that the normal liver received, or equivalent uniform dose (EUD) 
to the liver.  The eligibility criteria were 1-3 lesions, greatest less than 6 cm in size, Childs A/B, and no 
extrahepatic disease. Patients were treated with gated proton beam therapy using 4D treatment planning 
techniques. Generally, patients have been treated to a dose of 45-75 Gy (RBE) in 15 fractions.  The study 
was a dose escalation trial based on liver EUD. The dose that each patient was treated to was based not 
only on the liver EUD at each step but had to comply with protocol defined normal tissue constraints 
(bowel, chest wall).  To date, there have been no local failures or radiation-induced liver disease through 3 
of the first 4 dose levels.   
 

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6 
Because of the limitations of the EUD based liver concept as a dose escalation platform, as well as the non 
dose-limiting nature of liver with proton therapy, we have decided to proceed with a modification of the 
approach taken by the Tsukuba group (13).  Investigators at Tsukuba have treated 165 patients (192 
tumors) with a similar 15 fraction protocol to a median dose of 72 Gy.  Patients with tumor sizes of 10 cm 
or greater were allowed on the study. Central tumors (within 2 cm of the porta hepatis) were treated to 66 
Gy in 22 fractions because of concerns of toxicity. Local control at 5 years was an impressive 86.9%.  
Local control at 2 years was 90%. However 5 yr OS was only 23%, highlighting the out of field 
progression and comorbidities in these patients.  In this study, we propose a treatment schedule of 15 
fractions of proton beam radiation with an expected 2 yr LC of > 85%.  Because we anticipate treating 
large tumors generally greater than 3 cm, we will seek to improve upon a RFA local control rate of ~ 50% 
to 80% with proton beam therapy.   
 
2.4  
Correlative Studies Background  
Preclinical and clinical work in the Steele Lab and elsewhere has identified the stromal-derived factor 1 
alpha (SDF1α) as an attractive candidate for biomarker of resistance to various therapies, but its role after 
proton beam radiation therapy is unknown. Based on findings from preliminary studies, we propose here to 
evaluate the changes in blood circulating SDF1α and circulating myeloid cells before, during and after a 
three-week schedule of proton beam radiation therapy, and to explore potential associations between the 
changes in these biomarkers and resistance to treatment. In exploratory studies, we will evaluate several 
other cytokines using multiplex protein array (Meso-Scale Discovery, Inc.). 
 
Circulating cell populations will be evaluated by fluorescence-based flow cytometry. Protein concentration 
in plasma will be measured using ELISA kits for SDF1 and MSD multiplex kits for cytokines (IL-1, IL-6, 
IL-8 and TNF-) vascular growth factors (VEGF, sVEGFR1, PlGF and bFGF). These techniques have 
been used in the Steele Lab for over 8 years to evaluate patients’ samples.   
3.  PARTICIPANT SELECTION 
3.1  
Eligibility Criteria 
Participants must meet the following criteria on screening examination to be eligible to participate in the 
study: 
 
3.1.1  
Patients must have a biopsy proven unresectable or locally recurrent intrahepatic 
cholangiocarcinoma. Otherwise, patients must have a diagnosis of an unresectable or locally 
recurrent hepatocellular cancer using either pathology of the liver tumor or radiologic imaging and 
an elevated AFP.   Patients with a single lesion must be 12 cm or less in greatest dimension.  For 
patients with two lesions, no lesion may be greater than 10 cm in greatest dimension.  For patients 
with three lesions, no lesion may be greater than 6cm in greatest dimension.  Patients may have 

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single or multinodular tumors (up to 3).  There must be no evidence of extrahepatic tumor.  Portal 
vein involvement or thrombosis is allowed. 
3.1.2  
Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
>20 mm with conventional techniques or as >10 mm with spiral CT scan. See 
Section 10 for the evaluation of measurable disease. 
3.1.3    Patients may have had prior chemotherapy, targeted biological therapy (ie sorafenib, etc…), 
surgery, transarterial chemoembolization (TACE), radiofrequency ablation, or cryosurgery 
for their disease.  5-fluorouracil, capecitabine and sorafenib must be discontinued prior to 
study entry, with no wash-out period required.    Nitrosoureas and  mitomycin C must be 
discontinued at least 6 weeks prior to study entry.  All other agents must be discontinued at 
least 4 weeks prior to study entry.  Patients may not have had prior radiation to the affected 
area. 
3.1.4 
 Patients must be 18 years of age or older. 
3.1.5    Expected survival must be greater than three months. 
3.1.6   ECOG performance status <2.  
3.1.7 
Participants must have normal organ and marrow function as defined below, all of which must 
be obtained within two weeks prior to study registration date: 
 
Absolute neutrophil count > 750/mcL 
 
Platelets > 25,000/mcL 
 
Total bilirubin ≤  4.0 X institutional upper limit of normal 
 
AST (SGOT)/ALT (SGPT) < 6.0 X institutional upper limit of normal 
 
Creatinine </= 2mg/dl or creatinine clearance > 60 mL/min/1.73 m2 (Calculated per 
Cockroft & Gault formula) for subjects with creatinine levels above institutional 
normal. 
3.1.8 
If patient has underlying cirrhosis, only Child-Pugh classification Group A or Group B patients 
should be included in this study.   Clinical assessment of ascites and encephalopathy is required.  
Child-Pugh classification must be determined for all study participants at the time of eligibility 
analysis.  Note albumin and PT/INR are required for Child-Pugh classification; these labs should 
be drawn with other labs required for eligibility analysis. 
 
 
 

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Table 1:  Child-Pugh classification of liver function 
 
Score 
 
 
1 
2 
 
3 
Acites 
 
 
Absent 
Slight to moderate 
Severe 
Encephalopathy  
Absent 
Slight to moderate                     Severe 
Serum albumin 
 
>3.5 g/dl 
3-3.5 g/dl 
<3 g/dl 
Serum bilirubin  
<2 mg/dl 
2-3 mg/dl 
>3 mg/dl 
Prolongation of prothrombin time 
<4 seconds 
4-6 seconds 
>6 seconds 
Score of 5 to 6 corresponds to Child-Pugh class A 
Score of 7 to 11 corresponds to Child-Pugh class B 
Score of 12 to 15 corresponds to Child-Pugh class C 
 
3.1.9    The effects of radiation on the developing human fetus are known to be teratogenic.  
Therefore, male and female patients of child-bearing potential must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry 
and for the duration of study participation. Female patients of child bearing potential must also 
have a negative serum pregnancy test. 
 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her treating physician immediately. 
3.1.10   Individuals with a history of other malignancies are eligible if they have been disease-free for at 
least 5 years and are deemed by the investigator to be at low risk for recurrence of that 
malignancy. Individuals with the following cancers are eligible if diagnosed and treated within 
the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.  
 
3.1.11   Ability to understand and the willingness to sign a written informed consent document.  
3.2       Exclusion Criteria 
3.2.1. 
 Women who are pregnant or lactating.  
3.2.2.   Patients with evidence of non-hepatic metastatic disease. 
3.2.3.   Local conditions or systemic illnesses which would reduce the local tolerance to radiation 
treatment, such as serious local injuries, active collagen vascular disease, etc. 
3.2.4    Prior liver directed radiation treatment. 
3.2.5    Patients may have no serious medical illness, which may limit survival to less than 3 months. 
3.2.6    Patient may have no serious psychiatric illness/social situations which would limit compliance 
with study requirements.  

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3.2.7   Patients who have had chemotherapy (other than 5-fluorouracil, capecitabine, or sorafenib) or 
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the 
study or those who have not recovered from adverse events (with the exception of anticipated 
chronic late effects from chemotherapy not expected to be exacerbated by radiation) due to 
agents administered within the timeframes described in 3.1.3 above. 
3.2.8   Patients may not be receiving any other study agents. 
3.2.9  
Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,  
3.2.10 Individuals with a history of a different malignancy are ineligible except for the following 
circumstances; They have been disease-free for at least 5 years and are deemed by the investigator 
to be at low risk for recurrence of that malignancy.  
3.2.11    Because no dosing or adverse event data are currently available on the use of high dose liver              
radiation participants <18 years of age are excluded from this study.  
3.3    Inclusion of Women, Minorities and Other Underrepresented Populations 
We do not expect the inclusion and exclusion criteria to either over or under-represent women, 
minorities, or underrepresented populations. 
 
4. REGISTRATION PROCEDURES 
4.1  
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Patient Entry 
Patients must be registered with the DF/HCC Quality Assurance Office for Clinical Trials (QACT) 
(
 prior to the start of treatment. Any patient not registered to 
the protocol prior to the start of treatment will be ineligible.  The following information will be provided to 
the QACT: 
- Registering physician (PI or coI) name, telephone number, and pager number 
- Protocol name and number, and Date treatment begins 
- Patient name, Date of birth, Patient ID number, Primary physician, Primary treatment institution,  
Confirmation of eligibility 
- Copy of signed consent form.  
- Patient must start treatment within 1 month of registration 
 

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DF/HCC institutions will register eligible participants with the QACT central registration system. 
Registration must occur prior to the initiation of therapy. Any participant not registered to the 
protocol before treatment begins will be considered ineligible and registration will be denied.  
 
A member of the study team will confirm eligibility criteria and complete the protocol-specific 
eligibility checklist.  
Following registration, participants may begin protocol treatment.  Issues that would cause treatment 
delays should be discussed with the Principal Investigator.  If a participant does not receive protocol 
therapy following registration, the participant’s protocol status must be changed. Notify the QACT 
Registrar of participant status changes as soon as possible. 
 
4.2  
Registration Process for DF/HCC and DF/PCC Institutions 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM Eastern 
Standard Time. In emergency situations when a participant must be registered during off-hours or 
holidays, call the QACT registration line at 
 and follow the instructions for registering 
participants after hours.   
The registration procedures are as follows: 
1. 
Obtain written informed consent from the participant prior to the performance of any study 
related procedures or assessments. 
2. 
Complete the protocol-specific eligibility checklist using the eligibility assessment documented 
in the participant’s medical/research record. To be eligible for registration to the study, the 
participant must meet each inclusion and exclusion criteria listed on the eligibility 
checklist.  
3. 
Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 
  
4. 
The QACT Registrar will (a) validate eligibility, (b) register the participant on the study, and 
(c) randomize the participant when applicable.  
5. 
The QACT Registrar will send an email confirmation of the registration and/or randomization 
to the person initiating the registration immediately following the registration and/or 
randomization.  

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4.3  
General Guidelines for Other Participating Institutions   
    Please see section 5.7 of the Data Safety Monitoring Plan.  
 
4.4    
Registration Process for Other Participating Institutions 
Please see section 5.7 of the Data Safety Monitoring Plan.  
 
5. TREATMENT PLAN  
5.1 
Treatment Program 
 
5.1.1 
Assessments During Treatment 
- Vital Signs: Pulse, Blood Pressure, Temperature obtained weekly  
- Lab tests: CBC with diff (WBC, HGB, PLT, ANC, ALC), Liver and renal function tests (SGOT, 
SGPT, Total Bilirubin, Alkaline Phosphatase, Creatinine, BUN and Creatinine Clearance 
calculated with Cockroft and Gault formula), LDH and Tumor markers (CEA, CA 19-9, alpha 
fetal protein) will be obtained weekly during treatment on study days 1, 8, 15 and the day of 
the last radiation treatment.  
                           
Patients will be seen at least once per week by a physician and a radiation oncology nurse while 
undergoing radiation treatment and will be assessed for acute toxicity. 
 
5.1.2     Radiation Therapy 
 
  
 
5.1.2.1   Pre-planning and Simulation Procedures 
Prior to radiation planning, patients will undergo placement of fiducial seeds according to 
institutional procedures.  If placement of fiducials is contraindicated in a patient, or if a 
patient is deemed too high risk for implanting procedure, the patient may proceed with 
study participation without fiducials at the discretion of the treating investigator. 
 
5.1.2.2   Treatment Planning 
Patients will undergo an abdominal 4D CT scan in the treatment position. Treatment 
planning will be done on a 4D CT-based planning system. If the motion of the GTV is 
less than or equal to 10mm, an ITV will be defined.  If the motion is greater than 10mm, 
gating or deep inspiration breath hold (DIBH) will be used.  For proton treatments, the 
patient will be in a customized immobilization device in the appropriate position. The 
treatment planning CT is to be performed with the patient in this device. The radiation 
oncologist will define the target and the non-target tissues/structures of interest on each 
section and specify the radiation dose constraints for each of the sensitive structures 
(uninvolved liver, kidney, large and small bowel, stomach, spinal cord). The treatment 

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volume is defined as the tumor, visualized on the CT and/or MRI.  Clinical Target 
Volume (CTV) expansion will be 0.5-1 cm at treating physician’s discretion.  The PTV 
shall be defined relative to the CTV on the basis of lateral uncertainties alone in the range 
of 0.5 to 1.0 cm.  (Adjustments shall be made within the beam-design algorithm to take 
into account differences, if any, between the margins needed to account for uncertainties 
along the beam direction (range uncertainties) and those included in the lateral 
uncertainty defined PTV.) 
 
5.1.2.3    Dose Fractionation and Specification 
Proton treatments will be delivered at the Francis H. Burr Proton Therapy Center at the 
Massachusetts General Hospital using a 240 MeV cyclotron. At MDACC, proton 
treatments will be delivered at the MDACC Proton Therapy Center using a 250 MeV 
synchrotron.  At the Roberts Proton Facility at the University of Pennsylvania, proton 
treatments will be delivered using a 230 MeV cyclotron.  All treatments will be 
administered as one daily fraction, 5 days per week over 3 weeks. The RBE for proton 
irradiation is set at 1. 1. Thus, the dose unit, Gy (RBE), is proton dose in Gy X RBE of 1. 
1. Based on the analysis of the results of the University of Michigan liver protocol there 
were no cases of liver toxicity for the average liver dose less than 30 Gy delivered in 1.5 
Gy per fraction. In our protocol we intend to use 15 fractions, 5 daily fractions per 
week.  
 
For peripheral tumors the total dose will be as follows: 
67.5 Gy (RBE) (NTD 81 Gy10, 101 Gy3 ) in 15 fractions 
 
For central tumors (within 2 cm of porta hepatis), fractionation will be as follows: 
58 Gy (RBE) (NTD 67 Gy10, 79.6 Gy3) 
 
Underdosing of the PTV will be permitted to maintain normal tissue constraints as 
described below.  However 90% of the PTV should receive the prescription dose. Dose 
de-escalation will be permitted to maintain a liver EUD below 20 Gy (RBE) and a mean 
liver dose < 24 Gy (RBE).  If dose is de-escalated to below 45 Gy (RBE), the patient will 
be removed from study and referred as appropriate for further management. 
 
Normal Tissue Constraints: 
Spinal cord max dose: 30 Gy (RBE) 
Stomach max dose: 42 Gy (RBE) 
Bowel (including duodenum, small bowel, large bowel) max dose: 45 Gy (RBE) 

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Kidney V14 (volume receiving 14 Gy (RBE) < 30%) 
Liver-GTV: EUD < 20 Gy (RBE), mean dose < 24 Gy (RBE)- whichever is lower. 
Heart Max dose: 45 Gy (RBE), V40<10% 
Chest Wall: no more than 2ccs may receive >60 Gy (RBE) 
 
The deviations in dose constraints described above are considered planning deviations 
only and will not constitute protocol deviations. Treatment plans that include minor 
planning deviations may be delivered as part of this protocol. Treatment plans that 
include major planning deviations may be delivered on this protocol with the review and 
approval of the PI prior to treatment start. All relevant DVH data regarding doses to 
critical structures will be maintained in the study database for analysis. 
 
Treatment will be administered on an outpatient basis. Expected toxicities and 
potential risks as well as dose modifications for are described in Section 6 
(Expected Toxicities and Dosing Delays/Dose Modifications). No investigational 
or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
5.2 
Pre-treatment Criteria 
              Baseline staging requirements: 
 
All assessments must be completed within 6 weeks of study entry, unless otherwise noted.  
5.2.1  Complete history and physical examination by radiation oncologist and responsible medical 
oncologist or surgeon. 
5.2.2  Laboratory evaluation: CBC with diff (WBC, HGB, PLT, ANC, ALC), Liver and renal function 
tests (SGOT, SGPT, Total Bilirubin, Alkaline Phosphatase, Creatinine, BUN and Creatinine 
Clearance calculated with Cockroft and Gault formula), LDH and Tumor markers (CEA, CA 19-9, 
alpha fetal protein)   sodium, potassium, chloride, carbon dioxide, , calcium, phosphorous,PT/INR, 
Albumin, Child-Pugh classification, and tumor markers (CEA, CA 19-9, alpha fetal protein). Lab 
tests must be completed within 2 weeks of study entry.  
5.2.3  Thoracic CT scan to exclude lung and mediastinal metastases.  
5.2.4  Abdominal and Pelvic CT scan to exclude non-hepatic disease or metastases. 5.2.5  Hepatic MRI is 
required if any lesion is difficult to visualize and/or measure on the Abdominal/Pelvic CT scan.   
 
5.3  
Proton Beam Delivery  
All charged particle treatment will be given with the patient at the Francis H. Burr Proton Therapy Center, 
MD Anderson Proton Therapy Center, or the University of Pennsylvania Roberts Proton Facility.  Film or 
digital images will be taken prior to each treatment in accordance with the proton center's standard practice 

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for all patients. These images are used to verify the position of the patient and the aperture.  These images 
are permanently stored electronically for each patient. Respiratory gating or deep inspiration breath hold 
(DIBH) is recommended to account for respiratory excursion if tumor motion is > 10mm.  Treatment may 
start any day of the week except Friday. 
 
5.4  
General Concomitant Medication and Supportive Care Guidelines 
There are no required concomitant medications in this study.  No other cytotoxic therapy or radiotherapy 
may be used during study treatment.  Patients may receive all concomitant therapy deemed necessary to 
provide optimal support.   
 5.5 
Duration of Therapy 
Proton radiation therapy will in most instances be completed within 3 weeks of the start of treatment (15 
consecutive hospital business days). This may be extended if patients require a break from treatment. 
Criteria for break would include any G3 or G4 toxicity. All labs will be assessed by the treating physician 
to determine whether they are considered clinically significant or not clinically significant and treatment 
will be held at their discretion. All patients experiencing any of the following events will be taken off 
treatment: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Participant decides to withdraw from the study, or 
 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
5.6 
Duration of Follow Up  
Study participants will be followed for five years from the completion of study treatment or until death, 
whichever occurs first.  Participants will be removed from follow-up when any of the criteria listed in 
Section 5.5 apply.  Participants removed from treatment  or follow-up will be followed for survival 
outcomes and a 2 years analysis of local control. 
5.7 
Criteria for Removal from Study  
Participants will be removed from study upon death or withdrawal of consent. The reason for 
study removal and the date the participant was removed must be documented in the medical 
record and recorded in the study-specific case report form (CRF). Alternative care options will 
be discussed with the participant, if applicable. 

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In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator Ted Hong, MD at 
 
 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
6.1  
Potential Toxicity 
Radiation side effects are typically divided into those that occur acutely (during radiation and up to 3 
months after radiation) and those that occur later (>3 months post-radiation). Common acute radiation side 
effects include fatigue, skin irritation or erythema, elevated liver function tests, nausea, low platelet count, 
decreased blood counts, abdominal pain or cramps, decreased/ loss of appetite, vomiting, slow wound 
healing, weight loss, indigestion, gastritis, radiation esophagitis, and diarrhea. Typically, these side effects 
can be controlled with medication.  
Late side effects that are unlikely to occur but would include rib microfracture, nerve damage, 
inflammation and scarring of liver, mucosal ulceration and tissue damage, ulceration or perforation of 
stomach/ bowel, pain, inflammation, or scarring of kidneys, stomach and bowel, development of new 
cancer,  hepatic injury (hepatitis), renal injury, gastric, bowel obstruction and spinal cord injury. Another 
rare but serious late side effect is the development of second tumors. It is hoped that proton radiation will 
substantially reduce both acute and late side effects by reducing the amount of normal tissue that is 
irradiated.  
 
Dose delays and modifications will be made using the following recommendations. Toxicity assessments 
will be done using NCI Common Terminology Criteria for Adverse Events (CTCAE v3.0) which is 
available at http://ctep.cancer.gov/reporting//ctc html).  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All toxicities that are Grade 2 or higher and determined to be possibly, probably or definitely related to the 
study intervention or study procedures will be collected on the Toxicity case report forms from the time of 
the first dose of study treatment, through the study and until the final study visit. Participants continuing to 
experience toxicity at the off study visit may be contacted for additional assessments until the toxicity has 
resolved or is deemed irreversible.  
6.2  
Anticipated Toxicities  

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A list of the adverse events and potential risks associated with the agents administered in this study appear 
below and will determine whether dose delays and modifications will be made or whether the event 
requires expedited reporting in addition to routine reporting.  
 
CAEPRs for Proton Beam Radiotherapy to the Liver 
Very likely: These symptoms usually recover in the first few weeks following completion of 
radiation therapy 
• Irritation, redness and discoloration of the skin in the radiation area. 
• Fatigue (tiredness) 
 
Likely 
 
Decreased blood counts 
 
 Low platelet count 
 
Elevated LFTs 
 
Abdominal pain or cramps 
 
Nausea 
 
Less likely 
 
Diarrhea 
 
Decreased/ loss of appetite 
 
Vomiting 
 
Slow wound healing 
 
Weight loss 
 
Indigestion 
 
Gastritis 
 
Radiation Esophagitis 
 
Rib microfracture 
 
Rare 
 
Damage to the liver which could result in inflammation and scarring of the liver. This could 
lead to jaundice and possibly cirrhosis. Efforts to prevent excessive liver irradiation will be 
made to minimize the chance of these side effects 
 
While radiation can cause mucosal ulceration, other tissues may be damaged which may 
require surgery and may be life-threatening. 
 
Stomach and bowel are protected well from excessive dose of radiation. However, overdosing 
the stomach or bowel can lead to ulceration or perforation. 

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 
Pain, inflammation or scarring of your kidneys, stomach and bowel. These organs are 
protected well from excessive dose of radiation.  Therefore, it is unlikely that patients will 
experience symptoms of injury to these organs  
 
Nerve damage 
 
Development of a new cancer resulting from treatment may happen many years after 
completing treatment 
 
Spinal cord injury 
6.3  
Toxicity Management 
Most radiation toxicities during the course of treatment are self-limited and resolve with a treatment 
break.  Therefore, any Grade 3 or 4 acute toxicity will result in a treatment break until it resolves to Grade 2 
or less, with the exception of labs. All labs will be assessed by the treating physician to determine whether 
they are considered clinically significant or not clinically significant and treatment will be held at their 
discretion. If a participant experiences a Grade 3 or 4 hematological toxicity, the participant is allowed to 
receive a colony stimulating factor to aid in the resolution. 
6.4  
Dose Modifications/Delays 
Grade 3 or 4 acute toxicity will result in a treatment break until it resolves to Grade 2 or less,  with the 
exception of any Grade 3 Baseline labs that fit the eligibility criteria. Thrombocytopenia will only result in 
a treatment break if it becomes a Grade 4. All labs will be assessed by the treating physician to determine 
whether they are considered clinically significant or not clinically significant and treatment will be held at 
their discretion. If a treatment break of > 14 days is needed, the patient will be removed from study. 
7.  DRUG FORMULATION AND ADMINISTRATION: Not applicable 
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1 
Circulating Biomarkers 
Participation in the correlative blood sample studies will be offered to study participants at MGH only. 
 
Based on findings from preliminary studies, we propose here to evaluate the changes in blood circulating 
SDF1α and circulating myeloid cells before, during, and after a three-week schedule of proton beam 
radiation therapy, and to explore potential associations between the changes in these biomarkers and 
resistance to treatment. In exploratory studies, we will evaluate several other cytokines using multiplex 
protein array (Meso-Scale Discovery, Inc.). 
 
8.1.1 Experimental Design 

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Blood will be drawn by venipuncture, and the first 7-10 ml blood will be excluded or used for other 
analysis. The following 8 ml will be collected in an EDTA tube. The EDTA tube with the blood 
sample will be shipped in wet ice within 2 hours of drawing for further processing at Steele 
Laboratory at MGH.  We will analyze the correlation between plasma SDF1α and circulating 
myeloid cells with multiple measures of outcome (ORR, TTP, OS) in advanced liver cancer 
patients after proton beam radiation therapy. 
 
8.1.2  Collection 
To this end we will measure circulating biomarkers  
(i) 
pretreatment 
(ii) 
during proton beam radiation therapy at days 1, 8, 15 and the last day of radiation 
treatment 
(iii) 
one month post-completion of the proton beam radiation treatment; and  
(iv) 
at the time of disease progression 
 
Samples will be collected at the following time points- 
a. 
Prior to the start of therapy 
b.  
Within 72 hours of start of therapy. 
c.       Day 8, 15 and the day of the last radiation treatment.  
d. 
1 month after completion of therapy. 
e.  
following  radiologic progression   
 
8.1.3  Shipping Instructions 
 
The tube containing the blood should be shipped with the following information 
1. 
Study Number at the DF/HCC 
2. 
Patient number on the study 
3. 
Patient’s initials 
4. 
Treating physician’s name 
5. 
Date of collection 
6. 
Date of shipping 
 
The tube of blood should be placed in a sealable container and placed in a box with the necessary 
information. The box should be marked Biohazard.  
 
  
 
 

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9. STUDY CALENDAR 
9.1 
Required Data 
Lab evaluations must be completed within 2 weeks of study entry. All other baseline assessments must be completed 
within 6 weeks of study entry. All study assessments should be administered +/- 3 days of the protocol-specified 
date, unless otherwise noted. 
Data Set 
Prior to 
Study Entry 
Weekly Visit During 
Radiation Therapy
At Follow-Up 
(3) 
Age 
X 
 
 
Sex 
X 
 
 
H&P (including clinical 
assessment of ascites and 
encephalopathy at baseline and 
follow up) 
X 
                   X 
X 
Toxicity Assessment 
X 
X 
X 
Vital Signs (pulse, blood 
pressure, temperature) 
 
X 
 
CBC with diff (WBC, HGB, 
PLT, ANC, ALC) 
X 
X 
 
PT/INR, Albumin, Child-Pugh 
classification 
X 
 
X 
Renal Function Tests (BUN, 
creatinine, calculated creatinine 
clearance per Cockroft & Gault) 
X 
X 
 
Liver Function Tests (SGOT, 
SGPT, T bili, Alk Phos) & LDH 
X 
X 
X 
Tumor markers (CEA, CA 19-9) 
Alpha Fetal Protein 
X 
X 
X 
Beta-HCG 
(women of child-bearing 
potential) 
X 
 
 
Tumor Measurement 
X 
 
twice yearly (1) 
Abdominal and Pelvic 
CTand/or hepatic MRI 
X 
 
twice yearly (1) 
Thoracic CT 
X 
 
twice yearly 
Peripheral Blood for correlative 
studies (optional) 
X 
X (2) 
X (2) 
 
Notes: 
(1) Imaging and tumor measurements in follow up are required for study data twice yearly.  Additional imaging 
studies may be obtained for clinical follow up at the discretion of the treating clinicians.   For study participants 
who receive follow up care at institutions other than the treating institution, imaging reports and scans must be sent 
to the treating institution to be included in the study data set. 
(2) Peripheral blood will be obtained with clinical labs at pretreatment, during proton beam radiation therapy at 
days 1, 8, 15 and the last day of radiation treatment. (this blood draw is optional and will be offered to study 
participants at MGH only) 

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(3) Follow up assessments will be due at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post 
treatment, with a visit window of +/- 3 weeks for the 1 month follow up and+/- 6 weeks for all other follow up 
dates. 
 
9.2  
Data Collection  
Weekly on-study labs are to be drawn on study days 1, 8, 15 and the day of the last radiation treatment. All 
patients will be evaluated initially, and at 1, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months 
post treatment. Each follow-up examination will consist of interval history and  physical examination, 
toxicity assessment, liver function tests, LDH, PT INR, albumin, Child-Pugh classification and tumor 
markers (CEA , CA 19-9,alpha feta protein).  Baseline and follow up physical examination will include 
clinical assessment of encephalopathy and ascites for calculation of Child-Pugh Score.  Assessment of the 
liver tumor by CT and/ or MRI will be performed at time of abdominal imaging twice yearly for two years 
and then yearly for three years. Chest CT will be obtained twice yearly for two years and then yearly for 
three years.  Additional imaging studies may be obtained for clinical follow up at the discretion of the 
treating clinicians.  For study participants who receive follow up care at institutions other than the treating 
institution, imaging reports and scans must be sent to the treating institution to be included in the study data 
set. 
 
10. MEASUREMENT OF EFFECT  
10.1  
Toxicity and Complications 
 
Acute and late morbidity of radiation treatment will be scored using the Common Terminology Criteria for 
Adverse Events 3.0 (CTCAE 3.0; see Appendix 11)  
 
 
 
10.2   
Tumor Response: RECIST Criteria 
 
Complete Response (CR): Disappearance of entire lesion, with no additional evidence of disease Partial 
Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of the primary lesion, 
taken as reference the baseline sum LD. 
 
 
Progressive Disease (PD): At least a 20% increase in the LD of the lesion, taken as the 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. 
 
10.3  
Local Failure 

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Local failure is defined as: evidence of tumor growth/regrowth in any direction beyond that present of the 
pre-treatment imaging studies in the treated lesion(s).  Intrahepatic recurrence elsewhere in the liver is 
defined as any new lesion in the liver.  The imaging studies are to be comparable in technical factors. 
 
10.4   
Marginal failure 
 
Marginal failure is defined as appearance of tumor growth at the margin of the target volume 
 
10.5   
Nodal failure 
 
Failure in regional lymph nodes: porta-hepatis, para-aortic, diaphragmatic. 
 
10.6 
Distant Failure 
 
Defined as appearance of tumor at sites beyond regional nodal and marginal site. 
 
10.7   
Overall Survival 
Duration measured from registration until death or censored at date of last follow-up for patients still alive.  
11. ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse Events 
As above, the CTCAE 3.0 will be used to grade all acute and late radiation effects and Adverse Events.   
 
Report of Adverse Events to the IRB 
Adverse events will be reported to each site’s IRB in accordance with the local IRB guidelines.  All adverse events 
will also be reported to the Coordinating Center and all participating sited as described in the attached Data and 
Safety Monitoring Plan (Appendix III). 
 
11.1      General  
Adverse event collection and reporting is a routine part of every clinical trial. This study will use the 
descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
version 3.0 (CTCAE v3.0) that is available at http://ctep.cancer.gov/reporting//ctc.html 
 
Information on all adverse events, whether reported by the participant, directly observed, or detected by 
physical examination, laboratory test or other means, will be collected, recorded, followed and reported as 
described in the following sections.  
 
Adverse events experienced by participants will be collected and reported from initiation of study 
intervention, throughout the study, and within 30 days of the last study treatment. Participants who 
experience an ongoing adverse event or related to a study procedures and/or study treatment beyond 30 

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days will continue to be contacted by a member of the study team until the event is resolved, stabilized, or 
determined to be irreversible by the participating investigator.  
 
Participants should be instructed to report any serious post-study event(s) that might reasonably be related 
to participation in this study. The investigator should notify the IRB, the Coordinating Center and any other 
applicable regulatory agency of any unanticipated death or adverse event occurring after a participant has 
discontinued or terminated study participation that may reasonably be related to the study.  
 
11.2  
Definitions  
11.2.1  Adverse Event (AE) 
 
 
An adverse event is any undesirable sign, symptom or medical condition or experience that develops or 
worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they induce 
clinical signs or symptoms or require treatment or further diagnostic tests.  
 
11.2.2  Serious adverse event (SAE) 
 
A serious adverse event is an undesirable sign, symptom, or medical condition which: 
 
is fatal or life-threatening; 
 
requires or prolongs inpatient hospitalization; 
 
results in persistent or significant disability/incapacity; 
 
constitutes a congenital anomaly or birth defect; or 
 
jeopardizes the participant and requires medical or surgical intervention to prevent one of 
the outcomes listed above.  
Events not considered to be serious adverse events are hospitalizations for: 
 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
 
respite care 
 
11.2.3 Expectedness  
 
Adverse events can be 'Expected' or 'Unexpected’.  
 

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11.2.3.1 Expected adverse event 
Expected adverse events are those that have been previously identified as resulting from 
administration of the treatment.  For the purposes of this study, an adverse event is considered 
expected when it appears in the protocol and/or  informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
treatment.   
 
11.2.3.2. Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the protocol and/or informed consent 
document as a potential risk.   
 
11.2.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment.  
 
Unlikely - The AE is doubtfully related to the study treatment. 
 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
 

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11.3     Recording Adverse Events 
Adverse event information will be obtained at each contact with the participant. All adverse events will be 
recorded on the appropriate study-specific case report forms (CRFs).  
 
11.4 
Reporting Adverse Events  
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each participating 
investigator is required to abide by the reporting requirements set by the DF/HCC.  The study must be 
conducted in compliance with FDA regulations, local safety reporting requirements and reporting 
requirements of the principal investigator. 
 
Each adverse event will be assessed to determine if it meets the criteria for serious adverse event. If a 
serious adverse event occurs, expedited reporting will follow local policies, and federal guidelines and 
regulations as appropriate.  
 
It is the responsibility of the participating investigator to notify the Principal Investigator, and the local IRB 
of all serious adverse events as required in the protocol.  
 
The Principal Investigator will provide information with respect to adverse events and safe use of the study 
treatment (e.g., safety reports, Action Letters) to all participating investigators as described in the attached 
Data and Safety Monitoring Plan (DSMP) as soon as the information becomes available.  
 
11.5     Coordinating Center Notification by Investigator  
 
 
 
11.5.1 Serious Adverse Event Reporting Requirements 
 
All events meeting the criteria for Serious Adverse Event (see Section 11.2.2) that occur after the 
initial dose of study treatment, during treatment, or within 30 days of the last dose of treatment must be 
reported to the DF/HCC Overall Principal Investigator as serious adverse events.  This includes events 
meeting criteria outlined in Section 11.2 as well as the following: 
 
Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention. 
 
All Grade 4 (life-threatening or disabling) events that are unexpected or not specifically listed in 
the protocol as not requiring reporting 
 
All Grade 5 (fatal) events while the participant is enrolled and actively participating in the trial 
OR when the event occurs within 30 days of the last study intervention. 
Note: If the participant is in long-term follow-up, report death at the time of continuing review. 
 

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The participating investigator must report each serious adverse event, regardless attribution, to the DF/HCC 
Principal Investigator within 1 business day of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately (e.g., participant sought 
treatment elsewhere), the participating investigator is to report the event within 1 business day after learning 
of it and document the time of his or her first awareness of the adverse event. Report serious adverse events 
by email or fax to the Coordinating Center at: 
 
  
 
 
Within the following 1-2 business days, the participating investigator must provide follow-up information on 
the serious adverse event. Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will continue or discontinue study 
participation.  
 
11.5.2 Non-Serious Adverse Event Reporting Requirements 
Non-serious adverse events will be reported to the Principal Investigator on the toxicity Case Report 
Forms.   
 
 
11.6  
Institutional Review Board (IRB) Notification by Investigator 
 
The participating investigator will report all adverse events and serious adverse events to the Principal 
Investigator (or Protocol Chair) and to the local IRB according to the local IRB’s policies and procedures in 
reporting adverse events.  
 
The Principal Investigator (or Protocol Chair) will report adverse events and serious adverse events from all 
participating sites to the DFCI IRB according to the IRB’s policies and procedures in reporting adverse 
events.  
 
11.7   
Hospital Risk Management Notification by Investigator 
 
The participating investigator will report to the Principal Investigator (or Protocol Chair) and to local Risk 
Management any subject safety reports or sentinel events that require reporting according to institutional 
policy. 

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12. DATA AND SAFETY MONITORING 
 
12.1  
Data Reporting  
12.1.1 Method  
Data for this study will be collected and managed by the MGH Biostatistics Center.  Electronic 
Case Report Forms will be posted for use by all participating sites in TrialDB, and study staff at 
each site will be given access to enter CRF data electronically.   Data will be monitored by the 
MGH FHBPTC Senior Clinical Research Program Manager or designee.    
 
12.1.2 Data Submission  
The schedule for completion and submission of electronic case report forms to the MGH Biostatistics 
Center can be found in section 5.10 in the Data Safety Monitoring Plan. 
 
12.1.3 DICOM Data 
 
De-identified DICOM data from the proton plans for each study subject will be transmitted to the 
Advanced Technology Consortium QA Center at Washington University, St. Louis (ATC).  ATC will 
maintain the de-identified image data for analysis by investigators at all participating sites.  Treatment 
plans for all patients will be sent electronically to the ATC .The treatment planner or the physicist who 
performs the initial review of the plan will be responsible for transmitting these data.   Please see 
section 12.3.1 for more information.  
 
12.2  
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual 
data from this trial. The committee is composed of clinical specialists with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about participant safety will 
be addressed with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and accrual data.  
Information to be provided to the committee may include:  up-to-date participant accrual; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths while being treated and 
during active follow-up; any response information; audit results, and a summary provided by the study team. 
Other information (e.g. scans, laboratory values) will be provided upon request.  
 

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12.3  
Monitoring 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the Principal Investigator 
(or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to examine study-related 
activities and documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported in accordance with the protocol, institutional policy, Good Clinical 
Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 
protocol performance and completion.  
 
12.3.1 Quality Assurance and Rapid Review of Treatment Plans 
To ensure protocol compliance, the treatment plans for the first three patients treated at each site will 
be reviewed by the Principal Investigator and Participating Site’s PI.  As described above, plans will be 
submitted to the ATC for this protocol.  The plans will be sent to the ATC upon approval by the 
treating physician, and the PI and/or Participating Site PI will review and confirm protocol compliance 
within three working days of the start of treatment. 
 
13. REGULATORY CONSIDERATIONS 
13.1 
Declaration of Helsinki 
The PI will ensure that this study will be conducted in full conformity with the current version of the 
declaration of Helsinki and with U.S. FDA requirements 
 
13.2 
Patient Confidentiality 
The investigators will ensure that patient anonymity is maintained. 
 
13.3  
Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents must be 
submitted, reviewed and approved by a properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be approved by the lead 
site (DF/HCC) IRB prior to implementation. Any changes in study conduct must be reported to the 
IRB. The Principal Investigator (or Protocol Chair) will disseminate protocol amendment information 
to all participating investigators.  

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All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
13.4   
Informed Consent 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study, 
including an adequate explanation of the aims methods, anticipated benefits and potential 
hazards of the study to the patient.  The formal consent of a participant, using the IRB approved 
consent form, must be obtained by the Principal investigator or physician co-investigator before 
the participant is involved in any study-related procedure. The consent form must be signed and 
dated by the participant or the participant’s legally authorized representative, and by the person 
obtaining the consent.  If the patient does not speak English, an interpreter will be made available 
and the treating institution’s policy for obtaining research consent from non-English speaking 
patients will be followed.  The informed consent process will be documented in the patient’s medical 
record.  The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or research file.  
 
13.5  
Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
 
ICH Consolidated Good Clinical Practice: Guidelines (E6) 
www fda.gov/cder/guidance/iche6 htm  
 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr11 02.html 
 
Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr50 02.html  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr54 02.html  
 
Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  

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 
Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr312 02.html  
 
State laws 
 
Institutional research policies and procedures www.dfhcc harvard.edu/clinical-research-
support/clinical-research-operations-cro/policies-and-procedures 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be reported 
to the Principal Investigator and the IRB according to the local reporting policy.  
 
13.6  
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables 
the study to be fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not limited to hospital 
records, clinical charts, laboratory and pharmacy records, recorded data from automated instruments, 
microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
 
13.7  
Records Retention 
All study-related documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies.  
13.8  
Multi-center Guidelines 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard Cancer Center. 
The specific responsibilities of the Principal Investigator (or Protocol Chair), Coordinating Center, 
and Participating Institutions are presented in the Dana-Farber/Harvard Cancer Center Multi-Center Data 
and Safety Monitoring Plan (see Appendix II). 
 
The Principal Investigator/Coordinating Center is responsible for distributing all Safety Reports 
to all participating institutions for submission to their individual IRBs for action as required. 
 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse event 
reporting at each site.  
 

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14. STATISTICAL CONSIDERATIONS  
The primary objective is to demonstrate proton beam radiation of unresectable primary hepatocellular cancer is 
associated with local control of at least 80% at 2 years. The null hypothesis is based on a 2-year local control rate of 
55% following treatment of tumors >3cm with radiofrequency ablation (RFA), as discussed in 2.3.   However, the 
local control tends to much poorer in certain subgroups, including tumors unable to be treated by RFA and the 
largest tumors, thus 55% is used as an upper bound for the sample size considerations.  
 
14.1 
Study Design/Endpoints 
The primary endpoint is local control at 2 years, or equivalently, the absence of local failure as defined in 
10.3.  Starting with a total of 60 patients with unresectable primary hepatocellular cancer, we project 30 of 
them will be alive at 2 years for the evaluation of local control assuming a 2-year overall survival of 50%. 
The number of evaluable patients is a conservative assumption based on the historical RFA data and the 
Tsukuba proton data (13) showing a 2-year overall survival in the range of 50-70%. Analysis of 30 patients 
alive at 2 years will achieve 94% power to detect a local control rate of 80% if at least 21 of them were free 
of local failure. The decision rule is associated with 7% probability for accepting the proton protocol is 
associated with improved local control when the true rate is only 55% at 2 years. 
 
The rate of local control will be based on actuarial estimates, primarily at 2 years, using the Kaplan-Meier 
method. Time to local failure will be measured from the start of radiation therapy to the date of local 
failure, as defined in 10.3. Patients who have not failed locally will be censored at the time of last follow-
up. A minimum follow-up of 2 years will be required, while patients who die or drop out of the protocol 
prior to 2 years will be censored at that date. 
 
14.2    
Sample Size/Accrual Rate 
The accrual goal was previously revised to 60 patients in order to preserve high power for detecting a slightly 
smaller but clinically significant increase in local control to 80% at 2 years. Recently, emerging data suggest 
unresectable liver tumors represent clinically heterogeneous groups, in particular, intrahepatic 
cholangiocarcinomas are associated with a more favorable prognosis than primary hepatocellular cancers. 
Thus we propose to restrict the primary hypothesis in 14.1 to the major tumor group, namely patients with 
unresectable primary hepatocellular cancer. As intrahepatic cholangiocarcinomas constitute one-third of the 
present enrollment, we propose to continue with their accrual in order to estimate their failure and survival 
endpoints with reasonable precision for planning future studies for the specific population. Based on the 
observed distribution of the tumor groups, the target accrual is increased to a total of 90 patients in order to 
obtain 60 patients with unresectable primary hepatocellular cancer for testing the primary hypothesis in 
14.1.  
 

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Since the protocol was activated by MD Anderson Cancer Center at the end of September 2010, 47 patients 
have been enrolled by two participating institutions over a period of 13 months. As of March 2013, their 
combined accrual has reached 57 patients. We project the increased sample size will be reached within the 
next year and a half, as the protocol has expanded recently to a third institution. If a patient is found to be 
ineligible once registered and therefore taken off study and excluded from analysis, an additional 
patient may be enrolled and included in analysis. As specified in 5.6, the patients will be followed for 
at least 5 years from the completion of protocol treatment or until death, whichever occurs first.  
 
14.3    Stratification Factors 
Not applicable. 
14.4     Analysis of Secondary Endpoints 
The secondary endpoints of acute and late toxicity, tumor response, failure patterns and overall survival are 
defined in the modality review of 10.1-10.7. Toxicity and response data will be summarized in tables, with 
the exact binomial confidence interval reported for their rates. Time to failure and survival will be analyzed 
using standard methods for failure time data, primarily the Kaplan-Meier estimate, while differences 
between patient subgroups may be explored using the log-rank test. In particular, the increase in sample 
size will provide high precision for estimating the failure and survival endpoints separately for patients with 
hepatocellular cancer and cholangiocarcinoma.  
 
14.5  
Reporting and Exclusions 
Not Applicable 
 
15. PUBLICATION PLAN 
The results will be made public within 24 months of the end of data collection. A report may be published in a peer-
reviewed journal, or an abstract that meets the requirements of the International Committee of Medical Journal 
Editors. A full report of the outcomes will be made public no later than three (3) years after the end of data 
collection.  

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16. REFERENCES  
 
1. 
El-Serag, H.B. and A.C. Mason, Rising incidence of hepatocellular carcinoma in the United States. N Engl 
J Med, 1999. 340(10): p. 745-50. 
 
2. 
Fong, Y., N. Kemeny, and T. Lawrence, Cancer of the Liver and Biliary Tree, in Principles and Practice of 
Oncology, V. DeVita, Hellman, S., Rosenberg, S., Editor. 2001. 
 
3. 
Landis SH, Murray T, Bolden S, Wingo PA.  Cancer Statistics, 1998.  CA Cancer J Clin 48:6-29. 1998. 
 
4. 
Solbiati L, Livraghi T, Goldberg SN, et al.  Percutaneous Radio-freequency ablation of hepatic metastases 
from colorectal cancer: Long-term results of 117 patients.  Radiology, 2001.  221:159-166. 
 
5. 
Dawson, L.A., et al., Escalated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for 
unresectable intrahepatic malignancies. J Clin Oncol, 2000. 18(11): p. 2210-8. 
 
6. 
Dawson, L.A., et al., Analysis of radiation-induced liver disease using the Lyman NTCP model. Int J Radiat 
Oncol Biol Phys, 2002. 53(4): p. 810-21. 
 
7. 
Dawson, L.A., R.K. Ten Haken, and T.S. Lawrence, Partial irradiation of the liver. Semin Radiat Oncol, 
2001. 11(3): p. 240-6. 
 
8. 
McGinn, C.J., et al., Treatment of intrahepatic cancers with radiation doses based on a normal tissue 
complication probability model. J Clin Oncol, 1998. 16(6): p. 2246-52. 
 
9. 
Lawrence, T.S., et al., The use of 3-D dose volume analysis to predict radiation hepatitis. International 
Journal of Radiation Oncology, Biology, Physics, 1992. 23(4): p. 781-8. 
 
10. 
Park, H., et al., Dose-response relationship in local radiotherapy for hepatocellular carcinoma. Int J Radiat 
Oncol Biol Phys, 2002. 54(1): p. 150-155. 
 
11. 
Cheng, J., et al., Radiation-induced liver disease after three-dimensional conformal radiotherapy for 
patients with hepatocellular carcinoma: dosimetric analysis and implication. Int J Radiat Oncol Biol Phys, 
2002. 54(1): p. 156-162. 
 
12. 
Cheng, J.C., et al., Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: 
clinical manifestation and dosimetric description. Radiother Oncol, 2002. 63(1): p. 41-5. 

Phase II Study of Protons for Liver Cancer    11.16.15 
 
 
 
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34 
 
13. 
Tokuuye, K, et al.  Gastrointestinal Malignancies in Proton and Charged Particle Radiotherapy, T.F. 
DeLaney and H.M. Kooy, Editors.  2007. 
 
14. 
Bujold, A, et al. Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced 
Hepatocellular Carcinoma, J. Clin Oncol. 2013. In press. 
 
 

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17. APPENDICES  
Appendix I: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly.  
5 
Dead. 
0 
Dead.