Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic Cholangiocarcinoma
Phase: PHASE3
Conditions: Stage III Intrahepatic Cholangiocarcinoma, Stage IVA Intrahepatic Cholangiocarcinoma
Sponsor: NRG Oncology

1                         NRG-GI001; version date March 20, 2017 
 
 
NRG ONCOLOGY 
 
NRG-GI001 
ClinicalTrials.gov NCT02200042 
 
RANDOMIZED PHASE III STUDY OF FOCAL RADIATION THERAPY FOR UNRESECTABLE, 
LOCALIZED INTRAHEPATIC CHOLANGIOCARCINOMA 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research 
Group, and SWOG. 
 
Principal Investigator/Radiation Oncology 
Theodore Hong, MD 
Massachusetts General Hospital 
100 Blossom Street 
Boston, MA 00214 
617-724-1159/Fax: 617-726-3603 
TSHONG1@mgh.harvard.edu  
 
Medical Oncology Co-Chair   
Andrew Zhu, MD 
Massachusetts General Hospital 
55 Fruit Street 
LH/POB, Room 232 
Boston, MA 00214 
617-643-3415/Fax: 617-724-3166 
azhu@partners.org 
 
Medical Physics Co-Chair   
Russell Ruo, MSc 
McGill University 
1650 Cedar Avenue 
Montreal, Quebec 
Canada H3G1A4 
514-934-8052/Fax: 514-934-8229 
russell.ruo@mcgill.ca  
  
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3198/Fax: 215-928-0153 
winterk@nrgoncology.org  
 
Radiation Oncology Co-Chairs  
Laura A. Dawson, MD 
Princess Margaret Cancer Centre 
University of Toronto 
610 University Avenue 
Toronto, ON  
Canada MSG 2M9 
416-946-2125/Fax: 416-946-6566 
Laura.dawson@rmp.uhn.on.ca  
 
Medical Oncology Co-Chair   
Milind Javle, MD 
University of Texas-MD Anderson Cancer Center 
1515 Holcombe Blvd., Box 0997 
Houston, TX 77030 
713-792-5435  
mjavle@mdanderson.org 
 
Medical Physics Co-Chair   
William Parker, MSc 
McGill University 
1650 Cedar Avenue 
Montreal, Quebec 
Canada H3G1A4 
514-934-8052/Fax: 514-934-8229 
william.parker@mcgill.ca  
 
 
 
 
 
 
 
 
 

2                         NRG-GI001; version date March 20, 2017 
 
 
 
NRG ONCOLOGY 
 
NRG-GI001 
 
RANDOMIZED PHASE III STUDY OF FOCAL RADIATION THERAPY FOR UNRESECTABLE, 
LOCALIZED INTRAHEPATIC CHOLANGIOCARCINOMA 
 
 
Protocol Agent (Not Applicable) (3/20/17) 
Agent 
Supply 
NSC # 
IND # 
 
 
 
Participating Sites 
 U.S. Only 
 Canada Only 
 U.S. and Canada 
 Approved International Member Sites 
 
 
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 3 
March 20, 2017 
April 10, 2017 
Amendment 2 
June 30, 2015 
July 13, 2015 
Amendment 1 
May 7, 2015 
June 1, 2015 
Activation 
September 29, 2014 
September 29, 2014 
Update 
September 2, 2014 
September 2, 2014 
Pre-Activation 
July 8, 2014 
September 2, 2014 
 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology. It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 

3                         NRG-GI001; version date March 20, 2017 
 
 
 
 
CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (3/20/17) 
For regulatory 
requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
 
Regulatory Submission 
Portal: (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-
tab under the Regulatory tab.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYST
EM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 

4                         NRG-GI001; version date March 20, 2017 
 
 
TABLE OF CONTENTS 
 
NRG-GI001 ................................................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................................................ 4 
SCHEMA  ...................................................................................................................................................... 6 
1.0 
INTRODUCTION ............................................................................................................................... 7 
1.1  
Intrahepatic Cholangiocarcinoma.................................................................................................. 7 
1.2  
Local-Regional Treatments for IHC .............................................................................................. 7 
1.3  
Gemcitabine/Cisplatin ................................................................................................................... 7 
1.4  
Radiation Therapy  ........................................................................................................................ 7 
2.0 
OBJECTIVES .................................................................................................................................. 10 
2.1 
Primary Objective  ....................................................................................................................... 10 
2.2 
Secondary Objectives  ................................................................................................................ 10 
3.0 
 PATIENT SELECTION .................................................................................................................. 10 
3.1 
Conditions for Patient Eligibility ................................................................................................... 10 
3.2 
Conditions for Patient Ineligibility  ............................................................................................... 11 
4.0 
 PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................... 11 
4.1 
Required Evaluations/Management  ........................................................................................... 11 
4.2 
Highly Recommended Evaluations/Management ....................................................................... 12 
5.0 
 REGISTRATION PROCEDURES .................................................................................................. 12 
5.1 
Digital RT Data Submission to NRG Oncology Using TRIAD ..................................................... 12 
5.2 
Pre-Registration Requirements for all Radiation Techniques  .................................................... 13 
5.3  
Regulatory Pre-Registration Requirements  ............................................................................... 14 
5.4  
Registration  ................................................................................................................................ 17 
6.0 
 RADIATION THERAPY/FUNCTIONAL IMAGING  ........................................................................ 17 
6.1 
Dose Specifications  .................................................................................................................... 18 
6.2 
Technical Factors ........................................................................................................................ 19 
6.3 
Localization, Simulation, and Immobilization  ............................................................................. 19 
6.4 
Treatment Planning/Target Volumes  ......................................................................................... 21 
6.5 
Critical structures dose constraints  ............................................................................................ 24 
6.6 
Compliance Criteria  .................................................................................................................... 25 
6.7 
Documentation and RT Quality Assurance Requirements  ........................................................ 27 
6.8 
Radiation Therapy Adverse Event Reporting .............................................................................. 28 
6.9 
Radiation Therapy Toxicity Assessment During Therapy ........................................................... 28 
6.10 
Radiation Modification Table ....................................................................................................... 29 
7.0 
 ADVERSE EVENT REPORTING REQUIREMENTS .................................................................... 30 
7.1 
Adverse Events (3/20/17) ............................................................................................................ 30 
7.2 
CTEP-AERS Expedited Reporting Requirements  ..................................................................... 31 
8.0 
 SURGERY ..................................................................................................................................... 33 
9.0 
 OTHER THERAPY ......................................................................................................................... 33 
9.1 
Permitted Supportive Therapy  ................................................................................................... 33 
9.2 
Non-permitted Supportive Therapy ............................................................................................. 33 
10.0 
TISSUE/SPECIMEN SUBMISSION  ............................................................................................... 33 
10.1 
Tissue/Specimen Submission ..................................................................................................... 33 
10.2 
Specimen Collection for Tissue Banking and Translational Research  ...................................... 34 
10.3 
Reimbursement ........................................................................................................................... 36 
10.4 
Confidentiality/Storage ................................................................................................................ 36 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 36 
11.1 
Study Parameters ....................................................................................................................... 36 
11.2 
Evaluation During Treatment ...................................................................................................... 36 
11.3 
Measurement of Response/Definition of Response ................................................................... 36 
11.4 
Criteria for Discontinuation of Protocol Treatment  ..................................................................... 37 
12.0 
DATA COLLECTION ....................................................................................................................... 38 
12.1 
Summary of Data Submission .................................................................................................... 38 
12.2 
Summary of Dosimetry Digital Data Submission ........................................................................ 38 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 39 

5                         NRG-GI001; version date March 20, 2017 
 
 
13.1 
Endpoints  ................................................................................................................................... 39 
13.2 
Stratification ................................................................................................................................ 39 
13.3 
Sample Size and Power Justification  ......................................................................................... 39 
13.4 
Analysis Plan  .............................................................................................................................. 40 
13.5 
Gender and Minorities ................................................................................................................. 42 
REFERENCES ............................................................................................................................................ 44 
APPENDIX I  ............................................................................................................................................... 46 
APPENDIX II ............................................................................................................................................... 49 
APPENDIX III .............................................................................................................................................. 50 
APPENDIX IV .............................................................................................................................................. 51 
APPENDIX V  .............................................................................................................................................. 52 
APPENDIX VI  ............................................................................................................................................. 54 
 
 
 
 
  

6                         NRG-GI001; version date March 20, 2017 
 
 
NRG ONCOLOGY 
 
NRG-GI001 
 
Randomized Phase III Study of Focal Radiation Therapy for Unresectable, Localized Intrahepatic 
Cholangiocarcinoma 
 
 
SCHEMA (3/20/17) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
⃰ Must have received 6 months of Gemcitabine/Cisplatin chemotherapy without progression.  If toxicity 
precludes 6 months of chemotherapy, at least 4 months of Gemcitabine/Cisplatin must have been 
administered. 
 
 
See Section 5.0 for credentialing requirements, Section 6.0 for radiation therapy details. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
 
Required Sample Size: 146 patients 
  
Questions that need to be answered at the time of study entry on the OPEN system are available at: 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1320  
 
 
 
 
Non-progressing 
patients who 
have completed 6 
months of 
Gemcitabine/ 
Cisplatin per 
institutional 
standard* 
 
 
 
 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
 
 
Tumor size  
(≤ 6cm vs. > 6cm) 
 
 
Satellite lesions 
(Yes vs. no)  
 
 
Months of chemo completed  
(4-5 vs 6) 
 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
 
Arm 1: 
Liver-directed Radiation 
Therapy  
 
 
Vs. 
 
Arm 2: 
Observation 
 
Randomization ratio 
(RT:Observation) = 2:1  

7                         NRG-GI001; version date March 20, 2017 
 
 
1.0 INTRODUCTION 
1.1  
Intrahepatic Cholangiocarcinoma 
Intrahepatic cholangiocarcinoma (IHC) is a rare gastrointestinal malignancy accounting for 5-20% 
of primary liver malignancies. The incidence of IHC is rising in the United States and Asia.  The 
prognosis of this disease remains dismal with a median survival of 19 months and long term 
survivors continue to be rare events (Shaib 2004; Endo 2008). This is partially due to the late 
manifestation of clinically significant signs or symptoms given the multiple drainage options 
around the tumor and the ability of the liver to compensate for the atrophic obstructed liver 
parenchyma. Complete resection remains the main treatment modality with curative intent. For 
patients with unresectable disease, the median survival is between 2.3 to 9 months (Endo 2008; 
Ohtsuka 2002).  Currently, the majority of intrahepatic cholangiocarcinoma patients are still 
unresectable (68%). Multiple intrahepatic tumors, locally advanced disease within the liver with 
vascular invasion, and nodal or distant metastatic disease are the most common reasons for 
unresectability (Endo 2008).  Multiple intrahepatic tumors, locally advanced disease within the 
liver with vascular invasion, and nodal or distant metastatic disease are the most common 
reasons for unresectability (Endo 2008).   
1.2  
Local-Regional Treatments for IHC 
Currently, the standard of care for unresectable IHC is a combination of chemotherapy with 
gemcitabine and cisplatin (gem/cis), based on the results of the ABC-02 trial demonstrating a 3 
month improvement in overall survival compared to gemcitabine alone (Valle 2010). Median PFS 
was improved from 5 months to 8 months. Interestingly, there is no current standard for local, 
liver-directed therapy, in spite of the observation that the primary tumor is the first site of 
progression in up to 70% of patients. 
 
Small single institution series have suggested that radiation therapy is beneficial to patients with 
IHC (Chen 2010; Tse 2008). However, the benefit of liver-directed radiation therapy has never 
been formally tested. 
1.3  
Gemcitabine/Cisplatin 
Gem/cisplatin as a control arm- chemotherapy backbone  
The ABC-02 trial was a phase III study which randomized 410 patients with advanced biliary 
cancer to gemcitabine vs. gem/cis.  Patients treated with gem/cis had an improvement in OS (8.1 
vs. 11.7 months, p<0.001) and PFS (5.0 vs. 8.0 months, p<0.001).  Based on this pivotal trial, 
gem/cisplatin is now the standard of care for unresectable biliary cancers. 
1.4  
Radiation Therapy (3/20/17) 
Radiation therapy for localized intrahepatic cholangiocarcinoma cancer   
The current literature for radiation therapy for unresectable, localized cholangiocarcinoma is 
limited.  Below is a review of the available literature identified in PubMed. 
 
The Fudan University Experience  
The role of radiation therapy for intrahepatic cholangiocarcinoma from Fudan University was first 
reported in 2006 (Zeng 2006) and updated in 2010 (Chen 2010).   As of the most recent update, 
84 patients with biopsy confirmed, unresectable intrahepatic cholangiocarcinoma were 
retrospectively evaluated.  Patients were deemed to have intrahepatic cholangiocarcinoma by 
IHC (CK 7, 19 + and CK 20, AFP, Hepa -) and negative evaluation by staging for other GI 
primaries.  Patients with Child-Pugh C cirrhosis were excluded from analysis.  In this study, 35 
patients received radiotherapy, and 49 patients did not.  There was no difference between the two 
groups in regards to age, gender, stage, size, multifocality, or size of tumor.  Radiation was given 
to the gross disease in 1.8-2.0 Gy/fraction to a dose of 30-60 Gy.  Fourteen percent of patients 
received less than 50 Gy, 60% received 50 Gy, and 26% of patients received over 50 Gy.  8.6% 
of patients achieved a radiographic complete response, and 28.5% achieved a partial response 
for a response rate of 37.1%. SD was observed in and additional 17 patients (48.6%).  Disease 

8                         NRG-GI001; version date March 20, 2017 
 
 
control was achieved at the time of first follow up in 85.7%.  One year survival for the radiation 
group and non-radiation groups were 38.5% versus 16.4%.  Two year survival for the radiation 
group and non-radiation groups were 9.6% versus 4.9%, respectively. Median survival times were 
9.5 ± 1.1 months versus 5.1 ± 0.3 months, respectively (log-rank P = 0.003).  These poor 
survivals are a reflection of the lack of use of chemotherapy in this study.  This study is severely 
limited by the heterogeneous population, the lack of chemotherapy, the retrospective nature, and 
heterogeneous radiotherapy dose.  However, this study suggests that radiotherapy may have 
some benefit in patients with intrahepatic cholangiocarcinoma 
 
SEER data 
A retrospective study of 3,839 patients with intrahepatic cholangiocarcinoma was evaluated from 
the Surveillance, Epidemiology, and End Results (SEER) database (Shinohara 2008).  Restricting 
analysis to patients who did not have surgery, patients receiving radiation had a median survival 
of 7 months, compared to 3 months with no radiation therapy.   Propensity score adjusted hazard 
ratios (controlling for age, race/ethnicity, stage, and year of diagnosis) remained significant for 
radiation therapy (HR = 0.67; CI 95% 0.58-0.76).  This analysis is limited by the lack of 
chemotherapy data and the retrospective nature of the study. 
 
Princess Margaret SBRT Phase I study 
A phase I study of 41 patients with primary liver tumors evaluated individualized stereotactic body 
radiotherapy (SBRT) (Tse 2008). Patients deemed not suitable for standard therapy, with Childs 
Pugh A cirrhosis were treated with a 6 fraction SBRT course individualized based on a 5%, 10%, 
and 20% risk of toxicity.  Thirty one patients had hepatocellular carcinoma (HCC) and 10 patients 
had intrahepatic cholangiocarcinoma.  The median dose delivered was 36 Gy (24-54 Gy). In the 
patients with intrahepatic cholangiocarcinoma, the median survival was 15.0 months, and the 1 
year overall survival was 58%.  Two out of ten patients with intrahepatic cholangiocarcinoma 
experienced unexpected transient biliary obstruction, presumably due to radiation edema. 
 
MGH/MDACC Phase II (ongoing, unpublished) 
Massachusetts General Hospital (MGH) has been treating patients with intrahepatic 
cholangiocarcinoma on two proton-based studies. In the first study (NCT 00465023), 15 patients 
with HCC, intrahepatic cholangiocarcinoma were treated on a pilot study, with doses ranging from 
45-75 Gy in 15 fractions. Following this study, a phase II study, currently ongoing, was initiated at 
MGH and MD Anderson (NCT 00976898).  On the phase II, patients with peripheral tumors 
received 67.5 Gy in 15 fractions. Patients with central tumors (defined as within 2 cm of the 
portahepatis) received 58.05 Gy in 15 fractions.  No concurrent chemotherapy was given. The 
phase II opened in April 2010 and to this point 57 patients have been enrolled.  Twenty one 
patients with IHC have been enrolled as of February 2013.  For this analysis, 21 patients have 
been treated and have had one set of 3 month staging scans.  With a median follow up 12 
months among surviving patients, a 1 and 2-year OS is 69% and 58% respectively and PFS is 
41% and 28% respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

9                         NRG-GI001; version date March 20, 2017 
 
 
 
 
Rationale for the 15 fraction conformal radiation alone schedule 
Conventional chemoradiation (50-54 Gy in 1.8-2.0 Gy/fraction with concurrent fluoropyrimidine) is 
the most widely used regimen for gastrointestinal cancers, but without surgery, the schedule has 
limited efficacy and ablative potential.  The SBRT approach used at Princess Margaret has 
ablative intent. However, given the biliary events seen in 20% of the intrahepatic 
cholangiocarcinoma patients, as well as the concern for late biliary strictures, the extreme 
hyprofractionated regimen has some potential safety issues. 
 
The 15 fraction schedule used in the MGH/MDACC phase II is associated with excellent efficacy. 
In the original pilot study, there were no local recurrences in the 15 patients treated (11 HCC, 3 
intrahepatic cholangiocarcinoma, 1 hepatic metastasis) with no late liver or biliary toxicity. 
   
 
 
58.5 Gy in 15 (yellow) vs. 67.5 in 15 (blue) - There are 50% local failures compared to 20% with 
67.5 Gy at 4 years based on the MDACC study.  (MDACC, 2002-2014 the results of this study 
have been submitted for publication.) 
 
(3/20/17) 
 
Overall Survival, 
MGH/MDACC phase II interim 
analysis (months) 

10                         NRG-GI001; version date March 20, 2017 
 
 
2.0  
OBJECTIVES 
 
 
2.1 
Primary Objective (3/20/17) 
2.1.1 
To evaluate liver-directed radiation therapy with respect to overall survival (OS) for patients with 
unresectable, localized intrahepatic cholangiocarcinoma. 
 
2.2  
Secondary Objectives (3/20/17) 
2.2.1. 
To evaluate liver-directed radiation therapy with respect to local control for patients with 
unresectable, localized intrahepatic cholangiocarcinoma. 
2.2.2 
To evaluate liver-directed radiation therapy with respect to adverse events for patients with 
unresectable, localized intrahepatic cholangiocarcinoma. 
2.2.3 
To evaluate liver-directed radiation therapy with respect to regional control for patients with 
unresectable, localized intrahepatic cholangiocarcinoma. 
2.2.4 
To evaluate liver-directed radiation therapy with respect to distant metastases for patients with 
unresectable, localized intrahepatic cholangiocarcinoma. 
2.2.5 
To evaluate liver-directed radiation therapy with respect to progression-free survival for patients 
with unresectable, localized intrahepatic cholangiocarcinoma. 
 
3.0  
PATIENT SELECTION (3/20/17) 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
Questions that need to be answered at the time of study entry on the OPEN system are available 
at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1320 
3.1 
Conditions for Patient Eligibility 
For questions concerning eligibility, please contact the study data manager. 
3.1.1 
Pathologically (histologically or cytologically) proven diagnosis of IHC without distant extrahepatic 
metastasis prior to study entry.  Patients with an adenocarcinoma suggestive of a 
pancreaticobiliary primary with radiographic findings consistent with an intrahepatic cholangio-
carcinoma are eligible. 
3.1.2 
Patient must have 1 lesion with a maximum AXIAL diameter of 12cm at the time of study entry. 
Up to 3 satellite lesions are permitted. Satellite lesions, are defined as lesions less than 2 cm that 
are within 1 cm of the periphery of the dominant lesion (GTV) are permitted. The satellite lesions 
are NOT included in the AXIAL diameter measurement. Regional Lymph Node involvement within 
the porta hepatis (as medial as SMV portal vein confluence) is permitted if nodes are deemed 
clinically positive (i.e. FDG avid) See Appendix V; 
 
3.1.3 
Appropriate stage for protocol entry, including no distant metastases, based upon the following 
minimum diagnostic workup: 
 
Pre–study entry Scan (REQUIRED for All Patients to confirm no progression): CT scan 
chest/abdomen/pelvis with multiphasic liver CT scan within 30 days prior to study entry. If CT 
contrast is contraindicated, CT chest without contrast and MRI of abdomen and pelvis is 
permitted (See Appendix IV and Section 4.1.5 for details); 
3.1.4 
Zubrod Performance Status 0-1 at the time of study entry; 
3.1.5 
Age ≥ 18; 
3.1.6 
CBC/differential obtained within 21 days prior to study entry, with adequate bone marrow function 
defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3;  
 
Platelets ≥ 75,000 cells/mm3;  
 
Total bilirubin <  2.5 mg/dl; 
 
AST (SGOT) and ALT (SGPT) < 5.0 X institutional upper limit of normal; 
 
Albumin ≥ 2.5mg/dl; 
 
Creatinine within normal institutional limits or creatinine clearance ≥ 60mL/min/1.73 m2 for 
subject with creatinine levels above institutional normal; 
 
Hemoglobin ≥ 9.0 g/dl. (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
9.0 g/dl is acceptable.) 

11                         NRG-GI001; version date March 20, 2017 
 
 
3.1.7 
Patient must provide study specific informed consent prior to study entry; 
3.1.8 
Negative bHCG prior to study entry if patient is pre or peri-menopausal. 
3.1.9     Must have received 6 months of Gemcitabine/Cisplatin chemotherapy without progression.  
Disease response to chemotherapy is also permitted.  If toxicity precludes 6 months of 
chemotherapy at least 4 months of Gemcitabine/Cisplatin must have been administered.   
3.2 
Conditions for Patient Ineligibility (3/20/17) 
3.2.1 
Multiple lesions that don’t meet the criteria as satellite lesions as defined in Section 3.1.2; 
3.2.2 
Extrahepatic metastases or malignant nodes beyond the periportal region.  Celiac, 
pancreaticoduodenal and para-aortic nodes> 2 cm are ineligible.  Note that benign non-
enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is 
permitted, even if the sum of enlarged nodes is > 2.0 cm;  
 
3.2.3 
Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal bleed at the 
time of study entry; 
3.2.4 
Prior radiotherapy to the region of the liver that would result in overlap of radiation therapy fields; 
3.2.5 
Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any time; 
3.2.6 
Direct tumor extension into the stomach, duodenum, small bowel or large bowel; 
3.2.7 
Prior invasive malignancy, excluding the current diagnosis, (except non-melanomatous skin 
cancer) unless disease free for a minimum of 3 years. (Note: carcinoma in situ of the breast, oral 
cavity, or cervix is all permissible); 
3.2.8 
Prior systemic chemotherapy for the study cancer other than gemcitabine/cisplatin; note that prior 
chemotherapy for a different cancer is allowable;  
3.2.9 
Currently receiving other anti-cancer agents; 
3.2.10 Participants who require anticoagulation should receive low-molecular weight or standard heparin 
and not warfarin;  
3.2.11 Prior surgery for the IHC.  (Liver resection is not allowed); 
3.2.12 Severe, active co-morbidity, defined as follows: 
 
Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 
months of study entry; 
 
Transmural myocardial infarction within the last 6 months of study entry; 
 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry; 
 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days prior to study entry;  
 
HIV positive with CD4 count < 200 cells/microliter. Note that patients who are HIV positive are 
eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) 
and have a CD4 count ≥ 200 cells/microliter at the time of study entry. Note also that HIV 
testing is not required for eligibility for this protocol; 
 
End-stage renal disease (ie, on dialysis or dialysis has been recommended). 
3.2.13 Pregnancy or women of childbearing potential and men who are sexually active and not 
willing/able to use medically acceptable forms of contraception; this exclusion is necessary 
because the treatment involved in this study may be significantly teratogenic; 
3.2.14 Grade 3 or higher peripheral neuropathy at the time of study entry. 
 
4.0  
PRETREATMENT EVALUATIONS/MANAGEMENT  
 
NOTE: This section lists baseline evaluations needed before the initiation of protocol 
treatment that do not affect eligibility. 
4.1 
Required Evaluations/Management (3/20/17) 
See Section 11.1; note that failure to perform one or more of these tests may result in 
assessment of a protocol violation.  
 
4.1.1 
Documentation of liver disease, including cirrhosis, Hepatitis history [Hepatitis B and Hepatitis C 
status, hemachromatosis, alcohol, autoimmune disease, non-alcoholic steatohepatitis (NASH)]; 

12                         NRG-GI001; version date March 20, 2017 
 
 
4.1.2 
CA19-9 and CEA within 21 days prior to study entry. 
4.1.3 
Alkaline phosphatase (ALP), phosphate, sodium, potassium, chloride, magnesium, calcium within 
21 days prior to study entry. 
4.1.4 
Documentation of any extrahepatic disease status, number of sites and sum of maximum 
diameter of extrahepatic disease. 
4.1.5 
Submission of IV contrast diagnostic or planning CT or MRI scan no later than 1 day after study 
entry (See Section 3.1.3 and Section 6.7 for details).  
For all patients, this scan must include:  
 
Contours of GTV (gross tumor volume = volume of all parenchymal and intrahepatic 
cholangiocarcinoma) 
 
Contours of the liver (whole liver including GTV)  
 
GTV Liver volume  
4.2 
Highly Recommended Evaluations/Management 
Note that these evaluations/interventions are highly recommended as part of good clinical care of 
patients on this trial but are not required.  
4.2.1 
If randomized to RT, consultation with interventional radiology or surgery for possible fiducial 
marker insertion and/or tissue expander placement to move tumor away from luminal GI 
structures if this is estimated to benefit the patient and center has expertise in these procedures.  
4.2.2     For all patients, the following criteria calculated from baseline CT or MR scans (see Section 4.1.5) 
should be met: 
 
Liver volume minus intrahepatic GTV > 700 cc. 
 
Intrahepatic tumor GTV/liver volume ratio <80%. 
 
Minimal distance from GTV to stomach, duodenum, small or large bowel > 1 cm. 
 
5.0  
REGISTRATION PROCEDURES 
Access requirements for OPEN, Medidata Rave, and TRIAD: 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and 
Access Management (IAM) account. This is the same account (user id and password) used for 
the CTSU members’ website. To obtain an active CTEP-IAM account, go to https://eapps-
ctep.nci.nih.gov/iam 
5.1 
Digital RT Data Submission to NRG Oncology Using TRIAD 
TRIAD is the American College of Radiology’s (ACR) image exchange application and it 
is used by NRG Oncology. TRIAD provides sites participating in NRG Oncology clinical 
trials a secure method to transmit DICOM RT and other objects.  TRIAD anonymizes and 
validates the images as they are transferred. 
 
TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be registered with 
The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP 
Identity and Access Management (IAM) account. Please refer to Section 5.0 of the 
protocol for instructions on how to request a CTEP-IAM account. 
 
To submit images, the site physics user must have been assigned the 'TRIAD site user' 
role on the relevant Group or CTSU roster. Users should contact your site Lead RA to be 
added to your site roster.  Users from other cooperative groups should follow their 
procedures for assignment of roster roles. 
 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will 
need to have the TRIAD application installed on his/her workstation to be able to 
submit images. TRIAD installation documentation can be found on the NRG 
Oncology/RTOG website Core lab tab.    

13                         NRG-GI001; version date March 20, 2017 
 
 
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD 
Support mailbox at TRIAD-Support@acr.org 
 
5.2 
Pre-Registration Requirements for all Radiation Techniques (3/20/17) 
 
For detailed information on the specific technology requirement required for this study, please 
refer to the table below and utilize the web link provided for detailed instructions. The check 
marks under the treatment modality columns indicate whether that specific credentialing 
requirement is required for this study. 
 
Proton therapy may be used on this protocol if the proton therapy treatment modality to be used 
has been approved by the Imaging and Radiation Oncology Core (IROC) Houston QA Center 
[formerly Radiological Physics Center (RPC)] and other credentialing procedures described 
above have been met.  Investigators using proton therapy must comply with the NCI proton 
guidelines for the Use of Proton Radiation Therapy in NCI Sponsored Cooperative Group Clinical 
Trials, which are available on the website of IROC Houston (http://irochouston.mdanderson.org). 
RT 
Credentialing 
Requirements 
 
 
Web Link for Procedures and Instructions: 
http://irochouston.mdanderson.org 
 
Treatment 
Modality 
Key Information  
 
SBRT 
3DCRT 
IMRT 
Proton 
Facility 
Questionnaire 
X 
X 
X 
X 
The IROC Houston electronic facility 
questionnaire (FQ) should be completed or 
updated with the most recent information about 
your institution. To access this FQ, email 
irochouston@mdanderson.org to receive your 
FQ link. 
Credentialing 
Status Inquiry 
Form 
X 
X 
X 
X 
To determine whether your institution needs to 
complete any further credentialing requirements, 
please complete the “Credentialing Status 
Inquiry Form” found under credentialing on the 
IROC Houston QA Center website 
(http://irochouston.mdanderson.org) 
Knowledge 
Assessment 
N/A 
N/A 
N/A 
N/A 
 
Benchmark 
Cases 
N/A 
N/A 
N/A 
N/A 
 

14                         NRG-GI001; version date March 20, 2017 
 
 
 
 
 
If the center is already credentialed for RTOG 1112 IGRT, no further credentialing is 
required, as long as the same techniques that were credentialed previously are to be used 
for this study.  The center must still complete and update a Facility Questionnaire. 
 
5.3  
Regulatory Pre-Registration Requirements (3/20/17) 
5.3.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Prior to the recruitment of a patient for this study, investigators must be registered members of a 
lead protocol organization.  Each investigator must have an NCI investigator number and must 
maintain an “active” investigator registration status through the annual submission of a complete 
investigator registration packet (FDA Form 1572 with original signature, current CV, 
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original 
signature) to the Pharmaceutical Management Branch (PMB), CTEP, DCTD, NCI.  These forms 
are available on the CTSU registered member web site 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, please 
contact the CTEP Investigator Registration Help Desk by email at 
<pmbregpend@ctep.nci.nih.gov. 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) 
application is a web-based application intended for use by both Investigators (i.e., all physicians 
Phantom 
Irradiation 
X 
X 
X 
X 
A liver phantom study provided by the IROC QA 
Center Houston must be successfully 
completed. Instructions for requesting and 
irradiating the phantom are found on the IROC 
Houston web site 
(http://irochouston.mdanderson.org). Note that 
only the most sophisticated technique needs to 
be credentialed, e.g., if credentialed for IMRT, 
3DCRT may be used. Tomotherapy, Cyberknife 
and proton treatment delivery modalities must 
be credentialed individually.   
IGRT 
Verification 
Study 
X 
X 
X 
X 
The institution must submit a sample of 
verification images showing their ability to 
reproducibly register daily IGRT information with 
a planning CT dataset (i.e., the GTV falls within 
the CT simulation defined PTV). The patient (“as 
if patient”) used for this study must have a target 
(or mock target) in the liver. The information 
submitted must include 2 IGRT datasets (from 2 
treatment fractions) for a single patient and must 
employ the method(s) that will be used for 
respiratory control for patients entered from a 
particular institution (e.g. abdominal 
compression, breath hold, etc). This information 
with a spreadsheet (the spreadsheet is available 
on the IROC Houston web site: 
http://irochouston.mdanderson.org 
Credentialing Notification Issued to: 
Institution 
 
 
 
 
IROC Houston QA Center will notify the 
institution and NRG Oncology that all desired 
credentialing requirements have been met. 

15                         NRG-GI001; version date March 20, 2017 
 
 
involved in the conduct of NCI-sponsored clinical trials) and Associates (i.e., all staff involved in 
the conduct of NCI-sponsored clinical trials).Associates will use the CTEP-IAM application to 
register (both initial registration and annual re-registration) with CTEP and to obtain a user 
account. Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with CTEP as an 
Investigator, which must be completed before a CTEP-IAM account can be requested.) An active 
CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ web site. Additional information 
can be found on the CTEP web site at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  For questions, please contact 
the CTEP Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients. Assignment of site registration status in the CTSU 
Regulatory Support System (RSS) uses extensive data to make a determination of whether a site 
has fulfilled all regulatory criteria including but not limited to: an active Federal Wide Assurance 
(FWA) number, an active roster affiliation with the Lead Network or a participating organization, a 
valid IRB approval, and compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not 
required to submit IRB approval documentation to the CTSU Regulatory Office. For sites using 
the CIRB, IRB approval information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform the CTSU which CIRB-
approved institutions aligned with the Signatory Institution are participating in the study. 
 
 
Downloading Site Registration Documents:   
Site registration forms may be downloaded from the NRG-GI001 protocol page located on the 
CTSU members’ web site.  Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the NRG Oncology link to expand, then select trial protocol NRG-GI001 
 
Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided.   
 
Requirements for NRG-GI001 site registration: 
 IRB approval letter (For sites not participating via the NCI CIRB); local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption Form, or 
combination is accepted.  
 CTSU RT Facilities Inventory Form (if applicable) 
     NOTE: Per NCI policy all institutions that participate on protocols with a radiation 
therapy component must participate in the Image and Radiation Oncology Core 
(IROC) monitoring program.  If this form has been previously submitted to CTSU it 
does not need to be resubmitted unless updates have occurred at the RT facility. 
 IRB/REB approved consent (International and Canadian sites only: English and native 
language versions*) 
*Note: Institutions must provide certification/verification of IRB/REB consent 
translation to NRG Oncology (described below). 

16                         NRG-GI001; version date March 20, 2017 
 
 
 IRB/REB assurance number renewal information as appropriate. 
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab  Regulatory 
Submission Portal 
When applicable, original documents should be mailed to:  
CTSU Regulatory Office 
             1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 Click on the Regulatory tab 
 Click on the Site Registration tab 
 Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Non-English Speaking Canadian and Non-North American Institutions: 
 
*Translation of regulatory documents is critical. The institution is responsible for all translation 
costs. All regulatory documents, including the IRB/REB approved consent, must be provided in 
English and in the native language. Certification of the translation is optimal but due to the 
prohibitive costs involved NRG Oncology will accept, at a minimum, a verified translation. A 
verified translation consists of the actual REB approved consent document in English and in the 
native language, along with a cover letter on organizational/letterhead stationery that includes the 
professional title, credentials, and signature of the translator as well as signed documentation of 
the review and verification of the translation by a neutral third party. The professional title and 
credentials of the neutral third party translator must be specified as well. 
 
5.3.2 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
Prior to clinical trial commencement, Canadian institutions must also complete and submit the 
following documents via the Regulatory Submission Portal to the CTSU Regulatory Office: 
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form.  
5.3.3 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
 
For institutions that do not have an approved LOI for this protocol: 
International sites must submit an LOI to NRG Oncology to receive approval to participate in this 
trial. For more details see link below: 
http://www.rtog.org/Researchers/InternationalMembers/LetterofIntent.aspx .  
For institutions that have an approved LOI for this protocol: 
 
All requirements indicated in your LOI Approval Notification must be fulfilled prior to enrolling 
patients to this study 

17                         NRG-GI001; version date March 20, 2017 
 
 
5.4  
Registration (5/7/15) 
5.4.1  
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have 
been met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have signed 
and dated all applicable consents and authorization forms.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). 
OPEN is a web-based registration system available on a 24/7 basis. To access OPEN, the site 
user 
must 
have 
an 
active 
CTEP-IAM 
account 
(check 
at 
< 
https://eappsctep. 
nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating organization 
roster. See Section 5.0 for obtaining a CTEP-IAM account. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN 
tab on the CTSU members’ web site https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
 
All patients have signed an appropriate consent form and HIPPA authorization form (if 
applicable).  
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information.  Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' side of the CTSU website at 
https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
 
In the event that the OPEN system is not accessible, participating sites can contact web support 
for assistance with web registration: websupport@acr.org or call the Registration Desk at (215) 
574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax 
in the eligibility checklist and will need the registering individual’s e-mail address and/or return fax 
number. This information is required to assure that mechanisms usually triggered by the OPEN 
web registration system (e.g. drug shipment and confirmation of registration) will occur.  
 
6.0  
RADIATION THERAPY/FUNCTIONAL IMAGING (3/20/17)  
Note: See Section 5.1 and 12.2 for information on installing TRIAD for submission of digital 
RT data prior to enrolling patients. 
 
Note: IGRT is required (see Section 6.3.3) 
 
Note: 3DCRT, IMRT, SBRT, Cobalt based IMRT/IGRT under MRI guidance, and Protons are 
allowed (see Section 6.2).  
 
Note: Pre-randomization imaging submission is required (see Section 6.7.1) 
 
Note: This protocol requires pre-approval of the contours and plan PRIOR TO DELIVERY 
of radiation treatment for the first 2 patients for both photons and/or protons (see Section 
6.7.2). Subsequent patient case submission is allowed only after approval of the first 
patient. 
 
Radiation therapy must begin within 6 weeks of study entry  

18                         NRG-GI001; version date March 20, 2017 
 
 
 
6.1 
Dose Specifications (3/20/17) 
The primary tumor(s) and any satellite lesions must be treated.  Prophylactic nodal radiation is 
not permitted.  A maximum of 3 satellite lesions are permitted. Please refer to Section 3.1.2 for 
eligibility requirements of primary tumor and satellite lesions. 
6.1.2 
Treatment Schedule:  Treatment will be delivered in 15 daily fractions. Patients will be treated 
weekdays. RT is to be delivered over 15 fractions delivered over 19-26 elapsed days. Variation 
Acceptable is 27-34 days. The allowable break between consecutive fractions is up to 3-4 days.  
 
 
 
 
6.1.3 
Prescription Dose  (3/20/17) 
 
Photons:   
The unit absorbed dose specifications is the Gray (Gy). The prescription dose may be 67.5 Gy, 
58.05 Gy, 52.5 Gy, 45 Gy, or 37.5 Gy in 15 fractions, based on normal tissue constraints (see 
Section 6.1.5). The lowest allowed prescription dose to the PTVs is 37.5 Gy.  
 
 
PTV Prescription Dose (Gy) 
Fraction size (Gy) 
37.5 
2.5 
45 
3.0 
52.5 
3.5 
58.05 
3.87 
67.5 
4.5 
 
 
Protons 
 
The unit for dose specification dose is Gy(RBE).  Doses are expressed in units of RBE-weighted 
absorbed dose, DRBE.  For protons the RBE is taken to be 1.1.  DRBE = 1.1 x D, where D 
represents the absorbed dose in Gy.  The prescription dose may be 67.5 Gy (RBE), 58.05 Gy 
(RBE), 52.5 Gy (RBE), 45 Gy (RBE), or 37.5 Gy (RBE) in 15 fractions, based upon normal tissue 
constraints (see section 6.1.5). The minimal planned prescription dose to PTVs is 37.5 Gy 
(RBE).  
 
PTV Prescription Dose (Gy RBE) 
Fraction size (Gy RBE) 
37.5 
2.5 
45 
3.0 
52.5 
3.5 
58.05 
3.87 
67.5 
4.5 
 
6.1.4 
Dose Specifications  
 
 
 
Photons 
 
The prescription isodose must encompass 95% of PTV (PTV VRx = 95%). The dose to multiple 
PTVs within the same patient may vary. If there are multiple PTVs, each should be planned for 
one of the prescription doses listed above, with each specific covering isodose planned to 
encompass 95% of each PTV (PTV VRx ≥ 95%). If a relative dose distribution is used the 
normalization (100% dose) is to the PTV receiving the highest prescription dose.   The highest 
allowable doses to the target volumes that maintain normal tissue constraints should be 
used (see Section 6.1.5). A goal is that 100% of the CTV is encompassed by the prescription 
dose (CTV VRx = 100%). 
 
 
Protons 

19                         NRG-GI001; version date March 20, 2017 
 
 
 
The prescription isodose (PTV VRx = 95%) for the target with the highest prescribed dose must 
encompass 95% of PTV (PTV VRx ≥ 95%).  The dose to multiple PTVs within the same patient 
may vary. If there are multiple PTVs, each must be planned for one of the prescription doses 
listed above, with each specific covering isodose planned to encompass at least 95% of each 
PTV (PTV VRx ≥ 95%). If a relative dose distribution is used for normalization (100% dose) is to 
the PTV receiving the highest prescription dose.   The highest allowable doses to the target 
volumes that maintain normal tissue constraints should be used (see Section 6.1.5). A goal 
is that 100% of the CTV is encompassed by the prescription dose (CTV VRx = 100%).   
 
6.1.5 
Dose Prescription Allocation Table (3/20/17) 
 
The Liver PTV dose prescription is based on the volume of normal tissues irradiated (correlated 
with mean liver dose), as well as the proximity of stomach, duodenum, small and large bowel (GI 
luminal structures) to the target volumes, as normal tissue constraints must be maintained in this 
study (see OAR does constraints in Section 6.5.1).  
 
 
In the absence of adjacent GI luminal structures that may limit dose, the PTV dose prescription 
should be as high as possible based on mean liver dose (MLD, defined as the mean dose to the 
liver minus all GTVs), with 5 potential dose levels.  
 
 
 
Priority dose constraint 
Mean Liver Dose, MLD 
(Gy or Gy (RBE)) 
PTV Prescription Dose 
(Gy or Gy (RBE)) 
22 Gy 
67.5Gy 
24 Gy 
58.05 Gy 
24 Gy 
52.5 Gy 
24 Gy 
45 Gy 
27 Gy 
37.5 Gy 
 
6.1.6 
If multiple PTVs are treated, the MLD should be evaluated with the prescription dose 
corresponding to the highest dose level of any PTV treated.  Queries should be directed to the 
study PI. 
6.2 
Technical Factors (3/20/17) 
6.2.1 
Equipment  
Photons – 3DCRT, IMRT 
Megavoltage equipment with photons of at least 6 MV, capable of daily image guidance (IGRT), 
and intensity modulation IMRT with multileaf collimator is required.  (Cobalt based IMRT/IGRT is 
permitted only if using the View Ray system under MRI guidance.)  In the case of robotic based 
delivery, treatment with cones, iris, or MLC are allowed, however, the institution must be 
credentialed for the specific mode of delivery used.  Inverse-planned IMRT, inverse-planned arc 
therapy, forward planned IMRT and conventional 3D-CRT are permitted. 
 
Protons  
The proton delivery system must deliver protons of sufficient energy to cover the target.   
6.2.2 
Image guided radiation therapy (IGRT): Daily pre-treatment IGRT is mandatory (See Section 
6.3.3). 
6.3 
Localization, Simulation, and Immobilization (3/20/17) 
 
6.3.1 
Immobilization 
 
Custom immobilization is recommended (e.g. With vacuum immobilization, patient positioning 
boards, knee cushions, and/or breath hold immobilization with active breathing control).  
6.3.2 
Simulation Image Acquisition 
 

20                         NRG-GI001; version date March 20, 2017 
 
 
A liver protocol CT (See Appendix IV) must be obtained for treatment planning. Treatment 
planning CT scans are required to define GTV. Multi-phasic IV contrast is recommended for the 
planning CT (arterial phase and/or delayed phase imaging recommended for GTV delineation, 
and venous phase for portal vein thrombosis delineation).  If oral contrast is used at simulation, 
similar timing and volume of oral contrast is suggested to be used at the time of treatment. 
 
Exhale breath hold CT or average phase CT (from 4D CT) may be used as the baseline CT for 
radiation therapy planning.  CT scans obtained during free breathing are strongly discouraged, 
but may be used if breath hold scanning is not possible for individual patients or if breathing 
motion is < 5 mm.  CT scans used for target delineation are recommended to be multi-phase IV 
contrast scans obtained in exhale breath hold.  Exhale breath hold is preferred as it most often is 
closer to the average position than inhale breath hold, and exhale is more reproducible than 
inhale.  If IV contrast scans cannot be obtained at the time of radiation planning, IV contrast CT 
scans from diagnostic radiology may be fused to the primary planning dataset to aid in target 
definition.  
 
If contraindications to IV CT contrast exist, contrast multiphase MR can be used to define GTV 
and may be fused to the primary planning dataset to aid in target definition. 
   
Any other relevant diagnostic imaging can be imported to the planning system to aid in target 
delineation. 
 
All scans used for target delineation should be fused to each other so that the livers are 
registered to each other for target delineation. Registration will be performed with the best fit 
liver-to-liver image registration, focusing on the region of the GTVs if deformation or rotation 
occurs between scans. Imaging details are in Appendix IV. 
 
  
It is recommended that arterial vascular contrast from the CT dataset be converted to water 
equivalent density if used for planning.  
 
A maximum slice thickness of 3 mm is allowed. 
 
6.3.3 
Localization / IGRT (3/20/17) 
 
IGRT images should be obtained on the treatment unit immediately before treatment to ensure 
proper alignment of the geometric center (i.e., isocenter) of the simulated fields. These IGRT 
images may include 1) three-dimensional (3D) or 4-dimensional (4D) volumetric images (either 
fan- or cone-beam CT with Megavoltage (MV) or kilovoltage (kV) x-ray) or 2) paired kV 2D 
images with fiducial markers. Planar 2D MV images are not permitted to be used as the only tool 
for IGRT. Daily IGRT using MRI is permitted when using Cobalt based IMRT/IGRT under MRI 
guidance. In all cases, the NRG Oncology/RTOG Image Guidance Guidelines must be followed.  
6.3.4 
Breathing Motion Assessment  
 
Measurement of target/liver breathing motion is required, unless breath hold is to be used for liver 
immobilization during treatment.  Motion may be assessed using 4D CT, fluoroscopy and/or cine 
MR.   
 
 
Breathing motion management is recommended if breathing motion is > 5 mm.   
 
 
Breathing motion assessed on 4DCT and adequately treated with PTV margins < 20mm is 
permitted without treatment time motion management (gating, tracking, ABC, etc.). 
 
If breath hold is used for liver immobilization, Liver position reproducibility in breath hold should 
be measured using fluoroscopy, CT or MRI. 
 
6.3.5 
Proton Specific Guidelines 
Localization, Simulation, and Immobilization Guidelines 

21                         NRG-GI001; version date March 20, 2017 
 
 
Patients must be simulated on a CT scanner, which has been commissioned for protons.  Proton 
compatible immobilization devices are required, as is a motion management system. 
Immobilization devices will not extend to the lower thorax so as to minimize proton entrance 
through them. For contrast-enhanced CT simulations (either breath-hold or free-breathing), the 
initial CT sequence will be the non-contrast scan for proton planning purposes and the 
subsequent scan will be the contrast scan for contouring. All oral contrast Hounsfield 
units will be overridden during planning and replaced with a Hounsfield unit of 1 (electron 
density = 1). Hounsfield units for lipiodol, fiducials and clips will remain unchanged during 
planning. Where possible the proton beam will not exit into GI mucosa. Breathing motion 
management is recommended if breathing motion is > 5 mm. Breathing motion assessed on 
4DCT and adequately treated with PTV margins < 20mm is permitted. Shadowing of dose along 
a beam behind radio-opaque fiducials is negligible and can be discounted during multi-beam 
proton planning. Where fiducials are used for breath-hold set-up, reproducibility of breathing 
amplitude on days of treatment compared to simulation will be confirmed prior to treatment 
delivery. 
 
A maximum slice thickness of 3 mm is allowed. 
 
Radiation doses shall be prescribed using the protocol specified definitions for GTV and CTV.  
For set-up uncertainties and target motion, additional margin (including proximal and distal), 
smearing, and range of modulation will be added on a per beam basis.  Proton treatment plans 
will be based upon a CT scanner for which the institution has defined an imaging protocol for 
protons which establishes the relationship between the CT number and the stopping power ratios. 
 
Proton resources for this protocol include: 
Michael T. Gillin, PhD 
Professor 
The University of Texas 
MD Anderson Cancer Center 
Department of Radiation Physics 
Phone: 713-563-2507/Fax: 713-563-2545 
mgillin@mdanderson.org 
 
Theodore Hong, MD 
Massachusetts General Hospital 
100 Blossom Street 
Boston, MA 00214 
617-724-1159/Fax: 617-726-3603 
TSHONG1@mgh.harvard.edu  
 
6.4 
Treatment Planning/Target Volumes (3/20/17) 
6.4.1 
The GTV is defined as all parenchymal (GTVp) and nodal IHC disease (GTVn) visualized on 
contrast enhanced CT and/or MRI, most often best seen on arterial phase (as peripheral 
hyperintensity) and/or venous or delayed phase (as hypointensity relative to liver) contrast 
enhancement imaging.  
 
Nodal and parenchymal lesions can be combined if they are to be treated to the same dose into 
one GTVpn.   Nodal lesions are to be treated to 40.5 Gy in 15 fx, unless the primary prescription 
dose is 37.5 Gy, in which case 37.5 Gy is acceptable.  Nodal lesions may also be underdosed to 
37.5 Gy to maintain normal tissue constraints. 
 
The prescription dose should be annotated to each GTV after the final plan is complete (e.g. 
GTV_45 for a 45 Gy target). 
 
6.4.2 
The Clinical Target Volume (CTV) 

22                         NRG-GI001; version date March 20, 2017 
 
 
 
It is expected that there will be no expansion from GTV to CTV for the majority of cases.  
However, CTV expansions to include regions at high risk for microscopic disease are permitted. 
Such CTVs may be treated to a minimal dose (37.5 Gy) or as high as the prescription dose for 
that GTV, at the investigator’s discretion.  The nomenclature follows that of the GTVs, (e.g. 
CTV_45 for the GTV_45). 
 
6.4.3 
The Planning Target Volume (PTV)  
Photons 
 
The Photon PTV will provide a margin around each CTV to compensate for set-up and internal 
organ motion. PTV nomenclature should follow CTV nomenclature guidelines. For example, 
PTV_45 for the PTV around the CTV_45.  
 
A minimum PTV margin of 4 mm around each CTV is required in all directions (for example if 
active breathing control is used with excellent reproducibility).  
 
The maximum permitted PTV margin of 20 mm is expected to be used uncommonly.  PTV 
margins ≤ 10 mm are a goal.  
 
Asymmetric PTV margins are permitted. The actual PTV used will depend on motion 
management used, the patients’ motion and reproducibility. PTVs should not be manually 
modified or cropped due to proximity of adjacent OARs. The PTVs include the ITV (internal target 
volume) that accounts for motion. 
 
Protons 
The Proton PTV will provide a margin around each CTV to compensate for uncertainties including 
set-up and internal organ motion, aperture margin definitions, compensator smearing, range of 
individual beams, and modulation width of the SOBP. PTV nomenclature should follow CTV 
nomenclature guidelines, in a similar manner to the photon PTV. For example, PTV_45 for the 
PTV around CTV_45.  For protons, the annotated dose refers to the RBE weighted dose.  Dose 
will be reported in Gy (RBE), where 1 Gy(RBE) = proton dose Gy x RBE (radiobiological effective 
dose), RBE = 1.1. 
 
A minimum PTV margin of 4 mm around the CTV is required in all directions (for example if active 
breathing control is used with excellent reproducibility).  
 
The maximum permitted PTV margin is 20 mm.  
 
Asymmetric PTV margins are permitted, depending on institution motion management, individual 
patients’ motion and reproducibility.  
 
Additionally, the effect of variations in the set-up of the target with respect to tissue 
inhomogeneities (e.g., employing compensator smearing technique, beam-specific PTV etc.), or 
range uncertainties (e.g., by expanding the prescribed range and modulation, to create distal and 
proximal field margins) should be addressed in the design of treatment fields for each beam 
direction. 
 
 
The proton distal target margin range: As suggested in ICRU Report 78, paragraph 5.1.4.4, an 
adjustment must be made within the beam-design algorithm to take into account the margins 
needed to account for uncertainties along the beam direction (i.e. range uncertainties) and those 
included in the traditional PTV (i.e. lateral uncertainties).  The proton distal target margin range 
will be determined as follows: 
 
Proton Distal Target Margin Range = distal aspect of the CTV + Range Calculation 
Uncertainty (generally 3.5%) + Set-up Margin + Internal Margin 
 
6.4.4 
Critical Normal Structures  (3/20/17) 

23                         NRG-GI001; version date March 20, 2017 
 
 
Note: All required structures must be labeled as listed below in the table for digital RT data 
submission.  Resubmission of data may be required if labeling of structures does not 
conform to the standard DICOM name listed. 
 
The following nomenclature is required:  
Description 
Name 
GTVn_37.5 
GTVn_3750 
GTVn_40.5 
 GTVn_4050 
GTVp_37.5 
GTVp_3750 
GTVp_45 
GTVp_4500 
GTVp_52.5 
GTVp_52.5 
GTVp_58.05 
GTVp_5805 
GTVp_67.5 
GTVp_6750 
CTVn_37.5 
CTVn_3750 
CTVn_40.5 
CTVn_4050 
CTVp_37.5 
CTVp_3750 
CTVp_45 
CTVp_4500 
CTVp_52.5 
CTVp_52.5 
CTVp_58.05 
CTVp_5805 
CTVp_67.5 
CTVp_6750 
PTVn_37.5 
PTVn_3750 
PTVn_40.5 
PTVn_4050 
PTVp_37.5 
PTVp_3750 
PTVp_45 
PTVp_4500 
PTVp_52.5 
PTVp_52.5 
PTVp_58.05 
PTVp_5805 
PTVp_67.5 
PTVp_6750 
Liver 
Liver 
Liver minus GTV 
Liver_nonGTV 
Esophagus 
Esophagus 
Stomach 
Stomach 
Duodenum 
Duodenum 
Small bowel* 
SmallBowel 
Large bowel* 
LargeBowel 
Cord* 
SpinalCord 
Cord PRV5 (cord +5mm)* 
SpinalCord_05  
R kidney 
Kidney_R 
L kidney 
Kidney_L 
Kidneys 
Kidneys 
External Patient Contour 
External  
Optional contours to be contoured if > 30 Gy is planned to include these 
organs include: 
Outer 0.5 cm of the body surface 
SkinOAR 
Chest wall* 
ChestWall 
Gall bladder 
GallBladder 
Common bile duct 
CommonBileDuct 
Heart 
Heart 

24                         NRG-GI001; version date March 20, 2017 
 
 
Inferior vena cava  
IVC 
 
* At minimum, these structures are required to be contoured at the level of the PTV and over any 
region receiving > 10 Gy. 
 
An upper abdominal/liver atlas, posted at the NRG Oncology/RTOG website, may be used as a 
guide for contouring. Note, all portions of the duodenum are recommended to be contoured. 
 
6.4.5 
Heterogeneity Corrections 
 
All dose distributions, photon and proton, shall include corrections for tissue heterogeneities.  For 
considerations regarding planning CT and heterogeneity correction, see Section 6.3.2 (for photon 
planning) and Section 6.3.5 (for proton planning). 
 
6.4.6 
Planning Technique 
Photons 
A minimum of 5 beams is recommended if using fixed field photon techniques.  Beam angles may 
be individualized to minimize the path length through the liver and through adjacent organs at 
risk. 
 
Protons 
A minimum of two beams should be used. Beam angles should avoid mucosal structures and 
minimize the amount of liver in the beam path. 
 
6.4.7 
Planning Goals 
Goals of planning are to maximize dose to the target volumes (see Section 6.5), while 
maintaining all normal tissue constraints (as defined in Section 6.5).  Reducing the maximal dose 
to all luminal gastrointestinal normal tissues should be a planning priority to reduce the risk of 
gastrointestinal toxicity.  
 
6.5 
Critical structures dose constraints (5/7/15) 
Note: All required structures must be labeled as listed in Section 6.4.4 for digital RT data 
submission.  Resubmission of data may be required if labeling of structures does not 
conform to the standard DICOM name listed. 
 
Dose values in this section should be read as physical dose for photons, or RBE-weighted  
dose for protons, in 15 fractions (assuming RBE = 1.1). Please see the table below. 
 
6.5.1  
Mandatory dose constraints 
 
Organ at risk 
Dose (Gy or Gy RBE) 
Esophagus max (to 0.5cc) 
D0.5cc ≤45 
Stomach max (to 0.5cc) 
D0.5cc ≤40 
Duodenum max (to 0.5cc) 
D0.5cc ≤45 
Small bowel max (to 0.5 cc) 
D0.5cc ≤45 
Large bowel max (to 0.5 cc) 
D0.5cc ≤48 
Cord + 5 mm max (0.5cc) 
D0.5cc ≤37.5  
Kidneys: Bilateral mean dose 
D0.5cc ≤ 12 Gy 
Note: If one kidney with mean dose > 12 Gy, the remaining (or only) kidney must have V12Gy < 10%. 

25                         NRG-GI001; version date March 20, 2017 
 
 
 
6.5.2 
Other dose constraints (not mandatory)  
 
Organ at risk 
Dose (Gy or Gy RBE) 
Stomach (to 5cc) 
D5cc ≤36 
Duodenum (to 5cc) 
D5cc ≤36 
Small Bowel (to 5cc) 
D5cc ≤36 
Heart (to 30cc) 
D30cc ≤45 
Great vessel (to 0.5cc) 
D0.5cc ≤70 
Skin (to 0.5cc) 
D0.5cc ≤48 
Chest wall (0.5cc) 
D0.5cc ≤70 
Gallbladder (0.5cc) 
D0.5cc ≤70 
Common bile duct* 
D0.5cc ≤70 
*Common bile duct max (0.5 cc) < 70 Gy (even though the bile duct is not often well visualized, it 
is always within the portal region and may be within high dose volumes for caudate lobe targets, 
so efforts to reduce hot spots in this region are warranted). 
6.6 
Compliance Criteria (3/20/17) 
The review process for this protocol is aimed at assuring correct contouring of target and critical 
structures, as well as appropriate planning. These reviews should avoid violations and deviations 
for this protocol.  Each treatment shall be judged according to the protocol guidelines, with 
variations and deviations defined below: 
 
6.6.1  
Delivery Compliance Criteria   
 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Start date after study entry 
within 6 weeks 
6-8 weeks 
>8 weeks 
Total elapsed treatment time to 
completion 
19-26 days 
27-34 days 
> 34 days 
Treatment interruptions 
3-4 days 
4-7 days 
>7 days 
 
6.6.2  
GTV Contouring Compliance 
 
Per protocol: No edits required 
 
Variation acceptable: Variations in GTV or CTV other than deviation unacceptable 
 
 
Deviation unacceptable: Definite HCC or enhancing thrombosis not contoured within GTV 
6.6.3 
PTV Compliance 
 
 
PTV Contouring 
 
 
Minimum PTV Margin 
Maximum PTV Margin 
Per Protocol 
≥ 4 mm 
≤ 20 mm 
Variation Acceptable 
3 – 4 mm 
20 – 25 mm 
Deviation Unacceptable 
< 3 mm 
> 25 mm 
 
PTV Dosimetry 
 
 
Target coverage for each PTV should be considered on its own. If there are multiple tumors, the 
primary (dominant) PTV should be labeled #1 (e.g. PTVp 4500). 
 
 

26                         NRG-GI001; version date March 20, 2017 
 
 
 
The intent is for prescription dose to cover 95% of each PTV (VRx>95%). If PTVs are not treated 
as per guidelines, this is a deviation unacceptable. The PTV should be treated to as high a 
dose as possible, respecting normal tissue constraints (as per Section 6.1.5), as a dose 
response has been observed.  Modifying required PTVs due to close proximity of adjacent 
OARs is not permitted. 
 
The following table describes variations and deviations in the prescription dose (dose covering 
95% of the PTV, D95%, PTV). Treating “per protocol” should always be the planning intent.   
 
 
PTVs (around GTVs) 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
V100%(%) 
≥95% 
≥90% 
<90% 
D99%(%)* 
≥95% 
≥90% 
<90% 
D1%(%)* 
≤ 130% 
≤ 140% 
>140% 
D0.03cc(%)* 
≤ 150% 
≥ 150% 
Prescription Dose (Gy) 
≥ 37.5 Gy 
< 37.5 Gy 
 
 
 
* The Dx(%) criteria are given in terms of  % of PTV prescription dose. (e.g. 100% = 45 Gy for 
a prescription of 45 Gy for PTVp_4500) 
 
Note: For PTVs < 2cm from the porta-hepatic, the maximum dose is 58.05 Gy 
 
Note: For nodal PTVs, the dose must be 40.5 Gy unless the prescription dose is 37.5 Gy or if 
normal tissue constraints require underdosing to 37.5 Gy 
 
Nodal PTVs (around non-GTVs CTVs) 
 
 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
V100%(%) 
≥95% 
≥85% 
<85% 
D99%(%)* 
≥95% 
≥85% 
<85% 
D1%(%)* 
≤ 130% 
≤ 140% 
>140% 
D0.03cc(%)* 
≤ 150% 
≥ 150% 
Prescription Dose (Gy) 
≥ 37.5 Gy 
< 37.5 Gy 
 
 
 
* The Dx(%) criteria are given in terms of  % of PTV prescription dose. (e.g. 100% = 45 Gy for 
a prescription of 45 Gy for PTV_45) 
 
Note: For PTVs < 2cm from the porta-hepatic, the maximum dose is 58.05 Gy 
 
Note: For nodal PTVs, the dose must be 40.5 Gy unless the prescription dose is 37.5 Gy or if 
normal tissue constraints require underdosing to 37.5 Gy 
 
Dose values in this section should be read as physical dose for photons, or RBE-weighted 
dose for protons (assuming RBE = 1.1).  
 
Note that lower doses than the dose-allocation schedule are acceptable if they are required due 
to adjacent GI luminal structures that may limit the deliverable dose 
 
6.6.4 
Compliance for Critical Structures (organs at risk, OARs) 
 

27                         NRG-GI001; version date March 20, 2017 
 
 
If non-hepatic OARs limit the prescription dose, the highest dose (from the 5 prescription doses 
listed in Section 6.1.5) should be used, while maintaining OAR dose constraints.  
 
Non-liver OARs 
Per Protocol 
Variation 
Acceptable 
Deviation 
Unacceptable 
Esophagus max (to 0.5 
cc) 
D0.5cc ≤ 45 Gy 
D0.5cc ≤ 48 Gy 
 
D0.5cc > 48 Gy 
 
Stomach max (to 0.5 cc) 
D0.5cc ≤ 40 Gy 
D0.5cc ≤ 45 Gy 
 
D0.5cc > 45 Gy 
 
Duodenum max (to 0.5 
cc) 
D0.5cc ≤ 45 Gy 
D0.5cc ≤ 48 Gy 
 
D0.5cc > 48 Gy 
 
Small bowel max (to 0.5 
cc) 
D0.5cc ≤ 45 Gy 
D0.5cc ≤ 48 Gy 
 
D0.5cc > 48 Gy 
 
Large bowel max (to 0.5 
cc) 
D0.5cc ≤ 48 Gy 
D0.5cc ≤ 51 Gy 
 
D0.5cc > 51 Gy 
 
Cord + 5 mm max 
(0.5cc) 
D0.5cc ≤ 37.5 
Gy 
D0.5cc ≤ 40 Gy 
 
D0.5cc > 40 Gy 
 
Kidneys: Bilateral mean 
dose 
Dmean ≤ 12 Gy 
Dmean ≤15 Gy 
Dmean  > 15 Gy 
Note 1: Dose distributions not meeting the “Variation Acceptable” dose limits 
will be scored at Deviation Unacceptable 
 
Note 2: Dose values in these tables should be read as physical dose for 
photons, or RBE-weighted dose for protons (assuming RBE = 1.1). 
 
 
Prescription dose 
Liver (minus GTV) mean dose, Dmean 
Per protocol 
Variation acceptable 
Deviation acceptable 
67.5 Gy 
22 Gy 
 ≤ 22.2 Gy 
> 22.2 Gy 
58.05 Gy 
24 Gy 
≤ 24.2 Gy 
> 24.2 Gy 
52.5 Gy 
24 Gy 
≤ 24.2 Gy 
> 24.2 Gy 
45 Gy 
24 Gy 
≤24.2 Gy 
> 24.2 Gy 
37.5 Gy 
27 Gy 
≤ 27.2 Gy 
> 27.2 Gy 
Dose values in these tables should be read as physical dose for photons, or RBE-
weighted dose for protons (assuming RBE = 1.1). 
 
 6.7 
Documentation and RT Quality Assurance Requirements (5/7/15) 
 
All digital data submission will be uploaded using TRIAD (see Section 12.2). 
 
6.7.1 
Pre-Randomization Imaging Submission for All Patients (including non-radiation patients) 
 
For all patients randomized, submission of IV contrast CT or MR must be submitted within one 
day of registration. This imaging may be done in radiation planning CT and/or may be done on 
diagnostic CT or MR imported to a radiation planning system or any platform that allows organ 
segmentation and data transfer.  The liver volume and the IHC and/or vascular thrombosis should 
be contoured. Any differences in the segmentation of tumor or liver or in the tumor: liver volume 
calculation will be recorded.   
6.7.2 
Pre-Treatment and Timely Review of RT Plans (5/7/15) 
The first two photon and/or proton cases to be treated at the site on this protocol will have a pre-
treatment review of their plans, i.e. the individual plan needs to be approved PRIOR to delivering 
any protocol RT treatment for patient or subsequent patients. These pre-treatment reviews are 
aimed at providing feedback from the co-chairs and IROC Philadelphia on the institution’s 
imaging, contours and treatment plan. After a pre-treatment review by the PI, suggestions 
regarding protocol RT compliance will be forwarded to the participating institution.  

28                         NRG-GI001; version date March 20, 2017 
 
 
 
In order to accomplish these reviews, digital data must be submitted in a rapid fashion. Three 
business days are required to complete a pre-treatment review. Feedback for the first registered 
patient must be received before the second patient is registered, and feedback for the second 
patient must be approved before the third patient is registered.  Following approval of a minimum 
of two cases, all subsequent cases will undergo a timely review.  More pre-treatment reviews will 
be required if deviations are seen in these reviewed plans. Thus, complete digital data must be 
submitted in a timely manner– at least 3 (business) days prior to planned start of therapy for pre-
treatment reviews and within 5 (business) days post RT completion for timely reviews.  All 
subsequent plans are reviewed in a timely review. Based on the results of any of the reviews 
described above, a request for additional pre-approval reviews might be necessary. 
 
 
Liver protocol CT scan and/or MR showing the extent of the tumor with contrast is required to be 
submitted. If multiple phases of CT and/or MR imaging, and/or if diagnostic CTs or MR imaging, 
are helpful for target delineation, multiple phase imaging datasets should be submitted. A 
maximum of three datasets per patient is to be submitted. These datasets should be submitted, 
registered as they were used for target delineation, which should be with the best fit liver-to-liver 
image registration, focusing on the region of the PTVs if deformation or rotation occurs between 
scans. 
6.7.3 
IGRT Data Review (5/7/15) 
IGRT images in treatment position for every fraction (and a table of subsequent “shifts”) are 
required to be archived at the site for possible future evaluation. 
6.7.4 
Treatment Interruptions 
 
Treatment interruptions should be clearly documented in the patient’s treatment record.  Total 
treatment time is recommended to be 19 days, with allowable total duration between 19 days and 
26 days (see Section 6.6.1). 
6.7.5 
Quality Assurance Documentation For Patients Not Treated 
 
In patients randomized to the RT arm who do not receive radiation, the intended and/or best 
treatment plan should be submitted with an explanation for why the patient did not start radiation 
therapy. 
6.7.6 
Planned Interim Analyses of Quality Assurance 
After the first 50 patients are enrolled and/or 25 patients are randomized to the RT arm 
(whichever comes first), the Radiation Oncology Chair and Co-Chair, along with a delegated team 
from IROC Houston, will summarize all QA results. All submitted imaging datasets for both arms 
of the study will be reviewed as well as imaging, contouring and IHC liver strata determination. 
Following this analysis, modifications to education material and/or the protocol to help prevent 
violations and deviation for future patients, may be recommended.   
 
Secondary reviews will occur after the first 100 and after all patients are enrolled, again with a 
plan to improve education material and/or the study if needed, with individual feedback to 
participating institutions. 
6.8 
Radiation Therapy Adverse Event Reporting 
See Section 7.6 for details on adverse event reporting. 
6.9 
Radiation Therapy Toxicity Assessment During Therapy 
The criteria used for grading toxicities that occur on this study is the Common Toxicity Criteria 
(CTC) version 4.0.  
 
Common (20-100%) 
 Fatigue (which generally goes away after the radiation therapy is completed) 
 Skin irritation, redness, itchiness, discomfort  
 
Occasional (4-20%) 

29                         NRG-GI001; version date March 20, 2017 
 
 
 Nausea, vomiting (during therapy) – more common if stomach or gastrointestinal 
track irradiated 
 Gastric, esophagus, small bowel or large bowel irritation/ulceration, bleeding, fistula, 
obstruction or changes in motility following therapy (may require medications or 
surgery) (<10% permanent changes) 
 Chest wall pain, rib fracture (< 10%) 
 Non-classic RILD includes elevation of liver enzymes and/or any decline in liver 
function within 12 weeks from start of therapy (~20%).  RILD can lead to liver failure 
that could lead to death. There is an increased risk of liver toxicity in patients with 
large tumors and in patients with pre-existing liver disease. 
 
Rare, but serious (<3%) 
 Radiation-induced liver disease (RILD) (<5%). Classic RILD is a clinical diagnosis of 
anicteric ascites, hepatomegaly and elevation of alkaline phosphatase relative to 
other transaminases that may occur 2 weeks to 3 months following radiation to the 
liver.   
 Permanent thrombocytopenia (<1%); this may lead to bleeding 
 Kidney injury (<1%); this may lead to changes on imaging and more rarely the need 
for medication. 
 
Patients will be assessed at least once during radiation therapy for toxicity (as per Appendix I).  
Radiation therapy will continue as planned as long as there is no grade 3 or 4 toxicity, bilirubin is 
<3 mg/dL, Child score is Child Pugh ≤7 and the treating physician recommends continuation.  
Otherwise, a delay in radiation therapy should occur with possible continuation of radiation if 
toxicity resolves as per Section 6.10. 
 
6.10 
Radiation Modification Table 
 
TOXICITY 
MODIFICATION 
Hematologic Toxicities 
grade 1 or 2 
Continue radiation 
grade 3  
Hold radiation until ≤ grade 2, then continue 
grade 4 
Hold radiation 1 week and until ≤ grade 2, then continue 
Gastrointestinal Toxicities 
grade 1 or 2 diarrhea 
Continue radiation 
grade ≥ 3 diarrhea 
Hold radiation until improves to ≤ grade 2, then resume  
grade 1 or 2 nausea or 
vomiting 
Initiate anti-emetics prior to radiation and as needed and 
continue radiation 
grade 3 nausea or vomiting 
Hold radiation until improves to ≤ grade 2, then resume 
with anti-emetics prior to radiation and as needed 
Hepatic Dysfunction 
bilirubin 1.3-3.0 mg/dL 
Continue radiation 
bilirubin > 3.0 mg/dL 
Hold radiation until improves to ≤ 3.0, then resume 
grade 1 or 2 AST or ALT 
Continue radiation 

30                         NRG-GI001; version date March 20, 2017 
 
 
grade 3, < 10x ULN AST or 
ALT 
Continue radiation 
grade 3, > 10x ULN AST or 
ALT 
Hold radiation until improves to ≤ grade 2, then resume  
grade 4 AST and ALT 
Hold radiation for one week and until improves to ≤ grade 
2, then resume  
Other non-hematologic Toxicities 
grade 1, 2 
Continue radiation 
grade 3  
Hold radiation until improves to ≤ grade 2, then resume 
grade 4 
Discontinue radiation 
 
 
7.0  
ADVERSE EVENT REPORTING REQUIREMENTS (3/20/17) 
 
7.1 
Adverse Events (3/20/17) 
 
This study will utilize the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 for adverse event (AE) reporting.  The CTCAE version 4.0 is located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.0. 
 
All adverse events (AEs) as defined in the tables below will be reported via the CTEP Adverse 
Event Reporting System (CTEP-AERS) application accessed via the CTEP web site 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1389817585865 
. 
 
7.1.1 
Adverse Events (AEs)  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related.  Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered related 
to the medicinal (investigational) product (attribution of unrelated, unlikely, possible, probable, or 
definite). (International Conference on Harmonisation [ICH], E2A, E6).  
7.1.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited reporting 
criteria defined in the table in section 7.6 will be reported in the CTEP-AERS.  SAEs that require 
24 hour CTEP-AERS notification are defined in the expedited reporting table in section 7.6.  
Contact the CTEP-AERS Help Desk if assistance is required. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in 
any of the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect;  
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy 
of a study participant must be reported via CTEP-AERS in an expedited manner. 

31                         NRG-GI001; version date March 20, 2017 
 
 
  
7.1.3 
Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in 
patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system 
within 30 days of AML/MDS diagnosis. 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 
 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
7.2 
CTEP-AERS Expedited Reporting Requirements (3/20/17) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported in CTEP-AERS, 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup  
 
Submitting a report via CTEP-AERS serves as notification to NRG and satisfies NRG 
requirements for expedited adverse event reporting. 
 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway.  
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Operations Center at 215-574-3191, for instances when Internet fails. Once internet 
connectivity is restored, an AE report submitted by phone must be entered electronically into 
CTEP-AERS.  
 
 
CTEP-AERS-24 Hour Notification requires that an CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-
AERS 24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. 
Serious adverse events that require 24 hour CTEP-AERS notification are defined in the 
expedited reporting table below. 
 
 
Supporting source document is not mandatory.  However, if the CTEP-AERS report 
indicates in the Additional Information section that source documentation will be provided, 
then it is expected.  If supporting source documentation accompanies an CTEP-AERS 
report, include the protocol number, patient ID number, and CTEP-AERS ticket number 

32                         NRG-GI001; version date March 20, 2017 
 
 
on each page. Contact the NRG Operations Center for submission details at 215-574-
3191. 
 
A serious adverse event that meets expedited reporting criteria outlined in the following 
table but is assessed by the CTEP-AERS System as “expedited reporting NOT required” 
must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must 
bypass the “NOT Required” assessment; the CTEP-AERS System allows submission of 
all reports regardless of the results of the assessment.  
 
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the 
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE 
section of the appropriate case report form (see Section 12.1). 
 
 
Arm 1 during RT:  Any Phase Study Utilizing Radiation Therapy (including chemoRT studies)1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalizatio
n 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite require 

33                         NRG-GI001; version date March 20, 2017 
 
 
reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 
Grade 3 adverse events 
 
 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials:  
 
For Arm 2, expedited adverse event reporting is not applicable; routine adverse event reporting on 
the case report form fulfills safety reporting requirements for all adverse events. 
 
 
8.0  
SURGERY 
Not applicable to this trial. 
 
9.0  
OTHER THERAPY  
9.1 
Permitted Supportive Therapy (3/20/17) 
 
All supportive therapy for optimal medical care will be given per institutional standards  
 
9.2 
Non-permitted Supportive Therapy 
 
None 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (3/20/17) 
NOTE: Patients must be offered the opportunity to participate in the correlative 
components of the study, such as tissue/specimen submission or quality of life 
assessment.  
 
If the patient consents to participate in the tissue/specimen component of the study, the site is 
required to submit the patient’s specimens as specified in Section 10.1 of the protocol. Note: 
Sites are not permitted to delete the tissue/specimen component from the protocol or from the 
sample consent. 
10.1 
Tissue/Specimen Submission  
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. NRG Oncology encourages participants in protocol 
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank – San 
Francisco provides tissue specimens to investigators for translational research studies. 
Translational research studies integrate the newest research findings into current protocols to 
investigate important biologic questions. In this study, tissue will be submitted to the NRG 
Oncology Biospecimen Bank for the purpose of tissue banking and translational research 
(recommended). 
 
For patients who have consented to participate in the tissue/blood component of the study (See 
sample informed consent). 

34                         NRG-GI001; version date March 20, 2017 
 
 
10.2 
Specimen Collection for Tissue Banking and Translational Research (3/20/17)   
The following must be provided in order for the case to be evaluable for the NRG Oncology 
Biospecimen Bank – San Francisco:  
10.2.1 One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it 
does not have to be the diagnostic slide itself.) 
10.2.2 A corresponding paraffin-embedded tissue block of the tumor (the block must match the H&E 
being submitted) or a 2 mm diameter core of tumor tissue, punched from the tissue block 
containing the tumor with a punch tool and submitted in a plastic tube labeled with the surgical 
pathology number. Note: A kit with the punch, tube, and instructions can be obtained free of 
charge from the Biospecimen Bank. Block or core must be clearly labeled with the pathology 
identification number and block number that correspond to the Pathology Report. 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.2.3 A Pathology Report documenting that the submitted block or core contains tumor. The report 
must include the NRG protocol number and patient’s case number. The patient’s name and/or 
other identifying information should be removed from the report. The surgical pathology numbers 
and date of procedure information must NOT be removed from the report. 
10.2.4 A Specimen Transmittal (ST) Form clearly stating that tissue is being submitted for the NRG 
Oncology Biospecimen Bank; if for translational research, this should be stated on the form. The 
form must include the NRG protocol number and patient’s case number.  
 
Serum, plasma, whole blood, and urine will be collected at study entry. In addition Serum and 
Plasma should be collected at 2 months from randomization and at documented progression. The 
following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen 
Transmittal (ST) Form documenting the date of collection of the biospecimen; the NRG protocol 
number, the patient’s case number, time point of study, and method of storage, for example, 
stored at -80 C, must be included. 
 
See Appendix VI for processing and shipping instructions 
 
10.2.5 Storage Conditions 
Store frozen specimens at -80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday). 
 
Please indicate on the ST Form the storage conditions used and time stored. 
 
10.2.6 Specimen Collection Summary (3/20/17) 
 
Specimens for Tissue Banking for Translational Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
At study entry 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A paraffin-embedded 
tissue block of the 
At study entry 
Paraffin-embedded 
tissue block or punch 
Block or punch 
shipped ambient 

35                         NRG-GI001; version date March 20, 2017 
 
 
primary tumor taken 
before initiation of 
treatment or a 2 mm 
diameter core of tissue, 
punched from the tissue 
block with a punch tool  
biopsy (must match 
the H&E slide being 
submitted)   
 
SERUM: 5-10 mL of 
whole blood in 1 red-top 
tube and centrifuge 
1) At study entry 
2) At 2 months from 
randomization  
3) At documented 
progression 
 
Frozen serum 
samples containing a 
minimum of 0.5 mL 
per aliquot in 1 mL 
cryovials (five ) 
Serum sent frozen on 
dry ice via overnight 
carrier 
PLASMA: 5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
1) At study entry 
2) At 2 months from 
randomization 
3) At documented 
progression 
 
Frozen plasma 
samples containing a 
minimum of 0.5 mL 
per aliquot in 1 mL 
cryovials (five) 
Plasma sent frozen on 
dry ice via overnight 
carrier 
Whole blood for DNA: 5-
10 mL of anticoagulated 
whole blood in EDTA 
tube #2 (purple/lavender 
top) and mix 
At study entry 
 
Note: If site missed this 
collection time point 
they may collect whole 
blood for DNA at a later 
time point instead but 
must note this on the 
ST Form. 
Frozen whole blood 
samples containing 1 
mL per aliquot in 1ml 
cryovials (three-five) 
Whole blood sent 
frozen on dry ice via 
overnight carrier 
10-20 mL clean-catch 
urine   
 
At study entry 
Two 5-10 mL urine 
aliquots in 2 sterile 15 
ml polypropylene 
centrifuge tubes.  
Store frozen at  
-
-
 
Urine sent frozen on 
dry ice via overnight 
carrier 
 
 
10.2.7 Submit materials for Tissue Banking and Translational Research as follows: 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco- Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen 
Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271;  NRGBB@ucsf.edu 
 

36                         NRG-GI001; version date March 20, 2017 
 
 
10.3 
Reimbursement 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per 
the requirements/methods specified by the NCTN Program. This information will be made 
available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) 
portal system. OPEN will serve as the registration system for all patient enrollments onto NCI-
sponsored NCTN trials, including this study, which will be transitioned into the new Program from 
the NCI-sponsored Cooperative Group Clinical Trials Program 
10.4 
Confidentiality/Storage  
(See the Patient Tissue Consent Frequently Asked Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for 
further details.) 
10.4.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s 
case number only. The NRG Oncology Biospecimen Bank – San Francisco database only 
includes the following information: the number of specimens received, the date the specimens 
were received, documentation of material sent to a qualified investigator, type of material sent, 
and the date the specimens were sent to the investigator. No clinical information is kept in the 
database. 
10.4.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, 
unless the patient has consented to storage for future studies. If at any time the patient withdraws 
consent to store and use specimens, the material will be returned to the institution that submitted 
it. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters 
See Appendix I 
11.2 
Evaluation During Treatment 
11.2.1 Once PD has occurred, patients need to follow the study on-treatment calendar.  Documentation 
of all subsequent therapies should occur. The follow-up schedule post-treatment is outlined in 
Appendix I.  
11.3 
Measurement of Response/Definition of Response  
11.3.1 See Appendix I (Study Parameter Table). Note, response in the irradiated volume is challenging 
to assess before 3 months post radiation therapy due to radiation change in the surrounding liver. 
Even at 3 months, changes in the surrounding liver around the IHC may represent radiation 
treatment change, rather than tumor progression. Thus, review of images by experienced 
radiologists is required, as is importance of relaying radiation information to the radiologists, to 
avoid inaccurate labeling of progression when liver changes are due to radiation effect on the 
liver. 
 
It is strongly recommended to use the same method of assessment (i.e. comparable scanners 
and imaging techniques) from one scan to the subsequent scans. For example, multi-phasic CT 
scans should be used with the same slice thickness for each follow-up scan. It would not be 
appropriate to compare a pre-treatment non-contrast liver MRI on a 0.5T scanner with 0.5 cm 
slice thickness to a post-treatment gadolinium enhanced MRI on a 3T scanner with 0.2 cm slice 
thickness (nor vice versa). If a patient develops a contraindication to CT IV contrast, then contrast 
MR may be used to follow the patient. If a patient develops a contraindication to MR IV contrast, 
then non-contrast MR and/or US is recommended for follow-up. Imaging details are outlined in 
Appendix IV.  

37                         NRG-GI001; version date March 20, 2017 
 
 
11.3.2 Response will be evaluated in this study using the international criteria proposed in the Reviewed 
Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1 (Eur J Cancer: 
2009: 45:228-247). Response will be assessed locally, with no planned central review. 
 
Overall response will be measured (based on assessment of target lesions), as well as irradiated 
lesion response (defined as response of the target measurable disease included in the radiation 
volume).  
 
Measurable disease is defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded), e.g. liver lesions ≥ 10mm by CT scan with slice 
thickness no greater than 5 mm, nodes ≥ 15mm in short axis by CT.   All tumor measurements 
should be recorded in millimeters. 
 
Non-measurable disease is defined as all other lesions (or sites of disease), including small 
lesions (longest diameter < 10 mm or pathologic lymph node ≥ 10mm and ≤ 15 mm) and any 
vascular thrombosis.  Other non-measureable disease includes ascites, pleural effusions. 
 
11.3.3 Response criteria: Evaluation of target lesions 
Target lesions:  All measureable lesions up to a maximum of two lesions per organ and 
five lesions in total, representative of all involved organs.  Target lesions should be 
selected on the basis of their size (longest diameters). 
 
Target irradiated lesions (for Radiation arm only): All measureable lesions up to a 
maximum of two lesions in the liver (including satellite), within the irradiated volume.  
Target lesions should be selected on the basis of their size (longest diameters) and their 
suitability for accurate repeated measurements.  The sum of longest diameters (in any 
dimension) of target lesions will be used to characterize the objective tumor response.  
 
Complete response (CR): Disappearance of all measurable target lesions. Any 
pathological nodes (whether target or non-target) must have reduction in short axis to < 
10mm. 
 
Partial response (PR): At least 30% decrease in the sum of the longest diameters of the 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive disease (PD): At least 20% increase in sum of the longest diameters of 
target lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  The appearance of one or 
more new lesions is also considered progression. Unequivocal, unambiguous 
progression of non-measurable disease is included as PD. Because of radiation changes 
may be confused for local progression, local progression of the irradiated must be seen 
on two consecutive scans, for a minimum total relative increase of 20% AND a minimum 
of 5 mm. 
 
11.4 
Criteria for Discontinuation of Protocol Treatment (3/20/17)  
 
Progression of disease as defined in Section 11.3.3; 
 
Unacceptable adverse events, as specified in Sections 6.0 and/or 7.0. 
 
Pregnancy 
 
Interruption in Radiation therapy >14 days  
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 

38                         NRG-GI001; version date March 20, 2017 
 
 
12.0 
DATA COLLECTION 
 
This study will utilize Medidata Rave® for remote data capture (RDC) of all data. Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate roles 
in RSS.  To access iMedidata/Rave see Section 5.0 of the protocol. 
 
Each person responsible for data entry must be on the NRG Oncology roster in order to receive 
access to Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS (Regulatory Support System), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 
from iMedidata (iMedidata-Notification@mdsol.com) to activate their account.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) using 
their CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner 
of the iMedidata page.  Please note, site users will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed.  Trainings will be in the form of 
electronic learnings (elearnings) and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen.   
 
Users that have not previously activated their iMedidata/Rave accounts will also receive a 
separate invitation from iMedidata to activate their account.  Account activation instructions are 
located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account 
Activation and Study Invitation Acceptance).  Additional information on iMedidata/Rave is 
available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the 
CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.   
12.1 
Summary of Data Submission (3/20/17) 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 
future studies using similar agents. Adverse events are reported in a routine manner at scheduled 
times during the trial using Medidata Rave. Additionally, certain adverse events must be reported 
in an expedited manner for more timely monitoring of patient safety and care. See section 7.5 and 
7.6 for information about expedited and routine reporting.   
 
Summary of Data Submission: Refer to the CTSU website. 
 
  
 
 
12.2 
Summary of Dosimetry Digital Data Submission (5/7/15) 
(Submit to TRIAD; see Section 5.1 for account access and installation instructions) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) ALL CASES 
 
Digital Data Submission – Baseline Diagnostic CT/MRI or Treatment Planning 
CT with IV contrast submitted to TRIAD  
Within 1 day of 
randomization 
Digital data submission includes the following: 
 
Contours of Liver and IHC and /or vascular thrombosis 
ARM 1 ONLY 
ITEM 
 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Treatment Plan submitted to TRIAD 
exported from treatment planning machine by Physicist 
 
CT data, critical normal structures, all GTV, CTV, and PTV contours 

39                         NRG-GI001; version date March 20, 2017 
 
 
 
Digital beam geometry for composite beam sets 
 
Doses for composite  sets of concurrently treated beams 
 
Digital DVH data for all required critical normal structures, GTV, CTV, 
and PTVs for total dose plan  
 
All required structures MUST be labeled per the Table in Section 
6.4.4 
 
The “NRG-GI001 Datasheet” is available in the Forms section of the 
web site 
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?stu
dy=1320. Submit via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, complete an online 
digital data transmission form (DDSI) located in the Core Lab Tab on the 
web site at    http://www.rtog.org/CoreLab/TRIAD.aspx 
 
 
 
Note: All simulation and portal films and/or digital film images will be kept by 
the institution and only submitted if requested. 
 
 
 
Final Dosimetry Information 
Within 1 week 
of RT end 
Radiotherapy Form  
Daily Treatment Record  
 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM 
IMAGES WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF 
REQUESTED. 
 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Endpoints (3/20/17) 
13.1.1 Primary Endpoint 
 
Overall survival (failure: death due to any cause) 
13.1.2 Secondary Endpoints 
 
Local progression (failure: per definition in Section 11.3.3) 
 
Regional progression (failure: progression of existing or appearance of new nodal 
disease, per definition in Appendix V) 
 
Distant metastases (failure: appearance of distant metastases) 
 
Progression-free survival (failure: local, regional, and/or distant progression, and death 
due to any cause) 
 
Adverse events (evaluated using CTCAE v 4.0) 
13.2 
Stratification (3/20/17) 
 
Patients will be stratified before randomization with respect to maximum tumor size (≤ 6cm vs. >6 
cm), presence of satellite lesions (yes vs. no), and months of chemotherapy completed (4-5 vs. 
6). The permuted block randomization treatment allocation schema described by Zelen (1974) will 
be used because it balances patient factors other than institution. 
 
13.3 
Sample Size and Power Justification (3/20/17) 
13.3.1 The primary hypothesis of the study is to determine if liver-directed radiation therapy results in a 
change in OS in patients with unresectable, localized intrahepatic cholangiocarcinoma. Patients 
who have received 4-6 months of gem/cis will be randomized between the radiation and no 
radiation treatment arms in a 2:1 fashion respectively. 
 
The required sample size for the primary endpoint of OS is based on the following conditions: 

40                         NRG-GI001; version date March 20, 2017 
 
 
 
 
OS times are exponentially distributed with (at least approximately) constant hazards in 
both treatment arms 
 
The control arm will have a 2-year OS of 18% (monthly hazard of 0.0714) 
 
The experimental arm will have a 2-year OS of 40% (monthly hazard of 0.0382) 
 
Hazard ratio (experimental/control) = 0.53 
 
Two-sided test at α=0.05 
 
Statistical power of 85% 
 
4 years of accrual and 1 year of follow-up 
 
Two interim significance tests and a final test based on the Lan DeMets alpha/beta 
spending functions [Lan 1983] 
 
Based on the conditions above and using the group sequential design method (Pocock 1977) 
with two interim analyses, 134 randomized patients are needed to obtain the 102 OS events 
required to detect the hypothesized increase in OS.  Guarding against ineligibility or lack-of-data 
rate of up to 8%, the targeted accrual of randomized patients is 146.   
 
13.3.2 Treatment other than the treatment arm to which the patient was randomized is not permitted per 
the protocol and will be considered non-compliant. However, as this will not prevent treatment 
crossovers (patients receiving the treatment to which they were not randomized) from occurring 
and the primary endpoint analyses will be done based on the arm to which the patient was 
randomized and the rate of treatment crossovers will be closely monitored.   
 
Table 1 shows the impact for 5%, 10%, and 15% crossover from the control arm to the 
experimental arm.  If the crossover rate falls between 5% and 15%, NRG Oncology will discuss 
with NCI the potential of amending the trial in order to adjust for this crossover, so as to maintain 
the original study parameters.  If the crossover rate reaches or exceeds 15%, NRG Oncology will 
discuss with NCI the feasibility of continuing the trial. 
 
Table 1: Impact of Crossover from control arm to experimental arm 
 
 
 
Crossover 
Rate 
Adjusted 5-yr 
Experimental 
Rate 
Type I Error 
(0.05 by 
Design) 
Increase in Accrual Time 
to Maintain Original 
Parameters 
 
 
5% 
0.389 
0.072 
4 mths 
 
 
10% 
0.378 
0.10 
8 mths 
 
 
15% 
0.367 
0.12 
14 mths 
 
 
13.3.3 Patient Accrual 
Patient accrual is projected to be 3 randomized cases per month, with a ramp-up period in the 
first 6 months. The expected monthly accrual in months 1 through 3 and months 4 through 6 
following amendment activation are 0 and 1, respectively. Assessment of accrual compliance will 
be based on the NCI Ph III accrual rules and will be monitored by the NRG Oncology Data 
Monitoring Committee (DMC).   If the total accrual during months 13 through 18 of the study is ≤ 
20% of the targeted accrual (< 4 cases in total), then the protocol will be discontinued per NCI-
CTEP accrual guidelines for phase III studies. If the total accrual during months 13 through 18 is 
between 21% and 49% (4 to 8 cases), then the protocol will continue to accrue subjects and will 
be evaluated again at the end of month 24.  If the accrual during months 22 through 24 is at least 
50% of the targeted accrual (≥ 5 cases in total), the NCI-CTEP accrual guidelines for phase III 
studies will have been met and the study will continue accrual; otherwise, the study will be 
discontinued.  
13.4 
Analysis Plan (3/20/17) 
13.4.1  Statistical Methods: 

41                         NRG-GI001; version date March 20, 2017 
 
 
Overall survival (OS) and progression-free survival (PFS) will be estimated by the Kaplan-Meier 
method [Kaplan 1958]. The distributions of OS and PFS estimates between the two arms will be 
compared using the log rank test [Mantel 1966].  OS and PFS times will be measured from the 
date of randomization to the date of death or last follow-up.  The Cox proportional hazard 
regression model will be used to analyze the effects of factors, in addition to treatment, which 
may be associated with OS or PFS.  Local, regional, and distant failures will be estimated by the 
cumulative incidence method (Kalbfleisch 1980) and the comparison of these endpoints between 
and experimental arm and the control arm will be done use Gray’s test (Gray1988). 
13.4.2  Interim Analysis to Monitor the Study Progress: 
Interim reports with statistical analyses will be prepared twice per year until the initial 
treatment results have been presented/published.  In general, the interim reports will 
contain the following information: 
 
patient accrual rate with a projected completion date (while the study is still 
accruing) 
 
total patients accrued  
 
distributions of important pretreatment and prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm. 
 
compliance rates of treatment delivery 
 
The interim reports will not contain the results from the treatment comparisons with 
respect to the primary endpoint (OS), or any secondary endpoints, with the exception of 
reporting of adverse events. 
 
Phase III trials are required by NCI Cooperative Group Program Guidelines to be 
reviewed by a Data and Safety Monitoring Committee (DSMC). To monitor the safety of 
this study, the NRG Oncology DMC will officially review this study twice per year and on 
an “as needed” basis in between Committee meetings. 
 
13.4.3 CDUS Reports 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
 
13.4.4 Significance Testing for Early Termination and/or Reporting 
Primary Endpoint: Overall Survival (OS) 
Two interim significance test of treatment difference for the primary endpoint of OS are 
planned based on the Lan DeMets alpha/beta spending functions [Lan 1983]. The timing 
of the interim analysis will be based on OS failure events (death due to any cause).  The 
maximum number of OS events required for the study is 102. Under the alternative 
hypothesis of a 20% difference in OS, the projected number of events and the nominal 
significance levels for rejecting the H0 or the H1 for this interim analysis are shown in the 
table below:   
 
Table 2: Nominal Significance Levels for Interim Analyses  
 
Interim 
Analysis 
Number of 
Events 
Reject H0  
if p ≤ 
Reject H1  
if p ≥  
#1 
34 
≤ 0.0002 
0.98 
#2 
68 
≤ 0.012 
0.36 
 
At each planned interim analysis, the p-value from the log-rank test assessing treatment 
differences with respect to OS will be compared to the nominal significance levels in 
Table 2 above.  If the computed p-value is less than or equal to the nominal significance 
level boundary for rejecting the H0, then accrual to the trial will be stopped (if applicable) 
and it will be concluded that the OS with radiation (Arm 1) is significantly different than 

42                         NRG-GI001; version date March 20, 2017 
 
 
without radiation (Arm 2) and the results will be reported.  If the computed p-value is 
greater than or equal to the nominal significance level boundary for rejecting the H1, then 
accrual to the trial will be stopped (if applicable) and the fact that it cannot be concluded 
that the OS with radiation (Arm 1) is significantly different than without radiation (Arm 2) 
will be reported. Otherwise, if neither boundary is crossed, accrual to the trial and/or 
follow-up (as applicable) will continue until the next/final analysis.    
 
In addition to accrual, distributions of pretreatment characteristics, frequency and severity 
of adverse events, and compliance with protocol treatment blinded efficacy results will be 
reported to the oversight NRG Oncology DMC, following the required number of events 
for the planned interim analysis. 
 
13.4.5 Analysis for Reporting the Initial Treatment Results 
 
The primary hypothesis of the study is to determine if liver-directed radiation therapy results in a 
change in OS in patients with unresectable, localized intrahepatic cholangiocarcinoma.  This 
major analysis will occur after at least 102 OS events (deaths) have occurred. It will include: 
 
 
tabulation of all cases entered and those excluded from the analyses with the reasons 
for exclusion given 
 
distributions of important prognostic baseline variables  
 
the frequencies and severity of adverse events by treatment arm. 
 
compliance rate of treatment delivery 
 
observed results with respect to the primary and secondary endpoints 
 
All eligible patients randomized will be included in the comparison and will be grouped by 
assigned treatment in the analysis.  The primary hypothesis of treatment difference in OS, 
assuming both interim analyses have been carried out, will be tested with a 2-sided significance 
level of 0.0463.  Additional analyses of treatment effect will be performed using the logistic 
regression model with the stratification factors included as fixed covariates, as well as any 
factors that show an imbalance between the arms (e.g. age, gender, race, etc.).  Where feasible, 
treatment comparisons with respect to the primary endpoint (OS) will be compared within each 
ethnic and racial category. 
13.5 
Gender and Minorities 
Both men and women of all races and ethnic groups are eligible for this study. In conformance 
with the national Institutes of Health (NIH) Revitalization Act of 1993 with regard to inclusion of 
women and minorities in clinical research, possible interactions between race/ethnicity and 
treatment have been considered. It is projected that 80% of the patients will be men and 20% 
women; 2% will be of Hispanic or Latino ethnicity; racial distribution will be 74% white, 20% 
Asian, 5% black or African American, and 1% across the other racial categories. Assuming no 
differences between the ethnicities, or among the races, the statistical power for detecting the 
hypothesized treatment difference in the randomized patients is 78% for males. The projected 
female, Hispanic/Latino and non-White accrual rates are too low for any meaningful treatment 
comparisons.  
 
The following table lists the projected randomized accrual by gender, ethnic, and racial 
categories. 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 

43                         NRG-GI001; version date March 20, 2017 
 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
             1 
2 
3 
Not Hispanic or Latino 
29 
114 
143 
Ethnic Category: Total of all subjects 
          30 
116 
146 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
6 
23 
29 
Black or African American 
2 
             5 
7 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
21 
87 
108 
Racial Category: Total of all subjects 
30 
116 
146 

44                         NRG-GI001; version date March 20, 2017 
 
 
REFERENCES 
 
Borger DR, Tanabe KK, Fan KC, et al.  Frequent mutation of isocitrate dehydrogenase (IDH)1 and IDH2 
in cholangiocarcinoma identified through broad-based tumor genotyping.The Oncologist . 2012; 17:72-79. 
PMID:22180306 
 
Chen Y, Zhao-Chong Z, Tang Z, et al.  Determining the role of external beam radiotherapy in 
unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients. BMC Cancer 2010; 
10:492. PMID 20840777 
Dawson LA, Eccles C, Craig T. Individualized image guided iso-NTCP based liver cancer SBRT. Acta 
Oncol. 2006:45(7):856-64. PMID: 16982550 
Dias-Santagata D, Ahkavanfard S, David SS, et al.  Rapid targeted mutational analysis of human 
tumours: a clinical platform to guide personalized cancer medicine.  EMBOMol Med. 2010; 2:1-13. PMID 
20432502 
 
Endo I, Gonen M, Yopp AC, et al. Intrahepatic Cholangiocarcinoma: Rising frequency, improved survival, 
and determinants of outcome after resection. Ann Surg .2008;248:84-96.PMID 18543039 
 
Gray RJ. A class of K-samples test for comparing the cumulative incidence of a competing risk. Ann 
Statistic;  16:1141-54, 
 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York, John Wiley & Sons, 
1980; pp.167-169.) 
 
Kaplan EL, Meier P. Non-parameteric estimation from incomplete observations. Journal American 
Statistical 
Association 1958;53:457-481. 
 
Lan, K. and E. DeMets, Discrete sequential boundaries for clinical trials. Biometrika, 1983. 70: p. 659-
663. 
 
Kutcher GJ, Burman C, Brewster, et al. Histogram reduction method for calculating complication 
probabilities for three-dimensional treatment planning evaluations. Int  J Radiation OncolBiolPhys. 1991 
May 15; 21(1):137-46. PMID: 2032884 
 
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer 
Chemother. Rep 1966:50: 163-70. 
 
Mizumoto M, Tokuuye K, Sugahara S, Nakayama H, et al: Proton beam therapy for hepatocellular 
carcinoma adjacent to the portahepatis. Int J RadiatOncolBiol Phys. 2008;71:462-467PMID 18243571 
 
Ohtsuka M, Ito H, Kimura F et al. Results of Surgical treatment of intrahepatic cholangiocarcinoma and 
clinicopathological factors influencing survival. British Journal of Surgery .2002;89:1525-31 PMID 
12445060 
 
Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 
1977;64:191-199. 
 
Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115-25 
PMID:15192785 
Shaib YH, Davila JA, McGlynn K, El-Serag HB. et al. Rising incidence of intrahepatic cholangiocarcinoma 
in the United States: a true increase? J Hepatol. 2004 Mar;40 (3):472-7. PMID 15123362 
 

45                         NRG-GI001; version date March 20, 2017 
 
 
Shinohara ET, Mitra N, Guo M, et al. Radiation therapy is associated with improved survival in the 
adjuvant and defniive treatment of intrahepatic cholangiocarcinoma.  Int  J Radiation 
OncolBiolPhys.2008;72;1495-1501. PMID 18472359 
 
Tse RV, Hawkins M, Lockwood G, et al.  Phase I study of individualized stereotactic body radiotherapy for 
hepatocellular carcinoma and intrahepatic cholangiocarcinomas.  J ClinOncol. 2008; 26:657-664. PMID 
18172187 
Valle J, Wasan H, Palmer D, et al. Cisplatin plus gemcitabine for biliary tract cancer.  N Engl J Med 2010; 
362:1273-81. PMID:20375404 
 
Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas.N Engl J Med. 2009;19: 765-73. 
PMID:19228619 
 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 1974; 27:365-75. 
 
Zeng ZC, Tang ZY, Fan J, et al.  Consideration of the role of radiotherapy for unresectable intrahepatic 
cholangiocarcinoma: a retrospective analysis of 75 patients. Cancer J. 2006;12:113–122 PMID 16630402 
 
 
 

46                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX I (3/20/17) 
STUDY PARAMETER TABLE: STUDY ENTRY ASSESSMENTS 
 
 
Assessments 
prior to study 
entry 
≤30 days prior to 
study entry 
≤21 days 
prior to 
study entry 
AT Study Entry 
Biopsy or cytology 
confirmed IHC  
X 
 
 
 
Performance Status 
X 
 
 
 
Height/Weight 
 
X 
 
 
CT Chest/Abdomen/ 
Pelvis w multiphasic liver 
CT OR CT chest without 
contrast and MRI of 
abdomen and pelvis 
 
X 
 
 
CBC w/ diff, ANC, platelets 
 
 
X 
 
Serum creatinine or 
creatinine clearance, ALT, 
AST, Bilirubin, Albumin 
 
 
X 
 
Alkaline phosphatase, 
phosphate, sodium, 
potassium, chloride, 
magnesium, calcium 
 
 
X 
 
 
CA 19-9, CEA 
 
 
X 
 
bHCG test (if applicable) 
X 
 
 
 
Urine sample (for 
consenting patients) 
 
 
X (See Section 
10.2.6 for details 
Blood collection (plasma 
and whole blood for DNA 
for consenting patients) 
 
 
X (See section 
10.2.6 for details) 
Tissue banking (for 
consenting patients) 
 
 
X (See section 
10.2.6 for details) 
Informed consent 
 
X 
 

47                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX I (3/20/17) 
(continued) 
STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT 
 
 
Assessments 
During RT 
(Arm 1 patients only) 
History/physical 
X per institutional standard 
Vital Signs  
X per institutional standard 
Weight 
X per institutional standard 
CBC w/diff, ANC, platelets 
X per institutional standard 
Alkaline phosphatase, phosphate, sodium, 
potassium, chloride, magnesium, calcium, Serum 
creatinine or creatinine clearance 
X per institutional standard 
ALT, AST, Bilirubin,  
X (Day 1, 8, and 15)  
Toxicity Assessment 
X per institutional standard 
Blood collection (for consenting patients) 
X (see Section 10.2.6 for details) 
 
 
 
 

48                         NRG-GI001; version date March 20, 2017 
 
 
 
APPENDIX I (3/20/17) 
(continued) 
STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW-UP 
 
 
Assessments 
At end of treatment 
Every 3 months from study 
entry for 3 years, then every 
6 months for 2 years  
(Arms 1 and 2) 
History/physical 
 
X 
Vital Signs and Performance status 
 
X 
Weight 
 
X 
CBC w/diff, ANC, platelets 
 
X 
ALP, phosphate, sodium, potassium, 
chloride, magnesium, calcium 
 
X 
CA 19-9, CEA 
X 
X 
Toxicity Assessment 
 
X 
CT Chest/ Abdomen/Pelvis  OR CT 
chest without contrast and MRI of the 
abdomen and pelvis if contrast in 
contraindicated 
 
X* 
Multi-phase liver CT or MRI 
 
X* 
* If the metastatic and liver specific assessments are encompassed within one test, that is acceptable. 

49                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX II 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry work of a light or sedentary nature.  For example, light 
housework, office work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more 
of waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 

50                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX III 
 
 
AJCC Staging System 
Edge SB, ed. AJCC Cancer Staging Manual 7th ed. New York, NY, 2010 
 
 
Primary Tumor (T) 
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
Tis Carcinoma in situ (intraductal tumor) 
T1 Solitary tumor without vascular invasion 
T2a Solitary tumor with vascular invasion  
T2b Multiple tumor with vascular invasion 
T3 Tumor perforating the visceral peritoneum or involving the local extra hepatic structures by direct 
invasion 
T4 Tumor(s) with periductal invastion* 
 
Regional Lymph Nodes (N) 
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastases 
N1 Regional lymph node metastases 
 
Distant Metastases (M) 
M0 No distant metastases 
M1 Distant metastases 
 
Stage Grouping 
Stage 0  
Tis 
 
N0 
M0 
Stage I   
T1  
 
N0  
M0 
Stage II  
T2  
 
N0  
M0 
Stage III  
T3  
 
N0  
M0 
Stage IVA  
T4 
 
N0 
M0 
 
 
Any T   
N1  
M0 
Stage IVB  
Any T   
Any N  M1 
 
 
Note: cTNM is the clinical classification, pTNM is the pathologic classification. 
* The pathologic definition of periductal invasion is the finding of a longitudinal growth pattern along the 
intrahepatic bile ducts on both gross and microscopic examination. 

51                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX IV 
 
Multi-Phase Intrahepatic Cholangiocarcinoma Imaging Protocol 
Recommended imaging for CT simulation and follow-up 
Multi-phase liver CT protocol using iodinated intravenous (IV) contrast will be obtained at 2.5 or 3 mm 
slice thickness. The four phase HCC protocol includes a non-contrast CT, arterial (A) phase imaging, 
portal venous (V) phase imaging and delayed (D) phase imaging. The A phase of imaging demonstrates 
hypervascularity of HCC. The V phase is often best for visualization of vascular thrombi. The D phase 
imaging demonstrates washout of HCC. All four phases are recommended for use at baseline diagnosis 
for HCC; A/V/D phase imaging is recommended for follow-up of HCC patients, with all phases including 
the whole liver and V or D phase including the entire abdomen. For CT simulation, at least 2 phases of 
imaging are recommended (A/V or A/D), with all phases including the whole liver and one phase including 
enough of the abdomen to develop a patient model for radiation planning. 
All multi-phase imaging is recommended to be obtained in breath hold, with the arms up when possible. 
The timing of imaging after IV contrast administration: Bolus Tracking technique 
The timing varies between 16 and 64 detector scanners (with image acquisition occurring faster on a 64 
detector CT scanner). It is recommended that IV contrast (e,g. Visipaque) 2cc/kg to a max of 180cc be 
injected @ 5cc/second using a minimum of 20G antecubital. IV bolus tracking, a commercially available 
technique, is recommended for use to control for variations in cardiac circulation time, to ensure the 
images are obtained during the correct phases of contrast enhancement. As is standard practice, a cursor 
is placed in the aorta at the level of the origin of the celiac axis and is used to detect when contrast 
arrives in the abdominal aorta and raises the attenuation value to 100 Hounsfield Units. For a 64 detector 
scanner, A, V and D phase scanning occurs 20, 60 and 180 seconds, respectively, after the 100HU 
threshold is reached. 
MR imaging 
If CT cannot be obtained due to contraindication, a non-contrast CT scan will be obtained, and gadolinium 
or Primovist/Eovist (Gd-EOB-DTPA) enhanced MRI will be utilized to facilitate target delineation. It is 
suggested that non-contrast and dynamically obtained T1 weighted sequences at a slice thickness of 
7mm at maximum be used. Details of the imaging protocol should be developed in collaboration with the 
diagnostic radiology department. 
If a patient has contraindications to CT and MR IV contrast, then non-contrast T1 weighted images may 
be used for target delineation, only if T1 weighted images demonstrate the HCC with clearly defined 
edges. 
 
 
 
 
 
 
 
 
 
 
 
 
 

52                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX V (5/7/15) 
 
Example of the porta hepatis 
 
Only lymph nodes in the vicinity of this structure are considered regional lymph nodes. No celiac, SMA, 
mesenteric, gastro-hepatic, or pancreaticoduodenal lymphadenopathy is permitted. Please contact Dr. 
Hong or Dawson if there is any question. 
 
 
 
 

53                         NRG-GI001; version date March 20, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

54                         NRG-GI001; version date March 20, 2017 
 
 
APPENDIX VI (3/20/17) 
 
Appendices for NRG Oncology Biospecimen Collection (as specified by the protocol). 
 
NRG Oncology FFPE Specimen Plug Kit Collection 
NRG Oncology Blood Collection Kit Instructions 
NRG Oncology Urine Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco- Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal (ST) Form has the consent boxes checked off.  
 
Check that all samples are labeled with the NRG Oncology study and case number, and include 
date of collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top 
of the container. If you can hear the slides shaking it is likely that they will break during 
shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do 
not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you 
shake the container the blocks are not shaking. If you can hear the block shaking might break 
during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States 
Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address 
(94115). Do NOT ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate 
bag and clearly identified. If possible keep Serum, Plasma, and Whole Bloods in separate 
bags. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at 
least 7 lbs). There should be plenty of dry ice under and above the specimens. If the volume of 
specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two 
separate boxes. Any Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and 
the site will be notified.  
o Send frozen specimens on dry ice via overnight courier to the address above. Specimens 
should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent 
thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples 
can be stored frozen at -
 until ready to ship. 
 
For Questions regarding collection/shipping please contact the NRG Oncology   
Biospecimen Bank – San Francisco by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 
or Fax: 415-476-5271.  

55                         NRG-GI001; version date March 20, 2017 
 
 
NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen 
Bank – San Francisco. The plug kit contains a shipping tube and a punch tool.    
 
Step 1 
If the block is stored cold, allow it to equilibrate for 30 minutes at room 
temperature. Place the punch tool on the paraffin block over the 
selected tumor area. (Ask a pathologist to select area with tumor.) 
Push the punch into the paraffin block. Twist the punch tool once 
around to separate the plug from the block. Then pull the punch tool 
out of the block. The punch should be filled with tissue sample. 
 
 
 
Step 2 
Label the punch tool with the proper specimen ID and block number.  
DON’T remove specimen from the punch. 
 
 
Use a separate punch tool for every specimen. Call or e-mail us if you 
have any questions or need additional specimen plug kits. 
 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to 
address below. Please do not mix specimens in the same tube.    
 
 
 
   
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please 
send the entire block to the NRG Oncology Biospecimen Bank – San Francisco and we will sample a plug 
from the block and return the remaining block to your facility.  Please indicate on the submission form the 
request to perform the plug procedure and return of the block. 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For 
Questions regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact 
the NRG Oncology Biospecimen Bank – San Francisco by e-mail: NRGBB@ucsf.edu or call 415-
476-7864/Fax 415-476-5271. 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco- Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.):  
For ALL Frozen Specimens or Trackable shipments 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS 

56                         NRG-GI001; version date March 20, 2017 
 
 
 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood  
Kit contents:  Sites are required to provide their own blood draw tubes for this study.  
Each kit includes supplies for all time points and one return shipping label for batch shipping of 
frozen samples from each case. 
 
Thirty-five (35) 1 ml cryovials 
 
Biohazard bags (7) and Absorbent shipping material (7) 
 
Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal (ST) Form and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum:  Red Top Tube (One ten ml or two 5ml red top tubes) 
 
Label five 1ml cryovials for the serum collected. Label them with the NRG Oncology study 
and case number, collection date, time, and time point, and clearly mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. 
 at room temperature is acceptable if 
done within 2 hours of draw but must be noted on the ST Form. 
3. Aliquot a minimum of 0.5 ml serum into five (5) cryovials as are necessary for the serum 
collected labeled with NRG Oncology study and case numbers, collection date/time, protocol 
time-point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as 
“serum”. 
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90 C, and 
store frozen until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form. 
 
(B) Plasma:  Purple Top EDTA tube #1 (one 10 ml or Two 5ml EDTA Tubes) 
 
Label five (5) 1ml cryovials for the plasma collected. Label them with the NRG Oncology 
study and case number, collection date, time, and time point, and clearly mark cryovials 
“plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 
spinning at room temperature is acceptable if done within 2 hours of draw but must be noted 
on the ST Form.  
3. If the interval between specimen collection and processing is anticipated to be more than one 
hour, keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into each of five (5) cryovials as 
necessary for the plasma collected labeled with NRG Oncology study and case numbers, 
collection date/time, time point collected and clearly mark specimen as “plasma”.  Avoid 
pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90C and 
store frozen until ready to ship on dry ice. See below for storage conditions.                             
 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
the ST Form.  
 
 
 

57                         NRG-GI001; version date March 20, 2017 
 
 
 
 
 
 
 
(C) Whole Blood for DNA:  Purple Top EDTA tube #2 (one 10 ml, or two 5ml EDTA tubes) 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with 
the NRG Oncology study and case number, collection date/time, and time point, and clearly mark 
cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can 
also be mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the 
blood collected (3 to 5) labeled with NRG Oncology study and case numbers, collection 
date/time, time point collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -80 
Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
ST Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for 
up to one week (please ship out Monday-Wednesday only; Canada: Monday-
Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily 
(please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-
Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 

58                         NRG-GI001; version date March 20, 2017 
 
 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard 
bag.  Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg 
minimum).  Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-
mail NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu 

59                         NRG-GI001; version date March 20, 2017 
 
 
 NRG ONCOLOGY URINE COLLECTION KIT INSTRUCTIONS 
This Kit is for collection, processing, storage, and shipping of urine specimens. 
 
Kit Contents: 
 
One (1) Sterile Urine collection cup 
 Two 15 ml polypropylene centrifuge 
tubes 
 
Two 7 ml disposable pipettes 
 Biohazard bags 
 
Absorbent paper towel 
 Parafilm for sealing outside of tubes 
 
Preparation and Processing of Urine Specimens: 
Process: 
 
A clean catch urine specimen will be collected. To collect the specimen, use the following 
instructions: 
o 
Males should wipe clean the head of the penis and females need to wipe between the 
labia with soapy water/cleansing wipes to remove any contaminants.  
o 
After urinating a small amount into the toilet bowl to clear the urethra of contaminants, 
collect a sample of urine in the collection cup. 
o 
After 10-25 mL urine has been collected, remove the container from the urine stream 
without stopping the flow of urine. 
o 
Finish voiding the bladder into the toilet bowl. 
 
Aliquot 5-10 mls of Urine into each of two 15 ml polypropylene centrifuge tubes (disposable 
pipets are provided in the kit). Do not fill with more than 10 mls to avoid cracking of tubes due 
to expansion during freezing. Replace the cap and tighten on the tubes. Make sure the cap is 
not cross-threaded or placed on incorrectly or leaking will occur.  
 
Use parafilm to seal the cap around the outside rim of the urine tube to prevent leakage.  
 
Discard remaining Urine and collection cup. 
 
Label the specimen with the NRG Oncology study and case number, collection date and 
time, time point of collection, and clearly mark specimens as “urine”. 
 
Wrap Urine Tubes with absorbent material (paper towels) and place into biohazard bag and 
seal the bag. Freeze and store Urine samples in a -20C or -80C freezer until ready to ship. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED with study number, case number, 
collection date/time, and time point collected (e.g. pretreatment, post-treatment). 
 
Storage and Shipping: 
Freezing and Storage: 
 
Urine specimens may be sent in batches or with other frozen biospecimens, if within 30-60 days 
of collection. Store at -20C or -80C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available:  
 
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
OR: 
 
Samples can be stored in plenty of Dry Ice for up to one week, replenishing daily (please 
ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to 
prevent thawing due to delivery delays.  Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the 
Styrofoam box. 
 
Place sealed specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 
lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and 
UN1895 stickers to outer cardboard box. 

60                         NRG-GI001; version date March 20, 2017 
 
 
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag 
and that there is enough room for plenty of dry ice. Add padding to avoid the dry ice from 
breaking the tubes. 
 
Samples received thawed will be discarded, and a notification will be sent immediately to the 
Principal Investigator and Clinical Research Assistant of the submitting institution. The institution 
should send a subsequent sample, collected as close as possible to the original planned 
collection date. 
 
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 
For questions regarding ordering, collection, or shipping of a Urine Collection Kit, please 
e-mail NRGBB@ucsf.edu or call (415)476-7864 or fax (415) 476-5271. 
 
 
Shipping Address: FedEx/UPS/Courier address (For all frozen samples) 
NRG Oncology Biospecimen Bank at UCSF 
2340 Sutter Street, Room S341, San Francisco, CA  94115 
Contact Phone: 415-476-7864