Randomized Phase III Study of Sorafenib Versus Stereotactic Body Radiation Therapy Followed by Sorafenib in Hepatocellular Carcinoma
Phase: PHASE3
Conditions: Adult Primary Hepatocellular Carcinoma, Advanced Adult Primary Liver Cancer, Recurrent Adult Primary Liver Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 1112 
 
(ClinicalTrials.gov NCT #: 01730937) 
 
 
Randomized Phase III Study of Sorafenib versus Stereotactic Body Radiation 
Therapy Followed by Sorafenib in Hepatocellular Carcinoma 
 
 
 
Amendment 12:  September 23, 2022 

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RTOG 1112, Version Date: September 23, 2022 
    NRG Oncology 
 
RTOG 1112 
 
RANDOMIZED PHASE III STUDY OF SORAFENIB VERSUS STEREOTACTIC BODY 
RADIATION THERAPY FOLLOWED BY SORAFENIB IN HEPATOCELLULAR 
CARCINOMA  
 
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 Medical Research 
Foundation Inc., and SWOG. 
 
Study Team (23-SEP-2022) 
Principal Investigator/Radiation Oncology  
Laura A. Dawson, MD 
Princess Margaret Hospital 
610 University Avenue 
Toronto, ON 
Canada M5G 2M9 
416-946-2132/Fax: 416-946-6566 
Laura.dawson@rmp.uhn.ca 
 
Medical Oncology Co-Chair 
Andrew Zhu, MD, PhD 
Massachusetts General Hospital Cancer Center 
Harvard Medical School 
55 Fruit Street 
LH/POB, Room 232 
Boston, MA 02114 
617-643-3415/Fax: 617-724-3166 
AZHU@PARTNERS.ORG 
Andrew.zhu@jiahui.com  
 
Medical Oncology Co-Chair 
Jennifer Knox, MD, MSc 
Princess Margaret Hospital 
University of Toronto 
610 University Avenue 
700U 7-724 
416-946-2399/Fax: 416-946-6546 
Toronto, ON 
Canada M5G 2M9 
Jennifer.Knox@uhn.ca 
 
Radiation Oncology Co-Chair (Protons) 
Sunil Krishnan, MD 
Mayo Clinic Florida 
Dept. of Radiation Oncology 
4500 San Pablo Road 
Jacksonville, FL 32224-1865 
904-953-2000  
krishnan.sunil@mayo.edu 
 
Translational Research Co-Chair 
Chandan Guha, MD  
Montefiore Medical Center- Moses Campus 
Department of Radiation Oncology 
111 East 210 Street 
Albert Einstein College of Medicine 
Bronx, NY 10467 
718-920-2702/Fax: 718-405-8551 
cguha@montefiore.org 
 
Quality of Life Co-Chair 
Lisa Kachnic, MD, FASTRO  
Department of Radiation Oncology 
Columbia University Irving Medical Center 
Herbert Irving Comprehensive Cancer Center 
622 West 168th Street 
New York, NY 10032 
212-305-9987/ Fax: 212-305-0015 
lak2187@cumc.columbia.edu 
 
Medical Physics Co-Chair (Protons) 
Michael T. Gillin, PhD 
Professor, Deputy Chair, Chief of Clinical 
Services 
The University of Texas 
MD Anderson Cancer Center 
Department of Radiation Physics 
1400 Pressler Street 
Unit 1420 
Houston, TX 77030 
713-563-2507/Fax: 713-563-2545 
mgillin@mdanderson.org 
 
Radiation Oncology Co-Chair 
Theodore S. Hong, MD 
Massachusetts General Hospital 
32 Fruit Street 
Boston, MA 02114 
617-726-5866 Fax: 617-726-3603 
tshong1@partners.org 
 

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RTOG 1112, Version Date: September 23, 2022 
(Continued on next page) 
Physics Co-Chair 
Tim Craig, PhD 
Princess Margaret Hospital 
University of Toronto 
610 University Avenue 
Toronto, ON Canada M5G 2M9 
416-946-4501 x3340/Fax: 416-946-6656 
Tim.Craig@rmp.uhn.on.ca 
Senior Statistician 
Kathryn Winter, MS 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3198/Fax: 215-928-0153 
winterk@nrgoncology.org 
 
 
NRG Oncology Contact Information(25-MAR-2020) 
 
 
Data Manager: 
For questions concerning eligibility or data 
submission 
Wendy Bergantz, RN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3230 
bergantzw@nrgoncology.org 
 
 
 
 
Debora Washington, RN, MSN 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3206 
washingtond@nrgoncology.org 
 
 
 
RTQA Questions:  
For questions concerning RT data submission 
 
 
 
 
 
 
RT Credentialing: 
Susan McNulty, BS, RT(R)(T), CMD 
IROC Philadelphia – RT QA Center 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8907 
smcnulty@acr.org 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
 
 
RT data submission to TRIAD: 
Triad-Support@acr.org 
 
 
Protocol Development:: 
For questions concerning protocol and informed 
consent versions & amendments 
 
 
 
 
Gastrointestinal Non-Colorectal Committee 
Chair: 
Fran Bradley 
NRG Oncology  
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-940-8893/Fax: 215-928-0153 
bradleyf@nrgoncology.org 
 
Christopher Crane, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, Box 22 
New York, NY 10065  
212-639-2112 
cranec1@mskcc.org   
 

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RTOG 1112, Version Date: September 23, 2022 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
Sorafenib 
Commercial 
724772 
Exempt 
 
Participating Sites (5/7/13) 
 US Only 
 Canada Only 
 US and Canada 
 Approved International Member Sites  
 
 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 12 
September 23, 2022 
N/A 
Amendment 11 
May 26, 2022 
N/A 
Amendment 10 
September 14, 2020 
N/A 
Amendment 9 
March 25, 2020 
NA 
Amendment 8 
August 19, 2019 
NA 
Amendment 7 
June 28, 2019 
NA 
Amendment 6 
May 13, 2019 
NA 
Amendment 5 
October 27, 2017 
NA 
Amendment 4 
February 23, 2016 
March 8, 2016 
Amendment 3 
August 26, 2014 
September 29, 2014 
Amendment 2 
August 8, 2014 
September 15, 2014 
Update 
April 29, 2014 
April 29, 2014 
Amendment 1 
November 21, 2013 
January 14, 2014 
Update 
May 7, 2013 
May 7, 2013 
Update 
April 24, 2013 
April 24, 2013 
Activation 
April 24, 2013 
April 24, 2013 
Update 
January 11, 2013 
January 11, 2013 
Pre-Activation 
November 30, 2012 
January 11, 2013 
 
NRG Oncology (27Oct2017) 
 
 
  
 
 
 
 
 
 
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. 
The following NCTN Study Champion(s) have been added to this trial: 
ALLIANCE:  Theodore S. Hong, MD   
SWOG:  Tim Mitin, MD, PhD 

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RTOG 1112, Version Date: September 23, 2022 
 
CONTACT  INFORMATION (23-SEP-2022) 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 (Sign in at www.ctsu.org,            
and select Regulatory > 
Regulatory Submission.)  
 
Institutions with patients waiting 
that are unable to use the 
Portal should alert the CTSU 
Regulatory Office immediately  
by phone or email: 1-866-651-
CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email : 1-888-823-
5923 or  
ctsucontact@westat.com. 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Refer to 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 page located on the CTSU members’ website located (https://www.ctsu.org).  
Access to the CTSU members’ web site is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log in 
with a CTEP-IAM username and password.  
 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS).   
For clinical questions (i.e. patient eligibility or treatment-related): Contact the study data manager 
listed on the NRG Oncology contact information table on the protocol cover page.  
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. 
For imaging data submission questions: 
IROCimagearchive@acr.org; please include trial number in the email subject line 
 
For TRIAD access and installation support: 
TRIAD-Support@acr.org 
Triadhelp.acr.org 
 
TRIAD Software Installation: 
https://triadinstall.acr.org/triadclient/  
 
 

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RTOG 1112, Version Date: September 23, 2022 
TABLE OF CONTENTS  
 
TABLE OF CONTENTS ..................................................................................................................................... 5 
SCHEMA  ....................................................................................................................................................... 8 
1.0 
INTRODUCTION ............................................................................................................................... 13 
1.1  
Hepatocellular Carcinoma (HCC) ................................................................................................ 13 
1.2  
Local-Regional Treatments for HCC ............................................................................................ 13 
1.3  
Sorafenib ..................................................................................................................................... 14 
1.4  
Radiation Therapy  ...................................................................................................................... 14 
1.5 
Rationale for Sorafenib and Radiation Therapy ......................................................................... 15 
1.6 
Clinical Experience with Sorafenib and Radiation Therapy  ....................................................... 16 
1.7 
Quality of Life (QOL) ................................................................................................................... 17 
1.8 
Biomarkers in HCC ...................................................................................................................... 18 
1.9       Protocol Overview ....................................................................................................................... 18 
2.0 
OBJECTIVES ..................................................................................................................................... 18 
2.1 
Primary Objective ....................................................................................................................... 18 
2.2 
Secondary Objectives ................................................................................................................. 18 
3.0 
PATIENT SELECTION ........................................................................................................................ 19 
3.1 
Conditions for Patient Eligibility  ................................................................................................ 19 
3.2 
Conditions for Patient Ineligibility  ............................................................................................. 20 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT ............................................................................ 21 
4.1 
Required Evaluations/Management  .......................................................................................... 21 
4.2 
Highly Recommended Evaluations/Management  ..................................................................... 21 
5.0  REGISTRATION, STUDY ENTRY PROCEDURES  ...................................................................................... 22 
    5.1 PRE-REGISTRATION REQUIREMENTS FOR ALL RADIATION TECHNIQUES ....................................... 23 
5.2  
Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT)  .................................. 25 
5.3 
 Pre-Registration Requirements for Intensity Modulated Radiation Therapy (IMRT) ................ 25 
5.4  
Pre-Registration Requirements for Proton Treatment Approach .............................................. 25 
5.5 
Digital Radiation Therapy Data Submission Using Transfer of Images and Data  ...................... 26 
5.6  
Regulatory Pre-Registration Requirements  ............................................................................... 27 
5.7  
OPEN Registration   ..................................................................................................................... 30 
6.0 
RADIATION THERAPY  ..................................................................................................................... 31 

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RTOG 1112, Version Date: September 23, 2022 
6.1 
Dose Specifications  .................................................................................................................... 32 
6.2 
Technical Factors ........................................................................................................................ 33 
6.3 
Localization, Simulation, and Immobilization  ............................................................................ 33 
6.4 
Treatment Planning/Target Volumes  ........................................................................................ 34 
6.5 
Critical Structures Maximal Doses  ............................................................................................. 37 
6.6 
Targets and Critical Structures  ................................................................................................... 37 
6.7 
Documentation Requirements  .................................................................................................. 38 
6.8 
Compliance Criteria .................................................................................................................... 39 
6.9 
Radiation Therapy and Imaging Quality Assurance Reviews  ..................................................... 40 
6.10 
Radiation Therapy Adverse Events ............................................................................................. 41 
6.11 
Radiation Therapy Adverse Event Reporting .............................................................................. 42 
6.12 
Radiation Therapy Toxicity Assessment During Therapy  .......................................................... 42 
7.0 
DRUG THERAPY  .............................................................................................................................. 43 
7.1 
Treatment  .................................................................................................................................. 43 
7.2 
Dose Modifications  .................................................................................................................... 49 
7.3 
Modality Review  ........................................................................................................................ 51 
7.4 
Adverse Events  .......................................................................................................................... 52 
7.5 
CTEP-AERS Expedited Reporting Requirements  ........................................................................ 53 
8.0 
SURGERY ......................................................................................................................................... 54 
9.0 
OTHER THERAPY .............................................................................................................................. 55 
9.1 
Permitted Supportive Therapy ................................................................................................... 55 
9.2 
Non-permitted Supportive Therapy  .......................................................................................... 55 
10.0 
TISSUE/SPECIMEN SUBMISSION  .................................................................................................... 55 
10.1 
Tissue/Specimen Submission ..................................................................................................... 55 
10.2 
Specimen Collection for Tissue Banking and Translational Research  ....................................... 55 
10.3 
Confidentiality/Storage   ............................................................................................................. 57 
11.0 
PATIENT ASSESSMENTS................................................................................................................... 57 
11.1 
Study Parameters ....................................................................................................................... 58 
11.2 
Evaluation During Treatment ..................................................................................................... 58 
11.3 
Measurement of Response  ........................................................................................................ 58 
11.4 
Criteria for Discontinuation of Protocol Treatment  .................................................................. 59 
11.5 
Health Related Quality of Life and Health Utility Assessments  ................................................. 60 

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RTOG 1112, Version Date: September 23, 2022 
12.0 
DATA COLLECTION .......................................................................................................................... 61 
12.1 DATA QUALITY PORTAL ....................................................................................................................... 61 
12.2 DATA SUBMISSION / DATA REPORTING  ............................................................................................. 61 
12.3 Summary of Dosimetry Digital Data Submission  ............................................................................... 64 
13.0 
STATISTICAL CONSIDERATIONS ....................................................................................................... 65 
13.1 Endpoints ........................................................................................................................................ 65 
13.2 Stratification  ................................................................................................................................... 65 
13.3  Sample Size and Power Justification  ............................................................................................. 65 
13.4 Power Information for Health Reported Quality of Life – FACT-Hepatobiliary Module (FACT-Hep) 
66 
13.5 
Analysis Plan  .............................................................................................................................. 67 
13.6 
Gender and Minorities  ............................................................................................................... 71 
REFERENCES  ............................................................................................................................................... 73 
APPENDIX I .................................................................................................................................................. 76 
APPENDIX II ................................................................................................................................................. 79 
APPENDIX III ................................................................................................................................................ 80 
APPENDIX IV ................................................................................................................................................ 81 
APPENDIX V  ................................................................................................................................................ 82 
APPENDIX VI  ............................................................................................................................................... 83 
APPENDIX VII ............................................................................................................................................... 84 
APPENDIX VIII  ............................................................................................................................................. 85 
APPENDIX IX  ............................................................................................................................................... 86 
APPENDIX X ................................................................................................................................................. 90 
 
 
 
 
 
  

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RTOG 1112, Version Date: September 23, 2022 
RADIATION THERAPY ONCOLOGY GROUP 
 
RTOG 1112 
 
Randomized Phase III Study of Sorafenib versus Stereotactic Body Radiation Therapy followed by 
Sorafenib in Hepatocellular Carcinoma 
 
SCHEMA (25-MAR-2020) 
 
 
 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
Vascular involvement  
(IVC, main portal vein/right or left main 
branch portal vein vs. other vascular 
involvement vs. none) 
 
Hepatitis B or B and C vs. C vs. other 
 
North American site vs. Non-North American 
site 
 
HCC volume/liver volume (<10% vs. 10-40 
vs. >40%) 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
 
Arm 1 
 
Daily sorafenib 
            
 
Arm 2 
 
SBRT alone  
(27.5 Gy – 50 Gy in 5 fractions) 
 
Followed by 
 
Sorafenib alone daily 
  
            
 
See Section 5.0 for radiation therapy credentialing details. See Section 7.0 for details/doses of sorafenib. 
 
 
Protocol treatment is encouraged to begin as soon as possible after study entry. Protocol treatment must 
begin within 21 days after study entry, unless extra time is needed for fiducial marker insertion, but not to 
exceed 28 days. 
 
 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Unsuitable for resection or transplant or radiofrequency ablation (RFA) 
Unsuitable for TACE or refractory to TACE 
Barcelona Clinic Liver Cancer Stage (BCLC) Intermediate (B) or Advanced (C) 
 
 
 
 
Required Sample Size: 292 
  

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RTOG 1112, Version Date: September 23, 2022 
ELIGIBILITY CHECKLIST (13-MAY-2019) 
 
(page 1 of 4) 
NRG Oncology Institution #   
 
RTOG 1112 
 
 
 
 
Case #  
 
 
 
      
                      Patients must have a diagnosis of HCC by at least one criterion listed below in Q1-3:        
1 ________(Y/N) Does the patient have pathologically (histologically or cytologically) proven diagnosis of 
HCC within ≤360 days prior to study entry? (The HCC must be >1cm). 
 
2______(Y/N) Does the patient have at least one solid liver lesion >1cm with arterial enhancement and 
delayed washout on multi-phasic computerized tomography (CT) or magnetic resonance  imaging (MRI) 
in the setting of cirrhosis or chronic hepatitis B or C without cirrhosis within ≤360  days prior to study 
entry? 
 
3_____(Y/N) Does the patient have enhancing vascular thrombosis (involving portal vein, IVC and/or 
hepatic vein) demonstrating early arterial enhancement and delayed washout  on multi-phasic CT or MRI, 
within ≤360  days prior to study entry in a patient with known HCC (diagnosed previously ≤720  days prior 
to study entry), using criteria in 3.1.1a or 3.1.1b of the protocol? 
 
4 ________(Y) Does the patient have measureable hepatic disease and/or presence of vascular tumor 
thrombosis (involving portal vein, IVC and/or hepatic vein) which may not be measureable as per 
RECIST, as defined in Section 11.0) on liver CT or MRI within 28 days prior to study entry? 
 
5 ________(Y) Has the patient had a history/physical examination, including examination for 
encephalopathy, ascites, weight, height,  and blood pressure within 14 days prior to study entry? 
 
6 ________(Y) Was an assessment by radiation oncologist and medical oncologist or hepatologist who 
specializes in treatment of HCC performed within 28 days prior to study entry? 
 
7 ________(Y/N) Did the patient have a Multiphasic liver CT or multiphasic liver MR scan-.  And CT chest  
with  CT or MR abdomen and CT or MR pelvis, or PET CT chest/abdomen/pelvis within 28 days prior to 
study entry? 
 
8 ________(Y) Was the Zubrod Performance Status 0-2 within 28 days prior to study entry? 
 
9 ________(Y) Did all blood work meet the requirements, per Section 3.1.6 of the protocol? 
 
10 ________(Y) Is the BCLC stage: Intermediate (B) or advanced (C) within 28 days prior to study entry? 
 
11 ________(Y) Is the Child-Pugh score A within 14 days prior to study entry? 
 
12 ________(Y) Age ≥ 18? 
 
13 ________(Y/N) Is the patient a woman of childbearing potential? 
            Y  If yes, does she agree to practice adequate contraception while on study and for at 
least 6 months following the last dose of radiation therapy and for at least 28 days 
following the last dose of sorafenib (whichever is later)? 
 
14 ________(Y/N) Is the patient a male? 
            Y  If yes, does he agree to practice adequate contraception while on study and for at least 
6 months following the last dose of radiation therapy and for at least 28 days following 
the last dose of sorafenib (whichever is later)? 
 
15 ________(Y) Is the patient unsuitable for resection or transplant or radiofrequency ablation (RFA)? 
 

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RTOG 1112, Version Date: September 23, 2022 
NRG Oncology Institution #   
 
RTOG 1112 
 
 
 
ELIGIBILITY CHECKLIST (27OCT2017) 
Case #  
 
 
 
     (page 2 of 4) 
 
16 ________(Y) Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or drug 
eluting beads (DEB) per Section 3.1.11 of the protocol? 
 
17 ________(Y/N) Has the patient received prior TACE or DEB? 
Y  If yes, was it > 28 days prior to study entry? 
 
18 ________(Y) Did the patient provide study-specific informed consent prior to study entry? 
 
19 ________(Y/N) Has the patient had a prior invasive malignancy (except non-melanomatous skin 
cancer)? 
Y  If yes has the patient been disease free for a minimum of 2 years? 
 
20 ________(N) Prior sorafenib use > 60 days? 
 
21 ________(N) Prior radiotherapy to the region of the liver that would result in excessive doses to 
normal tissues due to overlap of radiation therapy fields? 
 
22 ________(N) Prior selective internal radiotherapy/hepatic arterial Yttrium therapy? 
 
23 ________(N) Does the patient have any of the severe, active co-morbidity, as defined in Section 3.2.5 
of the protocol? 
 
24 ________(N) Does the patient have any one hepatocellular carcinoma > 15 cm in maximal diameter? 
 
25 ________(N) Is the total sum of maximal diameters of each definite parenchymal hepatocellular 
carcinomas or the maximal diameter of a single conglomerate HCC > 20 cm? 
 
26 ________(N) Are there more than 5 discrete intrahepatic parenchymal foci of HCC? 
 
27 ________(N) Is there direct tumor extension into the stomach, duodenum, small bowel or large bowel? 
 
28 ________(N) Is there measureable common or main branch biliary duct involvement with HCC? 
 
29 ________(N) Are there extrahepatic metastases or malignant nodes (that enhance with typical 
features of HCC) > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph 
node or two 2 cm lung lesions)? 
 
30. _______ (Y/NA) Is the patient HIV positive with CD4 count ≥ 350 cells/microliter and on highly active 
antiretroviral therapy? 
 
31 ________(N) Has the patient had a prior liver transplant? 
 
 

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RTOG 1112, Version Date: September 23, 2022 
NRG Oncology Institution #   
 
RTOG 1112 
 
 
 
ELIGIBILITY CHECKLIST (4/24/13) 
Case #  
 
 
 
     (page 3 of 4)  
 
The following questions will be asked at Study Registration:  
IMRT, SBRT, and IGRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION.  
PROTON CREDENTIALING IS REQUIRED IF USING PROTONS. 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient Initials (Last First Middle) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date 
 
 
         
17. 
Randomization date 
 
 
         
18. 
Medical oncologist’s name 
 
              (Y/N) 19. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 20.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
NRG Oncology Institution #   
 
RTOG 1112 
 
 
 
ELIGIBILITY CHECKLIST (27OCT2017) 
Case #  
 
 
 
     (page 4 of 4)  
 
 
              (Y/N) 22. 
Have you obtained the patient's consent for his or her blood to be kept for use in  
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease). 
 
              (Y/N) 23. 
Have you obtained the patient's consent to allow someone from this institution to  
 
 
 
contact him or her in the future to take part in more research?  
  
               (N/Y)  24. 
Did the patient agree to participate in the quality of life component? 
 
 
 
         
 
If no, please specify the reason from the following: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
 
               25. 
Vascular involvement 
 
 
(1) IVC/main portal vein/ right or left main branch portal vein or  
 
 
(2) other vascular involvement or  
 
 
 
(3) none 
 
 
               28. 
Hepatitis Status 
 
 
(1) B   
 
 
(2) C   
 
 
(3) other 
 
               29. 
Site 
 
 
(1) North American 
 
 
(2) Non-North American  
 
               30. 
HCC volume/(liver volume including HCC volumes) 
 
 
(1) <10% 
 
 
(2) 10-40% 
 
 
(3) >40% 
 
 
               31. 
Specify treatment technique/machine: 
 
 
(1) 3D-CRT 
 
 
(2) IMRT 
 
 
(3) Cyberknife 
 
 
(4) Protons 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/RTOG audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
1.0 INTRODUCTION 
1.1  
Hepatocellular Carcinoma (HCC) 
Hepatocellular carcinoma (HCC) is the fifth most common solid organ cancer and the third most 
common cause of cancer death globally, responsible for an estimated 600,000 deaths annually 
(Jemal 2010).  Although HCC is less common in North America, the incidence has increased from 
1.4 to 2.4 per 100,000 over the past two decades, and it is expected to continue to rise in parallel 
to the increasing incidence of Hepatitis C. 
  
Cirrhosis, due to alcohol, viral hepatitis, autoimmune hepatitis, hemochromatosis, or non-
alcoholic steatohepatitis (NASH) increases the risk of HCC developing.  Patients with Hepatitis C 
cirrhosis have a 5-20% 5-year cumulative incidence of HCC, and even in the absence of 
cirrhosis, hepatitis B infection is associated with a 15% risk of HCC. Many patients with cirrhosis 
have impaired liver function, and the degree of impairment impacts HCC prognosis and treatment 
options.  The most commonly used measure of liver function is the Child-Pugh classification, 
based on the presence or absence of ascites and encephalopathy as well as bilirubin, albumin, 
and INR levels (Appendix VII), with worse survival in Child Pugh class C and best in Child-Pugh 
class A, even in the absence of HCC.  The Model for End-Stage Liver Disease, or MELD 
(Appendix VIII), is a scoring system for assessing the severity of chronic liver disease and is 
useful in determining prognosis and prioritizing patients for receipt of a liver transplant. More 
recently it has been suggested to be useful in predicting survival in HCC patients (Huo 2007).  
The Barcelona Clinic Liver Cancer (BCLC) staging and treatment allocation system (Appendix V) 
is commonly used to describe HCC patients (Llovet JNCI 2008).  This system includes Child 
Pugh class in addition to tumor factors. 
 
Including operable patients, the overall 5 year survival of HCC patients is less than 10%, 
emphasizing the need for improved therapies. 
 
1.2  
Local-Regional Treatments for HCC 
Although cure is possible following surgery or liver transplant respectively for early stage HCC, 
most patients are not suitable for these therapies either due to medical contraindications, 
excessive burden of hepatic HCC, insufficient liver functional reserve.  The most widely accepted 
selection criteria for liver transplantation are the Milan criteria defined as a single tumor 5 cm or 
less or up to 3 tumors 3 cm or less, with no extrahepatic spread or macrovascular involvement.  
When such criteria are followed, transplantation is associated with a 5-year overall survival of 
approximately 70%, and the recurrence rate is less than 15%. Unfortunately, there is a 
substantial wait time for transplantation due to a limited availability of donors, so many patients 
drop off the wait list due to progression of HCC beyond the Milan criteria. For patients with a 
solitary HCC without vascular invasion, with Child Pugh A liver function, and no portal 
hypertension, partial liver resection is a treatment option.  Five year survival rates are 
approximately 50%.  Mortality in patients unsuitable for transplant or resection results 
predominantly from hepatic tumor progression.   
 
Local treatments for unresectable HCCs without portal vein thrombosis, include radiofrequency 
ablation (RFA) or other ablative approaches, which are associated with excellent local control 
(80-90%) for tumors away from large vessels and less than 3 cm, with reduced local control for 
larger tumors.     
 
For patients with large or multifocal tumors, regional therapies may be a treatment option.  
Hepatic tumors derive 80% of their blood supply from the hepatic artery, while the adjacent liver 
parenchyma is supplied by the portal vein, making hepatic arterial directed therapies, such as 
transarterial chemoembolization (TACE), drug eluding beads (DEB) or radioembolization, 
relatively tumor specific.  TACE has been shown in randomized trials to improve survival 
compared with symptomatic therapy alone, in patients without macrovascular involvement (Lo 
2002, Llovet 2002).  A recent review of TACE evidence concluded that absolute contraindications 
for TACE include severely reduced portal vein flow (e.g. from portal vein tumor or non-tumor 
occlusion) and untreatable arterial venous fistula. Relative contraindications included tumor size > 

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RTOG 1112, Version Date: September 23, 2022 
10 cm.  Patients with main portal vein thrombosis are not recommended to be treated with TACE 
(Raoul 2011).  There is more controversy in patients with segmental portal vein invasion.  The 
patients not suitable for TACE and/or with recurrent or refractory disease following TACE are the 
target HCC population for this study.  
 
1.3  
Sorafenib 
Sorafenib, a small molecule, tyrosine kinase inhibitor (TKI) with potent activity against the c-raf, 
VEGFfr2/3 and PDGF-alpha kinases (pathways involved in tumor proliferation and angiogenesis) 
is the standard therapy for locally advanced or metastatic HCC.  In patients with advanced BCLC 
stage HCC, two randomized controlled trials [Sorafenib HCC Assessment Randomized Protocol 
(SHARP) (Llovet NEJM 2008) and the Asian Pacific Trial (Cheng 2009)], demonstrated a 
significant improved survival of patients treated with sorafenib compared to placebo.  The SHARP 
trial of 602 HCC patients found an improvement in median survival from 7.9 to 10.7 months 
(p=0.00058, hazard ratio (HR) 0.69, confidence interval 0.55-0.88) and median time to 
progression from 2.8 to 5.5 months compared to placebo, with no significant difference in serious 
adverse events between the two treatment arms.  In patients with major vascular involvement or 
extrahepatic disease, the median survival was improved from 6.7 to 8.9 months.  In the Asian-
Pacific trial, overall median survival was improved from 4.2 to 6.5 months (HR 0.68).  Sorafenib 
has shown to be cost effective in the treatment of unresectable HCC using a Markov model of 
pooled phase III data (Carr 2010). Life-years gained were increased for sorafenib compared to 
best supportive care (mean ± standard deviation: 1.58 ± 0.17 vs. 1.05 ± 0.10 life-years 
gained/sorafenib patient and best supportive care, respectively). The majority of patients treated 
with Sorafenib eventually progress within the liver and die of liver failure, providing rationale to 
use local therapies in combination with Sorafenib. 
 
1.4  
Radiation Therapy (27Oct2017) 
Historically, external beam radiation therapy (RT) has not been used to treat HCC, primarily 
because beyond whole liver doses of 28Gy in 2Gy fractions, the risk of radiation induced liver 
disease (RILD) increases.  Classic RILD is a syndrome occurring most often within 2 months 
following radiation therapy, consisting of anicteric hepatomegaly and elevation of liver enzymes 
(ALP>AST). Treatment for RILD is limited and it may progress to liver failure, despite maximal 
supportive care.  The risk of RILD in patients with Child Pugh A HCC treated with a mean dose to 
the whole liver of 28 Gy in 2 Gy per fraction is 5%, and the risk following 36 Gy in 2Gy per fraction 
is 50%.  These threshold doses are reduced when the number of fractions is decreased (Pan 
2010).  Classic RILD is uncommon in modern radiation therapy series, when the dose to the liver 
can be kept below recommended levels.  Non-classic RILD, referring to any decline in liver 
function or liver toxicity, excluding classic RILD (e.g. elevated transaminases or reduction of Child 
Pugh score) is more common in HCC patients treated with RT.  It is more likely in patients with a 
higher Child Pugh score at baseline and in those with more advanced tumors requiring a larger 
volume of liver to be irradiated. 
 
Technological advances in radiation treatment planning, breathing motion management and 
image guided radiation therapy (IGRT), have made it possible for ablative doses of radiation to be 
delivered safely to focal unresectable HCC, using conformal RT, SBRT or protons.  Delivered 
doses have ranged from 60 to 90 Gy in 1.5 Gy fractions (Ben-Josef 2005) and 24 to 54 Gy in 6 
fractions (Tse 2008).  Objective response rates are 80-90% in HCCs less than 5 cm in maximal 
diameter, and in larger cancers (up to 15 cm), one year local control rates, defined as lack of 
progression of the irradiated lesions, range from 50% to 70%.  Improved local control and survival 
have been seen in patients treated with higher doses.  The median survival of patients with locally 
advanced HCC treated with a variety of fractionation ranges from 6 to 18 months (Mornex 2006, 
Seong 2009, Liang 2005, Liu 2004, Seong 2003, Zeng 2004, Li 2003, Guo 2003, Cheng 2000, 
Shim 2005, McIntosh 2009, Kim 2006).  The best reported outcomes are reported from Asia 
following particle therapy (Chiba 2005, Bush 2004, Kawashima 2005, Kato 2004, Tsujii 2004, 
Mizumoto 2008, Hata 2006, Sugarhara 2010). In one prospective study, patients with Child-Pugh 
A liver disease and potentially resectable single HCCs, had a 5 year survival of 56% following 
proton therapy (Fukumitsu 2009).  Given these results, the theoretical physical advantages of 

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RTOG 1112, Version Date: September 23, 2022 
proton therapy for HCC, and that few North American prospective proton studies have been 
conducted, there is a strong motivation to include protons in phase III studies of HCC RT. Proton 
and photon therapy have also been used to treat HCC with portal vein or inferior vena cava 
thrombosis (Huang 2009, Toya 2007, Koo 2010, Hata 2005, Yoon 2012). 
 
Stereotactic body radiation therapy (SBRT), sometimes referred to as SABR, is a promising 
treatment for HCC, associated with sustained responses in the majority of treated patients.  
SBRT for the treatment of unresectable HCC was first reported in 1995 (Blomgren 1995), and 
there is a growing SBRT experience, mostly in patients with small (< 6 cm) HCC (Mendez-
Romero 2006, Cardenes 2010, Kwon 2010, Seo 2010, Louis 2010), with a high local control at 1 
to 2 years (70-90%).  In one study of 38 HCC patients previously treated with TACE, 33 – 57 Gy 
was delivered in 3 fractions, with a 61% 2 year survival (Seo 2010).  Doses > 42 Gy in 3 fractions 
were associated with improved local control.  In another study of 48 patients with HCC treated 
with 3-fraction SBRT (30 – 39 Gy), 11 % of patients had a decline in Child-Pugh class, which was 
more likely if <800 cc of liver could be spared from 18 Gy or more (Son 2010). 
 
Normal tissue complication probability (NTCP) models have been used to describe the partial 
liver volume tolerance to radiation, and to prospectively assign dose to tumor for an individual 
liver cancer patient while maintaining the same estimated risk of liver complication for all patients 
(Ben Josef 2005). Using such an approach, an iso-toxic RT schedule that allows patients with 
HCC unsuitable for standard therapies to be treated in 6 fractions over two weeks using SBRT 
was developed at Princess Margaret Hospital (PMH), University of Toronto (Dawson 2006).  The 
dose per fraction was determined based on the effective volume of normal liver irradiated (Veff), 
accounting for changes in dose per fraction compared to the original NTCP model.  When the 
effective liver volume irradiated was low (Veff < 25%), doses of 54 Gy (9 Gy x 6) were delivered 
safely to HCCs, with excellent local control.  For patients requiring higher volumes of liver to be 
irradiated (Veff 25-80%), doses from 24 to 54 Gy (4 to 9 Gy x 6) were delivered safely, although 
local control was reduced.  The majority of first 31 Child-Pugh A HCC patients who completed 6 
fraction SBRT (med 36 Gy, 24 – 54 Gy, 6 fractions) in the phase I study (14 - Hepatitis B; 12 - 
Hepatitis C; 4 - alcoholic liver cirrhosis) had main or main branch portal vein tumor thrombosis.  
No classic RILD was observed. Eight patients had grade 3 liver enzymes three months following 
therapy (3 with preexisting grade 3 liver enzymes), and there was no treatment-related grade 4/5 
toxicity within 3 months following SBRT.  Five patients had a decline in Child-Pugh score 3 
months after SBRT (mostly in the presence of progressive HCC).  One patient developed grade 3 
thrombocytopenia. One year actuarial local control was 65% (95% CI 44-79%) and median 
survival was 11.7 months (95% CI 9.2-15.0 months). The median survival of the patients without 
portal vein thrombosis was 17.2 months (95% CI: 9-22.5 months) (Tse 2008).  These results are 
encouraging since all patients had HCC refractory to prior therapy (66%) or were unsuitable for 
other standard therapies (34%).  The most common site of first recurrence was in the liver outside 
the irradiated volume, providing rationale for studies combining regional or systemic therapies 
with SBRT.  
 
An updated analysis of the completed phase I and II Toronto SBRT studies of 102 Child-Pugh A 
HCC patients ineligible for local-regional therapies (38% Hepatitis B, 38% Hepatitis C, 25% 
alcohol; 55% portal vein thrombosis; 12% extrahepatic disease) treated with SBRT (median dose 
36 Gy in 6 fractions) from 2004 to July 2010 found a median survival of 17.0 months.  A dose 
response for local control was observed (Bujold 2013).  
 
1.5 
Rationale for Sorafenib and Radiation Therapy 
There is evidence of benefit from the combination of a variety of anti-angiogenic agents with 
radiation therapy at the pre-clinical level. Numerous pre-clinical models have documented 
improved outcome with the combination of RT and bevacizumab, PTK787, ZD6474, SU -11248, -
11657, -5416 and -6668, angiostatin, thrombospondin-1, antibody mediated blockade of VEGFR2 
(DC101 – mouse, and cp1C11 – human), blockade of alphaV/beta3 integrin signaling, and 
vascular disrupting agents (e.g. combretastatin, ZD6126, DMXAA) (Wilhelm 2004, Chang 2007, 
Winkler 2004).  In addition, increasing the oxygenation of tumors with Sorafenib is expected to 

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RTOG 1112, Version Date: September 23, 2022 
improve the therapeutic ratio of radiation therapy to HCC. Sorafenib possesses dual antitumor 
activity by inhibiting the MAPK/ERK pathway and inhibiting neovascularization (Jain 2000).  
Sorafenib has been shown to inhibit proliferation and induce apoptosis in two HCC lines in vitro 
while also inhibiting tumor growth in an in vivo model (Liu 2006).   
 
Another publication assessed combination treatment in a number of cell lines in vitro and HCT116 
human colorectal xenografts in a subcutaneous flank model in nude mice (Plastaras 2007).  Their 
data show that radiation followed by sorafenib appears to result in optimal anti-cancer effect 
compared to the concurrent administration of pre-treatment with sorafenib.   
 
1.6 
Clinical Experience with Sorafenib and Radiation Therapy (27Oct2017) 
Although there is rationale to combine local therapies with sorafenib in HCC, there are few clinical 
publications on the combination of Sorafenib or similar agents with RT.  One retrospective review 
of 23 patients from Taiwan with advanced HCC treated with RT and sunitinib (a TKI with similar 
mechanisms as sorafenib) has been published (Chi 2010).  Sixty percent of patients had two or 
more lesions and 22% had extrahepatic disease.  All were unresectable and unsuitable for 
transhepatic chemo-embolization (TACE).  Five patients had major portal vein thrombosis.  
Fifteen patients had Child-Pugh score A; 8 were Child-Pugh B.  All patients received sunitinib (25 
mg) at least 1 week before, during, and 2 weeks after radiation therapy. Thirteen patients 
continued maintenance sunitinib after RT until disease progression. The median radiation dose 
was 52.5 Gy in 15 fractions.  The objective response rate was 74%.  The 1-year survival rate was 
70%, with a median survival of 16 months. Maintenance sunitinib was the most significant factor 
for survival. The time to progression was 10 months in the maintenance group compared with 4 
months in the control group. There were three episodes of upper gastrointestinal bleeding and 
one episode of pancreatitis.  Ten patients had grade 2 or more elevation of liver enzymes, and 15 
developed grade 2 or more thrombocytopenia.  The authors concluded that conformal 
hypofractionated RT and sunitinib can be delivered safely in HCC patients.  
 
Another phase I study investigated concurrent sunitinib (25 – 35.7 mg) and 10 fraction conformal 
radiation therapy (40 – 50 Gy in 10 fractions) in 21 patients with 36 sites of oligometastases in 
various locations, including the liver (n=9).  No dose limiting toxicity was seen when sunitinib was 
delivered prior to, during and following RT (Chi 2010).  
 
Phase I studies of sorafenib and RT for liver cancer have been conducted at PMH, Toronto.  In 
one phase I study of 30 Gy in 10 fractions combined with escalating dose sorafenib prior to, 
during, and following RT, no dose limiting toxicity (DLT) was observed in patients with locally 
advanced HCC, several with massive portal vein thrombosis (Murray 2017)).  Two other phase I 
studies of six-fraction SBRT plus escalating dose sorafenib were conducted at PMH (Ng 2016, 
Goody 2017).  One study was for patients with liver metastases, and the other was for patients 
with HCC. Both studies combined SBRT (6 fraction) with sorafenib delivered 7 days pre-RT, 
during RT and post RT (1 week for metastases and continuous for HCC), to maximize RT 
sensitization by increasing tumor oxygenation, to increase the antitumor activity via the 
MAPK/ERK pathway and by inhibiting neovascularization that may occur post RT.  Fifteen 
patients with focal liver metastases were evaluable for toxicity (3 at dose level 200 mg po bid, 6 at 
dose level 600 mg po od and 6 at 800 mg po od for 4 weeks), with no DLT. Twelve evaluable 
patients with HCC were treated on study, with continued sorafenib post SBRT.  There was no 
DLT in three evaluable HCC patients treated with SBRT with a low effective liver volume (Veff 
30%) combined with 400 mg sorafenib po od.  In patients with a liver Veff of 30-60%, 2 of 3 
evaluable patients treated with sorafenib 400 mg po daily developed DLT (grade 4 small bowel 
obstruction and grade 3 GI bleed); thus sorafenib was de-escalated to 200 mg po daily.  One of 6 
evaluable patients at this dose level developed DLT (tumor rupture).  For the present study, the 
maximal permitted RT doses to the normal tissues have been reduced, compared to the above 
studies, and sorafenib will be delivered following RT (rather than concurrently with RT), to reduce 
the risk of toxicity.   
 

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RTOG 1112, Version Date: September 23, 2022 
1.7 
Quality of Life (QOL) 
1.7.1 
QOL Overview 
Quality of life (QOL) in HCC is understudied, but clearly of importance due to the expected poor 
overall survival in patients with advanced HCC, the co-morbidities that exist in these patients, the 
near universal presence of underlying liver disease and the potential for serious toxicity to occur 
from treatment. 
 
There are few published prospective studies using validated questionnaires to assess longitudinal 
QOL in patients with HCC receiving local or systemic therapies.  Ringash et al reported (in 
abstract) on prospective QOL assessment in liver metastases and HCC patients receiving SBRT 
using the FACT-Hep (Ringash 2008). In this phase I/II study of SBRT for unresectable liver 
cancers (35% HCC), QOL using the Functional Assessment of Cancer Therapy–Hepatobiliary 
(FACT-Hep) and European Organization for Research and Treatment of Cancer Core Quality of 
Life Questionnaire (EORTC QLQ-C30) was collected at baseline, and at 1, 3 and 6 months post-
treatment. Following SBRT, there was a trend for a decrease in QOL at 3 months; however, QOL 
at 6 months recovered in patients who were alive at that timepoint, suggesting a possible 
beneficial effect. 
 
Due to the paucity of QOL data in HCC and the potential benefit of localized SBRT on QOL, it will 
be important to measure differences in health-related QOL in HCC patients treated with Sorafenib 
as compared to SBRT followed by Sorafenib on this trial. If SBRT is associated with a sustained 
reduction in the burden of HCC compared to sorafenib alone, it may lead to improved QOL 
compared to sorafenib alone. 
1.7.2 
Functional Assessment of Cancer Therapy–Hepatobiliary (FACT-Hep) 
The FACT-Hep version 4 questionnaire will be used to measure QOL. The FACT-Hep is a 45-
item self-report instrument designed to measure health-related quality of life (HRQL) in patients 
with hepatobiliary cancers. The FACT-Hep is validated and presents good internal consistency, 
test–retest reliability, and convergent and discriminate validity in patients with hepatobiliary 
cancer and HCC (Heffernan 2002, Steel 2006, Wang 2007, Steel 2004). The validity of FACT-
Hep has recently been examined in a randomized controlled trial of an EGFRi or placebo (Cella 
2012) In this study, FACT-Hep scores showed significant decline for progressive disease versus 
stable disease (e.g. difference in FACT-Hep total score -12.58; p = 0.004). 
  
1.7.3 
EuroQol (EQ-5D) 
Patient-reported outcomes (PROs) are increasingly being incorporated into clinical trials for 
documentation of effects of treatment not measured by traditional endpoints, such as overall 
survival. This is important with interventions that may increase treatment-related side effects 
without positively impacting survival. Quality-adjusted survival is an endpoint that incorporates a 
patient’s utility or preference of the health state that is combined with the time spent in that health 
state (Glasziou 1990).  
 
The resultant is a quality-adjusted life-year (QALY).  Utility can be measured by different methods 
including Standard Gamble, Time Trade-Off, and Health Utilities Index III. The EuroQol (EQ-5D) 
is another instrument for measuring utilities. It is a 2-part questionnaire that takes the patient 
approximately 5 minutes to complete (Schultz 2002). The first part consists of 5 items covering 5 
dimensions, 
including: 
mobility, 
self-care, 
usual 
activities, 
pain/discomfort, 
and 
anxiety/depression.  Each dimension can be graded on 3 levels including: 1-no problem, 2-
moderate problems, and 3-extreme problems. There are 243 potential health states.  The second 
part is a visual analogue scale (VAS) valuing current health state, measured on a 20 cm, 10 
point-interval scale.  Either the index score or the VAS score can be used in the quality-adjusted 
survival analysis (Wu 2002). The benefit of measuring quality-adjusted survival is that it can be 
compared to the outcomes of other interventions across disease sites and can be used by health 
policy makers to rank interventions.  
 
The EQ-5D will be used to evaluate the effect of the addition of SBRT to sorafenib on quality-
adjusted survival in this trial.   
 

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RTOG 1112, Version Date: September 23, 2022 
1.8 
Biomarkers in HCC 
1.8.1 
Liver Toxicity 
The possibility for liver toxicity to occur following therapy for HCC limits the effectiveness of 
therapies for HCC, especially for patients with locally advanced HCC.  Sinusoidal obstructive 
syndrome is thought to be an important component of radiation induced liver disease; however 
the exact pathophysiology has not been clearly elucidated.  As children who develop veno-
occlusive disease (VOD) following transplant develop significant increases in plasminogen 
activator inhibitor type I, tissue plasminogen activator, and D-dimer and significant decreases in 
prothrombin time, antithrombin, and α2-antiplasmin at the time of their clinical diagnosis of veno-
occlusive disease (VOD), such factors may be useful for better understanding radiation (or 
sorafenib) induced liver sinusoidal obstructive syndrome related toxicity.   
 
In addition, transforming growth factor- ß is an important cytokine associated with tissue injury 
and wound healing and may be associated with non-specific liver disease, including  cirrhosis, 
chronic hepatitis, or toxicity, from sorafenib or radiation.  Other cytokines participate in the 
response to tissue injury, including proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis 
factor alpha.  Baseline levels and temporal variations in levels of these cytokines may provide 
insight to liver toxicity pathogenesis, and may also be related to patient reported fatigue and 
decline in QOL.  
1.8.2 
Prognostic Factors 
HCC specimen microvessel density (MVD), pERK (marker of signal transduction), VEGFR-2 
(marker of angiogenesis) and Ki-67 and MIB-1 (markers for proliferation) are potential prognostic 
markers in HCC. 
 
Circulating VEGF, soluble sVEGFR-s, Ang-1, Ang-2, PDGF, and sc-Kit have been correlated with 
sorafenib treatment response. Investigating changes in such potential biomarkers in a 
randomized trial may help to validate which biomarkers are most treatment predictive and/or 
prognostic. 
 
 
1.9       Protocol Overview 
A randomized phase III study of sorafenib versus SBRT followed by sorafenib for locally 
advanced HCC (unsuitable for or refractory to surgery, RFA or TACE) is proposed.  It is expected 
that the primary patient population will have BCLC stage C HCC, due primarily to tumor vascular 
thrombosis. The sequential timing of treatments in the experimental arm (SBRT followed by 
sorafenib), rather than concurrent sorafenib and SBRT, should reduce the risk of toxicity. The 
dose of sorafenib during the first 28 days following SBRT is half standard dose (200 mg po bid) 
based on the Toronto phase I experience to reduce potential increase in toxicity due to radiation 
sensitization that may occur during that time period following SBRT.  The primary endpoint is 
overall survival, and the hypothesis is that SBRT followed by sorafenib will improve survival in 
HCC patients by improving hepatic and vascular control of HCC, compared to sorafenib alone.  
 
 
2.0 OBJECTIVES 
2.1 
Primary Objective 
2.1.1 
To determine if SBRT improves overall survival in HCC patients treated with Sorafenib 
 
2.2 
Secondary Objectives  
2.2.1 
To determine the difference in time to progression (TTP) and progression-free survival (PFS) in 
HCC patients treated with Sorafenib compared to SBRT followed by Sorafenib 
2.2.2 
To measure differences in toxicity in HCC patients treated with Sorafenib versus SBRT followed 
by Sorafenib 
2.2.3 
To measure vascular thrombosis response post Sorafenib versus SBRT followed by Sorafenib  
2.2.4 
To measure differences in Health Related QOL and quality-adjusted survival in HCC patients 
treated with Sorafenib compared to SBRT followed by Sorafenib 
2.2.5 
Collection of biospecimens for future correlative studies to investigate differences in potential 
biomarkers in patients treated with Sorafenib versus SBRT followed by Sorafenib 
 

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RTOG 1112, Version Date: September 23, 2022 
 
3.0 PATIENT SELECTION 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
3.1 
Conditions for Patient Eligibility (13-MAY-2019) 
For questions concerning eligibility, please contact Data Management or the Study Chair (see 
second page of protocol). 
3.1.1 
Patients must have an HCC diagnosis (initial, recurrent, progressive and/or refractory to other 
therapies) by at least one criterion listed below ≤360 days prior to study entry 
a) Pathologically (histologically or cytologically) proven diagnosis of HCC. 
b) At least one solid liver lesion or vascular tumor thrombosis (involving portal vein, IVC 
and/or hepatic vein) > 1 cm with arterial enhancement and delayed washout on multi-
phasic computerized tomography (CT) or magnetic resonance imaging (MRI) in the 
setting of cirrhosis or chronic hepatitis B or C without cirrhosis. 
c) For patients whose CURRENT disease is vascular only: 
Enhancing vascular thrombosis (involving portal vein, IVC and/or hepatic vein) 
demonstrating early arterial enhancement and delayed washout on multi-phasic CT 
or MRI, in a patient with known HCC (diagnosed previously < 720 days), using 
criteria in 3.1.1a or 3.1.1b   
3.1.2 
Patients must have measureable hepatic disease and/or presence of vascular tumor thrombosis 
(involving portal vein, IVC and/or hepatic vein) which may not be measureable as per RECIST, as 
defined in Section 11.0) on liver CT or MRI, within 28 days PRIOR TO STUDY ENTRY 
3.1.3 
Appropriate for protocol entry based upon the following minimum diagnostic workup: 
• 
History/physical examination including examination for encephalopathy, ascites, weight, 
height, and blood pressure within 14 days prior to study entry 
• 
Assessment by radiation oncologist and medical oncologist or hepatologist who 
specializes in treatment of HCC within 28 days prior to study entry. 
• 
Pre-randomization Scan (REQUIRED for All Patients):  Within 28 days prior to study 
entry, multiphasic liver CT or multiphasic liver MR scan-.  See Appendix V and Section 
4.1.7 for details. 
• 
Within 28 days prior to study entry CT chest with CT or MR abdomen and CT or MR 
pelvis, or PET CT chest/abdomen/pelvis-.   
3.1.4 
Zubrod Performance Status 0-2 within 28 days prior to study entry 
3.1.5 
Age ≥ 18 
3.1.6 
All blood work obtained within 14 days prior to study entry with adequate organ marrow function 
defined as follows: 
• 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3  
• 
Platelets ≥ 60,000 cells/mm3 
• 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to 
achieve Hgb ≥ 8.0 g/dl is acceptable.) 
• 
AST and ALT < 6 times ULN 
• 
Serum creatinine ≤ 2 x ULN or creatinine clearance ≥ 60 mL/min 
3.1.7  
Patients must have BCLC stage: Intermediate (B) or advanced (C) (see Appendix IV) within 28 
days prior to study entry 
3.1.8 
Child-Pugh score A within 14 days prior to study entry (using INR from < 28 days is acceptable) 
3.1.9 
Women of childbearing potential and male participants must agree to practice adequate 
contraception while on study and for at least 6 months following the last dose of RT and for at 
least 28 days following the last dose of sorafenib (whichever is later). 
3.1.10 Unsuitable for resection or transplant or radiofrequency ablation (RFA) 
3.1.11 Unsuitable for or refractory to transarterial hepatic chemo-embolization (TACE) or drug eluting 
beads (DEB) for any of the following reasons, as described by Raoul et al (2011):  
• 
Technical contraindications: arteriovenous fistula, including surgical portosystemic 
shunt or spontaneous portosystemic shunt  

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RTOG 1112, Version Date: September 23, 2022 
• 
Severe reduction in portal vein flow: due to tumor portal vein, IVC or atrial invasion 
or bland portal vein occlusion 
• 
Medical contraindications including congestive heart failure, angina, severe 
peripheral vascular disease 
• 
Presence of extrahepatic disease 
• 
No response post TACE (or DEB) or progressive HCC despite TACE.  Prior TACE 
or DEB is allowed but must be > 28 days from study entry 
• 
Serious toxicity following prior TACE (or DEB). Prior TACE or DEB must be > 28 
days from study entry 
• 
Other medical comorbidities making TACE (or DEB) unsafe and/or risky (e.g. 
combination of relative contraindications including age > 80 years, tumor > 10 cm, 
> 50% replacement of the liver by HCC, extensive multinodular bilobar HCC, biliary 
drainage) 
3.1.12 Patients treated with prior surgery are eligible for this study if they otherwise meet eligibility 
criteria. 
3.1.13 Patient must be able to provide study-specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (27Oct2017) 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer and T1 renal cell carcinoma) 
unless disease free for a minimum of 2 years (Note that carcinoma in situ of the breast, oral 
cavity, or cervix are all permissible) 
3.2.2 
Prior sorafenib use > 60 days and/or grade 3 or 4 Sorafenib related toxicity. Note that prior 
chemotherapy for HCC or a different cancer is allowable. See Section 3.2.1. 
3.2.3 
Prior radiotherapy to the region of the liver that would result in excessive doses to normal tissues 
due to overlap of radiation therapy fields 
3.2.4 
Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any time 
3.2.5 
Severe, active co-morbidity, defined as follows: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization within the 
last 6 months PRIOR TO registration 
• 
Transmural myocardial infarction within the last 6 months prior to study entry 
• 
Unstable ventricular arrhythmia within the last 6 months prior to study entry 
• 
Acute bacterial or fungal infection requiring intravenous antibiotics within 28 days 
prior to study entry 
• 
Hepatic insufficiency resulting in clinical jaundice, encephalopathy and/or variceal 
bleed within 28 days prior to study entry 
• 
Bleeding within 28 days prior to study entry due to any cause, requiring transfusion 
• 
Thrombolytic therapy within 28 days prior to study entry. Subcutaneous heparin is 
permitted. 
• 
Known bleeding or clotting disorder 
• 
Uncontrolled psychotic disorder 
3.2.6 
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.  
3.2.7  
Maximal diameter of any one hepatocellular carcinoma > 15 cm 
3.2.8  
Total sum of maximum diameters of each definite parenchymal hepatocellular carcinoma within 
the liver or maximum diameter of a single conglomerate HCC > 20 cm 
3.2.9 
More than 5 discrete intrahepatic parenchymal foci of definite HCC 
3.2.10  Direct tumor extension into the stomach, duodenum, small bowel or large bowel 
3.2.11 
Measureable common or main branch biliary duct involvement with HCC 
3.2.12 
Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC) > 3.0  
 
cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph node or two 2 
cm lung lesions). 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. 
3.2.13 
Prior liver transplant 

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RTOG 1112, Version Date: September 23, 2022 
3.2.14 
HIV positive with CD4 count < (350) 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 ≥ (350) cells/microliter, and no known detectable viral load, at the time of study 
entry. Note also that HIV testing is not required for eligibility for this protocol 
 
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 (27OCT2017) 
4.1.1 
Assessment of degree of vascular involvement (IVC, main portal vein, right or left main branch 
portal vein versus other vascular involvement (e.g. peripheral portal branches, hepatic vein) 
versus none). See Appendix X for details. 
4.1.2 
Documentation of liver disease, including cirrhosis, Hepatitis history [Hepatitis B and Hepatitis C 
status, hemachromatosis, alcohol, autoimmune disease, non-alcoholic steatohepatitis (NASH)] 
4.1.3 
Alfa-feto protein (AFP) within 28 days prior to study entry 
4.1.4 
Bilirubin, INR, albumin, alkaline phosphatase (ALP), phosphate, sodium, potassium, chloride, 
magnesium, calcium within  
 
28 days prior to study entry 
4.1.5 
bHCG within 14 days prior to study entry if patient is pre or peri menopausal 
4.1.6 
Documentation of any extrahepatic disease status, number of sites and sum of maximum 
diameter of extrahepatic disease 
4.1.7 
Submission of IV contrast diagnostic or planning CT or MRI scan (See Section 3.1.3) within 1 
week of randomization for patients not randomized to SBRT (Note: This scan is used for the 
stratification factors of tumor:(liver [including all GTV]) ratio and the degree of vascular 
thrombosis, so the actual scan and measurements should be done as close to the time of study 
entry as possible.).  
For all patients, this scan should include: 
• 
Multiple phases of imaging if needed to best demonstrate the GTV ( e.g. arterial, 
venous and delayed) 
• 
Contours of GTV (gross tumor volume = volume of all parenchymal and vascular 
HCC) 
• 
Contours of the liver (whole liver including GTV)  
 
4.2 
Highly Recommended Evaluations/Management (27Oct2017) 
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 
Consultation by hepatologist within 28 days prior to study entry (strongly recommended if known 
Hepatitis B or C and/or the patient has never seen a hepatologist) 
4.2.2 
Work-up for Hepatitis B and Hepatitis C within 28 days prior to study entry (if Hepatitis status not 
previously documented) 
4.2.3 
Patients with known portal hypertension or known history of varices should have an endoscopic 
assessment of and appropriate treatment of varices within 6 months of study entry 
4.2.4 
Calculation of MELD score within 14 days prior to study entry (Appendix VII) 
4.2.5 
Assessment of vascular thrombosis (tumor thrombosis [e.g. with arterial enhancement and 
venous phase washout on CT or MRI] or bland thrombosis) 
4.2.6 
Documentation of prior HCC therapies 
4.2.7 
Documentation of any liver disease etiology and any other factors associated with liver disease   
4.2.8 
Initiation of treatment of viral Hepatitis B (if untreated) prior to study therapy, to be done under the 
supervision of hepatology 
4.2.9 
If randomized to SBRT, 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.  
4.2.10 
If randomized to SBRT, and stomach or duodenum is within irradiated volume (> 20 Gy), proton 
pump inhibitors are highly recommended to reduce the risk of SBRT related GI bleeding. 

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RTOG 1112, Version Date: September 23, 2022 
4.2.11 
If medically appropriate, discontinuation of regular (daily) phenytoin, carbamazepine, 
phenobarbital or dexamethasone 
4.2.12    For all patients, the following criteria calculated from baseline CT or MR scans (see Section 4.1.7) 
should be met: 
• 
Liver volume minus intrahepatic GTV > 700 cc. 
• 
Intrahepatic GTV/[liver volume (including the intrahepatic GTV)] ratio <80%. 
 
5.0  REGISTRATION, STUDY ENTRY PROCEDURES (23-SEP-2022) 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account at https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration 
type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete 
their annual registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.   
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications (e.g.,such 
as the Roster Update Management System [RUMS], OPEN, Rave,; acting as a primary site 
contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with limited 
access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and Institutional Review Boards (IRBs) covering their practice sites 
on the FDA Form 1572 in RCR to allow the following: 
• 
Add to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval. 
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), or consenting/treating/drug shipment investigator in OPEN must be rostered at the 
enrolling site with a participating organization.  
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm . For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
5.1 
Pre-Registration Requirements for all Radiation Techniques (27Oct2017) 
 
 
In order to be eligible to enroll patients onto this trial, the center must be credentialed for SBRT. 
See the credentialing table for details. SBRT credentialing consists of liver image-guided 
radiotherapy (IGRT) credentialing, as described in Section 5.2 below.  An additional component 
of the SBRT credentialing is the completion of the IGRT questions in Parts II and III of the Facility 
Questionnaire (see Section 5.1.3). If IMRT or protons are to be used, the center must be 
credentialed for these treatment modalities (see Sections 5.3 and 5.4).  Institutions using only 3D 
conformal delivery techniques must follow the same credentialing approach described for IMRT. 
Institutions using either 3D-CRT or IMRT need to be credentialed for IMRT only. Based on the 
answers to the questions in Part III of the Facility Questionnaire, the phantom provided for IMRT, 
3D-CRT or proton credentialing will come with a moving table when either gating or tracking are 
used for motion management.  Irradiation of an anthropomorphic phantom on a moving table, 
when dictated by the motion management technique, is the final part of the SBRT credentialing.  
 
RT 
Credentialing 
Requirements 
  
Web Link for Procedures and Instructions: 
http://irochouston.mdanderson.org 
  
Treatment 
Modality 
Key Information  
  
SBRT  
IMRT 
Proton 
Facility 
Questionnaire 
 
 
 
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 
 
 
 
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) 
Benchmark 
 
 
 
The benchmark case is to be downloaded and completed 
by the site before submission to a QA center.  

24 
RTOG 1112, Version Date: September 23, 2022 
Cases 
http://atc.wustl.edu/protocols/rtog/1112/1112.html 
Phantom 
Irradiation 
 
 
 
A liver phantom study provided by the IROC Houston QA 
Center 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.  The motion 
management technique must be used during phantom 
irradiation. Acceptable TPS/ algorithm must be used. 
IGRT 
Verification 
Study 
 
 
 
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   
Institution 
IROC Houston QA Center will notify the site that all 
desired credentialing requirements have been met.  The 
site will need to upload a PDF of the approval email from 
IROC Houston to the CTSU Regulatory Portal for RSS to 
be updated. 
 
5.1.1 
Only institutions that have met the technology requirements and that have provided the baseline 
physics information may enter patients onto this study. All proton facilities must have completed 
baseline approval steps in addition to credentialing steps. 
5.1.2 
IROC Houston will notify the institution when all requirements have been met and the 
institution is eligible to enter patients onto this study.  
General Radiation Credentialing Process 
The following are required for all techniques, including conformal non-IMRT, non-proton SBRT: 
A liver phantom study provided by the Imaging and Radiation Oncology Core (IROC) Houston 
(formerly Radiological Physics Center [RPC])], must be successfully completed. Instructions for 
requesting and irradiating the phantom are available on the IROC Houston web site at 
http://irochouston.mdanderson.org.  See the credentialing table for details; select “Credentialing” 
and “NRG Oncology”. Upon review and successful completion of the phantom irradiation, IROC 
will notify both the registering institution and NRG Oncology that the institution has completed this 
requirement. Subsequently, NRG Oncology will notify the institution that the site can enroll 
patients on the study.  Note that only the most sophisticated technique needs to be credentialed, 
e.g., if credentialed for IMRT, 3DCRT may be used. 
 
Each participating institution also must successfully complete and submit a protocol-specific 
Benchmark Plan (“Dry-Run” QA). The Benchmark Scan will be made available for downloading 
from IROC:  (http://atc.wustl.edu/protocols/rtog/1112/1112_benchmark.html).  See the 
credentialing table for details. The scan should be contoured and planned as per RTOG 1112. 
The completed benchmark case will be submitted to TRIAD and selecting “benchmark” on the 
drop down menu. The benchmark target contour, normal tissue contour and dosimetry will be 

25 
RTOG 1112, Version Date: September 23, 2022 
reviewed by the PI or her designee, who will notify IROC if the institution has successfully 
completed this requirement.  Feedback will be provided to the participating institution.  
 
5.2  
Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) (27OCT2017)  
5.2.1  
IGRT is required in this protocol and the center must be credentialed for its use. This means the 
institution must have met technology requirements and have provided the baseline physics 
information. This information is available at:  http://irochouston.mdanderson.org on the 1112 
protocol page. See the credentialing table for details. 
5.2.2 
IGRT Credentialing Process  
The institution must submit a sample of verification images demonstrating their ability to 
reproducibly register daily IGRT information with a planning CT dataset (i.e., the GTV falls within 
the CT simulation defined PTV). See the credentialing table for details.  A soft tissue surrogate for 
the GTV (e.g. liver, TACE cavity, inserted fiducial markers) must be used for alignment. Boney 
anatomy should not be used for alignment. 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 web site, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1112) 
will be reviewed by the Physics Co-Chair, assisted by IROC Phila RT. Upon approval of the 
images and spreadsheet, IROC Phila RT will notify the institution that it is credentialed to use 
IGRT.  Pre-treatment images may include three-dimensional (3D), 4-dimensional (4D) volumetric 
images (either fan- or cone-beam CT with Megavoltage (MV) or kilovoltage (kV) x-ray) or paired 
kV 2D images. 2D MV images are not permitted to be used as the only tool for IGRT. These 
images and the spreadsheet will be reviewed by the physicist PI or designee. Each different 
combination of IGRT technology and motion management technology should be credentialed in 
this manner; centers will receive feedback from this IGRT credentialing. Registration of the first 
patient to the protocol cannot proceed until approval for the “as if patient” is obtained.  
 
For each IGRT technology, in addition to each “as if patient” dataset, the images for all treatment 
fractions and offsets for the first two actual patients treated with SBRT on study should be 
submitted for review within 5 days of completion of therapy. Feedback will be communicated to 
the participating institution regarding IGRT credentialing. 
 
5.3 
 Pre-Registration Requirements for Intensity Modulated Radiation Therapy (IMRT) 
(27Oct2017) 
5.3.1 
In order to utilize IMRT on this study, the institution must have met specific technology 
requirements and have provided baseline physics information. Instructions for completing these 
requirements or determining if they already have been met are available on the IROC Houston 
web site. See the credentialing table for details.  
5.3.2 
If IMRT is to be used, review and successful completion of the Benchmark Plan (“Dry-Run” 
QA test) using IMRT is required, NRG Oncology will notify the registering institution that the 
institution has successfully completed this requirement for IMRT. 
5.3.3 
Participating institutions must use approved heterogeneity algorithms by IROC. Acceptable 
choices of algorithm are listed at 
http://rpc.mdanderson.org/rpc/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf   
5.3.4 
Sites using CyberKnife™ equipment must be credentialed for dose painting IMRT prior to 
enrolling patients on study.  See the credentialing table for details. 
5.3.5 
If an institution is credentialed for the use of IMRT on this study, this IMRT credentialing for the  
 
specific treatment modality will suffice for non-IMRT photon treatment delivery. As such the 
institution will not have to re-credential for non-IMRT photon treatment delivery. 
 
5.4  
Pre-Registration Requirements for Proton Treatment Approach (25-MAR-2020) 
5.4.1 
Proton Credentialing Process  

26 
RTOG 1112, Version Date: September 23, 2022 
Proton therapy may be used on this protocol.  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 websites of the RPCIROC Houston 
(http://irochouston.mdanderson.org), and. These requirements include, but are not limited to, 
completion of a proton facility questionnaire, a successful IROC Houston site visit, which 
identifies the proton technique(s) which can be used, annual monitoring of the proton beam 
calibration, e.g. IROC Houston’s monitoring program, and having established TRIAD account for 
submission of digital data. 
5.4.2     Dose will be reported in Gy (RBE), where 1 Gy(RBE) = proton dose Gy x RBE (radiobiological 
effective dose), RBE = 1.1. 
5.4.3 
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. 
5.4.4 
The IROC Houston will coordinate the completion of the proton therapy use approval process in 
conjunction with the appropriate other Quality Assurance Offices for any additional protocol 
specific credentialing requirements.  A specific proton liver phantom study provided by IROC 
Houston must be successfully completed (if the institution has not previously met this 
credentialing requirement for proton therapy). Instructions for requesting and irradiating the 
phantom are available on the IROC Houston web site at http://irochouston.mdanderson.org; 
select “Credentialing” and “NRG Oncology”. Upon review and successful completion of the 
phantom irradiation, IROC Houston will notify both the registering institution and NRG Oncology 
that the institution has completed this requirement. Subsequently, NRG Oncology will update the 
RSS database when all credentialing requirements have been met. 
5.4.5 
Proton resources for this protocol include: 
Medical Physics Co-Chair (Protons) 
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  
 
 
 
 
Radiation Oncology Co-Chair (Protons) 
Sunil Krishnan, MD 
Mayo Clinic Florida 
Dept. of Radiation Oncology 
4500 San Pablo Road 
Jacksonville, FL 32224-1865 
904-953-2000 
krishnan.sunil@mayo.edu 
 
5.4.6 
If protons are to be used, review and successful completion of the Benchmark Plan (“Dry-Run” 
QA test) using protons is required, the IROC Houston will notify both the registering institution 
and NRG Oncology that the institution has successfully completed this requirement for protons. 
 
5.5 
Digital Radiation Therapy Data Submission Using Transfer of Images and Data (26-MAY-
2022)   
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) 
image exchange application. TRIAD provides sites participating in clinical trials a secure 
method to transmit images. TRIAD anonymizes and validates the images as they are 
transferred. 
TRIAD Access Requirements: 

27 
RTOG 1112, Version Date: September 23, 2022 
• 
A valid Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) (CTEP-IAM) account.  
• 
Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR. Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in 
RCR. 
• 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access to 
TRIAD and may submit images for credentialing purposes, or for enrollments to which the 
provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to install the 
TRIAD application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR 
registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org 
or 1-703-390-9858. 
 
5.6  
Regulatory Pre-Registration Requirements (23-SEP-2022) 
 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional Review 
Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to activate new 
studies at the site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site under the local 
IRB. International sites should continue to submit Research Ethics Board (REB) approval to the 
CTSU Regulatory Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for Local Context 
(SSW) to the CIRB using IRB Manager to indicate their intent to open the study locally. The NCI 
CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory Office, but 
sites are required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to 
establish site preferences for applying NCI CIRB approvals across their Signatory Network. Site 
preferences can be set at the network or protocol level. Questions about establishing site 
preferences can be addressed to the CTSU Regulatory Office by email or calling 1-888-651-CTSU 
(2878). 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 

28 
RTOG 1112, Version Date: September 23, 2022 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Protocol Specific Requirements 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider. To manage provider associations or to add or remove associated 
providers, access the Provider Association page from the Regulatory section on the CTSU 
members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to 
at least one Imaging and Radiation Oncology Core (IROC) provider to participate on trials with an 
RTI component. Enrolling sites are responsible for ensuring that the appropriate agreements and 
IRB approvals are in place with their RTI provider. An individual with a primary role on a treating 
site any roster is required can to update the provider associations, though all individuals at a site 
may view provider associations, though all individuals at a site may view provider associations.  
To find who holds primary roles at your site, please view the Person Roster Browser under the 
RUMS link section on the CTSU website. 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston to verify 
credentialing status or to begin a new modality credentialing process. 
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated IROC 
Quality Assurance (QA) center. Upon the IROC QA center approving the RTI provider for the 
study modality, IROC will automatically send the approval to the Regulatory Support System 
(RSS) to comply with the protocol-specific requirement, unless otherwise noted at the bottom of 
the IROC Credentialing Approval notification.  IROC will continue to copy the provider and/or 
enrolling site on modality approvals. 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject in the 
OPEN credentialing screen and may need to answer additional questions related to treatment in 
the eligibility checklist.   
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and IRB/REB approved consent (applies to International and 
Canadian sites only: English and native language versions*) 
*Note: Institutions must provide certification/verification of IRB/REB consent translation to 
NRG Oncology Headquarters (described below). 
• 
Credentialing documentation received from IROC Houston must be uploaded to the 
CTSU Regulatory Portal for RSS to be updated. 
• 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC to begin 
the modality credentialing process.  
 
 
 
 

29 
RTOG 1112, Version Date: September 23, 2022 
*Non-English Speaking Canadian and Non-North American Institutions 
Translation of 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. 
 
Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents is 
restricted to institutions and its associated investigators and staff on a participating roster. To 
view/download site registration forms:   
• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of the screen 
o 
Enter the protocol number in the search field at the top of the protocol tree, or 
o 
Click on the By Lead Organization folder to expand, then select NRG and protocol 
number RTOG-1112 
• 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided. (Note: For sites 
under the CIRB, IRB data will load automatically to the CTSU.)  
Click on Documents, select Site Registration, and download and complete the forms provided.   
(Note: For sites under the CIRB, IRB data will load automatically to the CTSU) 
 
       
 
 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website, go to the   
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-CTSU 2878 in order to receive further 
instruction and support. 
 
Checking Site’s Registration Status: 
Site’s registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory  at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements as 
outlined within the protocol.  It does not reflect compliance with protocol requirements for 

30 
RTOG 1112, Version Date: September 23, 2022 
individuals participating on the protocol or the enrolling investigator’s status with the NCI or their 
affiliated networks. 
 
 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines [per section 6.2.5 of ICH E6(R2)]. 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, essential documents must be retained for 25 years following the completion of the trial at 
the participating site (25 years post final analysis, last data collected, or closure notification to 
REB, whichever is later), or until notified by the sponsor, NRG Oncology, that documents no 
longer need to be retained [per C.05.012 (4) of the FDR].  In addition, upon request by the 
auditor, REB or regulatory authority, the investigator/institution must make all required trial-related 
records available for direct access [per section 4.9.7 of ICH]. Prior to clinical trial commencement, 
Canadian institutions also must complete and submit the following documents to the CTSU 
Regulatory Office via the Regulatory Submission Portal: 
• 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form,  
• 
Qualified Investigator Undertaking Form, and  
• 
Research Ethics Board Attestation Form.  
 
 
Pre-Registration Requirements FOR INTERNATIONAL INSTITUTIONS 
             For institutions that have not been approved for this protocol, please contact NRG 
Headquarters for approval.  
 
 
5.7  
OPEN Registration  (13-MAY-2019) 
5.7.1  
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.   
 
Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available 
on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the Lead 
Protocol Organization (LPOs) registration/randomization systems or Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. OPEN 
will populate the patient enrollment data in NCI’s clinical data management system, Medidata 
Rave. 
Requirements for OPEN access:   
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the 
IVR or NPIVR must list the IRB number used on the site’s IRB approval on their Form FDA 1572 
in RCR.  
Prior to accessing OPEN, site staff should verify the following: 

31 
RTOG 1112, Version Date: September 23, 2022 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. 
Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
5.7.2 
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  19-AUG-2019 
Notes: See Section 5.5 for information on installing TRIAD for submission of digital RT data prior 
to enrolling patients. 
 
IMRT, SBRT, and Protons are allowed. The rationale for protons includes their ability to limit the 
dose to normal tissue, including the non-GTV liver tissue.  
 
For patients randomized to the SBRT arm, SBRT is to be delivered over 5 fractions delivered over 5 to 15  
days followed by Sorafenib. 
 
For patients who are taking sorafenib prior to randomization to SBRT (<60 days as per eligibility), the  
sorafenib is recommended to be held at least 2 to 5 days prior to the start of SBRT, and should not be 
delivered concurrently with SBRT. 
 
This protocol requires, at a minimum number, pre-treatment review of the contours and plan PRIOR 
TO DELIVERY of radiation treatment for the first three registered patients. More pre-treatment 
reviews will be required if deviations are seen in these reviewed plans. These pre-treatment reviews are 
aimed at providing feedback from the co-chairs and IROC on the institution’s imaging, contours and 
treatment plan. 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.  The 3 days start once complete 
data has been received.  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 three cases (in addition to the benchmark case described 
in Section 5.1.5), all subsequent cases will undergo a timely review. Thus, digital data must be submitted 
in a timely fashion for all plans. Data submission for a timely review must be within 5 days of completion 
of radiation therapy.  Based on the results of any of the reviews described above, a request for additional 
rapid reviews might be necessary. 
 
A liver protocol CT (Appendix V) must be obtained for treatment planning. 
 
Protocol treatment is encouraged to begin as soon as possible after study entry. Protocol 
treatment must begin within 21 days after study entry unless extra time is needed for fiducial 
marker insertion, but not to exceed 28 days. 

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RTOG 1112, Version Date: September 23, 2022 
 
6.1 
Dose Specifications (27Oct2017) 
6.1.1 
The primary tumor(s) and any tumor vascular thrombi must be treated.  Prophylactic nodal 
radiation is not permitted.  Treatment of non-tumor extrahepatic vascular thrombi, RFA cavities 
and prior TACE sites is not recommended unless the treating oncologist believes these regions 
are at high risk of containing microscopic HCC (e.g. HCC growing from a RFA cavity) and normal 
tissue limits can be maintained.   
6.1.2 
Treatment Schedule:  Treatment will be delivered in 5 fractions.  The time between fractions 
should be between 24 and 72 hours, with treatment delivered to all targets over 5 to 15 days (with 
10 days being the preferred treatment time).   The preferred inter-fraction interval is 48 hours. All 
lesions may be treated on the same day, or alternative lesions may be treated on alternate days, 
as long as the overall treatment time is 15 days at maximum.  When there are multiple target 
volumes, a composite plan demonstrating the composite doses to the targets, liver and other 
normal tissues must be submitted, and all planning guidelines must be met, as described in 
Section 6.5 (i.e. individual target plans are not to be submitted separately). 
6.1.3 
Prescription Dose   
Photons:  Absorbed dose: 27.5 Gy - 50 Gy in 5 fractions.  The prescription dose may be 50 Gy, 
45 Gy, 40 Gy, 35 Gy, 30 Gy or 27.5 Gy in 5 fractions, based on normal tissue constraints. The 
dose to multiple PTVs may be different.  The goal is to use the highest allowable prescription 
dose to the primary target, while respecting normal tissue constraints. The minimal planned 
prescription dose to PTVs is 27.5 Gy.  
Protons:  Absorbed dose:  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.   
Absorbed dose DRBE 27.5 Gy – 50 Gy in 5 fractions, with the prescription dose 50 Gy (RBE), 45 
Gy (RBE), 40 Gy (RBE), 35 Gy (RBE), 30 Gy (RBE) or 27.5 Gy (RBE) in 5 fractions, based upon 
normal tissue constraints. The minimal planned prescription dose to PTVs is 27.5 Gy (RBE). 
6.1.4 
Dose Specifications  
Photons: The prescription isodose should encompass 95% of PTV.  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, with normalization to the PTV receiving the highest dose.   The highest 
allowable doses to the target volumes that maintain normal tissue constraints should be 
used. A goal is that 100% of the CTV is encompassed by the prescription dose. The unit of dose 
is Gy. 
Protons: The prescription isodose is planned to encompass 95% of the PTV. 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, with normalization to the PTV receiving the highest dose. The 
highest allowable doses to the target volumes that maintain normal tissue constraints should be 
used. A goal is that 100% of the CTV is encompassed by the prescription dose.  The unit of dose 
is Gy(RBE). 
6.1.5 
Dose prescription: Is based on the volume of normal tissues irradiated (correlated with mean liver 
dose), as well as proximity of stomach, duodenum, small and large bowel (GI luminal structures) 
to the target volumes, as normal tissue constraints must be maintained in this study. 
 
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 6 potential dose levels: Use of effective liver volume (Veff) to aid in 
dose allocation is permitted (Appendix X).  If there are discrepancies in the Veff and MLD for the 
prescription dose allocation, MLD has priority.  A call to the clinical PI or physics PI is 
recommended if this occurs. 
 
Optional 
Constraint 
Priority 
Constraint 
Prescription Dose 
Liver Veff 
Allowed Mean 
Planned 
If the maximum allowed MLD is exceeded 

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RTOG 1112, Version Date: September 23, 2022 
Liver Dose 
[MLD] (Gy) 
Prescription 
Dose (Gy) 
at this planned dose 
 
< 25% 
13.0 
50 
Reduce to 45 Gy and re-evaluate 
25 - 29% 
15.0 
45 
Reduce to 40 Gy and re-evaluate 
30 - 34% 
15.0 
40 
Reduce to 35 Gy and re-evaluate 
35 - 44% 
15.5 
35 
Reduce to 30 Gy and re-evaluate 
45 - 54% 
16.0 
30 
Reduce to 27.5 Gy and re-evaluate 
55 - 64% 
17.0 
27.5 
Ineligible 
Dose values in this table should be read as physical dose for photons, or RBE-
weighted dose for protons (assuming RBE = 1.1). 
• 
Vascular tumor thrombosis (e.g., portal vein or other vascular HCC thrombosis or 
invasion) should be considered GTV and treated as per 6.1.5.  Non-tumor bland 
thrombosis is not recommended to be irradiated, but may be included as CTV 
(rather than GTV) if judged at risk of containing HCC.    
• 
Maximum dose within PTV = 150%. If multiple PTVs exist, 150% of the maximal 
PTV prescription dose is permitted for all PTVs. 
• 
Maximum dose outside PTV = 120% of the maximal PTV prescription. 
• 
Efforts should be made to keep the prescription dose and the 30Gy isodose as 
conformal as possible. 
• 
Different isodoses may cover different PTVs. If multiple PTVs, the MLD should be 
evaluated with the prescription dose corresponding to the highest dose level that 
any PTV is treated. Queries should be directed to the study PI, Dr. Dawson, or 
physics PI, Dr. Craig. 
 
6.2 
Technical Factors 
6.2.1 
Equipment (photons): Megavoltage equipment with photons of at least 6MV, capable of daily 
image guidance, with a multileaf collimator for intensity modulation is required. Inverse-planned 
IMRT, forward planned IMRT and conventional 3D CRT are permitted. 
Equipment (protons): The proton delivery system must deliver protons of sufficient energy to 
cover the target.  There is less integral dose with protons, which should reduce the risk of toxicity 
in patients with HCC.  
6.2.2 
CT based planning required. For non-proton plans, a minimum of 5 beam angles is strongly 
recommended. Arc therapy is permitted. 
6.2.3 
Image guided radiation therapy (IGRT): IGRT is mandatory. 
6.2.4 
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.  
 
6.3 
Localization, Simulation, and Immobilization (27Oct2017) 
6.3.1 
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 
Treatment planning CT scans will be 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 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 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 

34 
RTOG 1112, Version Date: September 23, 2022 
diagnostic radiology can be imported to the planning system to aid in target delineation and fused 
to the primary planning dataset to aid in target definition.  
 
Alternatively, an IV contrast multiphase liver MR may be used to define GTV. 
 
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 PTVs if deformation or rotation occurs 
between scans. Imaging details are in Appendix V. 
6.3.3 
Breathing motion assessment.  Measurement of target/liver breathing motion is required, unless 
breath hold is to be used for liver immobilization.  Motion may be assessed using 4D CT, 
fluoroscopy and/or cine MR. 
 
4D CT:  A 4D, or respiratory sorted, CT may be obtained for assessing motion if breath hold is not 
used for liver immobilization.   
 
Liver reproducibility of position in breath hold should be measured using fluoroscopy, CT or MRI.  
6.3.4 
Proton Specific Guidelines 
Localization, Simulation, and Immobilization Guidelines 
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. 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. 
 
6.4 
Treatment Planning/Target Volumes (27Oct2017) 
6.4.1 
The Gross Tumor Volume (GTV) is defined as all parenchymal and vascular HCC visualized 
on contrast enhanced CT and/or MRI, most often best seen on arterial phase (as hyperintensity) 
and/or venous or delayed phase (as hypointensity relative to liver).  GTVp1 should represent the 
‘primary parenchymal (=p) dominant (=1)’ GTV, upon which primary QA will be based.  
Subsequent lesions can be labeled as GTVp2, GTVp3, GTVp4 and GTVp5).  If ‘p’ is not included 
following “GTV”, the lesion will be assumed to be parenchymal. Vascular HCC thrombi (GTVv) 
most often are best seen on venous phase imaging as hypointensity relative to the contrast in the 
vessel,  Vascular HCC may be combined with parenchymal HCC (labeled as GTVp or GTVpv) if 
they are to be treated to the same dose.  
 
Non-tumor thrombi should not be considered as GTV; they should be excluded from contouring or 
may be included in the CTV (as per 6.4.2). Non-tumor extrahepatic vascular thrombi should not 
be treated as GTV or CTV.  
 
Small enhancing GTV in adjacent lymph nodes are permitted to be irradiated only if normal tissue 
limits are not exceeded.  They are not required to be irradiated, and no prophylactic nodal 
irradiation is allowed. 
 
The prescription dose should be annotated to each GTV after the final plan is complete (e.g. 
GTVp1_50 for a 50Gy target). 
 

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RTOG 1112, Version Date: September 23, 2022 
Diagnostic contrast CT or MR imaging may be fused with the planning CT if there is no IV 
contrast used in the planning CT (liver-to-liver fusion is recommended). 
6.4.2 
The Clinical Target Volume (CTV): For each GTVp, the CTV is defined as the GTV (CTVp1… 
CTVp5), with no expansion. The minimal CTVv is the GTVv, with no expansion. 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, including non-tumor vascular 
(v) thrombi (CTVv), prior TACE (t) sites (CTVt), or adjacent RFA (r) (or other ablation) sites 
(CTVr) are permitted.  Such CTVs may be treated to a microscopic dose (27.5 Gy) or up to as 
high as the prescription dose, at the investigator’s discretion.  Separate CTVs should be labeled 
CTVp1, CTVv2, CTVv3, CTVt4…etc. The prescription dose should be annotated to each CTV 
after the final plan is complete (e.g. CTVp1_50 for a 50Gy target, and CTVt2_27.5 for a CTV 
treated to 27.5 Gy). 
6.4.3 
The Planning Target Volume (PTV)  
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, 
PTVv for the PTV around the CTVv and PTVp1 and PTVp2 for PTVs around CTVp1 and CTVp2. 
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 is 20 mm, 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 due to proximity of adjacent OARs. The final PTVs should have dose annotated 
once the plan is final. Eg. PTVp1_50 and PTVv1_27.50 for targets treated to 50 cGy and 27.5Gy, 
respectively. 
 
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, PTVv_EN for 
the PTV around CTVv_EN. 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. The final PTVs 
should have RBE-weighted dose annotated once the plan is final. Eg. PTVp1_50 and 
PTVv1_27.5.  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. 
 
 
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 
Examples of target nomenclature 
Examples  
GTV 
CTV 
PTV 
Parenchymal (p) HCC, 
prescription dose  50Gy 
GTVp1_50 
Or GTV1_50 
Or GTV_50 
CTVp1_50 
Or CTV1_50  
Or CTV_50 
PTVp1_50 
Or PTV1_50 
Or PTV_50 
Vascular (v) HCC thrombosis,  
prescription dose of 45Gy 
GTVv1_45  
CTVv1_45  
PTVv1_45 
Combined parenchymal and 
vascular HCC, prescription dose 
45Gy 
GTVpv1_45 
or GTVp1_45 
CTVpv1_45 
or 
CTVp1_45 
PTVpv1_45 
or PTVp1_45 

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RTOG 1112, Version Date: September 23, 2022 
Nodal (n) HCC, prescription dose 
35Gy 
GTVn2_35 
CTVn2_35 
PTVn2_35 
Combined primary (p) and TACE 
(t) site, prescription dose 30Gy 
GTVpt1_30 or 
GTVp1_30 
CTVpt1_30 
or 
CTVp1_30 
PTVpt1_30 or 
PTVp1_30 
RFA (r) site, prescription dose 
27.5Gy 
- 
CTVr2_27.5 
PTVr2_27.5 
TACE (t) site, prescription dose 
27.5Gy 
- 
CTVt2_27.5 
PTVt2_27.5 
Non-HCC vascular (v) 
thrombosis,  prescription dose of 
27.5Gy 
- 
CTVv2_27.5 
PTVv2_27.5 
 
6.4.5 
Critical Normal Structures will be contoured. Structures must be labeled using the Standard 
Name via TRIAD or resubmission will be required.  
 
Description 
Standard Name 
Liver 
Liver 
Liver minus GTV 
Liver_nonGTV 
 
Esophagus 
Esophagus 
Stomach 
Stomach 
Duodenum 
Duodenum 
Small bowel* 
SmallBowel 
Large bowel* 
LargeBowel 
SpinalCord*^ 
SpinalCord 
SpinalCord PRV5mm*^ 
SpinalCord _05 
R kidney 
Kidney_R 
L kidney 
Kidney_L 
Kidneys 
Kidneys 
Optional contours to be contoured if > 30 Gy is planned to include these organs include: 
Skin 
External 
Chest wall*ŧ 
ChestWall 
Gall bladder 
Gallbladder 
Common bile duct 
Commonbileduct 
Heart 
Heart 
Inferior vena cava  
IVC 
 
* At minimum, these structures are required to be contoured at the level of the PTV and over any 
region received > 10 Gy. 
^Spinal canal and spinal canal PRV may be contoured instead of spinal cord and spinal cord 
PRV. 
ŧAs per lung SBRT RTOG atlas, the chest wall can be autosegmented from the ipsilateral lung 
with a 2-cm expansion in the lateral, anterior, and posterior directions. Anteriorly and medially, it 
ends at the edge of the sternum. Posteriorly and medially, it stops at the edge of the vertebral 
body with inclusion of the spinal nerve root exit site (Kong 2012). 
 
An upper abdominal/liver atlas and lung OAR atlas (RTOG 1106), posted on 
https://www.nrgoncology.org/ciro-gastrointestinal, may be used as a guide for contouring. For 
duodenum contouring, the first and second portions must be contoured for all cases and the third 
and fourth portions should also be contoured if those portions receive > 10 Gy. 
6.4.6 
Heterogeneity Corrections: All dose distributions, photon and proton, shall include corrections for 
tissue heterogeneities.  Arterial vascular contrast from the planning dataset is recommended to 
be converted to water equivalent density if used for planning. Planning datasets without 
intravenous contrast may be used for planning (and are required for protons). 

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RTOG 1112, Version Date: September 23, 2022 
6.4.7 
Goals of planning are to maximize dose to the target volumes, 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. Conformality of the prescription dose and the 30 Gy isodose are other 
goals.  
 
6.5 
Critical Structures Maximal Doses (27Oct2017) 
Dose values in this section should be read as physical dose for photons, or RBE-weighted 
dose for protons, in 5 fractions (assuming RBE = 1.1). 
6.5.1 
Esophagus max (to 0.5 cc):  
 
 
32 Gy  
 
 
6.5.2 
Stomach max (to 0.5 cc):  
 
 
30 Gy  
6.5.3 
Duodenum max (to 0.5 cc):   
 
 
30 Gy  
6.5.4 
Small bowel max (to 0.5 cc):   
 
 
30 Gy 
6.5.5 
Large bowel max (to 0.5 cc):  
 
 
32 Gy  
6.5.6 
Cord + 5 mm max (0.5cc):  
 
 
25 Gy 
6.5.7 
Kidneys:  
Bilateral mean dose < 10 Gy 
-OR- If there is one kidney mean dose > 10Gy, remaining (or only) kidney V10Gy < 10% 
6.5.8 
The following organ dose constraints are guidelines, not mandatory: 
Stomach (to 5 cc): 
 
 
< 25 Gy 
 
Duodenum (to 5 cc):  
 
< 25 Gy 
 
Small bowel (to 5 cc):  
 
< 25 Gy 
 
 
Liver minus all GTVs:   
 
> 700cc and V10Gy < 70% 
 
Heart max (30cc):  
 
 
< 30 Gy 
Great vessel max (0.5 cc):  
 
< 60 Gy 
Skin (external) max (0.5 cc):   
< 32 Gy 
Chest wall max (0.5 cc): 
 
< 50 Gy 
Gallbladder max (0.5 cc):  
 
< 55 Gy 
Common bile duct max (0.5 cc)  
< 50 Gy (even though the bile duct is not always 
well visualized, it is always within the portal region and may be within high dose 
volumes for central targets, so efforts to reduce hot spots in this region are warranted)  
 
6.6 
Targets and Critical Structures (27Oct2017) 
 
Note: All required structures must be labeled for digital RT data submission as listed in 
the table.  Resubmission of data may be required if labeling of structures does not 
conform to the standard dicom name listed. 
 
The following table outlines the naming of the various normal and critical structures for 
submission to TRIAD: 
 
Standard Name 
Description 
GTVp(1,2,3,…) 
All Parenchymal HCC 
GTVv(1,2,3,…) 
Vascular HCC thrombi or invasion 
CTVp(1,2,3,…) 
All Parenchymal HCC with no expansion of the 
GTV except where permitted in the protocol 
CTVv(1,2,3,…) 
Vascular HCC thrombi or invasion and may 
include expansion of the GTV 
PTVp(1,2,3,…)_dose 
All Parenchymal HCC with no more than a 20mm 
expansion of the CTVp. The dose that the PTV is 
treated to should be annotated, eg PTVp1_5000 
PTVv(1,2,3,…)_dose 
Vascular HCC thrombi or invasion with no more 
than a 20 mm expansion of the CTVv. The dose 
that the PTV is treated to should be annotated, 
eg. PTVv1_2750. 
Liver 
Liver* 

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RTOG 1112, Version Date: September 23, 2022 
Liver_nonGTV 
Liver minus GTV* 
Esophagus 
Esophagus 
Stomach 
Stomach 
Duodenum 
Duodenum 
SmallBowel 
Small Bowel 
LargeBowel 
Large Bowel 
SpinalCord 
Spinal Cord 
SpinalCord_05 
Spinal Cord PRV 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Left and Right Kidney 
External 
Outer patient contour 
GallBladder 
Gall Bladder - optional 
CommonBileDuct 
Common Bile Duct – optional 
Heart 
Heart – optional 
IVC 
Inferior vena Cava –optional 
⃰  In addition to excluding GTV from liver volume to calculate the “liver minus GTV” volume, the 
following non-functional regions should be excluded from the ‘liver’ region of interest, when 1)  
the volume can be confidently identified and contoured; and 2) volume is > 2cm diameter.  
1) Hepatic cysts 
2) RFA cavities 
 
Note that the liver and exclusion structures should all be defined in the same image set when 
creating the liver minus GTV volume (e.g. subtract the GTV from the liver on the image set 
used for dose calculation.  Do not contour and subtract the GTV on all phases of a 4DCT 
from the liver).  The liver and GTV contours should be based on a breath hold CT, even if the 
dose calculation is done based on an average CT, as per section 6.3.2. 
 
6.7 
Documentation Requirements (8/26/14) 
6.7.1 
Quality Assurance Documentation 
In patients randomized to the SBRT 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. 
 
For each institution, the full 3D dosimetry plans for the first three registered for this study and 
randomized to the SBRT arm will be reviewed in a pre-treatment review, PRIOR TO DELIVERY 
of radiation treatment. If these plans are within protocol compliance, then subsequent review of 
cases will be done in a timely review. Timely submission of all radiation plans is required for every 
patient treated on this study. The definition of timely submission for the patients requiring timely 
review is within 5 days of completion of radiation therapy. 
 
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. 
6.7.2 
Treatment Interruptions 
Treatment interruptions should be clearly documented in the patient’s treatment record.  Total 
treatment time is recommended to be 10 days, with allowable total duration between 5 days and 
15 days (see Section 6.8.1). 
6.7.3 
Diagnostic CT/MR Submission Prior to Randomization 

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RTOG 1112, Version Date: September 23, 2022 
The baseline diagnostic CT or MR or a planning CT must be uploaded via TRIAD.  The liver 
volume and the HCC and/or vascular thrombosis should be contoured in a radiation planning 
system or segmentation system prior to submission.   
6.7.4 
IGRT 
For each IGRT technology, in addition to each “as if patient” dataset where imaging and offsets 
are submitted for 2 sequential fractions, the images and offsets for all days for the first two actual 
patients treated on study should be archived at the site in the event the data would be requested 
for review by the PI for future analysis.. 
 
For all subsequent patients, the IGRT images in treatment position for every fraction (and a table 
of subsequent ‘shifts’) are required to be archived at the site for possible subsequent future 
evaluation. 
 
6.8 
Compliance Criteria 
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: 
6.8.1  
Total Treatment Duration 
Per protocol: All treatment falls within 15 calendar days 
Variation Acceptable: All treatments fall within 16 to 21 calendar days 
Deviation Unacceptable: All treatments that take 22 or more calendar days to complete 
6.8.2  
GTV 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 
6.8.3 
PTV Compliance 
PTV Contouring 
Per protocol: 
 
PTV > 4 mm and < 20 mm 
Variation acceptable: 
PTV 3-4 mm or 20-25 mm 
Deviation unacceptable PTV < 3 mm or > 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. 
The intent is for prescription dose to cover 95% of each PTV. 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). Treating “per protocol” should always be the planning intent. 
 
 
 
 
 
 
 
 
 
 
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.   
Dose to 95% PTV 
PTVs around GTVs * 
PTVs 
around 
non-GTV 
CTVs* 
per protocol 
prescription dose +/- 5% 
prescription dose +/- 5% 
variation acceptable 
90-95% or 105-110% of 
prescription dose, and ≥ 25 
Gy 
85-95% 
or 
105-115% of 
prescription dose and ≥ 25 
Gy 
deviation unacceptable 
<90% 
or 
>110% 
of 
prescription dose, or < 25 Gy 
<85% 
or 
>115% 
of 
prescription dose, or <25Gy 
Overall plan deviation 
unacceptable 
< 25 Gy 
 

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RTOG 1112, Version Date: September 23, 2022 
 
6.8.4 
Compliance for Critical Structures (organs at risk, OARs) 
If non-hepatic OARs limit the prescription dose, the highest dose (from the 6 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):  
Stomach max (to 0.5 cc):  
Duodenum max (to 0.5 cc):   
Small bowel max (to 0.5 cc):   
Large bowel max (to 0.5 cc):  
SpinalCord_05 + 5 mm max 
(0.5cc):  
Kidneys: Bilateral mean dose 
32 Gy 
30 Gy 
30 Gy 
30 Gy 
32 Gy 
25 Gy 
≤10 Gy 
> 32 but ≤34 Gy 
>30 but ≤32 Gy 
>30 but ≤32 Gy 
>30 but ≤32 Gy 
>32 but ≤34 Gy 
>25 but ≤28 Gy 
>10 but ≤12 Gy 
> 34 Gy 
> 32 Gy 
> 32 Gy 
> 32 Gy 
> 34 Gy 
> 28 Gy 
> 12 Gy 
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 
per protocol 
variation acceptable 
deviation unacceptable 
50 Gy  
45 Gy 
40 Gy 
35 Gy 
30 Gy 
27.5 Gy 
≤13 Gy 
≤15 Gy 
≤15 Gy 
≤15.5 Gy 
≤16 Gy 
≤17 Gy 
13-13.2 Gy 
 15-15.2 Gy 
 15-15.2 Gy 
 15.5-15.7 Gy 
 16-16.2 Gy 
 17-17.2 Gy 
> 13.2 Gy 
> 15.2 Gy 
> 15.2 Gy 
> 15.7 Gy 
> 16.2 Gy 
> 17.2 Gy 
Dose values in these tables should be read as physical dose for photons, or RBE-weighted 
dose for protons (assuming RBE = 1.1). 
 
6.9 
Radiation Therapy and Imaging Quality Assurance Reviews (27Oct2017) 
6.9.1 
Rapid and Timely Review of RT Plans 
For each technique (non-IMRT, non-proton SBRT, IMRT and/or protons), the first three patients 
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 treatment for patient or 
subsequent patients. After pre-treatment review by the PI, suggestions regarding protocol 
compliance will be forwarded to the participating institution. Pre-treatment review of all plans 
PRIOR to treatment delivery will continue until at least 3 plans have been submitted without 
deviations. If any protocol deviations are found in the first 3 plans, pre-treatment review will 
continue until at least at least three sequential plans have been approved without deviations.  All 
radiation plans need to be submitted in a timely manner– ideally at least 5 days prior to planned 
start of therapy for pre-treatment reviews and within 1 week (5 working days) post RT completion 
for timely reviews.  The remaining reviews will be completed remotely and be ongoing.  The final 
cases will be reviewed within 3 months after the study has reached the target accrual or as soon 
as IROC Philadelphia RT has received complete data for all cases enrolled, whichever comes 
first.  The scoring mechanism is: Per Protocol, Acceptable Variation and Deviation Unacceptable.   
 
All additional QA data (including actual treatment details) is to be submitted within 1 week of RT 
end. 
6.9.2 
Planned Interim Analyses of Quality Assurance 
After first 50 patients are enrolled and/or first 25 patients randomized to the SBRT arm 
(whichever comes first), the Radiation Oncology Chair and Co-Chairs, along with a delegated 
team from NRG Oncology, will summarize all QA results. All submitted imaging datasets for both 
arms of the study will be reviewed as will imaging, contouring and HCC: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.   
 

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RTOG 1112, Version Date: September 23, 2022 
Secondary reviews will occur after the first 100 and 200 patients are enrolled, again with a plan to 
improve education material and/or the study if needed, with individual feedback to participating 
institutions. 
6.9.3 
Pre-Randomization Imaging Submission for All Patients (including non-radiation patients) 
 
For all patients randomized, submission of IV contrast CT or MR with contouring of the HCC, 
(including vascular thrombi) and calculation of the HCC GTV/liver volume stratification factor is 
required. 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 first 3 cases per institution from patients randomized to the non-RT arm 
will be reviewed (timely) by the PI or designee.  Any differences in the segmentation of tumor or 
liver or in the tumor:liver volume calculation will be recorded.  Feedback to each institution will 
follow in a timely manner (regarding imaging quality or contouring). 
 
Rationale for use of the ratio of the GTV to liver volume as a stratification factor is that the ratio of 
HCC to liver volume is a known prognostic factor for HCC.  Prognosis is best in patients with a 
small volume of HCC, and toxicity is increased in those with a smaller volume of liver.  The 
GTV/liver volume takes into account both these factors.  Furthermore, in the radiation arm, the 
radiation dose is expected to be associated with local control probability.  Based on the PMH 
SBRT experience (Bujold 2012), dose is correlated with GTV/liver volume.  Stratification 
categories were based on values from a sample of patients treated at PMH.  Central review of 
assessment of the calculation of this stratification factor will help ensure the quality of calculation 
of GTV:liver, and will provide insight regarding the quality of imaging and selection of tumors for 
this study, even in the non-SBRT arm patients.  Feedback to centers may help improve quality or 
patient selection for future cases. 
 
6.10 
Radiation Therapy Adverse Events 
The criteria used for the grading of toxicities encountered in this study are Common Toxicity 
Criteria (CTC) version 4.0.  
 
Very likely (80-90%) 
• Fatigue (which generally goes away after the radiation therapy is completed) 
• Skin irritation, redness, itchiness, discomfort  
• Temporary changes in blood work (decrease in blood counts, increase in liver 
enzymes), without symptoms 
 
Less likely (30%) 
• 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%) 
 
Less likely, but serious (<20%) 
• 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.   
• 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. 
• 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. 

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RTOG 1112, Version Date: September 23, 2022 
 
6.11 
Radiation Therapy Adverse Event Reporting 
See Section 7.4 for details on adverse event reporting. 
 
6.12 
Radiation Therapy Toxicity Assessment During Therapy (27Oct2017) 
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 it 
resolves as per Section 6.12.1. 
 
If the patient discontinues radiation therapy prematurely, the patient may be considered for study 
sorafenib, if the Child score is Child Pugh ≤7 and the treating physician recommends protocol 
treatment continuation. 
 
 
6.12.1 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 
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 
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  
Child-Pugh score > 7 
Hold radiation until improves to Child-Pugh score ≤ 7 
 
 
Other non-hematologic Toxicities 
grade 1, 2 
Continue radiation 

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RTOG 1112, Version Date: September 23, 2022 
grade 3  
Hold radiation until improves to ≤ grade 2, then resume 
grade 4 
Discontinue radiation 
  
7.0 DRUG THERAPY (27OCT2017)  
 
Protocol treatment is encouraged to begin as soon as possible after study entry.  Protocol 
treatment must begin within 21 days after study entry, unless extra time is needed for fiducial 
marker insertion, but not to exceed 28 days. 
 
7.1 
Treatment (14-SEP-2020) 
 
Although sorafenib dosing is recommended as per the following sections, if clinically indicated, 
dose modifications (reductions or alternative dosing, never more than 400 mg po bid) are 
permitted, based on the investigator’s discretion taking into account the patient’s entire clinical 
picture. This may occasionally include starting patients at half dose sorafenib, even in the control 
arm. 
 
7.1.1 
Dose Definition 
 
ARM I 
(Control Arm) 
Day 1-Start Sorafenib 400mg BID daily (Dose level 0).  Each cycle=28 
continuous days. 
ARM 2 
(Experimental 
Arm) 
Sorafenib to start Day 1-5 post SBRT completion at 200mg BID (level -
1). Each cycle=28 days. 
Sorafenib will be increased to 400mg BID during cycle #2 if clinically 
appropriate, as per Section 7.1.1. 
 
For arm 2, the sorafenib may be escalated to full dose (400mg BID) during cycle #2 if there is no 
dose limiting toxicity requiring dose reduction as per Section 7.2.3, the Child score is Child Pugh 
≤7 and the treating physician recommends escalation.  If escalation is not recommended at cycle 
#2 for arm 2, escalation should be reconsidered at cycle #3 and each subsequent cycle if 
escalation is still not recommended.  For patients who discontinue radiation therapy prematurely, 
they should be considered for sorafenib, as per arm 2, according to the above guidelines.   
 
7.1.2 
Technique of Administration: Oral 
 
Availability/Supply: Commercially available. Sites must refer to the package insert for detailed 
pharmacologic and safety information.  Please see Sections 7.1-7.2 for administration 
instructions. Please refer to the current sorafenib package insert and the site-specific pharmacy 
for toxicity information and instructions for drug preparation, handling, and storage 
 
• 
Non-Canadian International Institutions: Please refer to your LOI Approval Notification. Your 
institution will be responsible for acquiring any drug noted in the protocol as commercially 
available and not provided for the study.  
 
7.1.3 
Duration of Treatment 
Arm 1 (Control Arm):  Sorafenib Alone 
Sorafenib will continue until progression, unacceptable toxicity or for a maximum of 5 years.   
Arm 2 (Experimental Arm):  SBRT Followed by Sorafenib   
Sorafenib will continue until progression, unacceptable toxicity or for a maximum of 5 years. 
 
All sorafenib doses that are held/missed should be documented. Patients who have missed a 
sorafenib dose should take the next scheduled dose.  There should not be any make-up of 
missed doses.  A drug diary (to be maintained at the site) is recommended to be used and 
reviewed at each follow-up visit. 

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RTOG 1112, Version Date: September 23, 2022 
 
Sorafenib dose de-escalation should occur for toxicity, as outlined in Section 7.2. Patients will be 
considered off protocol treatment if sorafenib is held for 3 weeks. 
 
Although sorafenib dosing is recommended as per the following sections, if clinically indicated, 
dose modifications (reductions or alternative dosing, never more than 400 mg po bid) are 
permitted, based on the investigator’s discretion taking into account the patient’s entire clinical 
picture. This may occasionally include starting patients at half dose sorafenib, even in the control 
arm. 
 
 
 
7.1.4 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for  
Sorafenib (BAY 43-9006; Nexavar, NSC 724772) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 2571 patients. Below is the CAEPR for Sorafenib 
(BAY 43-9006; Nexavar). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
 
 
Version 2.10, June 24, 20201 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
Chest pain - cardiac 
 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
GASTROINTESTINAL DISORDERS 
  
Abdominal pain 
 
 
 Abdominal pain (Gr 3) 
 
Ascites 
 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Gastrointestinal hemorrhage2 
 
 Gastrointestinal hemorrhage2 
(Gr 3) 
 
 
Gastrointestinal perforation3 
  

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RTOG 1112, Version Date: September 23, 2022 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Injury, poisoning and 
procedural complications - 
Other, specify (wound healing 
complication) 
  
INVESTIGATIONS 
  
 
Activated partial thromboplastin 
time prolonged 
 
 Activated partial thromboplastin 
time prolonged (Gr 2) 
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase increased  
 
 Alkaline phosphatase increased 
(Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased (Gr 3) 
Creatinine increased 
 
 
 Creatinine increased (Gr 3) 
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
 
GGT increased 
 
  
INR increased 
 
 
 INR increased (Gr 3) 
 
Investigations - Other 
(Bicarbonate-serum low) 
 
  
Lipase increased 
 
 
 Lipase increased (Gr 3) 
Lymphocyte count decreased 
 
 
 Lymphocyte count decreased 
(Gr 3) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count decreased 
 
 
 Platelet count decreased (Gr 4) 
Serum amylase increased 
 
 
 Serum amylase increased (Gr 3) 
 
 
Thyroid stimulating hormone 
increased 
  
Weight loss 
 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 
4) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 

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RTOG 1112, Version Date: September 23, 2022 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 3) 
 
Hypernatremia 
 
  
Hypoalbuminemia 
 
 
 Hypoalbuminemia (Gr 3) 
Hypocalcemia 
 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
 Hypokalemia (Gr 3) 
Hyponatremia 
 
 
 Hyponatremia (Gr 3) 
Hypophosphatemia 
 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Back pain 
 
 Back pain (Gr 3) 
 
Bone pain 
 
  
 
Muscle cramp 
 
  
 
Myalgia 
 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Treatment related secondary 
malignancy 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RENAL AND URINARY DISORDERS 
  
 
Acute kidney injury 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Respiratory hemorrhage5 
 
  
 
Voice alteration 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Alopecia 
 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Erythema multiforme 
  
Palmar-plantar 
erythrodysesthesia syndrome 
 
 
 Palmar-plantar 
erythrodysesthesia syndrome 
(Gr 3) 
 
Pruritus 
 
 Pruritus (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  

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RTOG 1112, Version Date: September 23, 2022 
 
 Adverse Events with Possible  
 Relationship to Sorafenib (BAY 43-9006; Nexavar) 
 (CTCAE 5.0 Term) 
[n= 2571] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Gastrointestinal hemorrhage may include Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal perforation may include Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small 
intestinal perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
4Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Respiratory hemorrhage may include bronchopulmonary hemorrhage, epistaxis, laryngeal hemorrhage, 
mediastinal hemorrhage, pharyngeal hemorrhage, and pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
6Febrile neutropenia is seen mostly in combination with other agents. 
 
 
 
 
Adverse events reported on sorafenib (BAY 43-9006; Nexavar) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that sorafenib (BAY 43-
9006, Nexavar) caused the adverse event:   
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(Thrombotic microangiopathy (e.g., TTP or HUS)); Febrile neutropenia6 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Palpitations; Pericardial effusion; 
Pericarditis; Right ventricular dysfunction; Sinus bradycardia; Sinus tachycardia; Supraventricular 
tachycardia; Ventricular arrhythmia; Ventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Tinnitus 
ENDOCRINE DISORDERS - Adrenal insufficiency; Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(color vision deficits); Eye disorders - Other (light to dark adaptation); Eye disorders - Other (retinal vein 
occlusion, bilat); Eye disorders - Other (retinal hemorrhage); Eye disorders - Other (visual field distortion); 
Flashing lights; Keratitis; Photophobia; Retinal detachment 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fistula; Anal mucositis; Anal pain; Anal 
ulcer; Cheilitis; Colitis; Colonic obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophageal pain; Esophagitis; Flatulence; Gastric ulcer; Gastritis; 

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RTOG 1112, Version Date: September 23, 2022 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal 
disorders - Other (small bowel NOS fistula); Gastrointestinal fistula; Hemorrhoids; Ileal fistula; Ileus; Oral 
pain; Pancreatitis; Proctitis; Rectal fistula; Rectal mucositis; Rectal obstruction; Rectal pain; Small 
intestinal obstruction; Stomach pain; Visceral arterial ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Facial pain; 
Flu like symptoms; Localized edema; Multi-organ failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic hemorrhage; Hepatobiliary disorders - Other 
(biliary obstruction secondary to multiple biliary stones) 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Cytokine release syndrome; Immune system 
disorders - Other (systemic inflammatory response syndrome) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Fall; Fracture; Hip 
fracture; Vascular access complication; Wound dehiscence 
INVESTIGATIONS - CPK increased; Cardiac troponin I increased; Cardiac troponin T increased; 
Cholesterol high; Ejection fraction decreased; Fibrinogen decreased; Investigations - Other (blood urea 
nitrogen high) 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Alkalosis; Dehydration; Hypermagnesemia; 
Hypertriglyceridemia; Hyperuricemia; Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Chest wall pain; 
Generalized muscle weakness; Joint range of motion decreased; Muscle weakness lower limb; Muscle 
weakness upper limb; Musculoskeletal and connective tissue disorder - Other (cramping); Myositis; Neck 
pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Myelodysplastic syndrome; Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of consciousness; 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Hydrocephalus; Ischemia 
cerebrovascular; Lethargy; Leukoencephalopathy; Memory impairment; Muscle weakness left-sided; 
Muscle weakness right-sided; Neuralgia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Seizure; Stroke; Syncope; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Libido decreased; Personality 
change; Psychosis 
RENAL AND URINARY DISORDERS - Chronic kidney disease; Hematuria; Nephrotic syndrome; 
Proteinuria; Renal and urinary disorders - Other (focal segmental glomerulosclerosis); Renal and urinary 
disorders - Other (right ureter rupture); Renal calculi; Renal hemorrhage; Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract obstruction; Urine discoloration 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Erectile dysfunction; Gynecomastia; 
Hematosalpinx; Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Spermatic cord hemorrhage; 
Testicular hemorrhage; Uterine hemorrhage; Vaginal fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchospasm; Hiccups; Hoarseness; Hypoxia; Laryngeal mucositis; Pharyngeal 
mucositis; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax; Pulmonary edema; 
Pulmonary fibrosis; Respiratory, thoracic and mediastinal disorders - Other (nasal septal perforation); 
Tracheal mucositis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythroderma; Hyperhidrosis; Nail loss; Pain of 
skin; Purpura; Rash acneiform; Scalp pain; Skin and subcutaneous tissue disorders - Other (non-life 
threatening squamous cell carcinoma of skin: keratocanthomas type); Skin hyperpigmentation; Skin 
hypopigmentation; Skin ulceration; Urticaria 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypotension; Phlebitis; Vascular disorders 
- Other (ruptured aortic aneurysm); Vasculitis 
 
Note: Sorafenib (BAY 43-9006; Nexavar) in combination with other agents could cause an exacerbation 
of any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
 
7.1.5 
Potential Drug Interactions 
• 
CYP3A4 Inducers 

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Chronic concomitant administration of rifampin with a single dose of sorafenib 
resulted in a 24% decrease in the combined AUC of sorafenib and its active 
primary metabolite when rifampin was co-administered with sorafenib. The clinical 
significance of this overall decrease in drug exposure is unknown. Other inducers 
of CYP3A4 activity (eg, hypericum perforatum [also known as St. John’s 
wort], phenytoin, carbamazepine, phenobarbital, and dexamethasone) may 
also increase the metabolism of sorafenib and decrease its exposure. 
• 
CYP2C9 Substrates 
The possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed in 
sorafenib-treated patients compared to placebo-treated patients. The concomitant 
treatment with sorafenib and warfarin did not result in changes in mean PT-INR 
compared to placebo. However, patients taking warfarin should have their INR 
checked regularly (see Product Monograph: WARNINGS AND PRECAUTIONS 
and PART II: DETAILED PHARMACOLOGY).  
• 
CYP Isoform-selective Substrates 
Concomitant administration of sorafenib and midazolam, dextromethorphan or 
omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and 
CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter 
the exposure of these agents. This indicates that sorafenib is neither an inhibitor 
nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical 
pharmacokinetic interactions of sorafenib with substrates of these enzymes are 
unlikely. 
• 
UGT1A9 Inhibitors 
An in vitro study has revealed a number of drugs affected UGT1A9-mediated 
sorafenib glucuronidation with an IC50 value below 100 μM. They were atorvastatin 
(IC50 = 67 μM), ketoconazole (87 μM), mefenamic acid (28 μM), erlotinib (69 μM), 
and niflumic acid (1.2 μM). T 
he clinical relevance of these drug interactions has not been tested. 
• 
Combination with Other Antineoplastic Agents 
Sorafenib is approved only as monotherapy in the treatment of RCC and HCC (see 
Product Monograph: INDICATIONS AND CLINICAL USE). In clinical studies, 
sorafenib has been administered together with a variety of other antineoplastic 
agents at their commonly-used dosing regimens, including gemcitabine, oxaliplatin, 
doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of 
gemcitabine or oxaliplatin. Concomitant treatment with sorafenib resulted in a 21% 
increase in the AUC of doxorubicin. When administered with irinotecan, whose 
active metabolite SN-38 is further metabolized by the UGT1A1 pathway, there was 
a 67-120% increase in the AUC of SN-38 and a 26-42% increase in the AUC of 
irinotecan. The clinical significance of these findings is unknown (see Product 
Monograph: WARNINGS AND PRECAUTIONS). A clinical study has revealed that 
administration of sorafenib with a 3-day break in dosing around administration of 
docetaxel resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase 
in docetaxel Cmax (see Product Monograph: WARNINGS AND PRECAUTIONS).  
7.1.6 
Storage 
Store at controlled room temperature (15ºC – 25ºC). Storage conditions should not exceed 25ºC. 
Stability 
The stability profile of the solid drug is excellent.  In solid form, sorafenib is stable at room 
temperature for up to 24 months, and it is insensitive to light.  The expiration date should be 
readily available on the label of commercially supplied sorafenib. 
 
 
7.2 
Dose Modifications (27Oct2017) 
NOTE: The dose modifications are recommended modifications. The final dosing should be 
based on the investigator’s discretion taking into account the patient’s entire clinical picture. The 
goal is that the patient will stay on the drug for as long as possible (even if reduced dose) if there 
is clinical benefit, no progression and the patient is tolerating sorafenib.   
 

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RTOG 1112, Version Date: September 23, 2022 
Protocol treatment may be dose modified based on criteria outlined in the dose modification table 
(Section 7.2.3).  For both arms, after each cycle (28 days), assessment for toxicity will be made.  
The sorafenib will be continued at the present dose (or escalated to full dose during cycle #2 or 
subsequent cycles for arm 2) if there is no dose limiting toxicity requiring dose reduction as per 
Section 7.2.3, the Child score is Child Pugh ≤7 and the treating physician recommends 
continuation.  If the Child Pugh score is B7, and the patient is otherwise suitable for sorafenib, 
sorafenib should be delivered at half dose. If at subsequent evaluations demonstrate recovery to 
CP <= 6 and no other competing toxicity then Sorafenib can be re-escalated to full dose. 
 
For both arms, it is not the intention to take patients off sorafenib early for minor changes in liver 
function. 
7.2.1 
Once reduced for toxicity, Sorafenib may or may not be re-escalated per the investigator’s 
discretion.  If dose reductions beyond dose level -2 are required or drug is held for more than 3 
weeks, all protocol therapy will be discontinued.  
 
If more than one of these apply, use the most stringent (i.e., the greatest dose reduction). 
 
7.2.2 
Dose Reduction Table  
  
Dose level 0 (starting dose, 800 mg po)  
2 x 200 mg po every 12 hours 
 
Dose level -1 (400 mg po)   
 
1 x 200 mg po every 12 hours 
 
Dose level -2 (200 mg po) 
1 x 200 mg po daily 
 
 
7.2.3  
Dose Modification Table   
NOTE:  The dose modifications are recommended as minimum required modifications. The final 
dosing should be based on the investigator’s discretion taking into account the patient’s entire 
clinical picture. The goal is that the patient will stay on the drug for as long as possible (even if 
reduced dose) if there is clinical benefit, no progression and the patient is tolerating sorafenib. 
 
TOXICITY 
MODIFICATION 
Hematologic Toxicities 
 
 
grade 1 or 2 
Continue sorafenib 
grade 3 
Continue sorafenib at one reduced dose level 
grade 4 or neutropenic fever 
Interrupt sorafenib until ≤ grade 2, then continue 
at one reduced dose level 
 
 
Gastrointestinal Toxicities 
grade 1 or 2 
Continue sorafenib 
grade ≥ 3 diarrhea 
Interrupt sorafenib until improves to ≤ grade 2, 
then resume sorafenib at one reduced dose level 
grade ≥ 3 nausea or vomiting despite antiemetics 
Interrupt sorafenib until improves to ≤ grade 2, 
then resume sorafenib at one reduced dose level 
 
 
Hepatic Dysfunction 
bilirubin 1.3-3.0 
Continue sorafenib 
bilirubin > 3.0 
Discontinue sorafenib 
Child-Pugh score > 7 
Interrupt sorafenib until improved to Child-Pugh 
score 7 or less. Sorafenib is to be re-started at 
half dose, if Child-Pugh score is B7, and it can be 
re-escalated to full dose if Child-Pugh score 
returns to A. 

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Skin Toxicity: Rash (Maculo-Papular) or  
Hand-Foot Skin Reaction  (HFSR; Palmar-Plantar Erythrodysesthesia) 
grade 1 
Continue sorafenib 
grade 2, 1st appearance 
Interrupt sorafenib until improves to ≤ grade 1, 
then resume sorafenib at the previous dose level 
grade 2, 2nd or 3rd appearance 
Interrupt sorafenib until improves to ≤ grade 1, 
then resume sorafenib at one reduced dose level 
grade 2, 4th appearance 
Discontinue sorafenib therapy 
grade 3, 1st or 2nd appearance 
Interrupt sorafenib until toxicity improves to  
≤ grade 1, then resume sorafenib at one reduced 
dose level 
grade 3, 3rd appearance 
Discontinue sorafenib  therapy 
 
Following a full cycle (one month) of reduced dose sorafenib with no rash or HFSR of ≥ grade 1 
severity, the dose of sorafenib may be re-escalated to the previous dose level. 
(Note: Re-escalation is allowed only in the case of skin toxicity.) 
 
 
Hypertension 
hypertension controlled with medication (to 
<140/90) 
Continue sorafenib 
hypertension >140/90 and ≤160/100 
Continue sorafenib 
Consider adding or adjusting anti-hypertensive 
medications 
persistent (>160/100) or symptomatic 
hypertension 
Interrupt sorafenib 
Resume when blood pressure improves to 
<160/100 
If sorafenib is interrupted for ≥3 weeks, 
discontinue sorafenib 
 
grade 4 
Discontinue sorafenib  therapy 
 
 
Other non-Hematologic Toxicities 
grade 1, 2 
Continue sorafenib 
grade 3 
Interrupt sorafenib until toxicity resolves to ≤ grade 
1, then reduce by one dose level 
grade 4 
Discontinue sorafenib  therapy 
 
7.2.4  
Toxicity Management 
Management of Skin Toxicity: At first occurrence of HFSR, independent of grade, supportive 
measures such as topical emollients, low potency steroids, or urea-containing cream should be 
administered. 
 
7.3 
Modality Review (8/26/14) 
The Medical Oncology Co-Chairs, Andrew Zhu, MD and/or Jennifer Knox, MD, will perform a 
Systemic Therapy Assurance Review of patients who receive protocol-specified systemic therapy 
in this trial.  The goal of the review is to evaluate protocol compliance.  The review process is 
contingent on timely submission of systemic therapy treatment data as specified in Section 12.1. 
The scoring mechanism is: Per Protocol/Acceptable Variation, Not Per Protocol, and Not 
Evaluable.  A report is sent to each institution once per year to notify the institution about 
compliance for each case reviewed in that year. 
   
This Systemic Therapy Assurance Review will be performed on an ongoing basis (for example, 
the first review after NRG Oncology receives complete data for 20 cases and the next review 
after NRG Oncology receives complete data for 20 more cases). The final cases will be reviewed 

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RTOG 1112, Version Date: September 23, 2022 
within 3 months after this study has reached the target accrual or as soon as NRG Oncology 
receives complete data for all cases, whichever occurs first. 
 
 
7.4 
Adverse Events (13-MAY-2019) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, 
CTEP-AERS, and case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS 
reporting beginning April 1, 2018; all study case report forms will continue to use CTCAE version 
4.0. All appropriate treatment areas should have access to a copy of CTCAE versions 4.0 and 
5.0, which can be downloaded from the CTEP web site 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm) 
 
 
7.4.1 
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).  
 
7.4.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited reporting 
criteria defined in the table in section 7.5 will be reported via CTEP-AERS.  SAEs that require 24 
hour CTEP-AERS notification are defined in the expedited reporting table in section 7.5.  Contact 
the CTEP-AERS Help Desk if assistance is required.  
 
Definition of an SAE: Any adverse experience occurring during any part of protocol treatment 
and 30 days after 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 risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in anexpedited 
manner. 
 
 
 
7.4.3 
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: 

53 
RTOG 1112, Version Date: September 23, 2022 
 
• 
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.  
 
7.5 
CTEP-AERS Expedited Reporting Requirements (27Oct2017) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the Adverse Event Expedited Reporting System, 
accessed via the CTEP web site, 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology 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 Oncology Operations Office 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 a 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 documentation is requested by NRG as needed to complete adverse 
event review. Supporting source documentation should include the protocol number, patient 
ID number, and CTEP-AERS ticket number on each page. Contact NRG Oncology at 1-215-
574-3191 for details to submit source documentation. 
• 
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). 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur within 30 Days of the Last Administration of the Commercially Available Agent 
1, 2 

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RTOG 1112, Version Date: September 23, 2022 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) 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. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
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 commercially available 
agent and have an attribution of possible, probable, or definite require 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 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing Commercially Available Agent: 
Not applicable 
 
8.0 SURGERY 
 
Not applicable to this study. 
 

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RTOG 1112, Version Date: September 23, 2022 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
9.1.1 
All supportive therapy for optimal medical care will be given during the study period at the 
discretion of the attending physician(s) within the parameters of the protocol and documented on 
each site’s source documents as concomitant medication.  
9.1.2 
Antiemetics (e.g. dopamine (D2) receptor antagonist or 5HT3 antagonists) should be considered 
to be used prior to each fraction of SBRT to prevent nausea if the stomach is anticipated to 
receive any radiation. They may also be used for symptomatic nausea or vomiting. 
9.1.3 
Antidiarrheals may be used to treat therapy induced diarrhea. 
9.1.4 
H2 blockers or proton pump inhibitors are strongly recommended if 20 Gy or more is delivered to 
the luminal gastrointestinal tract or at the treating physicians discretion. They should start before 
completion of SBRT and continue for at least 6 months. 
9.1.5 
Analgesics may be used to treat tumor or therapy induced pain. NSAIDS are recommended to be 
avoided to reduce luminal GI irritation. 
9.1.6 
In the occurrence of liver toxicity (including classic RILD, non-classic RILD or any CTCAE 4.0 
grade 4 toxicity or any sorafenib associated liver toxicity, occurring in the absence of HCC 
progression within 12 weeks of completion of radiation therapy), best supportive care and 
possible diuretics are recommended.  Steroids may be used, and a referral to a hepatologist is 
recommended.   
9.1.7 
Topical creams, emollients, balms, low potency steroids or urea containing creams are 
recommended for discomfort due to hand foot syndrome. 
9.1.8 
Anti-hypertensives should be used for sorafenib-induced increase in blood pressure. Calcium 
channel blockers are recommended. 
 
9.2 
Non-permitted Supportive Therapy (27OCT2017) 
9.2.1 
Anticoagulants are not recommended to be used to treat HCC related vascular thrombosis. They 
may be used for bland thrombosis or pulmonary emboli. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (27OCT2017) 
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 10.0 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. NRG Oncology Biospecimen Bank 
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). 
 
 
 
 
10.2 
Specimen Collection for Tissue Banking and Translational Research (27Oct2017) 
For patients who have consented to participate in the tissue/blood component of the study. The 
following must be provided in order for the case to be evaluable for the 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 (preferred, the block must match 
the H&E being submitted) or 10 unstained slides (5 micron cut onto positive charged slides) of 
tumor tissue. Block or slides must be clearly labeled with the pathology identification number and 
block number that corresponds to the Pathology Report. 

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RTOG 1112, Version Date: September 23, 2022 
• 
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 slides contains tumor. The report 
must include the NRG Oncology 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 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 – San Francisco; if for translational research, this should be stated 
on the form. The form must include the NRG Oncology protocol number and patient’s case 
number.  
 
For specimen collection: See Appendix IX for the specimen collection kits and instructions. The 
following materials must be provided to the NRG Oncology Biospecimen Bank – San Francisco: 
An ST documenting the date of collection of the biospecimen; the NRG Oncology protocol 
number, the patient’s case number, time point of study, and method of storage, for example, 
stored at -80° C, must be included. 
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 
 
Specimens for Tissue Banking/Translational Research 
Specimens taken from 
patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide 
 
Slide shipped ambient 
to NRGBB-SF 
A paraffin-embedded 
tissue block of the 
primary tumor taken 
before initiation of 
treatment 
Pre-treatment 
Paraffin-embedded 
tissue block. If a block 
is not available then 
10 unstained slides  
(5 micron cut onto 
positively charged 
slides)  
 
Block or slides shipped 
ambient 
 
SERUM: 5-10 mL of 
whole blood in 1 red-top 
tube and centrifuge 
Pre-treatment 
(baseline) 
 
1 and 3 months from 
study entry 
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 to NRGBB-SF in 
batch shipments 
PLASMA: 5-10 mL of 
Pre-treatment 
Frozen plasma 
Plasma sent frozen on 

57 
RTOG 1112, Version Date: September 23, 2022 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
(baseline) 
 
1 and 3 months from 
study entry 
 
At the time of 
progression and/or 
grade 4 liver toxicity 
(within 4 weeks) 
 
samples containing a 
minimum of 0.5 mL 
per aliquot in 1 mL 
cryovials (five) 
dry ice via overnight 
carrier to NRGBB-SF in 
batch shipments 
Whole blood for DNA: 5-
10 mL of anticoagulated 
whole blood in EDTA 
tube #2 (purple/lavender 
top) and mix 
Pre-treatment 
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 
1-2 mL per aliquot in 
2 mL cryovials (three) 
Whole blood sent 
frozen on dry ice via 
overnight carrier to 
NRGBB-SF in batch 
shipments 
 
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 
 
Courier Address (FedEx, UPS, etc.): For 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 
 
  
10.3 
Confidentiality/Storage  (13-MAY-2019) 
10.3.1 Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the patient’s 
case number only. The NRG Oncology Biospecimen Bank 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. 
10.3.2 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 
Patients must be offered the opportunity to participate in the correlative components of the study, 
such as quality of life (QOL) assessment. If the patient consents to participate in the QOL 
component of the study, sites are required to administer the baseline QOL and functional 
assessments prior to the start of protocol treatment. 
 

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RTOG 1112, Version Date: September 23, 2022 
11.1 
Study Parameters 
See Appendix I. Timing of all follow-up imaging and other assessments is from registration for 
both arms of the study. 
 
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 (25-MAR-2020) 
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 HCC 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 V.  
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). Response measurements, including response assessment of tumor thrombosis as per 
Section 11.3.3, will take place every 3 months, according to the schedule in Appendix I. 
 
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. 
• 
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) and their 
suitability for accurate repeated measurements.  Vascular thrombi will not be 
included as target lesions. 
Target irradiated lesions (for SBRT arm only): All measureable lesions up to a 
maximum of two lesions in the liver, 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. Vascular thrombi will not be included as target irradiated lesion, 

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RTOG 1112, Version Date: September 23, 2022 
unless vascular HCC is the only HCC present, in which case it can be used as 
the target lesion.  Response for vascular thrombi will follow Section 11.3.3. 
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. For vascular thrombosis (consistent with Section 11.3.3), this is defined 
as: 
 
 
 
a) Unequivocal, unambiguous new enhancing tumor thrombosis or 
b) Unequivocal, unambiguous increase in the volume of enhancing 
portion of thrombosis 
Stable disease (SD): No change or small changes that do not meet the above 
criteria for PR or PD, taking as reference the smallest sum diameters while on 
study. 
11.3.3 Vascular Thrombosis Response 
 There are no validated guidelines to monitor and report vascular thrombosis response. 
Consistent with RECIST1.1, thrombosis will be considered non-measurable disease.  Response 
of vascular thrombosis will be recorded as a secondary endpoint in this study, using the 
following guidelines: 
 
CR thrombosis: Complete resolution of thrombosis, with recanalization of vessel. 
 
PR thrombosis: any of 
 
  
a) Partial recanalization of thrombosis (if prior complete blockage) 
 
  
b) Unequivocal reduction in the maximal girth of thrombosis  
 
c) Unequivocal reduction in the volume, or elimination, of arterial enhancing 
portion of thrombosis 
 
  
PD thrombosis: any unequivocal, unambiguous,  
 
  
a) New enhancing tumor thrombosis 
b) Increase in the volume of enhancing portion of thrombosis 
Note that for “unequivocal progression” of thrombosis (non-measurable disease), the increase in 
overall tumor burden (enhancing thrombosis) must be comparable to the increase required for 
RECIST1.1 definition of PD of measurable disease (e.g. at least 73% increase in volume, which 
is similar to 20% increase in diameter, and at least a 5 mm absolute increase). 
 
SD thrombosis: any of  
 
a) No change or small changes that do not meet the above criteria for PR or PD, 
taking as reference the smallest sum diameters while on study. 
 
 
b) Increase in the volume of non-enhancing thrombosis  
 
 
c) New bland non-enhancing thrombosis 
 
11.4 
Criteria for Discontinuation of Protocol Treatment (8/26/14) 
11.4.1 Protocol treatment may be discontinued for any of the following reasons: 
• Progression of disease, as defined in Section 11.3. Note that there are no 
accepted guidelines for assessing progression or response of vascular HCC to 
therapy. Thus, discontinuation of protocol treatment should only occur in reaction 
to changes in vascular thrombosis response if the progression is unequivocal and 
of substantial magnitude (estimated > 73% increase in volume of enhancing 
vascular HCC and > 5 mm absolute increase) and the investigator believes 
discontinuation is in the patient’s best interest.  If there is any doubt about the 
‘unequivocal’ nature of the vascular progression, patients should remain on 
therapy. 

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RTOG 1112, Version Date: September 23, 2022 
• Unacceptable adverse event(s), as defined in Section 6.0 and/or 7.0 and/or 13.5.4      
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Pregnancy 
• Delay in protocol treatment > 3 weeks, as specified in Section 7.0. 
Reasons for discontinuation from protocol treatment should be documented in the patient’s 
medical record and case report Form (CRF). 
11.4.2 If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
11.4.3 Any salvage treatment will be recorded. If radiation therapy is offered for salvage post sorafenib 
in patients not randomized to SBRT, total dose, dose per fraction and overall time should be 
recorded and reported on the Salvage RT form.  In this situation, radiation therapy is only 
recommended if the patient meets eligibility criteria similar to baseline eligibility of this study.  
 
11.5 
Health Related Quality of Life and Health Utility Assessments (27Oct2017)   
11.5.1 Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) 
FACT-Hep version 4 is a 45-item self-report instrument designed to measure health-related 
quality of life (HRQL) in patients with hepatobiliary cancers. The FACT-Hep consists of the 27-
item FACT-General (FACT-G), which assesses generic QOL concerns, and the newly validated 
18-item Hepatobiliary Subscale (HS), which assesses disease-specific issues. Patients are asked 
to score each item for the past week on a 4-point likert scale (from 0 “not at all” and 4 “very 
much”).  The total FACT-Hep score is the sum of the four sub-scale scores and ranges from 0 to 
108; it takes less than 15 minutes to complete and is translated in 45 languages. The FACT-Hep 
is validated and presents good internal consistency, test–retest reliability, and convergent and 
discriminate validity in patients with hepatobiliary cancer and HCC Heffernan 2002, Steel 2006, 
Wang 2007, Steel 2004). The site research nurse or CRA is encouraged to be sensitive to each 
patient's demeanor. If patients appear particularly uncomfortable answering a question, they will 
be informed that they can skip that question.  Similarly, interviewers will give patients a short 
break if the patient appears fatigued or otherwise in need of a few minutes break. Note: The 
FACT-Hep has been validly translated into many languages and will be available in languages 
beyond English on the RTOG 1112 page of the CTSU website.  Patients eligible for QOL 
analyses need to provide informed consent, and translated FACT-Hep QOL questionnaires must 
be available in their primary language. 
 
FACT-Hep QOL will be administered at baseline, 3 months, 6 months and 12 months post 
initiation of protocol therapy.  Patients will be included in the QOL analyses only if they have 
provided both baseline and at least 1 subsequent measurement.  
11.5.2  EuroQol (EQ-5D) 
The EuroQol (EQ-5D) is a 2-part questionnaire measuring a patient’s utility or preference of their 
health state for the calculation of quality-adjusted survival that takes the patient approximately 5 
minutes to complete (Schultz 2002). The first part consists of 5 items covering 5 dimensions, 
including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension can be graded on 3 levels including: 1-no problem, 2-moderate problems, and 3-
extreme problems. There are 243 potential health states.  The second part is a visual analogue 
scale (VAS) valuing current health state, measured on a 20 cm, 10 point-interval scale.  Either the 
index score or the VAS score can be used in the quality-adjusted survival analysis (Wu 2002). 
The benefit of measuring quality-adjusted survival is that it can be compared to the outcomes of 
other interventions across disease sites and can be used by health policy makers to rank 
interventions.   
 
The EQ-5D will be administered at baseline, 3 months, 6 months and 12 months post initiation of 
protocol therapy.  Patients will be included in the quality-adjusted survival analyses only if they 
have provided both baseline and at least 1 subsequent measurement. 
11.5.3 Quality-Adjusted Survival 
The EQ-5D will be used to assess quality-adjusted survival. Quality-adjusted survival is the 
weighted sum of different time in different health states added up to a total quality-adjusted 

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RTOG 1112, Version Date: September 23, 2022 
survival time [U=sum of quality (qi) of health states K times the duration (si) spent in each health 
state] (Glasziou 1990). 
 
12.0 
DATA COLLECTION  
 
12.1 
Data Quality Portal (23-SEP-2022) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave 
Home section displays a table providing summary counts of Total Delinquencies and 
Total Queries. DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP 
Reports modules are available to access details and reports of unanswered queries, 
delinquent forms, forms with current status and timeliness reports. Review the DQP 
modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the 
CTSU website. Staff that have Rave study access can access the Rave study data using 
a direct link on the DQP. 
12.2 
Data Submission / Data Reporting (23-SEP-2022) 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. To accept the invitation, site staff must either click on the link in the email or log 
in to iMedidata via the CTSU members’ website under Data Management > Rave Home and click 
to accept the invitation in the Tasks pane located in the upper right corner of the iMedidata 
screen. Site staff 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 eLearning link in the Tasks pane located in the upper 
right corner of the iMedidata screen. If an eLearning is required for a study and has not yet been 
taken, the link to the eLearning will appear under the study name in the Studies pane located in 
the center of the iMedidata screen; once the successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and a Rave EDC link will replace the 
eLearning link under the study name.  

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RTOG 1112, Version Date: September 23, 2022 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the 
Rave section under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website in the Data Management > Rave section at www.ctsu.org/RAVE/ or by 
contacting the CTSU Help Desk at 1-888-823-5923 or e-mail at ctsucontact@westat.com.  
 
12.2.1 Summary of Data Submission  
 
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 for information about expedited and routine reporting.   
 
Folder 
Form/Item 
 
 
Registration via the OPEN System 
• 
Subject Enrollment Form 
 
 
Enrollment 
When pushed into RAVE there will 
be  5 forms  representing 
registration 
• 
Demography Form 
• 
Step Information Form 
• 
Treatment Assignment Form 
• 
Eligibility Checklist Form 
 
 
Baseline folder 
• 
Patient History Form (formerly known as the A5) 
• 
Work Up 
• 
Other Conditions 
• 
Lab Results 
• 
Pathology Report (Upload of report is required) 
• 
EQ-5D and FACT-HEP if consented for QOL 
• 
Digital Data (RT Plan)(Arm 2) 
• 
Pretreatment Scan (Arm 1) 
• 
Sorafenib Details (if received prior Sorafenib) 
Month 1 Visit-Arm 1 
• 
Lab Results 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events  
Sorafenib 
Month 1 Visit-Arm 2 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
• 
Lab Results 
• 
RT Administration Form 
• 
RT Treatment if was RT administered=“yes” 
• 
Protocol Specific RT if was RT 
administered=“yes”  
Month 2 Visit 
• 
Lab Results 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
Sorafenib 
Month 3 and 6 month visit  
• 
Lab Results 
Sorafenib 
• 
Patient Contact 

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RTOG 1112, Version Date: September 23, 2022 
• 
Followup-if Patient able to be Contacted =“yes” 
• 
Primary Cause of Death Form – if Patient’s Vital 
Status = “dead” 
• 
Disease Assessment Form – if Documented 
clinical assessment = “yes” 
• 
New Primary Cancer Form – if New Primary 
Cancer =“yes” 
• 
Non-protocol Treatment Form – if patient started 
on non-protocol cancer therapy =”yes” 
• 
Adverse Event Form/ Protocol Specific Adverse 
Events/Other Adverse Events - if new or 
continuing adverse events=“yes” 
• 
Salvage RT-if salvage RT=“yes” 
• 
EQ-5D/FACT-HEP- if consented to QOL 
Month 4 visit and monthly as long as 
Sorafenib is being administered 
• 
Lab Results 
• 
Other Labs 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
Sorafenib 
Month 9 visit 
• 
Lab Results 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
• 
Followup Form-if Patient able to be Contacted 
=“yes” 
• 
Primary Cause of Death Form – if Patient’s Vital 
Status = “dead” 
• 
Disease Assessment Form – if Documented 
clinical assessment = “yes” 
• 
New Primary Cancer Form – if New Primary 
Cancer =“yes” 
• 
Non-protocol Treatment Form – if patient started 
on non-protocol cancer therapy =“yes” 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Event- if new or continuing 
adverse events=“yes” 
• 
Salvage RT-if salvage RT=“yes” 
Month 12 visit 
• 
Lab Results 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
• 
Followup Form-if Patient able to be Contacted 
=“yes” 
• 
Primary Cause of Death Form – if Patient’s Vital 
Status = “dead” 
• 
Disease Assessment Form – if Documented 
clinical assessment = “yes” 
• 
New Primary Cancer Form – if New Primary 
Cancer =“yes” 
• 
Non-protocol Treatment Form – if patient started 
on non-protocol cancer therapy =“yes” 
• 
Adverse Event Form- if new or continuing 
adverse events=“yes” 
• 
Salvage RT-if salvage RT=yes 
• 
EQ-5D/FACT-HEP- if consented to QOL 
Month 15 and q 3 months 
• 
Lab Results 

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RTOG 1112, Version Date: September 23, 2022 
• 
Protocol Specific Adverse Events 
• 
Other Adverse Events 
• 
Followup Form-if Patient able to be Contacted 
=“yes” 
• 
Primary Cause of Death Form – if Patient’s Vital 
Status = “dead” 
• 
Disease Assessment Form – if Documented 
clinical assessment = “yes” 
• 
New Primary Cancer Form – if New Primary 
Cancer =“yes” 
• 
Non-protocol Treatment Form – if patient started 
on non-protocol cancer therapy =“yes” 
• 
Adverse Event Form- if new or continuing 
adverse events=“yes” 
• 
Salvage RT-if salvage RT=“yes” 
 
12.3 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.5 for 
account access and installation instructions) (13-MAY-2019) 
Pre Randomization Scan (All Patients) 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital Data Submission – Diagnostic or planning CT or MRI obtained within 
28 days prior to registration, include the following 
Within 1 week 
of 
randomization 
for Arm 1 
patients only 
and arm 2 
patients who 
do not end up 
having 
radiation 
therapy 
 
• 
Contours of liver and GTV 
• 
Volume (cc) of liver minus GTV (>700 cc non-tumor liver 
recommended) 
• 
Calculation of GTV/(liver including GTV) (80% recommended) 
 
ARM 2 ONLY  
Item 
Due 
Preliminary Dosimetry Information  
 
Digital Data Submission –Treatment Plan, including multiphasic CT and /or MRI 
submitted to TRIAD exported from treatment planning machine by Physicist 
Within 1 
week of 
start of 
RT 
Digital data submission includes the following: 
• 
CT data, critical normal structures, all GTV, CTV, and PTV contours  
• 
Digital beam geometry for initial and boost beam sets 
• 
Doses for initial 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 6.5. 
• 
The “RTOG 1112 Datasheet” is available in the Forms section of the 
RTOG1112 page of the CTSU website. Submit via TRIAD with the digital 
data listed above. 
Upon submission of the digital data via TRIAD, complete an online digital 
data transmission form located in the Forms section on the web site at    
http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1112 
 
 
 
Final Dosimetry Information 
Within 1 
week of 
Radiotherapy Form  

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RTOG 1112, Version Date: September 23, 2022 
Daily Treatment Record  
RT end 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES 
AND IGRT DATA WILL BE KEPT BY THE INSTITUTION AND ONLY 
SUBMITTED IF REQUESTED. 
 
 
NOTE: Copies of simulation and IGRT imaging and the complete RT daily treatment record for 
the previous original EBRT will be kept by the institution and only submitted if specifically 
requested.  
 
13.0 
STATISTICAL CONSIDERATIONS  
13.1 
Endpoints 
13.1.1 Primary Endpoint 
Overall survival (failure is death due to any cause) 
13.1.2 Secondary Endpoints 
• 
Time to progression (failure is defined per Section 11.3) 
• 
Progression free survival (failure is progression or death due to any cause)  
• 
Toxicity: using Common Toxicity Criteria (CTCAE) version 4.0. 
• 
Vascular thrombosis response 
• 
Health Related Quality of Life [measured by the Functional Assessment of Cancer 
Therapy–Hepatobiliary (FACT-Hep)] 
• 
Quality adjusted survival 
 
 
13.2 
Stratification (8/26/14) 
Patients will be stratified before randomization with respect to Vascular involvement (IVC/main 
portal vein/right or left main branch portal vein vs. other vascular involvement vs. none), Hepatitis 
(B or B and C vs. C vs. other), Site (North American vs. non-North American), and HCC 
volume/liver volume (<10% vs. 10-40 vs. >40%). The treatment allocation scheme described by 
Zelen (1974) will be used because it balances patient factors other than institution. 
 
13.3  
Sample Size and Power Justification (25-MAR-2020) 
13.3.1 The sample size calculations are based on the primary hypothesis that SBRT followed by 
sorafenib will increase overall survival as compared to sorafenib alone for patients with 
hepatocellular carcinoma. It is projected that 75% of the accrual will come from North American 
sites and 25% of the accrual will come from non-North American sites.  It is expected that 
approximately two-thirds of accrual will be patients with vascular thrombosis while one-third will 
be patients without vascular thrombosis.   
 
The sorafenib alone control arm median overall survival time (MST) is estimated to be 10.5 
months, based on the SHARP sorafenib arm MST of 10.7 months (Llovet 2008) and a recent 
study of 1073 HCC patients randomized to sorafenib versus sunitinib; the median overall survival 
time (MST) of the patients in the sorafenib arm was 10.0 months (versus 8.1 in the sunitinib arm) 
[Cheng 2011]. Approximately 75% of these patients were Asian-Pacific, demonstrating that 
outcomes in Asia have improved since the original Asian-Pacific sorafenib randomized trial 
(where MST was 6.5 months for sorafenib alone [Cheng 2009]).   
 
The RT sorafenib combination arm MST is hypothesized to be 14.5 months, based on the 
Toronto RT alone MST of 17.0 months (Bujold 2012) in 102 patients with advanced HCC treated 
with RT alone on study, as well as a retrospective study of RT and sunitinib from Taiwan with a 
MST of 16 months (Chi 2010). Other reports of RT alone for HCC patients with portal vein 
thrombosis demonstrate a range of MSTs from 10 to 15 months, in the absence of sorafenib. 
 
The required sample size for the primary endpoint of OS is based on the following conditions: 
• 
OS times are exponentially distributed with (at least approximately) constant 
hazards in both treatment arms 

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RTOG 1112, Version Date: September 23, 2022 
• 
The control arm will have a median OS of 10.5 months (monthly hazard of 0.066) 
• 
The experimental arm will have a median OS of 14.5 months (monthly hazard of 
0.0478) 
• 
Hazard ratio (experimental/control) = 0.72 
• 
One-sided test at α = 0.05 
• 
Statistical power of 80% 
• 
7 years of accrual (post ramp-up) with 1 year of follow-up 
• 
Three interim significance tests and a final test are planned using the Haybittle-
Peto (Lan 1983; O’Brien 1979) rule for efficacy and a more aggressive futility rule 
suggested by Weiand et al (1994). 
 
A total of 264 evaluable patients, using the group sequential design method (Pocock 1977) with 3 
interim analyses, will provide the 238 OS events required to determine if the addition of SBRT to 
sorafenib alone improves overall survival from 10.5 to 14.5 months (HR=0.72). Given the 
conditions above, and adjusting for ineligible/lost patients or patients that cannot meet the RT 
planning requirements, a total sample size of 292 patients will be required to be accrued 
uniformly over 7 years, post ramp-up period, with an additional 1 year of follow-up.  
 
13.3.2 Patient Accrual 
Patient accrual is projected to be 3 cases per month, with a ramp-up period in the first 6 months 
with no projected accrual.  Following this ramp-up period, accrual will be completed in 7 years. 
 
Projected accrual was based on a survey submitted in June 2011 by the RTOG to all full RTOG 
members, the members of the RTOG GI Steering Committee and interested Asian centers.  In 
brief, there were 43 respondents, including the 2 Asian centers. Twenty-eight centers planned to 
definitely open the study; 22 of these centers are already credentialed for RTOG lung or liver 
SBRT studies (excluding the 2 Asian centers).  An additional 13 centers were considering 
opening the study (all of these centers were credentialed for RTOG lung or liver SBRT studies).  
Based on the 22 credentialed RTOG non-Asian centers, 12 patients per month were estimated to 
be accrued to this study. Including the Asian centers, 17 patients per month were estimated to 
participate.  Accounting for some overestimation and lower than expected accrual in prior HCC 
studies, the actual expected accrual is 3 patients per month. 
 
If the total accrual during months 13 through 18 of the study is ≥ 50% of the targeted accrual (18 
or more cases), then the accrual will have met the NCI-CTEP Ph III accrual guidelines and will 
continue.  If the total accrual during months 13 through 18 of the study is ≤ 20% of the targeted 
accrual (≤ 7 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% (8 to 17 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 (≥ 9 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  
Power Information for Health Reported Quality of Life – FACT-Hepatobiliary Module (FACT-
Hep) (25-MAR-2020) 
The Functional Assessment of Cancer Therapy – Hepatobiliary (FACT-Hep) will be used to 
measure HRQOL. Protocol-eligible patients will be included in the QOL analysis only if they have 
provided baseline and at least one subsequent measurement. The FACT-Hep will be collected on 
all cases participating in this portion of the trial and will be collected at 4 time points: baseline, 3 
months, 6 months, and 12 months post initiation of protocol therapy. 
13.4.1 The primary HRQOL endpoint will be to determine whether patients treated with SBRT and 
sorafenib have an improved FACT-Hep score from baseline to 6 months, as measured by the 
proportion of patients on each treatment arm with improvement, defined as an increase in the 
FACT-Hep score of at least 5 points (minimally important difference), as compared to patients 
receiving sorafenib alone. The power calculations shown below cover a number of possible 

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RTOG 1112, Version Date: September 23, 2022 
proportions for improvement over the control arm. The power calculations are all based on a 1-
sided, α=0.05, chi-squared test and the listed patient participation rate (PPR) of the 320 evaluable 
patients required for the overall study. 
 
Power Calculations for FACT-Hep Score  
 
p0 
pa 
Power 
(84% PPR 
n/arm=111) 
Power 
(74% PPR 
n/arm=98) 
Power 
(64% PPR 
n/arm=85) 
0.10 
0.25 
91 
87 
83 
0.10 
0.30 
98 
97 
95 
0.20 
0.35 
81 
76 
71 
0.20 
0.40 
95 
93 
89 
0.30 
0.45 
75 
70 
65 
0.30 
0.50 
92 
89 
85 
0.40 
0.55 
73 
68 
62 
0.40 
0.60 
91 
88 
84 
0.50 
0.65 
73 
67 
63 
0.50 
0.70 
92 
89 
85 
 
 
*If the participation rate is higher, there will be more power to detect the hypothesized differences; 
if the participation rate is lower, there will be less power. 
 
13.4.2 A secondary HRQOL endpoint will be to determine whether patients treated with SBRT and 
sorafenib have an improved FACT-Hep score, as measured by the proportion of patients on each 
treatment arm with improvement, defined as an increase in the Trial Outcome Index (TOI) score 
of at least 7 points  (minimally important difference), as compared to patients receiving sorafenib 
alone.  The TOI scale consists of the physical well-being and functional well-being subscales from 
the FACT-G with hepatobiliary module.  The power calculations, with the same assumptions, are 
the same as shown in Section 13.4.1. 
13.4.3 Another secondary HRQOL endpoint will be to determine whether patients treated with SBRT and 
sorafenib have an improved NCCN/FACT-Hep Symptom Index (FHSI-18) score, as measured by 
the proportion of patients on each treatment arm with improvement, defined as an increase of at 
least 2 points  (minimally important difference), as compared to patients receiving sorafenib 
alone.  The FHSI-18 has a total of 18 items assessing common symptoms when treating 
advanced hepatobiliary disease. The power calculations, with the same assumptions, are the 
same as shown in Section 13.4.1. 
 
13.5 
Analysis Plan (26-MAY-2022) 
All analyses will be done based on the assigned treatment arm for all eligible patients entered. 
13.5.1 Statistical Methods 
Overall Survival 
Overall survival (OS) will be estimated by the Kaplan-Meier method (Kaplan 1958). The 
distribution of OS estimates between the 2 arms will be compared using the log rank test (Mantel 
1966).   OS time 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, that may be associated with OS.  
Progression-Free Survival 
Progression-free survival (PFS) will be estimated by the Kaplan-Meier method (Kaplan 1958). 
The distribution of PFS estimates between the 2 arms will be compared using the log rank test 
(Mantel 1966).   PFS time will be measured from the date of randomization to the date of first 
failure or last follow-up.  The Cox proportional hazard regression model will be used to analyze 
the effects of factors, in addition to treatment, that may be associated with PFS. 
Time-to-Progression (TTP) 

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Time-to-progression (TTP) will be estimated by the cumulative incidence method (Mantel 1966). 
The distribution of TTP estimates between the 2 arms will be compared using Gray’s test (Gray 
1988).   TTP time will be measured from the date of randomization to the date of first failure or 
last follow-up.  The Cox proportional hazard regression model will be used to analyze the effects 
of factors, in addition to treatment, that may be associated with TTP. 
13.5.2   Interim Analysis to Monitor the Study Progress 
Interim reports 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. 
 
13.5.3 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. 
13.5.4   Significance Testing for Early Termination and/or Reporting 
Unacceptable Toxicity 
To address the safety of SBRT followed by sorafenib, the rate of unacceptable adverse events 
will be evaluated on both treatment arms. This analysis will focus on the following AEs occurring 
within 90 days from the start of protocol treatment definitely or probably related to protocol 
treatment: 
a) grade 4 or 5 hepatic 
b) grade 4 or 5 gastrointestinal 
c) grade 4 thrombocytopenia associated with any bleeding or grade 5 thrombocytopenia 
d) Any grade 5 treatment-related adverse event 
 
Assuming no more than a 10% rate of the above AEs on the sorafenib alone arm, the study 
chairs have determined that an increase to a rate of 30% or greater on the SBRT followed by 
sorafenib arm will be considered to be unacceptable. One-hundred and fifty-four patients provide 
90% power to detect an increase in the rate of specified AEs from 10% to at least 30% with a 1-
sided alpha of 0.05, using a Chi-squared test for difference in proportions. If the p-value from the 
test described above is ≤ 0.05, the conclusion will be that the treatment-related unacceptable AE 
rate for the SBRT followed by sorafenib arm is at least 30% and accrual to the study will be 
stopped.  
 
Primary Endpoint: Overall survival (OS) 
 Three interim significance tests of treatment difference are planned. The timing of the interim 
analyses will be based on OS failure events, as described in Section 13.1.1.  The maximum 
number of events required for the study is 238. Under the alternative hypothesis that the addition 
of SBRT will increase median OS from 10.5 months to 14.5 months, the projected numbers of 
events and the nominal significance levels for rejecting the H0 or the H1 for each of these two 
interim analyses are shown in the table below:   
 
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
Nominal Significance Levels for Interim Analyses 
 
 
 
Interim Analysis 
Efficacy: 
Reject H0 if p(H0) 
≤ 
Futility: 
Reject H1 if Z(H0) 
≤ 
 
# Events (%) 
 
#1 
0.001 
0 
98 (41%) 
 
#2 
0.001 
0 
143 (60%) 
 
#3 
0.001 
0.385 
190 (80%) 
 
At each planned interim analysis, the p-value from the log-rank test assessing treatment efficacy 
and the Z-score assessing treatment futility with respect to OS will be compared to the nominal 
significance/critical levels in the table above.  If the computed p-value is less than or equal to the 
nominal significance level boundary for rejecting the H0 (efficacy), then accrual to the trial will be 
stopped (if applicable), it will be concluded that the OS with SBRT and sorafenib (Arm 2) is 
significantly higher than sorafenib alone (Arm 1) and the results will be reported.  If the Z-score is 
less than or equal to the nominal critical level boundary for rejecting the H1 (futility), then accrual 
to the trial will be stopped (if applicable) and it will be reported that it cannot be concluded that the 
OS with SBRT and sorafenib (Arm 2) is significantly higher than sorafenib alone (Arm 1).  
Otherwise, accrual to the trial or follow-up (as applicable) will continue until the next interim or 
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 NRG Oncology data monitoring committee (DMC), following the required number of events 
for each planned interim analysis.  
13.5.5 Analysis for Endpoints Related to HRQOL  
Distributions of QOL data collection patterns over all collection points in each treatment arm will 
be described.  To inspect the missing data mechanism for each tool, at least a graphical method 
will be used.  A missing completely at random (MCAR) mechanism exists when missing values 
are randomly distributed across all observations. A missing at random (MAR) mechanism exists 
when values are not randomly distributed across all observations, rather than one or more sub-
samples.  
 
If the missing data is MCAR, listwise deletion (complete case analysis) will be done. If the MAR 
assumption is supported by the data, then an imputation method such as multiple imputation will 
be applied to impute missing data.  
 
If the MAR assumption is not supported by the data, then adjusting for covariates (such as the 
baseline QOL score) might reduce the conditional association between outcomes and missing 
values. If missing data patterns look similar when stratified by such covariate(s), then an analysis 
that adjusts for such covariate(s) will be conducted and an imputation method such as multiple 
imputation will be applied. If approximate conditional independence cannot be obtained with any 
set of covariates, then MNAR (missing not at random) must be addressed by an explicit model for 
the missing data mechanism (Donaldson 2005) and then an imputation method such as multiple 
imputation will be applied. All results from the imputed analysis using the multiple imputation will 
be compared to the complete case analysis results to assess any potential biases.  
FACT-Hep Scoring and Analysis 
The FACT-Hep will be scored per the FACT-Hep Scoring Guidelines (Version 4 www.facit.org), 
with higher scores indicating better QOL. 
 
The primary objective in the HRQOL analysis is improvement in the FACT-Hep score, defined as 
an increase of 5 points or more from baseline to the assessment at 6 months from the start of 
protocol therapy.  Chi-squared tests will be used to test the null hypothesis that the proportion of 
patients categorized as “improved” will be the same for the 2 treatment arms, versus the 
alternative hypothesis that the proportion of patients categorized as “improved” is higher for the 
SBRT+sorafenib arm. 

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Improvement in the FACT-Hep score, as defined above, will also be compared between the 
treatment arms for changes from baseline to both 3 and 12 months with the same methodology 
as listed above. 
 
Correlation of baseline FACT-Hep and survival will be evaluated. 
  
EQ-5D Scoring and Analysis 
The quality-adjusted survival of each treatment will be evaluated and compared using EQ-5D if 
the primary endpoint supports the primary hypothesis. 
 
The EQ-5D is a 2-part self-assessment questionnaire. The first part consists of 5 items covering 5 
dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). Each 
dimension is measured by a 3-point likert scale (1-no problems, 2-moderate problems, and 3-
extreme problems). The second part is a visual analog scale (VAS) valuing the current health 
state measured by a 100-point scale with a 10-point interval (0-worst imaginable health state, 
100-best imaginable health state). We will transform the 5-item index score and VAS score into a 
utility score between 0 (worst health state) and 1 (best health state) for comparative purposes. 
Patients will complete the EQ-5D at the following time points: pretreatment (baseline), 3 months, 
6 months, and 12 months post initiation of protocol therapy. 
 
To examine trade-offs between the survival time and QOL, they will be combined for each patient 
into a single measurement: quality-adjusted life years (QALY). If (and only if) the primary endpoint  
hypothesis is substantiated, a quality-adjusted survival analysis will be conducted. The quality- 
adjusted survival analysis will not be done until after the primary endpoint results are published. 
QALY is defined by the weighted sum of different time episodes added up to a total quality- 
adjusted survival time. QALY will be analyzed at 2 time points: at 6 and 12 months from start of  
treatment, using the EQ-5D. 
13.5.6 Analysis for Reporting the Initial Treatment Results 
The primary hypothesis of this study is SBRT and sorafenib will increase the median OS from 
10.5 months to 14.5 months as compared to sorafenib alone for patients with hepatobiliary 
carcinoma. The timing of initial treatment results analysis will be as described in Section 13.5.7 
and 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 benefit will be tested 
using the log-rank statistic with a significance level of 0.05, given that the 3 interim analyses were 
carried out per Section 13.5.4.  Additional analyses of treatment effect will be performed using the 
Cox proportional hazard model with the stratification factor included as a fixed covariate, as well 
as any factors that show an imbalance between the arms (eg, age, gender, race, Zubrod status, 
etc.). 
13.5.7   Time-Driven Definitive Analysis  
The statistical analysis plan changes were done in accordance with the NCI Policy for Major 
Design Amendments for Ongoing Randomized Clinical Trials. The specifics for the changes were 
performed by a statistician independent from the trial. 
External circumstances have resulted in accrual closure with 177 eligible patients currently 
enrolled. Due to the limited sample size and observed event rate, coupled with concerns 
regarding adoption of new therapy among participants, the trial primary endpoint will be reported 

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RTOG 1112, Version Date: September 23, 2022 
at a fixed calendar date (July 1, 2022, or completion of this amendment, whichever is later). The 
targeted treatment effect (experimental/control HR = 0.72) and alpha level (one-sided 0.05) will 
remain unchanged from the original design.  
The primary endpoint analysis will thus be performed with the number of OS events reported 
through July 1, 2022 (or completion of this amendment, whichever is later). It is anticipated that at 
that time, at least 155 OS event will have been observed. The log-rank test with 155 OS events 
will have 65% power at one-sided alpha 0.05 to detect the targeted treatment effect 
(experimental/control HR of 0.72). 
 
13.6 
Gender and Minorities (23-SEP-2022) 
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 interaction between race/ethnicity and 
treatment has been considered. It is projected that 80% of the patients will be men and 20% 
women; 2% will be of Hispanic or Latino ethnicity and 98% will not; racial distribution will be 73% 
white, 2% black or African American, and 25% Asian. Assuming no differences between the 
ethnicities, or among the races, the statistical power for detecting the hypothesized treatment 
difference is 64% for males and 21% for females. Assuming no differences between genders or 
the ethnicities, the statistical power is 60% for whites and 25% for Asians. The projected non-
White/Asian accrual rate is too low for any meaningful treatment comparisons. Assuming no 
differences between the genders, or among the races, the statistical power for detecting the 
hypothesized treatment difference in non-Hispanic/Latino ethnicity will be 73%. The projected 
Hispanic/Latino accrual rate is too low for any meaningful treatment comparisons. 
 
The following table lists the projected accrual by gender, ethnic, and racial categories. 
 
 
 
Projected Distribution of Gender and Minorities  
DOMESTIC 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska 
Native 
0 
1 
0 
1 
2 
Asian 
1 
4 
0 
3 
8 
Native Hawaiian or other 
Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
3 
8 
1 
2 
14 
White 
10 
52 
3 
9 
74 
More than one race 
0 
1 
0 
2 
3 
TOTAL 
15 
66 
4 
17 
102 
 
 
 
 
 
 
 
FOREIGN 

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RTOG 1112, Version Date: September 23, 2022 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
 Male  
Female 
 Male  
American Indian or Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
9 
41 
0 
0 
50 
Native Hawaiian or other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
5 
0 
0 
6 
White 
24 
110 
0 
0 
134 
More than one race 
0 
0 
0 
0 
0 
TOTAL 
34 
156 
0 
0 
190 
 
 
 

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Sorafenib and Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma." International Journal of 
Radiation Oncology* Biology* Physics 94, no. 3 (2016): 580-587. 
O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549-556. 
Pan C, Dawson LA, Das SK, et al. Radiation-associated liver injury. Special QUANTEC Issue. Int J Radiat Oncol 
Biol Phys. 76(3): S94-S100, 2010. 
Plastaras JP, Kim SH, Liu YY, et al.  Cell cycle dependent and schedule-dependent antitumor effects of sorafenib 
combined with radiation. Cancer Res. 67(19): 9443-54, 2007. 
Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika. 1977;64:191-199. 
Raoul JL, Sangro B, Forner A, et al. Evolving strategies for the management of intermediate-stage hepatocellular 
carcinoma: Available evidence and export opinion on the use of transarterial chemoembolization. Cancer Treat 
Rev. 37(3): 212-220, 2011. 
Ringash J, Lockwood G, Lee M, et al. Responsiveness OF FACT-Hep and EORTC QLQ-C30 to Radiotherapy for 
Malignant Liver Tumors. Presented at ISOQOL. Abstract 1696, 2008. 
Schultz MW, Chen J, Woo HH, et al. A comparison of techniques for eliciting patient preference in patients with 
benign prostatic hyperplasia. J Urol. 168: 155-159, 2002. 
Seo YS, Kim MS, Yoo SY, et al: Preliminary result of stereotactic body radiotherapy as a local salvage treatment 
for inoperable hepatocellular carcinoma. J Surg Oncol 102:209-14, 2010 
Seong J, Park HC, Han KH, et al. Clinical results and prognostic factors in radiotherapy for unresectable 
hepatocellular carcinoma: a retrospective study of 158 patients. Int J Radiat Oncol Biol Phys. 55:329-336, 2003. 
Seong J, Lee IJ, Shim SJ, et al. A multicenter retrospective cohort study of practice patterns and clinical outcome 
on radiotherapy for hepatocellular carcinoma in Korea. Liver Int. 29: 147-52, 2009. 
Shim SJ, Seong J, Han KH, et al. Local radiotherapy as a complement to incomplete transcatheter arterial 
chemoembolization in locally advanced hepatocellular carcinoma. Liver Int. 25: 1189-1196, 2005. 
Son SH, Choi BO, Ryu MR, et al. Stereotactic body radiotherapy for patients with unresectable primary 
hepatocellular carcinoma: dose-volumetric parameters predicting the hepatic complication. Int J Radiat Oncol Biol 
Phys. 78: 1073-80, 2010. 
Steel J, Baum A, Carr B. Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic 
arterial infusion of cisplatin versus 90-yttrium microspheres (therasphere). Psychooncology. 13: 73–79, 2004. 
Steel JL, Eton DT, Cella D, et al. Clinically meaningful changes in health-related quality of life in patients 
diagnosed with hepatobiliary carcinoma. Ann Oncol 17(2): 304-312, 2006. 
Sugahara S, Oshiro Y, Nakayama H, et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat 
Oncol Biol Phys. 76: 460-466, 2010. 
Toya R, Murakami R, Baba Y, et al: Conformal radiation therapy for portal vein tumor thrombosis of hepatocellular 
carcinoma. Radiother Oncol. 84: 266-71, 2007. 
Tse R, Kim, J, Cummings, B, et al.  Phase I Study of Stereotactic Radiation Therapy for Primary Liver Cancer. J 
Clin Oncol. 26: 657-664, 2008. 
Tsujii H, Mizoe JE, Kamada T, et al. Overview of clinical experiences on carbon ion radiotherapy at NIRS. 
Radiother Oncol. 73(2):S41-49, 2004. 
Wang YB, Chen MH, Yan K, et al.  Quality of life after radiofrequency ablation combined with transcatheter 
arterial chemoembolization for hepatocellular carcinoma: comparison with transcatheter arterial 
chemoembolization alone. Qual Life Res. 16: 389–397, 2007. 
Wieand, S., Schroeder, G. and O'Fallon, J. R. (1994), Stopping when the experimental regimen does not appear 
to help. Statist. Med., 13: 1453–1458. doi: 10.1002/sim.4780131321 
Wilhelm SM, Carter C, Tang L., et al.  BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets 
the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis. 
Cancer Res. 64: 7099-7109, 2004. 
Winkler F, Kozin SV, Tong RT, et al.  Kinetic os Vascular Normalization by VEGFR2 Blockade Governs Brain 
Tumor Response to Radiation: Role of Oxygenation, Antiopoietin-1, and Matrix Metalloproteinases. Cancer Cell. 
6: 553-563, 2004. 
Wu AW, Jacobson KD, Frick DL, et al. Validity and responsiveness of the EQ-5D as a measure of health-related 
quality of life in people enrolled in an AIDS clinical trial. Qual Life Res. 11: 273-282, 2002. 
Yoon SM, Young-Suk L, Won HJ, et al.  Radiotherapy plus transarterial chemoembolization for hepatocellular 
carcinoma invading the portal vein: Long term patient outcomes.  Int J Radiat Oncol Biol Phys. 82: 2004-2011, 
2012. 
Zelen M. The randomization and stratification of patients to clinical trials. J Chron Dis. 27: 365-75, 1974. 
Zeng ZC, Tang ZY, Fan J, et al. A comparison of chemoembolization combination with and without radiotherapy 
for unresectable hepatocellular carcinoma. Cancer. 10: 307-316, 2004. 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX I 
STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (13-MAY-2019) 
 
Pre-Treatment Assessments 
(may be required for eligibility) 
≤360 days prior to 
study entry 
28 days prior to 
study entry 
14 days prior to 
study entry 
Biopsy, cytology ,radiographically  
confirmed HCC 
X 
 
 
History/physical* 
 
 
X 
Performance status 
 
X 
 
TNM stage, BCLC stage 
 
 
X 
Child Pugh score, MELD score 
 
 
X^ 
Assessment by radiation 
oncologist, medical oncologist or 
hepatologist 
 
X 
 
CBC w/diff, ANC, platelets  
 
 
X 
Serum creatinine or creatinine 
clearance, ALT, AST 
 
 
X 
Alpha-fetoprotein 
 
X 
 
Bilirubin, albumin, INR, ALP, 
phosphate, sodium, potassium, 
chloride, magnesium 
 
X 
 
Calcium 
 
X 
 
bHCG test (if applicable)  
 
 
X 
Multi-phasic liver CT or multi-
phasic liver MRI 
 
X 
 
CT chest and CT or MR abdomen 
and CT or MR pelvis, or PET CT 
chest/abdomen/pelvis  
 
X 
 
Quality of Life (for consenting 
patients) 
Pre-Treatment 
Tissue banking (for consenting 
patients) 
Pre-Treatment 
Plasma banking (for consenting 
patients) 
Pre-Treatment 
Whole blood banking (for 
consenting patients) 
Pre-Treatment 
Informed consent 
 
X 
*Including ascites, encephalopathy, weight, height, and blood pressure. 
^ INR < 28 days can be used for scoring < 14 days 
-Continued on next page- 
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX I 
STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT AND FOLLOW-UP (25-MAR-2020) 
 
Assessments 
SBRT  
During 
Sorafenib 
(Arm 1 and 2) 
Follow up for ALL 
Patients** 
(Arm 1 and 2) 
 
Arm 2 - 
Weekly 
(following 
at least 
one 
fraction) 
Arm 2 - 
Prior to 
starting 
sorafenib, 
post last 
SBRT 
fraction 
 
Monthly (or per 
local standard 
of care) 
 
Every 3 
months 
from study  
entry for 2 
years from 
study entry 
Then, 
every 6 
months  
History/physical* 
X 
X 
 
X 
X  
X 
Performance status 
X 
X 
 
X 
X  
X 
Child Pugh score, 
MELD score 
 
 
 
 
X 
X 
Assessment by 
radiation oncologist, 
medical oncologist 
or hepatologist 
X 
X 
 
X 
X  
X 
Assessment by 
medical oncologist 
and/or hepatologist 
 
X 
 
X 
 
 
CBC w/diff, ANC, 
platelets  
X 
 
 
X 
X  
X 
Serum creatinine or 
creatinine 
clearance, ALT, 
AST 
X 
 
 
X 
X  
X 
Bilirubin, albumin, 
INR, ALP, 
phosphate, sodium, 
potassium, chloride, 
magnesium 
 
 
 
X 
X  
 
Calcium 
 
 
 
 
X 
 
Alpha-fetoprotein 
 
 
 
 
X 
X 
Multi-phasic liver 
CT or multi-phasic 
liver MRI 
 
 
 
 
X (for 2 
years then 
every 6 
months) 
X 
CT chest 
 
 
 
 
 
X (annually 
only)  
X (annually 
only)  

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RTOG 1112, Version Date: September 23, 2022 
Adverse event eval 
(and as needed 
based on reporting 
requirements)† 
X 
X 
 
X 
X  
X 
Quality of Life (for 
consenting 
patients) 
 
 
 
 
3, 6, 12 
months 
only 
 
Plasma and whole 
blood banking (for 
consenting 
patients) 
 
 
 
 
1 and 3 
months 
only (see 
section 
10.2.6) 
 
Pill diary (do not send 
to NRG HQ) 
 
Daily during sorafenib 
*Including ascites, encephalopathy, weight, and blood pressure. 
** Including patients receiving sorafenib or patients who have discontinued sorafenib. 
† Including skin toxicity (in and out of RT volumes for SBRT arm). 
Note: For q monthly tests, +/- 2 week is permitted, and for q 3, 6 and 12 monthly tests, +/- 3 weeks is 
permitted. 
Pill diary: http://www.rtog.org/ClinicalTrials/NonStudySpecificForms.aspx 
After patients have been documented to have radiologic PD, the above follow-up is recommended, but not 
mandatory.                                                                                                                                                          
 

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RTOG 1112, Version Date: September 23, 2022 
 
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  
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX III 
 
AJCC Staging System 
Edge SB, ed. AJCC Cancer Staging Manual 7th ed. New York, NY, 2010 
 
HEPATOCELLULAR CARCINOMA 
 
Primary Tumor (T) 
 
TX 
Primary tumor cannot be assessed 
T0  
No evidence of primary tumor 
T1 
Solitary tumor without vascular invasion 
T2 
Solitary tumor with vascular invasion or 
Multiple tumors no more than 5 cm 
T3a 
Multiple tumors more than 5cm 
T3b 
Tumor involving a major branch of the portal or hepatic vein(s) 
T4 
Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the 
visceral peritoneum 
 
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) 
 
MX 
Distant metastases cannot be assessed 
M0  
No distant metastases 
M1  
Distant metastases 
 
Stage Grouping 
 
Stage I  
T1 
N0 
M0 
Stage II  
T2 
N0 
M0 
Stage IIIA 
T3a 
N0 
M0 
Stage IIIB 
T3b 
N0 
M0 
Stage IIIC 
T4 
N0 
M0 
Stage IVA 
Any T N1 
M0 
Stage IVB 
Any T Any N M1 
 
 
 
 
 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX IV 
 
BCLC Staging System 
 
 
 
 
* PST- Zubrod performance status 
 
 
Reference:  Llovet JM, Di Besceglie AM, Bruix J et al.  Design and endpoints of clinical trials in hepatocellular 
carcinoma. J Natl Cancer Inst 100:698-711, 2008 
 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX V (27OCT2017) 
 
Multi-Phase Hepatocellular Carcinoma Imaging Protocol 
 
Recommended imaging for hepatic 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 
Gadolinium or Primovist/Eovist (Gd-EOB-DTPA) enhanced liver MRI may be utilized to facilitate target delineation 
and should be used if there is a contraindication to IV CT contrast.  It is recommended that non-contrast-
enhanced 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 MR images may be 
used for target delineation, only if T1 weighted images demonstrate the HCC with clearly defined edges. 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX VI (27OCT2017) 
 
Child Pugh Classification of Liver Function 
 
 
Clinical and Biochemical Parameters 
Score (Points) for Increasing Abnormality 
  
 
 
 
1 
2 
3 
Encephalopathy 
 
 
None 
1 - 2   
3 - 4 
Ascites 
 
 
 
None 
Slight 
Moderate 
Non clinical trace ascites on imaging only is not mandated to be included as “mild ascites” (2 points). 
Instead it may receive 1 point on this study. 
Albumin (g/dL) 
 
 
> 3.5 
2.8 - 3.5 
< 2.8 
INR* 
 
 
 
< 1.7 
1.7 - 2.3 
> 2.3 
Bilirubin (mg/dL) 
  
  
1 - 2 
2 - 3 
> 3 
* INR = International Normalized Ratio for Prothrombin Time 
 
 
 
 
 
 
 
 
Class A 
5 - 6 points 
 
 
 
 
Class B 
7 - 9 points 
 
 
 
 
Class C 
10 - 15 points 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alternative Biochemical Units 
  
Score (Points) for Increasing Abnormality 
  
 
 
 
1 
2 
3 
Albumin (g/L) 
 
 
> 35  
28- 35 
< 28 
Bilirubin (umol/L) 
0-34.2 
34.3 - 51.3 
> 51.3 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
Stages of Hepatic Encephalopathy 
  
Stage 1 
Euphoria or depression, mild confusion, slurred speech, disordered sleep 
Stage 2 
Lethargy, moderate confusion 
 
  
Stage 3 
Marked confusion, incoherent speech, sleeping but arousable 
Stage 4 
Coma 
  
  
  
  
  
 
 
Reference:  Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma exchange blood transfusion. N Engl J 
Med 1966; 274 (9): 473-481 
 

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX VII 
 
Model for End-Stage Liver Disease (MELD) Score  
 
The MELD score is based on the patient’s bilirubin, creatinine and the INR to predict survival.  It is calculated 
according to the following formula: 
 
MELD = 9.57 * ln(serum creatinine in mg/dl) + 3.78 * ln(total serum bilirubin in mg/dl) + 11.2 * ln(INR) + 6.43 
 
If any value is less than one, it should be given a value of 1. 
 
 
Reference; Kamath PS, Kim WR (March 2007). "The model for end-stage liver disease (MELD)". Hepatology 45 
(3): 797–805. 
 
  

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RTOG 1112, Version Date: September 23, 2022 
APPENDIX VIII (8/26/14) 
 
Veff CALCULATION 
 
Use of effective liver volume (Veff) to aid in dose prescription is permitted if available, but it is not to be the 
primary tool used for dose allocation.  The following table is used as a guide.   If there are discrepancies in the 
Veff and mean liver dose (MLD) for the prescription dose allocation, MLD will be used for dose allocation.  A call 
to the clinical PI or physics PI is recommended if this occurs.  
 
Liver Veff 
Planned Prescription 
Dose (Gy) 
If the allowed Veff is exceeded at this 
planned dose 
< 25% 
50 
Reduce to 45 Gy and re-evaluate 
25 - 29% 
45 
Reduce to 40 Gy and re-evaluate 
30 - 34% 
40 
Reduce to 35 Gy and re-evaluate 
35 - 44% 
35 
Reduce to 30 Gy and re-evaluate 
45 - 54% 
30 
Reduce to 27.5 Gy and re-evaluate 
55 - 64% 
27.5 
Ineligible 
 
Veff must be calculated using the methods described in the references below.  The equation below may be used. 
 
 
n
i
ref
i
i d
d
v
Veff
1
∑






∆
=
 
 
where ∆vi is a volume bin of a differential DVH, di is the dose to that volume, and dref is the reference dose and n 
is the volume effect parameter (equal to 0.97 in this application).. The prescription dose is used as the 
reference dose in this study. 
 
1. 
Kutcher GJ BC, Brewster L et al. Histogram reduction method for calculating complication probabilities for three-
dimensional treatment planning evaluations. Int J Radiat Oncol, Biol, Phys 1991;21:137-146. 
2. 
Dawson LA,  Eccles C, Craig T.  Individualized Image Guided Iso-NTCP based Liver Cancer SBRT. Acta Oncol. 45: 
856 – 864, 2006. 
 
 

86 
RTOG 1112, Version Date: September 23, 2022 
APPENDIX IX (27Oct2017) 
APPENDICES FOR NRG Oncology BIOSPECIMEN COLLECTION 
 
NRG Oncology  
Blood Collection Kit Instructions 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For non-urgent 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 
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 Form (ST) 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. Place padding in top of container so that if you shake the container the blocks 
are not shaking. If you can hear the slides shaking it is likely that they will 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. 
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 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 -80° C until ready 
to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank 
by e-mail: NRGBB@ucsf.edu or phone: 415-476- 7864 or Fax: 415-476-5271. 

87 
RTOG 1112, Version Date: September 23, 2022 
 
 
 
 
APPENDIX IX (27OCT2017) 
 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS 
 
This Kit is for collection, processing, storage, and shipping of serum, plasma or whole blood (as specified 
by the protocol): 
 
• 
Kit contents (Note: Sites are responsible for providing blood draw tubes): 
• 
Thirty (30) 1 ml cryovials for plasma and serum – all time points 
• 
Three (3) 2 ml cryovials for whole blood 
• 
Biohazard bags (7) and Absorbent shipping material (7) 
• 
One Styrofoam container (inner) and Cardboard shipping (outer) box per case 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal Form (ST) and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube (one 10 ml or two 5ml) 
 
Label five 1ml cryovials for the serum collected. Label them with the study and case number, 
collection date, time point, and clearly mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4°C (preferred). If sites are 
unable to process samples at 4°C then spinning at room temperature is acceptable if done within 2 
hours of draw but must be noted on the ST. 
3. Aliquot a minimum of 0.5 ml serum into each of the five cryovials as necessary for the serum 
collected, labeled with study and case numbers, collection date, 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. 
 
(B) Plasma (if requested): Purple Top EDTA tube #1 (one 10 ml or two 5ml) 
 
Label five 1ml cryovials for the plasma collected. Label them with the study and case number, 
collection date, 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 RPM 
for 10 minutes at 4°C (preferred). If sites are unable to process samples at 4°C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the ST. 
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 the five cryovials as necessary 
for the plasma collected, labeled with study and case numbers, collection date, 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. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST. 

88 
RTOG 1112, Version Date: September 23, 2022 
APPENDIX IX (27OCT2017) 
 
NRG Oncology BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 (one 5 ml or 10ml tube) 
 
Label three 1ml cryovials as necessary for the whole blood collected. Label them with the study and case 
number, collection date, 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 1.0-2.0 ml blood into three 2ml cryovials as necessary for the blood 
collected, labeled with study and case numbers, collection date, time point collected and clearly mark 
specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80° Celsius. 
4. Store blood samples frozen until ready to batch 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. 
 
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 Form the storage conditions used and time stored. 
 
(continued on next page) 

89 
RTOG 1112, Version Date: September 23, 2022 
APPENDIX IX (27Oct2017) 
 
BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
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. 
 
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 – San Francisco 
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  
 
  

90 
RTOG 1112, Version Date: September 23, 2022 
APPENDIX X 
 
VASCULAR THROMBOSIS STRATIFICATION DIAGRAM 
 
One stratification factor is degree of vascular thrombosis.  The three strata are: 
1) Tumor thrombosis involving the IVC, the main portal vein or the right or left main branch portal vein. This 
includes any thrombi involving these vascular structures at least partially, defined as involving any of the IVC, 
main portal vein or the right or left main branches of the portal vein.  The right and left main branches of the portal 
vein are the first branches off the main portal vein, up to the first bifurcation of the right and left portal veins, as 
shown in the diagram below.   
2) Any other thrombosis (e.g. involving the more distal portal veins or hepatic veins) 
3) No vascular thrombosis.