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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
nrg oncology rtog 1112 randomized
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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   |
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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   |
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| 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   |
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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  
| (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                                                                                                       |
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| 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                                                                                                                                                              | 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                                                                                                    |
| RT Credentialing:                                                                                                                                                                                                         | 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                                                                                                                      | Fran Bradley NRG Oncology  50 South 16th Street, Suite 2800 Philadelphia, PA 19102 215-940-8893/Fax: 215-928-0153 bradleyf@nrgoncology.org                                                                                                                               |
| Gastrointestinal Non-Colorectal Committee  Chair:                                                                                                                                                                         | Christopher Crane, MD Memorial Sloan Kettering Cancer Center 1275 York Avenue, Box 22 New York, NY 10065  212-639-2112 cranec1@mskcc.org                                                                                                                                 |  
| 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 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.**  
| 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   |  
The following NCTN Study Champion(s) have been added to this trial:
ALLIANCE: Theodore S. Hong, MD SWOG: Tim Mitin, MD, PhD  
| 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.)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 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. | Data collection for this study will  be done exclusively through  Medidata Rave. Refer to the  data submission section of the  protocol for further instructions. |
| 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 Help Desk  with any OPEN-related questions by phone or email : 1-888-823- 5923 or  ctsucontact@westat.com.                                                                                            |                                                                                                                                                                   |
| Contact the CTSU Regulatory  Help Desk at 1-866-651-CTSU  (2878) for regulatory  assistance. 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/ |                                                                                                                                                                                                                        |                                                                                                                                                                   |  
| TABLE OF CONTENTS                                                                                                                                    |                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------|
| TABLE OF CONTENTS.                                                                                                                                   |                                                                                                                                   |
| SCHEMA .                                                                                                                                             |                                                                                                                                   |
| INTRODUCTION                                                                                                                                         |                                                                                                                                   |
| 1.0                                                                                                                                                  |                                                                                                                                   |
| 1.1                                                                                                                                                  | Hepatocellular Carcinoma (HCC) .                                                                                                  |
| 1.2                                                                                                                                                  | Local-Regional Treatments for HCC.                                                                                                |
| 1.3                                                                                                                                                  | SORAFENIB                                                                                                                         |
| 1.4                                                                                                                                                  | Radiation Therapy                                                                                                                 |
| Rationale for Sorafenib and Radiation Therapy ....................................................................................................15 |                                                                                                                                   |
| 1.5                                                                                                                                                  |                                                                                                                                   |
| 1.6                                                                                                                                                  | Clinical Experience with Sorafenib and Radiation Therapy  .....................................................................16 |
| QUALITY OF Life (QOL)                                                                                                                                |                                                                                                                                   |
| 1.7                                                                                                                                                  |                                                                                                                                   |
| 1.8                                                                                                                                                  | Biomarkers in HCC                                                                                                                 |
| 1.9                                                                                                                                                  | Protocol Overview                                                                                                                 |
| 2.0                                                                                                                                                  | OBJECTIVES .                                                                                                                      |
| 2.1                                                                                                                                                  | Primary Objective                                                                                                                 |
| 2.2                                                                                                                                                  | Secondary Objectives .                                                                                                            |
| 3.0                                                                                                                                                  | PATIENT SELECTION                                                                                                                 |
| 3.1                                                                                                                                                  | Conditions for Patient Eligibility                                                                                                |
| 3.2                                                                                                                                                  | Conditions for Patient Ineligibility                                                                                              |
| PRETREATMENT EVALUATIONS/MANAGEMENT                                                                                                                  |                                                                                                                                   |
| 4.0                                                                                                                                                  |                                                                                                                                   |
| 4.1                                                                                                                                                  | Required Evaluations/Management  .                                                                                                |
| Highly Recommended Evaluations/Management  .                                                                                                         |                                                                                                                                   |
| 4.2                                                                                                                                                  |                                                                                                                                   |
| 5.0  REGISTRATION, STUDY ENTRY PROCEDURES                                                                                                            |                                                                                                                                   |
| 5.1    PRE-REGISTRATION REQUIREMENTS FOR ALL RADIATION TECHNIQUES                                                                                    |                                                                                                                                   |
| 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                                                                       |
| 5.5                                                                                                                                                  | Digital Radiation Therapy Data Submission Using Transfer of Images and Data  .......................26                            |
| Regulatory Pre-Registration Requirements                                                                                                             |                                                                                                                                   |
| 5.6                                                                                                                                                  |                                                                                                                                   |
| 5.7                                                                                                                                                  | OEN Registration                                                                                                                  |
| 6.0                                                                                                                                                  | RADIATION THERAPY  .                                                                                                              |
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| 6.1                                                                                                                                                     | Dose Specifications  .                                                                                                                                                        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Technical Factors                                                                                                                                       |                                                                                                                                                                               |
| 6.2                                                                                                                                                     |                                                                                                                                                                               |
| 6.3                                                                                                                                                     | Localization, Simulation, and Immobilization                                                                                                                                  |
| Treatment Planning/Target Volumes  .                                                                                                                    |                                                                                                                                                                               |
| 6.4                                                                                                                                                     |                                                                                                                                                                               |
| 6.5                                                                                                                                                     | Critical Structures Maximal Doses  ................................................................................................................37                         |
| Targets and Critical Structures .....................................................................................................................37 |                                                                                                                                                                               |
| 6.6                                                                                                                                                     |                                                                                                                                                                               |
| 6.7                                                                                                                                                     | Documentation Requirements  ..........................................................................................................................38                      |
| Compliance Criteria                                                                                                                                     |                                                                                                                                                                               |
| 6.8                                                                                                                                                     |                                                                                                                                                                               |
| 6.9                                                                                                                                                     | Radiation Therapy and Imaging Quality Assurance Reviews ..............................................................40                                                      |
| 6.10                                                                                                                                                    | Radiation Therapy Adverse Events                                                                                                                                              |
| Radiation Therapy Adverse Event Reporting                                                                                                               |                                                                                                                                                                               |
| 6.11                                                                                                                                                    |                                                                                                                                                                               |
| 6.12                                                                                                                                                    | Radiation Therapy Toxicity Assessment During Therapy  ....................................................................42                                                  |
| 7.0                                                                                                                                                     | DRUG THERAPY  ..................................................................................................................................................43            |
| 7.1                                                                                                                                                     | T Treatment  .                                                                                                                                                                |
| 7.2                                                                                                                                                     | D Dose Modifications  .....................................................................................................................................................49 |
| 7.3                                                                                                                                                     | Modality Review  .                                                                                                                                                            |
| Adverse Events                                                                                                                                          |                                                                                                                                                                               |
| 7.4                                                                                                                                                     |                                                                                                                                                                               |
| 7.5                                                                                                                                                     | CTEP-AERS Expedited Reporting Requirements                                                                                                                                    |
| SURGERY                                                                                                                                                 |                                                                                                                                                                               |
| 8.0                                                                                                                                                     |                                                                                                                                                                               |
| 9.0                                                                                                                                                     | OTHER THERAPY                                                                                                                                                                 |
| 9.1                                                                                                                                                     | Permitted Supportive Therapy .                                                                                                                                                |
| 9.2                                                                                                                                                     | Non-permitted Supportive Therapy                                                                                                                                              |
| 10.0                                                                                                                                                    | TISSUE/SPECIMEN SUBMISSION                                                                                                                                                    |
| Tissue/Specimen Submission .                                                                                                                            |                                                                                                                                                                               |
| 10.1                                                                                                                                                    |                                                                                                                                                                               |
| 10.2                                                                                                                                                    | Specimen Collection for Tissue Banking and Translational Research  .                                                                                                          |
| Confidentiality/Storage  .                                                                                                                              |                                                                                                                                                                               |
| 10.3                                                                                                                                                    |                                                                                                                                                                               |
| 1.0                                                                                                                                                     | PATIENT ASSESSMENTS                                                                                                                                                           |
| Study Parameters .                                                                                                                                      |                                                                                                                                                                               |
| 11.1                                                                                                                                                    |                                                                                                                                                                               |
| 11.2                                                                                                                                                    | Evaluation During Treatment                                                                                                                                                   |
| 1.3                                                                                                                                                     | Measurement of Response                                                                                                                                                       |
| 1.4                                                                                                                                                     | Criteria for Discontinuation of Protocol Treatment  ........................................................................................59                                |
| Health Related Quality of Life and Health Utility Assessments  ...................................................................60                    |                                                                                                                                                                               |
| 1.5                                                                                                                                                     |                                                                                                                                                                               |  
| 12.0                                                                                                                                                        | DATA COLLECTION            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|
| 12.1 DATA QUALITY PORTAL                                                                                                                                    |                            |
| 12.2 DATA SUBMISSION / DATA REPORTING                                                                                                                       |                            |
| 12.3 Summary of Dosimetry Digital Data Submission  ......................................................................................................64 |                            |
| 13.0                                                                                                                                                        | STATISTICAL CONSIDERATIONS |
| 13.1 Endpoints .                                                                                                                                            |                            |
| 13.2 Stratification                                                                                                                                         |                            |
| 13.3  Sample Size and Power Justification  .                                                                                                                |                            |
| 13.4 Power Information for Health Reported Quality of Life - FACT-Hepatobiliary Module (FACT-Hep)                                                           |                            |
| 66                                                                                                                                                          | Analysis Plan  .           |
| 13.5                                                                                                                                                        |                            |
| 13.6                                                                                                                                                        | Gender and Minorities      |
| REFERENCES                                                                                                                                                  |                            |
| APPENDIX I                                                                                                                                                  |                            |
| APPENDIX II                                                                                                                                                 |                            |
| APPENDIX III .                                                                                                                                              |                            |
| APPENDIX IV                                                                                                                                                 |                            |
| APPENDIX V .                                                                                                                                                |                            |
| APPENDIX VI  .                                                                                                                                              |                            |
| APPENDIX VII                                                                                                                                                |                            |
| APPENDIX VIII  .                                                                                                                                            |                            |
| APPENDIX IX  .                                                                                                                                              |                            |
| APPENDIX X                                                                                                                                                  |                            |
radiation therapy oncology group rtog
table of contents

Randomized Phase III Study of Sorafenib versus Stereotactic Body Radiation Therapy followed by Sorafenib in Hepatocellular Carcinoma SCHEMA (25-MAR-2020)  
  
  
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)
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required sample size 292 (page

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)?
radiation therapy oncology group rtog
nrg oncology institution # rtog

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?
radiation therapy oncology group rtog
nrg oncology institution # rtog

1. Institutional person randomizing case.  
(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)?  
(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) |                                                                                                                                              |
| 15.   | Any care at VA or Military Hospital? |                                                                                                                                              |
| (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? |  
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  
16. Calendar Base Date  
17. Randomization date  
18. Medical oncologist's name
radiation therapy oncology group rtog
nrg oncology institution # rtog

(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
radiation therapy oncology group rtog
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 nonalcoholic 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 >
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 AsianPacific 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 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 (MendezRomero 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).
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1.5 rationale for sorafenib and

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 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.
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1.6 clinical experience with sorafenib

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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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 posttreatment. 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 45item 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 FACTHep 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, 2moderate 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 qualityadjusted survival in this trial.
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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 venoocclusive 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 venoocclusive 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.
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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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3.0 patient selection note per

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 multiphasic 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
- 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 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
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4.0 pretreatment evaluations/management note this

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)
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4.2 highly recommended evaluations/management (27oct2017)

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.  
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%.
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5.0 registration study entry procedures

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)                                                               | ✔     | ✔       | ✔    |     |      |  
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.
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5.1 pre-registration requirements for all

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                       | Web Link for Procedures and Instructions:                                                                                                                               |    |    |                                                                                                                                                                                                                                                                 |
| Requirements                        | http://irochouston.mdanderson.org Treatment  Key Information  Modality SBRT  Proton IMRT    The IROC Houston electronic facility questionnaire (FQ)                  |    |    |                                                                                                                                                                                                                                                                 |
| Facility                            |                                                                                                                                                                         |    |    |                                                                                                                                                                                                                                                                 |
| Questionnaire                       | 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.                                                                                                                                                             |  
  
| Cases               | http://atc.wustl.edu/protocols/rtog/1112/1112.html                                                                                                                                                                                                                                                                                                                                                                                                                           |    |                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|---------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|-------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |   | A liver phantom study provided by the IROC Houston QA |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Phantom             | Center must be successfully completed. Instructions for                                                                                                                                                                                                                                                                                                                                                                                                                      |    |                                                       |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| Irradiation         | 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 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.
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5.4 pre-registration requirements for proton

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.  
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.
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5.5 digital radiation therapy data

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:  
- 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.  
- An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating Organization (PO); and
- Compliance with all protocol-specific requirements (PSRs).
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triad installation additional requirements

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. 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)
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this study is supported by

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 to obtain an approved site registration status include:
- An active Federal Wide Assurance (FWA) number;  
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.
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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.
*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.
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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)
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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 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.
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pre-registration requirements for international institutions

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.
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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:  
- 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.
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6.0 radiation therapy 19-aug-2019 notes

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.  
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   | Priority     | Prescription Dose   |                                        |
|------------|--------------|---------------------|----------------------------------------|
| Constraint | Constraint   |                     |                                        |
| Liver Veff | Allowed Mean | Planned             | If the maximum allowed MLD is exceeded |  
| Liver Dose   | Prescription   | at this planned dose            |                                   |
|--------------|----------------|---------------------------------|-----------------------------------|
| [MLD] (Gy)   | Dose (Gy)      | Reduce to 45 Gy and re-evaluate |                                   |
| < 25%        | 13.0           | 50                              |                                   |
| 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 RBEweighted dose for protons (assuming RBE = 1.1).              |                |                                 |                                   |  
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 RBEweighted 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 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 liverto-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 setup, reproducibility of breathing amplitude on days of treatment compared to simulation will be confirmed prior to treatment delivery.
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6.4 treatment planning/target volumes (27oct2017)

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).  
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  
| Parenchymal (p) HCC,  prescription dose 50Gy Vascular (v) HCC thrombosis,  prescription dose of 45Gy Combined parenchymal and  vascular HCC, prescription dose  45Gy   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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  
PTVp1_50  
Or PTV1_50 Or PTV_50  
Vascular (v) HCC thrombosis,  
prescription dose of 45Gy  
GTVv1_45 CTVv1_45 PTVv1_45  
| GTVp1_50 Or GTV1_50 Or GTV_50   | PTVp1_50 Or PTV1_50 Or PTV_50   |                        |
|---------------------------------|---------------------------------|------------------------|
| GTVv1_45                        | CTVv1_45                        | PTVv1_45               |
| CTVp1_50 Or CTV1_50  Or CTV_50  |                                 |                        |
| GTVpv1_45                       | CTVpv1_45                       |                        |
| or GTVp1_45                     | or  CTVp1_45                    | PTVpv1_45  or PTVp1_45 |  
| Nodal (n) HCC, prescription dose                                      | GTVn2_35     | CTVn2_35    | PTVn2_35              |
|-----------------------------------------------------------------------|--------------|-------------|-----------------------|
| 35Gy Combined primary (p) and TACE                                    | GTVpt1_30 or | CTVpt1_30   |                       |
| (t) site, prescription dose 30Gy                                      | GTVp1_30     | or CTVp1_30 | PTVpt1_30 or PTVp1_30 |
| RFA (r) site, prescription dose                                       | -            | CTVr2_27.5  | PTVr2_27.5            |
| 27.5Gy TACE (t) site, prescription dose                               | -            | CTVt2_27.5  | PTVt2_27.5            |
| 27.5Gy Non-HCC vascular (v)  thrombosis, prescription dose of  27.5Gy | -            | CTVv2_27.5  | PTVv2_27.5            |  
| 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).  
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.  
| 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*                                                                                                                                                        |  
The following table outlines the naming of the various normal and critical structures for submission to TRIAD:  
| 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 |                              |  
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.
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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 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 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        | <85% | or | >115% | of |
| prescription dose, or < 25 Gy                                                            | prescription dose, or <25Gy                            |                          |          |           |      |    |       |    |
| Overall plan deviation                                                                   | < 25 Gy                                                |                          |          |           |      |    |       |    |
| unacceptable                                                                             |                                                        |                          |          |           |      |    |       |    |
| Dose values in this section should be read as physical dose for photons, or RBE-weighted |                                                        |                          |          |           |      |    |       |    |  
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.  
| 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                                                                                                                                                                                                           | > 13.2 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). ≤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 |                                                                 |                          |
radiation therapy oncology group rtog
6.9 radiation therapy and imaging

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.  
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.  
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             | Initiate anti-emetics prior to radiation and as needed and continue                    |                |
| vomiting                           | radiation                                                                              |                |
| grade 3 nausea or vomiting         | Hold radiation until improves to ≤ grade 2, then resume with antiemetics 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          | Continue radiation                                                                     |                |
| ALT 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                                                                     |                |  
| grade 3   | Hold radiation until improves to ≤ grade 2, then resume   |
|-----------|-----------------------------------------------------------|
| grade 4   | Discontinue radiation                                     |  
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.
radiation therapy oncology group rtog
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                     | Day 1-Start Sorafenib 400mg BID daily (Dose level 0). Each cycle=28                                                                                                                                      |
|---------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (Control Arm)             | 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.
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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.  
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.