A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer
Phase: PHASE3
Conditions: Head and Neck Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 0920 
 
(ClinicalTrials.gov NCT #: 00956007) 
 
 
A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab 
Locally-Advanced Resected Head and Neck Cancer 
 
 
Amendment 14:  May 11, 2023 

1 
RTOG 0920, Version Date: May 11, 2023 
 
NRG ONCOLOGY 
RTOG 0920 
A PHASE III STUDY OF POSTOPERATIVE RADIATION THERAPY (IMRT) +/- 
CETUXIMAB FOR LOCALLY-ADVANCED RESECTED HEAD AND NECK 
CANCER 
 
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 (11-MAY-2023) 
                Principal Investigator/Radiation Oncology 
Mitchell Machtay, MD 
Medical Oncology Co-Chair 
Milton S. Hershey Medical Center                                Lillian L. Siu, MD 
Penn State Health 
Princess Margaret Cancer Centre 
500 University Dr                    
700 University Avenue, OPG Building 
Hershey, PA 17033   
7th Floor, Suite 7-624 
717-531-4181 
Toronto, Ontario M5G 1Z5 Canada 
mmachtay@pennstatehealth.psu.edu                         416-946-2911/FAX 416-946-4467 
         
lillian.siu@uhn.on.ca 
 
 
 
Radiation Oncology Co-Chair 
Surgical Oncology Co-Chair 
Wade Thorstad, MD 
Christopher F. Holsinger, MD 
Washington University School of Medicine 
Stanford University School of Medicine 
4921 Parkview Place, Campus Box 8224 
875 Blake Wilbur Dr., CC-2227 
St. Louis, MO 63110 
Stanford, CA 95305 
314-362-8516/FAX 314-747-9557 
650-725-6500/FAX 650-725-8502 
wthorstad@radonc.wustl.edu 
holsinger@stanford.edu 
 
Radiation Oncology Co-Chair 
ECOG-ACRIN Co-Chair/Radiation Oncology 
Phuc Felix Nguyen-Tân, MD 
Harry Quon, MD 
CHUM Hospital Notre Dame 
Hospital of the University of Pennsylvania 
1560 Sherbrooke Street East 
3400 Spruce Street, 2 Donner 
Montreal, Quebec, CA H2L 4M1 
Philadelphia, PA 19104 
514-890-8254/FAX 514-412-7537 
215-614-0392/FAX 215-349-5445 
felix.nguyen.chum@ssss.gouv.qc.ca 
hquon2@jhmi.edu 
 
ECOG-ACRIN Co-Chair/Radiation Oncology 
Anthony Cmelak, MD 
Vanderbilt University Medical Center 
22nd at Pierce/B-1003 The Vanderbilt Clinic 
Nashville, TN 37232 
615-322-2555/FAX 615-591-5899 
Anthony.Cmelak@vanderbilt.edu 
(Study Team continued on next page) 

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RTOG 0920, Version Date: May 11, 2023 
 
NRG ONCOLOGY 
RTOG 0920 
A PHASE III STUDY OF POSTOPERATIVE RADIATION THERAPY (IMRT) +/- 
CETUXIMAB FOR LOCALLY-ADVANCED RESECTED HEAD AND NECK CANCER 
 
Study Team Continued (11-MAY-2023) 
 
 
 
Translational Research Co-Chair 
Medical Physics Co-Chair, U.S. 
Adam Dicker, MD, PhD 
Greg Bednarz, PhD 
Thomas Jefferson University 
UPMC Cancer Centers/Div. of Medical Physics 
111 S. 11th Street 
5150 Center Avenue, 5th floor/Suite 541 
Philadelphia, PA 19107 
Pittsburgh, PA 15232 
215-955-627/FAX 215-955-0412 
412-647-1163/FAX 412-647-1813 
adam.dicker@jefferson.edu   
bednarzg@upmc.edu 
             
Translational Research Co-Chair 
Christine Chung, MD 
Medical Physics Co-Chair, Canada 
Moffitt Cancer Center 
Stephen Breen, PhD, MCCPM 
12902 USF Magnolia Drive 
University of Toronto 
Tampa, FL 33612 
27 King’s College Cir 
813-745-4673FAX 813-449-8210 
Toronto, Ontario, Canada M5S 
Christine.Chung@Moffitt.org 
416-480-6100 X 87181/FAX 416-480-6801 
 
stephen.breen@sunnybrook.ca 
 
Pathology Co-Chair 
Quality of Life Co-Chair 
Adel El-Naggar, M.D., Ph.D. 
Clement K. Gwede, PhD, RN 
MD Anderson Cancer Center 
H. Lee Moffitt Cancer Center 
1515 Holcombe Blvd., Unit 085 
12902 Magnolia Drive MRC-CANCONT 
Houston, TX 77030 
Tampa, FL 33612 
713-792-3109/ FAX 713-792-5532 
813-745-3052/FAX 813-745-6525 
anaggar@mdanderson.org 
clement.gwede@moffitt.org 
 
Pathology Co-Chair 
Senior Statistician 
Richard Jordan, DDS, PhD 
Pedro A. Torres-Saavedra, PhD 
NRG Oncology Biospecimen Bank 
NRG Oncology 
University of California San Francisco 
 
        50 South 16th Street, Suite 2800  
340 Sutter Street, Room S341 
 Philadelphia, PA 19102 
San Francisco, CA 94115 
 215-717-0851/FAX 215-928-0153 
415-476-7864/FAX 415-476-5271                               torresp@nrgoncology.org 
Richard.jordan@ucsf.edu 
 
 
 
 
 

3 
RTOG 0920, Version Date: May 11, 2023 
 
NRG ONCOLOGY 
RTOG 0920 
A PHASE III STUDY OF POSTOPERATIVE RADIATION THERAPY (IMRT) +/- 
CETUXIMAB FOR LOCALLY-ADVANCED RESECTED HEAD AND NECK CANCER 
 
Title Page (Continued) 
NRG Oncology Contact Information (11-MAY-2023) 
Data Management 
For questions concerning eligibility or data 
submission 
 Holly LaPerriere and Jessica Leichtnam 
 NRG Oncology  
 50 South 16th Street, Suite 2800  
 Philadelphia, PA 19102 
215-940-8887 (LaPerriere) 
215-574-3241 (Leichtnam)  
 laperriereh@nrgoncology.org 
 leichtnamj@nrgoncology.org  
RTQA: 
For questions concerning RT data submission 
Dosimetrist 
Marsha Radden, R.T.(R)(T) 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-2757  
mradden@acr.org 
RTQA: 
For questions concerning RT Credentialing 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
RTQA: 
For questions concerning data submission to 
TRIAD 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and informed 
consent versions & amendments 
Protocol Associate  
Thien Nu Do 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3174 
dot@nrgoncology.org  
 
Head and Neck Cancer Committee Chair: 
Current Chair starting August 27, 2021: 
Sue S. Yom, MD, PhD 
 
Prior Chair: 
Quynh-Thu Le, MD, FACR, FASTRO 
 

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RTOG 0920, Version Date: May 11, 2023 
 
 
 
Document History 
Version/Update Date 
Broadcast Date 
Amendment 14 
May 11, 2023 
N/A 
Amendment 13 
March 8, 2018 
N/A 
Amendment 12 
January 26, 2018 
N/A 
Amendment 11 
November 13, 2017 
N/A 
Amendment 10 
January 25, 2016 
February 22, 2016 
Amendment 9 
May 18, 2015 
June 15, 2015 
Amendment 8 
November 3, 2014 
December 1, 2014 
Amendment 7 
April 7, 2014 
April 30, 2014 
Update 
October 3, 2013 
October 3, 2013 
Amendment 6 
January 23, 2013 
February 21, 2013 
Update 
June 14, 2012 
June 14, 2012 
Update 
April 5, 2012 
April 5, 2012 
Update 
February 23, 2012 
February 23, 2012 
Update 
February 13, 2012 
February 13, 2012 
Amendment 5 
January 17, 2012 
February 13, 2012 
Update 
November 15, 2011 
November 15, 2011 
Amendment 4 
October 5, 2011 
November 15, 2011 
Amendment 3 
December 6, 2010 
December 23, 2010 
Amendment 2 
June 21, 2010 
July 9, 2010 
Amendment 1 
June 4, 2010 
July 9, 2010 
Activation 
November 5, 2009 
November 5, 2009 
 
 
 
 
 
 
 
 
 
 
 
 
NRG Oncology 
1-800-227-5463, ext. 4189 
This protocol was designed and developed by NRG Oncology. It is intended to 
be used only in conjunction with institution-specific IRB approval for study 
entry. No other use or reproduction is authorized by NRG Oncology nor does 
NRG Oncology assume any responsibility for unauthorized use of this protocol. 

5 
RTOG 0920, Version Date: May 11, 2023 
 
NRG ONCOLOGY 
RTOG 0920 
A PHASE III STUDY OF POSTOPERATIVE RADIATION THERAPY (IMRT) +/- 
CETUXIMAB FOR LOCALLY-ADVANCED RESECTED HEAD AND NECK CANCER 
 
Title Page (Continued) (11-MAY-2023) 
 
 
CONTACT INFORMATION (11-MAY-2023) 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. (Sign in at 
www.ctsu.org, and select 
Regulatory > Regulatory 
Submission.) 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU 
Regulatory Office immediately 
by phone or email: 1-866-651-
CTSU (2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SYS 
TEM/ or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with 
any OPEN-related questions by 
phone or email: 1-888-823-5923, 
or ctsucontact@westat.com. 
Submit data electronically via the 
NRG Oncology/RTOG web site, 
www.rtog.org. 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU member’s website (https://www.ctsu.org). 
 
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 Roster Maintenance application and in most 
cases viewable and manageable via the Roster Update Management System (RUMS) on the CTSU 
members’ website. 
 
For clinical questions (i.e. patient eligibility or treatment-related): Contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 

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RTOG 0920, Version Date: May 11, 2023 
 
TABLE OF CONTENTS 
 
 
SCHEMA ................................................................................................................................................................... 8 
ELIGIBILITY CHECKLIST ........................................................................................................................................ 9 
1.0 INTRODUCTION .............................................................................................................................................. 14 
1.2 Study Design ..................................................................................................................................................... 16 
1.3 Clinical Studies of Cetuximab in Head and Neck Cancer ................................................................................. 17 
1.4 Safety of Cetuximab in SCCHN Clinical Studies  ............................................................................................. 19 
1.5 Summary of Results of Investigational Program ............................................................................................... 20 
1.6 Use of High-Technology Radiotherapy (IMRT, IGRT) ...................................................................................... 23 
1.7 Translational Science  ....................................................................................................................................... 24 
1.8 Quality of Life and Function Assessments ........................................................................................................ 27 
2.0 OBJECTIVES .................................................................................................................................................... 30 
2.2 Primary Objective .............................................................................................................................................. 30 
2.2 Secondary Objectives ....................................................................................................................................... 30 
2.3 Tertiary Objectives (Exploratory) ...................................................................................................................... 31 
3.0 PATIENT SELECTION ..................................................................................................................................... 31 
3.1 Conditions for Patient Eligibility ......................................................................................................................... 31 
3.2 Conditions for Patient Ineligibility ...................................................................................................................... 32 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT ....................................................................................... 33 
4.1 Required Evaluations/Management  ................................................................................................................. 33 
4.2 Highly Recommended Evaluations/Management ............................................................................................. 34 
5.0 REGISTRATION PROCEDURES  ................................................................................................................... 34 
5.1 RT-Specific Pre-Registration Requirments ....................................................................................................... 34 
5.2 Preregistration Requirements for Head and Neck Image-Guided Radiotherapy (IGRT) Treatment Approach 35 
5.3 Pre-Registration Requirements for IMRT Treatment Approach ....................................................................... 35 
5.4 Data Submission to RTOG Using TRIAD ......................................................................................................... 35 
5.5 Regulatory Pre-registration Requirements ....................................................................................................... 36 
5.6 Registration ....................................................................................................................................................... 39 
6.0 RADIATION THERAPY .................................................................................................................................... 40 
6.1 Dose Specifications for both Arms .................................................................................................................... 40 
6.2 Technical Factors .............................................................................................................................................. 40 
6.3 Localization, Simulation, and Immobilization .................................................................................................... 41 
6.4 Target and Normal Tissue Volume Definitions ................................................................................................. 41 
6.5 Treatment Planning and Delivery ...................................................................................................................... 42 
6.6 Critical Structures .............................................................................................................................................. 44 
6.7 Documentation Requirements for IMRT Treatment Approach ......................................................................... 45 
6.8 Compliance Criteria .......................................................................................................................................... 46 
6.9 R.T. Quality Assurance Reviews ...................................................................................................................... 46 
6.10 Radiation Therapy Adverse Events ................................................................................................................ 47 
6.11 Radiation Adverse Event Reporting ................................................................................................................ 47 
7.0 DRUG THERAPY ............................................................................................................................................. 47 
7.1 Arm 2 Treatment  .............................................................................................................................................. 48 
7.2 Cetuximab (IND Exempt)  ................................................................................................................................. 48 
7.3 Dose Modifications ............................................................................................................................................ 51 
7.4 Modality Review ................................................................................................................................................ 56 
7.5 Adverse Events ................................................................................................................................................. 57 
7.6 CTEP-AERS Expedited Reporting Requirements ............................................................................................ 58 
8.0 SURGERY ........................................................................................................................................................ 60 
8.1 Intermediate Risk of Recurrence ...................................................................................................................... 60 
8.2 Surgical Quality Assurance Reviews ............................................................................................. 60 
9.0 OTHER THERAPY ....................................................................................................................... 60 
9.1 Permitted Supportive Therapy ...................................................................................................... 60 
10.0 TISSUE/SPECIMEN SUBMISSION  ........................................................................................... 60 
10.1 Tissue/Specimen Submission ..................................................................................................... 60 

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RTOG 0920, Version Date: May 11, 2023 
 
10.2 Tissue Collection for EGFR: Required ........................................................................................ 61 
10.3 Tissue Collection for HPV Analysis: Required ............................................................................. 62 
10.4 Specimen Collection for Tissue Banking and Translational Research ......................................... 62 
10.5 Submission of materials for Tissue Banking and Translational Research ................................... 62 
10.6 Reimbursement .......................................................................................................................... 62 
10.7 Confidentiality/Storage ................................................................................................................ 63 
11.0 PATIENT ASSESSMENTS ......................................................................................................... 64 
11.1 Study Parameters ....................................................................................................................... 64 
11.2 Evaluation During Radiotherapy  ................................................................................................. 64 
11.3 Evaluation in Follow Up .............................................................................................................. 64 
11.4 Outcomes Criteria ....................................................................................................................... 64 
11.5 Quality of Life and Functional Assessments  ............................................................................... 65 
11.6 Criteria for Discontinuation of Protocol Treatment  ...................................................................... 66 
12.0 DATA COLLECTION…………………………………………………………………………………….. 66 
12.1 Summary of Data Submission  .................................................................................................... 67 
12.2 Summary of Dosimetry Digital Data Submission ......................................................................... 68 
13.0 STATISTICAL CONSIDERATIONS ............................................................................................ 68 
13.1 Primary Endpoint ........................................................................................................................ 68 
13.2 Secondary Endpoints .................................................................................................................. 68 
13.3 Tertiary Endpoints (Exploratory) .................................................................................................. 68 
13.4 Background and Sample Size Determination .............................................................................. 69 
13.5 Patient Accrual ........................................................................................................................... 78 
13.6 Randomization ............................................................................................................................ 78 
13.7 Analysis Plan .............................................................................................................................. 78 
13.8 Gender and Minorities................................................................................................................. 84 
REFERENCES  .................................................................................................................................. 86 
APPENDIX I ....................................................................................................................................... 92 
APPENDIX II ...................................................................................................................................... 95 
APPENDIX III ..................................................................................................................................... 98 
APPENDIX IV ..................................................................................................................................... 99 
APPENDIX V .................................................................................................................................... 101 
APPENDIX VI ................................................................................................................................ ……………….102 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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RTOG 0920, Version Date: May 11, 2023 
 
NRG ONCOLOGY 
RTOG 0920 
A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab 
for Locally-Advanced Resected Head and Neck Cancer 
SCHEMA (25-JAN-2016) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. IMRT is mandatory. Dose is 60 Gy prescribed to at least 95% of the PTV. If IGRT is used, it  
should be daily to assure that error/variance is < 3.5 mm. Note: 66 Gy is permitted and optional. 
B. Prior to stratification and randomization, all patients must consent to submission of tissue for 
required EGFR analysis; analysis results are expected in approximately 7-8 business days. At that 
time, patients with non-oropharyngeal carcinoma can be randomized. In addition, patients with 
oropharyngeal carcinoma must consent to use of the submitted tissue for required HPV  
analysis; analysis results are expected in approximately 7-10 business days. At that time, patients 
with oropharyngeal carcinoma can be randomized. See Section 5.5 for details of 
registration/randomization. 
 
(Note: The required analyses are not expected to cause delays in patients starting treatment,  
since this is an IMRT-mandatory study, and IMRT generally takes ≥ 7 days for institutional 
planning and QA procedures prior to start of RT). 
 
Patient Population: (See Section 3.0 for Eligibility) (17-JAN-2012) 
Pathologically proven diagnosis of squamous cell carcinoma (including variants such as verrucous 
carcinoma, spindle cell carcinoma, carcinoma NOS, etc.) of the head/neck (oral cavity, oropharynx or 
larynx); clinical stage T2-T4a, N0-2, M0 or T1, N1-2, M0. 
 
Required Sample Size: 700 
Arm 1: Radiation Therapy Alone 
R 
For all 
S 
EGFR Expression 
R 
RT, 2 Gy/day, in 30 fractions 
E 
patients: 
T 
1. High (≥ 80% of cells 
A 
for a total of 60 GyA 
G 
Mandatory 
R 
staining positive for EGFR) 
N 
I 
submission 
A 
2. Low (< 80% of cells 
D 
Arm 2: Radiation Therapy + Cetuximab 
S 
of tissue for 
T 
staining positive for EGFR) 
O 
At least 5 days prior to RT: 
T 
EGFRB 
I 
3. Not evaluable 
M 
cetuximab: Initial dose, 400 mg/m2 
E 
F 
I 
R 
For 
Y 
Primary Site 
Z 
RT, 2 Gy/day in 30 fractions for a total of 60 GyA 
oropharyngeal 
1. Oral cavity 
E 
plus cetuximab: 250 mg/m2/week x 6 weeks 
cancer 
2. Larynx 
patients: 
3. Oropharynx p16+ 
plus 
Mandatory 
4. Oropharynx p16- 
cetuximab: 250 mg/m2/week 
analysis for 
5. Oropharynx p16 not 
x 4 weeks post-RT 
HPVB 
Evaluable 
(cetuximab: 1 initial dose + 10 maintenance 
Use of IGRT 
doses, a total of 11 doses) 
1. No 
2. Yes 
Clinical Stage 
1. T1-3 
2. T4a 

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RTOG 0920, Version Date: May 11, 2023 
 
ELIGIBILITY CHECKLIST – STEP 1 (14-JUN-2012) 
Institution # 
(page 1 of 5) 
RTOG 0920 
Case # 
 
  
(Y) 1. Does the patient have a histologically proven diagnosis of squamous cell carcinoma 
(including variants such as verrucous carcinoma, spindle cell carcinoma, carcinoma 
NOS, etc.) of the head/neck (oral cavity, oropharynx or larynx)? 
 
  
(N) 2. 
Is the primary of the hypopharynx? 
 
  
(Y) 3. 
Is the tumor clinical stage T1, N1-2 or T2-4a, N0-2, M0? 
 
  
(N) 4. 
Does the patient have distant metastases? 
 
  
(Y) 5.  Was a general H&P by a Radiation Oncology and/or Medical Oncologist, an 
examination by an ENT/Head & Neck Surgeon, and chest x-ray (or chest CT scan or 
CT/PET of the chest) done within 8 weeks prior to registration? 
 
  
(Y) 6. Per the operative report, was a gross total resection of the primary tumor with curative 
intent completed within 7 weeks of registration? 
 
  
(Y) 7. Does the surgical pathology demonstrate one or more of the following “intermediate” 
risk factors? 
• 
Perineural invasion; 
• 
Lymphovascular invasion; 
• 
Single lymph node > 3 cm or ≥2 lymph nodes (all < 6 cm) [no extracapsular 
extension]; 
• 
Close margin(s) of resection (close margins defined as cancer extending to 
within 5 mm of a surgical margin); 
• 
T3 or T4a primary tumor; 
• 
T2 oral cavity cancer with > 5 mm depth of invasion. 
 
  
(Y) 8. 
Was the patient’s Zubrod Performance Status 0-1 within 2 weeks prior to registration? 
 
  
(Y) 9. 
Is the patient ≥ 18 years of age? 
 
  
(Y) 10. Does the patient have adequate bone marrow, hepatic, and renal function as specified 
in Sections 3.1.6-3.1.8? 
 
  
(Y) 11. Was the patient’s Na, K, Cl, glucose, Ca, Mg, and albumin levels assessed as required 
within 2 weeks prior to the start of registration? 
 
  
(Y) 12. For women of childbearing potential, was a serum pregnancy test completed within 2 
weeks of registration? 
 
  
(Y) 
If yes, was the serum pregnancy test negative? 
 
  
(Y/NA)13. If a woman of child bearing potential or a sexually active male, is the patient willing to 
use effective contraception while on treatment? 
 
  
(Y) 14.  Did the patient provide study specific informed consent prior to study entry including 
consent for tissue submission for EGFR and HPV analyses? 
 
  
(N) 15. 
Did the patient have a prior invasive malignancy? 
 
(Continued on next page) 

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RTOG 0920, Version Date: May 11, 2023 
 
ELIGIBILITY CHECKLIST – STEP 1 (23-JAN-2013) 
Institution # 
(page 2 of 5) 
RTOG 0920 
Case # 
 
  
(Y) 
If yes, is the prior malignancy within the parameters specified in Section 
3.2.1? 
 
  
(N) 16. 
 Per the operative and/or pathology report, were there positive margin(s) [tumor 
present at the cut or inked edge of the tumor], nodal extracapsular extension, and/or 
gross residual disease after surgery? 
 
  
(N) 17. 
 Did the patient have previous systemic chemotherapy or anti-EGF therapy for the 
study cancer? 
 
  
(N) 18. 
 Did the patient have previous irradiation to the head and neck that would result in 
overlap in radiation fields? 
 
  
(N) 19.  Does the patient have severe, active co-morbidity, as defined in Section 3.2.5.1- 
3.2.5.7? 
 
  
(N) 20.  Does the patient have grade 3-4 (CTCAE, v. 4) electrolyte abnormalities as specified 
in Section 3.2.5.8? 
 
  
(N) 21. Does the patient have a prior history of allergic reaction to cetuximab? 
 
 
The following questions will be asked at Study Registration: 
 
CREDENTIALING for IMRT (and IGRT, if used) IS REQUIRED BEFORE REGISTRATION. 
 
  
 
1. Institutional person randomizing case? 
 
  
(Y) 
2. Has the Eligibility Checklist been completed? 
 
  
(Y) 
3. In the opinion of the investigator, is the patient eligible? 
 
  
 
4. Date informed consent signed 
 
  
 
5. Patient Initials (First Middle Last) 
 
  
 
6. Verifying Physician 
 
  
 
7. Patient’s ID 
 
  
 
8. Date of Birth 
 
  
 
9. Race 
 
  
 
10. Ethnicity 
 
  
 
11. Gender 
 
(Continued on next page) 

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RTOG 0920, Version Date: May 11, 2023 
 
ELIGIBILITY CHECKLIST – STEP 1 (13-FEB-2013) 
Institution # 
(page 3 of 5) 
RTOG 0920 
Case # 
 
12. Country of Residence 
 
13. Zip Code (U.S. Residents) 
 
14. Method of Payment 
 
15. Any care at a VA or Military Hospital? 
 
16. Calendar Base Date 
 
17. Randomization date 
 
18. Medical Oncologist 
 
  
(Y/N)      19. Have you obtained the patient’s consent for his or her tissue to be kept for use   
in research to learn about, prevent, treat, or cure cancer? 
 
  
(Y/N)        20. Have you obtained the patient’s consent for his or her blood to be kept for use  
in research to learn about, prevent, treat, or cure cancer? 
 
  
(Y/N)       21. Have you obtained the patient’s consent for his or her tissue to be kept for use  
in research about other health problems (for example: causes of diabetes, 
Alzheimer’s disease, and heart disease)? 
 
  
(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: causes of diabetes, 
Alzheimer’s disease, and 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 ? 
 
  
(Y/N) 24. 
Tissue sent for HPV analysis? 
 
  
 
25. 
Disease Type (Oral cavity, Larynx, Oropharynx p16+, Oropharynx p16-, 
Oropharynx p16 not evaluable) 
 
  
(Y/N)   26. 
Use of IGRT? 
 
  
(Y) 
If yes, have pre-registration credentialing requirements in Section 5.2 been 
met? 
 
27. Clinical T-Stage (T1-3 vs. T4a) 
 
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/NRG Oncology audit. 
 
Completed by 
Date       
 

12 
RTOG 0920, Version Date: May 11, 2023 
 
ELIGIBILITY CHECKLIST – STEP 2 (25-JAN-2016) 
Institution # 
(page 4 of 5) 
RTOG 0920 
Case # 
(assigned for Step 1) 
 
  
 
1. Institutional person randomizing case 
 
  
(Y/N) 
2. Is the patient able to continue protocol treatment? 
 
  
 
3. 
 
 
 
 
 
  
 
If no, specify the reason the patient cannot continue to Step 2: 
1) progression of disease; 
2) patient refusal; 
3) physician preference; 
4) failure to submit tissue assay; 
5) other 
 
Specify the reason the patient cannot continue to Step 2. 
 
  
 
4. Patient Initials (First Middle Last) 
 
  
 
5. Verifying Physician 
 
  
 
6. Patient ID 
 
  
 
7.   Calendar Base Date (for Step 2) 
 
  
 
8.   Randomization date: (for Step 2) 
 
  
(Y/N) 
9. Patient has consented to take part in the Quality of Life Study? 
 
  
 
10. If no, provide reason: 
 
1) patient refused due to illness 
2) patient refused for other reason 
3) not approved by institutional IRB 
4) tool not available in patient’s language 
5) other reason 
 
  
 
If response is “2) Patient refused for other reason”, specify the reason. 
 
  
 
If response is “5) Other reason”, specify the reason the patient will not 
participate in the quality of life component of the study. 
 
  
(Y/N) 
11. If the patient agreed to participate in the quality of life component, did the 
patient agree to participate in VisionTree? 
 
  
(Y/N) 
12. Will IGRT be used for patient positioning and margin reduction? 
 
Continued on next page. 

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RTOG 0920, Version Date: May 11, 2023 
 
ELIGIBILITY CHECKLIST – STEP 2 
Institution # 
(page 5 of 5) 
RTOG 0920 
Case # 
(assigned for Step 1) 
 
 
13. Patient height 
 
 
14. Patient weight 
 
 
  
 
15. BSA 
 
 
 
Completed by   
 
Date 
  
 

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1.0 INTRODUCTION 
1.1 
Head and Neck Cancer — Postoperative Adjuvant Therapy 
There are approximately 40,000 new cases of head and neck squamous cell carcinoma  
(SCCHN) diagnosed each year in the United States. Almost all of these patients have non- 
metastatic disease and are candidates for local-regional therapy in the form of surgery, 
radiotherapy (RT), or both. In the last decade, a major advance has occurred in the management 
of head and neck cancer by the addition of chemotherapy to local-regional therapy for selected 
patients (Bourhis 2004). This generally has been in the form of cisplatin-based chemotherapy 
given concurrently during RT. There are extremely strong data in support of concurrent 
chemoradiotherapy for locally advanced (stage III/IV) head and neck cancer being treated non- 
surgically (Bourhis 2004; Adelstein 2003; Calais 1999; Brizel 1998). 
 
The adjuvant management of completely resected SCCHN is somewhat more controversial. In 
general, postoperative radiotherapy (PORT) is a standard of care for most stage III/IV and 
selected stage II resected cases (Forastiere 2001). In the last several years, several high-profile 
randomized trials have shown that the addition of concurrent chemotherapy to PORT improves 
outcomes for selected patients. The RTOG led a North American Intergroup trial comparing 
standard PORT with or without three cycles of high dose concurrent cisplatin (Cooper 2004). The 
patient population consisted of individuals who underwent complete resection but had positive 
resection margins at the primary tumor site, multiple pathologically positive lymph nodes in the 
neck, or one or more lymph nodes in the neck with extracapsular extension. This study showed 
the chemoradiotherapy had significantly improved local-regional control (LRC) and disease-free 
survival (DFS) but not overall survival, compared with PORT alone. The EORTC performed a 
very similar study of PORT +/- chemotherapy, showing that chemoradiotherapy improved overall 
survival in addition to LRC and DFS (Bernier 2004). 
 
Bernier, et al. (2005) subsequently performed a meta-analysis of the RTOG and EORTC trials. In 
this exploratory analysis, the primary subgroups of patients who benefited significantly from the 
addition of chemotherapy were those with positive resection margins and/or nodal extracapsular 
extension. Other patients did not have a significant benefit from high dose concurrent cisplatin. 
Specifically in RTOG 95-01, this refers to patients with multiple positive nodes (pN2) without 
extracapsular spread (ECS). In the EORTC study, this refers to a potpourri of patients, including: 
pathologic T3-4, N0 cancers (except T3, N0 larynx cancer), perineural and/or vascular invasion 
irrespective of T-stage, or oral/oropharynx cancer with lymph node involvement at Level IV or V. 
The failure of cisplatin to significantly improve survival or other clinical outcomes does not, 
however, mean that these patients have a very good or excellent prognosis. As shown below in 
Table 1, multiple series of data report a rate of local-regional failure between 15 and 35% for 
these patients, despite adjuvant RT. Most patients who suffer local-regional failure cannot be 
salvaged with additional anti-cancer treatment and proceed to die from their cancer. The exact 
rate of local-regional failure probably depends upon multiple factors, including the number of 
clinical risk factors present (as described by the University of Florida), treatment related factors 
(such as the quality of surgery and/or RT, as well as the amount of time required to deliver 
treatment), and currently poorly understood biological/molecular features of patients’ tumors. 
These complex factors make it very difficult to compare one study to another, particularly 
retrospective experiences harvested at different institutions over several decades. A relatively 
large prospective trial would thus provide valuable information to help physicians and patients 
more precisely identify the risk factors for local-regional recurrence (and other clinical outcomes) 
after surgery + RT. 

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Table 1: Outcomes in Patients with Resected Head and Neck Cancer with 
One or More Risk Factors for Recurrence (Other Than Positive Margin/ECS) 
 
Study 
Patient Population 
/Number of pts 
Local-regional 
Control 
Survival and/or 
Comments 
Cooper (RTOG 95-01) 
[2004] 
110 pts without ECS/+mgn 
but 2-4 + LN’s 
80% (crude) 
2-yr. DFS 63%. 
Cooper (RTOG 85-03) 
[1998] 
108 pts with negative 
margins, N0-1 nodal stage 
(without ECS) 
83% (5-yr.) 
EORTC 
101 pts with negative 
margins and no nodal ECS 
NS 
2-yr. OS ~60% 
Rosenthal (Penn) [2002] 
90 pts with clear margins 
and N0-1 nodal stage 
(without ECS) 
88% (3-yr.) 
3-yr. OS 81% 
Hinerman (Fla) [2004] 
60 pts with oral cavity CA 
and only 1 risk factor for 
recurrence 
83% (crude) 
Hinerman (Fla) [2006] 
82 pts with resected 
laryngopharynx CA and 
“close” (<5mm) margins 
85% (crude) 
Bastit (France) [2001] 
76 pts with resected pharynx 
CA and lymphovascular 
and/or perineural invasion 
75% (3-year) 
Fortin (Quebec) [2001] 
287 pts with T1-3 and 0-2 
nodes without ECS 
85% (crude) 
LRC was 77% for pts 
tx’d with Cobalt vs. 91% 
for 6MV 
Pfreunder (2000) 
66 pts with close but 
negative (<3mm) margins 
71% (5-yr) 
Sig. impact of RT dose 
(66 Gy cutoff) – 62% vs. 
80%. 
Lavaf (2007) 
Approx. 5,800 pts with 
SEER Stage II (regionally 
advanced by direct 
extension but no regional 
lymph nodes involved) 
Not available 
Approx. 50% 5-year 
survival 
TNM and margin status 
data are not available. 
Tumor size highly 
predictive (p<0.002) 
Langendijk (2005) 
110 pts with close (1-5 mm) 
margins 
65% (5-yr) 
Subgroup analyses from 
a retrospective series of 
801 pts treated with 
surgery + PORT. 
Langendijk (2005) 
128 pts with perineural 
invasion 
69% (5-yr) 
Langendijk (2005) 
155 pts with lymphovascular 
invasion 
67% (5-yr) 
 
The reason for the failure of high dose cisplatin to improve outcomes in patients without positive 
margins/ECS is unclear. It is possible that a benefit does exist, but that the RTOG and EORTC 
studies were “underpowered” to detect it. If this were the case, the magnitude of benefit from 
cisplatin is probably small. It is important to note that concurrent chemoradiotherapy (particularly 
with high dose cisplatin) significantly increases toxicity compared with RT alone (Trotti 2003). In 
particular, acute mucositis and dysphagia are dramatically increased with chemotherapy. High 
dose cisplatin also causes significant constitutional and systemic toxicities that are well 
recognized and independent of the concomitant administration of RT. It is theoretically possible 
that these systemic toxicities might interfere with the ability of patients to tolerate and receive 
maximally effective dose intensity of RT. Although RTOG 95-01 did not show any obvious 
differences in major/unacceptable deviations in dose delivery of RT between the RT alone and 
RT/cisplatin arms, it is possible that more subtle differences in RT delivery and dose intensity 
could exist. 

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Given the toxicity of high dose cisplatin, two recent randomized studies were designed to attempt 
to demonstrate a benefit to low dose carboplatin as a radiosensitizer during postoperative RT. 
While both of these studies were relatively small and underpowered, they did not show any 
obvious benefit to carboplatin during RT (Argiris 2008; Racadot 2008). Another strategy has been 
to administer postoperative chemotherapy alone prior to RT; to date, this has not shown 
significant improvement (Laramore 1992). 
1.2 
Study Design 
It is thus clear that alternatives to highly intense chemoradiotherapy (RT + high dose cisplatin) 
are needed in order to improve the therapeutic ratio for patients who are not candidates for 
concurrent chemoradiotherapy or for whom concurrent chemoradiotherapy is not necessarily 
indicated. Postoperative RT alone is the current standard of care for these patients, but it has a 
suboptimal outcome. 
1.2.1 
Epidermal Growth Factor Receptor (EGFR) 
Since the design and conduct of RTOG 95-01 and the EORTC trial, much has been learned 
about the biology of squamous cell carcinoma of the head and neck. Two of the most important 
areas of advances have been in the study of epidermal growth factor receptor (EGFR) and in 
the study of human papillomaviruses (HPV). 
 
EGFR is expressed at very high levels in the majority of human head and neck squamous cell 
carcinoma (SCC). Furthermore, pre-clinical data indicate that it is not merely a ‘bystander’ but  
is intimately associated with the malignant phenotype of SCCHN. EGFR activation in response 
to a ligand (e.g., EGF or TGF-alpha) results in phosphorylation of its intracytoplasmic tyrosine 
kinase domain, leading to a cascade of signal transduction within the cell. This ultimately leads 
to DNA synthesis, cell proliferation, anti-apoptosis, and transcription of growth factors such as 
pro-angiogenic molecules. Blockade of this pathway is an effective anti-neoplastic strategy; 
furthermore, EGFR blockade appears to result in radiosensitization. This hypothesis was 
proven in a randomized trial by Bonner, et al. (2006). In that study, patients with locally 
advanced, non-operative SCCHN were randomized to RT alone or RT with weekly cetuximab 
(an anti-EGFR monoclonal antibody). Local-regional control and survival were significantly 
improved with cetuximab. Specifically, the 3-year rate for freedom from local-regional 
progression and overall survival were 47% and 55% for RT/cetuximab, compared with 34% and 
45% for RT alone. The relative reduction in the risk of local-regional progression and dying 
were 32% (p=0.005) and 26% (p=0.03) [Bonner 2006]. 
1.2.2 
Cetuximab 
Cetuximab appears to have less toxicity than high dose cisplatin. In the phase III study of 
cetuximab and radiotherapy for locally advanced non-operative SCCHN, 93% of patients 
received the prescribed cetuximab dose, which compares very favorably to the compliance rate 
of high dose cisplatin in RTOG 95-01 (61%) [Bonner 2006]. Furthermore, the Bonner study 
showed no evidence that cetuximab increased the rate of ≥ Grade 3 mucositis or dysphagia, no 
evidence of an increased rate of late effects, and no evidence of a worsening of QOL relative to 
RT 
alone. 
This 
is 
in 
contrast 
to 
the 
literature 
with 
concurrent 
platinum-based 
chemoradiotherapy, which suggests that certain long-term side effects such as feeding tube 
dependence are greatly increased relative to RT alone. 
 
The positive results of the Bonner randomized trial has led to the FDA approval for cetuximab 
as concurrent treatment with RT for locally advanced head and neck cancer. Although the FDA 
approval was quite broad, subgroup analysis of this study offers some potential insight 
regarding patient selection. The overall survival benefit from the addition of cetuximab was 
most significant in oropharynx cancer (hazard ratio 0.62), moderately significant in larynx 
cancer (hazard ratio 0.87), and not significant in hypopharynx cancer (hazard ratio 0.94). Oral 
cavity cancer was not included in the Bonner study, since most patients with oral cavity are 
treated with surgery prior to RT rather than definitive RT. 
 
The Bonner study is not the only data in support of cetuximab as a valuable treatment against 
head and neck cancer. In platinum-refractory recurrent/metastatic SCCHN, cetuximab has a 
response rate of approximately 11%, (Vermorken 2007) providing further clinical evidence that 
it is working via a pathway (or pathways) distinct from DNA damaging agents such as platins or 
RT. In first-line therapy for recurrent/metastatic SCCHN, the addition of cetuximab to 5- 
FU/platinum significantly improved overall survival (Vermorken 2008). 

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Based upon the encouraging data described above, we propose testing cetuximab with 
postoperative RT for those patients who have a moderately high risk of recurrence and who do 
not clearly benefit from cisplatin concurrent chemotherapy. Specifically, the current study 
(RTOG 0920) will compare the current standard of care for these patients (RT alone) against 
RT with cetuximab. Our study is not identical to the Bonner design. In addition to the obvious 
difference that RTOG 0920 is a postoperative therapy study rather than a definitive RT study, 
there are major differences in study eligibility and stratification design. First, our study will 
include oral cavity cancer, since these patients are commonly treated with upfront surgery yet 
are at moderately high risk of local-regional recurrence. Our study will exclude patients with 
hypopharynx cancer, since they have a particularly poor prognosis irrespective of stage and 
treatment. (As noted above, the Bonner study did not show a benefit from the addition to 
cetuximab to RT for hypopharynx cancer). Fortunately, hypopharynx cancer is a relatively 
uncommon subtype of SCCHN in the U.S. and Canada. 
1.2.3 
Stratification by EGFR Expression 
In the Bonner study, which began in 1998, stratification was performed based upon Karnofsky 
Performance Status (60-80 vs. 90-100); nodal involvement (N0 vs. N+); T-stage (T1-3 vs. T4); 
and RT technique (standard once daily vs. bid/intensified). Tissue for EGFR testing was 
obtained in many patients, but this was not used in the a priori study design. EGFR testing 
consisted of simply staining for the presence or absence of EGFR via immunohistochemical 
staining; not surprisingly nearly 100% of the samples were EGFR positive. In contrast, our 
study proposes to stratify patients based upon quantitative extent of EGFR expression (low vs. 
high). This is based upon a previous analysis of RTOG data performed by Ang, et al. (2002), in 
which the amount of EGFR present on tumor cells was quantified using an optical density 
technique and the percentage of tumor area staining positive for EGFR (staining index) was 
measured. The median amount of EGFR expression was used as the cutoff for statistical 
analysis. This study showed that patients with “low” EGFR expression had significantly better 
local-regional control and survival than patients with high EGFR expression. Patients in Ang’s 
analysis were treated with definitive RT alone. It is less clear if this observation is true for 
patients treated with both surgery and RT. It is also unclear if a potent anti-EGFR agent would 
be more effective, equally effective, or less effective in patients with lower or higher expression 
of EGFR. However, it is very plausible to suspect that differences exist; thus, we propose to 
stratify patients a priori based upon the amount of EGFR expression. We also will perform a 
secondary subgroup analysis of outcomes based upon these separate strata. 
1.2.4 
Post-RT Cetuximab 
A final difference between the Bonner study and RTOG 0920 is that patients will continue to 
receive cetuximab for four weeks following the completion of RT. This is based upon preclinical 
data by Milas, et al. (2007) showing that radiocurability was improved by adding a few doses of 
cetuximab following RT plus concurrent cetuximab. More recent data indicate that this 
additional effect is mediated through reduction of the tumor cell clonogenicity and proliferation 
and also by enhancement of tumor necrosis most likely resulting from increased susceptibility 
of tumor vasculature and cells to cetuximab effect (see Attachment A) summarizing results 
presented at the 2008 AACR meeting). Since the goal of our clinical trial is the complete 
eradication of microscopic tumor cells and unequivocal cure of patients, these recent data must 
be taken very seriously. There is precedent for this design, including the EXTREME trial 
(Vermorken 2008) in which patients were randomized to chemotherapy alone or chemotherapy 
plus cetuximab. In that study (a positive study showing a benefit to cetuximab), chemotherapy 
was given for up to 6 cycles, but cetuximab was continued beyond chemotherapy. We believe 
that the addition of 4 weeks of cetuximab after RT will be well tolerated given the toxicity profile 
of RT/cetuximab. 
1.3 
Clinical Studies of Cetuximab in Head and Neck Cancer 
The efficacy and safety of cetuximab in combination with radiation therapy was studied in a 
randomized controlled trial of 424 patients with locally or regionally advanced squamous cell 
carcinoma of the head and neck (SCCHN) versus radiation therapy alone. In addition, cetuximab 
alone was studied in a single-arm, multi-center clinical trial in 103 patients with recurrent or 
metastatic SCCHN with documented progression within 30 days after 2-6 cycles of platinum- 
based chemotherapy. Since expression of EGFR has been detected in nearly all patients with 
head and neck cancer, patients enrolled in the head and neck cancer clinical studies were not 
required to have immunohistochemical evidence of EGFR expression prior to study entry. 

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1.3.1 
Randomized, Controlled Trial in SCCHN 
The efficacy and safety of cetuximab were studied in combination with radiation therapy in a 
randomized, controlled trial of 424 patients with locally or regionally advanced squamous cell 
carcinoma of the head and neck versus radiation alone. In a multi-center controlled clinical  
trial, 424 patients with Stage III/IV SCC of the oropharynx, hypopharynx, or larynx with no prior 
therapy were randomized 1:1 to receive cetuximab plus radiation therapy (211 patients) or 
radiation therapy alone (213 patients). Stratification factors were Karnofsky Performance  
Status (60-80 versus 90-100); nodal stage (N0 versus N+); tumor stage (T1-3 versus T4 using 
AJCC 1998 staging criteria); and radiation therapy fractionation (concomitant boost versus 
once-daily versus twice daily). Radiation therapy was administered from 6-7 weeks as once 
daily, twice daily, or concomitant boost. The planned radiation therapy regimen was chosen by 
the investigator prior to enrollment. For patients with ≥ N1 neck disease, a post-radiation 
therapy neck dissection was recommended. Starting 1 week before radiation, cetuximab was 
administered as a 400-mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of 
radiation therapy (6-7 weeks). All cetuximab-treated patients received a 20-mg test dose on 
Day 1. Cetuximab was administered 1 hour prior to radiation therapy, beginning week 2. 
 
Of the 424 randomized patients, 80% were male and 83% were Caucasian. The median age 
was 57 years (range 34-83). There were 258 patients enrolled in U.S. sites (61%) and 166 
patients (39%) in non-U.S. sites. Ninety percent of patients had baseline Karnofsky 
Performance Status ≥ 80; 60% had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal 
primary tumors; 28% had AJCC T4 tumor stage. The patient characteristics were similar across 
the study arms. Fifty-six percent of the patients received radiation therapy with concomitant 
boost, 26% received once-daily regimen, and 18% twice-daily regimen. 
 
The main outcome measure of this trial was duration of locoregional control. Overall survival 
was also assessed. Results are presented below: 
 
Cetuximab 
+ 
Radiation 
(n = 211) 
Radiation 
Alone 
(n = 213) 
Hazard Ratio 
(95% CL3) 
Stratified 
Log-rank 
p-value 
Locoregional control 
Median Duration 
24.4 mo 
14.0 mo 
0.68 0.52-0.89) 
0.005 
Overall Survival 
Median duration 
49.0 mo 
29.3 mo 
0.74 (0.57-0.97) 
0.03 
a Cl = confidence interval 
 
The EXTREME study (Vermorken 2008) was the first randomized study to demonstrate a 
benefit in overall survival (10.1 vs. 7.4 months, HR=0.797, p=0.036) with a molecular-targeted 
therapy added to the classical platinum plus fluorouracil combination in the first-line treatment 
of recurrent and/or metastatic SCCHN. Two hundred twenty-two patients in the control arm 
received 6 cycles of cisplatin or carboplatin plus fluorouracil, while 220 patients in the 
experimental arm received platinum and fluorouracil at the same doses in combination with 
weekly cetuximab. In this latter arm, patients could receive maintenance cetuximab alone for 6 
months after completion of the 6 treatment cycles with chemotherapy. Grade 3 or 4 adverse 
events were encountered in 76% of patients in the control arm versus 82% of patients of 
patients in the experimental arm (p=0.19). Bone marrow toxicity was more common in the 
control arm, whereas the addition of cetuximab to platinum and fluorouracil resulted in slightly 
more frequent hypomagnesemia, sepsis, vomiting, diarrhea, and acne-like rash. Ten deaths (3 
in the cetuximab group and 7 in the chemotherapy-alone group) were considered by the 
investigators to be treatment related. 
1.3.2 
Single-Arm Trials of SCCHN 
Cetuximab alone was studied in a single-arm, multi-center clinical trial in 103 patients with 
recurrent or metastatic SCCHN with documented progression within 30 days after 2-6 cycles of 

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RTOG 0920, Version Date: May 11, 2023 
 
a platinum-based chemotherapy. Patients received a 20-mg test dose of cetuximab on Day 1, 
followed by a 400-mg/m2 initial dose, and 250 mg/m2 weekly until disease progression or 
unacceptable toxicity. Upon progression, patients were given the option of receiving cetuximab 
plus the platinum regimen that they failed prior to enrollment. Tumor response and progression 
were assessed by an Independent Radiographic Review Committee (IRC). The median age 
was 57 years (range 23-77), 82% were male, 100% Caucasian, and 62% had a Karnofsky 
performance status of ≥ 80. The objective response rate on the monotherapy phase was 13% 
(95% confidence interval (7%-21%). Median duration of response was 5.8 months (range 1.2- 
5.8 months). 
1.4 
Safety of Cetuximab in SCCHN Clinical Studies (25-JAN-2016) 
Except where indicated, the data described below reflect exposure to cetuximab in 208 patients 
with locally or regionally advanced SCCHN who received cetuximab in combination with radiation 
and as monotherapy in 103 patients with recurrent or metastatic SCCHN. Of the 103 patients 
receiving cetuximab monotherapy, 53 continued to a second phase with the combination of 
cetuximab plus chemotherapy. Patients receiving cetuximab plus radiation therapy received a 
median of 8 doses (range 1-11 infusions). The population had a median age of 56; 81% were 
male and 84% Caucasian. Patients receiving cetuximab monotherapy, received a median of 11 
doses (range 1-45 infusions). The population had a median age of 57; 82% were male and 100% 
Caucasian. The most serious adverse reactions associated with cetuximab in combination with 
radiation therapy in patients with head and neck cancer were: 
 
▪ 
Infusion reaction (3%); 
▪ 
Cardiopulmonary arrest (2%); 
▪ 
Dermatologic toxicity (2.5%); 
▪ 
Mucositis (6%); 
▪ 
Radiation dermatitis (3%); 
▪ 
Confusion (2%); 
▪ 
Diarrhea (2%). 
 
Fourteen (7%) patients receiving cetuximab plus radiation therapy and 5 (5%) patients receiving 
cetuximab monotherapy, discontinued treatment primarily because of adverse events. 
 
The most common adverse events seen in 208 patients receiving cetuximab in combination with 
radiation therapy were acneiform rash (87%), mucositis (86%), radiation dermatitis (86%), weight 
loss (84%), xerostomia (72%), dysphagia (65%), asthenia (56%), nausea (49%), constipation 
(35%), and vomiting (29%). 
 
The most common adverse events seen in 103 patients receiving cetuximab monotherapy were 
acneiform rash (76%), asthenia (45%), pain (28%), fever (27%), and weight loss (27%). 
 
The data in the table below are based on the experience of 208 patients with locoregionally 
advanced SCCHN treated with cetuximab plus radiation therapy compared to 212 patients 
treated with radiation therapy alone (Cetuximab [Erbitux™] package insert, 2006). 
 
Incidence of Selected Adverse Events ( 10%) 
in Patients with Locoregionally Advanced SCCHN 
Body System 
Preferred Term 
Cetuximab plus Radiation 
(n=208) 
Radiation Therapy Alone 
(n=212) 
Grades 1 – 4 
Grades 3 and 4 
Grades 1 – 4 
Grades 3 and 4 
% of Patients 
Body as a Whole 
Asthenia/Malaise 
56 
4 
48 
5 
Fever1 
29 
1 
13 
<1 
Headache 
19 
<1 
8 
<1 
Infusion 
2 
Reaction 
15 
3 
2 
0 
Infection 
13 
1 
9 
1 
Chills1 
16 
0 
5 
0 
Digestive 
Mucositis/Stomatitis 
93 
56 
94 
52 

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Incidence of Selected Adverse Events ( 10%) 
in Patients with Locoregionally Advanced SCCHN 
Body System 
Preferred Term 
Cetuximab plus Radiation 
(n=208) 
Radiation Therapy Alone 
(n=212) 
Grades 1 – 4 
Grades 3 and 4 
Grades 1 – 4 
Grades 3 and 4 
% of Patients 
Xerostomia 
72 
5 
71 
3 
Dysphagia 
65 
26 
63 
30 
Nausea 
49 
2 
37 
2 
Constipation 
35 
5 
30 
5 
Vomiting 
29 
2 
23 
4 
Anorexia 
27 
2 
23 
2 
Diarrhea 
19 
2 
13 
1 
Dyspepsia 
14 
0 
9 
1 
Metabolic/Nutritional 
Weight Loss 
84 
11 
72 
7 
Dehydration 
25 
6 
19 
8 
Respiratory 
Pharyngitis 
26 
3 
19 
4 
Cough Increased 
20 
<1 
19 
0 
Skin/Appendages 
Acneiform Rash3 
87 
17 
10 
1 
Radiation Dermatitis 
86 
23 
90 
18 
Application Site Reaction 
18 
0 
12 
1 
Pruritus 
16 
0 
4 
0 
1 Includes cases also reported as infusion reactions 
2 Infusion reaction is defined as any event described at any time during the clinical study as “allergic 
reaction” or “anaphylactoid reaction” or any event on the first day of dosing described as “allergic 
reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever” or “dyspnea”. 
3 Acneiform rash as defined as any event described as “acne”, “rash”, “maculopapular rash”, 
“pustular rash”, “dry skin” or “exfoliative dermatitis”. 
 
1.4.1 
Late Radiation Toxicity 
The overall incidence of late radiation toxicities (any grade) was higher in cetuximab in 
combination with radiation therapy compared with radiation therapy alone. The following sites 
were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous 
tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 
35%), skin (42% versus 33%), brain (11% versus 9%), lung (11% versus 8%), spinal cord (4% 
versus 3%), and bone (4% versus 5%). The incidence of Grade 3 or 4 late radiation toxicities 
were generally similar between the radiation therapy alone and the cetuximab plus radiation 
treatment groups. 
1.5 
Summary of Results of Investigational Program 
1.5.1 
Clinically Relevant Adverse Events Related to Cetuximab 
Pooled adverse event (AE) data (preliminary or final) are available for 2,127 patients treated 
with cetuximab alone or in combination with chemotherapy and/or radiation therapy in 21 
ImClone studies, 9 Merck KgaA, 2 BMS, and 1 ECOG study. 
 
A total of 90.3% of the patients reported adverse events (AEs). Approximately two-thirds 
(64.8%) of patients reported at least one Grade 3 or 4 event. Cetuximab-related AEs were 
observed in 1,817 patients (85.4%). The most common composite groupings of adverse events 
deemed related to cetuximab as reported by investigators in all cetuximab trials (N = 1,817) 
include acneiform rash (76.2%), acne-like rash (72.4 %), fatigue/malaise/lethargy (30.1%), 
nausea/vomiting (24%), f mucositis/stomatitis (17.5 %), infusion-related symptoms (15.6%), 
diarrhea (15.4 %), and hypersensitivity reaction (5.3%). 
 
The development of acute interstitial pneumonitis in patients treated with EGFR-targeted 
agents has recently been described (Investigator Brochure; see Section 7.2.1 of the protocol to 
obtain a copy). 

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RTOG 0920, Version Date: May 11, 2023 
 
A detailed list of Serious Adverse Events (SAE) is presented in the Investigator Brochure. 
Noteworthy are SAEs leading to death: one from infusion reaction, and one from interstitial 
pneumonitis 
 
Except where indicated, the data described below reflect exposure to cetuximab in 774 patients 
with advanced metastatic colorectal cancer. Cetuximab was studied in combination with 
irinotecan (n=354) or as monotherapy (n=420). Patients receiving cetuximab plus irinotecan 
received a median of 12 doses (with 88/354 [25%] treated for over 6 months), and patients 
receiving cetuximab monotherapy received a median of 7 doses (with 36/420 [9%] treated for 
over 6 months). The population had a median age of 59 and was 59% male and 91% 
Caucasian. The range of dosing for patients receiving cetuximab plus irinotecan was 1-84 
infusions, and the range of dosing for patients receiving cetuximab monotherapy was 1-63 
infusions. 
 
The most serious adverse reactions associated with cetuximab were: 
▪ Infusion reaction (3%); 
▪ Dermatologic toxicity (1%); 
▪ Interstitial lung disease (0.4%); 
▪ Fever (5%); 
▪ Sepsis (3%); 
▪ Kidney failure (2%); 
▪ Pulmonary embolus (1%); 
▪ Dehydration (5%) in patients receiving cetuximab plus irinotecan, 2% in patients  
receiving cetuximab monotherapy; 
▪ Diarrhea (6%) in patients receiving cetuximab plus irinotecan, 0% in patients receiving 
cetuximab monotherapy. 
 
Thirty-seven (10%) patients receiving cetuximab plus irinotecan and 17 (4%) patients receiving 
cetuximab monotherapy discontinued treatment primarily because of adverse events. The most 
common adverse events seen in 354 patients receiving cetuximab plus irinotecan were 
acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), nausea (55%), abdominal pain 
(45%), and vomiting (41%). 
 
The most common adverse events seen in 420  patients receiving cetuximab monotherapy 
were acneiform rash (90%), asthenia/malaise (48%), nausea (29%), fever (27%), constipation 
(26%), abdominal pain (26%), headache (26%), and diarrhea (25%). 
 
Because clinical trials are conducted under widely varying conditions, adverse reaction rates 
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in practice. The adverse reaction 
information from clinical trials does, however, provide a basis for identifying the adverse events 
that appear to be related to drug use and for approximating rates. 
 
Data in patients with advanced colorectal carcinoma in the tables below are based on the 
experience of 354 patients treated with cetuximab plus irinotecan and 420 patients treated with 
cetuximab monotherapy. 
 
Incidence of Adverse Events ( 10%) in Patients with Advanced Colorectal Carcinoma 
Body System 
Preferred 
a 
Term 
Cetuximab plus Irinotecan 
(n=354) 
Cetuximab Monotherapy 
(n=420) 
Grades 1 - 4 
Grades 3 and 4 
Grades 1 - 4 
Grades 3 and 4 
% of Patients 
Body as a Whole 
Asthenia/Malaiseb 
73 
16 
48 
10 
Abdominal Pain 
45 
8 
26 
9 
Feverc 
34 
4 
27 
<1 
Pain 
23 
6 
17 
5 
Infusion 
d 
Reaction 
19 
3 
21 
2 

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RTOG 0920, Version Date: May 11, 2023 
 
Incidence of Adverse Events ( 10%) in Patients with Advanced Colorectal Carcinoma 
Body System 
Preferred 
a 
Term 
Cetuximab plus Irinotecan 
(n=354) 
Cetuximab Monotherapy 
(n=420) 
Grades 1 - 4 
Grades 3 and 4 
Grades 1 - 4 
Grades 3 and 4 
% of Patients 
Infection 
16 
1 
14 
1 
Back Pain 
16 
3 
10 
2 
Headache 
14 
2 
26 
2 
Digestive 
Diarrhea 
72 
22 
25 
2 
Nausea 
55 
6 
29 
2 
Vomiting 
41 
7 
25 
3 
Anorexia 
36 
4 
23 
2 
Constipation 
30 
2 
26 
2 
Stomatitis 
26 
2 
10 
<1 
Dyspepsia 
14 
0 
6 
0 
Hematic/Lymphatic 
Leukopenia 
25 
17 
<1 
0 
Anemia 
16 
5 
9 
3 
Metabolic/Nutritional 
Weight Loss 
21 
0 
7 
1 
Peripheral Edema 
16 
1 
10 
1 
Dehydration 
15 
6 
10 
3 
Nervous 
Insomnia 
12 
0 
10 
<1 
Depression 
10 
0 
7 
0 
Respiratory 
Dyspneac 
23 
2 
17 
7 
Cough Increased 
20 
0 
11 
1 
Skin/Appendages 
Acneiform Rashe 
88 
14 
90 
8 
Alopecia 
21 
0 
4 
0 
Skin Disorder 
15 
1 
4 
0 
Nail Disorder 
12 
<1 
16 
<1 
Pruritus 
10 
1 
11 
<1 
Conjunctivitis 
14 
1 
7 
<1 
a Adverse events that occurred (toxicity Grades 1 through 4) in 10% of patients with refractory colorectal 
carcinoma treated with cetuximab plus irinotecan or in 10% of patients with refractory colorectal carcinoma 
treated with cetuximab monotherapy. 
b Asthenia/malaise is defined as any event described as “asthenia”, “malaise”, or “somnolence”. 
c Includes cases reported as infusion reaction. 
d Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or 
“anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, 
“anaphylactoid reaction”, “fever”, “chills”, “chills and fever” or “dyspnea”. 
e Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry 
skin”, or “exfoliative dermatitis”. 
 
1.5.2 
Acne-Like Rash 
In clinical studies of cetuximab, dermatologic toxicities, including acneiform rash, skin drying 
and fissuring, and inflammatory and infectious sequelae (e.g., blepharitis, cheilitis, cellulitis, 
cyst) were reported. In patients with advanced colorectal cancer, acneiform rash was reported 
in 89% (686/774) of all treated patients, and was severe (grade 3 or 4) in 11% (84/774) of  
these patients. Subsequent to the development of severe dermatologic  toxicities,  
complications including S. aureus sepsis and abscesses requiring incision and drainage were 
reported. Non-suppurative acneiform rash described as “acne”, “rash”, “maculopapular rash”, 
“pustular rash”, “dry skin”, or “exfoliative dermatitis” was observed in patients receiving 
cetuximab plus irinotecan or cetuximab monotherapy. One or more of the dermatological 
adverse events were reported in 88% (14% grade 3) of patients receiving cetuximab plus 
irinotecan and in 90% (8% grade 3) of patients receiving cetuximab monotherapy. Acneiform 

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rash most commonly occurred on the face, upper chest, and back but could extend to the 
extremities and was characterized by multiple follicular- or pustular-appearing lesions. Skin 
drying and fissuring were common in some instances, and were associated with inflammatory 
and infectious sequelae (e.g., blepharitis, cellulitis, cyst). Two cases of S. aureus sepsis were 
reported. The onset of acneiform rash was generally within the first two weeks of therapy. 
Although in a majority of the patients the event resolved following cessation of treatment, in 
nearly half of the cases, the event continued beyond 28 days. 
1.5.3 
Nail Disorder 
A related nail disorder, occurring in 14% of patients (0.4% Grade 3), is characterized as a 
paronychial inflammation with associated swelling of the lateral nail folds of the toes and 
fingers, with the great toes and thumbs as the most commonly affected digits. 
1.5.4 
Infusion Reactions 
In clinical trials, severe, potentially fatal infusion reactions were reported, one leading to death 
(see Section 1.3). These events include the rapid onset of airway obstruction (bronchospasm, 
stridor, hoarseness), urticaria, and/or hypotension. In studies in advanced colorectal cancer, 
severe infusion reactions were observed in 3% of patients receiving cetuximab plus irinotecan 
and 2% of patients receiving cetuximab monotherapy. Grade 1 and 2 infusion reactions, 
including chills, fever, and dyspnea usually occurring on the first day of initial dosing, were 
observed in 16% of patients receiving cetuximab plus irinotecan and 19% of patients receiving 
cetuximab monotherapy. 
 
A 20-mg test dose was administered intravenously over 10 minutes prior to the initial dose to all 
patients in earlier studies. The test dose did not reliably identify patients at risk for severe 
allergic reactions. 
 
Severe infusion reactions occurred with the administration of cetuximab in approximately 3% of 
patients, rarely with fatal outcome (<1 in 1000). Approximately 90% of severe infusion  
reactions were associated with the first infusion of cetuximab despite the use of prophylactic 
antihistamines. These reactions were characterized by the rapid onset of airway obstruction 
(bronchospasm, stridor, hoarseness), urticaria, and/or hypotension. 
1.5.5 
Pulmonary Toxicity 
Interstitial lung disease (ILD) was reported in 3 of 774 (< 0.5%) patients with advanced 
colorectal cancer receiving cetuximab. Interstitial pneumonitis with non-cardiogenic pulmonary 
edema resulting in death was reported in one case. Two patients had pre-existing fibrotic lung 
disease and experienced an acute exacerbation of their disease while receiving cetuximab in 
combination with irinotecan. In the clinical investigational program, an additional case of 
interstitial pneumonitis was reported in a patient with head and neck cancer treated with 
cetuximab and cisplatin. The onset of symptoms occurred between the fourth and eleventh 
doses of treatment in all reported cases. 
1.6 
Use of High-Technology Radiotherapy (IMRT, IGRT) 
In parallel with the advances in understanding the biology of head and neck cancer and 
integrating targeted systemic therapies, there have been technological improvements in RT. The 
most widely publicized technique for improving the therapeutic ratio of RT is intensity modulated 
radiation therapy (IMRT) [Press 2008]. IMRT employs fundamentally different means of planning 
and delivery of photon irradiation compared with conventional head and neck RT. Specifically, 
conventional RT combines 3 or 4 large fields in which the RT dose to most normal structures 
(e.g., parotid glands, pharyngeal walls) is the same as the dose to the target volumes of the 
tumor bed and cervical lymphatics. IMRT combines numerous small and irregularly shaped 
radiation beams of variable intensities to achieve a radiation dose distribution that conforms  
much better to these target volumes. In particular, the radiation doses received by the parotid 
glands are dramatically decreased with IMRT. 
 
IMRT improves the dosimetry of RT – at least to the target volumes and the parotid glands – but 
its effects on clinical outcomes are less well documented. Small randomized trials of IMRT versus 
standard RT for nasopharynx cancer did not show a significant quality of life benefit (despite 
showing significantly increased parotid gland flow with IMRT) [Kam 2007; Pow 2006]. The RTOG 
now has performed two prospective (non-randomized) multi-center studies of IMRT. The first of 
these studies, RTOG 0022, was performed in early stage oropharynx cancer (treated with 
definitive RT rather than surgery). This study showed very good feasibility, toxicity profile, and 
excellent local control with IMRT (Eisbruch 2006). Long-term data, however, are still pending, 

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RTOG 0920, Version Date: May 11, 2023 
 
and cannot necessarily be extrapolated to more advanced head and neck cancer. A more 
intriguing analysis of IMRT within the RTOG experience has just been performed by Harari, et al. 
(2008). This was an analysis of RTOG 0234, a phase II randomized study of postoperative RT 
plus cetuximab, plus either cisplatin or docetaxel for high-risk resected SCCHN. Treating 
physicians were allowed to use IMRT or conventional 2D/3D radiotherapy. Both treatment arms 
were considered feasible without excessive toxicity. However, Harari’s analysis strongly 
suggested that acute toxicity (mucositis and skin) was greater in those patients treated with IMRT 
compared with conventional RT. Long-term data from RTOG 0234 are not yet available. 
 
Thus, despite some early evidence of advantages to IMRT, it does have limitations. Most notably, 
the emphasis has been on target volume coverage and parotid gland sparing. This may not be 
sufficient to improve the therapeutic ratio of head and neck irradiation. Other normal structures 
within the head and neck, such as the pharyngeal walls/constrictors may be important for post- 
RT eating function. With conventional IMRT, sparing structures other than the spinal cord/brain 
and parotids is complicated by their close proximity to the target volumes. Furthermore, the 
delivery of each day’s IMRT treatment cannot be routinely guaranteed to replicate the pre- 
planned IMRT blueprint. This daily setup variation/error is the result of many factors, such as 
changes in patient weight or shape between daily treatments and imperfections in daily alignment 
of patients by radiation technologists. Excessive day to day variances could theoretically  
increase treatment toxicity or risk underdosing the target volume (Hong 2006; Manning 2001). In 
order to circumvent the underdosing concern, target volumes are typically artificially expanded by 
up to 1 cm in all directions prior to beginning the planning process for IMRT. A clinical target 
volume (CTV) that contains 64 cc of tissue may thus need to be expanded to a 125-cc planning 
target volume (PTV). In other words, in order to guarantee sufficient RT to a region of interest, the 
total volume heavily irradiated is approximately doubled. This has significant implications for 
toxicity. 
 
Daily image-guided radiation therapy (IGRT) is a recently introduced technique to improve the 
accuracy of day-to-day radiotherapy, particularly IMRT. Each day, after the patient is positioned 
on the RT treatment table, multi-planar images of the target region are obtained before treatment. 
These images are correlated with the patient’s original, pre-planned images, and variances are 
detected and corrected prior to actual treatment. A variety of techniques exist for achieving IGRT 
(Tome 2001; Thilman 2006). Techniques for IGRT in the head and neck may include daily 
orthogonal megavoltage flat plane images (portal films); orthogonal kilovoltage images; non- 
radiation-based optical guidance systems; and Linear Accelerator mounted cone-beam computed 
tomography (CT) scan devices. These machines are available with software components to 
determine the magnitude of variance/errors detected relative to the pre-planning data. This 
technology is increasingly available at both academic and community radiation oncology 
departments. 
 
By using daily IGRT, it can be hypothesized that the magnitude of the CTV to PTV “safety 
margin” during pre-planning may be limited to 3 to 5 mm. Potentially even smaller margins might 
be feasible in selected cases. However, daily IGRT does not correct for all possible errors. For 
instance, intra-treatment motion of some structures within the head and neck (e.g., tongue or 
larynx) may occur and could significantly alter the geometry of target volumes and normal tissues 
during treatment. This trial will recommend a 5 mm CTV to PTV margin, although a specific 
margin will not be mandated (because this is subject to individual institutional processes). 
 
It is hypothesized that by using rigorously planned and delivered IMRT/IGRT, highly effective 
sparing of critical normal tissues in the head and neck can be achieved. It is hoped that this will 
manifest itself as reduced late Grade 2 and Grade 3 adverse events (AEs) [especially dysphagia] 
compared with historical controls, as well as improvement in patient-reported outcomes (PROs) 
with respect to head and neck specific functions (swallowing function, speech, xerostomia). 
1.7 
Translational Science (04-JUN-2010) 
This study has several embedded and integral translational science questions related to EGFR 
and HPV, respectively (this is in addition to harvesting and storing tissue samples for future 
exploratory analysis of other molecular factors in SCCHN). Presently, while much has been 
learned about the relationships among EGFR, HPV, and SCCHN, there is marked uncertainty 
regarding if and how this biological information should be used clinically. For example, the 
National Comprehensive Cancer Network (NCCN) guidelines do not currently recommend routine 

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RTOG 0920, Version Date: May 11, 2023 
 
testing for EGFR and/or HPV in SCCHN. If testing for one or both of these biologic factors were 
to be performed, there are no current recommendations at this time to alter therapy accordingly. 
In the future, however, it is likely that personalized intervention for SCCHN will be utilized in the 
clinic. For example, patients with HPV-related SCCHN might be irradiated to lower radiation 
doses than non-HPV related SCCHN (there are plans to test this hypothesis in other cooperative 
groups’ studies). Data from this study with respect to the prognosis of HPV-related cancers will  
be useful adjunctive data toward this goal. RTOG 0920 also will test a priori whether patients with 
high or low expression of EGFR (high defined as ≥ 80% of cells staining positive for EGFR; low 
defined as < 80% of cells staining positive) are more likely to benefit from an anti-EGFR agent 
(cetuximab). We predict that both subgroups will benefit but that patients with high expression of 
EGFR will nonetheless have a suboptimal outcome and thus, might benefit from additional 
intensification of treatment in future studies (e.g., combination RT/chemotherapy/anti-EGFR 
therapy). RTOG 0920 will be adequately powered to test this hypothesis. 
1.7.1 
Translational Study of EGFR and Its Ligands and Stratification Based on EGFR 
This study will require mandatory submission of tissue for analysis of EGFR and, for patients 
with oropharyngeal carcinoma, HPV, i.e., patients who do not have available tissue and/or 
refuse to consent to tissue submission will not be eligible. The reason for mandatory EGFR 
submission is that this study uses a highly specific anti-EGFR therapy (cetuximab). Although 
cetuximab binds to the EGFR with high specificity and has proven benefit for SCCHN, it 
appears that only a modest proportion of patients truly benefit significantly from this agent (i.e., 
11% response rate in platinum refractory disease; 13% absolute improvement in local-regional 
DFS compared with RT alone). Given that cetuximab is expensive and has toxicity, it is vital to 
identify the patient subpopulations that are most likely to benefit from this drug. At this time, it  
is unclear whether or not the levels of EGFR as assayed by immunohistochemistry correlate 
with activity (or lack of activity) of cetuximab. This differs from the situation for HER-2/breast 
cancer, in which amplification/overexpression is clearly associated with a positive response to 
the anti-HER-2 antibody trastuzumab. 
 
It is hypothesized, however, that patients with SCCHN whose tumors harbor a mutation known 
as the vIII variant may be less responsive to cetuximab. The EGFRvIII mutation results in a 
truncated protein at the extracellular ligand binding domain, and results in constitutive  
activation of the tyrosine kinase independent of the ligand binding. Because cetuximab exerts 
antitumor effects by inhibiting the ligand binding, the activity of EGFRvIII with ligand 
independent activation would not be inhibited by cetuximab and small molecule EGFR tyrosine 
kinase inhibitors (e.g., erlotinib) that work directly at the tyrosine kinase domain might be more 
effective. It is estimated that up to 40% of SCCHN samples express the vIII variant in addition 
to wild-type EGFR (EGFRwt). 
 
The question of the optimal methodology for analyzing and quantifying EGFR expression in 
SCCHN has been studied by investigators, including members of NRG Oncology. EGFR 
expression is ubiquitous in SCCHN and the levels of expression may be extremely high. Ang et 
al. studied the tissue samples from patients with non-operative locally advanced SCCHN 
treated in RTOG 90-03 (RT alone) [Ang 2002]. Tumor tissue samples were analyzed for EGFR 
expression using a technique to quantify the amount of immunohistochemical staining by an 
automated optical technique. The study showed a relatively broad range of EGFR mean optical 
density (MOD) or staining index (SI) among samples. There was a relatively high correlation 
between MOD and SI. The median MOD or SI for EGFR was used as a cutoff for binary 
analysis of outcomes. This resulted in an extremely strong correlation with overall survival, 
DFS, and local-regional control. 
 
Furthermore, there is mounting evidence that EGFR ligand levels as well as the receptor are 
important in the pathway activation and as marks of prognosis and prediction of cetuximab 
response. A gene expression study by Chung, et al. (2004) found that a molecular subtype of 
SCCHN in 21/60 tumors (35%) had higher expression of EGFR ligands, TGF-α, and 
amphiregulin, and had worse disease-free survival compared to other subtypes. In addition, a 
study by Khambata-Ford, et al. (2007) has shown that higher expression levels of amphiregulin 
and epiregulin associated with cetuximab response and disease-free survival (HR 0.4558, 95% 
CI 0.2284-0.6177) in recurrent/metastatic colon cancer patients. We will examine three ligands, 
TGF-α, amphiregulin and epiregulin, which are dominant ligands in squamous epithelium. To 
avoid possible bias in randomization of patients to the study, the patient’s physician or 

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institution cannot request the patient’s EGFR level from NRG Oncology until the patient has 
completed study treatment. 
1.7.2 
Translational Study of HPV and Stratification Based on HPV 
Another major change in the landscape of head and neck cancer research over the past 
decade has been the recognition of the increased incidence of HPV-related oropharynx cancer. 
HPV (mostly HPV 16) DNA can be detected in many human oropharyngeal SCC specimens, 
and strong evidence suggests that it is a causative agent. HPV infection is thought to cause 
cancer in the oropharynx by integration of the HPV early viral oncoproteins E6 and E7 into the 
genome of tonsillar mucosal epithelium; these oncoproteins induce tumorigenesis by 
deregulating the p53 and p16/Rb pathways (Gillison 2000). 
 
An emerging body of literature suggests that HPV-related SCCHN (oropharynx cancer) has a 
number of important biologic and clinical differences compared with traditional SCCHN. 
Retrospective analysis revealed that HPV associated oropharynx SCCHN has a significantly 
better prognosis than non-HPV associated disease, possibly due to improved responsiveness 
to RT +/- chemotherapy (Gillison 2000; Mellin 2000; Schwartz 2001; Ringstrom 2002). 
 
The above data strongly suggests that it is important to account for HPV in large scale clinical 
trials that include oropharynx cancer. Most notably, it is necessary to stratify for HPV-related 
cancer (yes vs. no) in order to assure that treatment arms are well balanced (An imbalance 
could very likely result in improved outcomes in the treatment arm that has more patients with 
HPV-related cancer). Thus, one of the stratifications in our study will be for HPV-related SCC of 
the oropharynx. Since HPV is not typically associated with non-oropharynx SCCHN, this will 
only specifically be done for oropharynx cancer. To avoid possible bias in randomization of 
patients to the study, the patient’s physician or institution cannot request the patient’s HPV 
status from NRG Oncology until the patient has completed study treatment. 
 
There is still controversy regarding the best method to detect HPV in oropharyngeal tumors. 
The probable gold standard is to perform DNA analysis using PCR-based techniques; however, 
the technique is prone to false-positivity and is likely to be unwieldy for a large multicenter 
cooperative group trial at this time. Another method is to detect HPV 16 DNA in tissue sections 
using in situ hybridization (ISH). This method has high sensitivity and specificity but is 
technically challenging to perform requiring specialized equipment, resources, and facilities to 
provide a robust and reproducible assay. Moreover, its application and dissemination to 
peripheral testing centers may prove to be challenging moving forward. A widely used 
alternative for the detection of HPV is the use of immunohistochemical staining (IHC) for the 
p16 protein (which is generally overexpressed in HPV-positive oropharynx cancer). When the 
HPV was detected by ISH and compared to p16 staining, 100% of HPV positive tumors by ISH 
were positive by p16 expression using IHC (Fakhry 2008). This assay is currently widely used 
and does not require specialized facilities, resources, and equipment beyond that which is 
currently used in most pathology laboratories. Moreover, quantification is simplified by the 
dichotomous staining pattern in tumor cells (positive or negative). Therefore, this trial proposes 
to use p16 expression as a surrogate marker to assess HPV status in oropharyngeal 
specimens. . 
1.7.3 
Translational Study of TP53 Mutation 
Loss of function in p53, a tumor suppressor protein, by mutation or rapid degradation by 
oncoproteins E6 due to HPV infection has been associated with SCCHN. The location of 
mutations within the gene, TP53, can manifest as abnormally truncated protein (nonsense 
mutation), disruption of DNA binding capacities (missence mutation), or no functional 
consequences (silent mutation). We hypothesize that the patients with functionally disruptive 
TP53 mutations will have poor overall survival and time to disease progression. This  
hypothesis is based on the recent study by Poeta ML, et al. (Poeta 2007). They found that 
53.3% of SCCHN patients had TP53 mutations; functionally non-disruptive 33%, disruptive 
20%, and wild type 47%. The patients with any TP53 mutations associated with the worse 
overall survival compared to wild-type TP53 (HR to death, 1.4; 95% confidence interval 1.1-1.8, 
p=0.009) while the association was stronger with functionally disruptive TP53 mutation (HR 1.7; 
1.3-2.4, p<0.001). Validation of the association will further the effort of clinical implementation  
of this assay and stratification of risks based on biology of the tumors. 
1.7.4 
Translational Study of CA Dinucleotide Repeats in EGFR Intron 1 

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There is evidence that the length of the repeats differ based on sex and race as well as the 
prognostic and predictive outcomes after standard of care and EGFR inhibitor treatments. We 
hypothesize that short CA dinucleotide repeats in EGFR intron 1 will associate with poor overall 
survival and time to disease progression. In a prognostic marker study of patients with 
metastatic colon cancer by Press, et al. (2008), women with both short repeats (< 20 CA(n) 
repeat alleles) had better overall survival while the opposite was true in men. Also, there are 
data that the numbers of repeats are predictive of EGFR inhibitor therapies. A study by Liu, et 
al. (2003), showed that Asians had a longer allele compared to Caucasians and African- 
Americans, suggesting that Asians would benefit more from EGFR inhibitors due to less 
expression of EGFR. In an Asian study of non-small cell lung cancer by Han, et al. (2007), a 
short CA repeat (sum of both alleles < or =37) was associated with better objective response to 
gefitinib (odds ratio 7.1, 95% confidence interval 1.2–40.8; p=0.029) and time-to progression 
(hazard ratio 0.54, 95% confidence interval 0.34–0.88; p=0.014), independent of EGFR 
mutation. However, the sex of the patients was not evaluated in the multivariate analyses. 
Based on these data and the diverse NRG Oncology patient population of mixed sex and race, 
the prognostic and predictive nature of this polymorphic variant can be further defined and 
validated. In addition, we will determine whole genome-wide single nucleotide polymorphism 
(SNP) using Affymetrix SNP chips to associate other polymorphic variants with response and 
toxicities as exploratory studies. 
1.8 
Quality of Life and Function Assessments (26-JAN-2018) 
It is now well established that cancer of the head and neck often has profoundly debilitating 
effects on quality of life (QOL), function, and performance. In a recently reported phase III trial of 
cetuximab and radiation therapy (RT) for head and neck squamous cell carcinoma (HNSCC), 
cetuximab did not significantly increase RT-associated adverse effects (Bonner 2006). This study 
also found that addition of cetuximab to RT significantly improved locoregional control and 
increased overall survival without adversely affecting QOL (Curran 2007). However, with this 
limited experience, the acute and long-term impact of cetuximab on QOL remains largely 
unknown. Thus, assessments of QOL and key functions such as eating/swallowing (dysphagia) 
and xerostomia (dry mouth) are included as secondary end points in the current study. 
 
QOL is a global, multidimensional construct that assesses the patient’s overall sense of well- 
being and how it relates to disease and disease treatment (Murphy 2007). Thus, QOL must be 
assessed from the patient’s perspective using validated patient-reported measures. As Murphy, 
et al. (2007) point out, an important issue in measuring QOL is the relationship of between 
function and the domains of QOL. It has been noted that evaluation of function separately from 
QOL yields distinct and important information that may not be captured in the context of QOL 
measures (Murphy 2007; Sarna 2008). Because function assessment may be undertaken using 
either subjective symptom measures or objective and clinician rated measures (Murphy 2007; 
Basch 2006; Jensen 2006), the relationship between patient reported function and QOL 
outcomes is not clear cut in the literature. Murphy, et al. (2007) recently concluded that the 
relationship between function and QOL in head and neck cancer varies and several studies have 
been conducted in an effort to further elucidate relationships. Recent studies using objective 
measures of dysphagia/swallowing and QOL measures found a correlation between aspiration 
measured by videofluoroscopy swallow studies and patient reported QOL measures (Nguyen 
2005; Campbell 2004). Similarly, in other studies, speech and communication impairment was 
associated with changes in speech and communication domains of QOL measures  (Meyer 
2004), and change in taste, xerostomia, and other oral symptoms were found to have a  
significant impact on QOL (Duke 2005; Epstein 2001; Epstein 1999). While some studies have 
found significant associations, a notable number have reported no associations between function 
and QOL measures (List 1996; Hanna 2004; Finizia 1998; Deleyiannis 1999; Moore 1996; 
Friedlander 2002; Hertrampf 2004). In this study, while objective assessments of dysphagia such 
as videofluorography or videofluoroscopic swallowing studies could be employed (Logemann 
2008), the cost and lack of appropriate technology and trained staff at most of the participating 
centers is prohibitive in a cooperative group setting. 
 
Furthermore, the relationship between observer-based (clinician-rated) toxicity/function scoring 
and patient reported QOL has been recently documented (Sarna 2008; Basch 2006; Jensen 
2006). In a cross-sectional study, Jensen (2006) showed poor to modest correlations between  
the DAHANCA toxicity scoring system and the various EORTC quality of life questionnaire 
domains. For example, clinician-rated dysphagia had the highest correlation with the EORTC 

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RTOG 0920, Version Date: May 11, 2023 
 
social eating component (r=.58, p<.01) [Jensen 2006]. Physician-rated dry mouth was more 
highly correlated with patient reported dry mouth (r=.72, p<.01). Sarna (2008) reported a 
disconnect between clinician-assessed dysphagia/esophagitis and patient-reported swallowing 
function and QOL in treated lung cancer patients (RTOG 9801). These findings demonstrate an 
important difference between patient- and physician-rated symptoms/function and highlight the 
importance of measuring patient reported function and QOL separately. 
 
Thus recognizing that QOL and functional outcome assessment are two distinct components that 
should be measured and discussed separately, these outcomes will be measured using validated 
patient reported outcome (PRO) instruments that derive directly from the patient perspective and 
using “objective” clinician-rated measures as summarized separately below. While this may not 
be an optimal approach, it allows the assessment of the correlations of QOL and functional 
measures in this study. 
1.8.1 
Quality of Life (QOL) Assessments 
Quality of life will be assessed using four validated, multidimensional patient-reported QOL 
measures including: the Functional Assessment of Cancer Therapy-Head & Neck (FACT- 
H&N); the Performance Status Scale for Head and Neck Cancer (PSS-HN); the University of 
Michigan Xerostomia-Related Quality of Life Scale (XeQOLS); the Dermatology Life Quality 
Index (DLQI), and the EuroQol (EQ-5D). 
 
The FACT-H&N is a multidimensional, patient self-report QOL instrument specifically designed 
and validated for use with head and neck cancer patients. The FACT-HN consists of a 27-item 
core scale (FACT-G) and is supplemented with a 12-item head and neck subscale targeting 
head and neck related symptoms and side effects (Cella 1993). The PSS-HN is a 
clinician/interviewer administered assessment that focuses on three functional areas: Normalcy 
of Diet, Eating in Public, and Understandability of Speech. The score on each of the three 
subscales ranges from 0-100, with higher scores indicating better performance (List 1996; List 
1999; List 2000). The EQ-5D has been more frequently employed in cooperative group studies 
as a general QOL measure and for cost-utility analysis. The EQ-5D is a two-part questionnaire 
that the patient can complete in approximately 5 minutes. The first part of the EQ-5D consists  
of five items covering five areas: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each of these areas is graded on three levels: 1=no problems; 2=moderate 
problems; and 3=extreme problems. Health states are then derived from combinations of the 
leveled responses to the five dimensions. The second part of the EQ-5D is a visual analogue 
scale (VAS) valuing current health state, with 0 at bottom of the scale (worst imaginable health 
state) and 100 at the top (best imaginable health state) [Wu 2002]. The XeQOLS instrument is 
patient self-report measure that consists of 15 items on a 5-point Likert-type scale covering 
mouth/throat dryness and its impact on four major domains of oral health-related quality of life: 
physical functioning, personal/psychological functioning, social functioning, and pain/discomfort 
issues (Logemann 2008; Cella 1993; List 1996). The XeQOLS takes the patient approximately 
5 minutes to complete. 
 
The Dermatology Life Quality Index (DLQI) will be used to explore the impact of cetuximab- 
induced rash on quality of life. It is expected that rash (acneiform; maculo-papular), pruritis,  
and other visible consequences (CTCAE, v. 4) associated with cetuximab-induced rash will 
have a significant negative impact on quality of life (Boone 2007; Agero 2006; Shikiar 2005). 
Although the DLQI (Finley 1994) is designed to assess the impact of a wide range of skin 
disease on patient quality of life (Lennox 2004; Lewis 2004; Hongbo 2005; Shikiar 2005; Basra 
2008), it has never been used in cancer-treatment related settings. Thus, use of DLQI will be 
exploratory in this study and represents the first time a dermatologic patient reported outcome 
measure is used for cetuximab-induced rash and in this population. The DLQI consists of 10 
items and covers 6 domains including symptoms and feelings, daily activities, leisure, work and 
school, personal relationships, and treatment. Response categories include "not at all," "a little," 
"a lot," and "very much," with corresponding scores of 0, 1, 2, and 3 respectively; the response 
"not relevant" (and unanswered items) are scored as "0". A total score is calculated by 
summing the score of all items, resulting in a maximum score of 30 and a minimum score of 0. 
Scale scores are calculated for each domain. Higher scores indicate poorer HRQL (i.e., more 
impairment). The DLQI will be administered a baseline and at 3, 12, and 24 months after the 
start of radiation therapy. The relationship between the DLQI and 3 CTCAE, v. 4 dermatology 

29 
RTOG 0920, Version Date: May 11, 2023 
 
items (rash: acneiform; rash: maculo-papular; and pruritus) will be assessed as well as the 
relationship between the DLQI and the other QOL instruments. 
 
The relationship between the EQ-5D and other QOL measures, such as the FACT-H&N, 
XeQOLS and the PSS-HN is not clearly understood. If the EQ-5D is highly correlated with 
either of these measures, it might provide an effective short form for collecting both QOL and 
utility data in HNSCC. The relationship of these 4 measures will be assessed in the current 
study. 
1.8.2 
Functional Assessments 
Dysphagia will be assessed using the Normalcy of Diet component of the PSS-HN and the 
clinician-rated CTCAE, v. 4 dysphagia (difficulty in swallowing) item. The PSS-HN Normalcy of 
Diet subscale assesses the degree to which a patient is able to eat a normal diet. Ten 
categories are arranged from easy-to-eat at the low end to hard-to-eat at the high end. Scores 
range from 0-100, with those scores closer to 100 representing high level of function. The PSS- 
HN subscale allows for assessment and calculation of the percentage of patients on oral intake 
and the percentage of patients eating a normal diet. This study will assess the correlation 
between the CTCAE, v. 4 dysphagia (difficulty in swallowing) item and the PSS-HN Normalcy  
of Diet Scale at 3, 12, and 24 months from the end of radiation. Logemann (2008) found 
statistically significant decline at 3 months post-treatment (compared to pre-treatment baseline) 
in other measures of swallowing (percentage of patients eating < 50% orally; percentage of 
patients eating a normal diet), and the pattern of changes from these two measures was 
comparable to changes identified by videofluoroscopic swallow studies, suggesting that the 
former are suitable measures for evaluating swallowing function. The PSS-HN scale allows for 
assessment and calculation of similar outcome measures (i.e., percentage of patients on oral 
intake and percentage normal diet) in this trial. 
 
To assess xerostomia and its impact on QOL in this study, the clinician-rated CTCAE, v. 4 dry 
mouth item and the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) 
will be used. The correlation between the CTCAE, v. 4 dry mouth item and the XeQOLS scale 
score will be assessed at 3, 12, and 24 months from the end of radiation. 
1.8.3 
Timeframe of Assessments 
These patient-reported QOL and function measures and the clinician-assessed measures will 
be administered at baseline and at 3, 12, and 24 months from the end of radiation. The 3- 
month QOL assessment was chosen to coincide with usual practice of seeing a head and 
patient 2 weeks after completion of radiation therapy. This assessment will provide the 
immediate impact of radiation therapy +/- cetuximab on QOL. The 12-month QOL assessment 
was chosen to coincide with usual practice of seeing a head and patient 1 year after completion 
of radiation therapy. The Radiation Oncologists expect at this time that almost all acute 
toxicities related to radiation will be resolved, and they are interested in assessing the patient’s 
QOL at that time. These 2 assessment time points for PRO outcomes are routinely used in 
NRG Oncology and other head and neck studies. PRO assessment has been added at 24 
months from the start of radiation therapy to provide long-term data on cetuximab treated 
patients and on IGRT/IGRT treated patients. That time point was chosen because 80 to 90% of 
the patients who will progress do so by 2 years. For patients who are disease free then, the 
issue, it is felt, becomes the long-term sequelae of the treatments. 
1.8.4 
Optional Online Completion of QOL Assessments 
Missing data are a significant problem, particularly for QOL assessments. Unlike data for 
traditional endpoints, such as survival, QOL data can never be obtained retrospectively if it is 
not provided by the patient at the appropriate time point. This limits researchers’ ability to 
accurately perform QOL statistical analyses and  negatively impacts the clinical relevance of 
this effort. Typically, QOL forms are filled out in hardcopy (paper). To provide a more 
convenient method of completing QOL assessments, NRG Oncology is working with  
VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on this study the option of 
completing their QOL forms online from any location that has a computer with Internet access, 
including the patient’s home, and provides reminders to patients to complete the assessments. 
 
VisionTree has developed a new tool, VisionTree Optimal Care (VTOC), a HIPAA-secure, user 
friendly, web-based software system (Gorgulho 2005; Gorgulho 2007; Pedroso 2006). The 
VTOC tool contains a web-based system for global patient and trial administration access, 
which allows improved compliance and accuracy of data collection, validation, and reporting. It 

30 
RTOG 0920, Version Date: May 11, 2023 
 
is compliant with the Title 21, Code of Federal Regulations, Part 11 statistical process control 
system and provides a mobile solution for clinical trials. QOL data are collected with Microsoft 
Excel and PDF export of reports. VTOC also has mobile messaging and e-mail reminders. 
Surveys 
can 
be 
“pushed” 
to 
patients 
for 
completion 
at 
timed 
intervals 
(see 
http://www.visiontree.com for details). VisionTree has many clinical partners and clients, 
including ASTRO, University of California-San Francisco, Baylor College of Medicine, Duke 
University, Emory University, Harvard Medical School, Henry Ford Hospital, and University of 
Pennsylvania. ASTRO utilizes VisionTree outcomes online for maintenance of certification and 
for capturing quality measures. This technology would allow consenting patients on this study  
to fill out their QOL forms online from any location and to receive e-mail reminders to complete 
assessments. E-mail reminders also can be sent to research associates (RAs) at the 
appropriate institutions to remind them that a QOL time point window is about to close so that a 
patient can be contacted to fill out QOL information on time, before it becomes “missing data”. 
 
In a pilot RTOG study (RTOG 0828), the compliance rate of patients completing QOL 
assessments at 6 months significantly improved using electronic technology. Based on this  
pilot data, NRG Oncology is offering VisionTree as an option in other studies, including this 
one. Patients preferring to complete hardcopy QOL assessments can do so. 
 
For this trial, the baseline QOL forms must be completed in hardcopy at the time of enrollment. 
To complete subsequent QOL forms online, patients must have an e-mail address that they 
consent to use so that e-mail reminders may be sent to them. The patient’s e-mail address also 
will be used for password-protected access to VTOC. Patients who are interested in 
participating but do not yet have an e-mail address can obtain one for free from a number of 
sources (e.g. Yahoo!, Hotmail, or AOL). Patients will receive a login card (either printed or sent 
via e-mail) with which to log in using the secure, web-based VTOC portal. VTOC meets all 
HIPAA guidelines and is encrypted (via 128-bit SSL) for the security, privacy, and confidentiality 
of QOL information. It is similar to the secure login commonly used when performing online 
banking. The login card can then be kept and maintained by the patient. 
 
The patient’s e-mail address only will be used by NRG Oncology for this purpose. Patients will 
be sent e-mail reminders to complete QOL forms. A typical e-mail reminder would read: “Your 
Quality of Life forms for the study, RTOG 0920, are now due. Please go to 
http://www.optimalcare.com, use your secure login, and complete the online forms. If any 
questions make you feel uncomfortable, you may skip those questions and not give an answer. 
If you have any questions, please e-mail or call your research associate at [insert RA e-mail 
address] or [insert RA telephone number]. Thank you for participating in this study.” The 
reminders will be created by NRG Oncology and placed into a study template that will be sent 
to patients at customized intervals (at the time points when QOL forms are due). The first 
reminder will be sent at the beginning of the “window” to complete a QOL form, with a second 
reminder halfway through the window period if the QOL forms are not yet completed at that 
time point. A maximum of 3 reminders will be sent for each of the 4 QOL time points (following 
the baseline QOL forms, which are completed in hardcopy). After a patient has completed all 
forms in the portal, a dialogue box will appear that says “Thank you for completing your Quality 
of Life forms,” and the patient will no longer receive any remaining notices for that time point. 
The site RA or study administrator will be informed through the VTOC “At-A-Glance” form 
management system when QOL forms have been completed. 
 
 
2.0 OBJECTIVES 
2.1 Primary Objective 
Test whether the addition of cetuximab to radiation therapy will improve overall survival (OS) in 
postoperative patients with intermediate risk following surgery 
2.2 
Secondary Objectives (04-JUN-2010) 
2.2.1 
Assess the impact of the addition of cetuximab to postoperative radiation therapy on the 
following: 
• Disease-free survival (DFS); 
• Acute dysphagia, dry mouth, skin toxicity, and other toxicities (CTCAE, v. 4) and their 
relationships to patient-reported outcomes at 3 months; 

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RTOG 0920, Version Date: May 11, 2023 
 
• Late dysphagia, dry mouth, skin toxicity, and other toxicities (CTCAE, v. 4) and their 
relationships to patient-reported outcomes at 12 and 24 months. 
2.2.2 
Tumor analysis of EGFR, specifically extent of EGFR overexpression by immunohistochemical 
(IHC) and FISH analysis, EGFRvIII expression, as well as association of these assay data with 
OS and DFS; 
2.2.3 
Tumor analysis of HPV infection (as defined by in situ hybridization), specifically, within the 
cohort of patients with oropharynx cancer, to perform an exploratory analysis of the impact of 
HPV on DFS and OS in this patient subset; 
2.2.4 
Tumor DNA analyses of TP53 mutations for response prediction to cetuximab and prognosis; 
2.2.5 
Germline DNA analyses of polymorphic variants in EGFR intron repeats for response prediction 
to cetuximab. 
2.3 
Tertiary Objectives (Exploratory) 
2.3.1 
Assess the impact of the addition of cetuximab to postoperative radiation therapy on the 
following: 
• Local-regional control; 
• Patient-reported quality of life (QOL), swallowing, xerostomia, and skin toxicity based on 
head and neck specific instruments, including: the Performance Status Scale for Head and 
Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck 
(FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale 
(XeQOLS), and the Dermatology Life Quality Index (DLQI); 
• Cost-utility analysis using the EuroQol (EQ-5D). 
2.3.2 
To evaluate the utility of IGRT as a means of enhancing the efficacy (i.e., local-regional control) 
of IMRT while reducing the acute and/or late toxicity (particularly xerostomia) and improving 
patient-reported outcomes (particularly scores with the XeQOLS); 
2.3.3 
To retrospectively compare the local regional control rate for patients treated with IMRT alone 
(no IGRT or cetuximab) with similar patients treated with external beam radiation alone in the 
postoperative trial, RTOG 95-01. 
 
 
3.0 PATIENT SELECTION (07-APR-2014) 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED. For questions 
concerning eligibility, please contact the study data manager. 
 
3.1 
Conditions for Patient Eligibility (17-JAN-2012) 
3.1.1 
Pathologically (histologically) proven diagnosis of squamous cell carcinoma (including variants 
such as verrucous carcinoma, spindle cell carcinoma, carcinoma NOS, etc.) of the head/neck 
(oral cavity, oropharynx or larynx); Note: Hypopharynx primaries are excluded because these 
patients have both a poor prognosis and high likelihood of post-radiation complications. 
3.1.2 
Clinical stage T1, N1-2 or T2-4a, N0-2, M0 including no distant metastases, based upon the 
following minimum diagnostic workup: 
• General history and physical examination by a Radiation Oncologist and/or Medical 
Oncologist within 8 weeks prior to registration; 
• Examination by an ENT or Head & Neck Surgeon, within 8 weeks prior to registration; a 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended 
but not required. 
• Chest x-ray (at a minimum) or chest CT scan (with or without contrast) or CT/PET of chest 
(with or without contrast) within 8 weeks prior to registration. 
3.1.3 
Gross total resection of the primary tumor with curative intent must be completed within 7 
weeks of registration with surgical pathology demonstrating one or more of the following 
“intermediate” risk factors: 
• Perineural invasion; 
• Lymphovascular invasion; 
• Single lymph node > 3 cm or ≥ 2 lymph nodes (all < 6 cm) [no extracapsular extension]; 
• Close margin(s) of resection, defined as cancer extending to within 5 mm of a surgical 
margin, and/or an initially focally positive margin that is subsequently superseded by 
intraoperative negative margins. Similarly, patients whose tumors had focally positive 
margins in the main specimen but negative margins from re-excised samples in the region  
of the positive margin are eligible. For questions or ambiguities about an individual case, 
contact Dr. Machtay and/or Dr. Holsinger prior to enrolling the patient. 

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RTOG 0920, Version Date: May 11, 2023 
 
• Pathologically confirmed T3 or T4a primary tumor; for questions or ambiguities about an 
individual case, contact Dr. Machtay and/or Dr. Holsinger prior to enrolling the patient. 
• T2 oral cavity cancer with > 5 mm depth of invasion. 
3.1.4 
Zubrod Performance Status of 0-1 within 2 weeks prior to registration; 
3.1.5 
Age ≥ 18; 
3.1.6 
CBC/differential obtained within 4 weeks prior to registration on study, with adequate bone 
marrow function defined as follows: 
• Absolute granulocyte count (AGC) ≥ 1,500 cells/mm3; 
• Platelets ≥ 100,000 cells/mm3; 
• Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 
8.0 g/dl is acceptable). 
3.1.7 
Adequate hepatic function, defined as follows: 
• Total bilirubin < 2 x institutional ULN within 2 weeks prior to registration; 
• AST or ALT < 3 x institutional ULN within 2 weeks prior to registration. 
 
3.1.8 
Adequate renal function, defined as follows: 
• 
Serum creatinine < 2 x institutional ULN within 2 weeks prior to registration or; 
creatinine clearance (CC) ≥ 50 ml/min within 2 weeks prior to registration determined by 
24-hour collection or estimated by Cockcroft-Gault formula: 
 
CCr male = [(140 – age) x (wt in kg)] 
[(Serum Cr mg/dl) x (72)] 
 
CCr female = 0.85 x (CrCl male) 
3.1.9 
Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing 
potential; 
3.1.10 
The following assessments are required within 2 weeks prior to the start of registration: Na, K, 
Cl, glucose, Ca, Mg, and albumin. Note: Patients with an initial magnesium < 0.5 mmol/L (1.2 
mg/dl) may receive corrective magnesium supplementation but should continue to receive 
either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation 
(e.g., magnesium oxide) at the investigator’s discretion. 
3.1.11 
Women of childbearing potential and male participants who are sexually active must agree to 
use a medically effective means of birth control; 
3.1.12 
Patients must provide study specific informed consent prior to study entry, including consent for 
mandatory tissue submission for EGFR and for oropharyngeal patients, HPV analyses. 
3.2 
Conditions for Patient Ineligibility (23-JAN-2013) 
3.2.1 
Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a 
minimum of 3 years; noninvasive cancers (For example, carcinoma in situ of the breast, oral 
cavity, or cervix are all permissible) are permitted even if diagnosed and treated < 3 years ago. 
Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of 
patients with bilateral tonsil cancers or patients with T1-2, N0, M0 resected differentiated  
thyroid carcinoma, who are eligible. 
3.2.2 
Per the operative and/or pathology report, positive margin(s) [defined as tumor present at the 
cut or inked edge of the tumor], nodal extracapsular extension, and/or gross residual disease 
after surgery; Note: Patients whose tumors had focally positive margins in the main specimen 
but negative margins from re-excised samples in the region of the positive margin are eligible 
(see Section 8.1). For questions or ambiguities about an individual case, contact Dr. Machtay 
and/or Dr. Holsinger prior to enrolling the patient. 
3.2.3 
Prior systemic chemotherapy or anti-EGF therapy for the study cancer; note: prior 
chemotherapy or anti-EGF therapy for a different cancer is allowable. See Section 3.2.1. 
3.2.4 
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields; 
3.2.5 
Severe, active co-morbidity, defined as follows: 
• 
Unstable angina and/or congestive heart failure requiring hospitalization within 6 months 
prior to registration; 
• 
Transmural myocardial infarction within 6 months prior to registration; 
• 
Acute bacterial or fungal infection requiring intravenous antibiotics at the time of 
registration; 

33 
RTOG 0920, Version Date: May 11, 2023 
 
• 
Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy at the time of registration; 
• 
Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen 
therapy or is thought to require oxygen therapy within 1 year prior to registration; 
• 
Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, 
however, that laboratory tests for coagulation parameters are not required for entry into this 
protocol. 
• 
Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note: 
HIV testing is not required for entry into this protocol. The need to exclude patients with 
AIDS from this protocol is necessary because the treatments involved in this protocol may 
be significantly immunosuppressive. Protocol-specific requirements may also exclude 
immuno-compromised patients. 
• 
Grade 3-4 electrolyte abnormalities (CTCAE, v. 4): 
➢ Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 
12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels; 
➢ Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L); 
➢ Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite 
intervention to normalize levels; 
➢ Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels; 
➢ Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels. 
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 
Prior allergic reaction to cetuximab. 
 
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
Note: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility. 
4.1 
Required Evaluations/Management (25-JAN-2016) 
4.1.1 
Dental evaluation with management according to the guidelines in Appendix IV within 3 months 
prior to the start of treatment; 
4.1.2 
Assessment of swallowing function/dysphagia using CTCAE, v. 4 criteria within 2 weeks prior  
to the start of treatment. 
4.1.3 
Patients must be offered the opportunity to participate in the tissue/specimen collection for 
banking and translational research. If the patient consents to participate in this component, the 
site is required to submit the patient’s specimens. Note: Sites are not permitted to delete the 
tissue/specimen component from the protocol or from the sample consent form. 
4.1.4 
If the patient consents to participate in the quality of life (QOL) component of the study, sites 
are required to administer the baseline QOL and functional assessments prior to the start of 
treatment: the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N); the 
Dermatology Life Quality Index (DLQI); the Performance Status Scale for Head and Neck 
Cancer (PSS-HN); the University of Michigan Xerostomia-Related Quality of Life Scale 
(XeQOLS); and the EuroQol (EQ-5D). 
 
Patients who consent to participate in the quality of life (QOL) component of this study have 
the option of completing QOL forms online from any location, including home, via VisionTree 
Optimal Care (VTOC). Patients without e-mail or Internet access are still able to participate 
in the QOL component of the study by completing hardcopy (paper) forms. Indeed, at any 
time, any patient may choose to fill out their QOL form using the hardcopy form. 
 
If the patient wishes to complete QOL assessments online, the patient must have an e-mail 
address that they consent to use for this purpose. Patients’ e-mail addresses are necessary 
so that e-mail reminders may be sent to them to remind them to fill out QOL forms that are 
due. The patient’s e-mail address also will be used for password-protected access to VTOC. 
Patients who are interested in participating but do not yet have an e-mail address can obtain 
one for free from a number of sources (e.g.,Yahoo!, Hotmail, or AOL). Note: The site RA is 
responsible for setting up the patient’s account on VTOC. The RA may do so by logging on 
the VTOC portal at the following link: https://rtog.optimalcare.com - medical team. RA login 

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RTOG 0920, Version Date: May 11, 2023 
 
information will be provided by VTOC after the patient is randomized to the study. The 
patient’s VTOC account must be set up within 14 days after randomization. 
 
See Section 11.5.6 for further details. 
4.2 
Highly Recommended Evaluations/Management 
4.2.1 
Baseline postoperative re-staging/imaging of head, neck, and chest (e.g., CT with contrast, or 
CT/PET with or without contrast, and/or MRI of the head and neck) within 4 weeks prior to the 
start of treatment to rule out occult/rapid postoperative recurrence and/or second primary 
cancer; Note: Review of the RT treatment planning CT scan with the radiologist is acceptable. 
4.2.2 
Evaluation for prophylactic gastrostomy tube placement (especially if the patient is ≥ 10%  
below ideal body weight) within 4 weeks prior to the start of treatment; 
4.2.3 
EKG within 8 weeks prior to the start of treatment. 
 
 
 
5.0 REGISTRATION PROCEDURES (03-NOV-2014) 
Access requirements for OPEN and TRIAD: 
Site staff will need to be registered with CTEP and have a valid and active CTEP Identity and Access 
Management (IAM) account. This is the same account (user id and password) used for the CTSU members' 
web site. To obtain an active CTEP-IAM account, go to https://eapps-ctep.nci.nih.gov/iam. 
 
NOTE: FOR THIS STUDY, IMRT IS MANDATORY; IGRT IS OPTIONAL and can be used without IGRT 
credentialing if not used for reducing margins. IGRT is mandatory when using reduced margins and 
for this, sites must be head and neck IGRT credentialed. 
 
 
5.1 RT-Specific Pre-Registration Requirements (13-NOV-2017) 
For detailed information on the specific technology requirement required for this study, please refer to the 
table below and utilize the web link provided for detailed instructions. The check marks under the 
treatment modality columns indicate whether that specific credentialing requirement is required for this 
study. Specific credentialing components may require you to work with various QA centers; however, the 
IROC Houston QA Center will notify your institution and NRG Headquarters when all credentialing 
requirements have been met and the institution is RT credentialed to enter patients onto this study. 
• 
Credentialing documentation received from IROC Houston for this trial-See section 5.1 Table for 
details. 

35 
RTOG 0920, Version Date: May 11, 2023 
 
Credentialing 
Requirements 
Web Link for Procedures and Instructions: [www.irochouston.meanderson.org 
Treatment 
Modality 
Key Information 
Photo 
ns 
Facility 
Questionnaire 
✓ 
The IROC Houston electronic facility questionnaire (FQ) should be 
completed or updated with the most recent information about your 
institution. To access this FQ, email irochouston@mdanderson.org to 
receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
✓ 
To determine if your institution has completed the requirements above, 
please complete a “Credentialing Status Inquiry Form” found under 
Credentialing on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org ). 
Phantom 
Irradiation 
✓ 
An IMRT Head and neck phantom irradiation provided by the IROC 
Houston QA Center must be successfully completed. Instructions for 
requesting and irradiating the phantom are found on the IROC Houston web 
site (http://irochouston.mdanderson.org). Note that an institution, depending 
on its treatment delivery modalities, may be required to irradiate a phantom 
on different delivery machines such as TomoTherapy and CyberKnife 
IGRT 
Verification 
Study 
For 
reduced 
margins 
only 
Institutions using reduced margins must be credentialed for bony tissue 
IGRT. Find details on CTSU’s website (https://www.ctsu.org) and the IROC 
Houston QA Center website (http://irochouston.mdanderson.org) Institutions 
that have previously been approved for IGRT may not need to repeat 
credentialing. 
Credentialing Issued to: 
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 
approval email from IROC Houston to the CTSU Regulatory Portal for RSS 
to be updated. 
 
 
5.2 
Preregistration Requirements for Head and Neck Image-Guided Radiotherapy (IGRT) 
Treatment Approach (For sites treating with reduced margins) (13-NOV-2017) 
5.2.1 
In order to utilize head and neck IGRT for reduced margins, the center must be credentialed for 
its use. See chart in section 5.1. 
 
5.3 
Pre-Registration Requirements for IMRT Treatment Approach (13-NOV-2017) 
In order to utilize IMRT on this study, the institution must have met specific technology 
requirements and have provided baseline physics information. See chart in section 5.1. 
5.4 
Digital RT Data Submission to RTOG Using TRIAD (11-MAY-2023) 
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: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT systems; 
• 
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; and 
• 
TRIAD Site User role on an NCTN, ETCTN, or other relevant roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access to TRIAD and 
may submit images for credentialing purposes, or for enrollments to which the provider is linked in 
OPEN. 

36 
RTOG 0920, Version Date: May 11, 2023 
 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD 
application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org or 1-703-390-
9858. 
 
5.5 
Regulatory Pre-registration Requirements (11-MAY-2023) 
5.5.1 
CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations require sponsors to select qualified investigators. 
National Cancer Institute (NCI) policy requires all individuals contributing to NCI-sponsored trials to 
register with their qualifications and credentials 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. Investigators and clinical site staff who are significant 
contributors to research must register in the Registration and Credential Repository (RCR). The RCR is a 
self-service online person registration application with electronic signature and document submission 
capability. 
RCR utilizes five person registration types. 
• 
Investigator (IVR) — MD, DO, or international equivalent; 
• 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or graduate 
level researchers (e.g., PhD); 
• 
Associate Plus (AP) — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications 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) 
✔ 
✔ 
✔ 
 
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: 
• 
Addition to a site roster; 
• 
Selection as the treating, credit, or drug shipment investigator or consenting person in OPEN; 
• 
Ability to be name 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), 
consenting/treating/drug shipment investigator in OPEN must be rostered at the enrolling site with a 
participating organization.  
 

37 
RTOG 0920, Version Date: May 11, 2023 
 
Refer to the NCI RCR page on the CTEP website for additional information. For questions, please 
contact the RCR Help Desk by email at RCRHelpDesk@nih.gov. 
 
5.5.2 CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval 
 
As of March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB) in order to participate in Cancer Therapy Evaluation Program 
(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. 
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 (SSW) for 
Local Context to the CIRB using IRBManager 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). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status 
following processing of the IRB/REB approval record: 
• 
Have an active CTEP status; 
• 
Have an active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster; 
• 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
• 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile;  
• 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
• 
Have the appropriate CTEP registration type for the protocol.  
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 their associated investigators and staff on a 
participating roster. To view/download site registration forms:   
• Log in to the CTSU members’ website (https://www.ctsu.org); 
• Click on the Protocols tab 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 0920. 
•    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.)  
 
 
 

38 
RTOG 0920, Version Date: May 11, 2023 
 
Requirements for RTOG 0920 site registration: 
• 
IRB approval (for sites not participating via the NCI CIRB; local IRB documentation, 
an IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects 
Assurance Identification/IRB Certification/Declaration of Exemption Form, or 
combination is accepted) 
• IROC Credentialing Status Inquiry (CSI) Form 
• NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling 
site must be aligned to a RTI provider. To manage provider associations access the 
Provider 
Association 
tab 
on 
the 
CTSU 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove associated 
providers. Sites must be linked to at least one IROC credentialed provider to 
participate on trials with an RT component. IRB/REB approved consent (English  
and native language versions*) 
*Note: Institutions must also provide certification/verification of consent 
translation to NRG Oncology 
• IRB/REB assurance number renewal information, as appropriate 
• Credentialing documentation received from IROC Houston must be uploaded to the 
CTSU Regulatory Portal for RSS to be updated. 
 
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. 
 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
 
To access the Regulatory Submission Portal log in 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 by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org to receive further instruction and support. 
 
Checking Site’s Registration Status: 
Site 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 NCI or their affiliated networks. 
5.5.3 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
 
In addition to the requirements above, Canadian institutions 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 

39 
RTOG 0920, Version Date: May 11, 2023 
 
. 
5.5.4 
Pre-Registration Requirements for Shipment of Cetuximab 
US and Canadian Institutions: 
All pre-registration requirements must be met before calling to register the first case.  
Institutions must electronically complete (versus hand write) a Study Agent Shipment Form 
(SASF) available on the CTSU protocol website. U.S. and Canadian institutions must fax the 
SASF to the CTSU Regulatory Office (Fax 215-569-0206) as soon as the individual responsible 
for the study agent has been identified. 
 
Non-Canadian International Institutions: 
Please refer to your LOI Approval Notification. 
5.6 
Registration (11-MAY-2023) 
5.6.1 
Summary of Procedures 
This study incorporates a two-step registration process. 
All patients must consent to submission of tissue for EGFR analysis; see Section 10.2 for 
details of submission. Oropharyngeal carcinoma patients also must consent to submit tissue 
for HPV analysis; see Section 10.3 for details of submission. All patients can be registered 
after completing the Eligibility Checklist, STEP 1 via online registration; see Section 5.6.2 for 
online registration instructions. 
 
Institutions must submit the required tissue block for EGFR analysis to the NRG Oncology 
Biospecimen Bank (see Section 10.5 for shipping information), using the case number obtained 
from STEP 1 registration. The Biospecimen Bank will determine the adequacy of the tissue and 
will send 2 unstained slides to Dr. Adel El-Naggar for EGFR analysis. The results of EGFR 
analysis are expected in approximately 7-8 business days, and NRG Oncology will inform sites 
by e-mail of the completion of the EGFR analysis. At this point, non-oropharyngeal 
carcinoma patients may be randomized; sites must complete the Eligibility Checklist, STEP 2 
via online registration. Note: EGFR analysis must be performed for all patients before 
proceeding to STEP 2. 
 
For patients with oropharyngeal carcinoma: the Biospecimen Bank will process 4 unstained 
slides from the tissue block submitted (for EGFR analysis) and will send the slides to Dr. Adel 
El-Naggar for HPV analysis. The results of the HPV analysis are expected in approximately 7- 
10 business days, and NRG Oncology will inform sites by e-mail of the completion of the HPV 
analysis. At this point, oropharyngeal carcinoma patients may be randomized; sites must 
complete the Eligibility Checklist, STEP 2 via online registration. 
 
Physicians or institutions can request the patient’s EGFR level and/or HPV status from NRG 
Oncology (215-717-0837 or 215-574-3170) after the patient has completed study treatment. 
5.6.2 
OPEN Registration Instructions 
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 LPOs’ registration/randomization systems or the Theradex Interactive Web Response 
System (IWRS) for retrieval of patient registration/randomization assignment.  
Requirements for OPEN access:   
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
Have an approved site registration for the 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.  
 
 
 

40 
RTOG 0920, Version Date: May 11, 2023 
 
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 Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may 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. 
 
6.0 RADIATION THERAPY (18-MAY-2015) 
See Section 5.4 for information on installing TRIAD for submission of digital RT data prior to enrolling 
patients. 
 
Note: FOR THIS STUDY, IMRT IS MANDATORY. IGRT IS OPTIONAL and can be used without IGRT 
credentialing if not used for reducing margins. IGRT is mandatory when using reduced margins, and 
for this, sites must be head and neck IGRT credentialed. 
 
Protocol treatment must begin within 2 weeks after Step 2 registration (randomization). 
 
6.1 
Dose Specifications for both Arms 
The prescribed radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size (total of 30 
fractions). Radiotherapy should begin on a Monday, Tuesday or Wednesday. The daily dose of 2 
Gy will be prescribed such that 95% of the PTV60 volume receives at least 60 Gy. As described 
in Section 6.4, PTV56 and PTV66 also may be defined. The spinal cord dose may not exceed 48 
Gy to any volume larger than 0.03 cc. 
6.2 
Technical Factors (13-NOV-2017) 
6.2.1 
Treatment Planning/Delivery: Megavoltage energy photon beam irradiation is required. Any 
treatment planning and delivery system that has been credentialed for head and neck IMRT by 
the IROC Houston is acceptable. 
6.2.2 
Image Guidance for IGRT (see Section 5.2.2): Daily image guidance of IMRT may be achieved 
using any one or more of the following techniques: 
▪ Orthogonal kilovoltage (KV) images, e.g. ExacTrac; 
▪ Linear-accelerator mounted kV and MV conebeam CT images; 
▪ Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 
▪ Other mechanism, after discussion with the Study Chair and Medical Physics Co-chair. 
 
The institution’s procedure to register treatment day imaging dataset with the reference 
dataset should comply with the following recommendations: 
▪ Region-of-Interest (ROI) or “clip box” for fusion should be set to encompass the high 
dose PTV and adjacent spinal cord; if the supraclavicular region is a part of the target 
volume the ROI should extend to the C6 level; 
▪ If the fusion software allows the user to create an irregular ROI (e.g., ExacTrac), 
treatment room objects seen on in-room X-rays should be excluded from the 
registration; 
▪ Both manual (e.g., based on bony anatomy) and automatic (e.g., based on mutual 
information) types of registration can be used; the result of the fusion must be visually 
checked for the alignment of the bony anatomy, such as vertebral bodies and 
applicable soft tissue structures (e.g., optic nerves and/or optic chiasm). 
Following the registration, the translational and (if the appropriate technology is available) 
rotational corrections should be applied to the treatment couch. If all the variances are less 
than 2.5 mm (this typically corresponds to one half of the usual PRV margin), the treatment 
can proceed without correction (however, the physician/team may elect to perform 
adjustments even for a variance < 2.5 mm). If one or more corrections are 2.5-5 mm, 
adjustment is necessary prior to treatment; however, re-imaging is not mandatory. If one or 
more of the corrections are larger than 5 mm, the imaging must be repeated in addition to 
performing table/positioning adjustments. 
 

41 
RTOG 0920, Version Date: May 11, 2023 
 
Management of Radiation Dose to the Patient from IGRT 
Radiation doses from IGRT are small enough dose contributions that if there is only one 
imaging study done per treatment session, the dose does not need to be incorporated into 
treatment planning and is not expected to have any clinical relevance to the patient. 
However, the imaging dose to the patient may become significant if repeated studies are 
done for patients with severe set up problems (e.g., requiring frequent corrections of more 
than 5 mm). It is recommended that patients demonstrating severe set up problems during 
the first week of treatment be moved to a treatment with larger margins. 
6.3 
Localization, Simulation, and Immobilization 
6.3.1 
Patients must have an immobilization device (e.g., aquaplast mask) made prior to treatment 
planning CT scan. 
6.3.2 
The treatment planning CT scan should be performed with IV contrast so that the major vessels 
of the neck are easily visualized. The treatment planning CT scan must be performed with the 
immobilization device and in the treatment position. Slice thickness should be 0.3 cm. 
6.4 
Target and Normal Tissue Volume Definitions (13-NOV-2017) 
6.4.1 
Definition of Target Volumes 
CTV60: This volume will receive 2 Gy per day. CTV60 will include the primary tumor bed 
(based on preoperative imaging, preoperative physical exam/endoscopy, operative findings, 
pathologic findings) plus region(s) of grossly involved lymphadenopathy. This volume may 
approach the skin but should not approach < 2mm. It is recognized that after surgery, there 
can be considerable distortion of normal anatomy. If possible, map preoperative GTV(s)  
onto the postoperative radiation therapy planning CT scan, and add appropriate margins for 
microscopic spread (1.5-2 cm). 
 
CTV60 also will include the ipsilateral pathologically positive hemineck (if both sides of the 
neck are proven pathologically positive, CTV60 will include both sides). This generally 
means encompassing nodal levels 2a, 3, and 4 for all cases. Nodal levels 1, 2b, 5a, and 5b 
are included in CTV60 in selected circumstances. For example, level 1 must be included for 
oral cavity cancer but is not mandatory for larynx cancer. Level 5a must be included for 
oropharynx cancer but is not mandatory for larynx cancer. For questions, contact the 
Principal Investigator, Dr. Machtay, or one of the Radiation Oncology Co-Chairs, Drs. 
Thorstad, Nguyen-Tan, and Quon. 
 
CTV56: This will include all other regions felt to be at risk for harboring microscopic cancer 
that do not meet the criteria for CTV60. For example, this would apply to the contralateral 
hemineck being irradiated electively for base of tongue cancer. This volume should not 
approach the skin < 5 mm. This volume will receive approximately 1.85 Gy per day. 
 
CTV66 Optional: This may be defined at the discretion of the treating radiation oncologist. 
This would include a region or regions felt to be at especially high risk for recurrence (e.g., 
an area of very close margin of resection). Note: This area will be receiving a daily fraction 
size of 2.2 Gy and thus, the volume of CTV66 should be kept as small as possible. 
 
Planning Target Volumes (PTVs): In general, the PTV should not go outside of the skin 
surface; if it does exceed the skin surface, the application of bolus material over this portion 
of the PTV may be considered but is generally not recommended. It is also allowable to 
define two PTV’s for a given CTV: 1) PTV Planning, which extends beyond the skin surface 
and is used for planning treatment segments; and 2) PTV Evaluation, which does not reach 
the skin surface within 2 mm and is used for evaluation of the dose volume histogram to 
determine if treatment goals have been met. 
PTV Expansion Without Daily IGRT 
For those institutions that are not using daily IGRT (see Section 6.2.2), the minimum CTV- 
to-PTV expansion should be 5 mm (a larger expansion may be necessary for a target 
volume subject to significant inter-fraction variability such as the tongue). In general, the 
CTV-to-PTV expansion (without IGRT) should not exceed 10 mm. 
 
PTV Expansion With Daily IGRT 
For those institutions that are using daily IGRT (see Section 6.2.2), the minimum CTV-to- 
PTV expansion is 2.5 mm (a larger expansion may be necessary for a target volume 
subject to significant intra-fraction variability, such as the non-immobilized oral tongue).In 
general, the CTV-to-PRV expansion (with IGRT) should not exceed 5 mm. 
6.4.2 
Definition of Normal Tissues/Organs at Risk (OARs) 

42 
RTOG 0920, Version Date: May 11, 2023 
 
Spinal Cord: The cord begins at the cranial-cervical junction (i.e., the top of the C1 vertebral 
body). Superior to this is brainstem and inferior to this is cord. The inferior border of the 
spinal cord is at approximately T3-4 (i.e., just below the lowest slice level that has PTV on  
it). The spinal cord shall be defined based on the treatment planning CT scan. In addition, 
however, a Planning Risk Volume (PRV) spinal cord shall be defined. The PRVcord = cord + 
5 mm in each dimension. This is irrespective of whether or not IGRT is used. 
 
Brainstem: The inferior most portion of the brainstem is at the cranial-cervical junction where 
it meets the spinal cord. For the purposes of this study, the superior most portion of the 
brainstem is approximately at the level of the top of the posterior clinoid. The brainstem shall 
be defined based on the treatment planning CT scan. In addition, however, a Planning Risk 
Volume (PRV) brainstem shall be defined. The PRVbrainstem = brainstem + 3 mm in each 
dimension. 
 
Lips and Oral Cavity: These should be contoured as 2 separate structures as the goal is to 
keep the lip dose much lower than the oral cavity dose. The definition of lips is self- 
explanatory. For non-oral cavity cancers, the oral cavity will be defined as a composite 
structure consisting of the anterior ½ to 2/3 of the oral tongue/floor of mouth, buccal mucosa, 
and palate. For oral cavity cancers, the oral cavity will be defined as the subset of this 
composite structure that does not overlap with PTV. 
 
Parotid Glands: Parotid glands will be defined based on the treatment planning CT scan. 
Parotid gland volume will not include any portion of any of the CTVs, although they can 
overlap the PTVs. 
 
OARpharynx: This will be defined as the “uninvolved” posterior pharyngeal wall plus 
adjacent constrictor muscles. This extends from the superior constrictor region (the inferior 
pterygoid plates level) to the cricopharyngeal inlet (posterior cricoid cartilage level). This 
should not overlap the PTVs. 
 
Cervical Esophagus: This will be defined as a tubular structure that starts at the bottom of 
OARpharynx and extends to the thoracic inlet. 
 
Glottic/Supraglottic Larynx (GSL): Obviously, for patients who have had a total 
laryngectomy, this structure is not applicable. This will be defined as a “triangular prism 
shaped” volume that begins just inferior to the hyoid bone and extends to the cricoid 
cartilage inferiorly and extends from the anterior commissure to include the arytenoids. This 
includes the infrahyoid but not suprahyoid epiglottis. 
 
Mandible: This includes the entire boney structure of the mandible from TMJ through the 
symphysis. It is recognized that for oral cavity cancers, this may overlap with CTVs and 
PTVs. 
 
Unspecified Tissue Outside the Targets: This will be defined as tissue located between the 
skull base and thoracic inlet that is not included in either the target volumes or the normal 
tissues described above. 
6.5 
Treatment Planning and Delivery 
6.5.1 
Management of the Low Neck/Supraclavicular Region (Match vs. No Match) 
It is recognized that comprehensive head and neck irradiation incorporating IMRT can be done 
in 1 of 2 ways, either of which is permitted for this study. 
1. Match: The upper cervical lymphatics and primary tumor bed are treated with IMRT. The 
lower cervical lymphatics and supraclavicular region are treated with a single AP (or 
occasionally APPA for larger patients with posterior neck at high risk) non-IMRT technique. 
The latter non-IMRT field(s) is matched to the upper neck IMRT fields. This technique 
requires comprehensive mid-line spinal cord blocking in the lower neck fields. This  
technique also allows for a simultaneous blocking of portions of the larynx, hypopharynx, 
and cervical esophagus in the lower neck fields. In general, this technique is appropriate for 
irradiation of cancers of the oral cavity or oropharynx. 
2. No Match: The entire clinical target volume (CTV) [upper and lower neck and primary tumor 
bed] is irradiated with IMRT. There is no match line between upper and lower portions of the 

43 
RTOG 0920, Version Date: May 11, 2023 
 
regions at risk. In this technique, limiting radiotherapy dose to organs at risk (OARs), e.g., 
the cervical esophagus, is entirely achieved by inverse treatment planning via IMRT 
algorithms. This technique in general is appropriate for irradiation of cancers of the larynx 
and/or oral/pharyngeal cancers that involve the hypopharynx. 
6.5.2 
Dose to Supraclavicular Nodal Region 
Regardless of whether technique 1 (Match) or technique 2 (No Match) is used, the dose to the 
supraclavicular nodal region may be limited to 50 Gy if level 4 nodes were dissected and found 
to be negative or in the case of oral cavity cancer with level 3 nodes dissected and found to be 
negative. 
6.5.3 
IMRT Dose Prescription to PTVs 
See Section 6.4.1 for definitions of CTVs and PTVs. As described in Section 6.1, prescribed 
radiotherapy dose will be 60 Gy in 2 Gy once-daily fraction size. For inverse planning IMRT, the 
goal is for 95% of the PTV60 to receive ≥ 2 Gy with a minimum dose (cold spot) of no less than 
56 Gy. It is recognized that portions of the PTV60 close to the skin may receive significantly 
less than 56 Gy. This is acceptable as long as cold spots within PTV60 do not exist at a depth 
deeper than 8 mm beneath the skin (see Section 6.8, compliance criteria). 
 
For prioritization, PTV60 will be the highest priority target structure. PTV66 and PTV56, if 
applicable, will be ranked in the IMRT planning as lower priority than PTV60 although higher 
priority than normal structures other than spinal cord and brain stem. 
6.5.4 
IMRT Dose Constraints to Normal Structures 
Spinal Cord: The PRVcord (as defined in Section 6.4.2.) should not exceed 48 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). The spinal cord PRV 
should not exceed 50 Gy to any volume in excess of 0.01 cc. In treatment planning, the 
spinal cord PRV should be given the highest priority. 
 
Brainstem: The PRVbrainstem (as defined in Section 6.4.2.) should not exceed 52 Gy to any 
volume in excess of 0.03 cc (approximately 3 mm x 3 mm x 3 mm). In treatment planning, 
the PRVbrainstem should be given less priority than the PRVcord but more priority than the 
other critical structures listed below. 
 
Lips: Reduce the dose as much as possible. The mean dose should be < 20 Gy. For non- 
oral cavity cancers, the maximum dose will be < 30 Gy. For oral cavity cancers, the 
maximum dose will be < 50 Gy. 
 
Oral Cavity: Reduce the dose as much as possible. For non-oral cavity cancers, the mean 
dose should be < 30 Gy. For oral cavity cancers, the mean dose should be < 50 Gy. Efforts 
should be made to avoid hot spots (> 60 Gy) within the oral cavity, particularly for non-oral 
cavity cancers. 
 
Parotid Glands: In most cases, it will be easier to spare one parotid than the other. The 
treatment planning goal will be for this individual parotid gland to receive a mean dose of < 
26 Gy. Additional planning goals may include: 1) At least 50% of one parotid will receive < 
30 Gy; and/or 2) At least 20 cc of parotid tissue (from the combination of both glands) will 
receive < 20 Gy. 
OARpharynx: Reduce the dose as much as possible. Some recommended (but not 
mandatory) treatment goals include: 1) No more than 33% of the OARpharynx exceeds 50 
Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the OARpharynx exceeds 60 Gy. 
 
Cervical Esophagus: Reduce the dose as much as possible. For oral or oropharyngeal 
cancer, some recommended (but not mandatory) treatment goals include: 1) No more than 
33% of the esophagus exceeds 45 Gy; 2) Mean dose < 35 Gy; 3) No more than 15% of the 
esophagus exceeds 54 Gy. For larynx cancer, higher doses are expected and permitted. 
Some recommended doses (but not mandatory) treatment goals include: 1) No more than 
33% of the esophagus exceeds 50 Gy; 2) Mean dose < 45 Gy; 3) No more than 15% of the 
esophagus exceeds 60 Gy. 
 
Glottic and Supraglottic larynx (GSL): Reduce the dose as much as possible. In patients with 
resected oral or oropharyngeal carcinoma, it is recommended that the dose to the larynx 
should be kept < 45 Gy whenever feasible. 

44 
RTOG 0920, Version Date: May 11, 2023 
 
Mandible: Reduce the dose as much as possible. It is recognized that particularly for oral 
cavity cancers, significant portions of the mandible will overlap the CTVs and/or PTVs; 
however, hot spots within the mandible should be avoided. It is recommended that  
maximum dose within the mandible be < 66 Gy. 
 
Unspecified Tissue Outside the Targets: For the typical case in which there is no CTV66, no 
more than 5% of unspecified tissue can receive greater than 58 Gy and no more than 1% or 
1cc of unspecified tissue can receive 64 Gy or more. When a boost is used to increase the 
dose to high risk regions to as much as 66 Gy, these numbers can be increased. In this 
case, no more than 5% of the unspecified dose should exceed the level of the boost dose, 
and no more than 1% or 1 cc should exceed the boost dose value plus 10%. 
6.5.5 
Prioritization for IMRT Planning 
1. Spinal Cord 
2. Brainstem 
3. PTV60 
4. PTV56 (if applicable) 
5. PTV66 (if applicable) 
6. a. OARpharynx 
b. Parotid gland contralateral to primary tumor site 
7. a. GSL 
b. Esophagus 
8. a. Lips 
b. Oral Cavity 
9. a. Parotid gland ipsilateral to primary tumor site 
b. Mandible 
10. Unspecified tissue outside the targets 
 
 
6.6 
Critical Structures (25-JAN-2016) 
Note: All structures marked “required” in the table below must be contoured and submitted for 
review. Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name as listed. 
 
The following table outlines the naming of the various normal and critical structures for submission to 
TRIAD. 
 
Standard Name 
Description 
CTV_6000 
Primary Tumor Bed plus 
involved nodes. 
Required 
CTV_5600 
At risk regions 
Required when applicable 
CTV_6600 
Optional higher dose region; 
should be kept small as 
possible. 
Required when applicable 
PTV_6000 
CTV-PTV 5 mm margin without 
IGRT; 2.5 mm with Daily IGRT. 
Required 
PTV_6000-08 
PTV_6000, not including portion 
of PTV_6000 near (<8 mm) skin 
Required 
PTV_5600 
CTV-PTV 5 mm margin without 
IGRT; 2.5 mm with Daily IGRT. 
Required when applicable 
PTV_5600, not including portion 

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RTOG 0920, Version Date: May 11, 2023 
 
PTV_5600-08 
of PTV_5600 near (<8 mm) skin 
Required when applicable 
PTV_6600 
CTV-PTV 5 mm margin without 
IGRT; 2.5 mm with Daily IGRT. 
Required when applicable 
PTV_6600-08 
PTV_6600, not including portion 
of PTV_6600 near (<8 mm) skin 
Required when applicable 
NonPTV6000 
External minus PTV_6000 
Required 
SpinalCord 
Spinal Cord 
Required 
SpinalCord_05 
Planning risk Volume of 5 mm 
Required 
BrainStem 
Brain Stem 
Required 
BrainStem_03 
Planning Risk Volume of 3 mm 
Required 
Parotid_L 
Left Parotid 
Required 
Parotid_R 
Right Parotid 
Required 
OralCavity 
Oral Cavity 
Required 
Lips 
Lips 
Required 
Mandible 
Mandible 
Required 
Pharynx 
Uninvolved posterior pharyngeal 
wall plus adjacent constrictor 
muscles; should not include 
PTVs 
Required 
Esophagus_Up 
Cervical Esophagus 
Required 
LarynxGSL 
Glottic/Supraglottic larynx 
Required 
External 
External border of patient used 
to define Unspecified Tissue. 
Required 
 
 
6.7 
Documentation Requirements for IMRT Treatment Approach (13-NOV-2017) 
• Pre-treatment Radiation therapy planning CT scan; 
• If IGRT is not used, then orthogonal images that localize the isocenter placement of IMRT 
are required. This information should be archived by the submitting institution, so it can be 
made available for possible future review; 
6.7.1 
Additional Documentation Requirements for IGRT Treatment Approach 
If an IGRT treatment approach is utilized, the following documentation is required: 

46 
RTOG 0920, Version Date: May 11, 2023 
 
• IGRT images obtained on the first day of treatment; 
• One IGRT image data set per week of treatment; Note: Sites should retain all daily 
images. Any or all of the institution’s daily images may be subject to auditing. 
• Spreadsheet that includes data on daily pre-treatment variances based on analysis of daily 
IGRT. See CTSU website (https://www.ctsu.org) for the spreadsheet. 
6.8 
Compliance Criteria (03-NOV-2014) 
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) for 
the treatment break(s). Treatment breaks, if necessary, ideally should not exceed five treatment 
days at a time and ten treatment days total. Treatment breaks should be allowed only for 
resolution of severe acute toxicity and/or for intercurrent illness and not for social or logistical 
reasons. Any treatment break(s) exceeding two treatment days for reasons other than 
toxicity/illness will be considered a protocol deviation. 
 
Per Protocol 
Minor Variation 
Major Variation 
Total RT dose to PTV_6000 (to 
95%) of PTV_6000) 
60-64 Gy 
58-60 or 64-66 
Gy 
<58 or > 66 Gy 
Minimum dose (“cold 
spot” 
within PTV_6000, not including 
portion of PTV_6000 near (<8 
mm) skin) 
56-60 Gy 
54-56 Gy 
< 54 Gy 
Maximum dose (“hot spot”) 
within PTV_6000* 
< 70 Gy 
70-72 Gy 
> 72 Gy 
Maximum 
dose 
(“hot 
spot” 
outside of PTV_6000) 
< 66 Gy 
66-70 Gy 
> 70 Gy 
Total RT dose to PTV_5600 (to 
95%) of PTV_5600) 
56-60 
54-56 or 60-62 
<54 or >62 
Minimum dose (“cold 
spot” 
within PTV_5600, not including 
portion of PTV near (<8 mm) 
skin) 
52-56 
50-52 
<50 
Total RT dose to PTV_6600 (to 
95%) of PTV_6600) 
66-70 
64-66 or 70-72 
<64 or >72 
Minimum dose (“cold 
spot” 
within PTV_6600, not including 
portion of PTV near (<8 mm) 
skin) 
62-66 
60-62 
<60 
Definition of CTV_6000 
Based on case review by study chair 
Definition of PTV_6000 
Based on case review by study chair. 
Total RT dose to 
SpinalCord_05(0.03 cc) 
< 48 Gy 
48-50 Gy 
> 50 Gy 
Total RT dose to 
SpinalCord_05(0.01 cc) 
< 50 Gy 
50-52 Gy 
> 52 Gy 
Definition of SpinalCord_05 
Based on case review by study chair 
Overall RT treatment time 
< 45 days 
46-50 days (without 
a medically 
appropriate 
indication for delay). 
> 50 days 
(without a 
medically 
appropriat 
e 
indication 
for delay). 
Non-Medically Indicated 
Treatment Interruptions 
0-2 
2-4 
>4 
*Not including the region of PTV60 that falls within PTV66 (if applicable) 
 
6.9 
R.T. Quality Assurance Reviews (07-APR-2014) 
The Principal Investigator/Radiation Oncology Chair, Mitchell Machtay, MD, and the Radiation 
Oncology Co-Chairs, Wade Thorstad, MD, and Phuc Felix Nguyen-Tân, MD, will perform RT 
Quality Assurance Reviews. These reviews will be ongoing. RT Quality Assurance reviews will be 
facilitated by IROC Philadelphia. 

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RTOG 0920, Version Date: May 11, 2023 
 
6.10 
Radiation Therapy Adverse Events (26-JAN-2018) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for AE reporting. 
CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study 
case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should 
have access to a copy of  CTCAE versions 4.0 and 5.0, which can be downloaded from the 
CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Grade 3 therapy-induced mucositis and/or dysphagia are expected to develop in about one third 
to one half of patients. Nutritional evaluation prior to the initiation of therapy for a prophylactic 
gastrostomy (PEG) tube placement is highly recommended. Placement of a feeding tube should 
be recorded on the appropriate case report form (see Section 12.1), as should use of a feeding 
tube during and after treatment (e.g., greater than or less than 50% of nutrition by tube). Other 
common radiation adverse events include: fatigue, weight loss, regional alopecia, xerostomia, 
hoarseness, transient ear discomfort, dysgeusia, and skin erythema and desquamation within the 
treatment fields. 
 
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. Much less 
common radiation adverse events include: mandibular osteoradionecrosis (< 5% incidence with 
attention to the dental recommendations provided in Appendix IV), and cervical myelopathy (< 
1% with restriction of spinal cord dose to ≤ 45 Gy). 
6.11 
Radiation Adverse Event Reporting 
See CTEP-AERS Expedited Reporting Requirements in Sections 7.5 and 7.6. 
 
 
7.0 DRUG THERAPY (07-APR-2014) 
Protocol treatment must begin within 2 weeks after Step 2 registration (randomization). 
 
7.1 
Arm 2 Treatment (03-NOV-2014) 
7.1.1 
Cetuximab Initial Dose (Prior to RT): Patients on Arm 2 will receive an initial dose of cetuximab, 
400 mg/m2, intravenously (i.v.) over 120 minutes. No chemotherapy or radiation will be given 
this day, and the 400 mg/m2 initial dose of cetuximab will precede the first 250 mg/m2 dose of 
cetuximab and the first radiation treatment by at least 5 days (the day of the loading dose is not 
included in these 5 days). The infusion rate of cetuximab must never exceed 5 mL/min. 
 
Cetuximab weeks 2-7 (concurrent with RT): Patients on Arm 2 will receive cetuximab, 250 
mg/m2, intravenously (i.v.) over 60 minutes on a weekly schedule. The infusion rate of 
cetuximab must never exceed 5 mL/min. Cetuximab will be given once a week on Monday or 
Tuesday before or after radiation therapy for a total of 6 doses. 
 
Cetuximab weeks 8-11 (post-completion of RT): Patients on Arm 2 will receive cetuximab, 250 
mg/m2, intravenously (i.v.) over 60 minutes, on a weekly schedule after the completion of 
radiation therapy, for a total of 4 additional doses. The infusion rate of cetuximab must never 
exceed 5 mL/min. For these 4 additional doses, cetuximab should be given once a week for a 
total of 4 doses. There should be at least 5 days between two consecutive doses. 
 
Note: Patients receive a total of 11 doses of cetuximab over 11 weeks, including the initial 
loading dose, 6 maintenance doses concurrent with radiation therapy, and 4 additional 
maintenance doses post-completion of radiation therapy. 
 
In cases of delay in the completion of radiation therapy, then the concurrent doses of  
cetuximab may continue beyond week 7 without dose interruption until radiation therapy is 
completed, and then be followed by weekly infusion of the remaining doses of cetuximab post- 
radiation therapy. The total of number of cetuximab doses should remain as 11 and should not 
exceed 11. For example, if a patient receives the initial cetuximab loading dose, plus 7 
maintenance doses concurrent with radiation therapy, then 3 additional maintenances doses 
post-completion of radiation therapy should be given. 

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RTOG 0920, Version Date: May 11, 2023 
 
CAUTION: Infusion reactions may occur during or following cetuximab administration. 
Most infusion reactions occur with the first infusion of cetuximab, but some patients’ 
first infusion reactions have been reported following subsequent doses (a severe 
reaction occurred in one patient following the 8th dose). The infusion reaction may 
occur during the infusion or be delayed until any time after the infusion. All patients will 
be premedicated with diphenhydramine hydrochloride, 50 mg, (or an equivalent 
antihistamine) by i.v. 30-60 minutes prior to the first dose of cetuximab in an effort to 
prevent an infusion reaction. At the discretion of the treating physician, dexamethasone, 20 
mg, and an H2 blocker also may be administered i.v. Premedications are recommended prior  
to subsequent doses, but at the Investigator’s discretion, the dose of diphenhydramine or 
dexamethasone may be reduced. 
 
The medical staff must closely observe patients for treatment-related adverse events, 
especially infusion reactions (see Sections 1.4 and 1.5 for details and Section 7.3.4 for 
management) during the cetuximab infusion and during a post-infusion observation hour. For 
the initial cetuximab infusion, vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) should be monitored prior to the administration of cetuximab, a half hour into the 
infusion, at the completion of the infusion, and 60 minutes post the infusion in an area with 
resuscitation equipment and other agents (epinephrine, prednisone equivalents, etc.) available. 
A nurse must be present in the immediate treatment area throughout the infusion and 
observation period. A physician must be in close proximity to the patient treatment area. In the 
event that a patient experiences an infusion reaction, see Section 7.3.4 for proper 
management. 
 
For subsequent infusions, vital signs should be taken pre- and post-infusion; however, it is 
recommended that the patient be observed for 1 hour post infusion. For the duration that 
patients are on study therapy, adverse event monitoring will be done continuously. Patients will 
be evaluated for adverse events at each visit and are to be instructed to call their physician to 
report any clinically significant adverse events between visits. Patients should be instructed 
to report any delayed reactions to the investigator immediately. 
7.2 
Cetuximab (IND Exempt) (08-MAR-2018) 
Refer to package insert and investigator brochure for additional information. Note the black box 
warning for cardiopulmonary arrest in patients receiving radiation therapy in combination with 
cetuximab. 
7.2.1 
Formulation 
Cetuximab is an anti-EGFR receptor humanized chimeric monoclonal antibody. Cetuximab is 
expressed in SP2/0 myeloma cell line, grown in large scale cell culture bioreactors, and purified 
to a high level purity using several purification steps including protein A chromatography, ion 
exchange chromatography, low pH treatment, and nanofiltration. Cetuximab is not known to be 
a vesicant. 
7.2.2 
Safety Precautions 
Appropriate mask, protective clothing, eye protection, gloves and Class II vertical-laminar- 
airflow safety cabinets are recommended during preparation and handling. 
7.2.3 
Preparation and Administration 
Cetuximab must not be administered as an i.v. push or bolus. 
Cetuximab must be administered with the use of a low protein binding 0.22-micrometer in-line 
filter. 
 
Cetuximab is supplied as a 50-mL, single-use vial containing 100 mg of cetuximab at a 
concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and 
colorless and may contain a small amount of easily visible white amorphous cetuximab 
particulates. DO NOT SHAKE OR DILUTE. 
 
Cetuximab can be administered via infusion pump or syringe pump. 
Infusion Pump: 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike or other appropriate transfer device may be used). 
2. Fill cetuximab into a sterile evacuated container or bag such as glass containers, 
polyolefin bags (e.g., Baxter Intravia), ethylene vinyl acetate bags (e.g., Baxter Clintec), 
DEHP plasticized PVC bags (e.g., Abbott Lifecare), or PVC bags. 

49 
RTOG 0920, Version Date: May 11, 2023 
 
3. Repeat procedure until the calculated volume has been put in to the container. Use a 
new needle for each vial. 
4. Administration must be through a low protein binding 0.22-micrometer in-line filter 
(placed as proximal to the patient as practical). 
5. Affix the infusion line and prime it with cetuximab before starting the infusion. 
6. Maximum infusion rate should not exceed 5 mL/min. 
7. Use 0.9% saline solution to flush line at the end of infusion. 
 
Syringe Pump: 
1. Draw up the volume of a vial using a sterile syringe attached to an appropriate needle 
(a vented spike may be used). 
2. Place the syringe into the syringe driver of a syringe pump and set the rate. 
3. Administration must be through a low protein binding 0.22-micrometer in-line filter rated 
for syringe pump use (placed as proximal to the patient as practical). 
4. Connect up the infusion line and start the infusion after priming the line with cetuximab. 
5. Repeat procedure until the calculated volume has been infused. 
6. Use a new needle and filter for each vial. 
7. Maximum infusion rate should not exceed 5 mL/min. 
8. Use 0.9% saline solution to flush line at the end of infusion. 
 
Cetuximab should be piggybacked to the patient’s infusion line. 
 
Following the cetuximab infusion, a one-hour observation period is required. 
7.2.4 
Adverse Events 
Cetuximab may be associated with significant toxicities, most commonly fatigue, skin 
rash/folliculitis and paronychia, and gastrointestinal effects, nausea and diarrhea. 
Hypomagnesia is common. Of greatest concern is the potential for an allergic reaction, possibly 
anaphylaxis; see Section 7.3 for details. 
 
Other adverse events: 
• 
Blood and lymphatic system: Anemia; 
• 
Ear and labyrinth disorders: External ear inflammation, tinnitus; 
• 
Eye disorders: Conjunctivitis, dry eye, uvelitis, watering eyes; 
• 
Gastrointestinal disorders: Diarrhea, nausea, abdominal pain, cheilitis, constipation, dry 
mouth, dyspepsia, oral mucositis, vomiting; 
• 
General disorders and administration site conditions: Fatigue, fever, chills, edema limbs, 
flu-like symptoms, infustion-related reaction, non-cardiac chest pain; 
• 
Metabolism and nutritional disorders: Anorexia, dehydration, hypocalcemia, 
hypomagnesemia; 
• 
Musculoskeletal and connective tissue disorders: arthralgia, back pain, myalgia; 
• 
Nervous system disorders: Headache, syncope; 
• 
Respiratory, thoracic, and mediastinal disorders: Allergic rhinitis, bronchospasm, cough, 
dyspnea, hoarseness, and rarely, pneumonitis and non-cardiogenic pulmonary edema; 
• 
Skin and subcutaneous tissue disorders: dry skin, rash acneiform, rash maculo-papular, 
alopecia, nail loss, photosensitivity, pruritus, purpura, skin ulceration, urticaria, and rarely, 
Palmar-plantar erythrodysesthesia syndrome; 
• 
Vascular disorders: hypotension, thromboembolic event. 
 
Note: Cetuximab in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
7.2.5 
Storage Requirements/Stability 
Store vials under refrigeration at 2 C to 8 C (36 F to 46 F). DO NOT FREEZE. Increased 
particulate formation may occur at temperatures at or below 0C. This product contains no 
preservatives. Preparations of cetuximab in infusion containers are chemically and physically 
stable for up to 12 hours at 2 C to 8 C (36 F to 46 F) and up to 8 hours at controlled room 
temperature (20 C to 25 C; 68 F to 77 F). Discard any remaining solution in the infusion 
container after 8 hours at controlled room temperature or after 12 hours at 2 to 8 C. Discard 
any unused portion of the vial. 

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RTOG 0920, Version Date: May 11, 2023 
 
7.2.6 
Supply 
Eli Lilly and Company (Eli Lilly) or its local affiliate will supply cetuximab free of charge to 
patients on study in the United States and Canada. The product is a sterile, clear, colorless 
liquid of pH 7.0 to 7.4, which may contain a small amount of easily visible, white, amorphous 
cetuximab particulates. Each single-use 50-mL vial contains 100 mg of cetuximab at a 
concentration of 2 mg/mL and is formulated in a preservative-free solution containing 8.48 
mg/mL sodium chloride, 1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42mg/mL 
sodium phosphate monobasic monohydrate, and Water for injection, USP. 
7.2.7 
Drug Ordering and Accountability 
Eli Lilly and Company (Eli Lilly) or its local affiliate will supply cetuximab free of charge to 
patients on study in the United States and Canada. In the U.S., the drug will be distributed by a 
vendor, Biologics/McKesson., under contract to NRG Oncology. Please see shipping timelines 
in the section below. In Canada, the drug will be distributed by Eli Lilly Canada. 
 
U.S. and Canadian Institutions 
All pre-registration requirements must be met before calling to register the first case.  
Institutions must electronically complete (versus hand write) a Study Agent Shipment Form 
(SASF) available on the CTSU website. U.S. and Canadian institutions must fax the SASF to 
the CTSU Regulatory Office via the Regulatory Submission Portalas soon as the individual 
responsible for the study agent has been identified. This must be done prior to registration of 
the institution’s first case. 
 
Biologics/McKesson will ship a patient-specific supply of cetuximab with enough quantity to 
complete protocol treatment for a 200-pound individual (58 vials) once the site has randomized 
the patient. Since doses are dependent on the patient’s BSA, sites can obtain additional per- 
patient supply for individuals over 200 pound by contacting Biologics/McKesson. It is possible 
that sites will have more than one cetuximab clinical study ongoing at the same time. It is 
imperative that only product designated for RTOG 0920 be utilized for this study. RTOG 0920 
product must be segregated from other investigational or marketed product. 
 
Cetuximab will be placed in a temperature controlled cooler with 3 pounds of gel packs. U.S. 
shipments will be sent via FedEx for Priority Overnight delivery for orders received 4 p.m. EST, 
Monday through Thursday. Orders received after 4 p.m. EST Monday through Thursday will be 
processed and shipped next business morning. For Canadian sites, Eli Lilly Canada will  
ship the drug. Sites should allow 10 business days to receive drug. 
 
Drug deliveries are restricted during weekends and holidays. Biologics/McKesson observes 
the following holidays: New Year’s Day, Memorial Day, July 4th, Labor Day, 
Thanksgiving Day and the Friday following Thanksgiving Day, Christmas Eve, and 
Christmas Day. 
 
Eli Lilly Canada observes the following holidays. Sites should plan ahead to 
accommodate patients being treated during restricted times. 
 
Event 
Date 
New Year’s Day 
January 1, Friday 
Family Day 
February 15, Monday 
Good Friday 
March 25, Friday 
Victoria Day 
May 23, Monday 
Canada Day 
July 1, Friday 
Eli Lilly Canada office closure 
July 4, Monday 
Civic Holiday 
August 1, Monday 
Labour Day 
September 5, Monday 
Thanksgiving 
October 10, Monday 
Christmas Day 
December 25, Sunday 
Boxing Day 
December 26, Monday 
Eli Lilly Canada office closure 
December 30, Friday 
 
Inside each shipping container will be a disposable electronic unit (TagAlert™) to ensure the 
product has remained at the appropriate temperature during shipping. This unit will be attached 

51 
RTOG 0920, Version Date: May 11, 2023 
 
to an information card. The LCD display will show OK (indicating no alarm has been triggered) 
or a black bar and the number(s) 1-4 (indicating an alarm/alarms have been triggered). Should 
an alarm be triggered, follow the instructions on the attached information card. Display results 
should be recorded on the packing list. For questions regarding drug requisitioning, contact 
Biologics/McKesson. 
 
Upon notification of a new patient enrollment in the U.S., Biologics/McKesson will place an 
outbound call to the site contact to confirm that the site’s shipment is being processed. 
Biologics/McKesson distribution team will monitor packages throughout the duration of transit 
via the FedEx web site and FedEx One Call Solution (live support). Real-time monitoring 
enables Biologics/McKesson to mitigate potential delivery delays. 
 
 
 
Questions about supply and delivery should be directed to: 
 
McKesson Specialty Health 
Clinical Research Services 
845 Regent Boulevard, Suite 100B 
Irving, TX 75093 
Email: clinicalresearchservices@mckesson.com 
Phone: Toll Free 800-693-4906 
Fax: 919-256-0794 
 
Non-Canadian International Institutions 
Please refer to your LOI Approval Notification. 
7.2.8 
Handling and Dispensing of Investigational Product 
Investigational product should be stored in a secure area according to local regulations.  It is 
the responsibility of the Investigator to ensure that investigational product is only dispensed to 
study patients. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
7.2.9 
Drug Destruction 
Opened vials must be disposed of at the site as chemotherapy or biohazardous waste, 
provided documented procedures for destruction are in place. At the completion of the study,  
all unused drugs will be destroyed at the site according to the institution's policy for drug 
destruction. It is the responsibility of the Investigator to ensure that a current record of 
investigational product disposition is maintained at each study site where investigational 
product is inventoried and disposed, including dates and quantities. If approved procedures for 
destruction are not in place and/or for questions regarding cetuximab destruction, please 
contact Biologics/McKesson at 800-693-4906. 
7.3 
Dose Modifications (23-JAN-2013) 
7.3.1 
Cetuximab Dose Levels 
 
Study Agent 
Starting Dose 
Dose Level –1 
Dose Level –2 
Cetuximab 
400 mg/m2 (week 1 
only) 
Cetuximab 
250 mg/m2 (weekly) 
200 mg/m2 
(weekly) 
150 mg/m2 (weekly) 
Note: If a weight change of ≥ 10% occurs, the cetuximab dose should be adjusted. 
 
7.3.2 
Cetuximab Dose Modifications for Hematologic Adverse Events 
Cetuximab will not be dose reduced or held for hematologic adverse events, such as 
neutropenia, neutropenic fever, or thrombocytopenia. 

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7.3.3 
Cetuximab Dose Modifications for Non-Hematologic Adverse Events 
 
Toxicity Grade 
(CTCAE, v. 4) 
Cetuximab Dose a 
Renal-Calculated 
Creatinine Clearance 
≥ 50 mL/min 
Maintain dose levels 
< 50 mL/min 
Maintain dose levels 
Fatigue (Asthenia) 
≥ Grade 3 
Maintain dose levels 
Nausea/Vomiting 
≤ Grade 2 with maximal 
medical management 
≥ Grade 3 with maximal 
medical management 
Maintain dose levels 
Hold drug until ≤ grade 2, then resume at same 
dose level or reduce by 1 dose level 
Other non-hematologic 
Adverse Events b, c 
Grade 4 (In the RT field, or possibly related 
to cetuximab, or likely to be exacerbated by 
continuation of cetuximab) 
Hold drug until ≤ grade 3, then resume at 1 dose 
level reduction 
Grades 2-4 (out of RT field that does not 
reverse to Grade 1 at time of treatment, or 
unrelated to cetuximab, or unlikely to be 
exacerbated by continuation of cetuximab) 
Maintain dose levels 
For grade 4 out of RT field toxicity, drug should be 
held until < grade 3 and then resumed at the same 
level or reduced by 1 dose level 
aDose levels are relative to the previous dose. Dose reductions of cetuximab below the –2 dose 
level will not be allowed. In any case of cetuximab treatment delay, there will be no re-loading 
infusion, and all subsequent treatment will be at the assigned dose level. 
bWith the exception of infusion reaction or acne-like rash (rash/desquamation); 
cFor depressed K or Mg, administer replacement therapy. Chemotherapy should continue at the 
discretion of the treating physician. (see table below for management of hypomagnesemia). 
 
Hypomagnesemia 
Electrolyte repletion, principally magnesium, was necessary in some patients treated with 
cetuximab and in severe cases, intravenous replacement was required. The time to resolution 
of electrolyte abnormalities is not well known, hence monitoring during and after cetuximab 
treatment is recommended: 
 
CTCAE, 
v. 4 Grade 
Serum Magnesium 
Guidelines for management 
Action 
mg/dL 
mmol/L 
1 
< LLN – 1.2 
< LLN – 0.5 
Consider replacement with IV 
magnesium sulphate 2-5 g in 
normal saline or D5W. Infusion 
schedule based on institutional 
guidelines. 
Maintain dose and 
schedule 
2 
< 1.2 – 0.9 
< 0.5 – 0.4 
As above for grade 1 and consider 
prophylactic weekly infusion of 
magnesium and/or oral 
magnesium supplementation (e.g. 
magnesium oxide) if grade 2 of 
higher hypomagnesemia persists. 
Maintain dose and 
schedule 
3 
< 0.9 – 0.7 
< 0.4 – 0.3 
As above for grades 1 and 2 
Hold cetuximab until 
recovery to < grade 2, 
then resume at same dose 
level or reduce by 1 dose 
level 
4 
< 0.7 
< 0.3 
As above for grades 1 and 2 
Hold cetuximab until 
recovery to < grade 2, 
then resume at same dose 
level or reduce by 1 dose 
level 

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7.3.4 
Cetuximab Infusion Reaction Management 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aStudy Therapy Retreatment Following Infusion Reactions: Once a cetuximab infusion rate has been 
decreased due to an infusion reaction, it will remain decreased for all subsequent infusions. If the subject has 
a second infusion reaction with the slower infusion rate, the infusion should be stopped, and the subject 
should receive no further cetuximab treatment. If a subject experiences a Grade 3 or 4 infusion reaction at any 
time, the subject should receive no further cetuximab treatment. If there is any question as to whether an 
observed reaction is an infusion reaction of Grades 1-4, the Study Chair or Medical Oncology Co-Chairs 
should be contacted immediately to discuss and grade the reaction. 
 
7.3.5 
Cetuximab Special Instructions 
If cetuximab is omitted for more than four consecutive infusions for adverse events due to 
cetuximab, or for an intercurrent illness (e.g., infection) requiring interruption of therapy, the 
subject should be discontinued from further cetuximab therapy. Cetuximab doses held due to 
toxicity should not be made up. If a cetuximab dose is missed for reasons unrelated to drug 
toxicity, then the missed dose may be made up at the discretion of the investigator, at the next 
appropriate time point according to Section 7.1.1. If adverse events prevent the administration 
of cetuximab, the subject may continue to receive radiation therapy. 
Management of Cetuximab Infusion Reactions 
Severe or life threatening (grade 3 or 4) infusion reactions require the immediate interruption 
of cetuximab therapy and permanent discontinuation from further treatment. Appropriate 
medical therapy including epinephrine, corticosteroids, intravenous antihistamines, 
bronchodilators, and oxygen should be available for use in the treatment of such reactions. 
Patients should be carefully observed until the complete resolution of all signs and 
symptoms. 
 
In clinical trials, mild to moderate infusion reactions were managed by slowing the infusion 
rate of cetuximab and by continued use of antihistamine pre-medications (e.g., 
diphenhydramine) in subsequent doses. If the patient experiences a mild or moderate 
CTCAE, v. 4 
Adverse Event Grade 
Treatment Guidelinesa 
Grade 1: 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
For mild infusion reactions manifesting only as delayed drug fever, consider 
administering prophylactic antihistamine medications for subsequent doses. 
Maintain the cetuximab dose, but slow the infusion rate by 50%. 
Acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) may be 
administered prior to subsequent cetuximab infusions, if not otherwise 
contraindicated in subjects. 
Grade 2: 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
For moderate infusion reactions manifesting only as delayed drug fever, slow 
the infusion rate for cetuximab by 50% and consider administering 
antihistamine medications and/or steroidal medications. Maintain the cetuximab 
dose. Acetaminophen or a non-steroidal anti-inflammatory drug (NSAID) may 
be administered prior to subsequent cetuximab infusions, if not otherwise 
contraindicated in subjects. 
Grade 3: 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for 
clinical sequelae 
Severe infusion reactions require immediate interruption of cetuximab 
infusion and permanent discontinuation from further treatment with 
cetuximab. Appropriate medical therapy including epinephrine, corticosteroids, 
diphenhydramine, bronchodilators, and oxygen should be available for use in 
the treatment of such reactions.  Subjects should be carefully observed until 
the complete resolution of all signs and symptoms. 
Grade 4: 
Life-threatening 
consequences; urgent 
intervention indicated 
NO FURTHER STUDY DRUG THERAPY. Life threatening infusion reactions 
require immediate interruption of cetuximab infusion and permanent 
discontinuation from further treatment with cetuximab. Appropriate 
medical therapy including epinephrine, corticosteroids, diphenhydramine, 
bronchodilators, and oxygen should be available for use in the treatment of 
such reactions. Subjects should be carefully observed until the complete 
resolution of all signs and symptoms. 

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(grade 1 or 2) infusion reaction, the infusion rate should be permanently reduced by 50%. 
For grade 1 or 2 reactions manifesting only as delayed drug fever, see below. 
 
Cetuximab should be immediately and permanently discontinued in patients who experience 
severe (grade 3 or 4) infusion reactions. 
 
Treatment of Isolated Drug Fever 
In the event of isolated drug fever, the investigator must use clinical judgment to determine if 
the fever is related to the study drug or to an infectious etiology. 
 
If a patient experiences isolated drug fever, for the next dose, pre-treat with acetaminophen 
or non-steroidal anti-inflammatory agent (investigator discretion), repeat antipyretic dose 6 
and 12 hours after cetuximab infusion. The infusion rate will remain unchanged for future 
doses. 
 
If a patient experiences recurrent isolated drug fever following pre-medication and post- 
dosing with an appropriate antipyretic, the infusion rate for subsequent dosing should be 
50% of previous rate. If fever recurs following infusion rate change, the investigator should 
assess the patient’s level of discomfort with the event and use clinical judgment to determine 
if the patient should receive further cetuximab. 
 
Cetuximab-related Rash 
➢ Manifestations 
Rash associated with EGFR-inhibitors is a relatively new dermatologic condition. It 
appears to be “acneiform” but it is NOT considered a form of acne; rather, it is a form of 
folliculitis. Skin changes may be manifested in a number of ways: erythema; follicle 
based papules, which may ulcerate; pain; itching; cosmetic disturbance; and/or nail 
disorders. The rash may become infected and transform into cellulitis. 
➢ Grading of Cetuximab-induced Rash 
According to physician judgment, if a patient experiences grade 3 rash (according to 
any of the terms below), cetuximab treatment adjustments should be made according 
to the Cetuximab Dose Modification table below. In patients with mild and moderate 
skin adverse events, cetuximab should continue without adjustment. 
 
NOTE: Rash intensity (i.e., the size and number of papules or the level of discomfort 
and extent of erythema) may be an important consideration. However, the absolute 
number of lesions, without associated physical discomfort, does not necessarily 
constitute a basis for a dose reduction or delay. Rash considered “intolerable”  
(because of pain, itching, or appearance) or that has failed to respond to symptomatic 
management may be considered grade 3 and thus prompt dose reduction or delay of 
cetuximab. The clinical judgment of the treating physician is critical to grading 
and will ultimately dictate dose modification. 
➢ Acute Skin Changes 
• Rash Occurring Outside of the Radiation Field: Should be graded using the 
following CTCAE, v. 4 terms. A rash complicated by secondary infection or cellulitis 
should be graded per additional CTCAE terms. 

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RTOG 0920, Version Date: May 11, 2023 
 
1 
2 
3 
4 
Pruritus* 
Mild of localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL 
- 
Rash/acneiform* 
Papules and/or 
pustules covering 
Papules and/or pustules 
covering 10-30% BSA, 
Papules and/or pustules 
covering >30% BSA, 
Papules and/or 
pustules 
<10% BSA, which 
which may or may not be 
which may or may not 
covering any % 
may or may not be 
associated with symptoms 
be associated with 
BSA, which may 
associated with 
of pruritus or 
symptoms of pruritus or 
or may not be 
symptoms of pruritus 
tenderness; associated 
tenderness; limiting self 
associated 
or tenderness 
with psychosocial impact; 
care ADL; associated 
with symptoms of 
limiting 
with local superinfection 
pruritus or 
instrumental ADLI 
with oral antibiotics 
tenderness and 
indicated 
are associated 
with extensive 
superinfection 
with IV antibiotics 
indicated; life 
threatening 
consequences 
Paronychia* 
Nail fold edema or 
erythema; disruption 
Localized intervention 
indicated; oral intervention 
Surgical intervention or 
IV antibiotics indicated; 
- 
of the cuticle 
indicated (e.g., antibiotic, 
limiting self 
antifungal, antiviral); 
care ADL 
nail fold edema or 
erythema with pain; 
associated with discharge 
or nail plate 
separation; limiting 
instrumental ADL 
*Onset of grade 3 will require modification. See the table below, ”Cetuximab Dose Modification Guidelines for 
Dermatologic Changes”. 
• Rash Occurring Inside the Radiation Field: Acute radiation dermatitis may be 
exacerbated by cetuximab or chemotherapy. The severity of such rash should be 
graded using CTCAE, v. 4 criteria for radiation dermatitis (table below). 
 
1 
2 
3 
4 
Radiation recall 
Faint erythema or 
Moderate to brisk 
Moist desquamation 
Life-threatening 
reaction 
dry desquamation 
erythema; patchy moist 
other than skin folds 
consequences; 
(dermatologic); 
desquamation, mostly 
and creases; bleeding 
skin necrosis or 
Dermatitis radiation 
confined to skin folds 
induced by minor 
ulceration of full 
− 
and creases; moderate 
edema 
trauma or abrasion 
thickness dermis; 
spontaneous 
bleeding from 
involved site; skin 
graft indicated 
 
➢ Late Skin Changes A potential late change of interest is consequential scarring/pock 
marking in or out of the radiation field. This may be reported by using the 
MedDRA code, “Skin and subcutaneous tissue disorders - Other, specify”, with the 
following protocol-specific grading scale as guidance: 
• Grade 1: Mild (seen only on close inspection) 
• Grade 2: Moderate (scarring, intervention or cosmetic coverage/intervention 
indicated) 
• Grade 3: Severe (significant disfigurement, deep scarring, or ulceration) 
• Grade 4: Deep cratering/scarring, skin necrosis, or disabling 

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Cetuximab Dose Modification Guidelines for Dermatologic Changes (≥ Grade 3) 
Cetuximab 
Outcome 
Cetuximab Dose 
Modification 
1st occurrence 
Delay infusion 1 to 2 
weeks 
Improvement to ≤ 
Grade 2 
Continue at 250 mg/m2 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
2nd occurrence 
Delay infusion 1 to 2 
weeks 
Improvement to ≤ 
Grade 2 
Reduce dose to 200 mg/m2 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
3rd occurrence 
Delay infusion 1 to 2 
weeks 
Improvement to ≤ 
Grade 2 
Reduce dose to 150 mg/m2 
No Improvement; 
remains grade 3 
Discontinue cetuximab 
4th occurrence 
Discontinue cetuximab 
 
Drug Related Rash Management 
Patients developing dermatologic adverse events while receiving cetuximab should be 
monitored for the development of inflammatory or infectious sequelae, and appropriate 
treatment of these symptoms initiated. Below are suggestions for managing cetuximab- 
induced rash*: 
▪ 
Antibiotics: The benefit of routine antibiotics in uncomplicated (uninfected) rash is 
unclear. Some clinicians have used oral minocycline (Minocin), mupirocin  
(Bactroban), or topical clindamycin (Cleocin). Rash complicated by cellulitis should be 
treated with appropriate antibiotics based on clinical judgment or microbial sensitivity 
analysis. 
▪ 
Antihistamines: Benadryl or Atarax may be helpful to control itching. 
▪ 
Topical Steroids: The benefit of topical steroids is unclear. 
▪ 
Retinoids: No data to support use. Use is not advised. 
▪ 
Benzoyl peroxide: Should NOT be used--may aggravate rash. 
▪ 
Makeup: Rash can be covered with makeup; this should not make it worse (use a 
dermatologist-approved cover-up, e.g., Dermablend, or any other type of foundation). 
Remove makeup with a skin-friendly liquid cleanser, e.g., Neutrogena, Dove, or Ivory 
Skin Cleansing Liqui-Gel. 
▪ 
Moisturizers: Use emollients to prevent and alleviate the skin dryness, e.g., 
Neutrogena Norwegian Formula Hand Cream or Vaseline Intensive Care Advanced 
Healing Lotion. 
▪ 
Sunlight: It is recommended that patients wear sunscreen and hats and limit sun 
exposure while receiving cetuximab as sunlight can exacerbate any skin reactions  
that may occur. 
▪ 
Over-the-counter medications: Over-the-counter acne vulgaris medications (e.g., 
benzoyl peroxide) are not advised. This rash is not like acne vulgaris and these 
treatments could make it worse. 
*Adapted from Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated 
rash: Future directions for management and investigation outcomes from the HER1/EGFR 
Inhibitor Rash Management Forum. The Oncologist. 10:345–356, 2005. 
7.4 
Modality Review (07-APR-2014) 
The Medical Oncology Co-Chair, Lillian L. Siu, MD, will perform a Systemic Therapy Assurance 
Review of all patients who receive or are to receive cetuximab in this trial. The goal of the review 
is to evaluate protocol compliance. The review process is contingent on timely submission of 
chemotherapy treatment data as specified in Section 12.1. The scoring mechanism is: Per 
Protocol, Not Per Protocol, and Not Evaluable. A report is sent to each institution once per 
year to notify the institution about compliance for each case reviewed in that year. 

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RTOG 0920, Version Date: May 11, 2023 
 
The Medical Oncology Co-Chair, Dr. Siu, will perform a Quality Assurance Review after complete 
data for the first 20 cases enrolled has been received at IROC Philadelphia. Dr. Siu will perform 
the next review after complete data for the next 20 cases enrolled has been received at IROC 
Philadelphia. The final cases will be reviewed within 3 months after this study has reached the 
target accrual or as soon as complete data for all cases enrolled has been received at IROC 
Philadelphia, whichever occurs first. 
7.5 
Adverse Events (26-JAN-2018) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for AE reporting. 
CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; all study 
case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should 
have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP 
web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be 
reported via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via 
either 
the 
CTEP 
web 
site 
(https://eapps- 
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet 
fails. Once internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
7.5.1 
Adverse Events (AEs) 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. Therefore, an AE can be any unfavorable  
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, unlikely, 
possible, probable, or definite). (International Conference on Harmonisation [ICH], E2A, E6). 
[CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm]. 
 
7.5.2 
Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited 
reporting criteria defined in the table in section 7.6 will be reported via CTEP-AERS. SAEs that 
require 24 hour CTEP-AERS notification are defined in the expedited reporting table in section 
7.6. Contact the CTEP-AERS Help Desk if assistance is required. 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results 
in any of the following outcomes: 
▪ 
Death; 
▪ 
A life-threatening adverse drug experience; 
▪ 
Inpatient hospitalization or prolongation of existing hospitalization; 
▪ 
A persistent or significant disability/incapacity; 
▪ 
A congenital anomaly/birth defect. 
▪ 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE drug experience, when, based upon  
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited manner. 
7.5.3 
Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment  
in patients on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system 
within 30 days of AML/MDS diagnosis. 

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RTOG 0920, Version Date: May 11, 2023 
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the 
event: 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified. 
7.6 
CTEP-AERS Expedited Reporting Requirements (25-JAN-2016) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table 
below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed 
via 
the 
CTEP 
web 
site, 
https://eapps- 
ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613. 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG 
Oncology’s requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve 
radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only 
pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to 
the NRG Oncology Operations Office at 1-800-227-5463, ext. 4189, for instances when Internet 
fails. Once internet connectivity is restored, an AE report submitted by phone must be entered 
electronically into CTEP-AERS. 
 
• 
CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
• 
Supporting source document is not mandatory. However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected. If supporting source documentation accompanies a CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to the NRG Oncology dedicated SAE FAX, 215-717-0990. 
• 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS as “expedited reporting NOT required” must still be 
reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS allows submission of all reports regardless of the 
results of the assessment. 
 
CTEP defines expedited AE reporting requirements for phase 2 and 3 trials as described in the 
table below. Important: All AEs reported via CTEP-AERS also must be reported on the AE 
section of the appropriate case report form (see Section 12.1). As of 2/1/16, NRG Oncology will 
submit all SAEs to Eli Lilly Global Patient Safety, FAX 866-644-1697 or 317-453-3402. 

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Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event 
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP- 
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days 
of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
NOTE: Deaths clearly due to progressive disease should NOT be reported via CTEP-AERS but rather should 
be reported via routine reporting methods (e.g., CDUS and/or CTMS). 

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RTOG 0920, Version Date: May 11, 2023 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements 
for Phase 2 and 3 Trials Utilizing an Agent under a Non-CTEP IND: 
Not applicable to this study. 
 
8.0 SURGERY (23-JAN-2013) 
8.1 
Intermediate Risk of Recurrence 
Patients must have been found to have an “intermediate” risk of recurrence (see Section 3.1.3) after 
having undergone gross total surgical resection with curative intent of the primary tumor of the oral cavity, 
oropharynx, or larynx (excluding lip, nasopharynx, or sinuses) within 7 weeks of registration. Patients with 
a positive margin by intraoperative frozen section during any part of the primary tumor resection are 
eligible for this study, provided that a subsequent negative margin supercedes this initially positive 
margin. Only patients with positive margins on final pathology would be excluded from this study. 
Concurrent neck dissection should be performed with patients initially staged cN1 and above. However, 
for cN0 patients, selective neck dissection may or may not be required. 
 
The following should be reported on the Operative Note (S2): 
• Documentation of whether a transoral versus “open” transcervical approach was used in 
assessing the primary tumor; 
• Documentation of how the neck was managed: excisional biopsy, superselective, standard 
selective neck, or modified radical; 
• Documentation of whether robotics or laser microsurgery was used for visualization of the 
primary tumor during surgery. 
8.2 
Surgical Quality Assurance Reviews 
The Surgical Oncology Co-Chair, Dr. Holsinger, will perform a modified Quality Assurance Review after 
complete data for the first 50 cases enrolled has been received at NRG Oncology. This quality assurance 
review will specifically examine the issues related to eligibility and the presence of intermediate risk of 
recurrence (see Section 3.1.3). No S1 case report form is required for this study. 
 
Dr. Holsinger will perform the next review after complete data for the next 50 cases enrolled has been 
received at NRG Oncology. The final cases will be reviewed within 3 months after this study has reached 
the target accrual or as soon as complete data for all cases enrolled has been received at NRG 
Oncology, whichever occurs first. 
 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the discretion of the 
attending physician(s) within the parameters of the protocol and documented on each site’s source 
documents as concomitant medication. These may include analgesics, anti-emetics, topical mouth rinses, 
skin creams/ointments, etc. The use of amifostine as a radioprotector is not allowed. The use of 
granulocyte colony-stimulating factor or erythropoietin is not allowed. Any exceptions must be approved by 
the Principal Investigator, Dr. Machtay, or Medical Oncology Co-Chair, Dr. Siu. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION (07-APR-2014) 
10.1 
Tissue/Specimen Submission (07-APR-2014) 
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved 
through careful block storage and processing. NRG Oncology encourages participants in protocol 
studies to consent to the banking of their tissue. The NRG Oncology Biospecimen Bank provides 
tissue specimens to investigators for translational research studies. Translational research 
studies integrate the newest research findings into current protocols to investigate important 
biologic questions. Note: The NRG Oncology Biospecimen Bank will provide collection kits and 
instructions at no charge for the submission of specimens in this protocol. 
 
In this study, it is required that tissue will be submitted to the NRG Oncology Biospecimen Bank 
for the purpose of EGFR analysis and HPV assay for oropharyngeal carcinomas. In addition, it is 
highly recommended (but optional) that fresh and archival tissues and blood be submitted for 
banking for future translational research. The NRG Oncology Biospecimen Bank provides tissue 
specimens to investigators for approved studies. Translational research studies integrate the 
newest research findings into current protocols to investigate important biologic questions. 

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RTOG 0920, Version Date: May 11, 2023 
 
10.2 
Tissue Collection for EGFR: Required (13-NOV-2017) 
Patients must consent to participate in submission of tissue for EGFR expression levels. 
 
Tissue from a biopsy or surgical specimen will be obtained, formalin fixed, and paraffin  
embedded in tissue blocks. Institutions must ship tissue blocks from patients to the NRG 
Biospecimen Bank by overnight courier. Prepaid Federal Express Labels can be requested from 
the Biospecimen Bank for this purpose (see Section 10.5 for contact information). Upon 
determination that the specimen is adequate, 2 unstained sections will be sent to the Pathology 
Co-Chair, Dr. Adel El-Naggar, for quantitative analysis of EGFR by immunohistochemistry. EGFR 
analysis results are expected in approximately 7-8 business days. The specific hypothesis is that 
the relative improvement in disease-free survival (DFS) will be similar for patients with high 
(defined as ≥ 80% of cells staining positive for EGFR) or low (defined as < 80% of cells staining 
positive) EGFR expression. However, the absolute values for DFS will be significantly greater for 
patients with low EGFR expression. Physicians or institutions can request the patient’s EGFR 
level from NRG Oncology (215-574-3154 or 215-574-3170) after the patient has completed study 
treatment. 
 
Institutions that are unable to submit a tissue block for the required EGFR analysis (and for 
patients with oropharyngeal carcinoma, the required HPV analysis) may instead take 6 unstained 
sections from the block then obtain three 3 mm core punches of the block and re-imbed the core 
punches into a recipient paraffin for submission. Institutions can request an FFPE specimen plug 
kit (see Appendix V) from the NRG Oncology Biospecimen Bank free of charge for this purpose: 
415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
If an institution is uncomfortable with obtaining the unstained sections and punches and wants to 
retain the tissue block, the site can send the entire block to the NRG Biospecimen Bank, and the 
Bank will obtain the unstained sections and the core punches from the block and return the 
remaining block to the site. Please indicate this request (to obtain the sections, perform the core 
punch procedure, and return the block) on the submission form. Note: For oropharyngeal 
carcinoma patients, there is a 10-day turnaround needed for HPV assays, so institutions should 
send the block by overnight courier to the Biospecimen Bank as soon as possible with their 
request. 
 
The following material must be provided to the NRG Biospecimen Bank for EGFR expression: 
10.2.1 
Representative H & E stained slides (slides can be duplicate cut stained H&E; does not have to 
be diagnostic slide). 
10.2.2 
Corresponding Tissue Block (the block must match the H&E diagnostic slide) 
• 
A Pathology Report documenting that the submitted block contains tumor; the report must 
include the NRG Oncology protocol number and patient’s case number. The patient’s name 
and/or other identifying information should be removed from the report. The surgical 
pathology numbers and information must NOT be removed from the report. 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
• 
A copy of the gross description of the tumor must accompany the specimen in order to 
evaluate the closest margin and distance. 
• 
A Specimen Transmittal (ST) Form stating that the tissue is being submitted for central 
review. 
Sites 
can 
access 
the 
form 
(no 
password 
required) 
at 
http://www.rtog.org/members/forms/list.html (under “Pathology”). The form must include the 
NRG Oncology protocol number and the patient’s case number. If the patient is also 
enrolled on other NRG Oncology trials, this should be indicated on the form. 
• 
EGFR analysis will be performed for every case by the Pathology Co-Chair, Adel El- 
Naggar. 

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RTOG 0920, Version Date: May 11, 2023 
 
10.3 
Tissue Collection for HPV Analysis: Required (05-OCT-2011) 
Patients with oropharyngeal carcinoma must consent to participate in use of submitted 
tissue for HPV analysis by p16 immunohistochemistry. 
 
For patients with oropharyngeal carcinoma, the NRG Oncology Biospecimen Bank will process 4 
unstained sections from the tissue block (submitted for EGFR analysis) and will send the sections 
to Dr. Adel El-Naggar who will determine HPV status by p16 immunohistochemistry within 7-10 
business days. Specific hypotheses include: 1) HPV negative patients will have greater absolute 
benefit from the addition of cetuximab compared to HPV positive patients because HPV positive 
patients have an extremely good prognosis and the addition of cetuximab in the postoperative 
adjuvant setting may not add more benefit to RT alone; 2) HPV positivity will associate with low 
EGFR expression because the HPV positive tumors may not be driven by EGFR but by viral 
oncogene E6/E7 causing the loss of p53 and Rb; 3) EGFRvIII will associate with HPV negativity 
and treatment failure due to ligand-independent constitutive activation of the receptor, escaping 
the effects of cetuximab. Physicians or institutions can request the patient’s HPV status from 
NRG Oncology (215-574-3154 or 215-574-3170) after the patient has completed study treatment. 
10.4 
Specimen Collection for Tissue Banking and Translational Research: Highly Recommended (But 
Optional) (13-NOV-2017) 
Patients must be offered the opportunity to participate in the tissue/specimen collection for 
banking and translational research. If the patient consents to participate in this component, the 
site is required to submit the patient’s specimens as specified below. Note: Sites are not 
permitted to delete the tissue/specimen component from the protocol or from the sample consent 
form. 
10.4.1 
Peripheral Blood: Plasma, Serum, and Whole Blood 
Note: Blood for research should be collected prior to the start of treatment (radiation therapy 
alone OR radiation + cetuximab) (see Appendix I). 
 
The following materials need to be provided to the NRG Oncology Biospecimen Bank: A 
Specimen Transmittal Form documenting the date of collection of the biospecimen; the NRG 
Oncology protocol number, the patient’s case number, time point of study, and method of 
storage (for example, stored at -80° C) must be included. 
 
A blood collection kit can be obtained free of charge from the Biospecimen Bank. See 
Appendix VI for detailed collection instructions, including information pertaining to the 
blood collection kit. Note: The kit includes a shipping label. 
 
Storage Conditions 
Store frozen specimens at –80 C (-70C to -90C) until ready to ship. If a -80C Freezer is not 
available: 
• Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to  
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out 
Monday-Wednesday only Canada: Monday-Tuesday). 
OR: 
• Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only 
Canada: Monday-Tuesday). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
10.4.2 
Translational Research: TP53 Mutations and EGFR Intron 1 
A recent study by Poeta, et al. (2007) has shown that patients with TP53 mutations have poor 
overall survival and time to disease progression compared to patients with TP53 wild type after 
surgical resection. We will determine the TP53 mutation status in this study to validate the 
association and to further the effort of clinical implementation of this assay and stratification of 
risks based on biology of the tumors. 
 
There is evidence that the length of the repeats in EGFR Intron 1 may be prognostic and 
predictive of outcomes after standard of care and EGFR inhibitor treatments (Press 2008; Liu 
2003; Han 2007). We will examine the CA dinucleotide repeats in EGFR intron 1 and 
associations with poor overall survival and time to disease progression. By studying a diverse 

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NRG Oncology patient population of mixed sex and race, the prognostic and predictive nature 
of this polymorphic variant can be further defined and validated. In addition, we will determine 
whole genome-wide single nucleotide polymorphism (SNP) in these patients using Affymetrix 
SNP chips to associate other polymorphic variants with response and toxicities as exploratory 
studies. 
10.4.3 
Summary of Specimens for Tissue Banking and Translational Research 
 
Specimens taken from patient: 
Submitted as: 
Shipped: 
One H&E stained slide of the 
primary tumor 
H&E stained slide: Must match 
block or unstained slides 
submitted 
Slide shipped ambient to 
NRGBB-SF 
Formalin-fixed paraffin embedded 
tumors 
Tissue block. If a block is not 
available then 10 unstained slides 
(5 micron cut onto positively 
charged slides) 
Blocks/slides sent ambient 
SERUM: 5-10 mL of whole blood in 1 
red-top tube and centrifuge 
Frozen serum samples containing 
minimum of 0.5 mL per aliquot in 1 
mL cryovials (five) 
Serum sent frozen on dry 
ice via overnight carrier to 
NRGBB-SF in batch 
shipments 
PLASMA: 5-10 mL of anticoagulated 
whole blood collected in EDTA tube#1 
(purple/lavender top) and centrifuge 
Frozen plasma samples containing a 
0.5 mL per aliquot in 1 mL cryovials 
(five to ten) 
Plasma sent frozen on dry ice 
via overnight carrier 
Whole blood for DNA: 5-10 mL of 
anticoagulated whole blood in 
EDTA tube #2 (purple/lavender top) 
and mix 
Frozen whole blood samples 
containing 1-2 mL per aliquot in 12 
mL cryovials (three) 
Whole blood sent frozen on 
dry ice via overnight carrier to 
NRGBB-SF in batch 
shipments 
Note: Blood for research should be collected prior to the start of treatment (radiation therapy 
alone OR radiation + cetuximab) (see Appendix I). 
 
10.5 
Submission of materials for Tissue Banking and Translational Research (13-NOV-2017) 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank—San Francisco 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Frozen Specimens 
NRG Oncology Biospecimen Bank—San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
10.6 
Reimbursement (03-NOV-2014) 
NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the 
requirements/methods specified by the new National Clinical Trials Network (NCTN) Program. This 
information will be made available with the other registration materials in the Oncology Patient Enrollment 
Network (OPEN) portal system. 
10.7 
Confidentiality/Storage (05-OCT-2011) 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspxfor 
further details.) 
10.7.1 
Upon receipt, the specimen is labeled with the NRG Oncology protocol number and the 
patient’s case number only. The NRG Oncology Biospecimen Bank database only includes the 
following information: the number of specimens received, the date the specimens were 
received, documentation of material sent to a qualified investigator, type of material sent, and 

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the date the specimens were sent to the investigator. No clinical information is kept in the 
database. 
10.7.2 
Specimens for tissue banking will be stored for an indefinite period of time. Specimens for 
central review will be retained until the study is terminated. Specimens for the translational 
research component of this protocol will be retained until the specimen is consumed/exhausted 
or study is terminated, unless the patient has consented to storage for future studies. If at any 
time the patient withdraws consent to store and use specimens, the material will be returned to 
the institution that submitted it. 
 
11.0 
PATIENT ASSESSMENTS 
11.1 
Study Parameters (06-DEC-2010): See Appendix I for a summary of assessments and time frames. 
11.1.1 
Gross total resection/surgical pathology must be completed within 7 weeks prior to registration. 
11.1.2 
A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be done 
within 8 weeks prior to registration. 
11.1.3 
An examination by an ENT or Head & Neck Surgeon must be done within 8 weeks prior to 
registration. A laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is 
recommended but not required. 
11.2 
Evaluation During Radiotherapy (08-MAR-2018) 
11.2.1 
A general history & physical by a Radiation Oncologist and/or Medical Oncologist must be done 
weekly. 
11.2.2 
Arm 2 patients must have Na, K, Cl, glucose, Ca, Mg, and albumin testing every 3 weeks 
during radiation therapy, every 3 weeks after radiation therapy is completed, and during 
maintenance cetuximab infusion (weeks 8-11, and then every 3 weeks after the last dose of 
cetuximab, for a total of 9 weeks (weeks 12-20). 
11.2.3 
Biopsy of any lesion(s) suspicious for tumor recurrence is urged. 
11.2.4 
Arm 2 patients should have serum creatinine or creatinine clearance, AST or ALT, and bilirubin 
every 3 weeks after radiation therapy is completed, and during maintenance cetuximab infusion 
(weeks 8-11). 
11.3 
Evaluation in Follow Up (07-APR-2014) 
11.3.1 
A general history and physical by one of the following: a Radiation Oncologist, Medical 
Oncologist, an ENT, or a Head and Neck Surgeon must be done at 1 and 3 months post-XRT, 
then q3 months for 2 years, every 6 months for 3 years, then annually. A 
laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is recommended at 
these time points but is not required. 
11.3.2 
Chest imaging (at minimum a chest x-ray or chest CT or CT/PET of chest) is required once per 
year for a total of 5 image sets. 
11.3.3 
Biopsy of any lesion(s) suspicious for tumor recurrence is urged. 
11.4 
Outcomes Criteria 
11.4.1 
No evidence of disease (NED): All patients must have not measurable tumor following surgery. 
11.4.2 
Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable 
to a second primary neoplasm; both imaging and biopsy confirmation are strongly 
recommended. LRR will be further subdivided into three subcategories: 
In-Field Local-Regional Relapse 
Review of the imaging of the local-regional relapse and the patient’s previous IMRT 
treatment data reveals that the “epicenter” of the local-regional relapse is within CTV60 and 
received an estimated dose of at least 50 Gy. 
 
Marginal Local-Regional Relapse 
Review of the imaging of the local-regional relapse and the patient’s previous IMRT 
treatment data reveals that the “epicenter” of the local-regional relapse was “near” CTV60. 
This is defined as an estimated dose to this region that is between 20 and 50 Gy. 
 
Out-of-Field Local-Regional Relapse 
Review of the imaging of the local-regional relapse and the patient’s previous IMRT 
treatment data reveals that the “epicenter” of the local-regional relapse was not near CTV60 
or CTV56 and received an estimated dose < 20 Gy. An example would be recurrence in the 
retropharyngeal nodal space for a patient with oral cavity cancer. 
11.4.3 
Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); biopsy is 
recommended where possible. A solitary lung mass/nodule should be considered a second 
primary upper aerodigestive neoplasm unless proven otherwise. If there is any question 

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whether or not a malignancy is a recurrence of the original primary cancer versus a new 
primary, contact the Principal Investigator, Dr. Machtay. 
11.4 4 Second Primary Neoplasm: All second primary neoplasms will be biopsy proven with 
documentation of specific histology. Modified rigorous criteria for a second primary (below) 
have been adapted from the definition by Warren and Gates (1932). Localized non-melanoma 
skin cancers are not considered new primary tumors. 
• 
A distinct lesion separated from the primary tumor site by > 2 cm of normal epithelium; 
• 
A new cancer with different histology; 
• 
Any cancer, regardless of head and neck mucosal subsite, occurring 5 or more years after 
initial treatment; 
• 
In the lung, new primary tumors, if squamous cell cancer, must have histologic findings of 
dysplasia or CIS. 
11.4.5 Second Primary Upper Aerodigestive Neoplasm: The  emergence  of  a  new,  invasive  
malignancy in the upper aerodigestive tract as a second primary should be documented. These 
neoplasms include lung cancer, esophageal cancer (including GE junction cancer), or 2nd 
primary head and neck cancer that is clearly remote from the index cancer (e.g., pyriform sinus 
cancer developing in a patient whose original diagnosis was tongue cancer). If there is any 
question whether or not a malignancy is a recurrence of the original primary cancer versus a 
new primary, contact the Principal Investigator, Dr. Machtay. 
11.5 
Quality of Life and Functional Assessments (25-JAN-2016) 
The assessments will be completed prior to the start of treatment (baseline) and at 3, 12, and 24 
months from the end of RT. 
11.5.1 
The Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) is a 
multidimensional, patient-self report quality of life (QOL) instrument specifically designed and 
validated for use with head and neck patients. The patient can complete the assessment in 5- 
10 minutes. The site research nurse or CRA is encouraged to be sensitive to each patient's 
demeanor. If patients appear particularly uncomfortable answering a question, they will be 
informed that they can skip that question. Similarly, interviewers will give patients a short break 
if the patient appears fatigued or otherwise in need of a few minutes break. 
11.5.2 
The Performance Status Scale for Head and Neck Cancer (PSS-HN) consists of assessment of 
three functional areas (subscales): Normalcy of Diet, Eating in Public, and Understandability of 
Speech. The site research nurse or clinical research associate (CRA) will administer the PSS- 
HN. Interviewers are encouraged to be sensitive to each patient's demeanor. If patients appear 
particularly uncomfortable answering a question, they will be informed that they can skip that 
question. Similarly, interviewers will give patients a short break if the patient appears fatigued  
or otherwise in need of a few minutes break. The interviewer rates the patient on each scale 
based on the patient’s responses to targeted questions. The PSS-HN takes approximately 5 
minutes to complete. 
11.5.3 
The EuroQol (EQ-5D) has been frequently used in cooperative group studies as a general QOL 
measure and for cost-utility analysis It is a two-part questionnaire that the patient can complete 
in approximately 5 minutes. The site research nurse or CRA should encourage the patient not 
to skip questions on the EQ-5D or take breaks during the completion of this questionnaire, as 
this will invalidate the assessment. If this occurs, sites will document it on the HP case report 
form. 
11.5.4 
The University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) consists of 15 
items covering four major domains of oral health-related quality of life: physical functioning, 
personal/psychological functioning, social functioning, and pain/discomfort issues. The patient 
can respond to the 15 items in the scale in approximately 5 minutes. The Scale is only  
available in English. 
11.5.5 
The Dermatology Life Quality Index (DLQI) consists of 10 items and covers 6 domains  
including symptoms and feelings (e.g., felt itchy, sore, painful, embarrassed), daily activities, 
leisure, work and school, personal relationships, and treatment. Response categories include 
"not at all," "a little," "a lot," and "very much," with corresponding scores of 0, 1, 2, and 3 
respectively; the response "not relevant" (and unanswered items) are scored as "0".Items A 
total score is calculated by summing the score of all items, resulting in a maximum score of 30 
and a minimum score of 0. Scale scores are calculated for each domain. Higher scores indicate 
poorer HRQL (i.e., more impairment). The patient can complete the DLQI in approximately 5 
minutes. 
11.5.6 
Optional Online Completion of QOL Assessments 

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Patients who consent to participate in the quality of life (QOL) component of this study have the 
option of completing QOL forms online from any location, including home, via VisionTree 
Optimal Care (VTOC). The baseline QOL forms must be completed in hardcopy at the time of 
enrollment, but all subsequent QOL forms can be completed by the patient online. Patients 
without e-mail or Internet access can participate in the QOL component of the study by 
completing hardcopy (paper) forms. Indeed, at any time, any patient may choose to fill out their 
QOL form using the hardcopy form. The QOL forms completed via VTOC are identical to the 
hardcopy forms; this technology does not add to or change the QOL assessments in this study. 
 
If the patient wishes to complete QOL assessments online, the patient must have an e-mail 
address that they consent to use for this purpose. Patients’ e-mail addresses are necessary so 
that e-mail reminders may be sent to them to remind them to fill out QOL forms that are due. 
The patient’s e-mail address also will be used for password-protected access to VisionTree 
Optimal Care (VTOC), Patients who are interested in participating but do not yet have an e-mail 
address can obtain one for free from a number of sources (e.g.,Yahoo!, Hotmail, or AOL).  
Note: The site RA is responsible for setting up the patient’s account on VTOC. The RA may do 
so by logging on the VTOC portal at the following link: https://rtog.optimalcare.com - medical 
team. RA login information will be provided by VTOC after the patient is randomized to the 
study. The patient’s VTOC account must be set up within 14 days after randomization. 
 
VTOC will send patients e-mail reminders to complete QOL forms.. The first reminder will be 
sent at the beginning of the window for completion of the form, with a second reminder sent 
halfway through the window, if the form has not yet been completed. A maximum of 3 
reminders will be sent for each of the 4 QOL assessment time points. After the patient has 
completed all forms, a dialogue box will appear thanking the patient for completing the QOL 
form(s), and the patient will no longer receive reminders for that time point. 
 
Site Research Associates (RAs) will receive training in the use of VTOC via NRG Oncology 
webinars and educational sessions. The RA or study administrator will be informed via the 
VTOC “At a Glance” form management system when QOL forms have been completed or  
when the window for a particular form has closed. If the site RA receives a notice that forms 
have not been completed, she or he will contact the patient to remind the patient to fill out the 
QOL form or inquire why the forms have not been completed. The RA will complete the cover 
page for each form that was not completed (either via VTOC or in hardcopy) and will submit the 
cover page to NRG Oncology (see Section 12.1). 
 
11.6 
Criteria for Discontinuation of Protocol Treatment (23-JAN-2013) 
▪ 
Unacceptable toxicity; see Sections 6.9 and 7.3 for further information. 
▪ 
Progression of disease; 
▪ 
Development of a 2nd primary upper aerodigestive tract malignancy (e.g., lung cancer, 
esophagus cancer, 2nd primary head and neck cancer); 
▪ 
A delay in protocol treatment, as specified in Section 7.3. 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
 
12.0 
DATA COLLECTION (11-MAY-2023)                      
 
Data should be submitted electronically via the NRG Oncology/RTOG web site, www.rtog.org. 
Patients will be identified by initials only (first middle last); if there is no middle initial, a hyphen will be 
used (first-last). Last names with apostrophes will be identified by the first letter of the last name. 

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12.1 
Summary of Data Submission (07-APR-2014) 
 
Item 
Due 
Demographic Form (A5) 
Initial Evaluation Form (I1)* 
Operative Note (S2) 
Surgical Pathology Report (S5) 
Pathology Report [biopsy report] (P1) 
Slides/Blocks (P2) 
Functional Assessment of Cancer Therapy-H &N 
[FACT] (FA) 
Performance Status Scale for H & N Cancer [PSS- 
HN] (QP) 
EuroQol [EQ-5D] (HP) 
University of Michigan Xerostomia-Related Quality 
of Life Scale [XeQOLS] (L4) 
Dermatology Life Quality Index [DLQI] (DL) 
Within 2 weeks of study entry 
 
 
 
 
 
Note: QOL forms completed online will be stored 
on the VisionTree, Inc. web site and transferred to 
NRG Oncology. 
 
Treatment Form (TF)* 
Arm 2: At the completion or discontinuation of 
cetuximab 
 
Initial Follow-up Form (F0)* 
Within 1 week of end of RT 
 
 
 
Follow-up Form (F1)* 
From completion of RT, q3 months for 2 years, q6 
months for 3 years, then annually; also at death 
 
[FACT] (FA) 
[PSS-HN] (QP) 
[EQ-5D] (HP) 
[XeQOLS] (L4) 
[DLQI] (DL) 
At 3, 12, and 24 months from the end of RT 
 
Note: QOL forms completed online will be stored 
on the VisionTree, Inc. web site and transferred to 
NRG Oncology. 
 
 
QOL Forms Cover Sheets 
Within 1 month of the QOL form being due (Note: 
Completed only if the patient did not complete a 
specific QOL form or if the patient completed a 
hardcopy of the form. 

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12.2 
Summary of Dosimetry Digital Data Submission (Submit to TRIAD; see Section 5.4 for account 
access and installation instructions.) (13-NOV-2017) 
 
Item 
Due 
Preliminary Dosimetry Information (DD) 
 
Digital data submission includes the following: 
• 
DICOM CT Image 
• 
DICOM Structure 
• 
DICOM Dose 
• 
DICOM RT Plan 
• 
All required structures MUST be labeled per the table in Section 6.6. 
• 
Submit via TRIAD with the digital data listed above. 
Upon submission of the digital data via TRIAD, complete a Digital Data 
Submission Information form (DDSI) located at 
  www.irocqa.org/Resources/TRIAD-for-RT-QA 
Within 1 week of 
start of RT 
 
IGRT Submission via TRIAD (see Section 6.7.1 for details) 
Within 1 week of 
IGRT images obtained on first day of treatment (IG) 
One IGRT image data set per week of treatment (IG) 
IGRT Data Collection Spreadsheet on daily variances (SG) 
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND/OR DIGITAL FILM IMAGES 
WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
RT end 
 
Final Dosimetry Information 
Within 1 week of 
Radiotherapy Form (T1) via web 
Daily Treatment Record (T5) [copy to HQ only] 
RT end 
 
 
13.0 
STATISTICAL CONSIDERATIONS (23-JAN-2013) 
13.1 
Primary Endpoint 
Overall survival (OS) 
13.2 
Secondary Endpoints 
• 
CTCAE, v. 4 adverse events: dysphagia, dry mouth, and skin and their relationships with patient- 
reported outcomes at 3 months; 
• 
CTCAE, v. 4 adverse events: dysphagia, dry mouth, and skin and their relationships with patient- 
reported outcomes at 12 and 24 months; 
• 
Other CTCAE, v. 4 acute ( 90 days from start of RT) adverse events; 
• 
Other CTCAE, v. 4 late (> 90 days from start of RT) adverse events; 
• 
Disease-free survival (DFS). 
13.3 
Tertiary Endpoints (Exploratory) (06-DEC-2010) 
• 
Local-regional control; 
• 
Quality of life as measured by Functional Assessment of Cancer Therapy-Head & Neck (FACT- 
HN) at baseline and 3, 12, and 24 months from end of RT; 
• 
Xerostomia as measured by University of Michigan Xerostomia-Related Quality of Life Scale 
(XeQOLS) at baseline and 3, 12, and 24 months from end of RT; 
• 
Swallowing as measured by the normalcy of diet subscale in Performance Status Scale for Head 
and Neck Cancer (PSS-HN) at baseline and 3, 12, and 24 months from end of RT; 
• 
Quality of life measured as measured by the EuroQol (EQ-5D) at baseline and 3, 12 and 24 
months from end of RT; 
• 
Skin toxicity as measured by the Dermatology Life Quality Index (DLQI) at baseline and 3, 12, 
and 24 months from end of RT. 

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13.4 
Background and Sample Size Determination 
13.4.1 
Background and Sample Size Determination for Cetuximab Question 
The target study population for this trial includes, but is not limited to, all patients that would 
have been eligible for either the RTOG 9501 or the EORTC 22931 trials, except for patients 
with positive margins and/or extracapsular extension (ECE). The subset of patients with 
positive margins and/or ECE did exceedingly poor in terms of efficacy outcomes and is 
excluded from this trial. The primary hypothesis is that the addition of cetuximab to 
postoperative radiation therapy (RT) will improve overall survival (OS) when compared to RT 
alone. A secondary endpoint includes a comparison of disease-free survival (DFS) and a 
tertiary (exploratory endpoint includes a comparison of local-regional control (LRC). The 
survival experience for patients who did not have either positive margins or ECE and were 
treated with postoperative RT on the RTOG 9501 and EORTC 22931 trials will be used as an 
estimate for the control arm. In RTOG 9501, there were 94 such patients; 45 of those patients 
have died. Their estimated yearly hazard rate based on a 3-year Kaplan-Meier (1958) survival 
estimate was 0.1697 with a 95% confidence interval (CI) [0.1183, 0.2304]. In EORTC 22931, 
there were 56 such patients; 23 of those patients have died. Their estimated yearly hazard rate 
based on a 3-year Kaplan-Meier survival estimate was 0.1654 (0.1002, 0.2466). For planning 
purposes, the survival rate for the control arm will be assumed to follow an exponential 
distribution with a yearly hazard rate for OS of 0.1697. The results from the completed Bonner 
phase III trial show that there was a 26% reduction in the risk of death rate when cetuximab 
was given before and concurrently with RT without cisplatin (Bonner 2006). Therefore, this 
study will test for a similar effect for cetuximab when given in conjunction with postoperative RT 
in reducing the death rate. 
 
The statistical software EaST for group sequential design was used for calculating the sample 
size with the Haybittle-Peto boundary for efficacy where the 3 interim significance levels were 
set at 0.005; then the significance level 0.0183 for the final analysis was derived in order to 
preserve a 0.025 significance level for the entire study. Futility will be tested using the lower 
boundary based on testing the alternative hypothesis at 0.005 level and because it was shown 
to have very little effect on the type I error, there will be no adjustment made to the sample size 
(Freidlin 2002). 
 
Three hundred seven-two deaths will be required to detect a 26% reduction in the death rate 
with 80% statistical power using a 1-sided test at the 0.025 significance level with 3 interim 
tests. Six hundred thirty-four patients accrued over 6.6 years will be required. Adjusting by 
approximately 10% to allow for ineligibility and lack of data, the total sample size required  
will be 700 patients. The maximum study duration, including follow-up requirements, under  
the above constraints is 9.6 years, if the 3-year survival rate for the control arm is 60.1%. 
 
In addition, a subset analysis using only HPV negative (HPV-) patients will compare the 
treatment arms. Patients with an oropharyngeal primary site who are either HPV positive 
(HPV+) or have unknown HPV status will be excluded in this analysis. Patients with a primary 
site other than oropharyngeal will be assumed to be HPV- because of the exceedingly low 
reported prevalence rate of HPV. It is estimated from RTOG 9501 and the EORTC trials that 
35% of patients will be entered on RTOG 0920 with an oropharyngeal primary. In the 
completed ECOG trial, 23991, prospectively evaluating HPV status, 61% of the patients with an 
oropharyngeal primary were HPV+, and in the completed trial, RTOG 0129, the preliminary 
results from a retrospective review of HPV status in 122 oropharyngeal patients show a 63% 
incidence of HPV+ patients (Pajak 2008). The assumption will be made for analyses that all 
patients with non-oropharyngeal primaries are HPV negative (HPV-). In light of these data, it is 
projected that 20% of the RTOG 0920 study population will be HPV+. Restricted to the 508 (= 
0.80 * 634) HPV- patients, there will be 80% statistical power to detect a 28% reduction in the 
OS failure rate using a 1-sided test at the 0.025 significance level, assuming that the trial is not 
reported earlier. This subset analysis will be done when there are 294 deaths among the HPV- 
patients. If the hazard rate for the control arm is approximately the same for HPV- patients as it 
is for all patients, 294 deaths are projected to occur for the subset analysis, approximately at 
the same time as the 372 deaths have occurred for the final treatment analysis of the entire 

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population. However, the hazard rate for HPV- patients is expected to be higher and thus, the 
subset analysis certainly can be performed at the same time as the “definitive” protocol 
treatment analysis. 
13.4.2 
Background and Statistical Power Determination for Evaluating the Addition of IGRT to IMRT 
The yearly failure rate for the endpoint LRC in patients who did not have either positive margins 
or ECE and were treated with postoperative RT on the RTOG 9501 trial will be used as an 
estimate for the patients treated with IMRT but without IGRT (Table 1 below). For planning 
purposes, the following assumptions will be made to simplify the calculations: 
1. The use of IMRT would not appreciably change the LRC rates observed in RTOG 9501 
with RT; 
2. The addition of cetuximab to postoperative RT will not appreciably change the LRC 
rates; 
3. The yearly LRC failure rates in Table 1 will be used. 
 
Table 1: Estimated Yearly Local-Regional Failure Rates 
 
Year 
Projected RTOG 0920 IMRT Alone 
Observed RTOG 9501 RT Alone 
1 
13.5% 
13.0% 
2 
13.5% 
13.4% 
3 
4.0% 
4.7% 
4 
4.0% 
3.5% 
5+ 
0.1% 
0.0% 
 
Currently, there are only a limited number of academic and community institutions using IGRT. 
During this study, the number of institutions using IGRT is expected to increase as the 
technology becomes more readily available on modern Linacs. Although it is projected now  
that 40% of patients will have received IMRT + IGRT, 3 other various percentages (30, 50, and 
60%) also will be evaluated. Reductions of 25% and 30% in the LRC failure rate with the 
additional of IGRT will be evaluated. The significance level for a two-sided test was set at 0.05. 
The monthly accrual rate, its duration, and the follow-up interval from the sample size  
derivation for the cetuximab question were used. The statistical power for each scenario was 
derived by using the Lakatos method (1986). 
Table 2: Statistical Power Associated with Evaluating the Addition of IGRT 
 
Percentage of patients 
treated 
with IMRT and IGRT 
25% reduction 
in local-regional failure rate 
with IMRT and IGRT 
30% reduction 
in local-regional failure rate 
with IMRT and IGRT 
30% 
0.37 
0.51 
40% 
0.43 
0.58 
50% 
0.45 
0.61 
60% 
0.44 
0.60 
 
As seen in Table 2, the statistical power is quite low for all scenarios. Given the results from the 
Bonner trial (2006), we do expect that cetuximab will reduce the local-regional failure rate; 
therefore, the statistical power will even be lower. Therefore, the impact of IGRT only will be 
estimated and reported with its 95% confidence interval. Furthermore, the estimate for IGRT 
effect will be derived from a Cox model with pathologic T-stage, performance score, and 
protocol treatment as covariates. These variables were selected to adjust for possible 
imbalance, since patients were not randomized between IMRT and IMRT+IGRT, This result will 
be viewed as hypothesis generating, not as definitively testing the addition of IGRT. 

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13.4.3 
Background for Evaluating Local Regional Control in IMRT (without IGRT) Treated Patients 
Since the intergroup postoperative randomized trial, RTOG 95-01, completed accrual in 2000, 
radiation planning and delivery has evolved. It is generally accepted that intensity modulated 
radiation therapy (IMRT) will minimize late toxicity (especially xerostomia) [Kam 2007; Pow 
2006]. It has been assumed that IMRT will not “significantly” reduce the local-regional control 
(LRC) rates, but presently, there are no randomized studies available that definitively have 
tested this hypothesis. It should be noted that there are no published results from uncontrolled 
series to suggest that IMRT may compromise LRC rates. With the current widespread use of 
IMRT in the treatment of head and neck cancer, it would not be possible to launch a definitive 
randomized trial to test this question. For example, in the recently completed randomized trial 
for locally advanced head and neck cancer, RTOG 0522, 85% of patients are treated with 
IMRT. 
 
The assumption that IMRT will not seriously compromise LRC rates will be assessed twice 
against the RTOG 95-01 LRC rates using the cohort of patients treated with IMRT alone in 
RTOG 0920. The first assessment will occur after these patients have  been  potentially 
followed for 1 year and the second time after potential follow up for 2 years. In RTOG 95-01, 
86% [95% confidence interval 79-93] and 78% (70-87) LRC rates were observed at 1 and 2 
years, respectively in the 93 patients treated with external beam irradiation only and that would 
have been eligible for RTOG 0920 (table below). Based upon these rates, it is projected that 
the 1- and the 2-year LRC rates would be 90% and 80% in RTOG 0920. An absolute decrease 
of 10% or more in either yearly estimated rate is considered unacceptable and would call into 
question the assumption about IMRT not adversely affecting LRC. If such a decrease is 
observed at either special analysis, the patient accrual to 0920 will be suspended. The NRG 
Oncology Data Monitoring Committee will review the results from the analysis and make a 
recommendation about the study’s future disposition (e.g., discontinuation of further patient 
entries) to the NRG Oncology Group Co-Chair who, in turn, will act upon that recommendation. 
A particular concern is that the RTOG 0920 patients may be more elderly and possibly sicker 
than the RTOG 95-01 patients. The RTOG 95-01 trial had more stringent eligibility criteria 
because the patients could be randomized to receive concurrent chemotherapy with radiation 
therapy. 
 
Assuming that the true LRC rate at 2 years is 80% with external beam irradiation, the 2-sided 
95% confidence interval (assuming a binominal distribution) around it would have 70% as its 
lower limit with 64 evaluable patients. That sample size would result in 2-sided  99%  
confidence interval around an assumed true LRC rate at one year of 90% with 80% as its lower 
limit. The 2 interim analyses will be performed once the data are mature enough for the first 70 
patients assigned to the radiation alone arm and for whom the participating institution does not 
elect to treat with IGRT added to IMRT. The additional 6 patients entered beyond the required 
64 guards against loss to follow up and retrospective ineligibility. The timing of these analyses 
depends not only on the patient accrual rate but also on the percentage of patients treated 
without IGRT added to IMRT. With a projected patient accrual rate of 108 patients per year, 54 
would be randomized to receive RT alone. If 80% of these patients initially entered are treated 
with IMRT but not with IGRT, the 2 special interim analyses are projected to occur at 3 and 4 
years from the time the study opens to patient accrual. If that percentage is 70% instead of 
80%, it will take an additional 6 months. These time intervals take into account the period of 
time to accrue the required 70 patients, the designated risk period for local-regional failure (one 
and two years), and an additional 6 months for data collection and analysis. 

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RTOG 95-01 
Local-regional Control 
Patients Potentially Eligible for RTOG 0920 
 
RT only arm 
 
Year 
Estimate 
(%) 
95% CI (%) 
Cumulative 
Failures 
At Risk 
0 
100.0 
-- 
0 
93 
1 
86.0 
78.9, 93.1 
13 
71 
2 
78.4 
69.9, 86.8 
20 
58 
3 
76.2 
67.4, 84.9 
22 
49 
Total 
22 
 
 
13.4.4 
Background and Statistical Power Determination for Evaluating Various Tumor Markers 
EGFR Expression Levels 
The specific hypothesis is that the relative improvement in OS will be similar for patients with 
high EGFR expression (defined as ≥ 80% of cells staining positive for EGFR) or low EGFR 
expression (defined as < 80% of cells staining positive). However, the absolute values for 
OS will be significantly greater for patients with low EGFR expression. 
 
Although baseline EGFR expression is a stratification variable for treatment assignment, all 
patients may not have it available for analysis. The protocol has strict time constraints to 
start postoperative RT. Since it is entirely possible that the initially submitted pathologic 
material maybe inadequate to determine HPV status and/or EGFR level within that time 
period, the patients will be classified as not evaluable for treatment randomization. However, 
every attempt will be made to appropriately classify these patients with respect to these 2 
variables for tumor marker analysis. It is conservatively projected that the baseline EGFR 
expression will be available on 90% of the patients. The hypotheses will be tested with a 
Cox regression model with 3 covariates: 1) assigned treatment; 2) baseline EGFR 
expression; and 3) treatment by EGFR expression interaction. The covariate for baseline 
EGFR expression tests whether the patients with low EGFR have better OS while the 
covariate for interaction tests whether the treatment effect is similar within each EGFR 
subgroup. For planning purposes, it is assumed that patient accrual will not be discontinued 
in the trial or that trial is not reported early because of highly significant results. So at the 
time of final treatment analyses, there will be at least 335 deaths (= 0.90 * 372 events) 
observed in all patients and 247 deaths ( = 0.90 * 274 events) in HPV- patients. It is 
projected that 40% to 60% of patients will be in the low EGFR group. 
 
The equation described by Schoenfeld (1981) was used to calculate statistical power: 
Number of failures = (z 1- α/2 + z 1- β)2 / (ln HR)2 w (1 – w), where 
z 1- α/2 = normal deviate for the significance level 
z 1- β = normal deviate for the statistical power 
HR = hazard ratio comparing favorable risk group (low EGFR values) to unfavorable risk 
group (high EGFR values) 
w = prevalence rate of risk group 
 
Table 3 below provides the statistical power to detect hazard ratios for OS of 1.50, 1.75, and 
2.00 for prevalence rates of 40% or 50% or 60% in all patients and in HPV- patients. As 
seen in the table, there will be good power to detect a hazard ratio of 1.50 or greater. In fact, 
there is 80% statistical power to detect ratio of at least 1.4 in both patient groups. The 

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statistical power for DFS would be higher since its failure rate would be higher than death 
rate; thus resulting in more events. 
 
Table 3: Statistical Power for All Patients and for HPV- with 2-Sided 5% Alpha 
 
All patients (335 deaths) 
HPV- patients(247 deaths) 
Hazard Ratio 
Hazard Ratio 
Prevalence 
1.50 
1.75 
2.00 
1.50 
1.75 
2.00 
40% (or 
60%) 
0.95 
0.99 
0.99 
0.87 
0.99 
0.99 
50% 
0.95 
0.99 
0.99 
0.88 
0.99 
0.99 
 
In order to properly test the hypothesis that the treatment effect on OS is the same within 
each EGFR subgroup, a minimum relative 20% difference would have to be ruled out with 
90% statistical power. Using the method of Peterson and George (1993), that would require 
over 3,000 cases under the following assumptions: 
 
1. The patients are equally divided by EGFR subgroup and treatment assignment; 
2. The high EGFR subgroup failed 1.5 times faster than low EGFR subgroup; 
3. 86 (= 0.90 * 96) analyzable patients accrued per year for 6.6 years, and all patients 
were followed potentially for 3.0 years. 
Modifying any of these assumptions will not substantially decrease the number of cases 
because of the small difference to detect. The estimate for interaction along with its 95% 
confidence will be reported. The closer this estimate is to 1, the more support is for the 
hypothesis that the treatment effect is the same within each EGFR subgroup. 
 
HPV Positivity and Negativity 
The following 3 hypotheses will be examined: 
1. HPV negative patients will have greater absolute benefit from the addition of 
cetuximab compared to HPV positive patients; 
2. HPV positivity will associate with low EGFR expression because the HPV positive 
tumors may not be driven by EGFR but by viral oncogene E6/E7, causing the loss of 
p53 and Rb; 
3. EGFRvIII will associate with HPV negativity and treatment failure due to ligand- 
independent constitutive activation of the receptor, escaping the effects of 
cetuximab. 
 
Hypothesis 1: 
Although HPV status is a stratification variable for treatment assignment, all patients may  
not have it available for analysis. Since it is entirely possible that the initially submitted 
pathologic material may be inadequate to determine HPV status and/or EGFR level, patients 
will be classified as not evaluable for treatment randomization. However, every attempt will 
be made to appropriately classify these patients with respect to these 2 variables for tumor 
marker analysis. It is conservatively projected that the HPV expression will be available on 
90% of the patients. The hypothesis will be tested with a Cox regression model with the 
following covariates: 1) treatment, 2) HPV status, and 3) treatment by HPV status 
interaction. The covariate for interaction tests whether the treatment effect is similar for the 
HPV+ and the HPV - patients. For planning purposes, it is assumed that the patient accrual 
will not be discontinued in the trial or that trial is not reported early because of highly 
significant results. At the time of final treatment analyses, there will be at least 335 deaths (= 
0.90 * 372 events) observed in all patients. It is projected that 20% of patients will be HPV+. 
Using the method of Peterson and George (1993), an effect size of 50% or greater for this 
interaction can be detected with 80% statistical power under the following assumptions: 
1. The patients are equally divided by treatment assignment within each HPV status; 
2. The HPV- subgroup failed 1.5 times faster than the HPV+ subgroup; 
3. The hazard ratio associated with smallest treatment effect ranges between 0.85 and 
1.00; 

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4. 86 (=0.90 * 96) patients accrued per year for 6.6 years, and all patients were 
followed potentially for 3.0 years. 
Modifying any of these assumptions will not substantially change the effect because only 
20% of the patients are projected to be HPV+. The estimate for the treatment by HPV status 
interaction with its 95% confidence will be reported. A smaller effect for DFS would be 
detected, since its failure rate would be higher than the death rate; thus resulting in more 
events. 
Hypothesis 2: 
Although both baseline EGFR level and HPV status are stratification variables for treatment 
assignment, all patients may not have these data available for analysis. Since it is entirely 
possible that the initially submitted pathologic material may be inadequate to determine HPV 
status and/or EGFR level, patients will be classified as not evaluable for treatment 
randomization. However, every attempt will be made to appropriately classify these patients 
with respect to these 2 variables for tumor marker analysis. It is conservatively projected that 
the HPV expression will be available on 90% of the patients. It is projected that 20% of 
patients will be HPV+. There are no definitive data available to estimate the percentage of 
the HPV+ patients with low EGFR values; however, a published study showed 65% of p16 
(surrogate of HPV status) positive tumors had low EGFR expression (Reimers 2007). With a 
projected sample size of 112 HPV+ patients and 457 HPV- patients and 80% statistical 
power, the detectable difference in the rate of patients with low EGFR values between these 
2 subgroups would be approximately 0.15. 
 
Hypothesis 3: 
Although both baseline EGFR level and HPV status are stratification variables for treatment 
assignment, all patients may not have these data available for analysis. Since it is entirely 
possible that the initially submitted pathologic material may be inadequate to determine HPV 
status and/or EGFR level, the patients will be classified as not evaluable for treatment 
randomization. However, every attempt will be made to appropriately classify these patients 
with respect to these 2 variables for tumor marker analysis. It is conservatively projected that 
both the HPV status and EGFR expression will be available on 90% of the patients. 
However, EGFRvIII may not be determined in all patients because of limited tissue  
available. For planning proposes, it is projected that 90% of patients with both HPV status 
and baseline EGFR expression also will have a EGFRvIII value and that 20% of these 
patients will be HPV+. There are no data available to estimate the percentage of the HPV- 
patients with EGFRvIII present. With a projected sample size of 101 HPV+ patients and 411 
HPV- patients and 80% statistical power, the detectable difference in the rate of patients  
with EGFRvIII present between these 2 subgroups will be approximately 0.16. 
EGFR Ligand Expression Levels 
The specific hypothesis is that patients with high values of EGFR ligand expressions 
(defined as the 4th quartile) will have better OS and DFS than patients with low values 
(defined as the 1-3rd quartile). 
 
For planning purposes, it is assumed that EGFR ligand expression can be determined in 
75% of the patients and that patient accrual will not be discontinued in the trial or that trial is 
not reported early because of highly significant results. At the time of final treatment 
analyses, there will be at least 279 (= 0.75 * 372) deaths (events) observed in all patients 
and 220 ( = 0.75 * 294 ) deaths (events) in HPV- patients. It is projected that 25% of  
patients will be in the group with high EGFR ligand expression. 
 
The equation described by Schoenfeld (1981) was used to calculate statistical power: 
Hazard ratio in this instance compares favorable risk group (high expressions) to 
unfavorable risk group (low expressions) and prevalence rate is for favorable risk group. 
 
Table 4 below provides the statistical power to detect hazard ratios for OS of 1.50, 1.75, and 
2.00 in all patients and in HPV- patients. As seen in the table, there will be good power to 
detect a hazard ratio of 1.50 or greater in both patient groups. If DFS was used instead of 
OS, there would be more failures at time of the analysis and thus, more statistical power. 
Hence, there is 99% statistical power to detect a ratio of ≥ 2.00, reported by Khambata-Ford 
(2007) for DFS in recurrent/metastatic colon patients. 

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Table 4: Statistical Power for All Patients 
and for HPV- with 2-Sided 5% Alpha 
 
All patients (279 events) HPV- patients (220 events) 
Hazard Ratio 
Hazard Ratio 
1.50 
1.75 
2.00 
1.50 
1.75 
2.00 
0.83 
0.98 
0.99 
0.74 
0.94 
0.99 
 
Evaluation of TP53 Mutations 
The specific hypothesis is that the patients with TP53 mutations will have poorer OS and 
DFS than patients with wild-type TP53 mutations. 
 
For planning purposes, the following assumptions will be made: 
1. TP53 mutation status can be determined in 75% of the patients; 
2. 50% of patients will have TP53 mutations; 
3. Mutations will be distributed as follows: functionally non-disruptive=33% and 
functionally disruptive=20%. Thus, approximately 50% of all patients are projected  
to have no TP53 mutations; 
4. Patient accrual will not be discontinued in the trial or that trial is not reported early 
because of highly significant results; 
5. Since the comparison will be made between patients with TP53 mutations and 
patients with wild-type TP53, there will be at least 140 (= 372 * 0.75) deaths  
(events) observed in these 2 patient groups at the time of final treatment analyses; 
6. After assessing the TP53 mutational status, the mutations will be categorized into 
functionally non-disruptive and disruptive mutations for a subset analysis to further 
investigate the clinical effects of the mutations. 
 
The equation described by Schoenfeld (1981) was used to calculate statistical power: 
 
Hazard ratio in this instance compares unfavorable risk group (TP53 mutation) to 
unfavorable risk group (wild-type TP53). The prevalence rate of favorable risk group was set 
at 0.50 but also prevalence rates of 0.40 and 0.60 will be evaluated. Table 5 below shows 
statistical power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 for prevalence rates  
of 40% or 50% or 60% in all patients. As seen in the table, there will be excellent statistical 
power (> 90%) to detect a hazard ratio of ≥ 1.50, and 80% statistical power to detect a ratio 
of at least 1.4 in all patients. The statistical power for DFS would be higher since its failure 
rate would be higher than the death rate; thus resulting in more events. 
 
Table 5: Statistical Power for All Patients with 2-Sided 5% Alpha 
 
All patients (279 deaths) 
Hazard Ratio 
Prevalence of pts with 
wild type TP53 
1.50 
1.75 
2.00 
40% 
0.91 
0.99 
0.99 
50% 
0.92 
0.99 
0.99 
60% 
0.91 
0.99 
0.99 
 
Evaluation of Polymorphic Variants in CA Dinucleotide Repeats in EGFR Intron 1 
The specific hypothesis is that short CA dinucleotide repeats in EGFR intron 1 will be 
associated with poor OS and DFS. 
 
For planning purposes, it is assumed that dinucleotide repeats in EGFR intron 1 can be 
determined in 75% of the patients and that patient accrual will not be discontinued in the trial 
or that trial is not reported early because of highly significant results. It is projected that 25% 

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RTOG 0920, Version Date: May 11, 2023 
 
of the study population will be female and < 5% will be Asian. At the time of final treatment 
analyses, there will be at least 279 (= 0.75 * 372) deaths (events) observed in all patients 
and 80 (= 0.25 * 0.75 * 294 ) deaths (events) in female patients. 
 
The equation described by Schoenfeld (1981) was used to calculate statistical power: 
 
Hazard ratio in this instance compares favorable risk group (short CA dinucleotide repeats in 
EGFR intron 1) to unfavorable risk group (long CA dinucleotide repeats in EGFR intron 1) 
and the prevalence rate is for the favorable risk group.  Table 6 below shows statistical 
power to detect hazard ratios for OS of 1.50, 1.75, and 2.00 for prevalence rates of 40% or 
50% or 60% in all patients and in only female patients. As seen in the table, there will be 
excellent statistical power (> 90%) to detect a hazard ratio of 1.50 or greater and 80% 
statistical power to detect ratio of at least 1.4 in all patients. However, there is only adequate 
statistical power (> 80%) to detect large ratio in the female patients. The statistical power for 
DFS would be higher since its failure rate will be higher than death rate; thus resulting in 
more events. 
 
Table 6: Statistical Power for All Patients and Only Female Patients with 2-Sided 5% Alpha 
 
All Patients (279 deaths) 
Female Patients (80 deaths) 
Hazard Ratio 
Hazard Ratio 
Prevalence 
1.50 
1.75 
2.00 
1.50 
1.75 
2.00 
40% (or 60%) 
0.91 
0.99 
0.99 
0.42 
0.68 
0.85 
50% 
0.92 
0.99 
0.99 
0.44 
0.70 
0.87 
 
13.4.5 
Background and Statistical Power Determination for Evaluating Factors Associated with Long- 
Term, Post-Radiotherapy Adverse Events and Patient-Reported Outcomes (PROs) 
In this trial, long-term adverse events will be graded using CTCAE, v. 4, with particular attention 
to dysphagia, dry mouth , and skin toxicity (rash: acneiform; rash: maculo-papular; and 
pruritus). However, it is recognized that CTCAE (physician graded) does not always reflect the 
patient experience and quality of life (QOL). Therefore, patient-reported outcomes (PROs) will 
be studied with head and neck specific instruments, including: the Performance Status Scale 
for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & 
Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale 
(XeQOLS), the Dermatology Life Quality Index (DLQI), and a cost-utility analysis will be done 
using the EuroQol (EQ-5D). Data will be collected at the baseline and at 3, 12, and 24 months 
from the start of treatment. 
 
The following 5 hypotheses will be examined: 
1. PROs will be similar in the 2 arms (i.e., the use of cetuximab does not result in 
decreased QOL); 
2. Patients treated with IMRT + IGRT will have improved XeQOLS scores compared with 
patients treated with IMRT; 
3. Clinician-rated functional assessment of dysphagia (CTCAE, v. 4 dysphagia) is at least 
moderately correlated (r ≥ 0.20) with its PRO assessment (the Normalcy of Diet 
component of the PSS-HN); 
4. Clinician-rated functional assessment of xerostomia (CTCAE, v. 4 dry mouth) is at least 
moderately correlated (r ≥ 0.20) with its PRO assessment (the XeQOLS); 
5. Clinician-rated skin toxicity (CTCAE, v. 4 rash: acneiform; rash: maculo-papular; and 
pruritus) is at least moderately correlated (r ≥ 0.20) with its PRO assessment (the 
DLQI); 
6. The EQ-5D is highly correlated (r ≥ 0.50) with FACT-H&N, XeQOLS, the PSS-HN, and 
DLQI. 
 
Hypothesis 1: 
The primary question of interest is whether the addition of cetuximab to postoperative radiation 
therapy (RT) at 12-month assessment results in poorer PROs. In the Bonner study with 

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patients who received definitive RT, the addition of cetuximab did not adversely affect QOL. 
The effect of the addition of cetuximab at 3 months from start of RT also will be evaluated. 
 
In this trial, the participation in the QOL component of the study is optional for patients. In the 
past, RTOG has not evaluated QOL in any postoperative RT trial; therefore, the projected 
percentage of patients with PRO/QOL data for the 12-month assessment will be based on the 
ongoing phase III trial, RTOG 0522, testing the addition of cetuximab to chemoradiation. RTOG 
0522 uses the same PRO/QOL instruments, with the exception of the University of Michigan 
15-item Xerostomia Related Quality of Life Scale (XeQOLS). In the first 78 patients entered  
into RTOG 0522 with potentially 12-month follow up, approximately 50% had both the baseline 
and the 12-month assessment; therefore, it is projected that half of the patients entered onto 
RTOG 0920 will have both assessments (158 patients per arm). Hypothesis 1 will be tested 
using the following 3 endpoints: 
 
A. University of Michigan 15-item Xerostomia Related Quality of Life Scale (XeQOLS) 
The endpoint for the XeQOLS will be differences between arms in the mean XeQOLS 
score for the baseline and the 12-month assessment. Only patients alive at 10 months with 
baseline (XeQOLS) scores will initially be included in this analysis. With 158 patients per 
arm and an effect size of 0.32 or higher, where the effect size is 
 = 1 −  2 
 , where  is the common s tan dard deviation, under 
assumption 
of 
normal 
distribution, there is 80% statistical power to detect this effect. 
B. Normalcy of Diet Subscale in the Performance Status Scale for Head and Neck Cancer 
(PSS-HN) 
For the PSS-HN scale, the frequency of patients with scores of ≤ 50 (considered to be 
impaired swallowing or speech) on each of the 3 subscales (Normalcy of Diet; Eating in 
Public; and Understandability of Speech) will be estimated along with its 95% confidence 
interval for each treatment regimen at 12 months from start of treatment. These  
frequencies will be compared between the 2 treatments using the z-statistic for testing 
binomial proportions. Only patients alive at 10 months with baseline diet subscale scores 
will be included in this analysis. There are no data available to estimate the percentage of 
the patients on the postoperative RT arm with impaired swallowing or speech at 12 months 
in this study population. With projected sample size of 158 patients per arm and 80% 
statistical power, the detectable difference would be approximately 0.16 between the 
treatment arms. 
C. Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N) 
The primary patient-reported endpoint for the FACT-H&N will be differences between arms 
in the mean FACT-H&N score for the baseline and the 12-month assessment. Only 
patients alive at 10 months with baseline FACT-H&N scores will be included in this 
analysis. With 158 patients per arm and an effect size of 0.32 or higher, where the effect 
size is 
 = 1 −  2 
 , where  is the common s tan dard deviation, there is 80% statistical 
power to detect this effect. 
 
Hypothesis 2: 
The ideal way to determine whether patients treated with IMRT + IGRT will have improved 
Xerostomia Related Quality of Life Scale (XeQOLS) scores would be in a study in which 
patients are randomly assigned to IMRT +/- IGRT. This randomization would not be possible 
because many NRG Oncology institutions do not have IGRT capabilities or because some 
radiation devices with IGRT capabilities cannot be utilized without IGRT. 
 
As the proposed study is written, the treating institution decides on a patient-by-patient basis 
whether or not IGRT will be utilized. An exploratory analysis will be performed looking at this 
question. The analysis will be done with multivariate regression models to correct for potential 
prognostic factors, including protocol cetuximab treatment, tumor site, stage, patient age, 
pretreatment performance status, and type and extent of surgery performed prior to IMRT. The 
number of patients available for analysis will be for the same as for the protocol treatment 
evaluation described above. It is expected that the number of institutions with IGRT capabilities 
will steadily increase over the time in which the study is active and by the time the study is 
complete, most institutions will have IGRT capabilities. 

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RTOG 0920, Version Date: May 11, 2023 
 
The same 12-month PRO/QOL endpoints will be analyzed in a similar fashion for the treatment 
comparison. The statistical power associated with the evaluation of the 12-month PRO/QOL 
endpoints was generated under the assumption that 40% (i.e., 126) of 316 patients will have 
received IMRT + IGRT, and 60% (i.e., 190) will receive IMRT without IGRT. The primary 
patient-reported endpoint for the XeQOLS and FACT-H&N respectively will be differences 
between arms in their respective mean score for the baseline and the 12-month assessment. 
Only surviving patients at 10 months with their baseline scores will initially be included in this 
analysis. With 126 patients treated with IMRT + IGRT, 190 patients treated with IMRT without 
IGRT and an effect size of 0.33 or higher, where the effect size is 
 = 1 −  2 
 , where  is the common s tan dard deviation, under 
assumption 
of 
normal 
distribution, there is 80% statistical power to detect this effect. 
 
For the PSS-HN diet subscale, the frequency of patients with scores of ≤ 50 (considered to be 
impaired swallowing) will be compared between IMRT +/- IGRT using the z-statistic for testing 
binomial proportions. Only surviving patients at 10 months with baseline diet subscale scores 
will be included in this analysis. There are no data available to estimate the percentage of the 
patients on postoperative RT arm with impaired swallowing at 12 months in this study 
population. With projected sample size of 126 IMRT+ IGRT patients and 190 IMRT without 
IGRT patients and 80% statistical power, the detectable difference would be approximately 
0.17. 
 
Hypotheses 3-5: 
Patients with a PRO data collection form received within 2 months of the 12-month assessment 
will be included in the analyses of these hypotheses, as long as they had a clinical assessment 
of dry mouth, dysphagia, and skin toxicity (rashacneiform; rashmaculo-papular; and pruritus) 
during that study timeframe. It is projected that there will be approximately 300 such patients. 
 
Hypothesis 6: 
Patients with an EQ-5D data form received within 2 months of the 12-month assessment will be 
included in the analyses of this hypothesis, as long as they had at least one of the other PRO 
data forms (FACT-H&N, XeQOLS, the PSS-HN, and DLQI) completed during that study 
timeframe. It is projected that there will be approximately 300 such patients. 
13.5 
Patient Accrual 
The study design is based on a 79-month accrual period with an average of approximately 9.0 
patient entries per month. However, during the first 6 months following activation, little accrual is 
anticipated while the trial is approved by institutional IRBs. It is projected that 11 patients in total 
will be entered during study months 1-6 (none in months 1-3; 3 patients in the 4th month; and 4 
patients in months 5-6), and then the average monthly accrual rate after study month 6 will be 9.5 
patients. If the total accrual during months 13 through 18 of the study is ≤ 20% of the targeted 
accrual (≤ 11 cases in total), then the protocol will be discontinued per NCI-CTEP accrual 
guidelines for phase III studies. If the total accrual is between 21-49%, then the protocol will 
continue to accrue subject to approval of the NRG Oncology Data Monitoring Committee (DMC) 
and NCI-CTEP. If continued, the study has to accrue at least 50% of targeted accrual (≥ 15 cases 
in total) during months 22 through 24 in order to remain open beyond 2 years. 
13.6 
Randomization (23-FEB-2012) 
Patients will be stratified by 4 variables: Pretreatment EFGR level (high [≥ 80% of cells staining 
positive for EGFR] vs. low [< 80% of cells staining positive for EGFR] vs. EGFR not evaluable); 
Primary Site (Oral cavity, Larynx, Oropharynx HPV positive, Oropharynx HPV negative, 
Oropharynx HPV not evaluable); use of IGRT (no vs. yes), and clinical stage (T1-3 vs. T4a). To 
avoid possible bias in randomization of patients to the study, the patient’s HPV status will not be 
provided to the patient’s physician or institution until the patient has completed study treatment. 
The treatment allocation scheme described by Zelen (1974) will be used because it balances 
patient factors other than institution. The protocol has strict time constraints to  start  
postoperative RT. 
13.7 
Analysis Plan (11-MAY-2023) 
13.7.1 
Statistical Methods 
This study will be analyzed using all eligible patients with follow up based on the treatment arm 
to which they were randomized, regardless if they started the assigned treatment. In addition, a 

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second efficacy comparison will be performed as a sensitivity analysis for the primary endpoint 
of survival using all patients entered on RTOG 0920 by their randomized treatment assignment. 
 
The Spearman method will be used to calculate the correlation coefficients with their  
associated 95% confidence levels. 
 
DFS and OS rates will be estimated using the Kaplan-Meier method (1958). The distributions of 
the OS and DFS will be compared between treatment arms with a one-sided, stratified log rank 
test (Mantel 1966). The patients will be stratified by EGFR level (high vs. low vs. not evaluable) 
and primary site/HPV status (oropharyngeal HPV positive vs. oropharyngeal HPV negative/oral 
cavity/larynx vs. oropharyngeal HPV not evaluable). Since the use of IGRT is not projected to 
significantly affect overall survival, it was not included as a stratification variable for the 
cetuximab efficacy analysis. This minimizes the number of cells for the log rank test. Since 
protocol treatment has to start within 2 weeks of protocol registration, it is expected that some 
of patients will not have an EGFR level and/or HPV status available at the time of 
randomization because the tissue submission was inadequate; these patients will be 
randomized as not evaluable. Most of these patients subsequently will have the unknown value 
for the stratification variable determined. However, values of the stratification variables at the 
time of randomization will be used for both OS and DFS endpoints in primary/secondary 
efficacy analysis. It is very possible that some stratification cells defined by oropharyngeal HPV 
positive patients or oropharyngeal HPV undetermined patients may have less than 20 patients. 
In those situations, the oropharyngeal HPV undetermined patients will be considered HPV 
positive and the cells combined accordingly. Sensitivity analysis also will be performed, 
restricting it to patients with known values for both stratification variables that are either before 
or after randomization. 
 
Local-regional progressions in head and neck cancer trial mostly occur during the first two 
years and so death or distant metastasis without LRP can greatly influence the treatment  
effect, the associated p-value, and hence the interpretation of the trial. Therefore, local- 
regional control will be analyzed the following two ways: 
 
1. Cumulative incidence curves comparing the treatment arms where LRP is considered 
as a failure and death or distant metastasis without LRP as a competing risk 
(Kalbfleisch 1980). The distributions of this failure pattern will be compared between 
treatment arms with the failure-specific log rank test (Prentice 1978). 
2. Cumulative incidence curves comparing the treatment arms where death or distant 
metastasis with LRP is considered as a failure and LRP as a competing risk 
(Kalbfleisch 1980). The distributions of this failure pattern will be compared between 
treatment arms with the failure-specific log rank test (Prentice 1978). 
 
The results from two approaches in this exploratory analysis for objectives (Sections 2.3.1 and 
2.3.2) will be reported.  Approach  1  will  provide  an  estimate  the  efficacy  for  new 
treatment (cetuximab) and new radiation technique (IGRT) respectively and will be interpreted 
supporting their use if the associated p-value is less than p < 0.10 and if approach 2 does not 
show for patients treated with cetuximab or IGRT an increase in death rate without 
LRP progression especially during the first two years. 
 
All failure times will be measured from the date of treatment randomization to the date of  
failure, competing risk, or last follow up. Table 7 shows how each first event will be counted for 
LRC and DFS. Anything not explicitly in the table (e.g., second primary tumor) is not  
considered an event, and the patient will continue to be followed for failure. For OS, death from 
any cause will be considered a failure. 

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Table 7: Definition of Failure for LRC and DFS 
 
First Event 
Local-Regional 
Control (1) 
Local-Regional 
Control (2) 
Disease-free 
Survival 
None 
Censored 
Censored 
Censored 
Local-regional progression or 
recurrence 
Failure 
Competing risk 
Failure 
Distant metastasis 
Competing risk 
Failure 
Failure 
Death due to study cancer or from 
unknown causes 
Failure 
Competing risk 
Failure 
Death due to any other reason 
Competing risk 
Failure 
Failure 
 
For the endpoints in Sections 13.1.2.1, 13.1.2.2, and 13.1.2.3, only adverse events (AEs) 
assessed to be definitely, probably, or possibly related (if relationship is missing, it will be 
assumed to be definitely, probably, or possibly) to protocol treatment will be considered. The 
rates of ≥ grade 3 acute and late AEs (specifically, dry mouth, dysphagia, skin, and all) will be 
estimated using a binomial distribution along with their associated 95% confidence intervals 
and will be compared using Fisher’s exact test between the 2 treatment groups. 
 
A 2-sided van Elteren’s test with α = 0.05 will be used to test whether the distribution of the 
Functional Assessment of Cancer Therapy-Head & Neck [FACT-H&N] and University of 
Michigan Xerostomia-Related Quality of Life Scale [XeQOLS] at 3, 12, and 24 months from 
start of RT scores is the same in the treatment arms. Van Elteren’s test is an extension of the 
stratified Wilcoxon rank-sum test. It will be obtained from the generalized Cochran-Mantel- 
Haenszel (CMH) test for mean difference using the standardized midranks (also known the 
modified ridit scores) [Stokes 1995]. 
13.7.2 
Interim Analysis to Monitor Study Progress 
Interim reports will be prepared twice each year until the final analysis has been accepted for 
presentation or publication. In general, these reports will contain information about the accrual 
rate with projected completion date for the accrual phase, exclusion rates and reasons, 
pretreatment characteristics of patients accrued, compliance rate of treatment delivered with 
respect to the protocol prescription, and the frequency and severity of adverse events. The 
NRG Oncology Data Monitoring Committee (DMC) will review the study twice a year with 
respect to patient accrual and morbidity. The DMC also will review the study on an “as needed” 
basis. After this study has been opened 1.5 years, the study design assumptions made about 
percentage of HPV+ oropharyngeal patients entered on 0920 will be checked semiannually. If 
the observed frequency of HPV+ patients is greater by at least 10% than the projected 
frequency of 20%, the implication of this increased frequency will be assessed in terms of when 
the projected final (definitive) treatment analysis will be performed. If timing of that analysis is 
lengthened by more than a year, a recommendation of increasing the sample size will be 
explored. 
13.7.3 
Significance Testing for Early Termination and Reporting 
Three interim treatment comparisons will be performed when the following are observed: 25% 
(93 deaths), 50% (186 deaths), and 75% (279 deaths) of the 372 required number of deaths. 
Only the primary endpoint of survival will be tested in the interim analysis. The efficacy will be 
tested using Haybittle-Peto boundaries of 0.005 for interim tests and 0.0183 for final analysis to 
preserve an overall alpha level of 0.025 for the study. The futility will be tested using the lower 
boundary based on testing the alternative hypothesis at 0.005 level. The results will be reported 
to the NRG Oncology DMC with the treatment blinded. 

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Table 8: Nominal Significance Levels 
 
Interim Test 
Number of Events 
p-value for Efficacy 
p-value for Futility 
1 
93 
 0.005 
< 0.005 
2 
186 
 0.005 
< 0.005 
3 
279 
≤ 0.005 
< 0.005 
Final 
Analysis 
372 
 0.0183 
N/A 
 
At each planned interim analysis, the results from the test for assessing treatment efficacy and 
futility will be reported to the NRG Oncology DMC. The responsible statistician may  
recommend early reporting of the results and/or stopping accrual (if applicable) of the trial if the 
treatment effect, with respect to OS, is highly significant or if it is not likely to be; that is, if the p- 
value is less than the nominal value specified in a sequential design for either efficacy or futility. 
Before making such a recommendation, the accrual rate, treatment compliance, safety of the 
treatments, and the importance of the study also are taken into consideration with the p-value. 
The DMC will then make a recommendation about the trial to the NRG Oncology Group Chair. 
13.7.4 
First Special Interim Analysis of Local Regional  Control  (LRC)  in  IMRT  Treated  Patients 
The interim analysis will be performed on the first 70 patients assigned to the radiation alone 
arm and for whom the participating institution does not elect to treat with IMRT and IGRT. It will 
occur after these 70 patients have been potentially followed for 1 year. The 1-year rate for  
LRC will be computed, and if it is less than 80%, the patient accrual to 0920 will be 
suspended. The NRG Oncology Data Monitoring Committee will review the results from the 
analysis as soon as possible and make a recommendation about the study’s future disposition 
(e.g., discontinuation of further patient entries) to the NRG Oncology Group Chair who, in turn, 
will act upon that recommendation. The analysis will include pretreatment characteristics of this 
patient cohort. 
13.7.5 
Second Interim Analysis of Local Regional Control (LRC) in IMRT Treated Patients 
The interim analysis will be performed on the first 70 patients assigned to the radiation alone 
arm and for whom the participating institution does not elect to treat with IMRT and IGRT It will 
occur after these 70 patients have been potentially followed for 2 years. The 2-year rate for 
LRC will be computed, and if it is less than 70%, the patient accrual to 0920 will be suspended. 
The NRG Oncology Data Monitoring Committee will review the results from the analysis as 
soon as possible and make a recommendation about the study’s future disposition (e.g., 
discontinuation of further patient entries) to the NRG Oncology Group Chair who, in turn, will 
act upon that recommendation. The analysis will include pretreatment characteristics of this 
patient cohort. 
13.7.6 
Analysis for Reporting the Initial Cetuximab Treatment Results First 
The analysis reporting these treatment results will be carried out as described in Section 13.7.7. 
Only eligible patients with both on-study and follow-up information will be included in the 
primary treatment analysis. The usual components of this analysis are: 
• Tabulation of all cases entered and any excluded from analysis with reasons for 
exclusion; 
• Patient accrual rate; 
• Institutional accrual; 
• Distribution of important baseline prognostic variables; 
• Frequency and severity of adverse events; 
• Observed results with respect to the endpoints described in Section 13.1. 
 
The difference in OS between the control arm and the experimental arm will be tested using the 
stratified one-side log-rank test at the significance level of 0.0183 given that the 3 interim 
analyses are carried out and show no statistical significance. The stratification will be done by 
EGFR level (high vs. low vs. not evaluable) and primary site/HPV status (oropharyngeal HPV 
positive vs. oropharyngeal HPV negative/oral cavity/larynx vs. not evaluable) [See Section 

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13.5.1]. The differences in DFS times between the treatment arms will be tested with the one- 
sided, stratified log rank test as described above at the 0.025 significance level given no interim 
analysis. Differences in LRC will be tested as described in Section 13.5.1. 
 
A subset analysis using only HPV- patients will compare the protocol treatment arms with 
respect to the primary and all the secondary endpoints (Section 13.2.1). In addition, subset 
analyses using patients treated with each radiation technique (IMRT alone vs. IMRT+ IGRT) 
will compare the protocol treatment arms with respect to the secondary endpoints of adverse 
events (Sections 13.1.2.1-13.1.2.3). 
13.7.7 
Time-Driven Definitive Analysis:  
The statistical analysis plan changes were done in accordance with the NCI Policy for Major 
Design Amendments for Ongoing Randomized Clinical Trials. The specifics for the changes 
were performed by a statistician independent from the trial. 
 
Due to a lower than expected event rate for the primary endpoint, overall survival (OS), 
throughout the trial (the trial will not reach the third interim analysis for possibly three more 
years), the primary endpoint analysis will be performed with the number of OS events reported 
through June 1, 2023 (or completion of this amendment, whichever is later). The proposed date 
allows for a minimum of 5 years of potential follow-up on all randomized patients. The primary 
endpoint analysis will use a one-sided alpha of 0.0183 as specified in the initial design (see first 
paragraph in Section 13.7.2). The original study design called for randomization of 634 patients 
(increased to 700 to allow for ineligibility and dropouts), which was projected to yield 372 
events, providing 80% power to detect a hazard ratio (HR) of 0.74, based on a one-sided, three 
interim analyses, and stratified logrank test at the overall 0.025 alpha level. 
 
Analysis of OS in the control arm using data as of 3/15/2023 yields estimated 5- and 10-year 
survival rates of 69% and 57%, respectively, with a total of 95 observed events (deaths) among 
287 patients. The number of observed events in years 5, 6, 7, 8, and 9 post-randomization was 
10, 1, 1, 3, 3, and 3, respectively.  With an additional 3 months of follow-up received to June 1, 
we therefore expect to see only about 1-2 additional deaths in the control arm, and thus 
assume there will be 97 control deaths and 97*.74=72 experimental arm deaths, or 169, by this 
time.   
 
The table below gives the power to detect an HR of 0.74 based on 169 events, as well as the 
HR that can be detected with 169 events at powers of 55%, 66%, and 79%. 
 
Projected # of OS events in 
both arms by 6/1/2023 
HR 
Power 
(1-sided alpha of 0.0183) 
169 
0.74 
45% 
169 
0.71 
55% 
169 
0.68 
66% 
169 
0.64 
79% 
Thus, there will be 45% power to detect the original assumed HR of 0.74.  With 79% power, a 
true HR of 0.64 can be detected. Note that this revised analysis plan was developed 
independent of any information from accruing data other than the current control group event 
rate. 
 
13.7.8 
Analysis for Reporting the Results with Addition of IGRT to IMRT 
The analysis of RT delivery technique (IMRT vs. IMRT with IGRT) will be done at same time as 
the initial cetuximab treatment analysis. Its results probably will be considered exploratory since 
the patients were randomized to the RT delivery technique. They will be reported separately 
from the cetuximab results. Only eligible patients who started IMRT and with follow-up 
information will be included in this analysis. The components of this analysis are: 
• 
Tabulation of all cases entered and any excluded from analysis with reasons for 
exclusion by RT techniques; 
• 
Distribution of important baseline prognostic variables and protocol treatment 
assignment by RT techniques; 
• 
Frequency and severity of adverse events by RT techniques. 
 
 

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The estimate for IGRT effect on LRC will be derived from a Cox model with other factors added 
to correct for possible serious imbalance in their distributions between the techniques. The 
estimate for IGRT effect on the XeQOLS and the FACT respectively will be derived from 
multivariate regression models with other factors added to correct for possible serious 
imbalance in their distributions between the two treatment technique patient groups. These 
imbalances are possible since patients are not randomized between IMRT and IMRT+ IGRT. 
The other factors include cetuximab treatment, tumor site, stage, patient age, pretreatment 
performance status, and type and extent of surgery performed prior to IMRT, These results will 
be viewed as hypothesis generating, not as definitively testing the addition of IGRT. 
13.7.9 
Analysis for Reporting PRO Data 
The analysis for hypotheses 1 and 3-6 in Section 13.2.4 will be done following the analyses of 
cetuximab treatment and the RT delivery techniques. The analysis of hypothesis 2 will be done 
as part of RT delivery technique analysis (Section 13.5.5) The results from these analyses will 
be considered exploratory, since the patient’s participation was strictly voluntary for each PRO 
assessment. The results probably will be reported separately from the cetuximab treatment 
results. Only eligible patients with follow-up information will be included in these analyses. 
13.7.10 
Analysis for Reporting Tumor Markers 
The analysis for the hypotheses for various tumor markers in Section 13.2.3 will be done 
following the analyses of cetuximab treatment and the RT delivery techniques. The results will 
be reported separately. Only eligible patients with both on-study and follow-up information will 
be included in these analyses. 
 
 
 

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13.8 
Gender and Minorities 
Men and women of all races and ethnic groups are eligible for this study. 
 
In conformance with the National Institutes of Health Revitalization Act of 1993 with regard to 
inclusion of women and minorities in clinical research, we have considered the possible 
interactions (treatment by race and treatment by gender). The study was designed under the 
assumption of the same results between the gender and among the races. Based on accrual to 
RTOG’s previous protocol, RTOG 0234, we project that 78% of patients enrolled on this study will 
be male, 90% white, and 4% Hispanic. The following table provides the projected number of 
patients in each race, ethnicity, and gender group. 
 
Projected Distribution of Gender and Minorities 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
4 
15 
19 
Not Hispanic or Latino 
172 
509 
681 
Ethnic Category: Total of all subjects 
176 
524 
700 
Racial Category 
American Indian or Alaskan Native 
0 
3 
3 
Asian 
3 
7 
10 
Black or African American 
3 
30 
33 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
170 
484 
654 
Racial Category: Total of all subjects 
176 
524 
700 

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2294-301, 1996. PMID: 8635098 

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APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (23-JAN-2013) 
*See Sections 11.1-11.3 for exceptions and details 
 
Assessments 
Within 8 wks prior to 
registration 
Within 4 wks prior to 
registration 
Within 2 wks prior to 
registration 
General H&P by Rad Onc 
and/or Med Onc 
X* 
ENT/Surgeon’s exam 
X* 
CT with contrast, or CT/PET, 
and/or MRI of H & N 
Recommended within 4 weeks prior to treatment 
Chest x-ray (or chest CT or 
CT/PET) 
X 
Pathology Assessment (Gross 
total resection within 7 wks 
prior to registration) 
X* 
Performance status 
X 
CBC w/ diff & AGC 
X 
Bilirubin, AST or ALT 
X 
Serum creatinine or creatinine 
clearance 
X 
Na, K, Cl, glucose, Ca, Mg, 
albumin 
X 
Serum pregnancy test (if 
applicable) 
X 
Dental eval 
Within 3 months prior to start of treatment 
Assessment of swallowing 
function 
Within 2 weeks prior to treatment 
Eval for G-tube placement 
Recommended within 4 weeks prior to treatment 
EKG 
Recommended within 8 weeks prior to treatment 
QOL/Functional Assessments: 
FACT-H&N; PSS-HN; EQ-5D; 
XeQOLS; DLQI 
Prior to treatment (Baseline) 

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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING RT (23-JAN-2013) 
*See Sections 11.1-11.3 for exceptions and details 
 
Assessments 
Weekly 
Every 3 wks 
As clinically indicated 
General H&P by Rad Onc 
and/or Med Onc 
X* 
CT with contrast, or CT/PET, 
and/or MRI of H & N 
X 
Chest x-ray (or chest CT or 
CT/PET) 
X 
Biopsy 
If suspicion of tumor 
recurrence 
Performance status 
X 
CBC w/ diff & AGC 
Prior to start of 
treatment 
Bilirubin, AST or ALT 
X 
Serum creatinine or 
creatinine clearance 
X 
Na, K, Cl, glucose, Ca, Mg, 
albumin 
X* 
Adverse event eval 
X 
Blood for research-if patient 
consents 
Prior to start of 
treatment 

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APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP (08-MAR-2018) 
*See Sections 11.1-11.3 for exceptions and details 
 
Both Arms: At 1 mo. 
post-XRT 
Both Arms: 
q3 mos. post-XRT, 
then q3 mos. x 2 yrs, 
q6 mos. x 3 yrs, then 
annually 
Both Arms: As 
clinically indicated 
General H&P by Rad Onc 
and/or Med Onc 
See Section 11.3 for details of assessments 
ENT/Surgeon’s exam 
CT with contrast, or CT/PET, 
and/or MRI of H & N 
As clinically indicated 
After 5 years, as 
clinically indicated 
Chest x-ray (or chest CT or 
CT/PET) 
X* 
Biopsy 
If suspicion of tumor 
recurrence 
Performance status 
X 
X 
CBC w/ diff & AGC 
X 
X 
Bilirubin, AST or ALT 
X* 
Serum creatinine or 
creatinine clearance 
See Section 11.2 for details of assessments 
Na, K, Cl, glucose, Ca, Mg, 
albumin 
See Section 11.2 for details of assessments 
Assessment of swallowing 
function 
X 
X 
Adverse event eval 
X 
X 
QOL/Functional 
Assessments: FACT-H&N; 
PSS-HN; EQ-5D; XeQOLS; 
DLQI 
At 3, 12, and 24 months from the end of radiation treatment 

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

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APPENDIX III: AJCC STAGING SYSTEM, 6TH EDITION 
 
 
 
 
STAGING-PRIMARY TUMOR (T) 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
 
LIP and ORAL CAVITY 
 
TX 
Primary tumor cannot be assessed 
T0 
No evidence of primary tumor 
Tis 
Carcinoma in situ 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4 (lip) 
Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face 
(i.e., chin or nose) 
T4a (oral 
cavity) 
Tumor invades adjacent structures (e.g., through cortical bone, into deep [extrinsic] muscle of 
tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of 
face 
T4b 
Tumor invades masticator space, pterygoid plates or skull base and/or encases internal 
carotid artery 
 
 
PHARYNX 
 
Oropharynx 
T1 
Tumor 2 cm or less in greatest dimension 
T2 
Tumor more than 2 cm but not more than 4 cm in greatest dimension 
T3 
Tumor more than 4 cm in greatest dimension 
T4a 
Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or 
mandible. 
T4b 
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base 
or encases carotid artery. 

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APPENDIX III (Continued) 
 
 
LARYNX 
 
Supraglottis 
T1 
Tumor limited to one subsite of supraglottis with normal vocal cord mobility 
T2 
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region 
outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform 
sinus) without fixation of the larynx. 
T3 
Tumor limited to larynx with vocal cord fixation and/or invades any of the following: 
postcricoid area, pre-epiglottic tissues, paraglottic space, and/or minor thyroid cartilage 
erosion (e.g., inner cortex). 
T4a 
Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, 
thyroid, or esophagus). 
T4b 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
 
Glottis 
T1 
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal 
mobility 
T1a 
Tumor limited to one vocal cord 
T1b 
Tumor involves both vocal cords 
T2 
Tumor extends to supraglottis and/or subglottis, or with impaired vocal cord mobility 
T3 
Tumor limited to the larynx with vocal cord fixation, and/or invades paraglottic space, and/or 
minor thyroid cartilage erosion (e.g., inner cortex). 
T4a 
Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, 
thyroid, or esophagus). 
T4b 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 
 
Subglottis 
T1 
Tumor limited to the subglottis 
T2 
Tumor extends to vocal cord(s) with normal or impaired mobility 
T3 
Tumor limited to larynx with vocal cord fixation 
T4a 
Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., 
trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, 
thyroid, or esophagus). 
T4b 
Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures. 

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APPENDIX III (Continued) 
 
REGIONAL LYMPH NODES (N) Excluding Nasopharynx 
 
NX 
Regional lymph nodes cannot be assessed 
N0 
No regional lymph node metastasis 
N1 
Metastasis in a single ipsilateral node, 3 cm or less in greatest dimension 
N2 
Metastasis in a single ipsilateral node, more than 3 cm, but not more than 6 cm in greatest 
dimension, or in multiple ipsilateral lymph nodes, none greater than 6 cm in greatest 
dimension, or bilateral or contralateral nodes, none more than 6 cm in greatest dimension 
N2a 
Metastasis in a single ipsilateral node more than 3 cm, but not more than 6 cm in greatest 
dimension 
N2b 
Metastasis in multiple ipsilateral nodes, none more than 6 cm in greatest dimension 
N2c 
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest 
dimension 
N3 
Metastases in a lymph node, more than 6 cm in greatest dimension 
 
DISTANT METASTASIS (M) 
 
MX 
Distant metastasis cannot be assessed 
M0 
No distant metastasis 
M1 
Distant metastasis 
 
 
 
STAGE GROUPING Excluding Nasopharynx 
Stage 0 
Tis, N0, M0 
Stage I 
T1, N0, M0 
Stage II 
T2, N0, M0 
Stage III 
T3, N0, M0 
T1-3, N1, M0 
Stage IVA 
 T4a, N0-2, M0 
Any T, N2, M0 
Stage IVB 
T4b, Any N, MO 
Any T, N3, M0 
Stage IVC 
Any T, Any N, M1 

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APPENDIX IV: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS 
 
 
Dental Care for Irradiated Patients 
Goals for a dental care program include: 
1. To reduce incidence of bone necrosis. 
2. To reduce incidence of irradiation caries. 
3. To allow proper fitting of dentures following treatment. 
 
Pre-irradiation Care and Procedures 
The patients may be grouped into four groups in accordance with the problems they present prior to irradiation. 
 
Group 1 
Includes edentulous patients. They may require surgical removal of any symptomatic cysts, infected retained root 
tips, or alveolar hyperplasia. These patients require hygiene instruction and precautionary instruction about 
trauma with premature use of a prosthesis. 
 
Group 2 
Includes those with poor dental hygiene, including those patients whose teeth are beyond repair by ordinary 
dental procedure, those with generalized oral sepsis, those with generalized periodontal disease, and those with 
chronic periapical abscesses or granulomas. 
 
Procedures performed on this group include removal of all remaining teeth prior to irradiation with primary closure 
and surgical preparation of the alveolar ridges to laterally support a prosthesis. There should be antibiotic 
coverage during the healing stage and adequate time prior to the start of radiation therapy. These patients need 
complete hygiene instruction and precautionary instruction about premature use of a prosthesis. 
 
Group 3 
Includes those in whom dental condition is fair, including those patients whose teeth are restored, ordinary dental 
procedures, periodontal pockets are less than 3 mm deep, carious lesions are not in proximity to the pulp, and no 
more than 20 restorable carious lesions are present. X-ray examinations show at least 1/2 of the bone still 
present around root surfaces. These patients require removal of any teeth that are non-salvageable in 
accordance with the above and restorations of the remaining teeth as required. The patients are instructed for 
dental prophylaxis and the patients utilize custom-made fluoride carriers. 
 
Group 4 
Includes those in whom dental hygiene is good. This includes patients who do not have severe malocclusion in 
whom few carious lesions are present. Carious lesions are not in close proximity to the pulp and are correctable 
by conventional methods. These patients require periodontal evaluation and dental prophylaxis training, 
restorations as needed, no extractions prior to radiation therapy, and fitting for custom carriers. 
 
Extraction of Teeth 
If extraction of teeth is necessary prior to radiation therapy, the bone must be contoured so that closure at the 
extraction site is possible. All loose spicules and sharp projections must be removed. The approximation of the 
gingival tissue must be such that the closure is neither too loose nor too tight. At least 10 days are required for 
adequate healing prior to initiation of therapy. 
 
Causative Factors 
The major causative factors appear to be the reduction of the amount of saliva and secondarily, reduced pH in the 
mouth. This occurs following high dose radiation to the major salivary glands using parallel opposed fields. The 
decay process usually occurs in the first year following radiation therapy. It tends to occur more quickly in teeth 
which have a large amount of root cementum exposed to those teeth with large amounts of plaque formation 
present. Doses of radiation in excess of 20 Gy to salivary tissue place the teeth at risk. 
 
Preventive Program 
The rationale behind the use of fluoride treatments is to make the tooth surfaces less susceptible to the decay 
process. This is accomplished by a combination of increasing fluoride concentration on the tooth surface and by 
the effect of fluoride on the plaque and flora that are present in the oral cavity. Adequate results are obtained by: 
1) cleansing the teeth thoroughly, followed by a good home care dental prophylaxis program, 2) construction of 

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APPENDIX IV (Continued) 
 
fluoride carriers, custom-made mouth guards, which provide local application of fluoride solution to the gingiva 
and tooth surfaces. Fluoride carriers are made individually with the use of casts. Material used for making a 
mouth guard is "Sta-Guard" plastic used in conjunction with vacutrole unit produced by Jelrus Technical Products, 
Corp., both of which are available through local dental supply. This material is molded to the cast impression and 
allowed to harden. A fluoride solution prepared at the M.D. Anderson Hospital is now available from the Emerson 
Laboratories, Inc., Dallas, Texas 75221. It has been used to coat the plastic carrier for use in the mouth. The 
patients are instructed to cleanse their teeth prior to placement of the carrier.  It is then worn in place for 5 
minutes each day. The patients are instructed to rinse their mouths thoroughly following the use of the carrier. 
This will be continued for an indefinite period of time. Close follow-up is necessary. 
 
Results 
In the 5-1/2 year program at the M.D. Anderson Hospital beginning in 1966, a study of 304 patients shows that 
the incidence of necrosis of the jaw was reduced to approximately 21% compared to 37% prior to initiation of the 
study. Groups 3 and 4 patients randomized with and without fluoride treatment showed reduction in radiation 
carries from 67% to 34% among Group 3 patients, and from 65% to 22% among Group 4 patients. 
 
Failure to Control Decay 
Management of failure to control radiation decay includes silver fillings with continued use of fluoride treatments. 
If the decay process is sufficiently advanced that a filling will no longer stay in place, these teeth are merely 
smoothed so that there will be no sharp, irritating edges. The mere existence of such a decayed tooth is not 
necessarily reason for extraction, for it must be remembered that extraction could lead to complications such as 
bone necrosis. 
 
Pulp exposure resulting from the decay process can usually be handled by use of antibiotics and/or root-canal 
therapy. 
 
Hypersensitivity of Teeth 
Occasionally, a patient will exhibit extreme sensitivity of the teeth secondary to diminished amounts of saliva. 
This has been shown to be reduced in incidence with the fluoride treatments. Should this problem become 
manifest, increasing the fluoride treatment to 10 to 15 minutes 3 times a day is recommended. 
 
Infections 
Infections occurring in patients under or after radiation therapy are best managed conservatively with good oral 
hygiene, irrigation and flushing procedures, and systemic antibiotics. 
 
Bone Necrosis 
The patients receiving radiation therapy to a high dose to the head and neck region have increased susceptibility 
to bone necrosis for several reasons including: impairment of normal metabolism, increased susceptibility to 
infection and severely limited repair process. Bone necrosis occurs most often after dental or oral surgery in 
patients who have been previously radiated. Conservative management should be tried first, though in more 
aggressive lesions a more radical approach may ultimately be necessary. 

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APPENDIX V: NRG ONCOLOGY FFPE SPECIMEN PLUG KIT INSTRUCTIONS (13-NOV-2017) 
 
This Kit allows sub-sampling of an FFPE block for submission to the NRG Oncology Biospecimen Bank. 
The plug kit contains a shipping tube and a punch tool. 
 
Step 1 
 If the block is stored cold, allow it to equilibrate for 30 minutes at room 
temperature. Place the punch tool on the paraffin block over the selected tumor 
area. (Ask a pathologist to select area with tumor.) Push the punch into the paraffin 
block. Twist the punch tool once around to separate the plug from the block. Then 
pull the punch tool out of the block. The punch should be filled with tissue sample. 
 
 
 
Step 2 
 Label the punch tool with the 
proper specimen ID and Block ID. 
DON’T remove specimen from the 
punch. 
 
Use a separate punch tool for 
every specimen. Call or e-mail us if 
you have any questions or need 
additional specimen plug kits. 
Site that have the capacity to 
embed the blocks may do so. They 
should submit a fresh H&E from 
the punch block. 
 
 
 
Step 3 
Once punch tool is labeled, place in shipping tube and mail to address 
below. Please do not mix specimens in the same tube. 
 
 
 
 
We will remove core specimen from the punch, embed in a paraffin block, and label with specimen ID. 
 
*NOTE: If your facility is uncomfortable obtaining the plug but wants to retain the tissue block, please send the 
entire block to the NRG Oncology Biospecimen Bank- San Francisco and we will sample a plug from the block 
and return the remaining block to your facility. Please indicate on the ST form the request to perform the plug 
procedure and return of the block. Include a return request form with a return airbill 
 
Ship specimen plug kit, specimen in punch tool, and all paperwork to the address below. For questions 
regarding collection/shipping or to order an FFPE Specimen Plug Kit, please contact the NRG Oncology 
Biospecimen Bank by e-mail: NRGBB@ucsf.edu or call 415-476-7864/Fax 415-476-5271. 
 
U.S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank—San Francisco 
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
 
Courier Address (FedEx, UPS, etc.): For Frozen Specimens or Trackable shipments 
NRG Oncology Biospecimen Bank—San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 

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APPENDIX VI: NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (13-NOV-2017) 
This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
Kit contents: (Note: Sites are responsible for providing blood draw tubes): 
 
• 
Thirty (30) 1 ml cryovials for plasma and serum – all time points 
• 
Three (3) 2 ml cryovials for whole blood 
• 
Biohazard bags (7) and Absorbent shipping material (7) 
• 
One Styrofoam container (inner) and Cardboard shipping (outer) box per case 
• 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
• 
Specimen Transmittal (ST) Form and Kit Instructions 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube 
❑ 
Label five1ml cryovials for the serum collected. Label them with the study and case number, 
collection date, time point, and clearly mark cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are 
unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 
hours of draw but must be noted on the ST Form. 
3. Aliquot a minimum of 0.5 ml serum into each of the five as many cryovials as are necessary for the 
serum collected labeled with study and case numbers, collection date, protocol time-point collected 
(e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”. 
4. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90 C, and store 
frozen until ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST 
Form. 
(B) Plasma (If requested): Purple Top EDTA tube #1 
❑ 
Label five1ml cryovials for the plasma collected. Label them with the study and case number, 
collection date, and time point, and clearly mark cryovials “plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM 
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the ST Form. 
3. If the interval between specimen collection and processing is anticipated to be more than one hour, 
keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot a minimum of 0.5 ml plasma into each of the five cryovials as necessary 
for the plasma collected labeled with study and case numbers, collection date, time point collected and 
clearly mark specimen as “plasma”. Avoid pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze tubes upright at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice. 
7. See below for storage conditions. 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the ST 
Form. 
(continued on next page) 

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RTOG 0920, Version Date: May 11, 2023 
 
APPENDIX VI 
 
BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 (one 5 ml or 10 ml tube) 
❑ 
Label three1ml cryovials as necessary for the whole blood collected..Label them with the study and case 
number, collection date, and time point, and clearly mark cryovials “blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0-2.0ml blood into three 2mlcryovials as necessary for the blood 
collected labeled with study and case numbers, collection date, time point collected and clearly mark 
specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze tubes upright immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to batch ship on dry ice. 
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on ST 
Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
❑ 
Store at –80C (-70C to -90C) until ready to ship. 
If a -80C Freezer is not available, 
▪ 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
▪ 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
▪ 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday 
only; Canada: Monday-Tuesday only). 
❑ 
Please indicate on Specimen Transmittal (ST) Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
❑ 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent 
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted. 
❑ 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
❑ 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard bag. 
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). 
Add padding to avoid the dry ice from breaking the tubes. 
❑ 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
(continued on next page) 

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APPENDIX VI 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
❑ 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
❑ 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
NRGBB@ucsf.edu or call (415)476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank—San Francisco 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu