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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
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This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network of NCTN organizations: the Alliance for Clinical Trials in Oncology, ECOG-ACRIN Medical Research Foundation, Inc., and SWOG.  
Study Team (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 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)
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
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Study Team Continued (11-MAY-2023)
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 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  
| 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:                                                                                                                                         | Dosimetrist                                                                                                                                                                                                                   |
| For questions concerning RT data submission                                                                                                   | Marsha Radden, R.T.(R)(T) NRG Oncology 50 South 16th Street, Suite 2800 Philadelphia, PA 19102 215-717-2757  mradden@acr.org                                                                                                  |
| RTQA:                                                                                                                                         | http://irochouston.mdanderson.org                                                                                                                                                                                             |
| For questions concerning RT Credentialing                                                                                                     | 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 |                                                                                                                                                                                                                               |  
| 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  |
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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.
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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.)                                                                                                           | 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. | 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. |
| Institutions with patients waiting  that are unable to use the Portal  should alert the CTSU  Regulatory Office immediately  by phone or email: 1-866-651- CTSU (2878), or  CTSURegHelp@coccg.org to  receive further instruction and support.                                                                       | Contact the CTSU Help Desk with  any OPEN-related questions by  phone or email: 1-888-823-5923,  or ctsucontact@westat.com.                                                                                                    |                                                                                                                                                                                        |
| Contact the CTSU Regulatory  Help Desk at 1-866-651-CTSU  (2878), or  CTSURegHelp@coccg.org for  regulatory assistance. The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific page located on the CTSU 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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table of contents

| SCHEMA                                                                                                                                                                         |                                       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| ELIGIBILITY CHECKLIST                                                                                                                                                          |                                       |
| 1.0 INTRODUCTION                                                                                                                                                               |                                       |
| 1.2 Study Design .                                                                                                                                                             |                                       |
| 1.3 Clinical Studies of Cetuximab in Head and Neck Cancer                                                                                                                      |                                       |
| 1.4 Safety of Cetuximab in SCCHN Clinical Studies  .                                                                                                                           |                                       |
| 1.5 Summary of Results of Investigational Program                                                                                                                              |                                       |
| 1.6 Use of High-Technology Radiotherapy (IMRT, IGRT) .                                                                                                                         |                                       |
| 1.7 Translational Science                                                                                                                                                      |                                       |
| 1.8 Quality of Life and Function Assessments                                                                                                                                   |                                       |
| 2.0 OBJECTIVES                                                                                                                                                                 |                                       |
| 2.2 Primary Objective                                                                                                                                                          |                                       |
| 2 Secondary Objectives .                                                                                                                                                       |                                       |
| 2.3 Tertiary Objectives (Exploratory)                                                                                                                                          |                                       |
| 3.0 PATIENT SELECTION                                                                                                                                                          |                                       |
| 3.1 Conditions for Patient Eligibility .                                                                                                                                       |                                       |
| 3.2 Conditions for Patient Ineligibility ............................................................................................................................32        |                                       |
| 4.0 PRETREATMENT EVALUATIONS/MANAGEMENT .................................................................................................33                                    |                                       |
| 4.1 Required Evaluations/Management                                                                                                                                            |                                       |
| 4.2 Highly Recommended Evaluations/Management ...........................................................................................................34                    |                                       |
| 5.0 REGISTRATION PROCEDURES  .                                                                                                                                                 |                                       |
| 5.1 RT-Specific Pre-Registration Requirments                                                                                                                                   |                                       |
| 5.2 Preregistration Requirements for Head and Neck Image-Guided Radiotherapy (IGRT) Treatment Approach35                                                                       |                                       |
| 5.3 Pre-Registration Requirements for IMRT Treatment Approach ............................................................................35                                   |                                       |
| 5.4 Data Submission to RTOG Using TRIAD ..................................................................................................................35                   |                                       |
| 5.5 Regulatory Pre-registration Reguirements ..........................................................................................................36                      |                                       |
| 5.6 Registration .                                                                                                                                                             |                                       |
| 6.0 RADIATION THERAPY  ....................................................................................................................................................40  |                                       |
| 6.1 Dose Specifications for both Arms .......................................................................................................................40                |                                       |
| 6.2 Technical Factors                                                                                                                                                          |                                       |
| 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                                                                                                                                                        |                                       |
| 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                                                                                                                                         |                                       |
| 7.0 DRUG THERAPY ...........................................................................................................................................................47 |                                       |
| 7.1 Arm 2 Treatment  ..................................................................................................................................................48      |                                       |
| 7.2 Cetuximab (IND Exempt)  .......................................................................................................................................48          |                                       |
| 7.3 Dose Modifications                                                                                                                                                         |                                       |
| 7.4 Modality Review                                                                                                                                                            |                                       |
| 7.5 Adverse Events .                                                                                                                                                           |                                       |
| 7.6 CTEP-AERS Expedited Reporting Requirements .                                                                                                                               |                                       |
| 8.0 SURGERY                                                                                                                                                                    |                                       |
| 8.1 Intermediate Risk of Recurrence ...................................................................................................................................60      |                                       |
| 8.2 Surgical Quality Assurance Reviews                                                                                                                                         |                                       |
| 9.0 OTHER THERAPY                                                                                                                                                              |                                       |
| 9.1 Permitted Supportive Therapy .                                                                                                                                             |                                       |
| 10.0 TISSUE/SPECIMEN SUBMISSION  .                                                                                                                                             |                                       |
| 10.1 Tissue/Specimen Submission                                                                                                                                                |                                       |
| 6                                                                                                                                                                              | RTOG 0920, Version Date: May 11, 2023 |  
| 10.2 Tissue Collection for EGFR: Required                                                                                            |
|--------------------------------------------------------------------------------------------------------------------------------------|
| 10.3 Tissue Collection for HPV Analysis: Required                                                                                    |
| 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 .                                                                                                                 |
| 10.7 Confidentiality/Storage                                                                                                         |
| 1.0 PATIENT ASSESSMENTS                                                                                                              |
| 1.1 Study Parameters .                                                                                                               |
| 1.2 Evaluation During Radiotherapy .                                                                                                 |
| 1.3 Evaluation in Foliow Up                                                                                                          |
| 1.4 Outcomes Criteria                                                                                                                |
| 1.5 Quality of Life and Functional Assessments .                                                                                     |
| 1.6 Criteria for Discontinuation of Protocol Treatment .                                                                             |
| 12.0 DATA COLLECTION                                                                                                                 |
| 12.1 Summary of Data Submission                                                                                                      |
| 12.2 Summary of Dosimetry Digital Data Submission                                                                                    |
| 13.0 STATISTICAL CONSIDERATIONS                                                                                                      |
| 13.1 Primary Endpoint                                                                                                                |
| 13.2 Secondary Endpoints                                                                                                             |
| 13.3 Tertiary Endpoints (Exploratory)                                                                                                |
| 13.4 Background and Sample Size Determination                                                                                        |
| 13.5 Patient Accrual .                                                                                                               |
| 13.6 Randomization                                                                                                                   |
| 13.7 Analysis Plan .                                                                                                                 |
| 13.8 Gender and Minorities                                                                                                           |
| REFERENCES                                                                                                                           |
| APPENDIX I .                                                                                                                         |
| APPENDIX II                                                                                                                          |
| APPENDIX III .                                                                                                                       |
| APPENDIX IV                                                                                                                          |
| APPENDIX V                                                                                                                           |
| APPENDIX VI                                                                                                                          |  
7
nrg oncology rtog 0920
table of contents

A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer  
| SCHEMA (25-JAN-2016) 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                                                     |                             |                                             |                                           |    |                                                    |
| A. IMRT is mandatory. Dose is 60 Gy prescribed to at least 95% of the PTV. If IGRT is used, it |                             |                                             |                                           |    |                                                    |  
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.
eligibility checklist - step 1
table of contents

(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?
eligibility checklist - step 1
(continued on next page)

(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 3.2.5.13.2.5.7?  
(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?
eligibility checklist - step 1
the following questions will be

1. Institutional person randomizingcase?  
(Y) 2. Has the Eligibility Checklist beencompleted? (Y) 3. In the opinion of the investigator, is the patient eligible?
(Continued on next page)  
| 4. Date informed consent signed   |
|-----------------------------------|  
| 5. Patient Initials (First MiddleLast)   |
|------------------------------------------| | 6. VerifyingPhysician   |
|-------------------------|  
| 7. Patient's ID   |
|-------------------|  
| 8. Date ofBirth   |
|-------------------|  
| 9. Race 10. Ethnicity 11. Gender   |
|------------------------------------|
eligibility checklist - step 1
eligibility checklist - step 1

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
eligibility checklist - step 2
eligibility checklist - step 1

1. Institutional person randomizingcase
(Y/N) 2. Is the patient able to continue protocoltreatment?  
  
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 MiddleLast)  
 5. VerifyingPhysician 6. PatientID
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, providereason:
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 marginreduction?
Continued on next page.  
ELIGIBILITY CHECKLIST - STEP 2 Institution \# (page 5 of 5) RTOG 0920 Case \# (assigned for Step 1)  
  
Completed by Date
eligibility checklist - step 2
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 nonmetastatic 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 nonsurgically (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.  
| One or More Risk Factors for Recurrence (Other Than Positive Margin/ECS)                           |                                                                                                                         |                |                                                                                                                      |
|----------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------|----------------|----------------------------------------------------------------------------------------------------------------------|
| Study                                                                                              | Patient Population                                                                                                      | Local-regional | Survival and/or                                                                                                      |
| /Number of pts                                                                                     | Control                                                                                                                 | Comments       |                                                                                                                      |
| Cooper (RTOG 95-01)                                                                                | 110 pts without ECS/+mgn                                                                                                | 80% (crude)    | 2-yr. DFS 63%.                                                                                                       |
| [2004]                                                                                             | but 2-4 + LN's                                                                                                          |                |                                                                                                                      |
| Cooper (RTOG 85-03)                                                                                | 108 pts with negative                                                                                                   |                |                                                                                                                      |
| [1998]                                                                                             | margins, N0-1 nodal stage  (without ECS)                                                                                | 83% (5-yr.)    |                                                                                                                      |
| EORTC                                                                                              | 101 pts with negative                                                                                                   | NS             | 2-yr. OS ~60%                                                                                                        |
| margins and no nodal ECS                                                                           |                                                                                                                         |                |                                                                                                                      |
| 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                                                                                               | 85% (crude)    | LRC was 77% for pts                                                                                                  |
| nodes without ECS                                                                                  | tx'd with Cobalt vs. 91%  for 6MV                                                                                       |                |                                                                                                                      |
| Pfreunder (2000)                                                                                   | 66 pts with close but                                                                                                   | 71% (5-yr)     | Sig. impact of RT dose                                                                                               |
| negative (<3mm) margins                                                                            | (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)                                                                                             | 65% (5-yr)     |                                                                                                                      |
| margins                                                                                            | Subgroup analyses from                                                                                                  |                |                                                                                                                      |
| Langendijk (2005)                                                                                  | 128 pts with perineural                                                                                                 | 69% (5-yr)     | a retrospective series of                                                                                            |
| invasion                                                                                           | 801 pts treated with  surgery + PORT.                                                                                   |                |                                                                                                                      |
| Langendijk (2005)                                                                                  | 155 pts with lymphovascular                                                                                             | 67% (5-yr)     |                                                                                                                      |
| invasion                                                                                           |                                                                                                                         |                |                                                                                                                      |
| The reason for the failure of high dose cisplatin to improve outcomes in patients without positive |                                                                                                                         |                |                                                                                                                      |  
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.  
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).  
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 platinumbased 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.  
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/m2initial 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.  
| Cetuximab                                                         | +   |
|-------------------------------------------------------------------|-----|
| Radiation  (n = 211)                                              |     |
| Locoregional control  Overall Survival a Cl = confidence interval |     |  
Median Duration 24.4 mo 14.0 mo 0.68 0.52-0.89) **0.005**  
Median duration 49.0 mo 29.3 mo 0.74 (0.57-0.97) **0.03**  
| Radiation  Alone (n = 213)   |
|------------------------------|  
| Hazard Ratio   | Stratified        |
|----------------|-------------------|
| (95% CL3 )     | Log-rank  p-value |  
The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented below: 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 a platinum-based chemotherapy. Patients received a 20-mg test dose of cetuximab on Day 1, followed by a 400-mg/m2initial 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 1.25.8 months).
eligibility checklist - step 2
1.4 safety of cetuximab in

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 Cetuximab plus Radiation Radiation Therapy Alone (n=208) (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 |
| Body System Preferred Term                                                                                                                                                            |    |    |    |    |  
| Incidence of Selected Adverse Events ( 10%)                                                                                                                                                                                                                                                                                                                                             |    |    |    |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|----|----|
| in Patients with Locoregionally Advanced SCCHN Cetuximab plus Radiation Radiation Therapy Alone (n=208) (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". Body System Preferred Term |    |    |    |    |  
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.
eligibility checklist - step 2
1.5 summary of results of

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).  
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 Cetuximab plus Irinotecan  Cetuximab Monotherapy  (n=354) (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  |
| Body System  Preferred                                                                                                                                                                                                       | a  |    |    |    |
| Term                                                                                                                                                                                                                         |    |    |    |    |  
| Incidence of Adverse Events ( 10%) in Patients with Advanced Colorectal Carcinoma Cetuximab plus Irinotecan  Cetuximab Monotherapy  (n=354) (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  Body System  Preferred a Term |    |    |    |    |  
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 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.
eligibility checklist - step 2
1.6 use of high-technology radiotherapy

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, 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 postRT 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 preplanned 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; nonradiation-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 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 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 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 AfricanAmericans, 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 wellbeing 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
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 (FACTH&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 cetuximabinduced 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 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 PSSHN 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 3month 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 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.
eligibility checklist - step 2
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;
- 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.
eligibility checklist - step 2
3.0 patient selection (07-apr-2014) note

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.  
- 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)]  
| 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; |  
- 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 normalizelevels.  
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.
eligibility checklist - step 2
4.0 pretreatment evaluations/management note this

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 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.
eligibility checklist - step 2
5.0 registration procedures (03-nov-2014) access

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.
eligibility checklist - step 2
note for this study imrt

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.
eligibility checklist - step 2
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.  
| Web Link for Procedures and Instructions: [www.irochouston.meanderson.org Treatment  Key Information Modality   |                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                   |
|-----------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Credentialing  Requirements                                                                                     | Photo                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                   |
| ns                                                                                                              | 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. To determine if your institution has completed the requirements above,                                                                                                                                      |                                                                                                                                                                                                                                                                                                                   |
| Credentialing                                                                                                   | ✓                                                                                                                                                                                                                                                                                                                                                                                                                                           | please complete a "Credentialing Status Inquiry Form" found under                                                                                                                                                                                                                                                 |
| Status Inquiry                                                                                                  | Credentialing on the IROC Houston QA Center website                                                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                   |
| Form                                                                                                            | (http://irochouston.mdanderson.org ).                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                   |
| Questionnaire                                                                                                   | ✓                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                                                                   |
| Facility                                                                                                        | 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 |                                                                                                                                                                                                                                                                                                                   |
| Phantom  Irradiation                                                                                            | ✓                                                                                                                                                                                                                                                                                                                                                                                                                                           | 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. |
| For  reduced  margins  only                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                   |
| IGRT                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                   |
| Verification  Study                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                   |
| Credentialing Issued to:                                                                                        | IROC Houston QA Center will notify the site that all desired credentialing                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                   |
| Institution                                                                                                     | 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.                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                   |
eligibility checklist - step 2
5.2 preregistration requirements for head

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.  
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 1-703-3909858.
eligibility checklist - step 2
5.5 regulatory pre-registration requirements (11-may-2023)

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. 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).
eligibility checklist - step 2
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.
eligibility checklist - step 2
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.)  
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.
eligibility checklist - step 2
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.
eligibility checklist - step 2
5.5.3 pre-registration requirements for canadian

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
.
eligibility checklist - step 2
5.5.4 pre-registration requirements for shipment

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)**
eligibility checklist - step 2
5.6.1 summary of procedures this

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 710 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.  
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.
eligibility checklist - step 2
6.0 radiation therapy (18-may-2015) see

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.