nrg oncology rtog 1016
phase iii trial of radiotherapy

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.
nrg oncology rtog 1016
study team (6/3/14)

Co-Principal Investigator/Radiation Oncology Radiation Oncology Co-Chair  
Andy Trotti, MD Paul Harari, MD Moffitt Cancer Center/University of South Florida University of Wisconsin Hospital 12902 Magnolia Drive 600 Highland Avenue Tampa, FL 33612 Madison, WI 53792 813-745-3547/FAX 813-745-7231 608-263-5009/FAX 608-262-6256 trotti@moffitt.org harari@humonc.wisc.edu Co-Principal Investigator/Pathology &  
Translational Research Surgical Oncology Co-Chair  
Maura Gillison, MD, PhD Erich Sturgis, MD, MPH Ohio State University Medical Center MD Anderson Cancer Center  
420 W. 12th Avenue, Room 690 1515 Holcombe Blvd  
Columbus, OH 43210 Houston, TX 77030 614-247-4589/FAX 614-688-4245 713-792-5432/FAX 713-794-4662 maura.gillison@osumc.edu esturgis@mdanderson.org Medical Oncology Co-Chair Medical Physics Co-Chair David J. Adelstein, MD James Galvin, PhD Cleveland Clinic Taussig Cancer Institute Jefferson Medical College  
9500 Euclid Avenue, Desk R35 111 S. 11th Street  
Cleveland, OH 44195 Philadelphia, PA 19107  
216-444-9310/FAX 216-444-9464 215-955-8855/FAX 215-955-0412 adelstd@ccf.org james.galvin@mail.tju.edu  
Radiation Oncology Co-Chair Medical Physics and Radiobiology Co-Chair Avraham Eisbruch, MD Søren Bentzen, PhD  
University of Michigan Medical Center University of Maryland  
1500 E. Medical Center Drive, Box 0010 655 W. Baltimore St., HH 109D Ann Arbor, MI 48109 Baltimore, MD 21201  
734-936-9337/FAX 734-763-7370 410-706-8506/FAX 410-706-8548  
eisbruch@umich.edu sbentzen@som.umaryland.edu  
Study Chairs continued on next page
nrg oncology rtog 1016 phase
study team (continued) (2/23/16)

Pathology Co-Chair Hearing Assessment Co-Chair Richard Jordan, DDS, PhD Christina L. Runge, PhD
NRG Oncology Biospecimen Bank Medical College of Wisconsin University of California San Francisco 9200 W. Wisconsin Avenue 1657 Scott St., Rm 223 Milwaukee, WI 53226 San Francisco, CA 94115 414-805-5562/FAX 414-805-7936 415-476-7864/FAX 415-476-5271 chrunge@mcw.edu richard.jordan@ucsf.edu Quality of Life Co-Chair ECOG-ACRIN Co-Chair/Medical Oncology Jolie Ringash, MD, MSc Barbara Burtness, MD The Princess Margaret Hospital Yale University School of Medicine 610 University Avenue 333 Cedar Street Toronto, Ontario, Canada M5G 2M9 New Haven, CT 06520 416-946-4662/FAX 416-946-2111 203-737-7636/FAX 203-785-4116 jolie.ringash@rmp.uhn.on.ca Barbara.Burtness@yale.edu PRO-CTCAE Co-Chair ECOG-ACRIN Co-Chair/Surgical Oncology Ethan Basch, MD John A. Ridge, MD Univ. Of N. Carolina-Chapel Hill Fox Chase Cancer Center 170 Manning Dr., Physician's Office Bldg. 333 Cottman Avenue Chapel Hill, NC 27599 Philadelphia, PA 19111 919-843-3055/FAX 919-966-6735 215-728-3517/FAX 215-214-4222 ebasch@med.unc.edu drew.ridge@fccc.edu Cost Utility Co-Chair Senior Statistician André Konski, MD Qiang Zhang, PhD The Chester County Hospital NRG Oncology 701 E. Marshall Street 1818 Market Street, Suite 1720 West Chester, PA 19380 Philadelphia, PA 19103 610-431-5530/FAX 610-431-5144 215-574-3197/FAX 215-928-0153 andre.konski@uphs.upenn.edu ZhangQ@nrgoncology.org Employment Status Co-Chair Victoria Blinder, MD, MSc Memorial Sloan-Kettering Cancer Center 307 E. 63rd Street, Second Floor New York, NY 10065 646-735-8078/FAX 646-735-0011 blinderv@mskcc.org
nrg oncology rtog 1016 phase
study team (continued) (2/23/16)

| Protocol Agents (10/17/13)   |            |       |        |
|------------------------------|------------|-------|--------|
| Agent                        | Supply     | NSC # | IND #  |
| Cisplatin                    | Commercial | N/A   | Exempt |
| Cetuximab                    | Commercial | N/A   | Exempt |  
Participating Sites (10/17/13)
US Only Canada Only US and Canada Approved International Member Sites  
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.  
| Document History     |                     |                   |
|----------------------|---------------------|-------------------|
|                      | Version/Update Date | Broadcast Date    |
| Amendment 8          | February 23, 2016   | March 28, 2016    |
| Closure              | July 31, 2014       | July 31, 2014     |
| Amendment 7          | July 16, 2014       | July 31, 2014     |
| Amendment 6          | June 3, 2014        | July 31, 2014     |
| Update               | March 26, 2014      | March 26, 2014    |
| Update               | December 10, 2013   | December 10, 2013 |
| Re-Opened to Accrual | October 17, 2013    | December 10, 2013 |
| Amendment 5          | October 17, 2013    | December 10, 2013 |
| Amendment 4          | June 25, 2013       | August 5, 2013    |
| Closure              | June 25, 2013       | August 2, 2013    |
| Update               | December 4, 2012    | December 4, 2012  |
| Amendment 3          | September 20, 2012  | December 4, 2012  |
| Amendment 2          | June 28, 2012       | July 17, 2012     |
| Update               | January 9, 2012     | January 9, 2012   |
| Amendment 1          | December 14, 2011   | January 9, 2012   |
| Update               | November 3, 2011    | November 3, 2011  |
| Update               | June 9, 2011        | June 9, 2011      |
| Activation           | June 9, 2011        | June 9, 2011      |
phase iii trial of radiotherapy
study team (continued) (2/23/16)

| CANCER TRIALS SUPPORT UNIT (CTSU) CONTACT INFORMATION (2/23/16)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                        |                                                                                                                                                    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|
| To submit site                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | For patient enrollments:                                                                               | Submit study data directly to the Lead                                                                                                             |
| registration documents:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Cooperative Group unless otherwise  specified in the protocol:                                         |                                                                                                                                                    |
| CTSU Regulatory Office  1818 Market Street, Suite  1100  Philadelphia, PA 19103  Phone - 1-866-651-CTSU  Fax - 215-569-0206  Email:  CTSURegulatory@ctsu.coc cg.org (for submitting  regulatory documents only)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Please refer to Section 5.0 of the protocol for  instructions on using the  OPEN system.               | NRG Oncology  1818 Market Street, Suite 1720  Philadelphia, PA 19103  Submit data electronically via the NRG  Oncology/RTOG web site, www.rtog.org |
| Contact the CTSU Help  Desk with any OPENrelated questions at  ctsucontact@westat.com.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Do not submit study data or forms to  CTSU Data Operations. Do not copy the  CTSU on data submissions. |                                                                                                                                                    |
| The most current version of the study protocol and all supporting documents must be downloaded  from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  Access to the CTSU members' web site is managed through the Cancer Therapy and Evaluation  Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on  with CTEP-IAM username and password.  For patient eligibility or treatment-related questions Contact the Study PI of the Lead Protocol  Organization.  For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU  Help Desk by phone or e-mail:  CTSU General Information Line - 1-888-823-5923, or ctsucontact@westat.com. All calls and  correspondence will be triaged to the appropriate CTSU representative.  For detailed information on the regulatory and monitoring procedures for CTSU sites please  review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members' web  site https://www.ctsu.org > education and resources tab > CTSU Operations Information >CTSU  Regulatory and Monitoring Policy  The CTSU web site is located at https://www.ctsu.org |                                                                                                        |                                                                                                                                                    |
phase iii trial of radiotherapy
table of contents (3/26/14)

| Table of Contents (3/26/14)                                                                                                                                |                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA .                                                                                                                                                   |                                                                                                                                                   |
| ELIGIBILITY CHECKLIST - STEP 1 .                                                                                                                           |                                                                                                                                                   |
| ELIGIBILITY CHECKLIST –STEP 2                                                                                                                              |                                                                                                                                                   |
| 1.0                                                                                                                                                        | INTRODUCTION                                                                                                                                      |
| 1.1                                                                                                                                                        | Background .                                                                                                                                      |
| 1.2                                                                                                                                                        | RTOG 1016 Trial Design and Rationale .                                                                                                            |
| 1.3                                                                                                                                                        | RATIONALE FOR ELIGIBILITY                                                                                                                         |
| 1.4                                                                                                                                                        | RATIONALE FOR STUDY Arms .                                                                                                                        |
| Toxicity, Patient-Reported Outcomes (PROs) and Quality of Life (QOL) ...............................................20                                     |                                                                                                                                                   |
| 1.5                                                                                                                                                        | OO                                                                                                                                                |
| 1.6                                                                                                                                                        |                                                                                                                                                   |
| 1.7                                                                                                                                                        | Epidemiological and Translational Research ....................................................................................................30 |
| 2.0                                                                                                                                                        | OBJECTIVES                                                                                                                                        |
| 2.1                                                                                                                                                        | Primary Objective                                                                                                                                 |
| 2.2                                                                                                                                                        | Secondary Objectives .                                                                                                                            |
| 3.0                                                                                                                                                        | PATIENT SELECTION                                                                                                                                 |
| 3.1                                                                                                                                                        | Conditions for Patient Eligibility .                                                                                                              |
| 3.2                                                                                                                                                        | Conditions for Patient Ineligibility .                                                                                                            |
| 4.0                                                                                                                                                        | PRETREATMENT EVALUATIONS/MANAGEMENT                                                                                                               |
| 4.1                                                                                                                                                        | Required Evaluations/Management                                                                                                                   |
| 4.2                                                                                                                                                        | Highly Recommended Evaluations/Management                                                                                                         |
| 5.0                                                                                                                                                        | REGISTRATION PROCEDURES                                                                                                                           |
| 5.1                                                                                                                                                        | Image-Guided Radiotherapy (IGRT)                                                                                                                  |
| 5.2                                                                                                                                                        | Pre-Registration Reguirements for IGRT Treatment Approach ............................................................40                          |
| Pre-Registration Reguirements for IMRT Treatment Approach                                                                                                  |                                                                                                                                                   |
| 5.3                                                                                                                                                        | D Digital RT Data Submission Using TRIAD .....................................................................................................41  |
| 5.4                                                                                                                                                        |                                                                                                                                                   |
| 5.5                                                                                                                                                        | Regulatory Pre-Registration Reguirements ............................................................................................41           |
| 5.6                                                                                                                                                        | Registration for Use of  the CASI System and iPAD................................................................................43               |
| 5.7                                                                                                                                                        | Registration .                                                                                                                                    |
| 6.0                                                                                                                                                        | RADIATION THERAPY                                                                                                                                 |
| 6.1                                                                                                                                                        | Dose Specifications                                                                                                                               |
| 6.2                                                                                                                                                        | T THE PROPER OF THE PROPER                                                                                                                        |
| 6.3                                                                                                                                                        | Localization, Simulation, and Immobilization ........................................................................................47           |
| 6.4                                                                                                                                                        | T Treatment Planning/Target Volumes                                                                                                               |
| 6.5                                                                                                                                                        | T The Planning and Delivery .                                                                                                                     |
| 6.6                                                                                                                                                        | CC                                                                                                                                                |
| 6.7                                                                                                                                                        | Documentation Requirements for IMRT Approach .                                                                                                    |
| 6.8                                                                                                                                                        | CC                                                                                                                                                |
| R.T. Quality Assurance Reviews                                                                                                                             |                                                                                                                                                   |
| 6.9                                                                                                                                                        |                                                                                                                                                   |
| 6.10                                                                                                                                                       | Radiation Therapy Adverse Events                                                                                                                  |
| 6.11                                                                                                                                                       | Radiation Therapy Adverse Event Reporting                                                                                                         |
| 7.0                                                                                                                                                        | DRUG THERAPY .                                                                                                                                    |
| T Treatment                                                                                                                                                |                                                                                                                                                   |
| 7.1                                                                                                                                                        |                                                                                                                                                   |
| 7.2                                                                                                                                                        | Cisplatin (for Arm 1 patients)                                                                                                                    |
| 7.3                                                                                                                                                        | Cetuximab (for Arm 2 patients) .                                                                                                                  |
| 7.4                                                                                                                                                        | Dose Modifications for Cisplatin                                                                                                                  |
| 7.5                                                                                                                                                        | Dose Modifications for Cetuximab .                                                                                                                |
| 7.6                                                                                                                                                        | Modality Review                                                                                                                                   |
| 7.7                                                                                                                                                        | Adverse Events .                                                                                                                                  |
| 7.8                                                                                                                                                        | CTEP-AERS Expedited Reporting Requirements                                                                                                        |
| 8.0                                                                                                                                                        | SURGERY                                                                                                                                           |
| 8.1                                                                                                                                                        | Post-Treatment Imaging/Timing                                                                                                                     |
| 8.2                                                                                                                                                        | Post-Treatment Surgical Salvage of Residual Disease ..........................................................................67                  |
| 9.0                                                                                                                                                        | OTHER THERAPY                                                                                                                                     |
| Permitted Supportive Therapy ...........................................................................................................................67 |                                                                                                                                                   |
| 9.1                                                                                                                                                        |                                                                                                                                                   |  
| 9.2                                                                                                          | Non-permitted Supportive Therapy .................................................................................................................68   |
|--------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|
| 10.0                                                                                                         | TISSUE/SPECIMEN SUBMISSION .                                                                                                                           |
| 10.1                                                                                                         | Tissue/Specimen Submission .                                                                                                                           |
| 10.2                                                                                                         | Specimen Collection For Central p16 Analysis .................................................................................................68       |
| 10.3                                                                                                         | Specimen Collection for Tissue Banking and Translational Research ...............................................69                                    |
| RE RESEARCH AND IN THE PROPOSITION A                                                                         |                                                                                                                                                        |
| 10.4                                                                                                         | Confidentiality/Storage                                                                                                                                |
| 10.5                                                                                                         |                                                                                                                                                        |
| 11.0                                                                                                         | PATIENT ASSESSMENTS                                                                                                                                    |
| 11.1                                                                                                         | Study Parameters.                                                                                                                                      |
| 11.2                                                                                                         | Pre-Treatment Evaluations                                                                                                                              |
| 1.3                                                                                                          | Evaluation During Radiotherapy .                                                                                                                       |
| 1.4                                                                                                          | Evaluation in Follow Up                                                                                                                                |
| 1.5                                                                                                          | Measurement of Response/Progression                                                                                                                    |
| 1.6                                                                                                          | Criteria for Discontinuation of Protocol Treatment ............................................................................................72      |
| 1.7                                                                                                          |                                                                                                                                                        |
| 12.0                                                                                                         | DATA COLLECTION                                                                                                                                        |
| 12.1                                                                                                         | Summary of Data Submission .                                                                                                                           |
| 12.2                                                                                                         | Summary of Dosimetry Digital Data Submission ...........................................................................................75             |
| 13.0                                                                                                         | STATISTICAL CONSIDERATIONS                                                                                                                             |
| 13.1                                                                                                         | Primary Endpoint                                                                                                                                       |
| Secondary Endpoints                                                                                          |                                                                                                                                                        |
| 13.2                                                                                                         |                                                                                                                                                        |
| 13.3                                                                                                         | Randomization and Stratification ...................................................................................................................76 |
| 13.4                                                                                                         | Sample Size                                                                                                                                            |
| 13.5                                                                                                         | Analysis Plan                                                                                                                                          |
| 13.6                                                                                                         | Statistical Considerations for Translational Research ..............................................................................81                 |
| 13.7                                                                                                         | Statistical Considerations for Quality of Life .                                                                                                       |
| 13.8                                                                                                         | Gender and Minorities                                                                                                                                  |
| REFERENCES                                                                                                   |                                                                                                                                                        |
| APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS...................................95            |                                                                                                                                                        |
| APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT ............................ 96              |                                                                                                                                                        |
| APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS IN FOLLOW UP                                                  |                                                                                                                                                        |
| APPENDIX II:  ZUBROD PERFORMANCE SCALE                                                                       |                                                                                                                                                        |
| APPENDIX III: STAGING SYSTEM                                                                                 |                                                                                                                                                        |
| APPENDIX IV: MANAGEMENT OF DENTAL PROBLEMS IN IRRADIATED PATIENTS ..........................103              |                                                                                                                                                        |
| APPENDIX V: INSTRUCTIONS FOR RTOG 1016 BIOSPECIMEN COLLECTION .......................................... 105 |                                                                                                                                                        |
| APPENDIX VI: DENTAL TOOTH COUNT DIAGRAM                                                                      |                                                                                                                                                        |
| APPENDIX VII: RTOG 1016 DENTAL EFFECTS HEALTH SCALE                                                          |                                                                                                                                                        |
nrg oncology
table of contents (3/26/14)

RTOG 1016 Phase III Trial of Radiotherapy Plus Cetuximab versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer  
|                                                                                                                                                                                | T Stage            |                                       |                                |                                            |                                            |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------|---------------------------------------|--------------------------------|--------------------------------------------|--------------------------------------------|
|                                                                                                                                                                                | 1. T1-2            |                                       |                                |                                            |                                            |
| R                                                                                                                                                                              | S                  | 2. T3-4                               | R                              | Arm 1 (Control):                           |                                            |
| E                                                                                                                                                                              | T                  | N Stage                               | A                              | Accelerated IMRT, 70 Gy for 6 weeks        |                                            |
| G                                                                                                                                                                              | Mandatory p16      | R                                     | 1. N0-2a                       | N                                          | + high dose DDP (100 mg/m2 ) Days 1 and 22 |
| I                                                                                                                                                                              | analysis           | A                                     | 2. N2b-3                       | D                                          | (Total: 200 mg/m2 )                        |
| S                                                                                                                                                                              | T                  | Zubrod                                | O                              |                                            |                                            |
| T                                                                                                                                                                              | I                  | Performance                           | M                              | Arm 2: Accelerated IMRT, 70 Gy for 6 weeks |                                            |
| E                                                                                                                                                                              | F                  | Status                                | I                              | + cetuximab (400 mg/m2 )                   |                                            |
| R                                                                                                                                                                              | Y                  | 1. 0                                  | Z                              | loading dose pre-IMRT, then                |                                            |
|                                                                                                                                                                                | 2. 1               | E                                     | 250 mg/m2  weekly during IMRT, |                                            |                                            |
|                                                                                                                                                                                | Smoking History    | and for 1 week after IMRT for a total |                                |                                            |                                            |
|                                                                                                                                                                                | 1. ≤ 10 pack-years | of 8 doses of cetuximab               |                                |                                            |                                            |
|                                                                                                                                                                                | 2. > 10 pack-years |                                       |                                |                                            |                                            |
| Patients must be positive for p16, determined by the Innovation Center CLIA lab at The  Ohio State University (OSU) prior to Step 2 registration (randomization); see 10.2 for |                    |                                       |                                |                                            |                                            |  
2. > 10 pack-years  
Patients must be positive for p16, determined by the Innovation Center CLIA lab at The  
Ohio State University (OSU) prior to Step 2 registration (randomization); see 10.2 for  
details of tissue submission. Patients must consent to submission of tissue for this analysis. Patients also must consent to provide their smoking history by completing that portion of the computer-assisted self interview (CASI) head and neck risk factor survey tool.  
For this study, IMRT is mandatory. IGRT credentialing is mandatory when using PTV margins < 5 mm. See Section 5.0 for required pre-registration credentialing for IMRT (and for IGRT, if used for margin reduction).  
Patient Population: (See Section 3.0 for Eligibility) Squamous cell carcinoma of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); stage T1-2, N2a-3, or T3-4 any N; patient tumor must be p16 positive
nrg oncology
eligibility checklist - step 1

____ (Y) 1. Is there pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls)? **Note**: Cytologic diagnosis from a cervical lymph node (from a paraffin block, not from smears) is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage).  
______(Y) 2. Does the patient have clinically or radiographically evident measurable disease at the primary site or at nodal stations? (Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving < 4 nodes are permitted and considered as non-therapeutic nodal excisions. Fine needle aspirations of the neck are insufficient due to limited tissue for central review. Biopsy specimens from the primary or nodes measuring at least 3mm-5mm are required).  
_____(Y) 3. Does the patient have clinical stage T1-2, N2a-N3 or T3-4, any N including no distant metastasis?  
_____(Y) 4. Was a general history and physical examination performed by a radiation oncologist and medical oncologist within 8 weeks prior to registration?  
_____(Y) 5. Was the patient examined by an ENT or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to registration?  
_____(Y) 6. Was the imaging specified in Section 3.1.4.3 performed within 8 weeks prior to registration?  
_____(Y) 7. Was the patient's Zubrod Performance Status 0-1 within 2 weeks prior to registration? _____(Y) 8. Is the patient > 18 years of age? _____(Y) 9. Does the patient have adequate bone marrow, hepatic, and renal function as specified in Section 3.1?  
_____(Y) 10. Has the patient agreed to provide their smoking history via the computer-assisted self interview (CASI) head and neck risk factor survey?  
_____(Y) 11. 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) 12. If a woman of child bearing potential or sexually active male, is the patient willing to use effective contraception throughout their participation in the treatment phase of the study and at least 60 days following the last study treatment?  
Continued on next page
eligibility checklist - step 1
nrg oncology institution # rtog

_____(Y) 13. If the patient is HIV positive, does the patient have no prior AIDS-defining illness and have CD4 cells of at least 350/mm3?  
_____(Y) 14. Did the patient provide study specific informed consent prior to study entry, including consent for mandatory submission of tissue for required, central p16 review and consent to participate in the computer-assisted self interview (CASI) survey questions regarding smoking history?  
_____(N) 15. Does the patient have cancer considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip) nasopharynx, hypopharynx, or larynx?  
_____(N) 16. Does the patient have a carcinoma of the neck of unknown primary origin? _____(N) 17. Does the patient have Stage T1-2, N0-1 cancer? _____(N) 18. Does the patient have distant metastasis or adenopathy below the clavicles? _____(N) 19. Was a gross total excision of both primary and nodal disease performed? (This includes tonsillectomy, local excision of primary site and nodal excision that remove all clinically and radiographically evident disease).  
_____(N) 20. Does the patient have simultaneous primaries or bilateral tumors? _____(N) 21. Does the patient have prior invasive malignancy (except non-melanomatous skin cancer)
unless disease free for a minimum of 3 years?  
_____(N) 22. Did the patient have prior systemic chemotherapy for the study cancer? (prior chemotherapy for a different cancer is allowable).  
_____(N) 23. Did the patient have prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields?  
_____(N) 24. Does the patient have any of the severe, active co-morbidities specified in Section 3.2? _____(N) 25. Does the patient have a prior allergic reaction to cisplatin or cetuximab? _____(N) 26. Has the patient received prior cetuximab or other anti-EGFR therapy?
eligibility checklist - step 1
eligibility checklist - step 1

(Y) 2. Has the Eligibility Checklist been completed? 9. Race 10. Ethnicity 11. Gender  
(Y/N) 22. Have you obtained the patient's consent for his or her blood to be kept for use in research about other health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
| (Y) 3.   | In the opinion of the investigator, is the patient eligible?   |                                                                                                                                                                                                       |
|----------|----------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| (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)? |  
4. Date informed consent signed  
5. Patient Initials (First Middle Last) 6. Verifying Physician 7. Patient ID 8. Date of Birth 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's name
eligibility checklist - step 1
eligibility checklist -step 1 (10/17/13)

(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. Did the patient agree to complete the entire computer-assisted self interview
(CASI) survey (not just the required smoking history portion) at baseline?  
| (Y/N)   | 25.   | Did the patient agree to complete the demographic work status questionnaire at   |
|---------|-------|----------------------------------------------------------------------------------|  
26 Specify T stage (T1-2 vs. T3-4) 27. Specify N stage (N0-2a vs. N2b-3) 28. Zubrod performance status (0 vs. 1)  
(Y/N) 29. Will IGRT be used for patient positioning?  
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  
| The patient's smoking history for stratification will be provided to NRG Oncology  by the required completion of the computer-assisted self interview (CASI) head  and neck risk factor survey by the patient (see Section 3.1.10).   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| (Y/N) 30.   | Will IGRT be used for patient positioning and margin reduction?   |
|-------------|-------------------------------------------------------------------|
eligibility checklist -step 2 (10/17/13)
eligibility checklist -step 1 (10/17/13)

1. Institutional person randomizing case  
 (Y/N) 2. Is the patient able to continue protocol treatment? 3. If no, specify the reason the patient cannot continue to Step 2:
1) progression of disease; 2) patient is not p16 positive; 3) patient refusal; 4) physician preference; 5) failure to submit tissue assay; 6) other Specify the reason the patient cannot continue to Step 2.  
  
7. Calendar Base Date (for Step 2) 8. Randomization date: (for Step 2)
______ (Y/N) 9. Is the patient positive for p16 (determined by the OSU Innovative Center CLIA lab)? Completed by Date  
  
  
4. Patient's Initials 5. Verifying Physician 6. Patient's ID number
eligibility checklist -step 2 (10/17/13)
1.0 introduction 1.1 background

1.1.1 Oropharynx Cancer: Current State of Practice and Purpose of This Trial Non-operative management of oropharynx cancer has become the preferred approach over the last decade (NCCN). Advances in combining systemic therapy and radiation technology have been associated with improved survival and declining use of surgery, although at the cost of increased acute and late toxicity burden (GORTEC; TAME; RTOG 0129). The extent to which improved outcomes are attributable to advances in therapy or shifts in the biology and etiology of oropharynx carcinoma is now under intense scrutiny (Gillison 2010). The recent recognition and rapid rise in the incidence of human papilloma virus-associated carcinoma of the oropharynx has prompted a re-evaluation of past trial outcomes and a call for HPV-specific studies to rigorously evaluate new prognostic factors and new treatment approaches with less morbidity. The overall goal of this trial is to identify a less toxic approach in HPV-associated cancer of the oropharynx with the high survival currently associated with aggressive chemoradiation approaches. We aim to show that targeted bioradiation will substantially reduce the burden of acute toxicity, result in faster recovery and return to function, carry lower rates of late effects, with similar rates of long-term survivorship, compared to conventional chemoradiation. Acknowledgments: Clinical aspects of the present study design were informed by numerous investigators in the head and neck research community who participated in discussions conducted by the NCI Previously Untreated Locally-Advanced Task Force (PULA) (a subcommittee of the NCI H&N Steering Committee) led by Drs. David Adelstein and Drew Ridge, as well as contributions form the Quality of Life (QOL)/Toxicity Working Group led by Jolie Ringash under the direction of PULA. The translational objectives and biospecimen selections were informed by numerous investigators who participated in discussions conducted by the NCI Head and Neck Tumor Biology and Imaging Task Force lead by Drs. John Waldron and Thomas Carey.  
1.1.2 Lessons from Past Phase III Trials Altered fractionation in radiation therapy (RT) alone has been shown to improve local-regional control (LRC) with small impact on survival. Concurrent chemoradiation became standard of care with larger gain in survival (meta-analysis). RTOG 0129 compared once a day RT with accelerated RT plus chemotherapy. There was not a difference in tumor control or survival outcomes. While the role of fractionation in the chemotherapy setting has not been fully settled, this trial suggests that accelerated RT can be traded for 1 dose of cisplatin to effectively offset tumor repopulation. When considering all head and neck cancer sites, randomized clinical trials investigating primary radiotherapy alone have demonstrated that hyperfractionation with either accelerated or concomitant boost primary radiation therapy improved local-regional control in comparison to standard fractionation radiotherapy (Fu 2000). Meta-analyses indicate that these altered fractionation schedules may translate into survival gains (Bourhis 2006). Six-fractions per week (weeks 2-6) is supported by the DAHANCA randomized trial (Overgaard 2003) and has become a common U.S. standard (NCCN H&N Guidelines 2010; http://www.nccn.org/professionals/physician_gls/f_guidelines.asp). This schedule facilitates the application of IMRT using integrated boost planning (dose painting) and has become the most common technique among NRG Oncology centers. This will also be the standard used in RTOG 1016. With regards to chemoradiation, only a few randomized controlled trials have restricted enrollment to patients with a diagnosis of oropharyngeal cancer, and the majority have compared primary radiotherapy to chemoradiotherapy. A GORTEC trial (94-01) demonstrated improved 5-year overall survival, disease-free survival, and local-regional control with chemoradiotherapy with carboplatin/5-FU compared to standard fractionation radiotherapy
(Denis 2004). An Italian 3-arm phase III trial restricted to oropharyngeal cancer patients demonstrated a similar, although non-significant, doubling of overall, relapse-free, and localregional control with standard fractionation radiotherapy and concomitant carboplatin/5-FU
therapy when compared to radiotherapy alone (either standard or hyperfractionated radiotherapy) [Fallai 2006]. Meta-analyses also indicate superior survival for patients when treated with concurrent chemoradiotherapy when compared to standard fractionation radiotherapy alone, and subgroup analyses indicate patients with oropharyngeal cancer benefit
(Pignon 2009). There is an estimated 6.5% absolute benefit in survival at 5-years with concomitant chemotherapy, and the benefit appears superior for platinum monotherapy when compared to other chemotherapy regimens.  
1.1.3 Epidermal Signaling, Head and Neck Cancer. and Radiation Response 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. Inhibition of EGFR signaling by means of either antibody blockage of EGF binding or small molecule inhibition of the cytoplasmic tyrosine kinase domain has been shown to increase radiation responsiveness in vitro. Extensive clinical data indicate that EGFR over expression is associated with poor overall survival and decreased local-regional control after radiotherapy. A recently completed correlative study in RTOG 90-03 confirmed that EGFR expression, as measured by immunohistochemistry, was higher than the median and was associated with a greater risk of death and local-regional recurrence when compared to tumors with expression at or lower than the median (Chung 2010).  
1.1.4 Clinical Trials of Cetuximab and Radiation Therapy Cetuximab is a humanized monoclonal mouse antibody that binds to the extracellular ligand binding domain of the EGFR, thereby preventing activation and dimerization of the receptor. Cetuximab blockade disrupts EGFR signal transduction and results in inhibition of tumor growth and metastasis in animal models. Cetuximab is FDA approved for therapy of metastatic colon cancer and in combination with radiation therapy for the primary treatment of head and neck cancer. The efficacy and safety of cetuximab were studied in combination with radiation therapy (RT) in a randomized, controlled trial of 424 patients with locally or regionally advanced squamous cell carcinoma of the head and neck versus radiation alone. In a multi-center controlled clinical trial, 424 patients with Stage III-IV SCC of the oropharynx, hypopharynx, or larynx with no prior therapy were randomized 1:1 to receive cetuximab plus radiation therapy (211 patients) or radiation therapy alone (213 patients). Stratification factors were Karnofsky Performance Status (60-80 versus 90-100); nodal stage (N0 versus N+); tumor stage (T1-3 versus T4 using AJCC 1998 staging criteria); and radiation therapy fractionation (concomitant boost versus once-daily versus twice daily). Radiation therapy was administered from 6-7 weeks as once daily, twice daily, or concomitant boost. The planned radiation therapy regimen was chosen by the investigator prior to enrollment. For patients with ≥ N1 neck disease, a post-radiation therapy neck dissection was recommended. Starting 1 week before radiation, cetuximab was administered as a 400 mg/m2 initial dose, followed by 250 mg/m2 weekly for the duration of radiation therapy (6-7 weeks). All cetuximab-treated patients received a 20-mg test dose on Day 1. Cetuximab was administered 1 hour prior to radiation therapy, beginning week 2.  
Of the 424 randomized patients, 80% were male and 83% were Caucasian. The median age was 57 years (range 34-83). There were 258 patients enrolled in U.S. sites (61%) and 166 patients (39%) in non-U.S. sites. Ninety percent of patients had baseline Karnofsky Performance Status ≥ 80; 60% had oropharyngeal, 25% laryngeal, and 15% hypopharyngeal primary tumors; 28% had AJCC T4 tumor stage. The patient characteristics were similar across the study arms. Fifty-six percent of the patients received radiation therapy with concomitant boost, 26% received once-daily regimen, and 18% twice-daily regimen. The main outcome measure of this trial was duration of locoregional control. Overall survival was also assessed. Results are presented below:  
| Table 1; Summary of Endpoints from the Phase III Trial of Radiation +/- Cetuximab  Cetuximab +  Radiation  (n = 211)  Radiation  Alone  (n = 213)  Hazard Ratio  Stratified  (95% Cl3 )  Log-rank   p-value   |         |         |                  |       |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|---------|------------------|-------|
| Locoregional control  Median Duration                                                                                                                                                                         | 24.4 mo | 14.0 mo | 0.68 (0.52-0.89) | 0.005 |
| Overall Survival  Median duration                                                                                                                                                                             | 49.0 mo | 29.3 mo | 0.74 (0.57-0.97) | 0.03  |
| a Cl = confidence interval                                                                                                                                                                                    |         |         |                  |       |  
These data lead to FDA approval of the combination of cetuximab and radiation therapy for initial therapy of patients with local-regionally advanced head and neck cancer (Bonner 2004).  
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 quality of life (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. Updated results with 5-year survival were recently reported and demonstrated 5-year survival of 45.6% in the cetuximab plus radiotherapy group versus 36.4% in the radiotherapy alone group (Bonner 2010). An analysis of associations between patient and tumor factors and overall survival was performed and offers some potential insight regarding patient selection. Patients with oropharyngeal primary tumors, early T stage, advanced N stage, high Karnofsky performance status, male gender, and young age demonstrated benefit from the addition of cetuximab to radiation. Concomitant boost radiotherapy also was associated with improved survival, whereas response appeared independent of EGFR expression. It has been noted that many of these patient and clinical factors also are associated with a diagnosis of an HPVassociated head and neck cancer, supporting a hypothesis that cetuximab may be preferentially beneficial to this group of patients. However, tumor specimens are not available for HPV determination in this trial, so a direct testing of this hypothesis is not possible. Furthermore, data indicate a paradoxical inverse association between HPV presence and EGFR expression and that EGFR expression may be associated with poor local-regional control only in the HPV-negative patient population (Hong 2010) RTOG 0522, comparing accelerated RT and cisplatin with or without cetuximab, completed accrual in early 2009. Results expected in 2011 should clarify the role of cetuximab in the chemoradiation setting. Approximately 70% of the patients in this trial had cancers of oropharynx origin. Approximately 70% of those are anticipated to be HPV-associated (approximately 440 patients). RTOG 0522 did not include prospective HPV testing and is not expected to lead to a clear answer regarding best management in the HPV subset.  
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).  
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.  
1.1.5 Human Papillomavirus and Head and Neck Cancer In 2007, a panel of experts convened by the International Agency for Research on Cancer reviewed data on the relationship between HPV and head and neck cancer and concluded that HPV is a cause of oropharynx and possibly oral cavity cancer (IARC Monographs 2007). HPVassociated cancers have been shown to be distinct from HPV-negative cancers with regard to risk factor profiles (Gillison 2008), clinical and molecular characteristics (Gillison 2000), treatment response and prognosis (reviewed in Lassen 2010). HPV-associated cancers arise from the lingual and palatine tonsils within the oropharynx, are poorly differentiated and present with early T stage and advanced N stage. When compared to patients with HPV-negative tumors, patients with HPV-positive tumors are more frequently male, young, and with good performance status (Ang 2010). First reported by Gillison and colleagues to be associated with survival (Gillison 2000), a meta-analysis of retrospective studies reported that patients with HPV-positive status oropharynx cancers had an estimated 50% reduction in risk of death when compared to patients with HPV-negative tumors (Ragin 2007).  
1.1.6 Secondary Analysis of HPV in Clinical Trials More recently, secondary analyses of several prospective multicenter clinical trials have confirmed tumor HPV status to be an important predictor of prognosis for patients with head and neck squamous cell carcinoma (Table 2). In the only trial to date to prospectively evaluate the effect of tumor HPV status on survival outcomes, ECOG investigators reported that response rates to an induction regimen of paclitaxel and carboplatin were higher for HPV-positive than HPV-negative patients (Fahkry 2008). Chemoradiation with weekly paclitaxel and standard fractionation radiotherapy to 70 Gy was administered after induction. After a median follow up of approximately 40 months, both progression-free (PFS) and overall survival (OS) were superior for the HPV-positive patients. In the analysis restricted to the oropharynx patients, patients with HPV-positive tumors had less than half the risk of death when compared to HPV-negative patients; however, adjustment was made only for performance status due to small sample size. University of Michigan investigators so reported higher response rates to a single cycle of cisplatin and 5-FU among HPV-positive patients when compared to HPV-negative patients. After concurrent chemoradiation with high-dose cisplatin and standard fractionation radiotherapy to 70 Gy, patients with HPV-positive tumors had improved OS and disease-specific survival, but the sample size was insufficient for adjustment for other prognostic factors (Worden 2008). In a DAHANCA 5 trial in which patients with stage I-IV pharyngeal cancer were treated with standard fractionation radiation therapy to 66-68 GY, p16 positive tumors (as surrogate for tumor HPV status) had improved local-regional control (LRC) and disease-free survival after adjustment for tumor and nodal stage (Lassen 2009). A phase III trial in which patients were randomized to chemoradiation with cisplatin plus or minus tirapazamine observed improved 2year overall and failure-free survival in oropharynx patients with p16 positive tumors. There was a trend toward improved local-regional control with the addition of tirapazamine for p16negative patients (Rischin2010). A previously reported DAHANCA analysis similarly suggested a differential response to the hypoxic radiosensitizer nimorazole in favor of the p16 negative patient, but the sample size for the p16 positive subset was small and many p16 positive tumors were non-oropharyngeal primary tumors in this analysis (Lassen 2010). From these analyses it can be concluded that HPV-positive tumors have higher response rates to platinumbased induction chemotherapy, radiation alone, or chemoradiation and that the survival difference between HPV-positive and negative patients observed in prospective analyses is similar to that observed in retrospective case series. Additionally, the improved survival among HPV-positive patients appears to be independent of the specific treatment approach, as long as the approach is within the standard of care. However, all of these trials were of insufficient size to demonstrate that the improved survival for the HPV-positive patient is independent of other important prognostic factors, including smoking.  
| Table 2: Tumor HPV Status and Survival Outcomes in Reported Prospective Clinical Trials   |                                |                            |                            |                     |                           |      |      |
|-------------------------------------------------------------------------------------------|--------------------------------|----------------------------|----------------------------|---------------------|---------------------------|------|------|
| Author and Cooperative Grp                                                                                           | N                              | XRT                        | Induction                            | Concurrent                     | Media                     | HPV  |      |
| n F/U                                                                                     | HPV+                           | Time                       | +                          | HPV                     | Hazard  Ratio  HPV+  vs - |      |      |
| Pvalu e                                                                                           |                                |                            |                            |                     |                           |      |      |
| 2                                                                                         | cycles                         |                            |                            |                     |                           |      |      |
| paclitaxel  175mg/m 2  carbo  AUC6                                                        | weekly  paclitaxel  30mg/m2 x  | 2-                         | 0.00                       |                     |                           |      |      |
| 7                                                                                         | 39 mo                          | 40%                        | year                       | 95%                 | 62%                       | 5    | 0.36 |
| Fakhry                                                                                    | 70                             |                            |                            |                     |                           |      |      |
| ECOG                                                                                      | 96                             | Gy                         | cisplatin  +/-  tirapazami | 2-                  | 0.00                      |      |      |
| ne                                                                                        | 27 mo                          | 28%                        | year                       | 94%                 | 77%                       | 7    | 0.29 |
| Rischin                                                                                   | 70                             |                            |                            |                     |                           |      |      |
| TROG                                                                                      | 195                            | Gy                         | none                       |                     |                           |      |      |
| Gillison  RTOG  0129                                                                      | 323                            | 70- 72  Gy                 | none                       | cisplatin  100mg/m2 | 3-                        | 0.00 |      |
| x2 or 3                                                                                   | 4.8 yrs                        | 64%                        | year                       | 79%                 | 46%                       | 2    | 0.44 |
| 3                                                                                         | cycles                         |                            |                            |                     |                           |      |      |
| taxotere  75mg/m2  cisplatin  100mg/m 2  5-FU  1000mg/ m2/day x  4                        | weekly  carboplatin  AUC 1.5 x | 5-                         | <0.0                       |                     |                           |      |      |
| 7                                                                                         | 67 mo                          | 50%                        | year                       | 93%                 | 35%                       | 01   | 0.2  |
| 70- 74  Gy                                                                                |                                |                            |                            |                     |                           |      |      |
| Settle  TAX324                                                                            | 119                            | nimorazale  1200mg/m 2/day | >60                        | 5-                  | 0.00                      |      |      |
| x 30                                                                                      | mo                             | 22%                        | year                       | 62%                 | 26%                       | 3    | 0.44 |
| Lassen  DHA  NCA5                                                                         | 156                            | 62- 68  Gy                 | none                       |                     |                           |      |      |  
NRG Oncology investigators recently reported an analysis of the effect of tumor HPV status on survival outcomes in RTOG 0129 (Ang 2010) in which patients with advanced stage III-IV head and neck cancers (excluding T1, T2-N1 and M1) were randomized to receive accelerated radiation with 2 doses of high-dose cisplatin (100 mg/m2), or standard fractionation and 3 cycles of high dose cisplatin. In an analysis restricted to oropharynx patients, 64% were found to have HPV-positive tumors. Patients with HPV-positive tumors had significantly superior OS and PFS after a median follow up of 4.5 years (Figure 1). Patients with HPV- positive tumors had a 58% reduction in the risk of death and a 51% reduction in risk of progression or death after adjustment for other factors, including age, race, t stage, n stage, smoking, and treatment assignment. HPV-positive patients had significantly improved LRC and a reduced rate of second cancers, and although a slight reduction in risk of distant metastases (DM) was observed at 3 years (8.7 vs. 14.6, p= 0.23), it was not statistically significant (Table 3). In this trial, there was very high agreement between tumor HPV status and p16 expression by immunohistochemistry, and stratification of results by p16 status in lieu of HPV status yielded similar findings. Lower rates of local-regional failure and deaths due to other causes among HPV-positive patients were subsequently reported in an analysis of oropharynx patients enrolled in a phase III trial in which patients with stage III-IV disease were randomized to  
  
receive concurrent high dose cisplatin with or without tirapazamine and standard fractionation
(Rischin, 2010).  
| First failure, all patients          | (n=206)                               | (n=117)                | (n=215)     | (n=101)     |       |       |            |       |       |
|--------------------------------------|---------------------------------------|------------------------|-------------|-------------|-------|-------|------------|-------|-------|
| Local-regional progression           | 25 ( 12.1%) 31 ( 26.5%) 27 ( 12.6%)   | 29 ( 28.7%)            |             |             |       |       |            |       |       |
| Local-regional progression & distant |                                       | 1 (                    | 0.5%)       | 2 (         | 1.7%) | 1 (   | 0.5%)      | 2 (   | 2.0%) |
| metastases  Distant metastases       | 21 ( 10.2%) 17 ( 14.5%) 21 (          | 9.8%)                  | 15 ( 14.9%) |             |       |       |            |       |       |
| Dead-study cancer NOS                | 2 (                                   | 1.0%)                  | 7 (         | 6.0%)       | 2 (   | 0.9%) | 7 (        | 6.9%) |       |
| Dead-no progression                  | 17 (                                  | 8.3%) 15 ( 12.8%) 16 ( | 7.4%)       | 15 ( 14.9%) |       |       |            |       |       |
| Alive-no progression                 | 140 ( 68.0%) 45 ( 38.5%) 148 ( 68.8%) | 33 ( 32.7%)            |             |             |       |       |            |       |       |
| First failure, failures only         | (n=66)                                | (n=72)                 | (n=67)      | (n=68)      |       |       |            |       |       |
| Local-regional progression           | 25 ( 37.9%)                           | 31 ( 43.1%)            | 27 ( 40.3%) | 29 ( 42.6%) |       |       |            |       |       |
| Local-regional progression & distant | 1 (                                   | 1.5%)                  | 2 (         | 2.8%)       | 1 (   | 1.5%) | 2 (        | 2.9%) |       |
| metastases  Distant metastases       | 21 ( 31.8%)                           | 17 ( 23.6%)            | 21 ( 31.3%) | 15 ( 22.1%) |       |       |            |       |       |
| Dead-study cancer NOS                | 2 (                                   | 3.0%)                  | 7 (         | 9.7%)       | 2 (   | 3.0%) | 7 ( 10.3%) |       |       |
| Dead-no progression                  | 17 ( 25.8%)                           | 15 ( 20.8%)            | 16 ( 23.9%) | 15 ( 22.1%) |       |       |            |       |       |
eligibility checklist -step 2 (10/17/13)
1.2 rtog 1016 trial design

This is a randomized phase III, 2 arm trial. The control arm is accelerated radiotherapy (RT), 70 Gy in 6 weeks (AFX-C) plus concurrent high dose CDDP for 2 cycles. This will be compared to accelerated RT (70 Gy in 6 weeks) plus weekly cetuximab, as used in the Bonner and RTOG 0522 trials, which included 8 doses of cetuximab.  
This is a head-to-head comparison of concurrent chemoradiation (RT + CDDP) versus RT plus a molecular targeting agent (cetuximab) that has been approved by the FDA for frontline therapy in locoregionally advanced head and neck cancer. The prevailing global practice (per NCCN and H&N
investigators) is that radiation plus cetuximab is used as a less toxic alternative to chemoradiation for those patients not medically fit for cisplatin-based concurrent chemoradiation. This stems from the large body of clinical trial data supporting the use of concurrent chemoradiation versus only a single mature trial testing radiation plus cetuximab. It is possible, however, that the more favorable toxicity profile associated with cetuximab relative to CDDP could be utilized in the care of patients with a relatively good prognosis. Subsite and secondary analyses strongly suggest that the best outcomes with RT plus cetuximab were achieved in younger oropharynx patients treated with altered fractionation (Bonner 2010), without any detriment of quality of life (QOL), as compared to RT alone (Bonner 2006). The optimal indication for cetuximab has been a major question in head and neck cancer since approval by the FDA. This is a unique opportunity to formally compare outcomes for these 2 approaches in prognostically favorable oropharynx cancer patients medically fit for cisplatin-based chemoradiation using biomarker-directed (HPV) patient selection. This trial is designed as a classical non-inferiority study, and a 9-percentage point lower boundary at 5 years was selected for the inferiority margin for the cetuximab arm. Given the relative survival benefit associated with the addition of platinum-based chemotherapy (HR 0.81, 95%CI 0.78-0.86; Pignon 2009) or cetuximab (HR 0.74, 95%CI 0.57-0.97; Bonner 2004) to radiotherapy, it is reasonable to consider it unlikely that accelerated radiation therapy with cetuximab will reach this level of non-inferiority. The primary outcome measure is the hazard ratio between the 2 trial arms. The selection of a threshold for inferiority is a safeguard against the unexpected possibility that there is a direct interaction between HPV status and the effect of cetuximab or CDDP in combination with radiation. Acute and late toxicity are important secondary domains that will be carefully recorded and may help in defining appropriate care for HPV-related head and neck squamous cell carcinoma (HNSCC) in the future. There also will be sufficient power to test the possibility that RT plus cetuximab may be superior to chemoradiation. The existing level I evidence endorsed by the FDA, strong preliminary data in the oropharynx population, and independent prognostic value of HPV status all support equipoise in this phase III comparison. While recent studies also have suggested smoking history as an independent determinant of outcome, the proposed trial provides an excellent opportunity to test this hypothesis. In addition, other large phase III trials are in progress (NCIC-CTG) or in planning stages (TROG), which will compare radiation plus molecular targeting agents versus chemoradiation in oropharynx cancer (NCIC-CTG and TROG, personal communications, 2010). The NCIC-CTG and TROG trials will use a fully humanized antibody (panitumumab) thought to be similar in activity to cetuximab but with lesser dermatologic and allergic toxicity profiles. In the proposed trial, cetuximab was chosen, as currently there is level I evidence for the efficacy of this agent. The study chairs feel that changing the molecular targeted agent may introduce an unknown confounder in the interpretation of the trial if non-inferiority is rejected on the basis of trial outcome. The NCIC-CTG trial, opened approximately 18 months ago, stratifies by anatomic subsite, includes HPV testing, and compares accelerated RT, 70 Gy in 6 weeks, plus panitumumab to standard fractionation RT, 70 Gy in 7 weeks, with high dose cisplatin. TROG is developing a study for HPV-positive cancers comparing RT, 70 Gy, plus panitumumab to RT, 70 Gy, with weekly cisplatin. Thus, a large volume of data is anticipated testing the targeted bioradiation approach against chemoradiation in the HPV-associated population to be available in the future. A future intergroup meta-analysis, after completion of the individual studies, would have considerable statistical power to narrow the margin of non-inferiority assuming that these interventions are equally effective. NRG Oncology has a large experience with cetuximab in head and neck cancer (RTOG 0234 and 0522) in which safety and compliance has been demonstrated. The conduct of multiple EGFR-inhibitor confirmatory trials is desirable as it can potentially alleviate concern by NCCN head and neck panel members of having a single supporting trial. The application of cetuximab in HPV-associated cancers provides a rare opportunity to validate the activity of this agent, in a biomarker selected population when it is generally not possible to repeat a trial after an agent is approved by the FDA based on a single phase III trial.
eligibility checklist -step 2 (10/17/13)
1.3 rationale for eligibility

Eligibility will include all Stage III-IV HPV-positive patients (as determined by the surrogate, p16 expression), excluding T1-2, N0-1 or M1. The decision to include patients with more than a 10 pack-year smoking history was a difficult one. However, this trial design incorporates a comparison of 2 standard-ofcare treatment options for patients with oropharynx cancer, independent of tumor HPV status or smoking status. Furthermore, while the recursive partitioning analysis of 0129 strongly suggests smoking is an independent prognostic factor, this is based on an unplanned analysis of trial data. This trial will provide the opportunity for prospective evaluation of these findings.
eligibility checklist -step 2 (10/17/13)
1.5 toxicity patient-reported outcomes (pros)

Note: The Quality of Life (QOL) component closed to accrual on 2/28/13 (with the exception of the optional baseline Work Status Questionnaire and baseline BRASS; see Sections 11.7.5 and 11.7.6). For patients already enrolled on the QOL component, sites must submit follow-up QOL as specified in Section 12.1 and in Appendix I, Assessments in Follow Up.  
The overall goal of this trial is to identify a high-survival, less-toxic approach in HPV-associated cancer of the oropharynx. The aim is to show that targeted bioradiation will substantially reduce the burden of acute toxicity, improve swallowing function and recovery, and improve overall QOL, as compared to conventional chemoradiation. As such, this is the first U.S. phase III trial to formally address the tandem priorities of cure and recovery from HPV-associated H&N cancer.  
1.4 Rationale for Study Arms Retrospective comparison for outcomes of HPV-positive versus HPV-negative cancers using different treatment strategies (RT alone, surgery/post-op RT, induction chemoradiation followed by chemoradiation) have consistently reported improved outcomes and prognosis for the former group (Table 2).  
A recent update of the Bonner cetuximab trial has confirmed improved long term (5-year) survival and local regional control (Bonner 2010). Subgroup analyses (forest plots) have indicated improved hazard ratios for oropharynx (versus other sites), twice a day (versus once a day), N0 (vs. N1-3) , and T1-3 (vs. T4). A recent additional analysis comparing once a day versus twice a day fractionation demonstrated a strong advantage with altered fractionation (AF: either hyperfractionation or accelerated concomitant boost) over conventional fractionation (CF) [Bonner, personal communication. May 2010; manuscript in process). This argues for using AF in the cetuximab arm of RTOG 1016.  
Recent analysis of the DAHANCA trials 6 and 7 suggest accelerated RT is beneficial in both HPVpositive and HPV-negative cancers (Overgaard 2010).  
Analysis of RTOG 0129 revealed that patients randomized to receive either accelerated fractionation radiotherapy with concomitant boost with 2 cycles of high-dose cisplatin or standard fractionation radiotherapy with 3 cycles of high-dose cisplatin had similar overall and progressionfree survival. The hazard ratios associated with treatment assignment were similar among HPVpositive and HPV-negative patients. Although there were no differences in high-grade acute or late toxic events, several toxicities known to be associated with cisplatin were significantly lower in the 2 versus 3 cycles, including hematologic and metabolic toxicities. However, late grade 3-4 mucous membrane toxicities were higher in the accelerated arm (4% vs. 1%, p=0.04). In addition, in RTOG 0129, only 69% of patients treated with SFX received all 3 planned cycles of cisplatin, while 88% of patients treated with AFX-C received both planned cycles. Thus, the accelerated arm had higher treatment compliance and fewer cisplatin-related hematologic and metabolic events. In a non-inferiority design, per-protocol analysis is usually considered as a sensitivity measure in addition to intent-to-treat analysis, so it is essential to have good compliance.  
Based on these aggregate data suggesting the benefit of acceleration in RT alone and acceleration in RT + cetuximab, the transmutability of time, and chemotherapy (acceleration~1 cycle of chemotherapy), and the need to control for time as a treatment variable impacting tumor repopulation, accelerated fractionation (with 2 cycles of cisplatin in arm 1) has been selected for both arms of this trial.  
Survival (the primary study endpoint) is expected to be high (> 80%) in both study arms. Understanding the magnitude of differences in toxicity and the patients' perspective in health-related outcomes is vitally important to future decision-making and treatment selection for this patient population.  
Protocol-specific Toxicity Assessments are defined as evaluations (critical to the primary trial analysis)
performed by the clinical team (doctor, nurse and research associate) and will include clinician-reporting and grading of CTCAE (v. 4) symptoms, findings on physical examination, and laboratories. Patient-Reported Outcome (PRO) assessments are reported directly by the patient, without assistance from health care providers or staff. PRO tools for this study include all quality of life (QOL) surveys, the behavior and risk factor survey (BRASS), work status survey (as affected by cancer diagnosis and treatment) and a new tool, the PRO-CTCAE, that permits direct patient-reporting of side effects and health status from the patient perspective. Six time points have been chosen for protocol-specific Toxicity and PRO assessments (see Sections 1.5.1 and 1.5.2). The tools and time points selected are designed to capture most of the short and longer term effects of modern combined modality therapies using IMRT. Short term assessments include baseline status, end of treatment (week 5 or 6 of radiation) where the maximum changes from acute toxicity will likely be seen, and 2 acute recovery assessments at 3 and 6 months, when swallowing function generally returns and some patients are able to begin to return to work. Most late phase changes will be evident between 6 months and 2 years when swallowing function may continue to improve and certain late effects will appear (e.g. dry mouth, pain syndromes, soft tissue necrosis, bone necrosis). Protocol-specific Toxicity and PRO assessments will evaluate and compare (and hypothesize and project differences between) concurrent cisplatin-radiation versus cetuximab-radiation in the following areas:  
Quality of Life and Patient Reported Outcomes (PROs)
Improved acute phase global QOL (baseline to 6 months);
Improved acute phase swallowing QOL domain; Same or better late phase (2-year) swallowing QOL domain; Improved return to work status; Comparison of clinician and patient reporting of toxicity (CTCAE and PRO-CTCAE);
Comparison of patient-reported hearing changes (HHIA-S)
Explore cost utility analysis via the EuroQol (EQ-5D) and medicare cost sampling and modeling.
*This study will focus on 2 hypothesis-defined Toxicity and PRO outcomes that are critical for decision making in future treatment selection decisions: Overall acute toxicity burden (T-score) and long-term swallowing function (QOL swallowing domain).  
We hypothesize that:
1) overall acute toxicity burden (T-score) in the cetuximab arm will be significantly lower than the cisplatin arm, and 2) long-term (2-year) swallowing function (QOL swallowing domain) in the cetuximab arm will be better than or similar to the concurrent cisplatin arm.
Interpretation of combined primary (survival) and secondary (Toxicity-PRO) endpoints:  
Clinician Reported Toxicity Endpoints Reduction in 10 key acute toxicity rates by > 50%;
*Reduction in overall number of acute high-grade events (T-score) by > 50%;
Reduction in acute high-grade (3-4) dysphagia by > 50%; Reduction in feeding tube usage by > 50%;
Reduction in 4 key late effects by > 50%;
Comparison of rates of in- and out-of-field skin effects; Comparison of hearing by standardized audiometric testing for ototoxicity.
Assuming the primary endpoint (non-inferior survival) is met and both of these toxicity outcome goals are met, then concurrent cetuximab and radiotherapy would be considered an effective and less toxic alternative to concurrent cisplatin, in locally advanced HPV-associated carcinoma of the oropharynx.  
The principle endpoint that will power the QOL analysis is a significant difference in the QOL swallowing domain. While QOL reporting has been optional in previous NRG Oncology H&N trials, more than 90% of patients have chosen to participate. Toxicity-PRO data collection will be monitored twice a year to ensure adequate participation. Once sufficient Toxicity-PRO data are collected (~400 patients), protocol-specific PRO assessments will be discontinued (for approximately the last 300 patients enrolled), in order to minimize resource and patient data collection burdens.  
1.5.1 Schedule of Toxicity-PRO Assessments Protocol-specific Toxicity-PRO assessments will occur on a limited schedule over the first 2 years (see the sections below). After 2 years, these protocol-specific Toxicity and PRO assessments will be discontinued. Routine follow up and cancer status evaluations will occur as per the NRG Oncology traditional follow-up schedule during and after completion of the 2-year Toxicity and PRO outcomes evaluation phase. Beyond 2 years, hard coding of CTCAE late effects will revert to the NRG Oncology standard collection method similar to RTOG 0522 (9 hard-coded items).  
Although pre-determined analytic Toxicity and PRO assessments will be collected at only 6 time-points, all follow-up evaluations performed over the first 2 years (baseline, end treatment, 1, 3, 6, 9 12, 15, 18, 21, and 24 months) will include case report forms (CRFs) instructing sites regarding collection of hard coded CTCAE terms. This is to avoid the need for 2 separate forms at different assessment points over the first 2 years. Note: Previous NRG Oncology head and neck trials have collected data on a follow-up calendar based on time from the beginning of radiation therapy. For RTOG 1016, all assessments (including cancer status evaluations and Toxicity-PRO assessments) will be administered from the end of the 6-week course of radiation. In Arm 2, cetuximab will be given 1 week prior and 1 week after completion of radiation (this is not expected to substantially change the reported toxicity rates that identify the worst grade of events over the preceding interval).  
Protocol-Specific Toxicity Assessments will take place at 11 assessment time points per routine NRG Oncology follow-up schedule: baseline, end of treatment, and at 1, 3, 6, 9, 12, 15, 18, 21, and 24 months from the end of treatment.  
Protocol-Specific PRO Assessments will occur at 6 of the 11 routine assessment time points: baseline, end of treatment, and at 3, 6, and 12 months from the end of treatment. Importance and Feasibility of Toxicity and PRO Data Collection Rigorous collection of Toxicity and PRO outcomes are equally as important as the collection of survival data for the comparative evaluation of the risks and benefits in this trial. The data collection plan for RTOG 1016 is overall very similar to data collection tools and work burdens of recent NRG Oncology H&N trials. NRG Oncology H&N trials (RTOG 0129 and 0522) have had good compliance to QOL data capture in the first 2 years of follow-up (63% at 1 year 0522; 59% at 2 years 0129), indicating that the current study will have sufficient power to discern differences in 2 year QOL domains. Compliance with collecting functional outcomes on RTOG 0522 using the PSS-H&N also has been strong at the critical time points chosen for this trial: 81% at end of treatment, 65% at 1 year, 53% at 2 years (RTOG 0522). The addition of a Work Status survey, the H&N PRO-CTCAE tool, and the Hearing Handicap Inventory for Adults (HHIA-S) are the new PRO tools included in this study, adding less than 10-15 min to each evaluation. Compared to the traditional alcohol/tobacco-related head and neck population, the HPV population has a higher education level, stronger social support, and is likely to be comfortable with web and tablet-based methods of information sharing.  
Patients choosing to enroll in this study, which focuses on the goals of cure and recovery, should be capable and motivated to report their outcomes directly using computer-assisted self interview (CASI). Electronic survey methods, now widely used in health outcomes research, have been shown to reduce burden for patients, improve data quality and staff work efficiency, and to enhance data privacy.  
1.5.2 Clinician-reported Toxicity Assessment Tools Toxicity-related tools will be collected and reported by clinical staff at 11 assessments on the standard NRG Oncology schedule: baseline, end of treatment, and at 1, 3, 6, 12, 15, 18, 21, and 24 months from the end of treatment.  
Traditional clinician-reported endpoints will be captured by "hard-coding" data capture on case report forms. Collectively, completion of these forms requires < 30 minutes for the patientclinician-research associate interaction.  
Hard-coded CTCAE events (10-15 minutes);
Nutrition/feeding tube (5 minutes); Dental status (< 5 minutes). As discussed below in Section 1.5.3, these clinician-reported data should be obtained after the patient has completed the QOL PRO tools. This order of patient reporting first, followed by clinician reporting is important to follow as much as possible, both for research purposes and to help the patients get their needs and any toxicity clarifications addressed.  
1.5.3 PRO and QOL Assessment Tools Six PRO tools will be completed by the patient at 6 assessment time points: baseline, end of treatment, and at 3, 6, and 12 months from the end of treatment.  
EORTC QLQ-C30 (7 minutes);
EORTC QLQ H&N35 (7 minutes);
EuroQol (EQ-5D) [1 minute]; PRO-CTCAE (< 5 minutes); Work Status Questionnaire (< 2 minutes);
The Hearing Handicap Inventory for Adults (HHIA-S) [< 2 minutes]. See Section 11.7 for a description and source for each tool. As demonstrated in other recent NRG Oncology head and neck trials, we anticipate over 90% participation (by separate consent) in the QOL component of this trial (defined as the package of PRO tools listed above).  
Some of the questions in this QOL package will seem redundant, including repetition of the same areas by the clinical team. This repetition is a key aim of the study (patients to report some information directly and reduce a portion of the clinical interview in future trials). It is anticipated that this will facilitate efficiency of the clinical encounter in this trial (shorter interviews), since the patient will have recently thought about these side effects and their quality of life issues. In addition to the tablet-based application, as a back up, the surveys will be available through an web-based internet application.  
As discussed above in Section 1.5.2, patients will complete electronic surveys in clinic (on tablet PCs or online) prior to the clinical encounter. Every attempt to collect the QOL PROs prior to clinician visit should be made, but if not possible, very soon thereafter.  
1.5.4 CTCAE Clinical versus Patient-Reported CTCAE (PRO-CTCAE) Assessments Approximately 25 protocol-specific adverse event (AE) items will be assessed and reported by the clinical team (using CTCAE, v. 4) and separately reported by the patient (see the sections below) at each of the 6 protocol-specific Toxicity and PRO assessment time points. PROCTCAE endpoints were selected for comparison that can be primarily (and some preferentially)
reported by the patient.  
1.5.5 Quality of Life In comparing the use of concurrent cisplatin and radiation versus concurrent cetuximab and radiation, the main differences in toxicity and QOL are expected to be short term (up to 6 months). Currently, there are only limited data documenting the short-term effects of concurrent treatment on QOL in head and neck cancer. NRG Oncology has significant experience with using the FACT-H&N tool to measure long-term QOL (RTOG 90-03 and 0522); however, these studies have collected data at only baseline, 1 year, and beyond. Thus, the paired EORTC
QOL tools, the QLQ-C30 and QLQ-H&N35, will be used in this trial, as these assessments have been documented to be more comprehensive and sensitive to short-term changes in several head and neck studies, as described below.  
Curran reported QOL in the randomized phase III trial comparing radiation alone to radiation plus cetuximab using the EORTC tools at 4 weeks and 4, 8, and 12 months post- treatment (Curran 2007). Data compliance was high in both arms (80-89% at 4 months and 65-73% at 1 year). There were no significant differences between the arms over time, arguing that the addition of cetuximab to radiation had no impact on QOL measures. In particular, skin effects did not appear to impact social or role functioning. Most relevant to the current trial, the Curran (2007) study detected large post-baseline decreases (at 4 weeks post-RT) for worst post-baseline scores for all QLQ-C30 and QLQH&N35 multi-item symptom scales particularly for swallowing (34.2), sensory problems (41.2)
and social eating scales (34.4). This is in contrast to only 6% change in short-term (at 2-month follow up) global and domain-specific values using the FACT-H&N tool in the Trans-Tasmanian Radiation Oncology Group (TROG) QOL study reported by Ringash, in which 3 cycles of cisplatin was used, with or without tirapazamine (Ringash 2009). In the Curran cetuximab study, significant declines also were noted for all multi-item sub-scales of the QLQ-H&N35, particularly for the swallowing, sensory, and social eating sub-scales. All QLQ-H&N35 single item scales showed a worsening of symptoms from baseline, including: teeth, trismus, dry mouth, cough, feeling ill, pain medications, supplements, and feeding tube use. All QOL measures improved during a several month recovery period and returned to baseline by 1 year, as noted in several H&N QOL studies (Curran 1998; Abdel-Wahab 2005; Ringash 2009). Similar sizable short-term decreases in QOL measures have been noted using the EORTC tools in a large nasopharynx IMRT cohort (Fang 2008) and the Tax 324 trial (van Herpen 2010), supporting the choice of the EORTC tools as particularly sensitive to short-term change. In addition, the EORTC tools represent one of the most comprehensive measures of global and head and neck-specific QOL. The QLQ-H&N35 includes several areas (trismus, sticky saliva, cough, and teeth) not covered by the FACT-H&N. The FACT-H&N single item question about swallowing and eating functions is vague, whereas the EORTC tools contain more relevant phrasing and multi-item scales for both swallowing and senses. The items in the EORTC tools will complement the limited item set selected for the PRO-CTCAE evaluation (see PRO-CTCAE section below). Based on our comparative analysis of QOL data from trials evaluating chemoradiation or cetuximab and radiation, the EORTC paired tools are the most likely to detect differences in short-term QOL as a consequence of differences in the toxicity profiles associated with each agent. Due to the higher acute toxicity burden associated with cisplatin, larger declines in shortterm QOL are anticipated in the cisplatin arm.  
1.5.6 Swallowing Function **(6/25/13)**
Diminished swallowing function has been shown to be the key injury with the greatest impact on QOL (Langendijk 2008). A requirement for feeding tube support may interfere with role and social functioning and is associated with significant stigma, psychological distress, and cost. Measuring the outcomes of swallowing function can performed in a number of ways, including diet assessment, videofluoroscopy, and patient perspectives. Objective assessments using barium swallow tests, etc., are not feasible in a large phase III study, in part due to a lack of technical standards. There is no gold standard for swallowing assessment (Langendijk 2008). As a critical trial endpoint, a number of measurement methods for swallowing will be used:
Clinician-reported swallowing assessment tools; Hard-coded CTCAE events (Dysphagia); Feeding tube use; Weight loss;
*EORTC QLQ H&N35 Swallowing Domain; PRO-CTCAE (dysphagia).  
We have compared and contrasted data on swallowing function between the Bonner trial and the RTOG 0522 oropharynx cohort: CTCAE Dysphagia (60% vs. 30%), peak feeding tube
(69% vs. 39%), and feeding tube rates at 1 year (28% vs. 18%). Comparative data on the PSSH&N-Diet subscale are not available; however, based on differences in the other measures listed, a similar 40-50% difference is projected at 3-6 months. We anticipate feeding tube rates in the cetuximab arm will be the same or better than in the cisplatin arm of RTOG 1016.  
Feeding tube placement will be at the discretion of local investigators. Increased application of IMRT organ sparing techniques (as described in Sections 6.5.3 and 6.5.4), smaller average primary tumor volumes in HPV cancers, increasing sophistication of supportive care, and increased awareness of swallowing therapy during treatment, make swallowing outcomes projections uncertain.  
1.5.7 Skin Toxicity The absence of cisplatin-related effects in the cetuximab arm will be somewhat offset by higher rates of out-of-field rash and possibly higher in-field, high-grade skin reactions associated with cetuximab. The potential impact of rash on social and role functioning will be explored by comparing these domains in the QLQ-H&N35. As noted in the cetuximab QOL study (Curran 2007), these skin reactions recover within 4-6 weeks and did not affect the overall QOL measure or the H&N specific QOL domains of social functioning or role functioning as measured by the EORTC-QLQ tools in their study; however, these tools do not inquire specifically about skin effects. Skin (both in and out of the H&N-irradiated area) will be evaluated using specific hard-coded clinician-reported CTCAE items. We have significant experience with collecting hard-coded cetuximab-related skin events on more than 450 patients on RTOG 0522. Since cetuximab and cisplatin are given concurrent with accelerated radiation (which is responsible for most of the local effects), determining the contribution of each agent on in-field skin toxicity or detecting differences in overall or domain-specific areas of QOL is not anticipated. The focus will be on clinician-reported CTCAE skin toxicity, and patient-reported perspectives on skin and other selected toxicities using the PRO-CTCAE items.  
1.5.8 Acute and Late Toxicity Profiles General Toxicity Profiles It is generally accepted that cisplatin and cetuximab involve very different toxicity profiles and that the overall burden of acute toxicity is lower with cetuximab. Cisplatin enhances radiation-related epithelial reactions, causes life-threatening neutropenia, and carries high gastrointestinal effects. Chemoradiation has been shown to impact QOL and head and neckspecific domains for up to 1 year (data below). Functional outcomes from chemoradiation
(dry mouth, dental effects, swallowing disorders, neurosensory, and mood disorders) can persist for the remainder of survivorship, which is expected to be > 70% at 5 years in the HPV-associated head and neck population. Cetuximab combined with radiation causes an acneiform rash in > 85% patients and may enhance in-field skin reactions, but otherwise has a low agent-specific toxicity profile. Because there is no dose reduction of radiation, it is anticipated that only a few late effect or long-term toxicities (cisplatin-related) will be lower in the cetuximab arm: auditory, pain, and neurosensory. However, consequential effects on mucosa, soft tissue, and neural tissues may increase the risk of fibrosis, dysphagia, cranial neuropathies, or other late effects. These events will be collected using specific ToxicityPRO tools for up to 2 years; standard late effects methods will be used thereafter. NRG
Oncology follows all patients for life to collect long-term survivorship issues.
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estimated differences in acute toxicity

To estimate the expected rates of toxicity in RTOG 1016, acute toxicity data was extracted from RTOG 0522 (using identical chemoradiation to RTOG 1016), specifically for a cohort of oropharynx cancers treated with IMRT (N=278 for acute, and N= 270 for late toxicity). The median follow-up on this cohort is 1.9 years (range: 0.3- 4.0). The acute toxicity data from Bonner study was examined as well as data from the cohort of oropharynx patients treated with IMRT from the RTOG 0522 trial. Late toxicity was not reported in the Bonner study. RTOG 0522 used CTCAE v. 3.0 and select CTC terms were "hard-coded" to ensure assessments at standard time-points: 5 acute effect terms were collected and 10 late effect terms through this method. While there are several pitfalls in comparing toxicity data between 2 different trials, the large difference in acute toxicity profiles between cisplatin and cetuximab suggest this approach is reasonable for projecting rates between the 2 arms of the current study. Approximately 60% of the patients in the Bonner trial received altered fractionation, whereas all patients on RTOG 0522 received accelerated radiation. No patients in the Bonner trial received IMRT (all 2D), whereas all patients in the 0522 cohort received IMRT. All patients enrolled on RTOG 1016 will receive IMRT.  
Based on comparative review of these data, detectable reductions are anticipated in 10 specific acute effects items in which cetuximab is expected to carry significantly lower (>
50% reduction) acute toxicity: (auditory < 10 versus 28%); bone marrow-leukopenia/anemia (5% versus 71%), grade 3+ dysphagia (26% versus 61%), grade 3+ nausea (2% versus 12%), vomiting (3% versus 8%), peripheral sensory (0% versus 6%), pain (28% versus 71%), renal (0% versus 7%), and fatigue (4% versus 10%). Estimated Difference in Overall Acute Toxicity Burden (T-score) Routine reporting of adverse events will be performed using the CTCAE v. 4.0 terminology and grading system. Data will be summarized by the traditional listing of all event terms by body system and by grade. The "worst grade summary method" (WGSM) of reporting toxicity profiles, as long practiced by the cooperative groups will be reported, including a summary of lower toxicity (grade 1-2) versus higher toxicity (grade 3-4) events. This traditional representation of toxicity profiles permits a broad overview and sense of toxicity burden for each treatment approach.  
NRG Oncology investigators have noted that the WGSM is prone to systematic underreporting in combined modality treatment programs (Trotti 2007). This is due to a number of factors, including loss of data when patients experience more than 1 event in each grade category. This reporting issue was evaluated and an alternative summary method was developed for acute toxicity burden (T-score; relative toxicity burden value) that includes all high grade events experienced by a treatment group. An analysis of > 2300 patients treated between 1990 and 2000 in 5 trials involving 13 treatment groups of increasing treatment intensity showed a relative 5-fold difference across treatment approaches, whereas the traditional WGSM showed only a 2-fold difference. The figure below demonstrates that under-reporting was systematic and occurred to a greater degree in the more intensive programs: once a day (T~100) versus twice a day radiation (T~150-200), single or multiagent chemotherapy (T~300-400), once a day radiation with multi-agent chemotherapy, or accelerated radiation with single or multi-agent chemotherapy (T~400-600). Of note, RTOG 99-14 used accelerated radiation (concomitant boost schedule) with 2 doses of concurrent cisplatin, mirroring the control arm of RTOG 1016. The relative T-value for this approach is at the upper end of the acute toxicity burden range tested by RTOG in the 1990s (a 2D RT era).  
  
RTOG 1016 will utilize accelerated radiation in both arms (70 Gy in 6 weeks, 6 fractions/week, weeks 2-6), and will compare cetuximab versus cisplatin. Since cetuximab has an overall lower toxicity profile, and events are generally concentrated in one organ
(skin), we estimate relative T-scores to be in the range of 200 for the cetuximab arm and approximately 400 for the cisplatin arm. This would indicate an approximate 2-fold difference in toxicity burden. Acute toxicity burden is the major focus for testing this alternative method of treatment and is the main endpoint for the toxicity hypothesis. There is no widely accepted or common summary metric for this global measure. Relative T-values should be useful in quantitatively assessing differences in overall acute adverse event profiles and toxicity burden.
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estimated differences in late toxicity

Late toxicity rates of interest from the RTOG 0522 oropharynx cohort (N=270; median follow up of 1.9 years) were examined. Late toxicity was not reported by the Bonner study. Detectable reductions of > 50% are anticipated in 4 specific late effects items: auditory, hemoglobin, pain, and peripheral sensory neuropathy. Each of these late effects are likely related to cisplatin toxicities. Potential differences in swallowing function, fibrosis, and other late effects are discussed in the sections above.
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early deaths

Deaths due to toxicity or within 30 days of completing radiation were not reported in the Bonner study (it is assumed in the current study that there will be no toxic deaths from cetuximab). There is, however, some risk of severe allergic reaction to cetuximab. In RTOG 0522, grade 3-4 hypersensitivity occurred in 2.2% of oropharynx patients treated with IMRT on the cetuximab arm. In the RTOG 0522 oropharynx cohort (N=278), 6 patients (2.2%) died from toxicity or within 30 days of completing treatment (2 patients died of treatment-related causes and 4 additional patients died within 30 days of treatment from other causes). This is consistent with the experience for a similar patient population treated with the same regimen
(accelerated fractionation with concurrent cisplatin, but non-IMRT) on RTOG 0129 (2.8%).  
Early death is an important consideration in global assessment of risk and will be reported using standard definitions and methods.
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dental health

A direct observer-rated assessment of dental complications is desired to document shortand long-term dental health in HPV oral cancer survivors. CTCAE, v. 4.0 includes 1 term for tooth loss but does not quantify the degree of tooth loss and does not give a global assessment of dental and oral health. A literature review did not identify a well-validated general oral instrument. A simple 5-point global health dental scale was created for this trial (see Appendix VII). The language reflects assessment of oral hygiene and teeth at baseline by dentists in order to determine the need for extractions, cleaning, and future interventions; thus, it has high face and content validity. The 5-point ordinal scale, mimicking CTCAE structure, rates dental health as edentulous, excellent, good, fair, or poor.  
In addition to overall assessment of dental health changes over time, a dental "count" will be performed at each of the designated outcome assessments (Appendix I). This will involve simply counting the number of native teeth at each visit, not including bridges or partial or full dentures. A diagram of 32 teeth will be provided to assist in dental count. The percent change from baseline in number of teeth over time will be reported. Loss of teeth (up to 10 years follow up) should give a quantitative measure of changes in dental health in the HPVassociated population treated with IMRT.
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pro-ctcae

It is recognized that clinician-reported adverse events (AEs) may substantially under-report the incidence and severity of symptoms occurring as a consequence of treatment (Basch 2010). In response to this awareness, the NCI has developed a set of patient-reported items (called PRO-CTCAE) that complement the CTCAE and capture the patient's perspective on the subjective aspects of adverse events (Hay 2010). The potential for under-reporting of adverse events is particularly likely with symptoms such as fatigue, pain, and depression, which can only be gauged accurately by the person experiencing the symptom, and with long-term head and neck symptoms, such as mouth dryness, voice hoarseness, and difficulty swallowing, which are often subtle and may be difficult for clinicians to grade using standard CTCAE grading methods. Several CTCAE scales (e.g., taste changes, hair loss) only include 2-3 severity ratings, whereas the PRO-CTCAE offers a 5-point response scale. PRO-CTCAE H&N information will complement the clinician CTCAE reporting, as well as the other PRO measures.  
A collection of 25 H&N specific items, entitled "PRO-CTCAE H&N", (see separate attachments) will be used for the current study. The recall period or response frame for PRO-CTCAE items is 'within the past seven days'. This differs from the NRG Oncology traditional clinical evaluation which is ""since your last visit". This is an inherent and recognized difference in the 2 reporting systems. The goal of including PRO-CTCAE in this trial is 2-fold: 1) to gather further information for the NCI about the feasibility of implementing this measure in clinical trials and to examine its validity and sensitivity as a measure of the patient experience of adverse symptoms during treatment and across the early post-treatment period and through long-term follow-up; and 2) to characterize the patient experience of AEs immediately following treatment with targeted biotherapy (radiation + cetuximab) versus conventional chemoradiation (radiation + cisplatin) and during long-term follow up. As such, the aims will be:
1. Assess the feasibility of administering the PRO-CTCAE via paper (and/or electronic)
at selected time points, as measured by the proportion of patients who complete the form at each time point; 2. Compare patient versus clinician reporting of analogous adverse symptoms as measured by the PRO-CTCAE and CTCAE, respectively;  
3. Examine the validity of individual PRO-CTCAE items in relation to other PRO
measures being administered; 4. Compare the proportion of patients in each arm with each adverse symptom at each time point.
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work status

The ability of a patient who is gainfully employed prior to a cancer diagnosis to continue to work through treatment or return to work after treatment is an important factor in the societal and personal costs of cancer. Verdonck-deLeeuw, et al. (2010) recently reported employment and return to work status in 85 head and neck cancer survivors after surgery, radiation, or chemoradiation. The population was mixed in terms of head and neck anatomic subsites. Of the 53 patients who were employed at the time of diagnosis, 44 patients returned to work, (83%): 28 to the same work, 7 to adapted work, and 9 to other work. The median time to return to work was 6 months (range 0–24 months), and 71% of the patients returned to work within 6 months after treatment. Barriers to return to work included loss of appetite, decreased social functioning, anxiety, and oral dysfunction, such as xerostomia, trismus, sticky saliva, and problems with teeth, all of which are associated with head and neck cancer treatment.  
Information regarding employment and return to work status will be collected using brief a study-specific work status questionnaire, completed by patients without assistance from clinical or research staff, in less than 5 minutes. Computer assisted methods using skip patterning may shorten this time. This information will be collected on the same schedule as other Toxicity-PRO assessments (baseline, end of treatment, 3, 6, 12, and 24 months from end of treatment). Elements from the NRG Oncology standard demographics form will be used to determine the patient's age, education level, marital status, number of children, and number of comorbidities. We hypothesize that due to lower overall acute toxicity burden and faster recovery time, a significantly higher proportion of the patients treated with cetuximab will be able to continue working at least part-time during treatment, that patients treated with cetuximab will miss fewer days of work during and immediately after treatment, and that the time to return to full work will be shorter in the cetuximab arm compared to the cisplatin arm. The analysis will control for demographic, socioeconomic, health, and work-related variables, and include job type, income, insurance status, and employer accommodation.
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hearing handicap inventory for adults

Hearing loss significantly impacts QOL by causing communication breakdowns that elicit feelings of shame, guilt, and incompetency that negatively affect self-esteem and social identity (Hetu 1996). Individuals with handicapping hearing loss are less likely to engage in social interactions and tend to experience greater difficulty in the workplace than those with normal hearing (Tye-Murray 2009). Anti-neoplastic drugs, particularly cisplatin, cause permanent damage to the auditory system and can be exacerbated by concurrent radiotherapy. At particular risk are patients with good pre-treatment hearing levels, as this is a significant independent predictive factor for post-treatment hearing loss (Zuur 2007). As patients with HPV-associated oropharyngeal cancer often are younger with good performance status (Ang 2010), they typically have very good hearing and therefore, are at high risk for post-treatment hearing loss. Given the risk for auditory damage from chemoradiation and the potential social and vocational hardships this treatment may impose, hearing loss is a critical QOL outcome for this subject population. Hearing QOL outcomes will be measured using the Hearing Handicap Inventory for Adults screening version (HHIA-S) at each interval: baseline, end of treatment, and at 3, 6, 12, and 24 months from the end of treatment. The HHIA-S is a validated, 10-item self-assessment questionnaire designed to assess emotional and social/situational perceived hearing handicap (Newman 1990; Newman 1991). Patients will complete the questionnaire without the assistance of clinical or research staff in approximately 2 minutes. We hypothesize that the toxic effects of cetuximab on the auditory system will be significantly less than for cisplatin.  
1.6 Outcomes and Cost Effectiveness Incorporation of advanced technology and biologics into cancer treatment results in an increase in the incremental cost of care. As the cost of cancer care and health care overall rises, becoming a higher percentage of the U.S. Gross Domestic Product (GDP), an increasing emphasis is being placed on the value of higher cost interventions. An economic analysis has been incorporated into this study because cetuximab has a higher incremental cost as compared to cisplatin. NRG Oncology has used decision models informed with actual clinical trial data to perform economic analysis of clinical trials in the past
(Konski 2005; Konski 2006). The decision models have used costs which have been modelled; NRG Oncology has found the cost estimated by modelling is close to the actual cost as measured by relative value units multiplied by a Medicare conversion factor (Owen 2001; Konski 2009). The decision models also have used utilities that were obtained from the literature to inform the model instead of utilities actually collected from the trial participants themselves. This study will use the EuroQol (EQ-5D) to calculate the health-related quality of life (HRQOL) for patients. The HRQOL or quality adjusted survival is calculated by multiplying the utilities or preference for the patient's current health state by the time period, which can by expressed as a quality adjusted life year (QALY). The resultant economic analysis would be a cost-utility analysis, as it incorporates the HRQOL into the analysis. The EQ-5D will be used to calculate utilities and QALY on RTOG 0522.
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1.7 epidemiological and translational research

In the approximately 10-year period of enrollment and observation prior to analysis of this trial, we anticipate significant knowledge to be gained with regard to epidemiological and molecular differences between HPV-positive and HPV-negative patients and predictors of response to radiotherapy, cisplatin and cetuximab chemotherapy. Thus, the principal objective for the translational research for this study is to bank high quality biospecimens (serum, whole blood, paraffin tumor) on a very high proportion of patients who enroll in the trial. The specimens will be stored for future hypothesis generated research. 1.7.1 Objectives To determine the effect of tobacco exposure on overall and progression-free survival for patients with HPV-positive oropharynx cancer We hypothesize that tobacco exposure will be the strongest predictor of overall and progression-free survival in patients with HPV-positive cancer. The hazard of death will increase per unit increase in tobacco exposure (measured in pack-years or years of smoking) and will be independent of treatment assignment.  
To determine whether established risk factors for development of head and neck cancer (in addition to tobacco exposure) also are associated with overall and progression free survival.  
We hypothesize that genetic alterations associated with response to therapy and patient prognosis are largely determined by the risk factors which contributed to cancer development; therefore these factors will be stronger predictors of outcome than commonly used clinical parameters such as tumor stage.  
To determine whether specific molecular profiles (inclusive of genomic, proteomic, and mRNA or miRNA expression) in tumor, genomic DNA or serum (as appropriate) are associated with overall or progression-free survival; this will include analysis of interaction effects by treatment arm (e.g. determinants of cisplatin or cetuximab sensitivity or resistance).  
We hypothesize that distinct molecular biomarkers will be predictive of progression after treatment with cisplatin or cetuximab therapy.  
To investigate associations between changes in serum biomarkers or HPV-specific cellular immune responses measured at baseline and three months with overall or progression-free survival We hypothesize that HPV-specific T cell responses induced by chemoradiation or bioradiation (immune responses might be more prominent as some to the effect of cetuximab might be mediated through ADCC) will be associated with improved survival.  
1.7.2 Rationale Objective 1 Tobacco smoking is a major risk factor for head and cancer. In addition to its etiologic role, there is evidence that smoking alters treatment response, risk of recurrence, rates of second primary cancers, and overall survival for patients with head and neck cancer (Duffy 2009). Cigarette smoking during radiation therapy for early stage head and neck cancer increased risk of recurrence and death from cancer as well as death from any cause: smoking during therapy had a more pronounced effect on treatment outcomes than smoking during the year prior to or after completion of therapy (Meyer 2008). A history of smoking has been associated with reduced response to platinum-based induction chemotherapy (Fountzilas 1997) and also with lower rates of complete response to radiation therapy (Browman 1993). Epidemiological data indicate that tobacco smoking is not a strong co-factor for HPV-positive head and neck cancer (Gillison 2008; Applebaum 2007). With regard to survival outcomes, the independent effects of tobacco exposure and tumor HPV status on patient survival have been unclear, given the strong inverse correlation between the two. However, there is growing evidence that the biological behavior and treatment response of HPV-positive head and neck cancer may be modified by tobacco exposure. In a single-institution case-series of patients with tonsillar cancer, patients who were current smokers at diagnosis were found to have an estimated 4-fold increase in risk of cancer death when compared to former/never smokers after consideration of tumor stage and p21 and cyclin D expression (surrogates for HPV-positive disease) [Hafkamp 2008]. In bivariate analysis, the University of Michigan has reported that current smoking was associated with worse survival among patients with HPVpositive oropharyngeal cancer (Kumar 2008). In a more recent analysis from University of Michigan, patients with HPV-positive oropharynx cancer who were former or never smokers were less likely to develop distant metastases and disease-recurrence (in univariate analysis) when compared to HPV-positive current smokers (Maxwell 2010). In our analysis of RTOG 0129, both tumor HPV status and tobacco smoke exposure (measured in pack-years or duration of smoking) were strong and independent predictors of progression-free and overall survival for oropharynx cancer. In proportional hazards modeling, risk of death significantly increased by 1% per pack-year of tobacco exposure, after adjustment for tumor HPV status, age, race, T stage, N stage, and performance status. Recursive partitioning analysis was used to evaluate which factors of significance in a multivariate proportional hazard model had greatest influence on patient survival. In this analysis, the tumor HPV status of OPSCC was found to be the major determinant of OS in recursive partitioning analysis, followed by tobacco-smoking (≤ 10 vs. >10 pack-years), then nodal stage (N0-2a vs. N2b-3) for HPV-positive and tumor stage (T2-3 vs. T4) for HPVnegative OPSCC patients. This analysis classified OPSCC patients into three risk groups:
low (reference; 93% 3-year OS), intermediate (HR 3.54, 95% CI 1.91-6.57; 70.8% 3-year OS), and high-risk (HR 7.16, 95% CI 3.97-12.93; 46.2% 3-year OS) of death. HPV-positive patients were low-risk except smoking plus high (N2b-3) nodal stage assigned them to intermediate-risk, and HPV-negative patients were high-risk unless they were nonsmokers with T2-3 tumors and thus intermediate-risk. Smoking has been linked with specific genetic alterations such as p53 mutations and with specific and global methylation patterns in head and neck cancer (Marsit 2009), and these patterns may differ in HPV-positive vs negative cancers in smokers and non-smokers (Marsit 2006). However, the specific genetic or epigenetic changes induced by tobacco smoking that negatively effect the survival of both HPV positive and negative oropharynx cancer patients have not been clearly defined to date. The likelihood of such genetic "hits" appears to increase along a biological continuum of increasing tobacco pack-years. However, the 10 pack-year cut-point that best predicted survival in RTOG 0129 in recursive partitioning analysis is perhaps more useful for risk-based clinical trial design. This is the basis for the choice of the 10 pack-year cut-point used for stratification for RTOG 1016. It has previously been recommended that all cooperative groups assess tobacco exposure via a standardized and centralized questionnaire (Gritz 2005). For cancers in addition to head and neck cancer, tobacco exposure has been associated with clinical trial outcome by means of increased toxicity due to comorbidity, increased risk of second primary tumors, and perhaps by direct modification of the tumor response to treatment (Gritz 2005). Nicotine has been shown to interact with both the mitogen activated protein (MAP) kinase and akt pathways and may inhibit apoptosis in response to therapy (Heusch 1998); West 2003).  
Nicotine has been reported to reduce the cytotoxic effects of cisplatin and radiation of head and neck cancer cell lines in vitro (Onada 2001). Our data from RTOG 0129 further underscores the importance of measurement of tobacco exposure, given that HPV and tobacco were the strongest predictors of clinical outcome for oropharynx cancer patients.  
We will utilize a questionnaire to ascertain lifetime tobacco exposure at baseline. This questionnaire is based upon validated epidemiological surveys of tobacco exposure with high agreement with repeat testing (kappa>0.80) and strong associations with head and neck cancer risk (D'souza 2007; Gillison 2008). The survey obtains all data acquired in RTOG 9003, 0129, and 0522 as well as all the critical elements recommended for routine tobacco exposure measurement in clinical trials. The survey will collect data necessary for calculation of tobacco pack-years from cigarette use only for stratification because this is what was done in our analysis of RTOG 0129 (other sources of tobacco exposure were not previously measured by RTOG). Although < 5% of US tobacco smokers use forms other than cigarettes, to accomplish our research objectives (not for stratification) the survey collects data on lifetime use of pipe, cigar and smokeless tobacco. Standard conversion factors for cigar use and pipe use are used to account for non-cigarette smoking exposure. Ages at initiation and start of regular use (defined as daily for one month or more) and cessation of cigarette use will be obtained due to strong associations between years of use and PFS and OS in RTOG 9003 and 0129. Successful quit attempts of one year or longer, quantitative measures of intensity of use (e.g. cigarettes per day) will be obtained. After survey completion, a standard formula for calculation of lifetime, cumulative total-pack years of exposure that is programmed into the questionnaire will immediately provide a summary of patient exposure for stratification. Data will be automatically sent by e-mail to NRG Oncology staff.
eligibility checklist -step 2 (10/17/13)
objective 2

Cancer arises by the accumulation of genetic and epigenetic changes in genes involved in cell cycle control, signal transduction, apoptosis, tissue homeostasis and angiogenesis. Given the majority of head and neck squamous cell carcinomas are attributable to environmental exposures and lifestyle choices, the genetic events that promote carcinogenesis in the upper airway are largely environmentally induced. Indeed, it has been estimated that the majority of human cancers are attributable to environmental exposures. Tobacco use, alcohol drinking, oral human papillomavirus infection, Epstein-Barr infection, diets low in fruit and vegetables and high in processed meets, and poor oral hygiene (and possibly marijuana use) are established risk factors for head and neck cancers. These exposures (and perhaps as yet undetermined factors) are therefore likely responsible for the genetic profile of head and neck cancers. Alteration of the tumor suppressor gene p53 is a common early genetic event in head and neck cancers (Boyle 1993). Tobacco exposure is associated with the frequency and type of p53 mutations found in tumors (Brennan 1995). In an analysis by Brennan and colleagues, p53 mutations were present in 47% of smokers but only 14% of non-smokers. Patients without a history of smoking and drinking had p53 mutations which occur at CpG sites, indicating they occurred as a result of methylation, whereas the majority of mutations that occurred in smokers were consistent with tobacco-carcinogen induced mutations. p53 mutations identified in human lung cancers among patients with exposure to four human carcinogens (including benzo[a]pyrene) are identical to those induced by these carcinogens in exposed mice (Kucab 2010). Importantly, the type of p53 mutation is also associated with prognosis in patients with surgically resected head and neck cancer (Poeta 2007), after consideration of clinical factors such as tumor site, stage, and treatment.  
In HPV-positive oropharynx cancers, the p53 pathway is inactivated by protein-protein interaction with the HPV oncoprotein E6, which targets p53 for inactivation by the proteosome. Self-reported oral sexual behaviors have been associated with oral HPV infection and risk of HPV-associated cancers. In our analysis of RTOG 0129, tumor HPV
status was the single strongest predictor of patient prognosis, followed by measures of tobacco exposure and tumor stage. Therefore, it has been shown that the most important risk factors for development of head and neck cancer are also the greatest predictors of response to therapy and patient survival. This is likely because these factors determine the molecular profile of the cancers. We therefore propose to measure risk behaviors through epidemiologically sound methods, in order to further investigate associations between risk behaviors and patient prognosis. The survey covers the following domains: demographics, tobacco use, alcohol use, marijuana use, family history of cancer, diet, oral hygiene, and sexual behavior. Of particular interest in this analysis will be marijuana use. Whether marijuana use is a risk factor for head and neck cancer remains controversial. In case-control studies in which cases were not stratified by HPV status, marijuana use has (Zhang 1999) and has not
(Berthiller 2009) been associated with HNSCC, and in one study, was reported to reduce odds of HNSCC (Liang 2009). However, in a case-control study in which cases were stratified by HPV status, lifetime and cumulative measures of marijuana use were associated with HPV-positive but not HPV-negative HNSCC (Gillison 2008). Additionally, marijuana contains many of the same carcinogens as are found in tobacco smoke (Moir 2008). Therefore, marijuana use (together with or without tobacco use) may have the biological capability to modify the therapeutic response of a patient with an HPV-positive tumor analogous to tobacco smoking.
eligibility checklist -step 2 (10/17/13)
objective 3

As a greater understanding of molecular mechanisms underlying cancer pathogenesis is achieved, molecularly targeted therapy becomes a reality and predictors of response are identified. For example, only women with Her-2 positive breast cancer benefit from trastuzumab and patients with metastatic colon cancer with mutated KRAS do not benefit from cetuximab. As of 2010, there are no biomarkers predictive of response to cisplatin or cetuximab for patients with oropharynx cancer, regardless of tumor HPV status. What is clear is that: (1) tumor HPV status is the strongest, independent "molecular" prognostic factor identified to date for patients with head and neck cancer; (2) patients with HPVpositive tumors have half the risk of death when compared to HPV-negative patients, regardless of therapy as long as it is within the standard of care; and (3) the absolute difference in survival for the HPV-positive and HPV-negative patients at five years when treated with primary radiotherapy with or without concurrent chemotherapy is approximately 30%. Although tumor HPV status is predictive of improved survival, in 2010 it is not an indication for selection of any particular therapeutic agent or modality. During the eight-year period of enrollment and observation for this clinical trial, we anticipate considerable knowledge to be gained regarding molecular differences between HPV-positive and HPVnegative patients and predictors of response to therapy. Below, we discuss the state of the art in 2010, to provide examples of the type of analyses we expect to be able to perform with prospective collection of biospecimens from patients enrolled in this trial. We do expect, however, that the specific questions to be addressed, biomarkers to be evaluated and the methods used will change significantly over the next eight years. Our objective is to collect a range of samples at particular time points to facilitate future investigation.  
Predictors of disease progression or death among HPV-positive oropharynx patients: It is clear that progression-free survival is superior for HPV-positive oropharynx cancer patients when compared to HPV-negative patients. Disease progression or death nevertheless occurs in approximately 30% of HPV-positive patients at three years after treatment with accelerated fractionation radiotherapy and high dose cisplatin per RTOG 0129. While tobacco exposure (see above) appears to be important, as of 2010, expression of several proteins involved in signal transduction, cell-cycle control or apoptosis have been proposed as biomarkers of poor outcome in HPV-positive patients. These include EGFR expression (Hong 2010), cyclin D1 expression (Hafkamp 2009; Hong 2010), p53 expression (Wallace 2010), and Bcl-2 expression (Nichols 2010). However, all have yet to be prospectively investigated in a study of sufficient size to evaluate the independent effects of these markers among HPV-positive patients. Additionally, 16q loss has been associated with favorable survival for the HPV-positive patient by comparative genomic hybridization (Klussman 2009).  
All of these biomarkers, with the exception of 16q loss (evaluable by FISH), can be evaluated by immunohistochemistry on paraffin-embedded tissues. The table below shows the prevalence of these factors among patients with HPV-positive oropharynx cancer and associations with particular disease outcome measures.  
| Factor      | % HPV-positive   | Outcome                   | Hazard Ratio   | 95% CI   |
|-------------|------------------|---------------------------|----------------|----------|
| with factor | measure          | univariate                |                |          |
| EGFR        | 78               | Local-regional failure    | 6.6            | 2.1-40.0 |
| Cyclin D1   | 27               | Local-regional failure    | 3.5            | 1.9-7.2  |
| P21         | 63               | Disease-specific survival | 0.4            | NR       |
| Bcl-2       | 40               | Overall survival          | 4.0            | 1.2-13.6 |
| P53         | 40               | Disease-specific survival | 1.7            | NR       |
| 16q loss    | 29               | Overall survival          | NR             | NR       |  
Of particular interest for the HPV-positive patient is the role of cell mediated immunity against the viral tumor-specific antigens, E6 and E7, and patient prognosis. It has been hypothesized that primary therapy with chemo-radiation and resulting tumor-cell death may induce a cellular immune response specific to HPV-infected cells, contributing to improved patient prognosis. Indeed, HPV transformed mouse tonsillar epithelial cell tumors are cleared after exposure to cisplatin or radiation only in immune competent mice (Spanos 2009). Preliminary studies in human subjects are ongoing to investigate changes in HPVspecific CD8+ and CD4+ T cells before and after therapy.  
Much of the improved survival for the HPV-positive patient is attributable to improved localregional control. The risk of distant metastasis for the HPV-positive patient is nonsignificantly reduced. Several clinical trials have demonstrated that cisplatin administration can reduce the development of distant metastases for patients with head and neck cancer, but whether or not cetuximab has this potential is unclear. Individuals at risk for distant metastases and their response to therapy may, in theory, be measurable through detection of circulating tumor cells (CTC) or circulating nucleic acids at baseline, and changes before and after therapy might be predictive of distant failure. The number of CTC (cutpoint of ≥5 CTC per 7.5 mls blood) has been shown to be associated with poor prognosis in patients with early stage breast (Saloustro 2010), and metastatic prostate and lung cancer. In cervical cancer patients, a combination of EpCAM selection of CTC and RT-PCR for HPV oncogene transcripts was successful in detecting CTC in cervical cancer patients (Weismann 2009). However, the technology for selection of CTC from lymphocytes in peripheral blood is evolving (from size exclusion, density centrifugation, positive or negative antibody-based magnetic automatic cell sorter with microfluidics to fiber-optic array scanning technology) to approaches resulting in higher yields and detection in a higher proportion of patients (Pantel 2010; Lin 2010). However, in 2010, samples stored at room temperature require processing within 72 hours. Measurement of circulating nucleic acids derived from tumor cells may be more feasible in archived specimens. In the case of HPV-positive cancers, real-time PCR quantitation of the viral genome or transcripts in serum or plasma or whole blood would be tumor specific (Capone 2000). Although several biomarkers have been associated with prognosis for patients with head and neck cancer, (e.g. p53 mutations, EGFR expression, EGFR gene amplification), as of 2010, there are no biomarkers predictive of response to a specified therapy. The design of RTOG 1016 provides a unique opportunity for the prospective collection of biospecimens from a large cohort of patients with HPV-positive oropharynx cancer randomized to receive radiation sensitization with either cisplatin or cetuximab, two standard of care options for therapy for this patient population which have not been compared to date. This study design provides a unique opportunity to identify specific predictors of disease control and survival which may be: (1) observed in both treatment arms and therefore indicative of response to radiation therapy; (2) observed only in the cisplatin arm and therefore indicative of response 34 RTOG 1016, Version Date: 2/23/16 to a DNA damaging agent; (3) observed only in the cetuximab arm and therefore indicative of response to EGFR pathway inhibition. It must be emphasized that we describe factors below which would be investigated in 2010. However, we anticipate the state of the science to change significantly over the next eight years. Our objective is to collect and bank specimens which will be available to address important hypotheses which will advance the field when data are mature.  
Predictors of response or resistance to cetuximab therapy: Activation of the EGFR signaling pathway is frequently observed in head and neck squamous cell carcinoma, and elevated expression of EGFR is associated with poor survival, radiation resistance, and local-regional failure. Although inhibition of EGFR signaling with cetuximab has improved overall survival in combination with primary radiotherapy (Bonner 2006; Bonner 2010) or in combination with chemotherapy in the metastatic setting (Vermorken 2008), there are no biomarkers predictive of therapeutic benefit from cetuximab. For example, EGFR expression is not predictive (Bonner 2010) and EGFR activating mutations are infrequent in head and neck cancer (Sharafinski 2010). Potential biomarkers of interest as predictors of response to cetuximab therapy at this time would include: (1) EGFRvIII, a truncated form of the EGFR
possibly present in as many as 42% of HNSCC (Wheeler 2010). EGFRvIII would be expected to reduce response to cetuximab because the ligand binding and cetuximab binding sites are deleted (Sok 2006). (2) Loss of the tumor suppressor gene, Phosphatase protein homolog to tensin (PTEN,) an inhibitor of the PI3/akt signaling pathway activated by EGFR. PTEN loss would be expected to be associated with resistance to cetuximab; (3) EGFR ligand (EGF, TGF-alpha, amphiregulin, epiregulin, betacellulin and heparin-binding EGF-like growth factor) expression in tumors. Epiregulin and amphiregulin expression have been associated with improved response rate, progression-free survival, and overall survival in patients with KRAS wildtype colon cancer in response to cetuximab therapy (Jacobs 2009): (4) Nuclear EGFR expression. Translocation of EGFR to the nucleus has been associated with activation of cyclin D1, DNA-dependent protein kinase and resistance to cetuximab (Li 2009); (5) Tumor expression of IL-6 and NFK-beta or serum levels. These have been associated with resistance to cetuximab (Chen 2010). (6) Downstream indicators of EGFR signal transduction, e.g. p-EGFR, p-STAT signaling, pAKT; (7) Polymorphisms in the EGFR associated with skin rash (e.g. EGFR-R521K or CA-SSR) (Klinghammer 2010; Huang 2009). Development of a significant rash is the only strong and consistent predictor of clinical benefit from cetuximab therapy, but there are no identified predictors of skin rash development. (8) Serum proteomic profile classified as "poor" vs "good" for response to EGFR-target agents as measured by MALDI MS (VerisStrat, Biodesix, Inc Steamboat Springs CO). Analysis of three small clinical trials in head and neck cancer patients treated with gefitinib, erlotinib or cetuximab has revealed an association between a "good" profile and improved overall survival in univariate analysis, but no association with treatment with a taxane (Chung 2010). Cetuximab, being a monoclonal antibody (mAb), may exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC) via binding of the Fc portion of the mAb to Fcγ receptors expressed on macrophages and natural killer cells. Specific genetic polymorphisms in the FcγRIIa (CD 32, expressed primarily on macrophages) and FcγRIIIa (CD16, expressed on macrophages and NK cells) receptors can affect antibody affinity and target cell lysis (Bowles JA 2005). In support of this hypothesis, in vitro studies have shown effector cells expressing a homozygous FcγRIIIa-158V/V (valine) were more effective after cetuximab treatment at lysis of head and neck cancer cells expressing the EGFR and induced larger amounts of inflammatory cytokines and chemokines (Lopez-Albaitero 2009).  
Based on these studies, patients homozygous for FcγRIIa-131H/H (histidine) and FcγRIIIa158V/V (valine) would be expected to have higher binding affinity and greater ADCC in response to mAb therapy than carriers that are either heterozygous or homozygous for the FcγRIIa131R (arginine) or FcγRIIIa-158F(phenylalanine). Indeed, homozygous individuals for FcγRIIa-131H/H (histidine) and FcγRIIIa-158V/V (valine) were shown to have improvements in progression-free survival after treatment with cetuximab for colon cancer
(Bibeau 2009) and after treatment with trastuzumab for metastatic Her-2 positive breast cancer, (Musolino 2008) and were also shown to have higher response rates after treatment of follicular lymphoma with rituximab (Paiva 2008).  
Predictors of response or resistance to cisplatin therapy: Meta-analyses have determined that the addition of platinum chemotherapy given concurrently to radiation therapy yields the greatest absolute improvement in survival for patients with head and neck cancer. Cisplatin remains first line therapy in both the primary and recurrent/metastatic settings for head and neck cancer patients, and yet, in HPV-positive patients 30% will progress or die within three years. Several mechanisms of cisplatin resistance have been identified, (Basu 2010) but of particular interest is the role of DNA repair pathways that mediate cisplatin cytotoxicity.  
Paradoxically, polymorphisms in DNA damage repair pathways that might increase risk for HNSCC for an individual might also increase survival in response to DNA damaging agents such as radiation and cisplatin. Because of inherent genomic instability, somatic mutations in DNA repair pathways in cancers might induce greater radiation or chemosensitivity than that in normal tissue. Cisplatin cytotoxicity is primarily attributable to intra-strand crosslinks repaired by the nucleotide excision repair (NER) pathway. Activity of the NER pathway is associated with cisplatin sensitivity/resistance, in particular alterations in the level of ERCC1 mRNA or protein. Single nucleotide polymorphisms in NER pathway proteins ERCC1, XPD and XRCC1 are associated with overall survival in patients with stage IV head and neck cancer treated with cisplatin (Quintela-Fandino 2006). In a recently published metaanalysis, low expression of one of the NER pathway proteins, ERCC1, was associated with increased response and survival after cisplatin therapy in patients with advanced NSCLC (Chen 2010). Studies to date in head and neck cancer patients are inconsistent, but suggest ERCC1 expression may be associated with response to cisplatin and radiation therapy (Jun 2008; Handra-Luca 2007; Fountzilas 2009; Koh 2009). Co-expression of Snail and ERCC1 may identify tumors with cisplatin resistance (Hsu 2010). Additional DNA repair pathways, such as the mismatch repair pathways (MMR) implicated in familial colon cancer, may also be important in mediating cisplatin-induced apoptosis. In addition to the examples of specific pathways and mechanisms noted above, it must be acknowledged that technical improvements in genomic, transcriptional and miRNA profiling on paraffin embedded materials are being made rapidly. Such broad molecular profiling may identify as yet identified pathways important in overall survival in the entire study population or specific to one of the treatment arms.
eligibility checklist -step 2 (10/17/13)
2.0 objectives 2.1 primary objective

2.1.1 To determine whether substitution of cisplatin with cetuximab will result in comparable 5-year overall survival  
| 2.2   | Secondary Objectives (6/28/12)  2.2.1 To monitor and compare progression-free survival for "safety";  2.2.2 To compare patterns of failure (locoregional vs. distant);  2.2.3 To compare acute toxicity profiles (and overall toxicity burden);  2.2.4 To compare overall quality of life (QOL) short-term (< 6 months) and long-term (1 year)  2.2.5 To compare quality of life Swallowing Domains short-term and long-term;  2.2.6 To compare clinician-reported versus patient-reported CTCAE toxicity events;  2.2.7 To explore differences in the cost effectiveness of cetuximab as compared to cisplatin;  2.2.8 To explore differences in work status and time to return to work;  2.2.9 To compare patient-reported changes in hearing as measured by the HHIA-S;  2.2.10 To compare CTCAE, v. 4 late toxicity at 1, 2, and 5 years  2.2.11 To evaluate the effect of tobacco exposure (and other exposures) as measured by  standardized computer-assisted self interview (CASI) on overall survival and progression-free  survival;  2.2.12 To pilot computer-assisted self interview (CASI) collection of patient reported outcomes in a  cooperative group setting;  2.2.13 To determine whether specific molecular profiles are associated with overall or progression-free  survival;   |
|-------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
2.2.14 To investigate associations between changes in serum biomarkers or HPV-specific cellular immune responses measured at baseline and three months with overall or progression-free survival.
eligibility checklist -step 2 (10/17/13)
3.0 patient selection (6/3/14) note

3.1 Conditions for Patient Eligibility (6/25/13)
3.1.1 Pathologically (histologically or cytologically) proven diagnosis of squamous cell carcinoma
(including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls); Note: Paraffin-embedded cytology specimens are acceptable for p16 evaluation, but cytology smears are not.  
Cytologic diagnosis from a cervical lymph node) is sufficient in the presence of clinical evidence of a primary tumor in the oropharynx. Clinical evidence should be documented, may consist of palpation, imaging, or endoscopic evaluation, and should be sufficient to estimate the size of the primary (for T stage).  
3.1.2 Patients must be positive for p16, determined by the OSU Innovation Center CLIA lab prior to Step 2 registration (randomization); see 10.2 for details of tissue submission; 3.1.3 Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site.  
Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions. Fine needle aspirations of the neck are insufficient due to limited tissue for retrospective central review. Biopsy specimens from the primary or nodes measuring at least 35 mm are required.  
3.1.4 Clinical stage T1-2, N2a-N3 or T3-4, any N (AJCC, 7th ed.; see Appendix III), including no distant metastases, based upon the following minimum diagnostic workup:
General history and physical examination by a radiation oncologist and medical oncologist within 8 weeks prior to registration; Examination by an ENT or head and neck surgeon, including laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) within 8 weeks prior to registration; One of the following combinations of imaging is required within 8 weeks prior to registration:
a) A CT scan of the neck (with contrast) and a chest CT scan (with or without contrast); b) or an MRI of the neck (with contrast) and a chest CT scan (with or without contrast);
c) or a CT scan of neck (with contrast) and a PET/CT of neck and chest (with or without contrast);
d) or an MRI of the neck (with contrast) and a PET/CT of neck and chest (with or without contrast).  
Note: A CT scan of neck and/or a PET/CT performed for radiation planning and read by a radiologist may serve as both staging and planning tools.  
3.1.5 Zubrod Performance Status 0-1 within 2 weeks prior to registration 3.1.6 Age ≥ 18; 3.1.7 CBC/differential obtained within 2 weeks prior to registration on study, with adequate bone marrow function, defined as follows:
Absolute neutrophil count (ANC) > 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.  
3.1.8 Adequate hepatic function, defined as follows:
Bilirubin < 2 mg/dl within 2 weeks prior to registration; AST or ALT < 3 x the upper limit of normal within 2 weeks prior to registration; 3.1.9 Adequate renal function, defined as follows:  
Serum creatinine < 1.5 mg/dl 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)]  
| self interview (CASI) head and neck risk factor survey tool.   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 3.1.11                                                         | Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing  potential;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| 3.1.12                                                         | Women of childbearing potential and male participants must agree to use a medically effective  means of birth control throughout their participation in the treatment phase of the study and  until at least 60 days following the last study treatment.                                                                                                                                                                                                                                                                                                                                                                                                                           |
| 3.1.13                                                         | Patients who are HIV positive but have no prior AIDS-defining illness and have CD4 cells of at  least 350/mm3  are eligible. Patient HIV status must be known prior to registration. Patients must  not be sero-positive for Hepatitis B (Hepatitis B surface antigen positive or anti-hepatitis B core  antigen positive) or sero-positive for Hepatitis C (anti-Hepatitis C antibody positive). However,  patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible  (e.g. patients immunized against hepatitis B). HIV-positive patients must not have multi-drug  resistant HIV infection or other concurrent AIDS-defining conditions. |
| 3.1.14                                                         | Patient must provide study specific informed consent prior to study entry, including consent for  mandatory submission of tissue for required, central p16 review and consent to participate in  the computer-assisted self interview (CASI) survey questions regarding smoking history.                                                                                                                                                                                                                                                                                                                                                                                           |
| 3.2.1                                                          | Cancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge,  buccal or lip), nasopharynx, hypopharynx, or larynx, even if p16 positive, are excluded.  Carcinoma of the neck of unknown primary site origin (even if p16 positive) are excluded from  participation.                                                                                                                                                                                                                                                                                                                                                                              |
| 3.2.2                                                          | Stage T1-2, N0-1;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
| 3.2.3                                                          | Distant metastasis or adenopathy below the clavicles;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| 3.2.4                                                          | Gross total excision of both primary and nodal disease; this includes tonsillectomy, local  excision of primary site, and nodal excision that removes all clinically and radiographically  evident disease.                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| 3.2.5                                                          | Simultaneous primaries or bilateral tumors;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
| 3.2.6                                                          | Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a  minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all  permissible);                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 3.2.7                                                          | Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different  cancer is allowable;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| 3.2.8                                                          | Prior radiotherapy to the region of the study cancer that would result in overlap of radiation  therapy fields;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| 3.2.9                                                          | Severe, active co-morbidity, defined as follows:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
| 3.2.9.1                                                        | Unstable angina and/or congestive heart failure requiring hospitalization within the last 6  months;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| 3.2.9.2                                                        | Transmural myocardial infarction within the last 6 months;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| 3.2.9.3                                                        | Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
| 3.2.9.4                                                        | Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring  hospitalization or precluding study therapy within 30 days of registration;                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| 3.2.9.5                                                        | Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however,  that laboratory tests for liver function and coagulation parameters are not required for entry  into this protocol.                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| 3.2.9.6                                                        | Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition with  immune compromise greater than that noted in Section 3.1.13; note, however, that 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 immunocompromised patients.  
3.2.10 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.  
3.2.11 Prior allergic reaction to cisplatin or cetuximab; 3.2.12 Prior cetuximab or other anti-EGFR therapy.
eligibility checklist -step 2 (10/17/13)
4.0 pretreatment evaluations/management note this

4.1 Required Evaluations/Management **(6/3/14)**
4.1.1 Na, K, Cl, glucose, Ca, Mg, and albumin within 2 weeks prior to the start of treatment as part of standard of care pre-treatment management; 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.  
4.1.2 Protocol-specific dental assessment (see Appendices VI and VII) by a physician or designee
(such as a physician's assistant, nurse or nurse practitioner, or a dentist/hygienist) to assess number of teeth and overall dental health within 8 weeks prior to the start of treatment with management according to the guidelines in Appendix IV;
4.1.3 Audiogram within 12 weeks prior to start of treatment; 4.1.4 Protocol-specific assessment of swallowing by clinical staff via CTCAE, v. 4 (dysphagia) within 4 weeks prior to the start of treatment; 4.1.5 If the patient consents to complete the entire head and neck risk factor survey at baseline
(optional) via the computer-assisted self-interview (CASI), sites are required to provide it following Step 1 registration.  
4.1.6 If the patient consents to complete the optional demographic Work Status Questionnaire
(baseline) via the iPAD, sites are required to provide it after Step 1 Registration.  
The Quality of Life (QOL) component closed to accrual on 2/28/13. Note: For patients  
already enrolled on the QOL component, sites must submit follow-up QOL as specified in Section 12.1. 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 protocol treatment: QLQ-C30, QLQH&N35, EQ-5D, PRO-CTCAE-H&N, HHIA-S, and Work Status Questionnaire (baseline);
eligibility checklist -step 2 (10/17/13)
4.2 highly recommended evaluations/management

4.2.1 EKG within 8 weeks prior to start of treatment; 4.2.2 "Whole body" PET scan within 8 weeks prior to start of treatment; "whole body" PET/CT may be limited to neck and chest. Note: CT scan of neck and/or PET/CT performed for radiation planning may serve as both staging and planning tools.  
4.2.3 Evaluation by a nutritionist and/or swallowing therapist within 2 weeks prior to the start of treatment, to include evaluation for placement of prophylactic gastrostomy or other type of feeding tube; note: The decision to place a feeding tube should be individualized and may consider a number of factors including: prior weight loss, current nutritional status, size and location of the primary tumor (impacting high dose target volume), availability of feeding tube placement services, availability of speech and swallowing specialists, and social support. Feeding tubes may be placed after start of treatment at the discretion of the clinical team. If a tube is placed, the site will document on the appropriate case report form (see Section 12.1) if the tube was placed prophylactically (as a preventative measure) or therapeutically (because of nutritional compromise or other clinical indications).
eligibility checklist -step 2 (10/17/13)
5.0 registration procedures (10/17/13) 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. Note: This trial is not utilizing the services of the ITC for dosimetry digital treatment data submission. See below for information on installing TRIAD for submission of digital RT data prior to enrolling patients. Note: FOR THIS STUDY, IMRT IS MANDATORY. Use of IGRT and IGRT credentialing is MANDATORY when using PTV margins < 5 mm.  
5.1 Image-Guided Radiotherapy (IGRT) (6/3/14)
If an institution uses IGRT for margin reduction, that institution must be credentialed **both for IMRT and** for head and neck image-guided radiotherapy (IGRT) in order to be eligible to enroll patients onto this trial. Sites that have been approved by NRG Oncology for head and neck IGRT credentialing will not have to re-credential for IGRT on this study. Institutions can use IGRT as a patient setup aid without credentialing, but standard margins must be used until they complete the credentialing process. The institution or investigator must update an existing or complete a new Facility Questionnaire specifically for this study. This information is available on the Imaging and Radiation Oncology Core (IROC) Houston (former Radiological Physics Center [RPC]) web site at http://irochouston.mdanderson.org.  
5.2 Pre-Registration Requirements for Image-Guided Radiotherapy (IGRT) Treatment Approach (for sites that utilize this approach for margin reduction) **(6/3/14)** 5.2.1 In order to utilize IGRT for margin reduction, the center must be credentialed for its use. This means the institution must have met technology requirements and have provided the baseline physics information. This information is available on the NRG Oncology/RTOG web site: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016 .  
In order to become credentialed for head and neck IGRT, the institution must have already become credentialed for head and neck IMRT. Institutions that have not been credentialed by NRG Oncology to perform head and neck IMRT MUST apply for IMRT credentialing as described below in Section 5.3.  
5.2.2 IGRT Credentialing Process Each institution interested in using reduced margins will be required to undergo credentialing for head and neck IGRT (review of at least one case from each institution). The first step is for the institution or investigator to update an existing or complete a new Facility Questionnaire and a Credentialing Status Inquiry Form. This information is available on the IROC Houston web site, http://irochouston.mdanderson.org. **Note**: Sites that have been approved for Head and Neck IGRT credentialing will not have to repeat IGRT credentialing for this trial. Next, the institution must submit a series of daily treatment images along with a spreadsheet of IGRT data from an anonymized head and neck cancer patient. See the NRG Oncology/RTOG web site, http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016, for the spreadsheet. This series must include a minimum of 5 daily pre-treatment images. These images must be selected to fall on 5 sequential treatment days. Pre-treatment images may include three-dimensional (3D) volumetric images (either fan- or cone-beam CT with Megavoltage (MV) or kilovoltage (KV) x-ray or Orthogonal (MV or KV) 2D images. These images and the spreadsheet will be reviewed by the Medical Physics Co-chairs, Søren Bentzen, PhD, and/or James Galvin, PhD, prior to credentialing. IGRT data and the completed spreadsheet are submitted to TRIAD. Select Benchmark submission (see Section 5.4). IROC
Houston will notify the institution that the institution is credentialed.  
5.3 Pre-Registration Requirements for IMRT Treatment Approach (6/3/14)
5.3.1 In order to utilize IMRT on this study, the institution must have met specific technology requirements and have provided baseline physics information. Instructions for completing these requirements or determining if they already have been met are available on the IROC Houston web site. Visit http://irochouston.mdanderson.org and select "Credentialing" and "Credentialing Status Inquiry".  
An IMRT phantom study with IROC Houston must be successfully completed (if the institution has not previously met this IMRT credentialing requirement on another NRG Oncology IMRT
Head and Neck study). Instructions for requesting and irradiating the phantom are available on the IROC Houston web site, http://irochouston.mdanderson.org; select "Credentialing" and
"NRG Oncology". Upon review and successful completion of the phantom irradiation, IROC
Houston will notify both the registering institution and NRG Oncology that the institution has completed this requirement. Subsequently, IROC Houston will notify the institution that the IMRT credentialing requirement has been met.
eligibility checklist -step 2 (10/17/13)
5.4 digital rt data submission

TRIAD is the American College of Radiology's (ACR) image exchange application and it is used by NRG Oncology. TRIAD provides sites participating in NRG Oncology clinical trials a secure method to transmit DICOM RT and other objects. TRIAD anonymizes and validates the images as they are transferred.  
TRIAD Access Requirements:
Site physics staff who will submit images through TRIAD will need to be registered with The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP Identity and Access Management (IAM) account. Please refer to Section 5.0 of the protocol for instructions on how to request a CTEP-IAM account.  
To submit images, the site physics user must have been assigned the 'TRIAD site user' role on the relevant Group or CTSU roster. Users should contact your site Lead RA to be added to your site roster. Users from other cooperative groups should follow their procedures for assignment of roster roles.  
RAs are able to submit standard of care imaging through the same method.
eligibility checklist -step 2 (10/17/13)
triad installations when a user

This process can be done in parallel to obtaining your CTEP-IAM account username and password. If you have any questions regarding this information, please send an e-mail to the TRIAD Support mailbox at TRIAD-Support@acr.org.