Radiation Therapy With Cisplatin or Cetuximab in Treating Patients With Oropharyngeal Cancer

Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy is more effective with cisplatin or cetuximab in treating oropharyngeal cancer.

PURPOSE: This phase III trial is studying radiation therapy with cisplatin or cetuximab to see how well it works in treating patients with oropharyngeal cancer.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer; Precancerous Condition
• Intervention / Treatment: Drug: cisplatin; Radiation: IMRT; Biological: cetuximab

Detailed Description

OBJECTIVES:

Primary

• To determine whether substitution of cisplatin with cetuximab will result in comparable 5-year overall survival.

Secondary

• To monitor and compare progression-free survival for "safety".
• To compare patterns of failure (locoregional vs distant).
• To compare acute toxicity profiles (and overall toxicity burden).
• To compare overall quality of life (QOL) short-term (< 6 months) and long-term (1 year).
• To compare QOL Swallowing Domains short-term and long-term.
• To compare clinician-reported versus patient-reported CTCAE toxicity events.
• To explore differences in the cost effectiveness of cetuximab as compared to cisplatin.
• To explore differences in work status and time to return to work.
• To compare patient-reported changes in hearing.
• To compare CTCAE v. 4 late toxicity at 1, 2, and 5 years.
• 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.
• To pilot CASI collection of patient reported outcomes in a cooperative group setting.
• To determine whether specific molecular profiles are associated with overall or progression-free survival.
• To investigate associations between changes in serum biomarkers or human papilloma virus (HPV)-specific cellular immune responses measured at baseline and three months with overall or progression-free survival.

OUTLINE: This is a multicenter study. Patients are stratified according to T stage (T1-2 vs T 3-4), N stage (N0-2a vs N2b-3), Zubrod performance status (0 vs 1), and smoking history (≤ 10 pack-years vs > 10 pack-years). Patients are randomized to 1 of 2 treatment arms.

Patients may complete quality-of-life questionnaires and risk factors for head and neck cancer surveys at baseline, periodically during study, and at follow-up for 1 year.

After completion of study therapy, patients are followed up at 1-3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 987
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill Cancer Centre at McGill University
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Cancer Center
  • California
    • Auburn, California, United States, 95603
      • Auburn Radiation Oncology
    • Burbank, California, United States, 91505
      • Roy and Patricia Disney Family Cancer Center at Providence Saint Joseph Medical Center
    • Cameron Park, California, United States, 95682
      • Radiation Oncology Centers - Cameron Park
    • Carmichael, California, United States, 95608
      • Mercy Cancer Center at Mercy San Juan Medical Center
    • Chico, California, United States, 95926
      • Enloe Cancer Center at Enloe Medical Center
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center
    • Oakland, California, United States, 94611
      • Kaiser Permanente - Division of Research - Oakland
    • Rohnert Park, California, United States, 94928
      • Rohnert Park Cancer Center
    • Roseville, California, United States, 95661
      • Radiation Oncology Center - Roseville
    • Sacramento, California, United States, 95815
      • Radiological Associates of Sacramento Medical Group, Incorporated
    • Sacramento, California, United States, 95819
      • Mercy General Hospital
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Santa Clara, California, United States, 95051
    • South San Francisco, California, United States, 94080
      • Kaiser Permanente Medical Center - South San Francisco
    • Vacaville, California, United States, 95687
      • Solano Radiation Oncology Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Rocky Mountain Cancer Centers - Aurora
    • Boulder, Colorado, United States, 80301-9019
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Englewood, Colorado, United States, 80110
      • Swedish Medical Center
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
  • Connecticut
    • New Britain, Connecticut, United States, 06050
      • George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus
  • Delaware
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Deerfield Beach, Florida, United States, 33064-3596
      • North Broward Medical Center
    • Jacksonville, Florida, United States, 32207
      • Baptist Cancer Institute - Jacksonville
    • Jacksonville, Florida, United States, 32207
      • Integrated Community Oncology Network at Southside Cancer Center
    • Jacksonville, Florida, United States, 32258
      • Baptist Medical Center South
    • Jacksonville Beach, Florida, United States, 32250
      • Integrated Community Oncology Network
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Orange Park, Florida, United States, 32073
      • Integrated Community Oncology Network - Orange Park
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • Orlando, Florida, United States, 32806
      • M.D. Anderson Cancer Center at Orlando
    • Palatka, Florida, United States, 32177
      • Florida Cancer Center - Palatka
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • Saint Augustine, Florida, United States, 32086
      • Flagler Cancer Center
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Atlanta, Georgia, United States, 30303
      • Georgia Cancer Center for Excellence at Grady Memorial Hospital
    • Gainesville, Georgia, United States, 30501
      • Northeast Georgia Medical Center
    • Savannah, Georgia, United States, 31403-3089
      • Curtis and Elizabeth Anderson Cancer Institute at Memorial Health University Medical Center
    • Savannah, Georgia, United States, 31405
      • Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Northwest Community Hospital
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60657
      • Creticos Cancer Center at Advocate Illinois Masonic Medical Center
    • Chicago, Illinois, United States, 60612-3785
      • John H. Stroger, Jr. Hospital of Cook County
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Evanston, Illinois, United States, 60201-1781
      • Evanston Hospital
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
    • Springfield, Illinois, United States, 62702
      • Cancer Institute at St. John's Hospital
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St. Francis Hospital and Health Centers - Beech Grove Campus
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Fort Wayne, Indiana, United States, 46805
      • Parkview Regional Cancer Center at Parkview Health
    • Goshen, Indiana, United States, 46526
      • Center for Cancer Care at Goshen General Hospital
    • Indianapolis, Indiana, United States, 46219
      • Community Regional Cancer Care at Community Hospital East
    • Indianapolis, Indiana, United States, 46256
      • Community Regional Cancer Care at Community Hospital North
    • Mishawaka, Indiana, United States, 46545-1470
      • Michiana Hematology-Oncology, PC - South Bend
    • Muncie, Indiana, United States, 47303-3499
      • Cancer Center at Ball Memorial Hospital
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Des Moines, Iowa, United States, 50309
      • John Stoddard Cancer Center at Iowa Methodist Medical Center
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
    • Overland Park, Kansas, United States, 66210
      • Kansas City Cancer Centers - Southwest
    • Prairie Village, Kansas, United States, 66208
      • CCOP - Kansas City
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille P. Markey Cancer Center at University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center at University of Louisville
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Mary Bird Perkins Cancer Center - Baton Rouge
    • New Orleans, Louisiana, United States, 70121
      • CCOP - Ochsner
  • Maine
    • Scarborough, Maine, United States, 04074
      • Maine Center for Cancer Medicine and Blood Disorders - Scarborough
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • St. Agnes Hospital Cancer Center
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Medical Center - Burlington
    • Danvers, Massachusetts, United States, 01923
      • NSMC Cancer Center - Peabody
    • Fall River, Massachusetts, United States, 02721
      • Hudner Oncology Center at Saint Anne's Hospital - Fall River
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Cancer Center
    • Battle Creek, Michigan, United States, 49017
      • Battle Creek Health System Cancer Care Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Butterworth Hospital at Spectrum Health
    • Grand Rapids, Michigan, United States, 49503
      • Lacks Cancer Center at Saint Mary's Health Care
  • Minnesota
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
  • Mississippi
    • Pascagoula, Mississippi, United States, 39581
      • Regional Cancer Center at Singing River Hospital
  • Missouri
    • Cape Girardeau, Missouri, United States, 63703
      • Cancer Institute of Cape Girardeau, LLC
    • Kansas City, Missouri, United States, 64154
      • Kansas City Cancer Centers - North
    • Kansas City, Missouri, United States, 64131
      • Kansas City Cancer Centers - South
    • Springfield, Missouri, United States, 65807
      • Hulston Cancer Center at Cox Medical Center South
    • St Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
    • St Louis, Missouri, United States, 63141
      • Barnes-Jewish West County Hospital
    • St Louis, Missouri, United States, 63141
      • CCOP - St. Louis-Cape Girardeau
    • St Louis, Missouri, United States, 63141
      • David C. Pratt Cancer Center at St. John's Mercy
  • Montana
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Estabrook Cancer Center
    • Omaha, Nebraska, United States, 68198
      • Nebraska Medical Center
  • Nevada
    • Reno, Nevada, United States, 89502
      • Renown Institute for Cancer at Renown Regional Medical Center
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
      • Payson Center for Cancer Care at Concord Hospital
    • Dover, New Hampshire, United States, 03820
      • Seacoast Cancer Center at Wentworth - Douglass Hospital
    • Keene, New Hampshire, United States, 03431
      • Kingsbury Center for Cancer Care at Cheshire Medical Center
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Long Branch, New Jersey, United States, 07740-6395
      • Monmouth Medical Center
    • Sparta, New Jersey, United States, 07871
      • Frederick R. and Betty M. Smith Cancer Treatment Center
    • Voorhees Township, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131-5636
      • University of New Mexico Cancer Center
  • New York
    • Binghamton, New York, United States, 13905
      • Lourdes Regional Cancer Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Rochester, New York, United States, 14620
      • Highland Hospital of Rochester
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospitals - Memorial Campus
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Greensboro, North Carolina, United States, 27403-1198
      • Moses Cone Regional Cancer Center at Wesley Long Community Hospital
    • Kinston, North Carolina, United States, 28501
      • Kinston Medical Specialists
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44309-2090
      • Summa Center for Cancer Care at Akron City Hospital
    • Barberton, Ohio, United States, 44203
      • Barberton Citizens Hospital
    • Cincinnati, Ohio, United States, 45267
      • Charles M. Barrett Cancer Center at University Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center at Fairview Hospital
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
    • Maumee, Ohio, United States, 43537-1839
      • Northwest Ohio Oncology Center
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Cancer Center at Hillcrest Hospital
    • Mentor, Ohio, United States, 44060
      • Lake/University Ireland Cancer Center
    • Middleburg Heights, Ohio, United States, 44130
      • Southwest General Health Center
    • Oregon, Ohio, United States, 43616
      • St. Charles Mercy Hospital
    • Sylvania, Ohio, United States, 43560
      • Flower Hospital Cancer Center
    • Toledo, Ohio, United States, 43623
      • St. Anne Mercy Hospital
    • West Chester, Ohio, United States, 45069
      • Precision Radiotherapy at University Pointe
    • Westlake, Ohio, United States, 44145
      • UHHS Westlake Medical Center
    • Wooster, Ohio, United States, 44691
      • Cancer Treatment Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at St. Francis Hospital
  • Oregon
    • Clackamas, Oregon, United States, 97015
      • Clackamas Radiation Oncology Center
    • Medford, Oregon, United States, 97504
      • Dubs Cancer Center at Rogue Valley Medical Center
    • Medford, Oregon, United States, 97504
      • Providence Cancer Center at PMCC
    • Portland, Oregon, United States, 97239-3098
      • Knight Cancer Institute at Oregon Health and Science University
    • Portland, Oregon, United States, 97213-2967
      • Providence Cancer Center at Providence Portland Medical Center
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Rosenfeld Cancer Center at Abington Memorial Hospital
    • East Stroudsburg, Pennsylvania, United States, 18301
      • Dale and Frances Hughes Cancer Center at Pocono Medical Center
    • Gettysburg, Pennsylvania, United States, 17325
      • Adams Cancer Center
    • Hanover, Pennsylvania, United States, 17331
      • Cherry Tree Cancer Center
    • Langhorne, Pennsylvania, United States, 19047
      • St. Mary Regional Cancer Center
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Reading, Pennsylvania, United States, 19612-6052
      • McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
    • York, Pennsylvania, United States, 17405
      • York Cancer Center at Apple Hill Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Greenville, South Carolina, United States, 29615
      • CCOP - Greenville
    • Greenville, South Carolina, United States, 29605
      • Cancer Centers of the Carolinas - Faris Road
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
    • Spartanburg, South Carolina, United States, 29307
      • Cancer Centers of the Carolinas - Spartanburg
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Rapid City Regional Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Galveston, Texas, United States, 77555-0361
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030-4009
      • M. D. Anderson Cancer Center at University of Texas
  • Utah
    • Murray, Utah, United States, 84157
      • Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
    • Ogden, Utah, United States, 84403
      • Val and Ann Browning Cancer Center at McKay-Dee Hospital Center
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center - Provo
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at University of Utah
    • Salt Lake City, Utah, United States, 84106
      • Utah Cancer Specialists at UCS Cancer Center
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Cancer Institute at Sentara Norfolk General Hospital
    • Virginia Beach, Virginia, United States, 23454
      • Coastal Cancer Center at Sentara Virginia Beach General Hospital
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Cancer Center
    • Seattle, Washington, United States, 98101
      • CCOP - Virginia Mason Research Center
    • Vancouver, Washington, United States, 98684
      • Northwest Cancer Specialists at Vancouver Cancer Center
    • Yakima, Washington, United States, 98902
      • North Star Lodge Cancer Center at Yakima Valley Memorial Hospital
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • Edwards Comprehensive Cancer Center at Cabell Huntington Hospital
    • Wheeling, West Virginia, United States, 26003
      • Schiffler Cancer Center at Wheeling Hospital
  • Wisconsin
    • Appleton, Wisconsin, United States, 54911
      • Theda Care Cancer Institute
    • Green Bay, Wisconsin, United States, 54307-3508
      • St. Vincent Hospital Regional Cancer Center
    • Green Bay, Wisconsin, United States, 54303
      • St. Mary's Hospital Medical Center - Green Bay
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Center for Cancer and Blood
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
    • Marinette, Wisconsin, United States, 54143
      • Bay Area Cancer Care Center at Bay Area Medical Center
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Cancer Center
    • Milwaukee, Wisconsin, United States, 53295
      • Veterans Affairs Medical Center - Milwaukee
    • Wausau, Wisconsin, United States, 54401
      • University of Wisconcin Cancer Center at Aspirus Wausau Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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).
2. Patients must be positive for p16, determined by central review prior to randomization.
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 3-5 mm are required.

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 ear, nose, and throat (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:

     1. A computerized tomography (CT) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
     2. or a magnetic resonance imaging (MRI) scan of the neck (with contrast) and a chest CT scan (with or without contrast);
     3. or a CT scan of neck (with contrast) and a positron emission tomography (PET)/CT of neck and chest (with or without contrast);
     4. 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.

5. Zubrod Performance Status 0-1 within 2 weeks prior to registration
6. Age ≥ 18;

7. Complete blood count (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 (Hgb) > 8.0 g/dl; Note: The use of transfusion or other intervention to achieve Hgb > 8.0 g/dl is acceptable.

8. Adequate hepatic function, defined as follows:

   • Bilirubin < 2 mg/dl within 2 weeks prior to registration;
   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x the upper limit of normal within 2 weeks prior to registration;

9. Adequate renal function, defined as follows:

   • Serum creatinine < 1.5 mg/dl within 2 weeks prior to registration or creatinine clearance (CCr) ≥ 50 ml/min within 2 weeks prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula:

   CCr male = [(140 - age) x (wt in kg)] [(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CCr male)

10. Patients must provide their smoking history (for stratification) via the computer-assisted self interview (CASI) head and neck risk factor survey tool.
11. Negative serum pregnancy test within 2 weeks prior to registration for women of childbearing potential;
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.
13. Patients who are human immunodeficiency virus (HIV) positive but have no prior acquired immune deficiency syndrome (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.
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.

Exclusion Criteria:

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.
2. Stage T1-2, N0-1;
3. Distant metastasis or adenopathy below the clavicles;
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.
5. Simultaneous primaries or bilateral tumors;
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);
7. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable;
8. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;

9. Severe, active co-morbidity, defined as follows:

   • 9.1 Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months;
   • 9.2 Transmural myocardial infarction within the last 6 months;
   • 9.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration;
   • 9.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days of registration;
   • 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.
   • 9.6 Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (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 immuno-compromised patients.
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.
11. Prior allergic reaction to cisplatin or cetuximab;
12. Prior cetuximab or other anti-EGFR therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IMRT + Cisplatin; Intensity-modulated radiotherapy (IMRT) with concurrent cisplatin	Drug: cisplatin; 100 mg/m2 IV on days 1 and 22 of IMRT; Radiation: IMRT; 35 fractions over 6 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 70 Gy.; Other Names: intensity-modulated radiation therapy; intensity-modulated radiotherapy
Active Comparator: IMRT + Cetuximab; Intensity-modulated radiotherapy (IMRT) with concurrent cetuximab	Radiation: IMRT; 35 fractions over 6 weeks, 6 fractions per week, 2 Gray per fraction to total dose of 70 Gy.; Other Names: intensity-modulated radiation therapy; intensity-modulated radiotherapy; Biological: cetuximab; 400 mg/m2 IV 5-7 days before IMRT then 250 mg/m2 IV weekly for 7 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	An event for progression-free survival is local, regional, or distant disease progression or death due to any cause. Progression-free survival time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is the distribution of progression-free survival times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Time to Local-regional Failure	Failure for local-regional failure endpoint was defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown > 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression; distant metastasis and death due to other causes were considered competing risks. Local-regional failure time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of local-regional failure times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Time to Distant Metastasis	Failure for distant metastasis endpoint was defined as distant progression; local-regional failure and death due to any cause were considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of distant metastasis times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Time to Secondary Primary Cancer	Failure for second primary endpoint was defined as reporting of a new primary cancer; death due to any cause was considered a competing risk. Second primary time is defined as time from randomization to the date of second primary or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol endpoint is the distribution of second primary cancer times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Distribution of First Progression Events	The first event type for progression-free survival is counted for each participant. Possible first progression events are local, regional, or distant progression, any combination of these, or death. The frequency table of these events is also referred to as "Pattern of failure."	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Percentage of Participants Experiencing Early Death	Early death is defined as death due to adverse event or within 30 days of treatment completion.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: During Treatment	Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to end of treatment, approximately 6 weeks
Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 1 Month After End of Study Treatment	Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to approximately 2.5 months (1 month after the end of treatment)
Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 3 Months After the End of Study Treatment	Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to approximately 4.5 months (3 months after the end of treatment)
Percentage of Participants With Acute Grade 3-4 Treatment-related Adverse Events: 6 Months After the End of Study Treatment	Acute adverse events (AE) are defined as occurring within 180 days from the end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to approximately 7.5 months (6 months after the end of treatment)
Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 1 Year After the End of Study Treatment	Late adverse events (AE) are defined as > 180 days from end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to approximately 13.5 months (one year after the end of treatment)
Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 2 Years After the End of Study Treatment	Late adverse events (AE) are defined as > 180 days from end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From 180 days after end of treatment to two years after end of treatment.
Percentage of Participants With Late Grade 3-4 Treatment-related Adverse Events: 5 Years After the End of Study Treatment	Late adverse events (AE) are defined as > 180 days from end of treatment. "Treatment-related" means reported as definitely, probably, or possibly related to protocol treatment. AE were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE	From start of treatment to approximately 61.5 months (five years after the end of treatment)
Percentage of Participants With a Feeding Tube at 1 Year		From randomization to 1 year.
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events for Head and Neck (PRO-CTCAE H&N) at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment.		From randomization to 1 year after end of treatment.
EuroQol Five Dimension Scale (EQ-5D) at Baseline, End of Treatment, 3, 6, and 12 Months From End of Treatment.		From randomization to 1 year after end of treatment.
Work Status Questionnaire at Baseline, End of Treatment, 3, 6, and 12 Months.		From randomization to 1 year after end of treatment.
Percentage of Patients With Normal/Good Dental Health: Pretreatment	This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = "Normal: Edentulous, with no gingival disease"; 1 = "Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated." Ten year data is not yet available.	Before treatment
Percentage of Patients With Normal/Good Dental Health: 1 Year After End of Treatment	This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = "Normal: Edentulous, with no gingival disease"; 1 = "Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated."	1 year after end of treatment (approximately 13.5 months)
Percentage of Patients With Normal/Good Dental Health: 2 Years After End of Treatment	This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = "Normal: Edentulous, with no gingival disease"; 1 = "Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated."	2 years after end of treatment (approximately 25.5 months)
Percentage of Patients With Normal/Good Dental Health: 5 Years After End of Treatment	This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = "Normal: Edentulous, with no gingival disease"; 1 = "Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated."	5 years after end of treatment (approximately 61.5 months)
EORTC QLQ-C30 Global Health Status Score Change From Baseline at End of Treatment	The EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30) Global Health Status score measures a cancer patient's perception of their overall health and well-being and ranges from 0 (worst) to 100 (best). A positive change from baseline indicates improvement.	Baseline and end of treatment (6-7 weeks)
EORTC QLQ-C30 Global Health Status Score Change From Baseline at 3 Months From End of Treatment	The EORTC QLQ-C30 Global Health Status score measures a cancer patient's perception of their overall health and well-being and ranges from 0 (worst) to 100 (best). A positive change from baseline indicates improvement.	Baseline and 3 months from end of treatment. Treatment lasts 6-7 weeks.
EORTC QLQ-C30 Global Health Status Score Change From Baseline at 6 Months From End of Treatment	The EORTC QLQ-C30 Global Health Status score measures a cancer patient's perception of their overall health and well-being and ranges from 0 (worst) to 100 (best). A positive change from baseline indicates improvement.	Baseline and 6 months from end of treatment. Treatment lasts 6-7 weeks.
EORTC QLQ-C30 Global Health Status Score Change From Baseline at 12 Months From End of Treatment	The EORTC QLQ-C30 Global Health Status score measures a cancer patient's perception of their overall health and well-being and ranges from 0 (worst) to 100 (best). A positive change from baseline indicates improvement.	Baseline and 12 months from end of treatment. Treatment lasts 6-7 weeks
EORTC QLQ-H&N35 Swallowing Score Change From Baseline at End of Treatment	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Head and Neck Cancer Module (EORTC QLQ-H&N35) swallowing score measures patient-reported difficulty with swallowing various foods and liquid and ranges from 0 (no swallowing problems) to 100 (maximum swallowing difficulty). A positive change from baseline indicates worsening swallowing function.	Baseline and end of treatment (6-7 weeks)
EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 3 Months From End of Treatment.	The EORTC QLQ-H&N35 swallowing score measures patient-reported difficulty with swallowing various foods and liquid and ranges from 0 (no swallowing problems) to 100 (maximum swallowing difficulty). A positive change from baseline indicates worsening swallowing function.	Baseline and 3 months from end of treatment. Treatment lasts 6-7 weeks.
EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 6 Months From End of Treatment.	The EORTC QLQ-H&N35 swallowing score measures patient-reported difficulty with swallowing various foods and liquid and ranges from 0 (no swallowing problems) to 100 (maximum swallowing difficulty). A positive change from baseline indicates worsening swallowing function.	Baseline and 6 months from end of treatment. Treatment lasts 6-7 weeks.
EORTC QLQ-H&N35 Swallowing Score Change From Baseline at 12 Months From End of Treatment.	The EORTC QLQ-H&N35 swallowing score measures patient-reported difficulty with swallowing various foods and liquid and ranges from 0 (no swallowing problems) to 100 (maximum swallowing difficulty). A positive change from baseline indicates worsening swallowing function.	Baseline and 12 months from end of treatment. Treatment lasts 6-7 weeks.
Number of Participants by HHIA-S Category at Baseline	The Hearing Handicap Inventory for Adults Screen Version (HHIA-S) measures a person's perceived hearing handicap. Total score ranges from 0 to 40, with a higher score indicating more severe perceived hearing handicap, categorized as follows: No handicap: 0-8.; Mild-moderate handicap: 10-24.; Severe handicap: 26-40.	Baseline
Number of Participants by HHIA-S Category at End of Treatment	The Hearing Handicap Inventory for Adults Screen Version (HHIA-S) measures a person's perceived hearing handicap. Total score ranges from 0 to 40, with a higher score indicating more severe perceived hearing handicap, categorized as follows: No handicap: 0-8.; Mild-moderate handicap: 10-24.; Severe handicap: 26-40.	End of treatment (6-7 weeks)
Number of Participants by HHIA-S Category at 3 Months After End of Treatment	The HHIA-S measures a person's perceived hearing handicap. Total score ranges from 0 to 40, with a higher score indicating more severe perceived hearing handicap, categorized as follows: No handicap: 0-8.; Mild-moderate handicap: 10-24.; Severe handicap: 26-40.	3 months after end of treatment. Treatment lasts 6-7 weeks.
Number of Participants by HHIA-S Category at 6 Months After End of Treatment	The HHIA-S measures a person's perceived hearing handicap. Total score ranges from 0 to 40, with a higher score indicating more severe perceived hearing handicap, categorized as follows: No handicap: 0-8.; Mild-moderate handicap: 10-24.; Severe handicap: 26-40.	6 months after end of treatment. Treatment lasts 6-7 weeks.
Number of Participants by HHIA-S Category at 12 Months After End of Treatment	The HHIA-S measures a person's perceived hearing handicap. Total score ranges from 0 to 40, with a higher score indicating more severe perceived hearing handicap, categorized as follows: No handicap: 0-8.; Mild-moderate handicap: 10-24.; Severe handicap: 26-40.	12 months after end of treatment. Treatment lasts 6-7 weeks.
Percentage of Patients With Normal/Good Dental Health: 10 Years After End of Treatment	This study utilized a dental effects health scale from 0 (normal) to 4 (life-threatening dental condition). The percentage of participants with a value of 0 or 1 is reported: 0 = "Normal: Edentulous, with no gingival disease"; 1 = "Mild changes/good dental health: mild periodontal inflammation-routine cleaning indicated; < 5 restorations indicated; no extractions indicated."	10 years after end of treatment (approximately 121.5 months)
Overall Survival by KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) Variant Status	KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a gene that helps control how cells grow. Some people have a change in this gene, which can be detected (variant/non-variant) by a genetic test performed on tissue from their tumor. Research suggests that this change may influence how head and neck cancer responds to certain treatments. An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.
Progression-free Survival by KRAS Variant Status	KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a gene that helps control how cells grow. Some people have a change in this gene, which can be detected (variant/non-variant) by a genetic test performed on tissue from their tumor. Research suggests that this change may influence how head and neck cancer responds to certain treatments. An event for progression-free survival is local, regional, or distant disease progression or death due to any cause. Progression-free survival time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is the distribution of progression-free survival times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.
Overall Survival by Treatment Arm Within KRAS Variant Status Group	KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a gene that helps control how cells grow. Some people have a change in this gene, which can be detected (variant/non-variant) by a genetic test performed on tissue from their tumor. Research suggests that this change may influence how head and neck cancer responds to certain treatments. An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.
Progression-free Survival Within KRAS Variant Status	KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a gene that helps control how cells grow. Some people have a change in this gene, which can be detected (variant/non-variant) by a genetic test performed on tissue from their tumor. Research suggests that this change may influence how head and neck cancer responds to certain treatments. An event for progression-free survival is local, regional, or distant disease progression or death due to any cause. Progression-free survival time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is the distribution of progression-free survival times, for which the hazard ratio is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 214 deaths were reported. Median follow-up at time of analysis was 8.3 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival by Sex	NIH-required analysis. An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Overall Survival by Ethnicity	NIH-required analysis. An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years.
Overall Survival by Race	NIH-required analysis. An event for overall survival is death due to any cause. Survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol endpoint is hazard ratio, which is reported in the statistical analysis results. Five-year rate is reported simply as summary data; it is not the outcome measure.	From randomization to last follow-up. Analysis was to occur after 180 deaths were reported. Analysis occurred after 133 deaths were reported. Maximum follow-up at time of analysis was 6.5 years. Five-year rates are reported here.

Collaborators and Investigators

• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Investigators: Principal Investigator: Andy M. Trotti, MD, H. Lee Moffitt Cancer Center and Research Institute; Principal Investigator: Maura Gillison, MD, PhD, Ohio State University

Publications and helpful links

General Publications

• Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014 Nov;25(11):2101-2115. doi: 10.1093/annonc/mdu265. Epub 2014 Jul 23.
• Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RCK, Zhao W, Sturgis EM, Burtness B, Ridge JA, Ringash J, Galvin J, Yao M, Koyfman SA, Blakaj DM, Razaq MA, Colevas AD, Beitler JJ, Jones CU, Dunlap NE, Seaward SA, Spencer S, Galloway TJ, Phan J, Dignam JJ, Le QT. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019 Jan 5;393(10166):40-50. doi: 10.1016/S0140-6736(18)32779-X. Epub 2018 Nov 15.
• Quan DL, Grauer JS, Sunkara PR, Cramer JD. Surgical salvage of human papillomavirus-positive oropharyngeal cancer: Secondary analysis of a randomized controlled trial. Cancer. 2023 Feb 1;129(3):376-384. doi: 10.1002/cncr.34562. Epub 2022 Nov 19.
• Gharzai LA, Morris E, Schipper MJ, Kidwell KM, Nguyen-Tan PF, Rosenthal DI, Gillison ML, Jordan RC, Garden AS, Koyfman SA, Caudell JJ, Blakaj DM, Dunlap NE, Krempl GA, Longo JM, Jones CU, Gensheimer MF, Galloway TJ, DeMora L, Le QT, Shah JL, Suresh K, Mierzwa M. Treatment Interruption and Outcomes in Head and Neck Cancer: A Secondary Analysis of 3 Randomized Clinical Trials. JAMA Otolaryngol Head Neck Surg. 2025 Dec 4:e254203. doi: 10.1001/jamaoto.2025.4203. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2011
• Primary Completion (Actual): July 12, 2018
• Study Completion (Actual): September 4, 2025

Study Registration Dates

• First Submitted: February 22, 2011
• First Submitted That Met QC Criteria: February 22, 2011
• First Posted (Estimated): February 24, 2011

Study Record Updates

• Last Update Posted (Estimated): January 12, 2026
• Last Update Submitted That Met QC Criteria: December 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: stage III squamous cell carcinoma of the oropharynx; stage IV squamous cell carcinoma of the oropharynx; human papilloma virus infection
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Infections; Virus Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; DNA Virus Infections; Carcinoma; Tumor Virus Infections; Carcinoma, Squamous Cell; Pathological Conditions, Signs and Symptoms; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Papillomavirus Infections; Precancerous Conditions; Amino Acids, Peptides, and Proteins; Proteins; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Platinum Compounds; Radiotherapy; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Cetuximab; Cisplatin; Radiotherapy, Intensity-Modulated
• Other Study ID Numbers: RTOG-1016; CDR0000695731; NCI-2011-02638 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: NCT01302834
   Information comments: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive