Skip to main content

Transoral Surgery Followed by Low-Dose or Standard-Dose Radiation Therapy with or without Chemotherapy in Treating Patients with HPV Positive Stage III-IVA Oropharyngeal Cancer

Trial Status: Closed to Accrual

This randomized phase II trial studies how well transoral surgery followed by low-dose or standard-dose radiation therapy works in treating patients with human papilloma virus (HPV) positive stage III-IVA oropharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving radiation therapy with chemotherapy may kill any tumor cells that remain after surgery. It is not yet known how much extra treatment needs to be given after surgery.

Inclusion Criteria

  • REGISTRATION TO SURGERY (ARM S)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Patients must register to Step 1 prior to surgery
  • Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the oropharynx; patients must have been determined to have resectable oropharyngeal disease; patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible
  • Patients must have American Joint Committee on Cancer (AJCC) TNM tumor stage III, IV a, or IV b (with no evidence of distant metastases) as determined by imaging studies (performed < 30 days prior to registration) and complete neck exam from the skull base to the clavicles; the following imaging is required: computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI); the primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, or N2b based on clinical or radiographic criteria
  • Patients must have biopsy-proven cyclin-dependent kinase inhibitor 2A (p16)+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node; it is required that patients have a positive p16 immunohistochemistry (IHC) (as surrogate for HPV) status from either the primary tumor or metastatic lymph node
  • Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory; using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is recommended
  • No prior radiation above the clavicles
  • Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix, melanoma in-situ (if fully resected), and/or non-melanomatous skin cancer
  • Patients with the following within the last 6 months prior to registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study
  • Patients must not have evidence of extensive or “matted/fixed” pathologic adenopathy on preoperative imaging
  • Absolute neutrophil count >= 1,500/mm^3
  • Platelets >= 100,000/mm^3
  • Total bilirubin =< the upper limit of normal (ULN)
  • Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula
  • Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection
  • Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to registration
  • REGISTRATION/RANDOMIZATION TO STEP 2 - ARMS A, B, C AND D
  • Histopathologic assessment of surgical pathology must include examination for perineural invasion (PNI) and lymphovascular invasion (LVI) and reported as absent or present; the absence or presence of extracapsular extension (ECE) requires gross and microscopic assessment and is defined to be: * Absent (negative or nodal metastasis with smooth/rounded leading edge confined to thickened capsule/pseudocapsule), * Present - minimal (tumor extends =< 1 mm beyond the lymph node capsule), or * Present - extensive (gross, tumor extends > 1 mm beyond the lymph node capsule [includes soft tissue metastasis])
  • Patient must be stratified/classified into one of the following risk categories: * The highest risk feature assessed pathologically will determine the patient's category/treatment arm assignment ** Low risk: T1-T2, N0-N1 AND clear (> 3 mm) margins, AND no ECE or PNI/LVI ** High risk: any of the following features: one or more positive margin(s) with any T stage, OR “extensive” (> 1 mm) ECE, OR >= 5 metastatic lymph nodes (regardless of primary tumor margin status) * Intermediate risk: any of the following features: one or more “close” (< 3 mm) margin(s), OR “minimal” (=< 1 mm) ECE, OR N2a (1 or more lymph node > 3 cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter < 6 cm), OR with perineural invasion or lymphovascular invasion ** Unknown risk: patients found to have N2C or N3 disease on final pathologic analysis are at unknown risk for recurrence, but are not candidates for deintensified adjuvant therapy in this trial; these patients will be treated on Arm C ** Patients not categorized into the appropriate risk category will be considered ineligible for the study
  • Patient must be registered/randomized to Step 2 within a maximum of 7 weeks following surgery
  • Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Sharon A. Spencer
Phone: 205-934-0309

Arizona

Scottsdale
Mayo Clinic in Arizona
Status: CLOSED_TO_ACCRUAL
Contact: Michael L. Hinni
Phone: 855-776-0015

Arkansas

Little Rock
University of Arkansas for Medical Sciences
Status: CLOSED_TO_ACCRUAL
Contact: Emre A. Vural
Phone: 501-686-8274

California

Duarte
City of Hope Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Ellie G. Maghami
Phone: 800-826-4673
La Jolla
UC San Diego Moores Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Charles S. Coffey
Phone: 858-822-5354
Los Angeles
UCLA / Jonsson Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Abie H. Avraham Mendelsohn
Phone: 888-798-0719
Oakland
Kaiser Permanente Oakland-Broadway
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
Palo Alto
Stanford Cancer Institute Palo Alto
Status: CLOSED_TO_ACCRUAL
Contact: Floyd Christopher Holsinger
Phone: 650-498-7061
Rancho Cordova
Kaiser Permanente-Rancho Cordova Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
Rohnert Park
Rohnert Park Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
Roseville
The Permanente Medical Group-Roseville Radiation Oncology
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
Sacramento
Kaiser Permanente-South Sacramento
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
South Sacramento Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
San Francisco
UCSF Medical Center-Mount Zion
Status: CLOSED_TO_ACCRUAL
Contact: Sue Sun Yom
Phone: 877-827-3222
San Jose
Stanford Cancer Center South Bay
Status: CLOSED_TO_ACCRUAL
Contact: Floyd Christopher Holsinger
Phone: 650-498-7061
Santa Clara
Kaiser Permanente Medical Center - Santa Clara
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455
South San Francisco
Kaiser Permanente Cancer Treatment Center
Status: CLOSED_TO_ACCRUAL
Contact: Samantha Andrews Seaward
Phone: 626-564-3455

Colorado

Boulder
Rocky Mountain Cancer Centers-Boulder
Status: CLOSED_TO_ACCRUAL
Contact: Keren Sturtz
Phone: 303-777-2663
Colorado Springs
Penrose-Saint Francis Healthcare
Status: CLOSED_TO_ACCRUAL
Contact: Mehmet Sitki Copur
Phone: 800-998-2119
Rocky Mountain Cancer Centers-Penrose
Status: CLOSED_TO_ACCRUAL
Contact: Mehmet Sitki Copur
Phone: 800-998-2119
Denver
Porter Adventist Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Mehmet Sitki Copur
Phone: 800-998-2119

Connecticut

New Haven
Yale University
Status: CLOSED_TO_ACCRUAL
Contact: Benjamin L. Judson
Phone: 203-785-5702

Florida

Deerfield Beach
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Status: CLOSED_TO_ACCRUAL
Contact: Giovana R. Thomas
Phone: 305-243-2647
Miami
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Giovana R. Thomas
Phone: 305-243-2647
Orlando
AdventHealth Orlando
Status: CLOSED_TO_ACCRUAL
Contact: Lee M. Zehngebot
Phone: 407-303-2090

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: CLOSED_TO_ACCRUAL
Contact: Nabil F. Saba
Phone: 404-778-1868
Emory University Hospital Midtown
Status: CLOSED_TO_ACCRUAL
Contact: Nabil F. Saba
Phone: 404-778-1868

Hawaii

Honolulu
Queen's Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Jeffrey L. Berenberg
Phone: 808-524-6115

Illinois

Chicago
Northwestern University
Status: CLOSED_TO_ACCRUAL
Contact: Bharat B. Mittal
Phone: 312-695-1301
Evanston
NorthShore University HealthSystem-Evanston Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Mihir Kiran Bhayani
Phone: 847-570-2109
Springfield
Southern Illinois University School of Medicine
Status: CLOSED_TO_ACCRUAL
Contact: James Lloyd Wade
Phone: 217-876-4740

Iowa

Iowa City
University of Iowa / Holden Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Douglas Earl Laux
Phone: 800-237-1225

Kansas

Kansas City
University of Kansas Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Yelizaveta Shnayder
Phone: 913-945-7552

Kentucky

Lexington
University of Kentucky / Markey Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Thomas J. Gal
Phone: 859-257-3379

Maryland

Baltimore
Greater Baltimore Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Marshall A. Levine
Phone: 443-849-3706
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Wayne Martin Koch
Phone: 410-955-8804

Massachusetts

Boston
Boston Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Scharukh Jalisi
Phone: 617-638-8265
Brigham and Women's Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Donald James Annino
Phone: 617-724-5200
Dana-Farber Cancer Institute
Status: CLOSED_TO_ACCRUAL
Contact: Donald James Annino
Phone: 617-724-5200
Massachusetts General Hospital Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Donald James Annino
Phone: 617-724-5200

Michigan

Detroit
Henry Ford Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Robert Anthony Chapman
Phone: 313-916-1784

Missouri

Saint Louis
Siteman Cancer Center-South County
Status: CLOSED_TO_ACCRUAL
Contact: Ryan S. Jackson
Phone: 800-600-3606
Washington University School of Medicine
Status: CLOSED_TO_ACCRUAL
Contact: Ryan S. Jackson
Phone: 800-600-3606
Springfield
Mercy Hospital Springfield
Status: CLOSED_TO_ACCRUAL
Contact: Jay W. Carlson
Phone: 800-821-7532

Nebraska

Omaha
Nebraska Methodist Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Russell B. Smith
Phone: 402-354-5144
University of Nebraska Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Apar Kishor Ganti
Phone: 402-559-6941

New Hampshire

Lebanon
Dartmouth Hitchcock Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Thomas Horton Davis
Phone: 800-639-6918

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202

New Mexico

Albuquerque
University of New Mexico Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Andrew T. Cowan
Phone: 505-925-0366

New York

Bronx
Montefiore Medical Center - Moses Campus
Status: CLOSED_TO_ACCRUAL
Contact: Missak Haigentz
Phone: 973-971-5900
Montefiore Medical Center-Einstein Campus
Status: CLOSED_TO_ACCRUAL
Contact: Missak Haigentz
Phone: 973-971-5900
Montefiore Medical Center-Weiler Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Missak Haigentz
Phone: 973-971-5900
Commack
Memorial Sloan Kettering Commack
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202
Lake Success
Northwell Health / Center for Advanced Medicine
Status: CLOSED_TO_ACCRUAL
Contact: Dennis Harry Kraus
Phone: 516-734-8954
New Hyde Park
Long Island Jewish Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Dennis Harry Kraus
Phone: 516-734-8954
New York
Lenox Hill Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Dennis Harry Kraus
Phone: 516-734-8954
Memorial Sloan Kettering Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202
Sleepy Hollow
Memorial Sloan Kettering Sleepy Hollow
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202
Syracuse
State University of New York Upstate Medical University
Status: CLOSED_TO_ACCRUAL
Contact: Mark F. Marzouk
Phone: 315-464-5476
Uniondale
Memorial Sloan Kettering Nassau
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202
West Harrison
Memorial Sloan Kettering Westchester
Status: CLOSED_TO_ACCRUAL
Contact: Luc G.T. Morris
Phone: 212-639-7202

North Carolina

Durham
Duke University Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Walter Tsong Lee
Phone: 888-275-3853
Winston-Salem
Wake Forest University Health Sciences
Status: CLOSED_TO_ACCRUAL
Contact: Joshua D. Waltonen
Phone: 336-713-6771

Ohio

Cleveland
Case Western Reserve University
Status: CLOSED_TO_ACCRUAL
Contact: David J. Adelstein
Phone: 866-223-8100
Cleveland Clinic Foundation
Status: CLOSED_TO_ACCRUAL
Contact: David J. Adelstein
Phone: 866-223-8100
Columbus
Ohio State University Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Enver Ozer
Phone: 800-293-5066

Oregon

Portland
Oregon Health and Science University
Status: CLOSED_TO_ACCRUAL
Contact: Peter E. Andersen
Phone: 503-494-1080
Providence Portland Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Keith S. Lanier
Phone: 503-215-2614

Pennsylvania

Harrisburg
UPMC Pinnacle Cancer Center / Community Osteopathic Campus
Status: CLOSED_TO_ACCRUAL
Contact: David C. Weksberg
Phone: 717-724-6765
Philadelphia
Fox Chase Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Miriam N. Lango
Phone: 215-728-4790
Thomas Jefferson University Hospital
Status: CLOSED_TO_ACCRUAL
Contact: David Michael Cognetti
Phone: 215-955-6084
University of Pennsylvania / Abramson Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Gregory S. Weinstein
Phone: 800-474-9892
Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: CLOSED_TO_ACCRUAL
Contact: Robert Louis Ferris
Phone: 412-647-8073

South Carolina

Charleston
Medical University of South Carolina
Status: CLOSED_TO_ACCRUAL
Contact: Terry A. Day
Phone: 843-792-9321

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: James Lee Netterville
Phone: 800-811-8480

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: CLOSED_TO_ACCRUAL
Contact: Baran Devrim Sumer
Phone: 214-648-7097
Houston
M D Anderson Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Michael E. Kupferman
Phone: 713-792-3245

Virginia

Charlottesville
University of Virginia Cancer Center
Status: CLOSED_TO_ACCRUAL
Contact: Mark J. Jameson
Phone: 434-243-6322
Falls Church
Inova Fairfax Hospital
Status: CLOSED_TO_ACCRUAL
Contact: John Frederick Deeken
Phone: 703-970-6431
Hampton
Sentara Cancer Institute at Sentara CarePlex Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Scott S. Williams
Phone: 757-388-2406
Norfolk
Sentara Norfolk General Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Scott S. Williams
Phone: 757-388-2406
Virginia Beach
Sentara Virginia Beach General Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Scott S. Williams
Phone: 757-388-2406

Washington

Seattle
Fred Hutchinson Cancer Research Center
Status: CLOSED_TO_ACCRUAL
Contact: Eduardo Mendez
Phone: 206-616-8289
Seattle Cancer Care Alliance
Status: CLOSED_TO_ACCRUAL
Contact: Eduardo Mendez
Phone: 206-616-8289
University of Washington Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Eduardo Mendez
Phone: 206-616-8289

Wisconsin

Madison
University of Wisconsin Hospital and Clinics
Status: CLOSED_TO_ACCRUAL
Contact: Paul Maurice Harari
Phone: 877-405-6866
Milwaukee
Medical College of Wisconsin
Status: CLOSED_TO_ACCRUAL
Contact: Stuart J. Wong
Phone: 414-805-4380
Zablocki Veterans Administration Medical Center
Status: CLOSED_TO_ACCRUAL
Contact: Elizabeth M. Gore
Phone: 414-805-4380

PRIMARY OBJECTIVES:

I. Accrual, risk distribution, and surgical quality will be used to determine the feasibility of a prospective multi-institutional study of transoral surgery for HPV positive (+) oropharynx cancer followed by risk-adjusted adjuvant therapy.

II. To assess the oncologic efficacy following transoral resection and adjuvant therapy in patients determined to be at “intermediate risk” after surgical excision, the 2-year progression free survival (PFS) rate will be examined.

SECONDARY OBJECTIVES:

I. To estimate the patient distribution with various histologic risk features.

II. To assess and compare early and late toxicities associated with transoral surgery (TOS) and the different doses of adjuvant postoperative radiotherapy (PORT).

III. To evaluate swallowing function before and after TOS and risk-adjusted adjuvant therapy.

IV. To evaluate quality of life (QOL), swallowing perception and performance, voice outcomes, and head and neck symptoms.

TERTIARY OBJECTIVES:

I. To correlate tumor TP53 mutation and other associated mutation profile with pathologic findings, with PFS and other outcome parameters in patients with resectable HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) after the above treatments.

II. To evaluate radiation resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and correlate them with treatment efficacy.

III. To investigate the usefulness of biomarkers in predicting progression-free survival and biomarkers, including tumor ERCC1, EGFR, plasma cytokine/chemokines, cellular immunity to HPV, and oral HPV deoxyribonucleic acid (DNA).

OUTLINE: Patients are classified by risk status (low risk, intermediate risk, or high risk) and assigned to the appropriate treatment group. Patients classified as intermediate risk are randomized to 1 or 2 treatment arms.

ARM A (low risk): Patients undergo transoral surgical resection of the oropharyngeal tumor.

ARM B (intermediate risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo low-dose intensity modulated radiation therapy (IMRT) once daily (QD) five days a week for 5 weeks.

ARM C (intermediate or unknown risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6 weeks.

ARM D (high risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6-7 weeks. Patients also receive cisplatin intravenously (IV) over 60 minutes or carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.

After completion of study treatment, patients are followed up every 6 months for 3 years, and then every 12 months for 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
ECOG-ACRIN Cancer Research Group

Principal Investigator
Robert Louis Ferris

  • Primary ID E3311
  • Secondary IDs NCI-2013-00814
  • Clinicaltrials.gov ID NCT01898494