Clinical trial NCT01898494: 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
Official title: Phase II Randomized Trial of Transoral Surgical Resection Followed by Low-Dose or Standard-Dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Human Papilloma Virus Infection
Stage III Squamous Cell Carcinoma of the Oropharynx
Stage IVA Squamous Cell Carcinoma of the Oropharynx
Stage IVB Squamous Cell Carcinoma of the Oropharynx
Keywords: oropharynx cancer
HPV+
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2013-07-12
Enrollment: 519
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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 or by stopping them from dividing. 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.

Detailed description: 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 excision repair cross complementing 1 (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, epidermal growth factor receptor (EGFR), plasma cytokine/chemokines, cellular immunity to HPV, and oral HPV deoxyribonucleic acid (DNA).

OUTLINE: All patients undergo transoral surgery (TOS) in Step 1.

ARM S: Patients undergo transoral resection of the oropharyngeal tumor.

Then patients are classified by risk status (low risk, intermediate risk, or high risk) in Step 2 and assigned to the appropriate treatment group. Patients classified as intermediate risk are randomized to arms B or C.

ARM A (low risk; observation): Patients receive observation.

ARM B (intermediate risk): Patients undergo low-dose (50Gy) intensity modulated radiation therapy (IMRT) once daily (QD) over 25 fractions.

ARM C (intermediate risk): Patients undergo standard-dose (60Gy) IMRT QD over 30 fractions.

ARM D (high risk): Patients receive IMRT at 66 Gy QD for 33 fractions. Patients also receive cisplatin intravenously (IV) over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.

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

Eligibility criteria: Inclusion Criteria:

Registration to Surgery (Arm S)

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* 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 pre-registration) and complete head and neck exam; the following imaging is required: computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI)
* Patients must have biopsy-proven 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 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
* 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 and/or non-melanomatous skin cancer
* Patients with the following within the last 6 months prior to pre-registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study

  * Congestive heart failure \> NYHA Class II
  * Cerebrovascular accident (CVA)/transient ischaemic attack (TIA)
  * Unstable angina
  * Myocardial infarction
* 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

Registration/Randomization to Step2 - 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 (≥ 3mm) 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" (\> 1mm) ECE, OR ≥ 5 metastatic lymph nodes (regardless of primary tumor margin status)
  * Intermediate Risk: Any of the following features: one or more "close" (\< 3mm) margin(s), OR "Minimal" (≤ 1mm) ECE, OR N2a (1 or more lymph node \> 3cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter ≤ 6cm), 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

Exclusion Criteria:

Registration to Surgery (Arm S)

* Prior radiation above the clavicles
* Evidence of extensive or "matted/fixed" pathologic adenopathy on preoperative imaging
* Women must not be pregnant or breast-feeding due to the teratogenicity of chemotherapy; 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)
* Any intercurrent illness likely to interfere with protocol therapy or prevent surgical resection
* Uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to pre-registration

Primary outcomes:
measure: Progression-free Survival Rate at 2 Years
timeFrame: Assessed every 3 months for 2 years
measure: Proportion of Patients With Grade III or IV Oropharyngeal Bleeding or Positive Margins
timeFrame: Assessed during surgery and directly after surgery
Secondary outcomes:
measure: Distribution of Histologic Risk Status
timeFrame: Assessed after directly surgery
measure: Swallowing Function Before Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)
timeFrame: Assessed at baseline
measure: Swallowing Function After Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)
timeFrame: Assessed 4-6 weeks after surgery
measure: Quality of Life (QOL) at 6 Months After Treatment Assessed by Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-HN) Total Score
timeFrame: Assessed at 6 months after treatment
Other outcomes:
measure: Association Between TP53 Mutation and Progression-free Survival
timeFrame: Assessed every 3 months for 2 years, then every 6 months, up to 5 years
measure: Association Between Radiation Resistance Markers and Progression-free Survival
timeFrame: Assessed every 3 months for 2 year, then every 6 months, up to 5 years
measure: Usefulness of Biomarkers in Predicting Progression-free Survival
timeFrame: Assessed every 3 months for 2 years, then every 6 months, up to 5 years
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: Oakland
country: United States
facility: Kaiser Permanente Oakland-Broadway
state: California
city: Palo Alto
country: United States
facility: Stanford Cancer Institute
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mount Zion
state: California
city: Boulder
country: United States
facility: Rocky Mountain Cancer Centers-Boulder
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose-Saint Francis Healthcare
state: Colorado
city: Colorado Springs
country: United States
facility: Rocky Mountain Cancer Centers-Penrose
state: Colorado
city: Denver
country: United States
facility: Porter Adventist Hospital
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Deerfield Beach
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Orlando
state: Florida
city: Atlanta
country: United States
facility: Emory University Hospital Midtown
state: Georgia
city: Atlanta
country: United States
facility: Emory University/Winship Cancer Institute
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa/Holden Comprehensive Cancer Center
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky/Markey Cancer Center
state: Kentucky
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Harrisburg
country: United States
facility: PinnacleHealth Cancer Center-Community Campus
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania/Abramson Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Hampton
country: United States
facility: Sentara Cancer Institute at Sentara CarePlex Hospital
state: Virginia
city: Norfolk
country: United States
facility: Sentara Hospitals
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Virginia Beach General Hospital
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Zablocki Veterans Administration Medical Center
state: Wisconsin
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Robert Ferris
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ferris RL, Flamand Y, Weinstein GS, Li S, Quon H, Mehra R, Garcia JJ, Chung CH, Gillison ML, Duvvuri U, O'Malley BW Jr, Ozer E, Thomas GR, Koch WM, Gross ND, Bell RB, Saba NF, Lango M, Mendez E, Burtness B. Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol. 2022 Jan 10;40(2):138-149. doi: 10.1200/JCO.21.01752. Epub 2021 Oct 26.