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

Stage III Squamous Cell Carcinoma of the Oropharynx Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01898494
• Other study ID #: E3311
• Secondary ID: NCI-2013-00814E3
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 22, 2014
• Est. completion date: December 2024

Study information

• Verified date: March 2024
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 519
• Est. completion date: December 2024
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Squamous Cell
• Human Papilloma Virus Infection
• Oropharyngeal Neoplasms
• Papilloma
• Papillomavirus Infections
• Stage III Squamous Cell Carcinoma of the Oropharynx
• Stage IVA Squamous Cell Carcinoma of the Oropharynx
• Stage IVB Squamous Cell Carcinoma of the Oropharynx

Intervention

Procedure:
• Transoral surgery
Undergo transoral surgical resection

Radiation:
• intensity-modulated radiation therapy
Undergo standard-dose or low-dose IMRT

Drug:
• cisplatin
Given IV
• carboplatin
Given IV

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Rocky Mountain Cancer Centers-Penrose	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	University of Miami Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Porter Adventist Hospital	Denver	Colorado
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Sentara Cancer Institute at Sentara CarePlex Hospital	Hampton	Virginia
United States	PinnacleHealth Cancer Center-Community Campus	Harrisburg	Pennsylvania
United States	M D Anderson Cancer Center	Houston	Texas
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Zablocki Veterans Administration Medical Center	Milwaukee	Wisconsin
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Sentara Hospitals	Norfolk	Virginia
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Florida Hospital Orlando	Orlando	Florida
United States	Stanford Cancer Institute	Palo Alto	California
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	UCSF Medical Center-Mount Zion	San Francisco	California
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Sentara Virginia Beach General Hospital	Virginia Beach	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
ECOG-ACRIN Cancer Research Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 a — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Association Between TP53 Mutation and Progression-free Survival	Progression-free survival is defined as the time from registration to the appearance of new metastatic lesions or objective tumor progression or death, whichever occurs first. Kaplan-Meier estimate was used to characterize progression-free survival.	Assessed every 3 months for 2 years, then every 6 months, up to 5 years
Other	Association Between Radiation Resistance Markers and Progression-free Survival	Progression-free survival is defined as the time from registration to the appearance of new metastatic lesions or objective tumor progression or death, whichever occurs first. Kaplan-Meier estimate was used to characterize progression-free survival.	Assessed every 3 months for 2 year, then every 6 months, up to 5 years
Other	Usefulness of Biomarkers in Predicting Progression-free Survival	Progression-free survival is defined as the time from registration to the appearance of new metastatic lesions or objective tumor progression or death, whichever occurs first. Kaplan-Meier estimate was used to characterize progression-free survival.	Assessed every 3 months for 2 years, then every 6 months, up to 5 years
Primary	Progression-free Survival Rate at 2 Years	Progression-free survival is defined as the time from randomization/assignment of post-surgical treatment to the appearance of lesions, including primary, nodal or new site, or death, whichever occurs first. These patients are considered disease-free after surgery so the appearance of any lesions is counted as progression. Kaplan-Meier estimate was used to characterize progression-free survival rate at 2 years.	Assessed every 3 months for 2 years
Primary	Proportion of Patients With Grade III or IV Oropharyngeal Bleeding or Positive Margins	Surgery quality was evaluated based on grade 3-4 bleeding events per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 during surgery and positive margins after surgery. Per CTCAE v5.0, grade 3 = severe and grade 4 = life-threatening.; Having grade 3-4 bleeding or positive margins indicates worse outcomes.	Assessed during surgery and directly after surgery
Secondary	Distribution of Histologic Risk Status	Low Risk: T1-T2, N0-N1 AND clear (> 3mm) margins, AND no extranodal extension (ENE) or PNI/LVI.; Intermediate Risk: Any of the following features: one or more "close" (< 3mm) margin(s), OR "Minimal" (< 1mm) ENE, OR N2a (1 or more lymph node >3cm in diameter), OR N2b (2-4 lymph nodes positive, any diameter < 6cm), OR with perineural invastion or lymphovascular invasion.; High Risk: Any of the following features: one or more positive margin(s) with any T stage, OR "Extensive" (> 1mm) ENE, OR > 5 metastatic lymph nodes (regardless of primary tumor margin status).	Assessed after directly surgery
Secondary	Swallowing Function Before Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)	The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20-item written questionnaire. It evaluates the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. This instrument has been psychometrically validated in head and neck cancer patients. Two summary scores can be obtained from the MDADI: 1) global and 2) composite. The global scale is a single question, scored individually, to assess the overall impact that swallowing abilities have on quality of life ("my swallowing impacts my day-to-day life"). The composite MDADI score summarizes overall performance on remaining 19-items of the MDADI, as a weighted average of the physical, emotional, and functional subscale questions. This study reports the composite MDADI score. The summary MDADI scores are normalized to range from 20 (extremely low functioning) to 100 (high functioning).	Assessed at baseline
Secondary	Swallowing Function After Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)	The MDADI measures swallowing-related quality of life (QOL) in patients with swallowing dysfunction in a 20-item written questionnaire. It evaluates the patient's physical (P), emotional (E) and functional (F) perceptions of swallowing dysfunction. This instrument has been psychometrically validated in head and neck cancer patients. Two summary scores can be obtained from the MDADI: 1) global and 2) composite. The global scale is a single question, scored individually, to assess the overall impact that swallowing abilities have on quality of life ("my swallowing impacts my day-to-day life"). The composite MDADI score summarizes overall performance on remaining 19-items of the MDADI, as a weighted average of the physical, emotional, and functional subscale questions. This study reports the composite MDADI score. The summary MDADI scores are normalized to range from 20 (extremely low functioning) to 100 (high functioning).	Assessed 4-6 weeks after surgery
Secondary	Quality of Life (QOL) at 6 Months After Treatment Assessed by Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-HN) Total Score	The FACT-H&N (version 4) consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H&N cancer-specific items (the HN subscale). FACT-G is a 27-item measure that assesses general cancer quality of life. FACT-HN total score ranges between 0 and 148. The higher the score, the better the QOL.	Assessed at 6 months after treatment