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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
519
Undergo transoral surgical resection
Undergo standard-dose or low-dose IMRT
Given IV
Given IV
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
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.
Time frame: Assessed every 3 months for 2 years
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.
Time frame: Assessed during surgery and directly after surgery
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).
Time frame: Assessed after directly surgery
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).
Time frame: Assessed at baseline
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).
Time frame: Assessed 4-6 weeks after surgery
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.
Time frame: Assessed at 6 months after treatment
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Kaiser Permanente Oakland-Broadway
Oakland, California, United States
Stanford Cancer Institute
Palo Alto, California, United States
UCSF Medical Center-Mount Zion
San Francisco, California, United States
Rocky Mountain Cancer Centers-Boulder
Boulder, Colorado, United States
Penrose-Saint Francis Healthcare
Colorado Springs, Colorado, United States
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