Phase II Randomized Trial of Transoral Surgical Resection Followed by Low-Dose or Standard-Dose IMRT in Resectable p16+ Locally Advanced Oropharynx Cancer
Overview
- Phase
- Phase 2
- Intervention
- Transoral surgery
- Conditions
- Human Papilloma Virus Infection
- Sponsor
- ECOG-ACRIN Cancer Research Group
- Enrollment
- 519
- Locations
- 58
- Primary Endpoint
- Proportion of Patients With Grade III or IV Oropharyngeal Bleeding or Positive Margins
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
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.
Investigators
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)
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
Arms & Interventions
Arm S (Surgery) then Arm A (Low risk, observation)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, low risk patients are under observation.
Intervention: Transoral surgery
Arm S (Surgery) then Arm B (Intermediate risk, low-dose IMRT)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, intermediate risk patients receive low-dose IMRT (50 Gy) QD five days a week for 5 weeks.
Intervention: Transoral surgery
Arm S (Surgery) then Arm B (Intermediate risk, low-dose IMRT)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, intermediate risk patients receive low-dose IMRT (50 Gy) QD five days a week for 5 weeks.
Intervention: intensity-modulated radiation therapy
Arm S (Surgery) then Arm C (Intermediate risk, standard-dose IMRT)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, intermediate risk patients receive standard-dose IMRT (60 Gy) QD five days a week for 6 weeks.
Intervention: Transoral surgery
Arm S (Surgery) then Arm C (Intermediate risk, standard-dose IMRT)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, intermediate risk patients receive standard-dose IMRT (60 Gy) QD five days a week for 6 weeks.
Intervention: intensity-modulated radiation therapy
Arm S (Surgery) then Arm D (High risk, IMRT, chemotherapy)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, high risk patients then receive IMRT (66Gy) QD five days a week for 6-7 weeks. Patients also receive cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.
Intervention: Transoral surgery
Arm S (Surgery) then Arm D (High risk, IMRT, chemotherapy)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, high risk patients then receive IMRT (66Gy) QD five days a week for 6-7 weeks. Patients also receive cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.
Intervention: intensity-modulated radiation therapy
Arm S (Surgery) then Arm D (High risk, IMRT, chemotherapy)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, high risk patients then receive IMRT (66Gy) QD five days a week for 6-7 weeks. Patients also receive cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.
Intervention: cisplatin
Arm S (Surgery) then Arm D (High risk, IMRT, chemotherapy)
Patients undergo transoral surgical resection of the oropharyngeal tumor. After transoral surgical resection of the oropharyngeal tumor, high risk patients then receive IMRT (66Gy) QD five days a week for 6-7 weeks. Patients also receive cisplatin IV over 60 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.
Intervention: carboplatin
Outcomes
Primary Outcomes
Proportion of Patients With Grade III or IV Oropharyngeal Bleeding or Positive Margins
Time Frame: Assessed during surgery and directly after surgery
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.
Progression-free Survival Rate at 2 Years
Time Frame: Assessed every 3 months for 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.
Secondary Outcomes
- Swallowing Function Before Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)(Assessed at baseline)
- Quality of Life (QOL) at 6 Months After Treatment Assessed by Functional Assessment of Cancer Therapy - Head and Neck Cancer (FACT-HN) Total Score(Assessed at 6 months after treatment)
- Distribution of Histologic Risk Status(Assessed after directly surgery)
- Swallowing Function After Surgery Assessed Using MD Anderson Dysphagia Inventory (MDADI)(Assessed 4-6 weeks after surgery)