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

• ClinicalTrials.gov Identifier: NCT01898494
• Recruitment Status: Active, not recruiting
• First Posted: July 12, 2013
• Last Update Posted: October 26, 2020
• Sponsor: Eastern Cooperative Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Eastern Cooperative Oncology Group

Tracking Information

• First Submitted Date: July 10, 2013
• First Posted Date: July 12, 2013
• Last Update Posted Date: October 26, 2020
• Study Start Date: August 2013
• Actual Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 21, 2014)

• PFS rate [ Time Frame: Up to 2 years ]
  Defined as the proportion of patients alive and progression-free at 24 months. Kaplan-Meier estimates will be calculated. 90% exact binomial confidence intervals will be computed for each arm. The 2-year failure proportions that include second primary cancers from the head and neck region as event will also be reported.
• Accrual rate [ Time Frame: Up to 18 months ]
• Risk distribution [ Time Frame: Up to 18 months ]
  A 90% binomial confidence interval will be estimated for the percentage of patients in each risk group.
• Incidence of grade 3-4 bleeding events during surgery and positive margins after surgery, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: Up to 18 months ]
  The percentage will be deemed too high if 13 or more patients reported with grade 3-4 bleeding in the operating room or with positive margins, which corresponds to an empirical rate of 22%. A 90% binomial confidence interval will be estimated for these events.

Original Primary Outcome Measures (submitted: July 10, 2013)

• PFS rate [ Time Frame: Up to 2 years ]
  Defined as the proportion of patients alive and progression-free at 24 months. Kaplan-Meier estimates will be calculated.
• Accrual rate [ Time Frame: Up to 18 months ]
• Risk distribution [ Time Frame: Up to 18 months ]
  A 90% binomial confidence interval will be estimated for the percentage of patients in each risk group.
• Incidence of grade 3-4 bleeding events during surgery and positive margins after surgery, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: Up to 18 months ]
  The percentage will be deemed too high if 13 or more patients reported with grade 3-4 bleeding in the operating room or with positive margins, which corresponds to an empirical rate of 22%. A 90% binomial confidence interval will be estimated for these events.

Current Secondary Outcome Measures (submitted: July 21, 2014)

• Incidence of adverse events evaluated by the CTCAE version 4.0 [ Time Frame: Up to 3 years ]
  The difference between arms will be evaluated using Fisher's exact test.
• Overall survival [ Time Frame: Time from registration onto the study until death from any cause, assessed up to 3 years ]
  Kaplan-Meier estimates will be calculated, along with their corresponding 95% confidence intervals. The median, 1-year, and 2-year survival rates will be estimated.
• Swallowing function before and after treatment, evaluated using the modified barium swallow (MBS) ratings, performance status scale for head and neck cancer (PSS-HN) normalcy of diet scale, and the MD Anderson Dysphagia Inventory (MDADI) [ Time Frame: Up to 2 years ]
  Descriptive statistics will be provided (by arm) for swallowing function, evaluated using the MBS ratings, PSS-HN normalcy of diet scale, and the validated survey MDADI instrument. Longitudinal analysis will be performed, by arm, on each of these measures.
• Voice before and after treatment, evaluated using the Voice Handicap Index-10 [ Time Frame: Up to 2 years ]
  Longitudinal analysis will be performed, by arm, on each of these measures.
• Change in patient reported quality of life (QOL) as measured by Functional Assessment of Cancer Therapy-Head and Neck [ Time Frame: Baseline up to 6 months post radiation therapy ]
  Patient QOL will be grouped as "improved" (change >= 7 points, 6 months post-radiation therapy vs. baseline), "worsened" (change =< -7 points) and "stable" (-6 =< change =< 6).

Original Secondary Outcome Measures (submitted: July 10, 2013)

• Toxicity evaluated using the Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 3 years ]
  The difference between arms will be evaluated using Fisher's exact test.
• Overall survival [ Time Frame: Time from registration onto the study until death from any cause, assessed up to 3 years ]
  Kaplan-Meier estimates will be calculated, along with their corresponding 95% confidence intervals. The median, 1-year, and 2-year survival rates will be estimated.
• Swallowing function before and after treatment, evaluated using the modified barium swallow (MBS) ratings [ Time Frame: Up to 2 years ]
• Change in patient reported quality of life (QOL) as measured by Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) [ Time Frame: Baseline up to 6 months post radiation therapy ]
  Patient QOL will be grouped as "improved" (change >= 7 points, 6 mo post-RT vs. baseline), "worsened" (change =< -7 points) and "stable" (-6 =< change =< 6).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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: 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 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 3 months for 2 years and then every 6 months for 1 year.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

Intervention

• Procedure: therapeutic conventional surgery
  Undergo transoral surgical resection
• Radiation: intensity-modulated radiation therapy
  Undergo low-dose IMRT
  Other Name: IMRT
• Drug: cisplatin
  Given IV
  Other Names:

  • CACP
  • CDDP
  • CPDD
  • DDP
• Drug: carboplatin
  Given IV
  Other Names:

  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
• Radiation: intensity-modulated radiation therapy
  Undergo standard-dose IMRT
  Other Name: IMRT
• Other: laboratory biomarker analysis
  Correlative studies
• Other: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment

Study Arms

• Experimental: Arm A (TOS)
  Patients undergo transoral surgical resection of the oropharyngeal tumor.
  Interventions:

  • Procedure: therapeutic conventional surgery
  • Other: laboratory biomarker analysis
  • Other: quality-of-life assessment
• Experimental: Arm B (TOS, low-dose IMRT)
  Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo low-dose IMRT QD five days a week for 5 weeks.
  Interventions:

  • Procedure: therapeutic conventional surgery
  • Radiation: intensity-modulated radiation therapy
  • Other: laboratory biomarker analysis
  • Other: quality-of-life assessment
• Experimental: Arm C (TOS, standard-dose IMRT)
  Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6 weeks.
  Interventions:

  • Procedure: therapeutic conventional surgery
  • Radiation: intensity-modulated radiation therapy
  • Other: laboratory biomarker analysis
  • Other: quality-of-life assessment
• Experimental: Arm D (TOS, standard-dose IMRT, chemotherapy)
  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 IV over 60 minutes or carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.
  Interventions:

  • Procedure: therapeutic conventional surgery
  • Drug: cisplatin
  • Drug: carboplatin
  • Radiation: intensity-modulated radiation therapy
  • Other: laboratory biomarker analysis
  • Other: quality-of-life assessment

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 7, 2017): 511
• Original Estimated Enrollment (submitted: July 10, 2013): 377
• Estimated Study Completion Date: February 2023
• Actual Primary Completion Date: September 2020 (Final data collection date for primary outcome measure)

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 < 4 weeks 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 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 nodal stage N1-N2b confirmed by clinical or radiographic methods (clinically N0 patients are not eligible)
• 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 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
• 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 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)
• 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 pre-registration
• REGISTRATION/RANDOMIZATION TO STEP 2 - ARMS A, B, C AND D AND REGISTRATION TO STEP 3

• 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)
• Patients must have ECOG performance status 0 or 1
• Patient must be registered/randomized within 5-7 weeks following surgery
• Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01898494
• Other Study ID Numbers: E3311; NCI-2013-00814 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ECOG-E3311; E3311 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); E3311 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U10CA021115 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Eastern Cooperative Oncology Group
• Study Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Ferris; ECOG-ACRIN Cancer Research Group

• PRS Account: Eastern Cooperative Oncology Group
• Verification Date: October 2020