Radiotherapy vs. Trans-Oral Surgery for HPV-Negative Oropharyngeal Squamous Cell Carcinoma

A Phase II Randomized Trial for HPV-Negative Oropharyngeal Squamous Cell Carcinoma: Radiotherapy vs. Trans-Oral Surgery (ORATOR)

The goal of this randomized phase II study is a formal comparison of radiotherapy versus trans-oral surgery as the primary treatment of HPV-negative patients with early-stage oropharyngeal carcinoma.

Study Overview

• Status: Recruiting
• Conditions: Head and Neck Cancer; Oropharyngeal Squamous Cell Carcinoma
• Intervention / Treatment: Radiation: Radiation; Procedure: Trans-Oral Surgery (TOS) + Neck Dissection

Detailed Description

This study is designed as a randomized phase II study. Patients will be randomized between current standard of care treatment (Arm 1) vs. TOS (Arm 2) in a 1:1 ratio. Additionally, patients will be stratified according to T stage (T1 vs. T2); N stage (N0/1 vs. N2/3)

The randomized phase II design is required for three reasons:

1. The randomization will provide an appropriate control group to serve as a comparator for the experimental arm. Historical or contemporaneous non-randomized controls would not be appropriate due to the multitude of biases that could be introduced by patient selection and other confounders.
2. A small sample size will allow for adequate power to assess for progression-free survival, and also an assessment of quality of life, overall survival and toxicity.
3. The results will allow for a decision as to whether a multi-institutional phase III trial is warranted, and inform the design of such a trial.

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Regional Cancer Program
      • Contact: Danielle MacNeil, MD; Phone Number: 519-658-8600; Email: Danielle.Macneil@lhsc.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18 years or older
• Willing to provide informed consent
• ECOG performance status 0-2
• Histologically confirmed squamous cell carcinoma
• HPV-negative tumor, as determined by: negative p16 status, real time PCR or in-situ hybridization. Central confirmation is not required prior to randomization. Equivocal/uncertain HPV status will be allowed on trial.
• Primary tumor site in the oropharynx (includes tonsil, soft palate, base of tongue, walls of oropharynx)
• Tumor stage: T1 or T2, with likely negative resection margins at surgery
• Nodal stage: N0-3. Patients with positive nodal disease and extranodal extension on imaging may be included at the surgeon's discretion, if the nodal disease is deemed resectable by the operating surgeon.
• Eligible for curative intent treatment, with likely negative resection margins at surgery. For patients where adequate transoral access is in question, they will first undergo an examination under anesthesia prior to randomization to ensure adequate exposure can be obtained.
• Blood work obtained within 4 weeks prior to randomization, with adequate bone marrow function, hepatic, and renal function, as determined by the investigator.
• Patient assessed by a radiation oncologist and surgeon and presented at multidisciplinary tumor board prior to randomization. If not feasible, case can be discussed with study Principal Investigator.

Exclusion Criteria:

• Serious medical comorbidities or other contraindications to radiotherapy, chemotherapy or surgery
• Prior history of head and neck cancer within 5 years
• Prior head and neck radiation at any time
• Metastatic disease
• Inability to attend full course of radiotherapy or follow-up visits
• Prior invasive malignant disease unless disease-free for at least 5 years or more, with the exception of non-melanoma skin cancer
• Unable or unwilling to complete QOL questionnaires
• Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1, Radiation +/- Chemotherapy; Standard Treatment (Radiation +/- Chemotherapy)	Radiation: Radiation; Standard of Care: Radiation +/- Chemotherapy; Other Names: Chemotherapy, if required
Experimental: Arm 2, TOS + Neck Dissection; Trans-oral Surgery (TOS) + Neck Dissection (plus radiation is required)	Procedure: Trans-Oral Surgery (TOS) + Neck Dissection; Trans-Oral Surgery (TOS) + Neck Dissection (plus radiation, if required); Other Names: Radiation, if required

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease-Specific Survival	Time from randomization to death from cancer	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Time from randomization to death from any cause	5 years
Progression-Free Survival	Defined as time from randomization to death from any cause	5 years
Local-Regional Failure	Defined as time from randomization to first local-regional failure (analyzed as cumulative incidence function with death as competing event)	5 years
Distant Failure	Defined as time from randomization to first distant failure or metastasis (analyzed as cumulative incidence function with death as competing event)	5 years
Any Failure	Defined as time from randomization to first local-regional failure or distant failure, whichever occurs first (analyzed as cumulative incidence function with death as competing event)	5 years
Quality of Life	Quality of Life using the following questionnaire: MD Anderson Dysphagia Inventory (MDADI)	Baseline to 5 years follow up
Quality of Life	Quality of Life using the following questionnaire: EORTC QLQ-C30	Baseline to 5 years follow up
Quality of Life	Quality of Life using the following questionnaire: H&N35 scale	Baseline to 5 years follow up
Quality of Life	Quality of Life using the following questionnaire: Voice Handicap Index (VHI-10)	Baseline to 5 years follow up
Quality of Life	Quality of Life using the following questionnaire: Neck Dissection Impairment Index (NDII)	Baseline to 5 years follow up
Quality of Life	Quality of Life using the following questionnaire: Patient Neurotoxicity Questionnaire (PNQ)	Baseline to 5 years follow up
Toxicity profile of both study arms using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 4	To determine toxicity profile of both study arms using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) Version 4	Randomization until 5 years follow up
Feeding tube rate at 1 year	Measure other functional measurements such as feeding tube rate at 1 year	Baseline to 1 year post treatment
CTCAE Dysphagia Grade	Measure other functional measurements such as CTCAE Dysphagia grade	Baseline to 5 years post treatment

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Investigators: Principal Investigator: Danielle MacNeil, M.D., London Regional Cancer Program, London Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2020
• Primary Completion (Anticipated): February 1, 2028
• Study Completion (Anticipated): February 1, 2028

Study Registration Dates

• First Submitted: January 6, 2020
• First Submitted That Met QC Criteria: January 6, 2020
• First Posted (Actual): January 7, 2020

Study Record Updates

• Last Update Posted (Actual): September 4, 2020
• Last Update Submitted That Met QC Criteria: September 2, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: Randomized; Radiotherapy; Trans-Oral Surgery; HPV-Negative
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Head and Neck Neoplasms; Neoplasms, Squamous Cell; Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck
• Other Study ID Numbers: ORATOR 3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No