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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: 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. 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. 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.

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

Conditions
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Head and Neck Cancer, Oropharyngeal Squamous Cell Carcinoma

Intervention / Treatment
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* Radiation: Radiation
* Procedure: Trans-Oral Surgery (TOS) + Neck Dissection


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2 Arm study randomized in a 1:1 ratio
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, Trans-Oral Surgery, HPV-Negative, Randomized