Primary Radiotherapy Versus Primary Surgery for HPV-Associated Oropharyngeal Cancer (ORATOR2)

A Randomized Trial of Treatment De-Escalation for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: Radiotherapy vs. Trans-Oral Surgery (ORATOR II)

The goal of this randomized treatment de-escalation study is to formally compare outcomes in HPV related oropharyngeal cancer tumors treated with a primary radiotherapy versus a primary surgical approach, to provide a high level of evidence to guide the selection of treatment options for a subsequent phase III trial

Study Overview

• Status: Active, not recruiting
• Conditions: Oropharyngeal Cancer
• Intervention / Treatment: Radiation: Radiation; Procedure: Transoral Surgery (TOS) + Neck Dissection

Detailed Description

The goal of this randomized treatment de-escalation study is to formally compare outcomes in HPV related oropharyngeal cancer tumors treated with a primary radiotherapy versus a primary surgical approach, to provide a high level of evidence to guide the selection of treatment options for a subsequent phase III trial

The study will compare overall survival rates relative to historical controls for de-intensified primary radiotherapy [60 GY +/- chemotherapy] versus transoral surgery (TOS) and neck dissection [+/- adjuvant 50Gy radiotherapy] in patients with early T-stage HPV-positive squamous cell carcinoma of the oropharynx and to compare quality of life (QOL) profiles.

The study will require a sample size of 140 patients randomized in a 1:1 ratio between the two arms. Arm 1 (radiotherapy +/1 chemotherapy) and Arm 2 (TOS)

Patients will be followed for a total of 5 years

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Queensland
    • Gold Coast, Queensland, Australia
      • Gold Coast University Hospital
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1G1
      • BC Cancer
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital Research Institute
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Research Institute
    • Toronto, Ontario, Canada, M5G 2C4
      • University Health Network
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age 18 years or older
• willing to provide informed consent
• ECOG performance status 0-2
• Histologically confirmed squamous cell carcinoma
• P16 positive, or HPV positive
• Primary tumor site in the oropharynx (includes tonsil, soft palate, base of tongue, walls of oropharynx)
• 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.
• Smokers and non-smokers are included. Patients will be stratified by ,<10 pack years smoking history versus > or equal to 10 pack years.
• Tumor stage (AJCC 8th edition): T1 or T2
• Nodal stage (AJCC 8th edition): N0, N1, or N2
• For patients who may require chemotherapy (ie, patients with multiple lymph nodes positive or a single node more than 3 cm in size, in any plane, CBC/differential within 4 weeks prior to randomization with adequate bone marrow function, hepatic, and renal function defined as: Hemoglobin ≥ 80 g/L; Absolute neutrophil count ≥ 1.5 x 10 9/L, platelets ≥ 100 x 10 9/L, bilirubin ≤ 35 umol/L, AST or ALT ≤ 3 x the upper limit of normal; serum creatinine ≤ 130 umol/L or creatinine clearance ≥ 50 ml/min
• patients assessed at head and neck multidisciplinary clinic (with assessment by radiation oncologist and surgeon) and presented at multidisciplinary tumor board prior to randomization

Exclusion Criteria:

• unambiguous clinical or radiological evidence of extranodaal extension on pre-treatment imaging. This includes the presence of matted notes, defined as 3 or more nodes that are abutting with loss of intervening fat planes
• 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
• 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; Transoral Surgery (TOS) + Neck Dissection (plus radiation, if required)	Procedure: Transoral Surgery (TOS) + Neck Dissection; Transoral 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
Overall Survival	Time from randomization to death from any cause	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life 1 year post treatment	Quality of life 1 year post treatment as assessed with the MD Anderson Dysphagia Inventory (MDADI)	1 year post treatment
Progression free survival comparison with historical controls	Defined as time from randomization to death from any cause	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 to 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
Speech intelligibility	Measure other functional measurements such as speech intelligibility	baseline to 5 years post treatment
Normalcy of diet	Measure other functional measurements such as normalcy of diet	baseline to 5 years post treatment
2 year progression-free survival comparison between Arm 1 and Arm 2	Time from randomization to disease progress at any site or death from any cause	2 years

Collaborators and Investigators

• Sponsor: Lawson Health Research Institute
• Investigators: Principal Investigator: David Palma, Lawson Health Research Institute

Publications and helpful links

General Publications

• Palma DA, Prisman E, Berthelet E, Tran E, Hamilton S, Wu J, Eskander A, Higgins K, Karam I, Poon I, Husain Z, Enepekides D, Hier M, Sultanem K, Richardson K, Mlynarek A, Johnson-Obaseki S, Odell M, Bayley A, Dowthwaite S, Jackson JE, Dzienis M, O'Neil J, Chandarana S, Banerjee R, Hart R, Chung J, Tenenholtz T, Krishnan S, Le H, Yoo J, Mendez A, Winquist E, Kuruvilla S, Stewart P, Warner A, Mitchell S, Chen J, Parker C, Wehrli B, Kwan K, Theurer J, Sathya J, Hammond JA, Read N, Venkatesan V, MacNeil SD, Fung K, Nichols AC. Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma: The ORATOR2 Phase 2 Randomized Clinical Trial. JAMA Oncol. 2022 Jun 1;8(6):1-7. doi: 10.1001/jamaoncol.2022.0615.
• Nichols AC, Lang P, Prisman E, Berthelet E, Tran E, Hamilton S, Wu J, Fung K, de Almeida JR, Bayley A, Goldstein DP, Eskander A, Husain Z, Bahig H, Christopoulous A, Hier M, Sultanem K, Richardson K, Mlynarek A, Krishnan S, Le H, Yoo J, MacNeil SD, Mendez A, Winquist E, Read N, Venkatesan V, Kuruvilla S, Warner A, Mitchell S, Corsten M, Rajaraman M, Johnson-Obaseki S, Eapen L, Odell M, Chandarana S, Banerjee R, Dort J, Matthews TW, Hart R, Kerr P, Dowthwaite S, Gupta M, Zhang H, Wright J, Parker C, Wehrli B, Kwan K, Theurer J, Palma DA. Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial. BMC Cancer. 2020 Feb 14;20(1):125. doi: 10.1186/s12885-020-6607-z.

Study record dates

Study Major Dates

• Study Start (Actual): January 26, 2018
• Primary Completion (Estimated): August 15, 2028
• Study Completion (Estimated): August 15, 2028

Study Registration Dates

• First Submitted: June 28, 2017
• First Submitted That Met QC Criteria: July 4, 2017
• First Posted (Actual): July 6, 2017

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 4, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Head and Neck Cancer; Transoral Surgery
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Head and Neck Neoplasms; Pharyngeal Diseases; Stomatognathic Diseases; Otorhinolaryngologic Diseases; Oropharyngeal Neoplasms
• Other Study ID Numbers: ORATOR2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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