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

Abstract

Background: Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two deescalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. Methods: This is a multicenter phase II study randomizing one hundred and forty patients with T1-2 N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± deescalated adjuvant radiotherapy (50-60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. Discussion: This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials.

Modern treatment outcomes for early T-stage oropharyngeal cancer treated with intensity-modulated radiation therapy at a tertiary care institution

“…However, due to short- and long-term toxicities, and due to the fact that HPV-associated OPSCC is more sensitive to chemotherapy and radiation than HPV-negative OPSCC, there has been much interest in treatment de-escalation [ 23 , 24 ]. Some current strategies under investigation include weekly cisplatin instead of high-dose cisplatin, lower radiation dose, or decreased adjuvant radiation and/or chemotherapy after surgery [ 25 – 27 ]. Other strategies, such as using the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab, have conclusively been shown to provide inferior survival without meaningfully improving quality of life which only further highlights the importance of balancing toxicity with survival [ 28 , 29 ].…”

The Evolution of Care of Cancers of the Head and Neck Region: State of the Science in 2020

“…The results of this trial suggest that appropriate treatment modalities for OPSCC should be made on a case-by-case basis [44]. The ORATOR2 trial (NCT 03210103) is currently underway to assess the effect of 2 de-escalation protocols, primary RT (lowered to 60 Gy) versus TORS, on survival and treatment toxicities [46].…”

Preservation of swallowing in resected oral cavity squamous cell carcinoma: examining radiation volume effects (PRESERVE): study protocol for a randomized phase II trial

“…Enrollment can begin once the plan and QA have been approved at the London Regional Cancer Program. Centres who have been accredited for ORATOR [ 38 ] or ORATOR2 [ 40 ] are exempt from this requirement.…”

“…Organs at Risk (OAR) definitions, dose constraints and planning priorities are adapted from the following protocols: RTOG protocols 1016 [36] (Arm 1) and RTOG 0920 [37] (Arm 2), NCIC-CTG HN6, ORATOR [38,39] and ORATOR2 [40], and are described in Additional file 1.…”