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

Abstract

Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown.

Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC.

Design, setting, and participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up.

Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings).

Main outcomes and measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects.

Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively).

Conclusions and relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes.

Trial registration: Clinicaltrials.gov Identifier: NCT03210103.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Palma reported grants from the Ontario Institute for Cancer Research during the conduct of the study. Dr Berthelet reported grants from Eisai and Sanofi-Genzyme outside the submitted work. Dr Karam reported honorarium from Pfizer outside the submitted work. Dr Dzienis reported honoraria from MSD, Novartis, and BMS and advisory board service for Novartis. Dr Kuruvilla reported advisory board service and honorarium from AstraZeneca, Bristol Myers Squibb, Merck, and Sanofi outside the submitted work. Dr Nichols reported grants from Novartis Canada outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

RT indicates radiotherapy; TOS + ND, transoral surgery and neck dissection.

Figure 2.. Preliminary Analyses of Time-to-Event Outcomes for Overall Survival and Progression-Free Survival Stratified by Treatment Arm

RT indicates radiotherapy; TOS + ND, transoral surgery and neck dissection.