Assessment of Toxic Effects and Survival in Treatment Deescalation With Radiotherapy vs Transoral Surgery for HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Abstract

IMPORTANCEThe 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 PARTICIPANTSThis 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 MEASURESThe 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. RESULTSOverall, 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 RELEVANCEIn 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.

The Sinai Robotic Surgery Trial in HPV-related oropharyngeal squamous cell carcinoma (SIRS 2.0 trial) – study protocol for a phase II non-randomized non-inferiority trial

“…Multiple studies report favorable swallowing outcomes using TORS for resection of oropharyngeal cancers (12-18). Additionally, the phase 2 randomized ORATOR and ORATOR2 trials demonstrated similar MDADI scores for the RT and TORS treatment arms of their studies up to 3 years of follow up (19,20). Taken together, patient reported quality-of-life is at least comparable, if not better, for TORS when compared to CRT.…”

Human Papillomavirus-Related Non-Metastatic Oropharyngeal Carcinoma: Current Local Treatment Options and Future Perspectives

“…In an attempt to preserve organ function, avoid surgical complications and potentially achieve excellent treatment outcomes with decreased toxicity, some studies have focused on reduction of the primary RT dose. A randomized phase II study (ORATOR2) compared upfront TORS plus ND followed by a reduced-dose adjuvant RT (50 Gy in 25 fractions or 60 Gy in 30 fractions if there were positive margins or ENE) with a primary de-escalated RT (60 Gy) with weekly cisplatin 40 mg/m 2 [ 72 ]. Overall, 61 patients with T1-2 N0-2 AJCC 8th edition HPV+ OPSCC were randomized; 31 in the TORS group and 30 in the primary RT group.…”

“…Patients in both treatment arms in ORATOR2 achieved good swallowing outcomes at one year after the treatment. Grade 2–5 adverse events occurred in 67% of the patients in the RT group compared to 71% in the TORS group [ 72 ]. Careful patient selection and high-level surgical expertise in high-volume centers are of paramount importance for an uncomplicated procedure of TORS in HPV+ OPSCC.…”

“…In recent randomized trials evaluating the exact role of TORS in the treatment of HPV+ OPSCC patients, the resection margin status (negative, close, positive) has been identified as a major risk factor for treatment deintensification and serves as a pivotal tool for patient stratification into risk groups receiving control or test treatments. However, the exact definition of negative, close, and positive margins differed substantially across the individual studies [ 31 , 46 , 72 , 96 ]. The E3311 trial [ 31 ] defined negative resection margins as >3 mm, close margins as <3 mm, and positive margins as <1 mm, which, among other risk factors, stratified the patients into low-, intermediate-, and high-risk groups, where observation, adjuvant RT 50 or 60 Gy (random allocation), or adjuvant CRT with 66 Gy was indicated [ 31 ].…”

Current Evidence of a Deintensification Strategy for Patients with HPV-Related Oropharyngeal Cancer

“…The ORATOR-2 trial is a prospective phase II randomized trial comparing definitive deintensified CRT and transoral surgery [ 32 ]. Patients were eligible as T1-2N0-2M0 according to the AJCC, 8th edition, which also represents T1-2N0-2 by the AJCC, 7th edition.…”