Outcomes by time to adjuvant therapy in E3311, a phase II trial of transoral surgery (TOS) followed by pathology-based adjuvant treatment in HPV-associated (HPV+) oropharynx cancer (OPC): A trial of the ECOG-ACRIN Cancer Research Group.
Authors: Ferris Robert L. , Flamand Yael , Quon Harry , Weinstein Gregory S. , Mehra Ranee , Garcia Joaquin J. , Kim Seungwon , O'malley Bert W. , Ozer Enver , Thomas Giovana R. , Koch Wayne , Kupferman Michael Elliot , Bell Richard Bryan , Patel Mihir , Lango Miriam , Burtness Barbara 
Published: June 2023

6036 Background: E3311 is a phase II randomized study of intermediate risk HPV+ OPC patients who underwent TOS by credentialed surgeons and were then treated by pathology-guided, deintensified post-operative treatment. Recent retrospective population data suggest that time to post-operative radiotherapy (PORT) > 6 weeks is associated with worse progression-free survival (PFS). Methods: We retrospectively analyzed demographics, pathologic characteristics, and oncologic outcomes in E3311 by time to initiation of PORT (short vs long, exploring both 6 and 7 weeks postop as the cutpoint). Binary and categorical variables were compared using a chi-square test (or a Fisher’s exact test for small sample sizes). Ordinal variables were compared using a Wilcoxon rank sum test. PFS and overall survival (OS) were estimated using the Kaplan-Meier method and compared using a log-rank test, which was stratified by intermediate- (Arms B/C) vs high-risk (Arm D). Results: Among 321 evaluable patients, the median time to initiation of PORT was 5.1 weeks (range 0.7-15.7); 5.0 (0.7-15.7) for Arm B, 5.1 (2.4-7.0) for Arm C, 5.6 (3.6-7.9) for Arm D. No significant difference in PFS or OS was observed whether PORT commenced by 6 or 7 weeks postoperatively, compared with longer time to initiation of PORT (p = 0.62 and 0.65, p = 0.30 and p = 0.41, respectively). 3-yr PFS rates were 93.5% (95% CI: 89.4%, 96.0%) among those treated ≤6 weeks, and 91.2% (95% CI: 81.4%, 95.9%) among those treated > 6 weeks; 3-yr OS rates were 96.1% (95% CI: 92.7%, 98.0%) among those treated ≤6 weeks, and 94.1% (95% CI: 84.9%, 97.8%) among those treated > 6 weeks. No significant differences in outcomes were observed between intermediate risk treatment arms (deintensified (50Gy) or standard dose (60Gy) RT). Additional demographic and pathologic characteristics, including primary site, margin status, histologic grade, stage, and extranodal extension were not significantly different between those with short vs long time to PORT, whether 6 or 7 weeks was used as the cutpoint. There were more T2 tumors in those treated > 7 weeks postop (84% vs. 49%, p = 0.007). PS = 1 patients were more numerous among those with shorter time to PORT (10% vs 0%, with the 7 week cutpoint). Conclusions: In contrast to retrospective NCDB data, intermediate- and high-risk HPV+ OPC patients enrolled on E3311 had favorable 3-yr PFS and OS rates that were not significantly worse when adjuvant therapy was started > 6 wks or > 7wks. These results argue against a survival advantage for initiation of PORT within 6 or 7 weeks for early-stage HPV+ OPC managed with high-quality transoral resection. The optimal time window to initiate PORT in HPV+ OPC patients remains to be determined. Clinical trial information: NCT01898494 .