The Prognostic Value of Radiological Extranodal Extension in HPV-Positive Oropharyngeal Carcinoma Treated by (Chemo-)Radiation

Abstract

<h3>Purpose/Objective(s)</h3> In HPV-positive (HPV+) oropharyngeal carcinoma (OPC), N-status is defined exclusively by size and laterality of lymph node metastasis. In HPV-unrelated head and neck cancers, extranodal extension has already been included in the clinical N-categories of the TNM-staging system. There is emerging evidence that the presence of radiological extranodal extension (rENE) impacts prognosis and survival for HPV+ OPC. The hypothesis of this study is that the presence of rENE in node positive HPV+ OPC is associated with worse outcome, and rENE may be used to improve prognostication. <h3>Materials/Methods</h3> Consecutive patients treated by definitive radiation or chemoradiation (organ-preservation), using IMRT, for node-positive HPV+ OPC between 2009 and 2018 were retrospectively registered. Baseline diagnostic MRI or CT scans (acquired <60 days of start of treatment) were retrospectively scored for the presence of rENE by two experienced head and neck radiologists, according to previously described methods (<i>Huang et al., JCO 2021</i>) and with scoring for level of certainty for the presence of rENE (<i>Panicek et al., AJR 2016</i>). Outcome measures included Overall Survival (OS), Disease Free Survival (DFS), Locoregional Control (LRC) and Distant Control (DC); each were stratified for rENE status. Multivariate analysis for OS was used to investigate the independent prognostic value of rENE. <h3>Results</h3> This cohort consisted of 111 patients with node-positive HPV+ OPC, treated by organ-preservation. Median age was 62.8 years, gender was male in 78% and female in 22% of cases, median number of pack years of smoking was 15 (range 0-113). T-stage (according to TNM-8) was as follows: T1 in 21, T2 in 34, T3 in 21 and T4 in 35 cases. N-stage consisted of: N1 in 66 cases, N2 in 11 cases and N3 in 1 case. TNM-group staging was stage I in 48, stage II in 27 and stage III in 36 cases. rENE was present (rENE+) in 39 cases (35%) and absent (rENE-) in 72 cases (65%). Median follow-up of all patients was 57 months (range 2-156); median follow-up of patients alive at last follow-up was 63 months (range 31-156). Patients with rENE+ had inferior 5-year OS compared to those with rENE-: 57% vs. 76% (Log-rank p-value = 0.018), inferior 5-year DFS (51% vs. 71%, p-value = 0.016), and inferior 5-year DC (81% vs. 91%, p-value = 0.11) but there was no meaningful difference in 5-year LRC (86% vs. 90%, p-value =0.49). In multivariate analyses, the following factors were independently associated with OS: N-stage (N2 vs. N1, HR 2.66, p-value = 0.01), age (HR 1.05, p-value = 0.005), smoking pack years (HR 1.02, p-value = 0.035) and rENE (HR 2.38, p-value = 0.024). <h3>Conclusion</h3> rENE is indeed an important prognostic factor in a contemporary single-institutional cohort of patients with HPV+ OPC, and is independent of N-stage. rENE may potentially be used to further refine the TNM staging system.