1021 - Prognostic Value of Image-Identified Extranodal Extension and Potential Role in Cn Classification in HPV-Negative Oropharyngeal Cancer: A Multi-Center Cohort Study

S. H. Huang¹, J. Su², F. J. P. Hoebers³, S. A. Koyfman⁴, E. Yu⁵, E. Bartlett⁵, A. Postma⁶, W. Palm⁶, J. Lee⁷, S. Stock⁷, A. Spreafico⁸, J. Waldron¹, A. Hoeben⁹, R. W. Davis⁴, W. Xu¹⁰, and B. OSullivan¹¹; ¹Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, ²Department of Biostatistics, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, ³MAASTRO, Maastricht, Netherlands, ⁴Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, ⁵Department of Medical Imaging, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, ⁶Maastricht University Medical Center, Department of Radiology and Nuclear Medicine, Maastricht, Netherlands, ⁷Cleveland Clinic, Department of Diagnostic Radiology, Cleveland, OH, ⁸Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, ⁹Department of Medical Oncology, Division of Medical Oncology, Department of Internal Medicine, GROW-School of Oncology and Developmental Biology Maastricht University Medical Center+, Maastricht, Netherlands, ¹⁰Department of Biostatistics, Princess Margaret Cancer Center/University of Toronto, Toronto, ON, Canada, ¹¹CHUM (The University of Montreal Hospital Centre), Montreal, QC, Canada

Purpose/Objective(s): Clinical extranodal extension (cENE) is a cN modifier in TNM8 for HPV-negative oropharyngeal cancer (HPV– OPC). Emerging data suggests that image-identified ENE (iENE) is also prognostic, and may be more sensitive in identifying subgroups with poor prognosis. We hypothesize that iENE can replace cENE and provide additional prognostication to the cN classification for HPV– OPC. Materials/

Methods: We pooled HPV– OPC patients treated with definitive (chemo-)radiation from 2008-2019 at 3 academic centers in Europe, US, and Canada. Pre-treatment CT/MRI of cN+ cases were reviewed by neuroradiologists from each institution using internationally accepted criteria for iENE-positive/negative (iENE+/iENE–). Overall survival (OS) was compared by iENE status. Multivariable analysis (MVA) calculated adjusted hazard ratio (AHR) to confirm the prognostic value of iENE. New cN classifications were proposed based on AHR of iENE and TNM7 N categories. The performance of TNM staging proposals were evaluated against TNM8 using established criteria.
Results: A total of 536 patients were identified, including 141 (26%) cN0, 272 (51%) iENE–, and 123 (23%) iENE+ (39 iENE+ were also cENE+). Median follow-up was 5.4 years. Five-year OS was similarly low for iENE+/cENE– (27%) and cENE+ (22%) patients, and inferior to iENE– (45%) and N0 (56%) patients (p<0.01). MVA confirmed the prognostic value of iENE+ status (AHR 1.6, 95% CI 1.2-2.3, p<0.01) when adjusted for TNM8 N, T categories, smoking pack-years, performance status, and systemic therapy, with higher C-index vs the MVA without iENE (0.67 vs 0.65). Based on the AHR of TNM7 N by iENE status, we propose to either classify any iENE+ to N3 (AHR1) (i.e. replacing cENE with iENE within the current TNM8 cN structure) or classify iENE+ as one-stratum higher (AHR2) (similar to the TNM8 pN structure). Stage grouping (including both cN0 and cN+ cases) using the two cN proposals outperformed TNM8 stage grouping, with AHR2 ranking the first (Table).
Conclusion: This multicenter study confirms that iENE can provide additional prognostic value over cENE, supporting replacement of cENE by iENE in future cN classifications. Up-classifying iENE+ by one-stratum higher within the TNM7 cN structure provides the best performance. The findings require independent validation. Table. AHR (TNM7 cN by iENE) and Stage Performance Evaluation

MVA			Stage Performance [Score (Rank)]
TNM7 cN	AHR (95% CI)	p value	Criterion	Stage with TNM8 cN	Stage with AHR1 cN	Stage with AHR2 cN
N1 & iENE-	Reference	<0.001	HR Consistency	2.0 (1)	2.2 (3)	2.1 (2)
N1 & iENE+	1.4 (0.4- 4.7)	0.55	HR Discrimination	0.8 (3)	0.3 (2)	0.2 (1)
N2 & iENE-	1.4 (1.0- 2.0)	0.09	Outcome Prediction by Stage	11.2 (3)	11.6 (2)	11.8 (1)
N2 & iENE+	2.4 (1.6- 3.7)	<0.001	HR Difference +/- Stage	14.7 (3)	15.8 (2)	16.2 (1)
N3	2.1 (1.3- 3.6)	0.004	Sample Size Balance	0.7 (3)	0.6 (1)	0.6 (2)
			Overall Standardized Score (Rank)	4.0 (3)	1.7 (2)	0.9 (1)