Importance: A subset of Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) eighth edition TNM stage I and II human papillomavirus–positive oropharyngeal carcinoma has undesirable outcomes, which might have contributed to a lack of success in phase III deintensification trials. Refining clinical stage groups, especially in the overabundant cN1/stage I group, has become important for treatment selection.Objective: To assess the prognostic importance of pretreatment lymph node (LN) characteristics to optimize case distribution and outcome homogeneity within the N classification system.Design, Setting, and Participants: This is an international multi-institutional retrospective prognostic cohort study. Analysis of human papillomavirus–positive oropharyngeal carcinoma treated curatively from 4 institutions (International Collaboration of Oropharyngeal Cancer Network for N-Classification [ICON-N] dataset) provided a refined clinical staging proposal; an independent dataset (Centre Hospitalier de l’Université de Montréal [CHUM] dataset) validated the proposal. Neuroradiologists reviewed pretreatment computed tomography and/or magnetic resonance imaging for nodal features, including presence or absence of abnormal LN(s), retropharyngeal LN, laterality, number of abnormal LN, and imaging-detected extranodal extension (iENE). Data were collected from February to May 2023, and data were analyzed from June to July 2023.Exposures: Definitive chemoradiotherapy/radiotherapy or definitive surgery with or without postoperative chemoradiotherapy/radiotherapy.Main Outcomes and Measures: The primary end point was overall survival. A Cox proportional hazards multivariable model was used to estimate adjusted hazard ratios (AHRs) and to derive an optimal clinical TNM stage classification (AHR-stage schema) incorporating the strongest prognostic nodal features within the UICC/AJCC eighth edition TNM framework after confirming the prognostication of iENE status. The performance (according to overall normalized scores and ranking) of the AHR-stage schema against the current UICC/AJCC eighth edition TNM staging system was evaluated for hazard consistency, hazard discrimination, prognostic importance, and sample size balance. Validation was performed in the CHUM dataset.Results: The ICON-N dataset comprised 2053 patients, including 1898 (92.5%) with cN-positive disease and 155 (7.5%) with cN0 disease; a total of 298 (14.5%) were female, and the mean (SD) age was 60.6 (9.3) years. iENE-positive disease was identified in 710 of 1898 patients with cN-positive disease (37.4%). The median (range) follow-up was 5.1 (0.1-14.7) years. iENE was the strongest prognostic nodal feature in multivariable analysis; the AHR for iENE-positive vs iENE-positive disease was 2.43 (95% CI, 1.96-3.03) in the ICON-N dataset and 2.04 (95% CI, 1.28-3.23) in the CHUM dataset (n = 451). Reclassifying iENE-positive cases 1 stratum higher for N categorization without altering iENE-negative cases yielded an AHR-stage schema that outperformed the current TNM staging system in disease-free and overall survival with a lower (ie, better) overall normalized score (2 vs 3).Conclusions and Relevance: In this study, reclassifying each N category 1 stratum higher for iENE-positive disease resulted in better disease-free and overall survival. The proposed new classification outperformed the currently TNM staging system in risk stratification and may facilitate future clinical trial design, outcomes research, and patient care.

Radiation late toxicities (RLTs) are complications of curative-intent radiotherapy (RT) for head and neck cancer (HNC) and are increasingly relevant due to younger age at diagnosis and improved survival outcomes. We conducted a cohort study of HNC patients who received ≥50 Gy as part of curative treatment between January 2003 and December 2020 at a Canadian quaternary cancer center. Risk factors for severe RLTs (≥RTOG Grade 3) were evaluated using time-to-event analyses. Actuarial rates of RLT and overall survival (OS) were estimated using competing risk and Kaplan–Meier methods, respectively. Cox proportional hazard models identified factors associated with RLT and OS. Among 7622 patients, 12.6% (n = 958) developed RLTs without disease progression, with a 5-year actuarial incidence of 16% (95% CI: 15–16). A survivors subgroup (n = 4650) with ≥2 years of follow-up and no recurrence was also identified. Modifiable risk factors for RLTs included RT technique, dose, neck irradiation, neck dissection, smoking status, and chemotherapy (p ≤ 0.012). Non-modifiable factors included younger age, female sex, and oral cavity primaries (p ≤ 0.012). In multivariable analysis, RLTs were associated with increased mortality (HR = 2.1, 95% CI: 1.8–2.5, p < 0.001), but RLT's impact on OS was lessened among patients referred to the Adult Radiation Late Effects Clinic (ARLEC) (HR = 1.7, 95% CI: 1.3–2.4). RLTs are common and associated with worse survival among HNC survivors. Identification of modifiable risk factors provides opportunities for prevention. Multidisciplinary management of RLTs in specialized clinics may help improve the outcomes in this growing survivorship population. No external funding was utilized for this study.

Risk-tailored approaches are the backbone of contemporary clinical research and treatment in oncology. Attention to risk-stratification model development, especially concerning the choice and emphasis of prognostic factors to include in a model, is essential to understanding prognosis and implementing strategies to advance treatment, e.g. selecting patients for differing treatments or strategies for exploration in clinical trials, including defining eligibility for trials and determining useful stratifications in the design of randomised controlled trials. Prognostic factors can be classified as pre-treatment factors and dynamic factors. Pre-treatment baseline factors refer to those factors that exist prior to any intervention or treatment for the setting under consideration. The outcomes of HPV-positive oropharyngeal carcinoma (HPV+ OPC) patients can be stratified based on a number of parameters, that usually include some description of smoking status, patient characteristics such as age, performance status, and conventional TNM disease stage. Emerging areas that may be considered now or in the future also include extranodal extension (ENE), baseline circulating HPV DNA (HPV-ctDNA), and TME (tumour micro-environment) among others. Dynamic factors refer to those emerging during and post-treatment. The latter concept is obviously not new and has traditionally influenced post-initial management approaches of head and neck cancer for many years, such as when making decisions based on pathological findings after surgery (e.g. pathological size, tumour extension, resection margin status and the presence of ENE status in the resected specimen). However, the current discussion will focus on important emerging strategies within the same paradigm, e.g. response to induction therapy, and changes in HPV-ctDNA. Compared to traditional smoking-related HPV-negative OPC, HPV+ OPC is a different disease with very different biological and clinical behaviour and it is important to re-appraise traditional prognostic factors as well to appreciate the clinical relevance of emerging biomarkers. This chapter summarizes updates concerning prognostic factors and risk stratification in HPV+ OPC that may realistically influence management or investigation of the disease in the short term.