Validation of the 9th AJCC Staging System for NPC in Non-High-Incidence Areas in China

Background: Nasopharyngeal carcinoma (NPC) is a malignancy with marked geographic variation, with over 80% of global cases found in Southeast and East Asia. However, the characteristics of NPC in non-high-incidence areas in China (such as Jiangsu, Zhejiang, and Anhui provinces) remain understudied. These regions show different EBV prevalence, environmental exposures, and socioeconomic factors compared to endemic regions, which may affect tumor biology and treatment response. The 9th edition AJCC/UICC TNM staging system (TNM-9) introduces critical revisions to improve risk stratification-particularly in N classification-based on new imaging and biological insights like radiologic extranodal extension (rENE). However, its applicability to non-high-incidence populations remains unclear and requires validation. Objectives: To validate the prognostic performance of TNM-9 compared to TNM-8 in non-high-incidence NPC populations, assessing survival outcomes (OS, PFS, DMFS, LRFS) and model performance (C-index, AUC, etc.). To explore subtypes among locally advanced NPC (LA-NPC) under TNM-9 for potential treatment intensification or de-escalation strategies. To assess the clinical significance of ENE among N3 patients and its impact on survival and treatment response. To develop risk models based on anatomic features of advanced nodal involvement to enhance personalized treatment planning. Design and Methods: Study Type: Multicenter retrospective cohort study. Sites: Tertiary cancer centers in Jiangsu, Zhejiang, and Anhui. Sample Size: Approximately 1,401 patients diagnosed between 2011 and 2023. Inclusion Criteria: Adults aged 18-75 with newly diagnosed, untreated NPC from non-high-incidence regions who underwent complete MRI and standard chemoradiotherapy. Exclusion Criteria: Prior treatment, severe comorbidities, pregnancy, or incomplete data. Treatment: Patients received standard radiotherapy-based treatment according to CSCO guidelines, including IMRT with or without induction/adjuvant chemotherapy or targeted/immunotherapy. Endpoints: Primary: Overall Survival (OS) Secondary: Progression-Free Survival (PFS), Distant Metastasis-Free Survival (DMFS), and Local Recurrence-Free Survival (LRFS) Model Metrics: Harrell's C-index, time-dependent ROC, Brier score Statistical Analysis: Kaplan-Meier survival curves, log-rank tests, univariable and multivariable Cox regression. Prognostic models compared via performance metrics. Bootstrap used for internal validation. Subgroup analyses explore survival differences under TNM-9 stratification. Safety Evaluation: Though retrospective, adverse events are extracted from clinical records, including grade ≥3 toxicities from radiotherapy, chemotherapy, and immunotherapy. Particular attention is given to immune-related adverse events (irAEs) and treatment discontinuations. Ethics and Data Handling: The study complies with the Declaration of Helsinki. No experimental interventions are involved. All data are anonymized and securely stored; informed consent is obtained as per GCP guidelines. Significance: This study addresses the gap in NPC staging validation in non-high-incidence populations. It aims to confirm the utility of TNM-9 in real-world Chinese cohorts outside high-incidence areas and explore refined treatment strategies for LA-NPC. The findings could impact staging policy, risk stratification, and clinical decision-making, supporting more personalized NPC management across diverse regions.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

Inclusion Criteria:

* Age 18-75 years old and gender
* Long-term residence in a non-high prevalence area for nasopharyngeal cancer
* Histologically confirmed primary nasopharyngeal cancer (without any treatment)
* Completed MRI examination of nasopharynx and neck with image quality meeting the needs of imaging analysis
* All receiving a standard comprehensive treatment plan with radiotherapy as the core
* Adequate bone marrow, liver, and kidney function (meeting laboratory index thresholds)
* ECOG 0-1, KPS ≥ 70 points, and life expectancy \> 3 months
* No previous history of immune disorders

Exclusion Criteria:

* Received radiotherapy, chemotherapy, or surgery to the primary site or lymph nodes
* Severe underlying disease (heart failure, renal failure, etc.), uncontrolled active infection, active autoimmune disease, or history of autoimmune disease requiring immunosuppressive therapy
* Pregnant or breastfeeding females
* Irregular radiotherapy or missing treatment data

• BACKGROUNDWu LR, Zhang XM, Xie XD, Lu Y, Wu JF, He X. Validation of the 8th edition of AJCC/UICC staging system for nasopharyngeal carcinoma: Results from a non-endemic cohort with 10-year follow-up. Oral Oncol. 2019 Nov;98:141-146. doi: 10.1016/j.oraloncology.2019.09.029. Epub 2019 Oct 4. PMID 31586896
• BACKGROUNDChen YP, Liu X, Zhou Q, Yang KY, Jin F, Zhu XD, Shi M, Hu GQ, Hu WH, Sun Y, Wu HF, Wu H, Lin Q, Wang H, Tian Y, Zhang N, Wang XC, Shen LF, Liu ZZ, Huang J, Luo XL, Li L, Zang J, Mei Q, Zheng BM, Yue D, Xu J, Wu SG, Shi YX, Mao YP, Chen L, Li WF, Zhou GQ, Sun R, Guo R, Zhang Y, Xu C, Lv JW, Guo Y, Feng HX, Tang LL, Xie FY, Sun Y, Ma J. Metronomic capecitabine as adjuvant therapy in locoregionally advanced nasopharyngeal carcinoma: a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial. Lancet. 2021 Jul 24;398(10297):303-313. doi: 10.1016/S0140-6736(21)01123-5. Epub 2021 Jun 7. PMID 34111416
• BACKGROUNDYang X, Ren H, Li Z, Peng X, Fu J. Combinations of radiotherapy with immunotherapy in nasopharyngeal carcinoma. Int Immunopharmacol. 2023 Dec;125(Pt A):111094. doi: 10.1016/j.intimp.2023.111094. Epub 2023 Oct 23. PMID 37871379
• BACKGROUNDCai S, Huang Z, Chen Z, Li Y, Su J, Chen R, Xu S, Wang J, Qiu S. A nomogram integrating clinical stage and pre-EBV DNA to identify the cycles of induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma. Radiat Oncol. 2025 Jun 4;20(1):93. doi: 10.1186/s13014-025-02672-1. PMID 40468367
• BACKGROUNDLu T, Hu Y, Xiao Y, Guo Q, Huang SH, O'Sullivan B, Fang Y, Zong J, Chen Y, Lin S, Chen Y, Pan J. Prognostic value of radiologic extranodal extension and its potential role in future N classification for nasopharyngeal carcinoma. Oral Oncol. 2019 Dec;99:104438. doi: 10.1016/j.oraloncology.2019.09.030. Epub 2019 Oct 22. PMID 31654937
• BACKGROUNDJiang W, Wang GY, Qin GJ, Zhang WQ, Zhu XD, Han YQ, Lei F, Shen LF, Yang KY, Cui CY, Tang LL, Mao YP, Chen L, Guo R, Li L, Wu Z, Xu GQ, Zhou Q, Huang J, Huang SH, Li JB, Liu LZ, Ma J, Du XJ. Advanced image-identified extranodal extension of retropharyngeal lymph nodes in the refinement of N classification for nasopharyngeal carcinoma. Cell Rep Med. 2025 Feb 18;6(2):101942. doi: 10.1016/j.xcrm.2025.101942. Epub 2025 Feb 11.