Risk Stratification in T4 or N3 Nasopharyngeal Carcinoma

Lin-Feng Guo; Lu-Chao Zhu; Yi-Feng Yu; Zhen-Zhen Lu; Qin Lin; San-Gang Wu

doi:10.4143/crt.2025.573

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Original Article Head and Neck cancer Risk Stratification in T4 or N3 Nasopharyngeal Carcinoma: Lin-Feng Guo, Lu-Chao Zhu, Yi-Feng Yu, Zhen-Zhen Lu, Qin Lin, San-Gang Wu; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2026;58(3):728-737.
DOI: https://doi.org/10.4143/crt.2025.573
Published online: August 12, 2025

Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China

Correspondence: Qin Lin, Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
Tel: 86-5922139531 E-mail: linqin05@163.com

Co-correspondence: San-Gang Wu, Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China
Tel: 86-5922139531 E-mail: wusg@xmu.edu.cn

*Lin-Feng Guo and Lu-Chao Zhu contributed equally to this work.

• Received: May 28, 2025 • Accepted: August 11, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
This study aimed to investigate the prognostic heterogeneity among stage III nasopharyngeal carcinoma (NPC) patients according to the 9th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system to identify potential subgroups requiring tailored therapeutic strategies.
Materials and Methods
We retrospectively included stage III patients (T1-3N3 or T4N0-3) who were diagnosed with NPC between January 2015 and December 2021 according to the 9th edition of the AJCC/UICC staging system. Kaplan-Meier method and multivariable Cox regression analyses were used for statistical analysis.
Results
A total of 309 patients were included in this study. A total of 92/309 (29.8%) patients developed locoregional recurrence and/or distant metastasis with a median follow-up of 52.9 months. Those with T4N3 disease had significantly lower distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) but comparable locoregional relapse-free survival (LRFS) to those with T1-3N3 and T4N0-2 disease. Those with T4N3 disease had comparable LRFS but significantly lower 5-year DMFS (78.7% vs. 44.7%, p < 0.001), PFS (65.7% vs. 27.6%, p < 0.001), and OS (77.1% vs. 45.9%, p < 0.001) compared to those with stage T4N0-2 and T1-3N3 diseases. Similar results were confirmed using the multivariate analysis.
Conclusion
Our study demonstrates the prognostic heterogeneity of stage III disease within the 9th edition NPC staging system. T4N3 category should be considered separately and treated as a distinct entity regardless of the staging editions.
Key words: Nasopharyngeal carcinoma, Staging system, Survival, Risk stratification, Prognostic heterogeneity

Introduction

Nasopharyngeal carcinoma (NPC) exhibits a pronounced geographical distribution, with more than 70% of cases concentrated in East and Southeast Asia, notably in endemic areas such as Southern China [1]. A substantial number of NPC patients are diagnosed with locoregionally advanced disease, primarily due to the tumor’s anatomical location and the tendency for occult primary lesions, which frequently hinder early detection [2,3]. In patients with locoregionally advanced nasopharyngeal carcinoma (LANPC), the combination of induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) has achieved a 5-year overall survival (OS) rate nearing 90% [4,5].

The 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system categorized T4N0-3 and T1-3N3 NPC as stage IVA, highlighting the aggressive characteristics of these subgroups. However, the updated 9th edition, officially implemented in 2025, has reclassified these patients as stage III [6], largely due to enhanced treatment outcomes resulting from advancements in radiotherapy techniques and systemic therapies [7,8]. While this reclassification reflects current treatment efficacy, it may introduce heterogeneity within the newly defined stage III cohort, as T4 and N3 diseases have historically shown differing survival patterns [9,10]. This raises the question of whether survival rates differ among subgroups classified as stage T4 or N3 in the 9th edition of the AJCC/UICC staging system. This study aimed to explore the prognostic heterogeneity among 9th edition stage III NPC patients (T1-3N3 or T4N0-3) to identify potential subgroups that may benefit from customized therapeutic approaches.

Materials and Methods

1. Patient selection

This retrospective study included patients diagnosed with NPC at the First Affiliated Hospital of Xiamen University from January 2015 to December 2021. Inclusion criteria included: (1) histologically confirmed stage III NPC based on the 9th edition of the AJCC/UICC tumor-node-metastasis (TNM) staging system; (2) an Eastern Cooperative Oncology Group performance status of 0 or 1; and (3) treated with intensity-modulated radiotherapy (IMRT). Exclusion criteria included a history of secondary malignancies before NPC diagnosis or failure to complete the prescribed radiotherapy regimen.

2. Study variables

The analysis incorporated the following demographic and clinical variables: age, sex, smoking status, alcohol consumption, T category, N category, clinical stage, pretreatment plasma Epstein-Barr virus–DNA (EBV-DNA) levels, and chemotherapy history. Smoking status was categorized as never smokers and ever smokers, with the latter further divided into former smokers (those who quit smoking more than one year prior) and current smokers (those who smoked within the past year). In the 8th edition of the AJCC/UICC staging system, stage IVA primarily encompassed T1-4N3 and T4N0-2, which were reclassified as stage III in the 9th edition. Additionally, individuals presenting with advanced radiologic extranodal extension, which encompasses the involvement of adjacent muscles, skin, and/or the neurovascular bundle, have been reclassified as stage N3. Meanwhile, patients whose primary tumors have invaded the inferior orbital fissure have been reclassified as stage T4 [6].

3. Chemotherapy and radiotherapy

Following institutional protocols, patients classified as stage IVA under the 8th edition of the AJCC/UICC staging system were advised to undergo IC combined with CCRT. Patients would be recommended for three cycles of platinum-based IC followed by two cycles of platinum-based CCRT. The IC regimens utilized at our institution included docetaxel plus cisplatin/nedaplatin, docetaxel plus cisplatin/nedaplatin/lobaplatin plus 5-fluorouracil or S1, or gemcitabine plus cisplatin/nedaplatin. Due to its reduced renal toxicity, nedaplatin or lobaplatin-based IC was preferred for patients ineligible for cisplatin [11]. During CCRT, concurrent cisplatin, nedaplatin, or lobaplatin was administered based on findings from prior prospective randomized trials [12,13]. Chemotherapy cycles were repeated every three weeks. All patients underwent IMRT, with prescribed doses of 70 gray (Gy)/32-33 fractions (f) to the primary nasopharyngeal tumor, 66-70 Gy/32-33f to metastatic neck lymph nodes, 62 Gy/32-33f to the high-risk clinical target volume, and 56 Gy/32-33f to the low-risk clinical target volume.

4. Follow-up and survival outcomes

Patients were monitored according to institutional guidelines, with evaluations every three months for the first 3 years, every 6 months during the fourth and fifth years, and annually thereafter. Routine follow-up assessments included physical examinations, plasma EBV-DNA testing, and comprehensive imaging of the head and neck, chest, abdomen, and bones. Positron emission tomography-computed tomography was recommended for individuals with detectable plasma EBV-DNA or suspected disease recurrence based on imaging findings. Study endpoints comprised locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and OS. LRFS was defined as the duration from NPC diagnosis to local or regional recurrence, or both. DMFS represented the interval from diagnosis to distant metastasis. PFS was measured from diagnosis to disease progression or death from any cause, while OS was defined as the time from diagnosis to death from any cause.

5. Statistical analysis

Descriptive statistics were used to summarize the clinical characteristics of patients. Differences between groups were assessed using the chi-square test or Fisher’s exact test. The receiver operating characteristic (ROC) curve was adopted to identify the optimal cut-off point of the EBV-DNA level in relation to PFS, and the maximal area under the curve value was chosen as the cut-off for model construction. Survival curves were generated using the Kaplan-Meier method, and differences between subgroups were assessed via the log-rank test. Multivariable Cox regression analyses were employed to identify independent prognostic factors associated with survival outcomes. All statistical analyses were performed using SPSS ver. 22.0 (IBM Corp.) and MedCalc Statistical Software ver. 23.0.2 (MedCalc Software Ltd.). A p-value of < 0.05 was considered statistically significant.

Results

1. Patient baseline characteristics

During this period, a total of 770 new patients of non-metastatic NPC were diagnosed in our institution. There were 244 and 305 patients diagnosed as stage N1 and N2 according to the 8th edition of the staging system, respectively. Among them, six patients (2.5%) were initially classified as N1 but upstaged to N3 according to the 9th edition of the staging criteria. In addition, 19 patients (6.2%) were initially classified as N2 but upstaged to N3 according to the 9th edition of the staging criteria. No patients were reclassified as stage T4 due to invasion of the inferior orbital fissure. Therefore, a total of 309 eligible patients were included in this study. The baseline clinicopathological characteristics of the patients are summarized in Table 1. The median age was 51 years (range, 16 to 88 years). Most patients were male (n=226, 73.1%) and had the World Health Organization (WHO) III subtype (n=266, 86.1%). Disease stage distribution was as follows: T1N3 (n=27, 8.7%), T2N3 (n=44, 14.2%), T3N3 (n=78, 25.2%), T4N0 (n=7, 2.3%), T4N1 (n=54, 17.5%), T4N2 (n=73, 23.6%), and T4N3 (n=26, 8.4%). The median pretreatment plasma EBV-DNA level was 1010.5 IU/mL (range, 0 to 260,000 IU/mL). The findings from the ROC curve analysis indicated that a cutoff of 566 IU/mL was the most optimal for predicting PFS (p=0.008) (Fig. 1). Regarding treatment, 283 (91.6%) received IC and 257 (83.2%) received CCRT.

2. Survival and patterns of disease failure

With a median follow-up of 52.9 months (range, 1 to 121 months), a total of 92/309 (29.8%) patients developed treatment failure: locoregional recurrence (LRR) alone in 25 patients (27.2%); distant metastasis (DM) alone in 57 (62.0%); and both LRR and DM in 10 (10.9%) (Fig. 2). Among these patients, 25 experienced LRR (27.2%), 57 had DM (62.0%), and 10 had both LRR and DM (10.9%). Among 35 patients with LRR, 25 experienced nasopharyngeal recurrence, eight had cervical lymph node recurrence, and two showed recurrence in both the nasopharynx and neck simultaneously. Among total of 33 patients with either isolated recurrence involving cervical lymph node or nasopharynx (including 10 with DM), it is notable that all patients (100%) with cervical lymph node recurrence developed in those with N3 stage disease (p=0.010). In those with nasopharyngeal recurrence, 17 patients (68.0%) had T4 stage while eight (32.0%) had T1-3 stage (p < 0.001). The median time to LRR was 23.6 months (range, 8 to 86 months), and the median time to DM was 13.1 months (range, 5 to 61 months). For the entire cohort, the 3-/5-year LRFS, DMFS, PFS, and OS rates were 90.9%/86.4%, 79.7%/76.1%, 67.5%/62.5%, and 80.8%/74.5%, respectively. For patients with stage T4 disease, the 5-year LRFS, DMFS, PFS, and OS rates were 85.7%, 76.5%, 59.9%, and 70.4%, respectively. In addition, the 5-year LRFS, DMFS, PFS, and OS rates for patients with stage N3 disease were 86.3%, 71.9%, 59.9%, and 73.9%, respectively.

3. Comparison of survival outcomes among different subgroups

The Kaplan-Meier analysis was used to describe the survival curves of patients. We divided the patients into the following three groups for analysis: T1-3N3, T4N0-2, and T4N3. The results showed that those with T4N3 disease had significantly lower DMFS, PFS, and OS but comparable LRFS to those with T1-3N3 and T4N0-2 disease. The 5-year DMFS was 76.0%, 82.4%, and 44.7% in those with T1-3N3, T4N0-2, and T4N3 diseases, respectively (p < 0.001) (Fig. 3A). The 5-year PFS was 65.5%, 66.2%, and 27.6% in those with T1-3N3, T4N0-2, and T4N3 diseases, respectively (p=0.001) (Fig. 3B). The 5-year OS was 78.7%, 75.2%, and 45.9% in those with T1-3N3, T4N0-2, and T4N3 diseases, respectively (p < 0.001) (Fig. 3C). The 5-year LRFS was 87.2%, 86.9%, and 81.5% in those with T1-3N3, T4N0-2, and T4N3 diseases, respectively (p=0.429) (Fig. 3D). However, comparable DMFS (p=0.1893), PFS (p=0.786), and OS (p=0.073) were found among those with T1-3N3 and T4N0-2 diseases.

We combined patients in the T1-3N3 and T4N0-2 groups to compare the survival differences between patients with stage T4N3 disease. The results showed that those with stage T4N3 disease had significantly lower DMFS, PFS, and OS when compared to those with stage T1-3N3 and T4N0-2 diseases. However, their LRFS rates were comparable. The 5-year DMFS was 78.7% and 44.7% in those with stage T1-3N3 and T4N0-2 diseases and stage T4N3 disease, respectively (p < 0.001) (Fig. 4A). The 5-year PFS was 65.7% and 27.6% in those with stage T1-3N3 and T4N0-2 diseases and stage T4N3 disease, respectively (p < 0.001) (Fig. 4B). The 5-year OS was 77.1% and 45.9% in those with stage T1-3N3 and T4N0-2 diseases and stage T4N3 disease, respectively (p < 0.001) (Fig. 4C). The 5-year LRFS was 86.9% and 81.5% in those with stage T1-3N3 and T4N0-2 diseases and stage T4N3 disease, respectively (p=0.194) (Fig. 4D). There was no significant difference in the patterns of disease failure between the two stages (p=0.736)

4. Prognosis analysis

We first assessed the independent prognostic impacts of T4 and N3 in patients (Table 2). Age, sex, smoking history, alcohol consumption, histological type, pretreatment EBV-DNA levels, tumor stage, nodal stage, and chemotherapy history were included in the first multivariable Cox regression model. The results showed that tumor stage and nodal stage were the independent prognostic factors associated with DMFS, PFS, and OS. Those with stage T4 disease had significantly lower DMFS (hazard ratio [HR], 2.342; 95% confidence interval [CI], 1.197 to 4.583; p=0.013), PFS (HR, 2.731; 95% CI, 1.578 to 4.726; p < 0.001), and OS (HR, 3.858; 95% CI, 2.005 to 7.421; p < 0.001) compared to those with T1-3 disease. Those with stage N3 disease had significantly lower DMFS (HR, 3.119; 95% CI, 1.497 to 6.498; p=0.002), PFS (HR, 2.375; 95% CI, 1.350 to 4.178; p=0.003), and OS (HR, 2.380; 95% CI, 1.256 to 4.509; p=0.008) compared to those with N0-2 disease.

A second Cox-regression analysis included the following variables: age, sex, smoking history, alcohol consumption, histological type, pretreatment EBV-DNA levels, chemotherapy history, and the subset of clinical stages into the multivariate analysis (Table 3). The results showed that T4N3 was an independent adverse prognostic factor for DMFS (HR, 2.342; 95% CI, 1.197 to 4.583; p=0.013, compared to those with T1-3N3), PFS (HR, 2.731; 95% CI, 1.578 to 4.726; p < 0.001, compared to those with T1-3N3), and OS (HR, 3.858; 95% CI, 2.005 to 7.421; p < 0.001), while it was not associated with LRFS (HR, 1.752; 95% CI, 0.569 to 5.395; p=0.328, compared to those with T1-3N3 in the multivariate analysis). However, comparable LRFS (p=0.704), DMFS (p=0.318), PFS (p=0.516), and OS (p=0.063) were found between those with T4N0-2 and T1-3N3 diseases (Table 3). In addition, age at diagnosis, EBV-DNA levels, smoking history, IC history, and CCRT history were also associated with survival outcomes.

Discussion

Our study offers significant insights into the prognostic heterogeneity observed in stage III NPC under the 9th edition of the AJCC/UICC staging system, particularly among patients previously categorized as stage IVA in the 8th edition. A key observation is that T4N3 disease exhibits markedly inferior survival outcomes compared to other substages, such as T1-3N3 and T4N0-2, underscoring the necessity for enhanced risk stratification. Therefore, regardless of the different editions of the staging system, the T4N3 category ought to be treated as a distinct entity.

The 9th edition of the AJCC/UICC staging system reclassified T4Nany or TanyN3, previously designated as stage IVA in the 8th edition, into a new stage III framework, which encompasses approximately 38.0% of all newly diagnosed NPC patients [6]. However, distinct failure patterns emerged between T4 and N3 disease. Patients with T4 stage NPC experienced higher rates of LRR and DM, potentially attributable to suboptimal target dose coverage and the extensive vascular network surrounding the skull base, which may facilitate distant spread [9,10]. Conversely, N3 disease was associated with the highest risk of DM, with a 5-year DM rate of approximately 40%, likely due to the presence of microscopic metastatic deposits at diagnosis [9,10]. In our cohort, 29.8% of patients experienced disease progression, with 62.0% presenting DM, 27.2% exhibiting LRR, and 10.9% demonstrating both LRR and DM. While the widespread adoption of IMRT has improved local control, distant recurrence remains the primary cause of treatment failure in this patient population [14-16].

The data in the 9th edition staging system included seven subgroups within stage III, yet the staging criteria did not further analyze potential differences among these subgroups. However, the 5-year OS rates for patients with T4N2-3 appear worse compared to those with T1-3N3 and T4N0-1 (74.6% vs. 83.5% vs. 84.9%) [6]. This suggests inherent heterogeneity in survival outcomes within this subgroup, warranting further investigation to optimize individualized treatment strategies.

Our study identified that T4N3 disease is associated with significantly poorer DMFS, PFS, and OS compared to other subgroups (T1-3N3, T4N0-2), which exhibited comparable prognoses. This substantial divergence between T4N3 and other substages (T1-3N3 and T4N0-2) underscores the limitations of grouping these patients under a single stage, suggesting that the current staging system may inadequately stratify high-risk patients, particularly those with T4N3 disease. In the 9th edition staging system, the N classification has incorporated radiologic extranodal extension as an additional staging factor, building upon the previous criteria. This inclusion has resulted in an approximate increase of 6% in the patient population compared to the original classification [6]. Despite these advancements in the staging system, there remains a significant knowledge gap. As of yet, no studies have comprehensively explored the potential heterogeneity among patients with NPC at T4 or N3 stages according to the 9th edition of the staging system. Uncovering such heterogeneity could offer valuable insights into the distinct biological behaviors and clinical outcomes of patients, thereby facilitating the development of more personalized treatment strategies and improving patient care. Previous research based on the 8th edition staging system has explored survival differences among patients with T4 or N3 disease. For instance, Lin et al. [17] compared survival outcomes between T1-3N3 and T4N3 patients (97.3% of whom received IC), and found that T4N3 patients had significantly worse 5-year LRFS (69.3% vs. 82.7%, p=0.043), DMFS (57.2% vs. 77.7%, p=0.016), PFS (43.9% vs. 68.9%, p=0.004), and OS (42.2% vs. 82.8%, p < 0.001). Similarly, Niu et al. [15] reported that T4N3 patients (all patients received IC) had significantly inferior DMFS (HR, 3.286; p=0.001), PFS (HR, 2.821; p=0.001), and OS (HR, 3.501; p < 0.001) compared to T1-3N3 patients. Our findings align with these studies, reinforcing the notion that T4 tumors with N3 nodal involvement exhibit aggressive biological behavior and a higher propensity for hematogenous spread. Therefore, irrespective of which edition of the staging system is used, the T4N3 category should be considered separately.

The comparable LRFS among the three substages suggests that modern radiotherapy effectively achieves local control, but systemic therapy intensification may be necessary to address distant micrometastases. Conversely, Huang et al., in a study based on the 8th edition staging, found that T1-4N3 patients had significantly worse LRFS, DMFS, and OS compared to T4N0-2 patients but observed no significant survival differences among T1N3, T2N3, T3N3, and T4N3 subgroups. Notably, only 72.9% of patients in this study received IC, which may have influenced survival assessments [18].

Proposing a reclassification into stage T1-3N3 and T4N0-2 diseases and stage T4N3 disease significantly improved prognostic discrimination, which is critical for clinical decision-making, including individualized treatment planning and patient counseling. The high rates of IC (91.6%) and CCRT (83.2%) reflect current aggressive treatment protocols for advanced NPC. However, the poor outcomes in T4N3 patients suggest that standard therapies are insufficient for this subgroup, and more potential treatment strategies should be explored for this patient subset, such as incorporating immunotherapy or more intensive chemotherapy. Recent advancements in neoadjuvant or adjuvant therapies have significantly improved survival in LANPC. Extending neoadjuvant chemotherapy cycles or combining it with immunotherapy may enhance therapeutic efficacy, reduce distant metastases, and prolong survival [4,19,20]. Whole-course immunotherapy, including neoadjuvant and/or adjuvant approaches, has improved event-free survival, although no OS benefit has been observed due to limited follow-up [21,22]. Additionally, metronomic capecitabine or S1 has shown promise in improving survival outcomes in LANPC [23,24]. However, the optimal systemic treatment strategy remains under investigation, and long-term follow-up data are still lacking.

Several limitations of our study must be acknowledged. First, as a single-center study, it may be subject to selection bias, and the patient population may not fully represent all NPC cases, limiting generalizability to other regions or ethnic groups. Second, the relatively small sample size may reduce the statistical power and reliability of the results. Third, while the follow-up period was relatively long, it may still be insufficient to capture all long-term recurrence and metastasis events, as late-onset recurrence or metastasis could alter survival estimates.

In conclusion, our study highlights the prognostic heterogeneity within stage III NPC (T1-3N3 or T4N0-3) as defined by the 9th edition AJCC/UICC TNM staging system. T4N3 category should be considered separately and treated as a distinct entity regardless of the staging editions. Risk stratification within this staging holds the promise of guiding personalized treatment strategies, particularly for patients with stage T4N3 disease. However, given the inherent limitations of this study, further validation through large-scale, multicenter investigations is essential to confirm these findings and to advance the development of more precise staging criteria for NPC.

NOTES

Ethical Statement

The study was approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University, and informed consent was waived from the First Affiliated Hospital of Xiamen University due to the retrospective nature of the study. This research was conducted on humans in accordance with the Helsinki Declaration of 1975, as revised in 2013 (http://ethics.iit.edu/ecodes/node/3931).

Author Contributions

Conceived and designed the analysis: Guo LF, Zhu LC, Yu YF, Lu ZZ, Lin Q, Wu SG.

Collected the data: Guo LF, Zhu LC, Yu YF, Lu ZZ, Lin Q, Wu SG.

Contributed data or analysis tools: Guo LF, Zhu LC, Yu YF, Lu ZZ, Lin Q, Wu SG.

Performed the analysis: Guo LF, Zhu LC, Yu YF, Lu ZZ, Lin Q, Wu SG.

Wrote the paper: Guo LF, Zhu LC, Yu YF, Lu ZZ, Lin Q, Wu SG.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Funding

This study was partly supported by the Medical and Health Guidance Project of Xiamen City (No. 3502Z20244ZD1001 and 3502Z20224ZD1005).

Fig. 1.

Receiver operating characteristic curve analysis for assessing the optimal cut-off value of EBV-DNA levels on progression-free survival. AUC, area under the curve; EBV, Epstein-Barr virus.

Fig. 2.

The distribution of disease failure among patients with stage III nasopharyngeal carcinoma according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control staging system. DM, distant metastasis; LRR, locoregional recurrence.

Fig. 3.

The distant metastasis–free survival (A), progression-free survival (B), overall survival (C), and locoregional relapse–free survival (D) across the subset stages of stage III disease according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control staging system.

Fig. 4.

The distant metastasis–free survival (A), progression-free survival (B), overall survival (C), and locoregional relapse–free survival (D) after stratification into stage T4N0-2M0 and T1-3N3M0 diseases and stage T4N3M0 disease.

Table 1.

Patient baseline characteristics

Variables	No. (%) (n=309)
Age (yr)
< 50	139 (45.0)
≥ 50	170 (55.0)
Sex
Male	226 (73.1)
Female	83 (26.9)
Smoking history
No	165 (53.4)
Yes	144 (46.6)
Alcohol consumption
No	216 (69.9)
Yes	93 (30.1)
Histology
WHO I-II subtype	43 (13.9)
WHO III subtype	266 (86.1)
Clinical stage
T1N3	27 (8.7)
T2N3	44 (14.2)
T3N3	78 (25.2)
T4N0	7 (2.3)
T4N1	54 (17.5)
T4N2	73 (23.6)
T4N3	26 (8.4)
EBV-DNA status (IU/mL)
≤ 566	86 (27.8)
> 566	134 (43.4)
Unknown	89 (28.8)
Induction chemotherapy
No	26 (8.4)
Yes	283 (91.6)
Concurrent chemoradiotherapy
No	52 (16.8)
Yes	257 (83.2)

EBV, Epstein-Barr virus; N, node; T, tumor; WHO, World Health Organization.

Table 2.

Multivariable Cox regression analyses to assess the independent impacts of T4 and N3 on survival outcomes

Variable	LRFS			DMFS			PFS			OS
Variable	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Age (yr)
< 50	1			1			1			1
≥ 50	0.886	0.449-1.748	0.727	1.957	1.167-3.281	0.011	1.610	1.079-2.404	0.020	1.736	1.082-2.786	0.022
Sex
Male	1			1			1			1
Female	1.603	0.629-4.083	0.323	0.733	0.372-1.447	0.371	0.825	0.488-1.397	0.475	0.603	0.300-1.235	0.169
Smoking history
No	1			1			1			1
Yes	1.802	0.908-3.577	0.092	1.164	0.626-2.164	0.631	1.629	1.104-2.403	0.014	2.398	1.508-3.814	< 0.001
Alcohol consumption
No	1			1			1			1
Yes	0.663	0.271-1.625	0.369	1.071	0.588-1.952	0.822	0.869	0.544-1.390	0.558	1.017	0.592-1.748	0.951
Histology
WHO I-II subtype	1			1			1			1
WHO III subtype	1.130	0.430-2.972	0.805	0.694	0.356-1.353	0.284	0.915	0.532-1.573	0.748	1.184	0.615-2.279	0.614
Tumor stage
T1-3	1			1			1			1
T4	1.752	0.569-5.395	0.328	2.342	1.197-4.583	0.013	2.731	1.578-4.726	< 0.001	3.858	2.005-7.421	< 0.001
Nodal stage
N0-2	1			1			1			1
N3	2.025	0.639-6.416	0.230	3.119	1.497-6.498	0.002	2.375	1.350-4.178	0.003	2.380	1.256-4.509	0.008
EBV-DNA status (IU/mL)
≤ 566	1			1			1			1
> 566	1.822	0.640-5.191	0.261	2.866	1.365-6.016	0.005	3.148	1.776-5.578	< 0.001	2.436	1.256-4.723	0.008
Unknown	3.750	1.373-10.241	0.010	2.245	1.014-4.969	0.046	2.311	1.271-4.202	0.006	1.873	0.944-3.717	0.073
Induction chemotherapy
No	1			1			1			1
Yes	0.938	0.314-2.800	0.908	0.733	0.329-1.633	0.447	0.581	0.327-1.033	0.064	0.447	0.242-0.825	0.010
Concurrent chemoradiotherapy
No	1			1			1			1
Yes	0.649	0.213-1.034	0.060	0.548	0.311-0.967	0.038	0.437	0.277-0.688	< 0.001	0.315	0.192-0.517	< 0.001

CI, confidence interval; DMFS, distant metastasis–free survival; EBV, Epstein-Barr virus; HR, hazard ratio; LRFS, locoregional relapse–free survival; N, node; OS, overall survival; PFS, progression-free survival; T, tumor; WHO, World Health Organization.

Table 3.

Multivariable Cox regression analyses to assess the independent impacts of clinical stage on survival outcomes

Variable	LRFS			DMFS			PFS			OS
Variable	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Age (yr)
< 50	1			1			1			1
≥ 50	0.886	0.449-1.748	0.727	1.957	1.167-3.281	0.011	1.610	1.079-2.404	0.020	1.736	1.082-2.786	0.022
Sex
Male	1			1			1			1
Female	1.603	0.629-4.083	0.323	0.733	0.372-1.447	0.371	0.825	0.488-1.397	0.475	0.609	0.300-1.235	0.169
Smoking history
No	1			1			1			1
Yes	1.802	0.908-3.577	0.092	1.164	0.626-2.164	0.631	1.629	1.104-2.403	0.014	2.398	1.508-3.814	< 0.001
Alcohol consumption
No	1			1			1			1
Yes	0.663	0.271-1.625	0.369	1.071	0.588-1.952	0.822	0.869	0.544-1.390	0.558	1.017	0.592-1.748	0.951
Histology
WHO I-II subtype	1			1			1			1
WHO III subtype	1.130	0.430-2.972	0.805	0.694	0.356-1.353	0.284	0.915	0.532-1.573	0.748	1.184	0.615-2.279	0.614
Clinical stage
T1-3N3	1			1			1			1
T4N0-2	0.865	0.410-1.825	0.704	0.751	0.428-1.317	0.318	1.150	0.754-1.753	0.516	1.621	0.974-2.699	0.063
T4N3	1.752	0.569-5.395	0.328	2.342	1.197-4.583	0.013	2.731	1.578-4.726	< 0.001	3.858	2.005-7.421	< 0.001
EBV-DNA status (IU/mL)
≤ 566	1			1			1			1
> 566	1.822	0.640-5.191	0.261	2.866	1.365-6.016	0.005	3.148	1.776-5.578	< 0.001	2.436	1.256-4.723	0.008
Unknown	3.750	1.373-10.241	0.010	2.245	1.014-4.969	0.046	2.311	1.271-4.202	0.006	1.873	0.944-3.717	0.073
Induction chemotherapy
No	1			1			1			1
Yes	0.938	0.314-2.800	0.908	0.733	0.329-1.633	0.447	0.581	0.327-1.033	0.064	0.447	0.242-0.825	0.010
Concurrent chemoradiotherapy
No	1			1			1			1
Yes	0.469	0.213-1.034	0.060	0.548	0.311-0.967	0.038	0.437	0.277-0.688	< 0.001	0.315	0.192-0.517	< 0.001

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Risk Stratification in T4 or N3 Nasopharyngeal Carcinoma

Cancer Res Treat. 2026;58(3):728-737. Published online August 12, 2025

DOI: https://doi.org/10.4143/crt.2025.573

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Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Risk Stratification in T4 or N3 Nasopharyngeal Carcinoma

Fig. 1. Receiver operating characteristic curve analysis for assessing the optimal cut-off value of EBV-DNA levels on progression-free survival. AUC, area under the curve; EBV, Epstein-Barr virus.

Fig. 2. The distribution of disease failure among patients with stage III nasopharyngeal carcinoma according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control staging system. DM, distant metastasis; LRR, locoregional recurrence.

Fig. 3. The distant metastasis–free survival (A), progression-free survival (B), overall survival (C), and locoregional relapse–free survival (D) across the subset stages of stage III disease according to the 9th edition of the American Joint Committee on Cancer/Union for International Cancer Control staging system.

Fig. 4. The distant metastasis–free survival (A), progression-free survival (B), overall survival (C), and locoregional relapse–free survival (D) after stratification into stage T4N0-2M0 and T1-3N3M0 diseases and stage T4N3M0 disease.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Risk Stratification in T4 or N3 Nasopharyngeal Carcinoma

Variables	No. (%) (n=309)
Age (yr)
< 50	139 (45.0)
≥ 50	170 (55.0)
Sex
Male	226 (73.1)
Female	83 (26.9)
Smoking history
No	165 (53.4)
Yes	144 (46.6)
Alcohol consumption
No	216 (69.9)
Yes	93 (30.1)
Histology
WHO I-II subtype	43 (13.9)
WHO III subtype	266 (86.1)
Clinical stage
T1N3	27 (8.7)
T2N3	44 (14.2)
T3N3	78 (25.2)
T4N0	7 (2.3)
T4N1	54 (17.5)
T4N2	73 (23.6)
T4N3	26 (8.4)
EBV-DNA status (IU/mL)
≤ 566	86 (27.8)
> 566	134 (43.4)
Unknown	89 (28.8)
Induction chemotherapy
No	26 (8.4)
Yes	283 (91.6)
Concurrent chemoradiotherapy
No	52 (16.8)
Yes	257 (83.2)

Variable	LRFS			DMFS			PFS			OS
Variable	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Age (yr)
< 50	1			1			1			1
≥ 50	0.886	0.449-1.748	0.727	1.957	1.167-3.281	0.011	1.610	1.079-2.404	0.020	1.736	1.082-2.786	0.022
Sex
Male	1			1			1			1
Female	1.603	0.629-4.083	0.323	0.733	0.372-1.447	0.371	0.825	0.488-1.397	0.475	0.603	0.300-1.235	0.169
Smoking history
No	1			1			1			1
Yes	1.802	0.908-3.577	0.092	1.164	0.626-2.164	0.631	1.629	1.104-2.403	0.014	2.398	1.508-3.814	< 0.001
Alcohol consumption
No	1			1			1			1
Yes	0.663	0.271-1.625	0.369	1.071	0.588-1.952	0.822	0.869	0.544-1.390	0.558	1.017	0.592-1.748	0.951
Histology
WHO I-II subtype	1			1			1			1
WHO III subtype	1.130	0.430-2.972	0.805	0.694	0.356-1.353	0.284	0.915	0.532-1.573	0.748	1.184	0.615-2.279	0.614
Tumor stage
T1-3	1			1			1			1
T4	1.752	0.569-5.395	0.328	2.342	1.197-4.583	0.013	2.731	1.578-4.726	< 0.001	3.858	2.005-7.421	< 0.001
Nodal stage
N0-2	1			1			1			1
N3	2.025	0.639-6.416	0.230	3.119	1.497-6.498	0.002	2.375	1.350-4.178	0.003	2.380	1.256-4.509	0.008
EBV-DNA status (IU/mL)
≤ 566	1			1			1			1
> 566	1.822	0.640-5.191	0.261	2.866	1.365-6.016	0.005	3.148	1.776-5.578	< 0.001	2.436	1.256-4.723	0.008
Unknown	3.750	1.373-10.241	0.010	2.245	1.014-4.969	0.046	2.311	1.271-4.202	0.006	1.873	0.944-3.717	0.073
Induction chemotherapy
No	1			1			1			1
Yes	0.938	0.314-2.800	0.908	0.733	0.329-1.633	0.447	0.581	0.327-1.033	0.064	0.447	0.242-0.825	0.010
Concurrent chemoradiotherapy
No	1			1			1			1
Yes	0.649	0.213-1.034	0.060	0.548	0.311-0.967	0.038	0.437	0.277-0.688	< 0.001	0.315	0.192-0.517	< 0.001

Variable	LRFS			DMFS			PFS			OS
Variable	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Age (yr)
< 50	1			1			1			1
≥ 50	0.886	0.449-1.748	0.727	1.957	1.167-3.281	0.011	1.610	1.079-2.404	0.020	1.736	1.082-2.786	0.022
Sex
Male	1			1			1			1
Female	1.603	0.629-4.083	0.323	0.733	0.372-1.447	0.371	0.825	0.488-1.397	0.475	0.609	0.300-1.235	0.169
Smoking history
No	1			1			1			1
Yes	1.802	0.908-3.577	0.092	1.164	0.626-2.164	0.631	1.629	1.104-2.403	0.014	2.398	1.508-3.814	< 0.001
Alcohol consumption
No	1			1			1			1
Yes	0.663	0.271-1.625	0.369	1.071	0.588-1.952	0.822	0.869	0.544-1.390	0.558	1.017	0.592-1.748	0.951
Histology
WHO I-II subtype	1			1			1			1
WHO III subtype	1.130	0.430-2.972	0.805	0.694	0.356-1.353	0.284	0.915	0.532-1.573	0.748	1.184	0.615-2.279	0.614
Clinical stage
T1-3N3	1			1			1			1
T4N0-2	0.865	0.410-1.825	0.704	0.751	0.428-1.317	0.318	1.150	0.754-1.753	0.516	1.621	0.974-2.699	0.063
T4N3	1.752	0.569-5.395	0.328	2.342	1.197-4.583	0.013	2.731	1.578-4.726	< 0.001	3.858	2.005-7.421	< 0.001
EBV-DNA status (IU/mL)
≤ 566	1			1			1			1
> 566	1.822	0.640-5.191	0.261	2.866	1.365-6.016	0.005	3.148	1.776-5.578	< 0.001	2.436	1.256-4.723	0.008
Unknown	3.750	1.373-10.241	0.010	2.245	1.014-4.969	0.046	2.311	1.271-4.202	0.006	1.873	0.944-3.717	0.073
Induction chemotherapy
No	1			1			1			1
Yes	0.938	0.314-2.800	0.908	0.733	0.329-1.633	0.447	0.581	0.327-1.033	0.064	0.447	0.242-0.825	0.010
Concurrent chemoradiotherapy
No	1			1			1			1
Yes	0.469	0.213-1.034	0.060	0.548	0.311-0.967	0.038	0.437	0.277-0.688	< 0.001	0.315	0.192-0.517	< 0.001

Table 1. Patient baseline characteristics

EBV, Epstein-Barr virus; N, node; T, tumor; WHO, World Health Organization.

Table 2. Multivariable Cox regression analyses to assess the independent impacts of T4 and N3 on survival outcomes

Table 3. Multivariable Cox regression analyses to assess the independent impacts of clinical stage on survival outcomes