Survival among subgroups of patients with stage II nasopharyngeal carcinoma

To assess survival between subgroups (T1N1, T2N0, and T2N1) of patients with stage II nasopharyngeal carcinoma (NPC). This retrospective cohort study evaluated pathologically confirmed stage II NPC patients from The Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2016. The included patients were divided into three subgroups: T1N1, T2N0, and T2N1. Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method among the three subgroups. This study investigated 836 patients: 383 (45.8%) patients were in the T1N1 subgroup, 175 (20.9%) patients were in the T2N0 subgroup, and 278 (33.3%) patients were in the T2N1 subgroup. The 5-year OS (75.7%, 68.6%, and 75.7%) and CSS (85.3%, 83.4%, and 84.5%) were similar among the T1N1, T2N0, and T2N1 subgroups. Univariate and multivariate regression analyses revealed that the subgroup (T1N1, T2N0, and T2N1) of stage II NPC was not an independent prognostic factor for OS or CSS. Survival was comparable among subgroups (T1N1, T2N0, and T2N1) of stage II NPC patients. However, patients with T1N1, T2N0, and T2N1 stage disease who receive different treatments might have different prognoses.

www.nature.com/scientificreports/ Endpoints. Overall survival (OS) was the primary endpoint. OS was defined as the time from diagnosis to death as a result of any cause. Cancer-specific survival (CSS) was the secondary endpoint. CSS was defined as the time from diagnosis to death attributed to NPC.
Statistical analysis. Continuous characteristics of age were compared using Student's t test. Categorical variables of sex, race, WHO classification, and chemotherapy were analyzed by using the χ 2 test or Fisher's exact test.
The 5-year OS and CSS rates of the T1N1, T2N0, and T2N1 subgroups were calculated using Kaplan-Meier analysis. Differences between survival curves were compared using the log-rank test. Univariate regression analysis was performed to identify prognostic factors. Multivariable proportional hazards models adjusted for age, sex, race, WHO classification, and chemotherapy were performed to assess independent prognostic factors. The results are reported as hazard ratios (HRs) with 95% confidence intervals (CIs).
All statistical analyses were performed using SPSS Statistics Version 26.0 software (IBM Co., Armonk, NY, USA) and R software version 4.0.3 (http:// www.R-proje ct. org). P values were two-tailed. Values of P < 0.05 were considered statistically significant.

Results
Patient characteristics. The patient selection flowchart is shown in Fig. 1 Survival analysis of the T1N1, T2N0, and T2N1 subgroups. The 5-year OS rates were 75.7%, 68.6%, and 75.7% for the T1N1, T2N0, and T2N1 subgroups, respectively ( Fig. 2A). The 5-year OS of the three groups was not different in pairwise comparisons. The 5-year CSS rates were 85.3%, 83.4%, and 84.5% for the T1N1, T2N0, and T2N1 subgroups, respectively (Fig. 2B). The 5-year CSS of the three groups was not different.
Univariate regression analysis revealed that age, race, WHO classification, and chemotherapy were prognostic factors for OS. On the other hand, age and WHO classification were prognostic factors for CSS. However, the subgroup (T1N1, T2N0, and T2N1) was not a prognostic factor for OS and CSS (Table 2).

Discussion
It has been reported that the survival outcomes differ among patients with T1N1, T2N0, and T2N1 stage II NPC. Several studies have suggested that the T2N1 subgroup might be a unique subgroup with worse survival outcomes 4,13-15 . The worse survival outcomes in the T2N1 subgroup might be due to the following: First, parapharyngeal extension increased the risk of distant metastasis in stage II NPC patients [16][17][18] . The 5-year distant  www.nature.com/scientificreports/ metastasis-free survival with parapharyngeal extension was 12.6% lower than that in patients without parapharyngeal extension (73.6% vs. 86.2%) 18 . Moreover, the 5-year distant metastasis-free survival of stage T1 was significantly higher than that of stage T2 for patients with stage N1 19 . Second, several studies suggested that stage N1 was an independent prognostic risk factor 14,20-22 . In contrast, several studies have suggested that survival is similar among subgroups of stage II NPC [8][9][10][11] . Similarly, our study also revealed that the survival curves were comparable among the T1N1, T2N0, and T2N1 subgroups for OS and CSS. However, the T2N1 subgroup was more likely to receive chemotherapy (95.0%) in our study. This raised the question of whether chemotherapy increased the survival rate of the T2N1 subgroup. Survival analysis showed that chemotherapy improved 5-year OS (77.5% vs. 40.8%, P < 0.01) and CSS (85.8% vs. 62.3%, P < 0.01) in the T2N1 subgroup. Although there was an improvement in survival resulting from chemotherapy in the T2N1 subgroup, there were no survival differences among the T1N1, T2N0, and T2N1 subgroups.
However, some studies have reported that chemotherapy did not improve the survival of the T2N1 subgroup. A previous study indicated that radiotherapy alone provided comparable 5-year OS (77.19% vs. 68.28%; P = 0.06) in the T2N1 subgroup compared with chemoradiotherapy 23 . Moreover, other studies also found that chemoradiotherapy did not improve OS compared to radiotherapy alone in the T2N1 subgroup 9,11,15 . The differences among these studies might be due to the small sample size of the radiotherapy-alone subgroup. Similarly, the sample size  www.nature.com/scientificreports/ of patients who received radiotherapy alone was extremely small (10.8%) in our study, so it might not be sufficient for the statistical analysis. Although the results indicated that the 5-year OS and CSS were worse in the T2N1 subgroup than in the T2N0 subgroup, the result should be verified in another cohort with a large sample size.
The results of our study should be interpreted with caution. Tumors that invaded the medial pterygoid muscle and the lateral pterygoid muscle without other T3/T4 involvement were downstaged from stage T4 to T2 according to the 8th edition AJCC staging system 24,25 . It is possible that survival among subgroups of stage II NPC patients might be different according to the 8th edition AJCC staging system. Due to the limitations of the SEER database, data on medial pterygoid muscle/lateral pterygoid muscle involvement could not be extracted. Our retrospective study could not assess survival among subgroups of stage II NPC according to the 8th edition AJCC staging system. Further studies are needed to verify the results of our study based on the 8th edition AJCC staging system.
The limitations of this study should be noted. First, data on radiotherapy techniques could not be extracted given the limitations of the SEER database. It was reported that intensity-modulated radiation therapy was superior to two-dimensional conventional radiotherapy 26,27 . However, other studies have found no difference in OS between intensity-modulated radiation therapy and two-dimensional conventional radiotherapy [28][29][30] . Thus, the different radiotherapy techniques used in this study might not have impacted the results. Second, Epstein-Barr virus (EBV) DNA is reported to be a prognostic factor for NPC [31][32][33][34] . Chen et al. 35 reported that EBV DNA could improve the prognostic stratification of stage II NPC. However, EBV DNA data were not available due to the limitations of the SEER database in our study. Thus, our study could not assess the prognostic value of EBV DNA in stage II NPC. Third, we could not extract data on chemotherapy regimens and drugs. Thus, our study did not assess the impact of chemotherapy regimens on survival due to the lack of chemotherapy information.
In conclusion, the results of this retrospective cohort study suggested that survival among subgroups (T1N1, T2N0, and T2N1) of patients with stage II NPC was comparable based on the SEER database. However, subgroup analysis indicated that patients with T1N1, T2N0, and T2N1 stages receiving different treatments might have different prognoses. Further studies with large sample sizes are needed to identify prognostic risk factors for stage II NPC.