Our study incorporated a total of 178 patients diagnosed with ENI, comprising 152 node-negative and 26 node-positive patients. 3 patients with incomplete baselines were excluded. Among the node-negative patients, 96 received ENI while 53 did not. The comprehensive baseline clinicopathological characteristics are delineated in Table 1. Notably, in a real-world context, patients with T1-2 and Kadish A-B stages were less likely to receive ENI compared to those with T3-4 and Kadish C stages (p < 0.001; p < 0.001). Additionally, factors such as orbital invasion status (p = 0.002), surgical procedure (p < 0.001), and radiotherapy technique (p < 0.001) exhibited selection bias due to the retrospective nature of the study. Following a 1:1 PSM with Kadish stage, T stage, orbital invasion status, surgical procedure, and radiotherapy technique, two matched cohorts were established with balanced baseline demographics and disease characteristics (ENI group, n = 43 and non-ENI group n = 43, Table 1).

During a median follow-up period of 51.9 months (range, 1.6-165.7 months, 95% CI 44.2–59.7), the median OS, PFS, LRFS, and DMFS were 103.9 (95% CI 82.3-125.6), 79.1 (95% CI 58.9–99.2), 81.5 (95% CI 58.3-104.7), and 103.9 (95% CI 83.1-124.8) respectively in the N0 population.

Before PSM, patients treated with ENI had numerically longer PFS and LRFS, but the difference did not reach statistical significance using the log-rank test (Fig. 1A-D). After PSM, the OS (p = 0.021), PFS (p < 0.001), LRFS (p < 0.001) and DMFS (p = 0.026)were significantly longer in the ENI subgroup than in the non-ENI subgroup according to the log-rank test. (Fig. 2A-D, Table S1). Furthermore, ENI was retained as an independent factor of improved PFS and LRFS after multivariate Cox analyses (Table S2).

This figure presents survival outcomes stratified by ENI before PSM. It includes OS, PFS, LRFS, and DMFS

This figure shows survival outcomes stratified by ENI after PSM. It includes OS, PFS, LRFS, and DMFS

In the entire N0 population (n = 152), 50 patients were classified as T1-2, 99 as T3-T4, with 3 patients’ stages being unclear which were excluded. ENI was administered to 96 patients, including 19 (19.8%) in T1-2, 77(80.2%) in T3-4 (Table 1). Compared to T3 and T4, a lower proportion of patients with T1-2 received ENI.

To assess the value of ENI in early-stage patients, PSM was performed. In the real-world setting, surgical modalities (p = 0.009) and radiotherapy techniques (p = 0.001) exhibited selection bias due to the retrospective nature of the study (Table S3). After 1:1 PSM with surgical modalities and radiotherapy technique, two matched cohorts were created with balanced baseline demographics and disease characteristics (ENI group, n = 13 and non-ENI group n = 13).

Before PSM, the PFS and LRFS were numerically longer in the ENI positive subgroup, but the difference did not reach statistical significance (PFS, p = 0.647; LRFS, p = 0.427; Fig. 3). There was also no statistically significant difference in OS and DMFS. The results remained unchanged after PSM. Patients who received ENI did not have longer OS (p = 0.876), PFS (p = 0.599), LRFS (p = 0.204), or DMFS (p = 0.691) (Fig. 4). According to the limited cohort, performing ENI in T1-2 patients did not improve clinical survival.

This figure depicts survival outcomes stratified by ENI before PSM in the T1-2 subgroup. It includes OS, PFS, LRFS, and DMFS

This figure presents survival outcomes stratified by ENI after PSM in the T1-2 subgroup. It includes OS, PFS, LRFS, and DMFS

In the entire N0 cohort, 97 patients received ENI, and 53 did not. All patients underwent.

MRI or high-resolution and contrast-enhanced CT scans at our institution, facilitating independent evaluation of natural patterns of treatment failure. By the time of data cut-off, disease progression was documented in 47 patients (ENI subgroup, n = 22; non-ENI subgroup, n = 25). Among these 47 patients, 18 experienced regional cervical lymph node PD, 18 experienced original site PD, and 11 experienced distant metastasis.

In the non-ENI subgroup, 12 (48%) patients experienced regional cervical lymph node PD, 10 (40%) patients experienced original site PD, and 3 (12%) patient experienced distant metastasis. In the ENI subgroup, 6 (27%) patients experienced regional cervical lymph node PD, 8 (36.5%) patients experienced original site PD, and 8 (36.5%) patients experienced distant metastasis (Fig. 5A-B). Of the 53 patients of non-ENI subgroup, 12 patients (22.6%) developed nodal failure, compared with 6 of 96 (6.2%) patients who received ENI by the chi-square test (p < 0.001, Table S4).

To investigate the target volume area, we segmented the irradiation area into several subgroups: levels II, IB, III, V included and excepted, respectively. Notably, all patients.

who received ENI included level VIIa. Treatment failure was defined as the total combination of three PD patterns. The group excluding levels II and Ib suffered a high risk of treatment failure (II, p = 0.002; Ib, p = 0.043, Fig. 5C-D). Patients receiving level III included irradiation had a trend of lower treatment failure risk but did not reach statistical significance (p = 0.107, Fig. 5E). However, including level V in irradiation had no effect on improving the risk of treatment failure (p = 0.642, Fig. 5F).

This figure illustrates the pattern of treatment failure. Figure 5 A shows the pattern of PD in patients without ENI. Figure 5B shows the pattern of PD in patients with ENI. Figure 5 C to 5 F are bar charts of treatment failure in patients with ENI included at different levels (II, Ib, III, V). PD refers to progressive disease, and LN refers to lymph node metastasis

We further analyzed the dose of ENI. According to our institute’s data, the dose of level VIIa ranged from 55 Gy to 70 Gy, and the dose of levels Ib, II, and III ranged from 50 Gy to 65 Gy. Fourteen patients received ENI containing only VIIa in the target volume, while 82 patients received ENI containing levels Ib, II, and III. When setting 55 Gy as the cut-off dose, irradiation higher or lower than VIIa showed no statistical significance in affecting the treatment failure risk (p = 0.968, Fig. S1 A). However, an irradiation dose higher than 55 Gy at levels Ib, II, and III showed a lower risk of treatment failure (p = 0.03, Fig. S1 B). The dose of ENI need further comformation by prospective study.

In conclusion, ENI decreased the percentage of cervical lymph node disease progression. Including levels VIIa, II, and Ib in ENI may decrease the risk of PFS and LRFS. Therefore, ENI may provide potential clinical benefits in locally advanced N0 patients.

The postoperative radiotherapy subgroup was analysed separately as the vast majority of cohorts. Following 1:1 PSM in the postoperative subgroup, two matched cohorts were established with balanced baseline demographics and disease characteristics (ENI group, n = 32 and non-ENI group n = 32. Table S6). Before PSM, patients treated with ENI had numerically longer PFS and LRFS, but the difference did not reach statistical significance using the log-rank test (Fig. S2 A-D). After PSM, the PFS (p < 0.001) and LRFS (p = 0.0001) were significantly longer in the ENI subgroup than in the non-ENI subgroup according to the log-rank test (Fig. S2 E-H).