Introduction
The 5-year overall survival of nasopharyngeal carcinoma (NPC) has achieved 84% of non-metastatic cases with the use of intensity-modulated radiation therapy (IMRT) and optimal chemotherapy [
1‐
4]. Since the survival is prolonged, the late toxicities merit more attention. The most frequently observed late complication was xerostomia. 39.3–40.1% [
4‐
6] of patients reported xerostomia at more than 1 year post-radiation. Sparing of saliva glands is crucial to reduce xerostomia. IMRT is superior to conventional two-dimensional radiotherapy in preserving parotid function and results in less severe delayed xerostomia [
6]. Parotid-sparing IMRT for NPC preserved half of parotid excretion compared with baseline [
7]. However, sparing of parotid alone has increased salivary flow rate [
8], but inconsistently translated to improvement of patient-reported xerostomia [
6,
8‐
10].
Parotids produce most saliva under stimulation, while the submandibular glands (SMG) contribute to the majority of unstimulated saliva [
11]. SMG, together with minor salivary glands in the oral cavity, produce mucins that maintain subjective perception of hydration [
10]. It is reported that SMG salivary flow rate depends on mean dose and recovers over time up to a threshold of 39Gy [
12]. Restriction of mean dose of SMG less than 39Gy helps to improve observer–reported and patient-reported xerostomia [
9,
12,
13].
However, the SMG is often included in the target volume of NPC when level IB receives radiation. According to the protocol of RTOG 0225, clinical target volume (CTV) encompassed unilateral level I to level V. The routine of Prince of Wales Hospital in Hong Kong is to electively irradiate level IB to V with a total dose of 54-60 Gy for node-negative cases [
14]. However, a number of institutions in mainland of China [
4,
11,
15] do not recommend routinely including level IB in the irradiation volume. Currently, there is no consensus of criteria on elective irradiation of level IB. Zhang et al. [
11] has recently demonstrated that level IB-sparing IMRT should be feasible for patients without high risk factors for level IB metastasis. However, in this study, only a few factors were included in the analysis, such as T, N, level IIA and retropharyngeal metastasis, et al. More clinical characteristics should be incorporated in to the analysis for level IB metastasis, especially the details of involvement of various neck nodal levels. Hence, we performed this retrospective study, based on the elaborate analysis using the new delineation guidelines of nodal level involvement of Radiation Oncology Therapy Group (RTOG) [
16]. The aim of this study is to investigate the high-risk factors for metastasis of level IB and evaluate the feasibility of omission of elective irradiation to level IB in the subgroups without any of the high-risk factors. The objective of this study is to define the criteria of level IB-sparing radiation, in order to protect the function of submandibular glands and minimize late toxicities.
Discussion
Lymph node metastasis in NPC follows an orderly pattern along deep cervical lymph nodes. The most commonly involved regions include level II (70–87.4%) and retropharyngeal lymph nodes (69–75.1%), followed by level III, level IV and level V [
21,
22]. The probability of “skip” metastasis is quite low (varies between 0.5–7.9%) [
21]. The incidence of level IB metastasis in NPC is very low, varies from 2.2% to 4.3% [
18,
20‐
22] (the rate of our study was 2.4%). Level IB nodes receive efferent lymphatic from the level IA, the lower nasal cavity, the hard and soft palate, the maxillary and mandibular alveolar ridges, the cheek, the upper and lower lips, and most of the anterior tongue [
16]. Level IB nodes do not receive direct drainage from nasopharynx. Hence, it is reasonable not to include level IB in the CTV of all patients with NPC.
In recent study including 3100 cases of NPC [
22], all patients with level IB node involvement were simultaneously accompanied with level II lymphadenopathy. It is reasonable to assume that the enlargement of level II nodes blocks the routine pathway and causes reflux to level IB. Several studies [
11,
23] further proved this hypothesis. Yuan et al. [
23] reported that the diameter of level II was the only significant factor associated with level IB lymphadenopathy in multivariate analysis in NPC. Zhang et al. [
11] demonstrated that the diameter of level IIA > 20 mm or extracapsular spread of level IIA was an independent predictive factor for level IB metastasis. In consistence with previous study, our research indicated that the diameter of level IIA > 20 mm or extracapsular spread of level IIA was significantly associated with level IB lymphadenopathy. The extracapsular spread causes involvement of carotid sheath, which was proven to correlate with level IB metastasis in another study by Yi et al. [
24]. Taken together, the remarkable enlargement and spread of level IIA may result in blockage of routine drainage pathway, which causes reflux to its afferent lymph node-level IB. Bilateral involvement of cervical nodes were proven to be independent factor both in the present study and the report by Zhang et al. [
11] as well. Given the possibilities of bilateral lymphatic drainage when nasopharynx tumor crossed the midline, bilaterally lymphadenopathy further added to burden of level II, therefore, increased the possibility of reflux to level IB.
The correlation between oropharyngeal involvement and level IB lymphadenopathy was inconsistently reported. Oropharyngeal involvement was not an independent predictive factor in the study of Yi [
24] and Yuan [
24] et al., but was significant in the report by Zhang [
11] et al. Wang [
22] et al. reported that about one third of cases with level IB involvement accompanied with oropharyngeal infiltration. In the present study, oropharynx invasion was not significantly associated with level IB metastasis. It is probably due to the limited number of cases with oropharyngeal involvement and the underpowered test. The correlation between oropharyngeal involvement and level IB lymphadenopathy warrants further investigation. In addition, the nasal cavity involvement was not an independent predictive factor for level IB metastasis in the present study, which was similarly observed in previous studies [
11,
23,
24]. It is generally accepted that level IB receives lymphatic drainage of the anterior one third of nasal cavity [
24,
25]. However, tumor generally involves posterior one third of nasal cavity in NPC.
Furthermore, our study incorporated elaborate analysis of various neck nodal involvements into the risk-analysis of level IB metastasis, using the updated delineation guidelines of neck nodal levels [
16], which was not reported in previous analyses [
11,
23]. Our study revealed that level IIA accompanying with multiple adjacent levels involvement was associated with level IB metastasis in univariate analysis, but did not reach statistically significant level in multivariate analysis. Similarly, in another investigation [
23], four or more lymphatic drainage regions involved reached a marginal level (
p = 0.05) in univariate analysis, but was not at statistically significant level in multivariate analysis. In addition, Yi et al. [
24] demonstrated that level II/III/IV involvement was independent risk factor of level IIA metastasis in a cohort of patients treated with three-dimensional conformal radiotherapy. Given that multiple adjacent nodal levels involvement may block the level IIA efferent lymphatic drainage, it is reasonable to postulate that this may cause increased risk of reflux to level IB. Further investigation with a larger sample size is requested to confirm this postulation. Hence, we recommend taking this factor into consideration when evaluating the metastatic risk of level IB.
Given the low incidence of metastasis of level IB in NPC, it is reasonable not to include level IB in the CTV in the low-risk subgroup of level IB metastasis. A few studies have evaluated the feasibility of omitting irradiation to level IB in NPC. Chen et al. [
26] retrospectively investigated a cohort of 120 patients treated with level IB-spared IMRT. During 54 months of follow-up, four patients had regional recurrence and none located in level IB. However, the details of cervical nodal involvement were not mentioned in this study. Zhang et al. [
11] investigated a cohort of 1438 patients treated with IMRT and demonstrated the high-risk factors for level IB lymphadenopathy included the diameter of level IIA nodes ≥20 mm and/or level IIA nodes with extracapsular spread, positive bilateral nodes or oropharynx involvement at diagnosis. Patients without these risk factors were defined low-risk and none of them (0/904) experienced regional recurrence at level IB. Level IB irradiation was not an independent prognostic factor for locoregional control, distant metastasis and overall survival in low-risk subgroup. Similarly, Yi et al. [
24] developed a risk scoring models to predict level IB metastasis and divided patients into low-risk and high-risk subgroups. The model included factors such as the carotid sheath involvement, maximal diameter of the neck lymph node (≥ 20 mm) and involvement of level II/III/IV lymph nodes. In the low-risk group, level IB irradiation had no significant influence on overall survival, locoregional control and distant metastasis. Of note, patients in the prognostic study received three-dimensional conformal radiotherapy [
24].
In consistence with previous studies, our research defined the low-risk group as those without any of the following criteria: the diameter of level IIA nodes > 20 mm and/or level IIA nodes with extracapsular spread, positive bilateral cervical lymph nodes. In the low-risk subgroup without level IB irradiation, only one patient experienced regional recurrence at level IB. The percentage of level IB recurrence of those treated with level IB-sparing IMRT was only 0.46% (1/216). Level IB irradiation has no significant impact on regional control, distant metastasis and overall survival in the low-risk patients.
Interestingly, of the high-risk subgroup, those with elective irradiation of level IB tended to have a poorer regional control. Further analysis revealed that those with elective irradiation of level IB had a higher percentage of nodal necrosis and extracapsular spread, as well as greater maximal diameter of cervical nodes (data not shown, 43.06+/− 16.76 vs. 38.58 +/− 17.07 mm,
p = 0.049). Nodal necrosis [
27] and maximal diameter [
28,
29] were proven to be prognostic factor for regional relapse, thus partially explaining the intriguing results. In addition, level IB was electively included in the CTV by the attending physician’s decision, based on clinical and imaging characteristics. Therefore, patients with more adverse prognostic factors, tended to be treated with level IB irradiation.
In the present study, elective omission of level IB irradiation significantly reduced the mean dose of ipsilateral SMG, however, did not transfer to improvement of patient-reported xerostomia. One explanation is that there was no mandatory restriction of SMG dose during inverse planning in our institution at that time. According to a dose-effect study, the incidence of grade IV xerostomia dramatically increases once the mean dose of SMG exceeds a threshold of 39Gy. The saliva secretion of SMG could recover over time if the mean dose of SMG is below 39Gy [
12]. Once the mean dose of SMG exceeds 50Gy, the probability of grade IV toxicity is above 80% [
12]. In our study, more than 78% of patients received more than 50Gy to SMG even if the ipsilateral level IB was not included in the radiation volume. Thus, despite elective omission radiation of level IB, the improvement of patient-reported xerostomia was mild. Another reason is that several factors have influence on xerostomia, such as bilateral involvement of level II, oropharyngeal infiltration of bulky tumor, mean dose of parotid, mean dose of oral cavity where minor salivary glands disperse. Gensheimer et al. [
9] has shown that with careful dose constraint of parotid (mean dose < 24 Gy) and contralateral SMG (mean dose < 39 Gy), the contralateral SMG-sparing technique caused a notable and durable improvement of xerostomia. A future validation study that restrains the dose of parotid and spares SMG is warranted to confirm the benefit of elective omission of level IB in NPC.
A limitation of our study was the retrospective design. The incidence of level IB metastasis at diagnosis was relatively low. However, multivariate analysis indicated the significant risk factors for level IB involvement, which were well consistent with previous studies. Another limitation was no routine dose constraint for spared SMG in our institution at that time, which hampered the translation into the improvement of patient-subjective xerostomia.