In this study, we treated patients with locally advanced MSC using external beam irradiation combined with superselective IA chemotherapy, and the 5-year LC and OS were 67% and 50%, respectively. Our results were similar to those of other studies [5, 6]. The combination of IA chemotherapy and external radiation therapy or proton therapy can improve LC and OS [7, 13]. Homma et al. reported good results for 5-year LC (66%) and 5-year OS for stage cT4a (67%) and cT4b (57%) after external radiotherapy and IA chemotherapy . Zenda et al. reported a 1-year LC of 77% and 3- and 5-year OS rates of 59% and 55%, respectively, for unresectable paranasal sinus and nasal cavity cancers after proton therapy . ENI was not conducted in these studies, including ours, for cN0 cases.
Two of seventeen patients with cN+ who received ENI in this study developed regional node failure. This incidence was similar to that of patients with cN0, who did not receive ENI. In addition, the 5-year DMFS and 5-year OS rates in both groups were similar (Table 3). However, there were more patients with high-grade late AEs in the cN+ and ENI group than in the cN0 and non-ENI group (41% vs. 13%, respectively; p = 0.03). Feng et al. reported grade 3 dysphagia in 8% of cases and aspiration on videofluoroscopy in 44% of cases 3 months after irradiation with a high radiation dose (mean, 64 Gy) to the pharyngeal constrictor muscle . If ENI is performed for all patients with T3 and T4 disease, the incidence of late high-grade AEs may increase with prolonged survival . Therefore, it is necessary to select appropriate candidates for ENI to maximize the clinical benefit in locally advanced MSC.
We divided tumor invasion into six directions, and found that only posterior (to the pterygoid plates) and caudal (to the oral cavity) extension correlated significantly with regional failure. Jeon et al. divided extra-maxillary sinus involvement of the tumor into four directions, and reported that destruction of the posterior wall was a significant risk factor for regional failure in cN0 MSC . We attempted to analyze the relationship between the incidence of regional recurrence and the direction of the tumor invasion according to the classification by Jeon et al.. We identified 33 patients with destruction of the posterior wall; however, this was not a significant predictive factor (P = 0.3). The categories of destructions of the posterior wall in the study by Jeon et al. included a wide range of extensions (infratemporal fossa involvement), as well as T3 and T4 tumors in the UICC classification . Therefore, we divided the classification of the posterior wall destruction by Jeon et al. into two categories: lateral extension (to the masticator space) and posterior extension (to the pterygoid plates) to identify more appropriate risk factors for regional failure. Extension to the pterygoid plates falls into the T4a category in the UICC classification . Other studies reported that ENI for cN0 cases is necessary only if the tumor extends to a contiguous area, such as the nasopharynx or oral cavity, where lymphatic flow is rich [9, 10]. In the studies, regional failure occurred in only T4b cases of nasopharyngeal invasion, and only two cases showed nasopharyngeal extension in our series. All nasopharyngeal invasions were included in the classification of posterior extension, in our study, because tumors reach this region via the pterygoid plates. In this study, the incidences of posterior wall destruction, invasion of the pterygoid plates, and nasopharyngeal invasion were 87%, 53%, and 5% in 33, 20, and 2 of 38 cN0 cases, respectively. Additionally, our patients had advanced MSC (91% of patients were cT4), and most had destruction of the posterior wall. Therefore, invasion of the pterygoid plates and oral cavity were considered more appropriate risk factors for regional recurrence. We were able to identify patients with a higher risk of regional recurrence more precisely using our new categorization of tumor extension. Regional failure affects distant metastases and OS [4, 11, 16, 17]. We did not perform ENI for cN0 patients, so its usefulness is still unknown. However, according to our analysis of the risk factors for regional recurrence and OS in cN0 cases (Table 3), these patients were considered good candidates for ENI.
To confirm our results, we also examined the risk factors for LN metastases present at diagnosis in the cN+ group. Invasion of the pterygoid plates was the only factor correlated with LN metastases, which supported the results in the cN0 cases. In a multi-center retrospective study by Homma et al., the incidence of LN metastases was significantly higher in cases of nasopharyngeal or oral invasion at presentation among 128 cases of T4 MSC . In all cases of nasopharyngeal invasion, invasion of the pterygoid plates was also observed, which is consistent with our results. Other factors, such as T-stage, PS, or age, showed no association with regional failure.
Regional failure occurred mainly at levels I and II in this study, as reported previously . However, recurrence was also observed in level III in both cN0 and cN+ cases. This may be because of differences between IA chemotherapy and systemic chemotherapy. IA chemotherapy is effective only in the arterial perfusion territory; therefore, this method cannot eradicate tumor cells located in the regions far from the primary tumor. Although contralateral neck irradiation for ENI is recommended in the guidelines , this approach is controversial. In our study, we encountered very few contralateral regional failures with or without ENI, despite the finding that the majority of these cases were advanced, with extension into midline structures, namely the oral cavity, nasopharynx, and nasal cavity. These results may obviate the need for contralateral neck irradiation for ENI.
The median irradiation dose to the primary site and LN metastases in our study was 60 Gy, which is lower than the general definitive irradiation dose reported in other studies [3, 5, 6]. The American College of Radiology (ACR) guidelines recommend a definitive irradiation dose of at least 66 Gy . The irradiation dose was reported as 65 Gy in 26 fractions or 70 Gy in 35 fractions in previous studies, even in external beam radiotherapy and IA chemotherapy [5, 6]. We previously reported the treatment results of the combination of superselective IA chemotherapy and radiation therapy, and the total dose of 60 Gy was effective and safe in that setting. Therefore, we treated the patients in this report using the same radiation dose . Previous studies reported high frequencies of the high-grade late adverse event of optic neuropathy (35%) when combining irradiation therapy with IA chemotherapy. Compared with these results, the frequency in our study was relatively low (2/55), and this may be due to the lower radiation dose. Further evidence of the usefulness and optimal procedure for IA chemotherapy will be obtained by an ongoing Phase III clinical trial (University Hospital Medical Information Network (UMIN) Clinical Trials Registry number: UMIN000013706).
The current study has several limitations associated with its retrospective design. First, the diagnostic imaging modalities performed before and after treatment were not standardized. The role of MRI and PET-CT is very important for head and neck tumors . In the early phase of this study, treatment was sometimes started without evaluation by MRI (24/55) or PET-CT (42/55) because of the limited availability of these imaging modalities. Second, external beam radiotherapy was provided using mainly 3DCRT (44/55). Our results, which showed that severe late AEs increased in the ENI group, may have been influenced by the external irradiation technique . Some researchers have reported that IMRT may decrease the number of these AEs . The number of IMRT cases was small in this study, and the relationship between ENI and severe late AEs is unclear. Third, when regional failure was suspected, pathological examination was not performed in all cases; 3/9 cases were diagnosed according to imaging findings. Finally, differences between IA and intravenous chemotherapy might have affected regional control.
In conclusion, ENI for advanced MSC increased the incidence of severe late toxicities. Invasion of the pterygoid plates and oral cavity were high-risk factors for regional failure in cN0 cases, and these patients may be suitable candidates for ENI.