INN as a severe complication can present during or after radiotherapy on NPC patients. However, little is known about the outcomes for its extremely low incidence in the IMRT era. The clinical characteristics and prognosis of INN are different from those in the 2D era. In this study, most cases had pseudomembrane during or at the end of radiotherapy. Moreover, the severity of INN was lessened than previous studies, which seemed to have little effect on patients’ survival under the treatment of anti-inflammation, nasal flushing and nutritional support. Our data also determined that combined with chemotherapy or target treatment was not associated with developing INN after initial radiation. In contrast, the accumulative radiation dose was the only independent risk factor.
The crude incidence rate of INN was 1-2.9% among the NPC population11,12,14, and 3.3% in patients treated with IMRT while 2.3% with 2D radiotherapy11. Compared to 2D radiation therapy, IMRT enables target volumes to receive higher doses, which may increase the incidence of INN. Notably, these studies enrolled patients with local recurrence receiving re-irradiation, which contributed to INN occurrence. As reported, 15.2%-31.5% of locally recurrent patients would experience INN following re-irradiation with IMRT13,24,25. Instead, INN is rare for the primary NPC; only 1.9% of patients treated at our center developed INN after first irradiation. Several literatures tried to explain the mechanism of INN. A theoretical deduction accepted wildly is that chronic repair cannot compensate for tissue breakdown. Infection, hypoxia, hypervascularity, and nutritional deficiency are reported as essential roles in the process of INN7,11. Our study showed that most patients (38/53, 71.7%) had pseudomembrane at the middle or the end of radiotherapy. It can provide conditions easy to infection, which impairs the normal nasopharynx mucosa, increases hypoxia status and aggravates the damage. Therefore, pseudomembrane may predict the occurrence of INN.
As previously reported, most INN patients would suffer different degrees of symptoms like headache, foul odor and recurrent bleeding9. Our data showed that patients mainly manifested mild headaches and foul odor, few of whom needed powerful pain relievers. To analyze the severity, INN was ranked into three stages according to MRI characteristics. Previous studies indicated that significant patients suffered INN in the middle or severe stage. Deep parapharyngeal ulcer could invade the internal carotid artery, which may cause fatal bleeding and death. 26.9%-45% of patients with INN got the internal carotid artery involved, resulting in severe adverse event7,15. In the devastating late complications, the incidence rate of osteoradionecrosis was even up to 10.1%16. Moreover, internal carotid artery exposure and osteoradionecrosis have been identified as prognostic factors impacting the quality of life and endangering life. However, INN also showed less severity in our study than in previous trials. No one developed osteoradionecrosis, and 62.2% of patients were in the early stage, which only calls for conservative or medical treatment. The main reason may be that published reports enrolled many cases receiving re-irradiation at the primary site. Of these patients, 44% had grade≥3 INN17. In patients with middle-stage INN, four had sudden massive bleeding, and one died from a blood vessel burst. Traditional repeated endoscopic debridement is generally applied for patients with carotid artery exposure and rupture, but only 13.4–28.6% of patients can be cured18. Even novel surgical management achieved limited clinical efficacy9,18,19. However, our study revealed that INN was not an independent prognostic factor for OS and PFS, which indicated that INN had limited influence on patients’ survival after the primary IMRT. It may be due to the low severity levels of INN and better treatment approaches nowadays.
Intensive treatment strategies, such as combining neoadjuvant, adjuvant chemotherapy or molecular targeted therapy with concurrent chemoradiation, may increase the local tissue damage, which aggravates irradiation-induced injuries and hinders the healing of the ulcer. At worse, the survival benefit of these strategies is uncertain for locally advanced NPC20,21,22. Therefore, we aimed to investigate whether the intensive treatment strategies would increase the risk of INN occurrence. A propensity-score matching methodology was used to balance other potential risk factors, such as T stage, gender, age, pathological type, biomarkers of nutritional status (hemoglobin, albumin, body mass index), and inflammation status (C-reactive protein, necrosis before re-irradiation), which were reported by published researches11,12,13,17. As a result, our study noted that adding chemotherapy or targeted therapy did not increase the risk of developing INN, as in line with other studies11,23. However, the response to neoadjuvant chemotherapy may be a predictor. Yan et al. showed that patients with stable disease response to neoadjuvant chemotherapy were more prone to suffer INN than those with partial response23. The poor response revealed the blood and oxygen supply deficiency in primary tumor tissue, less radiosensitivity, and lower recovery capability.
Furthermore, the accumulated prescription dose to the GTV plays a vital role in the INN occurrence. Hua et al. observed that a total dose over 120 Gy of 2 courses of radiation was significantly associated with INN. Similarly, Yu et al. reported that a third of patients with INN received an accumulated dose over 141.5 Gy13. However, a lower rate of INN occurs in patients with initial radiation, and whether the radiation dose is a risk factor needs to be determined. Li et al. indicated that the D3cc was an independent predictor for INN in primary NPC patients, which should be limited under 73.67 Gy26. On the contrary, Fei et al. reported that dose-volume (tumor volume and ratio of tumor volume exposed to 74 Gy to GTV) did not affect the incidence of INN, neither did boost doses, which seems incompatible with clinical experience12. Given the small sample (only nine patients developed INN in this study), the result should be hardly definitive. In our series, both univariate and multivariate analysis showed that boost dose was related to INN occurrence, following other studies. However, the optimal cut-off point of accumulated dose could not be identified by ROC analysis for the poor prediction efficiency (AUC=0.521). Due to the occurrence of INN, it was associated with many other factors, only one achieving insufficient prognostic capacity.
This study also has some limitations. Firstly, we enrolled a small sample of patients due to the low incidence of INN. Small group population will reduce prediction capability, and further studies should confirm the forecasting performance. Then the follow-up was irregular which contributed to the insufficient clinical information of some patients. The various indicators of nutrition and infection status, including the dynamic change, could make the analysis more complicated. It is hard to contain all the potential risk factors. What is more, as a single-center retrospective study, selection bias cannot be avoided.