In the present study, for patients with NPC who were treated with radical IMRT, we found that sex, necrosis before re-irradiation, accumulated total prescription dose to the GTV, and recurrent tumor volume are risk factors for LNN. We therefore constructed a feasible prognostic model that included these factors to predict the risk of developing LNN.
IMRT has been proven to improve tumor control and decrease acute and late toxicities when compared with conventional radiation technology [7, 8, 10, 20–22]. However, some severe late toxicities of IMRT, especially LNN, have adversely affected patients’ quality of life and survival. According to previous studies, 11%–32% of NPC patients with severe late adverse events underwent re-irradiation with IMRT, which resulted in nasopharyngeal necrosis [9, 15, 21]. Even worse, approximately 45% of nasopharyngeal necrosis later involved the internal carotid artery and resulted in LNN . Hemostasis by gelatin sponge compression and nasopharyngeal packing through the anterior and/or posterior nares are the standard therapies. Internal/external carotid artery ligation, stent implantation, and other surgery treatments are applied when necessary [23–27]. Unfortunately, the cure rate remains very low despite the hemostasis. It is urgent to identify re-irradiated NPC patients who are at high risk of developing LNN.
Many studies cited dosage as an important risk factor for the severity of necrosis [13–15, 17, 19, 23]. Bedwinek et al.  reported that osteonecrosis occurred in 9% of patients with oral carcinoma and NPC who received radiotherapy if the dose was more than 70 Gy. Similarly, Mark et al.  observed that 22% of patients who received a dose greater than 75 Gy experienced osteoradionecrosis. In their study, 28 patients (18.4%) experienced nasopharyngeal necrosis after initial irradiation with a dose over 70 Gy. However, the incidence was much higher for re-irradiated patients. Hua et al.  reported that 14 of 28 (50%) patients developed nasopharyngeal necrosis after re-irradiation with an accumulated prescription dose over 120 Gy. In our study, univariate analysis showed that both the accumulated prescription dose to the GTV and the mean re-irradiation dose were statistically related to LNN, and multivariate analysis showed that the accumulated prescription dose to the GTV was an independent risk factor for LNN. Additionally, large recurrent tumor volume is usually considered one of the independent factors of poor survival in recurrent NPC . Han et al.  showed that the OS of NPC patients with small recurrent tumor volume (≤38 cm3) was 1.6 times longer than that of patients with larger recurrent tumor volume (>38 cm3) when treated with IMRT. Moreover, Hua et al.  found that the recurrent tumor volume >42 cm3 was an independent predictor of OS in patients with locally recurrent NPC who were re-irradiated with IMRT. In our study, we found that a recurrent tumor volume ≥25.38 cm3 was an independent prognostic factor for LNN; this tumor volume was much lower than those in previous reports discussing survival status, suggesting that re-irradiation of large recurrent tumors should be administered with caution. Re-irradiation is usually the last chance for cure after a patient’s first relapse; therefore, for patients at high risk of developing LNN, decreasing the re-irradiation dose or the recurrent tumor volume might be feasible methods to prevent LNN. Considering that reducing the re-irradiation dose would likely result in worse control of NPC recurrence, administering neoadjuvant chemotherapy to decrease the tumor volume may lower the risk of developing LNN and improve the local control rate and the survival rate [29, 30]. Future clinical trials combining chemotherapy, molecular targeted therapy, and radiotherapy are expected to determine the optimal re-irradiation dose for patients with recurrent NPC.
A generally accepted mechanism of injury after irradiation is a hypovascular–hypoxic–hypocellular condition that causes the breakdown of local tissue, exposing bone, and the formation of sequestra . The inflammation caused by this non-healing wound may, in turn, increase the demand of the local tissue for energy, oxygen, and other metabolites, which may lead to more serious collagen destruction and cell death . This is a reasonable explanation for our findings. We found that necrosis before re-irradiation was an independent risk factor for LNN. Of the 41 patients with nasopharyngeal necrosis after the first irradiation, 12 (29.3%) progressed to LNN after re-irradiation with IMRT. Re-irradiation aggravated injuries caused by the first irradiation, which increased oxygen demand in these aggravated areas. At the same time, previous repair processes, such as fibrosis, may also constrain the local blood supply, which can hinder the healing of necrosis after re-irradiation. As previously reported, weekly debridement and excision of necrotic tissue under nasopharyngeal endoscopy, daily nasopharyngeal irrigation, intravenous nutrition, and systematic antibiotic therapy can improve some cases to a certain extent , which may diminish the need for procedures to treat nasopharyngeal necrosis. Thus, once nasopharyngeal necrosis is diagnosed, timely and effective treatment is necessary.
Finally, we found that women were more likely than men to develop LNN, suggesting that intrinsic biological traits, such as sensitivity to radiation, repair ability, and hormone levels, may contribute to a patient’s likelihood of developing LNN. Future investigations should study the relationship between necrosis and sex.
This study had several limitations. First, quick and effective measures are very important for hemorrhage rescue, but treatments of massive nasopharyngeal bleeding varied considering expense, distance, and clinical medical condition. Massive nasopharyngeal bleeding involving the internal maxillary artery could be rescued with effective treatment, such as hemostasis by gelatin sponge compression, nasopharyngeal packing, artery ligation, and other surgical measures . However, carotid artery rupture is a common result of LNN, which results in a high mortality . In this study, we could not analyze ruptured arteries because of insufficient clinical data. Second, this study had a relatively small patient population, which diminishes the relevance of the results. Last, as a retrospective study, the patient population’s clinical characteristics were diverse; therefore, an observational prospective study is necessary to validate this scoring system.