3 Discussion
According to the National Comprehensive Cancer Network (NCCN), carotid artery invasion is a sign of poor prognosis, such as oral cavity cancer, P16oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer other than nasopharyngeal cancer. MR images were used to predict carotid artery invasion [9]: circumferential involvement of 270° or less of the wall meant no invasion, and more than 270° meant wall invasion. Based on our comparison of the survival rates in three degrees of carotid artery invasion (<180°, 180°≤IG<270°, and ≥270°), although the difference was not statistically significant, it showed that the survival rate tended to decrease with an increase degree of invasion. However, patients with LANC with carotid artery invasion have a better prognosis, compared with other head and neck tumors. In this study, 130 LANC patients with carotid artery invasion were treated with induction chemotherapy followed by CCRT ± an EGFR inhibitor. Five-year survival rates were: PFS=75.2%; DMFS=76.8%; LNRFS=90.0%; LRFS=93.9%; NRFS=95.8% and OS=87.2%. Side effects were mild and well-tolerated; survival rates were similar to those observed in other studies [10-11].
Shen C et al. [12] showed that anemia is closely related to tumor hypoxia, which may lead to tumor resistance to radiotherapy and treatment failure. In this study, we found that the 5-year OS of patients with the lowest hemoglobin levels (≤110 g/L) was significantly lower than that of patients with hemoglobin levels >110 g/L during radiotherapy. Therefore, we believe that patients should actively monitor and treat anemia.
Other studies have shown that patients whose primary tumor located in the pharyngeal recess, and who experienced inflammation and an opening incisor tooth distance <1 cm, had a greater probability of fatal bleeding after radiotherapy [13]. Yamazaki et al. [14] and Cheng et al. [15] believed that the pharyngeal recess is part of the petrosal region of the internal carotid artery where the tumor easily invades the internal carotid artery and surrounding bone. If the pharyngeal recess infected, the surrounding tissues may become necrotic, which may cause rupture of the internal carotid artery and fatal bleeding. Similarly, the primary site of the three cases were all the pharyngeal recess, with more than 270 º carotid artery invasion and restricted mouth opening.
Fatal bleeding is common in previous studies, Zheng et al. [16] found that 1.5% of nasopharyngeal carcinoma patients with IMRT experienced fatal bleeding. Wu et al.[13] showed that 52.9% (45/85) of such patients (stage I-IV) occurred fatal bleeding, with 20 patients died. In our study, all patients were stage III-IV, 32 cases with carotid artery invasion <180° and 37 cases with 180°≤IG<270°, no patients suffered fatal neck hemorrhage.
Sixty one patients with carotid artery invasion ≥270°, among whom three patients died of neck hemorrhage, the overall incidence was only 2.3% (3/130), which was attributable to nasopharyngeal necrosis (2 of whom were diabetics and 1 received re-radiation after recurrence). Most scholars believe that radiation, trauma and infection cause nasopharyngeal necrosis [14]. Re-radiation increases the risk of necrosis of the nasopharynx and neck hemorrhage [17]. The 2 diabetics had uncontrollable infection with local necrosis. The patient who received re-radiation was exposed to a cumulative radiation dose of 137.5 Gy and developed osteoradionecrosis of the nasopharynx seven months after radiotherapy. Another patient with the primary site of the nasopharyngeal wall was treated with surgery after recurrence, and he survived without fatal bleeding. Surgery may be a better option than re-radiation for patients with carotid artery invasion ≥270° who experience recurrence.
In our study, 127 patients without massive hemorrhage benefited from the application of induction/concurrent chemotherapy and HT. Induction chemotherapy can reduce tumor load, enlarge the space between the carotid artery and the tumor body and produce a greater safety margin, thereby reducing damage to important tissues and organs caused by radiotherapy. Dionisi et al. [18] showed that CCRT could further shrink the tumor body, accelerate blood supply to surrounding tissues, and reduce the incidence of mucosal necrosis. HT has many dosimetric advantages, such as delivering a more precise dosage to the target tissue(s) and reducing radiation exposure to critical surrounding organs, thereby improving local control with less radiation damage [19]. In addition, multivariate analysis showed that use of an EGFR inhibitor was an independent prognostic factor for PFS and DMFS. Previous studies have shown that adding CTX/NTZ to CCRT may improve OS, DFS and DMFS [20-24], which is consistent with our results. EGFR inhibitors also have been shown to have significant anti-proliferation, pro-apoptosis and anti-angiogenesis effects, which may further control the recurrence of tumors and improve the sensitivity of tumors to radiotherapy and chemotherapy [25].
In conclusion, 130 patients with LANC surrounding the carotid artery were treated with a comprehensive treatment regimen, 95.7% of the patients successfully completed the entire courses, producing desirable outcomes and a low incidence of fatal hemorrhage. Improved outcomes may be possible with the application of new proton and other radiotherapy technologies and new PD-1 immuno-targeted drugs in patients with nasopharyngeal carcinoma. The primary site located in the pharyngeal recess with more than 270 º carotid artery invasion and restricted mouth opening, especially diabetics, should actively control blood glucose levels and prevent infection. Nasopharyngeal necrosis should be actively treated by antibiotics and hyperbaric oxygen, removing by oxygen nasal endoscope regularly.
Abbreviations: Arrowheads indicate the ICA; LANC, Locally advanced nasopharyngeal carcinoma; MRI, magnetic resonance imaging; ICA, internal carotid artery; T1WI, T1-weighted imaging
EGFR, epidermal growth factor receptor inhibitor; PFS, progression-free survival; DMFS, distant metastasis-free survival; LNRFS, local nodal recurrence-free survival; LRFS, local recurrence-free survival; NRFS, nodal recurrence-free survival; OS, overall survival
T: docetaxel; P: cisplatin; F: 5-fluorouracil; G: Gemcitabine; D: Doxorubicin
HR3, Nimotuzumab; C-225, Cetuximab; HT, helical tomography