Discussion
In this study, no risk factors for post radiation MEE in NPC patients were identified. Including specifically, radiation doses to the eustachian tube, TVP and LVP muscles.
Much progress was made in the last decades in the treatment of NPC. Today the primary treatment is RT, mainly IMRT, for early-stage NPC, and a combination of concurrent platinum-based chemotherapy with RT for locoregional advanced disease.11
Since introduced, it is well known that radiation treatment for NPC is associated with various morbidities and in particular otologic complications, due to the inclusion of the temporal bone in the radiation fields.3,4,12–14
Previous studies demonstrated a wide range of data regarding the prevalence of MEE in irradiated patients. 8% to 48% of NPC patients undergoing conventional radiotherapy develop persistent or recurrent post irradiation MEE.4,9,12,15
In our study fourteen patients (19.2%) presented with MEE at disease diagnosis. Following radiotherapy, in half of these patients a resolution of their MEE was noted. Post radiation persistent MEE was observed in a quarter (24.6%) of patients.
Interestingly, advanced T stage, which has been observed to be risk factor for MEE at presentation due to association with skull base and pterygoid plates invasion adjacent to the ET and its dilating muscles, was not identified to be such a risk factor for post radiation MEE in our study. Similar findings were also observed in the study by Chung-Han Hsin et. al.18, examining post-irradiated ears in 105 patients with NPC treated with RT.
Unlike previous studies, we also performed an analysis of histopathological factors, including tumor histopathology, EBV tumor staining and Ki-67 marker. We did not identify these features to be risk factors for post radiation MEE as well as for MEE at NPC diagnosis.
Surprisingly, although modern radiotherapy techniques (IMRT) are considered more precise and with minimized collateral damage, previous studies16–18 as well as our current study showed no protective effect against post irradiation MEE with IMRT compared to 3D-CRT. 31% of patients treated with IMRT developed MEE similar to 29.4% in the 3D-CRT group (p=0.9).
The etiology of post radiation MEE is hypothesized to be associated with either obstruction or functional impairment of the eustachian tube; and/or middle ear mucosal injury.14,19,20 Middle ear mucosal injury is thought to be related to radiation-induced toxicity leading to impairment of the mucosal and ciliary function.14,21,22 Radiation injury to the cartilaginous eustachian tube may cause synechia formation and fibrosis, leading to physical obstruction of the ET. Alternatively, irradiation of the muscles involved in the patency and dilatation of the ET – Levator veli palatini and more importantly the Tensor veli palatini may lead to their atrophy or fibrosis. Previous studies focused on radiation doses to the NP, the middle ear itself and the ET16-18 as risk factors for post radiation MEE, but none thus far examined radiation doses to the ET muscles.
In this study, analysis of radiation doses showed no correlation or difference between the delivered dose to the ET, LVP and TVP and development of MEE.
Previous studies suggested that radiation doses of 80Gy and higher are associated with middle ear injury21,22. However, these doses exceed the conventional therapeutic doses. In our study, examination of the radiation doses delivered to the middle ear itself demonstrated no difference between patients who developed MEE and those who did not. In addition, the doses delivered to the middle ears in this study were far from the toxic level reported in previous publications.
Of note, our study results may be limited due to our cohort size and the study’s retrospective nature with the inherent biases. Nonetheless, it provides a comprehensive analysis of patient, tumor and treatment factors and their association with the development of post radiation MEE, and the first to our knowledge, to examine tumor parameters and the radiation doses delivered to the muscles involved in the patency of the ET.
In conclusion, no risk factors for postirradiation MEE were identified, including total radiation doses and specific doses to the middle ear, ET and ET muscles. Thus, all NPC patients receiving treatment should be evaluated for post radiation MEE and receive appropriate treatment when necessary. Further studies are needed to understand the risk factors and pathophysiology of post radiation MEE in NPC patients.