Post-radiation sinusitis is associated with recurrence in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy

Between November 2007 and June 2013, 230 histologically diagnosed non-metastatic NPC patients were treated with IMRT at Kaohsiung Medical University Hospital in Kaohisung, Taiwan. For each patient, various pretreatment evaluations were conducted, including a history and physical examination, dental evaluation, blood test, nasoendoscopy, computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck, chest X-ray, bone scan, and abdominal sonography or positron emission tomography (PET). Tumors were staged according to the 2010 American Joint Committee on Cancer (AJCC) staging classifications [16]. Histologic classifications were made according to the 2005 World Health Organization (WHO) pathologic classification [17].

IMRT was delivered via either helical tomotherapy (HT; Accuray Incorporated, Sunnyvale, CA) or volumetric modulated arc therapy (VMAT; RapidArc, Varian Medical Systems, Palo Alto, CA). Patients were immobilized in a supine position with a thermoplastic mask covering the head and neck. A CT simulation with a slice thickness of 3 mm was performed, and target and normal structures were delineated on a Pinnacle treatment planning system (Phillips Healthcare, The Netherlands). The gross tumor volume (GTV) included the macroscopic primary tumor and involved lymph nodes of more than 10 mm in diameter. The clinical target volume high (CTVhigh) included the GTV with an expansion of 3 mm. The CTVmid was designed to include areas at risk for microscopic involvement, including the entire nasopharynx, the retropharyngeal nodal regions, the skull base, the clivus, the pterygoid fossa, the parapharyngeal space, the sphenoid sinus, the posterior third of the nasal cavity/maxillary sinuses and the pterygopalatine fossa, and lymph nodes at levels II–III, level VA, and the retropharyngeal space (ipsilateral level IB was included if the N stage was positive). Level IV and level VB were included in the CTVlow. The planning target volume (PTV) was defined as the CTV with 3-mm margins in all dimensions. However, in areas in which the CTV was adjacent to critical normal structures (e.g., the brainstem), the margin was reduced to 1 mm. The prescribed doses for PTVhigh, PTVmid, and PTVlow were 69.96-70Gy in 33–35 fractions, 59.4-63Gy in 33–35 fractions, and 54.45-56Gy in 33–35 fractions, respectively. The organs at risk (OAR) (i.e., the brainstem, spinal cord, lenses, eyes, optic nerves, chiasm, mandible, parotid glands, oral cavity, and throat) were contoured, and dose limitations were set modified based on the radiation therapy oncology group (RTOG) 0225 trial [18]. During treatment, kilovoltage cone beam CT (CBCT) image guidance for VMAT or megavoltage CT (MVCT) image guidance for HT was utilized to verify the tumor position.

For stage II-IVB patients, combined chemotherapy was needed and was provided based on the clinician’s assessment, with the factors considered including the patient’s age, The Eastern Cooperative Oncology Group (ECOG) scale of performance status, co-morbidities, tumor extent, and the patient’s own preferences. Neoadjuvant chemotherapy (NACT) followed by RT, concurrent chemo-RT (CCRT), and neoadjuvant chemotherapy followed by concurrent chemo-RT (NACCRT) were all accepted treatment options. For patients receiving NACT, the chemotherapy was administered as 2–3 cycles of cisplatin 70 mg/m² on day 1 and 5-fluorouracil 500–1000 mg/m² on days 2–5, every 3 weeks. For patients receiving CCRT, 2–3 cycles of cisplatin 70 mg/m² were delivered at 3-week intervals, or 6–7 cycles of cisplatin 30 mg/m² were delivered weekly. Two patients received concurrent cetuximab with radiotherapy.

After completion of the treatment, routine follow-ups were conducted every 3 months during the first 3 years, and then every 6 months thereafter. These follow-up evaluations consisted of a physical examination, nasoendoscopy, CT or MRI scan, chest x-ray, and abdominal sonography. Late toxicities were recorded in medical documents during follow up.Sinusitis was defined radiologically via CT scan or MRI scan [19‐21]. The diagnosis criteria were as follows: enhanced scan showing fluid accumulation or opacification in the paranasal sinuses, or thickened sinus mucosa with trapped secretion, effusion, or air/fluid in the sinus cavity. Pre-radiation sinusitis was defined according to the imaging performed at the time of diagnosis, while post-radiation sinusitis was defined according to the imaging performed more than 6 months after the radiotherapy. Massive improvement from pre-radiation sinusitis was also regarded as negative post-radiation sinusitis. The occurrence of sinusitis was determined by CJH, MCPS and PTF.

The statistical analysis was performed using SPSS 19.0 software. Several endpoints were evaluated: overall survival (OS), disease-free survival (DFS), freedom from local failure (FFLF), and freedom from distant failure (FFDF). The determinations of local relapse and distant metastasis were made based on physical examinations or radiographic images or were proven by pathological reports. The durations of DFS, FFLF, and FFDF were calculated from the date of completion of the main treatment to the date of documented failure, death from any cause, or the date of the last follow-up. The duration of OS was measured from the date of the diagnosis until death or the date of the last visit. The Kaplan-Meier method was used to calculate the cumulative OS, DFS, FFLF, and FFDF. Different prognostic factors were analyzed using the log-rank test. Among the statistically significant factors identified by univariate analysis, strongly related factors with P < 0.01 were selected for multivariate analysis. The Cox proportional-hazards model was used for multivariate analysis. The ENTER method was used. P < 0.05 was considered significant.