Introduction
Nasopharyngeal carcinoma (NPC) is endemic in southern China and Southeast Asia, with an annual incidence of 15–50 cases per 100 000 population.Reference Wee, Ha, Loong and Qian1 Radiotherapy (RT) is a popular initial treatment option for NPC. The irradiated fields encompass the primary site and regional lymph nodes.Reference Porter, Leung, Ambrose, Cheung and van Hasselt2 The primary fields must include the posterior nasal cavity, ethmoid sinuses and sphenoid sinus;Reference Payne3 hence, sinonasal tissue is inevitably irradiated because of its close location to the nasopharynx.
Rhinosinusitis is one of the most common untoward side effects at follow up.Reference Zubizarreta, D'Antonio, Raslawski, Gallo, Preciado and Casak4 The damage caused by RT to the nasal epithelium, and the drainage through sinus openings, are responsible for the incidence of post-irradiation rhinosinusitis,Reference Lou, Chen and Tai5 which is very bothersome and affects patients’ quality of life.
Endoscopic sinus surgery has been performed to improve symptoms in these patients, but poor wound healing and intra-operative bleeding may still occur,Reference Civantos, Yoskovitch and Casiano6, Reference Su, Jiang, Chiang and Lin7 and the long-term post-operative effects of endoscopic sinus surgery remain unclear.Reference Hu, Tan, Lin, Cheng and Huang8 The treatment of post-irradiation rhinosinusitis remains controversial. Fluticasone propionate aqueous nasal spray (e.g. Flixonase® aqua) is a topical nasal formulation of the anti-inflammatory corticosteroid fluticasone propionate. This study aimed to evaluate the effect of fluticasone propionate aqueous nasal spray on NPC patients with RT-induced chronic rhinosinusitis.
Materials and methods
Study design
A prospective, randomised, parallel-arm trial was conducted at the Department of Radiation Oncology of the Fifth Affiliated Hospital of Sun Yat-sen University, which is the only treatment centre in Zhuhai for nasopharyngeal carcinoma (NPC) patients who need RT. Before the study began, approval was obtained from the Ethics Committees of the Fifth Affiliated Hospital of Sun Yat-sen University, and written informed consent was obtained from all enrolled patients.
Participants
From December 2011 to December 2013, NPC patients who underwent RT and subsequently developed rhinosinusitis were enrolled in this prospective study. The diagnosis of rhinosinusitis in these patients, which is similar to that in patients with common chronic rhinosinusitis, was supported by: (1) general complaints of mucopurulent rhinorrhoea, nasal obstruction, facial pain, headache or an impaired sense of smell, with symptoms persisting for more than 12 weeks; (2) nasal endoscopic symptoms of mucopus in the nasal cavities or/and middle meatus, or oedematous mucosal change around the ostiomeatal area; or (3) computed tomography (CT) evidence of mucosal abnormalities in the paranasal sinuses. Patients were excluded if they had: suffered from chronic rhinosinusitis before RT; a recurrent tumour; received topical or systemic steroid therapy within the previous eight weeks; received nasal or oral antihistamines within the previous two weeks; or suffered severe acute bacterial rhinosinusitis.
Interventions
The subjects were randomly allocated to one of two groups. One group received fluticasone propionate aqueous nasal spray 200 µg (50 µg in each nostril twice daily) and irrigated each nostril with 120 ml normal saline per side (twice daily for six months, using the provided syringe). The other group performed the same nasal irrigation twice daily for six months, but did not use the fluticasone propionate aqueous nasal spray.
A questionnaire, nasal endoscopy and CT were used to evaluate rhinosinusitis severity at the beginning of treatment, and at three and six months after treatment.
Clinical data collection and outcome measures
Patients evaluated their current symptoms of nasal blockage, decreased sense of smell, rhinorrhoea and headache subjectively on a 10-point visual analogue scale (VAS), with responses ranging from very poor (score of 0) to very good (score of 10). An aggregate of the four symptom scores was calculated (overall symptom score).
Improvement in rhinosinusitis-related quality of life was measured with the Sino-Nasal Outcome Test-20 (SNOT-20). This is a validated, self-administered questionnaire that uses a five-point Likert scale to assess how severely a patient's rhinosinusitis symptoms affect their quality of life.Reference Piccirillo, Merritt and Richards9
Nasal endoscopic examinations were performed with rigid nasal endoscopes. The Lund–Kennedy endoscopy score was used to rank the subjective appearance of nasal endoscopy findings.Reference Lund and Kennedy10 The items for measurement included polyps, oedema, discharge, scarring and crusting. Possible scores for each side ranged from 0 to 10, with the total score ranging from 0 to 20.
The CT scans were scored using the Lund–Mackay staging system.Reference Lund and Mackay11 Briefly, the CT shadow of each sinus (maxillary, frontal, anterior ethmoidal, posterior ethmoidal and sphenoidal, and the ostiomeatal complexes) was assigned a score of: 0, no abnormality; 1, partial opacification; or 2, total opacification. Each side was considered separately. The maximum possible total score was 24.
The sinus CT scans and nasal endoscopic findings, and all scores, were evaluated by two of the authors (Z Liao and L Guo), who were blinded to each patient's grouping.
Statistical analysis
Data were analysed by intention-to-treat analysis and using SPSS® statistical software, version 15.0. An independent t-test (or Wilcoxon signed rank test) was used to compare each score between the two groups at each evaluation point. A paired t-test was used to compare every score within each group between evaluation times. Repeated measures analysis of variance (ANOVA) was performed to compare the variation tendency of each score between the two groups. A p-value of < 0.05 was considered statistically significant.
Results
Participant flow is summarised in Figure 1. A total of 63 subjects were randomly allocated to the 2 groups. The subjects in each arm of the study were similar with respect to age, radiation dose, cancer stage, and interval between RT and rhinosinusitis (Table I).
Consolidated Standards of Reporting Trials (‘CONSORT’) flow diagram describing participant flow through the study.
Demographic and clinical data
SD = standard deviation; F = female; M = male; RT = radiotherapy; UICC = Union for International Cancer Control; mth = months
Irrespective of group (fluticasone propionate aqueous nasal spray with nasal irrigation, or nasal irrigation only), patients had significantly lower endoscopic, VAS (overall symptom, blocked nose and headache) and SNOT-20 scores at three and six months after treatment than before treatment (Table II) (p < 0.05). There was no significant pre- and post-treatment difference in CT scores for either group, or in smell VAS score for the fluticasone propionate aqueous nasal spray group (Table II) (p > 0.05).
Pre- and post-treatment scores
Data represent means ± standard deviations, unless indicated otherwise. *Independent t-test; †repeated measures analysis of variance; ‡significant intergroup comparisons (p < 0.05) by paired t-test for pre-treatment versus three months after treatment; **significant intergroup comparisons (p < 0.05) by paired t-test for pre-treatment versus six months after treatment. Mth = months; CT = computed tomography; VAS = visual analogue scale; SNOT-20 = Sino-Nasal Outcome Test-20
Comparison of the scores between the two groups by independent t-tests revealed that patients in the fluticasone propionate aqueous nasal spray group had significantly lower endoscopic and VAS scores (overall symptom, blocked nose and headache) at three and six months after treatment (Table II) (p < 0.05), and lower SNOT-20 scores at three months after treatment (Table II) (p = 0.013).
Repeated measures ANOVA showed that both groups had similar mean baseline endoscopy scores (Table II) (p = 0.339). The reduction in endoscopy scores at three months after treatment was greater in the fluticasone propionate aqueous nasal spray group (Table II) (F = 22.56, p < 0.001). At six months, the reduction was even greater with the fluticasone propionate aqueous nasal spray therapy (Table II) (F = 27.01, p < 0.001), such that overall improvement in endoscopic change was better in the fluticasone propionate aqueous nasal spray with nasal irrigation group than in the nasal irrigation only group (Table II) (F = 23.87, p < 0.001) (Figure 2). The same phenomena were observed when we analysed the VAS scores (overall symptoms, blocked nose and headache) and SNOT-20 scores (Figures 3–6).
Endoscopy scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
Overall visual analogue scale symptom scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
Blocked nose visual analogue scale scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
Headache visual analogue scale scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
Sino-Nasal Outcome Test-20 (SNOT-20) scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
With regard to the rhinorrhoea VAS scores, patients in both groups had similar mean baseline scores (Table II) (p = 0.081), and there appeared to be a decline in scores for both groups. The improvement in rhinorrhoea VAS scores in the fluticasone propionate aqueous nasal spray with nasal irrigation group was not significantly different from that in the nasal irrigation only group (Table II) (F = 2.44, p = 0.1025) (Figure 7).
Rhinorrhoea visual analogue scale scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
The lines representing the changes in CT scores for the two groups almost overlap (Figure 8; see also Table II) (F = 0.01, p = 0.9890). As previously mentioned, there was not much improvement after treatment, for either group (Table II) (p > 0.05).
Computed tomography (CT) scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
There was no significant difference between the two groups for decreased sense of smell VAS scores (Table II) (F = 0.21, p = 0.8149), and the downward trend of the line remained inconspicuous (Figure 9).
Decreased sense of smell visual analogue scale scores from pre-treatment to six months post-treatment in the fluticasone propionate aqueous nasal spray with nasal irrigation group and nasal irrigation only group. Mth = months
Both the fluticasone propionate aqueous nasal spray and the nasal irrigation were well tolerated. No serious adverse events occurred during the study, and no safety issues of clinical importance were identified.
Discussion
According to the 2012 Cancer Registry annual report, about 120 nasopharyngeal carcinoma (NPC) patients per year underwent radiation treatment for the first time in our hospital. Post-irradiation rhinosinusitis is one of the most common untoward side effects for these patients, significantly reducing their quality of life and increasing healthcare costs. As Huang et al. reported, RT in NPC patients leads to sinus mucosal diseases in at least two-thirds of patients, with the maxillary, anterior ethmoid and posterior ethmoid sinuses being most readily affected.Reference Huang, Huang, Lee, Ng and Chang12 When post-irradiation rhinosinusitis appears as a complication, patients are referred to otolaryngologists for management.
The exact pathophysiology of chronic rhinosinusitis remains unclear, but the mucosal inflammatory response to RT may play an important role in the pathogenesis of post-irradiation rhinosinusitis.Reference Nicolatou-Galitis, Sarri, Bowen, Di Palma, Kouloulias and Niscola13 In a hamster cheek pouch model of radiation mucositis, messenger RNA levels of tumour necrosis factor-α (TNF-α) and interleukin (IL)-1β in oral mucosal tissue correlated with mucositis severity.Reference Sonis, Peterson, Edwards, Lucey, Wang and Mason14 Tumour necrosis factor-α and IL-1β induce cyclo-oxygenase-2, a key enzyme in the inflammatory process, responsible for the increased production of proinflammatory prostanoids. These prostanoids, notably prostaglandin E2 and prostacyclin, mediate tissue injury.
Another possible pathogenesis of post-irradiation rhinosinusitis is impaired mucociliary clearance. Kamel et al. found that the delay time for post-RT mucociliary clearance in NPC patients gradually worsened with time for up to six months, and then stabilised and persisted.Reference Kamel, Al-Badawy, Khairy, Kandil and Sabry15 Another study demonstrated long-term radiation damage to the nasal epithelium in patients with NPC, including epithelial sloughing, loss of cilia and ciliary dysmorphism.Reference Lou, Chen and Tai5 Furthermore, irreversible impairment of mucociliary function resulted in disordered sinus drainage, which allowed bacteria to invade the sinus cavity more easily.Reference Deng and Tang16 When post-irradiation rhinosinusitis appears, the rhinosinusitis itself may also induce the formation of dysmorphic cilia, which subsequently exacerbates the already impaired nasomucociliary clearance. This reciprocal interaction leads to a vicious cycle in the pathogenesis of post-irradiation rhinosinusitis.
Several kinds of treatment have been applied for post-irradiation rhinosinusitis, including endoscopic sinus surgery and nasal irrigation. Endoscopic sinus surgery has potential disadvantages of poor wound healing and intra-operative bleeding,Reference Civantos, Yoskovitch and Casiano6, Reference Su, Jiang, Chiang and Lin7 as previously mentioned. Nasal irrigation is the most popular treatment for post-irradiation rhinosinusitis. The mechanisms of nasal irrigation are physical cleansing, enhancement of mucociliary function and the removal of local inflammatory mediators.Reference Heatley, McConnell, Kille and Leverson17, Reference Tomooka, Murphy and Davidson18 However, a study by Liang et al. showed that, with or without nasal irrigation, patients presented with nasal symptoms during RT and remained symptomatic during the following six months.Reference Liang, Kao, Lin, Tseng, Su and Hsin19 Our results show that the nasal irrigation only group had significantly lower endoscopy and symptom scores at three and six months after treatment than before treatment. This suggests that irrigation can relieve post-irradiation rhinosinusitis to some extent in NPC patients.
The findings of the present study indicate that patients with post-irradiation rhinosinusitis who received fluticasone propionate aqueous nasal spray combined with irrigation had fewer nasal complaints (overall symptoms, blocked nose and headache), a better quality of life (as indicated by SNOT-20 scores) and less severe endoscopic findings than those who only received nasal irrigation, at three and six months after treatment. Combined therapy provided greater improvements in nasal symptoms, quality of life and endoscopy scores than nasal irrigation alone. In previous studies, nasal steroids have proved effective in treating chronic rhinosinusitis.Reference Snidvongs, Kalish, Sacks, Craig and Harvey20 The present study, however, is the first randomised trial to prospectively evaluate the use of nasal steroids in a population of patients with a diagnosis of post-irradiation rhinosinusitis.
In the present trial, the effectiveness of fluticasone propionate aqueous nasal spray in treating post-irradiation rhinosinusitis was due to the mechanism of steroids. Intranasal steroids have a potent anti-inflammatory activity which is achieved by regulating gene expression, interfering with multiple steps in the inflammatory process.Reference Levenson and Greenberger21 For example, they can inhibit cyclo-oxygenase-2 and attenuate the large amounts of prostaglandins produced during inflammation. At the same time, they can reduce the production of interleukins (IL-1, IL-2, IL-3, IL-5, IL-6 and IL-8) and TNF-α. After the radiation mucositis has disappeared, the cilia gradually return to normal and impaired nasomucociliary clearance recovers. The vicious cycle of post-irradiation rhinosinusitis is then broken, although further nasal mucosal biopsies are needed to elucidate its pathogenesis.
Our results showed no significant differences in CT scores between the two groups at every evaluation time point, and neither group showed any significant improvements after treatment. This indicates that neither therapy (fluticasone propionate aqueous nasal spray combined with irrigation, or nasal irrigation alone) changed the post-irradiation rhinosinusitis CT scores, despite the reduction in nasal symptom and endoscopy scores. This might be interpreted as follows. Firstly, the association between chronic rhinosinusitis and CT findings continues to be controversial. Several previous reports have indicated no association between symptom severity and CT scan severity.Reference Hwang, Irwin, Griest, Caro and Nesbit22, Reference Bachert, Hormann and Mosges23 Computed tomography findings should be interpreted only in conjunction with an evaluation of symptoms and endoscopic examination, owing to high rates of false-positive and false-negative findings with CT.Reference Okuyemi and Tsue24 Secondly, the recession of mucosal inflammation in the sinuses is far slower than in the nasal cavity, which is reflected in the CT findings.
The strengths of this study include the prospective, randomised, parallel-arm design, which attempted to minimise the risk of bias in outcome measurements. The two groups (fluticasone propionate aqueous nasal spray with nasal irrigation group, and nasal irrigation only group) were similar (there were no significant differences) with regard to important factors that may influence rhinosinusitis severity, including radiation dose and cancer stage. This increases our confidence that the study accurately assessed the impact of the intervention. In addition, in an effort to reduce experimenter bias, the CT scans and nasal endoscopic findings, and all scores, were evaluated blindly. Furthermore, two validated qualitative surveys were used to quantify subjective quality of life and symptoms.
Limitations of the study include the small sample size and the short follow-up duration. Future studies should include larger numbers of patients and a longer follow-up period, which would help to strengthen our conclusions.
• Post-irradiation rhinosinusitis is a common side effect in nasopharyngeal carcinoma patients; treatment remains controversial
• In this study, nasal steroid therapy was associated with improved nasal symptoms, quality of life and endoscopic findings
• Nasal steroids are a safe, well-tolerated, effective therapy for patients with post-irradiation rhinosinusitis
Generally speaking, we conclude that nasal steroids are a safe, well-tolerated, inexpensive and effective therapy for patients with post-irradiation rhinosinusitis. Future well-designed, large-scale investigations on this topic, focusing on the long-term efficacy of intranasal steroids for post-irradiation rhinosinusitis, are still required.
Acknowledgements
The authors are grateful to the individuals who assisted with data collection and provided advice, including Mr Huabin Li, Mr Haiyu Hong and Miss Chuntao Deng.
