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Long-term complications associated with the management of sinonasal malignancies: a single center experience
Abstract
Objective. The aim of this study was to review the long-term complications associated with treatment of patients with sinonasal malignancies (SNMs) and risk factors for these complications.
Methods. A retrospective analysis of all patients treated for SNMs at a tertiary care center between 2001 and 2018. A total of 77 patients were included. The primary outcome measure was post-treatment long-term complications.
Results. Overall, long-term complications were identified in 41 patients (53%), and the most common were sinonasal (22 patients, 29%) and orbital/ocular-related (18 patients, 23%). In a multivariate regression analysis, irradiation was the only significant predictor of long-term complications (p = 0.001, OR = 18.86, CI = 3.31-107.6). No association was observed between long-term complications and tumour stage, surgical modality, or radiation dose/modality. Mean radiation dose ≥ 50 Gy to the optic nerve was associated with grade ≥ 3 visual acuity impairment (100% vs 3%; p = 0.006). Radiation therapy for disease recurrence was associated with additional long-term complications (56% vs 11%; p = 0.04).
Conclusions. Treatment of SNMs has substantial long-term complications, which are significantly associated with radiation therapy.
Introduction
Sinonasal malignancies (SNMs) comprise less than 3% of head and neck cancers 1. Most SNMs originate from the nasal cavity, followed by the maxillary and ethmoid sinuses 2,3. The majority of patients present with advanced-stage disease. The management of SNMs is challenging owing to their histologic diversity and anatomical proximity to the orbit and critical neurovascular structures 4,5. SNMs are associated with a significant recurrence rate of 30%, and high rates of morbidity and mortality reaching up to 40% 6,7.
Therapeutic management of SNMs includes surgery, radiotherapy (RT) and chemoradiotherapy (CRT). Surgical treatment, when feasible, constitutes an essential part of management 8,9. Adjuvant RT/CRT is frequently used in advanced-stage or positive margins diseases. Multimodal therapy, consisting of surgery and adjuvant RT/CRT, is associated with improved prognosis 10-14.
Despite the complexity of SNMs, treatment-related long-term complications are scarcely reported in the literature. The present study aims to investigate the treatment-related long-term complications in patients with primary and recurrent SNMs.
Materials and methods
Study design and subjects
This was a retrospective analysis of all patients treated for SNMs at a tertiary centre between 2001 and 2018 following approval by the local Institutional Review Board. Patients were included in the study if they had a primary SNM with minimum follow-up period of 6 months between treatment to data collection or death. Patients with insufficient follow-up data were excluded.
Our follow-up protocol included nasal endoscopy every 2-3 months and CT or MRI every 6 months during the first two years post-treatment. Subsequently, nasal endoscopy was performed every 4-6 months until 5 years post-treatment, and then annually. Imaging was performed at 6-12 months intervals during long-term follow-up. In 2012, PET-CT every 6-12 months was introduced for the surveillance protocol of aggressive histologies such as mucosal melanomas or poorly differentiated carcinomas.
Data collection
Data collected included demographics, tumour characteristics, surgical and oncological treatment details, post-treatment complications and outcomes. Comorbidity was evaluated with the Charlson Comorbidity Index 15. Complications were assessed retrospectively by chart review. The primary outcome measure was post-treatment long-term complications. The secondary outcome measure was long-term complications following management for disease recurrence. Long-term complications were defined as those that lasted over 6 months following management or appearing ≥ 6 months post-treatment.
Chronic rhinosinusitis (CRS) was defined according to the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis 16. Radiation-induced toxicity was evaluated with the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 17. Orbital complications were defined as a manifestation that involved the orbit and orbital adnexa. Ocular complications included radiation-induced visual acuity impairment (VAI), cataract, retinopathy and keratoconjunctivitis sicca.
Statistical analysis
Data was analysed using the Statistical Package for the Social Sciences (SPSS) software v.23.0 (IBM Corp. Armonl, NY). Associations between categorical variables were examined using c2 test or Fisher’s exact test. Associations between continuous variables were examined using the Mann-Whitney non-parametric test. Predictive factors associated with long-term complications were evaluated using univariate and multivariate binary logistic regressions. Odds ratio (OR) and 95% confidence interval (CI) were analysed. A two-sided p-value < 0.05 was considered significant.
Results
Patients and tumour characteristics
The cohort included 77 patients. Median age was 65.2 years (range, 22-96), and the male-to-female ratio was 1.33:1. Mean follow-up time was 48.5 months (range, 7-219). Squamous cell carcinoma (SCC) was the most common tumor histology in 35 patients (45.5%). Most SNMs originated from the nasal cavity (36 patients, 47%) and the majority of patients presented with advanced-stage SNM (48 patients, 62%). Clinical characteristics of the study population are presented in Table I.
Treatment modalities
The most common treatment modality was surgery with or without adjuvant RT/CRT (64 patients, 83%) (Tab. I), and the remaining patients received definitive RT/CRT. Surgical modalities used were: external approach in 32 patients (50%) (five of whom underwent anterior maxillary wall reconstruction with a fibula free flap); endoscopic approach in 27 patients (42%) and a combined approach in 5 patients (8%).
Of 60 irradiated patients, 37 (62%) were treated with intensity-modulated radiation therapy (IMRT). Eleven patients received concomitant neck irradiation (14%).
Long-term complications
Overall, 41 patients (53%) suffered from long-term post-treatment-related complications, of which 17 patients (41%) required surgical intervention. The mean time between the end of treatment and the onset of the complications was 7.3 months (range, 0.4-24.1). In 5 patients (12.2%), treatment-related complications were observed during treatment and lasted longer than 6 months post-treatment. The incidence was significantly higher in patients with advanced-stage disease compared to patients with early-stage disease (62.5% vs 38%, p = 0.036). Table II summarises the long-term complications. The most common were sinonasal complications (22 patients, 29%). Sixteen patients (21%) suffered from CRS, the majority of whom had received RT/CRT with or without surgery (14 patients, 87.5%). Seven patients ultimately underwent endoscopic sinus surgery (ESS). Ten (13%) patients, of whom four with CRS as well, suffered from radiation-induced intranasal synechiae resulting in nasal obstruction requiring surgical intervention.
Orbital-related complications (16 patients, 21%) included epiphora (12 patients), three of whom requiring dacryocystorhinostomy (DCR), chronic pain (3 patients), ptosis (2 patients), diplopia (2 patients) and ectropion (1 patient). These complications occurred more often in patients treated with surgery and adjuvant RT compared to surgery alone (32% vs 0%; p = 0.009).
Ocular complications (8 patients, 10%) included radiation-induced grade ≥ 3 VAI (5 patients), radiation-induced grade ≥ 2 keratoconjunctivitis sicca (4 patients), grade ≥ 3 retinal detachment following radiotherapy (2 patients), and radiation-induced grade 3 cataract (1 patients). One patient underwent orbital exenteration due to radiation-induced toxicity. VAI occurred more often in T4 disease compared to T1-3 disease (15% vs 0%; p = 0.012).
Four patients (5%) suffered from post-radiation grade ≥ 3 trismus, leading to feeding tube insertion. Radiation-induced grade ≥ 3 dysphagia was identified in 7 patients (9%) who presented with weight loss and malnutrition, and occurred more often in patients treated with definitive RT/CRT compared to other patients (31% vs 4%, p = 0.013). Six patients were temporarily managed with nasogastric tube insertion or parenteral nutrition, and one patient with severe dysphagia (grade 4) admitted for percutaneous endoscopic gastrostomy (PEG) tube insertion.
Grade ≥ 3 osteoradionecrosis of the maxillary bone was observed in 5 patients (6.5%), two of whom underwent maxillectomy and free flap reconstruction. Three patients were treated with hyperbaric oxygen therapy, and two patients underwent surgical debridement of necrotic bone.
Three patients (4%) presented with radiation-induced grade ≥ 2 neuropathy of the trigeminal nerve branches, leading to hypoesthesia of V2 (2 patients) and V1 (one patient) territories.
Other long-term complications included hyposmia (4 patients, 5%), facial or neck radiation-induced grade ≥ 2 hyperpigmentation or dermatitis (3 patients, 4%), and radiation-induced hypothyroidism (2 patients, 3%). Radiation-induced hypothyroidism was associated with radiation to the neck (18% vs 0%; p = 0.019).
Treatment modality and long-term complications
Overall, long-term complications occurred mostly in patients treated with adjuvant or definitive RT/CRT compared to patients treated with surgery alone (65% vs 12%; p < 0.001) (Tab. II). No significant differences in the rate of long-term complications were observed between RT only compared to CRT (62.5% vs 70%; p = 0.566), between definitive or adjuvant RT/CRT (53% vs 68%; p = 0.35), or IMRT versus external beam radiation therapy (EBRT) (73% vs 52%; p = 0.101).
Of 64 surgically-treated patients (83%), 34 suffered from long-term complications (53%), the vast majority of whom received adjuvant therapy (32 patients, 94%). The correlation between surgical modality (open, endoscopic or combined approaches) and long-term complications rate was not statistically significant (56% vs 52% vs 40%; p = 0.805).
Of note, of 22 patients who suffered from long-term sinonasal complications, in 18 (82%) the initial treatment modality was surgical (7 open, 10 endoscopic, one combined), with the majority receiving post-operative RT/CRT (16/18 patients). In 4 patients, the initial treatment modality was definitive RT/CRT (18%). Type of surgical approach was not associated with long-term sinonasal complications (22% vs 37% vs 20%; p = 0.442).
Predictive factors for long-term post-management complications
Univariate and multivariate logistic regression analyses were conducted to identify predictive factors of long-term post-treatment complications. In a univariate regression model that included all patients (Tab. III), radiation therapy and advanced-stage disease (p = 0.001, p = 0.039, respectively) were identified as significant predictors of long-term post-treatment complications. Variables with a two-sided p-value < 0.2 from univariate analysis were included in a multivariate analysis (smoking, disease stage, radiation therapy and radiation modality). Radiation therapy was the only factor significantly associated with an increased risk for long-term complications (p = 0.001, OR = 18.86, CI = 3.31-107.6).
In a univariate regression model that included only irradiated patients (60 patients), no significant predictors of long-term post-treatment complications were identified. Definitive vs adjuvant therapy, RT vs CRT and higher radiation doses were not associated with long-term complications (p = 0.344, p = 0.567, p = 0.372, respectively).
In a univariate regression model that included only patients treated with post-operative adjuvant RT/CRT (47 patients), no variables were identified as significant predictors of long-term post-treatment complications. Type of surgical approach was not associated with long-term complications (p = 0.467).
Radiation field analysis
Total radiation doses were available in 48 cases (80%), and radiation fields doses in 34 cases (57%). Median planning target volume (PTV) radiation dose were overall 64.8 Gy (range, 42-70.8; SD, 13.85), 68.7 Gy (range, 61-71; SD, 4.06) for 7 patients who received definitive treatment, and 65.0 Gy (range, 42-71; SD, 7.84) for 41 patients who received adjuvant treatment. Median radiation doses were 30.5 Gy to the optic nerve (range, 0.6-72.5), 25.4 Gy to the chiasm (range, 2.5-51.1) and 17.4 Gy to the orbits (range, 0.3-52.8).
Figure 1 illustrates the mean doses to the optic nerve in patients with and without radiation-induced grade ≥ 3 VAI. All patients who received a mean radiation dose ≥ 50 Gy to the optic nerve presented with grade ≥ 3 VAI compared to one patient who received a mean radiation dose < 50 Gy (100% vs 3%; p = 0.006).
Analysis of the impact of the mean PTV revealed that high radiation doses (> 60 Gy) were not associated with an increased rate of long-term complications (72% vs 58%; p = 0.476).
Long-term complications associated with treatment for recurrent disease
Disease recurrence was noted in 24 patients (31%): 15 patients with local recurrence (62%), 5 patients with locoregional recurrence (21%) and 4 patients with distant metastases (17%). SCC was the most common tumor histology (9 patients, 37.5%), followed by mucosal melanoma (7 patients, 29%), and esthesioneuroblastoma (3 patients, 12.5%). Management and complications of patients with disease relapse are demonstrated in Table IV. The common therapeutic modality for disease recurrence was surgery with or without adjuvant therapy (15 patients, 62.5%). Three patients died before treatment could be administered. Long-term complications associated with treatment for disease recurrence was documented in 9 patients (37.5%). The most common were grade ≥ 3 dysphagia in additional 3 patients (12.5%) and radiation-induced grade ≥ 2 hypoesthesia associated with the maxillary division of the trigeminal nerve (V2) in an additional 2 patients (8%). A higher rate of new long-term complications was observed in irradiated patients compared to non-irradiated patients (56% vs 11%; p = 0.04).
Discussion
The long-term complications associated with the management of SNMs has scarcely been reported in the literature. In the present study, we observed a significant rate (53%) of long-term complications associated with the treatment of SNMs, including sinonasal (29%), orbital and ocular (23%), dysphagia (9%), hyposmia (4%) and dermatitis (4%), as well as other complications, including maxillary bone osteoradionecrosis (6.5%), trismus (5%), and cranial nerves neuropathies (4%). Post-treatment complications were significantly more frequent in patients treated with adjuvant or definitive CRT/RT as opposed to surgery alone. Radiation therapy was the sole significant predictor of increased risk for post-treatment long-term complications.
Interestingly, although endoscopic resection of SNMs allows detailed visualisation of sinonasal anatomy and preservation of uninvolved structures compared to open approaches, the literature lacks data comparing the long-term complications associated with these approaches. In the present study, surgical modality was not associated with long-term complications, although nearly all patients with long-term complications received RT/CRT which may have concealed the effect of surgical modality on these complications. This thus underscores the impact of adjuvant RT/CRT on long-term complications.
Only a few studies have reported radiation-induced toxicities in SNM patients. Patel et al. 19 analysed radiation-induced complications in129 patients with SNMs and reported 21% high-grade radiation toxicity rate (ocular toxicities, dermatitis and dysphagia), and 32% treatment-related sinonasal complications. However, they did not differentiate between acute and long-term complications, in contrast to our study analysing only long-term (> 6 months) complications. Askoxylakis et al. 20 reported their experience with 122 patients with SNMs managed by IMRT with or without surgery. They observed 34.4% late toxicities (> 90 days) including dysgeusia or dysosmia, and 34% ocular toxicities, including chronic tearing, vision reduction, light sensitivity and cataract. Nonetheless, 32% of these patients were treated for recurrent tumours, and probably biasing towards an increased complication rate. In our study, primary and recurrent patients were analysed separately and long-term complications were defined as those over 6 months post-treatment. Lastly, Sharma et. al. 21, analysing late toxicities (6.4 years post treatment) in a small group of 27 patients with SNMs, reported that 81% of patients with SNMs treated with IMRT suffered from late toxicity, including 19% ocular toxicity, 22% radiation-related hypopituitarism, 11% impaired olfactory function, and 63% impaired cognitive and physical function. They concluded that although radiotherapy has improved over the last decade, long-term toxicity remains considerable. Yet, none of the above studies, analysed the contribution of surgery and surgical modality to long-term complications.
In recent years, the role of particle-beam radiation therapy (PBRT) typically using accelerated proton or carbon-ion has been studied in the treatment of patients with SNMs 22,23. Hu et. al. 22 analysed disease control and toxicity profiles of 111 patients with SNMs treated with definitive or salvage PBRT, and found that 19.8% of patients experienced late toxicity, of whom only 3.6% suffered from grades 3-4 late toxicity, including decreased vision, xerostomia and osteonecrosis. They concluded that PBRT results in a low toxicity rate and good disease control. Mirandola et al. 23 showed, based on normal tissue complication probability models and additional explanatory dose-volume histogram parameters, that patients with locally advanced sinonasal cancer and orbital invasion could profit from proton therapy compared to IMRT in terms of optical and central nervous system organs at risk sparing. These results warrant further investigation as PBRT seems to offer similar disease control but with fewer long-term complications. However, at present, the patients who may benefit the most from PBRT modality should be selected wisely due to the higher costs and limited availability of this radiation modality 23.
Analysis of risk factors for radiation-induced long-term complications in our patient cohort revealed that radiation dose, radiation modality (IMRT vs external beam radiation), and timing of radiation (adjuvant vs definitive) were not predictors of long-term complications. Advanced tumour stage and radiation therapy were the only factors significantly associated with long-term complications in univariate analysis. In multivariate analysis, however, no risk factors for long-term complications, excluding radiation therapy, were identified. Patel et al. 19 observed that post-treatment complications occurred more often in patients who underwent CRT and the only factor associated with an increased risk of acute and late high-grade radiation toxicity on multivariate analysis was age < 65 years.
Site-specific long-term complications
Sinonasal complications including chronic rhinosinusitis and intranasal synechiae were the most common long-term complications encountered in our study cohort. Nearly all received adjuvant or definitive RT/CRT, and no correlation was found between treatment modality and long-term sinonasal complications. Ultimately, most patients underwent surgery to treat these complications. Patel et al.19 found that early and late sinonasal complications, including secondary sinusitis and nasal stenosis, occurred more often in patients who were treated by CRT with or without surgery compared to surgery alone, although no association with radiation modality or dose was found, similar to our study.
Additional site-specific long-term complications observed in our study included orbital and ocular complications, dysphagia, trismus, osteoradionecrosis, cranial neuropathies and hypothyroidism. Orbital-related complications were found more often in patients treated with surgery and adjuvant RT compared to surgery alone. The study results indicate a dose-response relationship for VAI among irradiated patients. Grade ≥ 3 VAI occurred more often in patients who received a high radiation dose above 50 Gy to the optic nerve compared to patients who received lower doses. These findings are supported by other studies that also found that radiation doses above 50-55 Gy to the optic nerve increased the risk of radiation-induced optical neuropathy and VAI 21,24. Hypothyroidism was associated with neck radiation, and radiation-induced dysphagia was observed significantly more often in patients receiving definitive RT/CRT compared to other patients.
Long-term morbidity with treatment for disease recurrence
Compared to previous publications, we were also interested in analysing complications associated with treatment for disease recurrence. Similar to previous studies 25,26, disease recurrence rate was 31% and the most common therapeutic modality was surgery with or without adjuvant therapy. The long-term complications rate in this subgroup was 37.5%, and the most common were dysphagia and cranial nerve V neuropathy. Radiation therapy for disease recurrence was associated with a higher rate of additional long-term complications compared to non-radiation treatment. Popovtzer et al. 27 reviewed 66 patients who underwent reirradiation therapy of recurrent head and neck cancers and found grade ≥ 3 late complications among 19 patients (29%). Similar to our study, the most common complication was dysphagia.
Study limitations
In this study, a comprehensive analysis of the treatment-related long-term complications of SNMs and their risk factors, in both primary and recurrent tumours, was conducted. We are aware that our small sample of patients, the study’s retrospective nature and heterogeneity of SNMs in terms of histology and treatment protocol limit the results. However, as these tumours are rare, the majority of studies analysing patients with SNM have similar limitations. Moreover, as this topic has been scarcely studied, with few studies with mixed groups of patients, we believe this study provides valuable data for both surgeons and oncologists treating these patients when discussing treatment options and long-term morbidities associated with the various treatment modalities.
Conclusions
SNM treatment-related long-term complications is substantial and may have a considerable impact on quality of life of patients. Irradiation therapy appears to be the dominant risk factor irrespective of radiation dose or radiation modality. Radiation therapy for disease recurrence was associated with a high rate of complications as well. Future studies focusing on therapeutic modalities minimising morbidity are warranted.
Conflict of interest statement
The authors declare no conflict of interest.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author contributions
ES, EGL: had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; EGL, ES: concept and design; EGL, DY, IV: data collection; EGL, ES: analysis and interpretation of data; EGL: drafting of the manuscript; ST, AM, AP, ES: critical revision of the manuscript for important intellectual content; EGL: statistical analysis; ST: administrative, technical, or material support; ES: supervision.
Ethical consideration
This study was approved by the Institutional Ethics Committee of the Rabin Medical Center, Israel (protocol number 0044-18-RMC).
The research was conducted ethically, with all study procedures being performed in accordance with the requirements of the World Medical Association’s Declaration of Helsinki.
Available data
Data available on request from the authors.
Figures and tables
Figure 1.Mean doses to the optic nerve in patients with and without radiation-induced grade ≥ 3 visual acuity impairment. Gy: Gray.
| Characteristics | All patients (n = 77) |
|---|---|
| Males, no. (%) | 44(57) |
| Median age, years (range) | 65 (22-96) |
| Smoker, no. (%) | 28(36) |
| CCI > 2, no. (%) | 45(58) |
| Histology, no. (%) | |
| SCC | 35 (45.5) |
| Sarcoma | 10(13) |
| Mucosal melanoma | 9(12) |
| Esthesioneuroblastoma | 8(10) |
| Adenoid cystic carcinoma | 5 (6.5) |
| SNUC | 3(4) |
| Adenocarcinoma | 2(3) |
| Chondrosarcoma | 2(3) |
| Acinic cell carcinoma | 1(1) |
| Mucoepidermoid carcinoma | 1(1) |
| Sarcomatoid carcinoma | 1(1) |
| Tumour location, no. (%) | |
| Nasal cavity | 36(47) |
| Maxillary sinus | 24(31) |
| Ethmoid sinus | 9(12) |
| Sphenoid sinus | 5(6) |
| Frontal sinus | 3(4) |
| Tumour stage, no. (%) | |
| Stage I | 15 (19.5) |
| Stage II | 14(18) |
| Stage III | 13(17) |
| Stage IV | 35 (45.5) |
| Management, no. (%) | |
| Surgery alone | 17(22) |
| Surgery with adjuvant RT | 31(40) |
| Surgery with adjuvant CRT | 16(21) |
| Definitive RT/CRT | 13(17) |
| Radiation modality, no. (%) | |
| External beam radiation | 23(38) |
| IMRT | 37(62) |
| Radiation dose, no. (%) | |
| < 60 Gy | 12(25) |
| ≥ 60 Gy | 36(75) |
| CCI: Charlson comorbidity index; SCC: squamous cell carcinoma; SNUC: sinonasal undifferentiated carcinoma; RT: radiotherapy; CRT: chemoradiotherapy; IMRT: intensity-modulated radiation therapy; Gy: Gray. | |
| Complications | All patients (n = 77) | Surgery alone (n = 17) | Surgery with adjuvant RT (n = 31) | Surgery with adjuvant CRT (n = 16) | Definitive RT / CRT (n = 13) | P |
|---|---|---|---|---|---|---|
| Long-term complications, no. (%) | 41(53) | 2(12) | 20 (64.5) | 12(75) | 7(54) | 0.001* |
| Orbital-related† | 16(21) | 0 | 10(32) | 5(31) | 1(8) | 0.013* |
| Chronic rhinosinusitis | 16(21) | 2(12) | 6(19) | 5(31) | 3(23) | 0.558 |
| Intranasal synechiae | 10(13) | 0 | 5(16) | 2 (12.5) | 3(23) | 0.219 |
| Ocular-related‡ | 8(10) | 0 | 5(16) | 2 (12.5) | 1(8) | 0.354 |
| Dysphagia | 7(9) | 0 | 1(3) | 2 (12.5) | 4(31) | 0.013* |
| Osteoradionecrosis | 5 (6.5) | 0 | 3(10) | 1(6) | 1(8) | 0.705 |
| Trismus | 4(5) | 0 | 1(3) | 3(19) | 0 | 0.084 |
| Hyposmia | 4(5) | 0 | 1(3) | 2 (12.5) | 1(8) | 0.3 |
| Cranial nerve neuropathy | 3(4) | 0 | 0 | 2 (12.5) | 1(8) | 0.077 |
| Dermatitis/hyperpigmentation | 3(4) | 0 | 1(3) | 1(6) | 1(8) | 0.581 |
| Hypothyroidism | 2(3) | 0 | 1(3) | 1(6) | 0 | 0.82 |
| RT: radiotherapy; CRT: chemoradiotherapy. * Statistically significant. † Orbital-related complications included epiphora, chronic pain, ptosis, diplopia, ectropion. ‡ Ocular-related complications included visual acuity impairment, keratoconjunctivitis sicca, retinal detachment and cataract. | ||||||
| All patients (N = 77) | No complications (N = 41) | Complications (N = 36) | Univariate | Multivariate† | |||
|---|---|---|---|---|---|---|---|
| P | OR (95% CI) | P | OR (95% CI) | ||||
| Gender, no. (%) | |||||||
| Female | 33(43) | 16(44) | 17(42) | ||||
| Male | 44(57) | 20(56) | 24(59) | 0.792 | 0.89 (0.36-2.19) | ||
| Median age, years (range) | 65 (22-96) | 67 (22-93) | 65 (26-96) | 0.573 | 0.99 (0.96-1.02) | ||
| Smoker, no. (%) | |||||||
| No | 49(64) | 26(72) | 23(56) | ||||
| Yes | 28(36) | 10(28) | 18(44) | 0.145 | 2.04 (0.78-5.29) | 0.128 | 2.71 (0.75-9.83) |
| CCI, no. (%) | |||||||
| ≤ 2 | 32(42) | 13(36) | 19(46) | ||||
| > 2 | 45(58) | 23(64) | 22(54) | 0.364 | 0.65 (0.26-1.64) | ||
| Stage, no. (%) | |||||||
| 1-2 | 29(38) | 18(50) | 11(27) | ||||
| 3-4 | 48(62) | 18(50) | 30(73) | 0.039* | 2.73 (1.05-7.06) | 0.661 | 1.31 (0.39-4.34) |
| Management, no. (%) | |||||||
| Surgery alone | 17(22) | 15(42) | 2(5) | ||||
| Adjuvant or definitive RT/CRT | 60(78) | 21(58) | 39(95) | 0.001* | 13.93 (2.90-66.81) | 0.001* | 18.86 (3.31-107.6) |
| Surgery type, no. (%) | |||||||
| Open | 32(50) | 14(47) | 18(53) | ||||
| Endoscopic | 27(42) | 13(43) | 14(41) | 0.736 | 0.84 (0.30-2.34) | ||
| Combined | 5(8) | 3(10) | 2(6) | 0.503 | 0.52 (0.76-3.54) | ||
| RT/CRT, no. (%) | |||||||
| RT | 40(67) | 15(71) | 25(64) | ||||
| CRT | 20(33) | 6(29) | 14(36) | 0.567 | 1.40 (0.44-4.43) | ||
| Radiation modality, no. (%) | |||||||
| External beam radiation | 23(38) | 11(52) | 12(31) | ||||
| IMRT | 37(62) | 10(48) | 27(69) | 0.104 | 2.48 (0.83-7.38) | 0.135 | 2.36 (0.77-7.29) |
| Radiation dose, no. (%) | |||||||
| < 60 Gy | 12(25) | 5(33) | 7(21) | ||||
| ≥ 60 Gy | 36(75) | 10(67) | 26(79) | 0.372 | 1.86 (0.48-7.23) | ||
| CCI: Charlson comorbidity index; RT: radiotherapy; CRT: chemoradiotherapy; IMRT: intensity-modulated radiation therapy; Gy: Gray; OR: odds ratio; CI: confidence interval; * Statistically significant. † Variables with a two-sided p-value < 0.2 from univariate analysis were included in a multivariate analysis. | |||||||
| Complications* | All patients (n = 24)** | Surgery with adjuvant RT (n = 5) | Definitive RT (n = 5) | Surgery with adjuvant CRT (n = 4) | Surgery alone (n = 4) | Surgery with adjuvant CT (n = 2) | Definitive CRT (n = 1) |
|---|---|---|---|---|---|---|---|
| Long-term complications, no. (%) | 9 (37.5) | 4(80) | 3(60) | 1(25) | 0 | 1(50) | 0 |
| Dysphagia | 3 (12.5) | 0 | 3(60) | 0 | 0 | 0 | 0 |
| Cranial nerve neuropathy | 2(8) | 2(40) | 0 | 0 | 0 | 0 | 0 |
| Trismus | 1(4) | 0 | 1(20) | 0 | 0 | 0 | 0 |
| Osteoradionecrosis | 1(4) | 1(20) | 0 | 0 | 0 | 0 | 0 |
| Chronic rhinosinusitis | 1(4) | 0 | 0 | 0 | 0 | 1(50) | 0 |
| Hyposmia | 1(4) | 1(20) | 0 | 0 | 0 | 0 | 0 |
| RT: radiotherapy; CRT: chemoradiotherapy; CT: chemotherapy. *Post-treatment complication for disease recurrence was defined as a new complication that was not present following initial management. **Three patients died before treatment was given. | |||||||
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