10.14639/0392-100X-N1902
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.
text/xml
1827-675X
1902
en
Ethan  Soudry
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
patient care
Long-term complications associated with the management of sinonasal malignancies: a single center experience
Text.Serial.Journal
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Rhinology
2023-05-16
2021-11-06
2023-05-19
2023-05-19
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1
Ethan  Soudry
2023/05/16
10.14639/0392-100X-N1902
203
Department of Otolaryngology - Head and Neck Surgery, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
1827-675X
patient care
en
211
Long-term complications associated with the management of sinonasal malignancies: a single center experience
https://www.actaitalica.it/article/download/1902/998
43
ACTA OTORHINOLARYNGOLOGICA ITALICA 2023;43:203-211; doi: 10.14639/0392-100X-N1902




Rhinology


Long-term complications associated
with the management of sinonasal malignancies:
a single center experience
Le complicazioni a lungo termine conseguenti al trattamento dei tumori maligni
nasosinusali: un’esperienza monoistituzionale
Einav G. Levin1,3, Sharon Tzelnick1,3, Daniel Yaacobi1, Igor Vainer1, Aviram Mizrachi 1,3, Aron Popovtzer 2,3, Ethan Soudry1,3
1
 Department of Otolaryngology - Head and Neck Surgery, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; 2 Davidoff Cancer
Center, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel


SUMMARY
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 meas-
ure 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 radia-
tion 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 sig-            Received: November 21, 2001
nificantly associated with radiation therapy.                                                     Accepted: October 28, 2022

KEY WORDS: nose, radiotherapy, long-term care, patient care                                       Correspondence
                                                                                                  Einav G. Levin
RIASSUNTO                                                                                         Department of Otorhinolaryngology - Head and
Obiettivo. Lo scopo dello studio è analizzare le complicazioni a lungo termine conseguenti        Neck Surgery
                                                                                                  Rabin Medical Center, Petah Tikva, Israel, 49100
al trattamento dei tumori maligni nasosinusali e i fattori di rischio associati a queste com-
                                                                                                  Tel. +972-3-937-6451
plicanze.                                                                                         E-mail: einav59@gmail.com
Metodi. È stata condotta un’analisi retrospettiva di tutti i pazienti trattati per un tumore
maligno nasosinusale in un centro di riferimento terziario tra il 2001 e il 2018. L’outcome
primario è stato il tasso di complicanze post-trattamento a lungo termine.                          How to cite this article: Levin EG, Tzelnick
Risultati. Nel complesso, le complicazioni a lungo termine sono state riscontrate in 41             S, Yaacobi D, et al. Long-term complications
pazienti (53%), e le più frequenti sono state le sinonasali (22 pazienti, 29%) e orbitarie/         associated with the management of sinonasal
                                                                                                    malignancies: a single center experience. Acta
oculari (18 pazienti, 23%). In un’analisi multivariata, la radioterapia è stato l’unico fattore
                                                                                                    Otorhinolaryngol Ital 2023;43:203-211. https://
predittivo di complicazioni a lungo termine (p = 0,001, OR = 18,86, CI = 3,31-107,6). Non           doi.org/10.14639/0392-100X-N1902
sono invece state riscontrate correlazioni con lo stadio del tumore, il trattamento chirurgi-
co, o la dose/modalità della radioterapia. Una dose media > 50 Gy al nervo ottico è asso-         © Società Italiana di Otorinolaringoiatria
ciata con un calo dell’acuità visiva di grado ≥ 3 (100% vs 3%; p = 0,006). La radioterapia        e Chirurgia Cervico-Facciale
per il trattamento delle recidive è associata ad un rischio addizionale di complicanze a
lungo termine (56% vs 11%; p = 0,04).                                                                            OPEN ACCESS
Conclusioni. Il trattamento dei tumori maligni nasosinusali presenta un alto rischio di
                                                                                                  This is an open access article distributed in accordance with
complicanze a lungo termine, che è significativamente correlato al trattamento radiotera-         the CC-BY-NC-ND (Creative Commons Attribution-Non-
pico.                                                                                             Commercial-NoDerivatives 4.0 International) license. The
                                                                                                  article can be used by giving appropriate credit and mentio-
PAROLE CHIAVE: nasosinusale, radioterapia, cura a lungo termine, cura del paziente                ning the license, but only for non-commercial purposes and
                                                                                                  only in the original version. For further information: https://
                                                                                                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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E.G. Levin et al.




Introduction                                                    term complications following management for disease re-
                                                                currence. Long-term complications were defined as those
Sinonasal malignancies (SNMs) comprise less than 3% of
                                                                that lasted over 6 months following management or appear-
head and neck cancers 1. Most SNMs originate from the
                                                                ing ≥ 6 months post-treatment.
nasal cavity, followed by the maxillary and ethmoid sinus-
                                                                Chronic rhinosinusitis (CRS) was defined according to the
es 2,3. The majority of patients present with advanced-stage
                                                                International Consensus Statement on Allergy and Rhinol-
disease. The management of SNMs is challenging owing to
                                                                ogy: Rhinosinusitis 16. Radiation-induced toxicity was eval-
their histologic diversity and anatomical proximity to the
                                                                uated with the Common Terminology Criteria for Adverse
orbit and critical neurovascular structures 4,5. SNMs are as-
                                                                Events (CTCAE) version 5.0 17. Orbital complications were
sociated with a significant recurrence rate of 30%, and high
                                                                defined as a manifestation that involved the orbit and orbital
rates of morbidity and mortality reaching up to 40% 6,7.
                                                                adnexa. Ocular complications included radiation-induced
Therapeutic management of SNMs includes surgery, ra-
                                                                visual acuity impairment (VAI), cataract, retinopathy and
diotherapy (RT) and chemoradiotherapy (CRT). Surgical
                                                                keratoconjunctivitis sicca.
treatment, when feasible, constitutes an essential part of
management 8,9. Adjuvant RT/CRT is frequently used in
                                                                Statistical analysis
advanced-stage or positive margins diseases. Multimodal
therapy, consisting of surgery and adjuvant RT/CRT, is as-      Data was analysed using the Statistical Package for the
sociated with improved prognosis 10-14.                         Social Sciences (SPSS) software v.23.0 (IBM Corp. Ar-
Despite the complexity of SNMs, treatment-related long-         monl, NY). Associations between categorical variables
term complications are scarcely reported in the literature.     were examined using c2 test or Fisher’s exact test. Associa-
The present study aims to investigate the treatment-related     tions between continuous variables were examined using
long-term complications in patients with primary and re-        the Mann-Whitney non-parametric test. Predictive factors
current SNMs.                                                   associated with long-term complications were evaluated
                                                                using univariate and multivariate binary logistic regres-
                                                                sions. Odds ratio (OR) and 95% confidence interval (CI)
Materials and methods                                           were analysed. A two-sided p-value < 0.05 was considered
Study design and subjects                                       significant.
This was a retrospective analysis of all patients treated for
SNMs at a tertiary centre between 2001 and 2018 follow-         Results
ing approval by the local Institutional Review Board. Pa-
tients were included in the study if they had a primary SNM     Patients and tumour characteristics
with minimum follow-up period of 6 months between treat-        The cohort included 77 patients. Median age was 65.2 years
ment to data collection or death. Patients with insufficient    (range, 22-96), and the male-to-female ratio was 1.33:1.
follow-up data were excluded.                                   Mean follow-up time was 48.5 months (range, 7-219).
Our follow-up protocol included nasal endoscopy every 2-3       Squamous cell carcinoma (SCC) was the most common
months and CT or MRI every 6 months during the first two        tumor histology in 35 patients (45.5%). Most SNMs origi-
years post-treatment. Subsequently, nasal endoscopy was         nated from the nasal cavity (36 patients, 47%) and the ma-
performed every 4-6 months until 5 years post-treatment,        jority of patients presented with advanced-stage SNM (48
and then annually. Imaging was performed at 6-12 months         patients, 62%). Clinical characteristics of the study popula-
intervals during long-term follow-up. In 2012, PET-CT           tion are presented in Table I.
every 6-12 months was introduced for the surveillance pro-
tocol of aggressive histologies such as mucosal melanomas       Treatment modalities
or poorly differentiated carcinomas.                            The most common treatment modality was surgery with or
                                                                without adjuvant RT/CRT (64 patients, 83%) (Tab. I), and
Data collection                                                 the remaining patients received definitive RT/CRT. Surgical
Data collected included demographics, tumour charac-            modalities used were: external approach in 32 patients (50%)
teristics, surgical and oncological treatment details, post-    (five of whom underwent anterior maxillary wall reconstruc-
treatment complications and outcomes. Comorbidity was           tion with a fibula free flap); endoscopic approach in 27 pa-
evaluated with the Charlson Comorbidity Index 15. Compli-       tients (42%) and a combined approach in 5 patients (8%).
cations were assessed retrospectively by chart review. The      Of 60 irradiated patients, 37 (62%) were treated with inten-
primary outcome measure was post-treatment long-term            sity-modulated radiation therapy (IMRT). Eleven patients
complications. The secondary outcome measure was long-          received concomitant neck irradiation (14%).



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                                                                                                             Treatment complications of sinonasal malignancies




Table I. Clinical characteristics of patients with sinonasal malignancies.               end of treatment and the onset of the complications was 7.3
 Characteristics                                           All patients                  months (range, 0.4-24.1). In 5 patients (12.2%), treatment-
                                                             (n = 77)                    related complications were observed during treatment and
 Males, no. (%)                                                   44 (57)                lasted longer than 6 months post-treatment. The incidence
 Median age, years (range)                                       65 (22-96)              was significantly higher in patients with advanced-stage dis-
 Smoker, no. (%)                                                  28 (36)                ease compared to patients with early-stage disease (62.5%
 CCI > 2, no. (%)                                                 45 (58)                vs 38%, p = 0.036). Table II summarises the long-term com-
 Histology, no. (%)                                                                      plications. The most common were sinonasal complications
   SCC                                                           35 (45.5)               (22 patients, 29%). Sixteen patients (21%) suffered from
   Sarcoma                                                        10 (13)                CRS, the majority of whom had received RT/CRT with or
   Mucosal melanoma                                               9 (12)                 without surgery (14 patients, 87.5%). Seven patients ul-
   Esthesioneuroblastoma                                          8 (10)                 timately underwent endoscopic sinus surgery (ESS). Ten
   Adenoid cystic carcinoma                                       5 (6.5)                (13%) patients, of whom four with CRS as well, suffered
   SNUC                                                            3 (4)
                                                                                         from radiation-induced intranasal synechiae resulting in na-
                                                                                         sal obstruction requiring surgical intervention.
   Adenocarcinoma                                                  2 (3)
                                                                                         Orbital-related complications (16 patients, 21%) included
   Chondrosarcoma                                                  2 (3)
                                                                                         epiphora (12 patients), three of whom requiring dacryo-
   Acinic cell carcinoma                                           1 (1)
                                                                                         cystorhinostomy (DCR), chronic pain (3 patients), ptosis
   Mucoepidermoid carcinoma                                        1 (1)
                                                                                         (2 patients), diplopia (2 patients) and ectropion (1 patient).
   Sarcomatoid carcinoma                                           1 (1)
                                                                                         These complications occurred more often in patients treat-
 Tumour location, no. (%)                                                                ed with surgery and adjuvant RT compared to surgery alone
   Nasal cavity                                                    36 (47)               (32% vs 0%; p = 0.009).
   Maxillary sinus                                                 24 (31)               Ocular complications (8 patients, 10%) included radia-
   Ethmoid sinus                                                   9 (12)                tion-induced grade ≥ 3 VAI (5 patients), radiation-induced
   Sphenoid sinus                                                   5 (6)                grade ≥ 2 keratoconjunctivitis sicca (4 patients), grade ≥ 3
   Frontal sinus                                                    3 (4)                retinal detachment following radiotherapy (2 patients), and
 Tumour stage, no. (%)                                                                   radiation-induced grade 3 cataract (1 patients). One patient
   Stage I                                                       15 (19.5)               underwent orbital exenteration due to radiation-induced
   Stage II                                                       14 (18)                toxicity. VAI occurred more often in T4 disease compared
   Stage III                                                      13 (17)                to T1-3 disease (15% vs 0%; p = 0.012).
   Stage IV                                                      35 (45.5)               Four patients (5%) suffered from post-radiation grade
 Management, no. (%)                                                                     ≥ 3 trismus, leading to feeding tube insertion. Radiation-
   Surgery alone                                                   17 (22)               induced grade ≥ 3 dysphagia was identified in 7 patients
   Surgery with adjuvant RT                                        31 (40)               (9%) who presented with weight loss and malnutrition, and
   Surgery with adjuvant CRT                                       16 (21)               occurred more often in patients treated with definitive RT/
   Definitive RT/CRT                                               13 (17)
                                                                                         CRT compared to other patients (31% vs 4%, p = 0.013).
                                                                                         Six patients were temporarily managed with nasogastric
 Radiation modality, no. (%)
                                                                                         tube insertion or parenteral nutrition, and one patient with
   External beam radiation                                         23 (38)
                                                                                         severe dysphagia (grade 4) admitted for percutaneous en-
   IMRT                                                            37 (62)
                                                                                         doscopic gastrostomy (PEG) tube insertion.
 Radiation dose, no. (%)
                                                                                         Grade ≥ 3 osteoradionecrosis of the maxillary bone was ob-
 < 60 Gy                                                           12 (25)               served in 5 patients (6.5%), two of whom underwent maxil-
 ≥ 60 Gy                                                           36 (75)               lectomy and free flap reconstruction. Three patients were
CCI: Charlson comorbidity index; SCC: squamous cell carcinoma; SNUC: sinonasal undif-
ferentiated carcinoma; RT: radiotherapy; CRT: chemoradiotherapy; IMRT: intensity-modu-
                                                                                         treated with hyperbaric oxygen therapy, and two patients
lated radiation therapy; Gy: Gray.                                                       underwent surgical debridement of necrotic bone.
                                                                                         Three patients (4%) presented with radiation-induced grade
                                                                                         ≥ 2 neuropathy of the trigeminal nerve branches, leading to
Long-term complications                                                                  hypoesthesia of V2 (2 patients) and V1 (one patient) ter-
Overall, 41 patients (53%) suffered from long-term post-                                 ritories.
treatment-related complications, of which 17 patients (41%)                              Other long-term complications included hyposmia (4 pa-
required surgical intervention. The mean time between the                                tients, 5%), facial or neck radiation-induced grade ≥ 2



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E.G. Levin et al.




Table II. Long-term complications of patients with sinonasal malignancies.
 Complications                                All patients Surgery alone                        Surgery with         Surgery with adjuvant           Definitive RT               P
                                               (n = 77)          (n = 17)                       adjuvant RT                  CRT                         / CRT
                                                                                                  (n = 31)                 (n = 16)                    (n = 13)
 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 compli-
cations included visual acuity impairment, keratoconjunctivitis sicca, retinal detachment and cataract.




hyperpigmentation or dermatitis (3 patients, 4%), and radi-                                      Predictive factors for long-term post-management
ation-induced hypothyroidism (2 patients, 3%). Radiation-                                        complications
induced hypothyroidism was associated with radiation to                                          Univariate and multivariate logistic regression analyses
the neck (18% vs 0%; p = 0.019).                                                                 were conducted to identify predictive factors of long-term
                                                                                                 post-treatment complications. In a univariate regression
Treatment modality and long-term complications                                                   model that included all patients (Tab. III), radiation therapy
Overall, long-term complications occurred mostly in pa-                                          and advanced-stage disease (p = 0.001, p = 0.039, respec-
tients treated with adjuvant or definitive RT/CRT com-                                           tively) were identified as significant predictors of long-term
pared to patients treated with surgery alone (65% vs 12%;                                        post-treatment complications. Variables with a two-sided
p < 0.001) (Tab. II). No significant differences in the rate of                                  p-value < 0.2 from univariate analysis were included in
long-term complications were observed between RT only                                            a multivariate analysis (smoking, disease stage, radiation
compared to CRT (62.5% vs 70%; p = 0.566), between                                               therapy and radiation modality). Radiation therapy was
definitive or adjuvant RT/CRT (53% vs 68%; p = 0.35),                                            the only factor significantly associated with an increased
                                                                                                 risk for long-term complications (p = 0.001, OR = 18.86,
or IMRT versus external beam radiation therapy (EBRT)
                                                                                                 CI = 3.31-107.6).
(73% vs 52%; p = 0.101).
                                                                                                 In a univariate regression model that included only irradiat-
Of 64 surgically-treated patients (83%), 34 suffered from
                                                                                                 ed patients (60 patients), no significant predictors of long-
long-term complications (53%), the vast majority of whom
                                                                                                 term post-treatment complications were identified. Defini-
received adjuvant therapy (32 patients, 94%). The correla-
                                                                                                 tive vs adjuvant therapy, RT vs CRT and higher radiation
tion between surgical modality (open, endoscopic or com-                                         doses were not associated with long-term complications
bined approaches) and long-term complications rate was                                           (p = 0.344, p = 0.567, p = 0.372, respectively).
not statistically significant (56% vs 52% vs 40%; p = 0.805).                                    In a univariate regression model that included only patients
Of note, of 22 patients who suffered from long-term sinon-                                       treated with post-operative adjuvant RT/CRT (47 patients),
asal complications, in 18 (82%) the initial treatment modal-                                     no variables were identified as significant predictors of
ity was surgical (7 open, 10 endoscopic, one combined),                                          long-term post-treatment complications. Type of surgical
with the majority receiving post-operative RT/CRT (16/18                                         approach was not associated with long-term complications
patients). In 4 patients, the initial treatment modality was                                     (p = 0.467).
definitive RT/CRT (18%). Type of surgical approach was
not associated with long-term sinonasal complications                                            Radiation field analysis
(22% vs 37% vs 20%; p = 0.442).                                                                  Total radiation doses were available in 48 cases (80%), and



206
                                                                                                                              Treatment complications of sinonasal malignancies




Table III. Predictive factors for long-term complications
                                          All patients        No complications           Complications                    Univariate                           Multivariate†
                                           (N = 77)               (N = 41)                 (N = 36)                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.




radiation fields doses in 34 cases (57%). Median planning                                       to one patient who received a mean radiation dose < 50 Gy
target volume (PTV) radiation dose were overall 64.8 Gy                                         (100% vs 3%; p = 0.006).
(range, 42-70.8; SD, 13.85), 68.7 Gy (range, 61-71; SD,                                         Analysis of the impact of the mean PTV revealed that high ra-
4.06) for 7 patients who received definitive treatment, and                                     diation doses (> 60 Gy) were not associated with an increased
65.0 Gy (range, 42-71; SD, 7.84) for 41 patients who re-                                        rate of long-term complications (72% vs 58%; p = 0.476).
ceived adjuvant treatment. Median radiation doses were
30.5 Gy to the optic nerve (range, 0.6-72.5), 25.4 Gy to the                                    Long-term complications associated with treatment
chiasm (range, 2.5-51.1) and 17.4 Gy to the orbits (range,                                      for recurrent disease
0.3-52.8).                                                                                      Disease recurrence was noted in 24 patients (31%): 15 pa-
Figure 1 illustrates the mean doses to the optic nerve in                                       tients with local recurrence (62%), 5 patients with locore-
patients with and without radiation-induced grade ≥ 3 VAI.                                      gional recurrence (21%) and 4 patients with distant metas-
All patients who received a mean radiation dose ≥ 50 Gy                                         tases (17%). SCC was the most common tumor histology
to the optic nerve presented with grade ≥ 3 VAI compared                                        (9 patients, 37.5%), followed by mucosal melanoma (7 pa-



                                                                                                                                                                                   207
E.G. Levin et al.




                                                                                          Discussion
                                                                                          The long-term complications associated with the manage-
                                                                                          ment 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 in-
                                                                                          creased risk for post-treatment long-term complications.
                                                                                          Interestingly, although endoscopic resection of SNMs al-
                                                                                          lows detailed visualisation of sinonasal anatomy and pres-
                                                                                          ervation of uninvolved structures compared to open ap-
                                                                                          proaches, the literature lacks data comparing the long-term
Figure 1. Mean doses to the optic nerve in patients with and without radia-               complications associated with these approaches. In the
tion-induced grade ≥ 3 visual acuity impairment. Gy: Gray.                                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
tients, 29%), and esthesioneuroblastoma (3 patients, 12.5%).
                                                                                          concealed the effect of surgical modality on these compli-
Management and complications of patients with disease re-                                 cations. This thus underscores the impact of adjuvant RT/
lapse are demonstrated in Table IV. The common therapeutic                                CRT on long-term complications.
modality for disease recurrence was surgery with or without                               Only a few studies have reported radiation-induced toxici-
adjuvant therapy (15 patients, 62.5%). Three patients died                                ties in SNM patients. Patel et al. 19 analysed radiation-in-
before treatment could be administered. Long-term com-                                    duced complications in129 patients with SNMs and report-
plications associated with treatment for disease recurrence                               ed 21% high-grade radiation toxicity rate (ocular toxicities,
was documented in 9 patients (37.5%). The most common                                     dermatitis and dysphagia), and 32% treatment-related
were grade ≥ 3 dysphagia in additional 3 patients (12.5%)                                 sinonasal complications. However, they did not differenti-
and radiation-induced grade ≥ 2 hypoesthesia associated                                   ate between acute and long-term complications, in contrast
with the maxillary division of the trigeminal nerve (V2) in                               to our study analysing only long-term (> 6 months) com-
an additional 2 patients (8%). A higher rate of new long-term                             plications. Askoxylakis et al. 20 reported their experience
complications was observed in irradiated patients compared                                with 122 patients with SNMs managed by IMRT with or
to non-irradiated patients (56% vs 11%; p = 0.04).                                        without surgery. They observed 34.4% late toxicities (> 90


Table IV. Post-treatment long-term complications for disease recurrence.
 Complications*                             All         Surgery with     Definitive                  Surgery with          Surgery         Surgery with          Definitive
                                         patients        adjuvant RT         RT                      adjuvant CRT           alone          adjuvant CT              CRT
                                        (n = 24)**         (n = 5)        (n = 5)                       (n = 4)            (n = 4)            (n = 2)             (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.




208
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days) including dysgeusia or dysosmia, and 34% ocular            increased risk of acute and late high-grade radiation toxic-
toxicities, including chronic tearing, vision reduction, light   ity on multivariate analysis was age < 65 years.
sensitivity and cataract. Nonetheless, 32% of these patients
were treated for recurrent tumours, and probably bias-           Site-specific long-term complications
ing towards an increased complication rate. In our study,        Sinonasal complications including chronic rhinosinusitis
primary and recurrent patients were analysed separately          and intranasal synechiae were the most common long-term
and long-term complications were defined as those over 6         complications encountered in our study cohort. Nearly all
months post-treatment. Lastly, Sharma et. al. 21, analysing      received adjuvant or definitive RT/CRT, and no correla-
late toxicities (6.4 years post treatment) in a small group      tion was found between treatment modality and long-term
of 27 patients with SNMs, reported that 81% of patients          sinonasal complications. Ultimately, most patients under-
with SNMs treated with IMRT suffered from late toxicity,         went surgery to treat these complications. Patel et al.19
including 19% ocular toxicity, 22% radiation-related hy-         found that early and late sinonasal complications, includ-
popituitarism, 11% impaired olfactory function, and 63%          ing secondary sinusitis and nasal stenosis, occurred more
impaired cognitive and physical function. They concluded         often in patients who were treated by CRT with or without
that although radiotherapy has improved over the last dec-       surgery compared to surgery alone, although no association
ade, long-term toxicity remains considerable. Yet, none of       with radiation modality or dose was found, similar to our
the above studies, analysed the contribution of surgery and      study.
surgical modality to long-term complications.                    Additional site-specific long-term complications observed
In recent years, the role of particle-beam radiation therapy     in our study included orbital and ocular complications,
(PBRT) typically using accelerated proton or carbon-ion          dysphagia, trismus, osteoradionecrosis, cranial neuropa-
has been studied in the treatment of patients with SNMs 22,23.   thies and hypothyroidism. Orbital-related complications
Hu et. al. 22 analysed disease control and toxicity profiles
                                                                 were found more often in patients treated with surgery and
of 111 patients with SNMs treated with definitive or sal-
                                                                 adjuvant RT compared to surgery alone. The study results
vage PBRT, and found that 19.8% of patients experienced
                                                                 indicate a dose-response relationship for VAI among irra-
late toxicity, of whom only 3.6% suffered from grades 3-4
                                                                 diated patients. Grade ≥ 3 VAI occurred more often in pa-
late toxicity, including decreased vision, xerostomia and
                                                                 tients who received a high radiation dose above 50 Gy to
osteonecrosis. They concluded that PBRT results in a low
                                                                 the optic nerve compared to patients who received lower
toxicity rate and good disease control. Mirandola et al. 23
                                                                 doses. These findings are supported by other studies that
showed, based on normal tissue complication probability
                                                                 also found that radiation doses above 50-55 Gy to the optic
models and additional explanatory dose-volume histogram
parameters, that patients with locally advanced sinonasal        nerve increased the risk of radiation-induced optical neu-
cancer and orbital invasion could profit from proton therapy     ropathy and VAI 21,24. Hypothyroidism was associated with
compared to IMRT in terms of optical and central nervous         neck radiation, and radiation-induced dysphagia was ob-
system organs at risk sparing. These results warrant further     served significantly more often in patients receiving defini-
investigation as PBRT seems to offer similar disease con-        tive RT/CRT compared to other patients.
trol but with fewer long-term complications. However, at
present, the patients who may benefit the most from PBRT         Long-term morbidity with treatment for disease recurrence
modality should be selected wisely due to the higher costs       Compared to previous publications, we were also interest-
and limited availability of this radiation modality 23.          ed in analysing complications associated with treatment for
Analysis of risk factors for radiation-induced long-term         disease recurrence. Similar to previous studies 25,26, disease
complications in our patient cohort revealed that radiation      recurrence rate was 31% and the most common therapeutic
dose, radiation modality (IMRT vs external beam radia-           modality was surgery with or without adjuvant therapy. The
tion), and timing of radiation (adjuvant vs definitive) were     long-term complications rate in this subgroup was 37.5%,
not predictors of long-term complications. Advanced tu-          and the most common were dysphagia and cranial nerve V
mour stage and radiation therapy were the only factors sig-      neuropathy. Radiation therapy for disease recurrence was
nificantly associated with long-term complications in uni-       associated with a higher rate of additional long-term com-
variate analysis. In multivariate analysis, however, no risk     plications compared to non-radiation treatment. Popovtzer
factors for long-term complications, excluding radiation         et al. 27 reviewed 66 patients who underwent reirradiation
therapy, were identified. Patel et al. 19 observed that post-    therapy of recurrent head and neck cancers and found grade
treatment complications occurred more often in patients          ≥ 3 late complications among 19 patients (29%). Similar to
who underwent CRT and the only factor associated with an         our study, the most common complication was dysphagia.



                                                                                                                                 209
E.G. Levin et al.




Study limitations                                                  Available data
In this study, a comprehensive analysis of the treatment-re-       Data available on request from the authors.
lated long-term complications of SNMs and their risk fac-
tors, in both primary and recurrent tumours, was conducted.        References
We are aware that our small sample of patients, the study’s        1
                                                                        Resto VA, Deschler DG. Sinonasal malignancies. Otolaryn-
retrospective nature and heterogeneity of SNMs in terms of              gol Clin North Am 2004;37:473-487. https://doi.org/10.1016/
histology and treatment protocol limit the results. However,            S0030-6665(03)00159-2
as these tumours are rare, the majority of studies analysing       2
                                                                        López F, Lund VJ, Suárez C, et al. The impact of histologic phenotype
patients with SNM have similar limitations. Moreover, as                in the treatment of sinonasal cancer. Adv Ther 2017;34:2181-2198.
                                                                        https://doi.org/10.1007/s12325-017-0605-9
this topic has been scarcely studied, with few studies with        3
                                                                        Kilic S, Kilic SS, Baredes S, et al. Survival, morbidity, and quality-of-
mixed groups of patients, we believe this study provides val-           life outcomes for sinonasal and ventral skull base malignancies. Oto-
uable data for both surgeons and oncologists treating these             laryngol Clin North Am 2017;50:467-480. https://doi.org/10.1016/j.
patients when discussing treatment options and long-term                otc.2016.12.018
morbidities associated with the various treatment modalities.      4
                                                                        Khademi B, Moradi A, Hoseini S, et al. Malignant neoplasms of the
                                                                        sinonasal tract: report of 71 patients and literature review and analy-
                                                                        sis. Oral Maxillofac Surg 2009;13:191-199. https://doi.org/10.1007/
Conclusions                                                             s10006-009-0170-8
                                                                   5
                                                                        Danesh-Sani S-A, Sarafraz A, Chamani M, et al. Paranasal sinuses
SNM treatment-related long-term complications is substan-               malignancies: A 12-year review of clinical characteristics. Med Oral
tial and may have a considerable impact on quality of life of           Patol Oral Cirugia Bucal 2016;21:e626-e630. https://doi.org/10.4317/
                                                                        medoral.21170
patients. Irradiation therapy appears to be the dominant risk      6
                                                                        Myers LL, Nussenbaum B, Bradford CR, et al. Parana-
factor irrespective of radiation dose or radiation modality. Ra-        sal sinus malignancies: an 18-year single institution ex-
diation therapy for disease recurrence was associated with a            perience.      Laryngoscope        2002;112:1964-1969.        https://doi.
high rate of complications as well. Future studies focusing on          org/10.1097/00005537-200211000-00010
therapeutic modalities minimising morbidity are warranted.         7
                                                                        Dulguerov P, Jacobsen MS, Allal AS, et al. Nasal and parana-
                                                                        sal sinus carcinoma: are we making progress? A series of 220
                                                                        patients and a systematic review. Cancer 2001;92:3012-3029.
Conflict of interest statement                                          https://doi.org/10.1002/1097-0142(20011215)92:12<3012::aid-
The authors declare no conflict of interest.                            cncr10131>3.0.co;2-e
                                                                   8
                                                                        Contrera KJ, Woody NM, Rahman M, et al. Clinical management of
                                                                        emerging sinonasal malignancies. Head Neck 2020;42:2202-2212.
Funding                                                                 https://doi.org/10.1002/hed.26150
This research did not receive any specific grant from funding      9
                                                                        Castelnuovo P, Turri-Zanoni M, Battaglia P, et al. Sinonasal malignan-
agencies in the public, commercial, or not-for-profit sectors.          cies of anterior skull base: histology-driven treatment strategies. Oto-
                                                                        laryngol Clin North Am 2016;49:183-200. https://doi.org/10.1016/j.
Author contributions                                                    otc.2015.09.012
                                                                   10
                                                                        Bossi P, Saba NF, Vermorken JB, et al. The role of systemic therapy
ES, EGL: had full access to all the data in the study and
                                                                        in the management of sinonasal cancer: a critical review. Cancer Treat
take responsibility for the integrity of the data and the ac-           Rev 2015;41:836-843. https://doi.org/10.1016/j.ctrv.2015.07.004
curacy of the data analysis; EGL, ES: concept and design;          11
                                                                        Robin TP, Jones BL, Gordon OM, et al. A comprehensive compara-
EGL, DY, IV: data collection; EGL, ES: analysis and inter-              tive analysis of treatment modalities for sinonasal malignancies:
pretation of data; EGL: drafting of the manuscript; ST, AM,             NCDB Analysis of Sinonasal Malignancies. Cancer 2017;123:3040-
                                                                        3049. https://doi.org/10.1002/cncr.30686
AP, ES: critical revision of the manuscript for important          12
                                                                        Paré A, Blanchard P, Rosellini S, et al. Outcomes of multimodal man-
intellectual content; EGL: statistical analysis; ST: adminis-           agement for sinonasal squamous cell carcinoma. J Craniomaxillofac
trative, technical, or material support; ES: supervision.               Surg 2017;45:1124-1132. https://doi.org/10.1016/j.jcms.2017.05.006
                                                                   13
                                                                        Lund VJ, Clarke PM, Swift AC, et al. Nose and paranasal sinus tu-
Ethical consideration                                                   mours: United Kingdom National Multidisciplinary Guidelines.
                                                                        J Laryngol Otol 2016;130:S111-S118. https://doi.org/10.1017/
This study was approved by the Institutional Ethics Com-                S0022215116000530
mittee of the Rabin Medical Center, Israel (protocol num-          14
                                                                        Lee MM, Vokes EE, Rosen A, et al. Multimodality therapy in ad-
ber 0044-18-RMC).                                                       vanced paranasal sinus carcinoma: superior long-term results. Cancer
The research was conducted ethically, with all study pro-               J Sci Am 1999;5:219-223.
cedures being performed in accordance with the require-
                                                                   15
                                                                        Austin SR, Wong YN, Uzzo RG, et al. Why summary comorbid-
                                                                        ity measures such as the charlson comorbidity index and Elixhauser
ments of the World Medical Association’s Declaration of                 score work. Med Care 2015;53:E65-72. https://doi.org/10.1097/
Helsinki.                                                               MLR.0b013e318297429c




210
                                                                                                        Treatment complications of sinonasal malignancies




16
     Orlandi RR, Kingdom TT, Hwang PH, et al. International Consensus         22
                                                                                   Hu W, Hu J, Huang Q, et al. Particle beam radiation therapy for sinon-
     Statement on allergy and rhinology: rhinosinusitis. Int Forum Allergy         asal malignancies: single institutional experience at the Shanghai Pro-
     Rhinol 2016;6(Suppl. 1):S22-209. https://doi.org/10.1002/alr.21695.           ton and Heavy Ion Center. Cancer Med 2020;9:7914-7924. https://
17
     Common Terminology Criteria for Adverse Events (CTCAE). No-                   doi.org/10.1002/cam4.3393
     vember 27, 2017. https://ctep.cancer.gov/protocolDevelopment/elec-       23
                                                                                   Mirandola A, Russo S, Bonora M, et al. A patient selection approach
     tronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf.                 based on ntcp models and dvh parameters for definitive proton ther-
     Accessed April 15, 2019.                                                      apy in locally advanced sinonasal cancer patients. Cancers (Basel)
18
     Meccariello G, Deganello A, Choussy O, et al. Endoscopic nasal ver-           2022;14:2678. https://doi.org/10.3390/cancers14112678
     sus open approach for the management of sinonasal adenocarcino-          24
                                                                                   Danesh-Meyer HV. Radiation-induced optic neuropathy. J Clin Neu-
     ma: a pooled-analysis of 1826 patients. Head Neck 2016;38:E2267-              rosci 2008;15:95-100. https://doi.org/10.1016/j.jocn.2007.09.004
     E2274. https://doi.org/10.1002/hed.24182                                 25
                                                                                   Zocchi J, Pietrobon G, Campomagnani I, et al. The role of a post ther-
19
     Patel J, Chitguppi C, Vimawala S, et al. Treatment-related morbidity          apeutic surveillance program for sinonasal malignancies: analysis of
     in patients treated for sinonasal malignancy. Int Forum Allergy Rhinol        417 patients. Head Neck 2020;42:963-973. https://doi.org/10.1002/
     2020;10:526-532. https://doi.org/10.1002/alr.22509                            hed.26069
20
     Askoxylakis V, Hegenbarth P, Timke C, et al. Intensity modulated ra-     26
                                                                                   Meng X-J, Ao H-F, Huang W-T, et al. Impact of different surgical and
     diation therapy (IMRT) for sinonasal tumors: a single center long-term        post-operative adjuvant treatment modalities on survival of sinona-
     clinical analysis. Radiat Oncol 2016;11:17. https://doi.org/10.1186/          sal malignant melanoma. BMC Cancer 2014;14:608. https://doi.
     s13014-016-0595-9                                                             org/10.1186/1471-2407-14-608
21
     Sharma MB, Jensen K, Urbak SF, et al. A multidimensional co-             27
                                                                                   Popovtzer A, Gluck I, Chepeha DB, et al. The pattern of failure after
     hort study of late toxicity after intensity modulated radiotherapy            reirradiation of recurrent squamous cell head and neck cancer: im-
     for sinonasal cancer. Radiother Oncol 2020;151:58-65.https://doi.             plications for defining the targets. Int J Radiat Oncol 2009;74:1342-
     org/10.1016/j.radonc.2020.07.029                                              1347. https://doi.org/10.1016/j.ijrobp.2008.10.042




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