Long-Term Outcomes of Endoscopic Resection versus Open Surgery for Locally Advanced Sinonasal Malignancies in Combination with Radiotherapy

Abstract Objective  Our objective was to compare the long-term outcomes of endoscopic resection versus open surgery in combination with radiotherapy for locally advanced sinonasal malignancies (SNMs). Methods  Data for continuous patients with sinonasal squamous cell carcinoma and adenocarcinoma who received surgery (endoscopic or open surgery) combined with radiotherapy in our center between January 1999 and December 2016 were retrospectively reviewed. A 1:1 matching with propensity scores was performed. Overall survival (OS), progression-free survival (PFS), and local recurrence rate (LRR) were evaluated. Results  We identified 267 eligible patients, 90 of whom were included after matching: 45 patients in the endoscopy group and 45 in the open group. The median follow-up time was 87 months. In the endoscopic group, 84.4% of patients received intensity-modulated radiotherapy (IMRT), with a mean gross tumor volume (GTV) dose of 68.28 Gy; in the open surgery group, 64.4% of patients received IMRT, with a mean GTV dose of 64 Gy. The 5-year OS, PFS, and LRR were 69.9, 58.6, and 24.5% in the endoscopic group and 64.6, 54.4, and 31.8% in the open surgery group, respectively. Multivariable regression analysis revealed that the surgical approach was not associated with lower OS, PFS, or LRR. The overall postoperative complications were 13% in the endoscopic group, while 21.7% in the open group. Conclusion  For patients with locally advanced SNMs, minimally invasive endoscopic resection, in combination with a higher radiation dose and new radiation techniques such as IMRT, yields survival outcomes similar to those of open surgery in combination with radiotherapy.


Introduction
][3] Due to the insidiousness of these tumors in the early stage, patients are frequently diagnosed at locally advanced stages.Based on evidence from some retrospective studies, a combination of surgery and radiotherapy is the mainstay of sinonasal cancer management. 4ecause of the complexity of the sinonasal anatomy, open surgery has traditionally been regarded as the standard treatment to achieve en bloc resection. 5However, these patients are at high risk for developing postoperative complications as well as facial incisions and scarring.With advances in endoscopic surgical techniques, imaging guidance, and reconstruction methods, minimally invasive surgery has been introduced over the past two decades as an alternative to open surgery for the treatment of advanced sinonasal malignancies (SNMs).0][11] However, a challenge with endoscopic surgery is that tumors cannot be removed en bloc in some cases.Nevertheless, some studies have indicated that en bloc procedures are not always indispensable and that piecemeal resection is acceptable if radical removal of the tumor is guaranteed. 12,13In recent years, an increasing number of groups have begun to explore the application of endoscopic surgery for locally advanced malignant nasal cavities and paranasal sinus tumors.However, for patients with locally advanced SNMs, it remains unknown whether outcomes of endoscopic surgery combined with radiotherapy are equivalent to those of open surgery combined with radiotherapy.
Theoretically, a combination of endoscopic resection with radiotherapy offers some advantages; for example, the lesion can tolerate higher radiation doses than the open wound after surgery, which may result in a high local control rate.Due to a shorter healing time and fewer adverse events, endoscopic surgery offers the benefit of significantly decreased delays in adjuvant radiotherapy compared with open surgery. 14Moreover, new radiation techniques such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy, tomotherapy, and proton-beam therapy enable achieving well-defined and steep dose gradients close to the target volumes. 15,16egardless, randomized controlled trials comparing endoscopic surgery with open surgery are lacking to date, and previous observational studies have been limited by high heterogeneity regarding histopathologic subtype, tumor staging, adjuvant therapy, and short follow-up times.We assessed long-term survival outcomes after endoscopic versus open surgery using propensity score analysis to minimize bias.Furthermore, to the best of our knowledge, this is the largest report on the clinical effect of endoscopic surgery versus open surgery combined with radiotherapy for locally advanced SNMs.Finally, our study provides insight into Asian populations, whereas other studies have mainly involved Western populations.

Patients
This was a retrospective study (►Fig.1).Between January 1999 and December 2016, all consecutive patients at stage T3-4b (according to the 8th edition of the American Joint Committee on Cancer staging system) who underwent a combination of surgery and radiotherapy with squamous cell carcinoma (SCC) and adenocarcinoma (AC) from the nasal cavity and paranasal sinus in our center were included.Patients were excluded if they had a newly diagnosed malignant tumor in the previous 5 years or if follow-up information was incomplete.This study was approved by the local institutional review board.

Treatment
After clinical assessment and review of additional investigations, the multidisciplinary team decided on the final treatment modality.
The commonly used open surgical approaches included the lateral rhinotomy and maxillary swing approach.Based on the Weber-Ferguson approach, the incision can extend to Lynch incision, lower eyelid/upper eyelid incision, or upper lip median incision.According to the origin sites of tumors, resection of the medial/lower/upper part of the maxilla, total maxillectomy, extended maxillectomy with or without orbital exenteration, skull-base or intracranial resection.Regarding endoscopic surgery, according to the tumor range indicated by endoscopy and imaging examination, debulking the tumor aimed to identify the tumor origin and create a working space.The surrounding structures that obstruct a clear view of the tumor, such as the uncinate plate, middle turbinate, and inferior turbinate, were also resected if necessary.When the skull base bone was infiltrated, endoscopic endonasal resection could be extended to include the skull base.Then, the resulting skull base defect was reconstructed, which was preferably performed using autologous materials.Surgery margins were checked by frozen sections, and the lesions were removed as completely as possible.
All patients underwent preoperative or postoperative radiotherapy.The target volumes were delineated using an institutional treatment protocol defined as follows: the primary gross tumor volume (GTVp), the tumor bed volume (GTVtb), and the involved lymph nodes (GTVnd) were determined by imaging, clinical and endoscopic findings.In the postoperative setting, the preoperative imaging, pan-endoscopy reports, intraoperative findings, and the final pathology results were used to inform the delineation of GTVtb, which encompassed the area of tumor involved.If the primary tumor invaded the orbital structure, pterygopalatine fossa, or brain parenchyma, preoperative radiotherapy was preferred.Postoperative radiotherapy was recommended for selected risk factors, including advanced T stage, perineural/ lymphatic/vascular invasion, nonnegative surgical margin, and multiple positive nodes with or without extranodal extension.The dose prescribed was 60 to 70 Gy delivered within 5 to 6 weeks at the planning target volumes of PGTV (PGTVp/PGTVnd/PGTVtb).When the tumor extended into the pterygopalatine fossa or orbit, the dose was increased to more than 60 Gy, and 70 Gy was often considered.Besides, higher doses of postoperative radiotherapy (RT) (70 Gy) were recommended for extranodal extension or positive margins.The normal tissue dose constraints are shown in ►Supplementary Material S1 (available in the online version).
Systemic therapy was administered at the discretion of the multidisciplinary team, based on clinicopathologic factors, patient comorbidities, and preference.In most cases, the patients were treated with 80 to 100 mg/m 2 intravenous cisplatin every 3 weeks for two to three cycles or 50 to 60 mg/m 2 intravenous cisplatin weekly for five to six cycles.Alternatively, the patients were treated with nimotuzumab at a dose of 200 mg/m 2 once per week for a total of six to seven cycles.

Outcomes
The primary objective was to separately assess survival outcomes between the endoscopic and open surgery groups.Overall survival (OS) was defined as the date of initial diagnosis to death due to any cause or the last follow-up.Progression-free survival (PFS) was defined as the date of diagnosis to the date of recurrence or death from any cause; patients who were lost to follow-up were censored.The local recurrence rate (LRR), which was defined as recurrence at the site of the initial primary tumor, was also analyzed.

Statistical Methods
Before matching, normally distributed continuous data were compared using the independent samples t-test; the results are presented as means with standard deviations.Nonnormally distributed continuous data were compared using the Mann-Whitney U test, and the results are presented as medians with interquartile ranges (IQRs).Categorical data, which are presented as frequencies with percentages, were compared using the chi-square test with correction for continuity when necessary.Univariate and multivariate analyses were performed to identify prognostic factors associated with OS, PFS, and LRR for the entire dataset.Variables with a p-value < 0.2 in univariate analysis were included in multivariate analysis using Cox regression.
Logistic regression was performed to estimate predictors of endoscopic or open surgery use.Propensity scores were calculated given the covariates of variables estimated from the logistic regression mentioned above (including primary site, histopathologic subtype, T-stage, and N-stage) using another logistic regression model with a caliper of 0.2; 1:1 matching was performed with the nearest-neighbor algorithm.After matching, normally distributed continuous data were compared using the paired-samples t-test. 17The Wilcoxon signed-rank test was used for nonnormally distributed continuous data; categorical data were compared with McNemar's test.OS and PFS are described by the Kaplan-Meier (KM) curve, and a comparison of survival probabilities was performed using a Cox proportional hazards model due to the matched nature of the data. 18he LRR, which was compared using the Fine and Gray test, is depicted as cumulative incidence plots.Death without the event of interest was considered a competing risk event.The statistical analyses were performed with SPSS version 26 (IBM Corp) and R version 3.2 (http://www.R-project.org).All analyses were two-sided, with a p-value < 0.05 indicating significance.

Propensity Score Matching Analysis and Oncologic Outcomes
Factors associated with the use of endoscopic and open surgery were examined using logistic regression models, and the primary site, histopathology subtype, and Tstage were retained in the regression model.Moreover, N-stage was considered an essential survival predictor and was also included in the propensity score calculation.The 1:1 matching for endoscopic surgery versus open surgery resulted in 45 matched pairs, and

Univariate and Multivariate Analyses
Factors associated with OS, PFS, and LR were estimated in proportional hazards models for the unmatched cohort.In univariate analysis, the surgical approach did not show a significant correlation with OS or PFS.There was still no difference in multivariate analysis after adjustment for age, primary site, histopathological subtype, T stage, N stage, and adjuvant chemotherapy.In multivariate analysis, age older than 60 years, T4b and SCC appeared to be independent negative prognostic factors for OS, though only T stage was an independent prognostic factor for PFS.SCC and early T-stage tumors had a lower risk of developing LR, and the surgical approach seemed to have no impact on LRR.The detailed multivariate analysis data are shown in ►Table 3.

Discussion
The long-term outcomes of patients with locally advanced SNMs who received endoscopic surgery combined with radiotherapy remain unclear.In this retrospective study, we found that in combination with a higher radiation dose and new radiation techniques such as IMRT, minimally invasive endoscopic resection yielded survival outcomes similar to those of open surgery for locally advanced sinonasal carcinoma.
0][21][22][23][24] In a meta-analysis, Rawal et al 24 evaluated 35 studies and found that the 2-and 5-year OS rates of patients who underwent endoscopic endonasal resection were similar and sometimes higher than those of patients who underwent open craniofacial resection.In their study, 63% of patients had T1/T2 tumors, but staging data were not available for 22% of the cohort.Moreover, the histopathologic subtype had a high degree of heterogeneity, with the majority being esthesioneuroblastoma.In another pooled analysis of 15 studies, Higgins et al 23 observed a similar 5-year OS between these two surgical management strategies in early-stage SCC and esthesioneuroblastoma.Meccariello et al 25 performed another pooled analysis, showing that compared with open surgery, endoscopic management is associated with better OS and disease-free survival (DFS) across almost all T stages.However, 54.2% of patients in the endoscopic surgery group had T1/T2 tumors, whereas 38% of patients in the open surgery group had T1/T2 tumors.Additionally, there was no T-stage information available for 33% of the patients.The proportion of patients who received adjuvant RT was also different in these two groups.By analyzing National Cancer Database, Kilic et al 21 found no difference in OS and DFS between the two approaches for patients with sinonasal SCC.Similar to the studies mentioned above, the proportion of clinical stage was significantly different between the endoscopy group and the open surgery group.Additionally, we could not determine from the results whether the patients received adjuvant RT or chemotherapy.
Furthermore, studies have reported higher rates of OS or disease-specific survival among patients undergoing endoscopic resection than those undergoing open surgery. 9,10Both of these studies included a higher proportion of early-stage tumors in the endoscopy group than in the open group, as they set strict inclusion criteria for selecting patients to receive endoscopic resection.Although smaller tumors are indeed more likely to be treated endoscopically, with the application of endoscopic surgery in SNMs, surgeons have begun to explore its use for locally advanced tumors.Patients with early-stage disease accounted for the majority in the endoscopic group, but some locally advanced patients still underwent endoscopic surgery in previous studies.Even in Kilic's study, 21 more patients with IVB received endoscopic surgery than open surgery.The author speculated that the reason is that the surgeons may have been more skilled in endoscopic technique and prefer this approach for SNM.Therefore, for patients with locally advanced sinonasal carcinoma who undergo endoscopic surgery, it remains unknown whether survival outcomes after adjuvant radiotherapy are comparable to those of open surgery combined with radiotherapy.Oncologic outcomes in our study were slightly worse than those in previous studies.The primary reason might be that we enrolled patients with T3-4b-stage disease and those other authors included all stages or more early-stage diseases.Hagemann et al 20 performed a KM analysis stratified by T stage and reported a 5-year OS of 73.2 and 52% for T3 and T4 tumors, respectively, which was consistent with our results.For local recurrence, our results were no worse than those of other studies.In their single-arm study, Nakamaru et al 11 found that the 5-year local control rate (LCR) was 92.9% for patients with highly selected early-stage sinonasal SCC who underwent endoscopic surgery.In AC, Grosjean et al 26 reported a 3-year LCR of 71% in the transfacial group and 81.4% in the endoscopic group (p ¼ 0.392).Age older than 60 years, T4b and SCC appeared to be independent negative prognostic factors for OS.SCC and early T-stage tumors had a lower risk of developing LR.In our study, 75.8% of patients with AC were ACC, which might explain SCC had better local control.ACC was considered a low-grade malignancy with a history of slow growth.Kotelnikov et al 27 reported that the salivary gland tumors had a slower growth rate than SCC.Even for the lung metastases from ACC, the tumor-doubling time was very long (86-1,064 days with an average of 393 days.). 28The results of previous studies 29,30 were similar to ours in that the oncologic outcomes of SCC were better than SCCs.According to our results, the surgical approach does not appear to have an impact on OS, PFS, or LRR.
Surgical margin status is regarded as an independent risk factor for recurrence and survival. 20,31,32Some scholars have found that these two surgical groups are similar in negative surgical margin rate, at approximately 70 to 80%. 19,21,22,29,33egretfully, the status of the surgical margin cannot be compared between the two surgical groups in our series because some patients in the open surgery group underwent preoperative radiotherapy, promoting a higher R0 resection rate. 33,34Although the preoperative radiotherapy strategy is inconsistent with the practice of surgery combined with postoperative radiotherapy adopted by most international institutions, it does not violate the multimodality therapy in advanced disease recommended by National Comprehensive Cancer Network Guidelines.As the largest cancer treatment center in Asia, the preoperative RT strategy has been successfully utilized for head and neck carcinoma for decades, 35,36 and the results of clinical practice show that preoperative radiotherapy can improve the orbital retention rate without affecting survival outcomes. 34,37Furthermore, in our study, the rate of negative surgical margins was lower than that previously reported, especially in the endoscopic group, which may be explained by the fact that we enrolled patients with T3-4b disease.However, the high positive margin rate did not affect local control or OS for patients in the endoscopic group.The following two factors may explain this result.On the one hand, more patients in the endoscopic group were treated with IMRT instead of 2D RT or 3D conformal radiotherapy.On the other hand, patients in the endoscopic group received higher radiation doses than those in the open group.][40] This study demonstrates no significant difference in postoperative complications based on the surgical approach.Previous studies reported similar complication rates and comparable types.Abdelmeguid et al 29 found that postoperative CSF leak occurred in 5.9% of patients, all of whom had a pure endoscopic surgery.A study 41 of 36 patients treated with endoscopic resection and 18 treated with open resection found a trend toward a lower complication rate in the endoscopic group (endoscopic: 5.6%; open: 23.1%).Hagemann et al 20 reported that the risk of intraoperative bleeding and postoperative bleeding and hematoma formation was higher for patients undergoing open surgery (35.4%) as compared with endoscopic cases (26%).In Nicolai et al's 9 cohort of 184 patients, the overall complication rate was 6% in the endoscopic group and 16% in the open approach.In addition, most of the previous studies 19,21,42 showed a reduction in the length of hospital stay in the endoscopic approach group.
Our analysis had several limitations.First, as we mentioned above, preoperative radiotherapy is not a mainstream treatment mode.Due to the treatment preference, rather than contraindications, of our multidisciplinary tumor board, no patients in the endoscopic group received preoperative radiotherapy.Nevertheless, based on our previous study revealing that preoperative or postoperative radiotherapy is not associated with survival outcomes in SNSCC, 34 we believe that this bias would not have much impact on the results of the comparative analysis in the current study.Second, the number of patients included in the propensity score analysis was limited; thus, limited statistical power may have contributed to the statistically nonsignificant comparisons.Thus, larger cohorts are required to validate the results.

Conclusion
In conclusion, for patients with locally advanced sinonasal carcinoma, minimally invasive endoscopic resection in combination with a higher radiation dose and new radiation techniques such as IMRT yields survival outcomes similar to those of open surgery in combination with radiotherapy.

Ethics Approval and Consent to Participate
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of Institutional Review Board of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academic of Medical Sciences, and Peking Union Medical College.Informed consent was obtained from all individual participants included in the study.
tests indicated negligible differences across all demographics and clinicopathological variables in the matched cohort.However, there were some differences in treatment-level characteristics.For the endoscopy group, IMRTwas applied in 84.4% of patients, and the median dose of PGTV was higher, at 69.96 Gy than in the open surgery group.Of the patients who underwent open surgery, 64.4% were treated with IMRT and the median dose of PGTV was 66 Gy.Before propensity score matching (PSM), the median follow-up time was 76 months (IQR: 45-98 months) for endoscopic surgery and 100 months (IQR: 60-136 months) for open surgery.The 5-year and 10-year OS rates were 69.9 and 44.7% for patients receiving endoscopic surgery and 64.6 and 56.1% for patients receiving open surgery (hazard ratio [HR] ¼ 0.10, 95% confidence interval [CI]: 0.590-1.671,p ¼ 0.98; ►Figs. 2 and 3).The 5 and 10-year LRRs were 24.5 and 43.4% for patients in the endoscopic group and 31.8 and 36.3% for patients in the open group, respectively (HR ¼ 0.79; 95% CI: 0.426-1.449;p ¼ 0.28; ►Fig. 4).After PSM, the median follow-up time was 75 months (IQR: 45-99 months) for endoscopic surgery and 99 months (IQR: 57-120 months) for open surgery.Sixteen patients in the endoscopic group and 14 in the open group died.The 5-and 10-year OS rates were 69.2 and 47.6% in the endoscopic group and 76.4 and 58.2% in the open group, respectively (HR ¼ 1.30; 95% CI: 0.634-2.666;p ¼ 0.47); 5-and 10-year PFS rates were 60.9 and 48.5% and 62.1 and 46.7% in the endoscopic and open groups, respectively (HR ¼ 0.93; 95% CI: 0.494-1.766;p ¼ 0.83).The 5-and 10-year LRR were 25.3and 45% in the endoscopic group and 28.3 and 42% in the open group, respectively (HR ¼ 0.73; 95% CI: 0.347-1.530;p ¼ 0.4).

Fig. 4
Fig. 4 Cumulative incidence of local recurrence before (A) and after PSM (B).PSM, propensity score matching.

Table 2
Treatment-level characteristics

Table 3
Multivariate analysis of predictors for OS, PFS, and LR