Postoperative Radiotherapy or Chemoradiotherapy Versus Surgery Only in Non-Metastatic Head and Neck Adenoid Cystic Carcinoma: A Retrospective Analysis

Postoperative Radiotherapy or Chemoradiotherapy Versus Surgery Only in Non-Metastatic Head and Neck Adenoid Cystic Carcinoma: A Retrospective Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Postoperative Radiotherapy or Chemoradiotherapy Versus Surgery Only in Non-Metastatic Head and Neck Adenoid Cystic Carcinoma: A Retrospective Analysis Jinzi Liang, Shuhan Zhao, Alejandro Andree Alcas Villena, Wenjing Wang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9254166/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The optimal postoperative treatment (POT) strategy for non-metastatic head and neck adenoid cystic carcinoma (HNACC) remains controversial. This study aimed to evaluate whether postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT) provide survival benefits compared with surgery only (SO) in patients with HNACC. Materials and methods This retrospective study analyzed patients with non-metastatic HNACC who underwent curative-intent surgery between 2011 and 2023. Patients were categorized into SO, PORT, and POCRT groups. PORT and POCRT were collectively referred to as radiotherapy (RT)-based POT in this study. Survival outcomes, including overall survival (OS), progression-free survival (PFS), local failure–free survival (LFFS), and distant metastasis–free survival (DMFS), were evaluated using Kaplan–Meier analyses and Cox proportional hazards models. Results A total of 114 patients were included, comprising 35 treated with SO, 42 with PORT, and 37 with POCRT. With a median follow-up of 51.0 months, no significant differences in OS, PFS, LFFS, or DMFS were observed among the three groups in the overall cohort (all P > 0.05). PNI independently predicted worse OS (HR 3.425, 95% CI 1.316–8.913, P = 0.012) and PFS (HR 2.196, 95% CI 1.060–4.549, P = 0.034). In PNI patients, RT-based POT significantly improved LFFS versus SO (P = 0.032), while POCRT showed no clear advantage over PORT. Conclusion Survival outcomes were comparable among SO, PORT, and POCRT in non-metastatic HNACC. Patients with PNI may derive greater local control benefit from RT-based POT, warranting prospective validation. HNACC Postoperative treatment Adjuvant chemotherapy Adjuvant radiotherapy Perineural invasion Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Adenoid cystic carcinoma (ACC) is a rare malignancy, representing approximately 1% of head and neck cancers and about 10% of salivary gland malignancies [ 1 , 2 ] . Head and neck adenoid cystic carcinoma (HNACC) represents the most common carcinoma histology of the minor salivary glands and also frequently arises from the major salivary glands [ 1 ] . Beyond the salivary glands, HNACC may also arise at extra-salivary head and neck sites, including the lacrimal gland, the sinonasal tract, ceruminous glands, and mucosal sites of the upper aerodigestive tract [ 1 ] . Although HNACC typically follows an indolent clinical course, local recurrence and distant metastasis may occur even 5–15 years after definitive treatment, and long-term survival declines substantially over time with extended follow-up [ 2 – 5 ] . Previous studies have reported that approximately 40% of patients experience local recurrence within 5 years, and the rate of distant metastasis can be as high as 60%, most commonly involving the lungs [ 2 , 6 , 7 ] . Therefore, reducing the risks of recurrence and distant metastasis after initial definitive treatment remains a critical need for improving long-term outcomes. Surgical resection remains the primary curative-intent treatment for non-metastatic HNACC [ 1 , 6 , 8 , 9 ] . However, perineural invasion (PNI) is a characteristic pathological feature of ACC, which can constrain the extent of resection, render R0 resection more challenging, and adversely affect prognosis [ 1 , 2 , 10 , 11 ] . Accordingly, despite the lack of large randomized controlled trials, both the ASCO and NCCN guidelines recommend postoperative radiotherapy (PORT) as an important adjuvant strategy for patients with HNACC to improve local control [ 12 , 13 ] . In a retrospective study of HNACC, the local recurrence rate was significantly lower in patients treated with surgery plus PORT than in those treated with surgery only (SO; 16.9% vs. 31.0%) [ 6 ] . More recent evidence has also suggested that PORT is associated with improved survival in salivary gland ACC, in both early-stage and locally advanced disease [ 14 ] . Nevertheless, contradictory findings have been reported, with some studies showing comparable long-term outcomes between SO and PORT [ 15 , 16 ] . Furthermore, ACC generally exhibits limited sensitivity to conventional chemotherapy because of its indolent growth pattern, and no standardized chemotherapy regimen has been established [ 11 , 17 ] . Whether postoperative chemoradiotherapy (POCRT) provides additional benefit over PORT alone remains controversial, underscoring the need to better define postoperative treatment (POT) strategies, indications, and the subgroups most likely to benefit in HNACC [ 18 , 19 ] . Accordingly, we retrospectively compared outcomes between SO and surgery plus PORT or POCRT in a non-metastatic HNACC cohort, and further explored potential beneficiary subgroups, aiming to provide real-world evidence to inform individualized postoperative decision-making for this rare malignancy. Materials and Methods Patient population This retrospective study enrolled consecutive patients with HNACC treated at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, between January 1, 2011 and August 31, 2023. Inclusion criteria were as follows: (1) newly diagnosed ACC confirmed by pathology; (2) primary tumor located in the head and neck region; and (3) receipt of definitive surgical resection, with or without PORT or POCRT. Patients were excluded if they had metastatic disease at initial diagnosis, or had incomplete data precluding outcome assessment. Based on these criteria, 114 eligible patients were included in the final analysis (Fig. 1 ). This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki of the World Medical Association. Approval was obtained from the Ethics Committee of Wuhan Union Hospital. Patient treatment All 114 patients underwent surgical resection. Patients were categorized into three groups according to POT: Surgery only (SO), PORT, and POCRT. In this study, radiotherapy (RT)-based POT was defined as any POT that includes radiotherapy, encompassing both PORT and POCRT. PORT was generally initiated 4–6 weeks after surgery and delivered using intensity-modulated radiotherapy (IMRT). The high-risk clinical target volume (CTV1) included radiologic residual disease (if present), the tumor bed of positive margins, and involved nerve regions. The low-risk clinical target volume (CTV2) encompassed the tumor bed, the course of the trigeminal nerve and its branches, and elective cervical nodal drainage regions. Planning target volumes (PTVs) were generated by expanding the corresponding CTVs by 3 mm to account for setup uncertainty. The prescribed doses to PTV1 and PTV2 were 66–72 Gy and 54–66 Gy, respectively, delivered in 1.8–2.0 Gy per fraction, once daily, five fractions per week. Dose constraints for organs at risk were applied according to QUANTEC recommendations for conventionally fractionated radiotherapy. Patients in the POCRT group received cisplatin concurrently with radiotherapy at a dose of 100 mg/m² every 3 weeks or 40 mg/m² weekly. Assessments and follow-up PNI and surgical margin status were assessed independently by two experienced head and neck pathologists. Surgical margins were classified as R0 (microscopically negative margin), R1 (microscopically positive margin), or R2 (macroscopically residual disease). Patients were typically reviewed every 3 months during the first 2 years, every 6 months during years 3–5, and annually thereafter. Follow-up assessments included history and physical examination, contrast-enhanced magnetic resonance imaging (MRI) of the head and neck, chest computed tomography (CT), and abdominal ultrasonography or CT. Bone scan or positron emission tomography–computed tomography (PET-CT) was additionally performed when clinically indicated. The primary endpoint was progression-free survival (PFS), defined as the time from surgery to the first documented disease progression or death from any cause, whichever occurred first. Other endpoints included overall survival (OS), defined as the time from surgery to death from any cause; local failure–free survival (LFFS), defined as the time from surgery to local recurrence; and distant metastasis–free survival (DMFS), defined as the time from surgery to the first distant metastasis. Statistics Survival status was estimated using the Kaplan-Meier (KM) curves and compared with the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify factors associated with survival outcomes, and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. We used SPSS version 27 (IBM, Armonk, New York) for analysis. A two-tailed P value < 0.05 was considered statistically significant. Results Patient characteristics Table 1 summarizes the baseline characteristics of the enrolled patients. In the overall cohort (n = 114), the median age was 54 years (IQR, 47–61), and females (57.0%) outnumbered males. Tumors most commonly originated from the minor salivary glands (58.8%). More than half of patients presented with locally advanced disease (T3–T4, 55.3%), whereas nodal metastasis was uncommon (13/114). PNI was present in 41 patients (36.0%), and R2 resection was recorded in 20 (17.5%), with residual disease confirmed radiographically on postoperative CT, MRI, or PET-CT. According to treatment strategy, patients were grouped into SO, PORT, and POCRT, accounting for 35 (30.7%), 42 (36.8%), and 37 (32.5%) cases, respectively. Baseline characteristics were well balanced across groups, except for N stage. Table 1 Patient characteristics Characteristics Overall cohort N = 114 Surgery only N = 35 PORT N = 42 POCRT N = 37 P-value Sex, no. (%) 0.087 Female 65 (57.0%) 24 (68.6%) 25 (59.5%) 16 (43.2%) Male 49 (43.0%) 11 (31.4%) 17 (40.5%) 21 (56.8%) Age, years, median (IQR) 54 (47–61) 57 (49–62) 55 (47–63) 50 (46–56) 0.106 Site, no. (%) 0.439 Major salivary glands 34 (29.8%) 10 (28.6%) 15 (35.7%) 9 (24.3%) Minor salivary glands 67 (58.8%) 22 (62.9%) 20 (47.6%) 25 (67.6%) Extra-salivary sites* 13 (11.4%) 3 (8.6%) 7 (16.7%) 3 (8.1%) Clinical stage, no. (%) 0.263 I 18 (15.8%) 4 (11.4%) 8 (19.0%) 6 (16.2%) II 28 (24.6%) 12 (34.3%) 12 (28.6%) 4 (10.8%) III 29 (25.4%) 8 (22.9%) 11 (26.2%) 10 (27.0%) IV 39 (34.2%) 11 (31.4%) 11 (26.2%) 17 (45.9%) T stage, no. (%) 0.556 1 16 (14.0%) 5 (14.3%) 6 (14.3%) 5 (13.5%) 2 35 (30.7%) 13 (37.1%) 15 (35.7%) 7 (18.9%) 3 25 (21.9%) 6 (17.1%) 10 (23.8%) 9 (24.3%) 4 38 (33.3%) 11 (31.4%) 11 (26.2%) 16 (43.2%) N stage, no. (%) 0.020 0 101 (88.6%) 29 (82.9%) 42 (100.0%) 30 (81.1%) 1 7 (6.1%) 3 (8.6%) 0 (0.0%) 4 (10.8%) 2 6 (5.3%) 3 (8.6%) 0 (0.0%) 3 (8.1%) Perineural invasion, no. (%) 0.983 No 73 (64.0%) 22 (62.9%) 27 (64.3%) 24 (64.9%) Yes 41 (36.0%) 13 (37.1%) 15 (35.7%) 13 (35.1%) Resection margin, no. (%) 0.271 R0 61 (53.5%) 20 (57.1%) 25 (59.5%) 16 (43.2%) R1 24 (21.1%) 8 (22.9%) 7 (16.7%) 9 (24.3%) R2 20 (17.5%) 3 (8.6%) 7 (16.7%) 10 (27.0%) NA 9 (7.9%) 4 (11.4%) 3 (7.1%) 2 (5.4%) Ki-67 labeling index, no. (%) 0.092 ≤ 20% 36 (31.6%) 7 (20.0%) 13 (31.0%) 16 (43.2%) > 20% 19 (16.7%) 9 (25.7%) 5 (11.9%) 5 (13.5%) NA 59 (51.8%) 19 (54.3%) 24 (57.1%) 16 (43.2%) *Extra-salivary sites included the lacrimal gland, ceruminous gland, and upper respiratory tract; PORT: postoperative radiotherapy; POCRT: postoperative chemoradiotherapy; IQR: Interquartile Range; NA: Not applicable Treatment outcomes With a median follow-up of 51.0 months (95% CI, 39.9–62.1), 28 patients (24.6%) died and 39 (34.2%) experienced disease progression, 28 (24.6%) developed locoregional recurrence, and 8 (7.0%) developed distant metastasis. The median OS, PFS, and LFFS for the overall cohort were 99.0 (95% CI, 94.8–103.2), 76.0 (95% CI, 59.3–92.7), and 97.0 months (95% CI, 82.6–111.4), respectively, while the median DMFS was not reached. The 5-year OS, PFS, LFFS, and DMFS rates were 87.4%, 74.4%, 81.2%, and 91.0%, respectively. When patients were grouped into SO and RT-based POT, no significant differences were observed in OS, PFS, LFFS, or DMFS between the two groups (all P > 0.05, Fig. 2 ). Further stratification into SO, PORT, and POCRT likewise demonstrated no significant differences across groups for any survival endpoint (all P > 0.05, Fig. 2 ). Prognostic factors Univariable and multivariable Cox proportional hazards analyses were performed for OS, PFS, and LFFS (Table 2 ), while DMFS was not analyzed due to the small number of distant metastasis events. On univariable analysis, PNI was significantly associated with inferior OS (HR 2.835, 95% CI 1.158–6.938, P = 0.023) and PFS (HR 2.066, 95% CI 1.045–4.083, P = 0.037), and nodal metastasis was associated with worse PFS (HR 3.036, 95% CI 1.296–7.113, P = 0.011). Table 2 Univariable and multivariable analysis of prognostic factors Characteristics OS PFS LFFS HR (95% CI) P-value HR (95% CI) P-value HR (95% CI) P-value Univariable parameter Age (< 54 vs. ≥ 54) 0.807 (0.373, 1.743) 0.585 0.800 (0.426, 1.502) 0.487 0.568 (0.267, 1.208) 0.141 Gender (female vs. male) 1.148 (0.530, 2.489) 0.726 1.165 (0.613, 2.212) 0.641 1.355 (0.630, 2.914) 0.437 T stage (I-II vs. III-IV) 0.906 (0.422, 1.945) 0.801 0.746 (0.393, 1.419) 0.372 1.114 (0.526, 2.359) 0.779 Nodal metastasis (yes vs. no) 0.905 (0.257, 3.190) 0.876 3.036 (1.296, 7.113) 0.011 2.298 (0.767, 6.886) 0.137 Perineural invasion (yes vs. no) 2.835 (1.158, 6.938) 0.023 2.066 (1.045, 4.083) 0.037 1.633 (0.706, 3.777) 0.251 Resection margin (R0 vs. R1/R2) 0.513 (0.216, 1.218) 0.130 0.528 (0.267, 1.044) 0.066 0.734 (0.327, 1.647) 0.453 Treatment group (RT-based POT vs. SO) 1.225 (0.509, 2.948) 0.650 0.753 (0.392, 1.448) 0.395 0.493 (0.231, 1.052) 0.067 Multivariable parameter Nodal metastasis (yes vs. no) 0.624 (0.137, 2.840) 0.542 2.825 (1.128, 7.074) 0.027 2.066 (0.586, 7.281) 0.259 Perineural invasion (yes vs. no) 3.425 (1.316, 8.913) 0.012 2.196 (1.060, 4.549) 0.034 2.094 (0.847, 5.181) 0.110 Resection margin (R0 vs. R1/R2) 0.633 (0.258, 1.554) 0.318 0.618 (0.306, 1.248) 0.180 0.754 (0.324, 1.753) 0.511 Treatment group (RT-based POT vs. SO) 0.994 (0.379, 2.604) 0.990 0.620 (0.305, 1.263) 0.188 0.470 (0.207, 1.067) 0.071 HR: Hazard ratio; CI: Confidence interval; OS: Overall survival; PFS: Progression-free survival; LFFS: Local failure-free survival; RT-based POT: Radiotherapy-based postoperative treatment; SO: Surgery only In multivariable analysis, PNI remained an independent adverse prognostic factor for OS (HR 3.425, 95% CI 1.316–8.913, P = 0.012) and PFS (HR 2.196, 95% CI 1.060–4.549, P = 0.034), while nodal metastasis independently predicted poorer PFS (HR 2.825, 95% CI 1.128–7.074, P = 0.027). By contrast, treatment group (RT-based POT vs. SO) was not independently associated with OS, PFS, or LFFS (all P > 0.05), although a favorable trend toward improved LFFS was observed (HR 0.470, 95% CI 0.207–1.067, P = 0.071). Subgroup analysis Subgroup analyses were performed according to PNI status (Fig. 3 and Fig. 4 ). Among patients with PNI, no significant differences were observed between SO and RT-based POT in terms of OS (P = 0.099) or PFS (P = 0.053), whereas LFFS was significantly improved in the RT-based POT group compared with SO (P = 0.032; Fig. 3 A, C, E). When further stratified into SO, PORT, and POCRT, no significant differences were detected among the three groups for OS, PFS, or LFFS (P = 0.243, P = 0.117 and P = 0.089, respectively; Fig. 3 B, D, F). However, pairwise comparisons indicated that PORT was associated with improved PFS compared with SO in patients with PNI (P = 0.046). In contrast, among patients without PNI, no significant differences in OS, PFS, or LFFS were observed across treatment strategies (all P > 0.05, Fig. 4 ). Moreover, we performed subgroup analyses stratified by clinical stage (I–II vs III–IV) and margin status (R0 vs R1/R2), but no statistically significant differences were observed between treatment groups. Discussion There remains no consensus on optimal POT strategies for non-metastatic HNACC after curative-intent resection. Therefore, we retrospectively compared survival outcomes among patients treated with SO, PORT, and POCRT. Although no statistically significant differences in survival endpoints were observed across treatment groups in the overall cohort, RT-based POT was associated with better disease control in the PNI subgroup. To our knowledge, this may be the first real-world HNACC cohort study to systematically compare these three postoperative strategies, providing evidence to support individualized adjuvant decision-making for patients with high-risk PNI. Despite being widely recommended by guidelines as a standard postoperative strategy for high-risk HNACC, the evidence supporting PORT remains inconsistent, primarily due to the rarity of this malignancy, its protracted disease course, and the lack of randomized controlled trials [ 12 , 13 ] . Some studies have suggested that PORT reduces the risk of local recurrence, whereas others have reported limited long-term survival differences between PORT and SO [ 6 , 15 , 16 , 20 , 21 ] . In our overall cohort, we likewise did not observe significant differences in OS, PFS, LFFS, or DMFS between SO and RT-based POT, nor among the three strategies (SO, PORT, and POCRT). This may reflect the late occurrence of events in ACC, making between-group differences difficult to detect within a median follow-up of less than 5 years. On the other hand, grouping patients solely by treatment modality may obscure meaningful benefit signals in high-risk subpopulations. Given the biological propensity of ACC for PNI, we further performed stratified analyses among patients with PNI and observed that RT-based POT was associated with improved LFFS, thereby supporting a risk-adapted rather than universally applied postoperative strategy [ 1 , 10 , 11 ] . PNI is one of the most characteristic invasive patterns of HNACC [ 1 , 11 , 22 , 23 ] . Tumor cells can infiltrate discontinuously and in a “skip” manner along the perineurium and perineural spaces, and may spread over long distances toward the skull base, making it difficult for routine surgical margins to fully encompass occult microscopic disease [ 1 , 11 , 22 , 23 ] . Consistent with prior reports, PNI remained an independent adverse prognostic factor for OS and PFS in our multivariable Cox models, suggesting a robust and persistent association with the risks of disease progression and death [ 10 , 22 , 24 ] . Subgroup analyses further showed that, among patients with PNI, RT-based POT was associated with improved LFFS. This may be because radiotherapy can cover both the tumor bed and involved neural pathways, such that any benefit is more likely to be manifested first as a reduction in local failure risk [ 22 ] . Notably, when the PNI-positive subgroup was further divided into SO, PORT, and POCRT, the overall test did not reach statistical significance, whereas the pairwise comparison between SO and PORT showed borderline significance. Given the limited number of events and the issue of multiple comparisons, this finding may represent a chance signal and should be interpreted as exploratory. Future prospective validation in larger cohorts is warranted. HNACC generally shows limited sensitivity to conventional chemotherapy, and the role of POCRT therefore remains controversial [ 19 ] . A review of 114 studies suggested that chemotherapy is largely ineffective for most patients with HNACC, with the duration of objective responses typically limited to only a few months [ 25 ] . Accordingly, current evidence does not support POCRT as a routine postoperative approach, and its use may be better reserved for selected high-risk patients or clinical trial settings [ 26 , 27 ] . Consistent with this, we did not observe a clear survival advantage of POCRT over PORT in either the overall cohort or the PNI-positive subgroup. In the IMRT era, where local control is relatively favorable, concurrent cisplatin may offer limited incremental benefit, potentially due to poor penetration into the perineural microenvironment or insufficient activity against the slowly proliferating tumor cells characteristic of ACC. These observations underscore the need for mechanistic studies to identify molecular targets within neural-invasive niches, such as the CXCR4/SDF-1 axis, which has been implicated in ACC [ 28 ] . Notably, some retrospective studies have suggested that POCRT may improve locoregional control in subsets with high-risk features; however, these observations may be confounded by baseline imbalances, treatment-selection bias, differences in follow-up duration, and endpoint heterogeneity, and thus require validation in larger prospective cohorts [ 19 , 29 ] . Beyond postoperative management, neoadjuvant strategies may represent another potential avenue to improve outcomes in HNACC. It remains unclear whether neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy confers meaningful clinical benefit for patients with HNACC. In the era of immunotherapy, although immunotherapy-based neoadjuvant regimens have shown potential survival benefits in head and neck squamous cell carcinoma [ 30 , 31 ] , including our group’s single-arm phase II study, the role of neoadjuvant treatment in HNACC is still largely undefined [ 32 ] . Conceptually, neoadjuvant therapy may improve resectability and increase the likelihood of achieving an R0 resection, thereby potentially translating into better long-term disease control. However, prospective clinical studies evaluating neoadjuvant approaches in HNACC are currently lacking, and their efficacy and optimal patient selection require further investigation. While our study provides actionable insights, its retrospective design and single-center cohort may limit generalizability and introduce selection bias. Notably, baseline nodal stage was imbalanced across treatment groups, with no N1 or N2 cases in the PORT group. However, the overall number of N-positive patients was low (13/114), making this imbalance unlikely to significantly impact the results. Additionally, a median follow-up of 51 months may be inadequate for HNACC, given its propensity for late recurrence and distant metastasis, which could attenuate survival differences between adjuvant strategies. Therefore, prospective studies with larger sample sizes and extended follow-up are warranted to validate our findings and refine risk-adapted postoperative treatment selection. Conclusion In non-metastatic HNACC, survival outcomes were similar across SO, PORT, and POCRT. While it remains unclear whether POCRT is superior to PORT in PNI patients, this subgroup may benefit more from RT-based postoperative treatment, warranting further validation. Declarations Acknowledgements We thank all members of the group at the cancer center, Wuhan Union Hospital for their kindness and help. The study was approved by the Institutional Ethics Committee of Wuhan Union Hospital. Formal consent was waived because of the retrospective nature of this study. All individual-level data were anonymized and only available to authorized researchers. Authors’ contributions All authors contributed to the conception and drafting of the manuscript and have read and approved the final manuscript. Funding This research didn’t receive any form of sponsorship. Clinical trial number Not applicable. Competing interests The authors declare no competing interests. Ethics approval and consent to participate This research was approved by Ethics Committee of Wuhan Union Hospital. References Coca-Pelaz A, Rodrigo JP, Bradley PJ, Vander Poorten V, Triantafyllou A, Hunt JL, et al. Adenoid cystic carcinoma of the head and neck – An update. 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Adding concurrent chemotherapy to postoperative radiotherapy improves locoregional control but Not overall survival in patients with salivary gland adenoid cystic carcinoma-a propensity score matched study. Radiat Oncol. 2016;11:47. Vos JL, Elbers JB, Krijgsman O, Traets JJ, Qiao X, van der Leun AM, et al. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nature communications. 2021;12(1):7348. Ferrarotto R, Amit M, Nagarajan P, Rubin ML, Yuan Y, Bell D, et al. Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clinical Cancer Research. 2021;27(16):4557-65. Zhang Z, Wu B, Peng G, Xiao G, Huang J, Ding Q, et al. Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial. Clinical Cancer Research. 2022;28(15):3268-76. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9254166","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624876235,"identity":"4643841c-3fa4-46ef-8603-7ce757bbf13f","order_by":0,"name":"Jinzi Liang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Jinzi","middleName":"","lastName":"Liang","suffix":""},{"id":624876236,"identity":"a0d3c76b-e58e-49dd-9ca1-e55968022957","order_by":1,"name":"Shuhan Zhao","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Shuhan","middleName":"","lastName":"Zhao","suffix":""},{"id":624876239,"identity":"001948f7-0fd7-435c-96d6-114f7758f7d3","order_by":2,"name":"Alejandro Andree Alcas Villena","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Alejandro","middleName":"Andree Alcas","lastName":"Villena","suffix":""},{"id":624876240,"identity":"a1ba6259-b8e5-4a30-b6af-0fce45c5cb1c","order_by":3,"name":"Wenjing Wang","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Wang","suffix":""},{"id":624876241,"identity":"4459ae08-c62f-473b-b60d-318447b12d48","order_by":4,"name":"Chao Wan","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Wan","suffix":""},{"id":624876242,"identity":"6db375d1-04ac-47d3-a7eb-cfddb2b03692","order_by":5,"name":"Xixi Liu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Xixi","middleName":"","lastName":"Liu","suffix":""},{"id":624876243,"identity":"79ca6f30-1ce7-4aa0-afba-7e1173dcff42","order_by":6,"name":"Lu Wen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYHACxgMMFTY8/OyNjQ8+EKvnAMOZNDnJnsPNhjOI1sLYdtjY4EZ6mzQHMcoNjvceOMzDlpY4c+bDBmkGBjs53QZCWs6cSzjMw2OT2C+d2GBcwJBsbHaAgBazGzkGh3kkgLbMTmxInsFwIHEbQS333wC1GBxO3HDzYMNhHqK03ACq50kAeZ+xsZkoLfZncgwOzjkACuTEZsYZBkT4RbL9jOGDt/9AUXn8+Y8PFXZyBLWgAQPSlI+CUTAKRsEowAEADf9KlFBEdYkAAAAASUVORK5CYII=","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Lu","middleName":"","lastName":"Wen","suffix":""}],"badges":[],"createdAt":"2026-03-28 16:25:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9254166/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9254166/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107500121,"identity":"1320c6b8-14b9-4486-975c-a63d8ae38c47","added_by":"auto","created_at":"2026-04-22 05:44:14","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":94636,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eACC: adenoid cystic carcinoma; RT-based POT: radiotherapy-based postoperative treatment; PORT: postoperative radiotherapy; POCRT: postoperative chemoradiotherapy\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9254166/v1/8cef3ae127ebb334eb0c5a98.png"},{"id":108976507,"identity":"eabb0431-842b-42f1-bb7d-f5f7655d6031","added_by":"auto","created_at":"2026-05-11 11:23:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":203793,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier curves of survival outcomes in the overall cohort.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA (OS), C (PFS), E (LFFS), and G (DMFS) compare surgery only versus radiotherapy-based postoperative treatment (RT-based POT). B (OS), D (PFS), F (LFFS), and H (DMFS) compare surgery only, postoperative radiotherapy (PORT), and postoperative chemoradiotherapy (POCRT).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9254166/v1/6bb30de29cfe6c111f3a4ce9.png"},{"id":107705332,"identity":"9f54ebb4-cc0e-4dc1-9ffb-2696bdcfd82f","added_by":"auto","created_at":"2026-04-24 09:11:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":125880,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier curves of survival outcomes in patients with perineural invasion.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA (OS), C (PFS), and E (LFFS) compare surgery only versus radiotherapy-based postoperative treatment (RT-based POT). B (OS), D (PFS), and F (LFFS) compare surgery only, postoperative radiotherapy (PORT), and postoperative chemoradiotherapy (POCRT).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9254166/v1/4d50df31f5a4ac681c77de42.png"},{"id":107500123,"identity":"ca6fa2e8-2419-44d7-8faa-bb24857cff16","added_by":"auto","created_at":"2026-04-22 05:44:14","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":166386,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier curves of survival outcomes in patients without perineural invasion.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA (OS), C (PFS), and E (LFFS) compare surgery only versus radiotherapy-based postoperative treatment (RT-based POT). B (OS), D (PFS), and F (LFFS) compare surgery only, postoperative radiotherapy (PORT), and postoperative chemoradiotherapy (POCRT).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-9254166/v1/7798adccbb1301c937a6c94a.png"},{"id":108979413,"identity":"a2a3bffb-266b-4036-947a-1beeb68f62da","added_by":"auto","created_at":"2026-05-11 11:58:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":860581,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9254166/v1/9f15883d-4f77-49ea-9ace-f03333d9e1d9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Postoperative Radiotherapy or Chemoradiotherapy Versus Surgery Only in Non-Metastatic Head and Neck Adenoid Cystic Carcinoma: A Retrospective Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAdenoid cystic carcinoma (ACC) is a rare malignancy, representing approximately 1% of head and neck cancers and about 10% of salivary gland malignancies \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Head and neck adenoid cystic carcinoma (HNACC) represents the most common carcinoma histology of the minor salivary glands and also frequently arises from the major salivary glands \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Beyond the salivary glands, HNACC may also arise at extra-salivary head and neck sites, including the lacrimal gland, the sinonasal tract, ceruminous glands, and mucosal sites of the upper aerodigestive tract \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Although HNACC typically follows an indolent clinical course, local recurrence and distant metastasis may occur even 5\u0026ndash;15 years after definitive treatment, and long-term survival declines substantially over time with extended follow-up \u003csup\u003e[\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Previous studies have reported that approximately 40% of patients experience local recurrence within 5 years, and the rate of distant metastasis can be as high as 60%, most commonly involving the lungs \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Therefore, reducing the risks of recurrence and distant metastasis after initial definitive treatment remains a critical need for improving long-term outcomes.\u003c/p\u003e \u003cp\u003eSurgical resection remains the primary curative-intent treatment for non-metastatic HNACC \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. However, perineural invasion (PNI) is a characteristic pathological feature of ACC, which can constrain the extent of resection, render R0 resection more challenging, and adversely affect prognosis \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Accordingly, despite the lack of large randomized controlled trials, both the ASCO and NCCN guidelines recommend postoperative radiotherapy (PORT) as an important adjuvant strategy for patients with HNACC to improve local control \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. In a retrospective study of HNACC, the local recurrence rate was significantly lower in patients treated with surgery plus PORT than in those treated with surgery only (SO; 16.9% vs. 31.0%) \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. More recent evidence has also suggested that PORT is associated with improved survival in salivary gland ACC, in both early-stage and locally advanced disease \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Nevertheless, contradictory findings have been reported, with some studies showing comparable long-term outcomes between SO and PORT \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Furthermore, ACC generally exhibits limited sensitivity to conventional chemotherapy because of its indolent growth pattern, and no standardized chemotherapy regimen has been established \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Whether postoperative chemoradiotherapy (POCRT) provides additional benefit over PORT alone remains controversial, underscoring the need to better define postoperative treatment (POT) strategies, indications, and the subgroups most likely to benefit in HNACC \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccordingly, we retrospectively compared outcomes between SO and surgery plus PORT or POCRT in a non-metastatic HNACC cohort, and further explored potential beneficiary subgroups, aiming to provide real-world evidence to inform individualized postoperative decision-making for this rare malignancy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eThis retrospective study enrolled consecutive patients with HNACC treated at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, between January 1, 2011 and August 31, 2023. Inclusion criteria were as follows: (1) newly diagnosed ACC confirmed by pathology; (2) primary tumor located in the head and neck region; and (3) receipt of definitive surgical resection, with or without PORT or POCRT. Patients were excluded if they had metastatic disease at initial diagnosis, or had incomplete data precluding outcome assessment. Based on these criteria, 114 eligible patients were included in the final analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki of the World Medical Association. Approval was obtained from the Ethics Committee of Wuhan Union Hospital.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePatient treatment\u003c/h3\u003e\n\u003cp\u003eAll 114 patients underwent surgical resection. Patients were categorized into three groups according to POT: Surgery only (SO), PORT, and POCRT. In this study, radiotherapy (RT)-based POT was defined as any POT that includes radiotherapy, encompassing both PORT and POCRT. PORT was generally initiated 4\u0026ndash;6 weeks after surgery and delivered using intensity-modulated radiotherapy (IMRT). The high-risk clinical target volume (CTV1) included radiologic residual disease (if present), the tumor bed of positive margins, and involved nerve regions. The low-risk clinical target volume (CTV2) encompassed the tumor bed, the course of the trigeminal nerve and its branches, and elective cervical nodal drainage regions. Planning target volumes (PTVs) were generated by expanding the corresponding CTVs by 3 mm to account for setup uncertainty. The prescribed doses to PTV1 and PTV2 were 66\u0026ndash;72 Gy and 54\u0026ndash;66 Gy, respectively, delivered in 1.8\u0026ndash;2.0 Gy per fraction, once daily, five fractions per week. Dose constraints for organs at risk were applied according to QUANTEC recommendations for conventionally fractionated radiotherapy. Patients in the POCRT group received cisplatin concurrently with radiotherapy at a dose of 100 mg/m\u0026sup2; every 3 weeks or 40 mg/m\u0026sup2; weekly.\u003c/p\u003e\n\u003ch3\u003eAssessments and follow-up\u003c/h3\u003e\n\u003cp\u003ePNI and surgical margin status were assessed independently by two experienced head and neck pathologists. Surgical margins were classified as R0 (microscopically negative margin), R1 (microscopically positive margin), or R2 (macroscopically residual disease).\u003c/p\u003e \u003cp\u003ePatients were typically reviewed every 3 months during the first 2 years, every 6 months during years 3\u0026ndash;5, and annually thereafter. Follow-up assessments included history and physical examination, contrast-enhanced magnetic resonance imaging (MRI) of the head and neck, chest computed tomography (CT), and abdominal ultrasonography or CT. Bone scan or positron emission tomography\u0026ndash;computed tomography (PET-CT) was additionally performed when clinically indicated.\u003c/p\u003e \u003cp\u003eThe primary endpoint was progression-free survival (PFS), defined as the time from surgery to the first documented disease progression or death from any cause, whichever occurred first. Other endpoints included overall survival (OS), defined as the time from surgery to death from any cause; local failure\u0026ndash;free survival (LFFS), defined as the time from surgery to local recurrence; and distant metastasis\u0026ndash;free survival (DMFS), defined as the time from surgery to the first distant metastasis.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eSurvival status was estimated using the Kaplan-Meier (KM) curves and compared with the log-rank test. Univariate and multivariate Cox proportional hazards models were used to identify factors associated with survival outcomes, and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. We used SPSS version 27 (IBM, Armonk, New York) for analysis. A two-tailed P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e summarizes the baseline characteristics of the enrolled patients. In the overall cohort (n\u0026thinsp;=\u0026thinsp;114), the median age was 54 years (IQR, 47\u0026ndash;61), and females (57.0%) outnumbered males. Tumors most commonly originated from the minor salivary glands (58.8%). More than half of patients presented with locally advanced disease (T3\u0026ndash;T4, 55.3%), whereas nodal metastasis was uncommon (13/114). PNI was present in 41 patients (36.0%), and R2 resection was recorded in 20 (17.5%), with residual disease confirmed radiographically on postoperative CT, MRI, or PET-CT. According to treatment strategy, patients were grouped into SO, PORT, and POCRT, accounting for 35 (30.7%), 42 (36.8%), and 37 (32.5%) cases, respectively. Baseline characteristics were well balanced across groups, except for N stage.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall cohort\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;114\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSurgery only\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;35\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePORT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePOCRT\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;37\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.087\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (57.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (43.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21 (56.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (47\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (49\u0026ndash;62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e55 (47\u0026ndash;63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e50 (46\u0026ndash;56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.439\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMajor salivary glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (29.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinor salivary glands\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (58.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (62.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (47.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (67.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtra-salivary sites*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.263\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (15.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6 (16.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (24.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (34.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (28.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (25.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (22.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (34.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 (45.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT stage, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (14.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (30.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (37.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (18.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (21.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (31.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN stage, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e101 (88.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (82.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42 (100.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (81.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (6.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (5.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerineural invasion, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.983\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (64.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (62.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (64.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (64.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (36.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (37.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (35.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13 (35.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (53.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (21.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (22.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (24.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (17.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (27.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (11.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (7.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (5.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi-67 labeling index, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (31.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (20.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (31.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (25.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (11.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (13.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (51.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (54.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16 (43.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*Extra-salivary sites included the lacrimal gland, ceruminous gland, and upper respiratory tract; PORT: postoperative radiotherapy; POCRT: postoperative chemoradiotherapy; IQR: Interquartile Range; NA: Not applicable\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment outcomes\u003c/h3\u003e\n\u003cp\u003eWith a median follow-up of 51.0 months (95% CI, 39.9\u0026ndash;62.1), 28 patients (24.6%) died and 39 (34.2%) experienced disease progression, 28 (24.6%) developed locoregional recurrence, and 8 (7.0%) developed distant metastasis. The median OS, PFS, and LFFS for the overall cohort were 99.0 (95% CI, 94.8\u0026ndash;103.2), 76.0 (95% CI, 59.3\u0026ndash;92.7), and 97.0 months (95% CI, 82.6\u0026ndash;111.4), respectively, while the median DMFS was not reached. The 5-year OS, PFS, LFFS, and DMFS rates were 87.4%, 74.4%, 81.2%, and 91.0%, respectively.\u003c/p\u003e \u003cp\u003eWhen patients were grouped into SO and RT-based POT, no significant differences were observed in OS, PFS, LFFS, or DMFS between the two groups (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Further stratification into SO, PORT, and POCRT likewise demonstrated no significant differences across groups for any survival endpoint (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003ePrognostic factors\u003c/h3\u003e\n\u003cp\u003eUnivariable and multivariable Cox proportional hazards analyses were performed for OS, PFS, and LFFS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), while DMFS was not analyzed due to the small number of distant metastasis events. On univariable analysis, PNI was significantly associated with inferior OS (HR 2.835, 95% CI 1.158\u0026ndash;6.938, P\u0026thinsp;=\u0026thinsp;0.023) and PFS (HR 2.066, 95% CI 1.045\u0026ndash;4.083, P\u0026thinsp;=\u0026thinsp;0.037), and nodal metastasis was associated with worse PFS (HR 3.036, 95% CI 1.296\u0026ndash;7.113, P\u0026thinsp;=\u0026thinsp;0.011).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariable and multivariable analysis of prognostic factors\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eLFFS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUnivariable parameter\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026lt;\u0026thinsp;54 vs. \u0026ge; 54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.807 (0.373, 1.743)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.800 (0.426, 1.502)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.568 (0.267, 1.208)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (female vs. male)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.148 (0.530, 2.489)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.165 (0.613, 2.212)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.641\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.355 (0.630, 2.914)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.437\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT stage (I-II vs. III-IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.906 (0.422, 1.945)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.801\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.746 (0.393, 1.419)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.372\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.114 (0.526, 2.359)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.779\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal metastasis (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.905 (0.257, 3.190)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.876\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.036 (1.296, 7.113)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.298 (0.767, 6.886)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerineural invasion (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.835 (1.158, 6.938)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.066 (1.045, 4.083)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.633 (0.706, 3.777)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.251\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin (R0 vs. R1/R2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.513 (0.216, 1.218)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.528 (0.267, 1.044)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.066\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.734 (0.327, 1.647)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.453\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment group (RT-based POT vs. SO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.225 (0.509, 2.948)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.650\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.753 (0.392, 1.448)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.493 (0.231, 1.052)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMultivariable parameter\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNodal metastasis (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.624 (0.137, 2.840)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.825 (1.128, 7.074)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.066 (0.586, 7.281)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.259\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePerineural invasion (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.425 (1.316, 8.913)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.196 (1.060, 4.549)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.094 (0.847, 5.181)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eResection margin (R0 vs. R1/R2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.633 (0.258, 1.554)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.318\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.618 (0.306, 1.248)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.754 (0.324, 1.753)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment group (RT-based POT vs. SO)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.994 (0.379, 2.604)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.990\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.620 (0.305, 1.263)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.188\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.470 (0.207, 1.067)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.071\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eHR: Hazard ratio; CI: Confidence interval; OS: Overall survival; PFS: Progression-free survival; LFFS: Local failure-free survival; RT-based POT: Radiotherapy-based postoperative treatment; SO: Surgery only\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn multivariable analysis, PNI remained an independent adverse prognostic factor for OS (HR 3.425, 95% CI 1.316\u0026ndash;8.913, P\u0026thinsp;=\u0026thinsp;0.012) and PFS (HR 2.196, 95% CI 1.060\u0026ndash;4.549, P\u0026thinsp;=\u0026thinsp;0.034), while nodal metastasis independently predicted poorer PFS (HR 2.825, 95% CI 1.128\u0026ndash;7.074, P\u0026thinsp;=\u0026thinsp;0.027). By contrast, treatment group (RT-based POT vs. SO) was not independently associated with OS, PFS, or LFFS (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05), although a favorable trend toward improved LFFS was observed (HR 0.470, 95% CI 0.207\u0026ndash;1.067, P\u0026thinsp;=\u0026thinsp;0.071).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eSubgroup analyses were performed according to PNI status (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Among patients with PNI, no significant differences were observed between SO and RT-based POT in terms of OS (P\u0026thinsp;=\u0026thinsp;0.099) or PFS (P\u0026thinsp;=\u0026thinsp;0.053), whereas LFFS was significantly improved in the RT-based POT group compared with SO (P\u0026thinsp;=\u0026thinsp;0.032; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, C, E). When further stratified into SO, PORT, and POCRT, no significant differences were detected among the three groups for OS, PFS, or LFFS (P\u0026thinsp;=\u0026thinsp;0.243, P\u0026thinsp;=\u0026thinsp;0.117 and P\u0026thinsp;=\u0026thinsp;0.089, respectively; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB, D, F). However, pairwise comparisons indicated that PORT was associated with improved PFS compared with SO in patients with PNI (P\u0026thinsp;=\u0026thinsp;0.046). In contrast, among patients without PNI, no significant differences in OS, PFS, or LFFS were observed across treatment strategies (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Moreover, we performed subgroup analyses stratified by clinical stage (I\u0026ndash;II vs III\u0026ndash;IV) and margin status (R0 vs R1/R2), but no statistically significant differences were observed between treatment groups.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere remains no consensus on optimal POT strategies for non-metastatic HNACC after curative-intent resection. Therefore, we retrospectively compared survival outcomes among patients treated with SO, PORT, and POCRT. Although no statistically significant differences in survival endpoints were observed across treatment groups in the overall cohort, RT-based POT was associated with better disease control in the PNI subgroup. To our knowledge, this may be the first real-world HNACC cohort study to systematically compare these three postoperative strategies, providing evidence to support individualized adjuvant decision-making for patients with high-risk PNI.\u003c/p\u003e \u003cp\u003eDespite being widely recommended by guidelines as a standard postoperative strategy for high-risk HNACC, the evidence supporting PORT remains inconsistent, primarily due to the rarity of this malignancy, its protracted disease course, and the lack of randomized controlled trials \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Some studies have suggested that PORT reduces the risk of local recurrence, whereas others have reported limited long-term survival differences between PORT and SO \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. In our overall cohort, we likewise did not observe significant differences in OS, PFS, LFFS, or DMFS between SO and RT-based POT, nor among the three strategies (SO, PORT, and POCRT). This may reflect the late occurrence of events in ACC, making between-group differences difficult to detect within a median follow-up of less than 5 years. On the other hand, grouping patients solely by treatment modality may obscure meaningful benefit signals in high-risk subpopulations. Given the biological propensity of ACC for PNI, we further performed stratified analyses among patients with PNI and observed that RT-based POT was associated with improved LFFS, thereby supporting a risk-adapted rather than universally applied postoperative strategy \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePNI is one of the most characteristic invasive patterns of HNACC \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Tumor cells can infiltrate discontinuously and in a \u0026ldquo;skip\u0026rdquo; manner along the perineurium and perineural spaces, and may spread over long distances toward the skull base, making it difficult for routine surgical margins to fully encompass occult microscopic disease \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. Consistent with prior reports, PNI remained an independent adverse prognostic factor for OS and PFS in our multivariable Cox models, suggesting a robust and persistent association with the risks of disease progression and death \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. Subgroup analyses further showed that, among patients with PNI, RT-based POT was associated with improved LFFS. This may be because radiotherapy can cover both the tumor bed and involved neural pathways, such that any benefit is more likely to be manifested first as a reduction in local failure risk \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Notably, when the PNI-positive subgroup was further divided into SO, PORT, and POCRT, the overall test did not reach statistical significance, whereas the pairwise comparison between SO and PORT showed borderline significance. Given the limited number of events and the issue of multiple comparisons, this finding may represent a chance signal and should be interpreted as exploratory. Future prospective validation in larger cohorts is warranted.\u003c/p\u003e \u003cp\u003eHNACC generally shows limited sensitivity to conventional chemotherapy, and the role of POCRT therefore remains controversial \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. A review of 114 studies suggested that chemotherapy is largely ineffective for most patients with HNACC, with the duration of objective responses typically limited to only a few months \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. Accordingly, current evidence does not support POCRT as a routine postoperative approach, and its use may be better reserved for selected high-risk patients or clinical trial settings \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Consistent with this, we did not observe a clear survival advantage of POCRT over PORT in either the overall cohort or the PNI-positive subgroup. In the IMRT era, where local control is relatively favorable, concurrent cisplatin may offer limited incremental benefit, potentially due to poor penetration into the perineural microenvironment or insufficient activity against the slowly proliferating tumor cells characteristic of ACC. These observations underscore the need for mechanistic studies to identify molecular targets within neural-invasive niches, such as the CXCR4/SDF-1 axis, which has been implicated in ACC \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Notably, some retrospective studies have suggested that POCRT may improve locoregional control in subsets with high-risk features; however, these observations may be confounded by baseline imbalances, treatment-selection bias, differences in follow-up duration, and endpoint heterogeneity, and thus require validation in larger prospective cohorts \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBeyond postoperative management, neoadjuvant strategies may represent another potential avenue to improve outcomes in HNACC. It remains unclear whether neoadjuvant radiotherapy or neoadjuvant chemoradiotherapy confers meaningful clinical benefit for patients with HNACC. In the era of immunotherapy, although immunotherapy-based neoadjuvant regimens have shown potential survival benefits in head and neck squamous cell carcinoma \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e, including our group\u0026rsquo;s single-arm phase II study, the role of neoadjuvant treatment in HNACC is still largely undefined \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Conceptually, neoadjuvant therapy may improve resectability and increase the likelihood of achieving an R0 resection, thereby potentially translating into better long-term disease control. However, prospective clinical studies evaluating neoadjuvant approaches in HNACC are currently lacking, and their efficacy and optimal patient selection require further investigation.\u003c/p\u003e \u003cp\u003eWhile our study provides actionable insights, its retrospective design and single-center cohort may limit generalizability and introduce selection bias. Notably, baseline nodal stage was imbalanced across treatment groups, with no N1 or N2 cases in the PORT group. However, the overall number of N-positive patients was low (13/114), making this imbalance unlikely to significantly impact the results. Additionally, a median follow-up of 51 months may be inadequate for HNACC, given its propensity for late recurrence and distant metastasis, which could attenuate survival differences between adjuvant strategies. Therefore, prospective studies with larger sample sizes and extended follow-up are warranted to validate our findings and refine risk-adapted postoperative treatment selection.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn non-metastatic HNACC, survival outcomes were similar across SO, PORT, and POCRT. While it remains unclear whether POCRT is superior to PORT in PNI patients, this subgroup may benefit more from RT-based postoperative treatment, warranting further validation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all members of the group at the cancer center, Wuhan Union Hospital for their kindness and help. The study was approved by the Institutional Ethics Committee of Wuhan Union Hospital. Formal consent was waived because of the retrospective nature of this study. All individual-level data were anonymized and only available to authorized researchers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the conception and drafting of the manuscript and have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research didn\u0026rsquo;t receive any form of sponsorship.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was approved by Ethics Committee of Wuhan Union Hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCoca-Pelaz A, Rodrigo JP, Bradley PJ, Vander Poorten V, Triantafyllou A, Hunt JL, et al. 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Patterns of care and survival of adjuvant radiation for major salivary adenoid cystic carcinoma. The Laryngoscope. 2017;127(9):2057-62.\u003c/li\u003e\n\u003cli\u003eMeyers M, Granger B, Herman P, Janot F, Garrel R, Fakhry N, et al. Head and neck adenoid cystic carcinoma: A prospective multicenter REFCOR study of 95 cases. European Annals of Otorhinolaryngology, Head and Neck Diseases. 2016;133(1):13-7.\u003c/li\u003e\n\u003cli\u003eIseli T, Karnell L, Graham S, Funk G, Buatti J, Gupta A, et al. Role of radiotherapy in adenoid cystic carcinoma of the head and neck. The Journal of Laryngology \u0026amp; Otology. 2009;123(10):1137-44.\u003c/li\u003e\n\u003cli\u003eLaurie SA, Ho AL, Fury MG, Sherman E, Pfister DG. Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review. The Lancet Oncology. 2011;12(8):815-24.\u003c/li\u003e\n\u003cli\u003eCavalieri S, Lombardi Stocchetti B, Crippa N, Silvestri C, Villa C, Ghelardi F, et al. Radiochemotherapy for salivary gland adenoid cystic carcinoma: survival assessment through a retrospective study exploiting real-world data extracted from data warehouse. ESMO Real World Data and Digital Oncology. 2025;9.\u003c/li\u003e\n\u003cli\u003eQiu Z, Wu Z, Zhou X, Lin M, Su Y, Tao Y. Platinum-based adjuvant chemoradiotherapy versus adjuvant radiotherapy in patients with head and neck adenoid cystic carcinoma. J Cancer Res Clin Oncol. 2024;150(4):195.\u003c/li\u003e\n\u003cli\u003eAli S, Palmer FL, Katabi N, Lee N, Shah JP, Patel SG, et al. Long‐term local control rates of patients with adenoid cystic carcinoma of the head and neck managed by surgery and postoperative radiation. The Laryngoscope. 2017;127(10):2265-9.\u003c/li\u003e\n\u003cli\u003eMichel G, Joubert M, Delemazure AS, Espitalier F, Durand N, Malard O. Adenoid cystic carcinoma of the paranasal sinuses: retrospective series and review of the literature. Eur Ann Otorhinolaryngol Head Neck Dis. 2013;130(5):257-62.\u003c/li\u003e\n\u003cli\u003eBakst RL, Glastonbury CM, Parvathaneni U, Katabi N, Hu KS, Yom SS. Perineural Invasion and Perineural Tumor Spread in Head and Neck Cancer. International Journal of Radiation Oncology, Biology, Physics. 2019;103(5):1109-24.\u003c/li\u003e\n\u003cli\u003eKhan AJ, DiGiovanna MP, Ross DA, Sasaki CT, Carter D, Son YH, et al. Adenoid cystic carcinoma: A retrospective clinical review. International Journal of Cancer. 2001;96(3):149-58.\u003c/li\u003e\n\u003cli\u003eBarrett AW, Speight PM. Perineural invasion in adenoid cystic carcinoma of the salivary glands: a valid prognostic indicator? Oral oncology. 2009;45(11):936-40.\u003c/li\u003e\n\u003cli\u003eDodd RL, Slevin NJ. Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. Oral Oncol. 2006;42(8):759-69.\u003c/li\u003e\n\u003cli\u003eThariat J, Ferrand FR, Fakhry N, Even C, Vergez S, Chabrillac E, et al. Radiotherapy for salivary gland cancer: REFCOR recommendations by the formal consensus method. European Annals of Otorhinolaryngology, Head and Neck Diseases. 2024;141(4):221-6.\u003c/li\u003e\n\u003cli\u003eDou S, Wang X, Xiao Y, Zhang L, Jiang W, Ye L, et al. Concurrent chemoradiotherapy versus radiotherapy alone in postoperative high-risk adenoid cystic carcinoma of the head and neck: A propensity score matched analysis. Clinical and Translational Radiation Oncology. 2025;53:100945.\u003c/li\u003e\n\u003cli\u003eZhang M, Zheng M, Dai L, Zhang WL, Fan HY, Yu XH, et al. CXCL12/CXCR4 facilitates perineural invasion via induction of the Twist/400A4 axis in salivary adenoid cystic carcinoma. J Cell Mol Med. 2021;25(16):7901-12.\u003c/li\u003e\n\u003cli\u003eHsieh CE, Lin CY, Lee LY, Yang LY, Wang CC, Wang HM, et al. Adding concurrent chemotherapy to postoperative radiotherapy improves locoregional control but Not overall survival in patients with salivary gland adenoid cystic carcinoma-a propensity score matched study. Radiat Oncol. 2016;11:47.\u003c/li\u003e\n\u003cli\u003eVos JL, Elbers JB, Krijgsman O, Traets JJ, Qiao X, van der Leun AM, et al. Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nature communications. 2021;12(1):7348.\u003c/li\u003e\n\u003cli\u003eFerrarotto R, Amit M, Nagarajan P, Rubin ML, Yuan Y, Bell D, et al. Pilot phase II trial of neoadjuvant immunotherapy in locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck. Clinical Cancer Research. 2021;27(16):4557-65.\u003c/li\u003e\n\u003cli\u003eZhang Z, Wu B, Peng G, Xiao G, Huang J, Ding Q, et al. Neoadjuvant chemoimmunotherapy for the treatment of locally advanced head and neck squamous cell carcinoma: a single-arm phase 2 clinical trial. Clinical Cancer Research. 2022;28(15):3268-76.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"HNACC, Postoperative treatment, Adjuvant chemotherapy, Adjuvant radiotherapy, Perineural invasion","lastPublishedDoi":"10.21203/rs.3.rs-9254166/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9254166/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe optimal postoperative treatment (POT) strategy for non-metastatic head and neck adenoid cystic carcinoma (HNACC) remains controversial. This study aimed to evaluate whether postoperative radiotherapy (PORT) or postoperative chemoradiotherapy (POCRT) provide survival benefits compared with surgery only (SO) in patients with HNACC.\u003c/p\u003e\u003ch2\u003eMaterials and methods\u003c/h2\u003e \u003cp\u003eThis retrospective study analyzed patients with non-metastatic HNACC who underwent curative-intent surgery between 2011 and 2023. Patients were categorized into SO, PORT, and POCRT groups. PORT and POCRT were collectively referred to as radiotherapy (RT)-based POT in this study. Survival outcomes, including overall survival (OS), progression-free survival (PFS), local failure\u0026ndash;free survival (LFFS), and distant metastasis\u0026ndash;free survival (DMFS), were evaluated using Kaplan\u0026ndash;Meier analyses and Cox proportional hazards models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 114 patients were included, comprising 35 treated with SO, 42 with PORT, and 37 with POCRT. With a median follow-up of 51.0 months, no significant differences in OS, PFS, LFFS, or DMFS were observed among the three groups in the overall cohort (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). PNI independently predicted worse OS (HR 3.425, 95% CI 1.316\u0026ndash;8.913, P\u0026thinsp;=\u0026thinsp;0.012) and PFS (HR 2.196, 95% CI 1.060\u0026ndash;4.549, P\u0026thinsp;=\u0026thinsp;0.034). In PNI patients, RT-based POT significantly improved LFFS versus SO (P\u0026thinsp;=\u0026thinsp;0.032), while POCRT showed no clear advantage over PORT.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSurvival outcomes were comparable among SO, PORT, and POCRT in non-metastatic HNACC. Patients with PNI may derive greater local control benefit from RT-based POT, warranting prospective validation.\u003c/p\u003e","manuscriptTitle":"Postoperative Radiotherapy or Chemoradiotherapy Versus Surgery Only in Non-Metastatic Head and Neck Adenoid Cystic Carcinoma: A Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-22 05:44:10","doi":"10.21203/rs.3.rs-9254166/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"86ebfbb0-eb9e-4591-9ecf-69c7a9d4f263","owner":[],"postedDate":"April 22nd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-04T23:28:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T08:50:38+00:00","index":20,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T22:23:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-22 05:44:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9254166","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9254166","identity":"rs-9254166","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}