Limited Benefit of Postoperative Chemoradiotherapy in Intermediate-Risk Locally Advanced Head and Neck Squamous Cell Carcinoma: Real-World Evidence from the IMRT Era

Limited Benefit of Postoperative Chemoradiotherapy in Intermediate-Risk Locally Advanced Head and Neck Squamous Cell Carcinoma: Real-World Evidence from the IMRT Era | 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 Limited Benefit of Postoperative Chemoradiotherapy in Intermediate-Risk Locally Advanced Head and Neck Squamous Cell Carcinoma: Real-World Evidence from the IMRT Era Qimiao Qiu, Yangchan Li, Qiuyue Tang, Yong Chen, Chengtao Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7795402/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background In the era of intensity-modulated radiotherapy (IMRT), the benefit of adding concurrent chemotherapy to postoperative radiotherapy (PORT) for intermediate-risk locally advanced head and neck squamous cell carcinoma (LA-HNSCC) without positive margins (R1) or extracapsular extension (ECE) remains controversial. Methods We retrospectively analyzed patients with intermediate-risk LA-HNSCC treated with postoperative chemoradiotherapy (POCRT) or PORT at our institution. Propensity score matching (PSM) was performed to balance baseline characteristics. Independent prognostic factors were identified through Cox regression analysis, and survival outcomes were compared between groups. Results After matching, 131 patients were included (39 POCRT, 92 PORT). Perineural Invasion (PNI) was an independent adverse factor for progression-free survival (PFS; HR 3.07,95% CI 1.46–6.69, P = 0.005), locoregional recurrence-free survival (LRRFS; HR 3.86, 95% CI 1.41–10.60, P = 0.009), and distant metastasis-free survival (DMFS; HR 5.76, 95% CI 1.09–30.59, P = 0.04). Lymphovascular invasion (LVI) was independently associated with worse overall survival (OS; HR 6.83, 95%CI 1.60–29.05, P = 0.009) and PFS (HR 4.02, 95%CI 1.21–13.37, P = 0.023). POCRT did not significantly improve OS, PFS, LRRFS, or DMFS compared to PORT. Conclusions In intermediate-risk LA-HNSCC patients treated with IMRT, PNI and LVI were key prognostic indicators, while POCRT conferred no survival advantage over PORT. These findings suggest the need for prospective validation before the routine use of POCRT in this subgroup. Head and neck squamous cell carcinoma postoperative chemoradiotherapy intensity-modulated radiotherapy intermediate-risk perineural invasion lymphovascular invasion Figures Figure 1 Introduction Head and neck cancers rank among the most prevalent malignancies worldwide, with more than 930,000 new cases and 460,000 deaths estimated worldwide in 2022 [1, 2]. In China, the disease burden is particularly high, accounting for a substantial proportion of cancer-related morbidity and mortality [2, 3]. Head and neck squamous cell carcinoma (HNSCC) is the predominant histopathological subtype, and its incidence remains consistently 3 times higher in men than in women [3]. For patients with locally advanced disease undergoing curative surgery, postoperative radiotherapy (PORT) is the cornerstone of adjuvant therapy, especially in the presence of adverse pathological features. The addition of concurrent chemotherapy to PORT (postoperative chemoradiotherapy, POCRT) has long been established as the standard of care for patients with high-risk features such as positive surgical margins (R1) or extracapsular extension (ECE), based on the pivotal RTOG 9501 and EORTC 22931 trials [4–6]. These studies demonstrated improved locoregional control (LRC) and disease-free survival (DFS) with POCRT compared to PORT alone, leading to guideline endorsement of POCRT for high-risk patients [7]. However, for patients without R1 or ECE but presenting with intermediate-risk features, such as pathological T3-4 stage (pT3-4), N2-3 nodal disease, perineural invasion (PNI), or lymphovascular invasion (LVI), the optimal postoperative strategy remains controversial. While some retrospective studies suggest potential benefit from concurrent chemotherapy in this subset [8–10], others report no significant survival advantage and raise concerns about overtreatment and toxicity [11–13]. Moreover, age and comorbidity may further modulate the therapeutic index of POCRT in this group [14]. Importantly, the therapeutic landscape has evolved with the widespread adoption of intensity-modulated radiotherapy (IMRT), which enables improved target conformity and normal tissue sparing, thereby reducing both acute and late toxicity. This technological advancement calls for a reassessment of the necessity of concurrent chemotherapy in intermediate-risk patients, especially considering the additional burden of cisplatin-related adverse events [11, 12]. In this context, we conducted a retrospective, propensity score-matched analysis to evaluate the clinical outcomes of POCRT versus PORT in patients with intermediate-risk, locally advanced HNSCC (LA-HNSCC) without R1 or ECE, all treated in the modern IMRT era. We also explored the prognostic impact of individual pathological risk factors to identify subgroups that may benefit from treatment intensification. Methods Population and Data Collection The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (No. [2025]492). Given the retrospective nature of the study, with no additional interventions and fully anonymized data, the requirement for individual informed consent was waived. Patients with locally advanced HNSCC (AJCC/UICC 8th edition pathologic stage III-IVB) who received initial treatment between January 2017 and December 2022 were retrospectively reviewed. Inclusion criteria were: (1) primary tumor in the oral cavity, oropharynx, larynx, or hypopharynx; (2) histologically confirmed squamous cell carcinoma; (3) underwent radical surgery without prior anticancer therapy; (4) negative surgical margins(R0) and no extracapsular extension;(5) presence at least one intermediate-risk factor (PNI, LVI, pT3-4, or pN2-3); and (6) receipt of PORT or POCRT at our institution. Exclusion criteria included: pregnancy or breastfeeding, ECOG performance status > 2, prior malignancies, or follow-up < 6 months post-treatment. Clinical and pathological data were collected from electronic medical records. Routine investigations during treatment and follow-up included comprehensive clinical assessment (history and physical examination), laboratory tests, and multi-modality imaging: contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck, chest CT, bone scintigraphy, and/or positron emission tomography-computed tomography (PET-CT). Pathological features such as tumor differentiation, PNI, LVI, R1 resection, and ECE were independently reviewed by two pathologists. Definition for R1, ECE, PNI, and LVI followed established histopathological criteria [15–18]. Treatment All patients received radical surgical resection followed by adjuvant IMRT. Radiotherapy planning adhered to the International Commission on Radiation Units and Measurements (ICRU) reports 50,62, and 83. Target volume delineation was guided by pre- and postoperative imaging. The clinical target volume (CTV) included the tumor bed and regional lymphatic areas; the planning target volume (PTV) extended 3–5 mm beyond the CTV. A typical dose of 60–66 Gy in 30–33 fractions was prescribed. Decisions regarding concurrent chemotherapy were based on pathological risk, performance status, and clinician discretion. Patients in the POCRT group received platinum-based chemotherapy (cisplatin or nedaplatin, 80 mg/m² every three weeks) for 2–3 cycles, adjusted to tolerance and comorbidities. All patients in both groups completed the planned treatment. Follow-up and Endpoints Patients were followed from the date of definitive surgery until death or last documented contact. Follow-up was scheduled every 3 to 6 months for the first 3 years, then every 6 to 12 months until year 5, and annually thereafter. Each visit included an assessment of the patient’s condition. Locoregional or distant failure was confirmed histologically whenever feasible; otherwise, unequivocal progression on serial imaging or FDG-PET was accepted. The primary endpoint was overall survival (OS), defined as time from surgery to death from any cause. Secondary endpoints included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). PFS was defined as the time from surgery to the date of first documented disease progression or death. LRRFS and DMFS were measured from surgery to the first locoregional recurrence, distant metastasis, respectively. Statistical Analysis Categorical variables were compared using chi-squared or Fisher’s exact test, as appropriate. Propensity score matching (PSM) was performed at a 1:3 matching ratio using the nearest-neighbor method without replacement, based on age, sex, tumor grade, T-stage, N-stage, PNI, and LVI. Survival curves were generated using the Kaplan–Meier method and compared using the log-rank test. Multivariable analysis was conducted using Cox proportional hazards models. Statistical significance was defined as a two-tailed p-value < 0.05. All analyses were performed in R (version 4.3.2; R Foundation for Statistical Computing). Results Baseline characteristics After excluding patients who received neoadjuvant therapy, presented with distant metastasis, ECE, R1, or underwent palliative treatment, a total of 190 patients with HNSCC were included. Among them, 41 patients (21.6%) received POCRT, while 149 patients (78.4%) underwent PORT alone. The baseline characteristics of the entire cohort are summarized in Table 1 . The median age of the cohort was 56 years (range: 21–77 years), and the male-to-female ratio was approximately 7:1. Patients who were younger, had lower T-stage, higher N-stage, or exhibited PNI were more likely to receive POCRT. A significant difference in T-stage distribution was observed between the two groups (P < 0.01). Following PSM at a matching ratio of 1:3, a balanced cohort of 131 patients was established, comprising 39 in the POCRT group and 92 in the PORT group. After matching, there were no significant differences between the groups in terms of age, sex, TN stage, tumor grade, PNI, and LVI (all P > 0.05). Table 1 Baseline characteristics of PORT and POCRT groups in the original cohort and matched cohort. Characteristics Original cohort (n = 190) Matched cohort (n = 131) PORT (%) POCRT (%) P -value PORT (%) POCRT (%) P -value Sample Size 149 41 - 92 39 - Age 0.12 0.73 < 60y 91(61.1) 31(75.6) 64(69.6) 29(74.4) ≥ 60y 58(38.9) 10(24.4) 28(30.4) 10(25.6) Gender 0.86 0.94 Female 18(12.1) 6(14.6) 12(13.0) 6(15.4) Male 131(87.9) 35(85.4) 80(87.0) 33(84.6) T-stage < 0.01 0.11 pT1-2 22(14.8) 15(36.6) 19(20.7) 14(35.9) pT3-4 127(85.2) 26(63.4) 73(79.3) 25(64.1) N-stage 0.15 0.6 pN0-N1 83(55.7) 17(41.5) 44(47.8) 16(41.0) pN2-N3 66(44.3) 24(58.5) 48(52.2) 23(59.0) Differentiation 0.07 0.82 Well 39(26.2) 16(39.0) 31(33.7) 15(38.5) Moderately 57(38.3) 8(19.5) 18(19.6) 8(20.5) Poorly 53(35.6) 17(41.5) 43(46.7) 16(41.0) PNI 0.42 1 Negative 120(80.5) 30(73.2) 71(77.2) 30(76.9) Positive 29(19.5) 11(26.8) 21(22.8) 9(23.1) LVI 0.47 1 Negative 134(89.9) 39(95.1) 86(93.5) 37(94.9) Positive 15(10.1) 2(4.9) 6(6.5) 2(5.1) Impact of POCRT on Survival Outcomes In the matched cohort, no statistically significant differences were observed in OS, PFS, LRRFS, or DMFS between patients receiving POCRT and those receiving PORT (Fig. 1 ). At the 3-year follow-up, OS, PFS, LRRFS, and DMFS rates were numerically higher in the PORT group than in the POCRT group (OS: 83.5% vs. 70.3%, P = 0.16; PFS: 73.6% vs. 59.2%, P = 0.20; LRRFS: 85.9% vs. 80.5%, P = 0.67; DMFS: 93.7% vs. 84.2%, P = 0.07). This trend persisted at 5 years for OS, PFS, and DMFS. Interestingly, 5-year LRRFS slightly favored POCRT (67.4% vs. 74.3%). Univariate and multivariate analysis Univariate analysis was conducted for demographic and clinicopathologic factors ( Table S1 ). Multivariable Cox regression identified PNI and LVI as independent prognostic factors (Table 2 ). PNI was significantly associated with poorer PFS (HR 3.07, 95% CI 1.46–6.69, P = 0.005), LRRFS (HR 3.86, 95% CI 1.41–10.60, P = 0.009), and DMFS (HR 5.76, 95% CI 1.09–30.59, P = 0.040). LVI was independently associated with inferior OS (HR 6.83, 95% CI 1.60-29.05, P = 0.009) and PFS (HR 4.02, 95% CI 1.21–13.37, P = 0.023). No significant association was observed between T-stage, N-stage, and survival outcomes. Table 2 Multivariate Cox analysis of the effect of prognostic factors in the matched cohort. Variable HR 95%CI p value OS LVI 6.83 1.60-29.05 p = .009 PFS PNI 3.07 1.41–6.69 p = .005 LVI 4.02 1.21–13.37 p = .023 LRRFS PNI 3.86 1.41–10.60 p = .009 DMFS PNI 5.76 1.09–30.59 p = .040 Discussion By excluding patients with high-risk pathological features such as R1 or ECE, our study focused specifically on individuals with intermediate-risk LA-HNSCC, characterized by factors such as pT3-4, pN2-3, PNI, LVI. The key finding was that PNI and LVI, rather than T or N stage, were independent predictors of poor survival. Notably, the addition of concurrent chemotherapy to postoperative radiotherapy (POCRT) did not confer survival benefits over PORT alone in any endpoint. These results challenge the applicability of current guidelines recommending POCRT for high-risk patients to those with intermediate-risk features [4, 5]. Although previous studies have demonstrated that advanced T and N stage negatively affect prognosis in HNSCC [19–21], our data did not support these associations. This may be attributed to differences in tumor subsites or the confounding impact of more aggressive histopathological features. Furthermore, the TNM staging system fails to consider critical pathological and microenvironmental factors that may drive tumor progression, which limits its prognostic precision in the era of personalized medicine. Our findings reinforce the prognostic significance of PNI and LVI, which are established histopathologic markers of aggressive tumor behavior across various malignancies[22–25]. In HNSCC, however, their therapeutic implications remain controversial [26–29]. The current study supports the role of PNI as a robust adverse prognostic factor across multiple survival outcomes, consistent with EORTC 22931 findings that classified PNI and LVI as high-risk features requiring intensified adjuvant therapy [5]. PNI has been associated with increased risk of local recurrence, distant metastasis, and poor survival in HNSCC involving multiple subsites [30–32]. The biological basis may lie in the capacity of squamous cell carcinoma (SCC) to track along the perineural space, up to 12 cm in some cases, which facilitates local extension and regional spread [33, 34]. Numerous studies have also linked PNI to cervical lymph node metastasis, particularly in oral cavity and oropharyngeal SCC [29, 34–36], suggesting it reflects more invasive phenotype [37, 38]. Moreover, PNI is a distinct pathological entity that may occur independently of lymphatic and vascular invasion, and could represent a route for distant dissemination [17]. Recent research has revealed that PNI is not merely passive infiltration, but an active process mediated by reciprocal signaling between nerves and tumor cells, involving neurotrophic factors such as NGF and BDNF [17, 39, 40]. Compared to PNI, LVI has received less attention, partly due to the challenges in its histological detection [26, 41]. While its prognostic relevance in OCSCC has been debated [42–45], our study demonstrates a significant association between LVI and both OS and PFS in the broader LA-HNSCC population. LVI likely reflects early metastatic potential and is a critical event in tumor angiogenesis and dissemination [46]. According to Huang et al., tumor emboli occur more frequently within larger lymphatic channels in deeper tissues than within smaller lymphatic vessels in superficial regions [47], providing a possible explanation for our findings. Despite the proven benefit of POCRT in high-risk patients based on RTOG 9501 and EORTC 22931[4, 5], our results suggest that such benefit may not extend to intermediate-risk patients in the IMRT era. This is consistent with findings from Liu et al., who showed that POCRT improved locoregional control only in subsets with pT3-4 or pN2-3, but not across all intermediate-risk groups[9]. Our findings contrast with those of Trifiletti et al., who reported only a marginal OS benefit with POCRT in all subgroups of LA-HNSCC without R1 or ECE [10]. A key consideration is the toxicity burden associated with POCRT. Cisplatin-based chemotherapy increases the incidence of acute mucositis, hematologic toxicity, and gastrointestinal complications, which may undermine its therapeutic benefit [5, 48]. In RTOG 9501, grade ≥ 3 adverse events occurred in 77% of patients receiving POCRT versus 34% in the PORT [4]. Such toxicity may necessitate treatment interruptions and/or a reduction in radiotherapy dose intensity. Therefore, in the absence of a compelling survival advantage, routine use of POCRT in intermediate-risk patients may not be justified. The RTOG 0920 trial demonstrates that postoperative cetuximab combined with radiotherapy significantly improves disease-free survival (DFS) in patients with LA-HNSCC at intermediate-risk, without a corresponding increase in severe toxicity. These findings suggest a potential alternative strategy for postoperative adjuvant therapy [49]. Several limitations of this study should be acknowledged. First, treatment-associated toxicity was not assessed, despite its clinical relevance. As previously noted, POCRT is generally associated with higher toxicity than PORT, and the observed OS benefit of POCRT may have been attenuated by unmeasured adverse effects not captured in our analysis. Second, the overall sample size was limited, particularly in the POCRT group, precluding further subgroup analyses. Lastly, while PSM minimized confounding from baseline inherent to this retrospective study, residual biases cannot be excluded. Conclusion In conclusion, this study identified PNI and LVI as independent prognostic factors in intermediate-risk LA-HNSCC without R1 or ECE, whereas pT3-4 and pN2-3 lacked prognostic value. POCRT provided no survival benefit over PORT alone. These findings suggest that POCRT may not be routinely warranted in this subgroup and highlight the need for prospective, randomized trials to better define the optimal adjuvant strategy. Abbreviations HNSCC Head and neck squamous cell carcinoma LA-HNSCC Locally advanced head and neck cancer POCRT Postoperative chemoradiotherapy PORT Postoperative radiotherapy R1 Positive margin ECE Extracapsular extension LVI Lymphovascular invasion PNI Perineural invasion PSM Propensity score matching OS Overall survival PFS Progression-free survival LRRFS Locoregional recurrence-free survival DMFS Distant metastasis-free survival DFS Disease-free survival RTOG Radiation Therapy Oncology Group EORTC European Organization for Research and Treatment of Cancer IMRT Intensity-modulated radiotherapy VMAT Volumetric-modulated arc therapy SCC Squamous cell carcinoma OSCC Oral squamous cell carcinoma OCSCC Oral cavity squamous cell carcinoma AJCC American Joint Committee on Cancer ICRU International Commission on Radiation Units and Measurements CTV Clinical target volume PTV Planning target volume Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (Approval No. [2025]492). All patient data were de-identified and analyzed retrospectively. The requirement for written informed consent was waived due to the retrospective nature of the study. Consent for publication Not applicable. Availability of data and materials The data that support the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors declare no competing interests. Funding This work was supported by the Science and Technology Program of Guangzhou (Grant No. 2023A04J2213), the Department of Science and Technology of Guangdong Province (Grant No. 2023A1515110903), and the National Natural Science Foundation of China (Grant No. 82400183). Author's contribution Q.Q. and Y.L. contributed equally to study design, data collection, statistical analysis, and manuscript drafting. Q.T. participated in data collection. Y.C. was responsible for chart and figure review. 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Association of lymphovascular space invasion with locoregional failure and survival in patients with node-negative oral tongue cancers. JAMA Otolaryngol Head Neck Surg. 2017;143(4):382-8. Fives C, Feeley L, O'Leary G, Sheahan P. Importance of lymphovascular invasion and invasive front on survival in floor of mouth cancer. Head Neck. 2016;38(S1):E1528-E34. Chen T-C, Wang C-P, Ko J-Y, Yang T-L, Hsu C-W, Yeh K-A, et al. The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients. Ann Surg Oncol. 2013;20:2388-95. Klotch DW, Muro-Cacho C, Gal T. Factors affecting survival for floor-of-mouth carcinoma. Otolaryngol Head Neck Surg. 2000;122(4):495-8. Guo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5(10):816-26. Huang SH, Hwang D, Lockwood G, Goldstein DP, O'Sullivan B. Predictive value of tumor thickness for cervical lymph‐node involvement in squamous cell carcinoma of the oral cavity: a meta‐analysis of reported studies. Cancer. 2009;115(7):1489-97. Galot R, Machiels J-P. Safety of drug treatments for head and neck cancer. Expert Opin Drug Saf. 2016;15(11):1527-39. Machtay M, Torres-Saavedra PA, Thorstad W, Nguyen-Tân PF, Siu LL, Holsinger FC, et al. Postoperative Radiotherapy±Cetuximab for Intermediate-Risk Head and Neck Cancer. J Clin Oncol. 2025:JCO-24-01829. Additional Declarations No competing interests reported. Supplementary Files TableS1.docx Table S1. Univariable Cox analysis of both demographic and clinicopathologic variables in matched cohort. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 11 Nov, 2025 Reviewers invited by journal 30 Oct, 2025 Editor invited by journal 09 Oct, 2025 Editor assigned by journal 07 Oct, 2025 Submission checks completed at journal 07 Oct, 2025 First submitted to journal 06 Oct, 2025 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-7795402","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":542232007,"identity":"08fc8278-f642-45a4-85a8-c517729f471b","order_by":0,"name":"Qimiao Qiu","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qimiao","middleName":"","lastName":"Qiu","suffix":""},{"id":542232008,"identity":"1196b2c6-2f3c-4a1a-9ec7-24218701b85c","order_by":1,"name":"Yangchan Li","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yangchan","middleName":"","lastName":"Li","suffix":""},{"id":542232009,"identity":"bd750e9c-e7c6-4ec2-a3e2-205cffbeaedb","order_by":2,"name":"Qiuyue Tang","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qiuyue","middleName":"","lastName":"Tang","suffix":""},{"id":542232010,"identity":"e11aa3e6-683b-4971-b7ae-9914b3474138","order_by":3,"name":"Yong Chen","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Chen","suffix":""},{"id":542232012,"identity":"0f88e726-84cf-4c70-aee7-4493c6de2c89","order_by":4,"name":"Chengtao Wang","email":"","orcid":"","institution":"First Affiliated Hospital of Sun Yat-sen 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1","display":"","copyAsset":false,"role":"figure","size":327669,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves comparing PORT and POCRT in the matched cohort (N = 131).\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7795402/v1/6fa98247eb30204654eb4199.jpg"},{"id":95664123,"identity":"d6dcc6b5-3b17-4353-a21e-0a7c5e320008","added_by":"auto","created_at":"2025-11-11 16:39:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1075408,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7795402/v1/3091ea90-dafb-4de3-bd5e-964d4060c869.pdf"},{"id":95663521,"identity":"9977bf26-2d40-4c4c-b05d-8a8025bce78b","added_by":"auto","created_at":"2025-11-11 16:39:03","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18766,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1. Univariable Cox analysis of both demographic and clinicopathologic variables in matched cohort.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7795402/v1/3f6e016b5d7175d2eacc2ab8.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Limited Benefit of Postoperative Chemoradiotherapy in Intermediate-Risk Locally Advanced Head and Neck Squamous Cell Carcinoma: Real-World Evidence from the IMRT Era","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHead and neck cancers rank among the most prevalent malignancies worldwide, with more than 930,000 new cases and 460,000 deaths estimated worldwide in 2022 [1, 2]. In China, the disease burden is particularly high, accounting for a substantial proportion of cancer-related morbidity and mortality [2, 3]. Head and neck squamous cell carcinoma (HNSCC) is the predominant histopathological subtype, and its incidence remains consistently 3 times higher in men than in women [3]. For patients with locally advanced disease undergoing curative surgery, postoperative radiotherapy (PORT) is the cornerstone of adjuvant therapy, especially in the presence of adverse pathological features.\u003c/p\u003e\u003cp\u003e The addition of concurrent chemotherapy to PORT (postoperative chemoradiotherapy, POCRT) has long been established as the standard of care for patients with high-risk features such as positive surgical margins (R1) or extracapsular extension (ECE), based on the pivotal RTOG 9501 and EORTC 22931 trials [4\u0026ndash;6]. These studies demonstrated improved locoregional control (LRC) and disease-free survival (DFS) with POCRT compared to PORT alone, leading to guideline endorsement of POCRT for high-risk patients [7].\u003c/p\u003e\u003cp\u003eHowever, for patients without R1 or ECE but presenting with intermediate-risk features, such as pathological T3-4 stage (pT3-4), N2-3 nodal disease, perineural invasion (PNI), or lymphovascular invasion (LVI), the optimal postoperative strategy remains controversial. While some retrospective studies suggest potential benefit from concurrent chemotherapy in this subset [8\u0026ndash;10], others report no significant survival advantage and raise concerns about overtreatment and toxicity [11\u0026ndash;13]. Moreover, age and comorbidity may further modulate the therapeutic index of POCRT in this group [14].\u003c/p\u003e\u003cp\u003eImportantly, the therapeutic landscape has evolved with the widespread adoption of intensity-modulated radiotherapy (IMRT), which enables improved target conformity and normal tissue sparing, thereby reducing both acute and late toxicity. This technological advancement calls for a reassessment of the necessity of concurrent chemotherapy in intermediate-risk patients, especially considering the additional burden of cisplatin-related adverse events [11, 12].\u003c/p\u003e\u003cp\u003eIn this context, we conducted a retrospective, propensity score-matched analysis to evaluate the clinical outcomes of POCRT versus PORT in patients with intermediate-risk, locally advanced HNSCC (LA-HNSCC) without R1 or ECE, all treated in the modern IMRT era. We also explored the prognostic impact of individual pathological risk factors to identify subgroups that may benefit from treatment intensification.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePopulation and Data Collection\u003c/h2\u003e\u003cp\u003e The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (No. [2025]492). Given the retrospective nature of the study, with no additional interventions and fully anonymized data, the requirement for individual informed consent was waived.\u003c/p\u003e\u003cp\u003ePatients with locally advanced HNSCC (AJCC/UICC 8th edition pathologic stage III-IVB) who received initial treatment between January 2017 and December 2022 were retrospectively reviewed. Inclusion criteria were: (1) primary tumor in the oral cavity, oropharynx, larynx, or hypopharynx; (2) histologically confirmed squamous cell carcinoma; (3) underwent radical surgery without prior anticancer therapy; (4) negative surgical margins(R0) and no extracapsular extension;(5) presence at least one intermediate-risk factor (PNI, LVI, pT3-4, or pN2-3); and (6) receipt of PORT or POCRT at our institution. Exclusion criteria included: pregnancy or breastfeeding, ECOG performance status\u0026thinsp;\u0026gt;\u0026thinsp;2, prior malignancies, or follow-up \u0026lt;\u0026thinsp;6 months post-treatment.\u003c/p\u003e\u003cp\u003eClinical and pathological data were collected from electronic medical records. Routine investigations during treatment and follow-up included comprehensive clinical assessment (history and physical examination), laboratory tests, and multi-modality imaging: contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck, chest CT, bone scintigraphy, and/or positron emission tomography-computed tomography (PET-CT). Pathological features such as tumor differentiation, PNI, LVI, R1 resection, and ECE were independently reviewed by two pathologists. Definition for R1, ECE, PNI, and LVI followed established histopathological criteria [15\u0026ndash;18].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAll patients received radical surgical resection followed by adjuvant IMRT. Radiotherapy planning adhered to the International Commission on Radiation Units and Measurements (ICRU) reports 50,62, and 83. Target volume delineation was guided by pre- and postoperative imaging. The clinical target volume (CTV) included the tumor bed and regional lymphatic areas; the planning target volume (PTV) extended 3\u0026ndash;5 mm beyond the CTV. A typical dose of 60\u0026ndash;66 Gy in 30\u0026ndash;33 fractions was prescribed.\u003c/p\u003e\u003cp\u003eDecisions regarding concurrent chemotherapy were based on pathological risk, performance status, and clinician discretion. Patients in the POCRT group received platinum-based chemotherapy (cisplatin or nedaplatin, 80 mg/m\u0026sup2; every three weeks) for 2\u0026ndash;3 cycles, adjusted to tolerance and comorbidities. All patients in both groups completed the planned treatment.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Endpoints\u003c/h3\u003e\n\u003cp\u003ePatients were followed from the date of definitive surgery until death or last documented contact. Follow-up was scheduled every 3 to 6 months for the first 3 years, then every 6 to 12 months until year 5, and annually thereafter. Each visit included an assessment of the patient\u0026rsquo;s condition. Locoregional or distant failure was confirmed histologically whenever feasible; otherwise, unequivocal progression on serial imaging or FDG-PET was accepted. The primary endpoint was overall survival (OS), defined as time from surgery to death from any cause. Secondary endpoints included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). PFS was defined as the time from surgery to the date of first documented disease progression or death. LRRFS and DMFS were measured from surgery to the first locoregional recurrence, distant metastasis, respectively.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eCategorical variables were compared using chi-squared or Fisher\u0026rsquo;s exact test, as appropriate. Propensity score matching (PSM) was performed at a 1:3 matching ratio using the nearest-neighbor method without replacement, based on age, sex, tumor grade, T-stage, N-stage, PNI, and LVI. Survival curves were generated using the Kaplan\u0026ndash;Meier method and compared using the log-rank test. Multivariable analysis was conducted using Cox proportional hazards models. Statistical significance was defined as a two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed in R (version 4.3.2; R Foundation for Statistical Computing).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBaseline characteristics\u003c/h2\u003e\u003cp\u003eAfter excluding patients who received neoadjuvant therapy, presented with distant metastasis, ECE, R1, or underwent palliative treatment, a total of 190 patients with HNSCC were included. Among them, 41 patients (21.6%) received POCRT, while 149 patients (78.4%) underwent PORT alone. The baseline characteristics of the entire cohort are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age of the cohort was 56 years (range: 21\u0026ndash;77 years), and the male-to-female ratio was approximately 7:1. Patients who were younger, had lower T-stage, higher N-stage, or exhibited PNI were more likely to receive POCRT. A significant difference in T-stage distribution was observed between the two groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Following PSM at a matching ratio of 1:3, a balanced cohort of 131 patients was established, comprising 39 in the POCRT group and 92 in the PORT group. After matching, there were no significant differences between the groups in terms of age, sex, TN stage, tumor grade, PNI, and LVI (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\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\u003eBaseline characteristics of PORT and POCRT groups in the original cohort and matched cohort.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\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=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\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=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eOriginal cohort (n\u0026thinsp;=\u0026thinsp;190)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e\u003cp\u003eMatched cohort (n\u0026thinsp;=\u0026thinsp;131)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePORT (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePOCRT (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePORT (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePOCRT (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-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\u003eSample Size\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\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\u003cp\u003e0.12\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;60y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e91(61.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31(75.6)\u003c/p\u003e\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\u003cp\u003e64(69.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e29(74.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;60y\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58(38.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10(24.4)\u003c/p\u003e\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\u003cp\u003e28(30.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10(25.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eGender\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\u003cp\u003e0.86\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.94\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\u003e18(12.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6(14.6)\u003c/p\u003e\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\u003cp\u003e12(13.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6(15.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\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\u003e131(87.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35(85.4)\u003c/p\u003e\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\u003cp\u003e80(87.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e33(84.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eT-stage\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\u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epT1-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22(14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15(36.6)\u003c/p\u003e\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\u003cp\u003e19(20.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14(35.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epT3-4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127(85.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26(63.4)\u003c/p\u003e\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\u003cp\u003e73(79.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e25(64.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eN-stage\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\u003cp\u003e0.15\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epN0-N1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e83(55.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17(41.5)\u003c/p\u003e\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\u003cp\u003e44(47.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e16(41.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epN2-N3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66(44.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24(58.5)\u003c/p\u003e\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\u003cp\u003e48(52.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e23(59.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDifferentiation\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\u003cp\u003e0.07\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWell\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39(26.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16(39.0)\u003c/p\u003e\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\u003cp\u003e31(33.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e15(38.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eModerately\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57(38.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8(19.5)\u003c/p\u003e\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\u003cp\u003e18(19.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8(20.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePoorly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53(35.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17(41.5)\u003c/p\u003e\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\u003cp\u003e43(46.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e16(41.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePNI\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\u003cp\u003e0.42\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e120(80.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30(73.2)\u003c/p\u003e\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\u003cp\u003e71(77.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e30(76.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29(19.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11(26.8)\u003c/p\u003e\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\u003cp\u003e21(22.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9(23.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLVI\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\u003cp\u003e0.47\u003c/p\u003e\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\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e134(89.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39(95.1)\u003c/p\u003e\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\u003cp\u003e86(93.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e37(94.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15(10.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2(4.9)\u003c/p\u003e\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\u003cp\u003e6(6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2(5.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eImpact of POCRT on Survival Outcomes\u003c/h3\u003e\n\u003cp\u003eIn the matched cohort, no statistically significant differences were observed in OS, PFS, LRRFS, or DMFS between patients receiving POCRT and those receiving PORT (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At the 3-year follow-up, OS, PFS, LRRFS, and DMFS rates were numerically higher in the PORT group than in the POCRT group (OS: 83.5% vs. 70.3%, P\u0026thinsp;=\u0026thinsp;0.16; PFS: 73.6% vs. 59.2%, P\u0026thinsp;=\u0026thinsp;0.20; LRRFS: 85.9% vs. 80.5%, P\u0026thinsp;=\u0026thinsp;0.67; DMFS: 93.7% vs. 84.2%, P\u0026thinsp;=\u0026thinsp;0.07). This trend persisted at 5 years for OS, PFS, and DMFS. Interestingly, 5-year LRRFS slightly favored POCRT (67.4% vs. 74.3%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eUnivariate and multivariate analysis\u003c/h3\u003e\n\u003cp\u003eUnivariate analysis was conducted for demographic and clinicopathologic factors (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). Multivariable Cox regression identified PNI and LVI as independent prognostic factors (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). PNI was significantly associated with poorer PFS (HR 3.07, 95% CI 1.46\u0026ndash;6.69, P\u0026thinsp;=\u0026thinsp;0.005), LRRFS (HR 3.86, 95% CI 1.41\u0026ndash;10.60, P\u0026thinsp;=\u0026thinsp;0.009), and DMFS (HR 5.76, 95% CI 1.09\u0026ndash;30.59, P\u0026thinsp;=\u0026thinsp;0.040). LVI was independently associated with inferior OS (HR 6.83, 95% CI 1.60-29.05, P\u0026thinsp;=\u0026thinsp;0.009) and PFS (HR 4.02, 95% CI 1.21\u0026ndash;13.37, P\u0026thinsp;=\u0026thinsp;0.023). No significant association was observed between T-stage, N-stage, and survival outcomes.\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\u003eMultivariate Cox analysis of the effect of prognostic factors in the matched cohort.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95%CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u0026nbsp;value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLVI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.60-29.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePFS\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.41\u0026ndash;6.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLVI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.21\u0026ndash;13.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLRRFS\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e3.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.41\u0026ndash;10.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDMFS\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\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePNI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.09\u0026ndash;30.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.040\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eBy excluding patients with high-risk pathological features such as R1 or ECE, our study focused specifically on individuals with intermediate-risk LA-HNSCC, characterized by factors such as pT3-4, pN2-3, PNI, LVI. The key finding was that PNI and LVI, rather than T or N stage, were independent predictors of poor survival. Notably, the addition of concurrent chemotherapy to postoperative radiotherapy (POCRT) did not confer survival benefits over PORT alone in any endpoint. These results challenge the applicability of current guidelines recommending POCRT for high-risk patients to those with intermediate-risk features [4, 5].\u003c/p\u003e\u003cp\u003eAlthough previous studies have demonstrated that advanced T and N stage negatively affect prognosis in HNSCC [19\u0026ndash;21], our data did not support these associations. This may be attributed to differences in tumor subsites or the confounding impact of more aggressive histopathological features. Furthermore, the TNM staging system fails to consider critical pathological and microenvironmental factors that may drive tumor progression, which limits its prognostic precision in the era of personalized medicine.\u003c/p\u003e\u003cp\u003eOur findings reinforce the prognostic significance of PNI and LVI, which are established histopathologic markers of aggressive tumor behavior across various malignancies[22\u0026ndash;25]. In HNSCC, however, their therapeutic implications remain controversial [26\u0026ndash;29]. The current study supports the role of PNI as a robust adverse prognostic factor across multiple survival outcomes, consistent with EORTC 22931 findings that classified PNI and LVI as high-risk features requiring intensified adjuvant therapy [5].\u003c/p\u003e\u003cp\u003ePNI has been associated with increased risk of local recurrence, distant metastasis, and poor survival in HNSCC involving multiple subsites [30\u0026ndash;32]. The biological basis may lie in the capacity of squamous cell carcinoma (SCC) to track along the perineural space, up to 12 cm in some cases, which facilitates local extension and regional spread [33, 34]. Numerous studies have also linked PNI to cervical lymph node metastasis, particularly in oral cavity and oropharyngeal SCC [29, 34\u0026ndash;36], suggesting it reflects more invasive phenotype [37, 38]. Moreover, PNI is a distinct pathological entity that may occur independently of lymphatic and vascular invasion, and could represent a route for distant dissemination [17]. Recent research has revealed that PNI is not merely passive infiltration, but an active process mediated by reciprocal signaling between nerves and tumor cells, involving neurotrophic factors such as NGF and BDNF [17, 39, 40].\u003c/p\u003e\u003cp\u003eCompared to PNI, LVI has received less attention, partly due to the challenges in its histological detection [26, 41]. While its prognostic relevance in OCSCC has been debated [42\u0026ndash;45], our study demonstrates a significant association between LVI and both OS and PFS in the broader LA-HNSCC population. LVI likely reflects early metastatic potential and is a critical event in tumor angiogenesis and dissemination [46]. According to Huang et al., tumor emboli occur more frequently within larger lymphatic channels in deeper tissues than within smaller lymphatic vessels in superficial regions [47], providing a possible explanation for our findings.\u003c/p\u003e\u003cp\u003eDespite the proven benefit of POCRT in high-risk patients based on RTOG 9501 and EORTC 22931[4, 5], our results suggest that such benefit may not extend to intermediate-risk patients in the IMRT era. This is consistent with findings from Liu et al., who showed that POCRT improved locoregional control only in subsets with pT3-4 or pN2-3, but not across all intermediate-risk groups[9]. Our findings contrast with those of Trifiletti et al., who reported only a marginal OS benefit with POCRT in all subgroups of LA-HNSCC without R1 or ECE [10].\u003c/p\u003e\u003cp\u003eA key consideration is the toxicity burden associated with POCRT. Cisplatin-based chemotherapy increases the incidence of acute mucositis, hematologic toxicity, and gastrointestinal complications, which may undermine its therapeutic benefit [5, 48]. In RTOG 9501, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred in 77% of patients receiving POCRT versus 34% in the PORT [4]. Such toxicity may necessitate treatment interruptions and/or a reduction in radiotherapy dose intensity. Therefore, in the absence of a compelling survival advantage, routine use of POCRT in intermediate-risk patients may not be justified. The RTOG 0920 trial demonstrates that postoperative cetuximab combined with radiotherapy significantly improves disease-free survival (DFS) in patients with LA-HNSCC at intermediate-risk, without a corresponding increase in severe toxicity. These findings suggest a potential alternative strategy for postoperative adjuvant therapy [49].\u003c/p\u003e\u003cp\u003eSeveral limitations of this study should be acknowledged. First, treatment-associated toxicity was not assessed, despite its clinical relevance. As previously noted, POCRT is generally associated with higher toxicity than PORT, and the observed OS benefit of POCRT may have been attenuated by unmeasured adverse effects not captured in our analysis. Second, the overall sample size was limited, particularly in the POCRT group, precluding further subgroup analyses. Lastly, while PSM minimized confounding from baseline inherent to this retrospective study, residual biases cannot be excluded.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this study identified PNI and LVI as independent prognostic factors in intermediate-risk LA-HNSCC without R1 or ECE, whereas pT3-4 and pN2-3 lacked prognostic value. POCRT provided no survival benefit over PORT alone. These findings suggest that POCRT may not be routinely warranted in this subgroup and highlight the need for prospective, randomized trials to better define the optimal adjuvant strategy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHNSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHead and neck squamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLA-HNSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLocally advanced head and neck cancer\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePOCRT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePostoperative chemoradiotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePORT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePostoperative radiotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eR1\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePositive margin\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eECE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eExtracapsular extension\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLVI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLymphovascular invasion\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePNI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePerineural invasion\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePSM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePropensity score matching\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOverall survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProgression-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLRRFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLocoregional recurrence-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDMFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDistant metastasis-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDFS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDisease-free survival\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eRTOG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRadiation Therapy Oncology Group\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eEORTC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEuropean Organization for Research and Treatment of Cancer\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eIMRT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIntensity-modulated radiotherapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eVMAT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eVolumetric-modulated arc therapy\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOral squamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOCSCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOral cavity squamous cell carcinoma\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAJCC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eICRU\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational Commission on Radiation Units and Measurements\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eClinical target volume\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePlanning target volume\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Board of the First Affiliated Hospital of Sun Yat-sen University (Approval No. [2025]492). All patient data were de-identified and analyzed retrospectively. The requirement for written informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\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\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Science and Technology Program of Guangzhou (Grant No. 2023A04J2213), the Department of Science and Technology of Guangdong Province (Grant No. 2023A1515110903), and the National Natural Science Foundation of China (Grant No. 82400183).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQ.Q. and Y.L. contributed equally to study design, data collection, statistical analysis, and manuscript drafting. Q.T. participated in data collection. Y.C. was responsible for chart and figure review. C.W. and Y.W. supervised the study and provided critical revisions to the manuscript.\u0026nbsp;All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-63. doi:10.3322/caac.21834.\u003c/li\u003e\n\u003cli\u003eHe S, Xia C, Li H, Cao M, Yang F, Yan X, et al. Cancer profiles in China and comparisons with the USA: a comprehensive analysis in the incidence, mortality, survival, staging, and attribution to risk factors. Sci China Life Sci. 2024;67(1):122-31. doi:10.1007/s11427-023-2423-1.\u003c/li\u003e\n\u003cli\u003eZheng RS, Chen R, Han BF, Wang SM, Li L, Sun KX, et al. [Cancer incidence and mortality in China, 2022]. Zhonghua Zhong Liu Za Zhi. 2024;46(3):221-31. doi:10.3760/cma.j.cn112152-20240119-00035.\u003c/li\u003e\n\u003cli\u003eCooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937-44. \u003c/li\u003e\n\u003cli\u003eBernier J, Domenge C, Ozsahin M, Matuszewska K, Lef\u0026egrave;bvre J-L, Greiner RH, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945-52. \u003c/li\u003e\n\u003cli\u003eBernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. 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Int J Radiat Oncol Biol Phys. 2012;84(5):1198-205. doi:10.1016/j.ijrobp.2012.05.008.\u003c/li\u003e\n\u003cli\u003eKim TH, Cha IH, Choi EC, Kim HR, Kim HJ, Kim SH, et al. Postoperative Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Oral Cavity Cancer in the Era of Modern Radiation Techniques. Frontiers in oncology. 2021;11:619372. doi:10.3389/fonc.2021.619372.\u003c/li\u003e\n\u003cli\u003eLeewiboonsilp T, Jianpinijnan C, Thokanit NS, Pattaranutaporn P, Ngamphaiboon N. Postoperative Radiation With or Without Concurrent Chemotherapy for Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma With Multiple Intermediate Risks: A Propensity Score-Matched Study. Cancer Med. 2025;14(5):e70746. doi:10.1002/cam4.70746.\u003c/li\u003e\n\u003cli\u003eChen MM, Colevas AD, Megwalu U, Divi V. Survival benefit of post-operative chemotherapy for intermediate-risk advanced stage head and neck cancer differs with patient age. 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Prognostic impact of lymphovascular and perineural invasion in squamous cell carcinoma of the tongue. Sci Rep. 2023;13(1):3828. doi:10.1038/s41598-023-30939-8.\u003c/li\u003e\n\u003cli\u003eBrockstein B, Haraf D, Rademaker A, Kies M, Stenson K, Rosen F, et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience. Ann Oncol. 2004;15(8):1179-86. \u003c/li\u003e\n\u003cli\u003eCadoni G, Giraldi L, Petrelli L, Pandolfini M, Giuliani M, Paludetti G, et al. Prognostic factors in head and neck cancer: a 10-year retrospective analysis in a single-institution in Italy. Acta Otorhinolaryngol Ital. 2017;37(6):458. \u003c/li\u003e\n\u003cli\u003eJohnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92. \u003c/li\u003e\n\u003cli\u003eBeard C, Chen M, Cote K, Loffredo M, Renshaw A, Hurwitz M, et al. Perineural invasion is associated with increased relapse after external beam radiotherapy for men with low-risk prostate cancer and may be a marker for occult, high-grade cancer. Int J Radiat Oncol Biol Phys. 2004;58(1):19-24. \u003c/li\u003e\n\u003cli\u003eOzaki H, Hiraoka T, Mizumoto R, Matsuno S, Matsumoto Y, Nakayama T, et al. The prognostic significance of lymph node metastasis and intrapancreatic perineural invasion in pancreatic cancer after curative resection. Surg Today. 1999;29:16-22. \u003c/li\u003e\n\u003cli\u003eGaliabovitch E, Hovens CM, Peters JS, Costello AJ, Battye S, Norden S, et al. Routinely reported \u0026lsquo;equivocal\u0026rsquo;lymphovascular invasion in prostatectomy specimens is associated with adverse outcomes. BJU Int. 2017;119(4):567-72. \u003c/li\u003e\n\u003cli\u003eRamnefjell M, Aamelfot C, Helgeland L, Akslen LA. 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The prognostic role of perineural invasion for survival in head and neck squamous cell carcinoma: a systematic review and meta-analysis. Cancers (Basel). 2024;16(14):2514. \u003c/li\u003e\n\u003cli\u003eRahima B, Shingaki S, Nagata M, Saito C. Prognostic significance of perineural invasion in oral and oropharyngeal carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97(4):423-31. \u003c/li\u003e\n\u003cli\u003eFagan JJ, Collins B, Barnes L, D\u0026apos;Amico F, Myers EN, Johnson JT. Perineural invasion in squamous cell carcinoma of the head and neck. Archives of otolaryngology\u0026ndash;head \u0026amp; neck surgery. 1998;124(6):637-40. \u003c/li\u003e\n\u003cli\u003eShin H-I, Bang J-I, Kim G-J, Sun D-I, Kim S-Y. Perineural Invasion Predicts Local Recurrence and Poor Survival in Laryngeal Cancer. J Clin Med. 2023;12(2):449. \u003c/li\u003e\n\u003cli\u003eBallantyne AJ, McCarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves. Am J Surg. 1963;106(4):651-67. doi:https://doi.org/10.1016/0002-9610(63)90074-6.\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;nez-Flores R, G\u0026oacute;mez-Soto B, Lozano-Burgos C, Niklander SE, Lopes MA, Gonz\u0026aacute;lez-Arriagada WA. Perineural invasion predicts poor survival and cervical lymph node metastasis in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2023;28(5):e496. \u003c/li\u003e\n\u003cli\u003eMaddox WA. Vicissitudes of head and neck cancer. Am J Surg. 1984;148(4):428-32. \u003c/li\u003e\n\u003cli\u003eWoolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck. 1995;17(6):463-72. \u003c/li\u003e\n\u003cli\u003eBallantyne A, McCarten AB, Ibanez ML. The extension of cancer of the head and neck through peripheral nerves. Am J Surg. 1963;106(4):651-67. \u003c/li\u003e\n\u003cli\u003eCarter R, Tanner N, Clifford P, Shaw H. Perineural spread in squamous cell carcinomas of the head and neck: a clinicopathological study. Clin Otolaryngol Allied Sci. 1979;4(4):271-81. \u003c/li\u003e\n\u003cli\u003eMisztal CI, Green C, Mei C, Bhatia R, Velez Torres JM, Kamrava B, et al. Molecular and cellular mechanisms of perineural invasion in oral squamous cell carcinoma: potential targets for therapeutic intervention. Cancers (Basel). 2021;13(23):6011. \u003c/li\u003e\n\u003cli\u003eBakst RL, Wong RJ. Mechanisms of perineural invasion. J Neurol Surg B Skull Base. 2016;77(02):096-106. \u003c/li\u003e\n\u003cli\u003eWoolgar JA. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2006;42(3):229-39. \u003c/li\u003e\n\u003cli\u003eCassidy RJ, Switchenko JM, Jegadeesh N, Sayan M, Ferris MJ, Eaton BR, et al. Association of lymphovascular space invasion with locoregional failure and survival in patients with node-negative oral tongue cancers. JAMA Otolaryngol Head Neck Surg. 2017;143(4):382-8. \u003c/li\u003e\n\u003cli\u003eFives C, Feeley L, O\u0026apos;Leary G, Sheahan P. Importance of lymphovascular invasion and invasive front on survival in floor of mouth cancer. Head Neck. 2016;38(S1):E1528-E34. \u003c/li\u003e\n\u003cli\u003eChen T-C, Wang C-P, Ko J-Y, Yang T-L, Hsu C-W, Yeh K-A, et al. The impact of perineural invasion and/or lymphovascular invasion on the survival of early-stage oral squamous cell carcinoma patients. Ann Surg Oncol. 2013;20:2388-95. \u003c/li\u003e\n\u003cli\u003eKlotch DW, Muro-Cacho C, Gal T. Factors affecting survival for floor-of-mouth carcinoma. Otolaryngol Head Neck Surg. 2000;122(4):495-8. \u003c/li\u003e\n\u003cli\u003eGuo W, Giancotti FG. Integrin signalling during tumour progression. Nat Rev Mol Cell Biol. 2004;5(10):816-26. \u003c/li\u003e\n\u003cli\u003eHuang SH, Hwang D, Lockwood G, Goldstein DP, O\u0026apos;Sullivan B. Predictive value of tumor thickness for cervical lymph‐node involvement in squamous cell carcinoma of the oral cavity: a meta‐analysis of reported studies. Cancer. 2009;115(7):1489-97. \u003c/li\u003e\n\u003cli\u003eGalot R, Machiels J-P. Safety of drug treatments for head and neck cancer. Expert Opin Drug Saf. 2016;15(11):1527-39. \u003c/li\u003e\n\u003cli\u003eMachtay M, Torres-Saavedra PA, Thorstad W, Nguyen-T\u0026acirc;n PF, Siu LL, Holsinger FC, et al. Postoperative Radiotherapy\u0026plusmn;Cetuximab for Intermediate-Risk Head and Neck Cancer. J Clin Oncol. 2025:JCO-24-01829. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Head and neck squamous cell carcinoma, postoperative chemoradiotherapy, intensity-modulated radiotherapy, intermediate-risk, perineural invasion, lymphovascular invasion","lastPublishedDoi":"10.21203/rs.3.rs-7795402/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7795402/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eIn the era of intensity-modulated radiotherapy (IMRT), the benefit of adding concurrent chemotherapy to postoperative radiotherapy (PORT) for intermediate-risk locally advanced head and neck squamous cell carcinoma (LA-HNSCC) without positive margins (R1) or extracapsular extension (ECE) remains controversial.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively analyzed patients with intermediate-risk LA-HNSCC treated with postoperative chemoradiotherapy (POCRT) or PORT at our institution. Propensity score matching (PSM) was performed to balance baseline characteristics. Independent prognostic factors were identified through Cox regression analysis, and survival outcomes were compared between groups.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAfter matching, 131 patients were included (39 POCRT, 92 PORT). Perineural Invasion (PNI) was an independent adverse factor for progression-free survival (PFS; HR 3.07,95% CI 1.46\u0026ndash;6.69, P\u0026thinsp;=\u0026thinsp;0.005), locoregional recurrence-free survival (LRRFS; HR 3.86, 95% CI 1.41\u0026ndash;10.60, P\u0026thinsp;=\u0026thinsp;0.009), and distant metastasis-free survival (DMFS; HR 5.76, 95% CI 1.09\u0026ndash;30.59, P\u0026thinsp;=\u0026thinsp;0.04). Lymphovascular invasion (LVI) was independently associated with worse overall survival (OS; HR 6.83, 95%CI 1.60\u0026ndash;29.05, P\u0026thinsp;=\u0026thinsp;0.009) and PFS (HR 4.02, 95%CI 1.21\u0026ndash;13.37, P\u0026thinsp;=\u0026thinsp;0.023). POCRT did not significantly improve OS, PFS, LRRFS, or DMFS compared to PORT.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn intermediate-risk LA-HNSCC patients treated with IMRT, PNI and LVI were key prognostic indicators, while POCRT conferred no survival advantage over PORT. These findings suggest the need for prospective validation before the routine use of POCRT in this subgroup.\u003c/p\u003e","manuscriptTitle":"Limited Benefit of Postoperative Chemoradiotherapy in Intermediate-Risk Locally Advanced Head and Neck Squamous Cell Carcinoma: Real-World Evidence from the IMRT Era","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 16:31:38","doi":"10.21203/rs.3.rs-7795402/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"8338122673362768717683564822914948508","date":"2025-11-11T08:08:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-30T16:41:29+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-09T07:01:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-07T22:16:21+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-07T22:15:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-10-07T03:30:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e8668794-a684-4aa7-a4fa-916c513113ee","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-11T16:31:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-11 16:31:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7795402","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7795402","identity":"rs-7795402","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}