Real-World Role of Adjuvant Radiotherapy after Neoadjuvant Treatment for Thoracic Esophageal Cancer

Real-World Role of Adjuvant Radiotherapy after Neoadjuvant Treatment for Thoracic Esophageal Cancer | 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 Real-World Role of Adjuvant Radiotherapy after Neoadjuvant Treatment for Thoracic Esophageal Cancer Yingxin Liu, Xiaojun Wang, Pudong Qian, Zixuan Ni, Yutao Li, Yatian Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8861751/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing surgery after neoadjuvant chemotherapy (NCT) or neoadjuvant chemoimmunotherapy (NICT) remain at risk of disease progression. Currently, adjuvant radiotherapy (ART) is not recommended following these treatment sequences due to a lack of high-level evidence supporting its efficacy. This real-world study preliminarily evaluates the potential role of ART in this clinical setting. Methods A sum of 324 ESCC patients who had surgery following NCT or NICT were included and divided into two groups: the neoadjuvant therapy with surgery (NA+S) group and the neoadjuvant therapy with surgery followed by adjuvant radiotherapy (NA+S+RT) group. The primary outcomes assessed were the two-year recurrence free survival (RFS) and overall survival (OS). The Kaplan-Meier method was utilized for survival analysis, while the Cox regression model was applied to determine the clinical factors linked to prognosis. Results The NA+S group (n=180) and the NA+S+RT group (n=144) showed no statistically significant differences in 2‑year RFS (71.8% vs 68.8%, P=0.661, 95% CI: 55.52‑63.95) or 2‑year OS (80.7% vs 74.3%, P=0.162, 95% CI: 60.44‑68.17), indicating that ART did not provide a survival benefit. Subgroup analysis showed no significant survival difference between patients with major pathological response (MPR) and those without (non-MPR). However, among ypN+ patients, RFS was significantly improved in the NA+S+RT group (60.6% vs 41.8%, P=0.005, 95% CI: 37.65‑50.90). Similarly, ypT3‑4 patients showed a survival benefit in 2‑year RFS after ART (65% vs 44.4%, P<0.05, 95% CI: 38.42‑52.33). The incidence of distant metastasis, especially to the lung, bone, and pleura, was notably greater in the NA+S+RT group than in the NA+S group (P<0.05). The results of the multivariate analysis identified ypN+ and non‑MPR as independent risk factors for both RFS and OS. Conclusion ART did not improve survival outcomes in the entire neoadjuvant therapy cohort; however, it conferred a survival benefit in patients with ypN+ disease or ypT3‑4 tumors. Thoracic esophageal cancer Neoadjuvant chemotherapy Neoadjuvant chemoimmunotherapy Adjuvant radiotherapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Esophageal cancer (EC) is a type of cancer that occurs frequently worldwide[ 1 ], with China exhibiting a notably elevated occurrence of esophageal squamous cell carcinoma (ESCC)[ 2 , 3 ]. Different combinations of surgery, chemotherapy, immunotherapy, and radiotherapy have improved outcomes in locally advanced EC[ 4 – 6 ]. Nonetheless, data from follow-up of the CROSS and NEOCRTEC5010 trials indicate that 40%–50% of patients still experience disease progression[ 4 , 5 ], and a retrospective study from our center reported local-regional recurrence in approximately 30% of patients[ 7 ]. Recent studies on neoadjuvant chemoimmunotherapy (NICT) have demonstrated acceptable toxicity and pathological complete response rates that are not inferior to those achieved with neoadjuvant chemoradiotherapy (NCRT) in locally advanced ESCC[ 8 – 10 ]. Furthermore, multiple reports indicate that the most common sites of recurrence after esophagectomy—with or without prior neoadjuvant therapy—are the supraclavicular and upper mediastinal lymph nodes[ 11 – 14 ]. Thus, it is crucial to create more efficient adjuvant strategies aimed at slowing down disease progression. Given these findings, adjuvant radiotherapy (ART) represents a promising approach to control locoregional recurrence and potentially improve survival. The CheckMate 577 trial established a landmark advance in adjuvant therapy for EC after surgery[ 15 ]. However, no survival benefit was observed in the Asian ESCC population, underscoring the need for further evidence and research to define appropriate indications for adjuvant therapy. Although radiotherapy can reduce locoregional recurrence and improve survival in EC[ 16 , 17 ], the role of ART in patients undergoing surgery after neoadjuvant chemotherapy (NCT) or NICT remains unclear. In real-world practice, a proportion of patients receiving NCT or NICT experience local recurrence during follow-up. Salvage radiotherapy for these recurrences is often limited by dose constraints for organs at risks and by challenges in target delineation. Consequently, this research intends to explore the impact of ART in ESCC patients following NCT or NICT. Patients and Materials Patients with EC who underwent surgery following NCT or NICT at the Affiliated Cancer Hospital of Nanjing Medical University from January 2018 to December 2023 were included. The inclusion criteria included were: (1) age 18–80 years; (2) receipt of NCT or NICT followed by surgery; (3) histologically or cytologically confirmed SCC. Exclusion criteria included were: (1) non-thoracic EC; (2) multiple primary tumors; (3) non-R0 resection; (4) loss to follow-up or missing data; (5) receipt of preoperative radiotherapy. Treatment Protocols All patients underwent a minimum of one treatment cycle. The NCT protocols incorporated taxane in combination with platinum-based agents (cisplatin, carboplatin, or nedaplatin), with some regimens additionally including tegafur (S-1) or fluorouracil. The immune checkpoint inhibitors used included: sintilimab, toripalimab, tislelizumab, camrelizumab, pembrolizumab, serplulimab, and nivolumab. ART was administered concurrently with chemotherapy in some patients. The median dose of ART was calculated at 47.8 Gy (with a range of 40.0–50.4 Gy), delivered via conventional fractionation five times weekly. The clinical target volume (CTV) predominantly included the lymphatic drainage regions in the bilateral supraclavicular and mediastinal areas, along with the tumor bed. Following multidisciplinary discussion, the CTV for tumors situated in the lower thoracic EC was also extended to include the left gastric lymphatic drainage region. Surgical Approach and Pathological Response Criteria All patients had surgery performed 4 to 6 weeks after finishing neoadjuvant therapy, following confirmation of no disease progression by contrast-enhanced CT scans of the chest and abdomen. The primary surgical approaches were Ivor-Lewis or McKeown esophagectomy, with a minority of patients undergoing open thoracotomy. A routine lymphadenectomy involving two or three fields was conducted for all patients. Additionally, cervical lymph node dissection was included when the surgeon suspected cervical nodal involvement. Pathological evaluation comprised assessment of histologic type, tumor grade, proximal/distal surgical margins, the count of affected lymph nodes, and the extent of tumor regression. The post-neoadjuvant pathological staging, referred to as ypTNM was methodically defined in accordance with the criteria set forth in the 8th edition of the TNM classification[ 18 ]. All pathological examinations were performed jointly by two senior pathologists from our center. The surgically excised tumor tissue showed no residual tumor cells under a microscope, indicating pathological complete remission (pCR). The tumor regression grade (TRG) was categorized in accordance with the 8th edition TNM standards: no viable tumor cells (TRG 0); denoted isolated single cancer cells or small clusters (TRG 1); residual tumor with evident regression (TRG 2); and minimal or no regression (TRG 3)[ 18 ]. TRG 0 and TRG 1 were defined as a major pathological response (MPR). Follow-up and Endpoints Post-treatment patient monitoring involves assessments every three months during the initial one to two years, followed by evaluations every six months in the third to fifth years after treatment. Post-treatment surveillance included a comprehensive physical examination, upper gastrointestinal barium study, neck ultrasonography, and enhanced CT scan of chest and abdomen and/or MRI. Where necessary, Positron emission tomography–computed tomography (PET-CT) scans and endoscopic pathological tissue biopsies shall be performed. This study's main objectives were to evaluate the two-year recurrence-free survival (RFS), which is the duration from the surgical procedure to the locoregional tumor reappearance, and overall survival (OS), which refers to the period from surgery until death from any cause. Local recurrence was characterized as a relapse occurring at the anastomotic location and/or in the cervical, mediastinal, or abdominal lymphatic nodes. Distant metastasis referred to hematogenous spread to other solid organs or structures. Statistical Analysis Categorical variables are expressed in terms of counts and percentages. A comparison of baseline characteristics between the neoadjuvant therapy combined with surgery (NA + S) group and the neoadjuvant therapy followed by surgery and then ART (NA + S+RT) group was performed utilizing the chi-square test. Differences in survival were analyzed using the Kaplan-Meier method, with significance assessed through the log-rank test. To identify risk factors for RFS and OS, Cox proportional hazards regression was applied. Variables that yielded a P value of less than 0.2 in univariate analysis were incorporated into the multivariate model that followed. All statistical analyses were carried out using SPSS software (version 27.0), with a statistically significant threshold set at P < 0.05. Results Patient Characteristics A total of 324 ESCC patients who met the eligibility criteria and underwent NCT or NICT were enrolled. Based on the receipt of ART, they were divided into the NA+S group (n=180) and the NA+S+RT group (n=144). Comparisons of baseline clinical characteristics revealed that the administration of ART was significantly associated with age, pretreatment clinical stage, neoadjuvant regimen, pathological differentiation grade, TRG grade, ypT stage, and ypN stage (all P < 0.05). In the NA+S+RT group, a greater percentage of ypN+ patients was observed, with figures of 65.67% compared to 34.33% in other groups. Additionally, 47.84% of the patients had 15 or more lymph node dissections (see Table 1). The overall median follow-up duration for the cohort reached 46 months (95% CI: 42.67–49.33). Survival The 2-year RFS rates for the non-ART cohort and the ART cohort were recorded at 71.8% and 68.8%, respectively (P=0.661, 95% CI: 55.52-63.95). In terms of OS rates after 2 years, the figures were 80.7% for the ART group and 74.3% for the non-ART group (P=0.162, 95% CI: 60.44-68.17) (Figure 1). While these variations did not reach statistical significance, the ART cohort exhibited a greater RFS rate at the 1-year mark (85.3% vs. 78.0%). Subgroup analysis based on pathological response showed that among non‑MPR patients, ART was associated with a higher 2‑year RFS rate (64.7% vs. 52.7%; P = 0.076; 95% CI: 43.57–55.29), though this did not reach statistical significance. No improvement was observed in 2‑year OS (65.7% vs. 67.0%; P = 0.931; 95% CI: 49.92–60.72). For the MPR subgroup, ART provided no benefit in either RFS or OS (Figure 2). Stratified by ypT stage, subgroup analysis indicated that neither RFS nor OS differed significantly between the treatment groups for patients with ypT0 or ypT1–2 disease (all P > 0.05; Figure 3). In patients presenting with ypT3–4 tumors, the OS difference between the NA+S+RT group and the NA+S group did not reach statistical significance (P = 0.051; 95% CI: 47.04–60.20). However, a notable trend indicating a higher 2-year OS was observed in the NA+S+RT group (67.5%) in comparison to the NA+S group (52.7%). Additionally, the NA+S+RT group showed a significant improvement in 2‑year RFS rate compared to the NA+S group (65% vs. 44.4%; P < 0.05; 95% CI: 38.42–52.33) (Figure 3). For patients with ypN0 disease, ART did not provide a significant benefit in either RFS or OS. In contrast, among ypN+ patients, ART was associated with a significantly better RFS (60.6% vs. 41.8%; P = 0.005; 95% CI: 37.65–50.90) (Figure 4). Multivariate analysis revealed that ypN+ and Non-MPR correlated with reduced RFS and OS, whereas having fewer than 15 lymph nodes dissected served as a negative prognostic indicator for RFS (Table 2). Recurrence Pattern The NA+S group predominantly experienced locoregional recurrence (n=52, 28.89%), including 7 cases of anastomotic recurrence. In contrast, Distant metastases were more common in the NA+S+RT group (30.56% vs. 11.11%; P < 0.001). Moreover, metastases to the lung, bone, and pleura occurred more frequently in patients who received ART (P<0.05) (Table 3). Discussion To date, guidelines still recommend surgery following NCRT for the treatment of locally advanced EC. However, with the publication of several phase II clinical trials of NICT demonstrating favorable tumor regression and manageable toxicity[ 8 , 9 ], as well as the recent results of the REVO[ 10 ] and ESCORT-NEO[ 19 ] trials, the use of NICT has become increasingly widespread in clinical practice for EC in China. Among ESCC patients undergoing neoadjuvant therapy and subsequent surgery, locoregional recurrence rates remain as high as 25%–30%, with mediastinal lymph nodes representing the most common sites of regional failure[ 7 , 11 , 12 , 20 ]. The addition of radiotherapy—particularly ART—to systemic therapy to improved local tumor control has been rarely reported. Therefore, this study explores the value of adjuvant radiotherapy by analyzing the survival of ESCC patients receiving NCT or NCT in the real world, with the goal of clarifying its clinical value and better informing post-neoadjuvant therapeutic decision-making. Previous research, including the CheckMate 577 trial[ 15 ] and several retrospective studies[ 21 , 22 ] suggest that ART can improve the prognosis of patients with high risk of metastasis. Additionally, a phase II clinical trial demonstrated that adjuvant chemoradiotherapy (ACRT) could enhance RFS in locally advanced ESCC patients with involved or close (≤ 1 mm) margins, extranodal extension (ENE), or ypN2–3 disease[ 23 ]. Our study found that ART did not improve 2-year RFS or OS in ESCC patients who received NCT or NICT. However, the 1-year RFS results suggest a potential short-term delay in recurrence. Furthermore, ART may still confer survival benefits in patients with residual tumor or ypN+ disease. The poorer survival observed in patients receiving adjuvant radiotherapy may be attributable to their higher baseline tumor burden. This is supported by a greater proportion of ypStage II-IV disease in the ART group compared to the NA + S group (36.11% vs. 21.60%), and more ypN+ patients (27.16% vs. 14.20%). Moreover, a previous meta-analysis indicated that postoperative ART following NCRT was associated with significantly increased mortality[ 24 ]. Another study also reported that ART after NCT did not improve—and might even reduce—overall survival in EC patients[ 25 ]. In EC patients with T2–3 disease, ART or ACRT is associated with a reduction in locoregional failure and an improvement in survival outcomes[ 26 – 28 ]. Therefore, we conducted a subgroup analysis based on ypT stage. Despite the absence of a significant RFS or OS benefit in the ypT0 or ypT1–2 subgroups, patients with ypT3–4 disease experienced a statistically significant improvement in 2-year RFS following ART (P < 0.05). Despite the lack of a significant difference in 2-year OS for the ypT3-4 subgroup, the ART group demonstrated a promising trend toward improved long-term survival outcomes. Multivariate analysis results suggest that ypN + and Non-MPR are associated with poor RFS and OS. Although the difference in RFS between treatment groups among non-MPR patients was not statistically significant, the NA + S+RT group showed a numerically higher RFS than the NA + S group, suggesting a potential benefit. Furthermore, ypN+ patients in the NA + S+RT group experienced a significant improvement in RFS (P < 0.05). While our survival analysis indicated that ART did not improve RFS or OS in ypN0 patients, it should be noted that another ongoing retrospective study at our center suggests a potential RFS benefit trend in ypT2–4N0 patients receiving ART. These results suggest that ART has potential value in patients with high ypTNM and lymph node involvement after neoadjuvant therapy. While radiotherapy is established to reduce locoregional recurrence[ 16 , 17 ], the present study did not demonstrate a significant reduction in local recurrence—including nodal and anastomotic failures—with ART (P > 0.05). Conversely, distant metastasis occurred at a higher incidence rate in the ART group (P < 0.05), with lung metastases representing the most common site of distant spread (14.58%). Several factors may explain these observations. First, the tolerability of adjuvant therapy is generally lower than that of neoadjuvant treatment[ 29 ]. Second, high-dose radiotherapy may induce "detrimental distant effect"[ 30 ], potentially increasing the risk of secondary thoracic malignancies in irradiated ESCC patients[ 31 ]. Finally, The proportion of patients with high tumor burden was high in the ART group, which is associated with poorer prognosis. This may further explain the increased incidence of thoracic metastases (e.g., lung and pleural) observed in the NA + S+RT group. Several limitations should be considered in this study. First, as a retrospective analysis, the data are subject to inherent potential biases. Factors such as postoperative complications and adverse effects of ART could not be fully accounted for. Second, the neoadjuvant treatment regimens were not uniform, and because pCR rates differ between NCT and NICT, these two groups were not analyzed separately, which may have introduced confounding factors. Third, detailed data regarding chemoradiation regimens, radiation doses, and treatment cycles were not available, precluding a comparative effectiveness analysis across different treatment protocols. Finally, the recurrence patterns observed here may not be generalizable to all ESCC patients. To precisely delineate recurrence patterns and confirm the survival outcomes observed here, future multicenter studies with larger cohorts are warranted. Conclusion Although ART did not improve overall survival in the entire cohort of locally advanced ESCC patients after neoadjuvant therapy and surgery, it may offer a survival benefit specifically for those with ypN+ disease or ypT3-4 tumors, irrespective of nodal status. The confirmation of these results will require further validation through large-scale, prospective studies. Abbreviations ESCC Esophageal squamous cell carcinoma EC Esophageal cancer NCT Neoadjuvant chemotherapy NICT Neoadjuvant chemoimmunotherapy NCRT Neoadjuvant chemoradiotherapy ART Adjuvant radiotherapy NA+S Neoadjuvant therapy with surgery NA+S+RT Neoadjuvant therapy with surgery followed by adjuvant radiotherapy CTV Clinical target volume ypTNM Post-neoadjuvant pathological stage ypT Post-neoadjuvant pathological tumor stage ypN Post-neoadjuvant pathological node staging pCR Pathological complete remission TRG Tumor regression grade MPR Major pathological response RFS Recurrence free survival OS overall survival Declarations Author contributions LYX, WXJ: Collected data, Performed analysis, Drafting of the manuscript. NZX,LYT: Collected data. QPD: Conceived and designed the analysis. LYT: Conceived and designed the analysis, Review the manuscript, Obtained funding. All authors approved the submitted manuscript. Funding This study was funded by National Natural Science Foundation of China(82403786). Availability of data and materials The data from the study is available from the corresponding author on reasonable request. Ethics approval and constant to participate This study was approved by the Ethics Committee of Jiangsu Cancer Hospital (approval number: KY-2024-108). The requirement for informed consent from participants was waived by the Ethics Committee in accordance with the ethical principles outlined in the Declaration of Helsinki. Acknowledgments The authors thank the patients and their families for making this study possible. The authors thank Lingfei Wei for the assistance in this study. Publication consent Not Applicable. Competing interests The authors declare no competing interests. References Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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J Clin Oncol. 2011;29(13):1715–21. Piffkó A, Yang K, Panda A, et al. Radiation-induced amphiregulin drives tumour metastasis. Nature. 2025;643(8072):810–9. Yi H, Li S, Lin Y, et al. Risk and prognosis of secondary thoracic cancers after radiation therapy for esophageal cancer. J Gastroenterol Hepatol. 2023;38(6):930–9. Tables Tables 1 to 3 are available in the supplementary files section Additional Declarations No competing interests reported. Supplementary Files Tables.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 22 Mar, 2026 Reviewers agreed at journal 13 Mar, 2026 Reviewers invited by journal 11 Mar, 2026 Editor assigned by journal 09 Mar, 2026 Editor invited by journal 13 Feb, 2026 Submission checks completed at journal 13 Feb, 2026 First submitted to journal 13 Feb, 2026 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-8861751","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":604464145,"identity":"4f9220d7-62ec-433f-8819-c3ffcf8dad69","order_by":0,"name":"Yingxin Liu","email":"","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingxin","middleName":"","lastName":"Liu","suffix":""},{"id":604464146,"identity":"f2da7404-dd7d-46ff-830c-46f391bb55a2","order_by":1,"name":"Xiaojun Wang","email":"","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaojun","middleName":"","lastName":"Wang","suffix":""},{"id":604464147,"identity":"642071ba-da43-47ef-9ecc-149953e0990e","order_by":2,"name":"Pudong Qian","email":"","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pudong","middleName":"","lastName":"Qian","suffix":""},{"id":604464148,"identity":"92ff5032-df8d-48e6-b504-0b00d389bee1","order_by":3,"name":"Zixuan Ni","email":"","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zixuan","middleName":"","lastName":"Ni","suffix":""},{"id":604464149,"identity":"cb8e1b5b-acfc-4541-becb-3da7a6fbf638","order_by":4,"name":"Yutao Li","email":"","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yutao","middleName":"","lastName":"Li","suffix":""},{"id":604464150,"identity":"3a9ac9d1-b6b6-4aac-8947-225aa4be7ae4","order_by":5,"name":"Yatian Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAr0lEQVRIiWNgGAWjYBACPhDxgceGh5+/gUgtbAzMDIwzZNJkJGccIEELM4/NYRuDhgRitUjkH2CckXOex4DhAOOHjzlEaUkG+uXMbR5z5gZmyZnbiNTCOLPnNo9lwwE2Zl5itTDz/jvHY3AggRQtPDwHSNHC89iAcQZPMo/kjIPNxPmFnz3xATAq7ez5+ZsPfvhIjBYGgQT2HxAWYwMx6kHWHCBS4SgYBaNgFIxcAAANDC6za9434gAAAABJRU5ErkJggg==","orcid":"","institution":"Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Province Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yatian","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2026-02-12 11:53:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8861751/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8861751/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104689505,"identity":"beee9527-41e9-45ca-8265-8eab4d6ab207","added_by":"auto","created_at":"2026-03-16 06:00:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113044,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan–Meier Analysis Comparing the NA+S and NA+S+RT Groups for Recurrence-Free Survival (A) and Overall Survival (B) in All Patients.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/558ff0c4a841a6f1fef322b0.png"},{"id":104689509,"identity":"5263fe31-e74b-4939-90a5-3cbe383caf53","added_by":"auto","created_at":"2026-03-16 06:00:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":204762,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRecurrence-Free Survival (RFS) and Overall Survival (OS) for the NA+S vs. NA+S+RT Groups in MPR and Non-MPR Patients. MPR: (A) RFS, (B) OS. non-MPR: (C) RFS, (D) OS.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/6d635a27d6261d8a2d3c4827.png"},{"id":104689506,"identity":"c4e4d087-0c52-4d36-ac2f-b64e52b9d529","added_by":"auto","created_at":"2026-03-16 06:00:33","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":143831,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRecurrence-Free Survival (RFS) and Overall Survival (OS) for the NA+S vs. NA+S+RT Groups Across ypT Stages. ypT0: (A) RFS, (B) OS. ypT1-2: (C) RFS, (D) OS. ypT3-4: (E) RFS, (F) OS.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/bd97f1bbeab767344908d436.png"},{"id":104808557,"identity":"392ff792-8a1f-4605-a9e9-4037b3cdf62e","added_by":"auto","created_at":"2026-03-17 12:38:39","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":150991,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRecurrence-Free Survival (RFS) and Overall Survival (OS) for the NA+S vs. NA+S+RT Groups in ypN0 and ypN+ Patients. ypN0: (A) RFS, (B) OS. ypN+: (C) RFS, (D) OS.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/6712626174a381e04a88e1f1.png"},{"id":104811440,"identity":"7ce53cbb-15a3-45ed-a60f-ecf9b45f1c37","added_by":"auto","created_at":"2026-03-17 12:59:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1238620,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/456f6990-fa4e-487c-bb5e-bb337f900bf3.pdf"},{"id":104689507,"identity":"d9723eb1-83a6-4179-8054-cf8d4815761f","added_by":"auto","created_at":"2026-03-16 06:00:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":38563,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8861751/v1/33b8573e65b4078c233d25a2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real-World Role of Adjuvant Radiotherapy after Neoadjuvant Treatment for Thoracic Esophageal Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer (EC) is a type of cancer that occurs frequently worldwide[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], with China exhibiting a notably elevated occurrence of esophageal squamous cell carcinoma (ESCC)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Different combinations of surgery, chemotherapy, immunotherapy, and radiotherapy have improved outcomes in locally advanced EC[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Nonetheless, data from follow-up of the CROSS and NEOCRTEC5010 trials indicate that 40%\u0026ndash;50% of patients still experience disease progression[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and a retrospective study from our center reported local-regional recurrence in approximately 30% of patients[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies on neoadjuvant chemoimmunotherapy (NICT) have demonstrated acceptable toxicity and pathological complete response rates that are not inferior to those achieved with neoadjuvant chemoradiotherapy (NCRT) in locally advanced ESCC[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Furthermore, multiple reports indicate that the most common sites of recurrence after esophagectomy\u0026mdash;with or without prior neoadjuvant therapy\u0026mdash;are the supraclavicular and upper mediastinal lymph nodes[\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, it is crucial to create more efficient adjuvant strategies aimed at slowing down disease progression. Given these findings, adjuvant radiotherapy (ART) represents a promising approach to control locoregional recurrence and potentially improve survival.\u003c/p\u003e \u003cp\u003eThe CheckMate 577 trial established a landmark advance in adjuvant therapy for EC after surgery[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, no survival benefit was observed in the Asian ESCC population, underscoring the need for further evidence and research to define appropriate indications for adjuvant therapy. Although radiotherapy can reduce locoregional recurrence and improve survival in EC[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the role of ART in patients undergoing surgery after neoadjuvant chemotherapy (NCT) or NICT remains unclear. In real-world practice, a proportion of patients receiving NCT or NICT experience local recurrence during follow-up. Salvage radiotherapy for these recurrences is often limited by dose constraints for organs at risks and by challenges in target delineation. Consequently, this research intends to explore the impact of ART in ESCC patients following NCT or NICT.\u003c/p\u003e"},{"header":"Patients and Materials","content":"\u003cp\u003ePatients with EC who underwent surgery following NCT or NICT at the Affiliated Cancer Hospital of Nanjing Medical University from January 2018 to December 2023 were included. The inclusion criteria included were: (1) age 18\u0026ndash;80 years; (2) receipt of NCT or NICT followed by surgery; (3) histologically or cytologically confirmed SCC. Exclusion criteria included were: (1) non-thoracic EC; (2) multiple primary tumors; (3) non-R0 resection; (4) loss to follow-up or missing data; (5) receipt of preoperative radiotherapy.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTreatment Protocols\u003c/h2\u003e \u003cp\u003eAll patients underwent a minimum of one treatment cycle. The NCT protocols incorporated taxane in combination with platinum-based agents (cisplatin, carboplatin, or nedaplatin), with some regimens additionally including tegafur (S-1) or fluorouracil. The immune checkpoint inhibitors used included: sintilimab, toripalimab, tislelizumab, camrelizumab, pembrolizumab, serplulimab, and nivolumab. ART was administered concurrently with chemotherapy in some patients. The median dose of ART was calculated at 47.8 Gy (with a range of 40.0\u0026ndash;50.4 Gy), delivered via conventional fractionation five times weekly. The clinical target volume (CTV) predominantly included the lymphatic drainage regions in the bilateral supraclavicular and mediastinal areas, along with the tumor bed. Following multidisciplinary discussion, the CTV for tumors situated in the lower thoracic EC was also extended to include the left gastric lymphatic drainage region.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurgical Approach and Pathological Response Criteria\u003c/h3\u003e\n\u003cp\u003eAll patients had surgery performed 4 to 6 weeks after finishing neoadjuvant therapy, following confirmation of no disease progression by contrast-enhanced CT scans of the chest and abdomen. The primary surgical approaches were Ivor-Lewis or McKeown esophagectomy, with a minority of patients undergoing open thoracotomy. A routine lymphadenectomy involving two or three fields was conducted for all patients. Additionally, cervical lymph node dissection was included when the surgeon suspected cervical nodal involvement.\u003c/p\u003e \u003cp\u003ePathological evaluation comprised assessment of histologic type, tumor grade, proximal/distal surgical margins, the count of affected lymph nodes, and the extent of tumor regression. The post-neoadjuvant pathological staging, referred to as ypTNM was methodically defined in accordance with the criteria set forth in the 8th edition of the TNM classification[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. All pathological examinations were performed jointly by two senior pathologists from our center. The surgically excised tumor tissue showed no residual tumor cells under a microscope, indicating pathological complete remission (pCR). The tumor regression grade (TRG) was categorized in accordance with the 8th edition TNM standards: no viable tumor cells (TRG 0); denoted isolated single cancer cells or small clusters (TRG 1); residual tumor with evident regression (TRG 2); and minimal or no regression (TRG 3)[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. TRG 0 and TRG 1 were defined as a major pathological response (MPR).\u003c/p\u003e\n\u003ch3\u003eFollow-up and Endpoints\u003c/h3\u003e\n\u003cp\u003ePost-treatment patient monitoring involves assessments every three months during the initial one to two years, followed by evaluations every six months in the third to fifth years after treatment. Post-treatment surveillance included a comprehensive physical examination, upper gastrointestinal barium study, neck ultrasonography, and enhanced CT scan of chest and abdomen and/or MRI. Where necessary, Positron emission tomography\u0026ndash;computed tomography (PET-CT) scans and endoscopic pathological tissue biopsies shall be performed.\u003c/p\u003e \u003cp\u003eThis study's main objectives were to evaluate the two-year recurrence-free survival (RFS), which is the duration from the surgical procedure to the locoregional tumor reappearance, and overall survival (OS), which refers to the period from surgery until death from any cause. Local recurrence was characterized as a relapse occurring at the anastomotic location and/or in the cervical, mediastinal, or abdominal lymphatic nodes. Distant metastasis referred to hematogenous spread to other solid organs or structures.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eCategorical variables are expressed in terms of counts and percentages. A comparison of baseline characteristics between the neoadjuvant therapy combined with surgery (NA\u0026thinsp;+\u0026thinsp;S) group and the neoadjuvant therapy followed by surgery and then ART (NA\u0026thinsp;+\u0026thinsp;S+RT) group was performed utilizing the chi-square test. Differences in survival were analyzed using the Kaplan-Meier method, with significance assessed through the log-rank test. To identify risk factors for RFS and OS, Cox proportional hazards regression was applied. Variables that yielded a P value of less than 0.2 in univariate analysis were incorporated into the multivariate model that followed. All statistical analyses were carried out using SPSS software (version 27.0), with a statistically significant threshold set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 324 ESCC patients who met the eligibility criteria and underwent NCT or NICT were enrolled. Based on the receipt of ART, they were divided into the NA+S group (n=180) and the NA+S+RT group (n=144). Comparisons of baseline clinical characteristics revealed that the administration of ART was significantly associated with age, pretreatment clinical stage, neoadjuvant regimen, pathological differentiation grade, TRG grade, ypT stage, and ypN stage (all P \u0026lt; 0.05). In the NA+S+RT group, a greater percentage of ypN+ patients was observed, with figures of 65.67% compared to 34.33% in other groups. Additionally,\u0026nbsp;47.84% of\u0026nbsp;the\u0026nbsp;patients\u0026nbsp;had 15 or more\u0026nbsp;lymph node dissections (see\u0026nbsp;Table 1). The\u0026nbsp;overall\u0026nbsp;median follow-up\u0026nbsp;duration\u0026nbsp;for the\u0026nbsp;cohort reached\u0026nbsp;46 months (95% CI: 42.67\u0026ndash;49.33).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSurvival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe 2-year RFS rates for the non-ART cohort and the ART cohort were recorded at 71.8% and 68.8%, respectively (P=0.661, 95% CI: 55.52-63.95). In terms of OS rates after 2 years, the figures were 80.7% for the ART group and 74.3% for the non-ART group (P=0.162, 95% CI: 60.44-68.17) (Figure 1). While these variations did not reach statistical significance, the ART cohort exhibited a greater RFS rate at the 1-year mark (85.3% vs. 78.0%). Subgroup analysis based on pathological response showed that among non‑MPR patients, ART was associated with a higher 2‑year RFS rate (64.7% vs. 52.7%; P = 0.076; 95% CI: 43.57\u0026ndash;55.29), though this did not reach statistical significance. No improvement was observed in 2‑year OS (65.7% vs. 67.0%; P = 0.931; 95% CI: 49.92\u0026ndash;60.72). For the MPR subgroup, ART provided no benefit in either RFS or OS (Figure 2).\u003c/p\u003e\n\u003cp\u003eStratified by ypT stage, subgroup analysis indicated that neither RFS nor OS differed significantly between the treatment groups for patients with ypT0 or ypT1\u0026ndash;2 disease (all P \u0026gt; 0.05; Figure 3). \u0026nbsp;In patients presenting with ypT3\u0026ndash;4 tumors, the OS difference between the NA+S+RT group and the NA+S group did not reach statistical significance (P = 0.051; 95% CI: 47.04\u0026ndash;60.20). However, a notable trend indicating a higher 2-year OS was observed in the NA+S+RT group (67.5%) in comparison to the NA+S group (52.7%). Additionally, the NA+S+RT group showed a significant improvement in 2‑year RFS rate compared to the NA+S group (65% vs. 44.4%; P \u0026lt; 0.05; 95% CI: 38.42\u0026ndash;52.33) (Figure 3). For patients with ypN0 disease, ART did not provide a significant benefit in either RFS or OS. In contrast, among ypN+ patients, ART was associated with a significantly better RFS (60.6% vs. 41.8%; P = 0.005; 95% CI: 37.65\u0026ndash;50.90) (Figure 4).\u003c/p\u003e\n\u003cp\u003eMultivariate analysis revealed that ypN+ and Non-MPR correlated with reduced RFS and OS, whereas having fewer than 15 lymph nodes dissected served as a negative prognostic indicator for RFS (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecurrence Pattern\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe NA+S group predominantly experienced locoregional recurrence (n=52, 28.89%), including 7 cases of anastomotic recurrence. In contrast, Distant metastases were more common in the NA+S+RT group (30.56% vs. 11.11%; P \u0026lt; 0.001). Moreover, metastases to the lung, bone, and pleura occurred more frequently in patients who received ART (P\u0026lt;0.05) (Table 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo date, guidelines still recommend surgery following NCRT for the treatment of locally advanced EC. However, with the publication of several phase II clinical trials of NICT demonstrating favorable tumor regression and manageable toxicity[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], as well as the recent results of the REVO[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] and ESCORT-NEO[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] trials, the use of NICT has become increasingly widespread in clinical practice for EC in China. Among ESCC patients undergoing neoadjuvant therapy and subsequent surgery, locoregional recurrence rates remain as high as 25%\u0026ndash;30%, with mediastinal lymph nodes representing the most common sites of regional failure[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The addition of radiotherapy\u0026mdash;particularly ART\u0026mdash;to systemic therapy to improved local tumor control has been rarely reported. Therefore, this study explores the value of adjuvant radiotherapy by analyzing the survival of ESCC patients receiving NCT or NCT in the real world, with the goal of clarifying its clinical value and better informing post-neoadjuvant therapeutic decision-making.\u003c/p\u003e \u003cp\u003ePrevious research, including the CheckMate 577 trial[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and several retrospective studies[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] suggest that ART can improve the prognosis of patients with high risk of metastasis. Additionally, a phase II clinical trial demonstrated that adjuvant chemoradiotherapy (ACRT) could enhance RFS in locally advanced ESCC patients with involved or close (\u0026le;\u0026thinsp;1 mm) margins, extranodal extension (ENE), or ypN2\u0026ndash;3 disease[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Our study found that ART did not improve 2-year RFS or OS in ESCC patients who received NCT or NICT. However, the 1-year RFS results suggest a potential short-term delay in recurrence. Furthermore, ART may still confer survival benefits in patients with residual tumor or ypN+ disease.\u003c/p\u003e \u003cp\u003eThe poorer survival observed in patients receiving adjuvant radiotherapy may be attributable to their higher baseline tumor burden. This is supported by a greater proportion of ypStage II-IV disease in the ART group compared to the NA\u0026thinsp;+\u0026thinsp;S group (36.11% vs. 21.60%), and more ypN+ patients (27.16% vs. 14.20%). Moreover, a previous meta-analysis indicated that postoperative ART following NCRT was associated with significantly increased mortality[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Another study also reported that ART after NCT did not improve\u0026mdash;and might even reduce\u0026mdash;overall survival in EC patients[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn EC patients with T2\u0026ndash;3 disease, ART or ACRT is associated with a reduction in locoregional failure and an improvement in survival outcomes[\u003cspan additionalcitationids=\"CR27\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, we conducted a subgroup analysis based on ypT stage. Despite the absence of a significant RFS or OS benefit in the ypT0 or ypT1\u0026ndash;2 subgroups, patients with ypT3\u0026ndash;4 disease experienced a statistically significant improvement in 2-year RFS following ART (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Despite the lack of a significant difference in 2-year OS for the ypT3-4 subgroup, the ART group demonstrated a promising trend toward improved long-term survival outcomes.\u003c/p\u003e \u003cp\u003eMultivariate analysis results suggest that ypN\u0026thinsp;+\u0026thinsp;and Non-MPR are associated with poor RFS and OS. Although the difference in RFS between treatment groups among non-MPR patients was not statistically significant, the NA\u0026thinsp;+\u0026thinsp;S+RT group showed a numerically higher RFS than the NA\u0026thinsp;+\u0026thinsp;S group, suggesting a potential benefit. Furthermore, ypN+ patients in the NA\u0026thinsp;+\u0026thinsp;S+RT group experienced a significant improvement in RFS (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). While our survival analysis indicated that ART did not improve RFS or OS in ypN0 patients, it should be noted that another ongoing retrospective study at our center suggests a potential RFS benefit trend in ypT2\u0026ndash;4N0 patients receiving ART. These results suggest that ART has potential value in patients with high ypTNM and lymph node involvement after neoadjuvant therapy.\u003c/p\u003e \u003cp\u003eWhile radiotherapy is established to reduce locoregional recurrence[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], the present study did not demonstrate a significant reduction in local recurrence\u0026mdash;including nodal and anastomotic failures\u0026mdash;with ART (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Conversely, distant metastasis occurred at a higher incidence rate in the ART group (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), with lung metastases representing the most common site of distant spread (14.58%). Several factors may explain these observations. First, the tolerability of adjuvant therapy is generally lower than that of neoadjuvant treatment[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Second, high-dose radiotherapy may induce \"detrimental distant effect\"[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], potentially increasing the risk of secondary thoracic malignancies in irradiated ESCC patients[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Finally, The proportion of patients with high tumor burden was high in the ART group, which is associated with poorer prognosis. This may further explain the increased incidence of thoracic metastases (e.g., lung and pleural) observed in the NA\u0026thinsp;+\u0026thinsp;S+RT group.\u003c/p\u003e \u003cp\u003eSeveral limitations should be considered in this study. First, as a retrospective analysis, the data are subject to inherent potential biases. Factors such as postoperative complications and adverse effects of ART could not be fully accounted for. Second, the neoadjuvant treatment regimens were not uniform, and because pCR rates differ between NCT and NICT, these two groups were not analyzed separately, which may have introduced confounding factors. Third, detailed data regarding chemoradiation regimens, radiation doses, and treatment cycles were not available, precluding a comparative effectiveness analysis across different treatment protocols. Finally, the recurrence patterns observed here may not be generalizable to all ESCC patients. To precisely delineate recurrence patterns and confirm the survival outcomes observed here, future multicenter studies with larger cohorts are warranted.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlthough ART did not improve overall survival in the entire cohort of locally advanced ESCC patients after neoadjuvant therapy and surgery, it may offer a survival benefit specifically for those with ypN+ disease or ypT3-4 tumors, irrespective of nodal status. The confirmation of these results will require further validation through large-scale, prospective studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eESCC \u0026nbsp; \u0026nbsp; Esophageal squamous cell carcinoma\u003c/p\u003e\n\u003cp\u003eEC \u0026nbsp; \u0026nbsp; \u0026nbsp; Esophageal cancer\u003c/p\u003e\n\u003cp\u003eNCT \u0026nbsp; \u0026nbsp; \u0026nbsp;Neoadjuvant chemotherapy\u003c/p\u003e\n\u003cp\u003eNICT \u0026nbsp; \u0026nbsp; Neoadjuvant chemoimmunotherapy\u003c/p\u003e\n\u003cp\u003eNCRT \u0026nbsp; \u0026nbsp; Neoadjuvant chemoradiotherapy\u003c/p\u003e\n\u003cp\u003eART \u0026nbsp; \u0026nbsp; \u0026nbsp;Adjuvant radiotherapy\u003c/p\u003e\n\u003cp\u003eNA+S \u0026nbsp; \u0026nbsp; Neoadjuvant therapy with surgery\u003c/p\u003e\n\u003cp\u003eNA+S+RT \u0026nbsp;Neoadjuvant therapy with surgery followed by adjuvant radiotherapy\u003c/p\u003e\n\u003cp\u003eCTV \u0026nbsp; \u0026nbsp; \u0026nbsp; Clinical target volume\u003c/p\u003e\n\u003cp\u003eypTNM \u0026nbsp; \u0026nbsp;Post-neoadjuvant pathological stage\u003c/p\u003e\n\u003cp\u003eypT \u0026nbsp; \u0026nbsp; \u0026nbsp; Post-neoadjuvant pathological tumor stage\u003c/p\u003e\n\u003cp\u003eypN \u0026nbsp; \u0026nbsp; \u0026nbsp; Post-neoadjuvant pathological node staging\u003c/p\u003e\n\u003cp\u003epCR \u0026nbsp; \u0026nbsp; \u0026nbsp; Pathological complete remission\u003c/p\u003e\n\u003cp\u003eTRG \u0026nbsp; \u0026nbsp; \u0026nbsp;Tumor regression grade\u003c/p\u003e\n\u003cp\u003eMPR \u0026nbsp; \u0026nbsp; \u0026nbsp;Major pathological response\u003c/p\u003e\n\u003cp\u003eRFS \u0026nbsp; \u0026nbsp; \u0026nbsp; Recurrence free survival\u003c/p\u003e\n\u003cp\u003eOS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;overall survival\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLYX, WXJ: Collected data, Performed analysis, Drafting of the manuscript. NZX,LYT:\u0026nbsp;Collected data. QPD: Conceived and designed the analysis. LYT: Conceived and designed the analysis, Review the manuscript, Obtained funding. All authors approved the submitted manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was\u0026nbsp;funded by\u0026nbsp;National Natural Science Foundation of China(82403786).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data from the study is available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and constant to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Jiangsu Cancer Hospital (approval number: KY-2024-108). The requirement for informed consent from participants was waived by the Ethics Committee in accordance with the ethical principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients and their families for making this study possible. The authors thank Lingfei Wei for the assistance in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication consent\u003c/strong\u003e\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"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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A Comparison of Clinicopathologic Outcomes and Patterns of Lymphatic Spread Across Neoadjuvant Chemotherapy, Neoadjuvant Chemoradiotherapy, and Neoadjuvant Immunochemotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma. Ann Surg Oncol. 2024;31(2):860\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao Q, Sun J, Zheng F, et al. Accurate location describe and management of lymph node recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma: a retrospective cohort study. Int J Surg. 2024;110(6):3440\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu YY, Dai L, Yang YB, et al. Long-Term Survival and Recurrence Patterns in Locally Advanced Esophageal Squamous Cell Carcinoma Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy Followed by Surgery. Ann Surg Oncol. 2024;31(8):5047\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Y, Liu J, Liu Z, et al. Two-year outcomes of clinical N2-3 esophageal squamous cell carcinoma after neoadjuvant chemotherapy and immunotherapy from the phase 2 NICE study. J Thorac Cardiovasc Surg. 2024;167(3):838\u0026ndash;e8471.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021;384(13):1191\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang W, Liu X, Xiao Z, et al. Postoperative intensity-modulated radiotherapy improved survival in lymph node-positive or stage III thoracic esophageal squamous cell carcinoma. Oncol Res Treat. 2015;38(3):97\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYap WK, Shih MC, Chang YC, et al. Adjuvant Chemoradiotherapy Associated with Improved Overall Survival in Resected Esophageal Squamous Cell Carcinoma after Neoadjuvant Chemoradiotherapy in Intensity-Modulated Radiotherapy Era. Biomedicines. 2022;10(11):2989.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRice TW, Patil DT, Blackstone EH. 8th edition AJCC/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice. Ann Cardiothorac Surg. 2017;6(2):119\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQin J, Xue L, Hao A, et al. Neoadjuvant chemotherapy with or without camrelizumab in resectable esophageal squamous cell carcinoma: the randomized phase 3 ESCORT-NEO/NCCES01 trial. Nat Med. 2024;30(9):2549\u0026ndash;57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang Y, Li Y, Qin J, et al. Mapping of Lymph Node Metastasis From Thoracic Esophageal Cancer: A Retrospective Study. Ann Surg Oncol. 2022;29(9):5681\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen C, Tian Z, Lin J et al. Adjuvant immunotherapy for esophageal squamous cell carcinoma after neoadjuvant chemoimmunotherapy: a multicenter real-world study. Int J Surg Published online September 24, 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie SH, Yang LT, Zhang H, et al. Adjuvant therapy provides no additional recurrence-free benefit for esophageal squamous cell carcinoma patients after neoadjuvant chemoimmunotherapy and surgery: a multi-center propensity score match study. Front Immunol. 2024;15:1332492.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo JC, Huang TC, Kuo HY, et al. Adjuvant chemoradiotherapy plus pembrolizumab for locally advanced esophageal squamous cell carcinoma with high risk of recurrence following neoadjuvant chemoradiotherapy: a single-arm phase II study. Cancer Immunol Immunother. 2024;73(11):230.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalthaner RA, Wong RK, Rumble RB, Zuraw L. Members of the Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care. Neoadjuvant or adjuvant therapy for resectable esophageal cancer: a systematic review and meta-analysis. BMC Med. 2004;2:35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng SY, Qi WX, Zhao SG, Chen JY. No survival benefit could be obtained from adjuvant radiotherapy in esophageal cancer treated with neoadjuvant chemotherapy followed by surgery: A SEER-based analysis. Front Oncol. 2022;12:897476.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao ZF, Yang ZY, Liang J, et al. Value of radiotherapy after radical surgery for esophageal carcinoma: a report of 495 patients. Ann Thorac Surg. 2003;75(2):331\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXiao ZF, Yang ZY, Miao YJ, et al. Influence of number of metastatic lymph nodes on survival of curative resected thoracic esophageal cancer patients and value of radiotherapy: report of 549 cases. Int J Radiat Oncol Biol Phys. 2005;62(1):82\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee Y, Samarasinghe Y, Lee MH, et al. Role of Adjuvant Therapy in Esophageal Cancer Patients After Neoadjuvant Therapy and Esophagectomy: A Systematic Review and Meta-analysis. Ann Surg. 2022;275(1):91\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYchou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011;29(13):1715\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePiffk\u0026oacute; A, Yang K, Panda A, et al. Radiation-induced amphiregulin drives tumour metastasis. Nature. 2025;643(8072):810\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYi H, Li S, Lin Y, et al. Risk and prognosis of secondary thoracic cancers after radiation therapy for esophageal cancer. J Gastroenterol Hepatol. 2023;38(6):930\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the supplementary files section\u003c/p\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":"Thoracic esophageal cancer, Neoadjuvant chemotherapy, Neoadjuvant chemoimmunotherapy, Adjuvant radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-8861751/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8861751/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003cbr\u003e\nPatients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing surgery after neoadjuvant chemotherapy (NCT) or neoadjuvant chemoimmunotherapy (NICT) remain at risk of disease progression. Currently, adjuvant radiotherapy (ART) is not recommended following these treatment sequences due to a lack of high-level evidence supporting its efficacy. This real-world study preliminarily evaluates the potential role of ART in this clinical setting.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nA sum of 324 ESCC patients who had surgery following NCT or NICT were included and divided into two groups: the neoadjuvant therapy with surgery (NA+S) group and the neoadjuvant therapy with surgery followed by adjuvant radiotherapy (NA+S+RT) group. The primary outcomes assessed were the two-year recurrence free survival (RFS) and overall survival (OS). The Kaplan-Meier method was utilized for survival analysis, while the Cox regression model was applied to determine the clinical factors linked to prognosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nThe NA+S group (n=180) and the NA+S+RT group (n=144) showed no statistically significant differences in 2‑year RFS (71.8% vs 68.8%, P=0.661, 95% CI: 55.52‑63.95) or 2‑year OS (80.7% vs 74.3%, P=0.162, 95% CI: 60.44‑68.17), indicating that ART did not provide a survival benefit. Subgroup analysis showed no significant survival difference between patients with major pathological response (MPR) and those without (non-MPR). However, among ypN+ patients, RFS was significantly improved in the NA+S+RT group (60.6% vs 41.8%, P=0.005, 95% CI: 37.65‑50.90). Similarly, ypT3‑4 patients showed a survival benefit in 2‑year RFS after ART (65% vs 44.4%, P\u0026lt;0.05, 95% CI: 38.42‑52.33). The incidence of distant metastasis, especially to the lung, bone, and pleura, was notably greater in the NA+S+RT group than in the NA+S group (P\u0026lt;0.05). The results of the multivariate analysis identified ypN+ and non‑MPR as independent risk factors for both RFS and OS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003cbr\u003e\nART did not improve survival outcomes in the entire neoadjuvant therapy cohort; however, it conferred a survival benefit in patients with ypN+ disease or ypT3‑4 tumors.\u003c/p\u003e","manuscriptTitle":"Real-World Role of Adjuvant Radiotherapy after Neoadjuvant Treatment for Thoracic Esophageal Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-16 06:00:28","doi":"10.21203/rs.3.rs-8861751/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-22T13:31:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"36244989355364591115496410306291552057","date":"2026-03-13T09:42:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-11T09:31:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-09T08:52:11+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-13T08:44:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-13T07:18:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2026-02-13T07:14:34+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":"a3562599-83bf-4b7f-9cc0-36a6e912623b","owner":[],"postedDate":"March 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-16T06:00:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-16 06:00:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8861751","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8861751","identity":"rs-8861751","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}