Comparison of Neoadjuvant Chemoimmunotherapy and Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Study with 3-Year Survival Analysis

Comparison of Neoadjuvant Chemoimmunotherapy and Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Study with 3-Year Survival Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of Neoadjuvant Chemoimmunotherapy and Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Study with 3-Year Survival Analysis Peiyuan Wang, Yujie Chen, Mengxia Lei, Hao He, Derong Zhang, Junpeng Lin, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4489788/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Oct, 2024 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Background Neoadjuvant chemoimmunotherapy (nCIT) for locally advanced esophageal squamous cell cancer (ESCC) has shown short-term benefits, but long-term survival outcomes are unclear. This study compares nCIT and neoadjuvant chemotherapy (nCT) in resectable ESCC. Patients and Methods: A retrospective analysis was conducted on ESCC patients who underwent nCT or nCIT followed by esophagectomy. Propensity score matching (PSM) with a caliper of 0.02 was employed to minimize bias. The primary endpoints included disease-free survival (DFS) and overall survival (OS). Results A total of 131 comparable pairs of ESCC patients receiving nCT and nCIT were selected for the final analysis. The nCIT had higher rates of pathological complete response (pCR) and major pathological response (mPR) compared to nCT. Additionally, nCIT led to significant tumor down-staging, higher rates of R0 resection, and increased lymph node clearance during surgery. Patients who received nCIT exhibited improved disease-free survival (DFS) and overall survival (OS) at the 3-year follow-up. The incidence of distant and mixed relapses was lower in the nCIT group compared to the nCT group. However, the risk of locoregional relapse was comparable between the two groups. Subgroup analyses showed that the benefits of nCIT were generally observed across most patient subgroups. Interestingly, in patients without pCR or mPR, nCIT still demonstrated better survival benefits than nCT. Conclusion nCIT demonstrated superior pathological response rates and improved 3-year DFS and OS compared to nCT alone in locally advanced ESCC, but long-term survival validation is needed. neoadjuvant chemoimmunotherapy neoadjuvant chemotherapy esophageal squamous cell cancer disease-free survival overall survival Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Esophageal squamous cell carcinoma (ESCC), primarily prevalent in Asia, contributes to the seventh-highest global cancer incidence and sixth- highest fatality rate 1 . However, the efficacy of surgery alone for locally advanced ESCC remains limited. As a result, neoadjuvant therapies in conjunction with surgery have emerged as the standard approach. Notably, neoadjuvant chemoradiotherapy (nCRT), established through studies like CROSS and NEOCRTEC5010, currently stands as the standard of care for operable locally advanced ESCC 2–5 . In East Asia, where the incidence of ESCC is even higher, neoadjuvant chemotherapy (nCT) is more commonly used as the treatment of choice 6 . After the launch of a new era in immunotherapy, immunotherapy has gained significant attention as a promising treatment strategy for advanced-stage ESCC. Clinical trials, such as KEYNOTE-590, CheckMate 648, and ESCORT-1st have played a cruial role in establishing the role of immunotherapy in the first-line treatment of ESCC 7–9 . Additionally, studies such as the NICE study have demonstrated the efficacy of neoadjuvant chemoimmunotherapy (nCIT) 10–12 . In our previous study, we demonstrated that tislelizumab combined with chemotherapy as neoadjuvant therapy for resectable ESCC resulted in high rates of major pathologic response (mPR) and pathologic complete remission (pCR), with acceptable tolerability, particularly with high-dose chemotherapy 13 . Until now, the most commonly published reports have been single-arm clinical trials with small sample sizes. There have been few studies that compare the survival outcomes of nCIT and nCT for patients with locally advanced ESCC. Shao-Wu Jing et al. conducted a study analyzing the efficacy and DFS between nCIT and nCT for patients with ESCC. Their findings confirmed that nCIT could improve DFS with good safety and feasibility. However, the nCIT cohort in their study had a small sample size and a short follow-up period. The aim of this study is to investigate whether nCIT provides a survival advantage compared to nCT followed by esophagectomy for patients with resectable locally advanced ESCC. 2 Materials and Methods 2.1 Patient selection We conducted a retrospective analysis of 1034 patients who underwent esophagectomy for resectable esophageal cancer at Fujian Cancer Hospital between May 2020 and May 2023. The inclusion criteria were as follows: ( 1 ) histopathologically confirmed squamous cell carcinoma, ( 2 ) thoracic ESCC, ( 3 ): patients who received nCT, nCIT following esophagectomy. The exclusion criteria were: ( 1 ) presence of pathological nonsquamous cell carcinoma components, ( 2 ) patients with previous or concurrent malignant tumors, ( 3 ) patients who received any other treatments prior to surgery, and ( 4 ) incomplete medical records. The 8th edition of the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system was used for staging. All procedures were performed in accordance with the 2013 edition of the Declaration of Helsinki, and the study protocol was approved by the Ethic Committee of our Hospital. Informed consent was waived due to the retrospective nature of the study, and anonymized data was collected retrospectively from our prospectively collated database. We first conducted an analysis on the entire cohort, followed by a propensity score-matched analysis as shown in Fig. 1 . For the preliminary analysis, we compared 157 ESCC patients who received nCT to 221 ESCC patients who received nCIT. The propensity score-matched (PSM) analysis included 131 propensity score-matched pairs, comparing patients who received nCT to those who received nCIT. 2.2 Neoadjuvant treatment regimens Patients in the nCIT group received 1–4 cycles of intravenous PD-1 inhibitors (pembrolizumab at a dose of 200mg, camrelizumab at a dose of 200mg, toripalimab at a dose of 240mg, sintilimab at a dose of 200mg, or tislelizumab at a dose of 200mg) every 3 weeks. Simultaneously, they received chemotherapy consisting of cisplatin combined with paclitaxel (TP) or abraxane (AP).Patients in the nCT group received 1–4 cycles of chemotherapy (TP or AP regimen) every 3 weeks. The median usage cycle of neoadjuvant therapy was 2 in both groups. Number of patients with different anti-PD-1 inhibitors used in the nCIT arm is shown in Supplementary Fig. 1. 2.3 Surgery and adjuvant therapy For patients deemed suitable for esophagectomy after clinical evaluation, the surgery was performed 4–8 weeks after completion of the last neoadjuvant therapy. Minimally invasive esophagectomy (MIE) was performed, which included 2-field or 3-field lymphadenectomy and gastric reconstruction. Adjuvant treatments were then administered based on the pathological tumor stage and the patient's recovery condition. Following multidisciplinary discussions, postoperative chemo-radiotherapy, chemotherapy alone, or chemo-immunotherapy might be recommended for patients with ypN+, ypT3 + or palliative resection. In the nCIT group, adjuvant therapy with intravenous PD-1 inhibitors might be recommended for 1 year after surgery. 2.4 Follow-up Surveillance evaluations were conducted every 3 months for the first 2 years after surgery, and subsequently, every 6 months thereafter. In these follow-up assessments, surveillance tests such as physical examinations, chest computed tomography (CT), and barium scans were regularly performed. Additionally, ultrasonography, endoscopy, positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI) were employed if necessary. 2.5 Study Endpoints The primary study endpoints included tumor regression grade (TRG), complete tumor resection (R0) rate, pCR rate, recurrence pattern, and surgical complications. The secondary endpoints were DFS and OS. As reported in our previous study 13 , pCR was defined as the absence of viable tumor cells in the resected specimen, while mPR was defined as < 10% viable residual tumor cells in the specimen. Pathological responses were evaluated independently by two experienced pathologists. The Becker system was used to evaluate TRG: TRG 1a (complete tumor regression), TRG 1b ( 50% viable tumor remaining) 14 . DFS referred to the time (in months) from surgery to the first documentation of recurrence or metastasis, while OS was defined as the time (in months) from surgery to the date of death or last follow-up. 2.6 Statistical analysis PSM was employed to create a well-balanced cohort by considering the full range of available explanatory factors 15 . A one-to-one matching analysis was conducted with a caliper width of 0.02 between the nCIT and nCT groups. Survival analyses were performed and compared using Kaplan-Meier curves and the log-rank test. Differences in clinicopathological features between the groups were assessed using the chi-square (χ2) test or t-test. Kaplan-Meier analysis with the log-rank test was utilized to compare survival among different subgroups. Statistical analyses were performed using SPSS software version 26.0 (IBM, New York, USA) and GraphPad Prism 5.0 software. A p-value of < 0.05 (two-sided) was considered statistically significant. 3 Results 3.1 Pre-matched demographics The average age in the nCT group was 61.14 (n = 157), while in the nCIT group, it was 61.94 (n = 221). The nCIT group had significantly higher clinical N stage and clinical TNM stage compared to the nCT group. Moreover, the nCIT group underwent more cycles of neoadjuvant therapy. There were no significant differences in terms of sex, BMI, tumor location, clinical T stage, or chemotherapy regimen between the two groups (Supplementary Table 1). 3.2 Comparisons of outcomes before matching All patients in both the nCIT and nCT groups successfully underwent esophagectomy. In comparison to the nCT group, the nCIT group exhibited a higher pathological response rate. The pCR was observed in 20.81% (46/221) of patients in the nCIT group, while it was only 11.47% (18/157) in the nCT group ( P = 0.053) (Fig. 2 A). Similarly, the mPR was higher in the nCIT group with 40.72% (90/221) compared to 19.75% (31/157) in the nICT group ( P = 0.002) (Fig. 2 B). Survival analysis was performed using Kaplan-Meier curves to compare the nCIT and nCT groups. The median follow-up period was 18 months in the nCIT group and 26 months in the nCT group. As depicted in Fig. 2 C-D, the nCIT group exhibited significantly better DFS and OS than compared to the nCT group (24-month DFS rate: 74.58% vs 53.51%; 36-month DFS rate: 58.57% vs 37.44%, P < 0.001; 24-month OS rate: 76.49% vs 60.77%, 36-month OS rate: 65.43% vs 51.96%, P = 0.003). Furthermore, we analyzed the pattern of post-surgery failure in both groups and found that the nCIT group had a lower incidence of overall failure compared to the nCT group (35.67% vs 22.62%). The risk of locoregional relapse was comparable between the nCIT and nCT groups (8.14% vs 8.28%). However, the risk of distant relapse (without locoregional relapse) was lower in the nCIT group. Notably, the risk of mixed relapse (with locoregional relapse) in the nCIT group was significantly lower than the nCT group (3.62% vs 10.83%, P < 0.01) (Fig. 2 E). Additionally, the relapse sites of both groups were further analyzed, revealing a lower incidence of relapse in all locations in the nCIT group compared to the nCT group. Moreover, the nCIT group exhibited a lower incidence of bone metastasis compared to the nCT group (5 cases vs 12 cases, P < 0.01). Similarly, brain metastasis was less frequent in the nCIT group compared to the nCT group ( P < 0.001) (Fig. 2 F). 3.3 Matched demographics The pre-operative demographics and comorbidities variables were propensity score matched through univariate analysis between nCT and nCIT group. Following matching (n = 131), the variables were not significantly different between the groups (Table 1 ). The clinical characteristics of post PSM patients were more balanced and included age, sex, tumor location, clinical T stage, clinical N stage, clinical TNM stage, chemotherapy regimen, neoadjuvant cycle. 3.4 Surgical treatment outcome After matching, the nCIT group demonstrated a superior pathological response compared to nCT group. The pCR rate was 19.85% (26/131) in the nCIT group, whereas it was only 11.45% (15/131) in the nCT group ( P = 0.131) (Fig. 3 A). Similarly, the mPR rate was higher in the nCIT group with 38.17% (50/131) compared to 19.85% (31/157) in the nCT group ( P = 0.019) (Fig. 3 B). Supplementary Table 2 presents the perioperative outcomes following esophagectomy. The nCIT group achieved better pathological response results compared to the nCT group in various aspects, including pathological T stage, pathological N stage, pathological TNM stage, nerve involvement, vascular invasion, number of positive lymph nodes, and TRG. These differences were statistically significant ( P < 0.05). Pathological downstaging also led to a higher R0 resection rate in the nCIT group ( P = 0.044). Interestingly, the number of lymph nodes removed in the nCIT group was 41.55 ± 1.59, while it was 32.27 ± 1.29 in the nCT group ( P < 0.001). There were no significant differences between the groups in terms of conversion to open surgery during the thoracic procedure, anastomotic leakage, postoperative hospital stay (days) and in-hospital and 90-day mortality. 3.5 Survival outcomes The median follow-up period was 21 months in the nCIT group and 26 months in the nCT group after matching. As depicted in Fig. 3 C-D, the nCIT group exhibited significantly better DFS and OS than compared to the nCT group (24-month DFS rate: 75.92% vs 44.06%; 36-month DFS rate: 55.00% vs 35.90%, P < 0.001; 24-month OS rate: 75.63% vs 58.75%, 36-month OS rate: 57.30% vs 50.18%, P = 0.014). In post-hoc exploratory analyses, an overall benefit in DFS was generally observed in favor of the nCIT group compared to the nCT group across most patient subgroups, except for females, in patients following esophagectomy after matching (Table 2 ). Similarly, an overall benefit in OS was generally observed in favor of the nCIT group compared to the nCT group across most patient subgroups, except for females, in patients following esophagectomy after matching (Table 3 ). However, it is important to interpret these exploratory analyses with caution. Furthermore, we conducted an analysis on the relationship between pathological response and survival. Before matching, patients who achieved pCR tended to have better DFS outcomes compared to those without pCR, regardless of whether they received immunologic agents or not. Additionally, among patients without pCR, the nCIT group demonstrated superior DFS compared to the nCT group (Fig. 4 A). Within the nCIT group, patients with mPR had better DFS than those without mPR. Moreover, regardless of whether patients had an mPR or not, the nCIT group exhibited improved DFS compared to the nCT group (Fig. 4 B). In terms of OS analysis, the nCIT group showed better survival compared to the nCT group among patients without pCR (Fig. 4 C). Within the nCIT group, patients with mPR had better OS compared to those without mPR. Furthermore, the OS of patients with mPR was better than those without mPR in the nCIT group (Fig. 4 D). After matching, in terms of DFS analysis, we observed that the nCIT group exhibited better survival compared to the nCT group among patients without pCR (Fig. 4 E). Similarly, the nCIT group also displayed improved survival rates compared to the nCT group among patients without pCR (Fig. 4 F). Concerning OS analysis, there were no significant differences observed between individuals with or without pCR within both the nCIT and nCT groups. However, the nCIT group still showed better survival rates than the nCT group among patients without pCR (Fig. 4 G). Additionally, there were no notable differences observed between patients with or without mPR. However, patients who achieved mPR tended to have better outcomes compared to those without mPR, regardless of whether they were in the nCIT or nCT groups (Fig. 4 H). 4 Discussion This study aimed to investigate the efficacy and survival outcomes of nCIT compared to nCT in patients with ESCC. To the best of our knowledge, this is the first study to report the 3-year DFS and OS rates in ESCC patients receiving nCT or nCIT. Additionally, it compares nCIT with nCT using the largest sample size from a single center in the same period, ensuring treatment consistency. Compared to nCT, the results showed that nCIT followed by esophagectomy led to higher rates of pCR and mPR, significant tumor down-staging, as well as a higher rate of R0 and an increased number of resected lymph nodes during the surgery. Patients who received nCIT also demonstrated better DFS and OS outcomes, which were sustained for at least 3 years of follow-up. At the 3-year follow-up mark, nCIT was associated with a lower incidence of distant and mixed relapses, but not with a reduction in locoregional relapse. Nowadays, there are several clinical single-arm studies of nCIT with abraxane regimen for ESCC, such as the NICE and TD-NICE trials 10,11 . However, the benefit of the abraxane regimen in neoadjuvant treatment for ESCC is still limited. Abraxane is a nanoparticle albumin-bound form of paclitaxel that offers the convenience of not requiring pretreatment with corticosteroids. In our previous reports, we identified patients receiving nCIT with chemotherapy dose intensity > 80%, and found that abraxane had higher rates of pCR and MPR compared to paclitaxel 13 . In our study, the rate of pCR in the nCT group (11.47% before matching; 11.45% after matching) were better than previously reported which may be attributed to receiving the abraxane regimen 16,17 . In the current study, we apply PSM to reduce the impact of potential confounding factors. Finally, we selected 131 pairs of comparable patients with ESCC who received nCT combined with nCIT for the final analysis after PSM. We confirmed that the rates of pCR and mPR in the nCIT group were better than those in the nCT group. Additionally, we found that postoperative anastomotic leakage, hospital stay, in-hospital mortality, and 90-day mortality were comparable between the two groups. Our findings are consistent with a previous report 16 . During our surgery, we observed that lymph node regression was more significant in the nCIT group than in the nCT group, and more lymph nodes were cleared in the nCIT group compared to those who received nCT. This observation aligns with previous reports 17,18 . Regarding the failure modes, the CROSS study showed that the effect of nCRT was mainly achieved by decreasing the risk of locoregional relapse rather than distant metastases 2 . In a propensity score-matched study conducted by Shao-Wu Jing et al., they compared the efficacy between nCIT and nCT and found that nCIT could significantly reduce local recurrence, but there was no significant difference in terms of metastasis 16 . However, our results showed a decrease in the risk of distant relapse, especially mixed relapse, rather than locoregional relapse. Additionally, nCIT was found to significantly reduce bone and brain metastasis. The lack of a significant difference in local recurrence may be attributed to our dissection of more lymph nodes compared to other studies 16 . Increased lymph node dissection not only aids in determining the pathological stage but also decreases the likelihood of local recurrence 19,20 . Survival outcomes may vary among different subgroups of esophageal cancer. Interaction analyses showed that the effect of nCIT tends to be more effective for ESCC compared to nCT in most subgroups. However, it is worth noting that statistical tests for interaction have limited power and may not capture all potential differences in relative effects between subgroups. In recent years, studies have demonstrated that the benefits of immune checkpoint inhibitors are influenced by gender 21,22 . In our study, we found that males derived greater clinical benefits from nCIT, while females experienced greater clinical benefits from nCT. This finding is consistent with a study by Conforti et al 23 . The underlying reasons for these gender-specific differences may be that gender can influence the effects of immune checkpoint inhibitors, or it could be due to our study enrolling a higher number of men than women. In future research, it is crucial to ensure greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women. This may involve exploring different immunotherapeutic approaches tailored for specific genders to optimize treatment outcomes. Previous studies have demonstrated that achieving an mPR or pCR after neoadjuvant therapy is associated with improved long-term outcomes 24,25 .However, our further analysis on the relationship between pathological response and survival revealed that within the nCIT or nCT groups, there were no significant differences in DFS or OS between patients who achieved pCR or mPR compared to those who did not, after matching. While pCR and mPR may increase the rate of achieving R0 resection, the impact on prolonging survival warrants further investigation in a larger and more diverse population. Additionally, the use of nivolumab as adjuvant therapy has been suggested for patients with R0 resected esophageal cancer with residual pathological disease 26 . However, for patients who achieved pCR, there are currently no specific recommendations for systemic therapy. It is important to note that in our study, patients who achieved a pCR in both groups did not necessarily experience a cure, as a significant proportion of them still had tumor recurrence or metastasis. Therefore, these findings suggest the need for improved systemic therapy options for patients who achieve a pCR. Although nCRT followed by surgery was found to have advantages in terms of pCR rate and overall survival benefit for ESCC 27 , another study comparing nCRT and nCT found that higher pCR rates in the nCRT group did not translate into longer survival 28 . Therefore, it is important to consider the potential impact of immunotherapy and conduct long-term follow-up studies to assess the efficacy of nCIT. In our own study, we observed that compared to nCT, nCIT provided higher 3-year survival rates, higher rates of R0 resection, and higher rates of pCR or mPR. However, there was no significant difference in survival between patients who achieved pCR or mPR and those who did not in the 3-year survival analysis. Interestingly, even in patients without pCR or mPR, nCIT still demonstrated better survival benefits compared to the nCT group. To further investigate the role of nCIT in the first-line treatment of locally advanced ESCC, a prospective study with a sufficient sample size is needed. However, it is important to note that this study had several limitations. Firstly, its retrospective nature introduces inherent biases that may impact the results. Additionally, the study was conducted in a single institution, which may limit the generalizability of the findings as institutional practices can vary. Moreover, the case number in the study was relatively small, potentially limiting the statistical power and precision of the results. Despite using propensity score matching to address treatment selection bias, it is still possible that some biases remain. The follow-up period in both groups was relatively short, and therefore, longer follow-up is needed to fully evaluate the long-term effects. Furthermore, the use of different immunotherapy drugs in the nCIT patients may introduce variability in the results. In conclusion, our study found that compared to nCT alone, nCIT showed better pathological response rates in patients with locally advanced ESCC. Additionally, nCIT was associated with improved DFS and OS in the 3-year survival analysis. However, it is important to note that further validation of long-term survival outcomes is still required. Declarations Conflict of interest The authors have no conflict of interest. Ethics Statement The studies involving human participants were reviewed and approved by The Ethics Committee of Fujian Cancer Hospital (No.K2023-276-01). Informed consent was waived due to the retrospective nature of the study. Funding Information This work was supported by the National Natural Science Foundation of China (Grant No. 82002497), the Science and Technology Program of Fujian Province (Nos. 2021J01442, 2023J011270) and Startup Fund for scientific research,Fujian Medical University (No. 2021QH1148). Author Contribution (I) Conception and design: Peiyuan Wang, Yujie Chen, Mengxia Lei; (II) Administrative support: Shuoyan Liu, Feng Wang; (III) Provision of study materials or patients: Hao He, Derong Zhang, Junpeng Lin , Hui Lin, Wenwei Wei, Peng Chen; (IV) Collection and assembly of data: Fengnian Zhuang, Weijie Chen,Hang Zhou, Pengqiang Gao; (V) Data analysis and interpretation: Peiyuan Wang, Yujie Chen, Mengxia Lei; (VI) Manuscript writing: All authors; (VII)Final approval of manuscript: All authors References Sung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin May 71(3):209–249 Eyck BM, van Lanschot JJB, Hulshof M et al (2021) Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol Jun 20(18):1995–2004 Oppedijk V, van der Gaast A, van Lanschot JJ et al (2014) Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol Feb 10(5):385–391 Chen D, Kong M, Sun J et al (2022) Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: Results from the phase III trial NEOCRTEC5010. J Thorac Cardiovasc Surg Aug 20 Yang H, Liu H, Chen Y et al (2021) Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg Aug 1(8):721–729 Kitagawa Y, Uno T, Oyama T et al (2019) Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2. Esophagus Jan 16(1):25–43 Luo H, Lu J, Bai Y et al (2021) Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA Sep 14(10):916–925 Kato K, Shah MA, Enzinger P et al (2019) KEYNOTE-590: Phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol Apr 15(10):1057–1066 Kato K, Doki Y, Ogata T et al (2023) First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus Apr 20(2):291–301 Liu J, Yang Y, Liu Z et al (2022) Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer Mar ;10(3) Yan X, Duan H, Ni Y et al (2022) Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Int J Surg Jul 103:106680 Yang W, Xing X, Yeung SJ et al (2022) Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer Jan ;10(1) Wang P, Lei M, Weng G et al (2023) High-dose chemotherapy sensitizes locally advanced esophageal squamous cell carcinoma to PD-1 blockade for a higher pathological complete response rate and survival. Transl Oncol Oct 36:101736 Langer R, Becker K (2018) Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy. Virchows Arch Feb 472(2):175–186 Austin PC (2011) An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivar Behav Res May 46(3):399–424 Jing SW, Zhai C, Zhang W et al (2022) Comparison of neoadjuvant immunotherapy plus chemotherapy versus chemotherapy alone for patients with locally advanced esophageal squamous cell carcinoma: A propensity score matching. Front Immunol 13:970534 Zhang B, Zhao H, Wu X et al (2023) Perioperative outcomes of neoadjuvant chemotherapy plus camrelizumab compared with chemotherapy alone and chemoradiotherapy for locally advanced esophageal squamous cell cancer. Front Immunol 14:1066527 Qiao Y, Zhao C, Li X et al (2022) Efficacy and safety of camrelizumab in combination with neoadjuvant chemotherapy for ESCC and its impact on esophagectomy. Front Immunol 13:953229 Guo X, Wang Z, Yang H et al (2023) Impact of Lymph Node Dissection on Survival After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: From the Results of NEOCRTEC5010, a Randomized Multicenter Study. Ann Surg Feb 1(2):259–266 Henckens SPG, Hagens ERC, van Berge Henegouwen MI, Meijer SL, Eshuis WJ, Gisbertz SS (2023) Impact of increasing lymph node yield on staging, morbidity and survival after esophagectomy for esophageal adenocarcinoma. Eur J Surg Oncol Jan 49(1):89–96 Conforti F, Pala L, Bagnardi V et al (2018) Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol Jun 19(6):737–746 Irelli A, Sirufo MM, D'Ugo C, Ginaldi L, De Martinis M (2020) Sex and Gender Influences on Cancer Immunotherapy Response. Biomedicines Jul 21 ;8(7) Conforti F, Pala L, Bagnardi V et al (2019) Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis. J Natl Cancer Inst Aug 1(8):772–781 Berger AC, Farma J, Scott WJ et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol Jul 1(19):4330–4337 Hellmann MD, Chaft JE, William WN Jr. et al (2014) Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol Jan 15(1):e42–50 Hermann RM, Christiansen H (2021) [A new standard is emerging: PD-1 maintenance therapy after neoadjuvant radiochemotherapy and curative resection of oesophageal and AEG carcinomas (CheckMate 577)]. Strahlenther Onkol Nov 197(11):1040–1042 Kamarajah SK, Markar SR (2021) Author response to: Neoadjuvant chemoradiotherapy or chemotherapy alone for oesophageal cancer: population-based cohort study. Br J Surg Aug 19(8):e279 Zhang G, Zhang C, Sun N et al (2022) Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for the treatment of esophageal squamous cell carcinoma: a propensity score-matched study from the National Cancer Center in China. J Cancer Res Clin Oncol Apr 148(4):943–954 Tables Tables 1-3 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table13.docx Supplementarylegends.docx SupplementaryFigure1.pdf SupplementaryTable1.docx SupplementaryTable2.docx Cite Share Download PDF Status: Published Journal Publication published 25 Oct, 2024 Read the published version in Journal of Cancer Research and Clinical Oncology → Version 1 posted Editorial decision: Revision requested 09 Oct, 2024 Reviews received at journal 08 Jun, 2024 Reviewers agreed at journal 03 Jun, 2024 Reviewers invited by journal 29 May, 2024 Editor assigned by journal 29 May, 2024 Submission checks completed at journal 29 May, 2024 First submitted to journal 28 May, 2024 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. 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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-4489788","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":312539118,"identity":"fa4bc8ee-f9ce-4839-aec2-fc1a00a2bca1","order_by":0,"name":"Peiyuan Wang","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peiyuan","middleName":"","lastName":"Wang","suffix":""},{"id":312539119,"identity":"68dcc49a-3e72-4639-a43d-52ab1c2d9654","order_by":1,"name":"Yujie Chen","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yujie","middleName":"","lastName":"Chen","suffix":""},{"id":312539120,"identity":"fcb93bc7-66c7-4a8f-8961-16264b95816e","order_by":2,"name":"Mengxia Lei","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mengxia","middleName":"","lastName":"Lei","suffix":""},{"id":312539121,"identity":"a4d4eb70-6e69-4e5d-81b9-cf9cea2713d2","order_by":3,"name":"Hao He","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"He","suffix":""},{"id":312539122,"identity":"97e8e41b-0f5c-4ab0-8820-0d9de59011c8","order_by":4,"name":"Derong Zhang","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Derong","middleName":"","lastName":"Zhang","suffix":""},{"id":312539123,"identity":"fb40b88f-0099-47bb-a4c4-5cb88a5d1e71","order_by":5,"name":"Junpeng Lin","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Junpeng","middleName":"","lastName":"Lin","suffix":""},{"id":312539124,"identity":"13976762-15da-41f6-b7ba-8b8bd59a509b","order_by":6,"name":"Hui Lin","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Lin","suffix":""},{"id":312539125,"identity":"4c135457-2144-4445-96a5-61333fcf7da7","order_by":7,"name":"Wenwei Wei","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenwei","middleName":"","lastName":"Wei","suffix":""},{"id":312539126,"identity":"34a94e92-f635-49df-8761-3eded20984ed","order_by":8,"name":"Peng Chen","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Chen","suffix":""},{"id":312539127,"identity":"091affab-cd2e-43b4-87dd-b8958c28bc26","order_by":9,"name":"Fengnian Zhuang","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fengnian","middleName":"","lastName":"Zhuang","suffix":""},{"id":312539128,"identity":"b2fa1218-d12a-40ba-9659-2898b9b4b422","order_by":10,"name":"Weijie Chen","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weijie","middleName":"","lastName":"Chen","suffix":""},{"id":312539129,"identity":"0f3f0850-e9e9-4cb2-8920-016b9d5d4113","order_by":11,"name":"Hang Zhou","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hang","middleName":"","lastName":"Zhou","suffix":""},{"id":312539130,"identity":"20dfd02d-b3fe-46a9-9331-7c8407a1bff5","order_by":12,"name":"Pengqiang Gao","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pengqiang","middleName":"","lastName":"Gao","suffix":""},{"id":312539131,"identity":"36f36b62-93b3-461a-bd00-a9bf78b7fd3f","order_by":13,"name":"Feng Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsUlEQVRIiWNgGAWjYDAC5gMMEgkVEnJs7O0HiNTClsAg8eCMjTEfz5kE4rVIPmxLS5wn4WBAnA6DY9yJNxLYDqe3STAkMPyo2EaMFt7NFgk8h3PbpBsPMPacuU1Yi9n93m0SCRJALTIHEpgZ24jRcowXqMXgcDobkCRFS0JaAvFa7MF+OWBj2AYM5INE+UWyjXfjzZ//JOTl29sPPvhRQYQWFHCARPWjYBSMglEwCnABAAxwPkpue/Q9AAAAAElFTkSuQmCC","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Feng","middleName":"","lastName":"Wang","suffix":""},{"id":312539132,"identity":"06265b95-1ead-4843-8ce5-08f54eb47c07","order_by":14,"name":"Shuoyan Liu","email":"","orcid":"","institution":"Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuoyan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-05-28 09:30:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4489788/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4489788/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00432-024-06004-w","type":"published","date":"2024-10-25T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58243959,"identity":"c20100a2-5a7f-495d-bee1-c0266b7757ff","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":276699,"visible":true,"origin":"","legend":"\u003cp\u003ePatient recruitment.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/5610ed01b2839464dff03a07.jpg"},{"id":58244772,"identity":"36e02222-e14a-4ee5-ad82-0b8d6e735515","added_by":"auto","created_at":"2024-06-13 02:15:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":451212,"visible":true,"origin":"","legend":"\u003cp\u003eOutcomes before matching. (A) Percentage of patients achieving pCR. (B) Percentage of patients achieving mPR. (C) Kaplan- Meier plot showing DFS rates between nCIT and nCT groups. (D) Kaplan-Meier plot showing OS rates between the nCIT and nCT groups. (E) Distribution of disease progression in the nCIT and nCT groups. (F) Distribution of recurrent sites in the nCIT and nCT groups. * \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05; ** \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.01.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/5e2e1fd9bf74aa8851622c81.jpg"},{"id":58243957,"identity":"bbf830ba-b97b-48cf-9c01-26f6597dc05c","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":314647,"visible":true,"origin":"","legend":"\u003cp\u003ePathological response rate and survival after matching. (A) Percentage of patients achieving pCR. (B) Percentage of patients achieving mPR. (C) Kaplan-Meier plot showing DFS rates between the nCIT and nCT groups after matching. (D) Kaplan-Meier plot showing OS rates between the nCIT and nCT groups after matching.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/df0a149b6aee3d0028ed2bb2.jpg"},{"id":58243960,"identity":"5b9fc33d-6a3c-4e2d-89cd-0ade66355b87","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":714043,"visible":true,"origin":"","legend":"\u003cp\u003eThe relationship between pathological response and survival in both groups. (A) Kaplan-Meier plot showing DFS outcomes between patients with pCR and those without pCR in both groups before matching. (B) Kaplan-Meier plot showing DFS outcomes between patients with mPR and those without mPR in both groups before matching. (C) Kaplan-Meier plot showing OS outcomes between patients with pCR and those without pCR in both groups before matching. (D) Kaplan-Meier plot showing OS outcomes between patients with mPR and those without mPR in both groups before matching. (E) Kaplan-Meier plot showing DFS outcomes between patients with pCR and those without pCR in both groups after matching. (F) Kaplan-Meier plot showing DFS outcomes between patients with mPR and those without mPR in both groups after matching. (G) Kaplan-Meier plot showing OS outcomes between patients with pCR and those without pCR in both groups after matching. (H) Kaplan-Meier plot showing OS outcomes between patients with mPR and those without mPR in both groups after matching. ICIs, immune checkpoint inhibitors.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/c7cdb14dacadadc6876d5144.jpg"},{"id":67681724,"identity":"14b69b29-8d30-41fd-864a-265219d64793","added_by":"auto","created_at":"2024-10-28 16:08:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2232941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/b73aeaa2-2cab-40f2-89d4-94d5f8085e6a.pdf"},{"id":58243961,"identity":"7fdc716a-892d-4c3d-8450-9f3cc9df5bc3","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":189827,"visible":true,"origin":"","legend":"","description":"","filename":"Table13.docx","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/b5ebedfaa6ba672cef534885.docx"},{"id":58244773,"identity":"74e23f94-e798-4dff-b465-fe8dde3b7146","added_by":"auto","created_at":"2024-06-13 02:15:12","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":15564,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarylegends.docx","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/f3b6da3056cf9d4d204c96ea.docx"},{"id":58243962,"identity":"42f41602-dc7f-4389-9348-c98a667fd930","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":17083,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/0ba3eb77f7fa56dcab0d065d.pdf"},{"id":58243963,"identity":"05dba202-501d-4494-b659-0bc6875cb44b","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":20292,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/9238fff0c9e06648a3f99b86.docx"},{"id":58243965,"identity":"518566b9-b79e-430b-a136-a3ed7ccfb28d","added_by":"auto","created_at":"2024-06-13 02:07:12","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":19435,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4489788/v1/3e2b17920aae7ee3eba1ddf6.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Neoadjuvant Chemoimmunotherapy and Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Study with 3-Year Survival Analysis","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eEsophageal squamous cell carcinoma (ESCC), primarily prevalent in Asia, contributes to the seventh-highest global cancer incidence and sixth- highest fatality rate \u003csup\u003e1\u003c/sup\u003e. However, the efficacy of surgery alone for locally advanced ESCC remains limited. As a result, neoadjuvant therapies in conjunction with surgery have emerged as the standard approach. Notably, neoadjuvant chemoradiotherapy (nCRT), established through studies like CROSS and NEOCRTEC5010, currently stands as the standard of care for operable locally advanced ESCC\u003csup\u003e2\u0026ndash;5\u003c/sup\u003e. In East Asia, where the incidence of ESCC is even higher, neoadjuvant chemotherapy (nCT) is more commonly used as the treatment of choice\u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAfter the launch of a new era in immunotherapy, immunotherapy has gained significant attention as a promising treatment strategy for advanced-stage ESCC. Clinical trials, such as KEYNOTE-590, CheckMate 648, and ESCORT-1st have played a cruial role in establishing the role of immunotherapy in the first-line treatment of ESCC\u003csup\u003e7\u0026ndash;9\u003c/sup\u003e. Additionally, studies such as the NICE study have demonstrated the efficacy of neoadjuvant chemoimmunotherapy (nCIT)\u003csup\u003e10\u0026ndash;12\u003c/sup\u003e. In our previous study, we demonstrated that tislelizumab combined with chemotherapy as neoadjuvant therapy for resectable ESCC resulted in high rates of major pathologic response (mPR) and pathologic complete remission (pCR), with acceptable tolerability, particularly with high-dose chemotherapy\u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUntil now, the most commonly published reports have been single-arm clinical trials with small sample sizes. There have been few studies that compare the survival outcomes of nCIT and nCT for patients with locally advanced ESCC. Shao-Wu Jing et al. conducted a study analyzing the efficacy and DFS between nCIT and nCT for patients with ESCC. Their findings confirmed that nCIT could improve DFS with good safety and feasibility. However, the nCIT cohort in their study had a small sample size and a short follow-up period. The aim of this study is to investigate whether nCIT provides a survival advantage compared to nCT followed by esophagectomy for patients with resectable locally advanced ESCC.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patient selection\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of 1034 patients who underwent esophagectomy for resectable esophageal cancer at Fujian Cancer Hospital between May 2020 and May 2023. The inclusion criteria were as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) histopathologically confirmed squamous cell carcinoma, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) thoracic ESCC, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e): patients who received nCT, nCIT following esophagectomy. The exclusion criteria were: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) presence of pathological nonsquamous cell carcinoma components, (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) patients with previous or concurrent malignant tumors, (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) patients who received any other treatments prior to surgery, and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) incomplete medical records. The 8th edition of the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system was used for staging. All procedures were performed in accordance with the 2013 edition of the Declaration of Helsinki, and the study protocol was approved by the Ethic Committee of our Hospital. Informed consent was waived due to the retrospective nature of the study, and anonymized data was collected retrospectively from our prospectively collated database.\u003c/p\u003e \u003cp\u003eWe first conducted an analysis on the entire cohort, followed by a propensity score-matched analysis as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. For the preliminary analysis, we compared 157 ESCC patients who received nCT to 221 ESCC patients who received nCIT. The propensity score-matched (PSM) analysis included 131 propensity score-matched pairs, comparing patients who received nCT to those who received nCIT.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Neoadjuvant treatment regimens\u003c/h2\u003e \u003cp\u003ePatients in the nCIT group received 1\u0026ndash;4 cycles of intravenous PD-1 inhibitors (pembrolizumab at a dose of 200mg, camrelizumab at a dose of 200mg, toripalimab at a dose of 240mg, sintilimab at a dose of 200mg, or tislelizumab at a dose of 200mg) every 3 weeks. Simultaneously, they received chemotherapy consisting of cisplatin combined with paclitaxel (TP) or abraxane (AP).Patients in the nCT group received 1\u0026ndash;4 cycles of chemotherapy (TP or AP regimen) every 3 weeks. The median usage cycle of neoadjuvant therapy was 2 in both groups. Number of patients with different anti-PD-1 inhibitors used in the nCIT arm is shown in Supplementary Fig.\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Surgery and adjuvant therapy\u003c/h2\u003e \u003cp\u003eFor patients deemed suitable for esophagectomy after clinical evaluation, the surgery was performed 4\u0026ndash;8 weeks after completion of the last neoadjuvant therapy. Minimally invasive esophagectomy (MIE) was performed, which included 2-field or 3-field lymphadenectomy and gastric reconstruction.\u003c/p\u003e \u003cp\u003eAdjuvant treatments were then administered based on the pathological tumor stage and the patient's recovery condition. Following multidisciplinary discussions, postoperative chemo-radiotherapy, chemotherapy alone, or chemo-immunotherapy might be recommended for patients with ypN+, ypT3\u0026thinsp;+\u0026thinsp;or palliative resection. In the nCIT group, adjuvant therapy with intravenous PD-1 inhibitors might be recommended for 1 year after surgery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Follow-up\u003c/h2\u003e \u003cp\u003eSurveillance evaluations were conducted every 3 months for the first 2 years after surgery, and subsequently, every 6 months thereafter. In these follow-up assessments, surveillance tests such as physical examinations, chest computed tomography (CT), and barium scans were regularly performed. Additionally, ultrasonography, endoscopy, positron emission tomography (PET)/CT, and magnetic resonance imaging (MRI) were employed if necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Study Endpoints\u003c/h2\u003e \u003cp\u003eThe primary study endpoints included tumor regression grade (TRG), complete tumor resection (R0) rate, pCR rate, recurrence pattern, and surgical complications. The secondary endpoints were DFS and OS. As reported in our previous study\u003csup\u003e13\u003c/sup\u003e, pCR was defined as the absence of viable tumor cells in the resected specimen, while mPR was defined as \u0026lt;\u0026thinsp;10% viable residual tumor cells in the specimen. Pathological responses were evaluated independently by two experienced pathologists. The Becker system was used to evaluate TRG: TRG 1a (complete tumor regression), TRG 1b (\u0026lt;\u0026thinsp;10% vital tumor tissue), TRG 2 (10\u0026ndash;50% residual tumor in the tumor bed), and TRG 3 (\u0026gt;\u0026thinsp;50% viable tumor remaining)\u003csup\u003e14\u003c/sup\u003e. DFS referred to the time (in months) from surgery to the first documentation of recurrence or metastasis, while OS was defined as the time (in months) from surgery to the date of death or last follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Statistical analysis\u003c/h2\u003e \u003cp\u003ePSM was employed to create a well-balanced cohort by considering the full range of available explanatory factors\u003csup\u003e15\u003c/sup\u003e. A one-to-one matching analysis was conducted with a caliper width of 0.02 between the nCIT and nCT groups. Survival analyses were performed and compared using Kaplan-Meier curves and the log-rank test. Differences in clinicopathological features between the groups were assessed using the chi-square (χ2) test or t-test. Kaplan-Meier analysis with the log-rank test was utilized to compare survival among different subgroups. Statistical analyses were performed using SPSS software version 26.0 (IBM, New York, USA) and GraphPad Prism 5.0 software. A p-value of \u0026lt;\u0026thinsp;0.05 (two-sided) was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e3.1 Pre-matched demographics\u003c/h2\u003e\n \u003cp\u003eThe average age in the nCT group was 61.14 (n\u0026thinsp;=\u0026thinsp;157), while in the nCIT group, it was 61.94 (n\u0026thinsp;=\u0026thinsp;221). The nCIT group had significantly higher clinical N stage and clinical TNM stage compared to the nCT group. Moreover, the nCIT group underwent more cycles of neoadjuvant therapy. There were no significant differences in terms of sex, BMI, tumor location, clinical T stage, or chemotherapy regimen between the two groups (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e3.2 Comparisons of outcomes before matching\u003c/h2\u003e\n \u003cp\u003eAll patients in both the nCIT and nCT groups successfully underwent esophagectomy. In comparison to the nCT group, the nCIT group exhibited a higher pathological response rate. The pCR was observed in 20.81% (46/221) of patients in the nCIT group, while it was only 11.47% (18/157) in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.053) (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eA). Similarly, the mPR was higher in the nCIT group with 40.72% (90/221) compared to 19.75% (31/157) in the nICT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eSurvival analysis was performed using Kaplan-Meier curves to compare the nCIT and nCT groups. The median follow-up period was 18 months in the nCIT group and 26 months in the nCT group. As depicted in Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eC-D, the nCIT group exhibited significantly better DFS and OS than compared to the nCT group (24-month DFS rate: 74.58% vs 53.51%; 36-month DFS rate: 58.57% vs 37.44%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 24-month OS rate: 76.49% vs 60.77%, 36-month OS rate: 65.43% vs 51.96%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003).\u003c/p\u003e\n \u003cp\u003eFurthermore, we analyzed the pattern of post-surgery failure in both groups and found that the nCIT group had a lower incidence of overall failure compared to the nCT group (35.67% vs 22.62%). The risk of locoregional relapse was comparable between the nCIT and nCT groups (8.14% vs 8.28%). However, the risk of distant relapse (without locoregional relapse) was lower in the nCIT group. Notably, the risk of mixed relapse (with locoregional relapse) in the nCIT group was significantly lower than the nCT group (3.62% vs 10.83%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eE). Additionally, the relapse sites of both groups were further analyzed, revealing a lower incidence of relapse in all locations in the nCIT group compared to the nCT group. Moreover, the nCIT group exhibited a lower incidence of bone metastasis compared to the nCT group (5 cases vs 12 cases, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, brain metastasis was less frequent in the nCIT group compared to the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003eF).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\"\u003e\n \u003ch2\u003e3.3 Matched demographics\u003c/h2\u003e\n \u003cp\u003eThe pre-operative demographics and comorbidities variables were propensity score matched through univariate analysis between nCT and nCIT group. Following matching (n\u0026thinsp;=\u0026thinsp;131), the variables were not significantly different between the groups (Table \u003cspan\u003e1\u003c/span\u003e). The clinical characteristics of post PSM patients were more balanced and included age, sex, tumor location, clinical T stage, clinical N stage, clinical TNM stage, chemotherapy regimen, neoadjuvant cycle.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003e3.4 Surgical treatment outcome\u003c/h2\u003e\n \u003cp\u003eAfter matching, the nCIT group demonstrated a superior pathological response compared to nCT group. The pCR rate was 19.85% (26/131) in the nCIT group, whereas it was only 11.45% (15/131) in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.131) (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eA). Similarly, the mPR rate was higher in the nCIT group with 38.17% (50/131) compared to 19.85% (31/157) in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eSupplementary Table\u0026nbsp;2 presents the perioperative outcomes following esophagectomy. The nCIT group achieved better pathological response results compared to the nCT group in various aspects, including pathological T stage, pathological N stage, pathological TNM stage, nerve involvement, vascular invasion, number of positive lymph nodes, and TRG. These differences were statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Pathological downstaging also led to a higher R0 resection rate in the nCIT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). Interestingly, the number of lymph nodes removed in the nCIT group was 41.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.59, while it was 32.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29 in the nCT group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There were no significant differences between the groups in terms of conversion to open surgery during the thoracic procedure, anastomotic leakage, postoperative hospital stay (days) and in-hospital and 90-day mortality.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003e3.5 Survival outcomes\u003c/h2\u003e\n \u003cp\u003eThe median follow-up period was 21 months in the nCIT group and 26 months in the nCT group after matching. As depicted in Fig. \u003cspan\u003e3\u003c/span\u003eC-D, the nCIT group exhibited significantly better DFS and OS than compared to the nCT group (24-month DFS rate: 75.92% vs 44.06%; 36-month DFS rate: 55.00% vs 35.90%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 24-month OS rate: 75.63% vs 58.75%, 36-month OS rate: 57.30% vs 50.18%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014).\u003c/p\u003e\n \u003cp\u003eIn post-hoc exploratory analyses, an overall benefit in DFS was generally observed in favor of the nCIT group compared to the nCT group across most patient subgroups, except for females, in patients following esophagectomy after matching (Table \u003cspan\u003e2\u003c/span\u003e). Similarly, an overall benefit in OS was generally observed in favor of the nCIT group compared to the nCT group across most patient subgroups, except for females, in patients following esophagectomy after matching (Table \u003cspan\u003e3\u003c/span\u003e). However, it is important to interpret these exploratory analyses with caution.\u003c/p\u003e\n \u003cp\u003eFurthermore, we conducted an analysis on the relationship between pathological response and survival. Before matching, patients who achieved pCR tended to have better DFS outcomes compared to those without pCR, regardless of whether they received immunologic agents or not. Additionally, among patients without pCR, the nCIT group demonstrated superior DFS compared to the nCT group (Fig. \u003cspan\u003e4\u003c/span\u003eA). Within the nCIT group, patients with mPR had better DFS than those without mPR. Moreover, regardless of whether patients had an mPR or not, the nCIT group exhibited improved DFS compared to the nCT group (Fig. \u003cspan\u003e4\u003c/span\u003eB).\u003c/p\u003e\n \u003cp\u003eIn terms of OS analysis, the nCIT group showed better survival compared to the nCT group among patients without pCR (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eC). Within the nCIT group, patients with mPR had better OS compared to those without mPR. Furthermore, the OS of patients with mPR was better than those without mPR in the nCIT group (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eD).\u003c/p\u003e\n \u003cp\u003eAfter matching, in terms of DFS analysis, we observed that the nCIT group exhibited better survival compared to the nCT group among patients without pCR (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eE). Similarly, the nCIT group also displayed improved survival rates compared to the nCT group among patients without pCR (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eF). Concerning OS analysis, there were no significant differences observed between individuals with or without pCR within both the nCIT and nCT groups. However, the nCIT group still showed better survival rates than the nCT group among patients without pCR (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eG). Additionally, there were no notable differences observed between patients with or without mPR. However, patients who achieved mPR tended to have better outcomes compared to those without mPR, regardless of whether they were in the nCIT or nCT groups (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003eH).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThis study aimed to investigate the efficacy and survival outcomes of nCIT compared to nCT in patients with ESCC. To the best of our knowledge, this is the first study to report the 3-year DFS and OS rates in ESCC patients receiving nCT or nCIT. Additionally, it compares nCIT with nCT using the largest sample size from a single center in the same period, ensuring treatment consistency.\u003c/p\u003e \u003cp\u003eCompared to nCT, the results showed that nCIT followed by esophagectomy led to higher rates of pCR and mPR, significant tumor down-staging, as well as a higher rate of R0 and an increased number of resected lymph nodes during the surgery. Patients who received nCIT also demonstrated better DFS and OS outcomes, which were sustained for at least 3 years of follow-up. At the 3-year follow-up mark, nCIT was associated with a lower incidence of distant and mixed relapses, but not with a reduction in locoregional relapse.\u003c/p\u003e \u003cp\u003eNowadays, there are several clinical single-arm studies of nCIT with abraxane regimen for ESCC, such as the NICE and TD-NICE trials\u003csup\u003e10,11\u003c/sup\u003e. However, the benefit of the abraxane regimen in neoadjuvant treatment for ESCC is still limited. Abraxane is a nanoparticle albumin-bound form of paclitaxel that offers the convenience of not requiring pretreatment with corticosteroids. In our previous reports, we identified patients receiving nCIT with chemotherapy dose intensity\u0026thinsp;\u0026gt;\u0026thinsp;80%, and found that abraxane had higher rates of pCR and MPR compared to paclitaxel\u003csup\u003e13\u003c/sup\u003e. In our study, the rate of pCR in the nCT group (11.47% before matching; 11.45% after matching) were better than previously reported which may be attributed to receiving the abraxane regimen\u003csup\u003e16,17\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the current study, we apply PSM to reduce the impact of potential confounding factors. Finally, we selected 131 pairs of comparable patients with ESCC who received nCT combined with nCIT for the final analysis after PSM. We confirmed that the rates of pCR and mPR in the nCIT group were better than those in the nCT group. Additionally, we found that postoperative anastomotic leakage, hospital stay, in-hospital mortality, and 90-day mortality were comparable between the two groups. Our findings are consistent with a previous report\u003csup\u003e16\u003c/sup\u003e. During our surgery, we observed that lymph node regression was more significant in the nCIT group than in the nCT group, and more lymph nodes were cleared in the nCIT group compared to those who received nCT. This observation aligns with previous reports\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRegarding the failure modes, the CROSS study showed that the effect of nCRT was mainly achieved by decreasing the risk of locoregional relapse rather than distant metastases\u003csup\u003e2\u003c/sup\u003e. In a propensity score-matched study conducted by Shao-Wu Jing et al., they compared the efficacy between nCIT and nCT and found that nCIT could significantly reduce local recurrence, but there was no significant difference in terms of metastasis\u003csup\u003e16\u003c/sup\u003e. However, our results showed a decrease in the risk of distant relapse, especially mixed relapse, rather than locoregional relapse. Additionally, nCIT was found to significantly reduce bone and brain metastasis. The lack of a significant difference in local recurrence may be attributed to our dissection of more lymph nodes compared to other studies\u003csup\u003e16\u003c/sup\u003e. Increased lymph node dissection not only aids in determining the pathological stage but also decreases the likelihood of local recurrence\u003csup\u003e19,20\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSurvival outcomes may vary among different subgroups of esophageal cancer. Interaction analyses showed that the effect of nCIT tends to be more effective for ESCC compared to nCT in most subgroups. However, it is worth noting that statistical tests for interaction have limited power and may not capture all potential differences in relative effects between subgroups. In recent years, studies have demonstrated that the benefits of immune checkpoint inhibitors are influenced by gender\u003csup\u003e21,22\u003c/sup\u003e. In our study, we found that males derived greater clinical benefits from nCIT, while females experienced greater clinical benefits from nCT. This finding is consistent with a study by Conforti et al\u003csup\u003e23\u003c/sup\u003e. The underlying reasons for these gender-specific differences may be that gender can influence the effects of immune checkpoint inhibitors, or it could be due to our study enrolling a higher number of men than women. In future research, it is crucial to ensure greater inclusion of women in trials and focus on improving the effectiveness of immunotherapies in women. This may involve exploring different immunotherapeutic approaches tailored for specific genders to optimize treatment outcomes.\u003c/p\u003e \u003cp\u003ePrevious studies have demonstrated that achieving an mPR or pCR after neoadjuvant therapy is associated with improved long-term outcomes\u003csup\u003e24,25\u003c/sup\u003e.However, our further analysis on the relationship between pathological response and survival revealed that within the nCIT or nCT groups, there were no significant differences in DFS or OS between patients who achieved pCR or mPR compared to those who did not, after matching. While pCR and mPR may increase the rate of achieving R0 resection, the impact on prolonging survival warrants further investigation in a larger and more diverse population.\u003c/p\u003e \u003cp\u003eAdditionally, the use of nivolumab as adjuvant therapy has been suggested for patients with R0 resected esophageal cancer with residual pathological disease\u003csup\u003e26\u003c/sup\u003e. However, for patients who achieved pCR, there are currently no specific recommendations for systemic therapy. It is important to note that in our study, patients who achieved a pCR in both groups did not necessarily experience a cure, as a significant proportion of them still had tumor recurrence or metastasis. Therefore, these findings suggest the need for improved systemic therapy options for patients who achieve a pCR.\u003c/p\u003e \u003cp\u003eAlthough nCRT followed by surgery was found to have advantages in terms of pCR rate and overall survival benefit for ESCC\u003csup\u003e27\u003c/sup\u003e, another study comparing nCRT and nCT found that higher pCR rates in the nCRT group did not translate into longer survival\u003csup\u003e28\u003c/sup\u003e. Therefore, it is important to consider the potential impact of immunotherapy and conduct long-term follow-up studies to assess the efficacy of nCIT. In our own study, we observed that compared to nCT, nCIT provided higher 3-year survival rates, higher rates of R0 resection, and higher rates of pCR or mPR. However, there was no significant difference in survival between patients who achieved pCR or mPR and those who did not in the 3-year survival analysis. Interestingly, even in patients without pCR or mPR, nCIT still demonstrated better survival benefits compared to the nCT group. To further investigate the role of nCIT in the first-line treatment of locally advanced ESCC, a prospective study with a sufficient sample size is needed.\u003c/p\u003e \u003cp\u003eHowever, it is important to note that this study had several limitations. Firstly, its retrospective nature introduces inherent biases that may impact the results. Additionally, the study was conducted in a single institution, which may limit the generalizability of the findings as institutional practices can vary. Moreover, the case number in the study was relatively small, potentially limiting the statistical power and precision of the results. Despite using propensity score matching to address treatment selection bias, it is still possible that some biases remain. The follow-up period in both groups was relatively short, and therefore, longer follow-up is needed to fully evaluate the long-term effects. Furthermore, the use of different immunotherapy drugs in the nCIT patients may introduce variability in the results.\u003c/p\u003e \u003cp\u003eIn conclusion, our study found that compared to nCT alone, nCIT showed better pathological response rates in patients with locally advanced ESCC. Additionally, nCIT was associated with improved DFS and OS in the 3-year survival analysis. However, it is important to note that further validation of long-term survival outcomes is still required.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of interest\u003c/h2\u003e \u003cp\u003eThe authors have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics Statement\u003c/h2\u003e \u003cp\u003e The studies involving human participants were reviewed and approved by The Ethics Committee of Fujian Cancer Hospital (No.K2023-276-01). Informed consent was waived due to the retrospective nature of the study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding Information\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant No. 82002497), the Science and Technology Program of Fujian Province (Nos. 2021J01442, 2023J011270) and Startup Fund for scientific research,Fujian Medical University (No. 2021QH1148).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003e(I) Conception and design: Peiyuan Wang, Yujie Chen, Mengxia Lei; (II) Administrative support: Shuoyan Liu, Feng Wang; (III) Provision of study materials or patients: Hao He, Derong Zhang, Junpeng Lin , Hui Lin, Wenwei Wei, Peng Chen; (IV) Collection and assembly of data: Fengnian Zhuang, Weijie Chen,Hang Zhou, Pengqiang Gao; (V) Data analysis and interpretation: Peiyuan Wang, Yujie Chen, Mengxia Lei; (VI) Manuscript writing: All authors; (VII)Final approval of manuscript: All authors\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL et al (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin May 71(3):209\u0026ndash;249\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEyck BM, van Lanschot JJB, Hulshof M et al (2021) Ten-Year Outcome of Neoadjuvant Chemoradiotherapy Plus Surgery for Esophageal Cancer: The Randomized Controlled CROSS Trial. J Clin Oncol Jun 20(18):1995\u0026ndash;2004\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOppedijk V, van der Gaast A, van Lanschot JJ et al (2014) Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol Feb 10(5):385\u0026ndash;391\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen D, Kong M, Sun J et al (2022) Prognostic value of recurrence pattern in locally advanced esophageal squamous cell carcinoma: Results from the phase III trial NEOCRTEC5010. J Thorac Cardiovasc Surg Aug 20\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Liu H, Chen Y et al (2021) Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg Aug 1(8):721\u0026ndash;729\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKitagawa Y, Uno T, Oyama T et al (2019) Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2. Esophagus Jan 16(1):25\u0026ndash;43\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo H, Lu J, Bai Y et al (2021) Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial. JAMA Sep 14(10):916\u0026ndash;925\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato K, Shah MA, Enzinger P et al (2019) KEYNOTE-590: Phase III study of first-line chemotherapy with or without pembrolizumab for advanced esophageal cancer. Future Oncol Apr 15(10):1057\u0026ndash;1066\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato K, Doki Y, Ogata T et al (2023) First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50). Esophagus Apr 20(2):291\u0026ndash;301\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Yang Y, Liu Z et al (2022) Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer Mar ;10(3)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan X, Duan H, Ni Y et al (2022) Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE). Int J Surg Jul 103:106680\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Xing X, Yeung SJ et al (2022) Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer Jan ;10(1)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang P, Lei M, Weng G et al (2023) High-dose chemotherapy sensitizes locally advanced esophageal squamous cell carcinoma to PD-1 blockade for a higher pathological complete response rate and survival. Transl Oncol Oct 36:101736\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanger R, Becker K (2018) Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy. Virchows Arch Feb 472(2):175\u0026ndash;186\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAustin PC (2011) An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. Multivar Behav Res May 46(3):399\u0026ndash;424\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJing SW, Zhai C, Zhang W et al (2022) Comparison of neoadjuvant immunotherapy plus chemotherapy versus chemotherapy alone for patients with locally advanced esophageal squamous cell carcinoma: A propensity score matching. Front Immunol 13:970534\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang B, Zhao H, Wu X et al (2023) Perioperative outcomes of neoadjuvant chemotherapy plus camrelizumab compared with chemotherapy alone and chemoradiotherapy for locally advanced esophageal squamous cell cancer. Front Immunol 14:1066527\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQiao Y, Zhao C, Li X et al (2022) Efficacy and safety of camrelizumab in combination with neoadjuvant chemotherapy for ESCC and its impact on esophagectomy. Front Immunol 13:953229\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuo X, Wang Z, Yang H et al (2023) Impact of Lymph Node Dissection on Survival After Neoadjuvant Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: From the Results of NEOCRTEC5010, a Randomized Multicenter Study. Ann Surg Feb 1(2):259\u0026ndash;266\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHenckens SPG, Hagens ERC, van Berge Henegouwen MI, Meijer SL, Eshuis WJ, Gisbertz SS (2023) Impact of increasing lymph node yield on staging, morbidity and survival after esophagectomy for esophageal adenocarcinoma. Eur J Surg Oncol Jan 49(1):89\u0026ndash;96\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConforti F, Pala L, Bagnardi V et al (2018) Cancer immunotherapy efficacy and patients' sex: a systematic review and meta-analysis. Lancet Oncol Jun 19(6):737\u0026ndash;746\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIrelli A, Sirufo MM, D'Ugo C, Ginaldi L, De Martinis M (2020) Sex and Gender Influences on Cancer Immunotherapy Response. Biomedicines Jul 21 ;8(7)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eConforti F, Pala L, Bagnardi V et al (2019) Sex-Based Heterogeneity in Response to Lung Cancer Immunotherapy: A Systematic Review and Meta-Analysis. J Natl Cancer Inst Aug 1(8):772\u0026ndash;781\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBerger AC, Farma J, Scott WJ et al (2005) Complete response to neoadjuvant chemoradiotherapy in esophageal carcinoma is associated with significantly improved survival. J Clin Oncol Jul 1(19):4330\u0026ndash;4337\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHellmann MD, Chaft JE, William WN Jr. et al (2014) Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint. Lancet Oncol Jan 15(1):e42\u0026ndash;50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHermann RM, Christiansen H (2021) [A new standard is emerging: PD-1 maintenance therapy after neoadjuvant radiochemotherapy and curative resection of oesophageal and AEG carcinomas (CheckMate 577)]. Strahlenther Onkol Nov 197(11):1040\u0026ndash;1042\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamarajah SK, Markar SR (2021) Author response to: Neoadjuvant chemoradiotherapy or chemotherapy alone for oesophageal cancer: population-based cohort study. Br J Surg Aug 19(8):e279\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang G, Zhang C, Sun N et al (2022) Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for the treatment of esophageal squamous cell carcinoma: a propensity score-matched study from the National Cancer Center in China. J Cancer Res Clin Oncol Apr 148(4):943\u0026ndash;954\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-3 is 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":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"neoadjuvant chemoimmunotherapy, neoadjuvant chemotherapy, esophageal squamous cell cancer, disease-free survival, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-4489788/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4489788/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e Neoadjuvant chemoimmunotherapy (nCIT) for locally advanced esophageal squamous cell cancer (ESCC) has shown short-term benefits, but long-term survival outcomes are unclear. This study compares nCIT and neoadjuvant chemotherapy (nCT) in resectable ESCC.\u003c/p\u003e\u003ch2\u003ePatients and Methods:\u003c/h2\u003e \u003cp\u003eA retrospective analysis was conducted on ESCC patients who underwent nCT or nCIT followed by esophagectomy. Propensity score matching (PSM) with a caliper of 0.02 was employed to minimize bias. The primary endpoints included disease-free survival (DFS) and overall survival (OS).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 131 comparable pairs of ESCC patients receiving nCT and nCIT were selected for the final analysis. The nCIT had higher rates of pathological complete response (pCR) and major pathological response (mPR) compared to nCT. Additionally, nCIT led to significant tumor down-staging, higher rates of R0 resection, and increased lymph node clearance during surgery. Patients who received nCIT exhibited improved disease-free survival (DFS) and overall survival (OS) at the 3-year follow-up. The incidence of distant and mixed relapses was lower in the nCIT group compared to the nCT group. However, the risk of locoregional relapse was comparable between the two groups. Subgroup analyses showed that the benefits of nCIT were generally observed across most patient subgroups. Interestingly, in patients without pCR or mPR, nCIT still demonstrated better survival benefits than nCT.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003enCIT demonstrated superior pathological response rates and improved 3-year DFS and OS compared to nCT alone in locally advanced ESCC, but long-term survival validation is needed.\u003c/p\u003e","manuscriptTitle":"Comparison of Neoadjuvant Chemoimmunotherapy and Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Study with 3-Year Survival Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-13 02:07:07","doi":"10.21203/rs.3.rs-4489788/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-09T11:24:24+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-09T01:30:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198220624504601552349602744039225150385","date":"2024-06-03T21:45:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-29T11:04:37+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-29T07:34:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-29T07:34:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2024-05-28T09:29:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"9dae9056-d178-45fc-9188-5640fb88f798","owner":[],"postedDate":"June 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T15:59:20+00:00","versionOfRecord":{"articleIdentity":"rs-4489788","link":"https://doi.org/10.1007/s00432-024-06004-w","journal":{"identity":"journal-of-cancer-research-and-clinical-oncology","isVorOnly":false,"title":"Journal of Cancer Research and Clinical Oncology"},"publishedOn":"2024-10-25 15:57:04","publishedOnDateReadable":"October 25th, 2024"},"versionCreatedAt":"2024-06-13 02:07:07","video":"","vorDoi":"10.1007/s00432-024-06004-w","vorDoiUrl":"https://doi.org/10.1007/s00432-024-06004-w","workflowStages":[]},"version":"v1","identity":"rs-4489788","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4489788","identity":"rs-4489788","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}