Immunotherapy in advanced esophageal squamous cell cancer: earlier or later?

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Shuang Wei, Zuoji Li, Tingting Liu, Guizhen Sun, Hongfu Sun, Wei Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4571189/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background and objective: Several large-scale phase III clinical trials have confirmed the survival benefit of immunotherapy in patients with locally advanced or metastatic esophageal cancer. The aim of this study is to investigate whether early use of immunotherapy can improve long-term survival. Methods: Patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) diagnosed from January 2018 to December 2021were retrospectively analyzed. According to the time of immunotherapy, patients were divided into early immunotherapy group (EIT group, first-line immunotherapy ) and late immunotherapy group (LIT group, second-line immunotherapy) . A 1:1 propensity score matching (PSM) was applied to balance the observable potential confounding factors between the two groups. The primary outcome was overall survival (OS). Results: A total of 359 patients were enrolled, after propensity score matching, the clinical features were well balanced between two groups included 107 patients each. The median OS was 15.7 months (95%CI: 12.81-18.59) in the EIT group and 17.7 months (95%CI: 14.89-20.57) in the LIT group, respectively. ( P =0.185, HR=1.25). The PFS1 of patients were 8.7 months (95%CI: 7.53-9.87) and 7.6 months (95%CI: 5.90-9.30),respectively, and the difference was statistically significant ( P =0.032, HR=0.72). The PFS2 of patients were 12.97months (95%CI: 11.37-14.58) and 12.93 months (95%CI: 11.65-14.21), respectively, and the difference was statistically significant( P =0.045,HR=0.73). Subgroup analysis showed that male patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy may have greater benefits. COX multivariate analysis showed that the EIT group and the differentiation degree of tumor had an impact on overall survival ( P： 0.03、0.04, HR: 0.73、0.70). Conclusions: For patients with locally advanced or metastatic advanced ESCC, earlyimmunotherapy can improve PFS without improving OS. immunotherapy esophageal squamous cell cancer overall survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Esophageal cancer (EC) is one of the most common malignant tumor in the world, and China is a high incidence area of EC. The morbidity and mortality ranked the sixth and fourth among all malignant tumors, respectively. Multiple phase III clinical studies,eg: Keynote-181 (1) , Attraction-3 (2) , Escort (3) , Rationale302 (4) , have suggested that,compared with chemotherapy alone, immunotherapy improved OS (from 6.2 months to 10.9 months) and progression-free survival (PFS) (from 1.6 months to 3.4 months) in the second-line treatment of EC. Following, multiple phase III clinical studies,eg: Keynote-590 (5) , Checkmate-648 (6) , Escort-1 (7) , Orient-15 (8) and Jupoiter-06 (9) have suggested that, compared with chemotherapy alone, chemotherapy combined with immunotherapy improved OS (from 9.8 months to 17.2 months) and PFS (from 5.3 months to 7.3 months) in the first-line treatment of EC. Previous studies have shown that efficacy of immune checkpoint inhibitors is increased in earlier lines of therapy across multiple tumour types compared with in later lines of therapy (10–14) . In the real world, however, it is rarely reported whether the first-line application of immunotherapy in locally advanced or metastatic EC can bring longer survival benefits. In this study, we retrospectively analyzed the survival of patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) treated with immunotherapy as the first- or second-line treatment, and explored the value of early application of immunotherapy. Materials and Methods 2.1. Data collection We retrospectively analyzed patients with locally advanced or metastatic ESCC in Shandong Cancer Hospital from January 2018 to December 2021. The inclusion criteria were as follows: ( 1 ).patients with pathologically confirmed ESCC; ( 2 ). patients initially with unresectable locally advanced or metastatic disease; ( 3 ). patients receiving immunotherapy as first-line or second-line treatment with more than 2 cycles; ( 4 ). complete imaging data were available for evaluation during treatment or follow-up; ( 5 ). Eastern Cooperative Oncology Group (ECOG) score 0–1. Exclusion criteria: ( 1 ). other pathological types of esophagus, such as adenocarcinoma, small cell carcinoma, etc. ( 2 ). combined with other tumors; ( 3 ). central nervous system metastasis According to the time of immunotherapy, patients were divided into early immunotherapy group (EIT group, first-line immunotherapy ) and late immunotherapy group (LIT group, second-line immunotherapy). The EIT group was defined as patients who initially received first-line immunotherapy or progressed to first-line immunotherapy after previous radical treatment. The LIT group was defined as patients who received second-line immunotherapy initially or locally advanced or progressed to second-line immunotherapy after previous treatment.The chemotherapy regime are paclitaxel or fluorouracil + platinum. The PD-1 inhibitors used among patients included pembrolizumab, toripalimab, sintilimab, envafolimab and camrelizumab. 2.2. Evaluation and Follow-up The primary end point was OS, defined as the time from diagnosis to death from any cause. The secondary endpoint were PFS1, PFS2, disease control rate, and treatment-related adverse events (TRAEs). PFS1 was defined as the time from diagnosis to disease progression or death from any cause. PFS2 was defined as the time from diagnosis to second disease progression or death from any cause. Disease control rate included complete response, partial response and stable disease. TRAEs were assessed within 90 days after the last dose of medication, and were assessed with the use of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The efficacy was evaluated every two courses during the treatment according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. After the end of treatment, the patients were followed up every three months for 2 years, and once every six months for 3–5 years. Disease progression was assessed by CT scan according to Recist1.1 criteria. 2.3. Statistical analysis Spss26.0 was used for statistical analysis. Clinical characteristics were compared by the Kruskal-Wallis test for continuous data and the chi-square test or Fisher's exact test for categorical data. OS and PFS were estimated by the Kaplan-Meier method and compared by the log-rank test. The propensity score-matched analysis (including variables: age, sex, ECOG score, tumor location, differentiation, metastatic sites, number of organs with metastases, chemotherapy regimens, immunedrugs) was performed using the one-to-one nearest neighbour method (ps 0.1). COX proportional hazards model was used for multivariate analysis to evaluate the possible factors affecting the OS of patients. Statistical results of P < 0.05 were considered statistically significant. Results 3.1. Patients and treatment A total of 359 patients with ESCC who met the inclusion criteria from January 2018 to December 2021 were included in the analysis. Among them, 122 patients were initial stage IV; Twenty-three patients with initially inoperable locally advanced disease were enrolled in the clinical trial and received first-line immunotherapy and chemotherapy. 119 patients were in the early stage (stage I+II) and received radical surgery + adjuvant/neoadjuvant therapy. Ninety-five patients with locally advanced disease who were initially inoperable were treated with radical chemoradiotherapy. According to the number of immunotherapy lines, the patients were divided into two groups: EIT group (252 cases) and LIT group (107 cases). The initial stage and treatment of the patients are shown in Table 1, the basic characteristics of the patients are shown in Table 2, and disease control rate is shown in Table 3. Table 1 The initial stage and treatment of the patients Table 2 Basic characteristics of the patients EIT group (n=252) (n,%) LIT group (n=107) (n,%) EIT group matched (n=107)(n,%) P value（psm） Age, years Median, range 62（41-82） 61（42-84） 62（42-84） 0.35 Sex 0.24 Male 222（88.1） 94（87.9） 88（82.2） Female 30（11.9） 13（12.1） 19（17.8） ECOG performance status 0.95 0 124（49.2） 53（49.5） 53（49.5） 1 128（50.8） 54（50.5） 54（50.5） Tumor location 0.17 Cervical segment 10（4.0） 2（1.9) 1（0.9） Upper thoracic segment 34（13.5） 13(12.1) 11（10.3） Middle thoracic segment 132（52.4） 48(44.9) 64（59.8） Lower thoracic segment 76（30.2） 44(41.1) 31（29） Differentiated degree 0.96 high differentiation 14（5.6） 8（7.5） 10（9.3） middle differentiation 73（29） 30（28） 29（27.1） low differentiation 65（25.8） 27（25） 28（26.2） uncertain 100（39.7） 42（39.3） 40（37.4） Site of metastasis 0.54 Liver 39（15.5） 10（9.3） 13（12.1） Lung 44（17.5） 16（15） 21（19.6） Bone 16（6.3） 4（3.7） 6（5.6） Lymph node 153（60.7） 77（72） 67（62.6） Number of organs with metastases 0.26 1 150（59.5） 71（66.4） 63（58.9） ≥2 102（40.5） 36（33.6） 44（41.1） Chemotherapy 0.66 PF 76（30.2） 35（32.7） 33（30.8） TP 151（59.9） 60（56.1） 63（58.9） Uncertain 25（9.9） 12（11.2） 11（10.3） Immunotherapy 0.16 Camrelizumab 121（48） 71（66.4） 65（60.7） Pembrolizumab 29（11.5） 2（1.9） 5（4.7） Sintilimab 63（25） 24（22.4） 23（21.5） envafolimab 7（2.8） 1（0.9） 3（2.8） Toripalimab 13（5.2） 3（2.8） 5（4.7） Comparison between LIT group and EIT group matched for P value The baseline clinical characteristics of all patients were comparable after propensity-score matching. The patient's gender, age, ECOG score, tumor location, degree of differentiation, metastatic site after progression, number of metastatic organs, chemotherapy regimens, different immune drugs used, and whether immunization combined with radiotherapy were analyzed (Table 4). COX proportional hazard model was used for multivariate analysis to explore the possible influencing factors on OS. Table 3 short-term efficacy evaluation First-line EIT group（n=252） （immune+chemotherapy） LIT group（n=107） （chemotherapy） Complete response 1（0.4%） 0 Partial response 80（31.7%） 24（22.5%） Stable disease 108（42.9%） 53（50.1%） Progressive disease 63（25%） 30（28%） Objective response 81（32.1%） 24（22.5%） Disease control 189（75%） 77（72.6%） Second-line EIT group (n=146) (chemotherapy） LIT group (n=107) (immunetherapy） Complete response 0 0 Partial response 23（15.7%） 21（19.5%） Stable disease 65（45%） 39（36.5%） Progressive disease 57（39.3%） 47 (44%) Objective response rate 23（15.7%） 21（19.5%） Disease control rate 88 (60.7%) 60 (56%) 3.2 Survival All patients were followed regularly until November 30, 2022 or death from any cause. The median duration of follow-up was 26.8 months in EIT group and 29.9 months in LIT group. In EIT group, 90 (35.7%) patients did not progress after first-line immunotherapy plus chemotherapy; Seven patients (4.8%) did not progress after second-line chemotherapy. After the progression of first-line immunotherapy plus chemotherapy, 16 patients (6.3%) did not receive second-line chemotherapy. Among them, 5 patients (2.0%) did not receive second-line treatment due to death, and 11 patients (4.4%) were unable to accept or refused second-line treatment due to poor health. In LIT group, all patients received second-line immunotherapy after progression on first-line therapy, and 16 patients (15%) were still receiving second-line immunotherapy without tumor progression as of the follow-up date. Of the patients who subsequently entered third-line therapy, 15.5% were in the EIT group and 30% were in the LIT group. After propensity score matching, 107 patients in EIT group were matched to those LIT group, and the median OS was 15.7 months (95%CI: 12.81-18.59) in EIT group and 17.7 months (95%CI: 14.89-20.57) in EIT group respectively, no statistically significant difference ( P =0.185, HR=1.25).(Figure 1). The median PFS1 of the two groups was 8.7 months (95%CI: 7.53-9.87) in the EIT group and 7.6 months (95%CI: 5.90-9.30) in the LIT group, with statistically significant difference ( P =0.032,HR=0.72).(Figure 2). The median PFS2 of the two groups was 12.97 months (95%CI: 11.37-14.58) in the EIT group and 12.93 months (95%CI: 11.65-14.21) in the LIT group, with statistically significant difference ( P =0.045,HR=0.73).(Figure 3) Subgroup analysis using PFS2 as the end point (Figure 4) showed that in male patients, younger than 65 years of age, esophageal tumor located in the middle thoracic segment, lymph node metastasis after progression, one organ metastasis, frist-line treatment without combination radiotherapy, and TP regimen (paclitaxel and platinum) combined chemotherapy, the combination of immunotherapy in the first-line treatment may have greater benefits than the second-line combination of immunotherapy. This also provides a reference for our clinical treatment options. COX proportional hazard model was established, and multivariate analysis showed (Table 4) that the EIT group ( P =0.03, HR=0.73) and differentiation degree of the tumor had an effect on overall survival ( P =0.04, HR=0.70). However, gender, age, ECOG score, tumor location, metastatic site, number of metastatic organs, chemotherapy regimen, immune drugs and whether immunotherapy combined with radiotherapy had no significant effect on OS. Treatment-related adverse effects are shown in Table 5. A total of 122 patients with stage IV in this retrospective data were selected and divided into two groups according to the addition of radiotherapy to the initial treatment: 67 patients with radiotherapy and 55 patients without radiotherapy. The median OS was 17.8 months and 15.8 months respectively ( P = 0.179). Table 4 Multivariate analysis Variables P value HR(95%CI） Sex 0.69 0.91（0.56-1.46） Age 0.11 0.78（0.58-1.05） ECOG 0.72 0.95（0.73-1.24） Location 0.87 0.98（0.81-1.19） Differentiation 0.04 0.70（0.50-0.99） Site of metastases 0.82 1.01（0.92-1.11） Number of organs with metastases 0.07 1.25 (0.98-1.60) Chemotherapy regimens 0.22 1.11（0.94-1.31） Immunetherapy regimens 0.44 1.04（0.94-1.15） Immune with or without radiotherapy 0.19 1.20（0.91-1.58） EIT group or LIT group 0.03 0.73 (0.55-0.98) Table 5 Adverse events related to treatment No. (%) of patients EIT group (n = 252) LIT group (n = 107) Any grade ≥Grade 3 Any grade ≥Grade 3 Treatment-related adverse events 249(98.9) 152 (60.4) 104 (97.0) 67 (62.5) Anemia 193 (75) 42 (16.5) 79 (74.2) 13 (12.5) White blood cell count decreased 157 (77.8) 63(25) 75 (70.3) 27 (25.6) Neutrophil count decreased 167 (66.5) 79 (31.2) 80 (63.5) 48 (45.4) Nausea 132 (52.4) 4 (1.5) 55 (51.3) 2 (1.7) Asthenia 122 (48.5) 6 (2.2) 46 (43.4) 3 (2.5) Decreased appetite 107 (42.5) 1 (0.5) 47 (44.1) 2 (1.5) Vomiting 89 (35.5) 6(2.4) 34 (31.7) 2 (2.0) Platelet count decreased 64 (25.5) 5(2.0) 25 (23.6) 2 (2.0) Weight decreased 60 (23.8) 2 (0.7) 23 (21.6) 2 (2.0) Aspartate aminotransferase increased 30 (12.1) 3 (1.0) 11 (10) 1 (1.0) Immune-related adverse events 252 (84.6) 98 (33.0) Reactive capillary endothelial proliferation 121 (48) 71 (66.4) Hypothyroidism 31 (12.3) 7 (6.5) Hyperthyroidism 6 (2.4) 1 (1.0) Rash 16 (6.4) 2 (2.0) Pneumonitis 16 (6.5) 2 (2.0) Discussion Treatment outcomes are poor for patients with advanced disease. The median OS rates are ~ 10 months and ~ 6 months for first-line and second-line chemotherapy, respectively, with objective response rates of ~ 30% and ~ 10% respectively (15) .With the advent of the immune era, immunotherapy has gradually become the standard treatment for advanced EC. Keynote-181 (1) confirmed the efficacy of pembrolizumab in PD-L1 cps ≥ 10 in patients with locally advanced esophageal cancer, there was a two-fold improvement in survival at 12 months (43% v 20%) compared with chemotherapy alone (fluorouracil combined with platinum). Therefore, in 2019, it became the first immune drug approved for second-line treatment of advanced esophageal cancer in the United States. Attraction-3 (2) confirmed that at a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17.6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (10.9 months vs 8.4 months, HR0.77, p = 0.019). With the overall success of immune drugs in second-line therapy, it is gradually advancing to first-line therapy. Keynote590 (5) reported that first-line Palizumab + chemotherapy (fluorouracil + platinum-based) versus first-line chemotherapy in locally advanced or metastatic esophageal cancer, regardless of the expression status of PD-L1 CPS, the first-line immunized group improved overall survival (12.4 months vs. 9.8 months; 0.73 [0.62–0.86]; p < 0.0001) and progression-free survival (6.3 months vs. 5.8 months; 0.65 [0.55–0.76]; p < 0.0001) have obvious benefit. The escort-1 (7) trial confirmed that first-line immunization + chemotherapy (paclitaxel + cisplatin) was better than chemotherapy alone (paclitaxel + cisplatin), overall survival and progression-free survival in Chinese population, which were 15.3 vs 12.0 months, respectively(HR 0.7) and 6.9 vs 5.6 months(HR 0.56). The Orient-15 (8) trial also demonstrated a survival benefit for Sintilimab in first-line chemotherapy (paclitaxel + cisplatin/fluorouracil + cisplatin). Overall survival (median 16.7 vs 12.5 months, HR0.63, 95%CI 0.51 to 0.78, P < 0.001) and progression-free survival (7.2 vs 5.7 months, HR 0.56, 95%CI 0.46 to 0.68, P < 0.001). Our retrospective data show that after PSM, the OS of 15.7 months with first-line immunotherapy plus chemotherapy in locally advanced or metastatic ESCC is consistent with the OS reported with camrelizumab (15.3 months) and sintilizumab (16.7 months), which is higher than the OS reported with pembrolizumab. One possible explanation for this discrepancy may be that a smaller proportion of patients in the control arm of the Keynote-590 study had been exposed to second-line immunotherapy. In terms of PFS, our data showed that the median PFS1 of the two groups was 8.7 months and 7.6 months, respectively( P = 0.032, HR = 0.72), which was similar to the HR values of the above three reports (0.65, 0.56, 0.56). The median PFS2 of the two groups was 12.97 months in the EIT group and 12.93 months in the LIT group, with statistically significant difference ( P = 0.045,HR = 0.73). Previous reports showed in non-small cell lung cancer, patients who have been previously treated with fewer lines of therapy (ie, in the first-line setting) might have less refractory and immunosuppressive tumour microenvironments than patients who have progressed on therapy. (19) Pembrolizumab plus chemotherapy in the Keynote-189 study reduced the risk of death by 44% in metastatic nonsquamous NSCLC. (20) Nivolumab as a second-line treatment reduced the risk of death by 27% in metastatic nonsquamous NSCLC. (21) The keynote-059 (14) trial showed that pembrolizumab monotherapy was effective, safe and well tolerated in locally advanced gastric or gastroesophageal junction cancer with at least two previous lines of therapy, regardless of PD-L1 expression. So, whether early application of immunotherapy is more effective is still controversial. It is also rarely reported whether first-line immunotherapy has a greater survival benefit than second-line immunotherapy in the treatment of locally advanced or metastastic esophageal cancer. Our retrospective real-world study showed no significant difference in overall survival between the use of first-line immunotherapy plus chemotherapy and chemotherapy alone in patients with locally advanced or metastatic esophageal cancer, but a benefit in progression-free survival was observed with the addition of immunotherapy to the first-line regimen. Our study showed there was no significant difference in overall survival between the two groups, which I believe is mainly due to the fact that twice as many patients in the LIT group as in the EIT group received third-line therapy by the date of follow-up (15.5%VS30%), which resulted in significantly longer overall survival in the LIT group. However, there was statistically significant differences in PFS1 and PFS2 between the two groups, further indicating the benefit of immune drugs in treatment, and the benefit was more significant in the early application. In EIT groups, our subgroup analysis showed that male patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy had better progression-free survival. In clinical practice, for young patients with lymph node metastasis or single organ metastasis, or when local radiotherapy cannot be added in time, immunotherapy should be given to patients timely. Fluorouracil combined with cisplatin is commonly used in combination chemotherapy in Western countries, while paclitaxel combined with platinum is preferred in China (16–17) . Our retrospective data also showed that more patients chose the paclitaxel plus platinum regimen. Previous retrospective reports (18) showed that there was no significant difference in the efficacy of the two regimens in esophageal cancer. However, our subgroup analysis suggests that when combined with immunotherapy, TP (paclitaxel plus platinum) regimen is preferred in the choice of chemotherapy regimen. Li (22) et al reported for the first time the difference in survival between first-line immunotherapy plus chemotherapy and chemotherapy alone in locally recurrent or advanced metastatic esophageal squamous cell carcinoma. In their retrospective study, there was no significant difference in overall survival (13.5 VS 13.1 months, p = 0.7) between immunotherapy plus chemotherapy and chemotherapy alone, while PFS1 was significantly different (7.1 VS 4.1 months, p = 0.001, HR0.53). Our retrospective data showed that the overall survival of first-line immunotherapy combined with chemotherapy and chemotherapy alone was 15.7 months and 17.7 months, respectively ( P = 0.185, HR1.25). PFS1 was 8.7 months and 7.6 months, respectively ( P = 0.032, HR0.72), which was consistent with the conclusions reported above. However, compared with this retrospective study, the number of patients in our article is larger, the follow-up time is longer, and the previous treatment history of the enrolled patients is more detailed, complex, and closer to the actual clinical treatment. Furthermore, we conducted subgroup analyses to inform our practice of which patients would be more inclined to be treated with immunotherapy in the first-line treatment. Advantages and defects Advantages: In this retrospective study, we compared whether the combination of immune and chemotherapy is beneficial over chemotherapy alone in the first-line treatment of patients with locally advanced or metastatic esophageal cancer. In addition, our real-world study included a larger number of cases and was closer to the actual clinical treatment situation than the study by li (22) et al. The results of subgroup analysis also have certain guiding value for our clinical practice. Defects: This article is a retrospective study, and the data may have a certain loss bias. The short follow-up time and some patients are still in treatment may have a certain impact on the calculation of survival time. In this retrospective study, PD-L1 expression status was unknown in most patients, and the effect of PD-L1 expression level on survival could not be assessed. Conclusion: For patients with locally advanced and metastatic esophageal cancer, early application of immunotherapy has a progression-free survival benefit. In clinical practice, patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy are inclined to be treated with immunotherapy in the first-line treatment. Declarations Acknowledgements Not applicable Funding Not applicable Ethics declarations This study was approved by the ethics committee of the Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences and Gaomi People’s Hospital.The study is retrospective amd only clinical information of patients will be collected without containning personal identifiers,interfering with patients’treatment plans,or posing physiological risks to patients.Informed consent was obtained from all patients before being included. Consent for publication Not applicable Competing interests The authors declare no competing interests. Additional information Publisher’s Note Springer Nature remains neutral wiht regard to jurisdictional calims in published maps and institutional affiliations. References Kojima T, Shah MA, Muro K, et al. KEYNOTE-181 Investigators. 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Jiang C, Liao FX, Rong YM, et al. Efficacy of taxane-based regimens in a first-line setting for recurrent and/or metastatic Chinese patients with esophageal cancer. Asian Pac J Cancer Prev. 2014;15(13):5493–8. Pacheco JM, Camidge DR, Doebele RC, Schenk E. A changing of the guard: immune checkpoint inhibitors with and without chemotherapy as first line treatment for metastatic non-small cell lung cancer. Front Oncol. 2019;9:195. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505–17. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627–39. Xu-Yuan Li. MD1 | Li-Sheng Huang MD2 | Hao-Quan Cai MD3 | First-line or second-line PD-1 inhibition in advanced oesophageal squamous cell carcinoma: A prospective, multicentre, registry study。J. Clin Pharm Ther. 2021;00:1–6. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4571189","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":315297804,"identity":"63dd0d8e-df6a-4da3-8097-71f2f6b091f9","order_by":0,"name":"Shuang Wei","email":"","orcid":"","institution":"Gaomi People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuang","middleName":"","lastName":"Wei","suffix":""},{"id":315297805,"identity":"48d8ceea-c7dc-4ec8-99e5-63a32fe6e44e","order_by":1,"name":"Zuoji Li","email":"","orcid":"","institution":"Gaomi People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zuoji","middleName":"","lastName":"Li","suffix":""},{"id":315297806,"identity":"eadd4aa9-2764-4b01-a505-fed94d55b4e1","order_by":2,"name":"Tingting Liu","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Tingting","middleName":"","lastName":"Liu","suffix":""},{"id":315297807,"identity":"3e9f033a-d287-4074-a81c-462103b88959","order_by":3,"name":"Guizhen Sun","email":"","orcid":"","institution":"Gaomi People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guizhen","middleName":"","lastName":"Sun","suffix":""},{"id":315297808,"identity":"51e937e6-bf49-44fd-8f59-9dcb0bd7cde5","order_by":4,"name":"Hongfu Sun","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Hongfu","middleName":"","lastName":"Sun","suffix":""},{"id":315297809,"identity":"0f1126d0-53ac-4b71-83aa-602608bfc160","order_by":5,"name":"Wei Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYDACdgaGA4wNEgwMxxsbH34gSgszTMuZw83GEsRqYWBsABI30tsEeIjRwd/MY3i4cIdFPt/Nh20MEgx2croNBLRIHOYxODzzjITlzNuJbQ8KGJKNzQ4QsuYwW8Jh3jYJA4Pbie0GEgwHErcR0iIP13LzYJsEDzFaDA4zH4BoucFIpBZDsJYzEgaSZxKBgWxAhF/kjjc2f+bdUWfAd/z4w4cfKuzkCHsfzZ2kKR8Fo2AUjIJRgAMAAOAoQ9t6jIz2AAAAAElFTkSuQmCC","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2024-06-12 15:06:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4571189/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4571189/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60199212,"identity":"37c5d0a0-7066-4106-95e3-3680e651fd81","added_by":"auto","created_at":"2024-07-13 02:23:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":30988,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival（months）\u003c/p\u003e","description":"","filename":"F1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4571189/v1/2a4c68000aca043d906e51dc.jpg"},{"id":60198861,"identity":"11ae73ff-c307-491c-a331-3e57b36dffde","added_by":"auto","created_at":"2024-07-13 02:15:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30278,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival 1（months）\u003c/p\u003e","description":"","filename":"F2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4571189/v1/bdfd198f5b4c0ca384cc642e.jpg"},{"id":60198863,"identity":"67b91370-60ad-46e4-b997-b3fbef1a146a","added_by":"auto","created_at":"2024-07-13 02:15:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":30089,"visible":true,"origin":"","legend":"\u003cp\u003eProgression-free survival 2（months）\u003c/p\u003e","description":"","filename":"F3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4571189/v1/34afed48be4ed2ba4ac737a3.jpg"},{"id":60198862,"identity":"8c6581be-7e2b-404f-9855-eddacf0bb4d7","added_by":"auto","created_at":"2024-07-13 02:15:01","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":134515,"visible":true,"origin":"","legend":"\u003cp\u003esubgroup analysis\u003c/p\u003e","description":"","filename":"F4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4571189/v1/e31bd0dfd49f062afd0f670c.jpg"},{"id":64075912,"identity":"0c51768b-a023-4ed6-9f7f-a3b1d59d5c75","added_by":"auto","created_at":"2024-09-06 08:48:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":715142,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4571189/v1/4c0f67ce-7e4a-40a1-ac43-430cf4180499.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Immunotherapy in advanced esophageal squamous cell cancer: earlier or later?","fulltext":[{"header":"Background","content":"\u003cp\u003eEsophageal cancer (EC) is one of the most common malignant tumor in the world, and China is a high incidence area of EC. The morbidity and mortality ranked the sixth and fourth among all malignant tumors, respectively. Multiple phase III clinical studies,eg: Keynote-181 \u003csup\u003e(1)\u003c/sup\u003e, Attraction-3 \u003csup\u003e(2)\u003c/sup\u003e, Escort\u003csup\u003e(3)\u003c/sup\u003e, Rationale302\u003csup\u003e(4)\u003c/sup\u003e, have suggested that,compared with chemotherapy alone, immunotherapy improved OS (from 6.2 months to 10.9 months) and progression-free survival (PFS) (from 1.6 months to 3.4 months) in the second-line treatment of EC. Following, multiple phase III clinical studies,eg: Keynote-590 \u003csup\u003e(5)\u003c/sup\u003e, Checkmate-648\u003csup\u003e(6)\u003c/sup\u003e, Escort-1 \u003csup\u003e(7)\u003c/sup\u003e, Orient-15 \u003csup\u003e(8)\u003c/sup\u003eand Jupoiter-06\u003csup\u003e(9)\u003c/sup\u003e have suggested that, compared with chemotherapy alone, chemotherapy combined with immunotherapy improved OS (from 9.8 months to 17.2 months) and PFS (from 5.3 months to 7.3 months) in the first-line treatment of EC. Previous studies have shown that efficacy of immune checkpoint inhibitors is increased in earlier lines of therapy across multiple tumour types compared with in later lines of therapy\u003csup\u003e(10\u0026ndash;14)\u003c/sup\u003e. In the real world, however, it is rarely reported whether the first-line application of immunotherapy in locally advanced or metastatic EC can bring longer survival benefits. In this study, we retrospectively analyzed the survival of patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) treated with immunotherapy as the first- or second-line treatment, and explored the value of early application of immunotherapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003cp\u003e2.1. Data collection\u003c/p\u003e\n \u003cp\u003eWe retrospectively analyzed patients with locally advanced or metastatic ESCC in Shandong Cancer Hospital from January 2018 to December 2021. The inclusion criteria were as follows: (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e).patients with pathologically confirmed ESCC; (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e). patients initially with unresectable locally advanced or metastatic disease; (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). patients receiving immunotherapy as first-line or second-line treatment with more than 2 cycles; (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). complete imaging data were available for evaluation during treatment or follow-up; (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). Eastern Cooperative Oncology Group (ECOG) score 0\u0026ndash;1.\u003c/p\u003e\n \u003cp\u003eExclusion criteria: (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e). other pathological types of esophagus, such as adenocarcinoma, small cell carcinoma, etc. (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e). combined with other tumors; (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). central nervous system metastasis\u003c/p\u003e\n \u003cp\u003eAccording to the time of immunotherapy, patients were divided into early immunotherapy group (EIT group, first-line immunotherapy ) and late immunotherapy group (LIT group, second-line immunotherapy). The EIT group was defined as patients who initially received first-line immunotherapy or progressed to first-line immunotherapy after previous radical treatment. The LIT group was defined as patients who received second-line immunotherapy initially or locally advanced or progressed to second-line immunotherapy after previous treatment.The chemotherapy regime are paclitaxel or fluorouracil\u0026thinsp;+\u0026thinsp;platinum. The PD-1 inhibitors used among patients included pembrolizumab, toripalimab, sintilimab, envafolimab and camrelizumab.\u003c/p\u003e\n \u003cp\u003e2.2. Evaluation and Follow-up\u003c/p\u003e\n \u003cp\u003eThe primary end point was OS, defined as the time from diagnosis to death from any cause. The secondary endpoint were PFS1, PFS2, disease control rate, and treatment-related adverse events (TRAEs). PFS1 was defined as the time from diagnosis to disease progression or death from any cause. PFS2 was defined as the time from diagnosis to second disease progression or death from any cause. Disease control rate included complete response, partial response and stable disease. TRAEs were assessed within 90 days after the last dose of medication, and were assessed with the use of the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The efficacy was evaluated every two courses during the treatment according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. After the end of treatment, the patients were followed up every three months for 2 years, and once every six months for 3\u0026ndash;5 years. Disease progression was assessed by CT scan according to Recist1.1 criteria.\u003c/p\u003e\n \u003cp\u003e2.3. Statistical analysis\u003c/p\u003e\n \u003cp\u003eSpss26.0 was used for statistical analysis. Clinical characteristics were compared by the Kruskal-Wallis test for continuous data and the chi-square test or Fisher\u0026apos;s exact test for categorical data. OS and PFS were estimated by the Kaplan-Meier method and compared by the log-rank test. The propensity score-matched analysis (including variables: age, sex, ECOG score, tumor location, differentiation, metastatic sites, number of organs with metastases, chemotherapy regimens, immunedrugs) was performed using the one-to-one nearest neighbour method (ps 0.1). COX proportional hazards model was used for multivariate analysis to evaluate the possible factors affecting the OS of patients. Statistical results of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e3.1.\u0026nbsp;Patients and treatment\u003c/p\u003e\n\u003cp\u003eA total of 359 patients with ESCC who met the inclusion criteria from January 2018 to December 2021 were included in the analysis. Among them, 122 patients were initial stage IV; Twenty-three patients with initially inoperable locally advanced disease were enrolled in the clinical trial and received first-line immunotherapy and chemotherapy. 119 patients were in the early stage (stage I+II) and received radical surgery + adjuvant/neoadjuvant therapy. Ninety-five patients with locally advanced disease who were initially inoperable were treated with radical chemoradiotherapy. According to the number of immunotherapy lines, the patients were divided into two groups: EIT group (252 cases) and LIT group (107 cases). The initial stage and treatment of the patients are shown in Table 1, the basic characteristics of the patients are shown in Table 2, and disease control rate is shown in Table 3.\u003c/p\u003e\n\u003cp\u003eTable 1 \u0026nbsp;The initial stage and treatment of the patients\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 Basic characteristics of the patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eEIT group\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n=252) (n,%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eLIT group\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(n=107) (n,%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eEIT group matched\u003c/p\u003e\n \u003cp\u003e(n=107)(n,%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eP value（psm）\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eAge, years\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMedian, range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e62（41-82）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e61（42-84）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e62（42-84）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e222（88.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e94（87.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e88（82.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e30（11.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e13（12.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e19（17.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eECOG\u0026nbsp;performance status\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.95\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e124（49.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e53（49.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e53（49.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e128（50.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e54（50.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e54（50.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eTumor location \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eCervical segment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e10（4.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e2（1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e1（0.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; Upper thoracic segment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e34（13.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e13(12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e11（10.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Middle thoracic segment \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e132（52.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e48(44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e64（59.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Lower thoracic segment \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e76（30.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e44(41.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e31（29）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eDifferentiated degree\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; high differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e14（5.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e8（7.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e10（9.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; middle differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e73（29）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e30（28）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e29（27.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; low differentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e65（25.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e27（25）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e28（26.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; uncertain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e100（39.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e42（39.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e40（37.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eSite of metastasis \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e39（15.5）\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e10（9.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e13（12.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Lung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e44（17.5） \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e16（15）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e21（19.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Bone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e16（6.3） \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e4（3.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e6（5.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e153（60.7） \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e77（72）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e67（62.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eNumber of organs with metastases\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 0.26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e150（59.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e71（66.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e63（58.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026ge;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e102（40.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e36（33.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e44（41.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003ePF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e76（30.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e35（32.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e33（30.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eTP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e151（59.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e60（56.1）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e63（58.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eUncertain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e25（9.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e12（11.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e11（10.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"5\" valign=\"top\"\u003e\n \u003cp\u003eImmunotherapy\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eCamrelizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e121（48）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e71（66.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e65（60.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003ePembrolizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e29（11.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e2（1.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e5（4.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eSintilimab \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e63（25）\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e24（22.4）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e23（21.5）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eenvafolimab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e7（2.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e1（0.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e3（2.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003eToripalimab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e13（5.2）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e3（2.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e5（4.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eComparison between LIT group and EIT group matched for P value\u003c/p\u003e\n\u003cp\u003eThe baseline clinical characteristics of all patients were comparable after propensity-score matching. The patient\u0026apos;s gender, age, ECOG score, tumor location, degree of differentiation, metastatic site after progression, number of metastatic organs, chemotherapy regimens, different immune drugs used, and whether immunization combined with radiotherapy were analyzed (Table 4). COX proportional hazard model was used for multivariate analysis to explore the possible influencing factors on OS.\u003c/p\u003e\n\u003cp\u003eTable 3 short-term efficacy evaluation\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eFirst-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eEIT group（n=252）\u003c/p\u003e\n \u003cp\u003e（immune+chemotherapy）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eLIT group（n=107）\u003c/p\u003e\n \u003cp\u003e（chemotherapy）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e1（0.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e80（31.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e24（22.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e108（42.9%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e53（50.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e63（25%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e30（28%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eObjective response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e81（32.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e24（22.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eDisease control\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e189（75%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e77（72.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eSecond-line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eEIT group (n=146)\u003c/p\u003e\n \u003cp\u003e(chemotherapy）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eLIT group (n=107)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(immunetherapy）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eComplete response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ePartial response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e23（15.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e21（19.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eStable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e65（45%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e39（36.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eProgressive disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e57（39.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e47 \u0026nbsp;(44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eObjective response\u0026nbsp;rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e23（15.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e21（19.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eDisease control\u0026nbsp;rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e88 \u0026nbsp;(60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e60 \u0026nbsp;(56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e3.2 \u0026nbsp;Survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients were followed regularly until November 30, 2022 or death from any cause. The median duration of follow-up was 26.8 months in EIT group and 29.9 months in LIT group. In EIT group, 90 (35.7%) patients did not progress after first-line immunotherapy plus chemotherapy; Seven patients (4.8%) did not progress after second-line chemotherapy. After the progression of first-line immunotherapy plus chemotherapy, 16 patients (6.3%) did not receive second-line chemotherapy. Among them, 5 patients (2.0%) did not receive second-line treatment due to death, and 11 patients (4.4%) were unable to accept or refused second-line treatment due to poor health. In LIT group, all patients received second-line immunotherapy after progression on first-line therapy, and 16 patients (15%) were still receiving second-line immunotherapy without tumor progression as of the follow-up date. Of the patients who subsequently entered third-line therapy, 15.5% were in the EIT group and 30% were in the LIT group.\u003c/p\u003e\n\u003cp\u003eAfter propensity score matching, 107 patients in EIT group were matched to those LIT group, and the median OS was 15.7 months (95%CI: 12.81-18.59) in EIT group and 17.7 months (95%CI: 14.89-20.57) in EIT group respectively, no statistically significant difference (\u003cem\u003eP\u003c/em\u003e=0.185, HR=1.25).(Figure 1). The median PFS1 of the two groups was 8.7 months (95%CI: 7.53-9.87) in the EIT group and 7.6 months (95%CI: 5.90-9.30) in the LIT group, with statistically significant difference (\u003cem\u003eP\u003c/em\u003e=0.032,HR=0.72).(Figure 2). The median PFS2 of the two groups was 12.97 months (95%CI: 11.37-14.58) in the EIT group and 12.93 months (95%CI: 11.65-14.21) in the LIT group, with statistically significant difference (\u003cem\u003eP\u003c/em\u003e=0.045,HR=0.73).(Figure 3)\u003c/p\u003e\n\u003cp\u003eSubgroup analysis using PFS2 as the end point (Figure 4) showed that in male patients, younger than 65 years of age, esophageal tumor located in the middle thoracic segment, lymph node metastasis after progression, one organ metastasis, frist-line treatment without combination radiotherapy, and TP regimen (paclitaxel and platinum) combined chemotherapy, the combination of immunotherapy in the first-line treatment may have greater benefits than the second-line combination of immunotherapy. This also provides a reference for our clinical treatment options.\u003c/p\u003e\n\u003cp\u003eCOX proportional hazard model was established, and multivariate analysis showed (Table 4) that the EIT group (\u003cem\u003eP\u003c/em\u003e=0.03, HR=0.73) and differentiation degree of the tumor had an effect on overall survival (\u003cem\u003eP\u003c/em\u003e=0.04, HR=0.70). However, gender, age, ECOG score, tumor location, metastatic site, number of metastatic organs, chemotherapy regimen, immune drugs and whether immunotherapy combined with radiotherapy had no significant effect on OS. Treatment-related adverse effects are shown in Table 5. A total of 122 patients with stage IV in this retrospective data were selected and divided into two groups according to the addition of radiotherapy to the initial treatment: 67 patients with radiotherapy and 55 patients without radiotherapy. The median OS was 17.8 months and 15.8 months respectively (\u003cem\u003eP\u003c/em\u003e = 0.179).\u003c/p\u003e\n\u003cp\u003eTable 4 Multivariate analysis\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHR(95%CI）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.91（0.56-1.46）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.78（0.58-1.05）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.95（0.73-1.24）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.98（0.81-1.19）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDifferentiation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.70（0.50-0.99）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSite of metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.01（0.92-1.11）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNumber of organs with metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.25 \u0026nbsp;(0.98-1.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eChemotherapy regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.11（0.94-1.31）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eImmunetherapy regimens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.04（0.94-1.15）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eImmune with or without radiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.20（0.91-1.58）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEIT group or LIT group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0.73 (0.55-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 5 \u0026nbsp;Adverse events related to treatment\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.468330134357004%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"63.531669865642996%\" colspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. (%) of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.848942598187314%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEIT group \u0026nbsp;(n\u0026thinsp;=\u0026thinsp;252)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.151057401812686%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLIT group \u0026nbsp;(n\u0026thinsp;=\u0026thinsp;107)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"26.50602409638554%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.19277108433735%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;Grade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.204819277108435%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAny grade\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.096385542168676%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;Grade 3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eTreatment-related adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e249(98.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e152 (60.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e104 (97.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e67 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e193 (75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e42 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e79 (74.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e13 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eWhite blood cell count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e157 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e63(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e75 (70.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e27 (25.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eNeutrophil count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e167 (66.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e79 (31.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e80 (63.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e48 (45.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e132 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e4 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e55 (51.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eAsthenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e122 (48.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e6 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e46 (43.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e3 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e107 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e47 (44.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e2 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eVomiting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e89 (35.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e6(2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e34 (31.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003ePlatelet count decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e64 (25.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e5(2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e25 (23.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eWeight decreased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e60 (23.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e2 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e23 (21.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eAspartate aminotransferase increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e30 (12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e3 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e11 (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eImmune-related adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e252 (84.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e98 (33.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eReactive capillary endothelial proliferation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e121 (48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e71 (66.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eHypothyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e31 (12.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e7 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eHyperthyroidism\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e6 (2.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003eRash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e16 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.39846743295019%\" valign=\"top\"\u003e\n \u003cp\u003ePneumonitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.85823754789272%\" valign=\"top\"\u003e\n \u003cp\u003e16 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.75095785440613%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.32567049808429%\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eTreatment outcomes are poor for patients with advanced disease. The median OS rates are ~\u0026thinsp;10 months and ~\u0026thinsp;6 months for first-line and second-line chemotherapy, respectively, with objective response rates of ~\u0026thinsp;30% and ~\u0026thinsp;10% respectively\u003csup\u003e(15)\u003c/sup\u003e.With the advent of the immune era, immunotherapy has gradually become the standard treatment for advanced EC. Keynote-181\u003csup\u003e(1)\u003c/sup\u003e confirmed the efficacy of pembrolizumab in PD-L1 cps\u0026thinsp;\u0026ge;\u0026thinsp;10 in patients with locally advanced esophageal cancer, there was a two-fold improvement in survival at 12 months (43% v 20%) compared with chemotherapy alone (fluorouracil combined with platinum). Therefore, in 2019, it became the first immune drug approved for second-line treatment of advanced esophageal cancer in the United States. Attraction-3\u003csup\u003e(2)\u003c/sup\u003econfirmed that at a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17.6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (10.9 months vs 8.4 months, HR0.77, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019).\u003c/p\u003e \u003cp\u003eWith the overall success of immune drugs in second-line therapy, it is gradually advancing to first-line therapy. Keynote590\u003csup\u003e(5)\u003c/sup\u003ereported that first-line Palizumab\u0026thinsp;+\u0026thinsp;chemotherapy (fluorouracil\u0026thinsp;+\u0026thinsp;platinum-based) versus first-line chemotherapy in locally advanced or metastatic esophageal cancer, regardless of the expression status of PD-L1 CPS, the first-line immunized group improved overall survival (12.4 months vs. 9.8 months; 0.73 [0.62\u0026ndash;0.86]; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and progression-free survival (6.3 months vs. 5.8 months; 0.65 [0.55\u0026ndash;0.76]; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) have obvious benefit. The escort-1\u003csup\u003e(7)\u003c/sup\u003etrial confirmed that first-line immunization\u0026thinsp;+\u0026thinsp;chemotherapy (paclitaxel\u0026thinsp;+\u0026thinsp;cisplatin) was better than chemotherapy alone (paclitaxel\u0026thinsp;+\u0026thinsp;cisplatin), overall survival and progression-free survival in Chinese population, which were 15.3 vs 12.0 months, respectively(HR 0.7) and 6.9 vs 5.6 months(HR 0.56). The Orient-15\u003csup\u003e(8)\u003c/sup\u003etrial also demonstrated a survival benefit for Sintilimab in first-line chemotherapy (paclitaxel\u0026thinsp;+\u0026thinsp;cisplatin/fluorouracil\u0026thinsp;+\u0026thinsp;cisplatin). Overall survival (median 16.7 vs 12.5 months, HR0.63, 95%CI 0.51 to 0.78, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and progression-free survival (7.2 vs 5.7 months, HR 0.56, 95%CI 0.46 to 0.68, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eOur retrospective data show that after PSM, the OS of 15.7 months with first-line immunotherapy plus chemotherapy in locally advanced or metastatic ESCC is consistent with the OS reported with camrelizumab (15.3 months) and sintilizumab (16.7 months), which is higher than the OS reported with pembrolizumab. One possible explanation for this discrepancy may be that a smaller proportion of patients in the control arm of the Keynote-590 study had been exposed to second-line immunotherapy. In terms of PFS, our data showed that the median PFS1 of the two groups was 8.7 months and 7.6 months, respectively(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032, HR\u0026thinsp;=\u0026thinsp;0.72), which was similar to the HR values of the above three reports (0.65, 0.56, 0.56). The median PFS2 of the two groups was 12.97 months in the EIT group and 12.93 months in the LIT group, with statistically significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045,HR\u0026thinsp;=\u0026thinsp;0.73).\u003c/p\u003e \u003cp\u003ePrevious reports showed in non-small cell lung cancer, patients who have been previously treated with fewer lines of therapy (ie, in the first-line setting) might have less refractory and immunosuppressive tumour microenvironments than patients who have progressed on therapy.\u003csup\u003e(19)\u003c/sup\u003e Pembrolizumab plus chemotherapy in the Keynote-189 study reduced the risk of death by 44% in metastatic nonsquamous NSCLC.\u003csup\u003e(20)\u003c/sup\u003e Nivolumab as a second-line treatment reduced the risk of death by 27% in metastatic nonsquamous NSCLC.\u003csup\u003e(21)\u003c/sup\u003e The keynote-059\u003csup\u003e(14)\u003c/sup\u003e trial showed that pembrolizumab monotherapy was effective, safe and well tolerated in locally advanced gastric or gastroesophageal junction cancer with at least two previous lines of therapy, regardless of PD-L1 expression.\u003c/p\u003e \u003cp\u003eSo, whether early application of immunotherapy is more effective is still controversial. It is also rarely reported whether first-line immunotherapy has a greater survival benefit than second-line immunotherapy in the treatment of locally advanced or metastastic esophageal cancer. Our retrospective real-world study showed no significant difference in overall survival between the use of first-line immunotherapy plus chemotherapy and chemotherapy alone in patients with locally advanced or metastatic esophageal cancer, but a benefit in progression-free survival was observed with the addition of immunotherapy to the first-line regimen.\u003c/p\u003e \u003cp\u003eOur study showed there was no significant difference in overall survival between the two groups, which I believe is mainly due to the fact that twice as many patients in the LIT group as in the EIT group received third-line therapy by the date of follow-up (15.5%VS30%), which resulted in significantly longer overall survival in the LIT group. However, there was statistically significant differences in PFS1 and PFS2 between the two groups, further indicating the benefit of immune drugs in treatment, and the benefit was more significant in the early application.\u003c/p\u003e \u003cp\u003eIn EIT groups, our subgroup analysis showed that male patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy had better progression-free survival. In clinical practice, for young patients with lymph node metastasis or single organ metastasis, or when local radiotherapy cannot be added in time, immunotherapy should be given to patients timely.\u003c/p\u003e \u003cp\u003eFluorouracil combined with cisplatin is commonly used in combination chemotherapy in Western countries, while paclitaxel combined with platinum is preferred in China\u003csup\u003e(16\u0026ndash;17)\u003c/sup\u003e. Our retrospective data also showed that more patients chose the paclitaxel plus platinum regimen. Previous retrospective reports \u003csup\u003e(18)\u003c/sup\u003e showed that there was no significant difference in the efficacy of the two regimens in esophageal cancer. However, our subgroup analysis suggests that when combined with immunotherapy, TP (paclitaxel plus platinum) regimen is preferred in the choice of chemotherapy regimen.\u003c/p\u003e \u003cp\u003eLi\u003csup\u003e(22)\u003c/sup\u003eet al reported for the first time the difference in survival between first-line immunotherapy plus chemotherapy and chemotherapy alone in locally recurrent or advanced metastatic esophageal squamous cell carcinoma. In their retrospective study, there was no significant difference in overall survival (13.5 VS 13.1 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.7) between immunotherapy plus chemotherapy and chemotherapy alone, while PFS1 was significantly different (7.1 VS 4.1 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001, HR0.53). Our retrospective data showed that the overall survival of first-line immunotherapy combined with chemotherapy and chemotherapy alone was 15.7 months and 17.7 months, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.185, HR1.25). PFS1 was 8.7 months and 7.6 months, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032, HR0.72), which was consistent with the conclusions reported above. However, compared with this retrospective study, the number of patients in our article is larger, the follow-up time is longer, and the previous treatment history of the enrolled patients is more detailed, complex, and closer to the actual clinical treatment. Furthermore, we conducted subgroup analyses to inform our practice of which patients would be more inclined to be treated with immunotherapy in the first-line treatment.\u003c/p\u003e \u003cp\u003eAdvantages and defects\u003c/p\u003e \u003cp\u003eAdvantages: In this retrospective study, we compared whether the combination of immune and chemotherapy is beneficial over chemotherapy alone in the first-line treatment of patients with locally advanced or metastatic esophageal cancer. In addition, our real-world study included a larger number of cases and was closer to the actual clinical treatment situation than the study by li \u003csup\u003e(22)\u003c/sup\u003e et al. The results of subgroup analysis also have certain guiding value for our clinical practice.\u003c/p\u003e \u003cp\u003eDefects: This article is a retrospective study, and the data may have a certain loss bias. The short follow-up time and some patients are still in treatment may have a certain impact on the calculation of survival time. In this retrospective study, PD-L1 expression status was unknown in most patients, and the effect of PD-L1 expression level on survival could not be assessed.\u003c/p\u003e \u003cp\u003eConclusion: For patients with locally advanced and metastatic esophageal cancer, early application of immunotherapy has a progression-free survival benefit. In clinical practice, patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy are inclined to be treated with immunotherapy in the first-line treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethics committee of the\u0026nbsp;Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences and\u0026nbsp;Gaomi People\u0026rsquo;s Hospital.The study is retrospective amd only clinical information of patients will be collected without containning personal identifiers,interfering with patients\u0026rsquo;treatment plans,or posing physiological risks to patients.Informed consent was obtained from all patients before being included.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003eAdditional information\u003c/p\u003e\n\u003cp\u003ePublisher\u0026rsquo;s Note\u003c/p\u003e\n\u003cp\u003eSpringer Nature remains neutral wiht regard to jurisdictional calims in published maps and institutional affiliations.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKojima T, Shah MA, Muro K, et al. KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 2020;38:4138\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:1506\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHUANG J, XU J, CHEN Y, et al. Camrelizumab versus investigator's choice of chemotherapy as second-line therapy for advanced or metastatic oesophageal squamous cell carcinoma (ESCORT): a multicentre, randomised, open-label, phase 3 study[J]. Lancet Oncol. 2020;21(6):832\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSHEN L, KATO K, KIM K B, et al. RATIONALE 302: Randomized, phase 3 study of tislelizumab versus chemoth erapy as second-line treatment for advanced unresectable/ metast atic esophageal squamous cell carcinoma[J]. J Clin Oncol. 2021;39(15suppl):4012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSUN JM, SHEN L, SHAH M A, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study[J]. Lancet. 2021;398(10302):759\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDOKI Y, AJANI J A, KATO K, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcin oma[J]. N Engl J Med. 2022;386(5):449\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo H, Lu J, Bai Y, et al. ESCORT-1st Investigators. 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. 2021;326:916\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLu Z. Junye Wang,Yongqian Shu,Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial.BMJ2022; 377: e068714.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWANG Z X, CUI C, YAO J, et al. Toripalimab plus chemotherapy in treatment-na\u0026iuml;ve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial[J]. Cancer Cell. 2022;40(3):277\u0026ndash;e2883.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReck M, Rodri, guez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N. Engl J Med. 2016;375:1823\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRibas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 28 melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16:908\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBang Y-J, Kang Y-K, Catenacci DV, et al. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients 29 with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019;22:828\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4:e180013.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKu GY. Systemic therapy for esophageal cancer: chemotherapy. Chin Clin Oncol. 2017;6(5):49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetrasch S, Welt A, Reinacher A, Graeven U, K\u0026ouml;nig M, Schmiegel W. Chemotherapy with cisplatin and paclitaxel in patients with locally advanced, recurrent or metastatic oesophageal cancer. Br J Cancer. 1998;78(4):511\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang X, Shen L, Li J, Li Y, Li J, Jin M. A phase II trial of paclitaxel and cisplatin in patients with advanced squamous-cell carcinoma of the esophagus. Am J Clin Oncol. 2008;31(1):29\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang C, Liao FX, Rong YM, et al. Efficacy of taxane-based regimens in a first-line setting for recurrent and/or metastatic Chinese patients with esophageal cancer. Asian Pac J Cancer Prev. 2014;15(13):5493\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePacheco JM, Camidge DR, Doebele RC, Schenk E. A changing of the guard: immune checkpoint inhibitors with and without chemotherapy as first line treatment for metastatic non-small cell lung cancer. Front Oncol. 2019;9:195.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGadgeel S, Rodr\u0026iacute;guez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu-Yuan Li. MD1 | Li-Sheng Huang MD2 | Hao-Quan Cai MD3 | First-line or second-line PD-1 inhibition in advanced oesophageal squamous cell carcinoma: A prospective, multicentre, registry study。J. Clin Pharm Ther. 2021;00:1\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"immunotherapy, esophageal squamous cell cancer, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-4571189/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4571189/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground and objective: Several large-scale phase III clinical trials have confirmed the survival benefit of immunotherapy in patients with locally advanced or metastatic esophageal cancer. The aim of this study is to investigate whether early use of immunotherapy can improve long-term survival.\u003c/p\u003e\n\u003cp\u003eMethods: Patients with locally advanced or metastatic esophageal squamous cell cancer (ESCC) diagnosed from January 2018 to December 2021were retrospectively analyzed. According to the time of immunotherapy, patients were divided into early immunotherapy group (EIT group, first-line immunotherapy ) and late immunotherapy group (LIT group, second-line immunotherapy) . A 1:1 propensity score matching (PSM) was applied to balance the observable potential confounding factors between the two groups. The primary outcome was overall survival (OS).\u003c/p\u003e\n\u003cp\u003eResults: A total of 359 patients were enrolled, after propensity score matching, the clinical features were well balanced between two groups included 107 patients each. The median OS was 15.7 months (95%CI: 12.81-18.59) in the EIT group and 17.7 months (95%CI: 14.89-20.57) in the LIT group, respectively. (\u003cem\u003eP\u003c/em\u003e=0.185, HR=1.25). The PFS1 of patients were 8.7 months (95%CI: 7.53-9.87) and 7.6 months (95%CI: 5.90-9.30),respectively, and the difference was statistically significant (\u003cem\u003eP\u003c/em\u003e=0.032, HR=0.72). The PFS2 of patients were 12.97months (95%CI: 11.37-14.58) and 12.93 months (95%CI: 11.65-14.21), respectively, and the difference was statistically significant(\u003cem\u003eP\u003c/em\u003e=0.045,HR=0.73). Subgroup analysis showed that male patients with middle thoracic esophageal cancer, younger than 65 years old, only one site of metastasis, only lymph node progression, no combined radiotherapy after progression and TP (paclitaxel plus platinum) regimen chemotherapy may have greater benefits. COX multivariate analysis showed that the EIT group and the differentiation degree of tumor had an impact on overall survival (\u003cem\u003eP：\u003c/em\u003e0.03、0.04, HR: 0.73、0.70).\u003c/p\u003e\n\u003cp\u003eConclusions: For patients with locally advanced or metastatic advanced ESCC, earlyimmunotherapy can improve PFS without improving OS.\u003c/p\u003e","manuscriptTitle":"Immunotherapy in advanced esophageal squamous cell cancer: earlier or later?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-13 02:14:56","doi":"10.21203/rs.3.rs-4571189/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1a9ad067-d3da-46ac-a400-520677eeb3a3","owner":[],"postedDate":"July 13th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-06T08:40:10+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-13 02:14:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4571189","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4571189","identity":"rs-4571189","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}