Three courses of treatment increase the efficacy of neoadjuvant immunochemotherapy in patients with local advanced ESCC without increasing TRAEs compared with two courses of treatment

Three courses of treatment increase the efficacy of neoadjuvant immunochemotherapy in patients with local advanced ESCC without increasing TRAEs compared with two courses of treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Three courses of treatment increase the efficacy of neoadjuvant immunochemotherapy in patients with local advanced ESCC without increasing TRAEs compared with two courses of treatment Yuanheng Huang, Xiaodong Su, Guo Guo, Guangyu Luo, Haoqiang He, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2301453/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 : Immune checkpoint (ICI) monotherapy and neoadjuvant immunochemotherapy has shown promising results in esophageal carcinoma. However, it is still unclear whether more courses in immunochemotherapy are better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods : This was a secondary analysis of the ChiCTR2000029807 clinical trial. Locally advanced ESCC patients have to receive three courses of camrelizumab (200mg every three weeks) plus nab-paclitaxel (260 mg/m2 every three weeks) and capecitabine (1250 mg/m2 every three weeks) before undergoing surgery. Patients received safety assessment, CT, and endoscopy (with endoscopic ultrasonography and mucosal biopsy) efficacy assessments before and in the second and third courses of treatment. We used the second and third courses' CT and endoscopic assessment results for comparison. Results : From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-PD-1 therapy and radical surgical resection. All Forty-three patients received safety assessments and CT efficacy assessments. Sixteen patients did not undergo an endoscopy examination during the second course of treatment because of esophageal stenosis or refused the endoscopy examination. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, which continued to increase the CT and endoscopy T downstaging rates by 16.3% and 25.9%, N downstaging rates by 7.0% and 11.1%, and ORR by 13.6 and 22.0%, respectively. Conclusions : No matter downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs. (www.chictr.org.cn number, ChiCTR2000029807) Esophageal cancer Immunochemotherapy three courses of treatment. Figures Figure 1 Figure 2 Introduction Esophageal cancer (EC) is the seventh most common malignancy and the sixth leading cause of cancer-related death worldwide ( 1 ). China is a high-incidence area of esophageal cancer, and more than 90% of esophageal cancer cases are squamous cell carcinoma (ESCC) ( 2 ). As a new treatment for esophageal cancer, anti-PD-(L)1 therapy can specifically block the combination of PD-1 or PD-L1 through the application of PD-(L)1 inhibitors and restore T cells' antitumor immune activities ( 3 ). Camrelizumab is a humanized high-affinity IgG4-kappa anti-PD-1 monoclonal antibody whose efficacy and safety have been verified in advanced ESCC. In the recent randomized phase III ESCORT-1st study ( 4 ), the additional use of camrelizumab to chemotherapy improved objective response rate (ORR) compared to chemotherapy alone and thus has been approved as a first-line treatment for unresectable advanced ESCC. In addition, neoadjuvant administration of PD-1 blockade combined with chemotherapy has also been shown to encourage antitumor activity in multiple malignancies, such as lung and colorectal cancer ( 5 , 6 ). However, its application in locally advanced ESCC has not yet been established. UpToDate, several clinical trials ( 7 , 8 ) have reported that neoadjuvant immunochemotherapy induced favorable clinical pathological responses and tolerated toxicity in patients with locally advanced ESCC. However, most of these studies have only focused on two courses of treatment. A recent randomized controlled non-small cell lung cancer clinical study ( 9 ) suggested that the major pathological response rate (MPR) of 3 courses of neoadjuvant immunochemotherapy was higher than that of 2 courses without increasing TRAEs. Those reports indicated that a two-course regimen might not be sufficient to clean minimal residual disease, which may lead to eventual postoperative recurrence. In our pilot study ( 10 ), three courses of neoadjuvant camrelizumab combined with chemotherapy showed promising efficacy in locally advanced ESCC without increased complications. Therefore, we further conducted this prospective phase II clinical trial to initially explore whether three courses of immunochemotherapy are better for locally advanced ESCC patients. Methods Patients and study design We conducted a single-arm, single-center, phase II trial investigating camrelizumab combined with chemotherapy followed by surgery in locally advanced ESCC. This study was a secondary analysis of these clinical trial data. Overall, the main inclusion criteria were listed as follows: 1) a diagnosis of stage T2–3, N0–3 locally advanced ESCC that was deemed to be resectable before enrollment; 2) no cervical lymph node metastasis or distant organ metastasis; 3) no secondary primary tumors; 4) Eastern Cooperative Oncology Group (ECOG) performance status score was 0 or 1; 5) no prior exposure to anti-cancer treatment, included radiotherapy, chemotherapy, immunotherapy, and targeted therapy. The current study was approved by the ethics committee of the Sun Yat-sen University Cancer Center and registered with www.chictr.org.cn , ChiCTR2000029807. All patients signed written informed consent. Procedure Patients enrolled in the study received three courses of PD-1 blockade combined with chemotherapy. For each course of treatment, all participants received a flat dose of camrelizumab (200 mg, ivgtt) plus a single dose of nab-paclitaxel (260 mg/m 2 , ivgtt) on day 1, and capecitabine was administered twice daily (1250 mg/m 2 ) on days 1 to 14. The regimen was repeated every three weeks. Granulocyte colony-stimulating factor (G-CSF) was applied prophylactically on day 4 of each course. At baseline and after the second and third neoadjuvant treatment course, contrasted-enhanced thoracic/abdominal computer tomography (CT), endoscopy (with endoscopic ultrasonography and mucosal biopsy), and cervical/supraclavicular ultrasonography were performed. Subsequently, we used the second and third course CT and endoscopic assessment results for comparison. Thoracoscopic esophagectomy with cervical esophagogastric anastomosis and modern two-field lymph node dissection was performed approximately 4–6 weeks after the last course of neoadjuvant therapy. Assessment of safety Safety- and treatment-related adverse events (TRAEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 ( 11 ). Safety was defined as no treatment-related death or serious TRAEs caused by neoadjuvant treatment. Assessment of response CT evaluation: According to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) ( 12 ), the assessment criteria for the CT assessment are listed as follows: Complete response (CR): All target lesions disappeared, and no new lesions were found. Partial response (PR): At least a 30% decrease in the sum of the greatest dimensions of the target lesions, taking the sum of the greatest dimensions at baseline as the reference; Stable disease (SD): Neither PR nor progressive disease (PD); PD: At least a 20% increase in the sum of the greatest dimensions of the target lesions, taking the smallest sum of the greatest dimensions recorded after the start of treatment as the reference; The objective response rate (ORR) was defined as the sum of CR and PR. Endoscopy evaluation: We noticed that endoscopic ultrasonography (EUS) was not used to evaluate tumors in the endoscopic evaluation criteria of the Japan Esophageal Society ( 13 ). Based on this, we added the changes in EUS T staging combined with the endoscopic evaluation criteria of the Japan Esophageal Society to evaluate the efficacy of treatment. The criteria details for the endoscopy assessment are presented as follows: Endoscopic Complete Response (eCR): Disappearance of endoscopic findings suggesting the presence of a tumor; the entire esophagus could be observed using endoscopy; negative endoscopic biopsy findings from the area of the primary lesion; no endoscopic findings of active esophagitis; and endoscopy showed no hypoechoic nodules at all anatomical levels of the esophagus. Endoscopic Partial Response (ePR): The tumor or surrounding bulge shrank or became flattened, the ulcer shrank; and endoscopy showed a decrease in the T stage from baseline. Endoscopic Stable Disease (eSD): The tumor mass showed no significant change from baseline, and endoscopy showed a T stage after treatment equal to that at baseline. Endoscopic Progressive Disease (ePD): The tumor grew significantly larger or progressed, and endoscopy indicated an increase in the T stage from baseline. The endoscopic objective response rate (eORR) was defined as the sum of eCR and ePR. Two senior imaging specialists and endoscopists reviewed all CT and endoscopy imaging data independently, and clinical staging was performed according to the TNM classification (8th Edition). ( 14 ). Statistical analyses The Mann-Whitney U test was used to compare continuous distributed variables, and the Wilcoxon signed-rank test was used to compare two related categorical variables among groups. All reported p -values were two-tailed. A p -value of < 0.05 was considered statistically significant. All analyses were performed using the SPSS 26.0 software package (SPSS, Chicago, IL, USA), and graphs were generated with GraphPad Prism version 9.0.3 (GraphPad Software, San Diego, CA, USA) and R 4.0.3. Results Baseline characteristics A total of 47 patients were enrolled in this study from May 2020 to December 2021 at Sun Yat-sen University Cancer Center. A total of 43 patients who had finished three courses of PD-1-based neoadjuvant immunochemotherapy were finally enrolled for analysis. Among them, thirty-eight patients were male, and nine patients were female. The median age of the entire cohort was 58.0 years (range 44–70 years). Eleven (23.4%) patients had stage II disease; thirty-six (76.6%) patients had stage III disease. More details of the clinical baseline characteristics of the patients are shown in Table 1 . Table 1 Baseline characteristics of the patients. Characteristics N = 43 Age, median (IQR*), years 57 (44–70) Gender, n (%) Male 34 (79.1) Female 9 (20.9) Tumor Site, n (%) Upper third 2 (4.7) Middle third 17 (39.5) Lower third 24 (55.8) Tumor differentiation, n (%) Well 5 (11.6) Moderately 27 (62.8) Poorly 11 (25.6) Clinical stage, n (%) I 0 (0) II 11 (25.6) III 32 (74.4) IV 0 (0) Clinical T stage, n (%) cT1 0 (0) cT2 12 (27.9) cT3 31 (72.1) cT4 0 (0) Clinical N stage, n (%) cN0 2 (4.7) cN1 18 (41.9) cN2 23 (53.4) cN3 0 (0) ECOG score, n (%) 0 38 (88.4) 1 5 (11.6) *IQR, interquartile range. The clinical stage was assessed using endoscopy (combined with EUS and mucosa biopsy) or computed tomography (CT) and was classified according to the Union for International Cancer Control (UICC) tumor–node–metastasis (TNM) classification, 8th Edition. Safety Three courses of treatment did not increase TRAEs compared to the second course (Table 2 ). Neoadjuvant use of camrelizumab in combination with nab-paclitaxel and capecitabine did not cause any previously unreported toxicities. All patients reported at least one adverse event during the neoadjuvant treatment, and most of the TRAEs were grade 1–2. The most common grade 1–2 TRAEs of the second and third courses of treatment were alopecia (30/69.7% versus 31/72.0%), reactive cutaneous capillary endothelial proliferation (RCCEP) (24/55.8% versus 28/65.1%), fatigue (25/58.1% versus 25/58.1%), anemia (23/53.5% versus 22/51.2%), muscle soreness (18/41.8% versus 18/41.8%), numbness of limbs (20/46.5% versus 20/46.5%), and increased alanine transaminase (9/20.9% versus 10/23.3%). Leukopenia occurred in only three (6.4%) patients in the second and third courses of treatment. Two (4.6%) in the second courses developed grade 3 − 4 adverse events treatment, including fatigue and limb numbness. Four (9.3%) in the third course of treatment developed grade 3 − 4 adverse events, including one with fatigue, one with limb numbness, one with anemia, and one with myocarditis. No grade 5 events or treatment-related mortality were observed. Table 2 Summary of treatment-related adverse events. All events The second course of treatment The third course of treatment p -value Total Grade 1–2 Grade 3–4 Total Grade 1–2 Grade 3–4 Alopecia 31 (72.1) 31 (72.1) 0 (0) 31 (72.1) 31 (72.1) 0 (0) 0.157 Reactive cutaneous capillary endothelial proliferation 24 (55.8) 24 (55.8) 0 (0) 28 (65.1) 28 (65.1) 0 (0) 0.046 Fatigue 24 (55.8) 23 (53.5) 1 (2.3) 25 (58.1) 24 (55.8) 1 (2.3) 0.317 Anemia 23 (53.5) 23 (53.5) 0 (0) 23 (53.5) 22 (51.2) 1 (2.3) 0.317 Muscle soreness 18 (41.7) 18 (41.7) 0 (0) 18 (41.7) 18 (41.7) 0 (0) 0.317 Limb numbness 20 (46.5) 19 (44.2) 1 (2.3) 20 (46.5) 19 (44.2) 1 (2.3) 0.564 Increased alanine transaminase 9 (20.9) 9 (20.9) 0 (0) 10 (23.3) 10 (23.3) 0 (0) 0.083 Constipation 7 (16.3) 7 (16.3) 0 (0) 7 (16.3) 7 (16.3) 0 (0) 1.000 Diarrhea 4 (9.3) 4 (9.3) 0 (0) 4 (9.3) 4 (9.3) 0 (0) 0.317 Immune-related hyperthyroidism 4 (9.3) 4 (9.3) 0 (0) 4 (9.3) 4 (9.3) 0 (0) 0.317 Leukopenia 2 (4.7) 2 (4.7) 0 (0) 2 (4.7) 2 (4.7) 0 (0) 1.000 Vomiting 2 (4.7) 2 (4.7) 0 (0) 2 (4.7) 2 (4.7) 0 (0) 1.000 Nausea 2 (4.7) 2 (4.7) 0 (0) 2 (4.7) 2 (4.7) 0 (0) 1.000 Immune-related hypothyroidism 2 (4.7) 2 (4.7) 0 (0) 2 (4.7) 2 (4.7) 0 (0) 1.000 Thrombocytopenia 2 (4.7) 2 (4.7) 0 (0) 2 (4.7) 2 (4.7) 0 (0) 0.317 Immune-related myocarditis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1.000 Cough 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1.000 Immune-related pneumonia 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1.000 Immune-related hepatitis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1.000 Immune-related nephritis 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0.000 All adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Downstaging analysis After the second and third courses of neoadjuvant immunochemotherapy, CT assessment found 28/65.1% versus 35/81.4% of patients had T downstaging, and 23/53.5% versus 26/60.5% of patients had N downstaging, respectively. Similarly, the endoscopy assessment found 17/63.0% versus 24/88.9% of patients had T downstaging, and 18/66.7% versus 21/77.8% of patients had N downstaging, respectively (Fig. 1 ). We found that the third course of treatment was higher than the second course in terms of T downstaging and N downstaging. In addition, one course of neoadjuvant therapy based on the second course increased the CT and the endoscopy T downstaging rates by 16.3% and 25.9%, and N downstaging rates by 7.0% and 11.1%, respectively. Clinical responses CT assessment: All 43 patients completed the CT assessment before treatment and the second and third courses after treatment. According to the RECIST 1.1 criteria, the second and third courses of neoadjuvant therapy resulted in a CR of 1/2.3% versus 3/7.0%, a PR of 28/65.1% versus 32/74.4%, and an SD of 14/32.6% vs. 8/18.6%, respectively. No patients with PD were found (Fig. 2 A). The objective response rate ORR was 67.4% versus 81.0%, respectively (Fig. 2 C). Compared with the second course of treatment, the third course of treatment could further convert 4/14.3% of PR patients into CR and 6/42.9% of SD patients into PR. The ORR of the third course of treatment was further increased by 13.6% compared with the second course of treatment, and statistical differences were found (Fig. 2 C). Endoscopy assessment: A total of 27 patients completed the endoscopy assessment before and after the second and third courses of treatment. According to the endoscopic diagnostic criteria of the Japanese Esophageal Society, the second and third courses of neoadjuvant therapy resulted in a 0/0% versus 5/18.5% of eCR, 17/63.0% versus 18/66.7% of ePR, and 10/37.0% versus 4/14.8% of eSD, respectively. No patients with ePD were found (Fig. 2 B). The objective response rate eORR was 63.0% versus 85.2% respectively (Fig. 2 C). Compared with the second course of treatment, the third course of treatment could further convert 5/29.4% of ePR patients to eCR, and 6/33.3% of eSD patients to ePR. The third course of eORR was further increased by 22.0% compared with the second course of treatment, and there was a statistical difference (Fig. 2 C). Discussion Neoadjuvant therapy combined with surgery is the standard treatment regimen for patients with locally advanced ESCC. Two courses of neoadjuvant chemoradiotherapy can benefit patient survival ( 15 ). However, a recent study reported that there is still a 23.9% distant metastasis rate remaining after two courses of treatment ( 16 ). For neoadjuvant immunochemotherapy, most clinical trials currently also focus on the effect of a two-courses regimen, which may lead to the limited efficacy of immunotherapy. In our previous pilot study ( 10 ), we found that three courses of neoadjuvant immunochemotherapy were safe, feasible, and effective. These results were further confirmed in this phase II trial. In terms of safety, the toxicity of the third course of camrelizumab combined with chemotherapy compared with the second course was tolerable. Most TRAEs were grade 1–2, similar to other two-course regimens. RCCEP induced by camrelizumab was found in 28/65.1% of patients after the third course of treatment, compared with 24/55.8% of patients in the second course of treatment. Similarly, the overall incidence of RCCRP after the third course of treatment was higher than that reported in other two-cycle regimen studies (26.1%-39.1%) ( 17 , 18 ). This difference may be due to the addition of one course of camrelizumab. Notably, a previous study ( 17 ) showed that more than half of patients developed leukopenia during neoadjuvant immunochemotherapy or chemoradiotherapy. Severe leukopenia may even lead to dose reduction or treatment discontinuation. In our cohort, the incidence of leukopenia was relatively low. Only 6.4% of patients had leukopenia during the second and third cycles. This difference can be attributed to two reasons. First, we use G-CSF prophylactically after each immunochemotherapy course. Second, we replaced platinum with capecitabine in our immunochemotherapy regimen. Capecitabine, an oral drug that can be converted to fluorouracil ( 19 ), in combination with paclitaxel, has shown comparable efficacy and lower toxicity than platinum-based regimens in head and neck squamous cell carcinoma and breast cancer ( 20 – 22 ). The drug's low toxicity makes it suitable for use in combination with PD-1 blockers. Overall, the toxicity of the three-course treatment regimen was manageable and worthy of promotion. In terms of efficacy, this study compared the CT and endoscopy assessment results of the second and third courses of treatment employing self-control. We found that an additional course of treatment after the second course was effective, increasing the CT and endoscopy T downstaging rates by 16.3% and 25.9%, N downstaging rates by 7.0% and 11.1%, and ORR by 13.6 and 22.0%, respectively. We observed that the T downstaging, N downstaging, ORR, CR, and PR rate assessed by CT or endoscopy after the third course of treatment was higher than that of the second course of therapy, and the SD rate was lower than the second course of treatment. Similarly, a recent randomized controlled non-small cell lung cancer clinical study ( 9 ) showed that after neoadjuvant immunochemotherapy in patients with lung squamous cell carcinoma, the MPR induced by three courses of neoadjuvant therapy was 60%, compared with 43.8% after two courses of treatment. Both groups were well tolerated; only 5% (3/60) had grade 3 immune-related adverse events. In 2021, a randomized controlled study ( 23 ) in Japan found that three courses of neoadjuvant chemotherapy resulted in better clinical responses without increased TRAEs or complications than two courses of neoadjuvant chemotherapy. It is worth noting that previous studies reported that the degree of lymphocyte infiltration in tumor tissue increased with more treatment courses ( 24 ). Another bladder cancer study also suggested that after three courses of anti-PD-1 therapy, the density of CD8 + T lymphocytes infiltrating the tumor stroma was significantly higher than before treatment ( 25 ). Those studies imply that more courses of immunotherapy may improve efficacy by fully activating the immune system to remove minimal residual tumor lesions. Therefore, immune system activation appeared to be more thorough after three courses of therapy than two courses, which may explain why three courses of treatment are more effective than two courses. Our findings suggested that three courses of treatment showed better clinical responses without increased TRAEs compared with two courses of treatment. However, short-term efficacy may affect long-term survival. Therefore, it is necessary to perform studies with large sample sizes in the future for further verification. Nonetheless, our study has some limitations. First of all, the sample size of our study was small. Second, this study is a single-center study. However, the single-center study design and self-controlled study approach made our data more consistent. Conclusion In summary, the downstaging rate and ORR of three courses of immunochemotherapy were better than that of two courses of treatment and without increasing TRAEs. Declarations Acknowledgments: The authors would like to acknowledge all patients participating in the study. Funding : This study was supported by the Science and Technology Program of Guangzhou, China (202103000064) and the Science and Technology Project of Guangdong Esophageal Cancer Research Institute (M202017). Conflicts of Interests: The author declares no conflicts of interest. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2301453","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":154403947,"identity":"2c3d0daa-5990-46d6-bd0c-692918479650","order_by":0,"name":"Yuanheng Huang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Yuanheng","middleName":"","lastName":"Huang","suffix":""},{"id":154403948,"identity":"314092fc-8247-4e3d-a5e0-756e451fbe47","order_by":1,"name":"Xiaodong Su","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Su","suffix":""},{"id":154403949,"identity":"a85fa204-bc2e-435b-8a56-4a9bd111c694","order_by":2,"name":"Guo Guo","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Guo","middleName":"","lastName":"Guo","suffix":""},{"id":154403950,"identity":"75e2278f-17e2-4f58-b2dd-f14fb1be2b62","order_by":3,"name":"Guangyu Luo","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Guangyu","middleName":"","lastName":"Luo","suffix":""},{"id":154403951,"identity":"a8231b57-609b-408e-b2e9-26fac9b7e146","order_by":4,"name":"Haoqiang He","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Haoqiang","middleName":"","lastName":"He","suffix":""},{"id":154403952,"identity":"3e19e9b0-a9f7-4128-8120-a8907f35359d","order_by":5,"name":"Peiqiang Cai","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Peiqiang","middleName":"","lastName":"Cai","suffix":""},{"id":154403953,"identity":"7363b774-b7fc-4f3c-a674-6915daac907c","order_by":6,"name":"Muyan Cai","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Muyan","middleName":"","lastName":"Cai","suffix":""},{"id":154403954,"identity":"6beb12b7-1f1c-4e76-913e-9a3a96627e3b","order_by":7,"name":"Haodong Yue","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Haodong","middleName":"","lastName":"Yue","suffix":""},{"id":154403955,"identity":"3d1631a0-7e7d-4cea-bf96-017ad6a17df0","order_by":8,"name":"Zhiqiang Wang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Zhiqiang","middleName":"","lastName":"Wang","suffix":""},{"id":154403956,"identity":"efe5c67b-6273-4c99-8529-aa158c6b6f8b","order_by":9,"name":"Guozhen Yang","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Guozhen","middleName":"","lastName":"Yang","suffix":""},{"id":154403957,"identity":"56a6f3d4-481c-459b-bd94-473907e9b329","order_by":10,"name":"Peng Lin","email":"","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Lin","suffix":""},{"id":154403958,"identity":"b3e2176e-85d2-470c-881a-52058d9ed6cc","order_by":11,"name":"Xu Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYDACCQglR7oWY9K1JDYQrUN+dvOzh1/bDqfPn5H+TOJHDYOcef8Cxs8FeLQwzjlmbixz5nDuhhs5ZpI9xxiMZW48YJaegUcLs0SCmbREBVCLRA6bNGMDQ+IMiQNszDx4tLBJpH+TljA4nC4PdBhxWngkgO75UHE4geEG0DqwFv4G/FokJHLKpBnOpBtuOPPG2LLnmISxhARjszQ+LUD3bJP82WYtL9+e/vDGjxobOQn+wwc/49MCAhBnCCSAbQUiIuKI8QeI5D8A5cIZo2AUjIJRMAogAABte0RC9Eq8wwAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen University Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Xu","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2022-11-22 13:44:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2301453/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2301453/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29607314,"identity":"e9d25111-8699-40af-ac63-6d92bec949ec","added_by":"auto","created_at":"2022-11-28 18:58:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":285769,"visible":true,"origin":"","legend":"\u003cp\u003eDownstaging to neoadjuvant camrelizumab combined with chemotherapy.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-2301453/v1/6d269048c795e4da99563acf.png"},{"id":29607315,"identity":"7fa64df5-4b87-4d68-9b01-6979fa69b86a","added_by":"auto","created_at":"2022-11-28 18:58:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":263892,"visible":true,"origin":"","legend":"\u003cp\u003eClinical responses to neoadjuvant camrelizumab combined with chemotherapy.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-2301453/v1/bafc6584177c9bb92bb53a95.png"},{"id":29607324,"identity":"725ae2f6-01fb-483a-ac2c-a4b532093088","added_by":"auto","created_at":"2022-11-28 18:59:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":513822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2301453/v1/095d864a-1bd1-4ee8-be94-bd570b005857.pdf"},{"id":29607316,"identity":"058f691c-db70-41e9-980e-708b86cf1bcf","added_by":"auto","created_at":"2022-11-28 18:58:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":513822,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2301453/v1/c1a5167a-02fb-487b-b107-71e970f81983.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Three courses of treatment increase the efficacy of neoadjuvant immunochemotherapy in patients with local advanced ESCC without increasing TRAEs compared with two courses of treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEsophageal cancer (EC) is the seventh most common malignancy and the sixth leading cause of cancer-related death worldwide (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). China is a high-incidence area of esophageal cancer, and more than 90% of esophageal cancer cases are squamous cell carcinoma (ESCC) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs a new treatment for esophageal cancer, anti-PD-(L)1 therapy can specifically block the combination of PD-1 or PD-L1 through the application of PD-(L)1 inhibitors and restore T cells' antitumor immune activities (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Camrelizumab is a humanized high-affinity IgG4-kappa anti-PD-1 monoclonal antibody whose efficacy and safety have been verified in advanced ESCC. In the recent randomized phase III ESCORT-1st study (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), the additional use of camrelizumab to chemotherapy improved objective response rate (ORR) compared to chemotherapy alone and thus has been approved as a first-line treatment for unresectable advanced ESCC. In addition, neoadjuvant administration of PD-1 blockade combined with chemotherapy has also been shown to encourage antitumor activity in multiple malignancies, such as lung and colorectal cancer (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, its application in locally advanced ESCC has not yet been established.\u003c/p\u003e \u003cp\u003eUpToDate, several clinical trials (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) have reported that neoadjuvant immunochemotherapy induced favorable clinical pathological responses and tolerated toxicity in patients with locally advanced ESCC. However, most of these studies have only focused on two courses of treatment. A recent randomized controlled non-small cell lung cancer clinical study (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) suggested that the major pathological response rate (MPR) of 3 courses of neoadjuvant immunochemotherapy was higher than that of 2 courses without increasing TRAEs. Those reports indicated that a two-course regimen might not be sufficient to clean minimal residual disease, which may lead to eventual postoperative recurrence.\u003c/p\u003e \u003cp\u003eIn our pilot study (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), three courses of neoadjuvant camrelizumab combined with chemotherapy showed promising efficacy in locally advanced ESCC without increased complications. Therefore, we further conducted this prospective phase II clinical trial to initially explore whether three courses of immunochemotherapy are better for locally advanced ESCC patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and study design\u003c/h2\u003e \u003cp\u003eWe conducted a single-arm, single-center, phase II trial investigating camrelizumab combined with chemotherapy followed by surgery in locally advanced ESCC. This study was a secondary analysis of these clinical trial data. Overall, the main inclusion criteria were listed as follows: 1) a diagnosis of stage T2\u0026ndash;3, N0\u0026ndash;3 locally advanced ESCC that was deemed to be resectable before enrollment; 2) no cervical lymph node metastasis or distant organ metastasis; 3) no secondary primary tumors; 4) Eastern Cooperative Oncology Group (ECOG) performance status score was 0 or 1; 5) no prior exposure to anti-cancer treatment, included radiotherapy, chemotherapy, immunotherapy, and targeted therapy.\u003c/p\u003e \u003cp\u003eThe current study was approved by the ethics committee of the Sun Yat-sen University Cancer Center and registered with \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.chictr.org.cn\" target=\"_blank\"\u003ewww.chictr.org.cn\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, ChiCTR2000029807. All patients signed written informed consent.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProcedure\u003c/h2\u003e \u003cp\u003ePatients enrolled in the study received three courses of PD-1 blockade combined with chemotherapy. For each course of treatment, all participants received a flat dose of camrelizumab (200 mg, ivgtt) plus a single dose of nab-paclitaxel (260 mg/m\u003csup\u003e2\u003c/sup\u003e, ivgtt) on day 1, and capecitabine was administered twice daily (1250 mg/m\u003csup\u003e2\u003c/sup\u003e) on days 1 to 14. The regimen was repeated every three weeks. Granulocyte colony-stimulating factor (G-CSF) was applied prophylactically on day 4 of each course. At baseline and after the second and third neoadjuvant treatment course, contrasted-enhanced thoracic/abdominal computer tomography (CT), endoscopy (with endoscopic ultrasonography and mucosal biopsy), and cervical/supraclavicular ultrasonography were performed. Subsequently, we used the second and third course CT and endoscopic assessment results for comparison.\u003c/p\u003e \u003cp\u003eThoracoscopic esophagectomy with cervical esophagogastric anastomosis and modern two-field lymph node dissection was performed approximately 4\u0026ndash;6 weeks after the last course of neoadjuvant therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of safety\u003c/h2\u003e \u003cp\u003eSafety- and treatment-related adverse events (TRAEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Safety was defined as no treatment-related death or serious TRAEs caused by neoadjuvant treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAssessment of response\u003c/h2\u003e \u003cp\u003eCT evaluation: According to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), the assessment criteria for the CT assessment are listed as follows:\u003c/p\u003e \u003cp\u003eComplete response (CR): All target lesions disappeared, and no new lesions were found.\u003c/p\u003e \u003cp\u003ePartial response (PR): At least a 30% decrease in the sum of the greatest dimensions of the target lesions, taking the sum of the greatest dimensions at baseline as the reference;\u003c/p\u003e \u003cp\u003eStable disease (SD): Neither PR nor progressive disease (PD);\u003c/p\u003e \u003cp\u003ePD: At least a 20% increase in the sum of the greatest dimensions of the target lesions, taking the smallest sum of the greatest dimensions recorded after the start of treatment as the reference;\u003c/p\u003e \u003cp\u003eThe objective response rate (ORR) was defined as the sum of CR and PR.\u003c/p\u003e \u003cp\u003eEndoscopy evaluation: We noticed that endoscopic ultrasonography (EUS) was not used to evaluate tumors in the endoscopic evaluation criteria of the Japan Esophageal Society (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Based on this, we added the changes in EUS T staging combined with the endoscopic evaluation criteria of the Japan Esophageal Society to evaluate the efficacy of treatment. The criteria details for the endoscopy assessment are presented as follows:\u003c/p\u003e \u003cp\u003eEndoscopic Complete Response (eCR): Disappearance of endoscopic findings suggesting the presence of a tumor; the entire esophagus could be observed using endoscopy; negative endoscopic biopsy findings from the area of the primary lesion; no endoscopic findings of active esophagitis; and endoscopy showed no hypoechoic nodules at all anatomical levels of the esophagus.\u003c/p\u003e \u003cp\u003eEndoscopic Partial Response (ePR): The tumor or surrounding bulge shrank or became flattened, the ulcer shrank; and endoscopy showed a decrease in the T stage from baseline.\u003c/p\u003e \u003cp\u003eEndoscopic Stable Disease (eSD): The tumor mass showed no significant change from baseline, and endoscopy showed a T stage after treatment equal to that at baseline.\u003c/p\u003e \u003cp\u003eEndoscopic Progressive Disease (ePD): The tumor grew significantly larger or progressed, and endoscopy indicated an increase in the T stage from baseline.\u003c/p\u003e \u003cp\u003eThe endoscopic objective response rate (eORR) was defined as the sum of eCR and ePR.\u003c/p\u003e \u003cp\u003eTwo senior imaging specialists and endoscopists reviewed all CT and endoscopy imaging data independently, and clinical staging was performed according to the TNM classification (8th Edition). (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eThe Mann-Whitney U test was used to compare continuous distributed variables, and the Wilcoxon signed-rank test was used to compare two related categorical variables among groups. All reported \u003cem\u003ep\u003c/em\u003e-values were two-tailed. A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. All analyses were performed using the SPSS 26.0 software package (SPSS, Chicago, IL, USA), and graphs were generated with GraphPad Prism version 9.0.3 (GraphPad Software, San Diego, CA, USA) and R 4.0.3.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eA total of 47 patients were enrolled in this study from May 2020 to December 2021 at Sun Yat-sen University Cancer Center. A total of 43 patients who had finished three courses of PD-1-based neoadjuvant immunochemotherapy were finally enrolled for analysis. Among them, thirty-eight patients were male, and nine patients were female. The median age of the entire cohort was 58.0 years (range 44\u0026ndash;70 years). Eleven (23.4%) patients had stage II disease; thirty-six (76.6%) patients had stage III disease. More details of the clinical baseline characteristics of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;43\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (IQR*), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (44\u0026ndash;70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (79.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Site, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper third\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiddle third\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (39.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLower third\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor differentiation, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerately\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (62.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoorly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (74.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical T stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (27.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecT4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical N stage, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (41.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (53.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecN3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG score, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (88.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*IQR, interquartile range.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eThe clinical stage was assessed using endoscopy (combined with EUS and mucosa biopsy) or computed tomography (CT) and was classified according to the Union for International Cancer Control (UICC) tumor\u0026ndash;node\u0026ndash;metastasis (TNM) classification, 8th Edition.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eThree courses of treatment did not increase TRAEs compared to the second course (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Neoadjuvant use of camrelizumab in combination with nab-paclitaxel and capecitabine did not cause any previously unreported toxicities. All patients reported at least one adverse event during the neoadjuvant treatment, and most of the TRAEs were grade 1\u0026ndash;2. The most common grade 1\u0026ndash;2 TRAEs of the second and third courses of treatment were alopecia (30/69.7% versus 31/72.0%), reactive cutaneous capillary endothelial proliferation (RCCEP) (24/55.8% versus 28/65.1%), fatigue (25/58.1% versus 25/58.1%), anemia (23/53.5% versus 22/51.2%), muscle soreness (18/41.8% versus 18/41.8%), numbness of limbs (20/46.5% versus 20/46.5%), and increased alanine transaminase (9/20.9% versus 10/23.3%). Leukopenia occurred in only three (6.4%) patients in the second and third courses of treatment. Two (4.6%) in the second courses developed grade 3\u0026thinsp;\u0026minus;\u0026thinsp;4 adverse events treatment, including fatigue and limb numbness. Four (9.3%) in the third course of treatment developed grade 3\u0026thinsp;\u0026minus;\u0026thinsp;4 adverse events, including one with fatigue, one with limb numbness, one with anemia, and one with myocarditis. No grade 5 events or treatment-related mortality were observed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of treatment-related adverse events.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAll events\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eThe second course of treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eThe third course of treatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade 1\u0026ndash;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGrade 1\u0026ndash;2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGrade 3\u0026ndash;4\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlopecia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e31 (72.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReactive cutaneous capillary endothelial proliferation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28 (65.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28 (65.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (53.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (58.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24 (55.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (53.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (53.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23 (53.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22 (51.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle soreness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e18 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimb numbness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (44.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (46.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19 (44.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased alanine transaminase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (20.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10 (23.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstipation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7 (16.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related hyperthyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related hypothyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.317\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related myocarditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCough\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related hepatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmune-related nephritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eAll adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eDownstaging analysis\u003c/h2\u003e \u003cp\u003eAfter the second and third courses of neoadjuvant immunochemotherapy, CT assessment found 28/65.1% versus 35/81.4% of patients had T downstaging, and 23/53.5% versus 26/60.5% of patients had N downstaging, respectively. Similarly, the endoscopy assessment found 17/63.0% versus 24/88.9% of patients had T downstaging, and 18/66.7% versus 21/77.8% of patients had N downstaging, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). We found that the third course of treatment was higher than the second course in terms of T downstaging and N downstaging. In addition, one course of neoadjuvant therapy based on the second course increased the CT and the endoscopy T downstaging rates by 16.3% and 25.9%, and N downstaging rates by 7.0% and 11.1%, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical responses\u003c/h2\u003e \u003cp\u003eCT assessment: All 43 patients completed the CT assessment before treatment and the second and third courses after treatment. According to the RECIST 1.1 criteria, the second and third courses of neoadjuvant therapy resulted in a CR of 1/2.3% versus 3/7.0%, a PR of 28/65.1% versus 32/74.4%, and an SD of 14/32.6% vs. 8/18.6%, respectively. No patients with PD were found (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The objective response rate ORR was 67.4% versus 81.0%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Compared with the second course of treatment, the third course of treatment could further convert 4/14.3% of PR patients into CR and 6/42.9% of SD patients into PR. The ORR of the third course of treatment was further increased by 13.6% compared with the second course of treatment, and statistical differences were found (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEndoscopy assessment: A total of 27 patients completed the endoscopy assessment before and after the second and third courses of treatment. According to the endoscopic diagnostic criteria of the Japanese Esophageal Society, the second and third courses of neoadjuvant therapy resulted in a 0/0% versus 5/18.5% of eCR, 17/63.0% versus 18/66.7% of ePR, and 10/37.0% versus 4/14.8% of eSD, respectively. No patients with ePD were found (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The objective response rate eORR was 63.0% versus 85.2% respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Compared with the second course of treatment, the third course of treatment could further convert 5/29.4% of ePR patients to eCR, and 6/33.3% of eSD patients to ePR. The third course of eORR was further increased by 22.0% compared with the second course of treatment, and there was a statistical difference (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eNeoadjuvant therapy combined with surgery is the standard treatment regimen for patients with locally advanced ESCC. Two courses of neoadjuvant chemoradiotherapy can benefit patient survival (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). However, a recent study reported that there is still a 23.9% distant metastasis rate remaining after two courses of treatment (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). For neoadjuvant immunochemotherapy, most clinical trials currently also focus on the effect of a two-courses regimen, which may lead to the limited efficacy of immunotherapy. In our previous pilot study (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), we found that three courses of neoadjuvant immunochemotherapy were safe, feasible, and effective. These results were further confirmed in this phase II trial.\u003c/p\u003e \u003cp\u003eIn terms of safety, the toxicity of the third course of camrelizumab combined with chemotherapy compared with the second course was tolerable. Most TRAEs were grade 1\u0026ndash;2, similar to other two-course regimens. RCCEP induced by camrelizumab was found in 28/65.1% of patients after the third course of treatment, compared with 24/55.8% of patients in the second course of treatment. Similarly, the overall incidence of RCCRP after the third course of treatment was higher than that reported in other two-cycle regimen studies (26.1%-39.1%) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). This difference may be due to the addition of one course of camrelizumab. Notably, a previous study (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) showed that more than half of patients developed leukopenia during neoadjuvant immunochemotherapy or chemoradiotherapy. Severe leukopenia may even lead to dose reduction or treatment discontinuation. In our cohort, the incidence of leukopenia was relatively low. Only 6.4% of patients had leukopenia during the second and third cycles. This difference can be attributed to two reasons. First, we use G-CSF prophylactically after each immunochemotherapy course. Second, we replaced platinum with capecitabine in our immunochemotherapy regimen. Capecitabine, an oral drug that can be converted to fluorouracil (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), in combination with paclitaxel, has shown comparable efficacy and lower toxicity than platinum-based regimens in head and neck squamous cell carcinoma and breast cancer (\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The drug's low toxicity makes it suitable for use in combination with PD-1 blockers. Overall, the toxicity of the three-course treatment regimen was manageable and worthy of promotion.\u003c/p\u003e \u003cp\u003eIn terms of efficacy, this study compared the CT and endoscopy assessment results of the second and third courses of treatment employing self-control. We found that an additional course of treatment after the second course was effective, increasing the CT and endoscopy T downstaging rates by 16.3% and 25.9%, N downstaging rates by 7.0% and 11.1%, and ORR by 13.6 and 22.0%, respectively. We observed that the T downstaging, N downstaging, ORR, CR, and PR rate assessed by CT or endoscopy after the third course of treatment was higher than that of the second course of therapy, and the SD rate was lower than the second course of treatment. Similarly, a recent randomized controlled non-small cell lung cancer clinical study (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) showed that after neoadjuvant immunochemotherapy in patients with lung squamous cell carcinoma, the MPR induced by three courses of neoadjuvant therapy was 60%, compared with 43.8% after two courses of treatment. Both groups were well tolerated; only 5% (3/60) had grade 3 immune-related adverse events. In 2021, a randomized controlled study (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) in Japan found that three courses of neoadjuvant chemotherapy resulted in better clinical responses without increased TRAEs or complications than two courses of neoadjuvant chemotherapy.\u003c/p\u003e \u003cp\u003eIt is worth noting that previous studies reported that the degree of lymphocyte infiltration in tumor tissue increased with more treatment courses (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Another bladder cancer study also suggested that after three courses of anti-PD-1 therapy, the density of CD8\u003csup\u003e+\u003c/sup\u003e T lymphocytes infiltrating the tumor stroma was significantly higher than before treatment (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Those studies imply that more courses of immunotherapy may improve efficacy by fully activating the immune system to remove minimal residual tumor lesions. Therefore, immune system activation appeared to be more thorough after three courses of therapy than two courses, which may explain why three courses of treatment are more effective than two courses.\u003c/p\u003e \u003cp\u003eOur findings suggested that three courses of treatment showed better clinical responses without increased TRAEs compared with two courses of treatment. However, short-term efficacy may affect long-term survival. Therefore, it is necessary to perform studies with large sample sizes in the future for further verification. Nonetheless, our study has some limitations. First of all, the sample size of our study was small. Second, this study is a single-center study. However, the single-center study design and self-controlled study approach made our data more consistent.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, the downstaging rate and ORR of three courses of immunochemotherapy were better than that of two courses of treatment and without increasing TRAEs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to acknowledge all patients participating in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e: \u003c/strong\u003eThis study was supported by the Science and Technology Program of Guangzhou, China (202103000064) and the Science and Technology Project of Guangdong Esophageal Cancer Research Institute (M202017).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interests: \u003c/strong\u003eThe author declares no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. 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JAMA Oncol. 2020;6(6):856\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJapan Esophageal S. Japanese Classification of Esophageal Cancer, 11th Edition: part II and III. Esophagus. 2017;14(1):37\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRice TW, Ishwaran H, Ferguson MK, Blackstone EH, Goldstraw P. Cancer of the Esophagus and Esophagogastric Junction: An Eighth Edition Staging Primer. J Thorac Oncol. 2017;12(1):36\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, et al. Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial. JAMA Surg. 2021;156(8):721\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu S, Wen J, Yang H, Li Q, Chen Y, Zhu C, et al. Recurrence patterns after neoadjuvant chemoradiotherapy compared with surgery alone in oesophageal squamous cell carcinoma: results from the multicenter phase III trial NEOCRTEC5010. Eur J Cancer. 2020;138:113\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Xing X, Yeung SJ, Wang S, Chen W, Bao Y, et al. Neoadjuvant programmed cell death 1 blockade combined with chemotherapy for resectable esophageal squamous cell carcinoma. J Immunother Cancer. 2022;10(1).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Yang Y, Liu Z, Fu X, Cai X, Li H, et al. Multicenter, single-arm, phase II trial of camrelizumab and chemotherapy as neoadjuvant treatment for locally advanced esophageal squamous cell carcinoma. J Immunother Cancer. 2022;10(3).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBentzen JKD, Kristensen CA, Overgaard M, Rytter C, Jensen K, Hansen HS. A Non Platinum Regimen for the Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Region. Results From an Extended Phase II Study With Paclitaxel and Capecitabine. Front Oncol. 2018;8:243.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBentzen JD, Hansen HS. Phase II analysis of paclitaxel and capecitabine in the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region. Head Neck. 2007;29(1):47\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcDonald F, Miles D. Xeloda and Taxotere: a review of the development of the combination for use in metastatic breast cancer. Int J Clin Pract. 2003;57(6):530\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShiraishi O, Makino T, Yamasaki M, Tanaka K, Yamashita K, Ishida T, et al. Two versus three courses of preoperative cisplatin and fluorouracil plus docetaxel for treating locally advanced esophageal cancer: short-term outcomes of a multicenter randomized phase II trial. Esophagus. 2021;18(4):825\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNecchi A, Anichini A, Raggi D, Briganti A, Massa S, Lucian\u0026ograve; R, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018;36(34):3353\u0026ndash;60.\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":"Esophageal cancer, Immunochemotherapy, three courses of treatment.","lastPublishedDoi":"10.21203/rs.3.rs-2301453/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2301453/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Immune checkpoint (ICI) monotherapy and neoadjuvant immunochemotherapy has shown promising results in esophageal carcinoma. However, it is still unclear whether more courses in immunochemotherapy are better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This was a secondary analysis of the ChiCTR2000029807 clinical trial. Locally advanced ESCC patients have to receive three courses of camrelizumab (200mg every three weeks) plus nab-paclitaxel (260 mg/m2 every three weeks) and capecitabine (1250 mg/m2 every three weeks) before undergoing surgery. Patients received safety assessment, CT, and endoscopy (with endoscopic ultrasonography and mucosal biopsy) efficacy assessments before and in the second and third courses of treatment. We used the second and third courses' CT and endoscopic assessment results for comparison.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-PD-1 therapy and radical surgical resection. All Forty-three patients received safety assessments and CT efficacy assessments. Sixteen patients did not undergo an endoscopy examination during the second course of treatment because of esophageal stenosis or refused the endoscopy examination. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, which continued to increase the CT and endoscopy T downstaging rates by 16.3% and 25.9%, N downstaging rates by 7.0% and 11.1%, and ORR by 13.6 and 22.0%, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: No matter downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs. (www.chictr.org.cn number, ChiCTR2000029807)\u003c/p\u003e","manuscriptTitle":"Three courses of treatment increase the efficacy of neoadjuvant immunochemotherapy in patients with local advanced ESCC without increasing TRAEs compared with two courses of treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-11-28 18:58:45","doi":"10.21203/rs.3.rs-2301453/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":"235fb638-666a-4ac3-99bf-37ffa2c19021","owner":[],"postedDate":"November 28th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-11-28T18:58:47+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-28 18:58:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2301453","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2301453","identity":"rs-2301453","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}