{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:53:47Z","timestamp":1759971227387,"version":"build-2065373602"},"reference-count":18,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2025,9,21]],"date-time":"2025-09-21T00:00:00Z","timestamp":1758412800000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Shanghai Key Laboratory of Proton","award":["23dz2261000"],"award-info":[{"award-number":["23dz2261000"]}]},{"name":"Clinical Research Special Project of Shanghai Municipal Health","award":["202340226"],"award-info":[{"award-number":["202340226"]}]},{"name":"Beijing Science and Technology Innovation Medical Development Foundation","award":["KC2021-JX-0170-9"],"award-info":[{"award-number":["KC2021-JX-0170-9"]}]},{"name":"Noncommunicable Chronic Diseases-National Science and Technology Major Project","award":["2023ZD0502200\uff0c2023ZD0502206"],"award-info":[{"award-number":["2023ZD0502200\uff0c2023ZD0502206"]}]},{"DOI":"10.13039\/501100008750","name":"SHDC","doi-asserted-by":"crossref","award":["SHDC2020CR2052B","SHDC2020CR4070"],"award-info":[{"award-number":["SHDC2020CR2052B","SHDC2020CR4070"]}],"id":[{"id":"10.13039\/501100008750","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shanghai Science and Technology Innovation Action Plan Medical Innovation Research Project","award":["23Y11904700"],"award-info":[{"award-number":["23Y11904700"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,9,4]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Oesophageal squamous cell carcinoma (ESCC) ranks among the most aggressive malignancies and carries a poor prognosis. Lymphocytes play a key role in combating infections and suppressing tumourigenesis. Many studies have established a close association between lymphocyte depletion and adverse therapeutic outcomes in oesophageal cancer. Nevertheless, high-quality data validating the clinical efficacy and safety of lymphocyte-sparing thoracic radiotherapy regimens for ESCC remain scarce.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Materials and methods<\/jats:title>\n                  <jats:p>This prospective, open-label, randomised controlled trial aims to determine whether lympho-nTRT-ESO reduces the incidence of acute grade 3\u20134 lymphopaenia in patients with ESCC undergoing neoadjuvant chemoradiotherapy (nCRT), compared with conventional thoracic radiotherapy (RT). A total of 212 participants will be enrolled and randomly allocated in a 1:1 ratio to either the lymphocyte-sparing RT (RT) group or the conventional RT group. All patients will receive standardised nCRT, which will deliver a total dose of 41.4\u2009Gy in 23 fractions. For the lymphocyte-sparing RT group, RT planning prioritises the planning target volume (PTV) coverage and conventional organ-at-risk (OAR) constraints while applying dose constraints to lymphocyte-related OARs (LOARs). These LOARs include the T1\u2013T12 vertebral bodies, ribs, spleen and major cardiovascular structures (heart and large blood vessels), with optimisation performed only after PTV coverage and standard OAR constraints are satisfied.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Ethics and dissemination<\/jats:title>\n                  <jats:p>This trial was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (RJ 2024\u2013210) on 11 July 2024 and registered on ClinicalTrials.gov (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06596954\">NCT06596954<\/jats:ext-link>) before participant recruitment. All participants should provide written informed consent to be eligible. We planed to publish the primary and secondary results of this study in scientific peer-reviewed journals and present at radiation oncology conferences.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" specific-use=\"clinicaltrial \" xlink:href=\"NCT06596954\">NCT06596954<\/jats:ext-link>\n                  <\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-096803","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T13:06:33Z","timestamp":1759928793000},"page":"e096803","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Sparing lymphocytes during preoperative adjuvant radiotherapy for oesophageal squamous cell carcinoma (SPARE): protocol for an open-label, randomised controlled trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct06596954","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06596954","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06596954","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5484-3343","authenticated-orcid":false,"given":"Wei-Xiang","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shujun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yibin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8812-622X","authenticated-orcid":false,"given":"Jiayi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4197-8887","authenticated-orcid":false,"given":"Shengguang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiao Tong University Medical School of medicine, Shanghai, China"},{"name":"Shanghai Key Laboratory of Proton-therapy, shanghai, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,9,21]]},"reference":[{"key":"2025092119300996000_15.9.e096803.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2025092119300996000_15.9.e096803.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(00)02570-4"},{"key":"2025092119300996000_15.9.e096803.3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.281.17.1623"},{"key":"2025092119300996000_15.9.e096803.4","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.03614"},{"key":"2025092119300996000_15.9.e096803.5","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1001\/jamasurg.2021.2373","article-title":"Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial","volume":"156","author":"Yang","year":"2021","journal-title":"JAMA Surg"},{"key":"2025092119300996000_15.9.e096803.6","doi-asserted-by":"crossref","first-page":"2568","DOI":"10.1245\/s10434-023-14811-7","article-title":"Perioperative lymphopenia is associated with increased risk of recurrence and worse survival following hepatectomy for hepatocellular carcinoma","volume":"31","author":"Tsilimigras","year":"2024","journal-title":"Ann Surg Oncol"},{"key":"2025092119300996000_15.9.e096803.7","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2023.1278723","article-title":"Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models","volume":"13","author":"van Rossum","year":"2023","journal-title":"Front Oncol"},{"key":"2025092119300996000_15.9.e096803.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2023.110030"},{"key":"2025092119300996000_15.9.e096803.9","doi-asserted-by":"crossref","first-page":"59757","DOI":"10.18632\/oncotarget.15760","article-title":"Association of immunologic markers from complete blood counts with the response to preoperative chemoradiotherapy and prognosis in locally advanced rectal cancer","volume":"8","author":"Jung","year":"2017","journal-title":"Oncotarget"},{"key":"2025092119300996000_15.9.e096803.10","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.ijrobp.2016.11.027","article-title":"Bone marrow-sparing intensity modulated radiation therapy with concurrent cisplatin for stage IB-IVA cervical cancer: an International Multicenter Phase II Clinical Trial (INTERTECC-2)","volume":"97","author":"Mell","year":"2017","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"2025092119300996000_15.9.e096803.11","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.radonc.2018.02.025","article-title":"High lymphocyte count during neoadjuvant chemoradiotherapy is associated with improved pathologic complete response in esophageal cancer","volume":"128","author":"Fang","year":"2018","journal-title":"Radiother Oncol"},{"key":"2025092119300996000_15.9.e096803.12","doi-asserted-by":"crossref","first-page":"e645","DOI":"10.1093\/oncolo\/oyad109","article-title":"Less irradiation to lymphocyte-related organs reduced the risk of G4 lymphopenia in esophageal cancer: re-analysis of prospective trials","volume":"28","author":"Tseng","year":"2023","journal-title":"Oncologist"},{"key":"2025092119300996000_15.9.e096803.13","doi-asserted-by":"crossref","first-page":"e606","DOI":"10.1093\/oncolo\/oyad094","article-title":"Association Between Lymphopenia and Survival Outcomes in Esophageal Carcinoma Patients Receiving Combined Immunotherapy and Chemoradiotherapy","volume":"28","author":"Cheng","year":"2023","journal-title":"Oncologist"},{"key":"2025092119300996000_15.9.e096803.14","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1111\/1759-7714.14898","article-title":"Pretreatment absolute lymphocyte count is an independent predictor for survival outcomes for esophageal squamous cell carcinoma patients treated with neoadjuvant chemoradiotherapy and pembrolizumab: An analysis from a prospective cohort","volume":"14","author":"Qi","year":"2023","journal-title":"Thorac Cancer"},{"key":"2025092119300996000_15.9.e096803.15","doi-asserted-by":"crossref","DOI":"10.1016\/j.ijrobp.2024.07.1777","article-title":"First exploration of the characterization and dosimetric predictors for absolute lymphocyte count changes during nCRT with or without pembrolizumab for esophageal squamous cell carcinoma: an analysis of a prospective cohort","volume":"120","author":"Qi","year":"2024","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"2025092119300996000_15.9.e096803.16","doi-asserted-by":"crossref","DOI":"10.1177\/1758835920926822","article-title":"A review of radiation-induced lymphopenia in patients with esophageal cancer: an immunological perspective for radiotherapy","volume":"12","author":"Wang","year":"2020","journal-title":"Ther Adv Med Oncol"},{"key":"2025092119300996000_15.9.e096803.17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.radonc.2022.10.019","article-title":"Lymphocyte sparing normal tissue effects in the clinic (LymphoTEC): a systematic review of dose constraint considerations to mitigate radiation-related lymphopenia in the era of immunotherapy","volume":"177","author":"Venkatesulu","year":"2022","journal-title":"Radiother Oncol"},{"key":"2025092119300996000_15.9.e096803.18","doi-asserted-by":"crossref","first-page":"224","DOI":"10.2307\/3577549","article-title":"Radiosensitivity of CD4 or CD8 positive human T-lymphocytes by an in vitro colony formation assay","volume":"123","author":"Nakamura","year":"1990","journal-title":"Radiat Res"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2024-096803","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T13:06:36Z","timestamp":1759928796000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2024-096803"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":18,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,21]]},"published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1136\/bmjopen-2024-096803"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2024-096803","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]}}}