Skeletal Muscle Volume by 3D Imaging and Long-term Survival in Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemotherapy

Skeletal Muscle Volume by 3D Imaging and Long-term Survival in Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemotherapy | 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 Skeletal Muscle Volume by 3D Imaging and Long-term Survival in Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemotherapy yuto maeda, Keisuke Kosumi, Hiroki Tsubakihara, Yoshihiro Hara, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6854181/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 Neoadjuvant chemotherapy (NAC) is commonly administered to improve long-term survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). This study investigated the impact of perioperative skeletal muscle mass index (SMI), assessed by 3D imaging, on survival outcomes. Methods We retrospectively reviewed 139 consecutive ESCC patients who underwent surgical resection following NAC. SMI was measured pre-NAC and post- NAC using 3D imaging, and post-NAC SMI was stratified into quartiles (Q1-Q4). We evaluated overall survival (OS) and relapse-free survival (RFS) in relation to these quartiles. Results Q1 (lowest SMI) group was significantly correlated with postoperative pneumonia (p = 0.03) and had poorer 3-year OS and RFS compared with Q2-Q4 group (P < 0.01). Multivariate analysis identified Q1 as an independent predictor of poor OS (hazard ratio, 3.22; 95%Confidence Interval, 1.86–5.57; P < 0.01). Conclusions Low SMI after NAC assessed by 3D imaging is an independent predictor of poor overall and relapse-free survival in patients undergoing radical resection for ESCC. These findings underscore the importance of maintaining SMI in 3D imaging after NAC. Gastrointestinal Surgery 3D imaging Esophageal cancer Neoadjuvant chemotherapy Skeletal muscle Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The incidence of esophageal squamous cell carcinoma (ESCC) has shown a progressive increase owing to the increased prevalence of the associated risk factors, such as tobacco and alcohol use. 1 , 2 Surgical resection remains the cornerstone of curative treatment for locally advanced resectable ESCC. However, treatment strategies have evolved to include definitive chemoradiotherapy (CRT) with active surveillance and salvage esophagectomy when necessary for local tumor control. 3 In Japan, neoadjuvant chemotherapy (NAC) is commonly employed for locally advanced ESCC due to its demonstrated benefits in improving long-term survival. 4 Despite these advancements, the adverse effects of NAC, including systemic toxicity, selection of chemoresistant tumor clones, and potential delays in surgery, present significant clinical challenges. Therefore, precise preoperative risk stratification after NAC is crucial to optimize treatment strategies and improve long-term outcomes. 5 – 7 Recent studies have highlighted the prognostic significance of skeletal muscle mass index (SMI) in gastrointestinal cancers. Specifically, preoperative sarcopenia has been associated with poor prognosis. 8 Sarcopenia is characterized by reduced muscle strength and walking speed and is commonly assessed using the SMI. Standardized methods for evaluating SMI are lacking, but computed tomography (CT) has been utilized as a screening tool 9 . NAC for ESCC has been reported to reduce SMI, and preoperative imaging evaluation is critical for improving long-term prognosis. 10 Traditionally, SMI evaluation has relied on cross-sectional areas obtained from CT images. However, these two-dimensional (2D) assessments have limitations in accurately capturing volumetric changes in muscle mass. Advances in imaging technology now enable 3D analysis using CT images, allowing for more precise and detailed evaluation of muscle volume and distribution. 11 However, studies utilizing three-dimensional (3D) imaging analysis to evaluate pre-operative SMI are scarce, and the prognostic significance of such assessments remains unclear. This 3D analysis provides the potential to better capture changes in skeletal muscle mass induced by NAC, thereby improving postoperative risk assessments and optimizing treatment strategies tailored to individual patients. The aim of this study is to elucidate the impact of post-NAC SMI, assessed using 3D imaging, on the prognosis of patients undergoing curative resection for ESCC. Materials and Methods Patient and Clinical Data This was a retrospective study of 139 consecutive patients who underwent operative resection for ESCC after NAC at the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University between January 2007 and December 2018. Data pertaining to the following clinical variables were retrieved: basic patient information (age, sex, and body mass index), total psoas volume (TPV) (pre-NAC and post-NAC), tumor characteristics (location and Union for International Cancer Control [UICC 8th edition] stage), regimen of NAC (FP: 5-fluorouracil and cisplatin, or DCF: docetaxel, cisplatin, and 5-fluorouracil), surgical technique (open esophagectomy, and minimally invasive esophagectomy), and postoperative complications. Postoperative complications were evaluated using the Clavien–Dindo classification system, with major complications defined as those of grade 3 or higher 12 . This study received approval from the Ethics Review Board of Kumamoto University Hospital (Approval No. 1909). All research procedures were conducted in compliance with the ethical principles outlined in the Declaration of Helsinki (1964 and subsequent amendments), as well as with institutional and national guidelines. Written informed consent, or its equivalent, was obtained from all participants prior to their inclusion in the study. Neoadjuvant treatment protocols and surgery Patients underwent two cycles of NAC with either FP or DCF, administered at 3–4 week intervals. In cases of severe adverse effects, such as myelosuppression or renal impairment, chemotherapy doses were reduced or discontinued, and surgery was performed without a second cycle. Surgical resection took place at least 3–4 weeks after NAC completion. Either open thoracic or thoracoscopic approaches were used. Esophagectomy was performed with either two-field or three-field lymphadenectomy, ensuring total mediastinal lymph node dissection. Gastric conduit reconstruction was carried out using either a hand-assisted laparoscopic or open laparotomy approach. All patients received standard enteral nutrition via jejunostomy. Imaging analysis SMI was assessed using CT scans obtained pre- and post-NAC, measuring the total psoas volume (TPV) with Ziostation2® (Ziosoft Inc., Tokyo, Japan). The thinnest available slices (0.625–5 mm) were selected for analysis. SMI was defined as TPV measured by the software divided by the square of the patient’s height (m²). Treatment Strategy and Follow-up Assessment To evaluate the clinical stage (cStage) prior to surgery, patients underwent routine examinations, including upper and lower gastrointestinal endoscopy, endoscopic ultrasound, and thoracoabdominal computed tomography (CT). Pathological staging was determined in accordance with the 8th edition of the Union for International Cancer Control (UICC) classification. After surgery, patients were followed up every three months. Recurrence was monitored through clinical assessments and CT imaging. Tumor markers were measured quarterly, and whole-body CT from the neck to pelvis was performed at least twice per year for a five-year period. Overall survival (OS) was defined as the interval from surgery to death from any cause or the last follow-up. Relapse-free survival (RFS) referred to the time from surgery until the first evidence of recurrence or death from any cause. Statistical analysis Comparisons between groups regarding clinicopathological and surgical-related characteristics were carried out using the chi-square test for categorical data and the Mann–Whitney U test for continuous variables. A P-value of less than 0.05 was considered statistically significant. The Kaplan–Meier method was applied for survival analysis, with univariate survival differences evaluated through the log-rank test. To determine hazard ratios (HRs), a multivariate Cox proportional hazards model was employed. Variables with a P-value below 0.05 were incorporated into the multivariate model and were further regarded as independent prognostic factors if they remained statistically significant. Results Demographic and clinical characteristics A total of 171 ESCC patients were assessed for eligibility, of whom 32 were excluded due to non-resectability or imaging difficulties (such as halo artifacts or cases where imaging did not include the pelvic region), resulting in a final cohort of 139 patients (Fig. 1 ). The median age was 68 years (range: 46–82), and 85% (n = 119) of the patients were male. Patients were stratified into quartiles (Q1–Q4) based on post-NAC SMI, with Q1 representing the lowest SMI and Q4 the highest (Table 1). The median pre-NAC SMI was 122.3 (48.6–214.9), and the post-NAC SMI was 115.7 (58.2–197.7), indicating a significant reduction in muscle mass following NAC (P < 0.01). Correlation Between BMI and SMI Spearman’s rank correlation analysis demonstrated a slightly positive relationship between BMI and SMI both before and after NAC (pre-NAC: R² = 0.37, P < 0.01; post-NAC: R² = 0.46, P < 0.01) (Table 2). Figure 2 shows the degree of decrease in SMI and BMI after NAC. Compared to pre-NAC level, the SMI showed a significant decrease after NAC in the overall cohort as well as in Q1-Q3 (Fig. 2 A and B). In contrast, the extent of decrease in BMI after NAC was not significant in the overall cohort and in any of the groups (Fig. 2 C and D). Comparison of SMI 2D and 3D As shown in the Fig. 3 , we evaluated SMI changes pre-NAC and post- NAC using both 3D and 2D. The 3D analysis demonstrated a significant reduction in SMI post- NAC compared to pre-NAC (Fig. 3 A and B), whereas 2D measurements did not clearly capture this atrophy (Fig. 3 C and D), highlighting the superior precision and detail of 3D evaluation. Impact of SMI on short- and long-term survival Table 1 summarizes the clinicopathological features, perioperative factors, and survival outcomes across different SMI quartiles. Q1 had significantly lower pre-NAC SMI compared to Q2–4 and showed the greatest reduction in SMI after NAC (P < 0.01). There were no significant between-group differences with respect to age, sex, performance status, regimen, stage, operative time, or blood loss. In terms of SMI change, Q1 showed an 8.8% decrease in SMI after NAC, which was significantly greater compared to Q2–4 (P < 0.01), as indicated by the Change of SMI. Q1 had a significantly higher incidence of postoperative pneumonia than Q2–4 (p = 0.03). Figure 4 shows the Kaplan–Meier curves for OS in each group. Q1 had significantly worse 3-year OS than Q2–4 (log-rank P < 0.01). Similarly, 3-year RFS was significantly worse in Q1 than in Q2–4 (log-rank P < 0.01). Multivariate analysis identified Q1 as an independent factor associated with poor OS (HR, 2.95; 95% CI, 1.703–5.124; P < 0.01) (Table 3). Discussion This study provides novel insights by being to demonstrate the prognostic impact of post- NAC SMI in ESCC patients through 3D imaging analysis. Unlike conventional cross-sectional measurements, the use of 3D volume analysis allowed for a more detailed and accurate assessment of muscle loss. In a previous study, excessive muscle loss after neoadjuvant concurrent CRT was found to be a significant poor prognostic factor for disease recurrence and OS in ESCC patients who underwent surgery. 13 However, these studies typically relied on cross-sectional measurements and did not classify patients based on post-NAC SMI. Our study divided patients into quartiles according to post-NAC SMI, considering that patients with initially low pre-NAC SMI may show a lower reduction rate, which could lead to misinterpretation of their actual muscle depletion. This approach allowed for a more precise evaluation of muscle status after NAC. One of the key strengths of this study is the utilization of 3D volumetric analysis for SMI assessment. Traditional 2D measurements might not fully capture skeletal muscle atrophy, whereas 3D evaluation enables a more comprehensive assessment of muscle volume changes. While previous research has relied on total psoas area (TPA) measurements, recent advances in imaging have shifted the focus toward volumetric assessment, which provides a more accurate representation of muscle status. 14 , 15 However, it is debatable whether area or volume is useful in CT. Our findings suggest that concerted efforts should be made to minimize the decline in SMI from pre- NAC to post- NAC to improve prognosis after ESCC surgery. For example, prehabilitation during NAC has been shown to promote retention of muscle and quality of life. 16 Dietary therapy using enteral nutrition or other methods for patients with tumor-induced symptoms or poor oral intake due to chemotherapy may also prevent reduction in SMI. 17 In addition, ESCC patients with significantly reduced SMI after NAC may have an improved prognosis if nutritional therapy is administered prior to surgery for ESCC. In contrast, studies in gastric cancer patients have shown that enteral nutrition during neoadjuvant chemotherapy can significantly reduce perioperative inflammation and boost immune function. 18 These findings suggest that nutritional therapy during NAC might help preserve SMI, thereby improving outcomes. As a result, nutritional support is likely to gain more attention as a complementary treatment during NAC for ESCC in the future. 18 We observed a slight correlation between SMI and BMI trends in our cohort; however, it is crucial to note that the volumetric decrease in SMI was often not mirrored by corresponding changes in BMI, highlighting the limitations of BMI in accurately capturing skeletal muscle loss. For instance, patients in Q1 experienced substantial skeletal muscle atrophy, particularly post- NAC, despite less noticeable changes in BMI. This suggests that muscle volume reduction may occur in a way that is not externally apparent, potentially due to factors like prolonged bed rest and chemotherapy toxicity. These findings underscore the importance of volumetric muscle assessment over BMI alone for prognostic evaluations. Some limitations of this study should be addressed. First, this was a single-center, retrospective study. Second, whether SMI depletion reflects the pre-cancer state or results from anorexia and cachexia cannot be easily determined. Third, the neoadjuvant chemotherapy regimens were not uniform among patients, which may have influenced both muscle loss and treatment outcomes. However, the present study shows a poor prognosis of low SMI after NAC for ESCC, underscoring the importance of nutritional management during NAC. In conclusion, 3D volumetric assessment of SMI post- NAC revealed that lower SMI is significantly associated with poorer OS and RFS in ESCC patients undergoing radical resection. This study underscores the potential of 3D imaging as a critical tool in the prognostic assessment and management of ESCC. Declarations Acknowledgments We thank H. Nikki March, PhD, Edanz Group (https://en-author-services.edanz.com/ac), for editing the draft of this manuscript. Approval of the research protocol The authors declare that they have no funding statement. N/A Informed Consent Written informed consent was obtained from all patients. N/A Registry and the Registration No. of the study/Trial Not applicable. Animal Studies Not applicable. Conflicts of interest Authors declare no conflict of interest for this article. Ethics statement Written informed consent was waived for the patients because of the retrospective nature of the study. Author contributions Study concept and design: Y. Maeda and M. Iwatsuki; acquisition of data: Y Maeda, M. Iwatsuki; analysis and interpretation of data: Y Maeda, M. Iwatsuki; writing of the manuscript: Y. Maeda, and M. Iwatsuki. All authors approved the final manuscript.. References Melhado RE, Alderson D, Tucker O (2010) The changing face of esophageal cancer. Cancers (Basel) Jun 28(3):1379–1404 Kawakatsu Y, Koyanagi YN, Oze I et al (2020) Association between Socioeconomic Status and Digestive Tract Cancers: A Case-Control Study. Cancers (Basel) Nov 4 ;12(11) Obermannová R, Alsina M, Cervantes A et al (2022) Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol Oct 33(10):992–1004 Sjoquist KM, Burmeister BH, Smithers BM et al (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol Jul 12(7):681–692 Kato H, Nakajima M (2013) Treatments for esophageal cancer: a review. Gen Thorac Cardiovasc Surg Jun 61(6):330–335 Nakatani M, Migita K, Matsumoto S et al (2017) Prognostic significance of the prognostic nutritional index in esophageal cancer patients undergoing neoadjuvant chemotherapy. Dis Esophagus Aug 1(8):1–7 Porschen R, Fischbach W, Gockel I et al (2019) [Not Available]. Z Gastroenterol Mar 57(3):336–418 Huang CH, Lue KH, Hsieh TC, Liu SH, Wang TF, Peng TC (2020) Association Between Sarcopenia and Clinical Outcomes in Patients With Esophageal Cancer Under Neoadjuvant Therapy. Anticancer Res Feb 40(2):1175–1181 Daly ÉBNB, Power LE, Cushen DG, MacEneaney SJ, Ryan P (2018) Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition? J Cachexia Sarcopenia Muscle Apr 9(2):295–305 Jang MK, Park C, Hong S, Li H, Rhee E, Doorenbos AZ (2020) Skeletal Muscle Mass Change During Chemotherapy: A Systematic Review and Meta-analysis. Anticancer Res May 40(5):2409–2418 Werthel JD, Boux de Casson F, Burdin V et al (2021) CT-based volumetric assessment of rotator cuff muscle in shoulder arthroplasty preoperative planning. Bone Jt Open Jul 2(7):552–561 Clavien PA, Camargo CA Jr., Croxford R, Langer B, Levy GA, Greig PD (1994) Definition and classification of negative outcomes in solid organ transplantation. Application in liver transplantation. Ann Surg Aug 220(2):109–120 Yoon HG, Oh D, Ahn YC et al (2020) Prognostic Impact of Sarcopenia and Skeletal Muscle Loss During Neoadjuvant Chemoradiotherapy in Esophageal Cancer. Cancers (Basel) Apr 10 ;12(4) Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpern EF, Sumner JE (2002) CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques initial observations. Radiology Nov 225(2):416–419 Mozley PD, Schwartz LH, Bendtsen C, Zhao B, Petrick N, Buckler AJ (2010) Change in lung tumor volume as a biomarker of treatment response: a critical review of the evidence. Ann Oncol Sep 21(9):1751–1755 Allen SK, Brown V, White D et al (2022) Multimodal Prehabilitation During Neoadjuvant Therapy Prior to Esophagogastric Cancer Resection: Effect on Cardiopulmonary Exercise Test Performance, Muscle Mass and Quality of Life-A Pilot Randomized Clinical Trial. Ann Surg Oncol Mar 29(3):1839–1850 Luo C, Xie K, Zhang C et al (2022) Efficacy of immunonutritional supplement after neoadjuvant chemotherapy in patients with esophageal cancer. J Cardiothorac Surg Mar 19(1):41 Zong L, Li H, Li S (2019) Effects of neoadjuvant chemotherapy combined with enteral nutrition on perioperative immunity, inflammation and intestinal flora in gastric cancer patients. J buon May-Jun 24(3):1113–1119 Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations The authors declare no competing interests. Supplementary Files Supplementtable.docx table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6854181","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":468585565,"identity":"88e29a3e-61bd-409e-8d67-a3de68a5710a","order_by":0,"name":"yuto 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11:55:54","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6854181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6854181/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84505977,"identity":"ef4e3eee-ae47-409d-af55-d85ebef089e1","added_by":"auto","created_at":"2025-06-12 18:49:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":71262,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flowchart\u003c/p\u003e\n\u003cp\u003eThe 139 patients with esophageal squamous cell carcinoma were divided into male and female quartiles according to skeletal muscle index (SMI) (Q1–4), with Q1 having the lowest SMI and Q4 having the highest SMI.\u003c/p\u003e","description":"","filename":"Figure31.png","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/e71b3effa60f6a3d3b81120d.png"},{"id":84506765,"identity":"c21dc15b-4544-427a-8bc5-814f78926b5a","added_by":"auto","created_at":"2025-06-12 18:57:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":140558,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of pre- and pre-operative\u003cstrong\u003e \u003c/strong\u003eSMI and BMI in the overall cohort and in different SMI quartiles\u003c/p\u003e\n\u003cp\u003eAfter NAC, there was a significant decrease in SMI in the total cohort (A) and in each quartile except Q4 (B). BMI did not decrease significantly in the total cohort (C) and in different quartiles (D).\u003c/p\u003e","description":"","filename":"Figure32.png","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/9c4be06d77891df0d047fed5.png"},{"id":84505981,"identity":"a894a9a7-2a19-40e1-bfc3-3e650a78db7a","added_by":"auto","created_at":"2025-06-12 18:49:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3500725,"visible":true,"origin":"","legend":"\u003cp\u003eSMI evaluated in the same patient\u003c/p\u003e\n\u003cp\u003eSMI (A) evaluated in 3D in pre-NAC and SMI (B) in post-NAC; 2D evaluated SMI in pre-NAC (C) and post-NAC at umbilical height.\u003c/p\u003e","description":"","filename":"Figure33.png","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/b9a35677c81fda93a8adc3a6.png"},{"id":84506978,"identity":"32ac1822-a22c-47e0-bc44-9e4883042410","added_by":"auto","created_at":"2025-06-12 19:05:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":107533,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for the overall survival of esophageal squamous cell carcinoma patients in different quartiles of SMI\u003c/p\u003e\n\u003cp\u003eQ1 shows significantly worse 3-year OS and RFS than Q2–4 (3-year OS, Q1: 41.3%; Q2: 72.8%; Q3: 73.8%; Q4: 80.0%; log-rank P \u0026lt; 0.01; 3-year RFS, Q1: 32.6%; Q2: 61.2%; Q3: 59.8%; Q4: 71.4%; log-rank P \u0026lt; 0.01).\u003c/p\u003e","description":"","filename":"Figure34.png","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/0dd307034e9658094d982bc5.png"},{"id":84507509,"identity":"2984dc72-9e59-4360-927d-843c5eb24bbd","added_by":"auto","created_at":"2025-06-12 19:13:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4509013,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/967f9989-2166-466c-97d5-f86a7cfbdd46.pdf"},{"id":84506763,"identity":"d7383b68-b2ce-421f-a82c-ca7ac1e55866","added_by":"auto","created_at":"2025-06-12 18:57:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17101,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Supplementtable.docx","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/0285d5fcd99ec7aa64fe4990.docx"},{"id":84505980,"identity":"12d5c566-ca53-4716-886a-d3e767d5ef53","added_by":"auto","created_at":"2025-06-12 18:49:46","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36697,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"table.docx","url":"https://assets-eu.researchsquare.com/files/rs-6854181/v1/6a1f9bc5b4f96a1faa37c84b.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSkeletal Muscle Volume by 3D Imaging and Long-term Survival in Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemotherapy\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe incidence of esophageal squamous cell carcinoma (ESCC) has shown a progressive increase owing to the increased prevalence of the associated risk factors, such as tobacco and alcohol use. \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Surgical resection remains the cornerstone of curative treatment for locally advanced resectable ESCC. However, treatment strategies have evolved to include definitive chemoradiotherapy (CRT) with active surveillance and salvage esophagectomy when necessary for local tumor control. \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In Japan, neoadjuvant chemotherapy (NAC) is commonly employed for locally advanced ESCC due to its demonstrated benefits in improving long-term survival. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Despite these advancements, the adverse effects of NAC, including systemic toxicity, selection of chemoresistant tumor clones, and potential delays in surgery, present significant clinical challenges. Therefore, precise preoperative risk stratification after NAC is crucial to optimize treatment strategies and improve long-term outcomes. \u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRecent studies have highlighted the prognostic significance of skeletal muscle mass index (SMI) in gastrointestinal cancers. Specifically, preoperative sarcopenia has been associated with poor prognosis. \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Sarcopenia is characterized by reduced muscle strength and walking speed and is commonly assessed using the SMI. Standardized methods for evaluating SMI are lacking, but computed tomography (CT) has been utilized as a screening tool \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. NAC for ESCC has been reported to reduce SMI, and preoperative imaging evaluation is critical for improving long-term prognosis. \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Traditionally, SMI evaluation has relied on cross-sectional areas obtained from CT images. However, these two-dimensional (2D) assessments have limitations in accurately capturing volumetric changes in muscle mass. Advances in imaging technology now enable 3D analysis using CT images, allowing for more precise and detailed evaluation of muscle volume and distribution. \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e However, studies utilizing three-dimensional (3D) imaging analysis to evaluate pre-operative SMI are scarce, and the prognostic significance of such assessments remains unclear. This 3D analysis provides the potential to better capture changes in skeletal muscle mass induced by NAC, thereby improving postoperative risk assessments and optimizing treatment strategies tailored to individual patients.\u003c/p\u003e \u003cp\u003eThe aim of this study is to elucidate the impact of post-NAC SMI, assessed using 3D imaging, on the prognosis of patients undergoing curative resection for ESCC.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient and Clinical Data\u003c/h2\u003e \u003cp\u003eThis was a retrospective study of 139 consecutive patients who underwent operative resection for ESCC after NAC at the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University between January 2007 and December 2018. Data pertaining to the following clinical variables were retrieved: basic patient information (age, sex, and body mass index), total psoas volume (TPV) (pre-NAC and post-NAC), tumor characteristics (location and Union for International Cancer Control [UICC 8th edition] stage), regimen of NAC (FP: 5-fluorouracil and cisplatin, or DCF: docetaxel, cisplatin, and 5-fluorouracil), surgical technique (open esophagectomy, and minimally invasive esophagectomy), and postoperative complications. Postoperative complications were evaluated using the Clavien\u0026ndash;Dindo classification system, with major complications defined as those of grade 3 or higher \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. This study received approval from the Ethics Review Board of Kumamoto University Hospital (Approval No. 1909). All research procedures were conducted in compliance with the ethical principles outlined in the Declaration of Helsinki (1964 and subsequent amendments), as well as with institutional and national guidelines. Written informed consent, or its equivalent, was obtained from all participants prior to their inclusion in the study.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eNeoadjuvant treatment protocols and surgery\u003c/h3\u003e\n\u003cp\u003ePatients underwent two cycles of NAC with either FP or DCF, administered at 3\u0026ndash;4 week intervals. In cases of severe adverse effects, such as myelosuppression or renal impairment, chemotherapy doses were reduced or discontinued, and surgery was performed without a second cycle. Surgical resection took place at least 3\u0026ndash;4 weeks after NAC completion. Either open thoracic or thoracoscopic approaches were used. Esophagectomy was performed with either two-field or three-field lymphadenectomy, ensuring total mediastinal lymph node dissection. Gastric conduit reconstruction was carried out using either a hand-assisted laparoscopic or open laparotomy approach. All patients received standard enteral nutrition via jejunostomy.\u003c/p\u003e\n\u003ch3\u003eImaging analysis\u003c/h3\u003e\n\u003cp\u003eSMI was assessed using CT scans obtained pre- and post-NAC, measuring the total psoas volume (TPV) with Ziostation2\u0026reg; (Ziosoft Inc., Tokyo, Japan). The thinnest available slices (0.625\u0026ndash;5 mm) were selected for analysis. SMI was defined as TPV measured by the software divided by the square of the patient\u0026rsquo;s height (m\u0026sup2;).\u003c/p\u003e\n\u003ch3\u003eTreatment Strategy and Follow-up Assessment\u003c/h3\u003e\n\u003cp\u003eTo evaluate the clinical stage (cStage) prior to surgery, patients underwent routine examinations, including upper and lower gastrointestinal endoscopy, endoscopic ultrasound, and thoracoabdominal computed tomography (CT). Pathological staging was determined in accordance with the 8th edition of the Union for International Cancer Control (UICC) classification. After surgery, patients were followed up every three months. Recurrence was monitored through clinical assessments and CT imaging. Tumor markers were measured quarterly, and whole-body CT from the neck to pelvis was performed at least twice per year for a five-year period. Overall survival (OS) was defined as the interval from surgery to death from any cause or the last follow-up. Relapse-free survival (RFS) referred to the time from surgery until the first evidence of recurrence or death from any cause.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eComparisons between groups regarding clinicopathological and surgical-related characteristics were carried out using the chi-square test for categorical data and the Mann\u0026ndash;Whitney U test for continuous variables. A P-value of less than 0.05 was considered statistically significant. The Kaplan\u0026ndash;Meier method was applied for survival analysis, with univariate survival differences evaluated through the log-rank test. To determine hazard ratios (HRs), a multivariate Cox proportional hazards model was employed. Variables with a P-value below 0.05 were incorporated into the multivariate model and were further regarded as independent prognostic factors if they remained statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and clinical characteristics\u003c/h2\u003e \u003cp\u003eA total of 171 ESCC patients were assessed for eligibility, of whom 32 were excluded due to non-resectability or imaging difficulties (such as halo artifacts or cases where imaging did not include the pelvic region), resulting in a final cohort of 139 patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The median age was 68 years (range: 46\u0026ndash;82), and 85% (n\u0026thinsp;=\u0026thinsp;119) of the patients were male. Patients were stratified into quartiles (Q1\u0026ndash;Q4) based on post-NAC SMI, with Q1 representing the lowest SMI and Q4 the highest (Table\u0026nbsp;1). The median pre-NAC SMI was 122.3 (48.6\u0026ndash;214.9), and the post-NAC SMI was 115.7 (58.2\u0026ndash;197.7), indicating a significant reduction in muscle mass following NAC (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCorrelation Between BMI and SMI\u003c/h3\u003e\n\u003cp\u003eSpearman\u0026rsquo;s rank correlation analysis demonstrated a slightly positive relationship between BMI and SMI both before and after NAC (pre-NAC: R\u0026sup2; = 0.37, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01; post-NAC: R\u0026sup2; = 0.46, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table\u0026nbsp;2). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the degree of decrease in SMI and BMI after NAC. Compared to pre-NAC level, the SMI showed a significant decrease after NAC in the overall cohort as well as in Q1-Q3 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and B). In contrast, the extent of decrease in BMI after NAC was not significant in the overall cohort and in any of the groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and D).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eComparison of SMI 2D and 3D\u003c/h2\u003e \u003cp\u003eAs shown in the Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, we evaluated SMI changes pre-NAC and post- NAC using both 3D and 2D. The 3D analysis demonstrated a significant reduction in SMI post- NAC compared to pre-NAC (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and B), whereas 2D measurements did not clearly capture this atrophy (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC and D), highlighting the superior precision and detail of 3D evaluation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eImpact of SMI on short- and long-term survival\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;1 summarizes the clinicopathological features, perioperative factors, and survival outcomes across different SMI quartiles. Q1 had significantly lower pre-NAC SMI compared to Q2\u0026ndash;4 and showed the greatest reduction in SMI after NAC (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). There were no significant between-group differences with respect to age, sex, performance status, regimen, stage, operative time, or blood loss. In terms of SMI change, Q1 showed an 8.8% decrease in SMI after NAC, which was significantly greater compared to Q2\u0026ndash;4 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01), as indicated by the Change of SMI. Q1 had a significantly higher incidence of postoperative pneumonia than Q2\u0026ndash;4 (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the Kaplan\u0026ndash;Meier curves for OS in each group. Q1 had significantly worse 3-year OS than Q2\u0026ndash;4 (log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Similarly, 3-year RFS was significantly worse in Q1 than in Q2\u0026ndash;4 (log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Multivariate analysis identified Q1 as an independent factor associated with poor OS (HR, 2.95; 95% CI, 1.703\u0026ndash;5.124; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) (Table\u0026nbsp;3).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides novel insights by being to demonstrate the prognostic impact of post- NAC SMI in ESCC patients through 3D imaging analysis. Unlike conventional cross-sectional measurements, the use of 3D volume analysis allowed for a more detailed and accurate assessment of muscle loss.\u003c/p\u003e \u003cp\u003eIn a previous study, excessive muscle loss after neoadjuvant concurrent CRT was found to be a significant poor prognostic factor for disease recurrence and OS in ESCC patients who underwent surgery. \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e However, these studies typically relied on cross-sectional measurements and did not classify patients based on post-NAC SMI. Our study divided patients into quartiles according to post-NAC SMI, considering that patients with initially low pre-NAC SMI may show a lower reduction rate, which could lead to misinterpretation of their actual muscle depletion. This approach allowed for a more precise evaluation of muscle status after NAC.\u003c/p\u003e \u003cp\u003eOne of the key strengths of this study is the utilization of 3D volumetric analysis for SMI assessment. Traditional 2D measurements might not fully capture skeletal muscle atrophy, whereas 3D evaluation enables a more comprehensive assessment of muscle volume changes. While previous research has relied on total psoas area (TPA) measurements, recent advances in imaging have shifted the focus toward volumetric assessment, which provides a more accurate representation of muscle status. \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e However, it is debatable whether area or volume is useful in CT.\u003c/p\u003e \u003cp\u003eOur findings suggest that concerted efforts should be made to minimize the decline in SMI from pre- NAC to post- NAC to improve prognosis after ESCC surgery. For example, prehabilitation during NAC has been shown to promote retention of muscle and quality of life. \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Dietary therapy using enteral nutrition or other methods for patients with tumor-induced symptoms or poor oral intake due to chemotherapy may also prevent reduction in SMI. \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e In addition, ESCC patients with significantly reduced SMI after NAC may have an improved prognosis if nutritional therapy is administered prior to surgery for ESCC. In contrast, studies in gastric cancer patients have shown that enteral nutrition during neoadjuvant chemotherapy can significantly reduce perioperative inflammation and boost immune function. \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e These findings suggest that nutritional therapy during NAC might help preserve SMI, thereby improving outcomes. As a result, nutritional support is likely to gain more attention as a complementary treatment during NAC for ESCC in the future. \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe observed a slight correlation between SMI and BMI trends in our cohort; however, it is crucial to note that the volumetric decrease in SMI was often not mirrored by corresponding changes in BMI, highlighting the limitations of BMI in accurately capturing skeletal muscle loss. For instance, patients in Q1 experienced substantial skeletal muscle atrophy, particularly post- NAC, despite less noticeable changes in BMI. This suggests that muscle volume reduction may occur in a way that is not externally apparent, potentially due to factors like prolonged bed rest and chemotherapy toxicity. These findings underscore the importance of volumetric muscle assessment over BMI alone for prognostic evaluations.\u003c/p\u003e \u003cp\u003eSome limitations of this study should be addressed. First, this was a single-center, retrospective study. Second, whether SMI depletion reflects the pre-cancer state or results from anorexia and cachexia cannot be easily determined. Third, the neoadjuvant chemotherapy regimens were not uniform among patients, which may have influenced both muscle loss and treatment outcomes. However, the present study shows a poor prognosis of low SMI after NAC for ESCC, underscoring the importance of nutritional management during NAC.\u003c/p\u003e \u003cp\u003eIn conclusion, 3D volumetric assessment of SMI post- NAC revealed that lower SMI is significantly associated with poorer OS and RFS in ESCC patients undergoing radical resection. This study underscores the potential of 3D imaging as a critical tool in the prognostic assessment and management of ESCC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank H. Nikki March, PhD, Edanz Group (https://en-author-services.edanz.com/ac), for editing the draft of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eApproval of the research protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no funding statement. N/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all patients. N/A\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistry and the Registration No. of the study/Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnimal Studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare no conflict of interest for this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was waived for the patients because of the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept and design: Y. Maeda and M. Iwatsuki; acquisition of data: Y Maeda, M. Iwatsuki; analysis and interpretation of data: Y Maeda, M. Iwatsuki; writing of the manuscript: Y. Maeda, and M. Iwatsuki. All authors approved the final manuscript..\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMelhado RE, Alderson D, Tucker O (2010) The changing face of esophageal cancer. Cancers (Basel) Jun 28(3):1379\u0026ndash;1404\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKawakatsu Y, Koyanagi YN, Oze I et al (2020) Association between Socioeconomic Status and Digestive Tract Cancers: A Case-Control Study. Cancers (Basel) Nov 4 ;12(11)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eObermannov\u0026aacute; R, Alsina M, Cervantes A et al (2022) Oesophageal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol Oct 33(10):992\u0026ndash;1004\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSjoquist KM, Burmeister BH, Smithers BM et al (2011) Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol Jul 12(7):681\u0026ndash;692\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKato H, Nakajima M (2013) Treatments for esophageal cancer: a review. Gen Thorac Cardiovasc Surg Jun 61(6):330\u0026ndash;335\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakatani M, Migita K, Matsumoto S et al (2017) Prognostic significance of the prognostic nutritional index in esophageal cancer patients undergoing neoadjuvant chemotherapy. Dis Esophagus Aug 1(8):1\u0026ndash;7\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePorschen R, Fischbach W, Gockel I et al (2019) [Not Available]. Z Gastroenterol Mar 57(3):336\u0026ndash;418\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang CH, Lue KH, Hsieh TC, Liu SH, Wang TF, Peng TC (2020) Association Between Sarcopenia and Clinical Outcomes in Patients With Esophageal Cancer Under Neoadjuvant Therapy. Anticancer Res Feb 40(2):1175\u0026ndash;1181\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaly \u0026Eacute;BNB, Power LE, Cushen DG, MacEneaney SJ, Ryan P (2018) Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition? J Cachexia Sarcopenia Muscle Apr 9(2):295\u0026ndash;305\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJang MK, Park C, Hong S, Li H, Rhee E, Doorenbos AZ (2020) Skeletal Muscle Mass Change During Chemotherapy: A Systematic Review and Meta-analysis. Anticancer Res May 40(5):2409\u0026ndash;2418\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWerthel JD, Boux de Casson F, Burdin V et al (2021) CT-based volumetric assessment of rotator cuff muscle in shoulder arthroplasty preoperative planning. Bone Jt Open Jul 2(7):552\u0026ndash;561\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClavien PA, Camargo CA Jr., Croxford R, Langer B, Levy GA, Greig PD (1994) Definition and classification of negative outcomes in solid organ transplantation. Application in liver transplantation. Ann Surg Aug 220(2):109\u0026ndash;120\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYoon HG, Oh D, Ahn YC et al (2020) Prognostic Impact of Sarcopenia and Skeletal Muscle Loss During Neoadjuvant Chemoradiotherapy in Esophageal Cancer. Cancers (Basel) Apr 10 ;12(4)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrasad SR, Jhaveri KS, Saini S, Hahn PF, Halpern EF, Sumner JE (2002) CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques initial observations. Radiology Nov 225(2):416\u0026ndash;419\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMozley PD, Schwartz LH, Bendtsen C, Zhao B, Petrick N, Buckler AJ (2010) Change in lung tumor volume as a biomarker of treatment response: a critical review of the evidence. Ann Oncol Sep 21(9):1751\u0026ndash;1755\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAllen SK, Brown V, White D et al (2022) Multimodal Prehabilitation During Neoadjuvant Therapy Prior to Esophagogastric Cancer Resection: Effect on Cardiopulmonary Exercise Test Performance, Muscle Mass and Quality of Life-A Pilot Randomized Clinical Trial. Ann Surg Oncol Mar 29(3):1839\u0026ndash;1850\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo C, Xie K, Zhang C et al (2022) Efficacy of immunonutritional supplement after neoadjuvant chemotherapy in patients with esophageal cancer. J Cardiothorac Surg Mar 19(1):41\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZong L, Li H, Li S (2019) Effects of neoadjuvant chemotherapy combined with enteral nutrition on perioperative immunity, inflammation and intestinal flora in gastric cancer patients. J buon May-Jun 24(3):1113\u0026ndash;1119\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Kumamoto University","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":"3D imaging, Esophageal cancer, Neoadjuvant chemotherapy, Skeletal muscle","lastPublishedDoi":"10.21203/rs.3.rs-6854181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6854181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeoadjuvant chemotherapy (NAC) is commonly administered to improve long-term survival in patients with locally advanced esophageal squamous cell carcinoma (ESCC). This study investigated the impact of perioperative skeletal muscle mass index (SMI), assessed by 3D imaging, on survival outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively reviewed 139 consecutive ESCC patients who underwent surgical resection following NAC. SMI was measured pre-NAC and post- NAC using 3D imaging, and post-NAC SMI was stratified into quartiles (Q1-Q4). We evaluated overall survival (OS) and relapse-free survival (RFS) in relation to these quartiles.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQ1 (lowest SMI) group was significantly correlated with postoperative pneumonia (p = 0.03) and had poorer 3-year OS and RFS compared with Q2-Q4 group (P \u0026lt; 0.01). Multivariate analysis identified Q1 as an independent predictor of poor OS (hazard ratio, 3.22; 95%Confidence Interval, 1.86–5.57; P \u0026lt; 0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLow SMI after NAC assessed by 3D imaging is an independent predictor of poor overall and relapse-free survival in patients undergoing radical resection for ESCC. These findings underscore the importance of maintaining SMI in 3D imaging after NAC.\u003c/p\u003e","manuscriptTitle":"Skeletal Muscle Volume by 3D Imaging and Long-term Survival in Esophageal Squamous Cell Carcinoma with Neoadjuvant Chemotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-12 18:49:42","doi":"10.21203/rs.3.rs-6854181/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":"ec696ba2-8de6-4fe3-b64e-553099df32d9","owner":[],"postedDate":"June 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":49748847,"name":"Gastrointestinal Surgery"}],"tags":[],"updatedAt":"2025-06-12T18:49:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-12 18:49:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6854181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6854181","identity":"rs-6854181","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}