Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab

Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab | 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 Article Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab Masatsune Shibutani, Hideki Tanda, Yuki Seki, Shinichiro Kashiwagi, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4958109/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract In later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) + bevacizumab (Bmab) therapy as a later-line treatment for mCRC and assessed the impact of cancer cachexia on chemotherapeutic efficacy using the CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI + Bmab therapy. Health sciences/Gastroenterology Health sciences/Oncology colorectal cancer cachexia FTD/TPI Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Trifluridine/thymidine phosphorylase inhibitor (FTD/TPI) is effective even in patients with metastatic colorectal cancer (mCRC) who are refractory to standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and is expected to further extend survival times in later-line therapy 1 . In addition, the survival benefit of adding bevacizumab (Bmab) to FTD/TPI has been reported 2 – 4 . The therapeutic effects of FTD/TPI + B therapy vary depending on the patient. It is possible that the cause is related to the host. Cancer cachexia is a multifactorial syndrome defined by the persistent loss of skeletal muscle mass that cannot be completely reversed by conventional nutrition support 5 . As cancer cachexia has been reported to be associated with reduced efficacy of chemotherapy 6 , in later-line treatments, where many patients with cancer cachexia or pre-cancer cachexia are included, there may be large differences in treatment efficacy depending on cancer cachexia. However, the diagnostic criteria for cancer cachexia are vague, making objective evaluation difficult. Recently, the cachexia Index (CXI), an index for evaluating cachexia, was developed by Jafri et al. 7 . The CXI calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio (NLR), can comprehensively evaluate sarcopenia, malnutrition, and systemic inflammation. This study aimed to assess the impact of cancer cachexia on chemotherapeutic efficacy using the CXI in patients treated with FTD/TPI + Bmab therapy for mCRC. Patients and Methods Patients This retrospective study included 80 patients who were treated with FTD/TPI + Bmab therapy for mCRC at the Osaka Metropolitan University Hospital between January 2016 and December 2023. All the patients enrolled in this study were refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Osaka City University (approval number: 2020-026). Written informed consent was obtained from all patients. All patients were given the opportunity to opt out of the study. Treatment Patients were treated with FTD/TPI 35 mg/m 2 orally twice a day on days 1–5 and 8–12 in a 28-day cycle, with Bmab 5 mg/kg administered intravenously every 2 weeks. Treatment was discontinued because of disease progression or unacceptable toxicity. Response evaluations using computed tomography (CT) were performed every 8–10 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 8 . Data collection We retrospectively collected clinical and laboratory data, including computed tomography (CT) findings, from the institution’s electronic medical records. Blood samples were obtained within 1 week before the initiation of FTD/TPI + Bmab therapy, and abdominal CT scans were performed within 1 month before the initiation of FTD/TPI + Bmab therapy. Calculation of the CXI The CXI based on the SMI (S-CXI) was calculated as follows: SMI (cm 2 /m 2 ) x serum albumin concentration (g/dL) / NLR. The CXI based on the psoas muscle index (P-CXI) was calculated as follows: The psoas muscle index (PMI [cm 2 /m 2 ]) x serum albumin concentration (g/dL) / NLR. Abdominal CT images taken within 1 month before the initiation of FTD/TPI + Bmab therapy were used to measure the skeletal muscle area (cm 2 ) and psoas muscle area (cm 2 ). The cross-sectional areas of the skeletal mass and psoas mass were measured at the level of the umbilicus using a 3-dimensional medical image analysis system SYNAPSE VINCENT® (Fuji-Film Corporation, Tokyo, Japan) (Fig. 1 a). The total volume of the psoas muscle was also measured semi-automatically using SYNAPSE VINCENT (Fig. 1 b). SMI (cm 2 /m 2 ) was calculated as the skeletal muscle area divided by the square of height (m 2 ). The PMI (cm 2 /m 2 ) was calculated as the psoas muscle area divided by the square of the height (m 2 ). The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. A receiver operating characteristic curve analysis was performed using the median progression-free survival status to determine the cutoff values of S-CXI and P-CXI separately in male and female patients, considering that muscle mass differs depending on sex. Statistical analysis All statistical analyses were performed using SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in CXI, clinicopathological factors, and treatment outcomes were analyzed using the chi-squared test, Fisher’s exact test, and Mann-Whitney U-test. The correlation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicators of muscle mass, such as the total volume of the psoas muscle calculated by a 3-dimensional analysis and the cross-sectional area of the skeletal muscle at the umbilicus level, was evaluated using Spearman’s rank correlation coefficient. The overall survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of death from any cause or the last follow-up. Progression-free survival was defined as the interval between the date of initiation of FTD/TPI + Bmab and the date of disease progression, death from any cause, or the last follow-up examination. An objective response was defined as a complete or partial response. Disease control was defined as a complete or partial response or stable disease. Survival curves were estimated using the Kaplan–Meier method, and differences in survival curves were assessed using a log-rank test. Two-sided P values of < 0.05 were considered to indicate statistical significance. Results The study population included 41 men and 39 women, and the median age of the overall population was 70 years (range: 36–88 years). The median follow-up period was 227 days. Seventy-three patients (91.3%) discontinued treatment due to progressive disease, and 3 patients (3.8%) discontinued treatment due to unacceptable adverse events. The median S-CXI in men and women was 69.76 (range: 5.22–285.63) and 49.62 (range: 17.36–209.61), respectively. The median P-CXI in men and women was 9.87 (range: 0.73–44.70) and 6.69 (range: 0.32–28.18), respectively. The median progression-free survival from the initiation of FTD/TPI + Bmab therapy was 108 days. ROC curve analyses revealed that the cutoff values of S-CXI for men and women were 72.8 and 33.6, respectively, while those of P-CXI for men and women were 9.97 and 5.57 (Fig. 2 ). Associations between S-CXI/P-CXI and clinicopathological factors The correlations between CXI and clinicopathological factors are shown in Table I. No correlation was observed between S-CXI/P-CXI and clinicopathological factors, except that low P-CXI tended to be more common in left-sided colorectal cancer. Results of a survival analysis according to the S-CXI/P-CXI The progression-free and overall survival rates were significantly worse in the low S-CXI group than in the high S-CXI group (p = 0.012 and p = 0.015, respectively) (Fig. 3 ). The progression-free and overall survival rates were significantly worse in the low P-CXI group than in the high P-CXI group (p = 0.022 and p = 0.006, respectively) (Fig. 4 ). Correlation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicator of muscle mass The cross-sectional area of the iliopsoas muscle at the umbilicus level was significantly associated with the total volume of the psoas muscle calculated by a 3-dimensional analysis (r = 0.887, p < 0.001) (Fig. 5 a). The cross-sectional area of the iliopsoas muscle at the umbilical level was also significantly associated with that of the skeletal muscle at the umbilical level (r = 0.700, p < 0.001) (Fig. 5 b). Discussion This study demonstrated that both S-CXI and P-CXI were significantly associated with progression-free and overall survival in patients with mCRC who were treated with FTD/TPI + Bmab therapy. Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle with or without a decrease in fat mass that cannot be fully reversed by conventional nutritional support 5 . Cancer cachexia is caused by anorexia, muscle atrophy, and increased energy consumption due to tumor necrosis factor-α and interleukin-6 9 . Evaluation of the muscle mass, body weight, physical function, and nutritional and inflammatory state are important for the assessment of cancer cachexia. Cancer cachexia reportedly accounts for > 30% of the direct causes of death in cancer patients 10 and requires careful attention in patients with advanced cancer. Metabolic changes associated with cancer cachexia may downregulate antitumor immunity 11 . In addition, cancer cachexia increases the adverse events associated with chemotherapy, leading to insufficient doses of chemotherapy 6 , 12 . Furthermore, myokines released from skeletal muscle and exerting antitumor effects may be reduced in patients with cancer cachexia, because patients with cancer cachexia often have a reduced skeletal muscle mass 13 , 14 . Therefore, the efficacy of chemotherapy may be lower in patients with cancer cachexia. The original method for calculating CXI is based on SMI 7 , but some follow-up reports have calculated CXI based on PMI 9 , 15 , 16 . In this study, both CXI based on SMI and CXI based on PMI were associated with the prognosis. The SMI calculation is complicated because there are many measurement points. On the other hand, PMI is relatively easy to calculate because it only requires measurement of the psoas muscle mass. Furthermore, a strong correlation was observed between SMI and PMI, which is consistent with a previous report by Abbas et al. 17 , and PMI is an important indicator of sarcopenia. Therefore, CXI based on PMI is a useful index for clinical application. In this study, a semi-automatic image analyzer was used to calculate muscle mass, whereas some previous reports have used manually measured long axis × short axis to calculate the psoas muscle mass 16 . Therefore, the results for the cross-sectional area of the muscle obtained in this study were extremely accurate. In previous reports, the skeletal muscle area and psoas muscle area at the third lumbar vertebra, which has been reported to reflect the muscle mass of the whole body 18 , were often used to evaluate the muscle area 19 – 21 . In contrast, we measured the muscle area at the level of the umbilicus in this study because the image analyzer that we used automatically analyzes muscle mass at the level of the umbilicus. However, because a correlation was observed between the total volume of the psoas muscle calculated by the 3-dimensional analysis and the cross-sectional area of the iliopsoas muscle at the umbilicus level, the cross-sectional area of the iliopsoas muscle at the umbilicus level used in this study may be a valid method for evaluating muscle mass. The present study was associated with several limitations. This study was principally limited by its small sample size and single-center, retrospective design. In addition, the cutoff value used in this study was a provisional value calculated from the data of the patients who were enrolled in this study. Therefore, large prospective studies should be conducted to confirm our findings and to determine a more accurate cutoff value for CXI as a prognostic marker. Conclusion Cancer cachexia is an important factor related to treatment efficacy in later-line treatment of mCRC, and CXI is a useful marker for evaluating cachexia. Declarations Competing interests The authors declare that they have no competing interests. Author Contribution MS designed the study, performed the statistical analysis, and drafted the manuscript. HT, YS, SK, TN, YF, DI, HK, TF, and KM collected clinical data and critically reviewed the manuscript. Acknowledgement We thank Dr. Brian Quinn, who provided medical writing services on behalf of JMC Ltd. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med . 372 , 1909-1919 (2015). Prager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, Pápai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med . 388 , 1657-1667 (2023). Shibutani M, Nagahara H, Fukuoka T, Iseki Y, Wang EN, Okazaki Y, Kashiwagi S, Maeda K, Hirakawa K, Ohira M. Combining Bevacizumab With Trifluridine/Thymidine Phosphorylase Inhibitor Improves the Survival Outcomes Regardless of the Usage History of Bevacizumab in Front-line Treatment of Patients With Metastatic Colorectal Cancer. Anticancer Res . 40 , 4157-4163 (2020). Kotani D, Kuboki Y, Horasawa S, Kaneko A, Nakamura Y, Kawazoe A, Bando H, Taniguchi H, Shitara K, Kojima T, Tsuji A, Yoshino T. Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer . 19 , 1253 (2019). Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol . 12 , 489-495 (2011). da Rocha IMG, Marcadenti A, de Medeiros GOC, Bezerra RA, Rego JFM, Gonzalez MC, Fayh APT. Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study. J Cachexia Sarcopenia Muscle . 10 , 445-454 (2019). Jafri SH, Previgliano C, Khandelwal K, Shi R. Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients. Clin Med Insights Oncol . 9 , 87-93 (2015). Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer . 45 , 228-247 (2009). Nakashima K, Haruki K, Kamada T, Takahashi J, Nakaseko Y, Ohdaira H, Furukawa K, Suzuki Y, Ikegami T. Usefulness of the cachexia index as a prognostic indicator for patients with gastric cancer. Ann Gastroenterol Surg . 7 , 733-740 (2023). Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD. Cachexia: a new definition. Clin Nutr . 27 , 793-799 (2008). Fujii H, Makiyama A, Iihara H, Okumura N, Yamamoto S, Imai T, Arakawa S, Kobayashi R, Tanaka Y, Yoshida K, Suzuki A. Cancer Cachexia Reduces the Efficacy of Nivolumab Treatment in Patients With Advanced Gastric Cancer. Anticancer Res . 40 , 7067-7075 (2020). Watanabe H, Oshima T. The Latest Treatments for Cancer Cachexia: An Overview. Anticancer Res . 43 , 511-521 (2023). Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab . 301 , E504-510 (2011). Aoi W, Naito Y, Takagi T, Tanimura Y, Takanami Y, Kawai Y, Sakuma K, Hang LP, Mizushima K, Hirai Y, Koyama R, Wada S, Higashi A, Kokura S, Ichikawa H, Yoshikawa T. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut . 62 , 882-889 (2013). Tanji Y, Furukawa K, Haruki K, Taniai T, Onda S, Tsunematsu M, Shirai Y, Yanagaki M, Igarashi Y, Ikegami T. Significant impact of cachexia index on the outcomes after hepatic resection for colorectal liver metastases. Ann Gastroenterol Surg . 6 , 804-812 (2022). Kamada T, Haruki K, Nakashima K, Takahashi J, Nakaseko Y, Suzuki N, Ohdaira H, Eto K, Ikegami T, Suzuki Y. Prognostic significance of the cachexia index in patients with stage I-III colorectal cancer who underwent laparoscopic surgery. Surg Today . 53, 1064-1072 (2023). Abbass T, Tsz Ho YT, Horgan PG, Dolan RD, McMillan DC. The relationship between computed tomography derived skeletal muscle index, psoas muscle index and clinical outcomes in patients with operable colorectal cancer. Clin Nutr ESPEN . 39 , 104-113 (2020). Portal D, Hofstetter L, Eshed I, Dan-Lantsman C, Sella T, Urban D, Onn A, Bar J, Segal G. L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients. Cancer Manag Res . 11 , 2579-2588 (2019). Yan XL, Wu LM, Tang XB, Li ZZ, Zhang Z, Jiang HJ, Chen ZT, Chen DH, Li JY, Shen X, Huang DD.Comparison of the cachexia index based on hand-grip strength (H-CXI) with the original CXI for the prediction of cancer cachexia and prognosis in patients who underwent radical colectomy for colorectal cancer. Front Nutr . 11 , 1290299 (2024). Matsunaga T, Satio H, Sakano Y, Makinoya M, Shimizu S, Shishido Y, Miyatani K, Hanaki T, Kihara K, Yamamoto M, Tokuyasu N, Takano S, Sakamoto T, Hasegawa T, Fujiwara Y. Prognostic significance of the cachexia index in patients with unresectable advanced gastric cancer receiving palliative chemotherapy: a retrospective single-center study. Surg Today . 54 , 231-239 (2024). Brown LR, Thomson GG, Gardner E, Chien S, McGovern J, Dolan RD, McSorley ST, Forshaw MJ, McMillan DC, Wigmore SJ, Crumley AB, Skipworth RJE. Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study. Br J Surg . 111 , znae098 (2024). Table Table I. Associations between S-CXI/P-CXI and clinicopathological factors. S-CXI P-CXI Factors Low (n=36) High (n=44) p-Value Low (n=31) High (n=49) p-Value Age (years) Median (range) 69 (44-83) 72 (36-88) 0.249 53 (44-88) 72 (36-85) 0.288 Performance status, n 0, 1 33 39 26 46 2 3 5 0.724 5 3 0.250 Location of primary tumor, n Right side 7 16 5 18 Left side 29 28 0.137 26 31 0.075 RAS status, n Wild type 19 18 14 23 Mutant type 13 26 0.163 15 24 >0.999 Unknown 4 0 2 2 Number of metastatic organs, n 1 14 21 14 21 ≥2 22 23 0.500 17 28 >0.999 S-CXI, cachexia index based on the skeletal muscle mass index; P-CXI, cachexia index based on the psoas muscle index Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 23 Sep, 2024 Reviews received at journal 22 Sep, 2024 Reviews received at journal 20 Sep, 2024 Reviewers agreed at journal 17 Sep, 2024 Reviewers agreed at journal 17 Sep, 2024 Reviewers invited by journal 17 Sep, 2024 Editor assigned by journal 17 Sep, 2024 Editor invited by journal 10 Sep, 2024 Submission checks completed at journal 22 Aug, 2024 First submitted to journal 22 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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-4958109","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":355711045,"identity":"83b6e579-596a-4201-aab8-ea66e1388701","order_by":0,"name":"Masatsune Shibutani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIie2QQQqCQBSG3yDY5oEtn1RGN1CEaCF1lUTQTXWGVrbxAEIdQgiipRC48gAug/ZRF8hmxHVju6D5GN5i4ON/7wdQKH6QXgo6EHqWAag3P2wrUbASyjB0ze1XCngXP8tbRQoOkul1ttL8Y7UuruzsgbaXxOCwiGwqdfdUbSKblSGwQ/5ZWVBQkJng6FStpsTiC7B0KUkhPybzReyYNkrdReEphPYko0bJOyjNLbh0qbxHth8HKL1FNHYjrC1jxxt7xnPLkTUm0EjMPt+HP3RSuQHsIabR7jOmDopCoVD8FW9GzkAEvjb4MgAAAABJRU5ErkJggg==","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Masatsune","middleName":"","lastName":"Shibutani","suffix":""},{"id":355711046,"identity":"fbfb913c-17c3-4156-9d2b-7ce8d392262f","order_by":1,"name":"Hideki Tanda","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hideki","middleName":"","lastName":"Tanda","suffix":""},{"id":355711047,"identity":"9fc201ff-edf4-4714-b484-20d2dbf4a7a4","order_by":2,"name":"Yuki Seki","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Seki","suffix":""},{"id":355711048,"identity":"148a1b2e-84d6-4465-aabc-9e0f805c73ef","order_by":3,"name":"Shinichiro Kashiwagi","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Shinichiro","middleName":"","lastName":"Kashiwagi","suffix":""},{"id":355711049,"identity":"6d757db1-ac37-4391-ae01-8fd56e1dd042","order_by":4,"name":"Tsuyoshi Nishiyama","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tsuyoshi","middleName":"","lastName":"Nishiyama","suffix":""},{"id":355711050,"identity":"50ae1e64-f6bf-40bd-a57e-b9c73f05fe52","order_by":5,"name":"Yasuhiro Fukui","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasuhiro","middleName":"","lastName":"Fukui","suffix":""},{"id":355711051,"identity":"a5ac3a51-23d9-462f-be73-3b0c24bf3586","order_by":6,"name":"Daiki Imanishi","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Daiki","middleName":"","lastName":"Imanishi","suffix":""},{"id":355711052,"identity":"b9fb93f0-a447-48f1-a1f6-912cf5b2ad2e","order_by":7,"name":"Hiroaki Kasashima","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hiroaki","middleName":"","lastName":"Kasashima","suffix":""},{"id":355711053,"identity":"f4562942-86d3-4405-a94a-a0e5f32f4f6d","order_by":8,"name":"Tatsunari Fukuoka","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tatsunari","middleName":"","lastName":"Fukuoka","suffix":""},{"id":355711054,"identity":"d97d3288-f280-4db6-a93a-3bcb0811340e","order_by":9,"name":"Kiyoshi Maeda","email":"","orcid":"","institution":"Osaka Metropolitan University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kiyoshi","middleName":"","lastName":"Maeda","suffix":""}],"badges":[],"createdAt":"2024-08-22 12:38:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4958109/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4958109/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-77766-z","type":"published","date":"2024-10-29T16:20:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66739136,"identity":"4f7c80a4-b293-4791-8619-0866f7a470b2","added_by":"auto","created_at":"2024-10-16 05:30:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":206710,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images of body composition components were reconstructed using the SYNAPSE VINCENT\u003csup\u003e® \u003c/sup\u003e3-dimensional medical image analysis system. (a) Cross-sectional computed tomography image at the level of the umbilicus. Areas colored in yellow and orange indicate the skeletal muscle area, and those colored green indicate the psoas muscle area. (b) Three-dimensional image construction. Green areas indicate the total volume of the psoas muscle.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/e84d555c53195a17c54da839.png"},{"id":66739135,"identity":"8c883282-88f9-48a4-b703-200a8152bf7a","added_by":"auto","created_at":"2024-10-16 05:30:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":107279,"visible":true,"origin":"","legend":"\u003cp\u003eA receiver operating characteristic curve analysis of the cachexia index. (a) The cachexia index based on the skeletal muscle mass index (S-CXI) in men. Area under curve=0.579, 95% confidence interval=0.398–0.759, p=0.389. (b) The cachexia index based on the psoas muscle mass index (P-CXI) in men. Area under curve=0.590, 95% confidence interval=0.409–0.772, p=0.322. (c) S-CXI in women. Area under curve=0.555, 95% confidence interval=0.370–0.740, p=0.535. (d) P-CXI in women. Area under curve=0.574, 95% confidence interval=0.392–0.756, p=0.431.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/bbc602a45c74998408dd6dbb.png"},{"id":66739134,"identity":"334e3b17-6b4d-4938-a161-8aba25d38700","added_by":"auto","created_at":"2024-10-16 05:30:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":142954,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for the progression-free (a) and overall survival (b) according to the cachexia index based on the skeletal muscle mass index (S-CXI). The low-S-CXI group showed a poorer prognosis in comparison to the high-S-CXI group with regard to progression-free and overall survival (p=0.012, p=0.015, respectively).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/1c4fcc0d6de8e38b85a46747.png"},{"id":66739133,"identity":"8c17f9d9-56a1-40cf-9b45-498b025c82ed","added_by":"auto","created_at":"2024-10-16 05:30:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":143274,"visible":true,"origin":"","legend":"\u003cp\u003eThe Kaplan-Meier survival curves for the progression-free (a) and overall survival (b) according to the cachexia index based on the psoas muscle index (P-CXI). The low-P-CXI group showed a poorer prognosis in comparison to the high-P-CXI group with regard to progression-free and overall survival (p=0.022, p=0.006, respectively).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/1ff98ae30f75ec9332ef1288.png"},{"id":66739137,"identity":"d95f61e2-b5d2-4ae8-9742-cbf173bbac44","added_by":"auto","created_at":"2024-10-16 05:30:13","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":126676,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between the cross-sectional area of the iliopsoas muscle at the level of the umbilicus and other indicator of muscle mass. (a) Correlation between the cross-sectional area of the iliopsoas muscle at the level of the umbilicus and the total volume of the psoas muscle calculated by a 3-dimensional analysis. (b) Correlation between the cross-sectional area of the iliopsoas muscle at the level of the umbilicus and that of the skeletal muscle at the level of the umbilicus.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/a588828ee0ad6851f3f791fb.png"},{"id":68207270,"identity":"72cea394-23a6-4a64-97f2-e751effda49b","added_by":"auto","created_at":"2024-11-04 16:36:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1075805,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4958109/v1/259ab12c-7342-46ce-9bfa-f05edfbbd812.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTrifluridine/thymidine phosphorylase inhibitor (FTD/TPI) is effective even in patients with metastatic colorectal cancer (mCRC) who are refractory to standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and is expected to further extend survival times in later-line therapy\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In addition, the survival benefit of adding bevacizumab (Bmab) to FTD/TPI has been reported\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe therapeutic effects of FTD/TPI\u0026thinsp;+\u0026thinsp;B therapy vary depending on the patient. It is possible that the cause is related to the host. Cancer cachexia is a multifactorial syndrome defined by the persistent loss of skeletal muscle mass that cannot be completely reversed by conventional nutrition support\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. As cancer cachexia has been reported to be associated with reduced efficacy of chemotherapy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, in later-line treatments, where many patients with cancer cachexia or pre-cancer cachexia are included, there may be large differences in treatment efficacy depending on cancer cachexia. However, the diagnostic criteria for cancer cachexia are vague, making objective evaluation difficult.\u003c/p\u003e \u003cp\u003eRecently, the cachexia Index (CXI), an index for evaluating cachexia, was developed by Jafri et al. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The CXI calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio (NLR), can comprehensively evaluate sarcopenia, malnutrition, and systemic inflammation.\u003c/p\u003e \u003cp\u003eThis study aimed to assess the impact of cancer cachexia on chemotherapeutic efficacy using the CXI in patients treated with FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy for mCRC.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective study included 80 patients who were treated with FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy for mCRC at the Osaka Metropolitan University Hospital between January 2016 and December 2023. All the patients enrolled in this study were refractory or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Osaka City University (approval number: 2020-026). Written informed consent was obtained from all patients. All patients were given the opportunity to opt out of the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003ePatients were treated with FTD/TPI 35 mg/m\u003csup\u003e2\u003c/sup\u003e orally twice a day on days 1\u0026ndash;5 and 8\u0026ndash;12 in a 28-day cycle, with Bmab 5 mg/kg administered intravenously every 2 weeks. Treatment was discontinued because of disease progression or unacceptable toxicity. Response evaluations using computed tomography (CT) were performed every 8\u0026ndash;10 weeks according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eWe retrospectively collected clinical and laboratory data, including computed tomography (CT) findings, from the institution\u0026rsquo;s electronic medical records. Blood samples were obtained within 1 week before the initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy, and abdominal CT scans were performed within 1 month before the initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCalculation of the CXI\u003c/h2\u003e \u003cp\u003eThe CXI based on the SMI (S-CXI) was calculated as follows: SMI (cm\u003csup\u003e2\u003c/sup\u003e /m\u003csup\u003e2\u003c/sup\u003e) x serum albumin concentration (g/dL) / NLR. The CXI based on the psoas muscle index (P-CXI) was calculated as follows: The psoas muscle index (PMI [cm\u003csup\u003e2\u003c/sup\u003e /m\u003csup\u003e2\u003c/sup\u003e]) x serum albumin concentration (g/dL) / NLR. Abdominal CT images taken within 1 month before the initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy were used to measure the skeletal muscle area (cm\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e) and psoas muscle area (cm\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). The cross-sectional areas of the skeletal mass and psoas mass were measured at the level of the umbilicus using a 3-dimensional medical image analysis system SYNAPSE VINCENT\u0026reg; (Fuji-Film Corporation, Tokyo, Japan) (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The total volume of the psoas muscle was also measured semi-automatically using SYNAPSE VINCENT (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). SMI (cm\u003csup\u003e2\u003c/sup\u003e /m\u003csup\u003e2\u003c/sup\u003e) was calculated as the skeletal muscle area divided by the square of height (m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). The PMI (cm\u003csup\u003e2\u003c/sup\u003e /m\u003csup\u003e2\u003c/sup\u003e) was calculated as the psoas muscle area divided by the square of the height (m\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e). The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. A receiver operating characteristic curve analysis was performed using the median progression-free survival status to determine the cutoff values of S-CXI and P-CXI separately in male and female patients, considering that muscle mass differs depending on sex.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS software package for Windows (SPSS, Chicago, IL, USA). The significance of differences in CXI, clinicopathological factors, and treatment outcomes were analyzed using the chi-squared test, Fisher\u0026rsquo;s exact test, and Mann-Whitney U-test. The correlation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicators of muscle mass, such as the total volume of the psoas muscle calculated by a 3-dimensional analysis and the cross-sectional area of the skeletal muscle at the umbilicus level, was evaluated using Spearman\u0026rsquo;s rank correlation coefficient. The overall survival was defined as the interval between the date of initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab and the date of death from any cause or the last follow-up. Progression-free survival was defined as the interval between the date of initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab and the date of disease progression, death from any cause, or the last follow-up examination. An objective response was defined as a complete or partial response. Disease control was defined as a complete or partial response or stable disease. Survival curves were estimated using the Kaplan\u0026ndash;Meier method, and differences in survival curves were assessed using a log-rank test. Two-sided P values of \u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe study population included 41 men and 39 women, and the median age of the overall population was 70 years (range: 36\u0026ndash;88 years). The median follow-up period was 227 days. Seventy-three patients (91.3%) discontinued treatment due to progressive disease, and 3 patients (3.8%) discontinued treatment due to unacceptable adverse events.\u003c/p\u003e \u003cp\u003eThe median S-CXI in men and women was 69.76 (range: 5.22\u0026ndash;285.63) and 49.62 (range: 17.36\u0026ndash;209.61), respectively. The median P-CXI in men and women was 9.87 (range: 0.73\u0026ndash;44.70) and 6.69 (range: 0.32\u0026ndash;28.18), respectively.\u003c/p\u003e \u003cp\u003eThe median progression-free survival from the initiation of FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy was 108 days. ROC curve analyses revealed that the cutoff values of S-CXI for men and women were 72.8 and 33.6, respectively, while those of P-CXI for men and women were 9.97 and 5.57 (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eAssociations between S-CXI/P-CXI and clinicopathological factors\u003c/h2\u003e \u003cp\u003eThe correlations between CXI and clinicopathological factors are shown in Table I. No correlation was observed between S-CXI/P-CXI and clinicopathological factors, except that low P-CXI tended to be more common in left-sided colorectal cancer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eResults of a survival analysis according to the S-CXI/P-CXI\u003c/h2\u003e \u003cp\u003eThe progression-free and overall survival rates were significantly worse in the low S-CXI group than in the high S-CXI group (p\u0026thinsp;=\u0026thinsp;0.012 and p\u0026thinsp;=\u0026thinsp;0.015, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The progression-free and overall survival rates were significantly worse in the low P-CXI group than in the high P-CXI group (p\u0026thinsp;=\u0026thinsp;0.022 and p\u0026thinsp;=\u0026thinsp;0.006, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cem\u003eCorrelation between the cross-sectional area of the iliopsoas muscle at the umbilicus level and other indicator of muscle mass\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe cross-sectional area of the iliopsoas muscle at the umbilicus level was significantly associated with the total volume of the psoas muscle calculated by a 3-dimensional analysis (r\u0026thinsp;=\u0026thinsp;0.887, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). The cross-sectional area of the iliopsoas muscle at the umbilical level was also significantly associated with that of the skeletal muscle at the umbilical level (r\u0026thinsp;=\u0026thinsp;0.700, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e5\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study demonstrated that both S-CXI and P-CXI were significantly associated with progression-free and overall survival in patients with mCRC who were treated with FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy.\u003c/p\u003e \u003cp\u003eCancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle with or without a decrease in fat mass that cannot be fully reversed by conventional nutritional support\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Cancer cachexia is caused by anorexia, muscle atrophy, and increased energy consumption due to tumor necrosis factor-α and interleukin-6\u003csup\u003e9\u003c/sup\u003e. Evaluation of the muscle mass, body weight, physical function, and nutritional and inflammatory state are important for the assessment of cancer cachexia. Cancer cachexia reportedly accounts for \u0026gt;\u0026thinsp;30% of the direct causes of death in cancer patients\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and requires careful attention in patients with advanced cancer.\u003c/p\u003e \u003cp\u003eMetabolic changes associated with cancer cachexia may downregulate antitumor immunity\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. In addition, cancer cachexia increases the adverse events associated with chemotherapy, leading to insufficient doses of chemotherapy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Furthermore, myokines released from skeletal muscle and exerting antitumor effects may be reduced in patients with cancer cachexia, because patients with cancer cachexia often have a reduced skeletal muscle mass\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Therefore, the efficacy of chemotherapy may be lower in patients with cancer cachexia.\u003c/p\u003e \u003cp\u003eThe original method for calculating CXI is based on SMI\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, but some follow-up reports have calculated CXI based on PMI\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. In this study, both CXI based on SMI and CXI based on PMI were associated with the prognosis. The SMI calculation is complicated because there are many measurement points. On the other hand, PMI is relatively easy to calculate because it only requires measurement of the psoas muscle mass. Furthermore, a strong correlation was observed between SMI and PMI, which is consistent with a previous report by Abbas et al. \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, and PMI is an important indicator of sarcopenia. Therefore, CXI based on PMI is a useful index for clinical application.\u003c/p\u003e \u003cp\u003eIn this study, a semi-automatic image analyzer was used to calculate muscle mass, whereas some previous reports have used manually measured long axis \u0026times; short axis to calculate the psoas muscle mass\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Therefore, the results for the cross-sectional area of the muscle obtained in this study were extremely accurate. In previous reports, the skeletal muscle area and psoas muscle area at the third lumbar vertebra, which has been reported to reflect the muscle mass of the whole body\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, were often used to evaluate the muscle area\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. In contrast, we measured the muscle area at the level of the umbilicus in this study because the image analyzer that we used automatically analyzes muscle mass at the level of the umbilicus. However, because a correlation was observed between the total volume of the psoas muscle calculated by the 3-dimensional analysis and the cross-sectional area of the iliopsoas muscle at the umbilicus level, the cross-sectional area of the iliopsoas muscle at the umbilicus level used in this study may be a valid method for evaluating muscle mass.\u003c/p\u003e \u003cp\u003eThe present study was associated with several limitations. This study was principally limited by its small sample size and single-center, retrospective design. In addition, the cutoff value used in this study was a provisional value calculated from the data of the patients who were enrolled in this study. Therefore, large prospective studies should be conducted to confirm our findings and to determine a more accurate cutoff value for CXI as a prognostic marker.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCancer cachexia is an important factor related to treatment efficacy in later-line treatment of mCRC, and CXI is a useful marker for evaluating cachexia.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMS designed the study, performed the statistical analysis, and drafted the manuscript. HT, YS, SK, TN, YF, DI, HK, TF, and KM collected clinical data and critically reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank Dr. Brian Quinn, who provided medical writing services on behalf of JMC Ltd.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e. \u003cstrong\u003e372\u003c/strong\u003e, 1909-1919 (2015).\u003c/li\u003e\n\u003cli\u003ePrager GW, Taieb J, Fakih M, Ciardiello F, Van Cutsem E, Elez E, Cruz FM, Wyrwicz L, Stroyakovskiy D, P\u0026aacute;pai Z, Poureau PG, Liposits G, Cremolini C, Bondarenko I, Modest DP, Benhadji KA, Amellal N, Leger C, Vidot L, Tabernero J; SUNLIGHT Investigators. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. \u003cem\u003eN Engl J Med\u003c/em\u003e. \u003cstrong\u003e388\u003c/strong\u003e, 1657-1667 (2023).\u003c/li\u003e\n\u003cli\u003eShibutani M, Nagahara H, Fukuoka T, Iseki Y, Wang EN, Okazaki Y, Kashiwagi S, Maeda K, Hirakawa K, Ohira M. Combining Bevacizumab With Trifluridine/Thymidine Phosphorylase Inhibitor Improves the Survival Outcomes Regardless of the Usage History of Bevacizumab in Front-line Treatment of Patients With Metastatic Colorectal Cancer. \u003cem\u003eAnticancer Res\u003c/em\u003e. \u003cstrong\u003e40\u003c/strong\u003e, 4157-4163 (2020).\u003c/li\u003e\n\u003cli\u003eKotani D, Kuboki Y, Horasawa S, Kaneko A, Nakamura Y, Kawazoe A, Bando H, Taniguchi H, Shitara K, Kojima T, Tsuji A, Yoshino T. Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. \u003cem\u003eBMC Cancer\u003c/em\u003e. \u003cstrong\u003e19\u003c/strong\u003e, 1253 (2019).\u003c/li\u003e\n\u003cli\u003eFearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. \u003cem\u003eLancet Oncol\u003c/em\u003e. \u003cstrong\u003e12\u003c/strong\u003e, 489-495 (2011).\u003c/li\u003e\n\u003cli\u003eda Rocha IMG, Marcadenti A, de Medeiros GOC, Bezerra RA, Rego JFM, Gonzalez MC, Fayh APT. Is cachexia associated with chemotherapy toxicities in gastrointestinal cancer patients? A prospective study. \u003cem\u003eJ Cachexia Sarcopenia Muscle\u003c/em\u003e. \u003cstrong\u003e10\u003c/strong\u003e, 445-454 (2019).\u003c/li\u003e\n\u003cli\u003eJafri SH, Previgliano C, Khandelwal K, Shi R. Cachexia Index in Advanced Non-Small-Cell Lung Cancer Patients. \u003cem\u003eClin Med Insights Oncol\u003c/em\u003e. \u003cstrong\u003e9\u003c/strong\u003e, 87-93 (2015).\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). \u003cem\u003eEur J Cancer\u003c/em\u003e. \u003cstrong\u003e45\u003c/strong\u003e, 228-247 (2009).\u003c/li\u003e\n\u003cli\u003eNakashima K, Haruki K, Kamada T, Takahashi J, Nakaseko Y, Ohdaira H, Furukawa K, Suzuki Y, Ikegami T. Usefulness of the cachexia index as a prognostic indicator for patients with gastric cancer. \u003cem\u003eAnn Gastroenterol Surg\u003c/em\u003e. \u003cstrong\u003e7\u003c/strong\u003e, 733-740 (2023).\u003c/li\u003e\n\u003cli\u003eEvans WJ, Morley JE, Argil\u0026eacute;s J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD. Cachexia: a new definition. \u003cem\u003eClin Nutr\u003c/em\u003e. \u003cstrong\u003e27\u003c/strong\u003e, 793-799 (2008).\u003c/li\u003e\n\u003cli\u003eFujii H, Makiyama A, Iihara H, Okumura N, Yamamoto S, Imai T, Arakawa S, Kobayashi R, Tanaka Y, Yoshida K, Suzuki A. Cancer Cachexia Reduces the Efficacy of Nivolumab Treatment in Patients With Advanced Gastric Cancer. \u003cem\u003eAnticancer Res\u003c/em\u003e. \u003cstrong\u003e40\u003c/strong\u003e, 7067-7075 (2020).\u003c/li\u003e\n\u003cli\u003eWatanabe H, Oshima T. The Latest Treatments for Cancer Cachexia: An Overview. \u003cem\u003eAnticancer Res\u003c/em\u003e. \u003cstrong\u003e43\u003c/strong\u003e, 511-521 (2023).\u003c/li\u003e\n\u003cli\u003eHojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. \u003cem\u003eAm J Physiol Endocrinol Metab\u003c/em\u003e. \u003cstrong\u003e301\u003c/strong\u003e, E504-510 (2011).\u003c/li\u003e\n\u003cli\u003eAoi W, Naito Y, Takagi T, Tanimura Y, Takanami Y, Kawai Y, Sakuma K, Hang LP, Mizushima K, Hirai Y, Koyama R, Wada S, Higashi A, Kokura S, Ichikawa H, Yoshikawa T. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise.\u003cem\u003e Gut\u003c/em\u003e. \u003cstrong\u003e62\u003c/strong\u003e, 882-889 (2013).\u003c/li\u003e\n\u003cli\u003eTanji Y, Furukawa K, Haruki K, Taniai T, Onda S, Tsunematsu M, Shirai Y, Yanagaki M, Igarashi Y, Ikegami T. Significant impact of cachexia index on the outcomes after hepatic resection for colorectal liver metastases. \u003cem\u003eAnn Gastroenterol Surg\u003c/em\u003e. \u003cstrong\u003e6\u003c/strong\u003e, 804-812 (2022).\u003c/li\u003e\n\u003cli\u003eKamada T, Haruki K, Nakashima K, Takahashi J, Nakaseko Y, Suzuki N, Ohdaira H, Eto K, Ikegami T, Suzuki Y. Prognostic significance of the cachexia index in patients with stage I-III colorectal cancer who underwent laparoscopic surgery. \u003cem\u003eSurg Today\u003c/em\u003e. \u003cstrong\u003e53,\u003c/strong\u003e 1064-1072 (2023).\u003c/li\u003e\n\u003cli\u003eAbbass T, Tsz Ho YT, Horgan PG, Dolan RD, McMillan DC. The relationship between computed tomography derived skeletal muscle index, psoas muscle index and clinical outcomes in patients with operable colorectal cancer. \u003cem\u003eClin Nutr ESPEN\u003c/em\u003e. \u003cstrong\u003e39\u003c/strong\u003e, 104-113 (2020).\u003c/li\u003e\n\u003cli\u003ePortal D, Hofstetter L, Eshed I, Dan-Lantsman C, Sella T, Urban D, Onn A, Bar J, Segal G. L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients. \u003cem\u003eCancer Manag Res\u003c/em\u003e.\u003cstrong\u003e 11\u003c/strong\u003e, 2579-2588 (2019).\u003c/li\u003e\n\u003cli\u003eYan XL, Wu LM, Tang XB, Li ZZ, Zhang Z, Jiang HJ, Chen ZT, Chen DH, Li JY, Shen X, Huang DD.Comparison of the cachexia index based on hand-grip strength (H-CXI) with the original CXI for the prediction of cancer cachexia and prognosis in patients who underwent radical colectomy for colorectal cancer. \u003cem\u003eFront Nutr\u003c/em\u003e. \u003cstrong\u003e11\u003c/strong\u003e, 1290299 (2024).\u003c/li\u003e\n\u003cli\u003eMatsunaga T, Satio H, Sakano Y, Makinoya M, Shimizu S, Shishido Y, Miyatani K, Hanaki T, Kihara K, Yamamoto M, Tokuyasu N, Takano S, Sakamoto T, Hasegawa T, Fujiwara Y. Prognostic significance of the cachexia index in patients with unresectable advanced gastric cancer receiving palliative chemotherapy: a retrospective single-center study. \u003cem\u003eSurg Today\u003c/em\u003e. \u003cstrong\u003e54\u003c/strong\u003e, 231-239 (2024).\u003c/li\u003e\n\u003cli\u003eBrown LR, Thomson GG, Gardner E, Chien S, McGovern J, Dolan RD, McSorley ST, Forshaw MJ, McMillan DC, Wigmore SJ, Crumley AB, Skipworth RJE. Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study. \u003cem\u003eBr J Surg\u003c/em\u003e. \u003cstrong\u003e111\u003c/strong\u003e, znae098 (2024).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable I. Associations between S-CXI/P-CXI and clinicopathological factors.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.846153846153847%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.19871794871795%\" colspan=\"2\"\u003e\n \u003cp\u003eS-CXI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.134615384615385%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0448717948717947%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.19871794871795%\" colspan=\"2\"\u003e\n \u003cp\u003eP-CXI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.576923076923077%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eFactors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003eLow (n=36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003eHigh (n=44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003eLow (n=31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003eHigh (n=49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003ep-Value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e69 (44-83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e72 (36-88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003e0.249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e53 (44-88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e72 (36-85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003e0.288\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003ePerformance status, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003e0, 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003e0.724\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003e0.250\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eLocation of primary tumor, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eRight side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eLeft side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003e0.137\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eRAS status, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eWild type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eMutant type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003e0.163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003eNumber of metastatic organs, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"28.75399361022364%\"\u003e\n \u003cp\u003e\u0026ge;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.105431309904153%\"\u003e\n \u003cp\u003e0.500\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"3.0351437699680512%\"\u003e\n \u003cp\u003e \u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.140575079872205%\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.543130990415335%\"\u003e\n \u003cp\u003e\u0026gt;0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eS-CXI, cachexia index based on the skeletal muscle mass index; P-CXI, cachexia index based on the psoas muscle index\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"colorectal cancer, cachexia, FTD/TPI","lastPublishedDoi":"10.21203/rs.3.rs-4958109/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4958109/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn later-line treatment of metastatic colorectal cancer (mCRC), there may be large differences in treatment efficacy depending on cancer cachexia. Recently, the cachexia index (CXI), which was calculated from the skeletal muscle mass index (SMI), serum albumin concentration, and neutrophil-to-lymphocyte ratio, was developed to evaluate cancer cachexia. We retrospectively examined the CXI of 80 patients who were treated with trifluridine/thymidine phosphorylase inhibitor (FTD/TPI)\u0026thinsp;+\u0026thinsp;bevacizumab (Bmab) therapy as a later-line treatment for mCRC and assessed the impact of cancer cachexia on chemotherapeutic efficacy using the CXI. Progression-free and overall survival rates were significantly worse in the low CXI group than in the high CXI group. As the cross-sectional area of the iliopsoas muscle was significantly associated with that of the skeletal muscle, the accuracy of the CXI based on the psoas mass index (P-CXI), which is easier to calculate than the SMI, in predicting treatment outcomes was equivalent to that of the CXI based on the SMI (S-CXI). Cancer cachexia is an important factor related to treatment efficacy in later-line treatments, such as FTD/TPI\u0026thinsp;+\u0026thinsp;Bmab therapy.\u003c/p\u003e","manuscriptTitle":"Impact of cancer cachexia on chemotherapeutic efficacy in patients with metastatic colorectal cancer who are treated with trifluridine/thymidine phosphorylase inhibitor + bevacizumab","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-16 05:30:05","doi":"10.21203/rs.3.rs-4958109/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-23T15:11:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-22T07:26:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-20T19:42:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144419945328285181349543973918487410841","date":"2024-09-17T17:15:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"206449637735208783730888776758962196076","date":"2024-09-17T16:13:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-17T15:54:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-17T15:44:56+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-09-10T09:49:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-22T13:22:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-08-22T12:36:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fadf4673-479d-4f28-9c59-0c8d2e83d337","owner":[],"postedDate":"October 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":37814946,"name":"Health sciences/Gastroenterology"},{"id":37814947,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2024-11-04T16:27:47+00:00","versionOfRecord":{"articleIdentity":"rs-4958109","link":"https://doi.org/10.1038/s41598-024-77766-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-29 16:20:21","publishedOnDateReadable":"October 29th, 2024"},"versionCreatedAt":"2024-10-16 05:30:05","video":"","vorDoi":"10.1038/s41598-024-77766-z","vorDoiUrl":"https://doi.org/10.1038/s41598-024-77766-z","workflowStages":[]},"version":"v1","identity":"rs-4958109","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4958109","identity":"rs-4958109","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}