Nutritional, Inflammatory, and CT-Derived Body Composition Changes During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: A Single-Center Retrospective Cohort 

Nutritional, Inflammatory, and CT-Derived Body Composition Changes During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: A Single-Center Retrospective Cohort | 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 Nutritional, Inflammatory, and CT-Derived Body Composition Changes During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: A Single-Center Retrospective Cohort Makoto Hasegawa, Tomoyuki Momma, Shizuka Kimura, Hitomi Ichinose, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8046965/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Purpose Evidence on how nutritional, inflammatory, and body composition indices change during adjuvant chemotherapy for stage II/III colorectal cancer (CRC) is limited. This study aimed to evaluate these longitudinal changes and identify preoperative predictors of treatment discontinuation and overall survival (OS). Methods This was a retrospective, single-center study of stage II/III CRC patients who were curatively resected and received adjuvant chemotherapy. Nutritional, inflammatory, and body composition indices (including body mass index [BMI], psoas muscle index [PMI], Psoas Muscle Density [PMD], modified Intramuscular Adipose Tissue Content [mIMAC], Geriatric Nutritional Risk Index [GNRI], Prognostic Nutritional Index [PNI], hemoglobin, albumin, lymphocyte, and platelet [HALP] score, neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR]) were obtained preoperatively and 6 months after initiating adjuvant chemotherapy. Subgroup analyses contrasted doublet therapy (CAPOX/FOLFOX) and monotherapy (S-1, UFT/LV, capecitabine). Results Among 142 patients (median age 67 years), several indices (BMI, GNRI, PNI, and HALP score) increased, whereas inflammatory indices (NLR and PLR) decreased from baseline to follow-up. Adjuvant therapy was discontinued in 45 patients (31.7%). Discontinuation predictors differed by regimen: for doublet therapy, poor preoperative nutritional/inflammatory status was significant, whereas for monotherapy, only older age was a predictor. Lower preoperative muscle quality (PMD, mIMAC), but not quantity (PMI), was significantly associated with poorer OS, while other nutritional/inflammatory indices were not. Conclusion Nutritional and inflammatory status was not uniformly worsened after adjuvant chemotherapy, with several indices showing improvement. Muscle quality indices were prognostic for OS, and preoperative nutritional/inflammatory indices helped identify patients at risk for discontinuation, especially for doublet therapy. colorectal cancer adjuvant chemotherapy nutritional assessment body composition myosteatosis Figures Figure 1 Figure 2 Figure 3 Introduction Colorectal cancer (CRC) is the third most common malignant tumor worldwide [ 1 ]. The standard of care for Stage III and high-risk Stage II CRC patients involves radical surgery followed by postoperative adjuvant chemotherapy to prevent recurrence and improve prognosis [ 2 ]. In Stage III CRC, the superiority of doublet therapy to monotherapy has been demonstrated; however, in elderly patients and high-risk Stage II patients, the superiority of doublet therapy over monotherapy has not been sufficiently demonstrated, and treatment should be determined on a case-by-case basis. Malnutrition is a common complication in patients with cancer, arising from both tumor-related factors and the adverse effects of medical or surgical anticancer treatments, and it is, therefore, important to identify malnutritional state as early as possible [ 3 ]. Although nutritional assessment is recommended for all cancer patients [ 3 ], the optimal assessment tool remains controversial, and no single instrument has been established as a standard in colorectal cancer care [ 4 , 5 ]. Several nutritional and inflammatory indices have been reported to influence both short- and long-term outcomes in CRC patients [ 4 , 6 – 9 ]. Beyond nutritional and inflammatory indices, body-composition indices (including body mass index [BMI], muscle quantity, and muscle quality) are clinically relevant in CRC [ 10 – 13 ]. The direction and magnitude of the association with BMI are inconsistent across different study cohorts [ 14 , 15 ]. Despite these insights, little is known about how nutritional status and body composition change during adjuvant chemotherapy or about the factors contributing to treatment discontinuation in CRC patients [ 9 , 14 ]. In this study, we investigated longitudinal changes in nutritional status and body composition during adjuvant chemotherapy, and identified preoperative parameters associated with short- and long-term outcomes as well as treatment discontinuation. Methods Study Design In this retrospective study, we analyzed patients who underwent radical surgery for Stage II/III CRC and received adjuvant chemotherapy at Fukushima Medical University Hospital from January 2013 to December 2023. The inclusion criteria were: (i) histopathologically confirmed diagnosis of colorectal adenocarcinoma; and (ii) curative resection. The exclusion criteria for this study were, (i) non-curative resection (microscopic or macroscopically positive margin), (ii) receipt of neoadjuvant chemotherapy and/or radiation therapy. This study was approved by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148) for a retrospective analysis of the collected data in accordance with the ethical standards of the Declaration of Helsinki of the World Medical Association. Nutritional assessment, counseling, and rehabilitation All patients received nutritional counseling for at least 30 minutes during their inpatient stay prior to postoperative discharge. Post-discharge counseling was not scheduled routinely but was offered to patients considered at high risk of frailty or malnutrition. Perioperative rehabilitation was delivered during their inpatient stay for surgery; no structured rehabilitation program was implemented after hospital discharge. Adjuvant chemotherapy At our institution, postoperative adjuvant chemotherapy is offered to patients with pathologic Stage III or high-risk Stage II CRC as described below following curative resection. General eligibility for treatment requires an Eastern Cooperative Oncology Group performance status of 0–1, adequate recovery from postoperative complications, preserved major organ function, and the absence of serious active comorbidities. The specific chemotherapy regimen is selected based on pathological stage, patient age, and an overall risk assessment. For patients under 70 years of age with Stage III CRC, our standard approach is doublet therapy with CAPOX (capecitabine and oxaliplatin), or FOLFOX (folinic acid plus 5-fluorouracil plus oxaliplatin). For patients aged 70 and older, and for those with high-risk Stage II CRC at any age, oral fluoropyrimidine monotherapy is preferred; acceptable options include S-1 (tegafur, gimeracil, oteracil potassium), UFT/LV (tegafur–uracil plus leucovorin), and capecitabine. High-risk features for Stage II CRC are defined by established guidelines and include T4 tumor (serosal invasion or direct invasion of adjacent organs), tumor perforation, poorly differentiated tumor histology, lymphovascular invasion or perineural invasion, an inadequate lymph node yield (< 12 lymph nodes sampled), and tumor budding. However, the presence of microsatellite instability-high (MSI-H) or defective mismatch repair (dMMR) is associated with a more favorable prognosis and confers little to no benefit from oral fluoropyrimidine monotherapy, which can be harmful [ 16 – 19 ]. Accordingly, we typically administer oxaliplatin-based doublet chemotherapy for stage III CRC, regardless of MSI-H/dMMR status. For high-risk Stage II CRC, adjuvant therapy is generally omitted in patients with MSI-H/dMMR status. Final treatment decisions are made through shared decision-making. Follow-up observation During the adjuvant chemotherapy period, laboratory data were collected prior to each treatment cycle. Following radical surgery, all patients were enrolled in a 5-year surveillance program. This protocol included the collection of serum tumor markers every 3 months. A computed tomography (CT) scan of the chest and abdomen was scheduled for approximately every 6 months. Data collection For each patient, data were collected at two time points: just before radical surgery (defined as the most recent measurements within 3 months preoperatively) and 6 months after initiation of adjuvant chemotherapy (using data from the first CT scan performed at or after this time point). The following variables were recorded: age, sex, height, weight, BMI, tumor stage, nutritional assessment tools (including Prognostic Nutritional Index [PNI], Geriatric Nutritional Risk Index [GNRI], neutrophil-to-lymphocyte ratio [NLR], hemoglobin-albumin-lymphocyte-platelet [HALP] score, and platelet-to-lymphocyte ratio [PLR]), body composition assessment tools (including Psoas Muscle Index [PMI], Psoas Muscle Density [PMD], modified Intramuscular Adipose Tissue Content [mIMAC]), blood biochemistry test results, discontinuation of adjuvant chemotherapy, and prognosis. Nutritional and inflammatory indices The following formula was used to calculate the nutritional and inflammatory indices. PNI = (10 × serum albumin [g/dL]) + (0.005 × total lymphocyte count [/µL]) GNRI = (14.89 × serum albumin [g/dL]) + (41.7 × (current body weight [kg] / ideal body weight [kg])) Ideal body weight was determined using the Lorentz equations: For men: Height [cm] − 100 - ((Height [cm] − 150) / 4) For women: Height [cm] − 100 - ((Height [cm] − 150) / 2.5) NLR = Neutrophil count [/µL] / Lymphocyte count [/µL] HALP score = (Hemoglobin [g/L] × Albumin [g/L] × Lymphocyte count [/L]) / (Platelet count [/L]) PLR = Platelet count [/µL] / Lymphocyte count [/µL] CT-derived body composition analysis All CT images were reviewed by one of the authors (M.S.) using EV Insite software (version 3.17.0.8; PSP Corporation, Tokyo, Japan). The reviewer was blinded to patient outcomes and performed the radiologic measurements as follows. Freehand regions of interest (ROIs) were drawn around both psoas muscles and the multifidus muscle on the same CT slice, carefully excluding areas of obvious macroscopic fat infiltration. Additionally, CT attenuation values (Hounsfield units, HU) of subcutaneous fat were measured by placing four circular ROIs within homogeneous areas of subcutaneous fat at the same level, avoiding major vessels (Fig. 1 ). PMI = (right + left psoas cross-sectional areas at L3) / height² (cm²/m²). PMD = mean HU of the psoas muscle at L3, average across right and left (HU) mIMAC = Mean CT value of ROIs in multifidus muscle (HU) - Mean CT value of ROIs in subcutaneous fat (HU) Statistical Analysis Continuous variables were presented as the median and interquartile range (IQR), while categorical variables were presented as numbers and percentages (n, %). Univariate relationships were analyzed using the Wilcoxon signed-rank test and Mann-Whitney U test. In addition to the overall analysis, we also performed subgroup analyses for doublet therapy (including CAPOX and FOLFOX) and monotherapy (including S-1, UFT/LV, and capecitabine). In the survival analyses, we assessed overall survival (OS) and disease-free survival (DFS). OS was defined as the interval from curative resection to death from any cause. DFS was defined as the interval from curative resection to disease recurrence or death from any cause, whichever occurred first. Patients without an event were censored at the date of their last follow-up or 5 years after resection, whichever came first. Kaplan-Meier curves were generated and between-group differences were evaluated using the log-rank test. Continuous variables were dichotomized at their respective medians; for body composition indices (PMI, PMD, and mIMAC), the sex-specific medians were used as cutoffs. All statistical analyses were performed using R software (version 4.5.1). The significant threshold was set at p < 0.05. Results Patient Characteristics A total of 142 patients were included in this study. The median age was 67 years (interquartile range [IQR], 61–73 years), and 79 patients (55.6%) were male. The pathological stage was high-risk Stage II in 39 patients (27.5%) and Stage III in 103 patients (72.5%). One hundred one patients (71.1%) received monotherapy, and 41 patients (28.9%) received doublet therapy. Dose reduction occurred in 31 patients (21.8%). Adjuvant chemotherapy was discontinued in 45 patients (31.7%); reasons were adverse events in 36 (80.0%), cancer recurrence in 5 (11.1%), worsening comorbidity in 2 (4.4%), and patient decision/voluntary withdrawal in 2 (4.4%) (Table 1). Longitudinal change in nutrition, inflammation, and body composition Nutritional and inflammatory indices were compared between the preoperative and post–adjuvant chemotherapy periods. In the overall cohort, significant increases were observed in BMI (median, 22.5 vs. 22.7 kg/m², p = 0.007), GNRI (103.0 vs. 104.1, p = 0.001), PNI (47.6 vs. 49.1, p < 0.001), and the HALP score (26.1 vs. 38.7, p < 0.001). Conversely, NLR (2.5 vs. 1.8, p < 0.001) and PLR (175.9 vs. 137.3, p < 0.001) decreased significantly. No significant changes were found in PMI, PMD, or mIMAC (Table 2). In the doublet group, the HALP score increased significantly (28.7 vs. 41.0, p < 0.001), while significant decreases were observed in the PMI (from 5.4 to 4.6 cm²/m², p = 0.008), NLR (from 2.5 to 1.7, p < 0.001), and PLR (from 178.7 to 121.3, p < 0.001). BMI, GNRI, PNI, PMD, and mIMAC showed no significant changes. In the monotherapy group, significant increases were observed in BMI (22.3 vs. 22.6, p = 0.014), GNRI (101.5 vs. 103.8, p < 0.001), PNI (47.2 vs. 49.3, p < 0.001), and the HALP score (25.5 vs. 36.4, p < 0.001). Conversely, NLR (2.4 vs. 2.0, p < 0.001) and PLR (174.0 vs. 140.8, p < 0.001) decreased significantly. Factors associated with discontinuation In terms of overall patients, there were no significant factors that contributed to discontinuation of adjuvant chemotherapy. In terms of doublet group (n = 41), the discontinuation group (n = 12) had a significantly lower preoperative GNRI (median, 102.4 vs 107.1, p = 0.019), PNI (median, 46.6 vs 50.3, p = 0.014), HALP score (median, 18.8 vs. 34.5, p = 0.011) and significantly higher preoperative NLR (3.5 vs. 2.2, p = 0.045) and PLR (252.8 vs. 154.9, p = 0.020) compared to the non-discontinuation group (n = 29). In contrast, among the monotherapy group (n = 101), the discontinuation group (n = 33) was significantly older than the non-discontinuation group (n = 68) (72.0 vs. 68.0 years, p = 0.018) (Table 3). Survival analyses Regarding DFS, none of the preoperative nutritional, inflammatory, or body composition indices were significantly associated with DFS (Fig. 2 , 3 ). In terms of OS, lower preoperative PMD (p = 0.022) and lower mIMAC (p = 0.0048) were significantly associated with poorer OS (Fig. 3 ). However, no significant association with OS was observed for other indices (Fig. 2 , 3 ). In addition, discontinuation of adjuvant chemotherapy was not significantly associated with either DFS or OS (Supplementary. 1). Discussion This study identified two novel findings. First, postoperative adjuvant chemotherapy does not necessarily worsen nutritional status; in fact, several indices improved during treatment. Second, preoperative nutritional status influenced the likelihood of treatment discontinuation, while mIMAC and PMD emerged as a significant predictor of long-term outcomes. To our knowledge, few studies have longitudinally evaluated both nutritional indices and CT-derived body composition during adjuvant chemotherapy for CRC, underscoring the originality of our work. In general, having a tumor and undergoing treatment, including chemotherapy and surgery, worsens nutritional status [ 3 ]. Conversely, we observed the opposite phenomenon. There are two possible explanations. First, tumor resection reduces disease-driven catabolism and systemic inflammation. CRC patients display reduced postprandial muscle protein synthesis and increased potential of muscle protein breakdown, but curative tumor resection reverses these derangements [ 20 ]. Previous studies reveal, CRC patients gain weight during postoperative adjuvant chemotherapy [ 21 – 23 ]. Beyond the previous study, demonstrating that not only BMI but also key nutritional markers (GNRI, PNI, and HALP score) improved, while inflammatory markers (NLR and PLR) decreased significantly. Second, we performed nutritional counseling prior to postoperative discharge, and post-discharge counseling for patients considered at high risk of frailty or malnutrition. Previous study also reported the effect of nutritional counseling and intervention for CRC patient after surgery [ 24 ]. In the doublet group, PMI decreased significantly despite stable BMI, suggesting selective loss of lean mass during intensive regimens (CAPOX and FOLFOX). This pattern underscores that weight gain does not necessarily indicate better nutritional status, because BMI does not reflect muscle mass and can be influenced by edema and changes in visceral or subcutaneous fat [ 25 ]. Prior studies likewise document postoperative weight gain during adjuvant chemotherapy in CRC [ 21 – 23 ]. This muscle loss may be mediated by inflammation, as prospective studies report marked increases in IL-8, TNF-α, and high-sensitive-CRP specifically in patients who develop sarcopenia during chemotherapy [ 26 ]. Taken together, these findings support closer monitoring of muscle metrics and early, targeted nutrition interventions for patients receiving oxaliplatin-based doublet therapy. In contrast to prior reports, we did not observe a significant association between older age and treatment discontinuation within the doublet group [ 27 , 28 ]. Possible explanation is selection bias (confounding by indication): clinicians preferentially prescribed monotherapy to older patients at baseline. This tendency is well-documented in population-based studies, which indicate that older adults are frequently undertreated with oxaliplatin-based doublet regimen and for shorter durations [ 27 ]. Rather than age, we identified several preoperative nutritional and inflammatory indices as significant predictors of treatment interruption in this group. While the predictive value of PNI and GNRI has been previously established [ 9 , 14 ], our study is among the first to demonstrate that the HALP score, NLR, and PLR are also valuable for identifying patients at risk of discontinuing doublet adjuvant chemotherapy. In the monotherapy group, we found that older age was the sole significant factor associated with the discontinuation of adjuvant chemotherapy. While previous studies have shown that older patients are more likely to discontinue doublet regimens [ 27 ], the impact of age on monotherapy adherence has been less clear. This is relevant as fluorouracil monotherapy is known to improve survival in elderly patients (aged 70 years and older) without significantly increasing most toxicities or treatment discontinuations, though leukopenia remains a known risk [ 29 ]. Although our findings point to an association between age and monotherapy discontinuation, this conclusion should be interpreted with caution due to significant selection bias in our study. In our survival analysis, the preoperative muscle quality indices PMD and mIMAC were both significantly associated with OS. These CT-derived indices reflect the degree of myosteatosis, where lower PMD and lower mIMAC signify greater myosteatosis and poorer muscle quality. Consistent with prior reports, mIMAC has predicted both short- and long-term outcomes across gastrointestinal malignancies [ 10 , 30 ]. PMD is a CT-based marker of muscle quality that reflects replacement of contractile fibers by adipose and connective tissue and correlates with physical performance [ 31 – 33 ]. In colorectal and other gastrointestinal cancers, low PMD predicts higher postoperative complication rates and poorer long-term outcomes, including worse overall survival [ 31 – 33 ]. Although the PMI was not significantly associated with OS in our cohort, muscle quality may be a more informative predictor than muscle quantity in this setting. This study did not assess motor function or physical activity, and no structured rehabilitation program was implemented in our cohort; therefore, the contribution of these factors to prognosis remains unclear. A previous study showed physical activity levels during chemotherapy cycles are low, particularly in the early phase of each cycle [ 34 ]. There is also evidence that exercise-based rehabilitation during adjuvant chemotherapy is feasible and safe [ 35 ], and that home-based exercise after completion of adjuvant treatment can improve quality of life and psychological health in colorectal cancer survivors [ 36 ]. Notably, a recent phase 3 trial reported that structured exercise after adjuvant chemotherapy improved disease-free survival and suggested longer OS in colon cancer [ 37 ], implying the hypothesis that preserving muscle quality through planned exercise may improve long-term outcomes. Future studies are therefore needed to determine whether targeted interventions, such as structured exercise, would be particularly beneficial for patients identified as having poor preoperative muscle quality and low motor function. Several limitations merit consideration. First, this was a retrospective, single-center study, which may limit generalizability. Second, heterogeneity in disease stage (II and III), regimen (doublet vs monotherapy), and treatment duration likely introduced selection bias and confounding by indication. Third, the relatively small sample size precluded multivariable regression analysis. Consequently, we could not adjust for potential confounders, and the influence of residual confounding cannot be ruled out. Fourth, isolating the effects of adjuvant chemotherapy from those of the preceding surgical procedure is challenging, as surgery itself is known to influence nutritional, inflammatory, and CT-derived body-composition indices. Finally, nutritional counseling, dietary intake, and physical activity were neither standardized nor quantified, potentially confounding the observed changes. Conclusion Adjuvant chemotherapy for Stage II/III colorectal cancer did not necessarily worsen nutritional status; instead, it was associated with improvements in several indices. However, intensive regimens such as CAPOX and FOLFOX may negatively affect skeletal muscle mass, as reflected by a decline in PMI. In patients receiving doublet therapy, preoperative GNRI, PNI, HALP score, as well as NLR and PLR, appeared to influence the tolerability of adjuvant chemotherapy. By contrast, in those receiving single-agent regimens, older age was the predominant factor associated with treatment discontinuation. Finally, with respect to long-term prognosis, only the preoperative muscle quality indices (PMD and mIMAC) were associated with OS, underscoring that muscle quality is likely more informative than muscle quantity (PMI) in this setting. Declarations Ethics approval: This study was approved by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148) for a retrospective analysis of the collected data in accordance with the ethical standards of the Declaration of Helsinki of the World Medical Association. Consent to participate statement: The requirement for informed consent was waived for this retrospective analysis by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148). Availability of data and materials: All data generated or analyzed during this study are included in this published article. Competing interests: The authors declare that they have no competing interests. Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions: Makoto Hasegawa and Hirokazu Okayama collected the data. Makoto Hasegawa analyzed the data and drafted the manuscript. Makoto Hasegawa, Tomoyuki Momma, Shizuka Kimura, Hitomi Ichinose, Hiroki Yago, Takahiro Sato, Misato Ito, Takuro Matsumoto, Daisuke Ujiie, Shun Chida, Hirokazu Okayama, Motonobu Saito, Wataru Sakamoto, and Koji Kono contributed to patient management, discussed the results, critically revised the manuscript, and approved the final version. 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Front Oncol 13:1189324. https://doi.org/10.3389/fonc.2023.1189324 Scarrold L, Stupart D, Watters D (2025) Psoas muscle density predicts elective colorectal surgical outcomes more accurately than psoas muscle area or indexed area. J Frailty Aging 14:100037. https://doi.org/10.1016/j.tjfa.2025.100037 Park H, Jung M, Kim MJ, et al (2020) Objectively measured physical activity during chemotherapy in colon cancer patients. Support Care Cancer 28:2597–2604. https://doi.org/10.1007/s00520-019-05049-9 Hatlevoll I, Oldervoll LM, Wibe A, et al (2021) Physical exercise during adjuvant chemotherapy for colorectal cancer-a non-randomized feasibility study. Support Care Cancer 29:2993–3008. https://doi.org/10.1007/s00520-020-05789-z Kim JY, Lee MK, Lee DH, et al (2019) Effects of a 12-week home-based exercise program on quality of life, psychological health, and the level of physical activity in colorectal cancer survivors: a randomized controlled trial. Support Care Cancer 27:2933–2940. https://doi.org/10.1007/s00520-018-4588-0 Courneya KS, Vardy JL, O’Callaghan CJ, et al (2025) Structured Exercise after Adjuvant Chemotherapy for Colon Cancer. N Engl J Med 393:13–25. https://doi.org/10.1056/NEJMoa2502760 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files 20251010table.xlsx Table 1. Patient characteristics and details of adjuvant chemotherapy including regimens and discontinuation Table 2. Longitudinal changes in nutritional, inflammatory, and body composition indices Table 3: Preoperative factors associated with the discontinuation of adjuvant chemotherapy supplementary1.jpg Supplementary 1. Kaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS) stratified by the discontinuation of adjuvant chemotherapy. The log-rank test was used to compare survival curves. Discontinuation of adjuvant chemotherapy was not significantly associated with either DFS or OS Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 29 Apr, 2026 Reviewers agreed at journal 26 Apr, 2026 Reviewers invited by journal 08 Dec, 2025 Editor assigned by journal 08 Dec, 2025 Submission checks completed at journal 13 Nov, 2025 First submitted to journal 06 Nov, 2025 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8046965","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":557203584,"identity":"f0422e56-e0b3-4108-8ab3-1ce109f8f075","order_by":0,"name":"Makoto 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14:42:33","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106519,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/a9ffb87b495b5397afe89fbc.html"},{"id":97992371,"identity":"58e2fb6e-565c-4ee2-a381-0cd823cab4d9","added_by":"auto","created_at":"2025-12-11 14:42:33","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":701779,"visible":true,"origin":"","legend":"\u003cp\u003eMeasurement of body composition parameters on an axial CT image at the third lumbar vertebra level. The psoas muscle (red), multifidus muscle (blue), and subcutaneous fat (yellow) are segmented for analysis. The psoas muscle index (PMI) is calculated by dividing the total psoas muscle area (cm²) by the patient's height squared (m²). The psoas muscle density (PMD) is measured as the mean attenuation of the muscle in Hounsfield units (HU) and reflects muscle quality. The modified Intramuscular Adipose Tissue Content (mIMAC) is defined as the mean CT value of the multifidus muscle minus that of the subcutaneous fat, serving as another key indicator of myosteatosis.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/296cc22564839667ef841bb3.jpg"},{"id":98425641,"identity":"5721f007-b5b4-4f48-8244-f5ccb3126b69","added_by":"auto","created_at":"2025-12-17 16:35:00","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1671308,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS) stratified by preoperative nutritional and inflammatory indices. The log-rank test was used to compare survival curves. None of the nutritional indices (Geriatric Nutritional Risk Index [GNRI], Prognostic Nutritional Index [PNI], or Hemoglobin, Albumin, Lymphocyte, and Platelet [HALP] score) or inflammatory indices (neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]) were significantly associated with OS and DFS.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/ea8442bd9064e0acaebb086d.jpg"},{"id":97992372,"identity":"fccf4ee8-ddf8-4124-96b6-b65787b89006","added_by":"auto","created_at":"2025-12-11 14:42:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":143799,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS) stratified by preoperative body composition indices. The log-rank test was used to compare survival curves. Lower preoperative psoas muscle density (PMD) (p = 0.022) and lower modified Intramuscular Adipose Tissue Content (mIMAC) (p = 0.0048) were significantly associated with poorer OS. In contrast, none of the body composition indices were significantly associated with DFS.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/a5a26d9a17c3b86181ff88fb.jpg"},{"id":98622981,"identity":"61e95fb1-edd4-4df8-9660-8f0f0ce5eaef","added_by":"auto","created_at":"2025-12-19 17:03:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3224594,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/db103227-540a-4c28-81a1-ed2cb44a1e3b.pdf"},{"id":98424736,"identity":"9ae1399e-3488-4d69-9fbf-65440e3ac901","added_by":"auto","created_at":"2025-12-17 16:33:45","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19087,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1. Patient characteristics and details of adjuvant chemotherapy including regimens and discontinuation\u003c/p\u003e\n\u003cp\u003eTable 2. Longitudinal changes in nutritional, inflammatory, and body composition indices\u003c/p\u003e\n\u003cp\u003eTable 3: Preoperative factors associated with the discontinuation of adjuvant chemotherapy\u003c/p\u003e","description":"","filename":"20251010table.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/34c4b0d545a57bf5c327ac08.xlsx"},{"id":97992375,"identity":"2bb9ac8f-dfd1-4629-9b40-51fec560dd04","added_by":"auto","created_at":"2025-12-11 14:42:33","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":362870,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary 1. Kaplan-Meier analysis of overall survival (OS) and disease-free survival (DFS) stratified by the discontinuation of adjuvant chemotherapy. The log-rank test was used to compare survival curves. Discontinuation of adjuvant chemotherapy was not significantly associated with either DFS or OS\u003c/p\u003e","description":"","filename":"supplementary1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8046965/v1/5d3dcc7ad65a8d0948b56902.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Nutritional, Inflammatory, and CT-Derived Body Composition Changes During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: A Single-Center Retrospective Cohort ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) is the third most common malignant tumor worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The standard of care for Stage III and high-risk Stage II CRC patients involves radical surgery followed by postoperative adjuvant chemotherapy to prevent recurrence and improve prognosis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In Stage III CRC, the superiority of doublet therapy to monotherapy has been demonstrated; however, in elderly patients and high-risk Stage II patients, the superiority of doublet therapy over monotherapy has not been sufficiently demonstrated, and treatment should be determined on a case-by-case basis.\u003c/p\u003e\u003cp\u003eMalnutrition is a common complication in patients with cancer, arising from both tumor-related factors and the adverse effects of medical or surgical anticancer treatments, and it is, therefore, important to identify malnutritional state as early as possible [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although nutritional assessment is recommended for all cancer patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], the optimal assessment tool remains controversial, and no single instrument has been established as a standard in colorectal cancer care [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Several nutritional and inflammatory indices have been reported to influence both short- and long-term outcomes in CRC patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Beyond nutritional and inflammatory indices, body-composition indices (including body mass index [BMI], muscle quantity, and muscle quality) are clinically relevant in CRC [\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The direction and magnitude of the association with BMI are inconsistent across different study cohorts [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite these insights, little is known about how nutritional status and body composition change during adjuvant chemotherapy or about the factors contributing to treatment discontinuation in CRC patients [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In this study, we investigated longitudinal changes in nutritional status and body composition during adjuvant chemotherapy, and identified preoperative parameters associated with short- and long-term outcomes as well as treatment discontinuation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eIn this retrospective study, we analyzed patients who underwent radical surgery for Stage II/III CRC and received adjuvant chemotherapy at Fukushima Medical University Hospital from January 2013 to December 2023. The inclusion criteria were: (i) histopathologically confirmed diagnosis of colorectal adenocarcinoma; and (ii) curative resection. The exclusion criteria for this study were, (i) non-curative resection (microscopic or macroscopically positive margin), (ii) receipt of neoadjuvant chemotherapy and/or radiation therapy. This study was approved by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148) for a retrospective analysis of the collected data in accordance with the ethical standards of the Declaration of Helsinki of the World Medical Association.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNutritional assessment, counseling, and rehabilitation\u003c/h3\u003e\n\u003cp\u003eAll patients received nutritional counseling for at least 30 minutes during their inpatient stay prior to postoperative discharge. Post-discharge counseling was not scheduled routinely but was offered to patients considered at high risk of frailty or malnutrition. Perioperative rehabilitation was delivered during their inpatient stay for surgery; no structured rehabilitation program was implemented after hospital discharge.\u003c/p\u003e\n\u003ch3\u003eAdjuvant chemotherapy\u003c/h3\u003e\n\u003cp\u003eAt our institution, postoperative adjuvant chemotherapy is offered to patients with pathologic Stage III or high-risk Stage II CRC as described below following curative resection. General eligibility for treatment requires an Eastern Cooperative Oncology Group performance status of 0\u0026ndash;1, adequate recovery from postoperative complications, preserved major organ function, and the absence of serious active comorbidities.\u003c/p\u003e\u003cp\u003eThe specific chemotherapy regimen is selected based on pathological stage, patient age, and an overall risk assessment. For patients under 70 years of age with Stage III CRC, our standard approach is doublet therapy with CAPOX (capecitabine and oxaliplatin), or FOLFOX (folinic acid plus 5-fluorouracil plus oxaliplatin). For patients aged 70 and older, and for those with high-risk Stage II CRC at any age, oral fluoropyrimidine monotherapy is preferred; acceptable options include S-1 (tegafur, gimeracil, oteracil potassium), UFT/LV (tegafur\u0026ndash;uracil plus leucovorin), and capecitabine.\u003c/p\u003e\u003cp\u003eHigh-risk features for Stage II CRC are defined by established guidelines and include T4 tumor (serosal invasion or direct invasion of adjacent organs), tumor perforation, poorly differentiated tumor histology, lymphovascular invasion or perineural invasion, an inadequate lymph node yield (\u0026lt;\u0026thinsp;12 lymph nodes sampled), and tumor budding. However, the presence of microsatellite instability-high (MSI-H) or defective mismatch repair (dMMR) is associated with a more favorable prognosis and confers little to no benefit from oral fluoropyrimidine monotherapy, which can be harmful [\u003cspan additionalcitationids=\"CR17 CR18\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Accordingly, we typically administer oxaliplatin-based doublet chemotherapy for stage III CRC, regardless of MSI-H/dMMR status. For high-risk Stage II CRC, adjuvant therapy is generally omitted in patients with MSI-H/dMMR status. Final treatment decisions are made through shared decision-making.\u003c/p\u003e\n\u003ch3\u003eFollow-up observation\u003c/h3\u003e\n\u003cp\u003eDuring the adjuvant chemotherapy period, laboratory data were collected prior to each treatment cycle. Following radical surgery, all patients were enrolled in a 5-year surveillance program. This protocol included the collection of serum tumor markers every 3 months. A computed tomography (CT) scan of the chest and abdomen was scheduled for approximately every 6 months.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eFor each patient, data were collected at two time points: just before radical surgery (defined as the most recent measurements within 3 months preoperatively) and 6 months after initiation of adjuvant chemotherapy (using data from the first CT scan performed at or after this time point). The following variables were recorded: age, sex, height, weight, BMI, tumor stage, nutritional assessment tools (including Prognostic Nutritional Index [PNI], Geriatric Nutritional Risk Index [GNRI], neutrophil-to-lymphocyte ratio [NLR], hemoglobin-albumin-lymphocyte-platelet [HALP] score, and platelet-to-lymphocyte ratio [PLR]), body composition assessment tools (including Psoas Muscle Index [PMI], Psoas Muscle Density [PMD], modified Intramuscular Adipose Tissue Content [mIMAC]), blood biochemistry test results, discontinuation of adjuvant chemotherapy, and prognosis.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eNutritional and inflammatory indices\u003c/h2\u003e\u003cp\u003eThe following formula was used to calculate the nutritional and inflammatory indices.\u003c/p\u003e\u003cp\u003ePNI = (10 \u0026times; serum albumin [g/dL]) + (0.005 \u0026times; total lymphocyte count [/\u0026micro;L])\u003c/p\u003e\u003cp\u003eGNRI = (14.89 \u0026times; serum albumin [g/dL]) + (41.7 \u0026times; (current body weight [kg] / ideal body weight [kg]))\u003c/p\u003e\u003cp\u003eIdeal body weight was determined using the Lorentz equations:\u003c/p\u003e\u003cp\u003eFor men: Height [cm] \u0026minus;\u0026thinsp;100 - ((Height [cm] \u0026minus;\u0026thinsp;150) / 4)\u003c/p\u003e\u003cp\u003eFor women: Height [cm] \u0026minus;\u0026thinsp;100 - ((Height [cm] \u0026minus;\u0026thinsp;150) / 2.5)\u003c/p\u003e\u003cp\u003eNLR\u0026thinsp;=\u0026thinsp;Neutrophil count [/\u0026micro;L] / Lymphocyte count [/\u0026micro;L]\u003c/p\u003e\u003cp\u003eHALP score = (Hemoglobin [g/L] \u0026times; Albumin [g/L] \u0026times; Lymphocyte count [/L]) / (Platelet count [/L])\u003c/p\u003e\u003cp\u003ePLR\u0026thinsp;=\u0026thinsp;Platelet count [/\u0026micro;L] / Lymphocyte count [/\u0026micro;L]\u003c/p\u003e\u003cp\u003e\u003cb\u003eCT-derived body composition analysis\u003c/b\u003eAll CT images were reviewed by one of the authors (M.S.) using EV Insite software (version 3.17.0.8; PSP Corporation, Tokyo, Japan). The reviewer was blinded to patient outcomes and performed the radiologic measurements as follows. Freehand regions of interest (ROIs) were drawn around both psoas muscles and the multifidus muscle on the same CT slice, carefully excluding areas of obvious macroscopic fat infiltration. Additionally, CT attenuation values (Hounsfield units, HU) of subcutaneous fat were measured by placing four circular ROIs within homogeneous areas of subcutaneous fat at the same level, avoiding major vessels (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003ePMI = (right\u0026thinsp;+\u0026thinsp;left psoas cross-sectional areas at L3) / height\u0026sup2; (cm\u0026sup2;/m\u0026sup2;).\u003c/p\u003e\u003cp\u003ePMD\u0026thinsp;=\u0026thinsp;mean HU of the psoas muscle at L3, average across right and left (HU)\u003c/p\u003e\u003cp\u003emIMAC\u0026thinsp;=\u0026thinsp;Mean CT value of ROIs in multifidus muscle (HU) - Mean CT value of ROIs in subcutaneous fat (HU)\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eContinuous variables were presented as the median and interquartile range (IQR), while categorical variables were presented as numbers and percentages (n, %). Univariate relationships were analyzed using the Wilcoxon signed-rank test and Mann-Whitney U test. In addition to the overall analysis, we also performed subgroup analyses for doublet therapy (including CAPOX and FOLFOX) and monotherapy (including S-1, UFT/LV, and capecitabine).\u003c/p\u003e\u003cp\u003eIn the survival analyses, we assessed overall survival (OS) and disease-free survival (DFS). OS was defined as the interval from curative resection to death from any cause. DFS was defined as the interval from curative resection to disease recurrence or death from any cause, whichever occurred first. Patients without an event were censored at the date of their last follow-up or 5 years after resection, whichever came first. Kaplan-Meier curves were generated and between-group differences were evaluated using the log-rank test. Continuous variables were dichotomized at their respective medians; for body composition indices (PMI, PMD, and mIMAC), the sex-specific medians were used as cutoffs.\u003c/p\u003e\u003cp\u003eAll statistical analyses were performed using R software (version 4.5.1). The significant threshold was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003eA total of 142 patients were included in this study. The median age was 67 years (interquartile range [IQR], 61\u0026ndash;73 years), and 79 patients (55.6%) were male. The pathological stage was high-risk Stage II in 39 patients (27.5%) and Stage III in 103 patients (72.5%). One hundred one patients (71.1%) received monotherapy, and 41 patients (28.9%) received doublet therapy. Dose reduction occurred in 31 patients (21.8%). Adjuvant chemotherapy was discontinued in 45 patients (31.7%); reasons were adverse events in 36 (80.0%), cancer recurrence in 5 (11.1%), worsening comorbidity in 2 (4.4%), and patient decision/voluntary withdrawal in 2 (4.4%) (Table\u0026nbsp;1).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eLongitudinal change in nutrition, inflammation, and body composition\u003c/h2\u003e\u003cp\u003eNutritional and inflammatory indices were compared between the preoperative and post\u0026ndash;adjuvant chemotherapy periods. In the overall cohort, significant increases were observed in BMI (median, 22.5 vs. 22.7 kg/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.007), GNRI (103.0 vs. 104.1, p\u0026thinsp;=\u0026thinsp;0.001), PNI (47.6 vs. 49.1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the HALP score (26.1 vs. 38.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Conversely, NLR (2.5 vs. 1.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and PLR (175.9 vs. 137.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) decreased significantly. No significant changes were found in PMI, PMD, or mIMAC (Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eIn the doublet group, the HALP score increased significantly (28.7 vs. 41.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), while significant decreases were observed in the PMI (from 5.4 to 4.6 cm\u0026sup2;/m\u0026sup2;, p\u0026thinsp;=\u0026thinsp;0.008), NLR (from 2.5 to 1.7, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and PLR (from 178.7 to 121.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). BMI, GNRI, PNI, PMD, and mIMAC showed no significant changes.\u003c/p\u003e\u003cp\u003eIn the monotherapy group, significant increases were observed in BMI (22.3 vs. 22.6, p\u0026thinsp;=\u0026thinsp;0.014), GNRI (101.5 vs. 103.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), PNI (47.2 vs. 49.3, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the HALP score (25.5 vs. 36.4, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Conversely, NLR (2.4 vs. 2.0, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and PLR (174.0 vs. 140.8, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) decreased significantly.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eFactors associated with discontinuation\u003c/h2\u003e\u003cp\u003eIn terms of overall patients, there were no significant factors that contributed to discontinuation of adjuvant chemotherapy. In terms of doublet group (n\u0026thinsp;=\u0026thinsp;41), the discontinuation group (n\u0026thinsp;=\u0026thinsp;12) had a significantly lower preoperative GNRI (median, 102.4 vs 107.1, p\u0026thinsp;=\u0026thinsp;0.019), PNI (median, 46.6 vs 50.3, p\u0026thinsp;=\u0026thinsp;0.014), HALP score (median, 18.8 vs. 34.5, p\u0026thinsp;=\u0026thinsp;0.011) and significantly higher preoperative NLR (3.5 vs. 2.2, p\u0026thinsp;=\u0026thinsp;0.045) and PLR (252.8 vs. 154.9, p\u0026thinsp;=\u0026thinsp;0.020) compared to the non-discontinuation group (n\u0026thinsp;=\u0026thinsp;29). In contrast, among the monotherapy group (n\u0026thinsp;=\u0026thinsp;101), the discontinuation group (n\u0026thinsp;=\u0026thinsp;33) was significantly older than the non-discontinuation group (n\u0026thinsp;=\u0026thinsp;68) (72.0 vs. 68.0 years, p\u0026thinsp;=\u0026thinsp;0.018) (Table\u0026nbsp;3).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eSurvival analyses\u003c/h2\u003e\u003cp\u003eRegarding DFS, none of the preoperative nutritional, inflammatory, or body composition indices were significantly associated with DFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In terms of OS, lower preoperative PMD (p\u0026thinsp;=\u0026thinsp;0.022) and lower mIMAC (p\u0026thinsp;=\u0026thinsp;0.0048) were significantly associated with poorer OS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). However, no significant association with OS was observed for other indices (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In addition, discontinuation of adjuvant chemotherapy was not significantly associated with either DFS or OS (Supplementary. 1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study identified two novel findings. First, postoperative adjuvant chemotherapy does not necessarily worsen nutritional status; in fact, several indices improved during treatment. Second, preoperative nutritional status influenced the likelihood of treatment discontinuation, while mIMAC and PMD emerged as a significant predictor of long-term outcomes. To our knowledge, few studies have longitudinally evaluated both nutritional indices and CT-derived body composition during adjuvant chemotherapy for CRC, underscoring the originality of our work.\u003c/p\u003e\u003cp\u003eIn general, having a tumor and undergoing treatment, including chemotherapy and surgery, worsens nutritional status [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Conversely, we observed the opposite phenomenon. There are two possible explanations. First, tumor resection reduces disease-driven catabolism and systemic inflammation. CRC patients display reduced postprandial muscle protein synthesis and increased potential of muscle protein breakdown, but curative tumor resection reverses these derangements [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Previous studies reveal, CRC patients gain weight during postoperative adjuvant chemotherapy [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Beyond the previous study, demonstrating that not only BMI but also key nutritional markers (GNRI, PNI, and HALP score) improved, while inflammatory markers (NLR and PLR) decreased significantly. Second, we performed nutritional counseling prior to postoperative discharge, and post-discharge counseling for patients considered at high risk of frailty or malnutrition. Previous study also reported the effect of nutritional counseling and intervention for CRC patient after surgery [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the doublet group, PMI decreased significantly despite stable BMI, suggesting selective loss of lean mass during intensive regimens (CAPOX and FOLFOX). This pattern underscores that weight gain does not necessarily indicate better nutritional status, because BMI does not reflect muscle mass and can be influenced by edema and changes in visceral or subcutaneous fat [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Prior studies likewise document postoperative weight gain during adjuvant chemotherapy in CRC [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. This muscle loss may be mediated by inflammation, as prospective studies report marked increases in IL-8, TNF-α, and high-sensitive-CRP specifically in patients who develop sarcopenia during chemotherapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Taken together, these findings support closer monitoring of muscle metrics and early, targeted nutrition interventions for patients receiving oxaliplatin-based doublet therapy.\u003c/p\u003e\u003cp\u003eIn contrast to prior reports, we did not observe a significant association between older age and treatment discontinuation within the doublet group [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Possible explanation is selection bias (confounding by indication): clinicians preferentially prescribed monotherapy to older patients at baseline. This tendency is well-documented in population-based studies, which indicate that older adults are frequently undertreated with oxaliplatin-based doublet regimen and for shorter durations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Rather than age, we identified several preoperative nutritional and inflammatory indices as significant predictors of treatment interruption in this group. While the predictive value of PNI and GNRI has been previously established [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], our study is among the first to demonstrate that the HALP score, NLR, and PLR are also valuable for identifying patients at risk of discontinuing doublet adjuvant chemotherapy.\u003c/p\u003e\u003cp\u003eIn the monotherapy group, we found that older age was the sole significant factor associated with the discontinuation of adjuvant chemotherapy. While previous studies have shown that older patients are more likely to discontinue doublet regimens [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], the impact of age on monotherapy adherence has been less clear. This is relevant as fluorouracil monotherapy is known to improve survival in elderly patients (aged 70 years and older) without significantly increasing most toxicities or treatment discontinuations, though leukopenia remains a known risk [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Although our findings point to an association between age and monotherapy discontinuation, this conclusion should be interpreted with caution due to significant selection bias in our study.\u003c/p\u003e\u003cp\u003eIn our survival analysis, the preoperative muscle quality indices PMD and mIMAC were both significantly associated with OS. These CT-derived indices reflect the degree of myosteatosis, where lower PMD and lower mIMAC signify greater myosteatosis and poorer muscle quality. Consistent with prior reports, mIMAC has predicted both short- and long-term outcomes across gastrointestinal malignancies [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. PMD is a CT-based marker of muscle quality that reflects replacement of contractile fibers by adipose and connective tissue and correlates with physical performance [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In colorectal and other gastrointestinal cancers, low PMD predicts higher postoperative complication rates and poorer long-term outcomes, including worse overall survival [\u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Although the PMI was not significantly associated with OS in our cohort, muscle quality may be a more informative predictor than muscle quantity in this setting.\u003c/p\u003e\u003cp\u003eThis study did not assess motor function or physical activity, and no structured rehabilitation program was implemented in our cohort; therefore, the contribution of these factors to prognosis remains unclear. A previous study showed physical activity levels during chemotherapy cycles are low, particularly in the early phase of each cycle [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. There is also evidence that exercise-based rehabilitation during adjuvant chemotherapy is feasible and safe [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and that home-based exercise after completion of adjuvant treatment can improve quality of life and psychological health in colorectal cancer survivors [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Notably, a recent phase 3 trial reported that structured exercise after adjuvant chemotherapy improved disease-free survival and suggested longer OS in colon cancer [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], implying the hypothesis that preserving muscle quality through planned exercise may improve long-term outcomes. Future studies are therefore needed to determine whether targeted interventions, such as structured exercise, would be particularly beneficial for patients identified as having poor preoperative muscle quality and low motor function.\u003c/p\u003e\u003cp\u003eSeveral limitations merit consideration. First, this was a retrospective, single-center study, which may limit generalizability. Second, heterogeneity in disease stage (II and III), regimen (doublet vs monotherapy), and treatment duration likely introduced selection bias and confounding by indication. Third, the relatively small sample size precluded multivariable regression analysis. Consequently, we could not adjust for potential confounders, and the influence of residual confounding cannot be ruled out. Fourth, isolating the effects of adjuvant chemotherapy from those of the preceding surgical procedure is challenging, as surgery itself is known to influence nutritional, inflammatory, and CT-derived body-composition indices. Finally, nutritional counseling, dietary intake, and physical activity were neither standardized nor quantified, potentially confounding the observed changes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAdjuvant chemotherapy for Stage II/III colorectal cancer did not necessarily worsen nutritional status; instead, it was associated with improvements in several indices. However, intensive regimens such as CAPOX and FOLFOX may negatively affect skeletal muscle mass, as reflected by a decline in PMI. In patients receiving doublet therapy, preoperative GNRI, PNI, HALP score, as well as NLR and PLR, appeared to influence the tolerability of adjuvant chemotherapy. By contrast, in those receiving single-agent regimens, older age was the predominant factor associated with treatment discontinuation. Finally, with respect to long-term prognosis, only the preoperative muscle quality indices (PMD and mIMAC) were associated with OS, underscoring that muscle quality is likely more informative than muscle quantity (PMI) in this setting.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148) for a retrospective analysis of the collected data in accordance with the ethical standards of the Declaration of Helsinki of the World Medical Association.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe requirement for informed consent was waived for this retrospective analysis by the Institutional Ethics Committee of Fukushima Medical University (approval number 30148).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMakoto Hasegawa and Hirokazu Okayama collected the data. Makoto Hasegawa analyzed the data and drafted the manuscript. Makoto Hasegawa, Tomoyuki Momma, Shizuka Kimura, Hitomi Ichinose, Hiroki Yago, Takahiro Sato, Misato Ito, Takuro Matsumoto, Daisuke Ujiie, Shun Chida, Hirokazu Okayama, Motonobu Saito, Wataru Sakamoto, and Koji Kono contributed to patient management, discussed the results, critically revised the manuscript, and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the secretaries of the Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, for their cooperation in literature collection.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEng C, Yoshino T, Ru\u0026iacute;z-Garc\u0026iacute;a E, et al (2024) Colorectal cancer. 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N Engl J Med 393:13\u0026ndash;25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2502760\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2502760\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"colorectal cancer, adjuvant chemotherapy, nutritional assessment, body composition, myosteatosis","lastPublishedDoi":"10.21203/rs.3.rs-8046965/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8046965/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eEvidence on how nutritional, inflammatory, and body composition indices change during adjuvant chemotherapy for stage II/III colorectal cancer (CRC) is limited. This study aimed to evaluate these longitudinal changes and identify preoperative predictors of treatment discontinuation and overall survival (OS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis was a retrospective, single-center study of stage II/III CRC patients who were curatively resected and received adjuvant chemotherapy. Nutritional, inflammatory, and body composition indices (including body mass index [BMI], psoas muscle index [PMI], Psoas Muscle Density [PMD], modified Intramuscular Adipose Tissue Content [mIMAC], Geriatric Nutritional Risk Index [GNRI], Prognostic Nutritional Index [PNI], hemoglobin, albumin, lymphocyte, and platelet [HALP] score, neutrophil-to-lymphocyte ratio [NLR], and platelet-to-lymphocyte ratio [PLR]) were obtained preoperatively and 6 months after initiating adjuvant chemotherapy. Subgroup analyses contrasted doublet therapy (CAPOX/FOLFOX) and monotherapy (S-1, UFT/LV, capecitabine).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 142 patients (median age 67 years), several indices (BMI, GNRI, PNI, and HALP score) increased, whereas inflammatory indices (NLR and PLR) decreased from baseline to follow-up. Adjuvant therapy was discontinued in 45 patients (31.7%). Discontinuation predictors differed by regimen: for doublet therapy, poor preoperative nutritional/inflammatory status was significant, whereas for monotherapy, only older age was a predictor. Lower preoperative muscle quality (PMD, mIMAC), but not quantity (PMI), was significantly associated with poorer OS, while other nutritional/inflammatory indices were not.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eNutritional and inflammatory status was not uniformly worsened after adjuvant chemotherapy, with several indices showing improvement. Muscle quality indices were prognostic for OS, and preoperative nutritional/inflammatory indices helped identify patients at risk for discontinuation, especially for doublet therapy.\u003c/p\u003e","manuscriptTitle":"Nutritional, Inflammatory, and CT-Derived Body Composition Changes During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: A Single-Center Retrospective Cohort ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-11 14:42:28","doi":"10.21203/rs.3.rs-8046965/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-29T22:39:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"62871507493903299929899749024930253318","date":"2026-04-26T22:27:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-12-08T19:51:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-08T19:48:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-13T23:55:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-11-06T10:34:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"208166ab-a3b3-43bc-992c-34d8575be71f","owner":[],"postedDate":"December 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-12-11T14:42:28+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-11 14:42:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8046965","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8046965","identity":"rs-8046965","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}