Low skeletal muscle radiodensity predicts response to avelumab maintenance treatment in patients with metastatic urothelial carcinoma

Low skeletal muscle radiodensity predicts response to avelumab maintenance treatment in patients with metastatic urothelial carcinoma | 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 Low skeletal muscle radiodensity predicts response to avelumab maintenance treatment in patients with metastatic urothelial carcinoma Nobuhiko Shimizu, Taku Naiki, Yosuke Sugiyama, Aya Naiki-Ito, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8486641/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The JAVELIN Bladder 100 trial demonstrated a significant survival benefit of avelumab maintenance therapy over best supportive care in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who achieved disease control after platinum-based chemotherapy. Although avelumab maintenance therapy is generally well tolerated, some patients experience rapid progression and prognostic factors are not well established. Methods: In this retrospective study, we investigated the prognostic significance of computed tomography–derived body composition indicators in 57 patients with la/mUC who received avelumab maintenance therapy between January 2019 and November 2023. These patients were from within a cohort of 85 patients who underwent first-line platinum-based chemotherapy. Patients were divided into two groups based on a low or high skeletal muscle radiodensity (SMD). Prognostic factors were determined by univariate and multivariate analyses. Results: Among patients treated with avelumab, median progression-free survival (PFS) was 6.4 months in the high SMD group versus 4.8 months in the low SMD group, while median overall survival was not reached versus 16.7 months, respectively. In a Cox proportional hazards model, only high SMD indicated a favorable prognosis for PFS (hazard ratio [HR]: 2.31, 95% confidence interval [CI]: 1.25–4.28), while high SMD was the independent predictor for better overall survival (HR: 2.29, 95% CI: 1.04–5.05). Discussion: Such results suggest that SMD is a potential prognostic factor for la/mUC cases undergoing avelumab maintenance therapy. avelumab metastatic urothelial carcinoma skeletal muscle radiodensity Figures Figure 1 Introduction Bladder cancer ranks as the ninth most commonly diagnosed malignancy worldwide. It represents »3% of all tumors and is thirteenth as a cause of deaths due to cancer globally [1]. Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of locally advanced or metastatic urothelial carcinoma (la/mUC), beginning with the introduction of pembrolizumab in a post-platinum setting [2]. As an antibody to anti–programmed death-ligand 1 (PD-L1), avelumab was endorsed in 2020 by the United States Food and Drug Administration as first-line maintenance therapy for patients who achieved disease control after platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 trial [3]. In Japan, avelumab was approved in February 2021 and is recommended in the Japanese Urological Association treatment guidelines [4]. Although avelumab maintenance therapy significantly improves survival, a substantial proportion of patients still experience early disease progression. Accordingly, reliable prognostic indicators are needed to determine those patients who will likely derive durable benefit from avelumab. Growing evidence indicates that various body composition indicators can influence cancer prognosis and antitumor immune responses. Sarcopenia, characterized by a depletion of skeletal muscle mass and strength [5], is prevalent across cancer populations and has been consistently associated with inferior outcomes, including reduced survival and poorer response to ICIs in many malignancies [6-11]. Myosteatosis, defined as increased intramuscular fat infiltration and impaired muscle quality, has also been reported as a negative prognostic factor in multiple malignancies, including those treated with ICIs [12-17]. Cross-sectional computed tomography (CT) at the third lumbar vertebrae (L3) level allows objective quantification of skeletal muscle mass, expressed as the skeletal muscle index (SMI) [18, 19], as well as assessment of muscle quality using skeletal muscle radiodensity (SMD) [20, 21]. A low SMI reflects sarcopenia, whereas low SMD corresponds to myosteatosis. However, evidence regarding the use of body composition in the prognosis of la/mUC cases undergoing avelumab maintenance therapy remains scarce. Therefore, this study aimed to assess the prognostic significance of sarcopenia and myosteatosis in patients with la/mUC treated with avelumab. Materials and Methods Patient enrollment We enrolled patients with la/mUC affecting their urinary bladder or upper urinary tract at Nagoya City University Hospital or two related institutions from January 2019 to November 2023. Specimens were examined histologically and a diagnosis made. The following selection criteria were used as follows: (1) an la/mUC diagnosis and one or more cycles of first-line chemotherapy; (2) unenhanced CT that was performed at the end of first-line chemotherapy; and (3) biopsied primary lesions or those that were surgically removed. We collected data and assessed it retrospectively. The Ethics Committee of Nagoya City University Hospital (Approval No. 60-18-0060) approved this retrospective investigation. Pathology samples that had been routinely collected previously were used as samples. Patients could opt out of this investigation at any time. This study was in accordance with the Declaration of Helsinki (2013 Fortaleza revision). Therapy Gemcitabine and cisplatin (GC) was used as first-line therapy. Patients underwent gemcitabine and carboplatin therapy if they could not be treated with cisplatin. The treatment of patients with a GC regimen was based on the following criteria: no significant hearing loss, < 2 grade neuropathy, creatinine clearance ≥ 60 mL/min, and no symptoms of heart failure in accordance with New York Heart Association class III or greater. Treatment with gemcitabine and carboplatin was used if any criteria were not met. The size of tumors was based on CT imaging. Patients underwent a physical examination. The Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. were used to assess patient responses to treatments. No progression, a complete response (CR), partial response (PR), or stable disease were obtained after first-line treatment. Patients received avelumab switch maintenance therapy (10 mg/kg by intravenous infusion every 2 weeks) if hematologic, hepatic, and renal functions were satisfactory. Disease progression as per RECIST criteria or the development of adverse events (AEs) that were not well tolerated meant that treatment was stopped. Progression-free survival (PFS) referred to the interval from the initiation of avelumab maintenance treatment to progression. Between the initiation of avelumab maintenance treatment and the death of a patient due la/mUC was considered overall survival (OS). The reporting of AEs was based on National Cancer Institute Common Terminology Criteria for AEs, version 4.0. Patient information was obtained from medical records of the abovementioned organizations on: gender, age, height and weight, tumor location (upper urinary tract or urinary bladder), radical surgery of primary site, visceral and lymph node metastasis, Eastern Cooperative Oncology Group performance status (ECOG–PS), and serum blood variables at the end of first-line treatment. Image protocols Unenhanced CT images at the conclusion of first-line chemotherapy of study participants were obtained. Parameters for CT images included the following information: the thickness of 5-mm slices, 120 kVp. An axial image at L3 for which both transverse processes were fully observed was identified for each patient. The area of skeletal muscle (including paraspinal, psoas, rectus abdominis, transversus abdominis, and internal and external oblique muscles) was based on Hounsfield unit (HU) thresholds of -29 and +150. After normalization by height squared, this was reported as the SMI (cm 2 /m 2 ). For the entire cross-sectional muscle area, the mean skeletal muscle radiation attenuation was reported as the SMD (HU). All image analyses were performed using Image J 1.54 (National Institute of Health, Bethesda, MD, USA, http://rsb.info.nih.gov/ij). Statistics The basis of cutoff values for the SMI defining sarcopenia was an Asian-based definition (< 36.2 cm 2 /m 2 used for males; < 29.6 cm 2 /m 2 used for females) [22]. As there is no clear standard cutoff for the SMD validated in patients with cancer, patients were placed into two groups on the basis of the sex-specific median of the SMD, which corresponds to 28.5 HU for males and 24.8 HU for females. Fisher’s exact test or a Mann–Whitney U test were used to determine differences based on categorical parameters. To determine cumulative rates of PFS and OS, Kaplan–Meier curves were used. To calculate significant differences a log-rank test was used. Cox proportional hazard regression analyses were used in univariate and multivariate analyses. Cut-off values used for each prognostic factor were derived from other investigations: age (≥ 65 vs. < 65 years), serum C-reactive protein (CRP) levels (≥ 0.3 vs. < 0.3 mg/dL), and neutrophil–lymphocyte ratio (NLR; ≥ 3 vs. < 3). Statistical significance was p < 0.05 with two-tailed p values used. The data collected was evaluated using a EZR statistical program from the Saitama Medical Center, Jichi Medical University (Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [23]. Results Patient characteristics and oncological outcomes We enrolled a total of 85 patients with la/mUC on first-line therapy. Of these, 57 patients underwent avelumab treatment. Based on the cut-off value, the total cohort was divided into low (n=42) and high (n=43) SMD groups. Table 1 outlines the characteristics of patients. Differences in patients’ variables after first-line treatment, which includes age, distribution of genders, body mass index, regimen of first-line chemotherapy, number of cycles in first-line chemotherapy, ECOG–PS, primary site, the frequency of visceral metastasis, resection of primary site, and response to first-line chemotherapy, were statistically insignificant between groups. When compared to the low SMD group, the high SMD group showed a significantly lower neutrophil-to-lymphocyte ratio (NLR) among laboratory parameters. In the cohort of patients treated with avelumab, no significant difference was found in PFS from the initiation of avelumab maintenance treatment between low and high SMI groups (Fig. 1a). However, the median PFS was significantly superior for the high SMD group (median 6.4 months, 95% confidence interval [CI]: 4.70–not reached [NR]) in comparison to the low SMD cohort (median 4.8 months, 95% CI: 2.30–6.21; Fig. 1b). Similarly, no significant difference in OS was noted between low and high SMI groups (Fig. 1c). However, the median OS from the start of avelumab maintenance treatment was significantly superior for the high SMD (median not applicable [NA], 95% CI: 15.8–NR) compared to the low SMD (median 16.7 months, 95% CI: 12.6–19.7; Fig. 1d) group. Univariate and multivariate analyses showed how high SMD was the sole independent prognostic factor for better PFS (hazard ratio [HR]: 2.31, 95% CI: 1.25–4.28; Table 2). In addition, high SMD and low NLR were independent prognostic factors for better OS (HR: 2.29, 95% CI: 1.04–5.05 and HR: 2.44, 95% CI: 1.11–5.37, respectively; Table 3). Adverse events Adverse events associated with avelumab switch maintenance treatment between low SMD and high SMD groups were analyzed (Table 4). Among grade ≥ 3 AEs, rash (4.3%) and diarrhea (4.3%) in the low SMD group, and pancreatitis (2.9%) and encephalitis (2.9%) in the high SMD group were recognized. Of these AEs, only encephalitis was uncontrollable and led to death. Since the total incidences of AEs were fundamentally low, a significant difference was not observed between the two groups with regard to AEs. Discussion Since the approval of avelumab maintenance therapy based on the JAVELIN Bladder 100 (JB100) phase 3 trial, several large real-world studies from various countries, including Japan, have been reported confirming its efficacy and safety [24-27]. Previous studies have identified potential prognostic factors for PFS and OS following avelumab initiation, such as ECOG-PS, CRP, metastatic sites, and inflammatory markers including interleukin-8, NLR, and the systemic immune-inflammation index [28, 29]. However, body composition parameters reflecting sarcopenia and myosteatosis, such as skeletal muscle mass and radiodensity, have not been evaluated in this setting. In this retrospective study, we demonstrated that high SMD at the initiation of avelumab maintenance therapy was significantly associated with longer PSF and OS. Several studies across various cancer types, including urothelial carcinoma, have reported that a low SMD is associated with poor outcomes in patients treated with immune checkpoint inhibitors [13-15]. Skeletal muscle has an important role in modulating the tumor microenvironment. This is because it secretes various myokines, including irisin and interleukin-15, which influence the immune response [30-32]. Reduced muscle quality may result in decreased secretion of these myokines to promote tumor growth and suppress anti-tumor immunity to affect patient survival. In the present study, the SMI, a representative CT-derived marker of sarcopenia, was not significantly associated with prognosis. To date, two studies from Japan have evaluated the prognostic effect of the SMI in patients with metastatic urothelial carcinoma, each adopting either the international or Prado definition for sarcopenia [33, 34] . A recent large-scale cohort investigation by Taguchi et al. [35] suggested that ethnic-specific cutoffs for low muscle mass were appropriate, leading to increased accuracy in the classification of patients and in predicting a prognosis; therefore, we applied the cutoff values for an Asian-based definition by Fujiwara et al. in the current analysis [22]. The absence of a significant association between SMI and survival in our cohort may partly be explained by patient selection bias since individuals who were eligible for avelumab maintenance therapy generally had favorable disease control and relatively preserved muscle mass. In addition, recent studies have demonstrated that the SMD and SMI are not always correlated, and that low SMD is more closely associated with frailty and impaired muscle strength even when muscle mass is preserved [36-38]. Skeletal muscle radiodensity may better capture the functional and immunologic decline that influences patient outcomes. In regard to clinicopathologic parameters besides sarcopenia, NLR ≥ 3 was revealed as an independent prognostic factor for OS, as also shown in previous studies [28]. The NLR is a biomarker of systemic inflammation caused by cancer progression [39]. Whereas NLR represents a tumor-related factor, the SMD reflects a host-related factor; therefore, evaluating patients from both perspectives may lead to a more comprehensive assessment of prognosis. After the findings of the EV-302 phase 3 trial [40], enfortumab vedotin and pembrolizumab (EV + PEM) used as first-line therapy in the United States and is the preferred choice in updated treatment guidelines, including those in Japan. The toxicity profile of EV + PEM includes peripheral neuropathy, hyperglycemia, and serious skin reactions; a considerable proportion of patients have difficulty continuing EV + PEM due to these toxicities. Furthermore, the optimal subsequent therapy after EV + PEM remains unclear. Even in this new therapeutic era, maintenance therapy with relatively favorable efficacy and safety profiles continues to offer meaningful benefits. As real-world sequential treatment data continue to accumulate, the optimal therapeutic sequence is expected to be better defined in the future. This study has several limitations. First, its retrospective design and relatively small sample size may limit the generalizability of our findings. Second, the cutoff value for SMD was determined using the median of our cohort, which might be specific to this study population. Further studies with larger cohorts are needed to establish an appropriate universal cutoff value. In summary, our findings indicate that the SMD, a convenient and reproducible CT-derived marker, may provide valuable prognostic information in patients treated with avelumab maintenance therapy. Declarations Ethics approval and informed patient consent Written informed consent was given by patients. Approval for this study was obtained from the ethics committee of Nagoya City University Hospital (#60-18-0060). The 1964 Declaration of Helsinki (2013 Fortaleza amendment) was used in guiding this study. Conflicts of interest The authors have no relevant financial or non-financial interests to disclose. Data and materials availability Raw data may be requested from the corresponding author. 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Gonda","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences and Medical School: Nagoya Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Masakazu","middleName":"","lastName":"Gonda","suffix":""},{"id":578402647,"identity":"a9196e25-e2b2-40d7-b1f9-081c54dd6ad9","order_by":10,"name":"Maria Aoki","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences and Medical School: Nagoya Shiritsu Daigaku Daigakuin Igaku Kenkyuka Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Aoki","suffix":""},{"id":578402648,"identity":"295792f3-1eb5-4a39-b3cb-1fec6274682a","order_by":11,"name":"Daiki Ishikawa","email":"","orcid":"","institution":"Nagoya City University Graduate School of Medical Sciences and Medical School: Nagoya Shiritsu Daigaku Daigakuin Igaku Kenkyuka 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1","display":"","copyAsset":false,"role":"figure","size":380993,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves showing PFS for low and high SMI groups without (a) and with avelumab maintenance treatment (b). Kaplan–Meier curves showing OS for low and high SMI groups without (c) and withavelumab maintenance treatment (d). CI: Confidence interval, n.s.: Not significant, OS: Overall survival, PFS: Progression-free survival, SMD: Skeletal muscle radiodensity, SMI: Skeletal muscle index\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/3c2a4c0432a1e340b6ab598f.jpg"},{"id":101752097,"identity":"8de27bc9-85ca-4225-80ef-26c00b486c5a","added_by":"auto","created_at":"2026-02-03 10:25:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":885495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/f1e31d4b-f8f0-4d12-9208-f4e47239f205.pdf"},{"id":101297424,"identity":"fbbde846-bd83-4b63-b353-a722157974df","added_by":"auto","created_at":"2026-01-28 09:27:07","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":28288,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/467efb2484cced95deedad46.docx"},{"id":101171068,"identity":"7415e258-f202-4740-b960-af950c6c748f","added_by":"auto","created_at":"2026-01-27 00:07:05","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":21735,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/4eb6ffe929b46cc760cb9e6e.docx"},{"id":101171069,"identity":"371cd100-1055-4b3d-bd04-f0dda83ee2ab","added_by":"auto","created_at":"2026-01-27 00:07:05","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":21687,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/6e5924ea00563d4f0984de58.docx"},{"id":101171071,"identity":"fcb898b7-a319-4837-b5c4-4fa903baa65a","added_by":"auto","created_at":"2026-01-27 00:07:05","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":22434,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8486641/v1/eb3b5dc69cc2c43c0733a1fa.docx"}],"financialInterests":"","formattedTitle":"Low skeletal muscle radiodensity predicts response to avelumab maintenance treatment in patients with metastatic urothelial carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBladder cancer ranks\u0026nbsp;as the\u0026nbsp;ninth\u0026nbsp;most commonly diagnosed malignancy worldwide. It represents\u0026nbsp;»3% of all tumors and is thirteenth as a cause of deaths due to cancer globally\u0026nbsp;[1]. Over the past decade, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of locally advanced or metastatic urothelial carcinoma (la/mUC), beginning with the introduction of pembrolizumab in a post-platinum setting\u0026nbsp;[2]. As an antibody to anti–programmed death-ligand 1 (PD-L1), avelumab was endorsed in 2020 by the United\u0026nbsp;States\u0026nbsp;Food and Drug Administration as first-line maintenance therapy for patients who achieved disease control after platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 trial\u0026nbsp;[3].\u0026nbsp;In Japan, avelumab was approved in February 2021 and is recommended in the Japanese Urological Association treatment guidelines\u0026nbsp;[4]. Although avelumab maintenance therapy significantly improves survival, a substantial proportion of patients still experience early disease progression. Accordingly, reliable prognostic indicators are needed to determine those patients who will likely derive durable benefit from avelumab.\u003c/p\u003e\n\u003cp\u003eGrowing evidence indicates that various body composition indicators can influence cancer prognosis and antitumor immune responses. Sarcopenia, characterized by a depletion of skeletal muscle mass and strength\u0026nbsp;[5], is prevalent across cancer populations and has been consistently associated with inferior outcomes, including reduced survival and poorer response to ICIs in many malignancies\u0026nbsp;[6-11]. Myosteatosis, defined as increased intramuscular fat infiltration and impaired muscle quality, has also been reported as a negative prognostic factor in multiple malignancies, including those treated with ICIs\u0026nbsp;[12-17]. Cross-sectional computed tomography\u0026nbsp;(CT)\u0026nbsp;at the third lumbar vertebrae\u0026nbsp;(L3)\u0026nbsp;level allows objective quantification of skeletal muscle mass, expressed as the skeletal muscle index (SMI)\u0026nbsp;[18, 19], as well as assessment of muscle quality using skeletal muscle radiodensity (SMD)\u0026nbsp;[20, 21]. A low SMI reflects sarcopenia, whereas\u0026nbsp;low\u0026nbsp;SMD corresponds to myosteatosis.\u0026nbsp;However, evidence regarding the use of body composition in the prognosis of la/mUC cases undergoing avelumab maintenance therapy remains scarce. Therefore, this study aimed to assess the prognostic significance of sarcopenia and myosteatosis in patients with la/mUC treated with avelumab.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003ePatient enrollment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe enrolled patients with la/mUC affecting their urinary bladder or upper urinary tract at Nagoya City University Hospital or two related institutions from January 2019 to November 2023. Specimens were examined histologically and a diagnosis made. The following selection criteria were used as follows: (1) an la/mUC diagnosis and one or more cycles of first-line chemotherapy; (2) unenhanced CT that was performed at the end of first-line chemotherapy; and (3) biopsied primary lesions or those that were surgically removed. We collected data and assessed it retrospectively. The Ethics Committee of Nagoya City University Hospital (Approval No. 60-18-0060) approved this retrospective investigation. Pathology samples that had been routinely collected previously were used as samples. Patients could opt out of this investigation at any time.\u0026nbsp;This study was in accordance with the Declaration of Helsinki\u0026nbsp;(2013 Fortaleza revision).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTherapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGemcitabine and cisplatin (GC) was used as first-line therapy. Patients underwent gemcitabine and carboplatin therapy if they could not be treated with cisplatin. The treatment of patients with a GC regimen was based on the following criteria: no significant hearing loss, \u0026lt; 2 grade neuropathy, creatinine clearance ≥ 60 mL/min, and no symptoms of heart failure in accordance with New York Heart Association class III or greater. Treatment with gemcitabine and carboplatin was used if any criteria were not met.\u0026nbsp;The size of tumors was based on CT imaging. Patients underwent a physical examination. The Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. were used to assess patient responses to treatments.\u0026nbsp;No progression, a\u0026nbsp;complete response (CR),\u0026nbsp;partial response (PR),\u0026nbsp;or stable disease were obtained after first-line treatment. Patients received avelumab switch maintenance therapy (10 mg/kg by intravenous infusion every 2 weeks) if hematologic, hepatic, and renal functions were satisfactory.\u0026nbsp;Disease progression as per RECIST criteria or the development of adverse events (AEs) that were not well tolerated meant that treatment was stopped. Progression-free survival (PFS) referred to the interval from the initiation of\u0026nbsp;avelumab maintenance treatment\u0026nbsp;to progression. Between the initiation of\u0026nbsp;avelumab maintenance treatment\u0026nbsp;and the death of a patient due la/mUC was considered overall survival (OS). The reporting of AEs was based on National Cancer Institute Common Terminology Criteria for AEs, version 4.0.\u0026nbsp;Patient information was obtained from medical records of the abovementioned organizations on: gender, age, height and weight, tumor location (upper urinary tract or urinary bladder), radical surgery of primary site, visceral and lymph node metastasis,\u0026nbsp;Eastern Cooperative Oncology Group performance status (ECOG–PS),\u0026nbsp;and serum blood variables at the end of first-line treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImage protocols\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnenhanced CT images at the conclusion of first-line chemotherapy of study participants were obtained. Parameters for CT images included the following information: the thickness of 5-mm slices, 120 kVp. An axial image at L3 for which both transverse processes were fully observed was identified for each patient. The area of skeletal muscle (including paraspinal, psoas, rectus abdominis, transversus abdominis, and internal and external oblique muscles) was based on Hounsfield unit (HU) thresholds of -29 and +150. After normalization by height squared, this was reported as the SMI (cm\u003csup\u003e2\u003c/sup\u003e/m\u003csup\u003e2\u003c/sup\u003e). For the entire cross-sectional muscle area, the mean skeletal muscle radiation attenuation was reported as the SMD (HU). All image analyses were performed using Image J 1.54 (National Institute of Health, Bethesda, MD, USA, http://rsb.info.nih.gov/ij).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe basis of cutoff values for the SMI defining sarcopenia was an Asian-based definition (\u0026lt; 36.2 cm\u003csup\u003e2\u003c/sup\u003e/m\u003csup\u003e2\u003c/sup\u003e used for males; \u0026lt; 29.6 cm\u003csup\u003e2\u003c/sup\u003e/m\u003csup\u003e2\u003c/sup\u003e used for females) [22]. As there is no clear standard cutoff for the SMD validated in patients with cancer, patients were placed into two groups on the basis of the sex-specific median of the SMD, which corresponds to 28.5 HU for males and 24.8 HU for females. Fisher’s exact test or a Mann–Whitney \u003cem\u003eU\u003c/em\u003e test were used to determine differences based on categorical parameters. To determine cumulative rates of PFS and OS, Kaplan–Meier curves were used. To calculate significant differences a log-rank test was used. Cox proportional hazard regression analyses were used in univariate and multivariate analyses. Cut-off values used for each prognostic factor were derived from other investigations: age (≥ 65 vs. \u0026lt; 65 years), serum C-reactive protein (CRP) levels (≥ 0.3 vs. \u0026lt; 0.3 mg/dL), and neutrophil–lymphocyte ratio (NLR; ≥ 3 vs. \u0026lt; 3).\u0026nbsp;Statistical significance was \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05 with two-tailed \u003cem\u003ep\u003c/em\u003e values used. The data collected was evaluated using a EZR statistical program from the Saitama Medical Center, Jichi Medical University (Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria)\u0026nbsp;[23].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics and oncological outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe enrolled a total of 85 patients with la/mUC on first-line therapy. Of these, 57 patients underwent avelumab treatment. Based on the cut-off value, the total cohort was divided into low (n=42) and high (n=43) SMD groups. Table 1 outlines the characteristics of patients. Differences in patients’ variables after first-line treatment, which includes age, distribution of genders, body mass index, regimen of first-line chemotherapy, number of cycles in first-line chemotherapy, ECOG–PS, primary site, the frequency of visceral metastasis, resection of primary site, and response to first-line chemotherapy, were statistically insignificant between groups. When compared to the low SMD group, the high SMD group showed a significantly lower neutrophil-to-lymphocyte ratio (NLR) among laboratory parameters. In the cohort of patients treated with avelumab, no significant difference was found in PFS from the initiation of avelumab maintenance treatment between low and high SMI groups (Fig. 1a). However, the median PFS was significantly superior for the high SMD group (median 6.4 months, 95% confidence interval [CI]: 4.70–not reached [NR]) in comparison to the low SMD cohort (median 4.8 months, 95% CI: 2.30–6.21; Fig. 1b). Similarly, no significant difference in OS was noted between low and high SMI groups (Fig. 1c). However, the median OS from the start of avelumab maintenance treatment was significantly superior for the high SMD (median not applicable [NA], 95% CI: 15.8–NR) compared to the low SMD (median 16.7 months, 95% CI: 12.6–19.7; Fig. 1d) group. Univariate and multivariate analyses showed how high SMD was the sole independent prognostic factor for better PFS (hazard ratio [HR]: 2.31, 95% CI: 1.25–4.28; Table 2). In addition, high SMD and low NLR were independent prognostic factors for better OS (HR: 2.29, 95% CI: 1.04–5.05 and HR: 2.44, 95% CI: 1.11–5.37, respectively; Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events associated with avelumab switch maintenance treatment between low SMD and high SMD groups were analyzed (Table 4). Among grade\u0026nbsp;≥\u0026nbsp;3 AEs, rash (4.3%) and diarrhea (4.3%) in the low SMD group, and pancreatitis (2.9%) and\u0026nbsp;encephalitis (2.9%)\u0026nbsp;in the high SMD group were recognized. Of these AEs, only\u0026nbsp;encephalitis\u0026nbsp;was uncontrollable and led to death. Since the total incidences of AEs were fundamentally low, a significant difference was not observed between the two groups with regard to AEs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince the approval of avelumab maintenance therapy based on the JAVELIN Bladder 100 (JB100) phase 3 trial, several large real-world studies\u0026nbsp;from various countries, including Japan, have been reported confirming its efficacy and safety [24-27]. Previous studies have identified potential prognostic factors for PFS and OS following avelumab initiation, such as ECOG-PS, CRP, metastatic sites, and inflammatory markers including interleukin-8, NLR, and the systemic immune-inflammation index [28, 29]. However, body composition parameters reflecting sarcopenia and myosteatosis, such as skeletal muscle mass and radiodensity, have not been evaluated in this setting. In this retrospective study, we demonstrated that high SMD at the initiation of avelumab maintenance therapy was significantly associated with longer PSF and OS. Several studies across various cancer types, including urothelial carcinoma, have reported that a low SMD is associated with poor outcomes in patients treated with immune checkpoint inhibitors [13-15]. Skeletal muscle has an important role in modulating the tumor microenvironment. This is because it secretes various myokines, including irisin and interleukin-15, which influence the immune response [30-32]. Reduced muscle quality may result in decreased secretion of these myokines to promote tumor growth and suppress anti-tumor immunity to affect patient survival.\u003c/p\u003e\n\u003cp\u003eIn the present study, the SMI, a representative CT-derived marker of sarcopenia, was not significantly associated with prognosis. To date, two studies from Japan have evaluated the prognostic effect of the SMI in patients with metastatic urothelial carcinoma, each adopting either the international or Prado definition for sarcopenia [33, 34]\u003cem\u003e.\u0026nbsp;\u003c/em\u003eA recent large-scale cohort investigation by Taguchi et al. [35] suggested that ethnic-specific cutoffs for low muscle mass were appropriate, leading to increased accuracy in the classification of patients and in predicting a prognosis; therefore, we applied the cutoff values for an Asian-based definition by Fujiwara et al. in the current analysis [22]. The absence of a significant association between SMI and survival in our cohort may partly be explained by patient selection bias since individuals who were eligible for avelumab maintenance therapy generally had favorable disease control and relatively preserved muscle mass. In addition, recent studies have demonstrated that the SMD and SMI are not always correlated, and that low SMD is more closely associated with frailty and impaired muscle strength even when muscle mass is preserved [36-38]. Skeletal muscle radiodensity may better capture the functional and immunologic decline that influences patient outcomes. In regard to clinicopathologic parameters besides sarcopenia, NLR ≥ 3 was revealed as an independent prognostic factor for OS, as also shown in previous studies [28]. The NLR is a biomarker of systemic inflammation caused by cancer progression [39]. Whereas NLR represents a tumor-related factor, the SMD reflects a host-related factor; therefore, evaluating patients from both perspectives may lead to a more comprehensive assessment of prognosis.\u003c/p\u003e\n\u003cp\u003eAfter the findings of the EV-302 phase 3 trial [40], enfortumab vedotin and pembrolizumab (EV + PEM) used as first-line therapy in the United States and is the preferred choice in updated treatment guidelines, including those in Japan. The toxicity profile of EV + PEM includes peripheral neuropathy, hyperglycemia, and serious skin reactions; a considerable proportion of patients have difficulty continuing EV + PEM due to these toxicities. Furthermore, the optimal subsequent therapy after EV + PEM remains unclear. Even in this new therapeutic era, maintenance therapy with relatively favorable efficacy and safety profiles continues to offer meaningful benefits. As real-world sequential treatment data continue to accumulate, the optimal therapeutic sequence is expected to be better defined in the future.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, its retrospective design and relatively small sample size may limit the generalizability of our findings. Second, the cutoff value for SMD was determined using the median of our cohort, which might be specific to this study population. Further studies with larger cohorts are needed to establish an appropriate universal cutoff value.\u003c/p\u003e\n\u003cp\u003eIn summary, our findings indicate that the SMD, a convenient and reproducible CT-derived marker, may provide valuable prognostic information in patients treated with avelumab maintenance therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and informed patient consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was given by patients. Approval for this study was obtained from the ethics committee of Nagoya City University Hospital (#60-18-0060). The 1964 Declaration of Helsinki (2013 Fortaleza amendment) was used in guiding this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and materials availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRaw data may be requested from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray F, Laversanne M, Sung H et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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N Engl J Med 390(10):875\u0026ndash;888. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMoa2312117\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2312117\" 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 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"avelumab, metastatic urothelial carcinoma, skeletal muscle radiodensity","lastPublishedDoi":"10.21203/rs.3.rs-8486641/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8486641/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe JAVELIN Bladder 100 trial demonstrated a significant survival benefit of avelumab maintenance therapy over best supportive care in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who achieved disease control after platinum-based chemotherapy. Although avelumab maintenance therapy is generally well tolerated, some patients experience rapid progression and prognostic factors are not well established.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this retrospective study, we investigated the prognostic significance of computed tomography–derived body composition indicators in 57 patients with la/mUC who received avelumab maintenance therapy between January 2019 and November 2023. These patients were from within a cohort of 85 patients who underwent first-line platinum-based chemotherapy. Patients were divided into two groups based on a low or high skeletal muscle radiodensity (SMD). Prognostic factors were determined by univariate and multivariate analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Among patients treated with avelumab, median progression-free survival (PFS) was 6.4 months in the high SMD group versus 4.8 months in the low SMD group, while median overall survival was not reached versus 16.7 months, respectively. In a Cox proportional hazards model, only high SMD indicated a favorable prognosis for PFS (hazard ratio [HR]: 2.31, 95% confidence interval [CI]: 1.25–4.28), while high SMD was the independent predictor for better overall survival (HR: 2.29, 95% CI: 1.04–5.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion:\u003c/strong\u003eSuch results suggest that SMD is a potential prognostic factor for la/mUC cases undergoing avelumab maintenance therapy.\u003c/p\u003e","manuscriptTitle":"Low skeletal muscle radiodensity predicts response to avelumab maintenance treatment in patients with metastatic urothelial carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-27 00:07:01","doi":"10.21203/rs.3.rs-8486641/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c4c898fb-2fa3-43b5-b79c-44126fac81fa","owner":[],"postedDate":"January 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-30T07:44:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-27 00:07:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8486641","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8486641","identity":"rs-8486641","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}