Cachexia Index is a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma Treated with Gemcitabine plus Cisplatin Chemotherapy

Cachexia Index is a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma Treated with Gemcitabine plus Cisplatin Chemotherapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cachexia Index is a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma Treated with Gemcitabine plus Cisplatin Chemotherapy Yoshihisa Mimura, Taku Naiki, Yosuke Sugiyama, Yoshihiko Tasaki, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3871561/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 objective of our study was to assess the cachexia index (CXI) as a prognostic indicator for patients with metastatic urothelial carcinoma (mUC) treated with gemcitabine plus cisplatin (GC) chemotherapy. Methods This study included 55 patients with mUC who underwent GC chemotherapy between 2008 and 2022 as first-line chemotherapy. The CXI at the start of chemotherapy was determined as follows: CXI = (serum albumin × skeletal muscle mass index)/(neutrophil count/lymphocyte count). Patients were categorized into two groups based on a median CXI value (CXI high and CXI low). We used Kaplan–Meier curves and multivariate Cox proportional hazards regression models to assess the association between the CXI and overall survival (OS). Results At the start of GC chemotherapy, significant differences were not found in patients' characteristics. The median OS was significantly shorter in the CXI low group (9.8 months [95% confidence interval (CI), 5.1–12.6]) than in the CXI high group (22.0 months [95% CI, 15.4–NA], P < 0.05). Multivariate analysis revealed that low CXI was a predictor of a poor prognosis ( P < 0.05, hazard ratio 2.446, 95% CI 1.087–5.501). Conclusion CXI might be useful as a prognostic indicator for patients with mUC undergoing first-line GC chemotherapy. cachexia index chemotherapy gemcitabine plus cisplatin metastatic urothelial carcinoma Figures Figure 1 Figure 2 Introduction Metastatic urothelial carcinoma (mUC), which encompasses malignancies of the urinary tract such as the bladder, renal pelvis, and ureter, is a highly malignant cancer with a 5-year survival rate of approximately 6% [ 1 ]. Cisplatin-based systemic chemotherapy has been the gold standard treatment for mUC for the past few decades [ 2 , 3 ]. Recently, immune checkpoint inhibitors (ICI), such as pembrolizumab and avelumab, have been approved for the treatment of mUC [ 4 , 5 ]. Moreover, enfortumab vedotin, which is an antibody–drug conjugated agent targeting nectin-4, has been newly approved for a post-platinum and ICI setting [ 6 ]. However, no drastic improvement in clinical outcome has been noted. Thus, cisplatin-based chemotherapy has remained the cornerstone of treatment for mUC. Both decreased skeletal muscle mass and malnutrition caused by chronic inflammation due to cancer are parts of the syndrome of symptoms that characterize cancer cachexia. The European Palliative Care Research Collaborative has defined cancer cachexia as “a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [ 7 ]. Cancer cachexia has been reported to appear in > 30% of patients with a diagnosis of cancer, and in 50–80% of patients with advanced cancer [ 7 ]. Clinical features of cancer cachexia that are pivotal include: systemic inflammation, a poor nutritional status, and a reduction in skeletal muscle mass. In patients with UC, approximately 70% are observed with cancer cachexia, especially skeletal muscle loss [ 8 ]. Cancer cachexia is associated with increased treatment-related toxicity, reduced treatment efficacy, and a poor prognosis. We previously described the relationship between nutritional status, a reduction in skeletal muscle mass, and clinical outcomes in patients with mUC [ 9 – 13 ]. Therefore, careful attention should be paid to patients with mUC in terms of cancer cachexia. The cachexia index (CXI) is a new indicator of cancer cachexia that is calculated by the following equation: CXI = serum albumin (g/dL) × skeletal muscle index (SMI, cm 2 /m 2 )/neutrophil to lymphocyte ratio (NLR). These variables incorporate the clinical measures of crucial features of cancer cachexia such as nutritional status, skeletal muscle mass, and systemic inflammation. Several reports exist describing CXI as an useful prognostic indicator for patients with cancer, such as those with lung cancer, hepatocellular carcinoma, and lymphomas [ 14 – 16 ]. In this study, we aimed to assess the usefulness of CXI as an indicator of prognosis in patients with mUC who underwent gemcitabine plus cisplatin chemotherapy. Materials and methods Study design and treatment Patient records were retrospectively reviewed to identify those with mUC who had received gemcitabine plus cisplatin chemotherapy as a first-line treatment between 2008 and 2022 at our hospital. A total of 94 patients were identified, although 19 patients were excluded due to a lack of computed tomography (CT) imaging conducted within one month before GC therapy. For 20 patients, CXI could not be calculated at the start of GC therapy due to a lack of laboratory data and they were therefore excluded, leaving a final study population of 55 patients. The ethics committee of Nagoya City University Hospital endorsed this study (approval no. 60-18-0060), which was performed using histopathological evaluations and with patient consent. Previously performed routine pathological diagnoses were the source of specimens used in this study. Patients were free to opt-out. This study was undertaken according to the Declaration of Helsinki (2013 Fortaleza revision). In this study, gemcitabine and cisplatin (GC) were used as first-line chemotherapy. This consisted of 1,000 mg/m 2 of gemcitabine that was given on days 1, 8, and 15, plus 70 mg/m 2 of cisplatin that was given on days 1 or 2. Adverse events during GC therapy were classified in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Calculation of neutrophil-lymphocyte ratio, skeletal muscle mass index, and cachexia index The neutrophil to lymphocyte ratio was determined as follows: NLR = number of peripheral neutrophils/number of peripheral lymphocytes. The SMI was calculated as follows: SMI = the area of skeletal muscle at the third lumbar vertebra (cm 2 )/height squared (m 2 ) [ 13 ]. The CXI was determined as follows: CXI = serum albumin (g/dL) × SMI (cm 2 /m 2 )/NLR. Statistical analyses Data were calculated as a mean with 95% confidence intervals (CI), ranges, medians, or frequencies (%). P -values of statistical significance were set at ∗ P < 0.05. Fisher’s exact test was used to assess differences in patient characteristics. Mann-Whitney U test was used to assess continuous variables. Overall survival (OS) and progression-free survival (PFS) calculated using a Kaplan–Meier method and log-rank test. Univariate and multivariate Cox regression analyses were used to assess the factors associated with OS. GraphPad Prism 9 software and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) were used in the statistical analyses performed [ 17 ]. Results Patients’ characteristics In this study, 55 patients were analyzed. The median CXI was calculated as 42.3 (range: 1.8–305.0). Therefore, patients were divided into two groups according to the median CXI value: CXI low and CXI high (Fig. 1 ). Patients’ characteristics were listed in Table 1 . The two groups did not show significant differences with regard to age, gender, origin organ of urothelial carcinoma, and metastasis sites. However, the mean hemoglobin level in the CXI low group was significantly lower than that in the CXI high group. Since the calculation of CXI is based on albumin, NLR, and SMI values, the mean NLR was significantly higher, and mean albumin and SMI levels were significantly lower in the CXI low group. Table 1 Patients’ characteristics Characteristics CXI high group (n = 28) CXI low group (n = 27) P value Median age, years (range) 70 (55–85) 71 (53–84) 0.595 Gender, n (%) Male 21 (75.0) 19 (70.4) 0.768 Female 7 (25.0) 8 (29.6) Origin organ of urothelial carcinoma, n (%) Bladder 19 (67.9) 15 (55.6) 0.412 Upper Urinary tract 9 (32.1) 12 (44.4) Metastasis, n (%) Liver 2 (7.1) 5 (18.5) 0.252 Lung 10 (35.7) 10 (37.0) 1 Others 3 (10.7) 9 (33.3) 0.055 Lymph nodes 21 (75.0) 19 (70.4) 0.768 Serum hemoglobin, g/dL (range) 12.55 (9.10–15.80) 10.70 (8.10–14.00) < 0.001 Serum albumin, g/dL (range) 3.75 (2.60–4.50) 2.90 (2.30-4.00) < 0.001 Median neutrophil count, /mm 3 (range) 3.4 (1.90–8.70) 7.00 (3.40–24.30) < 0.001 Median lymphocyte count, /mm 3 (range) 1.40 (0.70–3.10) 0.9 (0.30–1.80) < 0.001 Median NLR (range) 2.52 (0.94–4.42) 6.80 (3.88-81.00) < 0.001 Median SMI, cm 2 /m 2 (range) 53.86 (29.75–71.99) 40.62 (30.17–59.01) < 0.001 Median CXI (range) 67.35 (42.31-305.08) 17.56 (1.82–42.30) < 0.001 CXI, cachexia index; NLR, neutrophil lymphocyte ratio; SMI, skeletal mass index. CXI was a prognostic indicator for overall survival of mUC patients The median OS (mOS) of the CXI low group was significantly shorter than that of the CXI high group (10.0 months vs. 22.3 months, P < 0.05, Fig. 2 a). The median PFS of the CXI high and CXI low groups were 5.8 months and 4.3 months, respectively ( P = 0.1347, Fig. 2 b). Clinical efficacy and safety profiles are summarized in Tables 2 and 3. The best overall response (BOR) did not statistically differ between the two groups. We calculated the average relative dose intensity (RDI) and the RDI of gemcitabine and cisplatin, respectively; however, a statistical difference between CXI high and CXI low groups was not noted. The adverse events that occurred during GC therapy are shown in Table 3. The frequency of ≥ grade 3 anemia was significantly higher in the CXI low group than in the CXI high group. In comparison, the frequency of all grades of a creatinine increase was greater in the CXI high compared to CXI low group. Treatment histories are summarized in Table 4 . Statistical differences in prior and subsequent treatments were not noted between the two groups. Table 2 The clinical outcome and relative dose intensity of GC therapy CXI, cachexia index; CR, complete response; GC, gemcitabine plus cisplatin; NA, not assessable; PD, progressive disease; PR, partial response; RDI, relative dose intensity; SD, stable disease CXI high group (n = 28) CXI low group (n = 27) P value Best overall response, n (%) CR 0 (0.0) 0 (0.0) 0.611 PR 8 (29.6) 11 (40.7) SD 13 (48.16) 10 (37.0) PD 6 (22.2) 6 (22.2) NA 1 (3.6) 0 (0.0) Average RDI, % (range) 75.1 (57.3, 101.0) 79.2 (56.3, 98.9) 0.686 RDI of gemcitabine% (range) 65.4 (47.4, 101.3) 67.1 (37.2, 100.2) 0.662 RDI of cisplatin % (range) 87.5 (67.3, 102.6) 91.6 (59.8, 102.5) 0.893 Table 3. Profile of adverse events during GC therapy Adverse events CXI high group (n = 28) CXI low group (n = 27) No. of Pts, n (%) No. of grade 3–4 Pts, n (%) No. of Pts, n (%) No. of grade 3–4 Pts, n (%) Neutropenia 24 (85.7) 17 (60.7) 25 (92.6) 15 (55.6) Anemia 27 (96.4) 9 (32.1) 27 (100) 17 (63.0)* Thrombocytopenia 27 (96.4) 15 (53.6) 26 (96.3) 17 (63.0) AST increase 13 (46.4) 0 (0.0) 12 (44.4) 3 (11.1) ALT increase 18 (64.3) 1 (3.6) 20 (74.1) 1 (3.7) Creatinine increase 27 (96.4)* 0 (0.0) 19 (70.4) 1 (3.7) AST, aspartate aminotransferase; ALT, alanine aminotransferase; CXI, cachexia index; GC, gemcitabine plus cisplatin; Pts, patients. * p < 0.05, statistically significant. Table 4 Treatment histories GC, gemcitabine plus cisplatin; CXI, cachexia index. Prior treatment Treatment CXI high group (n = 28) CXI low group (n = 27) P value Neoadjuvant GC therapy, n (%) 5 (17.9) 3 (11.1) 0.595 Radical resection, n (%) 17 (60.7) 13 (48.1) 0.768 Adjuvant GC therapy, n (%) 10 (35.7) 3 (11.1) 0.055 Subsequent chemotherapy Cytotoxic agent, n (%) Gemcitabine + carboplatin 3 (10.7) 2 (7.4) 0.060 Gemcitabine + docetaxel 15 (53.6) 10 (37.0) Gemcitabine + paclitaxel 5 (17.9) 2 (7.4) Enfortumab vedotin 2 (7.1) 1 (3.7) Immune checkpoint inhibitor, n (%) Pembrolizumab 10 (35.7) 6 (22.2) 0.375 Univariate and multivariate analyses of patients who received GC Table 5 shows Cox proportional hazard regression analyses of baseline parameters and OS in 55 patients treated with GC therapy. Hemoglobin < 10 mg/dL, the existence of liver metastasis, and CXI low group correlated with OS in univariate analysis. Multivariate analysis revealed that only the CXI low group was a risk factor for OS (hazard ratio = 2.446, P < 0.05). Table 5 Univariate and multivariate cox regression analysis for overall survival outcome Parameters Univariate Multivariate HR 95% CI P value HR 95% CI P value Age at start of a treatment , ≥ 65 vs < 65 years 0.75 0.38–1.51 0.423 Gender , male vs. female 1.02 0.49–2.16 0.952 Albumin , < 4.0 g/dL vs. ≥4 g/dL 1.57 0.55–4.49 0.40 Hemoglobin , < 10 mg/dL vs. ≥10 mg/dL 2.42 1.13–5.18 0.023 1.453 0.63–3.37 0.383 Liver metastasis , yes vs.no 2.9 1.17–7.24 0.022 1.828 0.70–4.78 0.219 CXI, low group vs. high group 3.04 1.45–6.35 0.003 2.446 1.09–5.50 0.031 CI, confidence interval; CXI, cachexia index; HR, hazard ratio. Discussion In this investigation, we found that CXI acted as a prognostic indicator for the OS of patients with mUC treated with GC therapy. Several research groups analyzed the relationships between clinical outcome, such as the efficacy and safety of chemotherapy and inflammatory status [ 18 ], skeletal muscle mass [ 19 , 13 ], and nutritional status [ 9 , 11 , 20 ], respectively. However, such factors are cachexia-related parameters and therefore expected to intimately interact with each other. Since cancer cachexia has a complex pathophysiology, CXI would be an ideal index that gives a better estimate of ongoing cachexia. In mUC, a poor prognosis has been reported in patients with serum albumin levels less than the lower limit of normal, hemoglobin levels of < 10 mg/dL, or the existent of liver metastasis [ 21 ]. In this study, an analysis by multivariate cox regression highlighted a low CXI as an independent prognostic factor for patients with mUC even though according for these factors. Thus, CXI might be a novel prognostic indicator for mUC treated with GC therapy. We compared efficacy and safety profiles, such as BOR, RDI, and adverse event profiles between CXI low and high groups. The BOR and RDI did not show a significant difference between the two groups. Cancer cachexia has been reported to reduce the efficacy of chemotherapy in various cancer types [ 22 ]. Despite the same BOR or RDI, the shorter mOS of patients in the CXI low group is suggested to be affected by cancer cachexia. In this cohort, the incidence of anemia ≥ G3 is statistically greater in the CXI low compared to CXI high group. Cancer cachexia is associated with a higher incidence of adverse events during cancer therapy [ 23 ]. Therefore, careful monitoring of adverse events might be needed depending on the value of the CXI. We also compared treatment histories between the two groups. The systemic chemotherapy used for mUC has substantially changed over the past few years. In addition to the use of cytotoxic agents, such as gemcitabine and cisplatin, ICIs are also widely used in the treatment of mUC [ 4 , 24 ]. Moreover, enfortumab vedotin, an antibody–drug conjugate, is available as a third-line agent [ 6 ]. However, a difference in treatment history, including in the use of ICIs and enfortumab vedotin, was not noted between the two groups. This indicates that patients who had a low CXI at the start of first-line chemotherapy might not be benefit from these drugs. Therefore, the status of cachexia should be assessed in detail to order to make the most appropriate treatment decisions. There are several limitations in this study. We divided patients into two groups based on a median value of CXI of 42.3. Therefore, the optimal cut-off value of CXI might require further investigation. In comparison, Karmali et al. reported a cut-off value of 49.8 in patients with lymphoma [ 16 ]. Goh et al. reported a cut-off value of 53 in patients who had hepatocellular carcinoma and who underwent systemic chemotherapy [ 15 ]. Jafri et al. reported a cut-off value of 35 in patients with advanced non-small cell lung cancer [ 14 ]. Based on these reports; our cut-off value would be considered acceptable. In addition, owing to the retrospective nature of this study, bias was not controllable in patient’s selection. Therefore, a prospective interventional study is needed to verify our findings. In conclusion, we revealed that a low CXI might be useful as a prognostic indicator for patients with mUC under GC therapy. Declarations Ethics approval and patient consent Patients gave written informed consent. The ethics committee of Nagoya City University Hospital approved this investigation (#60-18-0060), which was performed according the Declaration of Helsinki (2013 Fortaleza) and as certified by all authors. Acknowledgments This work was supported by JSPS KAKENHI Grant Number JP20K16083. Conflicts of Interest The authors have no conflicts of interest to declare. Data and materials availability Any request for raw data should be made to the corresponding author. Authors’ contributions: All authors have read and approved the manuscript, and agree with its submission to this journal. Details regarding authorship, conflicts of interest, and ethics approval are given in the accompanying Author Submission Requirement Form. The contribution of each author to the manuscript was sufficient enough for each to take public responsibility for appropriate portions of the content. Yoshihisa Mimura and Taku Naiki critically revised the manuscript. Yoshihiko Tasaki, Kunihiro Odagiri, Toshiki Etani, Takashi Nagai, Moeko Iida, Yuka Kimura, Nanami Itoh, and Yuji Hotta acquired the data, and organized and drafted the manuscript. Takahiro Yasui and Yoko Furukawa-Hibi supervised the overall manuscript. 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Igakubu","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Nagai","suffix":""},{"id":269541057,"identity":"0189ceb3-f0d0-472d-abbf-bdec98afba36","order_by":7,"name":"Moeko Iida","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":"Moeko","middleName":"","lastName":"Iida","suffix":""},{"id":269541058,"identity":"62855cfd-1f39-4e53-816d-e72d872b64eb","order_by":8,"name":"Yuka Kimura","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":"Yuka","middleName":"","lastName":"Kimura","suffix":""},{"id":269541059,"identity":"2a8c30da-d295-424e-8fa1-11a06640a9df","order_by":9,"name":"Nanami Ito","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":"Nanami","middleName":"","lastName":"Ito","suffix":""},{"id":269541060,"identity":"471d8b8b-8795-44d3-8f8b-237cb70b1782","order_by":10,"name":"Yuji Hotta","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":"Yuji","middleName":"","lastName":"Hotta","suffix":""},{"id":269541061,"identity":"9a3d55f5-eb46-4c45-a219-2168794b07be","order_by":11,"name":"Takahiro Yasui","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":"Takahiro","middleName":"","lastName":"Yasui","suffix":""},{"id":269541062,"identity":"0feb1f33-3f6b-4167-a884-f3ad68d3e467","order_by":12,"name":"Yoko Furukawa-Hibi","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":"Yoko","middleName":"","lastName":"Furukawa-Hibi","suffix":""}],"badges":[],"createdAt":"2024-01-17 02:18:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3871561/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3871561/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50387101,"identity":"af7abb9d-5f3e-4949-911a-20dc418d65a2","added_by":"auto","created_at":"2024-01-30 17:54:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":821368,"visible":true,"origin":"","legend":"\u003cp\u003eCalculation of CXI at the start of GC therapy in patients with metastatic urothelial carcinoma\u003c/p\u003e\n\u003cp\u003eThe top and bottom of each box represents the 75th and the 25th percentile, respectively. The line in the middle represents the 50th percentile. The whiskers represent the highest and lowest values. CXI, cachexia index, GC, gemcitabine plus cisplatin\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3871561/v1/6db6cc8c4154d355c2403795.png"},{"id":50387102,"identity":"84062277-f6ea-4175-add8-80bf07c61cf2","added_by":"auto","created_at":"2024-01-30 17:54:23","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1909494,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves showing overall survival (a) and progression-free survival (b)\u003c/p\u003e\n\u003cp\u003ePatients were divided into two groups based on a CXI value of 42.3. CXI, cachexia index\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3871561/v1/828c812b31c115ab3a277abf.png"},{"id":51837186,"identity":"885653c2-5db4-4c0f-ac98-e91e5d795b5f","added_by":"auto","created_at":"2024-02-29 22:26:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":745612,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3871561/v1/1b63e1e9-1d5d-434f-99e6-490b7934e165.pdf"}],"financialInterests":"","formattedTitle":"Cachexia Index is a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma Treated with Gemcitabine plus Cisplatin Chemotherapy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMetastatic urothelial carcinoma (mUC), which encompasses malignancies of the urinary tract such as the bladder, renal pelvis, and ureter, is a highly malignant cancer with a 5-year survival rate of approximately 6% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cisplatin-based systemic chemotherapy has been the gold standard treatment for mUC for the past few decades [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recently, immune checkpoint inhibitors (ICI), such as pembrolizumab and avelumab, have been approved for the treatment of mUC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Moreover, enfortumab vedotin, which is an antibody\u0026ndash;drug conjugated agent targeting nectin-4, has been newly approved for a post-platinum and ICI setting [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, no drastic improvement in clinical outcome has been noted. Thus, cisplatin-based chemotherapy has remained the cornerstone of treatment for mUC.\u003c/p\u003e \u003cp\u003eBoth decreased skeletal muscle mass and malnutrition caused by chronic inflammation due to cancer are parts of the syndrome of symptoms that characterize cancer cachexia. The European Palliative Care Research Collaborative has defined cancer cachexia as \u0026ldquo;a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment\u0026rdquo; [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Cancer cachexia has been reported to appear in \u0026gt;\u0026thinsp;30% of patients with a diagnosis of cancer, and in 50\u0026ndash;80% of patients with advanced cancer [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Clinical features of cancer cachexia that are pivotal include: systemic inflammation, a poor nutritional status, and a reduction in skeletal muscle mass. In patients with UC, approximately 70% are observed with cancer cachexia, especially skeletal muscle loss [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Cancer cachexia is associated with increased treatment-related toxicity, reduced treatment efficacy, and a poor prognosis. We previously described the relationship between nutritional status, a reduction in skeletal muscle mass, and clinical outcomes in patients with mUC [\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Therefore, careful attention should be paid to patients with mUC in terms of cancer cachexia.\u003c/p\u003e \u003cp\u003eThe cachexia index (CXI) is a new indicator of cancer cachexia that is calculated by the following equation: CXI\u0026thinsp;=\u0026thinsp;serum albumin (g/dL) \u0026times; skeletal muscle index (SMI, cm\u003csup\u003e2\u003c/sup\u003e/m\u003csup\u003e2\u003c/sup\u003e)/neutrophil to lymphocyte ratio (NLR). These variables incorporate the clinical measures of crucial features of cancer cachexia such as nutritional status, skeletal muscle mass, and systemic inflammation. Several reports exist describing CXI as an useful prognostic indicator for patients with cancer, such as those with lung cancer, hepatocellular carcinoma, and lymphomas [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In this study, we aimed to assess the usefulness of CXI as an indicator of prognosis in patients with mUC who underwent gemcitabine plus cisplatin chemotherapy.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and treatment\u003c/h2\u003e \u003cp\u003ePatient records were retrospectively reviewed to identify those with mUC who had received gemcitabine plus cisplatin chemotherapy as a first-line treatment between 2008 and 2022 at our hospital. A total of 94 patients were identified, although 19 patients were excluded due to a lack of computed tomography (CT) imaging conducted within one month before GC therapy. For 20 patients, CXI could not be calculated at the start of GC therapy due to a lack of laboratory data and they were therefore excluded, leaving a final study population of 55 patients. The ethics committee of Nagoya City University Hospital endorsed this study (approval no. 60-18-0060), which was performed using histopathological evaluations and with patient consent. Previously performed routine pathological diagnoses were the source of specimens used in this study. Patients were free to opt-out. This study was undertaken according to the Declaration of Helsinki (2013 Fortaleza revision).\u003c/p\u003e \u003cp\u003eIn this study, gemcitabine and cisplatin (GC) were used as first-line chemotherapy. This consisted of 1,000 mg/m\u003csup\u003e2\u003c/sup\u003e of gemcitabine that was given on days 1, 8, and 15, plus 70 mg/m\u003csup\u003e2\u003c/sup\u003e of cisplatin that was given on days 1 or 2. Adverse events during GC therapy were classified in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCalculation of neutrophil-lymphocyte ratio, skeletal muscle mass index, and cachexia index\u003c/h2\u003e \u003cp\u003eThe neutrophil to lymphocyte ratio was determined as follows: NLR\u0026thinsp;=\u0026thinsp;number of peripheral neutrophils/number of peripheral lymphocytes. The SMI was calculated as follows: SMI\u0026thinsp;=\u0026thinsp;the area of skeletal muscle at the third lumbar vertebra (cm\u003csup\u003e2\u003c/sup\u003e)/height squared (m\u003csup\u003e2\u003c/sup\u003e) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The CXI was determined as follows: CXI\u0026thinsp;=\u0026thinsp;serum albumin (g/dL) \u0026times; SMI (cm\u003csup\u003e2\u003c/sup\u003e/m\u003csup\u003e2\u003c/sup\u003e)/NLR.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eData were calculated as a mean with 95% confidence intervals (CI), ranges, medians, or frequencies (%). \u003cem\u003eP\u003c/em\u003e-values of statistical significance were set at \u003csup\u003e\u0026lowast;\u003c/sup\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Fisher\u0026rsquo;s exact test was used to assess differences in patient characteristics. Mann-Whitney U test was used to assess continuous variables. Overall survival (OS) and progression-free survival (PFS) calculated using a Kaplan\u0026ndash;Meier method and log-rank test. Univariate and multivariate Cox regression analyses were used to assess the factors associated with OS. GraphPad Prism 9 software and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) were used in the statistical analyses performed [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e\n \u003cp\u003eIn this study, 55 patients were analyzed. The median CXI was calculated as 42.3 (range: 1.8\u0026ndash;305.0). Therefore, patients were divided into two groups according to the median CXI value: CXI low and CXI high (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients\u0026rsquo; characteristics were listed in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The two groups did not show significant differences with regard to age, gender, origin organ of urothelial carcinoma, and metastasis sites. However, the mean hemoglobin level in the CXI low group was significantly lower than that in the CXI high group. Since the calculation of CXI is based on albumin, NLR, and SMI values, the mean NLR was significantly higher, and mean albumin and SMI levels were significantly lower in the CXI low group.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients\u0026rsquo; characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI high group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI low group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age, years (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003cp\u003e(55\u0026ndash;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003cp\u003e(53\u0026ndash;84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.595\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (70.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e0.768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eOrigin organ of urothelial carcinoma, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eBladder\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (67.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003e0.412\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eUpper Urinary tract\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetastasis, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.252\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLung\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOthers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (33.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLymph nodes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (75.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (70.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum hemoglobin, g/dL (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.55\u003c/p\u003e\n \u003cp\u003e(9.10\u0026ndash;15.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.70\u003c/p\u003e\n \u003cp\u003e(8.10\u0026ndash;14.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum albumin, g/dL (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.75\u003c/p\u003e\n \u003cp\u003e(2.60\u0026ndash;4.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.90\u003c/p\u003e\n \u003cp\u003e(2.30-4.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian neutrophil count, /mm\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e \u003cstrong\u003e(range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.4\u003c/p\u003e\n \u003cp\u003e(1.90\u0026ndash;8.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.00\u003c/p\u003e\n \u003cp\u003e(3.40\u0026ndash;24.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian lymphocyte count, /mm\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e \u003cstrong\u003e(range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.40\u003c/p\u003e\n \u003cp\u003e(0.70\u0026ndash;3.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003cp\u003e(0.30\u0026ndash;1.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian NLR (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.52\u003c/p\u003e\n \u003cp\u003e(0.94\u0026ndash;4.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.80\u003c/p\u003e\n \u003cp\u003e(3.88-81.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian SMI, cm\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e/m\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sup\u003e \u003cstrong\u003e(range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53.86\u003c/p\u003e\n \u003cp\u003e(29.75\u0026ndash;71.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40.62\u003c/p\u003e\n \u003cp\u003e(30.17\u0026ndash;59.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian CXI (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.35\u003c/p\u003e\n \u003cp\u003e(42.31-305.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17.56\u003c/p\u003e\n \u003cp\u003e(1.82\u0026ndash;42.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\"\u003eCXI, cachexia index; NLR, neutrophil lymphocyte ratio; SMI, skeletal mass index.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003eCXI was a prognostic indicator for overall survival of mUC patients\u003c/h3\u003e\n\u003cp\u003eThe median OS (mOS) of the CXI low group was significantly shorter than that of the CXI high group (10.0 months vs. 22.3 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). The median PFS of the CXI high and CXI low groups were 5.8 months and 4.3 months, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.1347, Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). Clinical efficacy and safety profiles are summarized in Tables \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and 3. The best overall response (BOR) did not statistically differ between the two groups. We calculated the average relative dose intensity (RDI) and the RDI of gemcitabine and cisplatin, respectively; however, a statistical difference between CXI high and CXI low groups was not noted. The adverse events that occurred during GC therapy are shown in Table 3. The frequency of \u0026ge;\u0026thinsp;grade 3 anemia was significantly higher in the CXI low group than in the CXI high group. In comparison, the frequency of all grades of a creatinine increase was greater in the CXI high compared to CXI low group. Treatment histories are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Statistical differences in prior and subsequent treatments were not noted between the two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe clinical outcome and relative dose intensity of GC therapy CXI, cachexia index; CR, complete response; GC, gemcitabine plus cisplatin; NA, not assessable; PD, progressive disease; PR, partial response; RDI, relative dose intensity; SD, stable disease\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI high group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI low group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eBest overall response, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"5\"\u003e\n \u003cp\u003e0.611\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e(29.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(40.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e(48.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e(37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eNA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAverage RDI, % (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75.1\u003c/p\u003e\n \u003cp\u003e(57.3, 101.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e79.2\u003c/p\u003e\n \u003cp\u003e(56.3, 98.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.686\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRDI of gemcitabine% (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.4\u003c/p\u003e\n \u003cp\u003e(47.4, 101.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67.1\u003c/p\u003e\n \u003cp\u003e(37.2, 100.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.662\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRDI of cisplatin % (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.5\u003c/p\u003e\n \u003cp\u003e(67.3, 102.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91.6\u003c/p\u003e\n \u003cp\u003e(59.8, 102.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eProfile of adverse events during GC therapy\u003c/p\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"572\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.91608391608391%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCXI high group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.91608391608391%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCXI low group\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n = 27)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of Pts, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.257731958762886%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of grade 3\u0026ndash;4 Pts, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.742268041237114%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of Pts, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.257731958762886%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of grade 3\u0026ndash;4 Pts, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeutropenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003cp\u003e(85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e(60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e(92.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnemia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(96.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e(63.0)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eThrombocytopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(96.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003cp\u003e(96.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003cp\u003e(63.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAST increase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003cp\u003e(46.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(44.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e(11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eALT increase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e(64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(3.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e(74.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.16783216783217%\"\u003e\n \u003cp\u003e\u003cstrong\u003eCreatinine increase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003cp\u003e(96.4)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e(0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.783216783216783%\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e(70.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.132867132867133%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e(3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eAST, aspartate aminotransferase; ALT, alanine aminotransferase; CXI, cachexia index; GC, gemcitabine plus cisplatin; Pts, patients.\u003c/p\u003e\n \u003cp\u003e*\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05, statistically significant.\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eTreatment histories GC, gemcitabine plus cisplatin; CXI, cachexia index.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003ePrior treatment\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI high group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;28)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCXI low group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeoadjuvant GC therapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.595\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRadical resection, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (60.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (48.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.768\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjuvant GC therapy, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eSubsequent chemotherapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eCytotoxic agent, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGemcitabine\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e+ carboplatin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (10.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGemcitabine\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e+ docetaxel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (53.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGemcitabine\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e+ paclitaxel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (7.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEnfortumab vedotin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eImmune checkpoint inhibitor, n (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePembrolizumab\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003eUnivariate and multivariate analyses of patients who received GC\u003c/h2\u003e\n \u003cp\u003eTable \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e shows Cox proportional hazard regression analyses of baseline parameters and OS in 55 patients treated with GC therapy. Hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;10 mg/dL, the existence of liver metastasis, and CXI low group correlated with OS in univariate analysis. Multivariate analysis revealed that only the CXI low group was a risk factor for OS (hazard ratio\u0026thinsp;=\u0026thinsp;2.446, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariate and multivariate cox regression analysis for overall survival outcome\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eParameters\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at start of a treatment\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;\u0026thinsp;65 vs\u0026thinsp;\u0026lt;\u0026thinsp;65 years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.38\u0026ndash;1.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.423\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003emale vs. female\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49\u0026ndash;2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.952\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlbumin\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;4.0 g/dL vs. \u0026ge;4 g/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.55\u0026ndash;4.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHemoglobin\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;10 mg/dL vs. \u0026ge;10 mg/dL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.13\u0026ndash;5.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.453\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.63\u0026ndash;3.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.383\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eLiver metastasis\u003c/strong\u003e,\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eyes vs.no\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.17\u0026ndash;7.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.828\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.70\u0026ndash;4.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCXI, low group vs. high group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.45\u0026ndash;6.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.446\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.09\u0026ndash;5.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eCI, confidence interval; CXI, cachexia index; HR, hazard ratio.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this investigation, we found that CXI acted as a prognostic indicator for the OS of patients with mUC treated with GC therapy. Several research groups analyzed the relationships between clinical outcome, such as the efficacy and safety of chemotherapy and inflammatory status [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], skeletal muscle mass [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and nutritional status [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], respectively. However, such factors are cachexia-related parameters and therefore expected to intimately interact with each other. Since cancer cachexia has a complex pathophysiology, CXI would be an ideal index that gives a better estimate of ongoing cachexia. In mUC, a poor prognosis has been reported in patients with serum albumin levels less than the lower limit of normal, hemoglobin levels of \u0026lt;\u0026thinsp;10 mg/dL, or the existent of liver metastasis [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this study, an analysis by multivariate cox regression highlighted a low CXI as an independent prognostic factor for patients with mUC even though according for these factors. Thus, CXI might be a novel prognostic indicator for mUC treated with GC therapy.\u003c/p\u003e \u003cp\u003eWe compared efficacy and safety profiles, such as BOR, RDI, and adverse event profiles between CXI low and high groups. The BOR and RDI did not show a significant difference between the two groups. Cancer cachexia has been reported to reduce the efficacy of chemotherapy in various cancer types [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Despite the same BOR or RDI, the shorter mOS of patients in the CXI low group is suggested to be affected by cancer cachexia. In this cohort, the incidence of anemia\u0026thinsp;\u0026ge;\u0026thinsp;G3 is statistically greater in the CXI low compared to CXI high group. Cancer cachexia is associated with a higher incidence of adverse events during cancer therapy [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Therefore, careful monitoring of adverse events might be needed depending on the value of the CXI. We also compared treatment histories between the two groups. The systemic chemotherapy used for mUC has substantially changed over the past few years. In addition to the use of cytotoxic agents, such as gemcitabine and cisplatin, ICIs are also widely used in the treatment of mUC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, enfortumab vedotin, an antibody\u0026ndash;drug conjugate, is available as a third-line agent [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, a difference in treatment history, including in the use of ICIs and enfortumab vedotin, was not noted between the two groups. This indicates that patients who had a low CXI at the start of first-line chemotherapy might not be benefit from these drugs. Therefore, the status of cachexia should be assessed in detail to order to make the most appropriate treatment decisions.\u003c/p\u003e \u003cp\u003eThere are several limitations in this study. We divided patients into two groups based on a median value of CXI of 42.3. Therefore, the optimal cut-off value of CXI might require further investigation. In comparison, Karmali et al. reported a cut-off value of 49.8 in patients with lymphoma [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Goh et al. reported a cut-off value of 53 in patients who had hepatocellular carcinoma and who underwent systemic chemotherapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Jafri et al. reported a cut-off value of 35 in patients with advanced non-small cell lung cancer [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Based on these reports; our cut-off value would be considered acceptable. In addition, owing to the retrospective nature of this study, bias was not controllable in patient\u0026rsquo;s selection. Therefore, a prospective interventional study is needed to verify our findings.\u003c/p\u003e \u003cp\u003eIn conclusion, we revealed that a low CXI might be useful as a prognostic indicator for patients with mUC under GC therapy.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and patient consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients gave written informed consent. The ethics committee of Nagoya City University Hospital approved this investigation (#60-18-0060), which was\u0026nbsp;performed according the Declaration of Helsinki (2013 Fortaleza) and as certified by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by JSPS KAKENHI Grant Number JP20K16083.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData and materials availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAny request for raw data should be made to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eAll authors have read and approved the manuscript, and agree with its submission to this journal. Details regarding authorship, conflicts of interest, and ethics approval are given in the accompanying\u0026nbsp;Author Submission Requirement Form. The contribution of\u0026nbsp;each author to the manuscript was sufficient enough for each to take public responsibility for appropriate portions of the content.\u0026nbsp;Yoshihisa Mimura and Taku Naiki\u0026nbsp;critically revised the manuscript.\u0026nbsp;Yoshihiko Tasaki, Kunihiro Odagiri, Toshiki Etani, Takashi Nagai, Moeko Iida, Yuka Kimura, Nanami Itoh, and Yuji Hotta\u0026nbsp;acquired the data,\u0026nbsp;and organized and drafted the manuscript. Takahiro Yasui and Yoko Furukawa-Hibi supervised the overall\u0026nbsp;manuscript. Yosuke Sugiyama performed all statistical analyses. All the authors have read and approved of the final version of the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Wagle NS et al (2023) Cancer statistics, 2023. CA Cancer J Clin 73:17\u0026ndash;48\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Comprehensive Cancer Network Clinical Guidelines in Oncology Bladder Cancer version 3 (2023) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf\u003c/span\u003e\u003cspan address=\"https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEuropean Association of Urology Guidelines on muscle- invasive and metastatic bladder cancer. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer\u003c/span\u003e\u003cspan address=\"https://uroweb.org/guidelines/muscle-invasive-and-metastatic-bladder-cancer\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, de Wit R, Vaughn DJ et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. 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Curr Opin Support Palliat Care 15:260\u0026ndash;265\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNaiki T, Nagai T, Sugiyama Y et al (2021) First report of oncological outcome and prognostic analysis in a first-line setting of short hydration gemcitabine and cisplatin chemotherapy for patients with metastatic urothelial carcinoma. Oncology 99:622\u0026ndash;631\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugiyama Y, Naiki T, Tasaki Y et al (2023) GNRI sustainability during one cycle of first-line chemotherapy as a prognostic indicator in patients with metastatic urothelial carcinoma. Oncology 101:224\u0026ndash;233\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEtani T, Naiki T, Sugiyama Y et al (2020) Low geriatric nutritional risk index as a poor prognostic marker for second-line pembrolizumab treatment in patients with metastatic urothelial carcinoma: a retrospective multicenter analysis. 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Int J Urol 25:232\u0026ndash;238\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShimizu R, Honda, Ma, Teraoka S et al (2022) Sarcopenia is associated with survival in patients with urothelial carcinoma treated with systemic chemotherapy. Int J Clin Oncol 27:175\u0026ndash;183\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsieh MC, Rau K-M, Chiang P-H et al (2018) Impact of prognostic nutritional index on overall survival for patients with metastatic urothelial carcinoma. J Cancer 9:2466\u0026ndash;2471\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellmunt J, Choueiri TK, Fougeray R et al (2010) Prognostic factors in patients with advanced transitional cell carcinoma of the urothelial tract experiencing treatment failure with platinum-containing regimens. J Clin Oncol 28:1850\u0026ndash;1855\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMartin L, Senesse P, Gioulbasanis I et al (2015) Diagnostic criteria for the classification of cancer-associated weight loss. J Clin Oncol 33:90\u0026ndash;99\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFearon K, Strasser F, Anker SD et al (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489\u0026ndash;495\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePowles T, Park SH, Voog E et al (2020) Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med 383:1218\u0026ndash;1230\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"cachexia index, chemotherapy, gemcitabine plus cisplatin, metastatic urothelial carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-3871561/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3871561/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe objective of our study was to assess the cachexia index (CXI) as a prognostic indicator for patients with metastatic urothelial carcinoma (mUC) treated with gemcitabine plus cisplatin (GC) chemotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included 55 patients with mUC who underwent GC chemotherapy between 2008 and 2022 as first-line chemotherapy. The CXI at the start of chemotherapy was determined as follows: CXI = (serum albumin \u0026times; skeletal muscle mass index)/(neutrophil count/lymphocyte count). Patients were categorized into two groups based on a median CXI value (CXI high and CXI low). We used Kaplan\u0026ndash;Meier curves and multivariate Cox proportional hazards regression models to assess the association between the CXI and overall survival (OS).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAt the start of GC chemotherapy, significant differences were not found in patients' characteristics. The median OS was significantly shorter in the CXI low group (9.8 months [95% confidence interval (CI), 5.1\u0026ndash;12.6]) than in the CXI high group (22.0 months [95% CI, 15.4\u0026ndash;NA], \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Multivariate analysis revealed that low CXI was a predictor of a poor prognosis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, hazard ratio 2.446, 95% CI 1.087\u0026ndash;5.501).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCXI might be useful as a prognostic indicator for patients with mUC undergoing first-line GC chemotherapy.\u003c/p\u003e","manuscriptTitle":"Cachexia Index is a Prognostic Indicator in Patients with Metastatic Urothelial Carcinoma Treated with Gemcitabine plus Cisplatin Chemotherapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-30 17:54:19","doi":"10.21203/rs.3.rs-3871561/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 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-02-29T22:18:32+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-30 17:54:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3871561","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3871561","identity":"rs-3871561","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}