Association between discontinuation of anamorelin and immunotrophic index in patients with cancer-associated cachexia: a single-center retrospective study

Association between discontinuation of anamorelin and immunotrophic index in patients with cancer-associated cachexia: a single-center retrospective study | 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 Association between discontinuation of anamorelin and immunotrophic index in patients with cancer-associated cachexia: a single-center retrospective study Aiko Fukui, Ryosuke Ota, Atsushi Hirata This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6108504/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 Purpose Anamorelin, a ghrelin-like agonist, was the first drug approved for the treatment of cancer-associated cachexia in Japan; however, only a few studies have investigated what factors affect the discontinuation of anamorelin, and the observation periods of those studies were short. This study investigated the factors influencing the discontinuation of anamorelin after 4, 12, 24, and 48 weeks, to include longer observation periods than previously assessed. Methods This retrospective observational study investigated patients who received anamorelin for cancer-related cachexia between October 2021 and December 2023 at Kindai University Nara Hospital. We evaluated predictors of the discontinuation of anamorelin over 4, 12, 24, and 48 week observation periods after the start of treatment, and performed multivariate Cox regression analyses to calculate hazard ratios and 95% confidence intervals. Results Among the 93 patients included in this analysis, the median duration of administration (interquartile range) was 63 (2–674) days. Significant differences were observed for patients with a pre-treatment Eastern Cooperative Oncology Group Performance Status (PS) ≥ 2 in all observation periods, as well as a Prognostic Nutritional Index (PNI) ≤ 39.6 in the 12, 24, and 48 week observation periods. Conclusion This study revealed that a patient’s PS and PNI at the start of anamorelin therapy may affect the discontinuation of anamorelin. Therefore, in order to administer anamorelin for a longer period it is necessary to diagnose cancer-associated cachexia before PS and PNI begin to decline and start multidisciplinary intervention, including the administration of anamorelin. cancer-associated cachexia anamorelin immunotrophic index Eastern Cooperative Oncology Group Performance Status Prognostic Nutritional Index Figures Figure 1 1 Introduction Cancer-associated cachexia is a metabolic syndrome that occurs as cancer progresses, and presents with multiple symptoms including anorexia, loss of skeletal muscle mass, and metabolic changes in the liver and adipose tissue. It is though that its onset is related to inflammatory cytokines, such as glucocorticoids, tumor necrosis factor-α, interleukin-6, growth differentiation factors-11 and − 15, and parathyroid hormone-related peptide, as well as various factors produced by tumor cells [ 1 ]. Cancer-associated cachexia is common in patients with gastrointestinal malignancies, including gastric, esophageal, or pancreatic cancer [ 2 – 4 ], occurring in 50–80% of patients with advanced cancer [ 5 ], and has been reported to be a predictor of poor prognosis among patients with cancer, as it reduces the effectiveness of chemotherapy, increases side effects and treatment discontinuation, and affects overall survival rates [ 6 , 7 ]. Furthermore, because advanced cancer-associated cachexia is difficult to treat [ 8 , 9 ], early diagnosis as well as multidisciplinary interventions such as drug, nutritional, and exercise therapies and psychosocial interventions are required to improve patient outcomes [ 10 , 11 ]. While corticosteroids and progestational agents have been used as drug treatments for cancer-associated cachexia, a standard treatment has not been established in terms of their efficacy and adverse events [ 12 – 14 ]. Anamorelin, a ghrelin-like agonist introduced in Japan in April 2021, binds to the growth hormone secretagogue receptor type 1a and is the only approved treatment for cancer-associated cachexia in Japan. Anamorelin has been shown to improve lean body mass and appetite in an international joint phase III clinical trial (ROMANA-1/2) [ 15 ], a domestic phase II clinical trial (ONO-7643-04) [ 16 ], and a domestic phase III clinical trial (ONO-7643-05) [ 17 ]. These clinical trials reported that 62–66% of the patients treated with anamorelin completed the scheduled 12-week course and that it was well tolerated. Studies have reports that factors that affect the discontinuation of anamorelin include Eastern Cooperative Oncology Group Performance Status (PS) and Prognostic Nutritional Index (PNI) scores at the start of treatment [ 18 ]; however, the observation periods of these studies were short, and there is no clear consensus on which factors influence the discontinuation of treatment. In clinical practice, the administration period of anamorelin is sometimes longer than the standard observation period of 12 weeks evaluated in clinical trials due to early intervention for cancer-associated cachexia; therefore, longer-term observational studies are necessary. To that end, the purpose of this study was to investigate what factors influence the discontinuation of anamorelin over 4, 12, 24, and 48 week observation period, allowing for longer follow-up periods. 2 Methods 2.1 Patients Online Resource 1 presents a diagram of the study protocol. The inclusion criteria for this retrospective observational study were as follows: patients with advanced lung, gastric, pancreatic, or colorectal cancer who underwent anamorelin therapy for cancer-associated cachexia at Kindai University Nara Hospital between October 1, 2021 and December 31, 2023. The exclusion criteria were as follows: patients who transferred to another hospital, patients with inadequate clinical laboratory values prior to the initiation of treatment, and patients who underwent a dose reduction from standard dose 100 mg to 50 mg. The end date of the observation period for this study was June 30, 2024. 2.2 Variables Clinical and biochemical data were retrospectively obtained from patient medical records at Kindai University Nara Hospital. Covariates included age, sex, height, weight, body mass index, lean body mass estimated using the Boer [ 19 ], James [ 20 ], or Hume formula [ 21 ], PS [ 22 ], type of cancer, stage of disease, presence or absence of chemotherapy at the time of anamorelin initiation, duration of anamorelin administration, reason for discontinuing anamorelin, white blood cell count, absolute neutrophil count (ANC), total lymphocyte count (TLC), monocyte count (Mono), hemoglobin, platelet count (PLT), albumin (Alb), C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, and serum creatinine. We also evaluated the following immunotrophic indices reflecting inflammation and immunity in cancer patients: PNI, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein-albumin ratio (CAR), and modified Glasgow Prognostic Score (mGPS). PNI, NLR, PLR, LMR and CAR were estimated as follows: Alb (g/dL) × 10 + 0.005 × TLC (/mm3) [ 23 ], the ratio of ANC to TLC [ 24 ], the ratio of PLT to TLC [ 25 ], the ratio of TLC to Mono [ 26 ], and the ratio of CRP to Alb [ 27 ], respectively. mGPS was classified as described by Toiyama et al. [ 28 ], as follows: mGPS 0, Alb ≥ 3.5 g/dL and CRP ≤ 0.5 mg/dL; mGPS 1, Alb 0.5 mg/dL; and mGPS 2, Alb 0.5 mg/dL. 2.3 Outcome The primary study outcome was the discontinuation of anamorelin at 4, 12, 24, or 48 weeks after the start of treatment, and subjects were categorized as those who continued treatment during the observation period (continuation group) and those who discontinued treatment (discontinuation group). Models 1–4, based on the observation period length, were used for each group. 2.4 Statistical analysis Numerical variables were analyzed using the median as the cut-off value. We performed multivariate Cox regression analyses to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Variables for the multivariate Cox regression analyses were selected from explanatory variables with a univariate Cox regression p < 0.1. Statistical significance was set at p < 0.05. All analyses were performed using EZR (ver. 1.37), a statistical software that extends the functions of R and R Commander and is available free of charge at the website of the Department of Hematology, Saitama Medical Center, Jichi Medical University (Saitama City) [ 29 ]. 2.5 Ethical considerations All procedures in this study that involved human participants were performed in accordance with the ethical standards of the Institutional Research Committee as well as the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The protocol for this study was approved by the Ethics Committees of Kindai University Nara Hospital (Approval no. 781) on December 9, 2024. 3 Results 3.1 Patients A flowchart of the patient selection procedure is shown in Fig. 1 . Of the 105 patients with lung, gastric, pancreatic, or colorectal cancer who underwent anamorelin therapy during the study period, 93 were included in our analysis. The exclusions were as follows: 8 patients transferred to another hospital, 3 had inadequate clinical laboratory values prior to anamorelin administration, and 1 underwent a dose reduction to 50 mg. 3.2 Patient characteristics Table 1 shows the patient characteristics at the time of the first anamorelin administration. When evaluating by sex, the proportion of males was higher than females, at 62 patients (66.7%). The median (interquartile range [IQR]) age of the 93 included patients was 76 (70–79) years. Regarding the general patient condition at the time of the first administration, 10 patients (10.8%) had a PS = 0, 52 (55.9%) had a PS = 1, 28 (30.1%) had a PS = 2, and 3 (3.2%) had a PS = 3. None of the patients had a PS = 4. The distribution of cancers were as follows: 46 patients had lung cancer (49.5%), 20 had gastric cancer (21.5%), 19 had pancreatic cancer (20.4%), and 8 had colorectal cancer (8.6%). Additionally, 87 patients (93.5%) were undergoing chemotherapy or chemoradiotherapy and 6 (6.5%) were receiving palliative care. The median (IQR) immunotrophic indices were as follows: PNI, 39.6 (35.6–44.4); NLR, 3.14 (1.83–4.82); PLR, 158 (118–278); LMR, 2.31 (1.66–3.68); and CAR, 0.52 (0.09–1.41). Among the 93 included patients, 18 (19.3%), 26 (28.0%), 49 (52.7%) had an mGPS = 0, 1, and 2, respectively. The median duration of administration (IQR) was 63 (2–674) days, and the number of patients who discontinued treatment in each model was as follows: model 1, 31 (33.3%); model 2, 53 (57.0%); model 3, 71 (76.3%); and model 4, 83 (89.2%). 3.3 Reason for discontinuation of anamorelin The most common reason for discontinuing anamorelin during the 48-week observation period, the longest in this study, was exacerbation of the primary disease (n = 31; 37.3%), followed by adverse events such as decreased liver function and hyperglycemia (n = 11; 13.2%). The 7 cases (8.4%) that discontinued treatment due to ineffectiveness (no improvement in appetite or weight gain) and all did so within the first 4 weeks (Online Resource 2). 3.4 Analysis of factors associated with the discontinuation of anamorelin in models 1–4 The univariate analyses of models 1–4 using the Cox proportional hazards model revealed that a PS score ≥ 2 was one factor influencing the discontinuation of anamorelin in all of the models (Table 2). Furthermore, factors with a p < 0.1 in the univariate analyses were selected for the multivariate analyses, and significant differences were observed for a PS score ≥ 2 in all models (model 1: adjusted HR = 2.82, 95% CI = 1.33–5.95, p = 0.007; model 2: adjusted HR; 2.18, 95% CI; 1.22–3.88, p = 0.008; model 3: adjusted HR = 2.21, 95% CI = 1.29–3.80, p = 0.004; model 4: adjusted HR = 2.25, 95% CI = 1.33–3.80, p = 0.003). For PNI ≤ 39.6, no significant difference was observed in model 1, but a significant difference was observed among models 2–4 (model 1: adjusted HR; 1.57, 95% CI; 0.73–3.37, p = 0.244; model 2: adjusted HR; 1.97, 95% CI; 1.10–3.53, p = 0.022; model 3: adjusted HR = 2.10, 95% CI = 1.07–4.10, p = 0.030; model 4: adjusted HR = 1.79, 95% CI = 1.10–2.90, p = 0.019) (Table 3) . 4 Discussion This study investigated factors that influence the discontinuation of anamorelin across 4, 12, 24, and 48 week observation periods, and identified PS ≥ 2 and PNI ≤ 39.6 as independent risk factors for medication discontinuation. These findings may provide new evidence that is beneficial in clinical practice as pertains to the administration of anamorelin for the treatment of cancer-associated cachexia. In clinical practice, early diagnosis and intervention in cancer-related cachexia may result in an anamorelin administration period longer than the standard 12-week observation period evaluated in clinical trials. Therefore, in this study, we identified factors that affect the discontinuation of anamorelin during its long-term administration. Anamorelin is currently only approved and sold in Japan, and there are limited reports based on actual clinical practice. Therefore, understanding the patient characteristics suitable for the administration of anamorelin will contribute to the formulation of individualized treatment plans and provide useful information for future treatment with anamorelin. PS is said to be a prognostic factor for cancer treatment. In this study, the most common reason for discontinuing anamorelin was progression of the primary disease, which, including death, accounted for 46.9% of the discontinuations. Furthermore, patients who were still receiving anamorelin at 48 weeks had a PS = 0 or 1 at the start of treatment, with none having a PS score ≥ 2. Of the 11 patients who discontinued treatment due to adverse events, 8 discontinued within the first 4 weeks, and 5 had a PS score ≥ 2. In a subgroup analysis of the ONO-7643-04 trial, it was reported that adverse events in the anamorelin group were more common in patients with a poor PS score, with 38.4% of patients having a PS = 0–1 and 60.0% having a PS = 2 [ 30 ]. It is possible, therefore, that a decline in PS may have influenced discontinuation due to the occurrence of adverse events. Cancer-associated cachexia is classified into three stages: precachexia, cachexia, and refractory cachexia [ 31 ], and early intervention for precachexia is required to improve patient outcomes. The clinical characteristics of precachexia are anorexia and a weight loss ≤ 5% over the previous 6 months, while the criteria for starting anamorelin are poor oral intake, anorexia, and a weight loss ≥ 5% over the previous 6 months. Therefore, the stages of cancer-associated cachexia for which anamorelin is indicated are cachexia and refractory cachexia. In addition to the symptoms of cachexia, refractory cachexia also includes chemotherapy resistance, poor PS (World Health Organization score 3–4), and a prognosis < 3 months. Multidisciplinary interventions such as drugs, exercise, nutrition, and psychological therapy are not expected to be effective against refractory cachexia, and palliative interventions currently are the norm. In this study, we identified a PS score ≥ 2 as a factor influencing the discontinuation of anamorelin. The results suggest that, similar to other cancer-associated cachexia treatments, anamorelin therapy may be continued for a longer period if initiated at an earlier stage of cachexia and may be discontinued earlier if initiated at a later or refractory stage. Onodera et al. [ 23 ] reported that PNI was a risk predictor of perioperative complications in gastrointestinal cancer, with a PNI ≤ 40 considered a contraindication for resection and anastomosis. It has also been reported that a lower PNI is associated with shorter survival times in pancreatic, lung, and gastric cancers [ 32 – 34 ]. In this study, PNI was extracted as a risk factor for discontinuing anamorelin at 12, 24, and 48 weeks, but not at 4 weeks. Anamorelin should be discontinued approximately 3 weeks after the start of administration if weight gain or appetite improvement is not observed. In this study, all 7 cases of discontinuation due to lack of efficacy occurred within the first 4 weeks of treatment. Therefore, early discontinuation is considered to be due to a lack of efficacy and may have a different implication than discontinuation after continued administration. Furthermore, because PNI was not identified as a risk factor for discontinuation at 4 weeks, it is thought that PNI influences discontinuation when anamorelin is continued only after a certain degree of efficacy has been observed. Tsukiyama et al. [ 18 ] investigated factors influencing early the discontinuation of anamorelin within 4 weeks of starting the treatment and reported that a PS score ≥ 2 and PNI ≤ 30 were risk factors. These results were consistent ours in that a PS score ≥ 2 was a risk factor for the early discontinuation of anamorelin. Contrarily, Tsukiyama et al. [ 18 ] reported PNI as a factor influencing the early discontinuation (within 4 weeks), which differed from our findings. The reason for this is that in their study, 22.5% of patients had a PS score ≥ 3, and the median PNI was low, at 33, whereas in our study, only 3.2% of patients had a PS score ≥ 3 and the median PNI was 39.6. Therefore, it is thought that the patients in their study had a worse general condition and nutritional status than those in our study, resulting in PNI being extracted as a factor influencing the early discontinuation of anamorelin. This study has some limitations. First, because this was a retrospective study with a limited number of cases at a single institution, there is a risk of selection bias due to patient background, such as cancer type and PS. Second, this study focused only on the period of anamorelin administration, and did not include evaluation of changes in lean body mass or anorexia after anamorelin administration using a questionnaire. Third, the effects of concomitant medications, nutritional therapy, and exercise therapy could not be examined in this study. Despite these limitations, the strength of this study is that we were able to identify risk factors for the discontinuation of anamorelin treatment in cancer-associated cachexia over a longer observation period. Specifically, knowing that PS and PNI influence the discontinuation of anamorelin treatment may be useful for the treatment of cancer-associated cachexia in the future. 5 Conclusion In this study, a PS score ≥ 2 and PNI ≤ 39.6 were identified as factors influencing the discontinuation of anamorelin. Therefore, in order to continue anamorelin administration for a longer period, it is necessary to diagnose cancer-associated cachexia before PS and PNI begin to decline and start multidisciplinary intervention, including the administration of anamorelin. Declarations Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Competing interests: None. Author contributions: Aiko Fukui: Validation, Formal analysis, Investigation, Data Curation, Conceptualization, Writing - Original Draft. Ryosuke Ota: Methodology, Validation, Writing - Review & Editing. Atsushi Hirata: Methodology, Validation, Writing - Review & Editing, Supervision, Project administration. Ethics approval: All procedures in this study that involved human participants were performed in accordance with the ethical standards of the Institutional Research Committee as well as the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The protocol for this study was approved by the Ethics Committees of Kindai University Nara Hospital (Approval no. 781) on December 9, 2024. Consent to participate: Informed consent was obtained from all patients as opt-out forms on the hospital website. Consent to publish: Not applicable Acknowledgements None. 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Clinica chimica acta; international journal of clinical chemistry 486: 303–310. https://doi.org/10.1016/j.cca.2018.08.030 Wang SH, Zhai ST, Lin H (2016) Role of Prognostic Nutritional Index in patients with gastric cancer: a meta-analysis. Minerva medica 107: 322–327. Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files 00OnlineResource1Anamorelin.pdf Online Resource 1 Study protocol diagram. This diagram illustrates the timeline of covariate assessments, exclusion assessments, and follow-up periods for patients treated with anamorelin. Covariates such as clinical characteristics and laboratory values were assessed within specific windows prior to the initiation of therapy. Patients were followed up from the initiation of anamorelin until the occurrence of an event, such as therapy discontinuation, or censoring. The exclusion assessment window includes events such as inadequate clinical laboratory values prior to administration, and transfer to another hospital 00OnlineResource2Anamorelin.xlsx Table.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6108504","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":421731940,"identity":"8058ba70-fdb7-4b43-beb4-1373821f9523","order_by":0,"name":"Aiko Fukui","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYFACxgeMDQwSckCWAWODAQNjAzNYmA2PFmYDkBZjkrUwJDaAtQAtbSDkLP4GZjbJmW0W6Wvbmzcwzii4I9vfzsD44QcDXx4uLRIHgFo2tknkbjtzrIBxg8Ez4xmHGZglexjYinFac//9McmHIC03cgwYHxgcTmw4zMAgDfRLIi4XyoNsAWpJN7v/BqJlPtCW3/i0GEAdlmB2g8cA6LDDiRsOM7DhtcXwADOz5YxzEobbzqQVHJxhcNh442HGNsseA9x+kTvAzHizp6xO3uz44Y0Pe/4clp13/vDhGz8qjuEMMRRwAEKBosbgWAJRWpBBDelaRsEoGAWjYLgCAOkfWN1b/hJ9AAAAAElFTkSuQmCC","orcid":"","institution":"Department of Pharmacy, Kindai University Nara Hospital","correspondingAuthor":true,"prefix":"","firstName":"Aiko","middleName":"","lastName":"Fukui","suffix":""},{"id":421731941,"identity":"f3625f97-0aaf-4bd3-a311-4c7210c9a79d","order_by":1,"name":"Ryosuke Ota","email":"","orcid":"","institution":"Department of Pharmacy, Kindai University Nara Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ryosuke","middleName":"","lastName":"Ota","suffix":""},{"id":421731942,"identity":"37603a04-0ae9-456c-86dc-fb7c5cb7f85a","order_by":2,"name":"Atsushi Hirata","email":"","orcid":"","institution":"Department of Pharmacy, Kindai University Nara Hospital","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Hirata","suffix":""}],"badges":[],"createdAt":"2025-02-25 23:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6108504/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6108504/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":77801827,"identity":"4a17f05b-eee4-4caf-a0fc-a95b0af4e63b","added_by":"auto","created_at":"2025-03-05 16:41:16","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":358458,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram illustrating the composition of the study population\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6108504/v1/546c79ff25d9999dc0dd63cd.jpeg"},{"id":90140832,"identity":"69368603-faad-4aba-9b4c-d633b63ce58b","added_by":"auto","created_at":"2025-08-29 03:38:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":897089,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6108504/v1/f0427a7b-95fc-4549-a528-775381dd611a.pdf"},{"id":77801826,"identity":"a436a1f9-6971-4bd7-831d-1615fd0d96be","added_by":"auto","created_at":"2025-03-05 16:41:16","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":193319,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOnline Resource 1 \u003c/strong\u003eStudy protocol diagram. This diagram illustrates the timeline of covariate assessments, exclusion assessments, and follow-up periods for patients treated with anamorelin. Covariates such as clinical characteristics and laboratory values were assessed within specific windows prior to the initiation of therapy. Patients were followed up from the initiation of anamorelin until the occurrence of an event, such as therapy discontinuation, or censoring. The exclusion assessment window includes events such as inadequate clinical laboratory values prior to administration, and transfer to another hospital\u003c/p\u003e","description":"","filename":"00OnlineResource1Anamorelin.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6108504/v1/ceef4100aaba4c1dc3594921.pdf"},{"id":77802075,"identity":"386b1e67-6e27-49ef-b33b-3cb6073173fb","added_by":"auto","created_at":"2025-03-05 16:49:16","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13223,"visible":true,"origin":"","legend":"","description":"","filename":"00OnlineResource2Anamorelin.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6108504/v1/e16cef1a4a9cc5562aefb784.xlsx"},{"id":77801831,"identity":"7851d822-3513-4333-8fc3-5e1c7532ae80","added_by":"auto","created_at":"2025-03-05 16:41:16","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":77124,"visible":true,"origin":"","legend":"","description":"","filename":"Table.docx","url":"https://assets-eu.researchsquare.com/files/rs-6108504/v1/a9e227b3f37599e6d9665841.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Association between discontinuation of anamorelin and immunotrophic index in patients with cancer-associated cachexia: a single-center retrospective study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eCancer-associated cachexia is a metabolic syndrome that occurs as cancer progresses, and presents with multiple symptoms including anorexia, loss of skeletal muscle mass, and metabolic changes in the liver and adipose tissue. It is though that its onset is related to inflammatory cytokines, such as glucocorticoids, tumor necrosis factor-α, interleukin-6, growth differentiation factors-11 and \u0026minus;\u0026thinsp;15, and parathyroid hormone-related peptide, as well as various factors produced by tumor cells [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Cancer-associated cachexia is common in patients with gastrointestinal malignancies, including gastric, esophageal, or pancreatic cancer [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], occurring in 50\u0026ndash;80% of patients with advanced cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and has been reported to be a predictor of poor prognosis among patients with cancer, as it reduces the effectiveness of chemotherapy, increases side effects and treatment discontinuation, and affects overall survival rates [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Furthermore, because advanced cancer-associated cachexia is difficult to treat [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], early diagnosis as well as multidisciplinary interventions such as drug, nutritional, and exercise therapies and psychosocial interventions are required to improve patient outcomes [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. While corticosteroids and progestational agents have been used as drug treatments for cancer-associated cachexia, a standard treatment has not been established in terms of their efficacy and adverse events [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Anamorelin, a ghrelin-like agonist introduced in Japan in April 2021, binds to the growth hormone secretagogue receptor type 1a and is the only approved treatment for cancer-associated cachexia in Japan. Anamorelin has been shown to improve lean body mass and appetite in an international joint phase III clinical trial (ROMANA-1/2) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], a domestic phase II clinical trial (ONO-7643-04) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and a domestic phase III clinical trial (ONO-7643-05) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These clinical trials reported that 62\u0026ndash;66% of the patients treated with anamorelin completed the scheduled 12-week course and that it was well tolerated. Studies have reports that factors that affect the discontinuation of anamorelin include Eastern Cooperative Oncology Group Performance Status (PS) and Prognostic Nutritional Index (PNI) scores at the start of treatment [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; however, the observation periods of these studies were short, and there is no clear consensus on which factors influence the discontinuation of treatment.\u003c/p\u003e \u003cp\u003eIn clinical practice, the administration period of anamorelin is sometimes longer than the standard observation period of 12 weeks evaluated in clinical trials due to early intervention for cancer-associated cachexia; therefore, longer-term observational studies are necessary. To that end, the purpose of this study was to investigate what factors influence the discontinuation of anamorelin over 4, 12, 24, and 48 week observation period, allowing for longer follow-up periods.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003e2.1 Patients\u003c/h2\u003e\n \u003cp\u003eOnline Resource 1 presents a diagram of the study protocol. The inclusion criteria for this retrospective observational study were as follows: patients with advanced lung, gastric, pancreatic, or colorectal cancer who underwent anamorelin therapy for cancer-associated cachexia at Kindai University Nara Hospital between October 1, 2021 and December 31, 2023. The exclusion criteria were as follows: patients who transferred to another hospital, patients with inadequate clinical laboratory values prior to the initiation of treatment, and patients who underwent a dose reduction from standard dose 100 mg to 50 mg. The end date of the observation period for this study was June 30, 2024.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003e2.2 Variables\u003c/h2\u003e\n \u003cp\u003eClinical and biochemical data were retrospectively obtained from patient medical records at Kindai University Nara Hospital. Covariates included age, sex, height, weight, body mass index, lean body mass estimated using the Boer [\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e], James [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e], or Hume formula [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e], PS [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e], type of cancer, stage of disease, presence or absence of chemotherapy at the time of anamorelin initiation, duration of anamorelin administration, reason for discontinuing anamorelin, white blood cell count, absolute neutrophil count (ANC), total lymphocyte count (TLC), monocyte count (Mono), hemoglobin, platelet count (PLT), albumin (Alb), C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, and serum creatinine. We also evaluated the following immunotrophic indices reflecting inflammation and immunity in cancer patients: PNI, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), C-reactive protein-albumin ratio (CAR), and modified Glasgow Prognostic Score (mGPS).\u003c/p\u003e\n \u003cp\u003ePNI, NLR, PLR, LMR and CAR were estimated as follows: Alb (g/dL) \u0026times; 10\u0026thinsp;+\u0026thinsp;0.005 \u0026times; TLC (/mm3) [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e], the ratio of ANC to TLC [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e], the ratio of PLT to TLC [\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e], the ratio of TLC to Mono [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e], and the ratio of CRP to Alb [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e], respectively. mGPS was classified as described by Toiyama et al. [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e], as follows: mGPS 0, Alb\u0026thinsp;\u0026ge;\u0026thinsp;3.5 g/dL and CRP\u0026thinsp;\u0026le;\u0026thinsp;0.5 mg/dL; mGPS 1, Alb\u0026thinsp;\u0026lt;\u0026thinsp;3.5 g/dL or CRP\u0026thinsp;\u0026gt;\u0026thinsp;0.5 mg/dL; and mGPS 2, Alb\u0026thinsp;\u0026lt;\u0026thinsp;3.5 g/dL and CRP\u0026thinsp;\u0026gt;\u0026thinsp;0.5 mg/dL.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003e2.3 Outcome\u003c/h2\u003e\n \u003cp\u003eThe primary study outcome was the discontinuation of anamorelin at 4, 12, 24, or 48 weeks after the start of treatment, and subjects were categorized as those who continued treatment during the observation period (continuation group) and those who discontinued treatment (discontinuation group). Models 1\u0026ndash;4, based on the observation period length, were used for each group.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\n \u003cp\u003eNumerical variables were analyzed using the median as the cut-off value. We performed multivariate Cox regression analyses to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Variables for the multivariate Cox regression analyses were selected from explanatory variables with a univariate Cox regression \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1. Statistical significance was set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed using EZR (ver. 1.37), a statistical software that extends the functions of R and R Commander and is available free of charge at the website of the Department of Hematology, Saitama Medical Center, Jichi Medical University (Saitama City) [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003e2.5 Ethical considerations\u003c/h2\u003e\n \u003cp\u003eAll procedures in this study that involved human participants were performed in accordance with the ethical standards of the Institutional Research Committee as well as the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The protocol for this study was approved by the Ethics Committees of Kindai University Nara Hospital (Approval no. 781) on December 9, 2024.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Patients\u003c/h2\u003e\n \u003cp\u003eA flowchart of the patient selection procedure is shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 105 patients with lung, gastric, pancreatic, or colorectal cancer who underwent anamorelin therapy during the study period, 93 were included in our analysis. The exclusions were as follows: 8 patients transferred to another hospital, 3 had inadequate clinical laboratory values prior to anamorelin administration, and 1 underwent a dose reduction to 50 mg.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Patient characteristics\u003c/h2\u003e\n \u003cp\u003eTable\u0026nbsp;1 shows the patient characteristics at the time of the first anamorelin administration. When evaluating by sex, the proportion of males was higher than females, at 62 patients (66.7%). The median (interquartile range [IQR]) age of the 93 included patients was 76 (70\u0026ndash;79) years. Regarding the general patient condition at the time of the first administration, 10 patients (10.8%) had a PS\u0026thinsp;=\u0026thinsp;0, 52 (55.9%) had a PS\u0026thinsp;=\u0026thinsp;1, 28 (30.1%) had a PS\u0026thinsp;=\u0026thinsp;2, and 3 (3.2%) had a PS\u0026thinsp;=\u0026thinsp;3. None of the patients had a PS\u0026thinsp;=\u0026thinsp;4. The distribution of cancers were as follows: 46 patients had lung cancer (49.5%), 20 had gastric cancer (21.5%), 19 had pancreatic cancer (20.4%), and 8 had colorectal cancer (8.6%). Additionally, 87 patients (93.5%) were undergoing chemotherapy or chemoradiotherapy and 6 (6.5%) were receiving palliative care.\u003c/p\u003e\n \u003cp\u003eThe median (IQR) immunotrophic indices were as follows: PNI, 39.6 (35.6\u0026ndash;44.4); NLR, 3.14 (1.83\u0026ndash;4.82); PLR, 158 (118\u0026ndash;278); LMR, 2.31 (1.66\u0026ndash;3.68); and CAR, 0.52 (0.09\u0026ndash;1.41). Among the 93 included patients, 18 (19.3%), 26 (28.0%), 49 (52.7%) had an mGPS\u0026thinsp;=\u0026thinsp;0, 1, and 2, respectively. The median duration of administration (IQR) was 63 (2\u0026ndash;674) days, and the number of patients who discontinued treatment in each model was as follows: model 1, 31 (33.3%); model 2, 53 (57.0%); model 3, 71 (76.3%); and model 4, 83 (89.2%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Reason for discontinuation of anamorelin\u003c/h2\u003e\n \u003cp\u003eThe most common reason for discontinuing anamorelin during the 48-week observation period, the longest in this study, was exacerbation of the primary disease (n\u0026thinsp;=\u0026thinsp;31; 37.3%), followed by adverse events such as decreased liver function and hyperglycemia (n\u0026thinsp;=\u0026thinsp;11; 13.2%). The 7 cases (8.4%) that discontinued treatment due to ineffectiveness (no improvement in appetite or weight gain) and all did so within the first 4 weeks (Online Resource 2).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Analysis of factors associated with the discontinuation of anamorelin in models 1\u0026ndash;4\u003c/h2\u003e\n \u003cp\u003eThe univariate analyses of models 1\u0026ndash;4 using the Cox proportional hazards model revealed that a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 was one factor influencing the discontinuation of anamorelin in all of the models (Table 2). Furthermore, factors with a \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.1 in the univariate analyses were selected for the multivariate analyses, and significant differences were observed for a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 in all models (model 1: adjusted HR\u0026thinsp;=\u0026thinsp;2.82, 95% CI\u0026thinsp;=\u0026thinsp;1.33\u0026ndash;5.95, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007; model 2: adjusted HR; 2.18, 95% CI; 1.22\u0026ndash;3.88, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008; model 3: adjusted HR\u0026thinsp;=\u0026thinsp;2.21, 95% CI\u0026thinsp;=\u0026thinsp;1.29\u0026ndash;3.80, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004; model 4: adjusted HR\u0026thinsp;=\u0026thinsp;2.25, 95% CI\u0026thinsp;=\u0026thinsp;1.33\u0026ndash;3.80, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003). For PNI\u0026thinsp;\u0026le;\u0026thinsp;39.6, no significant difference was observed in model 1, but a significant difference was observed among models 2\u0026ndash;4 (model 1: adjusted HR; 1.57, 95% CI; 0.73\u0026ndash;3.37, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.244; model 2: adjusted HR; 1.97, 95% CI; 1.10\u0026ndash;3.53, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022; model 3: adjusted HR\u0026thinsp;=\u0026thinsp;2.10, 95% CI\u0026thinsp;=\u0026thinsp;1.07\u0026ndash;4.10, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030; model 4: adjusted HR\u0026thinsp;=\u0026thinsp;1.79, 95% CI\u0026thinsp;=\u0026thinsp;1.10\u0026ndash;2.90, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) (Table\u0026nbsp;3) .\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThis study investigated factors that influence the discontinuation of anamorelin across 4, 12, 24, and 48 week observation periods, and identified PS\u0026thinsp;\u0026ge;\u0026thinsp;2 and PNI\u0026thinsp;\u0026le;\u0026thinsp;39.6 as independent risk factors for medication discontinuation. These findings may provide new evidence that is beneficial in clinical practice as pertains to the administration of anamorelin for the treatment of cancer-associated cachexia.\u003c/p\u003e \u003cp\u003eIn clinical practice, early diagnosis and intervention in cancer-related cachexia may result in an anamorelin administration period longer than the standard 12-week observation period evaluated in clinical trials. Therefore, in this study, we identified factors that affect the discontinuation of anamorelin during its long-term administration. Anamorelin is currently only approved and sold in Japan, and there are limited reports based on actual clinical practice. Therefore, understanding the patient characteristics suitable for the administration of anamorelin will contribute to the formulation of individualized treatment plans and provide useful information for future treatment with anamorelin.\u003c/p\u003e \u003cp\u003ePS is said to be a prognostic factor for cancer treatment. In this study, the most common reason for discontinuing anamorelin was progression of the primary disease, which, including death, accounted for 46.9% of the discontinuations. Furthermore, patients who were still receiving anamorelin at 48 weeks had a PS\u0026thinsp;=\u0026thinsp;0 or 1 at the start of treatment, with none having a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2. Of the 11 patients who discontinued treatment due to adverse events, 8 discontinued within the first 4 weeks, and 5 had a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2. In a subgroup analysis of the ONO-7643-04 trial, it was reported that adverse events in the anamorelin group were more common in patients with a poor PS score, with 38.4% of patients having a PS\u0026thinsp;=\u0026thinsp;0\u0026ndash;1 and 60.0% having a PS\u0026thinsp;=\u0026thinsp;2 [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It is possible, therefore, that a decline in PS may have influenced discontinuation due to the occurrence of adverse events.\u003c/p\u003e \u003cp\u003eCancer-associated cachexia is classified into three stages: precachexia, cachexia, and refractory cachexia [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and early intervention for precachexia is required to improve patient outcomes. The clinical characteristics of precachexia are anorexia and a weight loss\u0026thinsp;\u0026le;\u0026thinsp;5% over the previous 6 months, while the criteria for starting anamorelin are poor oral intake, anorexia, and a weight loss\u0026thinsp;\u0026ge;\u0026thinsp;5% over the previous 6 months. Therefore, the stages of cancer-associated cachexia for which anamorelin is indicated are cachexia and refractory cachexia. In addition to the symptoms of cachexia, refractory cachexia also includes chemotherapy resistance, poor PS (World Health Organization score 3\u0026ndash;4), and a prognosis\u0026thinsp;\u0026lt;\u0026thinsp;3 months. Multidisciplinary interventions such as drugs, exercise, nutrition, and psychological therapy are not expected to be effective against refractory cachexia, and palliative interventions currently are the norm. In this study, we identified a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 as a factor influencing the discontinuation of anamorelin. The results suggest that, similar to other cancer-associated cachexia treatments, anamorelin therapy may be continued for a longer period if initiated at an earlier stage of cachexia and may be discontinued earlier if initiated at a later or refractory stage.\u003c/p\u003e \u003cp\u003eOnodera et al. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] reported that PNI was a risk predictor of perioperative complications in gastrointestinal cancer, with a PNI\u0026thinsp;\u0026le;\u0026thinsp;40 considered a contraindication for resection and anastomosis. It has also been reported that a lower PNI is associated with shorter survival times in pancreatic, lung, and gastric cancers [\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. In this study, PNI was extracted as a risk factor for discontinuing anamorelin at 12, 24, and 48 weeks, but not at 4 weeks. Anamorelin should be discontinued approximately 3 weeks after the start of administration if weight gain or appetite improvement is not observed. In this study, all 7 cases of discontinuation due to lack of efficacy occurred within the first 4 weeks of treatment. Therefore, early discontinuation is considered to be due to a lack of efficacy and may have a different implication than discontinuation after continued administration. Furthermore, because PNI was not identified as a risk factor for discontinuation at 4 weeks, it is thought that PNI influences discontinuation when anamorelin is continued only after a certain degree of efficacy has been observed.\u003c/p\u003e \u003cp\u003eTsukiyama et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] investigated factors influencing early the discontinuation of anamorelin within 4 weeks of starting the treatment and reported that a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 and PNI\u0026thinsp;\u0026le;\u0026thinsp;30 were risk factors. These results were consistent ours in that a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 was a risk factor for the early discontinuation of anamorelin. Contrarily, Tsukiyama et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] reported PNI as a factor influencing the early discontinuation (within 4 weeks), which differed from our findings. The reason for this is that in their study, 22.5% of patients had a PS score\u0026thinsp;\u0026ge;\u0026thinsp;3, and the median PNI was low, at 33, whereas in our study, only 3.2% of patients had a PS score\u0026thinsp;\u0026ge;\u0026thinsp;3 and the median PNI was 39.6. Therefore, it is thought that the patients in their study had a worse general condition and nutritional status than those in our study, resulting in PNI being extracted as a factor influencing the early discontinuation of anamorelin.\u003c/p\u003e \u003cp\u003eThis study has some limitations. First, because this was a retrospective study with a limited number of cases at a single institution, there is a risk of selection bias due to patient background, such as cancer type and PS. Second, this study focused only on the period of anamorelin administration, and did not include evaluation of changes in lean body mass or anorexia after anamorelin administration using a questionnaire. Third, the effects of concomitant medications, nutritional therapy, and exercise therapy could not be examined in this study.\u003c/p\u003e \u003cp\u003eDespite these limitations, the strength of this study is that we were able to identify risk factors for the discontinuation of anamorelin treatment in cancer-associated cachexia over a longer observation period. Specifically, knowing that PS and PNI influence the discontinuation of anamorelin treatment may be useful for the treatment of cancer-associated cachexia in the future.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn this study, a PS score\u0026thinsp;\u0026ge;\u0026thinsp;2 and PNI\u0026thinsp;\u0026le;\u0026thinsp;39.6 were identified as factors influencing the discontinuation of anamorelin. Therefore, in order to continue anamorelin administration for a longer period, it is necessary to diagnose cancer-associated cachexia before PS and PNI begin to decline and start multidisciplinary intervention, including the administration of anamorelin.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAiko Fukui: Validation, Formal analysis, Investigation, Data Curation, Conceptualization, Writing - Original Draft.\u003c/p\u003e\n\u003cp\u003eRyosuke Ota: Methodology, Validation, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003eAtsushi Hirata: Methodology, Validation, Writing - Review \u0026amp; Editing, Supervision, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures in this study that involved human participants were performed in accordance with the ethical standards of the Institutional Research Committee as well as the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The protocol for this study was approved by the Ethics Committees of Kindai University Nara Hospital (Approval no. 781) on December 9, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all patients as opt-out forms on the hospital website.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiddiqui JA, Pothuraju R, Jain M, Batra SK, Nasser MW (2020) Advances in cancer cachexia: Intersection between affected organs, mediators, and pharmacological interventions. 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Minerva medica 107: 322\u0026ndash;327.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":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":"cancer-associated cachexia, anamorelin, immunotrophic index, Eastern Cooperative Oncology Group Performance Status, Prognostic Nutritional Index","lastPublishedDoi":"10.21203/rs.3.rs-6108504/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6108504/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eAnamorelin, a ghrelin-like agonist, was the first drug approved for the treatment of cancer-associated cachexia in Japan; however, only a few studies have investigated what factors affect the discontinuation of anamorelin, and the observation periods of those studies were short. This study investigated the factors influencing the discontinuation of anamorelin after 4, 12, 24, and 48 weeks, to include longer observation periods than previously assessed.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective observational study investigated patients who received anamorelin for cancer-related cachexia between October 2021 and December 2023 at Kindai University Nara Hospital. We evaluated predictors of the discontinuation of anamorelin over 4, 12, 24, and 48 week observation periods after the start of treatment, and performed multivariate Cox regression analyses to calculate hazard ratios and 95% confidence intervals.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 93 patients included in this analysis, the median duration of administration (interquartile range) was 63 (2\u0026ndash;674) days. Significant differences were observed for patients with a pre-treatment Eastern Cooperative Oncology Group Performance Status (PS)\u0026thinsp;\u0026ge;\u0026thinsp;2 in all observation periods, as well as a Prognostic Nutritional Index (PNI)\u0026thinsp;\u0026le;\u0026thinsp;39.6 in the 12, 24, and 48 week observation periods.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study revealed that a patient\u0026rsquo;s PS and PNI at the start of anamorelin therapy may affect the discontinuation of anamorelin. Therefore, in order to administer anamorelin for a longer period it is necessary to diagnose cancer-associated cachexia before PS and PNI begin to decline and start multidisciplinary intervention, including the administration of anamorelin.\u003c/p\u003e","manuscriptTitle":"Association between discontinuation of anamorelin and immunotrophic index in patients with cancer-associated cachexia: a single-center retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-05 16:41:11","doi":"10.21203/rs.3.rs-6108504/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":"7350214f-a00d-4dfd-a8a8-c937a79a7b45","owner":[],"postedDate":"March 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-29T03:38:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-05 16:41:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6108504","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6108504","identity":"rs-6108504","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}