Prognostic Impact of Weight Loss During First-Line Chemotherapy in Patients with Extensive-Disease Small Cell Lung Cancer

Prognostic Impact of Weight Loss During First-Line Chemotherapy in Patients with Extensive-Disease Small Cell Lung Cancer | 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 Prognostic Impact of Weight Loss During First-Line Chemotherapy in Patients with Extensive-Disease Small Cell Lung Cancer Toshiya Fujisaki, Tateaki Naito, Satomi Kumaki, Shunichi Kataoka, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8002341/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Purpose The adverse prognostic impact of cancer cachexia is well recognized. We aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with extensive-disease small cell lung cancer (ED-SCLC). Methods We retrospectively reviewed 187 ED-SCLC patients treated between 2009 and 2021 and collected body weight at three time points: 6 months before, at the start of the first cycle, and at the beginning of the third cycle of initial chemotherapy. Based on pretreatment weight loss (defined by the Fearon criteria) and ≥ 2% weight loss during two cycles, we classified patients into four groups: those without weight loss both before and during chemotherapy (n = 75) (non-weight-loss group), those without weight loss before but with weight loss during chemotherapy (n = 34), those with weight loss before but not during chemotherapy (n = 46), and those with weight loss both before and during chemotherapy (n = 32). We evaluated survival outcomes and gastrointestinal toxicities during the first two cycles. Results Median overall survival (OS) differed significantly among the groups (p = 0.020), with the non-weight-loss group showing the most favorable survival than the other groups (adjusted hazard ratios, 1.51–1.65; all p ≤ 0.05). The non-weight-loss group experienced fewer grade ≥ 2 anorexia and nausea/vomiting events during the first two cycles. Conclusions In patients with ED-SCLC, the absence of weight loss before and during chemotherapy was associated with longer OS and fewer gastrointestinal toxicities, potentially underscoring the importance of appropriate management of gastrointestinal toxicities during chemotherapy, particularly in patients who did not experience weight loss before chemotherapy initiation. Cachexia Prognosis Small Cell Lung Carcinoma Weight loss Figures Figure 1 Figure 2 Figure 3 1. Introduction Cancer cachexia (CAC) is a multifactorial syndrome characterized by ongoing skeletal muscle loss, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to functional decline. [ 1 ] The presence of cancer cachexia before starting treatment has been linked to reduced survival, increased toxicities, and poorer quality of life [ 2 , 3 ], highlighting the importance of its early detection and management. In recent years, accumulating evidence has supported the efficacy of pharmacological agents for cancer cachexia [ 4 – 6 ], leading to increased clinical research efforts aimed at establishing effective supportive care strategies. Conversely, the prognostic significance of weight loss during anti-cancer treatment remains uncertain. Although several studies have indicated that weight loss during therapy is associated with unfavorable outcomes [ 7 ], its prognostic significance may differ according to baseline cachexia status, which has rarely been evaluated. Small cell lung cancer (SCLC) is a highly aggressive malignancy, and the presence of cachexia at the commencement of treatment has been associated with a poor prognosis. [ 8 ] Platinum-based chemo(immuno)therapy, the standard first-line treatment for extensive-disease SCLC (ED-SCLC), shows a high response rate, but frequently causes gastrointestinal toxicities such as anorexia, nausea, and vomiting, which can lead to weight loss. Nevertheless, the prognostic significance of weight loss during chemotherapy in ED-SCLC remains unclear. Therefore, in this retrospective study, we aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with ED-SCLC, stratified by cachexia status at chemotherapy initiation. We also assessed the association between weight loss and gastrointestinal toxicities, including anorexia and nausea or vomiting, during two cycles of first-line chemotherapy. 2. Materials and Methods 2.1 Study Design and Patients This was a single-center, retrospective cohort study conducted at Shizuoka Cancer Center, Japan. We included patients with ED-SCLC who received platinum-based chemotherapy, with or without immune checkpoint inhibitors, as first-line treatment between July 2009 and December 2021. Eligible patients were required to meet all of the following criteria: (1) no evidence of progressive disease after completion of the first two cycles of initial chemotherapy, (2) received at least three cycles of initial chemotherapy, and (3) availability of body weight data at the following three time points: 6 months before the start of initial chemotherapy, at the start of the first and third cycle of initial chemotherapy. The patients were classified according to the following two indicators of weight loss: (A) Pretreatment weight loss At the start of the first cycle of chemotherapy, the presence (CAC) or absence (non-CAC) of weitghtloss within 6 months, (B) Posttreatment weight loss At the start of the third cycle of chemotherapy, the presence (CAC) or absence (non-CAC) of weight loss from the beginning of the initial chemotherapy. We divided patients into the following four groups based on their weight change from (A) to (B): Group 1. non-CAC to non-CAC group: those without weight loss both before and during chemotherapy, Group 2. non-CAC to CAC group: those without weight loss before but with weight loss during chemotherapy, Group 3. CAC to non-CAC group: those with weight loss before but not during chemotherapy, Group 4. CAC to CAC group: those with weight loss both before and during chemotherapy. In (A), pretreatment weight loss (cachexia) was defined according to the criteria proposed by Fearon et al., which defines cachexia as weight loss of > 5%, or > 2% with a BMI < 20 kg/m², within 6 months. [ 1 ] In (B), posttreatment weight loss was defined as weight loss of ≥ 2% from the start of initial chemotherapy to the beginning of the third cycle (Table 1 ). The non-CAC to non-CAC group (group 1) was designated as the non-weight-loss group, while the remaining three groups (group2, 3, and 4) were categorized as the weight-loss groups. Table 1 Classification of patients according to weight loss before and during initial chemotherapy (A) Pretreatment weight loss (B) Posttreatment weight loss 1. non-CAC to non-CAC Absent Absent 2. non-CAC to CAC Absent Present 3. CAC to non-CAC Present Absent 4. CAC to CAC Present Present “Pretreatment weight loss” was defined as cachexia at the start of initial chemotherapy, according to the criteria of Fearon et al. (weight loss > 5%, or > 2% with BMI < 20 kg/m², within 6 months). “Posttreatment weight loss” was defined as ≥ 2% weight loss from the start of initial chemotherapy to the beginning of the third cycle. Abbreviations: CAC, cachexia; non-CAC, non-cachexia. 2.2 Data Collection and Study Assessment We collected the following data retrospectively from all patients: age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking history, clinical stage (based on the TNM Classification of Malignant Tumors, 9th edition), laboratory findings, body weight at each time point, and treatment information for initial and subsequent therapies. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 2.3 Outcomes The primary endpoints were progression-free survival (PFS) and overall survival (OS), both measured from the start of the third cycle of initial chemotherapy. PFS was defined as the time from the third cycle initiation to disease progression or death from any cause, whichever occurred first. OS was defined as the time from the third cycle initiation to death from any cause. Secondary endpoints were the frequency and severity of adverse events (AEs) during the first two cycles of initial chemotherapy, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Particular attention was given to anorexia, nausea, and vomiting as gastrointestinal toxicities. 2.4 Statistical analysis Categorical variables were compared using Fisher’s exact test, and continuous variables were compared using the Kruskal-Wallis test. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS were estimated using univariate and multivariate Cox proportional hazards models. All statistical analyses were performed with EZR version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). [ 9 ] Two-sided p-values < 0.05 were considered statistically significant. 2.5 Ethics This study was conducted in accordance with the Declaration of Helsinki. [ 10 ] The study protocol was approved by the institutional review board of Shizuoka Cancer Center (approval number: J2024-123-2024-1-2). Informed consent was waivered due to the retrospective nature of the study, and an opt-out approach was employed on the institutional website. 3. Results 3.1 Patient characteristics Among 346 patients with ED-SCLC who received first-line platinum-based chemo(immuno)therapy during the study period, 148 were excluded due to missing weight data at any of the three time points, 6 due to treatment discontinuation within two cycles, and 5 due to progressive disease as the best response. A total of 187 patients were included in the analysis: 75 in the non-CAC to non-CAC group, 34 in the non-CAC to CAC group, 46 in the CAC to non-CAC group, and 32 in the CAC to CAC group (Fig. 1 ). There were significant differences among the four groups in ECOG-PS, serum CRP levels, serum albumin levels, and Modified Glasgow Prognostic Score (mGPS). However, age, sex, and the proportion of Immune checkpoint inhibitor (ICI)-based regimens were not significantly different. Although no statistically significant difference in clinical stage distribution was observed among the four groups, the non-CAC to non-CAC group tended to have fewer patients with stage IVB. The median percentage change in body weight from the initiation of the first cycle to the initiation of the third cycle was + 1.1%, − 5.1%, + 2.1%, and − 4.9% in the non-CAC to non-CAC, non-CAC to CAC, CAC to non-CAC, and CAC to CAC groups, respectively (Table 2 ). Carboplatin plus etoposide with atezolizumab was the most frequent ICI-based regimen (22/187, 12%), while among non-ICI-based regimens, carboplatin plus etoposide predominated (96/187, 51%), followed by cisplatin plus irinotecan (29/187, 16%) and cisplatin plus etoposide (23/187, 12%) (Table S1 ). Table 2 Patient Characteristics at the Third Cycle Initiation of Initial Chemo(immuno)therapy Clinical feature All (N = 187) non-CAC to non-CAC (N = 75) non-CAC to CAC (N = 34) CAC to non-CAC (N = 46) CAC to CAC (N = 32) p -value a, b Age, median (range), years 70 (50–89) 69 (50–87) 72 (54–84) 69 (51–89) 70 (57–81) 0.27 a Sex, n (%) Female 34 (18) 13 (17) 6 (18) 8 (17) 7 (22) 0.94 b Male 153 (82) 62 (83) 28 (82) 38 (83) 25 (78) ECOG-PS, n (%) 0–1 163 (87) 70 (93) 30 (88) 39 (85) 23 (74) 0.046 b 2 23 (12) 5 (7) 3 (9) 7 (15) 8 (26) 3 1 (1) 0 (0) 1 (3) 0 (0) 0 (0) Clinical Stage*, n (%) IIIC 1 (1) 1 (1) 0 (0) 0 (0) 0 (0) 0.073 b IVA 59 (32) 32 (43) 10 (30) 10 (22) 7 (22) IVB 127 (68) 42 (56) 24 (71) 36 (78) 25 (78) First line treatment, n (%) Platinum combination plus ICI 26 (14) 11 (15) 7 (21) 4 (9) 4 (13) 0.49 b Platinum combination only 161 (86) 64 (85) 27 (79) 42 (91) 28 (88) Distant metastasis*, n (%) Brain 59 (32) 21 (28) 9 (26) 17 (37) 12 (38) 0.57 b Liver 61 (33) 20 (27) 13 (38) 16 (35) 12 (38) 0.52 b Serum CRP, mg/dL, median (range) 0.26 (0.02 to 20.23) 0.16 (0.02 to 5.05) 0.41 (0.03 to 6.97) 0.28 (0.02 to 3.43) 0.38 (0.02 to 20.23) 0.011 a Serum albumin, g/dL, median (range) 3.9 (2.3 to 4.6) 4.0 (2.4 to 4.5) 3.85 (3.3 to 4.5) 3.9 (2.6 to 4.3) 3.7 (2.3 to 4.6) 0.036 a mGPS, n (%) † 0 149 (80) 65 (87) 25 (74) 38 (83) 21 (66) 0.049 b 1 19 (10) 3 (4) 6 (18) 5 (11) 5 (16) 2 16 (9) 4 (5) 3 (9) 3 (7) 6 (19) Weight change, %, median (range) ‡ -0.3 (-17.9 to 16.8) + 1.1 (-1.9 to 15.5) -5.1 (-10.5 to -2.3) + 2.1 (-1.6 to 16.8) -4.9 (-17.9 to -2.1) NA Differences between groups were identified using a Kruskal-Wallis test, b Fisher’s exact test. Abbreviations: CAC, Cachexia; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ICI, Immune checkpoint inhibitor; mGPS, Modified Glasgow Prognostic Score; non-CAC, non-Cachexia; PS, performance status. * Assessed at diagnosis. † Three patients in non-CAC to non-CAC group whose mGPS were unknown were not included in statistical comparison. ‡ From first to third cycle initiation. 3.2 Treatment outcomes Best overall response to initial chemotherapy did not differ significantly among the four groups (Table S2). Median PFS, measured from the start of the third cycle of initial chemotherapy, was not significantly different among the groups (log-rank p = 0.062; Fig. 2 a). In contrast, median OS, also measured from the start of the third cycle of initial chemotherapy, differed significantly (log-rank p = 0.020), with the non-CAC to non-CAC group (non-weight-loss group) showing the most favorable survival (Fig. 2 b). Multivariate analysis, adjusted for ECOG-PS, clinical stage, age, and mGPS, confirmed that OS was significantly longer in the non-CAC to non-CAC group compared with the other groups (non-CAC to CAC: HR 1.65, 95% CI 1.08–2.53, p = 0.020; CAC to non-CAC: HR 1.51, 95% CI 1.00–2.29, p = 0.050; CAC to CAC: HR 1.62, 95% CI 1.01–2.60, p = 0.047), consistent with the results of univariate analysis (Table 3 ). Among patients with cachexia at the start of the initial chemotherapy (CAC to CAC and CAC to non-CAC groups), OS did not differ significantly between those who experienced weight loss during chemotherapy and those who did not (HR 0.83, 95% CI 0.51–1.35; p = 0.445; data not shown). Table 3 Cox Proportional Hazards Model for Overall Survival (Reference: non-CAC to non-CAC) Univariate Analysis Multivariate Analysis HR (95% CI) p -value HR (95% CI) p -value non-CAC to non-CAC 1.00 (Ref) 1.00 (Ref) non-CAC to CAC 1.77 (1.16 to 2.69) 0.008 1.65 (1.08 to 2.53) 0.020 CAC to non-CAC 1.74 (1.17 to 2.60) 0.006 1.51 (1.00 to 2.29) 0.050 CAC to CAC 2.00 (1.29 to 3.11) 0.002 1.62 (1.01 to 2.60) 0.047 Multivariate analysis was adjusted for ECOG­PS (0–1 vs. 2–3), clinical stage (IIIC and IVA vs. IVB), age (< 75 vs. ≥75), and mGPS (0 vs. 1–2). Abbreviations: CAC, cachexia; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; non-CAC, non-cachexia; OS, overall survival; PS, performance status. 3.3 Adverse events We summarized the frequency of AEs during the first two cycles of chemotherapy in Table S3. Significant between-group differences were observed in the incidence of hyponatremia and anemia (any grade), as well as leukopenia, anemia, anorexia, and nausea (≥ grade 3). With respect to gastrointestinal toxicities, grade ≥ 2 anorexia and nausea or vomiting occurred more frequently and with greater severity in all groups other than the non-CAC to non-CAC group (Fig. 3 a,b). 3.3 Exploratory analysis As shown in Table S4, the frequency of treatment-related death during initial chemotherapy did not differ significantly among the groups (p = 0.084), although it was lower in the non-CAC to non-CAC (1%) and non-CAC to CAC (0%) groups than in the CAC to non-CAC (4%) and CAC to CAC (9%) groups. The completion rate of four cycles of initial chemotherapy was also not significantly different among the groups (p = 0.062), but tended to be higher in the non-CAC to non-CAC (96%) and CAC to non-CAC (96%) groups compared with the non-CAC to CAC (85%) and CAC to CAC (84%) groups. Similarly, the use of subsequent chemotherapy did not differ significantly among the groups (p = 0.193), but was more common in the non-CAC to non-CAC group (80%) than in the non-CAC to CAC (65%), CAC to non-CAC (67%), and CAC to CAC (63%) groups. 4. Discussion We investigated the prognostic impact of weight loss developed during first-line chemotherapy in patients with ED-SCLC. The finding is that patients in the non-weight-loss group (non-CAC to non-CAC) had significantly longer OS than those in the weight-loss groups (non-CAC to CAC, CAC to non-CAC, and CAC to CAC), and they were less likely to experience anorexia, nausea, and vomiting during the first two cycles of chemotherapy. To the best of our knowledge, this is the first study in ED-SCLC to stratify patients according to cachexia status at chemotherapy initiation and examine the prognostic impact of weight loss developed during first-line chemotherapy. We have previously reported that the presence of cachexia, either before or after initial chemotherapy, was associated with a shorter OS in patients with advanced non-small cell lung cancer (NSCLC). [ 11 ] In Japanese patients with SCLC, those who had experienced weight loss before first-line chemotherapy had a lower response rate and tended to have a shorter OS. [ 8 ] Notably, our findings suggest that even in patients without cachexia at the time of chemotherapy initiation, the development of weight loss during chemotherapy may shorten OS. This suggest that preventing weight loss during chemotherapy may be clinically important in this population. In our study, among patients with cachexia at treatment initiation, no significant improvement in OS was observed even if further weight loss during chemotherapy did not occur. However, a previous study in advanced NSCLC has shown that weight gain during treatment is associated with improved prognosis [ 12 ], suggesting a possible survival benefit if weight gain can be achieved even in patients with cachexia. Patients in the non-weight-loss group exhibited a reduced frequency and severity of gastrointestinal toxicities, including anorexia and nausea or vomiting, during the two cycles of initial chemotherapy. We have previously reported, in a retrospective study of patients with NSCLC, that chemotherapy-induced anorexia was associated with both weight loss and reduced therapeutic efficacy. [ 13 ] Taken together, our findings suggest that, also in ED-SCLC, appropriate management of gastrointestinal toxicities during chemotherapy may help reduce weight loss and potentially contribute to improved survival outcomes. Recent advances in supportive pharmacological agents indicate the possibility of preventing weight loss, and potentially achieving weight gain, in patients undergoing anti-cancer treatment. Olanzapine has demonstrated efficacy in the treatment of chemotherapy-induced nausea and vomiting [ 14 – 18 ] and has also been associated with the stimulation of appetite and the occurrence of weight gain. [ 4 , 19 ] The American Society of Clinical Oncology (ASCO) guideline recommends low-dose olanzapine for adults with advanced cancer to improve appetite and promote weight gain. [ 20 ] Anamorelin, a selective ghrelin receptor agonist, significantly increased lean body mass in patients with advanced NSCLC and cachexia in phase 3 trials. [ 5 , 21 ] Ponsegromab, an anti–growth differentiation factor 15 (GDF-15) antibody targeting a cytokine implicated in cancer-related anorexia and weight loss, improved body weight, activity, and anorexia-related symptoms in patients with cancer cachexia in a phase II trial. [ 22 ] Preclinical studies have reported that GDF-15 contributes to platinum-based chemotherapy–induced cachexia and that its blockade may promote weight gain. [ 23 ] In patients who have not experienced weight loss at the time of treatment initiation, these agents and appropriate management of gastrointestinal toxicities may help prevent weight loss during treatment and improve survival outcomes. The present findings support the implementation of prospective trials to confirm their efficacy, which may also benefit patients with cachexia at the treatment initiation. Our study has several limitations. First, this was a retrospective study with a limited sample size, which may have reduced statistical power, and the impact of potential biases and unmeasured confounders cannot be ruled out. Second, as this was a single-institution study, the generalizability of our findings is limited and requires validation in other settings. Third, we were unable to determine the exact causes of weight loss, which may have included not only treatment-related toxicities but also psychological factors, comorbid conditions, and other contributors. Fourth, because measures of body composition (muscle and fat mass) and validated nutritional assessment tools were not available, detailed evaluation of lean body mass, sarcopenia, and malnutrition was not possible. Finally, although we graded AEs according to CTCAE criteria, the assessment of gastrointestinal toxicities was based on subjective observations from medical records, which limits our ability to validate agreement or reproducibility with patient-reported outcomes. In conclusion, among patients with ED-SCLC who received first-line platinum-based chemo(immuno)therapy, those who did not experience weight loss before and during chemotherapy (non-weight-loss group) had a significantly longer OS and a lower incidence of anorexia and nausea or vomiting during chemotherapy compared with those who experienced weight loss before or during chemotherapy (weight-loss group). These results potentially underscore the importance of appropriate management of anorexia and nausea or vomiting during chemotherapy, particularly in patients who have not experienced weight loss before chemotherapy initiation. Declarations Acknowledgments: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The authors thank the patients, their families, and all study investigators who contributed to the study. Authors’ Contributions: Toshiya Fujisaki : Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing–Original Draft Preparation, Visualization. Tateaki Naito : Conceptualization, Methodology, Writing–review and Editing, Supervision, Project Administration. Satomi Kumaki, Shunichi Kataoka, Shin Saito, Suguru Matsuda, Haruki Kobayashi, Ryo Ko, Kazushige Wakuda, Akira Ono, Haruyasu Murakami, Toshiaki Takahashi, Hirotsugu Kenmotsu : Conceptualization, and Writing–Review and Editing. Disclosure: Dr. Fujisaki reported receiving honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Kyowa Kirin, outside the submitted work. Dr. Naito reported receiving honoraria from ONO Pharmaceutical CO. Ltd and Tsumura & Co.; consulting fees from Pfizer Inc., Tensegrity Pharma, Inc., AstraZeneca K.K., Taiho Pharmaceutical Co. Ltd.; grands from Otsuka Pharmaceutical CO. Ltd., Kracie, Ltd., all outside the submitted work. Dr. Kataoka reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Saito reported receiving honoraria from AstraZeneca, outside the submitted work. Dr. Matsuda reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Kobayashi reported receiving honoraria from Eli Lilly K.K, Novartis Pharma K.K., Taiho Pharmaceutical Co.,LTD., AstraZeneca, Chugai Pharmaceutical Co.,LTD., Ono Pharmaceutical Co.,LTD., Bristol-Myers Squibb Company, and DAIICHI SANKYO COMPANY, outside the submitted work. Dr. Ko reported receiving honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, and Janssen Pharmaceutical; and grants from MSD, AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Nuvalent, Amgen, Novocure, and Daiichi Sankyo, all outside the submitted work. Dr. Wakuda reported receiving honoraria from Chugai Pharmaceutical Co.,Ltd, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K, Ono Pharmaceutical, MSD, Astrazeneca, Daiichi Sankyo, Janssen Pharmaceutical K.K., Takeda Pharmaceutical, Nihon Kayaku, and AMGEN; and grants from Chugai Pharmaceutical Co.,Ltd, AstraZeneca, Novartis, Abbvie, AMGEN, MSD, Daiichi Sankyo, Dizal Pharma, and Pfizer, all outside the submitted work. Dr. Ono reported receiving honoraria from Astrazeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical, Janssen Research & Development, Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharmaceuticals, and Taiho Pharmaceuticals, outside the submitted work. Dr. Murakami reported receiving honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, and Amgen; consulting fees from Chugai Pharmaceutical, GAIA BioMedicine, and Daiichi Sankyo; and research funding from AstraZeneca, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Bayer, Eli Lilly, Taiho Pharmaceutical, and Pfizer, all outside the submitted work. Dr. Takahashi reported receiving honoraria from AstraZeneca KK, Chugai PHARMACEUTICAL CO., LTD, MSD K.K., Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Pfizer Japan Inc., DAIICHI SANKYO CO., LTD, Amgen K.K., BMS Japan., TAIHO PHARMACEUTICAL CO., LTD, Takeda PHARMACEUTICAL CO LTD., ONO PHARMACEUTICAL CO., LTD., and Takeda PHARMACEUTICAL CO LTD.; and grants from AstraZeneca KK, MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., and AnHeart Therapeutics Inc., all outside the submitted work. Dr. Kenmotsu reported receiving honoraria from Amgen inc., AstraZeneca K.K., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Merck, MSD, Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Pfizer, Taiho Pharma, Takeda Pharmaceutical Co., Ltd, Janssen Pharmaceutical K.K., Thermo Fisher Scientific Inc., and Guardant; and grants from Ono Pharmaceutical Co, Ltd., Novartis Pharma K.K., Eli Lilly K.K, AstraZeneca K.K., and Loxo Oncology, all outside the submitted work. No other disclosures were reported. Funding: This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. Data Sharing Statement: The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. References Fearon K, Strasser F, Anker SD et al (2011) Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–495. doi: 10.1016/s1470-2045(10)70218-7 Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH (2018) Cancer-associated cachexia. Nat Rev Dis Primers 4:17105. doi: 10.1038/nrdp.2017.105 Zhang J, Tang X, Zhang W, Xu Y, Zhang H, Fan Y (2024) Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis. Clin Nutr 43:1618–1625. doi: 10.1016/j.clnu.2024.05.025 Yuan L, Li XY, Xu L, Quan SJ, Huang YB, Zheng H (2025) Effects of olanzapine in the improvement of body weight and appetite in patients with cancer or receiving chemotherapy: a systematic review and meta-analysis. Eur J Clin Pharmacol 81:45–63. doi: 10.1007/s00228-024-03770-x Temel JS, Abernethy AP, Currow DC et al (2016) Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol 17:519–531. doi: 10.1016/s1470-2045(15)00558-6 Groarke JD, Crawford J, Collins SM et al (2024) Ponsegromab for the Treatment of Cancer Cachexia. N Engl J Med 391:2291–2303. doi: 10.1056/NEJMoa2409515 Ryan AM, Prado CM, Sullivan ES, Power DG, Daly LE (2019) Effects of weight loss and sarcopenia on response to chemotherapy, quality of life, and survival. Nutrition 67–68:110539. doi: 10.1016/j.nut.2019.06.020 Shukuya T, Takahashi K, Shintani Y et al (2023) Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study. J Cachexia Sarcopenia Muscle 14:1274–1285. doi: 10.1002/jcsm.13216 Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458. doi: 10.1038/bmt.2012.244 (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama 310:2191–2194. doi: 10.1001/jama.2013.281053 Kimura M, Naito T, Kenmotsu H et al (2015) Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer 23:1699–1708. doi: 10.1007/s00520-014-2534-3 Patel JD, Pereira JR, Chen J et al (2016) Relationship between efficacy outcomes and weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients. Ann Oncol 27:1612–1619. doi: 10.1093/annonc/mdw211 Doshita K, Naito T, Matsuda S et al (2024) Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study. Thorac Cancer 15:1831–1841. doi: 10.1111/1759-7714.15403 Bymaster FP, Calligaro DO, Falcone JF et al (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87–96. doi: 10.1016/0893-133x(94)00129-n Hashimoto H, Abe M, Tokuyama O et al (2020) Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:242–249. doi: 10.1016/s1470-2045(19)30678-3 Navari RM (2014) Olanzapine for the prevention and treatment of chronic nausea and chemotherapy-induced nausea and vomiting. Eur J Pharmacol 722:180–186. doi: 10.1016/j.ejphar.2013.08.048 Navari RM, Qin R, Ruddy KJ et al (2016) Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 375:134–142. doi: 10.1056/NEJMoa1515725 Sakai H, Tsurutani J, Ozaki Y et al (2025) A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B). Ann Oncol 36:31–42. doi: 10.1016/j.annonc.2024.09.001 Ispoglou T, McCullough D, Windle A et al (2024) Addressing cancer anorexia-cachexia in older patients: Potential therapeutic strategies and molecular pathways. Clin Nutr 43:552–566. doi: 10.1016/j.clnu.2024.01.009 Roeland EJ, Bohlke K, Baracos VE, Smith TJ, Loprinzi CL (2023) Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol 41:4178–4179. doi: 10.1200/jco.23.01280 Guillory B, Splenser A, Garcia J (2013) The role of ghrelin in anorexia-cachexia syndromes. Vitam Horm 92:61–106. doi: 10.1016/b978-0-12-410473-0.00003-9 Breit SN, Brown DA, Tsai VW (2021) The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe? Annu Rev Physiol 83:127–151. doi: 10.1146/annurev-physiol-022020-045449 Breen DM, Kim H, Bennett D et al (2020) GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates. Cell Metab 32:938–950.e936. doi: 10.1016/j.cmet.2020.10.023 Additional Declarations Competing interest reported. Dr. Fujisaki reported receiving honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Kyowa Kirin, outside the submitted work. Dr. Naito reported receiving honoraria from ONO Pharmaceutical CO. Ltd and Tsumura & Co.; consulting fees from Pfizer Inc., Tensegrity Pharma, Inc., AstraZeneca K.K., Taiho Pharmaceutical Co. Ltd.; grands from Otsuka Pharmaceutical CO. Ltd., Kracie, Ltd., all outside the submitted work. Dr. Kataoka reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Saito reported receiving honoraria from AstraZeneca, outside the submitted work. Dr. Matsuda reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Kobayashi reported receiving honoraria from Eli Lilly K.K, Novartis Pharma K.K., Taiho Pharmaceutical Co.,LTD., AstraZeneca, Chugai Pharmaceutical Co.,LTD., Ono Pharmaceutical Co.,LTD., Bristol-Myers Squibb Company, and DAIICHI SANKYO COMPANY, outside the submitted work. Dr. Ko reported receiving honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, and Janssen Pharmaceutical; and grants from MSD, AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Nuvalent, Amgen, Novocure, and Daiichi Sankyo, all outside the submitted work. Dr. Wakuda reported receiving honoraria from Chugai Pharmaceutical Co.,Ltd, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K, Ono Pharmaceutical, MSD, Astrazeneca, Daiichi Sankyo, Janssen Pharmaceutical K.K., Takeda Pharmaceutical, Nihon Kayaku, and AMGEN; and grants from Chugai Pharmaceutical Co.,Ltd, AstraZeneca, Novartis, Abbvie, AMGEN, MSD, Daiichi Sankyo, Dizal Pharma, and Pfizer, all outside the submitted work. Dr. Ono reported receiving honoraria from Astrazeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical, Janssen Research & Development, Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharmaceuticals, and Taiho Pharmaceuticals, outside the submitted work. Dr. Murakami reported receiving honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, and Amgen; consulting fees from Chugai Pharmaceutical, GAIA BioMedicine, and Daiichi Sankyo; and research funding from AstraZeneca, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Bayer, Eli Lilly, Taiho Pharmaceutical, and Pfizer, all outside the submitted work. Dr. Takahashi reported receiving honoraria from AstraZeneca KK, Chugai PHARMACEUTICAL CO., LTD, MSD K.K., Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Pfizer Japan Inc., DAIICHI SANKYO CO., LTD, Amgen K.K., BMS Japan., TAIHO PHARMACEUTICAL CO., LTD, Takeda PHARMACEUTICAL CO LTD., ONO PHARMACEUTICAL CO., LTD., and Takeda PHARMACEUTICAL CO LTD.; and grants from AstraZeneca KK, MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., and AnHeart Therapeutics Inc., all outside the submitted work. Dr. Kenmotsu reported receiving honoraria from Amgen inc., AstraZeneca K.K., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Merck, MSD, Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Pfizer, Taiho Pharma, Takeda Pharmaceutical Co., Ltd, Janssen Pharmaceutical K.K., Thermo Fisher Scientific Inc., and Guardant; and grants from Ono Pharmaceutical Co, Ltd., Novartis Pharma K.K., Eli Lilly K.K, AstraZeneca K.K., and Loxo Oncology, all outside the submitted work. No other disclosures were reported. Supplementary Files SupplementaryImformation.docx Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 11 Mar, 2026 Reviews received at journal 11 Mar, 2026 Reviews received at journal 09 Mar, 2026 Reviews received at journal 02 Mar, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviews received at journal 18 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers invited by journal 07 Nov, 2025 Editor assigned by journal 07 Nov, 2025 Submission checks completed at journal 07 Nov, 2025 First submitted to journal 31 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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-8002341","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":546403982,"identity":"4bb27f68-c894-4e5e-8cd2-0277efc6afe6","order_by":0,"name":"Toshiya Fujisaki","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Toshiya","middleName":"","lastName":"Fujisaki","suffix":""},{"id":546403983,"identity":"6aaa7abc-b644-431b-8503-ac79964debb0","order_by":1,"name":"Tateaki Naito","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAsklEQVRIiWNgGAWjYLCCBAYGOSDFBsUEAA9YSwKDMYlagNYkNhClHATsGXgPfnj4wyZ9fvvhZ48rGPjyiLCFL1kiISEtd8OZNHPDMwxsxURo4TEAajmcu0GCh02ygYEN5EKCWox/ALWky88gQYsZyJYEhhtEaznMY2aRkJZmCPSLmWSDARF+YW/vMb75w8ZGXh4YYpINFccIhxgDMwrP4FgCYS1ooIZ0LaNgFIyCUTDsAQAbWTEQPEv/LwAAAABJRU5ErkJggg==","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Tateaki","middleName":"","lastName":"Naito","suffix":""},{"id":546403984,"identity":"0e17d364-b39d-42e1-85c6-cf9897507271","order_by":2,"name":"Satomi Kumaki","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Satomi","middleName":"","lastName":"Kumaki","suffix":""},{"id":546403985,"identity":"c6bbb370-63f6-413b-beac-0b7232fa9dbe","order_by":3,"name":"Shunichi Kataoka","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Shunichi","middleName":"","lastName":"Kataoka","suffix":""},{"id":546403986,"identity":"6b7b9a6e-c242-4a81-aa9b-72337b3b1bda","order_by":4,"name":"Shin Saito","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Shin","middleName":"","lastName":"Saito","suffix":""},{"id":546403987,"identity":"784ab3e0-a519-43c7-a12e-aedbc360c447","order_by":5,"name":"Suguru Matsuda","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Suguru","middleName":"","lastName":"Matsuda","suffix":""},{"id":546403988,"identity":"03949cdd-ea5c-425f-a711-1fcee0f2c8e9","order_by":6,"name":"Haruki Kobayashi","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Haruki","middleName":"","lastName":"Kobayashi","suffix":""},{"id":546403989,"identity":"a6892136-8ebd-4e40-aea3-30716816bbc7","order_by":7,"name":"Ryo Ko","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Ryo","middleName":"","lastName":"Ko","suffix":""},{"id":546403990,"identity":"8e7dc8dd-12ec-4223-9d7b-a44b96197d0a","order_by":8,"name":"Kazushige Wakuda","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Kazushige","middleName":"","lastName":"Wakuda","suffix":""},{"id":546403991,"identity":"65cf53e6-022a-4392-bc92-52a3cf480a72","order_by":9,"name":"Akira Ono","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Ono","suffix":""},{"id":546403992,"identity":"a4746c40-6164-4baf-aa7b-289371e6f58d","order_by":10,"name":"Haruyasu Murakami","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Haruyasu","middleName":"","lastName":"Murakami","suffix":""},{"id":546403996,"identity":"a46f8145-06dc-44c7-829e-8b23e8b8b2c1","order_by":11,"name":"Toshiaki Takahashi","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Toshiaki","middleName":"","lastName":"Takahashi","suffix":""},{"id":546403997,"identity":"000c29e0-8f20-413a-b82a-7ef3b2a252f4","order_by":12,"name":"Hirotsugu Kenmotsu","email":"","orcid":"","institution":"Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Kenmotsu","suffix":""}],"badges":[],"createdAt":"2025-11-01 02:23:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8002341/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8002341/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":96202145,"identity":"c7ddac19-5f3f-495d-a47b-9e2eabcc4a03","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":775387,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/8c9937e453274a4a7f04711a.docx"},{"id":96202137,"identity":"e81ad05e-bfb2-48ef-8b4f-99f7388e58c1","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16581,"visible":true,"origin":"","legend":"","description":"","filename":"d5c1e678758f40ecb7a69a88f28c7692.json","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/5870475f5ecdf782f90c0eae.json"},{"id":96202127,"identity":"cc9edde7-f275-475a-a1cb-822ca9d83034","added_by":"auto","created_at":"2025-11-18 16:39:13","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35584,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryImformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/c04b93a17e6b0712836bace2.docx"},{"id":96202157,"identity":"722ee312-5714-4082-aabc-50ae5e6c525e","added_by":"auto","created_at":"2025-11-18 16:39:18","extension":"xml","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":96995,"visible":true,"origin":"","legend":"","description":"","filename":"d5c1e678758f40ecb7a69a88f28c76921enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/5ce366b4f8cd052e50e58f37.xml"},{"id":96202132,"identity":"0f64c40c-8fad-4b60-86fb-6d41297a00a3","added_by":"auto","created_at":"2025-11-18 16:39:14","extension":"jpeg","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":176695,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/8a7b8d3476f8434044551f58.jpeg"},{"id":96202147,"identity":"66148d85-a83f-4847-bf5e-ec72f7790468","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":308898,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/87f08878aa7dc9ddfd6417a4.jpeg"},{"id":96202099,"identity":"4d772c54-48fe-43eb-81c9-ade8fb049049","added_by":"auto","created_at":"2025-11-18 16:39:10","extension":"jpeg","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":196995,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/5f7fb1873cd32c6f07411383.jpeg"},{"id":96202102,"identity":"dddbca95-334a-48fe-ad5b-6e8b773c615c","added_by":"auto","created_at":"2025-11-18 16:39:11","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112537,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/f7c386baab346ea8f1a3bdcf.png"},{"id":96202134,"identity":"f2d1494c-5b30-48dc-934c-37067f129103","added_by":"auto","created_at":"2025-11-18 16:39:14","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":68652,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/cbef6350be8ffd547cb54de2.png"},{"id":96202135,"identity":"c518ec4d-8dac-4709-b80b-2010492cf05c","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"png","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":57481,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/e3ecf7268836a4e7a65ff4a0.png"},{"id":96202139,"identity":"3a2a2473-894c-4765-8b6d-5ac77a2c898f","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91655,"visible":true,"origin":"","legend":"","description":"","filename":"d5c1e678758f40ecb7a69a88f28c76921structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/fa641d267326cbc3b2e40d38.xml"},{"id":96202144,"identity":"f182db37-c583-4daf-bcb7-769393a73de3","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":105613,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/92c1a9cd4c5f37efffde6e64.html"},{"id":96202136,"identity":"01c69b73-3cb0-427e-9106-08220181b6ed","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":176695,"visible":true,"origin":"","legend":"\u003cp\u003ePatient flow diagram. CAC, cachexia; non-CAC, non-cachexia; ED-SCLC, extensive-disease small cell lung cancer; PD, progressive disease\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/65e4629f1d81ea481bb82aef.jpeg"},{"id":96202146,"identity":"7606d543-8d0e-46c4-8030-37d309c32306","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":308898,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for progression-free survival (a) and overall survival (b), measured from the start of the third cycle of initial therapy. CAC, cachexia; CI, confidence interval; NA, not applicable; non-CAC, non-cachexia; OS, overall survival; PFS, progression-free survival\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/57f070268cb6a6508b04e992.jpeg"},{"id":96202141,"identity":"0124bee7-8cde-40db-a3bf-fb8940ea51cb","added_by":"auto","created_at":"2025-11-18 16:39:15","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":196995,"visible":true,"origin":"","legend":"\u003cp\u003eFrequency of CTCAE grade ≥2 anorexia (A) and nausea or vomiting (B) during the first and second cycles of treatment. Differences between groups were evaluated using Fisher’s exact test. CAC, cachexia; CTCAE, Common Terminology Criteria for Adverse Events; non-CAC, non-cachexia\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/34c1c68c4da20d92eff7187f.jpeg"},{"id":96256930,"identity":"b363df6e-a77e-4558-a1f5-b18ff8a5e9fa","added_by":"auto","created_at":"2025-11-19 07:50:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1596297,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/47d1658e-39ce-4010-8073-01362b2d29db.pdf"},{"id":96252065,"identity":"87216dcb-9a06-4a58-8c75-e32c28ab0e18","added_by":"auto","created_at":"2025-11-19 07:40:24","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":35584,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryImformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-8002341/v1/25f471471c1f1bc761090b6c.docx"}],"financialInterests":"Competing interest reported. Dr. Fujisaki reported receiving honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Kyowa Kirin, outside the submitted work. Dr. Naito reported receiving honoraria from ONO Pharmaceutical CO. Ltd and Tsumura \u0026 Co.; consulting fees from Pfizer Inc., Tensegrity Pharma, Inc., AstraZeneca K.K., Taiho Pharmaceutical Co. Ltd.; grands from Otsuka Pharmaceutical CO. Ltd., Kracie, Ltd., all outside the submitted work. Dr. Kataoka reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Saito reported receiving honoraria from AstraZeneca, outside the submitted work. Dr. Matsuda reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Kobayashi reported receiving honoraria from Eli Lilly K.K, Novartis Pharma K.K., Taiho Pharmaceutical Co.,LTD., AstraZeneca, Chugai Pharmaceutical Co.,LTD., Ono Pharmaceutical Co.,LTD., Bristol-Myers Squibb Company, and DAIICHI SANKYO COMPANY, outside the submitted work. Dr. Ko reported receiving honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, and Janssen Pharmaceutical; and grants from MSD, AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Nuvalent, Amgen, Novocure, and Daiichi Sankyo, all outside the submitted work. Dr. Wakuda reported receiving honoraria from Chugai Pharmaceutical Co.,Ltd, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K, Ono Pharmaceutical, MSD, Astrazeneca, Daiichi Sankyo, Janssen Pharmaceutical K.K., Takeda Pharmaceutical, Nihon Kayaku, and AMGEN; and grants from Chugai Pharmaceutical Co.,Ltd, AstraZeneca, Novartis, Abbvie, AMGEN, MSD, Daiichi Sankyo, Dizal Pharma, and Pfizer, all outside the submitted work. Dr. Ono reported receiving honoraria from Astrazeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical, Janssen Research \u0026 Development, Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharmaceuticals, and Taiho Pharmaceuticals, outside the submitted work. Dr. Murakami reported receiving honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, and Amgen; consulting fees from Chugai Pharmaceutical, GAIA BioMedicine, and Daiichi Sankyo; and research funding from AstraZeneca, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Bayer, Eli Lilly, Taiho Pharmaceutical, and Pfizer, all outside the submitted work. Dr. Takahashi reported receiving honoraria from AstraZeneca KK, Chugai PHARMACEUTICAL CO., LTD, MSD K.K., Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Pfizer Japan Inc., DAIICHI SANKYO CO., LTD, Amgen K.K., BMS Japan., TAIHO PHARMACEUTICAL CO., LTD, Takeda PHARMACEUTICAL CO LTD., ONO PHARMACEUTICAL CO., LTD., and Takeda PHARMACEUTICAL CO LTD.; and grants from AstraZeneca KK, MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., and AnHeart Therapeutics Inc., all outside the submitted work. Dr. Kenmotsu reported receiving honoraria from Amgen inc., AstraZeneca K.K., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Merck, MSD, Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Pfizer, Taiho Pharma, Takeda Pharmaceutical Co., Ltd, Janssen Pharmaceutical K.K., Thermo Fisher Scientific Inc., and Guardant; and grants from Ono Pharmaceutical Co, Ltd., Novartis Pharma K.K., Eli Lilly K.K, AstraZeneca K.K., and Loxo Oncology, all outside the submitted work. No other disclosures were reported.","formattedTitle":"Prognostic Impact of Weight Loss During First-Line Chemotherapy in Patients with Extensive-Disease Small Cell Lung Cancer","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCancer cachexia (CAC) is a multifactorial syndrome characterized by ongoing skeletal muscle loss, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to functional decline. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The presence of cancer cachexia before starting treatment has been linked to reduced survival, increased toxicities, and poorer quality of life [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], highlighting the importance of its early detection and management. In recent years, accumulating evidence has supported the efficacy of pharmacological agents for cancer cachexia [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], leading to increased clinical research efforts aimed at establishing effective supportive care strategies.\u003c/p\u003e\u003cp\u003eConversely, the prognostic significance of weight loss during anti-cancer treatment remains uncertain. Although several studies have indicated that weight loss during therapy is associated with unfavorable outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], its prognostic significance may differ according to baseline cachexia status, which has rarely been evaluated.\u003c/p\u003e\u003cp\u003eSmall cell lung cancer (SCLC) is a highly aggressive malignancy, and the presence of cachexia at the commencement of treatment has been associated with a poor prognosis. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Platinum-based chemo(immuno)therapy, the standard first-line treatment for extensive-disease SCLC (ED-SCLC), shows a high response rate, but frequently causes gastrointestinal toxicities such as anorexia, nausea, and vomiting, which can lead to weight loss. Nevertheless, the prognostic significance of weight loss during chemotherapy in ED-SCLC remains unclear.\u003c/p\u003e\u003cp\u003eTherefore, in this retrospective study, we aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with ED-SCLC, stratified by cachexia status at chemotherapy initiation. We also assessed the association between weight loss and gastrointestinal toxicities, including anorexia and nausea or vomiting, during two cycles of first-line chemotherapy.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study Design and Patients\u003c/h2\u003e\u003cp\u003eThis was a single-center, retrospective cohort study conducted at Shizuoka Cancer Center, Japan. We included patients with ED-SCLC who received platinum-based chemotherapy, with or without immune checkpoint inhibitors, as first-line treatment between July 2009 and December 2021. Eligible patients were required to meet all of the following criteria: (1) no evidence of progressive disease after completion of the first two cycles of initial chemotherapy, (2) received at least three cycles of initial chemotherapy, and (3) availability of body weight data at the following three time points: 6 months before the start of initial chemotherapy, at the start of the first and third cycle of initial chemotherapy. The patients were classified according to the following two indicators of weight loss:\u003c/p\u003e\u003cp\u003e(A) Pretreatment weight loss\u003c/p\u003e\u003cp\u003eAt the start of the first cycle of chemotherapy, the presence (CAC) or absence (non-CAC) of weitghtloss within 6 months,\u003c/p\u003e\u003cp\u003e(B) Posttreatment weight loss\u003c/p\u003e\u003cp\u003eAt the start of the third cycle of chemotherapy, the presence (CAC) or absence (non-CAC) of weight loss from the beginning of the initial chemotherapy.\u003c/p\u003e\u003cp\u003eWe divided patients into the following four groups based on their weight change from (A) to (B):\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eGroup 1. non-CAC to non-CAC group: those without weight loss both before and during chemotherapy,\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGroup 2. non-CAC to CAC group: those without weight loss before but with weight loss during chemotherapy,\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGroup 3. CAC to non-CAC group: those with weight loss before but not during chemotherapy,\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eGroup 4. CAC to CAC group: those with weight loss both before and during chemotherapy.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eIn (A), pretreatment weight loss (cachexia) was defined according to the criteria proposed by Fearon et al., which defines cachexia as weight loss of \u0026gt;\u0026thinsp;5%, or \u0026gt;\u0026thinsp;2% with a BMI\u0026thinsp;\u0026lt;\u0026thinsp;20 kg/m\u0026sup2;, within 6 months. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] In (B), posttreatment weight loss was defined as weight loss of \u0026ge;\u0026thinsp;2% from the start of initial chemotherapy to the beginning of the third cycle (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The non-CAC to non-CAC group (group 1) was designated as the non-weight-loss group, while the remaining three groups (group2, 3, and 4) were categorized as the weight-loss groups.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClassification of patients according to weight loss before and during initial chemotherapy\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(A) Pretreatment weight loss\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(B) Posttreatment weight loss\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1. non-CAC to non-CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2. non-CAC to CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3. CAC to non-CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAbsent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4. CAC to CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePresent\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003e\u0026ldquo;Pretreatment weight loss\u0026rdquo; was defined as cachexia at the start of initial chemotherapy, according to the criteria of Fearon et al. (weight loss\u0026thinsp;\u0026gt;\u0026thinsp;5%, or \u0026gt;\u0026thinsp;2% with BMI\u0026thinsp;\u0026lt;\u0026thinsp;20 kg/m\u0026sup2;, within 6 months).\u003c/p\u003e\u003cp\u003e\u0026ldquo;Posttreatment weight loss\u0026rdquo; was defined as \u0026ge;\u0026thinsp;2% weight loss from the start of initial chemotherapy to the beginning of the third cycle.\u003c/p\u003e\u003cp\u003eAbbreviations: CAC, cachexia; non-CAC, non-cachexia.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data Collection and Study Assessment\u003c/h2\u003e\u003cp\u003eWe collected the following data retrospectively from all patients: age, sex, Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking history, clinical stage (based on the TNM Classification of Malignant Tumors, 9th edition), laboratory findings, body weight at each time point, and treatment information for initial and subsequent therapies. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Outcomes\u003c/h2\u003e\u003cp\u003eThe primary endpoints were progression-free survival (PFS) and overall survival (OS), both measured from the start of the third cycle of initial chemotherapy. PFS was defined as the time from the third cycle initiation to disease progression or death from any cause, whichever occurred first. OS was defined as the time from the third cycle initiation to death from any cause. Secondary endpoints were the frequency and severity of adverse events (AEs) during the first two cycles of initial chemotherapy, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Particular attention was given to anorexia, nausea, and vomiting as gastrointestinal toxicities.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eCategorical variables were compared using Fisher\u0026rsquo;s exact test, and continuous variables were compared using the Kruskal-Wallis test. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PFS and OS were estimated using univariate and multivariate Cox proportional hazards models. All statistical analyses were performed with EZR version 1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Two-sided p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Ethics\u003c/h2\u003e\u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The study protocol was approved by the institutional review board of Shizuoka Cancer Center (approval number: J2024-123-2024-1-2). Informed consent was waivered due to the retrospective nature of the study, and an opt-out approach was employed on the institutional website.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Patient characteristics\u003c/h2\u003e\u003cp\u003eAmong 346 patients with ED-SCLC who received first-line platinum-based chemo(immuno)therapy during the study period, 148 were excluded due to missing weight data at any of the three time points, 6 due to treatment discontinuation within two cycles, and 5 due to progressive disease as the best response. A total of 187 patients were included in the analysis: 75 in the non-CAC to non-CAC group, 34 in the non-CAC to CAC group, 46 in the CAC to non-CAC group, and 32 in the CAC to CAC group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There were significant differences among the four groups in ECOG-PS, serum CRP levels, serum albumin levels, and Modified Glasgow Prognostic Score (mGPS). However, age, sex, and the proportion of Immune checkpoint inhibitor (ICI)-based regimens were not significantly different. Although no statistically significant difference in clinical stage distribution was observed among the four groups, the non-CAC to non-CAC group tended to have fewer patients with stage IVB. The median percentage change in body weight from the initiation of the first cycle to the initiation of the third cycle was +\u0026thinsp;1.1%, \u0026minus;\u0026thinsp;5.1%, +\u0026thinsp;2.1%, and \u0026minus;\u0026thinsp;4.9% in the non-CAC to non-CAC, non-CAC to CAC, CAC to non-CAC, and CAC to CAC groups, respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Carboplatin plus etoposide with atezolizumab was the most frequent ICI-based regimen (22/187, 12%), while among non-ICI-based regimens, carboplatin plus etoposide predominated (96/187, 51%), followed by cisplatin plus irinotecan (29/187, 16%) and cisplatin plus etoposide (23/187, 12%) (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient Characteristics at the Third Cycle Initiation of Initial Chemo(immuno)therapy\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical feature\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;187)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003enon-CAC to non-CAC\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003enon-CAC to CAC\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCAC to non-CAC\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;46)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCAC to CAC\u003c/p\u003e\u003cp\u003e(N\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003csup\u003ea, b\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, median (range), years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70 (50\u0026ndash;89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e69 (50\u0026ndash;87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72 (54\u0026ndash;84)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e69 (51\u0026ndash;89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e70 (57\u0026ndash;81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.27\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.94\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e153 (82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e62 (83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28 (82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e38 (83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25 (78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG-PS, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u0026ndash;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e163 (87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70 (93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30 (88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e39 (85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e23 (74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.046\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7 (15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical Stage*, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIIIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.073\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIVA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59 (32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32 (43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIVB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127 (68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e42 (56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24 (71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36 (78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25 (78)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFirst line treatment, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatinum combination plus ICI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (14)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4 (13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.49\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatinum combination only\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e161 (86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e64 (85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27 (79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e42 (91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e28 (88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDistant metastasis*, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBrain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59 (32)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e17 (37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.57\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61 (33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e16 (35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 (38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.52\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum CRP, mg/dL, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003cp\u003e(0.02 to 20.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003cp\u003e(0.02 to 5.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003cp\u003e(0.03 to 6.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003cp\u003e(0.02 to 3.43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003cp\u003e(0.02 to 20.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.011\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum albumin, g/dL, median (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.9\u003c/p\u003e\u003cp\u003e(2.3 to 4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003cp\u003e(2.4 to 4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.85\u003c/p\u003e\u003cp\u003e(3.3 to 4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.9\u003c/p\u003e\u003cp\u003e(2.6 to 4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.7\u003c/p\u003e\u003cp\u003e(2.3 to 4.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.036\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emGPS, n (%)\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e149 (80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65 (87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e25 (74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e38 (83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e21 (66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.049\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5 (16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3 (7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6 (19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight change, %, median (range) \u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.3\u003c/p\u003e\u003cp\u003e(-17.9 to 16.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e+\u0026thinsp;1.1\u003c/p\u003e\u003cp\u003e(-1.9 to 15.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-5.1\u003c/p\u003e\u003cp\u003e(-10.5 to -2.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e+\u0026thinsp;2.1\u003c/p\u003e\u003cp\u003e(-1.6 to 16.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-4.9\u003c/p\u003e\u003cp\u003e(-17.9 to -2.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e\u003cp\u003eDifferences between groups were identified using \u003csup\u003ea\u003c/sup\u003eKruskal-Wallis test, \u003csup\u003eb\u003c/sup\u003eFisher\u0026rsquo;s exact test.\u003c/p\u003e\u003cp\u003eAbbreviations: CAC, Cachexia; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; ICI, Immune checkpoint inhibitor; mGPS, Modified Glasgow Prognostic Score; non-CAC, non-Cachexia; PS, performance status.\u003c/p\u003e\u003cp\u003e* Assessed at diagnosis.\u003c/p\u003e\u003cp\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e Three patients in non-CAC to non-CAC group whose mGPS were unknown were not included in statistical comparison.\u003c/p\u003e\u003cp\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e From first to third cycle initiation.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Treatment outcomes\u003c/h2\u003e\u003cp\u003eBest overall response to initial chemotherapy did not differ significantly among the four groups (Table S2). Median PFS, measured from the start of the third cycle of initial chemotherapy, was not significantly different among the groups (log-rank p\u0026thinsp;=\u0026thinsp;0.062; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). In contrast, median OS, also measured from the start of the third cycle of initial chemotherapy, differed significantly (log-rank p\u0026thinsp;=\u0026thinsp;0.020), with the non-CAC to non-CAC group (non-weight-loss group) showing the most favorable survival (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Multivariate analysis, adjusted for ECOG-PS, clinical stage, age, and mGPS, confirmed that OS was significantly longer in the non-CAC to non-CAC group compared with the other groups (non-CAC to CAC: HR 1.65, 95% CI 1.08\u0026ndash;2.53, p\u0026thinsp;=\u0026thinsp;0.020; CAC to non-CAC: HR 1.51, 95% CI 1.00\u0026ndash;2.29, p\u0026thinsp;=\u0026thinsp;0.050; CAC to CAC: HR 1.62, 95% CI 1.01\u0026ndash;2.60, p\u0026thinsp;=\u0026thinsp;0.047), consistent with the results of univariate analysis (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Among patients with cachexia at the start of the initial chemotherapy (CAC to CAC and CAC to non-CAC groups), OS did not differ significantly between those who experienced weight loss during chemotherapy and those who did not (HR 0.83, 95% CI 0.51\u0026ndash;1.35; p\u0026thinsp;=\u0026thinsp;0.445; data not shown).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCox Proportional Hazards Model for Overall Survival (Reference: non-CAC to non-CAC)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnivariate Analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMultivariate Analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enon-CAC to non-CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00 (Ref)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00 (Ref)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enon-CAC to CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.77 (1.16 to 2.69)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.65 (1.08 to 2.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.020\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCAC to non-CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.74 (1.17 to 2.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.51 (1.00 to 2.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCAC to CAC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.00 (1.29 to 3.11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.62 (1.01 to 2.60)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e\u003cp\u003eMultivariate analysis was adjusted for ECOG\u0026shy;PS (0\u0026ndash;1 vs. 2\u0026ndash;3), clinical stage (IIIC and IVA vs. IVB), age (\u0026lt;\u0026thinsp;75 vs. \u0026ge;75), and mGPS (0 vs. 1\u0026ndash;2).\u003c/p\u003e\u003cp\u003eAbbreviations: CAC, cachexia; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; non-CAC, non-cachexia; OS, overall survival; PS, performance status.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Adverse events\u003c/h2\u003e\u003cp\u003eWe summarized the frequency of AEs during the first two cycles of chemotherapy in Table S3. Significant between-group differences were observed in the incidence of hyponatremia and anemia (any grade), as well as leukopenia, anemia, anorexia, and nausea (\u0026ge;\u0026thinsp;grade 3). With respect to gastrointestinal toxicities, grade\u0026thinsp;\u0026ge;\u0026thinsp;2 anorexia and nausea or vomiting occurred more frequently and with greater severity in all groups other than the non-CAC to non-CAC group (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea,b).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Exploratory analysis\u003c/h2\u003e\u003cp\u003eAs shown in Table S4, the frequency of treatment-related death during initial chemotherapy did not differ significantly among the groups (p\u0026thinsp;=\u0026thinsp;0.084), although it was lower in the non-CAC to non-CAC (1%) and non-CAC to CAC (0%) groups than in the CAC to non-CAC (4%) and CAC to CAC (9%) groups. The completion rate of four cycles of initial chemotherapy was also not significantly different among the groups (p\u0026thinsp;=\u0026thinsp;0.062), but tended to be higher in the non-CAC to non-CAC (96%) and CAC to non-CAC (96%) groups compared with the non-CAC to CAC (85%) and CAC to CAC (84%) groups. Similarly, the use of subsequent chemotherapy did not differ significantly among the groups (p\u0026thinsp;=\u0026thinsp;0.193), but was more common in the non-CAC to non-CAC group (80%) than in the non-CAC to CAC (65%), CAC to non-CAC (67%), and CAC to CAC (63%) groups.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eWe investigated the prognostic impact of weight loss developed during first-line chemotherapy in patients with ED-SCLC. The finding is that patients in the non-weight-loss group (non-CAC to non-CAC) had significantly longer OS than those in the weight-loss groups (non-CAC to CAC, CAC to non-CAC, and CAC to CAC), and they were less likely to experience anorexia, nausea, and vomiting during the first two cycles of chemotherapy.\u003c/p\u003e\u003cp\u003e To the best of our knowledge, this is the first study in ED-SCLC to stratify patients according to cachexia status at chemotherapy initiation and examine the prognostic impact of weight loss developed during first-line chemotherapy. We have previously reported that the presence of cachexia, either before or after initial chemotherapy, was associated with a shorter OS in patients with advanced non-small cell lung cancer (NSCLC). [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] In Japanese patients with SCLC, those who had experienced weight loss before first-line chemotherapy had a lower response rate and tended to have a shorter OS. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] Notably, our findings suggest that even in patients without cachexia at the time of chemotherapy initiation, the development of weight loss during chemotherapy may shorten OS. This suggest that preventing weight loss during chemotherapy may be clinically important in this population. In our study, among patients with cachexia at treatment initiation, no significant improvement in OS was observed even if further weight loss during chemotherapy did not occur. However, a previous study in advanced NSCLC has shown that weight gain during treatment is associated with improved prognosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], suggesting a possible survival benefit if weight gain can be achieved even in patients with cachexia.\u003c/p\u003e\u003cp\u003ePatients in the non-weight-loss group exhibited a reduced frequency and severity of gastrointestinal toxicities, including anorexia and nausea or vomiting, during the two cycles of initial chemotherapy. We have previously reported, in a retrospective study of patients with NSCLC, that chemotherapy-induced anorexia was associated with both weight loss and reduced therapeutic efficacy. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Taken together, our findings suggest that, also in ED-SCLC, appropriate management of gastrointestinal toxicities during chemotherapy may help reduce weight loss and potentially contribute to improved survival outcomes.\u003c/p\u003e\u003cp\u003eRecent advances in supportive pharmacological agents indicate the possibility of preventing weight loss, and potentially achieving weight gain, in patients undergoing anti-cancer treatment. Olanzapine has demonstrated efficacy in the treatment of chemotherapy-induced nausea and vomiting [\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and has also been associated with the stimulation of appetite and the occurrence of weight gain. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] The American Society of Clinical Oncology (ASCO) guideline recommends low-dose olanzapine for adults with advanced cancer to improve appetite and promote weight gain. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Anamorelin, a selective ghrelin receptor agonist, significantly increased lean body mass in patients with advanced NSCLC and cachexia in phase 3 trials. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Ponsegromab, an anti\u0026ndash;growth differentiation factor 15 (GDF-15) antibody targeting a cytokine implicated in cancer-related anorexia and weight loss, improved body weight, activity, and anorexia-related symptoms in patients with cancer cachexia in a phase II trial. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Preclinical studies have reported that GDF-15 contributes to platinum-based chemotherapy\u0026ndash;induced cachexia and that its blockade may promote weight gain. [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] In patients who have not experienced weight loss at the time of treatment initiation, these agents and appropriate management of gastrointestinal toxicities may help prevent weight loss during treatment and improve survival outcomes. The present findings support the implementation of prospective trials to confirm their efficacy, which may also benefit patients with cachexia at the treatment initiation.\u003c/p\u003e\u003cp\u003eOur study has several limitations. First, this was a retrospective study with a limited sample size, which may have reduced statistical power, and the impact of potential biases and unmeasured confounders cannot be ruled out. Second, as this was a single-institution study, the generalizability of our findings is limited and requires validation in other settings. Third, we were unable to determine the exact causes of weight loss, which may have included not only treatment-related toxicities but also psychological factors, comorbid conditions, and other contributors. Fourth, because measures of body composition (muscle and fat mass) and validated nutritional assessment tools were not available, detailed evaluation of lean body mass, sarcopenia, and malnutrition was not possible. Finally, although we graded AEs according to CTCAE criteria, the assessment of gastrointestinal toxicities was based on subjective observations from medical records, which limits our ability to validate agreement or reproducibility with patient-reported outcomes.\u003c/p\u003e\u003cp\u003eIn conclusion, among patients with ED-SCLC who received first-line platinum-based chemo(immuno)therapy, those who did not experience weight loss before and during chemotherapy (non-weight-loss group) had a significantly longer OS and a lower incidence of anorexia and nausea or vomiting during chemotherapy compared with those who experienced weight loss before or during chemotherapy (weight-loss group). These results potentially underscore the importance of appropriate management of anorexia and nausea or vomiting during chemotherapy, particularly in patients who have not experienced weight loss before chemotherapy initiation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThis research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors. The authors thank the patients, their families, and all study investigators who contributed to the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eToshiya Fujisaki\u003c/strong\u003e: Conceptualization, Methodology, Formal Analysis, Investigation, Data Curation, Writing\u0026ndash;Original Draft Preparation, Visualization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTateaki Naito\u003c/strong\u003e: Conceptualization, Methodology, Writing\u0026ndash;review and Editing, Supervision, Project Administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSatomi Kumaki, Shunichi Kataoka, Shin Saito, Suguru Matsuda, Haruki Kobayashi, Ryo Ko, Kazushige Wakuda, Akira Ono, Haruyasu Murakami, Toshiaki Takahashi, Hirotsugu Kenmotsu\u003c/strong\u003e: Conceptualization, and Writing\u0026ndash;Review and Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Fujisaki reported receiving honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, and Kyowa Kirin, outside the submitted work. Dr. Naito reported receiving honoraria from ONO Pharmaceutical CO. Ltd and Tsumura \u0026amp; Co.; consulting fees from Pfizer Inc., Tensegrity Pharma, Inc., AstraZeneca K.K., Taiho Pharmaceutical Co. Ltd.; grands from Otsuka Pharmaceutical CO. Ltd., Kracie, Ltd., all outside the submitted work. Dr. Kataoka reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Saito reported receiving honoraria from AstraZeneca, outside the submitted work. Dr. Matsuda reported receiving honoraria from Chugai PHARMACEUTICAL CO., LTD, outside the submitted work. Dr. Kobayashi reported receiving honoraria from Eli Lilly K.K, Novartis Pharma K.K., Taiho Pharmaceutical Co.,LTD., AstraZeneca, Chugai Pharmaceutical Co.,LTD., Ono Pharmaceutical Co.,LTD., Bristol-Myers Squibb Company, and DAIICHI SANKYO COMPANY, outside the submitted work. Dr. Ko reported receiving honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Daiichi Sankyo, MSD, Bristol-Myers Squibb, Takeda Pharmaceutical, and Janssen Pharmaceutical; and grants from MSD, AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Nuvalent, Amgen, Novocure, and Daiichi Sankyo, all outside the submitted work. Dr. Wakuda reported receiving honoraria from Chugai Pharmaceutical Co.,Ltd, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly K.K, Ono Pharmaceutical, MSD, Astrazeneca, Daiichi Sankyo, Janssen Pharmaceutical K.K., Takeda Pharmaceutical, Nihon Kayaku, and AMGEN; and grants from Chugai Pharmaceutical Co.,Ltd, AstraZeneca, Novartis, Abbvie, AMGEN, MSD, Daiichi Sankyo, Dizal Pharma, and Pfizer, all outside the submitted work. Dr. Ono reported receiving honoraria from Astrazeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical, Janssen Research \u0026amp; Development, Kyowa Kirin, MSD, Nippon Kayaku, Ono Pharmaceuticals, and Taiho Pharmaceuticals, outside the submitted work. Dr. Murakami reported receiving honoraria from Chugai Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Eli Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Takeda Pharmaceutical, Novartis, Daiichi Sankyo, and Amgen; consulting fees from Chugai Pharmaceutical, GAIA BioMedicine, and Daiichi Sankyo; and research funding from AstraZeneca, AbbVie, Daiichi Sankyo, Chugai Pharmaceutical, Bayer, Eli Lilly, Taiho Pharmaceutical, and Pfizer, all outside the submitted work. Dr. Takahashi reported receiving honoraria from AstraZeneca KK, Chugai PHARMACEUTICAL CO., LTD, MSD K.K., Janssen Pharmaceutical K.K., Eli Lilly Japan K.K., Pfizer Japan Inc., DAIICHI SANKYO CO., LTD, Amgen K.K., BMS Japan., TAIHO PHARMACEUTICAL CO., LTD, Takeda PHARMACEUTICAL CO LTD., ONO PHARMACEUTICAL CO., LTD., and Takeda PHARMACEUTICAL CO LTD.; and grants from AstraZeneca KK, MSD K.K., Janssen Pharmaceutical K.K., Amgen K.K., and AnHeart Therapeutics Inc., all outside the submitted work. Dr. Kenmotsu reported receiving honoraria from Amgen inc., AstraZeneca K.K., Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical Co, Ltd., Daiichi-Sankyo Co., Ltd., Eli Lilly K.K, Kyowa Hakko Kirin Co., Ltd., Merck, MSD, Novartis Pharma K.K., Ono Pharmaceutical Co, Ltd., Pfizer, Taiho Pharma, Takeda Pharmaceutical Co., Ltd, Janssen Pharmaceutical K.K., Thermo Fisher Scientific Inc., and Guardant; and grants from Ono Pharmaceutical Co, Ltd., Novartis Pharma K.K., Eli Lilly K.K, AstraZeneca K.K., and Loxo Oncology, all outside the submitted work. No other disclosures were reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement:\u003c/strong\u003e The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\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. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(10)70218-7\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(10)70218-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH (2018) Cancer-associated cachexia. Nat Rev Dis Primers 4:17105. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nrdp.2017.105\u003c/span\u003e\u003cspan address=\"10.1038/nrdp.2017.105\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhang J, Tang X, Zhang W, Xu Y, Zhang H, Fan Y (2024) Cancer cachexia as a predictor of adverse outcomes in patients with non-small cell lung cancer: A meta-analysis. Clin Nutr 43:1618\u0026ndash;1625. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clnu.2024.05.025\u003c/span\u003e\u003cspan address=\"10.1016/j.clnu.2024.05.025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYuan L, Li XY, Xu L, Quan SJ, Huang YB, Zheng H (2025) Effects of olanzapine in the improvement of body weight and appetite in patients with cancer or receiving chemotherapy: a systematic review and meta-analysis. Eur J Clin Pharmacol 81:45\u0026ndash;63. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00228-024-03770-x\u003c/span\u003e\u003cspan address=\"10.1007/s00228-024-03770-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTemel JS, Abernethy AP, Currow DC et al (2016) Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol 17:519\u0026ndash;531. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(15)00558-6\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(15)00558-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGroarke JD, Crawford J, Collins SM et al (2024) Ponsegromab for the Treatment of Cancer Cachexia. N Engl J Med 391:2291\u0026ndash;2303. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa2409515\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa2409515\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRyan AM, Prado CM, Sullivan ES, Power DG, Daly LE (2019) Effects of weight loss and sarcopenia on response to chemotherapy, quality of life, and survival. Nutrition 67\u0026ndash;68:110539. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.nut.2019.06.020\u003c/span\u003e\u003cspan address=\"10.1016/j.nut.2019.06.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShukuya T, Takahashi K, Shintani Y et al (2023) Epidemiology, risk factors and impact of cachexia on patient outcome: Results from the Japanese Lung Cancer Registry Study. J Cachexia Sarcopenia Muscle 14:1274\u0026ndash;1285. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/jcsm.13216\u003c/span\u003e\u003cspan address=\"10.1002/jcsm.13216\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452\u0026ndash;458. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/bmt.2012.244\u003c/span\u003e\u003cspan address=\"10.1038/bmt.2012.244\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e(2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Jama 310:2191\u0026ndash;2194. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2013.281053\u003c/span\u003e\u003cspan address=\"10.1001/jama.2013.281053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKimura M, Naito T, Kenmotsu H et al (2015) Prognostic impact of cancer cachexia in patients with advanced non-small cell lung cancer. Support Care Cancer 23:1699\u0026ndash;1708. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00520-014-2534-3\u003c/span\u003e\u003cspan address=\"10.1007/s00520-014-2534-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePatel JD, Pereira JR, Chen J et al (2016) Relationship between efficacy outcomes and weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients. Ann Oncol 27:1612\u0026ndash;1619. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/annonc/mdw211\u003c/span\u003e\u003cspan address=\"10.1093/annonc/mdw211\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDoshita K, Naito T, Matsuda S et al (2024) Exploring the relationship between anorexia and therapeutic efficacy in advanced lung cancer treatment: a retrospective study. Thorac Cancer 15:1831\u0026ndash;1841. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/1759-7714.15403\u003c/span\u003e\u003cspan address=\"10.1111/1759-7714.15403\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBymaster FP, Calligaro DO, Falcone JF et al (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87\u0026ndash;96. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0893-133x(94)00129-n\u003c/span\u003e\u003cspan address=\"10.1016/0893-133x(94)00129-n\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHashimoto H, Abe M, Tokuyama O et al (2020) Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 21:242\u0026ndash;249. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s1470-2045(19)30678-3\u003c/span\u003e\u003cspan address=\"10.1016/s1470-2045(19)30678-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNavari RM (2014) Olanzapine for the prevention and treatment of chronic nausea and chemotherapy-induced nausea and vomiting. Eur J Pharmacol 722:180\u0026ndash;186. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejphar.2013.08.048\u003c/span\u003e\u003cspan address=\"10.1016/j.ejphar.2013.08.048\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNavari RM, Qin R, Ruddy KJ et al (2016) Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. N Engl J Med 375:134\u0026ndash;142. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1056/NEJMoa1515725\u003c/span\u003e\u003cspan address=\"10.1056/NEJMoa1515725\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSakai H, Tsurutani J, Ozaki Y et al (2025) A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B). Ann Oncol 36:31\u0026ndash;42. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.annonc.2024.09.001\u003c/span\u003e\u003cspan address=\"10.1016/j.annonc.2024.09.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIspoglou T, McCullough D, Windle A et al (2024) Addressing cancer anorexia-cachexia in older patients: Potential therapeutic strategies and molecular pathways. Clin Nutr 43:552\u0026ndash;566. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.clnu.2024.01.009\u003c/span\u003e\u003cspan address=\"10.1016/j.clnu.2024.01.009\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoeland EJ, Bohlke K, Baracos VE, Smith TJ, Loprinzi CL (2023) Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol 41:4178\u0026ndash;4179. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/jco.23.01280\u003c/span\u003e\u003cspan address=\"10.1200/jco.23.01280\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGuillory B, Splenser A, Garcia J (2013) The role of ghrelin in anorexia-cachexia syndromes. Vitam Horm 92:61\u0026ndash;106. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/b978-0-12-410473-0.00003-9\u003c/span\u003e\u003cspan address=\"10.1016/b978-0-12-410473-0.00003-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBreit SN, Brown DA, Tsai VW (2021) The GDF15-GFRAL Pathway in Health and Metabolic Disease: Friend or Foe? Annu Rev Physiol 83:127\u0026ndash;151. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1146/annurev-physiol-022020-045449\u003c/span\u003e\u003cspan address=\"10.1146/annurev-physiol-022020-045449\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBreen DM, Kim H, Bennett D et al (2020) GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates. Cell Metab 32:938\u0026ndash;950.e936. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cmet.2020.10.023\u003c/span\u003e\u003cspan address=\"10.1016/j.cmet.2020.10.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Cachexia, Prognosis, Small Cell Lung Carcinoma, Weight loss","lastPublishedDoi":"10.21203/rs.3.rs-8002341/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8002341/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eThe adverse prognostic impact of cancer cachexia is well recognized. We aimed to evaluate the prognostic impact of weight loss during first-line platinum-based chemo(immuno)therapy in patients with extensive-disease small cell lung cancer (ED-SCLC).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe retrospectively reviewed 187 ED-SCLC patients treated between 2009 and 2021 and collected body weight at three time points: 6 months before, at the start of the first cycle, and at the beginning of the third cycle of initial chemotherapy. Based on pretreatment weight loss (defined by the Fearon criteria) and \u0026ge;\u0026thinsp;2% weight loss during two cycles, we classified patients into four groups: those without weight loss both before and during chemotherapy (n\u0026thinsp;=\u0026thinsp;75) (non-weight-loss group), those without weight loss before but with weight loss during chemotherapy (n\u0026thinsp;=\u0026thinsp;34), those with weight loss before but not during chemotherapy (n\u0026thinsp;=\u0026thinsp;46), and those with weight loss both before and during chemotherapy (n\u0026thinsp;=\u0026thinsp;32). We evaluated survival outcomes and gastrointestinal toxicities during the first two cycles.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eMedian overall survival (OS) differed significantly among the groups (p\u0026thinsp;=\u0026thinsp;0.020), with the non-weight-loss group showing the most favorable survival than the other groups (adjusted hazard ratios, 1.51\u0026ndash;1.65; all p\u0026thinsp;\u0026le;\u0026thinsp;0.05). The non-weight-loss group experienced fewer grade\u0026thinsp;\u0026ge;\u0026thinsp;2 anorexia and nausea/vomiting events during the first two cycles.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eIn patients with ED-SCLC, the absence of weight loss before and during chemotherapy was associated with longer OS and fewer gastrointestinal toxicities, potentially underscoring the importance of appropriate management of gastrointestinal toxicities during chemotherapy, particularly in patients who did not experience weight loss before chemotherapy initiation.\u003c/p\u003e","manuscriptTitle":"Prognostic Impact of Weight Loss During First-Line Chemotherapy in Patients with Extensive-Disease Small Cell Lung Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 16:38:35","doi":"10.21203/rs.3.rs-8002341/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-11T18:59:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T17:26:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T02:43:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T20:53:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3196884846347696421741156794619929544","date":"2026-02-18T14:35:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-18T07:32:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"295320354077251661006966206979963528552","date":"2026-02-18T06:23:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57333181099709909433470810119595147937","date":"2026-02-17T22:29:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"277886868250019643884913715134960708267","date":"2026-02-17T22:01:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-07T15:17:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-07T15:05:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-07T06:30:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-11-01T02:15:25+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3376cc57-245a-4033-94e8-01cf35b6258f","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-21T07:24:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 16:38:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8002341","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8002341","identity":"rs-8002341","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}