Clinical prognosis factor of ramucirumab monotherapy for advanced gastric cancer

Clinical prognosis factor of ramucirumab monotherapy for advanced gastric 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 Clinical prognosis factor of ramucirumab monotherapy for advanced gastric cancer Yoshinori Kikuchi, Sakae Nagaoka, Nobue Futawatari, Muneharu Fujisaki, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6902358/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted 12 You are reading this latest preprint version Abstract Background: The REGARD trial resulted in insurance approval for ramucirumab monotherapy, but it did not include Japanese patients. Since then, phase II trials and retrospective studies in Japanese patients have been published, but there have been few reports on prognostic factors. Methods : A total of 27 patients received ramucirumab monotherapy as a second-line treatment for gastric cancer at six institutions from September 2017 to December 2019. Results: The response rate was 3.7%, the disease control rate was 18.5%, the median progression-free survival time was 2.1 months, and the median survival time was 3.0 months. Six of the 27 patients received a 3rd line therapy, while 4 received nivolumab alone. Overall survival did not differ significantly between patients who received third-line treatment and those who did not. Survival curves showed no significant differences based on tumor markers (CEA and CA19-9), age, histology, lung metastasis, lymph node metastasis, or peritoneal metastasis; however, liver metastasis was a poor prognostic factor. Conclusions: Ramucirumab monotherapy was linked to a poor prognosis in older patients with gastric cancer who had a poor performance status, with liver metastasis being suggested as a poor prognostic factor. gastric cancer ramucirumab monotherapy prognostic factor Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Gastric cancer is the fourth leading cause of cancer-related deaths worldwide, with a median survival time of less than a year in advanced cases [ 1 ]. Ramucirumab (RAM) plus solvent-based paclitaxel or RAM plus nanoparticle albumin-bound paclitaxel are the most commonly used second-line treatments for gastric cancer [ 2 , 3 ]. RAM monotherapy is a second-line treatment option according to the REGARD trial [ 4 ]. However, RAM monotherapy is frequently chosen for patients who cannot use taxanes for medical reasons or whose performance status is poor, and because the number of patients is small, it has not been thoroughly studied. In this multi-institutional study, we looked at the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with unresectable advanced gastric cancer, performance status 1–2, and poor general condition who were treated with RAM monotherapy. Patients and Methods Patients By reviewing medical records from six hospitals (i.e., Toho University Omori Medical Center, Japanese Red Cross Medical Center, Toho University Ohashi Medical Center, The Jikei University Hospital, National Hospital Organization Tokyo Medical Center, and NTT Medical Center Tokyo) between September 2017 and December 2019, we retrospectively collected 27 cases. Every patient had a performance level of 1–2. As a second-line treatment, patients were given RAM (8 mg/kg) every two weeks. Evaluation of efficacy and statistical analysis Each hospital had one doctor in charge who determined the effect of the images using the RECIST guidelines (ver. 1.1) [ 5 ]. PFS and OS were calculated using Kaplan–Meier curves as the time between the start of RAM treatment and the time of confirmed disease progression or death. Differences in prognosis and survival were assessed using log-rank tests. All statistical analyses were carried out using EZR Ver.1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 6 ]. P-values of < 0.05 were used to indicate statistical significance. Results Patients’ characteristics and Response rate The median age of all patients (n = 27) was 74 years (36–90); 10 were younger than 70 years and 17 were older than 70 years. There were 18 men and 9 women. The HER2 status was HER2 3+, 2+, 1+, 0, and unknown in four, two, eight, eight, and five cases, respectively. Six patients were positive for liver metastasis, while 21 were negative. Lung metastases were positive in three cases but negative in 24. Lymph node metastases were positive in 18 cases but negative in nine. Peritoneal metastases were found in 14 cases and were negative in 13. Fourteen patients had CEA levels < 5 ng/ml, while 13 had levels ≥ 5 ng/ml. Twelve patients had CA19-9 levels < 37 U/ml, while 15 had levels of 37 U/ml. 21 patients received no third-line treatment, while six patients received third-line treatment. nivolumab in four cases and SOX in two cases. (Table 1 ) The response rate was 0 for complete response, 1 for partial response (3.7%), 4 for stable disease (14.8%), 15 for progressive disease (55.6%), and 7 for not being evaluated (25.9%). The overall response rate was 3.7%, while disease control was 18.5% (Table 1 ). Progression-free survival and overall survival rate The median progression-free survival (PFS) of the 27 patients was 2.1 months (Fig. 1 a), while the median overall survival (OS) was 3.0 months (Fig. 1 b). A comparison of OS with and without a 3rd line revealed a median OS of 9.1 months with a 3rd line versus 2.6 months without a 3rd line, but no significant difference between the two groups (Fig. 2 a, P = 0.264). A bar graph depicts the PFS and OS of 6 patients with the 3rd line. No features were found, especially in the groups treated with immune checkpoint inhibitors or chemotherapy (Fig. 2 b). The median PFS by tumor marker was 2.7 months in the CEA < 10 ng/ml group and 1.8 months in the CEA ≥ 10 ng/ml group, with little distinction between the two groups (Fig. 3 a, P = 0.654). The median PFS in the CA19-9 < 37U/ml group was 1.5 months, while the CA19-9 ≥ 37U/ml group was 3.0 months, with no significant difference between the two groups (Fig. 3 b, P = 0.698). The median PFS was 3.8 months for patients under 70 and 1.6 months for those over 70, with no significant difference between the two groups. However, the < 70 years age group indicated a trend toward longer PFS than the ≥ 70 years age group (Fig. 4 a, P = 0.06). The median PFS was 2.4 months in the intestinal type and 2.1 months in the diffuse type, with no considerable difference between the two groups (Fig. 4 b, P = 0.276) According to the comparison of PFS for each metastasis, the median PFS for liver metastasis was 1.5 months in the positive group and 3.0 months in the negative group. The negative group had a significantly longer PFS (Fig. 5 a, P < 0.001). The median PFS in the lung metastasis-positive group was 1.5 months, and the median PFS in the negative group was 2.4 months, with no significant difference between the two groups (Fig. 5 b, P = 0.554). The median PFS in the lymph node-positive group was 2.0 months, while in the lymph node-negative group it was 2.6 months, with no great difference between them (Fig. 5 c, P = 0.27). The median PFS for the positive peritoneal metastasis group was 1.9 months, while the median PFS for the negative group was 2.8 months, with no significant difference between the two groups (Fig. 5 d, P = 0.89). Multivariate analysis in PFS and OS A multivariate analysis of PFS was conducted, with liver metastasis and age as covariates. The findings revealed that the liver metastasis-positive group was an independent factor, with a hazard rate (HR) of 5.179 (95% CI: 1.624–16.51, P = 0.0054). The HR for patients aged ≥ 70 years was 1.309 (95% CI, 0.576–2.971; P = 0.5205), and was not an independent factor. Multivariate analysis of OS was performed using liver metastasis and 3rd line status as tabulated variables. The HR of 3.162 (95% CI: 1.078–9.276, P = 0.0361) in the group with positive liver metastasis was an independent factor, whereas the HR of 0.545 (95% CI: 0.210–1.42, P = 0.2124) in the group with 3rd line was not an independent factor (Fig. 6 ). Discussion We studied 27 patients who received RAM monotherapy as second-line treatment for gastric cancer. The findings indicated a very poor prognosis, with a median PFS of 2.1 months and a median OS of 3.0 months. Liver metastasis was an independent negative prognostic factor for PFS and OS.RAM, a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) to treat cancer [ 7 ].In Japan, it is recognized as an effective treatment for gastric, colorectal, non-small cell lung, and liver cancers with AFP levels of 400 ng/ml or higher [ 3 , 4 , 8 – 12 ]. RAM monotherapy is indicated for two diseases: gastric cancer and liver cancer (AFP > 400ng/ml). The response rate for RAM monotherapy (n = 238) in the REGARD trial was 3%, the DCR was 49%, the median PFS was 2.1 months, and the median OS was 5.2 months [ 4 ]. However, because the REGARD trial did not include Japanese patients, Yamaguchi et al. conducted a phase 2 study in Japanese patients, which found a response rate of 0%, DCR of 30.6%, median PFS of 6.6 weeks, and median OS of 8.6 months for RAM monotherapy (n = 36) [ 13 ]. Our results showed similarcomparable PFS, but inferior OS. The reason for this is that the median age in the REGARD study was 60 years, in the Yamaguchi et al. study was 66.5 years, and in our study was 74 years, all of which are quite old. Our study was retrospective in a general clinical setting and was most likely conducted on patients in poor general condition who could not receive taxanes; 21 of 27 patients (77.8%) were not chosen for the third-line treatment, and four of six patients in the third-line treatment were treated with nivolumab alone, implying that the patients in the study had very poor PS. It is well known that immune checkpoint inhibitors are less efficient in patients with poor PS. A meta-analysis in the field of lung cancer reported that patients with PS ≥ 2 had half the efficacy of those with PS 0–1[ 14 ]. According to our findings, it does not appear that nivolumab significantly extends OS versus SOX when comparing the two patients treated with SOX to the four patients treated with nivolumab. However, further investigation is required given the small number of cases. According to a subanalysis of the RAISE trial on colorectal cancer, Yoshino et al. found that patients with CEA ≤ 10ng/ml may benefit from this therapy [ 15 ]. As a result, we compared PFS with CEA and CA19-9 in gastric cancer and found no difference, particularly in tumor markers. When PFS was compared by the factor, patients under 70 years of age had a longer PFS, though the difference was not statistically significant when compared to patients over 70 years old. Liver metastases significantly decreased PFS. As a result, a multivariate analysis of PFS and OS with or without liver metastases, age, and third-line status as explanatory variables revealed that liver metastases were a poor prognostic factor for PFS and OS. Our findings are supported by a subanalysis of the REGARD and RAINBOW trials, which found no effect of ramcirumab on OS across age groups [ 16 ].In the case of lung cancer, a study of docetaxel + RAM treatment found that malignant pleural effusion, lung metastases, and liver metastases were not predictive of PFS[ 17 ]. A post-hoc analysis of the RAINBOW trial in gastric cancer found that RAM plus taxane was effective regardless of the presence or absence of liver metastases[ 17 ]. However, all of these studies used RAM in combination with chemotherapy rather than RAM alone. Although many retrospective studies of RAM monotherapy have been published, few have looked at prognostic factors. According to Paulson et al., patients treated with RAM monotherapy had a worse prognosis than those treated with ramucirumab combination therapy if they began later after diagnosis, were older, or had liver or peritoneal metastases [ 19 ]. This report supports our study’s findings. One limitation of this study is that it was a retrospective study with a small sample size and no PS validation. Furthermore, the number of liver metastases, liver function, and overall health status were not thoroughly investigated. Therefore, it is essential to determine whether age, PS, number of liver metastases, and percentage of tumors are related to prognosis in subsequent studies. Finally, this study indicates that liver metastasis is a very poor prognostic marker of RAM monotherapy for gastric cancer patients in poor overall health and that using nivolumab in third-line therapy does not improve the prognosis. Declarations Ethical Approval and Consent to Participate: The Ethics Committee of the Faculty of Medicine, Toho University authorized the study protocol (A22081_A21036_A22071_A22043_A20007_A19017_A16084 and M23008). Consent for Publication: Information about the study was made available on the institutional website, allowing potential participants to opt-out. Data availability statement: The data that support the findings of this study are available from the corresponding author, [YK], upon reasonable request. Funding Not Applicable References Zhang, X.-Y.; Zhang, P.-Y. Gastric cancer: Somatic genetics as a guide to therapy. J. Med. Genet. 2016, 54, 305–312. https://doi: 10.1136/jmedgenet-2016-104171. Hironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013; 31(35):4438-444. https://doi: 10.1200/JCO.2012.48.5805. Wilke H, Muro K, Cutsem EV, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11):1224-35. https://doi: 10.1016/S1470-2045(14)70420-6. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383(9911):31-9. https://doi: 10.1016/S0140-6736(13)61719-5. 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Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial. Eur J Cancer. 2017; 78: 61-69. doi: 10.1016/j.ejca.2017.03.007. Muro K, Cho JY, Bodoky G, et al. Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW. J Gastroenterol Hepatol. 2018; 33(4): 814-824. doi: 10.1111/jgh.14007. Matsumoto K, Tamiya A, Matsuda Y, et al. Impact of docetaxel plus ramucirumab on metastatic site in previously treated patients with non-small cell lung cancer: a multicenter retrospective study. Transl Lung Cancer Res. 2021;10(4): 1642-1652. doi: 10.21037/tlcr-20-1263. Ogata T, Narita Y, Wainberg ZA, et al. Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study. J Gastric Cancer. 2023;23(2): 289-302. doi: 10.5230/jgc.2023.23.e15. Paulson AS, Hess LM, Liepa AM, et al. Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices. Gastric Cancer. 2018; 21(5): 831-844. doi: 10.1007/s10120-018-0796-z. Table 1 Table 1 Patient characteristics at study HER2: human epidermal growth factor receptor type2 / CEA: carcinoembryonic antigen / CA19-9: carbohydrate antigen 19-9 / CR: complete response / PR: partial response / SD: stable disease / PD: progressive disease / NE: not evaluate Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2026 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted Editorial decision: Revision requested 07 Sep, 2025 Reviews received at journal 02 Sep, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviews received at journal 13 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviews received at journal 11 Aug, 2025 Reviewers agreed at journal 11 Aug, 2025 Reviewers agreed at journal 02 Jul, 2025 Reviewers invited by journal 29 Jun, 2025 Editor assigned by journal 29 Jun, 2025 Submission checks completed at journal 23 Jun, 2025 First submitted to journal 16 Jun, 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6902358","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":479284163,"identity":"2e75a6bf-f4a7-4456-89f7-7d32b22daf26","order_by":0,"name":"Yoshinori 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1","display":"","copyAsset":false,"role":"figure","size":46949,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of survival depicting outcomes for all patients (n = 27) who received ramucirumab as a standalone treatment. a) Progression-free survival and b) overall survival rates\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/5f41a59cfdf96f76af851680.png"},{"id":85848793,"identity":"617abb13-e3a6-4e7c-ba71-c0234ef30f90","added_by":"auto","created_at":"2025-07-02 10:05:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":48269,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier survival curves illustrating overall survival with and without the use of third-line treatment along with progression-free and overall survival for the six cases that received third-line therapy. a) A comparison of overall survival between those who did and did not receive third-line treatment and b) the length of PFS and OS in the six patients who underwent third-line treatment\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/f5dca9330de5ec5418e13607.png"},{"id":85848461,"identity":"37aa368c-065b-4b47-83c1-3c4797150bf4","added_by":"auto","created_at":"2025-07-02 09:57:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63089,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for tumor marker analysis. a) Progression-free survival comparison based on CEA level, and b) Progression-free survival comparison based on CA19-9 levels.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/130cba680b76196b32359fd0.png"},{"id":85848465,"identity":"0f1f42db-923d-4369-9aed-7244f710fb80","added_by":"auto","created_at":"2025-07-02 09:57:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":58465,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves categorized by age and pathology. a) Comparison of progression-free survival according to age, and b) comparison of progression-free survival based on pathology type.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/143f26408d7eb7f73ad6cc85.png"},{"id":85848468,"identity":"c38bc6d3-7dae-4b4d-a54a-7555f09a36a2","added_by":"auto","created_at":"2025-07-02 09:57:16","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":82204,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves for different types of metastatic lesions. a) Metastasis in the liver, b) Metastasis in the lungs, c) Metastasis in the lymph nodes, and d) Metastasis in the peritoneum.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/f1aa64a54400b1dc8f70eb96.png"},{"id":85850433,"identity":"3d9e6081-344e-431f-a1d9-d5e02b4161d2","added_by":"auto","created_at":"2025-07-02 10:13:16","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":39779,"visible":true,"origin":"","legend":"\u003cp\u003eMultivariate analysis of PFS and OS. The top row displays the PFS results and the bottom row presents the OS outcomes.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/1306f01a8e31e8d661d2b3e3.png"},{"id":100614777,"identity":"e5dde822-bd22-42fb-bc87-4d170989624e","added_by":"auto","created_at":"2026-01-19 17:24:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":876268,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6902358/v1/1c7c3f1f-0794-4186-a03a-078a49883ceb.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical prognosis factor of ramucirumab monotherapy for advanced gastric cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGastric cancer is the fourth leading cause of cancer-related deaths worldwide, with a median survival time of less than a year in advanced cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Ramucirumab (RAM) plus solvent-based paclitaxel or RAM plus nanoparticle albumin-bound paclitaxel are the most commonly used second-line treatments for gastric cancer [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. RAM monotherapy is a second-line treatment option according to the REGARD trial [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, RAM monotherapy is frequently chosen for patients who cannot use taxanes for medical reasons or whose performance status is poor, and because the number of patients is small, it has not been thoroughly studied.\u003c/p\u003e \u003cp\u003eIn this multi-institutional study, we looked at the prognostic factors for progression-free survival (PFS) and overall survival (OS) in patients with unresectable advanced gastric cancer, performance status 1\u0026ndash;2, and poor general condition who were treated with RAM monotherapy.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003e By reviewing medical records from six hospitals (i.e., Toho University Omori Medical Center, Japanese Red Cross Medical Center, Toho University Ohashi Medical Center, The Jikei University Hospital, National Hospital Organization Tokyo Medical Center, and NTT Medical Center Tokyo) between September 2017 and December 2019, we retrospectively collected 27 cases. Every patient had a performance level of 1\u0026ndash;2.\u003c/p\u003e \u003cp\u003eAs a second-line treatment, patients were given RAM (8 mg/kg) every two weeks.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEvaluation of efficacy and statistical analysis\u003c/h3\u003e\n\u003cp\u003e Each hospital had one doctor in charge who determined the effect of the images using the RECIST guidelines (ver. 1.1) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. PFS and OS were calculated using Kaplan\u0026ndash;Meier curves as the time between the start of RAM treatment and the time of confirmed disease progression or death. Differences in prognosis and survival were assessed using log-rank tests. All statistical analyses were carried out using EZR Ver.1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. P-values of \u0026lt;\u0026thinsp;0.05 were used to indicate statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics and Response rate\u003c/h2\u003e \u003cp\u003eThe median age of all patients (n\u0026thinsp;=\u0026thinsp;27) was 74 years (36\u0026ndash;90); 10 were younger than 70 years and 17 were older than 70 years. There were 18 men and 9 women. The HER2 status was HER2 3+, 2+, 1+, 0, and unknown in four, two, eight, eight, and five cases, respectively. Six patients were positive for liver metastasis, while 21 were negative. Lung metastases were positive in three cases but negative in 24. Lymph node metastases were positive in 18 cases but negative in nine. Peritoneal metastases were found in 14 cases and were negative in 13. Fourteen patients had CEA levels\u0026thinsp;\u0026lt;\u0026thinsp;5 ng/ml, while 13 had levels\u0026thinsp;\u0026ge;\u0026thinsp;5 ng/ml. Twelve patients had CA19-9 levels\u0026thinsp;\u0026lt;\u0026thinsp;37 U/ml, while 15 had levels of 37 U/ml. 21 patients received no third-line treatment, while six patients received third-line treatment. nivolumab in four cases and SOX in two cases. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe response rate was 0 for complete response, 1 for partial response (3.7%), 4 for stable disease (14.8%), 15 for progressive disease (55.6%), and 7 for not being evaluated (25.9%). The overall response rate was 3.7%, while disease control was 18.5% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProgression-free survival and overall survival rate\u003c/h3\u003e\n\u003cp\u003eThe median progression-free survival (PFS) of the 27 patients was 2.1 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea), while the median overall survival (OS) was 3.0 months (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eA comparison of OS with and without a 3rd line revealed a median OS of 9.1 months with a 3rd line versus 2.6 months without a 3rd line, but no significant difference between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, P\u0026thinsp;=\u0026thinsp;0.264). A bar graph depicts the PFS and OS of 6 patients with the 3rd line. No features were found, especially in the groups treated with immune checkpoint inhibitors or chemotherapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eThe median PFS by tumor marker was 2.7 months in the CEA\u0026thinsp;\u0026lt;\u0026thinsp;10 ng/ml group and 1.8 months in the CEA\u0026thinsp;\u0026ge;\u0026thinsp;10 ng/ml group, with little distinction between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, P\u0026thinsp;=\u0026thinsp;0.654). The median PFS in the CA19-9\u0026thinsp;\u0026lt;\u0026thinsp;37U/ml group was 1.5 months, while the CA19-9\u0026thinsp;\u0026ge;\u0026thinsp;37U/ml group was 3.0 months, with no significant difference between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb, P\u0026thinsp;=\u0026thinsp;0.698).\u003c/p\u003e \u003cp\u003eThe median PFS was 3.8 months for patients under 70 and 1.6 months for those over 70, with no significant difference between the two groups. However, the \u0026lt;\u0026thinsp;70 years age group indicated a trend toward longer PFS than the \u0026ge;\u0026thinsp;70 years age group (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, P\u0026thinsp;=\u0026thinsp;0.06). The median PFS was 2.4 months in the intestinal type and 2.1 months in the diffuse type, with no considerable difference between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, P\u0026thinsp;=\u0026thinsp;0.276)\u003c/p\u003e \u003cp\u003eAccording to the comparison of PFS for each metastasis, the median PFS for liver metastasis was 1.5 months in the positive group and 3.0 months in the negative group. The negative group had a significantly longer PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median PFS in the lung metastasis-positive group was 1.5 months, and the median PFS in the negative group was 2.4 months, with no significant difference between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb, P\u0026thinsp;=\u0026thinsp;0.554). The median PFS in the lymph node-positive group was 2.0 months, while in the lymph node-negative group it was 2.6 months, with no great difference between them (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec, P\u0026thinsp;=\u0026thinsp;0.27). The median PFS for the positive peritoneal metastasis group was 1.9 months, while the median PFS for the negative group was 2.8 months, with no significant difference between the two groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ed, P\u0026thinsp;=\u0026thinsp;0.89).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eMultivariate analysis in PFS and OS\u003c/h2\u003e \u003cp\u003eA multivariate analysis of PFS was conducted, with liver metastasis and age as covariates. The findings revealed that the liver metastasis-positive group was an independent factor, with a hazard rate (HR) of 5.179 (95% CI: 1.624\u0026ndash;16.51, P\u0026thinsp;=\u0026thinsp;0.0054). The HR for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years was 1.309 (95% CI, 0.576\u0026ndash;2.971; P\u0026thinsp;=\u0026thinsp;0.5205), and was not an independent factor.\u003c/p\u003e \u003cp\u003eMultivariate analysis of OS was performed using liver metastasis and 3rd line status as tabulated variables. The HR of 3.162 (95% CI: 1.078\u0026ndash;9.276, P\u0026thinsp;=\u0026thinsp;0.0361) in the group with positive liver metastasis was an independent factor, whereas the HR of 0.545 (95% CI: 0.210\u0026ndash;1.42, P\u0026thinsp;=\u0026thinsp;0.2124) in the group with 3rd line was not an independent factor (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe studied 27 patients who received RAM monotherapy as second-line treatment for gastric cancer. The findings indicated a very poor prognosis, with a median PFS of 2.1 months and a median OS of 3.0 months. Liver metastasis was an independent negative prognostic factor for PFS and OS.RAM, a fully human immunoglobulin G1 (IgG1) monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), has been developed by Eli Lilly (formerly ImClone Systems) to treat cancer [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].In Japan, it is recognized as an effective treatment for gastric, colorectal, non-small cell lung, and liver cancers with AFP levels of 400 ng/ml or higher [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. RAM monotherapy is indicated for two diseases: gastric cancer and liver cancer (AFP\u0026thinsp;\u0026gt;\u0026thinsp;400ng/ml).\u003c/p\u003e \u003cp\u003eThe response rate for RAM monotherapy (n\u0026thinsp;=\u0026thinsp;238) in the REGARD trial was 3%, the DCR was 49%, the median PFS was 2.1 months, and the median OS was 5.2 months [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, because the REGARD trial did not include Japanese patients, Yamaguchi et al. conducted a phase 2 study in Japanese patients, which found a response rate of 0%, DCR of 30.6%, median PFS of 6.6 weeks, and median OS of 8.6 months for RAM monotherapy (n\u0026thinsp;=\u0026thinsp;36) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Our results showed similarcomparable PFS, but inferior OS. The reason for this is that the median age in the REGARD study was 60 years, in the Yamaguchi et al. study was 66.5 years, and in our study was 74 years, all of which are quite old. Our study was retrospective in a general clinical setting and was most likely conducted on patients in poor general condition who could not receive taxanes; 21 of 27 patients (77.8%) were not chosen for the third-line treatment, and four of six patients in the third-line treatment were treated with nivolumab alone, implying that the patients in the study had very poor PS.\u003c/p\u003e \u003cp\u003eIt is well known that immune checkpoint inhibitors are less efficient in patients with poor PS. A meta-analysis in the field of lung cancer reported that patients with PS\u0026thinsp;\u0026ge;\u0026thinsp;2 had half the efficacy of those with PS 0\u0026ndash;1[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. According to our findings, it does not appear that nivolumab significantly extends OS versus SOX when comparing the two patients treated with SOX to the four patients treated with nivolumab. However, further investigation is required given the small number of cases.\u003c/p\u003e \u003cp\u003e According to a subanalysis of the RAISE trial on colorectal cancer, Yoshino et al. found that patients with CEA\u0026thinsp;\u0026le;\u0026thinsp;10ng/ml may benefit from this therapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. As a result, we compared PFS with CEA and CA19-9 in gastric cancer and found no difference, particularly in tumor markers. When PFS was compared by the factor, patients under 70 years of age had a longer PFS, though the difference was not statistically significant when compared to patients over 70 years old. Liver metastases significantly decreased PFS. As a result, a multivariate analysis of PFS and OS with or without liver metastases, age, and third-line status as explanatory variables revealed that liver metastases were a poor prognostic factor for PFS and OS. Our findings are supported by a subanalysis of the REGARD and RAINBOW trials, which found no effect of ramcirumab on OS across age groups [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].In the case of lung cancer, a study of docetaxel\u0026thinsp;+\u0026thinsp;RAM treatment found that malignant pleural effusion, lung metastases, and liver metastases were not predictive of PFS[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A post-hoc analysis of the RAINBOW trial in gastric cancer found that RAM plus taxane was effective regardless of the presence or absence of liver metastases[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, all of these studies used RAM in combination with chemotherapy rather than RAM alone. Although many retrospective studies of RAM monotherapy have been published, few have looked at prognostic factors. According to Paulson et al., patients treated with RAM monotherapy had a worse prognosis than those treated with ramucirumab combination therapy if they began later after diagnosis, were older, or had liver or peritoneal metastases [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. This report supports our study\u0026rsquo;s findings.\u003c/p\u003e \u003cp\u003eOne limitation of this study is that it was a retrospective study with a small sample size and no PS validation. Furthermore, the number of liver metastases, liver function, and overall health status were not thoroughly investigated. Therefore, it is essential to determine whether age, PS, number of liver metastases, and percentage of tumors are related to prognosis in subsequent studies.\u003c/p\u003e \u003cp\u003eFinally, this study indicates that liver metastasis is a very poor prognostic marker of RAM monotherapy for gastric cancer patients in poor overall health and that using nivolumab in third-line therapy does not improve the prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to Participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee of the Faculty of Medicine, Toho University authorized the study protocol (A22081_A21036_A22071_A22043_A20007_A19017_A16084 and M23008).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformation about the study was\u0026nbsp;made available\u0026nbsp;on the institutional website,\u0026nbsp;allowing\u0026nbsp;potential participants to opt-out.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, [YK], upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col class=\"decimal_type\"\u003e\n\u003cli\u003eZhang, X.-Y.; Zhang, P.-Y. Gastric cancer: Somatic genetics as a guide to therapy. J. Med. Genet. 2016, 54, 305\u0026ndash;312. https://doi: 10.1136/jmedgenet-2016-104171.\u003c/li\u003e\n\u003cli\u003eHironaka S, Ueda S, Yasui H, et al. Randomized, open-label, phase III study comparing irinotecan with paclitaxel in patients with advanced gastric cancer without severe peritoneal metastasis after failure of prior combination chemotherapy using fluoropyrimidine plus platinum: WJOG 4007 trial. J Clin Oncol. 2013; 31(35):4438-444. https://doi: 10.1200/JCO.2012.48.5805.\u003c/li\u003e\n\u003cli\u003eWilke H, Muro K, Cutsem EV, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014; 15(11):1224-35. https://doi: 10.1016/S1470-2045(14)70420-6.\u003c/li\u003e\n\u003cli\u003eFuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014; 383(9911):31-9. https://doi: 10.1016/S0140-6736(13)61719-5.\u003c/li\u003e\n\u003cli\u003eEisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.\u003c/li\u003e\n\u003cli\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transplant. 2013; 48: 452\u0026ndash;458. https://doi: 10.1038/bmt.2012.244.\u003c/li\u003e\n\u003cli\u003ePoole RM, Vaidya A. Ramucirumab: First Global Approval. Drugs. 2014; 74(9): 1047-58. doi: 10.1007/s40265-014-0244-2.\u003c/li\u003e\n\u003cli\u003eTabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015; 16(5): 499-508. doi: 10.1016/S1470-2045(15)70127-0.\u003c/li\u003e\n\u003cli\u003eGaron EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014; 384(9944): 665-73. doi: 10.1016/S0140-6736(14)60845-X.\u003c/li\u003e\n\u003cli\u003eYoh K, Hosomi Y, Kasahara K, et al. A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Lung Cancer. 2016: 99: 186-93. doi: 10.1016/j.lungcan.2016.07.019.\u003c/li\u003e\n\u003cli\u003eNakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(12): 1655-69. doi: 10.1016/S1470-2045(19)30634-5.\u003c/li\u003e\n\u003cli\u003eZhu AX, Kang Y-K, Yen C-J, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased \u0026alpha;-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20(2): 282-96. doi: 10.1016/S1470-2045(18)30937-9.\u003c/li\u003e\n\u003cli\u003eYamaguchi K, Fujitani K, Nagashima F, et al. Ramucirumab for the treatment of metastatic gastric or gastroesophageal junction adenocarcinoma following disease progression on first-line platinum- or fluoropyrimidine-containing combination therapy in Japanese patients: a phase 2, open-label study. Gastric Cancer. 2018; 21(6): 1041-1049. doi: 10.1007/s10120-018-0811-4.\u003c/li\u003e\n\u003cli\u003eTomasik B, Bieńkowski M, Braun M, et al. Effectiveness and safety of immunotherapy in NSCLC patients with ECOG PS score \u0026ge;2 - Systematic review and meta-analysis. Lung Cancer. 2021;158: 97-106. doi: 10.1016/j.lungcan.2021.06.004.\u003c/li\u003e\n\u003cli\u003eYoshino T, Obermannov\u0026aacute; R, Bodoky G, et al. Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial. Eur J Cancer. 2017; 78: 61-69. doi: 10.1016/j.ejca.2017.03.007.\u003c/li\u003e\n\u003cli\u003eMuro K, Cho JY, Bodoky G, et al. Age does not influence efficacy of ramucirumab in advanced gastric cancer: Subgroup analyses of REGARD and RAINBOW. J Gastroenterol Hepatol. 2018; 33(4): 814-824. doi: 10.1111/jgh.14007. \u003c/li\u003e\n\u003cli\u003eMatsumoto K, Tamiya A, Matsuda Y, et al. Impact of docetaxel plus ramucirumab on metastatic site in previously treated patients with non-small cell lung cancer: a multicenter retrospective study. Transl Lung Cancer Res. 2021;10(4): 1642-1652. doi: 10.21037/tlcr-20-1263.\u003c/li\u003e\n\u003cli\u003eOgata T, Narita Y, Wainberg ZA, et al. Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study. J Gastric Cancer. 2023;23(2): 289-302. doi: 10.5230/jgc.2023.23.e15.\u003c/li\u003e\n\u003cli\u003ePaulson AS, Hess LM, Liepa AM, et al. Ramucirumab for the treatment of patients with gastric or gastroesophageal junction cancer in community oncology practices. Gastric Cancer. 2018; 21(5): 831-844. doi: 10.1007/s10120-018-0796-z.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1 Patient characteristics at study\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"428\" height=\"771\" 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alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003eHER2: human epidermal growth factor receptor type2 / CEA: carcinoembryonic antigen / CA19-9: carbohydrate antigen 19-9 / CR: complete response / PR: partial response / SD: stable disease / PD: \u0026nbsp; progressive disease / NE: not evaluate\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"gastric cancer, ramucirumab monotherapy, prognostic factor","lastPublishedDoi":"10.21203/rs.3.rs-6902358/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6902358/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe REGARD trial resulted in insurance approval for ramucirumab monotherapy, but it did not include Japanese patients. Since then, phase II trials and retrospective studies in Japanese patients have been published, but there have been few reports on prognostic factors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: A total of 27 patients received ramucirumab monotherapy as a second-line treatment for gastric cancer at six institutions from September 2017 to December 2019.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe response rate was 3.7%, the disease control rate was 18.5%, the median progression-free survival time was 2.1 months, and the median survival time was 3.0 months. Six of the 27 patients received a 3rd line therapy, while 4 received nivolumab alone. Overall survival did not differ significantly between patients who received third-line treatment and those who did not. Survival curves showed no significant differences based on tumor markers (CEA and CA19-9), age, histology, lung metastasis, lymph node metastasis, or peritoneal metastasis; however, liver metastasis was a poor prognostic factor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Ramucirumab monotherapy was linked to a poor prognosis in older patients with gastric cancer who had a poor performance status, with liver metastasis being suggested as a poor prognostic factor.\u003c/p\u003e","manuscriptTitle":"Clinical prognosis factor of ramucirumab monotherapy for advanced gastric cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 09:57:12","doi":"10.21203/rs.3.rs-6902358/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-08T01:36:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T13:10:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"39937521204242885108923210006957164707","date":"2025-08-17T22:14:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-13T10:25:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"161280912443249511215516896261251262090","date":"2025-08-12T07:14:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-12T03:49:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242028617286580341403845528922342439384","date":"2025-08-12T01:41:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"133533722494355106137880756213033266493","date":"2025-07-02T11:03:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-29T23:31:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-29T23:26:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-23T11:49:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Gastrointestinal Cancer","date":"2025-06-16T06:46:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-gastrointestinal-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijgc","sideBox":"Learn more about [Journal of Gastrointestinal Cancer](https://www.springer.com/journal/12029)","snPcode":"12029","submissionUrl":"https://submission.nature.com/new-submission/12029/3","title":"Journal of Gastrointestinal Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0e483462-66c7-4c5e-99c5-40b062c3f339","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T16:48:09+00:00","versionOfRecord":{"articleIdentity":"rs-6902358","link":"https://doi.org/10.1007/s12029-026-01396-z","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2026-01-13 16:29:56","publishedOnDateReadable":"January 13th, 2026"},"versionCreatedAt":"2025-07-02 09:57:12","video":"","vorDoi":"10.1007/s12029-026-01396-z","vorDoiUrl":"https://doi.org/10.1007/s12029-026-01396-z","workflowStages":[]},"version":"v1","identity":"rs-6902358","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6902358","identity":"rs-6902358","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}