Safety and Efficacy of of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced gastric cancer: A systematic review and meta-analysis

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Methods A computerized systematic search of databases such as PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals was performed to find literature comparing apatinib combined with chemotherapy in the treatment of advanced gastric cancer.Literature search, quality assessment and data extraction were performed independently by two researchers. Stata 16 software was used to process and analyze the data. And, we assessed heterogeneity with I2 and p-value, and performed sensitivity analysis. Results A total of 1217 patients with advanced gastric cancer were included in 13 studies, including 652 patients in the apatinib combined with chemotherapy group and 565 in the chemotherapy group.Meta-analysis results showed that the objective response rate (ORR) of the observation group was better than that of the control group(0R = 2.49, 95% CI = 1.86–3.34), and the disease control rate (DCR) of the observation group was also better than that of the control group(OR = 2.78,95% CI = 2.11–3.66).The R0 resection rate was also statistically significant(OR = 2.31, 95% CI = 1.09–4.92).In addition, when comparing total adverse reactions (AEs) at any level, there was a statistical difference(OR = 1.61, 95%CI = 1.39–1.86). Conclusion Compared with the chemotherapy group, apatinib combined with chemotherapy has better efficacy and controllable safety in advanced gastric cancer. Meta-analysis of gastric cancer apatinib chemotherapy efficacy and safety Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 1.Introduction Gastric cancer (GC)is the fifth most common tumor in the world and the third leading cause of tumor-related death [ 1 ] .Among them, China has the highest incidence rate of GC, accounting for approximately 42.6% of the global incidence rate [ 2 ] .This is because Chinese GC patients have the characteristics of advanced stage, large tumor burden, strong heterogeneity and poor prognosis, and more effective treatments are needed to further improve the prognosis.Currently,the main treatments for GC include surgical resection, chemotherapy,radiotherapy, molecular targeted therapy, and immunotherapy.Surgical resection is the preferred treatment option for early-stage GC.However, most patients are already at an advanced stage when diagnosed and lose the chance of surgery [ 3 ] .Therefore, non-surgical options such as chemotherapy are particularly important.Chemotherapy is the first-line standard treatment for GC, often based on platinum (cisplatin or oxaliplatin) and fluoropyrimidine (fluorouracil, capecitabine or S-1) [ 4 , 5 ] .However, due to the high heterogeneity of GC, traditional therapy has poor long-term prognosis for most patients [ 6 ] .In Asia, the number of patients with advanced GC who have failed second-line treatment is rising.Therefore,after failure of first-line chemotherapy, further later-line treatment is urgently needed.In recent years,with the continuous development of tumor molecular biology technology,more and more molecular targeted drugs have been used clinically.Apatinib is one of the earliest tyrosine kinase inhibitors (TKIs) developed in China.It acts highly selectively on vascular endothelial growth factor receptor 2 (VEGFR-2) and inhibits c-Kit and c-Src Tyrosine kinase [ 7 , 8 ] .Its therapeutic dose can induce the apoptosis of tumor cells overexpressing VEGFR-2,block the migration and proliferation of vascular endothelial cells, reduce the density of tumor microvessels,inhibit tumor growth,thereby improving the efficacy [ 9 ] . Ahead and other studies [ 10 – 12 ] have shown that the apatinib group can significantly improve patient prognosis and demonstrate good anti-tumor activity.However, there are few reports on the treatment of advanced GC with apatinib combined with chemotherapy,and further evidence-based medical evidence is lacking.To the best of our knowledge, there is only one relevant meta-analysis in English in recent years.Therefore, we conducted the current meta-analysis.We used more stringent literature inclusion and exclusion criteria and more comprehensive indicators to analyze outcomes to comprehensively evaluate the effectiveness and safety of this therapy in the treatment of advanced GC. 2.Methods and materials 2.1 Search strategy The research protocol was conducted in accordance with PRISMA guidelines and registered in Prospero (CRD42023484497) [ 13 , 14 ] . We systematically searched PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals from September 2014 to November 2023 published research [ 14 , 15 ] .We focused on the analysis of apatinib combined with chemotherapy, and considering that some studies used drug replacement therapy, we did not use search terms such as “chemotherapy”.Finally, we used the following search terms: (Apatinib) AND (Neoplasm, Stomach) AND (Stomach Neoplasm) AND (Neoplasms, Stomach) AND (Gastric Neoplasms) AND (Gastric Neoplasm) AND (Cancer of Stomach) AND (Stomach Cancers) AND (Gastric Cancer) AND (Cancer, Gastric) AND (Cancer of the Stomach).In addition, we searched the clinical trial registration website ( http://www.clinicaltrials.gov ) and the Chinese trial data website ( http://www.chictr.org.cn ). 2.2 Selection, inclusion and exclusion criteria of studies First, we excluded irrelevant studies based on the retrieved titles, abstracts, and keywords.Secondly, all excluded studies were screened in full text according to the following inclusion and exclusion criteria.Inclusion criteria: 1.Research subjects: intermediate and advanced primary GC diagnosed by imaging and/or pathology; 2.Intervention: apatinib combined with chemotherapy regimen; 3.Control: chemotherapy regimen; 4.Administration time between the two groups Similar; 5.Endpoints: At least one predetermined endpoint should use sufficiently detailed methods, patient population characteristics, and survival data; 6.Study design: Randomized controlled trials (RCTs) and retrospective studies.We excluded irrelevant studies based on the following criteria: 1.Duplicate studies; 2.Patients with other tumors at the same time; 3.No full text; 4.Targeted therapy is other drugs (such as fruquintinib/trastuzumab) ; 5.The administration time of apatinib is < 2 cycles; 6.The quality of the literature is poor (studies with serious flaws in the research design, and studies with a high risk of bias assessment).Eligibility for these studies was then independently assessed by two investigators (Yuqi Li and Di Pan).If there is a disagreement, we will re-evaluate and discuss the studies and make a determination based on the final results.If it is still uncertain even after re-evaluation, a third researcher, Haiyan Wang, will evaluate his qualifications. 2.3 Data extraction and quality assessment For each included study,the following data were independently extracted and recorded by two investigators (Yuqi Li and Di Pan): ORR, DCR,R0 resection rate, AEs, author, year, study design type, intervention, chemotherapy regimen and dose, dose of apatinib, pathological type, patient characteristics, and analyzed after completing the data extraction form.After identifying studies for inclusion, we performed a quality assessment of the studies to understand the risk of bias for each study.Methodological quality of studies Researchers used the Oxford scoring system (Jadad) to assess RCT (Randomized Controlled Trial)quality and the Castle-Ottawa Scale (NOS) to assess non-RCT quality.The Jadad scale scores studies based on randomization, effective description of randomization methods, double-blinding, effective description of double-blinding, withdrawal, and withdrawal handling (1 point each), with a total score ranging from 0 (poor quality) to 7 (high quality) Does not vary; the NOS scale contains three quality parameters: selection (0–4 points), comparability (0–2 points), and outcome assessment (0–3 points). The article quality scores range (0–9 points): low (0–3 points), medium (4–6 points) and high (> 7 points) [ 15 ] . 2.4 Statistical analysis To extract and sort out relevant data, Di Pan and Yuqi Li conducted statistical analysis.Meta-analysis was performed using StataMP 16 software, and estimated odds ratios (ORs) and 95% confidence intervals (CIs) using the numbers of ORR, DCR, and AES were calculated.Heterogeneity analysis used Q test and I2 test. P ≥ value 0.05 or I2 ≤ value 50% indicates that the research results are homogeneous. Heterogeneity is divided into: low heterogeneity (25% < I2 < 50%), moderate heterogeneity (50% < I2 75%) [ 16 ] . If P ≥ 0.05 or I2 ≤ 50%, it indicates that there is homogeneity between the results of each study, and the fixed effect model is selected for meta analysis; if P 50%, the random effect model is selected for meta analysis.When heterogeneity is high, we need to conduct publication bias assessment, sensitivity analysis, and subgroup analysis to investigate the causes of heterogeneity.Sensitivity analysis was used to estimate the impact of each study on the stability of the results.All p -values are two-tailed and two-tailed. 3.Results 3.1 Literature search results We searched 1594 studies from 7 databases.Of these studies, 826 duplicate studies were excluded and two reviewers independently assessed the remaining 768 studies to determine their eligibility.Next, a total of 752 studies were excluded due to the following reasons: no control group (286); insufficient data (98); full text unavailable (143); quality assessment exclusion (139); combined PD-1/PD-L1 ( 89).Finally, a total of 13 studies were included [17–29] [ 17 – 29 ] .The detailed literature search process is shown in Fig. 1. 3.2 Basic characteristics and quality evaluation of included literature The characteristics of the studies finally included in the meta-analysis are shown in (Table 1).The studies were published between 2018 and July 2023, and were all conducted in China.The primary endpoint of this study is ORR and R0 resection rate; the secondary endpoint is DCR; the safety endpoint is any grade of AEs.A total of 1217 patients with advanced GC were included in 13 studies [ 17 – 29 ] , including 652 patients in the observation group and 565 patients in the control group.The pathological type was adenocarcinoma in 6 studies [ 17 , 19 , 21 , 25 , 26 , 28 ] , and 7 studies did not describe it [ 18 , 20 , 22 – 24 , 27 , 29 ] .Some are located at the gastroesophageal junction [ 17 , 25 , 26 ] , and the rest are located in the stomach.In the observation group, 9 studies [ 18 , 19 , 21 , 24 – 29 ] used low-dose apatinib (≥ 500 mg qd), and 3 studies [ 20 , 22 , 23 ] used high-dose apatinib. 1 item [ 17 ] is unknown.There are 8 studies using RCT [ 17 , 18 , 20 – 22 , 24 , 28 , 29 ] .There are 5 studies using retrospective research [19,23,25–27] [ 19 , 23 , 25 – 27 ] .According to the NOS scale, Yonglei Zhang 2021 [ 19 ] , Qiuju Wu 2019 [ 23 ] , Fengli Zhang 2020 [ 25 ] , Caiyun Nie 2023 [ 26 ] , Dan Hong 2021 [ 27 ] scored 8 points, 9 points, 8 points, 9 points, and 7 points respectively.More details of the quality evaluation are shown in Fig. 2.Based on the Cochrane risk of bias tool Bin Lu 2019 [ 17 ] , HF.Wang 2023 [ 18 ] , Zhengfeng Wang 2022 [ 21 ] , Min Yuan 2021 [ 22 ] , Sun Yun 2022 [ 24 ] , Shen Gao 2022 [ 29 ] , Yesong Guo 2018 [ 28 ] was assessed as low risk, and Pengzhe Zhou 2021 [ 20 ] was assessed as medium risk.The quality evaluation results are shown in Fig. 3. 3.3 Main outcome measures: ORR and resection rate The main outcome measures of this meta-analysis are ORR and resection rate. In 13 documents [ 17 – 29 ] ,, a total of 345 patients reported the ORR of treatment.The ORR of the observation group was better than that of the control group (OR = 2.49, 95% CI = 1.86–3.34).Heterogeneity analysis showed that there was no significant heterogeneity between studies (I2 = 14%, p = 0.304), and a meta-analysis effect model was used (Fig. 4). Four studies [ 19 – 21 , 24 ] reported the R0 resection rate, with a total of 268 cases.The results showed that the RO resection rate of the observation group was better than that of the control group (OR = 2.31, 95% CI = 1.09–4.92).The results showed that there was low heterogeneity (I2 = 0.00%, P = 0.935), and meta-analysis was used Effect model (Fig. 5). 3.4 Secondary outcome indicators: DCR and AEs Secondary outcome indicators include DCR and AEs. Thirteen included studies [ 17 – 29 ] reported DCR, involving a total of 780 patients. The results showed that the DCR of the observation group was also better than that of the control group (OR = 2.78, 95% CI = 2.11–3.66).Heterogeneity analysis showed that heterogeneity between studies using the fixed effects model was low (I2 = 0.0%, p = 0.842) (Fig. 6). Among adverse reactions of any grade, thrombocytopenia (OR = 0.88, 95%CI = 0.64–1.20) and leukopenia (OR = 1.12, 95%CI = 0.82–1.55) were not statistically significant between the observation group and the control group.Learn differences.However, compared with the control group, the risks of hypertension, hand-foot syndrome, and diarrhea were higher than those in the control group: hand-foot syndrome (OR = 2.28,95%CI = 1.60–3.25), hypertension (OR = 3.66, 95%CI = 2.60–5.15), diarrhea (OR = 1.43, 95%CI = 1.01–2.02); statistically significant.Furthermore, when comparing total AEs at any level, there was a statistical difference (OR = 1.61, 95%CI = 1.39–1.86) (Fig. 7).Therefore, we conclude that side effects were comparable between the study and control groups. 4.Discussion To the best of our knowledge, this is the first and most comprehensive meta-analysis of apatinib combined with chemotherapy in the treatment of primary intermediate and advanced GC.We included 13 studies [ 17 – 29 ] with a total of 1217 cases, all of which were assessed as high-quality studies.The results of this study showed that in terms of efficacy, the ORR, R0 resection rate, and DCR of the observation group were better than those of the control group and were statistically significant.In addition to clinical efficacy, we analyzed the adverse events caused by apatinib.Specific adverse events include: hypertension, anemia,thrombocytopenia,leukopenia,and diarrhea.Hypertension, hand-foot syndrome, and diarrhea in the observation group were higher than those in the control group and were statistically significant, which is consistent with the study by Xinyang Liu et al [ 30 ] .However, there were no significant differences in other adverse events between the two groups.Taken together, apatinib combined with chemotherapy can improve the efficacy of patients with advanced GC and has good safety.GC is a highly aggressive malignant tumor.Most patients are diagnosed at an advanced stage and often show symptoms such as distant lymphatic metastasis and pelvic metastasis.For these patients, systemic chemotherapy is the main treatment option [ 31 ] .Depending on human epidermal growth factor receptor 2 status, various combination regimens of fluoropyrimidine and platinum with/without trastuzumab are commonly used as first-line chemotherapy [ 32 ] .During or after first-line chemotherapy for advanced GC, the disease Progressive symptoms often develop rapidly with associated deterioration in performance status, making patients unsuitable for systemic therapy [ 33 ] .Ramucirumab as a single agent or in combination with paclitaxel (preferred) is a category 1 recommendation for second-line treatment [ 34 ] can significantly improve PFS and OS in GC patients after first-line treatment, either as monotherapy (REGARD [ 35 ] ) or in combination with paclitaxel (RAINBOW [ 36 ] ) [ 37 ] .However, regardless of the effectiveness of any currently available chemotherapy Regardless of the positive impact, the prognosis for patients with advanced GC remains hopeless, with a median survival of only 7–10 months in most large studies [ 31 ] .In recent years, with the development and progress of medicine, molecular targeted drug therapy has become a hot spot in clinical research, providing a new way to treat GC.The study by Caiyun Nie et al [ 28 ] proved that anti-angiogenic drugs combined with chemotherapy also have good results as a second-line treatment after failure of first-line treatment of metastatic GC.Apatinib is a new small molecule selective TKI that can inhibit multiple tumor-related kinases (TRK), such as VEGFR-2, and induce cell apoptosis, thereby inhibiting tumor proliferation in a variety of tumors [ 38 ] .One study pointed out that apatinib can significantly improve the anti-tumor efficacy of the drug, mainly because it significantly enhances the intracellular accumulation of DOX and Rho 123 in MDR cells, making MDR cells sensitive to anti-cancer drugs; and by directly Inhibiting ABCB1 and ABCG2 function reverses ABCB1- and ABCG2-mediated MDR, resulting in increased intracellular concentrations of substrate chemotherapeutic drugs [ 39 ] .In terms of drug dosage, regardless of whether the starting dose is 850 mg or ≤ 500 mg, patients taking oral apatinib have advantages in objective response rate and disease control rate compared with the chemotherapy group [ 40 ] . The clinical research recommendation for apatinib is also 850 mg/d [ 41 ] . However, in the study by Tian Chunyan [ 42 ] and others on the efficacy and safety of different doses of apatinib in patients with advanced GC, the initial dose was ≤ 500 mg. The efficacy of the drug is equivalent to that of patients taking the initial dose of 850 mg, while the safety and tolerability are better than the latter. Taken together, for patients with advanced GC who have good physical status or whose first-line chemotherapy is single drug/double drug combination therapy, oral apatinib at a low initial dose and in increasing doses has better efficacy and safety. Compared with other people’s research, our research has the following advantages.First,our study adopts more qualified literature inclusion and exclusion criteria; second, the number of samples included in the studies is larger than before, which enables us to evaluate the efficacy and safety of the data with strong stability; finally, we use more Comprehensive endpoints examined outcomes with full dose apatinib. However, our study still has some limitations.First, the studies included in this META included four retrospective studies and the sample size was small. Second, these studies are all from China, an area with a high incidence of GC. Third, such as the type of chemotherapy regimen and different doses of apatinib, the selection of these specific treatment regimens may be based on the patient’s physical condition and economic conditions, and there is a selection bias. Patients with good general conditions and economic conditions may be inclined to choose targeted therapy, while patients with general conditions and poor economic conditions may be willing to accept single therapy. Fourth, during quality assessment,the Jadad and NOS scales are subjectively conducted by researchers, and their assessment results may be biased.Finally, although we have taken into account the heterogeneity of the data in these studies, some other factors in the baseline characteristics of the study, such as the location, number and size of the tumors and other factors such as the general health status of the patients, are not consistent across the trials and may will confuse the conclusions.In summary,Apatinib combined with chemotherapy, as a treatment option for intermediate and advanced GC, shows better efficacy, and the safety is tolerable and controllable.This conclusion still needs to be verified by more large-sample, multi-center, and high-quality studies in the future.Despite the above limitations, this study still provides clinical guidance for the efficacy and safety of apatinib combined with chemotherapy in intermediate and advanced GC, and has certain clinical significance. Conclusion In this meta-analysis, we compared the efficacy and safety of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced GC.The results showed that compared with the chemotherapy group, apatinib combined with chemotherapy has better efficacy and controllable safety in advanced GC. Thus, this study supports the feasibility of this treatment for advanced. Declarations Author Contributions : (I) Conception and design: HY Wang, YQ Li,D Pan,HN Liu,ZY Yao; (II) Administrative support: HY Wang; (III) Provision of study materials or patients: YQ Li,D Pan,HN Liu,ZY Yao; (IV) Collection and assembly of data: YQ Li,D Pan,HN Liu,ZY Yao; (V) Data analysis and interpretation:HN Liu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Acknowledgments We thank all staff members involved in this study. Founding : None. Footnote Reporting Checklist:The meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare. Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. References BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA: a cancer journal for clinicians, 2018, 68(6): 394–424. WANG F H, SHEN L, LI J, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer [J]. Cancer communications (London, England), 2019, 39(1): 10. SEXTON R E, AL HALLAK M N, DIAB M, et al. 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WILKE H, MURO K, VAN CUTSEM E, 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 [J]. The Lancet Oncology, 2014, 15(11): 1224–35. IWASA S, BANDO H, PIAO Y, et al. The clinical position of ramucirumab-containing regimens for advanced gastric cancer: a review of clinical trial data [J]. Future oncology (London, England), 2022, 18(21): 2709–21. FERRARA N, GERBER H P, LECOUTER J. The biology of VEGF and its receptors [J]. Nature medicine, 2003, 9(6): 669–76. MI Y J, LIANG Y J, HUANG H B, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters [J]. Cancer research, 2010, 70(20): 7981–91. LI J, QIN S, XU J, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial [J]. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 2013, 31(26): 3219–25. QIN S K,LI J.Expert consensus on the clinical application of apatinib for gastric cancer [J].Journal of Clinical Oncology,2015, 20(9): 841–7. TIAN C Y,PENG R,BAI T T, et al. Adverse effects and efficacy of apatinib at different starting doses in advanced gastric cancer[J].Journal of Practical Oncology.2018, 33(1): 66–9. Tables Table 1 is available in the Supplementary Files section. Table 2. Quality assessment of NOS Study Selection Comparability Outcome/Exposure Global Score Yonglei Zhang 2021；15 4 2 2 8 Qiuju Wu 2019；19 4 2 3 9 Fengli Zhang 2020；21 4 2 2 8 Caiyun Nie 2023；22 4 2 3 9 Dan Hong 2021；23 3 2 2 7 Abbreviations: NOS, Castle-Ottawa Scale. Additional Declarations No competing interests reported. Supplementary Files TABLE1.docx TABLE 1 | The basic characteristics of studies included in the meta-analysis Abbreviations:GC:gastric cancer;FU:fluorouracil;PTX:taxanes;CPT:irinotecan；DOC:docetaxel;FLOT:neoadjurant chemotherapy with fluorouracil,leucovorin,oxaliplatin,and docetaxel;SOX:S-1 plus oxaliplatin;FU：fluorouracil;FOLF0X:5-FU,oxaliplatin and calcium folinate;DOS：docetaxel ,oxaliplatin,tegafur, gimeracil and oteracil;CapOx:capecitabine;RCT ;Randomized Controlled Trial;Jadad:Oxford scoring system;NOS: Castle-Ottawa Scale. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-3733354","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":258568574,"identity":"f377dae9-160f-41bd-b3c4-67476e231889","order_by":0,"name":"Yuqi Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuqi","middleName":"","lastName":"Li","suffix":""},{"id":258568575,"identity":"e7ff5841-ea12-4e23-9bca-f62adc19e489","order_by":1,"name":"Di Pan","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Di","middleName":"","lastName":"Pan","suffix":""},{"id":258568576,"identity":"24fd014f-849d-4f41-adc4-2d1e39676e9e","order_by":2,"name":"Haonan Liu","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Haonan","middleName":"","lastName":"Liu","suffix":""},{"id":258568577,"identity":"3e318083-7d3b-4fec-9aac-0cfad5838a35","order_by":3,"name":"Zhiyuan Yao","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhiyuan","middleName":"","lastName":"Yao","suffix":""},{"id":258568578,"identity":"aef93510-0efd-44b1-8bae-80ebfb314267","order_by":4,"name":"Haiyan Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYFACHgaGBCDFz9584MCHH6Rokew5lnhwZg+xWkDAYEaO8WEONiI0GJw/e/DDwza7PAOeMx8OA/XL84sdwK9FsuFcskRiW3KxOXvvhsMFFgyGM2cn4NfCz9hjANTCnLiz5+yGwzN4GBIMbhPQwsbMY/wjsa0+ccONnAeHediI0MLPxmMGtOUwSAsDcVoke3jMLBLOHU+c2XPMABjIEoT9YnD+jPHNH2XVif3szY8/fPhhI88vTUALGDAiokOCCOVg8IdYhaNgFIyCUTAiAQABi0lpEvcM/AAAAABJRU5ErkJggg==","orcid":"","institution":"","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Haiyan","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2023-12-10 08:59:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3733354/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3733354/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":48149810,"identity":"b820f594-916a-4d3b-84c1-c2aa0f47125e","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":134360,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of literature screening steps.\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/44159a9df968599a4645580e.jpg"},{"id":48152414,"identity":"08d30247-7750-4291-80e0-dd652b851680","added_by":"auto","created_at":"2023-12-13 19:54:15","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":16152,"visible":true,"origin":"","legend":"\u003cp\u003eQuality assessment of included studies (Risk of bias graph)\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/13e22952b6cafbbf35278b4f.png"},{"id":48149811,"identity":"1c24334e-f016-4f87-942d-0fa1a65b86ed","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":12311,"visible":true,"origin":"","legend":"\u003cp\u003eQuality assessment of included studies (Risk of bias summary)\u003c/p\u003e","description":"","filename":"Fig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/3b4c21a044e63bdb68b8f8ef.png"},{"id":48149818,"identity":"05c86be8-3219-4d3e-9c64-90e4ba2b96cc","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":58404,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the objective response rate in the apatinib combined with chemotherapy group versus the chemotherapy group for advanced gastric cancer Abbreviations: ORR,objective response rate; CI, confidence interval; OR, odds ratio;\u003c/p\u003e","description":"","filename":"Fig.4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/ad9e99883ba4b731bc9d885d.jpg"},{"id":48151068,"identity":"aab0e2e4-0e5e-4671-964b-73358330959f","added_by":"auto","created_at":"2023-12-13 19:38:15","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":41456,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the R0 resection rate in the apatinib combined with chemotherapy group versus the chemotherapy group for advanced gastric cancer Abbreviations: CI, confidence interval; OR, odds ratio;\u003c/p\u003e","description":"","filename":"Fig.5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/bb0d1d81e702b3d6bd59b58d.jpg"},{"id":48151071,"identity":"7476b4f8-22d0-4420-8804-455ae1776ca0","added_by":"auto","created_at":"2023-12-13 19:38:15","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":60647,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the disease control rate in the apatinib combined with chemotherapy group versus the chemotherapy group for advanced gastric cancer Abbreviations: DCR, disease control rate;CI, confidence interval; OR, odds ratio;\u003c/p\u003e","description":"","filename":"Fig.6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/88c6bd088d6015b76a3fa7de.jpg"},{"id":48149820,"identity":"457e7723-1b99-4e3f-a29c-d80aa8a951f0","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":260764,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of the adverse effects in the apatinib combined with chemotherapy group versus the chemotherapy group for advanced gastric cancer Abbreviations: AEs, adverse effects ;CI, confidence interval; OR, odds ratio;\u003c/p\u003e","description":"","filename":"Fig.7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/3506441d8908f1cf6a5a02a6.jpg"},{"id":48151993,"identity":"1c9b1cdf-9c5d-4ba1-b7fc-c1bf0a94f152","added_by":"auto","created_at":"2023-12-13 19:46:15","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":61887,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig.8.png","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/3b3ed7378896e1b27e4d996e.png"},{"id":48149816,"identity":"2dbc0058-1bb8-423b-9665-5e4b1477c0d3","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":45557,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version.\u003c/p\u003e","description":"","filename":"Fig.9.png","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/fef073d9f9e6aedf5eeeb7b4.png"},{"id":48149819,"identity":"78b3aa48-a18e-432f-9ea9-0a9a104467e6","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"png","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":104983,"visible":true,"origin":"","legend":"\u003cp\u003eSensitivity analysis of the combined objective response rate.\u003c/p\u003e","description":"","filename":"Fig.10.png","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/0677b730c00630d301691fa6.png"},{"id":49001920,"identity":"7bbd9394-9451-4fc5-9b21-8429336fcd32","added_by":"auto","created_at":"2023-12-30 19:37:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":958798,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/8a32f790-5a3b-4fc8-932d-e5fef088d1fa.pdf"},{"id":48149812,"identity":"89d89b25-3a42-4ebd-a618-f442b99f053e","added_by":"auto","created_at":"2023-12-13 19:30:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15862,"visible":true,"origin":"","legend":"\u003cp\u003eTABLE 1 | The basic characteristics of studies included in the meta-analysis\u003c/p\u003e\n\u003cp\u003eAbbreviations:GC:gastric cancer;FU:fluorouracil;PTX:taxanes;CPT:irinotecan；DOC:docetaxel;FLOT:neoadjurant chemotherapy with fluorouracil,leucovorin,oxaliplatin,and docetaxel;SOX:S-1 plus oxaliplatin;FU：fluorouracil;FOLF0X:5-FU,oxaliplatin and calcium folinate;DOS：docetaxel ,oxaliplatin,tegafur, gimeracil and oteracil;CapOx:capecitabine;RCT ;Randomized Controlled Trial;Jadad:Oxford scoring system;NOS: Castle-Ottawa Scale.\u003c/p\u003e","description":"","filename":"TABLE1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3733354/v1/564a0726a1f68ba44446be84.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety and Efficacy of of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced gastric cancer: A systematic review and meta-analysis ","fulltext":[{"header":"1.Introduction","content":"\u003cp\u003eGastric cancer (GC)is the fifth most common tumor in the world and the third leading cause of tumor-related death\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e.Among them, China has the highest incidence rate of GC, accounting for approximately 42.6% of the global incidence rate \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e.This is because Chinese GC patients have the characteristics of advanced stage, large tumor burden, strong heterogeneity and poor prognosis, and more effective treatments are needed to further improve the prognosis.Currently,the main treatments for GC include surgical resection, chemotherapy,radiotherapy, molecular targeted therapy, and immunotherapy.Surgical resection is the preferred treatment option for early-stage GC.However, most patients are already at an advanced stage when diagnosed and lose the chance of surgery\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.Therefore, non-surgical options such as chemotherapy are particularly important.Chemotherapy is the first-line standard treatment for GC, often based on platinum (cisplatin or oxaliplatin) and fluoropyrimidine (fluorouracil, capecitabine or S-1) \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.However, due to the high heterogeneity of GC, traditional therapy has poor long-term prognosis for most patients \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e.In Asia, the number of patients with advanced GC who have failed second-line treatment is rising.Therefore,after failure of first-line chemotherapy, further later-line treatment is urgently needed.In recent years,with the continuous development of tumor molecular biology technology,more and more molecular targeted drugs have been used clinically.Apatinib is one of the earliest tyrosine kinase inhibitors (TKIs) developed in China.It acts highly selectively on vascular endothelial growth factor receptor 2 (VEGFR-2) and inhibits c-Kit and c-Src Tyrosine kinase\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e.Its therapeutic dose can induce the apoptosis of tumor cells overexpressing VEGFR-2,block the migration and proliferation of vascular endothelial cells, reduce the density of tumor microvessels,inhibit tumor growth,thereby improving the efficacy\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Ahead and other studies \u003csup\u003e[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e have shown that the apatinib group can significantly improve patient prognosis and demonstrate good anti-tumor activity.However, there are few reports on the treatment of advanced GC with apatinib combined with chemotherapy,and further evidence-based medical evidence is lacking.To the best of our knowledge, there is only one relevant meta-analysis in English in recent years.Therefore, we conducted the current meta-analysis.We used more stringent literature inclusion and exclusion criteria and more comprehensive indicators to analyze outcomes to comprehensively evaluate the effectiveness and safety of this therapy in the treatment of advanced GC.\u003c/p\u003e"},{"header":"2.Methods and materials","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Search strategy\u003c/h2\u003e \u003cp\u003eThe research protocol was conducted in accordance with PRISMA guidelines and registered in Prospero (CRD42023484497) \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. We systematically searched PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals from September 2014 to November 2023 published research \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.We focused on the analysis of apatinib combined with chemotherapy, and considering that some studies used drug replacement therapy, we did not use search terms such as \u0026ldquo;chemotherapy\u0026rdquo;.Finally, we used the following search terms: (Apatinib) AND (Neoplasm, Stomach) AND (Stomach Neoplasm) AND (Neoplasms, Stomach) AND (Gastric Neoplasms) AND (Gastric Neoplasm) AND (Cancer of Stomach) AND (Stomach Cancers) AND (Gastric Cancer) AND (Cancer, Gastric) AND (Cancer of the Stomach).In addition, we searched the clinical trial registration website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.clinicaltrials.gov\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the Chinese trial data website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chictr.org.cn\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Selection, inclusion and exclusion criteria of studies\u003c/h2\u003e \u003cp\u003eFirst, we excluded irrelevant studies based on the retrieved titles, abstracts, and keywords.Secondly, all excluded studies were screened in full text according to the following inclusion and exclusion criteria.Inclusion criteria: 1.Research subjects: intermediate and advanced primary GC diagnosed by imaging and/or pathology; 2.Intervention: apatinib combined with chemotherapy regimen; 3.Control: chemotherapy regimen; 4.Administration time between the two groups Similar; 5.Endpoints: At least one predetermined endpoint should use sufficiently detailed methods, patient population characteristics, and survival data; 6.Study design: Randomized controlled trials (RCTs) and retrospective studies.We excluded irrelevant studies based on the following criteria: 1.Duplicate studies; 2.Patients with other tumors at the same time; 3.No full text; 4.Targeted therapy is other drugs (such as fruquintinib/trastuzumab) ; 5.The administration time of apatinib is \u0026lt;\u0026thinsp;2 cycles; 6.The quality of the literature is poor (studies with serious flaws in the research design, and studies with a high risk of bias assessment).Eligibility for these studies was then independently assessed by two investigators (Yuqi Li and Di Pan).If there is a disagreement, we will re-evaluate and discuss the studies and make a determination based on the final results.If it is still uncertain even after re-evaluation, a third researcher, Haiyan Wang, will evaluate his qualifications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data extraction and quality assessment\u003c/h2\u003e \u003cp\u003eFor each included study,the following data were independently extracted and recorded by two investigators (Yuqi Li and Di Pan): ORR, DCR,R0 resection rate, AEs, author, year, study design type, intervention, chemotherapy regimen and dose, dose of apatinib, pathological type, patient characteristics, and analyzed after completing the data extraction form.After identifying studies for inclusion, we performed a quality assessment of the studies to understand the risk of bias for each study.Methodological quality of studies Researchers used the Oxford scoring system (Jadad) to assess RCT (Randomized Controlled Trial)quality and the Castle-Ottawa Scale (NOS) to assess non-RCT quality.The Jadad scale scores studies based on randomization, effective description of randomization methods, double-blinding, effective description of double-blinding, withdrawal, and withdrawal handling (1 point each), with a total score ranging from 0 (poor quality) to 7 (high quality) Does not vary; the NOS scale contains three quality parameters: selection (0\u0026ndash;4 points), comparability (0\u0026ndash;2 points), and outcome assessment (0\u0026ndash;3 points). The article quality scores range (0\u0026ndash;9 points): low (0\u0026ndash;3 points), medium (4\u0026ndash;6 points) and high (\u0026gt;\u0026thinsp;7 points) \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eTo extract and sort out relevant data, Di Pan and Yuqi Li conducted statistical analysis.Meta-analysis was performed using StataMP 16 software, and estimated odds ratios (ORs) and 95% confidence intervals (CIs) using the numbers of ORR, DCR, and AES were calculated.Heterogeneity analysis used Q test and I2 test.\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026ge;\u0026thinsp;value 0.05 or \u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;value 50% indicates that the research results are homogeneous. Heterogeneity is divided into: low heterogeneity (25% \u0026lt; \u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;50%), moderate heterogeneity (50% \u0026lt; \u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;75%), and high heterogeneity (\u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;75%) \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. If \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026ge;\u0026thinsp;0.05 or \u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;50%, it indicates that there is homogeneity between the results of each study, and the fixed effect model is selected for meta analysis; if \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 or \u003cem\u003eI2\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50%, the random effect model is selected for meta analysis.When heterogeneity is high, we need to conduct publication bias assessment, sensitivity analysis, and subgroup analysis to investigate the causes of heterogeneity.Sensitivity analysis was used to estimate the impact of each study on the stability of the results.All \u003cem\u003ep\u003c/em\u003e-values are two-tailed and two-tailed.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Literature search results\u003c/h2\u003e \u003cp\u003eWe searched 1594 studies from 7 databases.Of these studies, 826 duplicate studies were excluded and two reviewers independently assessed the remaining 768 studies to determine their eligibility.Next, a total of 752 studies were excluded due to the following reasons: no control group (286); insufficient data (98); full text unavailable (143); quality assessment exclusion (139); combined PD-1/PD-L1 ( 89).Finally, a total of 13 studies were included [17\u0026ndash;29]\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.The detailed literature search process is shown in Fig.\u0026nbsp;1.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Basic characteristics and quality evaluation of included literature\u003c/h2\u003e \u003cp\u003eThe characteristics of the studies finally included in the meta-analysis are shown in (Table\u0026nbsp;1).The studies were published between 2018 and July 2023, and were all conducted in China.The primary endpoint of this study is ORR and R0 resection rate; the secondary endpoint is DCR; the safety endpoint is any grade of AEs.A total of 1217 patients with advanced GC were included in 13 studies \u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e, including 652 patients in the observation group and 565 patients in the control group.The pathological type was adenocarcinoma in 6 studies \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e, and 7 studies did not describe it\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.Some are located at the gastroesophageal junction \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, and the rest are located in the stomach.In the observation group, 9 studies \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003eused low-dose apatinib (\u0026ge;\u0026thinsp;500 mg qd), and 3 studies \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003eused high-dose apatinib. 1 item \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003eis unknown.There are 8 studies using RCT \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.There are 5 studies using retrospective research [19,23,25\u0026ndash;27]\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.According to the NOS scale, Yonglei Zhang 2021\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e, Qiuju Wu 2019\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e, Fengli Zhang 2020\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, Caiyun Nie 2023\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e, Dan Hong 2021 \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003escored 8 points, 9 points, 8 points, 9 points, and 7 points respectively.More details of the quality evaluation are shown in Fig.\u0026nbsp;2.Based on the Cochrane risk of bias tool Bin Lu 2019\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, HF.Wang 2023\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e, Zhengfeng Wang 2022\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e, Min Yuan 2021\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e, Sun Yun 2022\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e, Shen Gao 2022\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e, Yesong Guo 2018\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e was assessed as low risk, and Pengzhe Zhou 2021\u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e was assessed as medium risk.The quality evaluation results are shown in Fig.\u0026nbsp;3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Main outcome measures: ORR and resection rate\u003c/h2\u003e \u003cp\u003eThe main outcome measures of this meta-analysis are ORR and resection rate.\u003c/p\u003e \u003cp\u003eIn 13 documents \u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e,, a total of 345 patients reported the ORR of treatment.The ORR of the observation group was better than that of the control group (OR\u0026thinsp;=\u0026thinsp;2.49, 95% CI\u0026thinsp;=\u0026thinsp;1.86\u0026ndash;3.34).Heterogeneity analysis showed that there was no significant heterogeneity between studies (I2\u0026thinsp;=\u0026thinsp;14%, p\u0026thinsp;=\u0026thinsp;0.304), and a meta-analysis effect model was used (Fig.\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eFour studies\u003csup\u003e[\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e reported the R0 resection rate, with a total of 268 cases.The results showed that the RO resection rate of the observation group was better than that of the control group (OR\u0026thinsp;=\u0026thinsp;2.31, 95% CI\u0026thinsp;=\u0026thinsp;1.09\u0026ndash;4.92).The results showed that there was low heterogeneity (I2\u0026thinsp;=\u0026thinsp;0.00%, P\u0026thinsp;=\u0026thinsp;0.935), and meta-analysis was used Effect model (Fig.\u0026nbsp;5).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Secondary outcome indicators: DCR and AEs\u003c/h2\u003e \u003cp\u003eSecondary outcome indicators include DCR and AEs.\u003c/p\u003e \u003cp\u003eThirteen included studies \u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003ereported DCR, involving a total of 780 patients. The results showed that the DCR of the observation group was also better than that of the control group (OR\u0026thinsp;=\u0026thinsp;2.78, 95% CI\u0026thinsp;=\u0026thinsp;2.11\u0026ndash;3.66).Heterogeneity analysis showed that heterogeneity between studies using the fixed effects model was low (I2\u0026thinsp;=\u0026thinsp;0.0%, p\u0026thinsp;=\u0026thinsp;0.842) (Fig.\u0026nbsp;6).\u003c/p\u003e \u003cp\u003eAmong adverse reactions of any grade, thrombocytopenia (OR\u0026thinsp;=\u0026thinsp;0.88, 95%CI\u0026thinsp;=\u0026thinsp;0.64\u0026ndash;1.20) and leukopenia (OR\u0026thinsp;=\u0026thinsp;1.12, 95%CI\u0026thinsp;=\u0026thinsp;0.82\u0026ndash;1.55) were not statistically significant between the observation group and the control group.Learn differences.However, compared with the control group, the risks of hypertension, hand-foot syndrome, and diarrhea were higher than those in the control group: hand-foot syndrome (OR\u0026thinsp;=\u0026thinsp;2.28,95%CI\u0026thinsp;=\u0026thinsp;1.60\u0026ndash;3.25), hypertension (OR\u0026thinsp;=\u0026thinsp;3.66, 95%CI\u0026thinsp;=\u0026thinsp;2.60\u0026ndash;5.15), diarrhea (OR\u0026thinsp;=\u0026thinsp;1.43, 95%CI\u0026thinsp;=\u0026thinsp;1.01\u0026ndash;2.02); statistically significant.Furthermore, when comparing total AEs at any level, there was a statistical difference (OR\u0026thinsp;=\u0026thinsp;1.61, 95%CI\u0026thinsp;=\u0026thinsp;1.39\u0026ndash;1.86) (Fig.\u0026nbsp;7).Therefore, we conclude that side effects were comparable between the study and control groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"4.Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first and most comprehensive meta-analysis of apatinib combined with chemotherapy in the treatment of primary intermediate and advanced GC.We included 13 studies\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e with a total of 1217 cases, all of which were assessed as high-quality studies.The results of this study showed that in terms of efficacy, the ORR, R0 resection rate, and DCR of the observation group were better than those of the control group and were statistically significant.In addition to clinical efficacy, we analyzed the adverse events caused by apatinib.Specific adverse events include: hypertension, anemia,thrombocytopenia,leukopenia,and diarrhea.Hypertension, hand-foot syndrome, and diarrhea in the observation group were higher than those in the control group and were statistically significant, which is consistent with the study by Xinyang Liu et al\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e.However, there were no significant differences in other adverse events between the two groups.Taken together, apatinib combined with chemotherapy can improve the efficacy of patients with advanced GC and has good safety.GC is a highly aggressive malignant tumor.Most patients are diagnosed at an advanced stage and often show symptoms such as distant lymphatic metastasis and pelvic metastasis.For these patients, systemic chemotherapy is the main treatment option \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.Depending on human epidermal growth factor receptor 2 status, various combination regimens of fluoropyrimidine and platinum with/without trastuzumab are commonly used as first-line chemotherapy\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e.During or after first-line chemotherapy for advanced GC, the disease Progressive symptoms often develop rapidly with associated deterioration in performance status, making patients unsuitable for systemic therapy\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.Ramucirumab as a single agent or in combination with paclitaxel (preferred) is a category 1 recommendation for second-line treatment \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e can significantly improve PFS and OS in GC patients after first-line treatment, either as monotherapy (REGARD\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e) or in combination with paclitaxel (RAINBOW \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e) \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.However, regardless of the effectiveness of any currently available chemotherapy Regardless of the positive impact, the prognosis for patients with advanced GC remains hopeless, with a median survival of only 7\u0026ndash;10 months in most large studies \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.In recent years, with the development and progress of medicine, molecular targeted drug therapy has become a hot spot in clinical research, providing a new way to treat GC.The study by Caiyun Nie et al\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e proved that anti-angiogenic drugs combined with chemotherapy also have good results as a second-line treatment after failure of first-line treatment of metastatic GC.Apatinib is a new small molecule selective TKI that can inhibit multiple tumor-related kinases (TRK), such as VEGFR-2, and induce cell apoptosis, thereby inhibiting tumor proliferation in a variety of tumors\u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.One study pointed out that apatinib can significantly improve the anti-tumor efficacy of the drug, mainly because it significantly enhances the intracellular accumulation of DOX and Rho 123 in MDR cells, making MDR cells sensitive to anti-cancer drugs; and by directly Inhibiting ABCB1 and ABCG2 function reverses ABCB1- and ABCG2-mediated MDR, resulting in increased intracellular concentrations of substrate chemotherapeutic drugs \u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e.In terms of drug dosage, regardless of whether the starting dose is 850 mg or \u0026le;\u0026thinsp;500 mg, patients taking oral apatinib have advantages in objective response rate and disease control rate compared with the chemotherapy group \u003csup\u003e[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. The clinical research recommendation for apatinib is also 850 mg/d \u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. However, in the study by Tian Chunyan \u003csup\u003e[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e and others on the efficacy and safety of different doses of apatinib in patients with advanced GC, the initial dose was \u0026le;\u0026thinsp;500 mg. The efficacy of the drug is equivalent to that of patients taking the initial dose of 850 mg, while the safety and tolerability are better than the latter. Taken together, for patients with advanced GC who have good physical status or whose first-line chemotherapy is single drug/double drug combination therapy, oral apatinib at a low initial dose and in increasing doses has better efficacy and safety.\u003c/p\u003e \u003cp\u003eCompared with other people\u0026rsquo;s research, our research has the following advantages.First,our study adopts more qualified literature inclusion and exclusion criteria; second, the number of samples included in the studies is larger than before, which enables us to evaluate the efficacy and safety of the data with strong stability; finally, we use more Comprehensive endpoints examined outcomes with full dose apatinib. However, our study still has some limitations.First, the studies included in this META included four retrospective studies and the sample size was small. Second, these studies are all from China, an area with a high incidence of GC. Third, such as the type of chemotherapy regimen and different doses of apatinib, the selection of these specific treatment regimens may be based on the patient\u0026rsquo;s physical condition and economic conditions, and there is a selection bias. Patients with good general conditions and economic conditions may be inclined to choose targeted therapy, while patients with general conditions and poor economic conditions may be willing to accept single therapy. Fourth, during quality assessment,the Jadad and NOS scales are subjectively conducted by researchers, and their assessment results may be biased.Finally, although we have taken into account the heterogeneity of the data in these studies, some other factors in the baseline characteristics of the study, such as the location, number and size of the tumors and other factors such as the general health status of the patients, are not consistent across the trials and may will confuse the conclusions.In summary,Apatinib combined with chemotherapy, as a treatment option for intermediate and advanced GC, shows better efficacy, and the safety is tolerable and controllable.This conclusion still needs to be verified by more large-sample, multi-center, and high-quality studies in the future.Despite the above limitations, this study still provides clinical guidance for the efficacy and safety of apatinib combined with chemotherapy in intermediate and advanced GC, and has certain clinical significance.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn this meta-analysis, we compared the efficacy and safety of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced GC.The results showed that compared with the chemotherapy group, apatinib combined with chemotherapy has better efficacy and controllable safety in advanced GC.\u003c/p\u003e \u003cp\u003eThus, this study supports the feasibility of this treatment for advanced.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(I) Conception and design:\u0026nbsp;HY Wang,\u0026nbsp;YQ Li,D Pan,HN Liu,ZY Yao; (II) Administrative support:\u0026nbsp;HY Wang; (III) Provision of study materials or patients:\u0026nbsp;YQ Li,D Pan,HN Liu,ZY Yao; (IV) Collection and assembly of data:\u0026nbsp;YQ Li,D Pan,HN Liu,ZY Yao; (V) Data analysis and interpretation:HN Liu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all staff members involved in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFounding\u003c/strong\u003e: None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFootnote\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReporting Checklist:The meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta-Analyses statement.\u003c/p\u003e\n\u003cp\u003eConflicts of Interest: All authors have completed the ICMJE uniform disclosure form. The authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003eEthical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA: a cancer journal for clinicians, 2018, 68(6): 394\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWANG F H, SHEN L, LI J, et al. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer [J]. Cancer communications (London, England), 2019, 39(1): 10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSEXTON R E, AL HALLAK M N, DIAB M, et al. Gastric cancer: a comprehensive review of current and future treatment strategies [J]. Cancer metastasis reviews, 2020, 39(4): 1179\u0026ndash;203.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLORDICK F, CARNEIRO F, CASCINU S, et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up [J]. Annals of oncology: official journal of the European Society for Medical Oncology, 2022, 33(10): 1005\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGUAN W L, HE Y, XU R H. Gastric cancer treatment: recent progress and future perspectives [J]. Journal of hematology \u0026amp; oncology, 2023, 16(1): 57.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCARRASCO-GARCIA E, GARC\u0026iacute;A-PUGA M, AREVALO S, et al. Towards precision medicine: linking genetic and cellular heterogeneity in gastric cancer [J]. Therapeutic advances in medical oncology, 2018, 10(1758835918794628.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZHANG H. Apatinib for molecular targeted therapy in tumor [J]. Drug design, development and therapy, 2015, 9(6075-81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTIAN S, QUAN H, XIE C, et al. YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo [J]. Cancer science, 2011, 102(7): 1374\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLI J, ZHAO X, CHEN L, et al. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies [J]. BMC cancer, 2010, 10(529.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLI J, QIN S, WEN L, et al. 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European journal of epidemiology, 2010, 25(9): 603\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHIGGINS J P, THOMPSON S G, DEEKS J J, et al. Measuring inconsistency in meta-analyses [J]. BMJ (Clinical research ed), 2003, 327(7414): 557\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLU B, LU C, SUN Z, et al. Combination of apatinib mesylate and second-line chemotherapy for treating gastroesophageal junction adenocarcinoma [J]. The Journal of international medical research, 2019, 47(5): 2207\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWANG H F, WANG H H, YE X J, et al. Therapeutic effects and safety of apatinib mesylate on patients with gastric carcinoma peritoneal metastasis in SOX scheme [J]. European review for medical and pharmacological sciences, 2023, 27(14): 6627\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZHANG Y, ZHANG B, YANG J, et al. Perioperative Safety and Effectiveness of Neoadjuvant Therapy with Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel Plus Apatinib in Locally Advanced Gastric Cancer [J]. Cancer management and research, 2021, 13(2279\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZHOU P Z, GAO L, WU W, et al. Clinical effects of Apatinib combined with DOS neoadjuvant chemotherapy regimen in neoadjuvant chemotherapy for LAGC [J]. Pakistan journal of medical sciences, 2021, 37(7): 1890\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWANG Z, HE T, YU D, et al. Neoadjuvant apatinib plus tegafur/gimeracil/oteracil potassium (S\u0026ndash;1)/oxaliplatin chemotherapy vs. chemotherapy alone in patients with locally advanced gastric carcinoma [J]. Experimental and therapeutic medicine, 2022, 24(4): 625.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYUAN M, WANG Z, ZHANG Y, et al. Safety Analysis of Apatinib Combined with Chemotherapy in the Treatment of Advanced Gastric Carcinoma: A Randomised Controlled Trial [J]. Journal of oncology, 2021, 2021(5177140.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWU Q, FU Y, WEN W, et al. Efficacy and prognosis analyses of apatinib combined with S-1 in third-line chemotherapy for advanced gastric cancer [J]. Journal of BUON: official journal of the Balkan Union of Oncology, 2020, 25(2): 987\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSUN Y, FAN Y, YE Z, et al. Apatinib plus chemotherapy versus chemotherapy alone as neoadjuvant therapy in locally advanced gastric carcinoma patients: a prospective, cohort study [J]. Irish journal of medical science, 2023, 192(3): 1033\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZHANG F, YIN Y, NI T, et al. Treatment effect of apatinib combined chemotherapy as second-line or above therapy in patients with advanced gastric cancer or adenocarcinoma of the gastroesophageal junction [J]. Die Pharmazie, 2020, 75(8): 389\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNIE C, LV H, CHEN B, et al. High DCR and Better Survival in Patients with Advanced or Metastatic Gastric Cancer Receiving Anti-Angiogenic TKI plus Chemotherapy: A Real-World Study [J]. Technology in cancer research \u0026amp; treatment, 2023, 22(15330338221150561.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHONG D, WEI Y, ZANG A, et al. Effect of apatinib combined with chemotherapy on quality of life and related complications in patients with advanced gastric cancer [J]. Tropical Journal of Pharmaceutical Research, 2022, 20(8): 1715\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGUO Y, TANG J, HUANG X E, et al. Efficacy and toxicity of apatinib combined with or without chemotherapy for patients with advanced or metastatic chemotherapy-refractory gastric adenocarcinoma: A prospective clinical study [J]. Medicine, 2019, 98(6): e13908.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGAO S, LI X, SHI W, et al. Efficacy of the Low Dose Apatinib plus Chemotherapy on Advanced Gastric Carcinoma [J]. Journal of oncology, 2022, 2022(3009494.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLIU X, QIN S, WANG Z, et al. Early presence of anti-angiogenesis-related adverse events as a potential biomarker of antitumor efficacy in metastatic gastric cancer patients treated with apatinib: a cohort study [J]. Journal of hematology \u0026amp; oncology, 2017, 10(1): 153.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWAGNER A D, GROTHE W, HAERTING J, et al. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data [J]. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 2006, 24(18): 2903\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBANG Y J, VAN CUTSEM E, FEYEREISLOVA A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial [J]. Lancet (London, England), 2010, 376(9742): 687\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHAWKES E, OKINES A F, PAPAMICHAEL D, et al. Docetaxel and irinotecan as second-line therapy for advanced oesophagogastric cancer [J]. European journal of cancer (Oxford, England: 1990), 2011, 47(8): 1146\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAJANI J A, D'AMICO T A, BENTREM D J, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology [J]. Journal of the National Comprehensive Cancer Network: JNCCN, 2022, 20(2): 167\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFUCHS C S, TOMASEK J, YONG C J, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial [J]. Lancet (London, England), 2014, 383(9911): 31\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWILKE H, MURO K, VAN CUTSEM E, 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 [J]. The Lancet Oncology, 2014, 15(11): 1224\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIWASA S, BANDO H, PIAO Y, et al. The clinical position of ramucirumab-containing regimens for advanced gastric cancer: a review of clinical trial data [J]. Future oncology (London, England), 2022, 18(21): 2709\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFERRARA N, GERBER H P, LECOUTER J. The biology of VEGF and its receptors [J]. Nature medicine, 2003, 9(6): 669\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMI Y J, LIANG Y J, HUANG H B, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters [J]. Cancer research, 2010, 70(20): 7981\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLI J, QIN S, XU J, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial [J]. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 2013, 31(26): 3219\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQIN S K,LI J.Expert consensus on the clinical application of apatinib for gastric cancer [J].Journal of Clinical Oncology,2015, 20(9): 841\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTIAN C Y,PENG R,BAI T T, et al. Adverse effects and efficacy of apatinib at different starting doses in advanced gastric cancer[J].Journal of Practical Oncology.2018, 33(1): 66\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003eTable 2. Quality assessment of NOS\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSelection\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparability\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome/Exposure\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlobal\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\" valign=\"top\"\u003e\n \u003cp\u003eYonglei Zhang 2021；15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\" valign=\"top\"\u003e\n \u003cp\u003eQiuju Wu 2019；19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\" valign=\"top\"\u003e\n \u003cp\u003eFengli Zhang 2020；21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\" valign=\"top\"\u003e\n \u003cp\u003eCaiyun Nie 2023；22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.99099099099099%\" valign=\"top\"\u003e\n \u003cp\u003eDan Hong 2021；23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.513513513513514%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"19.45945945945946%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.765765765765767%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.27027027027027%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: NOS, Castle-Ottawa Scale.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Meta-analysis of gastric cancer, apatinib chemotherapy, efficacy and safety","lastPublishedDoi":"10.21203/rs.3.rs-3733354/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3733354/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eA meta-analysis was performed to compare the efficacy and safety of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced gastric cancer.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA computerized systematic search of databases such as PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, and VIP e-Journals was performed to find literature comparing apatinib combined with chemotherapy in the treatment of advanced gastric cancer.Literature search, quality assessment and data extraction were performed independently by two researchers. Stata 16 software was used to process and analyze the data. And, we assessed heterogeneity with I2 and p-value, and performed sensitivity analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 1217 patients with advanced gastric cancer were included in 13 studies, including 652 patients in the apatinib combined with chemotherapy group and 565 in the chemotherapy group.Meta-analysis results showed that the objective response rate (ORR) of the observation group was better than that of the control group(0R\u0026thinsp;=\u0026thinsp;2.49, 95% CI\u0026thinsp;=\u0026thinsp;1.86\u0026ndash;3.34), and the disease control rate (DCR) of the observation group was also better than that of the control group(OR\u0026thinsp;=\u0026thinsp;2.78,95% CI\u0026thinsp;=\u0026thinsp;2.11\u0026ndash;3.66).The R0 resection rate was also statistically significant(OR\u0026thinsp;=\u0026thinsp;2.31, 95% CI\u0026thinsp;=\u0026thinsp;1.09\u0026ndash;4.92).In addition, when comparing total adverse reactions (AEs) at any level, there was a statistical difference(OR\u0026thinsp;=\u0026thinsp;1.61, 95%CI\u0026thinsp;=\u0026thinsp;1.39\u0026ndash;1.86).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCompared with the chemotherapy group, apatinib combined with chemotherapy has better efficacy and controllable safety in advanced gastric cancer.\u003c/p\u003e","manuscriptTitle":"Safety and Efficacy of of apatinib combined with chemotherapy in the second-line and subsequent lines of advanced gastric cancer: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-13 19:30:10","doi":"10.21203/rs.3.rs-3733354/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"aafb8870-3239-422c-9bcd-00e8d71c7f95","owner":[],"postedDate":"December 13th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-30T19:29:16+00:00","versionOfRecord":[],"versionCreatedAt":"2023-12-13 19:30:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3733354","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3733354","identity":"rs-3733354","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}