Efficacy and safety of vascular-targeting agents plus chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal carcinoma patients：A multicenter observational clinical trial

Efficacy and safety of vascular-targeting agents plus chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal carcinoma patients：A multicenter observational clinical trial | 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 Efficacy and safety of vascular-targeting agents plus chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal carcinoma patients：A multicenter observational clinical trial Guanhong Luo, Guanjie Qin, Yixin Su, Yufei Pan, Jianxun Lu, Yueyun Xie, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4065562/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : Platinum-based chemotherapy is important for the treatment for recurrent or metastatic nasopharyngeal carcinomas (RM-NPCs). However, the prognosis of RM-NPC patients remains poor. This study evaluated the efficacy and safety of vascular-targeting agentsplus chemotherapy for RM-NPC treatment. Methods : This observational clinical trial, conducted at seven hospitals in Guangxi between January 2017 and December 2021, included 198 patients (158 males [79.8%]; median age, 51 years [IQR, 45–57years]). Chemotherapy was administered with and without vascular-targeting agents in 66 and 132 patients, respectively. The primary endpoint was progression-free survival (PFS), assessed by a blinded independent review committee according to RECIST v.1.1. The secondary end points were overall survival (OS) and safety. Results : After a median follow-up of 20 months, 31 (47.0%) and 82 (62.1%) deaths occurred in the combination therapy and chemotherapy alone groups, respectively. Median PFS was significantly higher in the combination group (7.0 months [95% CI, 5.7–8.3 months]) than in the chemotherapy alone group (5.0 months [95% CI, 4.1–5.9 months], P = 0.034), with a hazard ratio of 0.73 (95% CI, 0.54–0.98). The combination group exhibited a higher median OS compared to the chemotherapy alone group (37 months [95% CI, 21.3–52.7] vs. 20 months [95% CI, 13.0–27.0months], P = 0.047), representing a hazard ratio of 0.66 (95% CI, 0.45–0.97). In the combination therapy group, the most common adverse events were hypertension (n = 10/66 [15.1%]). Conclusion : The addition of vascular-targeting agents to chemotherapy for RM-NPC patients provided superior efficacy compared to chemotherapy alone, along with a manageable safety profile. Efficacy Nasopharyngeal carcinoma Targeted therapy plus chemotherapy Vascular targeting agents Anlotinib Apatinib Figures Figure 1 Highlights vascular-targeting agents plus chemotherapy demonstrated positive efficacy in patients with recurrent or metastatic nasopharyngeal carcinoma. vascular-targeting agents plus chemotherapy was well tolerated by nasopharyngeal carcinoma patients and had limited toxicity. The prognosis of patients with liver metastases treated with vascular-targeting agents plus chemotherapy was better. INTRODUCTION Nasopharyngeal carcinoma (NPC) is a head and neck cancer with an unbalanced geographical distribution; it is particularly prevalent in Southern China, East and Southeast Asia, and North Africa. Globally, approximately 129,000 new cases and 73,000 deaths attributed to NPCs are reported annually [1, 2]. The incidence of synchronous metastatic disease is about 5% in newly diagnosed patients. Additionally, approximately 20% of the non-metastatic NPC patients develop distant failure despite definitive treatments, accounting for the majority of deaths in these patients [3, 4]. Guideline-recommended platinum-based chemotherapy is an important treatment for metastatic NPC patients, but its efficacy in terms of median progression-free survival (PFS) and overall survival (OS) remains low [5]. Consequently, the treatment of recurrent or metastatic NPC (RM-NPC) patients remains a major challenge. Angiogenesis is an important step in the development of several malignant tumors, and vascular-targeting agents, including anlotinib and apatinib, are globally considered an important treatment for cancer. Apatinib is a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor (TKI) that selectively targets intracellular ATP-binding sites and has shown efficacy against various solid tumors [6–8]. Anlotinib (AL3818), an oral small-molecular TKI, exerts significant antiangiogenesis and anti-tumor growth effects by inactivating VEGFR and other factor receptors [9–11]. It is an important vascular-targeting agent and has been approved as the 3rd line treatment for locally advanced or metastatic non-small cell lung cancer. Vascular endothelial growth factor (VEGF) is highly expressed in NPCs and correlates with their survival, making them amenable to antiangiogenic therapy. A previous study reported VEGF overexpression in more than 60% of the clinical biopsy samples of NPC [12]. Co-expression of tumor VEGF and hypoxia-related growth factors in NPC is associated with poor prognosis, indicating the effectiveness of apatinib against NPC relapse and recurrences. In a phase II study of RM-NPCs, the observed objective response rate (ORR) was 36.4%, median OS was 16 months, and median PFS was 5.0 months in 33 patients. Vascular-targeting agents combined with chemotherapy are effective in the treatment of lung and colorectal cancers. These encouraging results prompted us to explore the efficacy of vascular-targeting agents combined with chemotherapy in RM-NPC patients, along with their potential synergistic effects. To our knowledge, the efficacy of vascular-targeting agents combined with chemotherapy has not previously been investigated in RM-NPC patients. This observational clinical trial aimed to evaluate the safety and efficacy of vascular-targeting agents combined with chemotherapy in RM-NPCs. METHODS Design of the study and its participants This was a multi-center, observational clinical trial conducted at seven hospitals in Guangxi between January 2017 and December 2021. The primary outcome measure was PFS. The secondary outcome measures were OS and adverse events (AEs). Patient data used in this study were anonymized, and all procedures were performed in accordance with the Declaration of Helsinki. The inclusion criteria were: (a) age of 18–75 years; (b) histological or cytological diagnosis of RM-NPC; (c) at least one cycle of vascular-targeting agents plus chemotherapy or chemotherapy alone following recurrence or metastasis; (d) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (e) at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1; (f) expected survival time > 3 months; (g) hemoglobin ≥ 90 g/L, absolute neutrophil count ≥ 1.5 × 10 9 /L, platelet count ≥ 80 × 10 9 /L, total bilirubin ≤ 1.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 ULN (≤ 5 ULN with liver metastasis), and serum creatinine ≤ 1.5 ULN.Exclusion criteria included: (a) previous vascular-targeting therapy; (b) difficulty in oral drug administration or absorption, including dysphagia, gastrointestinal resection, chronic diarrhea, and intestinal obstruction; (c) radiographic evidence of tumor invading tissues surrounding vital blood vessels; (d) pregnancy or breastfeeding; and (e) other simultaneous malignant tumors. Procedures and assessments In the combination therapy group, patients received conventional chemotherapy combined with vascular-targeting agents, including apatinib and anlotinib. Apatinib was administered orally at 250 mg once daily, with permitted dose interruptions and reductions (1–2 times) for toxicities that were not relieved by supportive treatment. The first dose reduction was to 250 mg for 2 days on/1 day off, followed by a second reduction to 250 mg on alternate days. Oral anlotinib (12 mg/d) was administered, defining each cycle as 2 weeks on-treatment followed by 1 week off-treatment. Treatment continued until disease progression or intolerance, with dose modifications (10 mg/d or 8 mg/d) based on protocol-defined criteria. Treatment was terminated if the dose of 8 mg/d could not be tolerated. Chemotherapy drugs included platinum, taxanes, fluoropyrimidine, and gemcitabine. Gemcitabine (1 g/m 2 ) was administered intravenously on days 1 and 8, with cisplatin (80 mg/m 2 ) intravenously on day 1. Paclitaxel (135 mg/m 2 ) and docetaxel (80 mg/m 2 ) were administered intravenously once every 21 days. Cisplatin (80 mg/m 2 ) and nedaplatin (80 mg/m 2 ) were administered intravenously once every 21 days. S-1 dosage was based on body surface area (BSA) (40 mg twice a day for BSA < 1.25 m 2 ; 50 mg twice a day for 1.25 m 2 ≤ BSA < 1.5 m 2 ; and 60 mg twice a day for BSA ≥ 1.5 m 2 ), given for 14 days, followed by a 7-day break, and repeated every 3 weeks for a maximum of four cycles or until disease progression, death, intolerable toxicity, or a patient-physician decision to terminate treatment. Fluorouracil (4 g/m 2 ) was administered via continuous intravenous infusion over 96 hours starting from day 1. Sequential dose interruptions or reductions were allowed for the management of toxicities, Grade ≥ 3 AEs, or intolerable Grade 2 AEs, ensuring that the interruptions did not exceed 2 weeks, and suspension did not exceed twice during each cycle. Baseline evaluation included a physical examination, ECOG status assessment, blood pressure measurement, complete blood count, blood chemistry panel, coagulation function test, routine urinalysis, routine stool test (occult blood testing), and baseline lesion evaluation through contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Treatment efficacy was assessed after every two cycles using contrast-enhanced CT or MRI. Follow-up after the last medication administration aimed to evaluate clinical outcomes, including toxicity, efficacy, and survival, until the patient’s death or data cutoff date. Endpoints The primary endpoint was PFS, defined as the duration from the initiation of vascular-targeting agents plus chemotherapy treatment to either disease progression or death from any cause. Secondary endpoints included OS, defined as the duration from the initiation of vascular-targeting agents plus chemotherapy treatment to death from any cause [13, 14]. Tumor response was assessed through imaging using RECIST 1.1 by an independent committee every two cycles until disease progression or death. AEs were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [15]. Statistical analysis This study was designed as an observational clinical trial, with PFS as the primary research endpoint and a follow-up duration of 20 months. Continuous variables were expressed as medians and interquartile range (IQR), and were compared using the t test. Categorical variables were presented as frequencies and percentages, and compared using the χ 2 test or Fisher’s exact test. Survival rates were estimated using the Kaplan-Meier method. Survival differences were compared using the log-rank test. Cox proportional hazards regression models were used to calculate the stratified hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). All statistical analyses were conducted using SPSS Statistics software, version 20.0. All P values were based on two-sided tests, with results deemed statistically significant at P ≤ 0 .05. Study oversight All participating centers' institutional review committees gave their approval for the trial program, which was carried out in compliance with the Declaration of Helsinki. Role of the funding source The funders of the study had no role in study design, data collection, data analysis, data interpretation, as well as writing the report. The corresponding author had the sole responsibility for choosing to submit the report for publication, and had complete access to all the data generated during the study. Results Patient characteristics Between January 2017 and December 2021, a total of 198 RM-NPC patients were enrolled in seven hospitals in Guangxi. Among them, 66 were in the vascular-targeting agents plus chemotherapy group, with 43 patients using anlotinib plus chemotherapy and 23 patients using apatinib plus chemotherapy. Additionally, 132 patients were included in the chemotherapy alone group. Baseline characteristics at treatment initiation are summarized in Table 1. The median age of the patients was 51 years (range: 45–57 years), and 79.8% were male. The most common metastatic sites at baseline were lungs (39.6%), bones (37.1%), and liver (35.1%). Vascular-targeting agents plus chemotherapy were administered to 32.7% of the patients, while 67.3% received chemotherapy alone. Baseline patient and tumor characteristics were balanced between the two treatment arms. Efficacy By the data cutoff on August 31, 2023, the median follow-up duration post-treatment was 20 months (IQR, 10–34 months) for both groups. Survival outcomes of the patients with RM-NPC are showed in Figure 1.In the combination therapy group, 31 of the 66 patients (47.0%) had died, compared to 82 of the 132 patients (62.1%) in the chemotherapy alone group. The median PFS in the combination therapy group was 7.0 months (95% CI, 5.7–8.3 months), significantly greater than that in the chemotherapy alone group (median PFS: 5.0 months [95% CI, 4.1–5.9 months]). The addition of vascular-targeting agents reduced the risk of disease progression by 27% (HR, 0.73 [95% CI, 0.54–0.98]; P = 0.034). Median OS was significantly longer in the combination group (37 months [95% CI, 21.3–52.7 months]) than in the chemotherapy alone group (20 months [95% CI, 13.0–27.0 months]), with a HR of 0.66 (95% CI, 0.45–0.97; P = 0.047). Multivariable analysis are summarized in Table 2. In multivariable analysis, the Combination therapy group was significantly associated with improved OS (combination group vs. chemotherapy alone, HR = 0.59, P = 0.013) and PFS (combination group vs. chemotherapy alone, HR = 0.71, P = 0.036). Liver metastasis and ECOG PS were also significantly associated with OS (liver metastasis vs. no metastasis, HR = 1.98, P = 0.001, ECOG PS 1 vs. 0, HR = 1.54, P = 0.029) and PFS (liver metastasis vs. no metastasis, HR = 1.43, P = 0.033, ECOG PS 1 vs. 0, HR = 1.45, P = 0.021). Subgroup analysis are summarized in Table 3 and Table 4, the liver metastasis group demonstrated significantly longer OS and PFS with combination therapy than with chemotherapy alone. The second-line treatment group showed significantly longer OS with combination therapy than with chemotherapy alone. ECOG PS 1 group exhibited significantly longer PFS with combination therapy than with chemotherapy alone. The lung metastasis group demonstrated significantly longer PFS with combination therapy than with chemotherapy alone. Safety Adverse events are summarized in Table 5,all 198 patients who received at least one dose of the study drug encountered at least one treatment-related AE (TRAE) during the study. The most prevalent TRAEs were leucopenia (54.0%), anemia (31.8%), proteinuria (30.3%), nausea (24.7%), and increased ALT (18.8%). However, the overall incidence of grade 3 or 4 TRAEs was low. The most common Grade 3 or 4 TRAEs included leucopenia (13.1%), neutropenia (9.6%), and thrombocytopenia (5.1%). No treatment-related deaths were observed. Hematologic AEs, biochemical AEs, electrolyte disturbances, and gastrointestinal AEs occurred with similar frequency in both arms. In the combination therapy group, the most common specific AEs were hypertension (n = 10/66; 15.2%), hand-foot syndrome (n = 20/66; 30.3%), proteinuria (n = 26/66; 39.4%), and hemorrhage (n = 7/66; 10.6%). In the combination therapy group, eight patients (12.1%) required one or more interruptions for vascular-targeting agents, and dose reductions were required in seven patients (10.6%). The most common reasons for dose reduction were hemorrhage (n = 4; 6.1%) and hand-foot syndrome (n = 3; 4.5%). In the chemotherapy group, dose reductions were required in 32 patients (24.2%). Discussion In this trial, RM-NPC patients who received vascular-targeting agents plus chemotherapy exhibited effective disease control with an acceptable toxicity profile. Subgroup analysis identified liver metastasis as a prognostic factor for treatment response. These findings support further clinical development of vascular-targeting agents plus chemotherapy for RM-NPCs, associated with dismal survival outcomes and limited treatment options. To our knowledge, this was the first study to report the efficacy and safety of vascular-targeting agents plus chemotherapy in the treatment of RM-NPCs. Apatinib and anlotinib, as oral vascular targeting agents for advanced tumors, demonstrated potential in our study. Combination therapy was associated with improved PFS and OS compared to chemotherapy alone, with manageable toxic profiles. Median PFS in the combination therapy and chemotherapy alone groups were 7.0 months and 5.0 months, respectively, representing a 27% reduction in the risk of disease progression. Median OS was significantly longer in the combination therapy group (37 months) than in the chemotherapy alone group (20 months), reflecting a 34% reduction in the risk of mortality. NPCs are known to be sensitive to platinum-based chemotherapy, with response rates ranging from 40–65%. Gemcitabine-cisplatin chemotherapy is an essential treatment for RM-NPCs, with response rates of 67% and a median OS of 29.1 months [16, 17]. The extension of full-dose chemotherapy after disease control may be challenging due to cumulative toxic effects and diminishing benefits. However, in the absence of further interventions, most patients with responsive metastatic NPCs experience disease progression soon after the first-line treatment. Compared with full-dose chemotherapy, combination therapy has good tolerability and could be an appealing strategy to further improve outcomes. There is a lack of standard second-line treatment regimens after the failure of first-line platinum-based chemotherapy for RM-NPC patients. These patients represent those with the most urgent unmet therapeutic needs. Several antiangiogenic multitargeted kinase inhibitors have been investigated in RM-NPCs. Early trials of sorafenib and sunitinib have demonstrated modest efficacy in RM-NPCs, but with a significant risk of fatal hemorrhage.[18, 19] In another study, apatinib therapy for RM-NPCs exhibited objective responses in 36% of the 33 patients, achieving a median PFS of 5 months and a median OS of 16 months. [20]In a phase II clinical study, the addition of the anti-VEGF antibody, bevacizumab, to paclitaxel plus carboplatin as first-line treatment failed to extend the PFS and OS of RM-NPC patients.[21] Molecular-targeted therapy has been extensively investigated for its effectiveness against specific genetic mutations, abnormal growth factor pathways, and angiogenesis in NPCs. Angiogenesis, influenced significantly by the microenvironment, is significantly regulated by VEGFR. Apatinib, a targeted therapy, selectively competes for ATP-binding sites on VEGFR-2, playing a crucial role in inhibiting angiogenesis. The high expression of VEGF and VEGFR in NPCs, along with the correlation of VEGF with survival outcomes, supports the use of antiangiogenic strategies in NPC treatment, particularly for RM-NPCs. The combination therapy group experienced more AEs than the chemotherapy alone group. In particular, hypertension, hand-foot syndrome, hemorrhage, and proteinuria occurred more frequently in the combination therapy group. As observed in previous studies, the administration of vascular-targeting agents, such as apatinib and anlotinib, was associated with hypertension and hand-foot syndrome, constituting the most common TRAEs. Grade 3 or 4 hand-foot syndrome (3.0%) and hemorrhage (1.5%) were the only severe AEs in the combination therapy group. However, most of the AEs were manageable through dose modifications, and no treatment-related deaths occurred. The safety profile of combination therapy appeared generally acceptable among patients receiving treatment for RM-NPCs[22, 23]. This study also had some limitations. First, this was a retrospective study and selection bias could not be excluded because of the lack of randomization. Second, the population size for the study was relatively small Third, the results of subgroup analysis may be limited by the small cohort size. Finally, only patients from Guangxi were enrolled in the trial, limiting the generalizability of the results. Future studies should assess the efficacy and safety of vascular-targeting agents plus chemotherapy in NPC patients from diverse ethnicities across different countries. CONCLUSIONS The addition of vascular-targeting agents to chemotherapy for the treatment of RM-NPCs exhibited superior efficacy compared to chemotherapy alone, along with a manageable safety profile. Further randomized controlled and prospective clinical studies with larger sample sizes are needed to confirm the efficacy of vascular-targeting agents combined with chemotherapy in RM-NPCs. Abbreviations RM-NPC Recurrent/metastatic nasopharyngeal carcinoma PFS Progression-free survival OS Overall survival NPC Nasopharyngeal carcinoma RECIST Response Evaluation Criteria in Solid Tumor AE Adverse event MRI Magnetic resonance imaging CT Computed tomography HR Hazard ratio CI Confidence interval VEGFR-2 Vascular endothelial growth factor receptor-2 ECOG Eastern Cooperative Oncology Group Declarations Ethics approval and consent to participate Studies involving human participants have been reviewed and approved by the Medical Ethics Committee of the Affiliated Hospital of Guilin Medical College . Informed consent to participate in this study was provided by the legal guardian/close relative of the participant. Consent for publication All authors read and approved the final manuscript for publication. Availability of data and material The data and material used to support the findings of this study are available from the corresponding author upon request. Funding Guangxi Medical and health key discipline construction project; The "139" Talent Cultivation Plan Program of Guangxi Medical High-level Backbone, The National Natural Science Foundation of China (No. 82160479); The CSCO Youth Innovative Oncology Research Fund (No. Y-Young2020-0520) Authors' contributions Wei Jiang, Guanjie Qin and Guanhong Luo conceived of the study, and participated in its design and coordination.Guanhong Luo, Guanjie Qin, Yixin Su, Yufei Pan, Jianxun Lu, Yueyun Xie,Bin Zhang,Jinxuan Dai, Xiangyun Kong, Yuan Xie, Xiaolan Ruan, Yunyan Mo, Ruyun Zhang and Wei Jiang participated in data collection.Guanhong Luo, Guanjie Qin, Yixin Su, Yufei Pan, Jianxun Lu, Yueyun Xie,Bin Zhang,Jinxuan Dai, Xiangyun Kong, Yuan Xie, Xiaolan Ruan, Yunyan Mo, Ruyun Zhang and Wei Jiang performed the statistical analysis.Wei Jiang and Guanhong Luo helped to draft the manuscript.All authors read and approved the final manuscript. Conflict of interest The authors declare that they have no conflict of interest. Ethical approval The study was approved by the Medical Ethics Committee of affiliated Hospital of Guilin Medical University. Informed consent Informed consent was obtained from all individual participants included in the study. Acknowledgements The authors are grateful to all patients and their families who participated in the study. References Chen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma JNasopharyngeal carcinoma. Lancet. 2019;394(10192):64-80. Erratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2020;70(4):313. Li AC, Xiao WW, Shen GZ, et al. Distant metastasis risk and patterns of nasopharyngeal carcinoma in the era of IMRT: long-term results and benefits of chemotherapy.Oncotarget.2015;6(27):24511-24521. Wong KCW, Hui EP, Lo K-W, et al. Nasopharyngeal carcinoma: an evolving paradigm. 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Apatinib for the treatment of metastatic or locoregionally recurrent nasopharyngeal carcinoma after failure of chemotherapy: A multicenter, single-arm, prospective phase 2 study. Cancer. 2021 Sep 1;127(17):3163-3171. Zhou T, Yang Y, Ma S, Lin L, Zhou T, Zhang C, Ding X, Wang R, Feng G, Chen Y, et al. Bevacizumab versus placebo in combination with paclitaxel and carboplatin as frst-line treatment for recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase II trial. ESMO Open. 2021;6(6):100313. Zhang Y, Han C, Li J, Zhang L, Wang L, Ye S, Hu Y, Bai L (2017)Efficacy and safety for Apatinib treatment in advanced gastric cancer: a real world study. Sci Rep 7:13208 Lin Y, Wu Z, Zhang J et al (2017) Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment. Tumor Biol39:101042831771103. Tables Table1 . Baseline Characteristics Characteristics combination therapy group（n=66) chemotherapy alone group(n=132) P Sex 0.802 Male 52(78.7%) 106（80.3%） Female 14（21.3%） 26（19.7%） metastasis at the initial diagnosis 0.575 Yes 20(30.3%) 35(27.2%) No 46(69.7%) 97(72.8%) initial TNM stage 0.292 III 26（39.4%） 42（31.8%） IVA 20（30.3%） 55（41.7%） IVB 20（30.3%） 35（26.5%） Age, years 1 > 50 30(45.5%) 60(45.5%) ≤ 50 36(54.5%) 72(54.5%) metastasis Liver metastasis 25（37.9%） 45（34.1%） 0.599 Lung metastasis 26（39.4%） 54（40.9%） 0.838 Bone metastasis 26（39.4%） 46（34.8%） 0.531 Other 7(10.6%) 11(8.3%) 0.556 metastasis site number 1 28（42.4%） 65（49.2%） 0.267 2 18（27.3%） 33（25.0%） 0.644 3 7（10.6%） 8（6.1%） 0.255 metastasis+Recurrent 0.674 Yes 9（13.6%） 21（15.9%） No 57(86.4%) 111(84.1%) ECOG PS 0.667 0 46(69.7%) 88(66.7%) 1 20(30.3%) 44(33.3%) Line of chemotherapy therapy 0.763 1 line of chemotherapy therapy 35（53.0%） 67(50.8%) 2 line of chemotherapy therapy 31（47.0%) 65(49.2%) immunotherapy 1 YES 12(18.2%) 24(18.2%) NO 54(81.8%) 108(81.8%) vascular targeting agents anlotinib 43(65.2%) apatinib 23(34.8%) Chemotherapy drugs 0.006 GP 11（16.7%） 40（30.3%) TP 14（21.2%） 46（34.8%） S-1 23（34.8%） 25(18.9%） other 13(19.7%) 12(9.1%) PF 5(7.6%) 9(6.8%) Abbreviations : ECOG , Eastern cooperative oncology group,FP, fluorouracil plus platinum; GP, gemcitabine plus platinum;TP, paclitaxel plus platinum Table 2 . multivariate analysis of PFS and OS OS PFS HR（95%CI） P HR（95%CI） P Liver metastasis 0.001 0.029 No 1.00 1.00 Yes 2.00（1.35-2.97） 1.44（1.04-1.99） Lung metastasis 0.571 0.969 No 1 1 Yes 0.89(0.60-1.33) 0.99(0.72-1.37) Bone metastasis 0.703 0.414 No 1 1 Yes 1.08(0.73-1.61) 0.88(0.64-1.20) Sex 0.427 0.219 Male 1 1 Female 0.83(0.52-1.32) 0.79(0.55-1.15) Age, years 0.884 0.176 ≤ 50 1 1 ＞50 1.03(0.71-1.50) 0.81(0.60-1.10) Number of treatment lines 0.117 0.021 1 1.00 1.00 2 1.35（0.93-1.98） 1.45（1.06-1.99） ECOG PS 0.026 0.02 0 1.00 1.00 1 1.55（1.05-2.28） 1.46（1.06-2.01） therapy group 0.013 0.036 combination therapy group 0.59(0.38-0.89) 0.71(0.52-0.98) Chemotheray alone group 1 1 ECOG PS, Eastern Cooperative Oncology Group performance status; PFS,progression-free survival;OS, overall survival Table 3 .PFS HRs (combination therapy group vs chemotherapy alone group) in subgroups Subgroups combination therapy group chemotherapy alone group HR(95%CI) (combination therapy group vs chemotherapy alone group) P Patients Median PFS（months） Patients Median PFS（months） All patients 66 7 132 5 0.73(0.56-0.99） 0.049 Liver metastasis Yes 25(37.9%) 7 45(34.1%) 6 0.55（0.33-0.91） 0.021 No 41(62.1%) 8 87(65.9%) 4 0.80（0.54-1.18） 0.259 Recurrence or metastasis at the initial diagnosis Yes 20(30.3%) 8 35(26.5%) 5 0.68（0.37-1.22） 0.196 No 46(69.7%) 7 97(73.5%) 5 0.76（0.53-1.11） 0.15 Number of treatment lines 1 35(53.0%) 8 67(50.8%） 6 0.75（0.49-1.16） 0.203 2 31(57.0%) 6 65(49.2%) 4 0.71（0.46-1.11） 0.135 Sex Male 52(78.8%) 7 106(80.3%） 5 0.75（0.53-1.06） 0.102 Female 14(21.2%) 8 26（19.7%） 7 0.65（0.32-1.29） 0.215 Age, years > 50 36(54.5%) 8 72（54.5%) 6 0.69（0.45-1.06） 0.093 ≤ 50 30(45.5%) 6 60（45.5%） 5 0.80（0.51-1.26） 0.335 ECOG 0 46(69.7%) 7 88（66.7%) 6 0.80（0.55-1.17） 0.251 1 20(30.3%) 7 44（33.3%） 4 0.55（0.32-0.94） 0.03 Lung metastasis Yes 26(39.3%) 8 54(40.9%) 6 0.55（0.33-0.91） 0.02 No 40(60.7%) 6 78(59.1%) 5 0.83（0.56-1.23） 0.341 Bone metastasis Yes 26(39.3%) 8 46(34.8%) 5 0.79（0.48-1.31） 0.359 No 40(60.7%) 7 86(65.2%) 6 0.72（0.48-1.07） 0.104 drugs 0.213 anlotinib 43(65.2%) 7 1 apatinib 23(34.8%) 8 0.70（0.40-1.23） ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS,progression-free survival; Table 4 .OS HRs (combination therapy group vs chemotherapy alone group) in subgroups Subgroups combination therapy group chemotherapy alone group HR(95%CI) (combination therapy group vs chemotherapy alone group) P Patients Median OS（months） Patients Median OS（months） All patients 66 37 132 20 0.67(0.44-1.00） 0.052 Liver metastasis Yes 25(37.9%) 23 45(34.1%) 11 0.45（0.25-0.83） 0.01 No 41(62.1%) NR 87(65.9%) 32 0.77（0.43-1.36） 0.363 Recurrence or metastasis at the initial diagnosis Yes 20(30.3%) NR 35(26.5%) 11 0.39（0.18-0.87） 0.021 No 46(69.7%) 32 97(73.5%) 25 0.82（0.51-1.33） 0.419 Number of treatment lines 1 35(53.0%) 37 67(50.8%） 30 0.89（0.51-1.55） 0.67 2 31(47.0%) NR 65(49.2%) 16 0.48（0.26-0.89） 0.019 Sex Male 52(78.8%) 37 106(80.3%） 20 0.71（0.45-1.12） 0.141 Female 14(21.2%) NR 26（19.7%） 25 0.49（0.18-1.32） 0.158 Age, years > 50 36(54.5%) 37 72（54.5%) 18 0.72（0.41-1.24） 0.235 ≤ 50 30(45.5%) NR 60（45.5%） 20 0.62（0.33-1.16） 0.132 ECOG 0 46(69.7%) 45 88（66.7%) 29 0.75（0.45-1.26） 0.279 1 20(30.3%) 31 44（33.3%） 13 0.54（0.27-1.10） 0.088 Lung metastasis Yes 26(39.3%) 45 54(40.9%) 20 0.55（0.28-1.09） 0.088 No 40(60.7%) 23 78(59.1%) 18 0.75（0.44-1.26） 0.251 Bone metastasis Yes 26(39.3%) 31 46(34.8%) 16 0.73（0.38-1.37） 0.321 No 40(60.7%) NR 86(65.2%) 23 0.61（0.35-1.06） 0.08 drugs 0.36 anlotinib 43(65.2%) 32 1 apatinib 23(34.8%) 45 0.70（0.33-1.50） ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival; Table 5. Cumulative acute adverse events combination therapy group(n=66) chemotherapy alone group(n=132) All Grades Grade1-2 Grade3-4 All Grades Grade1-2 Grade3-4 P（All Grades ） Hematologic adverse events Leukopenia 33（50.0%） 24（36.4%） 9（13.6%） 74（56.1%） 57(43.2%) 17(12.9%) 0.42 Neutropenia 11（16.7%） 6（9.1%） 5（7.6%） 23（17.4%) 9(6.8%) 14(10.6%) 0.894 Anemia 19（28.8%） 17（25.8%） 2（3.0%） 44(33.3%) 40(30.3%) 4(3.0%) 0.517 Thrombocytopenia 11（16.7%） 9（13.6%） 2（3.0%） 16(12.1%) 8(6.1%) 8(6.1%) 0.38 Biochemical adverse events Creatinine increase 3（4.5%） 2（3.0%） 1（1.5%） 3(2.3%) 3(2.3%) 0（0%） 0.379 ALT increased 9（13.6%） 9（13.6%） 0（0%） 29(22.0%) 27(20.5%) 2(1.5%) 0.16 AST increased 10（15.1%） 10（15.1%） 0（0%） 28(21.2%) 28(21.2%) 0（0%） 0.307 Total bilirubin increased 9（13.6%） 9（13.6%） 0（0%） 18(13.6%) 18(13.6%) 0（0%） 1 Electrolyte disturbance Hyponatremia 8（12.1%） 3（4.5%） 5（7.6%） 10(7.6%) 9(6.8%) 1（0.8%） 0.294 hypochloraemia 10（15.1%） 10（15.1%） 0（0%） 13(9.8%) 12(9.0%) 1（0.8%） 0.272 Hypokalemia 2（3.0%） 2（3.0%） 0（0%） 6(4.5%) 6(4.5%) 0（0%） 0.61 Gastrointestinal adverse events Nausea 16（24.2%） 16（24.2%） 0（0%） 33(25.0%) 33(25.0%) 0（0%） 0.907 Anorexia 11（16.7%） 11（16.7%） 0（0%） 23(17.4%) 23(17.4%) 0（0%） 0.894 other hematuresis 7（10.6%） 7（10.6%） 0（0%） 21(15.9%) 21(15.9%) 0（0%） 0.313 Proteinuria 26（39.4%） 26（39.4%） 0（0%） 34(25.8%) 34(25.8%) 0（0%） 0.049 fecal occult blood 5（7.6%） 5（7.6%） 0（0%） 12(9.1%) 12(9.1%) 0（0%） 0.72 Hand-foot syndrome 20（30.3%） 18（27.3%） 2（3.0%） 7(5.3%) 7(5.3%) 0（0%） 0.001 Hypertension 10（15.2%） 10（15.2%） 0（0%） 0（0%） 0（0%） 0（0%） 0.001 Hemorrhage 7（10.6%） 6（9.1%） 1（1.5%） 1（0.8%） 1（0.8%） 0（0%） 0.001 ALT Alanine aminotransferase, AST Aspartate aminotransferase Additional Declarations No competing interests reported. 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14:17:44","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4065562/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4065562/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53754208,"identity":"14a78b82-07da-433e-be88-04b65ad30ab1","added_by":"auto","created_at":"2024-03-29 18:57:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":639417,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival outcomes of the patients with RM-NPC. Kaplan-Meier plots showing overall survival (A) and progression-free survival(B).\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4065562/v1/24b7f7c2984f30577c8a9a5d.png"},{"id":55307319,"identity":"86e6c2d5-c10f-4484-876f-9337a04cfe36","added_by":"auto","created_at":"2024-04-25 13:49:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1041371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4065562/v1/37a81575-bdd5-497f-8c5c-0fe996c8af72.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of vascular-targeting agents plus chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal carcinoma patients：A multicenter observational clinical trial","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003evascular-targeting agents plus chemotherapy demonstrated positive efficacy in patients with recurrent or metastatic nasopharyngeal carcinoma.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;vascular-targeting agents plus chemotherapy was well tolerated by nasopharyngeal carcinoma patients and had limited toxicity.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;The prognosis of patients with liver metastases treated with vascular-targeting agents plus chemotherapy was better.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eNasopharyngeal carcinoma (NPC) is a head and neck cancer with an unbalanced geographical distribution; it is particularly prevalent in Southern China, East and Southeast Asia, and North Africa. Globally, approximately 129,000 new cases and 73,000 deaths attributed to NPCs are reported annually [1, 2]. The incidence of synchronous metastatic disease is about 5% in newly diagnosed patients. Additionally, approximately 20% of the non-metastatic NPC patients develop distant failure despite definitive treatments, accounting for the majority of deaths in these patients [3, 4]. Guideline-recommended platinum-based chemotherapy is an important treatment for metastatic NPC patients, but its efficacy in terms of median progression-free survival (PFS) and overall survival (OS) remains low [5]. Consequently, the treatment of recurrent or metastatic NPC (RM-NPC) patients remains a major challenge.\u003c/p\u003e \u003cp\u003eAngiogenesis is an important step in the development of several malignant tumors, and vascular-targeting agents, including anlotinib and apatinib, are globally considered an important treatment for cancer. Apatinib is a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor (TKI) that selectively targets intracellular ATP-binding sites and has shown efficacy against various solid tumors [6\u0026ndash;8]. Anlotinib (AL3818), an oral small-molecular TKI, exerts significant antiangiogenesis and anti-tumor growth effects by inactivating VEGFR and other factor receptors [9\u0026ndash;11]. It is an important vascular-targeting agent and has been approved as the 3rd line treatment for locally advanced or metastatic non-small cell lung cancer. Vascular endothelial growth factor (VEGF) is highly expressed in NPCs and correlates with their survival, making them amenable to antiangiogenic therapy. A previous study reported VEGF overexpression in more than 60% of the clinical biopsy samples of NPC [12]. Co-expression of tumor VEGF and hypoxia-related growth factors in NPC is associated with poor prognosis, indicating the effectiveness of apatinib against NPC relapse and recurrences. In a phase II study of RM-NPCs, the observed objective response rate (ORR) was 36.4%, median OS was 16 months, and median PFS was 5.0 months in 33 patients. Vascular-targeting agents combined with chemotherapy are effective in the treatment of lung and colorectal cancers. These encouraging results prompted us to explore the efficacy of vascular-targeting agents combined with chemotherapy in RM-NPC patients, along with their potential synergistic effects.\u003c/p\u003e \u003cp\u003eTo our knowledge, the efficacy of vascular-targeting agents combined with chemotherapy has not previously been investigated in RM-NPC patients. This observational clinical trial aimed to evaluate the safety and efficacy of vascular-targeting agents combined with chemotherapy in RM-NPCs.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign of the study and its participants\u003c/h2\u003e \u003cp\u003eThis was a multi-center, observational clinical trial conducted at seven hospitals in Guangxi between January 2017 and December 2021. The primary outcome measure was PFS. The secondary outcome measures were OS and adverse events (AEs). Patient data used in this study were anonymized, and all procedures were performed in accordance with the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eThe inclusion criteria were: (a) age of 18\u0026ndash;75 years; (b) histological or cytological diagnosis of RM-NPC; (c) at least one cycle of vascular-targeting agents plus chemotherapy or chemotherapy alone following recurrence or metastasis; (d) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; (e) at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1; (f) expected survival time\u0026thinsp;\u0026gt;\u0026thinsp;3 months; (g) hemoglobin\u0026thinsp;\u0026ge;\u0026thinsp;90 g/L, absolute neutrophil count\u0026thinsp;\u0026ge;\u0026thinsp;1.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, platelet count\u0026thinsp;\u0026ge;\u0026thinsp;80 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L, total bilirubin\u0026thinsp;\u0026le;\u0026thinsp;1.5 times the upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)\u0026thinsp;\u0026le;\u0026thinsp;2.5 ULN (\u0026le;\u0026thinsp;5 ULN with liver metastasis), and serum creatinine\u0026thinsp;\u0026le;\u0026thinsp;1.5 ULN.Exclusion criteria included: (a) previous vascular-targeting therapy; (b) difficulty in oral drug administration or absorption, including dysphagia, gastrointestinal resection, chronic diarrhea, and intestinal obstruction; (c) radiographic evidence of tumor invading tissues surrounding vital blood vessels; (d) pregnancy or breastfeeding; and (e) other simultaneous malignant tumors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eProcedures and assessments\u003c/h2\u003e \u003cp\u003eIn the combination therapy group, patients received conventional chemotherapy combined with vascular-targeting agents, including apatinib and anlotinib. Apatinib was administered orally at 250 mg once daily, with permitted dose interruptions and reductions (1\u0026ndash;2 times) for toxicities that were not relieved by supportive treatment. The first dose reduction was to 250 mg for 2 days on/1 day off, followed by a second reduction to 250 mg on alternate days. Oral anlotinib (12 mg/d) was administered, defining each cycle as 2 weeks on-treatment followed by 1 week off-treatment. Treatment continued until disease progression or intolerance, with dose modifications (10 mg/d or 8 mg/d) based on protocol-defined criteria. Treatment was terminated if the dose of 8 mg/d could not be tolerated.\u003c/p\u003e \u003cp\u003eChemotherapy drugs included platinum, taxanes, fluoropyrimidine, and gemcitabine. Gemcitabine (1 g/m\u003csup\u003e2\u003c/sup\u003e) was administered intravenously on days 1 and 8, with cisplatin (80 mg/m\u003csup\u003e2\u003c/sup\u003e) intravenously on day 1. Paclitaxel (135 mg/m\u003csup\u003e2\u003c/sup\u003e) and docetaxel (80 mg/m\u003csup\u003e2\u003c/sup\u003e) were administered intravenously once every 21 days. Cisplatin (80 mg/m\u003csup\u003e2\u003c/sup\u003e) and nedaplatin (80 mg/m\u003csup\u003e2\u003c/sup\u003e) were administered intravenously once every 21 days. S-1 dosage was based on body surface area (BSA) (40 mg twice a day for BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.25 m\u003csup\u003e2\u003c/sup\u003e; 50 mg twice a day for 1.25 m\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026le;\u0026thinsp;BSA\u0026thinsp;\u0026lt;\u0026thinsp;1.5 m\u003csup\u003e2\u003c/sup\u003e; and 60 mg twice a day for BSA\u0026thinsp;\u0026ge;\u0026thinsp;1.5 m\u003csup\u003e2\u003c/sup\u003e), given for 14 days, followed by a 7-day break, and repeated every 3 weeks for a maximum of four cycles or until disease progression, death, intolerable toxicity, or a patient-physician decision to terminate treatment. Fluorouracil (4 g/m\u003csup\u003e2\u003c/sup\u003e) was administered via continuous intravenous infusion over 96 hours starting from day 1. Sequential dose interruptions or reductions were allowed for the management of toxicities, Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs, or intolerable Grade 2 AEs, ensuring that the interruptions did not exceed 2 weeks, and suspension did not exceed twice during each cycle.\u003c/p\u003e \u003cp\u003eBaseline evaluation included a physical examination, ECOG status assessment, blood pressure measurement, complete blood count, blood chemistry panel, coagulation function test, routine urinalysis, routine stool test (occult blood testing), and baseline lesion evaluation through contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI). Treatment efficacy was assessed after every two cycles using contrast-enhanced CT or MRI. Follow-up after the last medication administration aimed to evaluate clinical outcomes, including toxicity, efficacy, and survival, until the patient\u0026rsquo;s death or data cutoff date.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEndpoints\u003c/h2\u003e \u003cp\u003eThe primary endpoint was PFS, defined as the duration from the initiation of vascular-targeting agents plus chemotherapy treatment to either disease progression or death from any cause. Secondary endpoints included OS, defined as the duration from the initiation of vascular-targeting agents plus chemotherapy treatment to death from any cause [13, 14]. Tumor response was assessed through imaging using RECIST 1.1 by an independent committee every two cycles until disease progression or death. AEs were evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) [15].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThis study was designed as an observational clinical trial, with PFS as the primary research endpoint and a follow-up duration of 20 months. Continuous variables were expressed as medians and interquartile range (IQR), and were compared using the \u003cem\u003et\u003c/em\u003e test. Categorical variables were presented as frequencies and percentages, and compared using the χ\u003csup\u003e2\u003c/sup\u003e test or Fisher\u0026rsquo;s exact test. Survival rates were estimated using the Kaplan-Meier method. Survival differences were compared using the log-rank test. Cox proportional hazards regression models were used to calculate the stratified hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). All statistical analyses were conducted using SPSS Statistics software, version 20.0. All \u003cem\u003eP\u003c/em\u003e values were based on two-sided tests, with results deemed statistically significant at \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0 .05.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStudy oversight\u003c/h2\u003e \u003cp\u003eAll participating centers' institutional review committees gave their approval for the trial program, which was carried out in compliance with the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRole of the funding source\u003c/h2\u003e \u003cp\u003eThe funders of the study had no role in study design, data collection, data analysis, data interpretation, as well as writing the report. The corresponding author had the sole responsibility for choosing to submit the report for publication, and had complete access to all the data generated during the study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween January 2017 and December 2021, a total of 198 RM-NPC patients were enrolled in seven hospitals in Guangxi. Among them, 66 were in the vascular-targeting agents plus chemotherapy group, with 43 patients using anlotinib plus chemotherapy and 23 patients using apatinib plus chemotherapy. Additionally, 132 patients were included in the chemotherapy alone group. Baseline characteristics at treatment initiation are summarized in Table 1. The median age of the patients was 51 years (range: 45\u0026ndash;57 years), and 79.8% were male. The most common metastatic sites at baseline were lungs (39.6%), bones (37.1%), and liver (35.1%). Vascular-targeting agents plus chemotherapy were administered to 32.7% of the patients, while 67.3% received chemotherapy alone. Baseline patient and tumor characteristics were balanced between the two treatment arms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBy the data cutoff on August 31, 2023, the median follow-up duration post-treatment was 20 months (IQR, 10\u0026ndash;34 months) for both groups. Survival outcomes of the patients with RM-NPC are showed in Figure 1.In the combination therapy group, 31 of the 66 patients (47.0%) had died, compared to 82 of the 132 patients (62.1%) in the chemotherapy alone group. The median PFS in the combination therapy group was 7.0 months (95% CI, 5.7\u0026ndash;8.3 months), significantly greater than that in the chemotherapy alone group (median PFS: 5.0 months [95% CI, 4.1\u0026ndash;5.9 months]). The addition of vascular-targeting agents reduced the risk of disease progression by 27% (HR, 0.73 [95% CI, 0.54\u0026ndash;0.98]; \u003cem\u003eP\u003c/em\u003e = 0.034). Median OS was significantly longer in the combination group (37 months [95% CI, 21.3\u0026ndash;52.7 months]) than in the chemotherapy alone group (20 months [95% CI, 13.0\u0026ndash;27.0 months]), with a HR of 0.66 (95% CI, 0.45\u0026ndash;0.97; \u003cem\u003eP \u003c/em\u003e= 0.047).\u003c/p\u003e\n\u003cp\u003eMultivariable analysis are summarized in Table 2. In multivariable analysis, the Combination therapy group was significantly associated with improved OS (combination group vs. chemotherapy alone, HR = 0.59, \u003cem\u003eP\u003c/em\u003e = 0.013) and PFS (combination group vs. chemotherapy alone, HR = 0.71, \u003cem\u003eP\u003c/em\u003e = 0.036). Liver metastasis and ECOG PS were also significantly associated with OS (liver metastasis vs. no metastasis, HR = 1.98, \u003cem\u003eP\u003c/em\u003e = 0.001, ECOG PS 1 vs. 0, HR = 1.54, \u003cem\u003eP\u003c/em\u003e = 0.029) and PFS (liver metastasis vs. no metastasis, HR = 1.43, \u003cem\u003eP \u003c/em\u003e= 0.033, ECOG PS 1 vs. 0, HR = 1.45, \u003cem\u003eP\u003c/em\u003e = 0.021).\u003c/p\u003e\n\u003cp\u003eSubgroup analysis are summarized in Table 3 and Table 4, the liver metastasis group demonstrated significantly longer OS and PFS with combination therapy than with chemotherapy alone. The second-line treatment group showed significantly longer OS with combination therapy than with chemotherapy alone. ECOG PS 1 group exhibited significantly longer PFS with combination therapy than with chemotherapy alone. The lung metastasis group demonstrated significantly longer PFS with combination therapy than with chemotherapy alone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events are summarized in Table 5,all 198 patients who received at least one dose of the study drug encountered at least one treatment-related AE (TRAE) during the study. The most prevalent TRAEs were leucopenia (54.0%), anemia (31.8%), proteinuria (30.3%), nausea (24.7%), and increased ALT (18.8%). However, the overall incidence of grade 3 or 4 TRAEs was low. The most common Grade 3 or 4 TRAEs included leucopenia (13.1%), neutropenia (9.6%), and thrombocytopenia (5.1%). No treatment-related deaths were observed. Hematologic AEs, biochemical AEs, electrolyte disturbances, and gastrointestinal AEs occurred with similar frequency in both arms. In the combination therapy group, the most common specific AEs were hypertension (n = 10/66; 15.2%), hand-foot syndrome (n = 20/66; 30.3%), proteinuria (n = 26/66; 39.4%), and hemorrhage (n = 7/66; 10.6%).\u003c/p\u003e\n\u003cp\u003eIn the combination therapy group, eight patients (12.1%) required one or more interruptions for vascular-targeting agents, and dose reductions were required in seven patients (10.6%). The most common reasons for dose reduction were hemorrhage (n = 4; 6.1%) and hand-foot syndrome (n = 3; 4.5%). In the chemotherapy group, dose reductions were required in 32 patients (24.2%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this trial, RM-NPC patients who received vascular-targeting agents plus chemotherapy exhibited effective disease control with an acceptable toxicity profile. Subgroup analysis identified liver metastasis as a prognostic factor for treatment response. These findings support further clinical development of vascular-targeting agents plus chemotherapy for RM-NPCs, associated with dismal survival outcomes and limited treatment options.\u003c/p\u003e \u003cp\u003eTo our knowledge, this was the first study to report the efficacy and safety of vascular-targeting agents plus chemotherapy in the treatment of RM-NPCs. Apatinib and anlotinib, as oral vascular targeting agents for advanced tumors, demonstrated potential in our study. Combination therapy was associated with improved PFS and OS compared to chemotherapy alone, with manageable toxic profiles. Median PFS in the combination therapy and chemotherapy alone groups were 7.0 months and 5.0 months, respectively, representing a 27% reduction in the risk of disease progression. Median OS was significantly longer in the combination therapy group (37 months) than in the chemotherapy alone group (20 months), reflecting a 34% reduction in the risk of mortality.\u003c/p\u003e \u003cp\u003eNPCs are known to be sensitive to platinum-based chemotherapy, with response rates ranging from 40\u0026ndash;65%. Gemcitabine-cisplatin chemotherapy is an essential treatment for RM-NPCs, with response rates of 67% and a median OS of 29.1 months [16, 17]. The extension of full-dose chemotherapy after disease control may be challenging due to cumulative toxic effects and diminishing benefits. However, in the absence of further interventions, most patients with responsive metastatic NPCs experience disease progression soon after the first-line treatment. Compared with full-dose chemotherapy, combination therapy has good tolerability and could be an appealing strategy to further improve outcomes.\u003c/p\u003e \u003cp\u003eThere is a lack of standard second-line treatment regimens after the failure of first-line platinum-based chemotherapy for RM-NPC patients. These patients represent those with the most urgent unmet therapeutic needs. Several antiangiogenic multitargeted kinase inhibitors have been investigated in RM-NPCs. Early trials of sorafenib and sunitinib have demonstrated modest efficacy in RM-NPCs, but with a significant risk of fatal hemorrhage.[18, 19] In another study, apatinib therapy for RM-NPCs exhibited objective responses in 36% of the 33 patients, achieving a median PFS of 5 months and a median OS of 16 months. [20]In a phase II clinical study, the addition of the anti-VEGF antibody, bevacizumab, to paclitaxel plus carboplatin as first-line treatment failed to extend the PFS and OS of RM-NPC patients.[21]\u003c/p\u003e \u003cp\u003eMolecular-targeted therapy has been extensively investigated for its effectiveness against specific genetic mutations, abnormal growth factor pathways, and angiogenesis in NPCs. Angiogenesis, influenced significantly by the microenvironment, is significantly regulated by VEGFR. Apatinib, a targeted therapy, selectively competes for ATP-binding sites on VEGFR-2, playing a crucial role in inhibiting angiogenesis. The high expression of VEGF and VEGFR in NPCs, along with the correlation of VEGF with survival outcomes, supports the use of antiangiogenic strategies in NPC treatment, particularly for RM-NPCs.\u003c/p\u003e \u003cp\u003eThe combination therapy group experienced more AEs than the chemotherapy alone group. In particular, hypertension, hand-foot syndrome, hemorrhage, and proteinuria occurred more frequently in the combination therapy group. As observed in previous studies, the administration of vascular-targeting agents, such as apatinib and anlotinib, was associated with hypertension and hand-foot syndrome, constituting the most common TRAEs. Grade 3 or 4 hand-foot syndrome (3.0%) and hemorrhage (1.5%) were the only severe AEs in the combination therapy group. However, most of the AEs were manageable through dose modifications, and no treatment-related deaths occurred. The safety profile of combination therapy appeared generally acceptable among patients receiving treatment for RM-NPCs[22, 23].\u003c/p\u003e \u003cp\u003eThis study also had some limitations. First, this was a retrospective study and selection bias could not be excluded because of the lack of randomization. Second, the population size for the study was relatively small Third, the results of subgroup analysis may be limited by the small cohort size. Finally, only patients from Guangxi were enrolled in the trial, limiting the generalizability of the results. Future studies should assess the efficacy and safety of vascular-targeting agents plus chemotherapy in NPC patients from diverse ethnicities across different countries.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe addition of vascular-targeting agents to chemotherapy for the treatment of RM-NPCs exhibited superior efficacy compared to chemotherapy alone, along with a manageable safety profile. Further randomized controlled and prospective clinical studies with larger sample sizes are needed to confirm the efficacy of vascular-targeting agents combined with chemotherapy in RM-NPCs.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eRM-NPC Recurrent/metastatic nasopharyngeal carcinoma \u003c/p\u003e\n\u003cp\u003ePFS Progression-free survival \u003c/p\u003e\n\u003cp\u003eOS Overall survival \u003c/p\u003e\n\u003cp\u003eNPC Nasopharyngeal carcinoma \u003c/p\u003e\n\u003cp\u003eRECIST Response Evaluation Criteria in Solid Tumor \u003c/p\u003e\n\u003cp\u003eAE Adverse event \u003c/p\u003e\n\u003cp\u003eMRI Magnetic resonance imaging \u003c/p\u003e\n\u003cp\u003eCT Computed tomography \u003c/p\u003e\n\u003cp\u003eHR Hazard ratio\u003c/p\u003e\n\u003cp\u003eCI Confidence interval\u003c/p\u003e\n\u003cp\u003eVEGFR-2 Vascular endothelial growth factor receptor-2\u003c/p\u003e\n\u003cp\u003eECOG Eastern Cooperative Oncology Group \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudies involving human participants have been reviewed and approved by the Medical Ethics Committee of the Affiliated Hospital of Guilin Medical College . Informed consent to participate in this study was provided by the legal guardian/close relative of the participant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript for publication.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data and material used to support the findings of this study are available from the corresponding author upon request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGuangxi Medical and health key discipline construction project; The \u0026quot;139\u0026quot; Talent Cultivation Plan Program of Guangxi Medical High-level Backbone, The National Natural Science Foundation of China (No. 82160479); The CSCO Youth Innovative Oncology Research Fund (No. Y-Young2020-0520)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWei Jiang,\u0026nbsp;Guanjie Qin\u0026nbsp;and\u0026nbsp;Guanhong\u0026nbsp;Luo\u0026nbsp;conceived of the study, and participated in its design and coordination.Guanhong\u0026nbsp;Luo, Guanjie Qin, Yixin Su, Yufei Pan, Jianxun Lu, Yueyun Xie,Bin Zhang,Jinxuan Dai, Xiangyun Kong, Yuan Xie,\u0026nbsp;Xiaolan Ruan, Yunyan Mo, Ruyun Zhang and Wei Jiang\u0026nbsp;participated in data collection.Guanhong\u0026nbsp;Luo, Guanjie Qin, Yixin Su, Yufei Pan, Jianxun Lu, Yueyun Xie,Bin Zhang,Jinxuan Dai, Xiangyun Kong, Yuan Xie,\u0026nbsp;Xiaolan Ruan, Yunyan Mo, Ruyun Zhang and Wei Jiang\u0026nbsp;performed the statistical analysis.Wei Jiang\u0026nbsp;and\u0026nbsp;Guanhong\u0026nbsp;Luo\u0026nbsp;helped to draft the manuscript.All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Medical Ethics Committee of affiliated Hospital of Guilin Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to all patients and their families who participated in the study.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eChen YP, Chan ATC, Le QT, Blanchard P, Sun Y, Ma JNasopharyngeal carcinoma. Lancet. 2019;394(10192):64-80. \u003c/li\u003e\n\u003cli\u003eErratum: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2020;70(4):313.\u003c/li\u003e\n\u003cli\u003eLi AC, Xiao WW, Shen GZ, et al. Distant metastasis risk and patterns of nasopharyngeal carcinoma in the era of IMRT: long-term results and benefits of chemotherapy.Oncotarget.2015;6(27):24511-24521. \u003c/li\u003e\n\u003cli\u003eWong KCW, Hui EP, Lo K-W, et al. Nasopharyngeal carcinoma: an evolving paradigm. Nat Rev Clin Oncol. 2021;18(11):679-695. \u003c/li\u003e\n\u003cli\u003eChan OS, Ngan RK (2014) Individualized treatment in stage IVC nasopharyngeal carcinoma. Oral Oncol 50:791\u0026ndash;797\u003c/li\u003e\n\u003cli\u003eBrower V (2016) Apatinib in treatment of refractory gastric cancer.Lancet Oncol 17:e137.\u003c/li\u003e\n\u003cli\u003eFornaro L, Vasile E, Falcone A (2016) Apatinib in advanced gastric cancer: A doubtful step forward. J Clin Oncol 34:3822\u0026ndash;3823.\u003c/li\u003e\n\u003cli\u003eLi J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L,Xu N, Cheng Y, Wang Z, Zheng L, Tao M, Zhu X, JiD, LiuX,YuH (2013) Apatinib for chemotherapy-refractory advanced metastatic gastric cancer:results from a randomized, placebo-controlled,parallel-arm, phase II trial. J Clin Oncol 31:3219\u0026ndash;3225.\u003c/li\u003e\n\u003cli\u003eSun Y, Niu W, Du F, Du C, Li S, Wang J, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi- target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 2016;9:105.\u003c/li\u003e\n\u003cli\u003eXie C, Wan X, Quan H, Zheng M, Fu L, Li Y, et al. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci. 2018;109:1207\u0026ndash;19.\u003c/li\u003e\n\u003cli\u003eLin B, Song X, Yang D, Bai D, Yao Y, Lu N. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFR\u0026beta; andFGFR1. Gene. 2018;654:77\u0026ndash;86.\u003c/li\u003e\n\u003cli\u003eHui EP, Chan AT, Pezzella F, Turley H, To KF, Poon TC, Zee B, Mo F, Teo PM, Huang DP, Gatter KC, Johnson PJ, Harris AL (2002)Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin CancerRes 8:2595\u0026ndash;2604\u003c/li\u003e\n\u003cli\u003eRoy C, Addison CL, Mazzarello S, Kuchuk I, Hutton B, Clemons M (2014) Assessment of therapeutic response through clinical assessment measures. In: Vassiliou V, Chow E, Kardamakis D (eds) bone metastases. Cancer metastasis - biology and treatment, vol. 21.Springer, Dordrecht.\u003c/li\u003e\n\u003cli\u003eSclanders B, Serednicka K, Riddell AM (2013) Measuring tumour response: RECIST 1.1 and beyond. Imaging 22:20110083.\u003c/li\u003e\n\u003cli\u003eSchoen MW, Basch E, Hudson LL, Chung AE, Mendoza TR,Mitchell SA, St Germain D, Baumgartner P, Sit L, Rogak LJ,Shouery M, Shalley E, Reeve BB, Fawzy MR, Bhavsar NA,Cleeland C, Schrag D, Dueck AC, Abernethy AP (2018)Software for administering the National Cancer Institute\u0026rsquo;s PatientReported Outcomes Version of the Common Terminology Criteria for Adverse Events: Usability study. JMIR Hum Factors 5:e10070.\u003c/li\u003e\n\u003cli\u003eZhang L, Huang Y, Hong S, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet (London, England). 2016;388(10054):1883-1892.\u003c/li\u003e\n\u003cli\u003e.Hong S.Zhang Y.Yu G.Peng P.Peng J.Jia J.et al.Gemcitabine plus cisplatin versus fluorouracil plus cisplatin as first-line therapy for recurrent or metastatic nasopharyngeal carcinoma: final overall survival analysis of GEM20110714 phase III study.J Clin Oncol. 2021; 39: 3273-3282\u003c/li\u003e\n\u003cli\u003eHui EP, Ma BBY, King AD, Mo F, Chan SL, Kam MKM, Loong HH, Ahuja AT, Zee BCY, Chan ATC. Hemorrhagic complications in a phase II study of sunitinib in patients of nasopharyngeal carcinoma who has previously received high-dose radiation. Ann Oncol. 2011;22(6):1280\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eElser C, Siu LL, Winquist E, Agulnik M, Pond GR, Chin SF, Francis P, Cheiken R, Elting J, McNabola A, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25(24):3766\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003eRuan X, Liang JH, Pan Y, Cai R, Zhang RJ, He Z, Yang X, Niu Z, Jiang W. Apatinib for the treatment of metastatic or locoregionally recurrent nasopharyngeal carcinoma after failure of chemotherapy: A multicenter, single-arm, prospective phase 2 study. Cancer. 2021 Sep 1;127(17):3163-3171.\u003c/li\u003e\n\u003cli\u003eZhou T, Yang Y, Ma S, Lin L, Zhou T, Zhang C, Ding X, Wang R, Feng G, Chen Y, et al. Bevacizumab versus placebo in combination with paclitaxel and carboplatin as frst-line treatment for recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase II trial. ESMO Open. 2021;6(6):100313.\u003c/li\u003e\n\u003cli\u003eZhang Y, Han C, Li J, Zhang L, Wang L, Ye S, Hu Y, Bai L (2017)Efficacy and safety for Apatinib treatment in advanced gastric cancer: a real world study. Sci Rep 7:13208\u003c/li\u003e\n\u003cli\u003eLin Y, Wu Z, Zhang J et al (2017) Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment. Tumor Biol39:101042831771103.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable1\u0026nbsp;\u003c/strong\u003e. Baseline Characteristics\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"671\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003ecombination therapy group（n=66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003echemotherapy alone group(n=132)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.802\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e52(78.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e106（80.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e14（21.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e26（19.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003emetastasis at the initial diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.575\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e35(27.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e97(72.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003einitial TNM stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.292\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e\u0026nbsp; III\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e26（39.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e42（31.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;IVA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e20（30.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e55（41.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;IVB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e20（30.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e35（26.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e\u0026gt; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e30(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e60(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e36(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e72(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003emetastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eLiver metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e25（37.9%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e45（34.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.599\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e26（39.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e54（40.9%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.838\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e26（39.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e46（34.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.531\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eOther\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e7(10.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e11(8.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003emetastasis site number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e28（42.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e65（49.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.267\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e18（27.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e33（25.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.644\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e7（10.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e8（6.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.255\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003emetastasis+Recurrent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.674\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e21（15.9%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e57(86.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e111(84.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"49.32935916542474%\" colspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.667\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e88(66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e44(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eLine of chemotherapy therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.763\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e1 line of chemotherapy therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e35（53.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e67(50.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003e2 line of chemotherapy therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e31（47.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e65(49.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eimmunotherapy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eYES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e12(18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e24(18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eNO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e54(81.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e108(81.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003evascular targeting agents\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eanlotinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e43(65.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eapatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e23(34.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eChemotherapy drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eGP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e11（16.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e40（30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eTP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e14（21.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e46（34.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"40.089418777943365%\"\u003e\n \u003cp\u003eS-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.08047690014903%\"\u003e\n \u003cp\u003e23（34.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.248882265275707%\"\u003e\n \u003cp\u003e25(18.9%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.581222056631892%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13(19.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e12(9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5(7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9(6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations\u003c/em\u003e: \u003cem\u003eECOG\u003c/em\u003e, Eastern cooperative oncology group,FP, fluorouracil plus platinum; GP,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003egemcitabine plus platinum;TP, \u003cstrong\u003epaclitaxel\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eplus\u0026nbsp;platinum\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003emultivariate analysis of PFS and OS\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"674\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.56973293768546%\" colspan=\"2\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.56973293768546%\" colspan=\"2\"\u003e\n \u003cp\u003ePFS\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"34.76394849785408%\"\u003e\n \u003cp\u003eHR（95%CI）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.236051502145923%\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.76394849785408%\"\u003e\n \u003cp\u003eHR（95%CI）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.236051502145923%\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eLiver metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e2.00（1.35-2.97）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.44（1.04-1.99）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.969\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.89(0.60-1.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.99(0.72-1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.703\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.414\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.08(0.73-1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.88(0.64-1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.219\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.83(0.52-1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.79(0.55-1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.884\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.176\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e＞50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.03(0.71-1.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.81(0.60-1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eNumber of treatment lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.35（0.93-1.98）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.45（1.06-1.99）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e\u0026nbsp;ECOG PS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.00\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.55（1.05-2.28）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1.46（1.06-2.01）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003etherapy group\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003ecombination therapy group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.59(0.38-0.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e0.71(0.52-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"30.86053412462908%\"\u003e\n \u003cp\u003eChemotheray alone group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.03560830860534%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.534124629080118%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG PS, Eastern Cooperative Oncology Group performance status; PFS,progression-free survival;OS, overall survival\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u003c/strong\u003e.PFS HRs (combination therapy group vs chemotherapy alone group) in subgroups \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"886\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\" rowspan=\"2\"\u003e\n \u003cp\u003eSubgroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.927765237020317%\" colspan=\"2\"\u003e\n \u003cp\u003ecombination therapy group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.072234762979683%\" colspan=\"2\"\u003e\n \u003cp\u003echemotherapy alone group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;HR(95%CI)\u003c/p\u003e\n \u003cp\u003e(combination therapy group\u0026nbsp;vs\u0026nbsp;chemotherapy alone group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;P\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.2972972972973%\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.675675675675677%\"\u003e\n \u003cp\u003eMedian PFS（months）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"26.35135135135135%\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.675675675675677%\"\u003e\n \u003cp\u003eMedian PFS（months）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.73(0.56-0.99）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eLiver metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e25(37.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e45(34.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.55（0.33-0.91）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e41(62.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e87(65.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.80（0.54-1.18）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.259\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eRecurrence or metastasis at the initial diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e35(26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.68（0.37-1.22）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.196\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e97(73.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.76（0.53-1.11）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eNumber of treatment lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e35(53.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e67(50.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.75（0.49-1.16）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.203\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e31(57.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e65(49.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.71（0.46-1.11）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.135\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e52(78.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e106(80.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.75（0.53-1.06）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e14(21.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e26（19.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.65（0.32-1.29）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e\u0026gt; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e36(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e72（54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.69（0.45-1.06）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e30(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e60（45.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.80（0.51-1.26）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.335\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e88（66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.80（0.55-1.17）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.251\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e44（33.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.55（0.32-0.94）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e26(39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e54(40.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.55（0.33-0.91）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e40(60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e78(59.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.83（0.56-1.23）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.341\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e26(39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e46(34.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.79（0.48-1.31）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.359\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e40(60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e86(65.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.72（0.48-1.07）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.702031602708804%\"\u003e\n \u003cp\u003edrugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.284424379232505%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.01354401805869%\"\u003e\n \u003cp\u003e0.213\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eanlotinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e43(65.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.675310033821873%\"\u003e\n \u003cp\u003eapatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.161217587373168%\"\u003e\n \u003cp\u003e23(34.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.19052987598647%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.852311161217587%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.26381059751973%\"\u003e\n \u003cp\u003e0.70（0.40-1.23）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.004509582863585%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; PFS,progression-free survival;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 4\u003c/strong\u003e.OS HRs (combination therapy group vs chemotherapy alone group) in subgroups\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"939\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\" rowspan=\"2\"\u003e\n \u003cp\u003eSubgroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.831735889243877%\" colspan=\"2\"\u003e\n \u003cp\u003ecombination therapy group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.855165069222576%\" colspan=\"2\"\u003e\n \u003cp\u003echemotherapy alone group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;HR(95%CI)\u003c/p\u003e\n \u003cp\u003e(combination therapy group\u0026nbsp;vs\u0026nbsp;chemotherapy alone group)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;P\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.130841121495326%\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.766355140186917%\"\u003e\n \u003cp\u003eMedian OS（months）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.33644859813084%\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.766355140186917%\"\u003e\n \u003cp\u003eMedian OS（months）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eAll patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.67(0.44-1.00）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.052\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eLiver metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e25(37.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e45(34.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.45（0.25-0.83）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e41(62.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e87(65.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.77（0.43-1.36）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.363\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eRecurrence or metastasis at the initial diagnosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e35(26.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.39（0.18-0.87）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e97(73.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.82（0.51-1.33）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.419\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eNumber of treatment lines\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e35(53.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e67(50.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.89（0.51-1.55）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e31(47.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e65(49.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.48（0.26-0.89）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e52(78.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e106(80.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.71（0.45-1.12）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.141\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e14(21.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e26（19.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.49（0.18-1.32）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e\u0026gt; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e36(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e72（54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.72（0.41-1.24）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e\u0026le; 50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e30(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e60（45.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.62（0.33-1.16）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.132\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eECOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e46(69.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e88（66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.75（0.45-1.26）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e20(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e44（33.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.54（0.27-1.10）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eLung metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e26(39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e54(40.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.55（0.28-1.09）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.088\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e40(60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e78(59.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.75（0.44-1.26）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.251\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003eBone metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e26(39.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e46(34.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.73（0.38-1.37）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.321\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e40(60.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e86(65.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.61（0.35-1.06）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.49946751863685%\"\u003e\n \u003cp\u003edrugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.68690095846645%\" colspan=\"4\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.252396166134186%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.561235356762514%\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eanlotinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e43(65.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.53091684434968%\"\u003e\n \u003cp\u003eapatinib\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.554371002132196%\"\u003e\n \u003cp\u003e23(34.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.473347547974413%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.300639658848613%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.270788912579956%\"\u003e\n \u003cp\u003e0.70（0.33-1.50）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.569296375266524%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; OS, overall survival;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eCumulative acute adverse events\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"982\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.68972533062055%\" colspan=\"3\"\u003e\n \u003cp\u003ecombination therapy group(n=66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.38657171922686%\" colspan=\"4\"\u003e\n \u003cp\u003echemotherapy alone group(n=132)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003eAll Grades\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade1-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Grade3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003eAll Grades\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e\u0026nbsp;Grade1-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e\u0026nbsp;Grade3-4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003eP（All Grades\u0026nbsp;）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003eHematologic adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.07629704984741%\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eLeukopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e33（50.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e24（36.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e74（56.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e57(43.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e17(12.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e11（16.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e6（9.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e5（7.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e23（17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e9(6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e14(10.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.894\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eAnemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e19（28.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e17（25.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e44(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e40(30.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e4(3.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.517\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eThrombocytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e11（16.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e16(12.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e8(6.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e8(6.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003eBiochemical adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.07629704984741%\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eCreatinine increase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e3（4.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e1（1.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e3(2.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.379\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eALT increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e29(22.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e27(20.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e2(1.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eAST increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e10（15.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e10（15.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e28(21.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e28(21.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.307\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eTotal bilirubin increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e9（13.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e18(13.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e18(13.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003eElectrolyte disturbance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.07629704984741%\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eHyponatremia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e8（12.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e3（4.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e5（7.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e10(7.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e9(6.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e1（0.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.294\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003ehypochloraemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e10（15.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e10（15.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e13(9.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e12(9.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e1（0.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.272\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eHypokalemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e6(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e6(4.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003eGastrointestinal adverse events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.07629704984741%\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eNausea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e16（24.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e16（24.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e33(25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e33(25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.907\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eAnorexia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e11（16.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e11（16.7%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e23(17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e23(17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.894\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.923702950152595%\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"75.07629704984741%\" colspan=\"7\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003ehematuresis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e7（10.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e7（10.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e21(15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e21(15.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eProteinuria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e26（39.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e26（39.4%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e34(25.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e34(25.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003e\u0026nbsp;fecal occult blood\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e5（7.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e5（7.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e12(9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e12(9.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eHand-foot syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e20（30.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e18（27.3%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e2（3.0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e7(5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e7(5.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eHypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e10（15.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e10（15.2%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.974515800203875%\"\u003e\n \u003cp\u003eHemorrhage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.436289500509684%\"\u003e\n \u003cp\u003e7（10.6%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.009174311926605%\"\u003e\n \u003cp\u003e6（9.1%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.213047910295616%\"\u003e\n \u003cp\u003e1（1.5%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.824668705402651%\"\u003e\n \u003cp\u003e1（0.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.499490316004078%\"\u003e\n \u003cp\u003e1（0.8%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.27624872579001%\"\u003e\n \u003cp\u003e0（0%）\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.766564729867483%\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eALT\u003c/em\u003e Alanine aminotransferase, \u003cem\u003eAST\u003c/em\u003e Aspartate aminotransferase\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":"Efficacy, Nasopharyngeal carcinoma, Targeted therapy plus chemotherapy, Vascular targeting agents, Anlotinib, Apatinib","lastPublishedDoi":"10.21203/rs.3.rs-4065562/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4065562/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Platinum-based chemotherapy is important for the treatment for recurrent or metastatic nasopharyngeal carcinomas (RM-NPCs). However, the prognosis of RM-NPC patients remains poor. This study evaluated the efficacy and safety of vascular-targeting agentsplus chemotherapy for RM-NPC treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This observational clinical trial, conducted at seven hospitals in Guangxi between January 2017 and December 2021, included 198 patients \u0026nbsp;(158 males [79.8%]; median age, 51 years [IQR, 45–57years]). Chemotherapy was administered with and without vascular-targeting agents in 66 and 132 patients, respectively. The primary endpoint was progression-free survival (PFS), assessed by a blinded independent review committee according to RECIST v.1.1. The secondary end points were overall survival (OS) and safety.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: After a median follow-up of 20 months, 31 (47.0%) and 82 (62.1%) deaths occurred in the combination therapy and chemotherapy alone groups, respectively. Median PFS was significantly higher in the combination group (7.0 months [95% CI, 5.7–8.3 months]) than in the chemotherapy alone group (5.0 months [95% CI, 4.1–5.9 months], \u003cem\u003eP\u003c/em\u003e = 0.034), with a hazard ratio of 0.73 (95% CI, 0.54–0.98). The combination group exhibited a higher median OS compared to the chemotherapy alone group (37 months [95% CI, 21.3–52.7] vs. 20 months [95% CI, 13.0–27.0months], \u003cem\u003eP\u003c/em\u003e = 0.047), representing a hazard ratio of 0.66 (95% CI, 0.45–0.97). In the combination therapy group, the most common adverse events were hypertension (n = 10/66 [15.1%]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: The addition of vascular-targeting agents to chemotherapy for RM-NPC patients provided superior efficacy\u003cstrong\u003e \u003c/strong\u003ecompared to chemotherapy alone, along with a manageable safety profile.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of vascular-targeting agents plus chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal carcinoma patients：A multicenter observational clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 18:56:55","doi":"10.21203/rs.3.rs-4065562/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":"910bbfcd-60fc-4c05-a69d-8b84155b63a3","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-25T13:35:47+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-29 18:56:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4065562","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4065562","identity":"rs-4065562","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}