Evidence of Anlotinib as First- or Second-line Monotherapy for Advanced Hepatocellular Carcinoma and Clinical Role of α-fetoprotein: a Multicenter Retrospective Study in China

Evidence of Anlotinib as First- or Second-line Monotherapy for Advanced Hepatocellular Carcinoma and Clinical Role of α-fetoprotein: a Multicenter Retrospective Study in China | 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 Article Evidence of Anlotinib as First- or Second-line Monotherapy for Advanced Hepatocellular Carcinoma and Clinical Role of α-fetoprotein: a Multicenter Retrospective Study in China Yanjiang Yin, Bowen Xu, Jianping Chang, Zhiyu Li, Xinyu Bi, Zhicheng Wei, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5766433/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background Anlotinib, a novel multi-targeting tyrosine kinase inhibitor (TKI), has been investigated in a variety of malignant tumors. This retrospective study was designed to investigate the efficacy and safety of anlotinib as first- or second-line therapy for advanced or metastatic hepatocellular carcinoma (HCC), and to identify early predictors for disease control. Methods This multicenter retrospective study included 158 patients with advanced HCC. 54 patients received anlotinib and 104 patients received sorafenib. Progression-free survival (PFS), overall survival (OS), and treatment response were compared. Subgroup analyses and biomarker evaluations were also conducted. Results The anlotinib group demonstrated significantly longer OS (16.0 months) compared to sorafenib (14.0 months; HR: 1.779; P = 0.002), while PFS was similar (5.0 vs. 4.0 months; HR: 1.217; P = 0.251). Drug-related adverse effects were comparable between groups, with no new safety concerns. Subgroup analyses revealed significant benefits of anlotinib in patients with baseline AFP ≥ 400 ng/mL and in HBV-positive individuals. As for anlotinib group, AFP reduction of ≥ 25% at 4 weeks post-treatment was an independent predictor of disease control ( P = 0.001). Conclusion Anlotinib showed promising efficacy and tolerability in Chinese patients. AFP response was an early predictor of disease control in patients with anlotinib treatment. Biological sciences/Cancer/Cancer therapy/Targeted therapies Biological sciences/Cancer/Gastrointestinal cancer Biological sciences/Cancer/Gastrointestinal cancer/Liver cancer Advanced hepatocellular carcinoma Anlotinib Tyrosine kinase inhibitor α-fetoprotein Prognostic factor Predictive factor Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Hepatocellular carcinoma (HCC) is the most common primary liver cancer in the world and ranks the third most common and second most fatal malignancy in China 1 , 2 . Chronic hepatitis B virus (HBV) infection is the key determinant of HCC development in Chinese patients 3 . The majority of patients with HCC are diagnosed with advanced disease, and only a few are eligible for potentially curative locoregional therapies. Due to the resistance to chemotherapy drugs, targeted therapy has been the standard care for advanced HCC since the first approval of sorafenib in 2007 4 . However, the clinical benefit of sorafenib is limited with the median overall survival (mOS) of 8.5–14.7 months in patients worldwide and 6.5–8.9 months in Asian patients 5 – 9 . The first drug to get approved for the treatment of HCC in patients who had progressed after sorafenib therapy was regorafenib, a small molecule inhibitor with a broader inhibition of kinases than sorafenib 10 . To date, these two drugs are the standard of care for advanced HCC as first- and second-line monotherapy. With a lot of recent translational research and clinical trials, other targeted agents, such as lenvatinib, apatinib and donafenib, have been approved for first- or second-line therapy 11 – 13 . But no monotherapy has shown significantly better clinical effects than sorafenib, and drug resistance and tumor recurrence also remain inevitable issues. Thus, an unmet need for more effective targeted drugs remains among patients with advanced HCC. Another clinical issue is to define biomarkers for targeted therapy and validate them in large-scale studies. HCC biomarkers are in urgent need in the following clinical fields: prognosis prediction; identification of a subgroup of patients for whom targeted therapy is more effective; early prediction of tumor response for targeted therapy. Alpha-fetoprotein (AFP) is a biomarker routinely assessed for the diagnosis and treatment of HCC. Some studies considered the pre-treatment AFP level as a prognostic factor and find its ability to screen patients who would benefit from targeted therapy 14 – 16 . Recently the post-treatment change of AFP level has been reported to predict tumor response although disagreement over the magnitude of the change still exists 17 – 20 . Other biomarkers such as blood-derived inflammatory markers and albumin-bilirubin (ALBI) grade have also been investigated for predicting survival of HCC patients 21 , 22 . Anlotinib is a novel tyrosine kinase inhibitor (TKI) with potential anti-neoplastic and anti-angiogenic activities. Compared to other TKIs, it has more targets, including vascular endothelial growth factor receptor (VEGFR) 1–3, platelet-derived growth factor receptors (PDGFR) α/β, fibroblast growth factor receptors (FGFR) 1–4, c-Kit, c-FMS and discoidin domain receptor 1 (DDR1) 23 . Anlotinib has shown promising efficacy and tolerable toxicity in many malignancies, including advanced non-small-cell lung cancer, advanced soft tissue sarcoma, metastatic renal cell carcinoma and advanced medullary thyroid cancer 24 – 27 . Previous experimental and clinical data have already demonstrated the antitumor effects of anlotinib on HCC 28 , 29 . Our team's previous single-arm clinical study demonstrated that anlotinib achieved a time to progression (TTP) of 5.9 months in first-line treatment and 4.6 months in second-line treatment 30 . However, the advantages of anlotinib compared to other targeted drugs and appropriate biomarkers are still unclear. This multicenter retrospective study was conducted to explore the efficacy and safety of anlotinib for first- and second-line therapy. And patients receiving sorafenib treatment served as the control group. Predictive factors for disease control after anlotinib treatment were also analyzed in this study. Materials and Methods Study Design Clinicopathological data of 210 patients diagnosed between May 2017 and July 2023 were retrieved from 3 tertiary medical research centers in China: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Qilu Hospital, Cheeloo College of Medicine, Shandong University. 55 patients received anlotinib monotherapy, while 155 patients received sorafenib monotherapy. Enrolled patients had a diagnosis of locally advanced or metastatic HCC. Diagnostic evaluation of HCC was based on liver biopsy or noninvasive measures combining imaging and blood tests. Eligible patients also conformed to the following inclusion criteria: age over 18 years old; Barcelona Clinic Liver Cancer (BCLC) stage B or C; Child–Pugh score < 8; an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1; at least one measurable lesion defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); normal function of vital organs; complete medical records, including imaging and prognostic information. Exclusion criteria included diagnosis of cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or fibrolamellar hepatocellular carcinoma (FLHC); existence of serious comorbidities; treatment history of immunotherapy. This study was approved by the Institutional Review Boards of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Ethical Approval Number: 21-197-2868) and Qilu Hospital of Shandong University (Ethical Approval Number: 2021-I2M-1-066). This study was conducted according to the Declaration of Helsinki. Because of the retrospective nature, this study was granted a full waiver of informed consent. All information provided by patients is maintained with confidentiality. Targeted drugs All patients in anlotinib group received treatment at a dose of 12 mg on day 1 through 14 of a 21-day cycle. Dosage reduction to 10 mg/day or even 8 mg/day would be proposed due to grade 3 or 4 hematologic toxicities. Sorafenib was taken 400 mg orally twice daily. Patients experiencing grade 4 hematologic toxicity or grade 2 non-hematologic toxicity require dose reduction. The dose reduction should not exceed two steps: the first reduction decreases the dose to 80% of the original dosage, and the second reduction decreases it to 50% of the original dosage. Patients received their assigned drugs until they were no longer benefiting from therapy or unacceptable toxic events occurred. Patients were regularly followed up by the investigators. Adverse events (AEs) were graded according to the Common Terminology Criteria Adverse Events version 4.0 (CTCAE 4.0). Radiological imaging was done for all patients every 6 weeks after the first intervention dose. Data Collection, Biomarkers, and Outcomes Laboratory test results were collected from the time of drug assignment to 30 days following treatment discontinuation. The cutoff date for follow-up was July 1, 2024. Percentage change of AFP, ALBI score, ALBI grade and three blood-derived inflammatory (neutrophil-to-lymphocyte ratio, NLR; platelet-to-lymphocyte ratio, PLR; prognostic nutritional index, PNI) markers were evaluated to predict disease control in HCC patients. Percentage change of AFP level was defined as (AFP level at 2, 4, 6 weeks after first dosage - AFP baseline level) / AFP baseline level. ALBI was a useful assessment tool for hepatic reserve function and ALBI score was calculated as follows: (log 10 bilirubin (µmol/L) × 0.66) + (albumin (g/L) × -0.085). The cutoff points for ALBI grades were as follows: ≤ -2.60 (ALBI grade 1), more than − 2.60 to ≤ -1.39 (ALBI grade2), and > -1.39 (ALBI grade 3) 31 . NLR was calculated by dividing the total number of neutrophils by lymphocytes. PLR was calculated by dividing the total platelets count by lymphocytes count. PNI was calculated by multiplying albumin (g/L) by absolute lymphocyte count. Tumor response was assessed using computed tomography (CT) scans or magnetic resonance imaging (MRI) examinations every 6 weeks by three radiologists independently and characterized by complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Not to be evaluated (NE) denoted treatment effects which were not recorded. When disagreement happened on imaging evaluation, a third doctor was requested to reevaluate. The primary end point was overall survival (OS). OS was defined as the time from the first dose of drugs medication to death from any cause. The secondary endpoints included progression­free survival (PFS), objective response rate (ORR), disease control rate (DCR), survival rates at 12 or 24 months, and PFS rates at 6 or 12 months. PFS referred to the time from the first dose of drugs medication to disease progression according to RECIST 1.1, or death from any cause, whichever occurred first. ORR was defined as the proportion of confirmed CR or PR at the best response. DCR was defined as the percentage of confirmed CR, PR, or SD at the best response. Statistical Analysis In this observational study, a 2:1 nearest neighbor propensity score matching (PSM) was used to achieve a balanced covariate distribution between the two treatment groups. Variables included in the propensity score calculation were provided in Table S1 . Statistical computation of PSM method was finished by the R package MatchIt (version 4.3.2) 32 . A caliper for matching process was set at 0.1. The Student’s t-test or the Wilcoxon rank-sum test was conducted to assess baseline comparability for continuous variables between the two groups. The mean and standard deviation (SD) were used to describe normally distributed continuous data, while the median and interquartile range (IQR) were used to describe non-normally distributed continuous data. Categorical variables were calculated using both frequencies and percentages. And they were compared by the Chi-square test or Fisher’s exact test. The OS and the PFS curves were obtained using the Kaplan-Meier (KM) method and compared by the log-rank test. The best cut-off values for hematological biomarkers were determined by the receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were conducted using the Cox proportional hazards model or logistic regression analysis to analyze factors associated with survival or disease control. Tests within each subgroup used an unstratified Cox proportional hazards model and the forest plots illustrated the test results. All statistical analyses were performed using RStudio version 1.4.1717 (Integrated Development Environment for R, Boston, MA) and SPSS version 26.0 (IBM Corp., Armonk, NY, USA). All tests were two-tailed, and P values < 0.05 were considered statistically significant. Results Baseline Clinical Characteristics Initially, a total of 210 patients with locally advanced or metastatic HCC were included in this study according to the inclusion and exclusion criteria ( Table S1 ). Compared to anlotinib group, patients in sorafenib group had incomparable composition ratio of Child–Pugh class ( P = 0.074). PSM analysis generated an assembly of 158 patients with a mean age of 52.7 years (SD = 9.7). 54 patients received anlotinib and 104 received sorafenib. Imbalances on patients’ characteristics between two groups were minimized (Table 1 ). Among the 158 patients, 141 (89.2%) were males, 127 (80.4%) had HBV infection, 66 (41.8%) had a baseline AFP level of more than 400 ng/mL, 70 (44.3%) had an ECOG PS score of 1, 122 (77.2%) were BCLC stage C, 16 (10.1%) were Child–Pugh class B (scores 7) and 107 (67.7%) were CNLC stage III. The median tumor size was 6.4 cm (IQR [4.3, 10.4]). The presence of distant metastasis happened in 73 (46.2%) patients, including 40 (25.3%) lung metastasis and 16 (10.1%) bone metastasis. 75 (47.5%) patients received targeted therapy for first-line therapy, and 83 (52.5%) patients received targeted therapy for second-line therapy. 80 patients underwent surgery during first or second-line treatment, accounting for 50.6% of the total population. Table 1 Baseline patient demographic and clinical characteristics (After PSM, n = 158). Characteristics Total Anlotinib Sorafenib P value n = 158 n = 54 n = 104 Age, years 52.7 (9.7) 52.3 (9.9) 52.9 (9.6) 0.722 Sex 1.000 Male 141 (89.2%) 48 (88.9%) 93 (89.4%) Female 17 (10.8%) 6 (11.1%) 11 (10.6%) Alcohol consumption 60 (38.0%) 22 (40.7%) 38 (36.5%) 0.731 Smoking history 36 (22.8%) 10 (18.5%) 26 (25.0%) 0.471 Family history of cancer 0.993 HCC 15 (9.5%) 5 (9.3%) 10 (9.6%) Other types 17 (10.8%) 6 (11.1%) 11 (10.6%) Not happened 126 (79.7%) 43 (79.6%) 83 (79.8%) Viral infection 1.000 HBV 127 (80.4%) 44 (81.5%) 83 (79.8%) HCV 1 (0.6%) 0 (0.0%) 1 (1.0%) Non-infected 30 (19.0%) 10 (18.5%) 20 (19.2%) AFP, > 400 ng/mL 51 (32.3%) 19 (35.2%) 32 (30.5%) 0.573 Ascites 12 (7.6%) 2 (3.7%) 10 (9.6%) 0.311 Cirrhosis 65 (41.1%) 22 (40.7%) 43 (41.3%) 1.000 ECOG PS score 1.000 0 88 (55.7%) 30 (55.6%) 58 (55.8%) 1 70 (44.3%) 24 (44.4%) 46 (44.2%) BCLC stage 0.937 B 36 (22.8%) 13 (24.1%) 23 (22.1%) C 122 (77.2%) 41 (75.9%) 81 (77.9%) Child–Pugh class 0.630 A (5 points) 118 (74.7%) 40 (74.0%) 78 (75.0%) A (6 points) 24 (15.2%) 7 (13.0%) 17 (16.3%) B (7 points) 16 (10.1%) 7 (13.0%) 9 (8.7%) CNLC stage 1.000 Stage II 51 (32.3%) 17 (31.5%) 34 (32.7%) Stage III 107 (67.7%) 37 (68.5%) 70 (67.3%) Tumor size, cm 6.4 [4.3, 10.4] 7.4 [4.3, 11.7] 6.3 [4.3, 9.9] 0.435 Tumor number 0.353 1 109 (69.0%) 41 (75.9%) 68 (65.4%) 2 10 (6.3%) 2 (3.7%) 8 (7.7%) Multiple 39 (24.7%) 11 (20.4%) 28 (26.9%) TBS 6.8 [4.6, 10.5] 7.5 [4.6, 11.8] 6.7 [4.6, 10.0] 0.468 MaVI 73 (46.2%) 25 (46.3%) 48 (46.2%) 1.000 PVTT 20 (12.7%) 7 (13.0%) 13 (12.5%) 1.000 Extrahepatic spread 94 (59.5%) 30 (55.6%) 64 (61.5%) 0.468 Distant metastasis 0.601 Lung 40 (25.3%) 14 (25.9%) 26 (25.0%) Bone 16 (10.1%) 6 (11.1%) 10 (9.6%) Other sites 21 (13.3%) 5 (9.3%) 16 (15.4%) Targeted therapy 0.704 First-line 75 (47.5%) 24 (44.4%) 51 (49.0%) Second-line 83 (52.5%) 30 (55.6%) 53 (51.0%) Categorical data are presented as n (%); continuous data are presented as mean (SD) or median [Q1, Q3]. SD, standard deviation; PSM, propensity score matching; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; CNLC stage, China Liver Cancer stage; TBS, tumor burden score; MaVI, macrovascular invasion; PVTT, portal vein tumor thrombosis; EHS, extrahepatic spread; TACE, transarterial chemoembolization. In anlotinib group, 24 (44.4%) patients received anlotinib as first-line therapy, whereas 30 (55.6%) patients received anlotinib as second-line therapy. 22 (40.7%) patients underwent surgery, and 21 (38.9%) patients underwent intra-arterial therapy. In sorafenib group, 51 (49.0%) patients received sorafenib as first-line therapy, whereas 53 (51.0%) patients received sorafenib as second-line therapy. 58 (55.8%) patients underwent surgery, and 42 (40.4%) patients underwent intra-arterial therapy. Overall Prognosis Analysis As shown in Figure S1 , the median follow-up time for whole patients was 13.0 months (range: 1.0–30.0 months). Overall median PFS was 5.0 months (95% confidence interval [CI]: 4.5–5.5 months) and overall median OS was 15.0 months (95% CI: 13.2–16.8 months). The 6-month or 12-month PFS rate was 28.3% (95% CI: 22.0-36.4%) or 1.6% (95% CI: 0.4–6.3%). The 12-month or 24-month survival rate was 56.4% (95% CI: 49.0-64.9%) or 2.5% (95% CI: 0.8–7.4%). Univariate and multivariate Cox regression analysis were used to explore prognostic factors for all 158 patients. The results of univariate analysis were presented in Table 2 . China Liver Cancer (CNLC) stage and macrovascular invasion (MaVI) were strongly associated with both PFS (CNLC, P = 0.001; MaVI, P = 0.001) and OS (CNLC, P = 0.016; MaVI, P = 0.031). Large tumor size (> 6 cm) and distant metastasis were found to have obviously negative effects on PFS (tumor size, P = 0.013; distant metastasis, P 400 ng/mL was a risk factor only for OS ( P = 0.005). Table 2 Univariate analysis of PFS and OS for the whole patients (n = 158). Factors PFS OS HR (95% CI) P value HR (95% CI) P value Age * (≤ 55 vs. >55 years) 0.908 (0.650–1.270) 0.574 1.153 (0.817–1.628) 0.418 Sex (Male vs. female) 0.853 (0.499–1.458) 0.562 1.292 (0.740–2.255) 0.368 HBV infection 0.957 (0.639–1.432) 0.830 0.866 (0.571–1.313) 0.498 AFP (≤ 400 vs. >400 ng/mL) 1.063 (0.761–1.485) 0.721 1.614 (1.152–2.262) 0.005 ECOG PS score (0 vs. 1) 0.871 (0.626–1.210) 0.410 0.874 (0.625–1.224) 0.435 BCLC stage (B vs. C) 1.249 (0.853–1.829) 0.253 1.108 (0.744–1.650) 0.613 CNLC stage (II vs. III) 2.346 (1.618–3.401) 0.001 1.548 (1.084–2.210) 0.016 Tumor size ** (≤ 6 vs. >6 cm) 1.530 (1.095–2.138) 0.013 0.987 (0.708–1.377) 0.939 MaVI 1.856 (1.316–2.616) 0.001 1.444 (1.034–2.016) 0.031 PVTT 0.830 (0.511–1.346) 0.449 0.953 (0.581–1.565) 0.850 EHS 1.186 (0.750–1.874) 0.466 1.239 (0.785–1.955) 0.358 Distant metastasis 2.086 (1.478–2.944) < 0.001 0.972 (0.685–1.379) 0.875 *Defined based on the mean value. **Defined based on the median value. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion; PVTT, portal vein tumor thrombosis; EHS, extrahepatic spread. The bold P value indicates statistically significant. The results of multivariate analysis were presented in Table 3 . Multivariate analysis indicated that distant metastasis was the only risk factor independently related to PFS (HR [hazard ratio]: 1.554; 95% CI: 1.028–2.350; P = 0.037). And high AFP (> 400 ng/mL) is an independent risk factor for poorer OS in patients (HR: 1.614; 95% CI: 1.147–2.270; P = 0.006). Moreover, KM curves were used to compare the impact of different independent risk factors on prognosis in the anlotinib group (Fig. 1 ). For patients receiving anlotinib, KM analysis showed distant metastasis significantly reduced the patients' PFS ( P < 0.001; median PFS: 2.0 months vs. 6.0 months; Fig. 1 A). And OS was prolonged in patients with a baseline AFP level ≤ 400 ng/mL ( P = 0.098; median OS: 20.0 months vs. 11.0 months; Fig. 1 B). Table 3 Multivariate analysis of PFS and OS for the whole patients (n = 158). Factors PFS OS HR (95% CI) P value HR (95% CI) P value AFP (≤ 400 vs. >400 ng/mL) - - 1.614 (1.147–2.270) 0.006 CNLC stage (II vs. III) 1.580 (0.903–2.764) 0.109 1.486 (0.937–2.357) 0.093 Tumor size ** (≤ 6 vs. >6 cm) 1.327 (0.937–1.879) 0.112 - - MaVI 1.200 (0.762–1.890) 0.432 1.078 (0.698–1.663) 0.736 Distant metastasis 1.554 (1.028–2.350) 0.037 - - **Defined based on the median value. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion. The bold P value indicates statistically significant. Clinical Efficacy and Safety 54 patients in anlotinib group and 104 patients in sorafenib group were included in efficacy and safety analysis. Median PFS in anlotinib group was 5.0 months (95% CI: 4.3–5.7 months) compared with 4.0 months (95% CI: 3.4–4.6 months) in sorafenib group (HR: 1.217; 95% CI: 0.862–1.718; P = 0.251) (Fig. 2 A). Median OS was found to be longer for patients receiving anlotinib (16.0 months, 95% CI: 12.4–19.6 months) than sorafenib (14.0 months, 95% CI: 12.4–15.6 months), and the difference between the two groups was statistically significant (HR: 1.779; 95% CI: 1.238–2.558; P = 0.002) (Fig. 2 B). Drug-related adverse effects (AEs) in patients were shown in Table 4 . 46 (85.2%) or 95 (91.3%) patients with anlotinib or sorafenib experienced drug-related AEs. Specifically, drug-related grade ≥ 3 AEs occurred in 15 (27.8%) or 39 (37.5%) patients with anlotinib versus sorafenib ( P = 0.296). The most common AE was diarrhea both in anlotinib (28 patients, 51.9%) and sorafenib (56 patients, 53.8%) group. Table 4 Drug-related adverse effects in patients receiving anlotinib (n = 54) vs. sorafenib (n = 104). Drug-related AEs Anlotinib Sorafenib P value (n = 54) (n = 104) Any AEs 46 (85.2%) 95 (91.3%) 0.360 Grade ≥ 3 15 (27.8%) 39 (37.5%) 0.296 Incidence ≥ 10% Diarrhea 28 (51.9%) 56 (53.8%) 0.944 Hypertension 21 (38.9%) 47 (45.2%) 0.448 Hand-foot syndrome 21 (38.9%) 48 (46.2%) 0.383 Fatigue 19 (35.2%) 29 (27.9%) 0.344 Decreased Hb count 17 (31.5%) 35 (33.7%) 0.783 Fever 14 (25.9%) 38 (36.5%) 0.178 Elevated AST 14 (25.9%) 28 (26.9%) 1.000 Rash 11 (20.4%) 28 (26.9%) 0.477 Pharyngalgia 10 (18.5%) 23 (22.1%) 0.748 Low back pain 10 (18.5%) 22 (21.2%) 0.855 Elevated bilirubin 9 (16.7%) 24 (23.1%) 0.463 Nausea 9 (16.7%) 18 (17.3%) 1.000 Vomiting 7 (13.0%) 16 (15.4%) 0.864 Liver dysfunction 6 (11.1%) 12 (11.5%) 1.000 AEs, adverse effects; Hb, hemoglobin; AST, aspartate aminotransferase. We separately analyzed the differences in the impact of anlotinib and sorafenib on clinical outcomes in first- and second-line treatments. Among all patients, 24 (44.4%) patients in anlotinib group and 51 (49.0%) in sorafenib group received targeted drugs as first-line therapy (Table 5 ). 2 (8.3%) patients achieved PR, 16 (66.7%) exhibited SD and no one achieved CR in anlotinib subgroup, yielding an ORR of 8.3% and DCR of 75.0%. And for sorafenib subgroup, 1 (2.0%) patient reached CR, 2 (3.9%) obtained PR and 35 (68.6%) achieved SD. The ORR was 5.9%, and the DCR was 74.5%, with no significant difference compared to the anlotinib subgroup (ORR, P = 0.921; DCR, P = 0.964). Median PFS was 5.0 months (95% CI: 2.6–7.4 months) with anlotinib and 4.0 months (95% CI: 3.4–4.6 months) with sorafenib (HR: 1.465; 95% CI: 0.885–2.425; P = 0.144) (Fig. 3 A). Median OS was improved in anlotinib subgroup versus sorafenib subgroup (20.0 vs. 15.0 months; HR: 1.588; 95% CI: 0.927–2.719; P = 0.077) (Fig. 3 B). Table 5 Tumor response and survival outcomes for patients receiving anlotinib (n = 54) vs. sorafenib (n = 104). Parameters First line (n = 75) Second line (n = 83) Anlotinib (n = 24) Sorafenib (n = 51) P value Anlotinib (n = 30) Sorafenib (n = 53) P value Tumor response 0.901 0.738 CR 0 1 (2.0%) 0 0 PR 2 (8.3%) 2 (3.9%) 3 (10.0%) 5 (9.4%) SD 16 (66.7%) 35 (68.6%) 17 (56.7%) 24 (45.3%) PD 4 (16.7%) 8 (15.7%) 8 (26.7%) 18 (34.0%) NE 2 (8.3%) 5 (9.8%) 2 (6.7%) 6 (11.3%) ORR 2 (8.3%) 3 (5.9%) 0.921 3 (10.0%) 5 (9.4%) 0.762 DCR 18 (75.0%) 38 (74.5%) 0.964 20 (66.7%) 29 (54.7%) 0.288 PFS rate 6 months 37.5% 19.6% 0.097 36.2% 27.8% 0.430 12 months 5.6% 2.0% 0.830 3.3% 0% 0.361 Survival rate 12 months 60.5% 64.4% 0.853 56.0% 47.7% 0.406 24 months 4.7% 0% 0.320 4.4% 3.3% 0.611 CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluated; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival. A total of 30 (55.6%) patients in anlotinib group and 53 (51.0%) in sorafenib group received targeted drugs as second-line therapy (Table 5 ). 3 (10.0%) patients achieved PR, and 17 (56.7%) exhibited SD in anlotinib subgroup, whereas 5 (9.4%) patients achieved PR, and 24 (45.3%) exhibited SD in sorafenib subgroup. No one achieved CR in either subgroup. The ORR was 10.0% or 9.4% ( P = 0.762), and the DCR was 66.7% or 54.7% ( P = 0.288), in the anlotinib and sorafenib subgroup, respectively. Median PFS was 5.0 months (95% CI: 4.3–5.7 months) versus 5.0 months (95% CI: 4.2–5.8 months) in anlotinib and sorafenib subgroup, respectively (HR: 0.969; 95% CI: 0.599–1.565; P = 0.948; Fig. 3 C). Median OS (13.0 vs. 11.0 months) was significantly improved with anlotinib versus sorafenib (HR: 1.966; 95% CI: 1.189–3.250; P = 0.010; Fig. 3 D). Subgroup Analysis Subgroup analysis was performed to identify which part of patients could benefit from anlotinib therapy. As shown in Fig. 4 A, the HR values for PFS continued to favour anlotinib versus sorafenib across most prespecified subgroups. But significant differences only existed in the subgroup of patients with a baseline AFP concentration of 400 ng/mL or greater (HR: 0.355; 95% CI: 0.197–0.637; P = 0.001). Subgroup comparisons of OS showed that anlotinib brought clear improvement in patients’ survival and significant differences were noted in most subgroups (Fig. 4 B). Anlotinib demonstrated better OS compared to sorafenib, regardless of whether the patients' AFP levels were above or below 400 ng/mL (AFP ≤ 400 ng/mL, HR: 0.505, 95% CI: 0.306–0.836, P = 0.008; AFP > 400 ng/mL, HR: 0.508, 95% CI: 0.298–0.867, P = 0.013). Anlotinib exhibited a significant advantage in HBV-positive patients (HR: 0.567; 95% CI: 0.380–0.848; P = 0.006); however, this effect was not observed in HBV-negative patients (HR: 0.689; 95% CI: 0.282–1.684; P = 0.414). KM curve was then to calculate median PFS and OS. For patients with an AFP concentration above the threshold of 400 ng/mL, median PFS was 7.0 months (95% CI: 4.6–9.4 months) in anlotinib subgroup versus 4.0 months (95% CI: 2.9–5.1 months) for sorafenib subgroup (HR: 2.820; 95% CI: 1.569–5.070; P < 0.001) (Fig. 5 A). Median OS was 12.0 months (95% CI: 10.0–14.1 months) for anlotinib subgroup versus 8.0 months (95% CI: 6.6–9.4 months) for sorafenib subgroup (HR: 1.967; 95% CI: 1.154–3.354; P = 0.010) (Fig. 5 B). Predictive Factors for Disease Control in Anlotinib Group For patients in anlotinib group, in order to identify early predictive factors which can predict disease control after anlotinib therapy, risk factors in Table 3 and several hematological biomarkers (NLR, PLR, PNI, ALBI score and grade, rate of change in AFP level at 2, 4, 6 weeks after first dosage) were included in predictive factors analysis. ROC analysis was conducted to obtain cutoff values of hematological biomarkers. Results of ROC analysis were summarized in Table S2 . The optimal cutoff values of NLR, PLR, PNI and ALBI score for disease control were determined as 3.0, 115, 55 and − 2.5. The result of ROC analysis showed that patients with disease control were well differentiated from those with disease progression when AFP decreased by ≥ 25% at 4 weeks after first dosage, or by ≥ 27% at 6 weeks after first dosage. The 4-week time window was selected as it offers an early assessment of treatment response, enabling timely evaluation of therapeutic efficacy. Finally, the cutoff used for the rate of change in AFP level was − 0.25 with specificity and sensitivity levels of 93.8% and 78.9% ( Figure S2 ). Accordingly, AFP response was defined as a reduction of ≥ 25% from the baseline level. Early predictors of disease control were analyzed in Table 6 and NLR, PLR, ALBI grade and AFP response were found to be significantly correlated with disease control in univariate analysis ( P = 0.033, 0.003, 0.025, < 0.001). Table 6 Univariate and multivariate analysis for predictors affecting disease control for patients in anlotinib group (n = 54). Factors Univariate analysis Multivariate analysis OR (95% CI) P value OR (95% CI) P value CNLC stage (II vs. III) 1.473 (0.415–5.029) 0.538 - - Tumor size ** (≤ 6 vs. >6 cm) 1.429 (0.442–4.764) 0.552 - - MaVI 1.157 (0.357–3.851) 0.808 - - Distant metastasis 0.399 (0.113–1.392) 0.146 - - NLR (≤ 3.0 vs. >3.0) 0.242 (0.059–0.838) 0.033 0.348 (0.032–2.877) 0.341 PLR (≤ 115 vs. >115) 0.141 (0.036–0.491) 0.003 0.098 (0.004–0.864) 0.062 PNI (≤ 55 vs. >55) 2.253 (0.593–11.11) 0.263 - - ALBI score (≤-2.5 vs. >-2.5) 0.296 (0.079–0.987) 0.055 - - ALBI grade (1 vs. 2,3) 0.272 (0.082–0.827) 0.025 0.417 (0.054–2.797) 0.367 AFP (≤ 400 vs. >400 ng/mL) 1.429 (0.442–4.764) 0.552 - - AFP response 2.129 (1.492–2.762) < 0.001 1.854 (1.364–2.476) 0.001 AFP response in anlotinib subgroup High-AFP subgroup (n = 19) 1.745 (1.087–2.665) 0.002 - - Low-AFP subgroup (n = 35) 1.475 (1.211–1.851) 0.018 - - **Defined based on the median value. OR, odds ratio; CI, confidence interval; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; PNI, prognostic nutritional index; ALBI, albumin–bilirubin; AFP, alpha-fetoprotein. The bold P value indicates statistically significant. Multivariate analysis showed only AFP response was an independent predictor for disease control in anlotinib group (OR [odds ratio]: 1.854; 95% CI: 1.364–2.476; P = 0.001). Moreover, patients in anlotinib group were divided into high-AFP (baseline AFP ≥ 400 ng/mL) and low-AFP (baseline AFP < 400 ng/mL) subgroup. Logistic regression analysis within each subgroup supported that AFP response was an early predictor of disease control both in high-AFP subgroup (OR: 1.745; 95% CI: 1.087–2.665; P = 0.002) and low-AFP subgroup (OR: 1.475; 95% CI: 1.211–1.851; P = 0.018). Discussion This multicenter retrospective real-world study revealed that the anlotinib showed promising efficacy and acceptable safety as monotherapy for patients with advanced HCC. Treatment with anlotinib or sorafenib was generally well-tolerated, and the most frequently recorded drug-related AE was diarrhea for both. Anlotinib exhibited a moderately lower incidence of grade ≥ 3 AEs compared to sorafenib (27.8% vs. 37.5%). The better efficacy profile of anlotinib versus sorafenib was mainly reflected by statistically significant extension in OS. Subgroup analysis demonstrated significant OS benefits of anlotinib in most subgroups, including those reflective of the characteristics of the Chinese HCC population, such as high AFP levels, positive HBV infection, and a higher proportion of patients with BCLC stage C. In comparison to western countries, patients presented with more advanced baseline disease status in China, which further underscores the positive therapeutic response of anlotinib. The REFLECT study demonstrated that lenvatinib as a first-line treatment exhibited clinical benefits comparable to sorafenib, with a median OS increase of 1.3 months (13.6 vs. 12.3 months, P > 0.05) 13 . A large-scale phase III clinical trial indicated that donafenib, a drug independently developed in China, was the only first-line TKI to show superior OS compared to sorafenib (12.1 vs. 10.3 months, P = 0.025) 12 . In this study, patients treated with anlotinib as first-line therapy achieved a longer median OS compared to those receiving sorafenib (20.0 vs. 15.0 months, P = 0.077). Currently, both donafenib and lenvatinib have been included in the standard for diagnosis and treatment of primary liver cancer in China, and large-sample, double-arm clinical trials are still needed to further validate the clinical therapeutic advantages of anlotinib 33 . Our team's prior research has demonstrated that anlotinib is a viable option for HCC refractory to first-line therapy, with a median TTP of 4.6 months 30 . Compared to the placebo control group, both regorafenib and apatinib, as second-line standard treatment regimens, have been shown to improve OS in patients (10.6 vs. 7.8 months, P < 0.001; 8.7 vs. 6.8 months, P = 0.048) 10 , 34 . Anlotinib also showed trend of OS improvement in this study (13.0 vs. 11.0 months, P = 0.010). The recurrence or progression of HCC is highly dependent on angiogenesis, as the formation of new blood vessels provides essential nutrients to support tumor cell proliferation. Compelling evidence has revealed that FGFR signaling plays an important role in HCC progression, angiogenesis and therapy-resistance 35 . For example, FGFR1/AKT/mTOR signaling pathway and FGF19/FGFR4 axis are responsible for sorafenib resistance 36 , 37 . On one hand, the pan-FGFR inhibition of anlotinib offers a potential solution to overcome HCC resistance to anti-angiogenic agents; On the other hand, its favorable safety profile enables sustained anti-angiogenic effects. Taken together, anlotinib shows promise as a potential standard second-line therapeutic option in the future. AFP has remained the main diagnostic and prognostic biomarker for HCC for decades. Many studies showed that high baseline AFP level appeared to be associated with worse patient survival 16 , 38 – 40 . This study revealed that baseline AFP level was identified as the only independent prognostic factor for patients’ OS. Moreover, Subgroup analysis revealed that significant PFS improvement was only observed for patients with a baseline AFP of 400 ng/mL or greater. Andrew et al. analyzed patients’ data from REACH-1 and REACH-2 phase 3 trial, and the results showed ramucirumab, an angiogenesis inhibitor, met its primary endpoint in the subgroup of patients with AFP levels above 400 ng/mL 15 , 16 . Another clinical trial reported that the magnitude of OS benefit brought by lenvatinib was greatest in patients with high AFP level (≥ 200 ng/mL) 13 . These data indicated AFP functioned as a biomarker for identifying subgroups of HCC patients and guiding adjustments in treatment strategies. Treatment response is generally evaluated by radiological technology. Although imaging techniques such as CT and MRI can visually reflect changes in tumor size following treatment, they also have certain limitations, including the subjectivity of radiologists, interference from tissue changes induced by pharmacological treatments, and the lack of standardized imaging guidelines for the evaluation of systemic therapy for HCC. Most importantly, imaging methods cannot predict treatment efficacy at an early stage. In addition to the diagnostic and prognostic significance of baseline AFP levels, numerous studies have proposed that changes in AFP levels during or following treatment may serve as surrogate biomarkers for assessing response to systemic and locoregional therapies 17 – 20 . However, there is considerable variability among studies in the criteria used to define AFP response, including the time window for AFP measurement after treatment and the magnitude of AFP level reduction. In this study, we found that AFP response (a reduction of ≥ 25% from the baseline level) can be used as a predictor for disease control in anlotinib group. This conclusion was validated in both the high-AFP and low-AFP subgroup. And the time window for AFP measurement was set as 4-week, enabling early evaluation for disease control. In recent years, with the widespread clinical application of immune checkpoint inhibitors (ICIs), a variety of immunotherapy regimens represented by ICIs have emerged in the field of hepatocellular carcinoma treatment. Results from IMbrave150 study demonstrated that the combination of atezolizumab and bevacizumab significantly prolonged mOS and mPFS compared with sorafenib 41 , 42 . Subgroup analysis indicated that the combination therapy also provided significant clinical benefits for Chinese patients. Several studies have shown that anlotinib, in addition to inhibiting tumor proliferation and angiogenesis, can enhance the infiltration of natural killer (NK) cells, antigen-presenting (APC) cells, and CD8 + T cells while inducing apoptosis of cancer-associated fibroblasts (CAFs) 43 – 46 . This process facilitates the transformation of an immunosuppressive microenvironment into an immune-activated microenvironment, thereby activating and initiating T cell recognition of tumor antigens to elicit antitumor immune responses. Considering the efficacy and safety profile of anlotinib, we believe that anlotinib, either as monotherapy or in combination with ICIs, holds significant clinical potential for patients who develop resistance to immunotherapy or experience immune-related adverse events (irAEs). Furthermore, clinical trials investigating the safety and efficacy of anlotinib in combination with ICIs are currently underway (ClinicalTrials.gov identifier: NCT05453383, NCT03825705, NCT04052152, and NCT06031480). In summary, anlotinib acts as an effective monotherapy agent for patients with unresectable or metastatic HCC. It also showed acceptable safety and tolerability. However, this study has some limitations. Firstly, because of the retrospective nature, this study utilized PSM analysis to filter the original data and minimize potential biases in outcome analysis. But clinical trials with a large sample size are still needed to further validate the clinical therapeutic advantages of anlotinib compared to sorafenib or other TKIs. Secondly, this study included only Chinese patients. Thus, future studies are required to evaluate the efficacy and safety of anlotinib in Western populations. Conclusion Anlotinib showed promising efficacy and tolerability in Chinese patients, both in the first- and second-line treatment. AFP response was an early predictor of disease control in patients with anlotinib treatment. Declarations Data Availability The clinical data supporting the conclusions of this article are available from the corresponding author upon reasonable request. Author Contributions Conceptualization, Y.J.Y. and B.W.X.; methodology, Y.J.Y. and B.W.X..; software, Y.J.Y. and B.W.X.; validation, J.P.C., Z.Y.L. and X.Y.B.; formal analysis, Y.J.Y. and B.W.X.; investigation, Y.J.Y.; resources, X.C. and J.Q.C.; data curation, Z.C.W.; writing—original draft preparation, Y.J.Y.; writing—review and editing, Y.J.Y. and B.W.X.; visualization, Y.J.Y.; supervision, X.C. and J.Q.C.; project administration, X.C. and J.Q.C.; funding acquisition, X.C. and J.Q.C. All authors have read and agreed to the published version of the manuscript. Funding This study was supported by the CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-066) and Sanming Project of Medicine in Shenzhen (No. SZSM201911006; No. SZSM202011010). Competing Interests All authors declare no conflict of interest. Ethics Declarations Due to the retrospective nature of the study, the Institutional Review Boards of Cancer Hospital of Chinese Academy of Medical Sciences and Qilu Hospital of Shandong University waived the need of obtaining informed consent. References Bray, F. et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J. Clin. 10.3322/caac.21834 (2024). Han, B. et al. Cancer incidence and mortality in China, Journal of the National Cancer Center 4, 47–53, (2022). 10.1016/j.jncc.2024.01.006 (2024). Singal, A. G., Kanwal, F. & Llovet, J. M. Global trends in hepatocellular carcinoma epidemiology: implications for screening, prevention and therapy. Nat. Rev. Clin. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5766433","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":400639344,"identity":"efbf83f2-d813-47c2-9a3e-cf0ece67776a","order_by":0,"name":"Yanjiang Yin","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yanjiang","middleName":"","lastName":"Yin","suffix":""},{"id":400639345,"identity":"66f7b14a-d6b8-4e7e-8b61-dbcc70d63b35","order_by":1,"name":"Bowen Xu","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Bowen","middleName":"","lastName":"Xu","suffix":""},{"id":400639346,"identity":"a52c0d2d-684c-4289-b5b8-92d81d1b78aa","order_by":2,"name":"Jianping Chang","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jianping","middleName":"","lastName":"Chang","suffix":""},{"id":400639348,"identity":"7a7a5243-d6b0-4734-8c9b-23e788553b0d","order_by":3,"name":"Zhiyu Li","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zhiyu","middleName":"","lastName":"Li","suffix":""},{"id":400639350,"identity":"dd861e00-6ed2-41a6-ba51-e6e4464025c3","order_by":4,"name":"Xinyu Bi","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xinyu","middleName":"","lastName":"Bi","suffix":""},{"id":400639352,"identity":"ee6dbe62-c04f-4bbf-a0e8-874e74aefbad","order_by":5,"name":"Zhicheng Wei","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital \u0026 Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zhicheng","middleName":"","lastName":"Wei","suffix":""},{"id":400639354,"identity":"b3458142-8848-4798-afcc-34b01cd781b9","order_by":6,"name":"Xu Che","email":"","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital \u0026 Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Che","suffix":""},{"id":400639356,"identity":"cb5e5864-2701-4080-8f5c-669d9d65ea3c","order_by":7,"name":"Jianqiang Cai","email":"data:image/png;base64,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","orcid":"","institution":"National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Jianqiang","middleName":"","lastName":"Cai","suffix":""}],"badges":[],"createdAt":"2025-01-05 06:53:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5766433/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5766433/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":73784938,"identity":"e8cff17e-f129-4b51-931d-dc8b54de6744","added_by":"auto","created_at":"2025-01-14 16:06:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":47764,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of (A) PFS and (B) OS for patients receiving anlotinib (n=54): (A) stratified by distant metastasis status; (B) stratified by baseline AFP level. \u003cem\u003eCI, confidence interval; PFS, progression-free survival; OS, overall survival; The bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/a60478bd21f3c325779eb705.png"},{"id":73784358,"identity":"951b0655-d9f6-44bf-b0aa-6f47305da965","added_by":"auto","created_at":"2025-01-14 15:58:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44651,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of (A) PFS and (B) OS between anlotinib group (n=54) and sorafenib group (n=104). \u003cem\u003eCI, confidence interval; PFS, progression-free survival; OS, overall survival; The bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/c6b4b360b193da0f28b7ec4c.png"},{"id":73784360,"identity":"983b6812-6982-4140-85eb-d1ab5cc67915","added_by":"auto","created_at":"2025-01-14 15:58:48","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":193397,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves between anlotinib group (n=54) and sorafenib group (n=104) either in first- or second-line treatment: (A) PFS curve in first-line treatment; (B) OS curve in first-line treatment; (C) PFS curve in second-line treatment; (D) OS curve in second-line treatment. \u003cem\u003eCI, confidence interval; PFS, progression-free survival; OS, overall survival; The bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure3AB.png","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/b94726bbbb6628ec472bc9be.png"},{"id":73784368,"identity":"c1057fce-6b4a-4828-96af-befdcda84096","added_by":"auto","created_at":"2025-01-14 15:58:48","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":783037,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot in prespecified subgroups with anlotinib (n=54) versus sorafenib (n=104): (A) Forest plot of PFS; (B) Forest plot of OS. \u003cem\u003eHR, hazard ratio; CI, confidence interval; PFS, progression-free survival; OS, overall survival; HBV, hepatitis B virus; AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; CNLC stage, China Liver Cancer stage; PVTT, portal vein tumor thrombosis. The bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure4A.png","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/fa990061429b4eaeda903e98.png"},{"id":73784942,"identity":"a985778d-0da2-4e1e-8b6c-eba4a92f8775","added_by":"auto","created_at":"2025-01-14 16:06:48","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":47044,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of (A) PFS and (B) OS for patients with a baseline AFP level above the threshold of 400 ng/mL between anlotinib group (n=27) and sorafenib group (n=39). \u003cem\u003eCI, confidence interval; PFS, progression-free survival; OS, overall survival; The bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/22b5fc8eb45116929c56cc2e.png"},{"id":73786318,"identity":"d694d013-294e-488e-8026-4db8afd05afe","added_by":"auto","created_at":"2025-01-14 16:23:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":19350849,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/2cf34c7e-48c6-41e1-a950-5669599c9003.pdf"},{"id":73784363,"identity":"1fb1d913-d6b8-4805-b30a-2898b244a0e9","added_by":"auto","created_at":"2025-01-14 15:58:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1026332,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-5766433/v1/3a5924374620fd808070d8fb.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evidence of Anlotinib as First- or Second-line Monotherapy for Advanced Hepatocellular Carcinoma and Clinical Role of α-fetoprotein: a Multicenter Retrospective Study in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is the most common primary liver cancer in the world and ranks the third most common and second most fatal malignancy in China \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Chronic hepatitis B virus (HBV) infection is the key determinant of HCC development in Chinese patients \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The majority of patients with HCC are diagnosed with advanced disease, and only a few are eligible for potentially curative locoregional therapies. Due to the resistance to chemotherapy drugs, targeted therapy has been the standard care for advanced HCC since the first approval of sorafenib in 2007 \u003csup\u003e4\u003c/sup\u003e. However, the clinical benefit of sorafenib is limited with the median overall survival (mOS) of 8.5\u0026ndash;14.7 months in patients worldwide and 6.5\u0026ndash;8.9 months in Asian patients \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. The first drug to get approved for the treatment of HCC in patients who had progressed after sorafenib therapy was regorafenib, a small molecule inhibitor with a broader inhibition of kinases than sorafenib \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. To date, these two drugs are the standard of care for advanced HCC as first- and second-line monotherapy. With a lot of recent translational research and clinical trials, other targeted agents, such as lenvatinib, apatinib and donafenib, have been approved for first- or second-line therapy \u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. But no monotherapy has shown significantly better clinical effects than sorafenib, and drug resistance and tumor recurrence also remain inevitable issues. Thus, an unmet need for more effective targeted drugs remains among patients with advanced HCC.\u003c/p\u003e \u003cp\u003eAnother clinical issue is to define biomarkers for targeted therapy and validate them in large-scale studies. HCC biomarkers are in urgent need in the following clinical fields: prognosis prediction; identification of a subgroup of patients for whom targeted therapy is more effective; early prediction of tumor response for targeted therapy. Alpha-fetoprotein (AFP) is a biomarker routinely assessed for the diagnosis and treatment of HCC. Some studies considered the pre-treatment AFP level as a prognostic factor and find its ability to screen patients who would benefit from targeted therapy \u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Recently the post-treatment change of AFP level has been reported to predict tumor response although disagreement over the magnitude of the change still exists \u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Other biomarkers such as blood-derived inflammatory markers and albumin-bilirubin (ALBI) grade have also been investigated for predicting survival of HCC patients \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnlotinib is a novel tyrosine kinase inhibitor (TKI) with potential anti-neoplastic and anti-angiogenic activities. Compared to other TKIs, it has more targets, including vascular endothelial growth factor receptor (VEGFR) 1\u0026ndash;3, platelet-derived growth factor receptors (PDGFR) α/β, fibroblast growth factor receptors (FGFR) 1\u0026ndash;4, c-Kit, c-FMS and discoidin domain receptor 1 (DDR1) \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Anlotinib has shown promising efficacy and tolerable toxicity in many malignancies, including advanced non-small-cell lung cancer, advanced soft tissue sarcoma, metastatic renal cell carcinoma and advanced medullary thyroid cancer \u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Previous experimental and clinical data have already demonstrated the antitumor effects of anlotinib on HCC \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Our team's previous single-arm clinical study demonstrated that anlotinib achieved a time to progression (TTP) of 5.9 months in first-line treatment and 4.6 months in second-line treatment \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, the advantages of anlotinib compared to other targeted drugs and appropriate biomarkers are still unclear.\u003c/p\u003e \u003cp\u003eThis multicenter retrospective study was conducted to explore the efficacy and safety of anlotinib for first- and second-line therapy. And patients receiving sorafenib treatment served as the control group. Predictive factors for disease control after anlotinib treatment were also analyzed in this study.\u003c/p\u003e"},{"header":"Materials and Methods","content":" \u003cp\u003e\u003cb\u003eStudy Design\u003c/p\u003e \u003cp\u003eClinicopathological data of 210 patients diagnosed between May 2017 and July 2023 were retrieved from 3 tertiary medical research centers in China: National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital \u0026amp; Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; and Qilu Hospital, Cheeloo College of Medicine, Shandong University. 55 patients received anlotinib monotherapy, while 155 patients received sorafenib monotherapy. Enrolled patients had a diagnosis of locally advanced or metastatic HCC. Diagnostic evaluation of HCC was based on liver biopsy or noninvasive measures combining imaging and blood tests. Eligible patients also conformed to the following inclusion criteria: age over 18 years old; Barcelona Clinic Liver Cancer (BCLC) stage B or C; Child\u0026ndash;Pugh score\u0026thinsp;\u0026lt;\u0026thinsp;8; an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1; at least one measurable lesion defined by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); normal function of vital organs; complete medical records, including imaging and prognostic information. Exclusion criteria included diagnosis of cholangiocarcinoma, combined hepatocellular-cholangiocarcinoma (cHCC-CCA) or fibrolamellar hepatocellular carcinoma (FLHC); existence of serious comorbidities; treatment history of immunotherapy.\u003c/p\u003e \u003cp\u003e This study was approved by the Institutional Review Boards of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Ethical Approval Number: 21-197-2868) and Qilu Hospital of Shandong University (Ethical Approval Number: 2021-I2M-1-066). This study was conducted according to the Declaration of Helsinki. Because of the retrospective nature, this study was granted a full waiver of informed consent. All information provided by patients is maintained with confidentiality.\u003c/p\u003e \u003cp\u003e\u003cb\u003eTargeted drugs\u003c/p\u003e \u003cp\u003eAll patients in anlotinib group received treatment at a dose of 12 mg on day 1 through 14 of a 21-day cycle. Dosage reduction to 10 mg/day or even 8 mg/day would be proposed due to grade 3 or 4 hematologic toxicities. Sorafenib was taken 400 mg orally twice daily. Patients experiencing grade 4 hematologic toxicity or grade 2 non-hematologic toxicity require dose reduction. The dose reduction should not exceed two steps: the first reduction decreases the dose to 80% of the original dosage, and the second reduction decreases it to 50% of the original dosage. Patients received their assigned drugs until they were no longer benefiting from therapy or unacceptable toxic events occurred. Patients were regularly followed up by the investigators. Adverse events (AEs) were graded according to the Common Terminology Criteria Adverse Events version 4.0 (CTCAE 4.0). Radiological imaging was done for all patients every 6 weeks after the first intervention dose.\u003c/p\u003e \u003cp\u003e\u003cb\u003eData Collection, Biomarkers, and Outcomes\u003c/p\u003e\u003cp\u003eLaboratory test results were collected from the time of drug assignment to 30 days following treatment discontinuation. The cutoff date for follow-up was July 1, 2024. Percentage change of AFP, ALBI score, ALBI grade and three blood-derived inflammatory (neutrophil-to-lymphocyte ratio, NLR; platelet-to-lymphocyte ratio, PLR; prognostic nutritional index, PNI) markers were evaluated to predict disease control in HCC patients. Percentage change of AFP level was defined as (AFP level at 2, 4, 6 weeks after first dosage - AFP baseline level) / AFP baseline level. ALBI was a useful assessment tool for hepatic reserve function and ALBI score was calculated as follows: (log\u003csub\u003e10\u003c/sub\u003e bilirubin (\u0026micro;mol/L) \u0026times; 0.66) + (albumin (g/L) \u0026times; -0.085). The cutoff points for ALBI grades were as follows: \u0026le; -2.60 (ALBI grade 1), more than \u0026minus;\u0026thinsp;2.60 to \u0026le; -1.39 (ALBI grade2), and \u0026gt; -1.39 (ALBI grade 3) \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. NLR was calculated by dividing the total number of neutrophils by lymphocytes. PLR was calculated by dividing the total platelets count by lymphocytes count. PNI was calculated by multiplying albumin (g/L) by absolute lymphocyte count.\u003c/p\u003e \u003cp\u003eTumor response was assessed using computed tomography (CT) scans or magnetic resonance imaging (MRI) examinations every 6 weeks by three radiologists independently and characterized by complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Not to be evaluated (NE) denoted treatment effects which were not recorded. When disagreement happened on imaging evaluation, a third doctor was requested to reevaluate. The primary end point was overall survival (OS). OS was defined as the time from the first dose of drugs medication to death from any cause. The secondary endpoints included progression\u0026shy;free survival (PFS), objective response rate (ORR), disease control rate (DCR), survival rates at 12 or 24 months, and PFS rates at 6 or 12 months. PFS referred to the time from the first dose of drugs medication to disease progression according to RECIST 1.1, or death from any cause, whichever occurred first. ORR was defined as the proportion of confirmed CR or PR at the best response. DCR was defined as the percentage of confirmed CR, PR, or SD at the best response.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eIn this observational study, a 2:1 nearest neighbor propensity score matching (PSM) was used to achieve a balanced covariate distribution between the two treatment groups. Variables included in the propensity score calculation were provided in \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e. Statistical computation of PSM method was finished by the R package MatchIt (version 4.3.2) \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. A caliper for matching process was set at 0.1. The Student\u0026rsquo;s t-test or the Wilcoxon rank-sum test was conducted to assess baseline comparability for continuous variables between the two groups. The mean and standard deviation (SD) were used to describe normally distributed continuous data, while the median and interquartile range (IQR) were used to describe non-normally distributed continuous data. Categorical variables were calculated using both frequencies and percentages. And they were compared by the Chi-square test or Fisher\u0026rsquo;s exact test. The OS and the PFS curves were obtained using the Kaplan-Meier (KM) method and compared by the log-rank test. The best cut-off values for hematological biomarkers were determined by the receiver operating characteristic (ROC) curve. Univariate and multivariate analyses were conducted using the Cox proportional hazards model or logistic regression analysis to analyze factors associated with survival or disease control. Tests within each subgroup used an unstratified Cox proportional hazards model and the forest plots illustrated the test results. All statistical analyses were performed using RStudio version 1.4.1717 (Integrated Development Environment for R, Boston, MA) and SPSS version 26.0 (IBM Corp., Armonk, NY, USA). All tests were two-tailed, and \u003cem\u003eP\u003c/em\u003e values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eBaseline Clinical Characteristics\u003c/p\u003e \u003cp\u003eInitially, a total of 210 patients with locally advanced or metastatic HCC were included in this study according to the inclusion and exclusion criteria (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). Compared to anlotinib group, patients in sorafenib group had incomparable composition ratio of Child\u0026ndash;Pugh class (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.074). PSM analysis generated an assembly of 158 patients with a mean age of 52.7 years (SD\u0026thinsp;=\u0026thinsp;9.7). 54 patients received anlotinib and 104 received sorafenib. Imbalances on patients\u0026rsquo; characteristics between two groups were minimized (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the 158 patients, 141 (89.2%) were males, 127 (80.4%) had HBV infection, 66 (41.8%) had a baseline AFP level of more than 400 ng/mL, 70 (44.3%) had an ECOG PS score of 1, 122 (77.2%) were BCLC stage C, 16 (10.1%) were Child\u0026ndash;Pugh class B (scores 7) and 107 (67.7%) were CNLC stage III. The median tumor size was 6.4 cm (IQR [4.3, 10.4]). The presence of distant metastasis happened in 73 (46.2%) patients, including 40 (25.3%) lung metastasis and 16 (10.1%) bone metastasis. 75 (47.5%) patients received targeted therapy for first-line therapy, and 83 (52.5%) patients received targeted therapy for second-line therapy. 80 patients underwent surgery during first or second-line treatment, accounting for 50.6% of the total population.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline patient demographic and clinical characteristics (After PSM, n\u0026thinsp;=\u0026thinsp;158).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnlotinib\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSorafenib\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c6\" namest=\"c5\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003cp\u003evalue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;158\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;54\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;104\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.7 (9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52.3 (9.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.9 (9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.722\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e141 (89.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (88.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e93 (89.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcohol consumption\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60 (38.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (40.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e38 (36.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (22.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.471\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFamily history of cancer\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther types\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (10.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (10.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNot happened\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e126 (79.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43 (79.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (79.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eViral infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHBV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 (80.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (81.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83 (79.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHCV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (0.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-infected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (19.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e20 (19.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP, \u0026gt;\u0026thinsp;400 ng/mL\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 (35.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (30.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAscites\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.311\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCirrhosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e65 (41.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (40.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (41.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG PS score\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (55.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (55.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 (44.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (44.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCLC stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.937\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (22.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (24.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (22.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e122 (77.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (75.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e81 (77.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChild\u0026ndash;Pugh class\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA (5 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e118 (74.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (74.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eA (6 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (15.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (16.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB (7 points)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (10.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (8.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNLC stage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (32.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (32.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e107 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (68.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (67.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size, cm\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.4 [4.3, 10.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4 [4.3, 11.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.3 [4.3, 9.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.435\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor number\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109 (69.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (75.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68 (65.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (6.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (7.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (24.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (20.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (26.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTBS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8 [4.6, 10.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5 [4.6, 11.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.7 [4.6, 10.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaVI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (46.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e48 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePVTT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (12.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (12.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtrahepatic spread\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e94 (59.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (61.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.468\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistant metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.601\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (25.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (25.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (25.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (10.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (9.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther sites\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (15.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTargeted therapy\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e0.704\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e75 (47.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (44.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (49.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecond-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (52.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (55.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (51.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCategorical data are presented as n (%); continuous data are presented as mean (SD) or median [Q1, Q3].\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eSD, standard deviation; PSM, propensity score matching; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; CNLC stage, China Liver Cancer stage; TBS, tumor burden score; MaVI, macrovascular invasion; PVTT, portal vein tumor thrombosis; EHS, extrahepatic spread; TACE, transarterial chemoembolization.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn anlotinib group, 24 (44.4%) patients received anlotinib as first-line therapy, whereas 30 (55.6%) patients received anlotinib as second-line therapy. 22 (40.7%) patients underwent surgery, and 21 (38.9%) patients underwent intra-arterial therapy. In sorafenib group, 51 (49.0%) patients received sorafenib as first-line therapy, whereas 53 (51.0%) patients received sorafenib as second-line therapy. 58 (55.8%) patients underwent surgery, and 42 (40.4%) patients underwent intra-arterial therapy.\u003c/p\u003e \u003cp\u003e\u003cb\u003eOverall Prognosis Analysis\u003c/p\u003e \u003cp\u003eAs shown in \u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e, the median follow-up time for whole patients was 13.0 months (range: 1.0\u0026ndash;30.0 months). Overall median PFS was 5.0 months (95% confidence interval [CI]: 4.5\u0026ndash;5.5 months) and overall median OS was 15.0 months (95% CI: 13.2\u0026ndash;16.8 months). The 6-month or 12-month PFS rate was 28.3% (95% CI: 22.0-36.4%) or 1.6% (95% CI: 0.4\u0026ndash;6.3%). The 12-month or 24-month survival rate was 56.4% (95% CI: 49.0-64.9%) or 2.5% (95% CI: 0.8\u0026ndash;7.4%).\u003c/p\u003e \u003cp\u003eUnivariate and multivariate Cox regression analysis were used to explore prognostic factors for all 158 patients. The results of univariate analysis were presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. China Liver Cancer (CNLC) stage and macrovascular invasion (MaVI) were strongly associated with both PFS (CNLC, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001; MaVI, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and OS (CNLC, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; MaVI, P\u0026thinsp;=\u0026thinsp;0.031). Large tumor size (\u0026gt;\u0026thinsp;6 cm) and distant metastasis were found to have obviously negative effects on PFS (tumor size, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; distant metastasis, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) while they had no significant influences on OS (tumor size, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.939; distant metastasis, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.875). AFP level\u0026thinsp;\u0026gt;\u0026thinsp;400 ng/mL was a risk factor only for OS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate analysis of PFS and OS for the whole patients (n\u0026thinsp;=\u0026thinsp;158).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e* (\u0026le;\u0026thinsp;55 \u003cem\u003evs.\u003c/em\u003e \u0026gt;55 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.908 (0.650\u0026ndash;1.270)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.574\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.153 (0.817\u0026ndash;1.628)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e (Male \u003cem\u003evs.\u003c/em\u003e female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.853 (0.499\u0026ndash;1.458)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.562\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.292 (0.740\u0026ndash;2.255)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHBV infection\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.957 (0.639\u0026ndash;1.432)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.866 (0.571\u0026ndash;1.313)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP\u003c/b\u003e (\u0026le;\u0026thinsp;400 \u003cem\u003evs.\u003c/em\u003e \u0026gt;400 ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.063 (0.761\u0026ndash;1.485)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.721\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.614 (1.152\u0026ndash;2.262)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG PS score\u003c/b\u003e (0 \u003cem\u003evs.\u003c/em\u003e 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.871 (0.626\u0026ndash;1.210)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.874 (0.625\u0026ndash;1.224)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.435\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCLC stage\u003c/b\u003e (B \u003cem\u003evs.\u003c/em\u003e C)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.249 (0.853\u0026ndash;1.829)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.108 (0.744\u0026ndash;1.650)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNLC stage\u003c/b\u003e (II \u003cem\u003evs.\u003c/em\u003e III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.346 (1.618\u0026ndash;3.401)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.548 (1.084\u0026ndash;2.210)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size\u003c/b\u003e** (\u0026le;\u0026thinsp;6 \u003cem\u003evs.\u003c/em\u003e \u0026gt;6 cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.530 (1.095\u0026ndash;2.138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.013\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.987 (0.708\u0026ndash;1.377)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.939\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaVI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.856 (1.316\u0026ndash;2.616)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.444 (1.034\u0026ndash;2.016)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.031\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePVTT\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.830 (0.511\u0026ndash;1.346)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.953 (0.581\u0026ndash;1.565)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.850\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEHS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.186 (0.750\u0026ndash;1.874)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.239 (0.785\u0026ndash;1.955)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.358\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistant metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.086 (1.478\u0026ndash;2.944)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.972 (0.685\u0026ndash;1.379)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.875\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003e*Defined based on the mean value.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003e**Defined based on the median value.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003ePFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; HBV, hepatitis B virus; AFP, alpha-fetoprotein; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion; PVTT, portal vein tumor thrombosis; EHS, extrahepatic spread.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eThe bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c7\" namest=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of multivariate analysis were presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Multivariate analysis indicated that distant metastasis was the only risk factor independently related to PFS (HR [hazard ratio]: 1.554; 95% CI: 1.028\u0026ndash;2.350; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.037). And high AFP (\u0026gt;\u0026thinsp;400 ng/mL) is an independent risk factor for poorer OS in patients (HR: 1.614; 95% CI: 1.147\u0026ndash;2.270; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). Moreover, KM curves were used to compare the impact of different independent risk factors on prognosis in the anlotinib group (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For patients receiving anlotinib, KM analysis showed distant metastasis significantly reduced the patients' PFS (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; median PFS: 2.0 months \u003cem\u003evs.\u003c/em\u003e 6.0 months; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). And OS was prolonged in patients with a baseline AFP level\u0026thinsp;\u0026le;\u0026thinsp;400 ng/mL (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.098; median OS: 20.0 months \u003cem\u003evs.\u003c/em\u003e 11.0 months; Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis of PFS and OS for the whole patients (n\u0026thinsp;=\u0026thinsp;158).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP\u003c/b\u003e (\u0026le;\u0026thinsp;400 \u003cem\u003evs.\u003c/em\u003e \u0026gt;400 ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.614 (1.147\u0026ndash;2.270)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNLC stage\u003c/b\u003e (II \u003cem\u003evs.\u003c/em\u003e III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.580 (0.903\u0026ndash;2.764)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.486 (0.937\u0026ndash;2.357)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size\u003c/b\u003e** (\u0026le;\u0026thinsp;6 \u003cem\u003evs.\u003c/em\u003e \u0026gt;6 cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.327 (0.937\u0026ndash;1.879)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaVI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.200 (0.762\u0026ndash;1.890)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.078 (0.698\u0026ndash;1.663)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.736\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistant metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.554 (1.028\u0026ndash;2.350)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.037\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003e**Defined based on the median value.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003ePFS, progression-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; AFP, alpha-fetoprotein; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eThe bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003cb\u003eClinical Efficacy and Safety\u003c/p\u003e\u003cp\u003e54 patients in anlotinib group and 104 patients in sorafenib group were included in efficacy and safety analysis. Median PFS in anlotinib group was 5.0 months (95% CI: 4.3\u0026ndash;5.7 months) compared with 4.0 months (95% CI: 3.4\u0026ndash;4.6 months) in sorafenib group (HR: 1.217; 95% CI: 0.862\u0026ndash;1.718; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.251) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Median OS was found to be longer for patients receiving anlotinib (16.0 months, 95% CI: 12.4\u0026ndash;19.6 months) than sorafenib (14.0 months, 95% CI: 12.4\u0026ndash;15.6 months), and the difference between the two groups was statistically significant (HR: 1.779; 95% CI: 1.238\u0026ndash;2.558; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Drug-related adverse effects (AEs) in patients were shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. 46 (85.2%) or 95 (91.3%) patients with anlotinib or sorafenib experienced drug-related AEs. Specifically, drug-related grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs occurred in 15 (27.8%) or 39 (37.5%) patients with anlotinib versus sorafenib (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.296). The most common AE was diarrhea both in anlotinib (28 patients, 51.9%) and sorafenib (56 patients, 53.8%) group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDrug-related adverse effects in patients receiving anlotinib (n\u0026thinsp;=\u0026thinsp;54) \u003cem\u003evs.\u003c/em\u003e sorafenib (n\u0026thinsp;=\u0026thinsp;104).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDrug-related AEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnlotinib\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSorafenib\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;104)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAny AEs\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (85.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95 (91.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.360\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (27.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39 (37.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIncidence\u0026thinsp;\u0026ge;\u0026thinsp;10%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (51.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (53.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.944\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (38.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (45.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.448\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (38.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48 (46.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.383\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (35.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29 (27.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.344\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased Hb count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (31.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (33.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.783\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (25.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (36.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.178\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated AST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (25.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (26.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (20.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (26.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.477\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePharyngalgia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (22.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.748\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow back pain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22 (21.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.855\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElevated bilirubin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (23.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.463\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (15.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.864\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (11.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (11.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAEs, adverse effects; Hb, hemoglobin; AST, aspartate aminotransferase.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe separately analyzed the differences in the impact of anlotinib and sorafenib on clinical outcomes in first- and second-line treatments. Among all patients, 24 (44.4%) patients in anlotinib group and 51 (49.0%) in sorafenib group received targeted drugs as first-line therapy (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). 2 (8.3%) patients achieved PR, 16 (66.7%) exhibited SD and no one achieved CR in anlotinib subgroup, yielding an ORR of 8.3% and DCR of 75.0%. And for sorafenib subgroup, 1 (2.0%) patient reached CR, 2 (3.9%) obtained PR and 35 (68.6%) achieved SD. The ORR was 5.9%, and the DCR was 74.5%, with no significant difference compared to the anlotinib subgroup (ORR, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.921; DCR, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.964). Median PFS was 5.0 months (95% CI: 2.6\u0026ndash;7.4 months) with anlotinib and 4.0 months (95% CI: 3.4\u0026ndash;4.6 months) with sorafenib (HR: 1.465; 95% CI: 0.885\u0026ndash;2.425; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.144) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Median OS was improved in anlotinib subgroup versus sorafenib subgroup (20.0 \u003cem\u003evs.\u003c/em\u003e 15.0 months; HR: 1.588; 95% CI: 0.927\u0026ndash;2.719; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.077) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTumor response and survival outcomes for patients receiving anlotinib (n\u0026thinsp;=\u0026thinsp;54) \u003cem\u003evs.\u003c/em\u003e sorafenib (n\u0026thinsp;=\u0026thinsp;104).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eFirst line (n\u0026thinsp;=\u0026thinsp;75)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eSecond line (n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnlotinib (n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSorafenib (n\u0026thinsp;=\u0026thinsp;51)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAnlotinib (n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSorafenib (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor response\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 (68.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (56.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24 (45.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (15.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18 (34.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (9.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 (11.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eORR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (5.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.921\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (10.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDCR\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (74.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.964\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29 (54.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.288\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePFS rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.097\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27.8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.430\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.361\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSurvival rate\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.853\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e56.0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.406\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluated; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA total of 30 (55.6%) patients in anlotinib group and 53 (51.0%) in sorafenib group received targeted drugs as second-line therapy (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). 3 (10.0%) patients achieved PR, and 17 (56.7%) exhibited SD in anlotinib subgroup, whereas 5 (9.4%) patients achieved PR, and 24 (45.3%) exhibited SD in sorafenib subgroup. No one achieved CR in either subgroup. The ORR was 10.0% or 9.4% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.762), and the DCR was 66.7% or 54.7% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.288), in the anlotinib and sorafenib subgroup, respectively. Median PFS was 5.0 months (95% CI: 4.3\u0026ndash;5.7 months) versus 5.0 months (95% CI: 4.2\u0026ndash;5.8 months) in anlotinib and sorafenib subgroup, respectively (HR: 0.969; 95% CI: 0.599\u0026ndash;1.565; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.948; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). Median OS (13.0 \u003cem\u003evs.\u003c/em\u003e 11.0 months) was significantly improved with anlotinib versus sorafenib (HR: 1.966; 95% CI: 1.189\u0026ndash;3.250; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD).\u003c/p\u003e\u003cp\u003e\u003cb\u003eSubgroup Analysis\u003c/p\u003e\u003cp\u003eSubgroup analysis was performed to identify which part of patients could benefit from anlotinib therapy. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA, the HR values for PFS continued to favour anlotinib versus sorafenib across most prespecified subgroups. But significant differences only existed in the subgroup of patients with a baseline AFP concentration of 400 ng/mL or greater (HR: 0.355; 95% CI: 0.197\u0026ndash;0.637; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Subgroup comparisons of OS showed that anlotinib brought clear improvement in patients\u0026rsquo; survival and significant differences were noted in most subgroups (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). Anlotinib demonstrated better OS compared to sorafenib, regardless of whether the patients' AFP levels were above or below 400 ng/mL (AFP\u0026thinsp;\u0026le;\u0026thinsp;400 ng/mL, HR: 0.505, 95% CI: 0.306\u0026ndash;0.836, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008; AFP\u0026thinsp;\u0026gt;\u0026thinsp;400 ng/mL, HR: 0.508, 95% CI: 0.298\u0026ndash;0.867, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013). Anlotinib exhibited a significant advantage in HBV-positive patients (HR: 0.567; 95% CI: 0.380\u0026ndash;0.848; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006); however, this effect was not observed in HBV-negative patients (HR: 0.689; 95% CI: 0.282\u0026ndash;1.684; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.414).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eKM curve was then to calculate median PFS and OS. For patients with an AFP concentration above the threshold of 400 ng/mL, median PFS was 7.0 months (95% CI: 4.6\u0026ndash;9.4 months) in anlotinib subgroup versus 4.0 months (95% CI: 2.9\u0026ndash;5.1 months) for sorafenib subgroup (HR: 2.820; 95% CI: 1.569\u0026ndash;5.070; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Median OS was 12.0 months (95% CI: 10.0\u0026ndash;14.1 months) for anlotinib subgroup versus 8.0 months (95% CI: 6.6\u0026ndash;9.4 months) for sorafenib subgroup (HR: 1.967; 95% CI: 1.154\u0026ndash;3.354; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e\u003cb\u003ePredictive Factors for Disease Control in Anlotinib Group\u003c/p\u003e \u003cp\u003eFor patients in anlotinib group, in order to identify early predictive factors which can predict disease control after anlotinib therapy, risk factors in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and several hematological biomarkers (NLR, PLR, PNI, ALBI score and grade, rate of change in AFP level at 2, 4, 6 weeks after first dosage) were included in predictive factors analysis. ROC analysis was conducted to obtain cutoff values of hematological biomarkers. Results of ROC analysis were summarized in \u003cb\u003eTable S2\u003c/b\u003e. The optimal cutoff values of NLR, PLR, PNI and ALBI score for disease control were determined as 3.0, 115, 55 and \u0026minus;\u0026thinsp;2.5. The result of ROC analysis showed that patients with disease control were well differentiated from those with disease progression when AFP decreased by \u0026ge;\u0026thinsp;25% at 4 weeks after first dosage, or by \u0026ge;\u0026thinsp;27% at 6 weeks after first dosage. The 4-week time window was selected as it offers an early assessment of treatment response, enabling timely evaluation of therapeutic efficacy. Finally, the cutoff used for the rate of change in AFP level was \u0026minus;\u0026thinsp;0.25 with specificity and sensitivity levels of 93.8% and 78.9% (\u003cb\u003eFigure S2\u003c/b\u003e). Accordingly, AFP response was defined as a reduction of \u0026ge;\u0026thinsp;25% from the baseline level. Early predictors of disease control were analyzed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e and NLR, PLR, ALBI grade and AFP response were found to be significantly correlated with disease control in univariate analysis (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033, 0.003, 0.025, \u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analysis for predictors affecting disease control for patients in anlotinib group (n\u0026thinsp;=\u0026thinsp;54).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFactors\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCNLC stage\u003c/b\u003e (II \u003cem\u003evs.\u003c/em\u003e III)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.473 (0.415\u0026ndash;5.029)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.538\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size\u003c/b\u003e** (\u0026le;\u0026thinsp;6 \u003cem\u003evs.\u003c/em\u003e \u0026gt;6 cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.429 (0.442\u0026ndash;4.764)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMaVI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.157 (0.357\u0026ndash;3.851)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.808\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDistant metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.399 (0.113\u0026ndash;1.392)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNLR\u003c/b\u003e (\u0026le;\u0026thinsp;3.0 \u003cem\u003evs.\u003c/em\u003e \u0026gt;3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.242 (0.059\u0026ndash;0.838)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.033\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.348 (0.032\u0026ndash;2.877)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePLR\u003c/b\u003e (\u0026le;\u0026thinsp;115 \u003cem\u003evs.\u003c/em\u003e \u0026gt;115)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.141 (0.036\u0026ndash;0.491)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.098 (0.004\u0026ndash;0.864)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePNI\u003c/b\u003e (\u0026le;\u0026thinsp;55 \u003cem\u003evs.\u003c/em\u003e \u0026gt;55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.253 (0.593\u0026ndash;11.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.263\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALBI score\u003c/b\u003e (\u0026le;-2.5 \u003cem\u003evs.\u003c/em\u003e \u0026gt;-2.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.296 (0.079\u0026ndash;0.987)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALBI grade\u003c/b\u003e (1 \u003cem\u003evs.\u003c/em\u003e 2,3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.272 (0.082\u0026ndash;0.827)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.417 (0.054\u0026ndash;2.797)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.367\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP\u003c/b\u003e (\u0026le;\u0026thinsp;400 \u003cem\u003evs.\u003c/em\u003e \u0026gt;400 ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.429 (0.442\u0026ndash;4.764)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.552\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP response\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.129 (1.492\u0026ndash;2.762)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.854 (1.364\u0026ndash;2.476)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP response in anlotinib subgroup\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-AFP subgroup (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.745 (1.087\u0026ndash;2.665)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow-AFP subgroup (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.475 (1.211\u0026ndash;1.851)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e-\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003e**Defined based on the median value.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eOR, odds ratio; CI, confidence interval; CNLC stage, China Liver Cancer stage; MaVI, macrovascular invasion; NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; PNI, prognostic nutritional index; ALBI, albumin\u0026ndash;bilirubin; AFP, alpha-fetoprotein.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003cem\u003eThe bold P value indicates statistically significant.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMultivariate analysis showed only AFP response was an independent predictor for disease control in anlotinib group (OR [odds ratio]: 1.854; 95% CI: 1.364\u0026ndash;2.476; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). Moreover, patients in anlotinib group were divided into high-AFP (baseline AFP\u0026thinsp;\u0026ge;\u0026thinsp;400 ng/mL) and low-AFP (baseline AFP\u0026thinsp;\u0026lt;\u0026thinsp;400 ng/mL) subgroup. Logistic regression analysis within each subgroup supported that AFP response was an early predictor of disease control both in high-AFP subgroup (OR: 1.745; 95% CI: 1.087\u0026ndash;2.665; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) and low-AFP subgroup (OR: 1.475; 95% CI: 1.211\u0026ndash;1.851; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter retrospective real-world study revealed that the anlotinib showed promising efficacy and acceptable safety as monotherapy for patients with advanced HCC. Treatment with anlotinib or sorafenib was generally well-tolerated, and the most frequently recorded drug-related AE was diarrhea for both. Anlotinib exhibited a moderately lower incidence of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 AEs compared to sorafenib (27.8% \u003cem\u003evs.\u003c/em\u003e 37.5%). The better efficacy profile of anlotinib versus sorafenib was mainly reflected by statistically significant extension in OS. Subgroup analysis demonstrated significant OS benefits of anlotinib in most subgroups, including those reflective of the characteristics of the Chinese HCC population, such as high AFP levels, positive HBV infection, and a higher proportion of patients with BCLC stage C. In comparison to western countries, patients presented with more advanced baseline disease status in China, which further underscores the positive therapeutic response of anlotinib.\u003c/p\u003e \u003cp\u003eThe REFLECT study demonstrated that lenvatinib as a first-line treatment exhibited clinical benefits comparable to sorafenib, with a median OS increase of 1.3 months (13.6 \u003cem\u003evs.\u003c/em\u003e 12.3 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. A large-scale phase III clinical trial indicated that donafenib, a drug independently developed in China, was the only first-line TKI to show superior OS compared to sorafenib (12.1 \u003cem\u003evs.\u003c/em\u003e 10.3 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025) \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In this study, patients treated with anlotinib as first-line therapy achieved a longer median OS compared to those receiving sorafenib (20.0 \u003cem\u003evs.\u003c/em\u003e 15.0 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.077). Currently, both donafenib and lenvatinib have been included in the standard for diagnosis and treatment of primary liver cancer in China, and large-sample, double-arm clinical trials are still needed to further validate the clinical therapeutic advantages of anlotinib \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur team's prior research has demonstrated that anlotinib is a viable option for HCC refractory to first-line therapy, with a median TTP of 4.6 months \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Compared to the placebo control group, both regorafenib and apatinib, as second-line standard treatment regimens, have been shown to improve OS in patients (10.6 \u003cem\u003evs.\u003c/em\u003e 7.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 8.7 \u003cem\u003evs.\u003c/em\u003e 6.8 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048) \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Anlotinib also showed trend of OS improvement in this study (13.0 \u003cem\u003evs.\u003c/em\u003e 11.0 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010). The recurrence or progression of HCC is highly dependent on angiogenesis, as the formation of new blood vessels provides essential nutrients to support tumor cell proliferation. Compelling evidence has revealed that FGFR signaling plays an important role in HCC progression, angiogenesis and therapy-resistance \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. For example, FGFR1/AKT/mTOR signaling pathway and FGF19/FGFR4 axis are responsible for sorafenib resistance \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. On one hand, the pan-FGFR inhibition of anlotinib offers a potential solution to overcome HCC resistance to anti-angiogenic agents; On the other hand, its favorable safety profile enables sustained anti-angiogenic effects. Taken together, anlotinib shows promise as a potential standard second-line therapeutic option in the future.\u003c/p\u003e \u003cp\u003eAFP has remained the main diagnostic and prognostic biomarker for HCC for decades. Many studies showed that high baseline AFP level appeared to be associated with worse patient survival \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. This study revealed that baseline AFP level was identified as the only independent prognostic factor for patients\u0026rsquo; OS. Moreover, Subgroup analysis revealed that significant PFS improvement was only observed for patients with a baseline AFP of 400 ng/mL or greater. Andrew et al. analyzed patients\u0026rsquo; data from REACH-1 and REACH-2 phase 3 trial, and the results showed ramucirumab, an angiogenesis inhibitor, met its primary endpoint in the subgroup of patients with AFP levels above 400 ng/mL \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Another clinical trial reported that the magnitude of OS benefit brought by lenvatinib was greatest in patients with high AFP level (\u0026ge;\u0026thinsp;200 ng/mL) \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. These data indicated AFP functioned as a biomarker for identifying subgroups of HCC patients and guiding adjustments in treatment strategies.\u003c/p\u003e \u003cp\u003eTreatment response is generally evaluated by radiological technology. Although imaging techniques such as CT and MRI can visually reflect changes in tumor size following treatment, they also have certain limitations, including the subjectivity of radiologists, interference from tissue changes induced by pharmacological treatments, and the lack of standardized imaging guidelines for the evaluation of systemic therapy for HCC. Most importantly, imaging methods cannot predict treatment efficacy at an early stage. In addition to the diagnostic and prognostic significance of baseline AFP levels, numerous studies have proposed that changes in AFP levels during or following treatment may serve as surrogate biomarkers for assessing response to systemic and locoregional therapies \u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. However, there is considerable variability among studies in the criteria used to define AFP response, including the time window for AFP measurement after treatment and the magnitude of AFP level reduction. In this study, we found that AFP response (a reduction of \u0026ge;\u0026thinsp;25% from the baseline level) can be used as a predictor for disease control in anlotinib group. This conclusion was validated in both the high-AFP and low-AFP subgroup. And the time window for AFP measurement was set as 4-week, enabling early evaluation for disease control.\u003c/p\u003e \u003cp\u003eIn recent years, with the widespread clinical application of immune checkpoint inhibitors (ICIs), a variety of immunotherapy regimens represented by ICIs have emerged in the field of hepatocellular carcinoma treatment. Results from IMbrave150 study demonstrated that the combination of atezolizumab and bevacizumab significantly prolonged mOS and mPFS compared with sorafenib \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Subgroup analysis indicated that the combination therapy also provided significant clinical benefits for Chinese patients. Several studies have shown that anlotinib, in addition to inhibiting tumor proliferation and angiogenesis, can enhance the infiltration of natural killer (NK) cells, antigen-presenting (APC) cells, and CD8\u003csup\u003e+\u003c/sup\u003e T cells while inducing apoptosis of cancer-associated fibroblasts (CAFs) \u003csup\u003e\u003cspan additionalcitationids=\"CR44 CR45\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. This process facilitates the transformation of an immunosuppressive microenvironment into an immune-activated microenvironment, thereby activating and initiating T cell recognition of tumor antigens to elicit antitumor immune responses. Considering the efficacy and safety profile of anlotinib, we believe that anlotinib, either as monotherapy or in combination with ICIs, holds significant clinical potential for patients who develop resistance to immunotherapy or experience immune-related adverse events (irAEs). Furthermore, clinical trials investigating the safety and efficacy of anlotinib in combination with ICIs are currently underway (ClinicalTrials.gov identifier: NCT05453383, NCT03825705, NCT04052152, and NCT06031480).\u003c/p\u003e \u003cp\u003eIn summary, anlotinib acts as an effective monotherapy agent for patients with unresectable or metastatic HCC. It also showed acceptable safety and tolerability. However, this study has some limitations. Firstly, because of the retrospective nature, this study utilized PSM analysis to filter the original data and minimize potential biases in outcome analysis. But clinical trials with a large sample size are still needed to further validate the clinical therapeutic advantages of anlotinib compared to sorafenib or other TKIs. Secondly, this study included only Chinese patients. Thus, future studies are required to evaluate the efficacy and safety of anlotinib in Western populations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAnlotinib showed promising efficacy and tolerability in Chinese patients, both in the first- and second-line treatment. AFP response was an early predictor of disease control in patients with anlotinib treatment.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch3\u003eData Availability\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThe clinical data supporting the conclusions of this article are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003ch3\u003eAuthor Contributions\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eConceptualization, Y.J.Y. and B.W.X.; methodology, Y.J.Y. and B.W.X..; software, Y.J.Y. and B.W.X.; validation, J.P.C., Z.Y.L. and X.Y.B.; formal analysis, Y.J.Y. and B.W.X.; investigation, Y.J.Y.; resources, X.C. and J.Q.C.; data curation, Z.C.W.; writing\u0026mdash;original draft preparation, Y.J.Y.; writing\u0026mdash;review and editing, Y.J.Y. and B.W.X.; visualization, Y.J.Y.; supervision, X.C. and J.Q.C.; project administration, X.C. and J.Q.C.; funding acquisition, X.C. and J.Q.C. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003ch3\u003eFunding\u0026nbsp;\u003c/h3\u003e\n\u003cp\u003eThis study was supported by the CAMS Innovation Fund for Medical Sciences (No. 2021-I2M-1-066) and Sanming Project of Medicine in Shenzhen (No. SZSM201911006; No. SZSM202011010).\u003c/p\u003e\n\u003ch3\u003eCompeting Interests\u003c/h3\u003e\n\u003cp\u003eAll authors declare no conflict of interest.\u003c/p\u003e\n\u003ch3\u003eEthics Declarations\u003c/h3\u003e\n\u003cp\u003eDue to the retrospective nature of the study, the Institutional Review Boards of Cancer Hospital of Chinese Academy of Medical Sciences and Qilu Hospital of Shandong University waived the need of obtaining informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBray, F. et al. 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Death Discov\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, 468. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41420-022-01256-2\u003c/span\u003e\u003cspan address=\"10.1038/s41420-022-01256-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2022).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Advanced hepatocellular carcinoma, Anlotinib, Tyrosine kinase inhibitor, α-fetoprotein , Prognostic factor, Predictive factor","lastPublishedDoi":"10.21203/rs.3.rs-5766433/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5766433/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAnlotinib, a novel multi-targeting tyrosine kinase inhibitor (TKI), has been investigated in a variety of malignant tumors. This retrospective study was designed to investigate the efficacy and safety of anlotinib as first- or second-line therapy for advanced or metastatic hepatocellular carcinoma (HCC), and to identify early predictors for disease control.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis multicenter retrospective study included 158 patients with advanced HCC. 54 patients received anlotinib and 104 patients received sorafenib. Progression-free survival (PFS), overall survival (OS), and treatment response were compared. Subgroup analyses and biomarker evaluations were also conducted.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe anlotinib group demonstrated significantly longer OS (16.0 months) compared to sorafenib (14.0 months; HR: 1.779; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), while PFS was similar (5.0 \u003cem\u003evs.\u003c/em\u003e4.0 months; HR: 1.217; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.251). Drug-related adverse effects were comparable between groups, with no new safety concerns. Subgroup analyses revealed significant benefits of anlotinib in patients with baseline AFP\u0026thinsp;\u0026ge;\u0026thinsp;400 ng/mL and in HBV-positive individuals. As for anlotinib group, AFP reduction of \u0026ge;\u0026thinsp;25% at 4 weeks post-treatment was an independent predictor of disease control (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAnlotinib showed promising efficacy and tolerability in Chinese patients. AFP response was an early predictor of disease control in patients with anlotinib treatment.\u003c/p\u003e","manuscriptTitle":"Evidence of Anlotinib as First- or Second-line Monotherapy for Advanced Hepatocellular Carcinoma and Clinical Role of α-fetoprotein: a Multicenter Retrospective Study in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-14 15:58:43","doi":"10.21203/rs.3.rs-5766433/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-04-28T18:25:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-26T00:59:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"261410090216664525225006302177900265730","date":"2025-04-24T08:05:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-23T10:07:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-22T13:25:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"143548465410775027393301205508053649354","date":"2025-04-22T10:32:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"243662084793533928925224204628605510989","date":"2025-04-22T08:16:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19312858285996850603260799186388493856","date":"2025-04-19T19:20:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-19T18:44:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-17T04:22:25+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-01-10T19:19:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-01-09T16:47:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-01-05T06:44:05+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2549d3c4-5025-49ae-b94c-526b1571b769","owner":[],"postedDate":"January 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":42704531,"name":"Biological sciences/Cancer/Cancer therapy/Targeted therapies"},{"id":42704532,"name":"Biological sciences/Cancer/Gastrointestinal cancer"},{"id":42704533,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Liver cancer"}],"tags":[],"updatedAt":"2025-08-04T04:23:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-14 15:58:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5766433","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5766433","identity":"rs-5766433","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}