Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab.

Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab. Takeshi Hatanaka, Satoru Kakizaki, Atsushi Hiraoka, Toshifumi Tada, and 35 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1739681/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Aim This study aims to validate the modified albumin-bilirubin grade and α-fetoprotein score (mALF score). Methods This retrospective study included a total 426 hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev) at 22 institutions in Japan from September 2020 to January 2022. Each patient was randomized 3:2 to a training set (n = 255) and a validation set (n = 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score. This score was evaluated in the validation set. Results We built the mALF score using mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37–4.05, p = 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49–4.55, p < 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9–90.8) in patients who meet neither of the criteria (mALF 0 points, n = 101), 61.7% (95% CI 44.5–74.9) in patients who meet either of the two criteria (mALF 1 point, n = 109), and 24.6% (95% CI 9.0-44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (p < 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0–8.0), and 3.8 months (95% CI 3.0-5.2), respectively, which amounted to a significant difference (p < 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%, p < 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months, p = 0.018). Conclusions The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev. mALF score immune checkpoint inhibitor prognosis α-fetoprotein mALBI grade Figures Figure 1 Figure 2 Figure 3 Introduction The choices of systemic therapies for advanced hepatocellular carcinoma (HCC) have increased. Although three regimens, namely atezolizumab and bevacizumab (Atez/Bev) [ 1 ], lenvatinib [ 2 ], and sorafenib [ 3 , 4 ], have already been approved as first-line treatments, Atez/Bev is recommended for first-line treatment according to recent guidelines [ 5 , 6 ], and is commonly used worldwide. While the expression of PD-L1 [ 7 ], and activated Wnt/β-catenin signaling [ 8 , 9 ] may be promising biomarkers to predict the clinical outcome of immune checkpoint inhibitors, reliable biomarkers are still lacking. Moreover, the predicting the survival of HCC patients receiving immune checkpoint inhibitor (ICI) treatment remains challenge. It is important to establish a simple scoring system that reflects the preserved liver function and oncologic prognostic factors. Therefore, the aim of current study was to newly develop and validate a simple score that can be applied to predict survival in patients treated with Atez/Bev. Methods Participants The present retrospective study included 426 HCC patients who received atezolizumab (1200 mg/body) and bevacizumab (15 mg/kg body weight) intravenously every 3 weeks in 22 institutions in Japan. Between September 2020 and January 2022, a total of 426 patients were included. We did not exclude any patients. These eligible patients were randomized 3:2 to a training set (n = 255) and a validation set (n = 171) (Fig. 1 ). Baseline characteristics, including age, sex, body mass index, chronic liver disease, biochemical parameters, liver function, and tumor stage were collected. The liver function was assessed according to the Child-Pugh score, and modified albumin-bilirubin (mALBI) grade [ 10 ]. The tumor stage was determined based on the Barcelona Clinic Liver Cancer (BCLC) system [ 6 ]. Evaluation on therapeutic outcome of Atez/bev treatment The Atez/Bev treatment was continued until the presence of disease progression or unacceptable adverse events were found. The tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST ver.1.1). The best radiological response was classified as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on local review. Progression-free survival (PFS) was computed from the date on which treatment with Atez/Bev was initiated to the date of disease progression or death from any cause, whichever came first. OS was calculated from the initiation date on which treatment with Atez/Bev was initiated to the date of death from any cause. Adverse events were graded based on The Common Terminology Criteria for Adverse Events version 5.0. Interruption or discontinuation of each drug was carried out according to the guidelines for Atez/Bev treatment provided by the manufacturer. Statistical analyses Categorical variables were reported as the number (percentage) and were compared using the chi-squared or Fisher’s exact test, as appropriate. Continuous variables were reported as the median (interquartile range) and compared using Mann-Whitney U test. We used Cox proportional hazards regression models to investigate prognostic factors. The number of explanatory variables depended on the number of events. The following factors were included as explanatory variables: age, sex, BCLC stage (0 or A or B vs. C or D), mALBI grade (1 or 2a vs. 2b or 3), and AFP (< 100 ng/ml vs. ≥100 ng/ml). PFS and survival curves were drawn using the Kaplan-Meier method and analyzed by a log-rank test. All reported p-values were 2-sided and p values of < 0.05 were considered statistically significant. All statistical analyses were conducted using EZR Ver. 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [ 11 ]. Results Patient profile in training and validation set The patient profiles of the training and validation sets are shown in Table 1 . The median age in the training set was 73 years, and 80.4% of the patients were male. Approximately 80% of the patients had a performance status (PS) of 0. The median body mass index was 23.9 (21.1, 26.1) kg/m 2 . The etiologies of liver disease were as follows: (HBV, n = 46 [18.0%]; HCV, n = 86 [33.6%]; alcohol, n = 47 (18.4%); and other, n = 77 [30.1%]). Therefore, virus-related liver disease accounted for 51.4% of the cases. The Child-Pugh scores was 5 points in 151 patients (59.2%), 6 points in 87 patients (34.1%), and ≥ 7 points in 17 patients (6.7%). The median ALBI score was − 2.36 (-2.70, -2.07). Accordingly, 87 (34.1%), 68 (26.7%), 97 (38.0%), and 3 patients (1.2%) were classified as grade 1, 2a, 2b, and 3, respectively. The BCLC stages were as follows; very early, n = 4 (1.6%); early, n = 27 (10.6%); intermediate, n = 106 (41.6%); advanced, n = 115 (45.1%); and terminal, n = 3 (1.2%). There were 75 patients (29.4%) with extrahepatic spread and 42 patients (16.5%) with macrovascular invasion. The patient characteristics of the validation set were similar to those of the training set. Table 1 Patient characteristics in the training and validation sets Variables Training set (n = 255) Validation set (n = 171) P-value Age, years 73.0 [68.0, 79.0] 74.0 [67.5, 80.0] 0.96 Male, n (%) 205 (80.4) 139 (81.3) 0.90 PS, n (%) 0 205 (80.4) 142 (83.0) 0.78 1 42 (16.5) 24 (14.0) ≥ 2 8 (3.1) 5 (2.9) BMI (kg/m 2 ) 23.9 [21.1, 26.1] 22.4 [20.8, 24.8] 0.012 Cause of liver diseases, n (%) HBV 46 (18.0)* 32 (18.7) 1.00 HCV 86 (33.6)* 58 (33.9) Alcohol 47 (18.4) 31 (18.1) Others 77 (30.1) 50 (29.2) Viral-related liver disease, n (%) 131 (51.4) 90 (52.6) 0.84 Child Pugh score, n (%) 5 151 (59.2) 101 (59.1) 1.00 6 87 (34.1) 58 (33.9) ≥ 7 17 (6.7) 12 (7.0) ALBI score -2.36 [-2.70, -2.07] -2.42 [-2.69, -2.13] 0.77 mALBI grade, n (%) 1 87 (34.1) 64 (37.4) 0.74 2a 68 (26.7) 39 (22.8) 2b 97 (38.0) 67 (39.2) 3 3 (1.2) 1 (0.6) Serum albumin (g/dL) 3.7 [3.3, 4.1] 3.8 [3.4, 4.1] 0.69 Total bilirubin (mg/dL) 0.8 [0.6, 1.0] 0.8 [0.6, 1.0] 0.96 Platelet count (10 9 /L) 13.8 [10.6, 19.0] 13.7 [10.6, 18.8] 0.97 Prothrombin time (%) 91.0 [81.2, 100.0] 90.0 [83.0, 100.0] 0.56 BCLC stage, n (%) Very early 4 (1.6) 1 (0.6) 0.12 Early 27 (10.6) 12 (7.0) Intermediate 106 (41.6) 62 (36.3) Advanced 115 (45.1) 96 (56.1) Terminal 3 (1.2) 0 (0.0) Extrahepatic spread, n (%) 75 (29.4) 63 (36.8) 0.11 Macrovascular invasion, n (%) 42 (16.5) 37 (21.8) 0.20 AFP ≥ 100 ng/ml, n (%) 99 (38.8) 77 (45.0) 0.23 DCP ≥ 100 mAU/ml**, n (%) 168 (66.4) 110 (64.7) 0.75 Data are reported as the median [IQR] or number (percentage). * Both HBs-Ag and anti-HCV Ab were positive in one patient. **Data were missing for three patients. AFP, α-fetoprotein; ALBI, albumin-bilirubin; anti-HCV Ab, anti-hepatitis C antibody; BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; DCP, des-gamma-carboxy prothrombin; HBV, hepatitis B virus; HCV, hepatitis C virus; HBs-Ag, hepatitis B virus surface antigen; mALBI, modified albumin-bilirubin; PS, performance status. Table 2 Results of the multivariate analysis in the training set Variables HR (95% CI) P-value Age Per 1 year 1.02 (0.99–1.06) 0.22 Sex Male 1 0.79 Female 0.91 (0.44–1.89) BCLC stage 0 or A or B 1 0.75 C or D 1.10 (0.61–1.98) mALBI grade 1 or 2a 1 0.002 2b or 3 2.36 (1.37–4.05) AFP < 100 ng/ml 1 < 0.001 ≥ 100 ng/ml 2.61 (1.49–4.55) AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; mALBI, modified albumin-bilirubin The efficacy and safety of Atez/Bev and the development of the modified albumin-bilirubin grade and α-fetoprotein score (mALF score) in the training set The best radiological response in the training set was classified as follows: CR, PR, SD, PD, and NE in CR, n = 5 (2.0%); PR, n = 62 (24.3%); SD, n = 118 (46.3%); PD, n = 36 (14.1%); and NE, n = 34 (13.3%) (Supplemental Table 1). The median PFS was 6.8 months (95% confidence interval 6.0–8.0: Supplemental Fig. 1a), and 129 events (50.6%) were identified at the time of the analysis. The median OS was not reached and the 1-year survival rate was 63.3% (95% CI 53.3–71.7: Supplemental Fig. 1b). Fifty-five patients (21.6%) were dead at the time of the analysis. The multivariate analysis revealed that mALBI grade 2b or 3 and AFP ≥ 100 ng/ml were unfavorable factors for OS (mALBI grade 2b or 3, hazard ratio [HR] 2.36, 95% CI 1.37–4.05, p = 0.002: AFP ≥ 100 ng/ml, HR 2.61, 95% CI 1.49–4.55, p < 0.001). Given that both the mALBI grade and AFP were prognostic factors and the numerical value of the HR was similar in the multivariate analysis, we developed a simple score named the m odified A lbumin-bi L irubin grade and α- F etoprotein score (mALF score). We assigned 1 point for mALBI grade 2b or 3 and 1 point for baseline AFP ≥ 100 ng/ml. The scores of the patients were determined as follows: mALF score 0 points (mALBI grade 1 or 2a and AFP < 100 ng/ml), 1 point (either mALBI grade 2b or 3, and AFP ≥ 100 ng/ml), and 2 points (both mALBI grade 2b or 3, and AFP ≥ 100 ng/ml). When patients were stratified according to their mALF scores, the objective response rate (ORR) and disease control rate (DCR) were numerically higher in patients with 0 points (30.7% and 77.2%, n = 101), followed by those with 1 point (27.5% and 72.5%, n = 109) and those with 2 points (13.3% and 62.2%, n = 45); the differences showed statistical significance (p = 0.08, and 0.17: Supplemental Table 1). The median PFS in patients with mALF scores of 0, 1, and 2 points was 9.5 months (95% CI 7.3-not applicable [NA]), 6.6 months (95% CI 6.0–8.0), and 3.8 months (95% CI 3.0-5.2), respectively; the difference was statistically significant (p < 0.001, concordance index 0.630: Fig. 2 a). The 1-year OS rates in patients with mALF scores of 0, 1, and 2 points were 82.7% (95% CI 68.9–90.8), 61.7% (95% CI 44.5–74.9), and 24.6% (95% CI 9.0-44.3), respectively, which amounted to a statistically significant difference (p < 0.001, concordance index 0.675: Fig. 2 b). There were no other significant differences among patients with mALF scores of 0, 1, and 2 points with the exception of any-grade decreased appetite (p = 0.04) and any-grade fever (p = 0.01: Table 3 ). Table 3 Adverse events according to the mALF score in the training and validation sets Training set Validation set Variables 0 points (n = 101) 1 point (n = 109) 2 points (n = 45) P-value 0 points (n = 60) 1 point (n = 77) 2 points (n = 34) P-value Diarrhea Any 5 (5.0) 12 (11.0) 4 (8.9) 0.28 4 (6.7) 1 (1.3) 1 (2.9) 0.23 Grade ≥ 3 0 (0.0) 1 (0.9) 1 (2.2) 0.36 1 (1.7) 0 (0.0) 0 (0.0) 0.39 Liver injury Any 10 (9.9) 11 (10.1) 5 (11.1) 0.97 5 (8.3) 11 (14.3) 8 (23.5) 0.13 Grade ≥ 3 2 (2.0) 2 (1.8) 4 (8.9) 0.05 0 (0.0) 4 (5.2) 1 (2.9) 0.20 Elevated blood pressure Any 17 (16.8) 18 (16.5) 7 (15.6) 0.98 12 (20.0) 8 (10.4) 2 (5.9) 0.10 Grade ≥ 3 5 (5.0) 7 (6.4) 2 (4.4) 0.85 1 (1.7) 2 (2.6) 0 (0.0) 0.63 Gastrointestinal tract bleeding Any 1 (1.0) 2 (1.8) 1 (2.2) 0.82 1 (1.7) 1 (1.3) 0 (0.0) 0.76 Grade ≥ 3 1 (1.0) 1 (0.9) 0 (0.0) 0.80 1 (1.7) 1 (1.3) 0 (0.0) 0.76 Decreased appetite Any 19 (18.8) 24 (22.0) 17 (37.8) 0.04 8 (13.3) 8 (10.4) 8 (23.5) 0.18 Grade ≥ 3 4 (4.0) 3 (2.8) 2 (4.4) 0.84 1 (1.7) 0 (0.0) 2 (5.9) 0.10 Protein urea Any 17 (16.8) 23 (21.1) 9 (20.0) 0.73 11 (18.3) 16 (20.8) 8 (23.5) 0.83 Grade ≥ 3 6 (5.9) 11 (10.1) 2 (4.4) 0.36 2 (3.3) 8 (10.4) 6 (17.6) 0.07 Fever Any 2 (2.0) 13 (11.9) 2 (4.4) 0.01 0 (0.0) 7 (9.1) 5 (14.7) 0.02 Grade ≥ 3 0 (0.0) 4 (3.7) 0 (0.0) 0.07 0 (0.0) 0 (0.0) 1 (2.9) 0.13 General fatigue Any 18 (17.8) 23 (21.1) 14 (31.1) 0.20 16 (26.7) 10 (13.0) 9 (26.5) 0.09 Grade ≥ 3 2 (2.0) 1 (0.9) 0 (0.0) 0.56 2 (3.3) 1 (1.3) 0 (0.0) 0.46 Hepatic edema Any 11 (10.9) 12 (11.0) 3 (6.7) 0.69 2 (3.3) 13 (16.9) 5 (14.7) 0.04 Grade ≥ 3 2 (2.0) 5 (4.6) 1 (2.2) 0.52 1 (1.7) 5 (6.5) 1 (2.9) 0.34 mALF score, mALBI grade and AFP score. The performance of mALF score in the validation set The mALF scores of the validation cohort were as follows: 0 points, n = 60 (35.1%), 1 point, n = 77 (45.0%); and 2 points, n = 34 patients (19.9%). The ORR in patients with a mALF score of 0 points was numerically higher in comparison to those with those with scores of 1 point or 2 points, but the difference was not statistically significant (p = 0.89: supplemental Table 2). The median PFS in patients with mALF scores of 0, 1, and 2 points was 9.3 months (95% CI 5.8-NA), 6.7 months (95% CI 3.8-9.0), and 4.7 months (95% CI 2.9–6.4), respectively. The 1-year OS rates in patients with a mALF score of 0 points was the highest (94.2%, 95% CI 78.5–98.5%), followed by patients with 1 point (61.7%, 95% CI 44.5–74.9) and patients with 2 points (46.3%, 95% CI 19.6–69.4). The PFS and the survival curve were well stratified by the mALF score (PFS, p < 0.018 concordance index 0.579; OS, p < 0.001 concordance index 0.602: Fig. 3 a and 3 b). The incidence of any-grade fever and any-grade of hepatic edema showed significant differences according to the mALF score (p = 0.02, and p = 0.04, respectively; Table 3 ). Discussion The major findings of the present study were the identification of mALBI grade 2b or 3, and AFP ≥ 100n g/ml as independent unfavorable prognostic factors in a multivariate analysis. Based on this, we built an easy, and widely applicable scoring system named the mALF score. The PFS and survival curve were well stratified by the mALF score in the training set and these results were confirmed in the validation set. Staging systems, including the Liver Cancer Study Group of Japan staging system [ 12 ] have been used to evaluate pure tumor factors. Other staging systems, such as the BCLC staging system [ 6 ], CLIP score [ 13 ], and JIS score [ 14 ], have been used to evaluate both the liver function and tumor factors. However, the inclusion of both tumor factors and the liver function is generally complicated. New evaluation methods for patients receiving systemic therapy are needed because many therapeutic agents have been developed. The liver function plays an important role in maintaining sequential systemic therapies, resulting in prolonged survival. The precise oncologic evaluation is necessary to predict the prognosis. Moreover, although Atez/Bev is recommended as first-line treatment according to recent guidelines, there has been no simple survival estimation model for patients receiving this regimen [ 5 , 6 ]. Accordingly, we built a simple applicable score that includes both the liver function and tumor factors. The ALBI score can be calculated based on only two variables: serum albumin and bilirubin [ 15 ]. According to data from a Japanese nationwide survey, the mALBI grade can evaluate the preserved liver function more precisely and accurately in comparison to the Child-Pugh classification [ 10 ]. In addition, the mALBI grade can predict and stratify the prognosis of HCC patients [ 10 ]. Indeed, the ALBI score plays an important role in predicting survival in advanced HCC patients treated with systemic agents, including atezolizumab plus bevacizumab [ 16 ], lenvatinib [ 17 ], sorafenib [ 18 ], and ramucirumab [ 19 , 20 ]. These findings were in line with the present results. Recently, we reported that the early interruption of Bev due to the AEs was relevant to PFS and OS in patients receiving Atez/Bev, and that Bev treatment was likely to be interrupted in patients with mALBI grade 2b [ 21 ]. Accordingly, a relatively poor liver function leads to the interruption of Bev treatment, resulting in poor PFS and OS, which supports the present results. AFP is a well-known tumor marker and is widely applied in the management of HCC for uses such as surveillance, diagnosis, treatment response monitoring, and prognostic factors [ 22 ]. AFP elevation is associated with a poor prognosis across all stages of HCC [ 23 ]. AFP elevation was also related to a high risk of tumor recurrence after surgical resection [ 24 ] and liver transplantation [ 25 ]. The analysis of transcriptome data, whole-exome sequencing data, and DNA methylome profiling demonstrated that AFP-high tumors showed a different phenotype, which was characterized by poor differentiation, enrichment of progenitor features and enhanced proliferation in comparison to AFP-low tumors [ 26 ]. This analysis also showed VEGF pathway enrichment in AFP-high tumors [ 26 ]. VEGF hampered the benefit and durability of the response of ICI via certain mechanisms [ 27 ]. Given these previous reports, HCC patients with AFP elevation are less responsive to Atez/Bev treatment and show a poor prognosis, which was consistent with the present results. The ORR was numerically the highest in patients with an mALF score of 0 points in both the training and validation set, followed by those with 1 point and 2 points; however, the differences were not significant. The reason for the lack of significance is probably due to the low statistical power. In comparison to tyrosine kinase inhibitor treatment, a longer treatment period is required to achieve a tumor response in patients receiving ICI treatment. Accordingly, with a longer observation period and a larger number of cases, significant differences may be observed among the mALF scores. There are significant differences in any-grade decreased appetite and any-grade fever in the training set, and in any-grade fever, and any-grade hepatic edema in the validation set. Any-grade fever was the only of these factors that was seems to be confirmed in the validation set. However, the incidence of any-grade fever was highest in patients with an mALF score of 1 point in the training set, followed by patients with 2 points and patients with 0 points. On the other hand, it was most frequently found in patients with an mALF score of 2 points in the validation set, followed by patients with 1 point and 0 points. That is, data concerning to any-grade fever in the training set were not confirmed in the validation set. A further study may be required to confirm whether or not the mALF score can predict the development of AEs during Atez/Bev treatment. The present study was associated with some limitations. First, the study population was relatively small. Second, the median OS was not reached at the time of the analysis due to the relatively short observation period. A longer observation period may affect the present results. Third, this study conducted in a retrospective manner and no patients were excluded. Therefore, patients with poor PS (≥ 2), a poor liver function (Child-Pugh score ≥ 7 or mALBI grade 3), and all BCLC stages were included. In conclusion, the mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev. Declarations Statement of Ethics All research procedures were approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (IRB No. 30-66) (UMIN000043219) and were performed in accordance with the Declaration of Helsinki. All patients included in the present study agreed and gave their written consent for the anonymous use of their clinical data for scientific research. Conflict of Interest Statement Takeshi Hatanaka received lecture fees from Eisai. Satoru Kakizaki received research grants from Abbvie. Atsushi Hiraoka received lecture fees from Eli Lilly, Bayer, and Chugai. Toshifumi Tada received lecture fees from AbbVie, and Eisai. Hiroko Iijima received research grants from Abbvie, Otsuka, and Sumitomo Dainippon Pharma. Takashi Kumada received lecture fees from Eisai. The other authors declare no conflicts of interest in association with the present study. Funding Sources This study was not supported by external funding. Author contributions TH, SK, AH, TTad, AN, and TK contributed to the concept, design and execution of the study. TH, SK, AH, TTad, MH, KKar, JT, MA, KTak, EI, SF, KTs, TI, KTaj, HOc, SY, HT, CO, TNi, NS, KKaw, HK, TTan, HOh, KN, AM, AT, TNa, NI, TO, TA, MI, AN, YK, SN, MK, HI, and YH contributed to data curation. TH performed statistical analyses and interpreted the data. TH, SK, AH, TTad, AN, and TK reviewed and edited the manuscript. All authors have read and approved the final version of the manuscript. Data Availability Statement The data associated with present study are available from the corresponding author upon reasonable request. 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Nat Rev Dis Primers. 2021;7:6. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200–7. Notarpaolo A, Layese R, Magistri P, Gambato M, Colledan M, Magini G, et al. Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC. J Hepatol. 2017;66:552–9. Montal R, Andreu-Oller C, Bassaganyas L, Esteban-Fabró R, Moran S, Montironi C, et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br J Cancer. 2019;121:340–3. Hack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 2020;16:975–89. Supplementary Files AtezBevmALFscoreSupplementalTable2022June08.xlsx Sup.Figure1.tif Supplemental Figure 1.PFS and OS in the training set. (a) The median PFS was 6.8 months (95% confidence interval 6.0-8.0), and 129 events (50.6%) were identified at the time of the analysis. (b) The median OS was not reached and the 1-year survival rate was 63.3% (95% CI 53.3-71.7). Fifty-five patients (21.6%) were dead at the time of the analysis.OS, overall survival; PFS, progression-free survival. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 10 Jun, 2022 Reviewers invited by journal 10 Jun, 2022 Editor assigned by journal 09 Jun, 2022 First submitted to journal 08 Jun, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1739681","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":112758672,"identity":"71b65364-476f-4689-bb56-425c4deb0d6d","order_by":0,"name":"Takeshi 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diagram of the patients with hepatocellular carcinoma. Atez/Bev, atezolizumab and bevacizumab; HCC, hepatocellular carcinoma.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/297967414a150979919e84c7.jpg"},{"id":22734615,"identity":"7dab03d8-1188-4843-991a-36401a0bcd97","added_by":"auto","created_at":"2022-06-16 15:46:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":259869,"visible":true,"origin":"","legend":"\u003cp\u003eThe PFS and OS according to the mALF score in the training set. (a) The median PFS according to the mALF scores was as follows: 0 points (n=101), 9.5 months (95% CI 7.3-not applicable); 1 point (n=109), 6.6 months (95% CI 6.0-8.0); and 2 points (n=45), 3.8 months (95% CI 3.0-5.2); this amounted to a statistically significant difference (p\u0026lt;0.001, concordance index 0.630). (b) The 1-year OS rates in patients with mALF scores of 0, 1, and 2 points were 82.7% (95% CI 68.9-90.8), 61.7% (95% CI 44.5-74.9), and 24.6% (95% CI 9.0-44.3), respectively, which amounted to a statistically significant difference (p\u0026lt;0.001, concordance index 0.675).\u003c/p\u003e\u003cp\u003eCI, confidence interval; mALF score, modified albumin-bilirubin grade and α-fetoprotein score; OS, overall survival; PFS, progression-free survival.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/02fbcc31455fc03503a92322.jpg"},{"id":22734618,"identity":"8a4ed54f-75fd-4b38-920b-e264043ebf7a","added_by":"auto","created_at":"2022-06-16 15:46:07","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":252253,"visible":true,"origin":"","legend":"\u003cp\u003eThe PFS and OS according to the mALF scores in the validation set. (a) The median PFS according to the mALF scores was as follows: 0 points (n=60), 9.3 months (95% CI 5.8-not applicable); 1 point (n=77), 6.7 months (95% CI 3.8-9.0); and 2 points (n=34), 4.7 months (95% CI 2.9-6.4). (b) The 1-year OS rate was highest in patients with a mALF score of 0 points (94.2%, 95% CI 78.5-98.5%), followed by patients with 1 point (61.7%, 95% CI 44.5-74.9) and 2 points (46.3%, 95% CI 19.6-69.4). The PFS and survival curve were well stratified by the mALF score (PFS, p\u0026lt;0.018 concordance index 0.579: OS, p\u0026lt;0.001 concordance index 0.602).\u003c/p\u003e\u003cp\u003eCI, confidence interval; mALF score, modified albumin-bilirubin grade and α-fetoprotein score; OS, overall survival; PFS, progression-free survival.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/5422783e0ccaf3946770c3cb.jpg"},{"id":22734619,"identity":"add98779-931f-4031-bf6e-1c9073661db3","added_by":"auto","created_at":"2022-06-16 15:46:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":699256,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/3da072ec-aabb-4777-b644-2d6cbf3bb922.pdf"},{"id":22734616,"identity":"65dc3c3a-ffe0-4475-a0cc-c38bbb029d6c","added_by":"auto","created_at":"2022-06-16 15:46:07","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13138,"visible":true,"origin":"","legend":"","description":"","filename":"AtezBevmALFscoreSupplementalTable2022June08.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/0e478d5c1b5733d5f5549415.xlsx"},{"id":22734617,"identity":"ea4ff65e-f223-456f-905a-fb2c13eaa137","added_by":"auto","created_at":"2022-06-16 15:46:07","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":621734,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplemental Figure 1.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003ePFS and OS in the training set. (a) The median PFS was 6.8 months (95% confidence interval 6.0-8.0), and 129 events (50.6%) were identified at the time of the analysis. (b) The median OS was not reached and the 1-year survival rate was 63.3% (95% CI 53.3-71.7). Fifty-five patients (21.6%) were dead at the time of the analysis.\u003c/p\u003e\u003cp\u003eOS, overall survival; PFS, progression-free survival.\u003c/p\u003e","description":"","filename":"Sup.Figure1.tif","url":"https://assets-eu.researchsquare.com/files/rs-1739681/v1/a69200bca0fff44ba75a42d8.tif"}],"financialInterests":"","formattedTitle":"Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe choices of systemic therapies for advanced hepatocellular carcinoma (HCC) have increased. Although three regimens, namely atezolizumab and bevacizumab (Atez/Bev) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], lenvatinib [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], and sorafenib [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], have already been approved as first-line treatments, Atez/Bev is recommended for first-line treatment according to recent guidelines [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and is commonly used worldwide. While the expression of PD-L1 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and activated Wnt/β-catenin signaling [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] may be promising biomarkers to predict the clinical outcome of immune checkpoint inhibitors, reliable biomarkers are still lacking. Moreover, the predicting the survival of HCC patients receiving immune checkpoint inhibitor (ICI) treatment remains challenge. It is important to establish a simple scoring system that reflects the preserved liver function and oncologic prognostic factors. Therefore, the aim of current study was to newly develop and validate a simple score that can be applied to predict survival in patients treated with Atez/Bev.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe present retrospective study included 426 HCC patients who received atezolizumab (1200 mg/body) and bevacizumab (15 mg/kg body weight) intravenously every 3 weeks in 22 institutions in Japan. Between September 2020 and January 2022, a total of 426 patients were included. We did not exclude any patients. These eligible patients were randomized 3:2 to a training set (n\u0026thinsp;=\u0026thinsp;255) and a validation set (n\u0026thinsp;=\u0026thinsp;171) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBaseline characteristics, including age, sex, body mass index, chronic liver disease, biochemical parameters, liver function, and tumor stage were collected. The liver function was assessed according to the Child-Pugh score, and modified albumin-bilirubin (mALBI) grade [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The tumor stage was determined based on the Barcelona Clinic Liver Cancer (BCLC) system [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEvaluation on therapeutic outcome of Atez/bev treatment\u003c/h2\u003e \u003cp\u003eThe Atez/Bev treatment was continued until the presence of disease progression or unacceptable adverse events were found. The tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST ver.1.1). The best radiological response was classified as a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) based on local review. Progression-free survival (PFS) was computed from the date on which treatment with Atez/Bev was initiated to the date of disease progression or death from any cause, whichever came first. OS was calculated from the initiation date on which treatment with Atez/Bev was initiated to the date of death from any cause. Adverse events were graded based on The Common Terminology Criteria for Adverse Events version 5.0. Interruption or discontinuation of each drug was carried out according to the guidelines for Atez/Bev treatment provided by the manufacturer.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eCategorical variables were reported as the number (percentage) and were compared using the chi-squared or Fisher\u0026rsquo;s exact test, as appropriate. Continuous variables were reported as the median (interquartile range) and compared using Mann-Whitney U test. We used Cox proportional hazards regression models to investigate prognostic factors. The number of explanatory variables depended on the number of events. The following factors were included as explanatory variables: age, sex, BCLC stage (0 or A or B vs. C or D), mALBI grade (1 or 2a vs. 2b or 3), and AFP (\u0026lt;\u0026thinsp;100 ng/ml vs. \u0026ge;100 ng/ml). PFS and survival curves were drawn using the Kaplan-Meier method and analyzed by a log-rank test. All reported p-values were 2-sided and p values of \u0026lt;\u0026thinsp;0.05 were considered statistically significant. All statistical analyses were conducted using EZR Ver. 1.55 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003ePatient profile in training and validation set\u003c/h2\u003e\n \u003cp\u003eThe patient profiles of the training and validation sets are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age in the training set was 73 years, and 80.4% of the patients were male. Approximately 80% of the patients had a performance status (PS) of 0. The median body mass index was 23.9 (21.1, 26.1) kg/m\u003csup\u003e2\u003c/sup\u003e. The etiologies of liver disease were as follows: (HBV, n\u0026thinsp;=\u0026thinsp;46 [18.0%]; HCV, n\u0026thinsp;=\u0026thinsp;86 [33.6%]; alcohol, n\u0026thinsp;=\u0026thinsp;47 (18.4%); and other, n\u0026thinsp;=\u0026thinsp;77 [30.1%]). Therefore, virus-related liver disease accounted for 51.4% of the cases. The Child-Pugh scores was 5 points in 151 patients (59.2%), 6 points in 87 patients (34.1%), and \u0026ge;\u0026thinsp;7 points in 17 patients (6.7%). The median ALBI score was \u0026minus;\u0026thinsp;2.36 (-2.70, -2.07). Accordingly, 87 (34.1%), 68 (26.7%), 97 (38.0%), and 3 patients (1.2%) were classified as grade 1, 2a, 2b, and 3, respectively. The BCLC stages were as follows; very early, n\u0026thinsp;=\u0026thinsp;4 (1.6%); early, n\u0026thinsp;=\u0026thinsp;27 (10.6%); intermediate, n\u0026thinsp;=\u0026thinsp;106 (41.6%); advanced, n\u0026thinsp;=\u0026thinsp;115 (45.1%); and terminal, n\u0026thinsp;=\u0026thinsp;3 (1.2%). There were 75 patients (29.4%) with extrahepatic spread and 42 patients (16.5%) with macrovascular invasion. The patient characteristics of the validation set were similar to those of the training set.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatient characteristics in the training and validation sets\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTraining set (n\u0026thinsp;=\u0026thinsp;255)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eValidation set (n\u0026thinsp;=\u0026thinsp;171)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73.0 [68.0, 79.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e74.0 [67.5, 80.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e205 (80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e139 (81.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePS, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e205 (80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e142 (83.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.78\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (14.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.9 [21.1, 26.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.4 [20.8, 24.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCause of liver diseases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHBV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e46 (18.0)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (18.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHCV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86 (33.6)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlcohol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (18.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOthers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77 (30.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (29.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eViral-related liver disease, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e131 (51.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90 (52.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChild Pugh score, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e151 (59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e101 (59.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 (33.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eALBI score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.36 [-2.70, -2.07]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-2.42 [-2.69, -2.13]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emALBI grade, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87 (34.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64 (37.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (22.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (38.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (39.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSerum albumin (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.7 [3.3, 4.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8 [3.4, 4.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal bilirubin (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8 [0.6, 1.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.8 [0.6, 1.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePlatelet count (10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.8 [10.6, 19.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.7 [10.6, 18.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProthrombin time (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91.0 [81.2, 100.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e90.0 [83.0, 100.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCLC stage, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVery early\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (1.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEarly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (10.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (7.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e106 (41.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62 (36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAdvanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e115 (45.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e96 (56.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTerminal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExtrahepatic spread, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75 (29.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (36.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMacrovascular invasion, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e37 (21.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e77 (45.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDCP\u0026thinsp;\u0026ge;\u0026thinsp;100 mAU/ml**, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e168 (66.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e110 (64.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eData are reported as the median [IQR] or number (percentage).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e* Both HBs-Ag and anti-HCV Ab were positive in one patient.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003e**Data were missing for three patients.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eAFP, \u0026alpha;-fetoprotein; ALBI, albumin-bilirubin; anti-HCV Ab, anti-hepatitis C antibody; BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; DCP, des-gamma-carboxy prothrombin; HBV, hepatitis B virus; HCV, hepatitis C virus; HBs-Ag, hepatitis B virus surface antigen; mALBI, modified albumin-bilirubin; PS, performance status.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eResults of the multivariate analysis in the training set\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePer 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.02 (0.99\u0026ndash;1.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.91 (0.44\u0026ndash;1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBCLC stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 or A or B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC or D\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.10 (0.61\u0026ndash;1.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emALBI grade\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 or 2a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2b or 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.36 (1.37\u0026ndash;4.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAFP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;100 ng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;100 ng/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.61 (1.49\u0026ndash;4.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"4\"\u003e\n \u003cp\u003eAFP, \u0026alpha;-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; mALBI, modified albumin-bilirubin\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/div\u003e\n \u003ch2\u003eThe efficacy and safety of Atez/Bev and the development of the modified albumin-bilirubin grade and \u0026alpha;-fetoprotein score (mALF score) in the training set\u003c/h2\u003e\n \u003cp\u003eThe best radiological response in the training set was classified as follows: CR, PR, SD, PD, and NE in CR, n\u0026thinsp;=\u0026thinsp;5 (2.0%); PR, n\u0026thinsp;=\u0026thinsp;62 (24.3%); SD, n\u0026thinsp;=\u0026thinsp;118 (46.3%); PD, n\u0026thinsp;=\u0026thinsp;36 (14.1%); and NE, n\u0026thinsp;=\u0026thinsp;34 (13.3%) (Supplemental Table\u0026nbsp;1). The median PFS was 6.8 months (95% confidence interval 6.0\u0026ndash;8.0: Supplemental Fig.\u0026nbsp;1a), and 129 events (50.6%) were identified at the time of the analysis. The median OS was not reached and the 1-year survival rate was 63.3% (95% CI 53.3\u0026ndash;71.7: Supplemental Fig.\u0026nbsp;1b). Fifty-five patients (21.6%) were dead at the time of the analysis.\u003c/p\u003e\n \u003cp\u003eThe multivariate analysis revealed that mALBI grade 2b or 3 and AFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml were unfavorable factors for OS (mALBI grade 2b or 3, hazard ratio [HR] 2.36, 95% CI 1.37\u0026ndash;4.05, p\u0026thinsp;=\u0026thinsp;0.002: AFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml, HR 2.61, 95% CI 1.49\u0026ndash;4.55, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Given that both the mALBI grade and AFP were prognostic factors and the numerical value of the HR was similar in the multivariate analysis, we developed a simple score named the \u003cstrong\u003em\u003c/strong\u003eodified \u003cstrong\u003eA\u003c/strong\u003elbumin-bi\u003cstrong\u003eL\u003c/strong\u003eirubin grade and \u0026alpha;-\u003cstrong\u003eF\u003c/strong\u003eetoprotein score (mALF score). We assigned 1 point for mALBI grade 2b or 3 and 1 point for baseline AFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml. The scores of the patients were determined as follows: mALF score 0 points (mALBI grade 1 or 2a and AFP\u0026thinsp;\u0026lt;\u0026thinsp;100 ng/ml), 1 point (either mALBI grade 2b or 3, and AFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml), and 2 points (both mALBI grade 2b or 3, and AFP\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml).\u003c/p\u003e\n \u003cp\u003eWhen patients were stratified according to their mALF scores, the objective response rate (ORR) and disease control rate (DCR) were numerically higher in patients with 0 points (30.7% and 77.2%, n\u0026thinsp;=\u0026thinsp;101), followed by those with 1 point (27.5% and 72.5%, n\u0026thinsp;=\u0026thinsp;109) and those with 2 points (13.3% and 62.2%, n\u0026thinsp;=\u0026thinsp;45); the differences showed statistical significance (p\u0026thinsp;=\u0026thinsp;0.08, and 0.17: Supplemental Table\u0026nbsp;1). The median PFS in patients with mALF scores of 0, 1, and 2 points was 9.5 months (95% CI 7.3-not applicable [NA]), 6.6 months (95% CI 6.0\u0026ndash;8.0), and 3.8 months (95% CI 3.0-5.2), respectively; the difference was statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, concordance index 0.630: Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). The 1-year OS rates in patients with mALF scores of 0, 1, and 2 points were 82.7% (95% CI 68.9\u0026ndash;90.8), 61.7% (95% CI 44.5\u0026ndash;74.9), and 24.6% (95% CI 9.0-44.3), respectively, which amounted to a statistically significant difference (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, concordance index 0.675: Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb). There were no other significant differences among patients with mALF scores of 0, 1, and 2 points with the exception of any-grade decreased appetite (p\u0026thinsp;=\u0026thinsp;0.04) and any-grade fever (p\u0026thinsp;=\u0026thinsp;0.01: Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab3\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eAdverse events according to the mALF score in the training and validation sets\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eTraining set\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"6\"\u003e\n \u003cp\u003eValidation set\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 points\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;101)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e1 point\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 points\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 points\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 point\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 points\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiarrhea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e12 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.23\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (9.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e11 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e2 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eElevated blood pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e18 (16.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7 (15.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e12 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e7 (6.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGastrointestinal tract bleeding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e2 (1.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDecreased appetite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (18.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e24 (22.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e17 (37.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8 (13.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e3 (2.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProtein urea\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e23 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e9 (20.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e11 (18.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (20.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (23.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (5.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e11 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (10.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e13 (11.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7 (9.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e4 (3.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGeneral fatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (17.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e23 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e14 (31.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e16 (26.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (13.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (26.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e1 (0.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHepatic edema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAny\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e11 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (11.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e13 (16.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (14.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.34\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"15\"\u003e\n \u003cp\u003emALF score, mALBI grade and AFP score.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eThe performance of mALF score in the validation set\u003c/h2\u003e\n \u003cp\u003eThe mALF scores of the validation cohort were as follows: 0 points, n\u0026thinsp;=\u0026thinsp;60 (35.1%), 1 point, n\u0026thinsp;=\u0026thinsp;77 (45.0%); and 2 points, n\u0026thinsp;=\u0026thinsp;34 patients (19.9%). The ORR in patients with a mALF score of 0 points was numerically higher in comparison to those with those with scores of 1 point or 2 points, but the difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.89: supplemental Table\u0026nbsp;2). The median PFS in patients with mALF scores of 0, 1, and 2 points was 9.3 months (95% CI 5.8-NA), 6.7 months (95% CI 3.8-9.0), and 4.7 months (95% CI 2.9\u0026ndash;6.4), respectively. The 1-year OS rates in patients with a mALF score of 0 points was the highest (94.2%, 95% CI 78.5\u0026ndash;98.5%), followed by patients with 1 point (61.7%, 95% CI 44.5\u0026ndash;74.9) and patients with 2 points (46.3%, 95% CI 19.6\u0026ndash;69.4). The PFS and the survival curve were well stratified by the mALF score (PFS, p\u0026thinsp;\u0026lt;\u0026thinsp;0.018 concordance index 0.579; OS, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 concordance index 0.602: Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb). The incidence of any-grade fever and any-grade of hepatic edema showed significant differences according to the mALF score (p\u0026thinsp;=\u0026thinsp;0.02, and p\u0026thinsp;=\u0026thinsp;0.04, respectively; Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe major findings of the present study were the identification of mALBI grade 2b or 3, and AFP\u0026thinsp;\u0026ge;\u0026thinsp;100n g/ml as independent unfavorable prognostic factors in a multivariate analysis. Based on this, we built an easy, and widely applicable scoring system named the mALF score. The PFS and survival curve were well stratified by the mALF score in the training set and these results were confirmed in the validation set.\u003c/p\u003e \u003cp\u003eStaging systems, including the Liver Cancer Study Group of Japan staging system [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] have been used to evaluate pure tumor factors. Other staging systems, such as the BCLC staging system [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], CLIP score [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and JIS score [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], have been used to evaluate both the liver function and tumor factors. However, the inclusion of both tumor factors and the liver function is generally complicated. New evaluation methods for patients receiving systemic therapy are needed because many therapeutic agents have been developed. The liver function plays an important role in maintaining sequential systemic therapies, resulting in prolonged survival. The precise oncologic evaluation is necessary to predict the prognosis. Moreover, although Atez/Bev is recommended as first-line treatment according to recent guidelines, there has been no simple survival estimation model for patients receiving this regimen [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Accordingly, we built a simple applicable score that includes both the liver function and tumor factors.\u003c/p\u003e \u003cp\u003eThe ALBI score can be calculated based on only two variables: serum albumin and bilirubin [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. According to data from a Japanese nationwide survey, the mALBI grade can evaluate the preserved liver function more precisely and accurately in comparison to the Child-Pugh classification [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In addition, the mALBI grade can predict and stratify the prognosis of HCC patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Indeed, the ALBI score plays an important role in predicting survival in advanced HCC patients treated with systemic agents, including atezolizumab plus bevacizumab [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], lenvatinib [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], sorafenib [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], and ramucirumab [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These findings were in line with the present results. Recently, we reported that the early interruption of Bev due to the AEs was relevant to PFS and OS in patients receiving Atez/Bev, and that Bev treatment was likely to be interrupted in patients with mALBI grade 2b [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Accordingly, a relatively poor liver function leads to the interruption of Bev treatment, resulting in poor PFS and OS, which supports the present results.\u003c/p\u003e \u003cp\u003eAFP is a well-known tumor marker and is widely applied in the management of HCC for uses such as surveillance, diagnosis, treatment response monitoring, and prognostic factors [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. AFP elevation is associated with a poor prognosis across all stages of HCC [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. AFP elevation was also related to a high risk of tumor recurrence after surgical resection [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and liver transplantation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The analysis of transcriptome data, whole-exome sequencing data, and DNA methylome profiling demonstrated that AFP-high tumors showed a different phenotype, which was characterized by poor differentiation, enrichment of progenitor features and enhanced proliferation in comparison to AFP-low tumors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This analysis also showed VEGF pathway enrichment in AFP-high tumors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. VEGF hampered the benefit and durability of the response of ICI via certain mechanisms [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Given these previous reports, HCC patients with AFP elevation are less responsive to Atez/Bev treatment and show a poor prognosis, which was consistent with the present results.\u003c/p\u003e \u003cp\u003eThe ORR was numerically the highest in patients with an mALF score of 0 points in both the training and validation set, followed by those with 1 point and 2 points; however, the differences were not significant. The reason for the lack of significance is probably due to the low statistical power. In comparison to tyrosine kinase inhibitor treatment, a longer treatment period is required to achieve a tumor response in patients receiving ICI treatment. Accordingly, with a longer observation period and a larger number of cases, significant differences may be observed among the mALF scores.\u003c/p\u003e \u003cp\u003eThere are significant differences in any-grade decreased appetite and any-grade fever in the training set, and in any-grade fever, and any-grade hepatic edema in the validation set. Any-grade fever was the only of these factors that was seems to be confirmed in the validation set. However, the incidence of any-grade fever was highest in patients with an mALF score of 1 point in the training set, followed by patients with 2 points and patients with 0 points. On the other hand, it was most frequently found in patients with an mALF score of 2 points in the validation set, followed by patients with 1 point and 0 points. That is, data concerning to any-grade fever in the training set were not confirmed in the validation set. A further study may be required to confirm whether or not the mALF score can predict the development of AEs during Atez/Bev treatment.\u003c/p\u003e \u003cp\u003eThe present study was associated with some limitations. First, the study population was relatively small. Second, the median OS was not reached at the time of the analysis due to the relatively short observation period. A longer observation period may affect the present results. Third, this study conducted in a retrospective manner and no patients were excluded. Therefore, patients with poor PS (\u0026ge;\u0026thinsp;2), a poor liver function (Child-Pugh score\u0026thinsp;\u0026ge;\u0026thinsp;7 or mALBI grade 3), and all BCLC stages were included.\u003c/p\u003e \u003cp\u003eIn conclusion, the mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll research procedures were approved by the Institutional Ethics Committee of Ehime Prefectural Central Hospital (IRB No. 30-66) (UMIN000043219) and were performed in accordance with the Declaration of Helsinki. All patients included in the present study agreed and gave their written consent for the anonymous use of their clinical data for scientific research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTakeshi Hatanaka received lecture fees from Eisai. Satoru Kakizaki received research grants from Abbvie. Atsushi Hiraoka received lecture fees from Eli Lilly, Bayer, and Chugai. Toshifumi Tada received lecture fees from AbbVie, and Eisai. Hiroko Iijima received research grants from Abbvie, Otsuka, and Sumitomo Dainippon Pharma. Takashi Kumada received lecture fees from Eisai. The other authors declare no conflicts of interest in association with the present study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTH, SK, AH, TTad, AN, and TK contributed to the concept, design and execution of the study. TH, SK, AH, TTad, MH, KKar, JT, MA, KTak, EI, SF, KTs, TI, KTaj, HOc, SY, HT, CO, TNi, NS, KKaw, HK, TTan, HOh, KN, AM, AT, TNa, NI, TO, TA, MI, AN, YK, SN, MK, HI, and YH contributed to data curation. TH performed statistical analyses and interpreted the data. TH, SK, AH, TTad, AN, and TK reviewed and edited the manuscript. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data associated with present study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFinn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894\u0026ndash;905.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. 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Hepatology 2021;73 Suppl 1:158\u0026ndash;191.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReig M, Forner A, Rimola J, Ferrer-F\u0026agrave;brega J, Burrel M, Garcia-Criado \u0026Aacute;, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022;76:681\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi XS, Li JW, Li H, Jiang T. Prognostic value of programmed cell death ligand 1 (PD-L1) for hepatocellular carcinoma: a meta-analysis. Biosci Rep 2020;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuiz de Galarreta M, Bresnahan E, Molina-S\u0026aacute;nchez P, Lindblad KE, Maier B, Sia D, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. 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Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiraoka A, Kumada T, Tada T, Hirooka M, Kariyama K, Tani J, et al. Atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma: Early clinical experience. Cancer Rep (Hoboken). 2022;5:e1464.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUeshima K, Nishida N, Hagiwara S, Aoki T, Minami T, Chishina H, et al. Impact of baseline ALBI grade on the outcomes of hepatocellular carcinoma patients treated with lenvatinib: A multicenter study. Cancers (Basel). 2019;11:952.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTada T, Kumada T, Toyoda H, Tsuji K, Hiraoka A, Michitaka K, et al. 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Association of early bevacizumab interruption with efficacy of atezolizumab plus bevacizumab for advanced hepatocellular carcinoma: A landmark analysis. Hepatology Research 2022;n/a.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGalle PR, Foerster F, Kudo M, Chan SL, Llovet JM, Qin S, et al. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma. Liver Int. 2019;39:2214\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLlovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eImamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38:200\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNotarpaolo A, Layese R, Magistri P, Gambato M, Colledan M, Magini G, et al. Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC. J Hepatol. 2017;66:552\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMontal R, Andreu-Oller C, Bassaganyas L, Esteban-Fabr\u0026oacute; R, Moran S, Montironi C, et al. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Br J Cancer. 2019;121:340\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHack SP, Spahn J, Chen M, Cheng AL, Kaseb A, Kudo M, et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncol. 2020;16:975\u0026ndash;89.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"hepatology-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hepi","sideBox":"Learn more about [Hepatology International](https://www.springer.com/journal/12072)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/hepi/default.aspx","title":"Hepatology International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"mALF score, immune checkpoint inhibitor, prognosis, α-fetoprotein, mALBI grade","lastPublishedDoi":"10.21203/rs.3.rs-1739681/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1739681/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eThis study aims to validate the modified albumin-bilirubin grade and α-fetoprotein score (mALF score).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included a total 426 hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev) at 22 institutions in Japan from September 2020 to January 2022. Each patient was randomized 3:2 to a training set (n\u0026thinsp;=\u0026thinsp;255) and a validation set (n\u0026thinsp;=\u0026thinsp;171). We investigated prognostic factors in the training set and developed an easily applicable mALF score. This score was evaluated in the validation set.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe built the mALF score using mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37\u0026ndash;4.05, p\u0026thinsp;=\u0026thinsp;0.002) and α-fetoprotein\u0026thinsp;\u0026ge;\u0026thinsp;100 ng/ml (HR 2.61, 95% CI 1.49\u0026ndash;4.55, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9\u0026ndash;90.8) in patients who meet neither of the criteria (mALF 0 points, n\u0026thinsp;=\u0026thinsp;101), 61.7% (95% CI 44.5\u0026ndash;74.9) in patients who meet either of the two criteria (mALF 1 point, n\u0026thinsp;=\u0026thinsp;109), and 24.6% (95% CI 9.0-44.3) in patients who meet both criteria (mALF 2 points, n\u0026thinsp;=\u0026thinsp;45); the difference was statistically significant (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0\u0026ndash;8.0), and 3.8 months (95% CI 3.0-5.2), respectively, which amounted to a significant difference (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points\u0026thinsp;=\u0026thinsp;94.2%/62.1%/46.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; median PFS, 0/1/2 points\u0026thinsp;=\u0026thinsp;9.3/6.7/4.7 months, p\u0026thinsp;=\u0026thinsp;0.018).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.\u003c/p\u003e","manuscriptTitle":"Development and validation of a modified albumin-bilirubin grade and α-fetoprotein score (mALF score) for hepatocellular carcinoma patients receiving atezolizumab and bevacizumab.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-16 15:46:05","doi":"10.21203/rs.3.rs-1739681/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-06-11T01:57:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-06-11T01:54:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-06-09T07:29:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hepatology International","date":"2022-06-08T18:50:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hepatology-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"hepi","sideBox":"Learn more about [Hepatology International](https://www.springer.com/journal/12072)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/hepi/default.aspx","title":"Hepatology International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5c7ea060-79f7-409c-b514-1fbbd07ca2cb","owner":[],"postedDate":"June 16th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2022-08-08T04:27:11+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-16 15:46:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1739681","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1739681","identity":"rs-1739681","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}