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  have been used to evaluate pure tumor factors. Other staging systems, such as the BCLC staging system , CLIP score , and JIS score , 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 . 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 . In addition, the mALBI grade can predict and stratify the prognosis of HCC patients . Indeed, the ALBI score plays an important role in predicting survival in advanced HCC patients treated with systemic agents, including atezolizumab plus bevacizumab , lenvatinib , sorafenib , 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 . 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 . AFP elevation is associated with a poor prognosis across all stages of HCC . AFP elevation was also related to a high risk of tumor recurrence after surgical resection  and liver transplantation . 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 . This analysis also showed VEGF pathway enrichment in AFP-high tumors . VEGF hampered the benefit and durability of the response of ICI via certain mechanisms . 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.