In this multicenter study of a large number of patients with unresectable HCC who received lenvatinib therapy, Cox proportional hazards modeling that included age, sex, ECOG-PS, HCC etiology, mALBI grade, α-fetoprotein, and BCLC stage as covariates showed that mALBI grade (1/2a vs. 2b/3) was independently associated with overall survival in patients with a Child–Pugh score of 5. Conversely, the survival analysis of patients with mALBI grade 1/2a and Child–Pugh class A showed no difference between patients with Child–Pugh class 5 vs. 6. In addition, the predictive power of the ALBI score for overall survival was superior to that of the Child–Pugh score in time-dependent ROC analysis. Furthermore, the optimal cut-off values of the ALBI score for predicting good survival in the 2 years from the start of lenvatinib treatment were nearly equal to the value separating mALBI grades 2a and 2b. These results suggest that the ALBI score is a better predictive marker for overall survival than the Child–Pugh score in patients with unresectable HCC who are treated with lenvatinib. In addition, the mALBI grade was able to predict good vs. poor prognosis in patients with a Child–Pugh score of 5, even though these patients are generally considered to have a good prognosis. Furthermore, patients with a mALBI grade of 1 or 2a had a similar prognosis regardless of whether their Child–Pugh score was 5 or 6.
Recently, Ueshima et al.  investigated the association between baseline liver function, as determined by the Child–Pugh score and ALBI grade, and the outcomes of 82 patients with unresectable HCC who were treated with lenvatinib. Their study patients were divided into four groups: (1) Child–Pugh score 5 and ALBI grade 1 (group 1; n = 27); (2) Child–Pugh score 5 and ALBI grade 2 (group 2; n = 19); (3) Child–Pugh score 6 (group 3; n = 30); and (4) Child–Pugh score ≥ 7 (group 4; n = 6). They found that the median times to treatment failure (i.e., time from the initial administration of lenvatinib to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, and any cause of death) were 8.9, 5.3, 5.9 and 0.3 months in groups 1, 2, 3, and 4, respectively (HR, 0.38; 95%CI, 0.18–0.80; p < 0.001) . In addition, overall survival was significantly better in patients with ALBI grade 1 than in those with ALBI grade 2 (HR, 0.12; 95%CI, 0.02–0.97); p < 0.01) . Although our study did not investigate the time to treatment failure, we showed that patients with mALBI grade 1, as well as those with 2a, had better overall survival than patients with mALBI grade 2b/3. In addition, we used time-dependent ROC analysis to demonstrate that the optimal cut-off values of the ALBI score during the 2 years after initiating lenvatinib treatment were nearly equal to the value that separated mALBI grades 2a and 2b, as opposed to that separating ALBI grades 1 and 2. One advantage of this study relative to that by Ueshima et al. is that the former included more patients with unresectable HCC who received lenvatinib therapy. In addition, this study statistically confirmed the optimal cut-off values of the ALBI score for predicting good overall survival in patients treated with lenvatinib.
Ando et al.  reported that mALBI grade 1/2a (odds ratio, 5.18; 95%CI, 1.465–18.31; p = 0.011) was an independent factor for possible treatment with second-line molecularly targeted agents in 141 HCC patients who received lenvatinib as first-line therapy. In addition, in a study by Hiraoka et al.  using a Japanese hospital-based administration database, the overall duration of systematic treatment in patients with advanced HCC was shorter in those with a baseline ALBI grade of 2b or 3 than in those with grade 1 or 2a (medians: 7.1, 6.7, 4.5, and 3.0 months for grades 1, 2a, 2b, and 3, respectively). In this study, we clarified that there was a significant difference in the post-treatment of lenvatinib rate between patients with mALBI grade 1/2a and those with grade 2b/3, even among those with good liver function as defined by a Child–Pugh score of 5.
The Child–Pugh classification system comprises five factors, specifically serum albumin, total bilirubin, prothrombin time, ascites, and encephalopathy . This system has been widely used to evaluate hepatic function and has been incorporated into the HCC staging system . However, the Child–Pugh classification is limited by the subjectivity involved in evaluating encephalopathy and ascites, and serum albumin levels are correlated with the severity of ascites . Furthermore, this system was originally developed for patients with cirrhosis, not HCC. The ALBI grade, which was recently developed as an objective parameter for liver function, is calculated using only serum albumin and total bilirubin levels. It has been shown to accurately assess the prognosis of patients with HCC, and is superior not only to the Child–Pugh classification [25, 26], but also to the liver damage classification system .
Hiraoka et al.  developed the new mALBI grading system, which divides ALBI grade 2 into 2a and 2b, by analyzing 46,681 HCC patients in a nationwide survey conducted in Japan. The mALBI grade showed a good ability to stratify prognosis in each TNM stage of the Liver Cancer Study Group of Japan , and there was a statistically significant difference between each mALBI grade in all TMN stages (p < 0.01). This study confirmed the utility of subdividing ALBI grade 2 into 2a and 2b for predicting survival in advanced HCC patients who received systemic therapy.
ROC analysis is generally used to evaluate the discriminatory power of a continuous variable for a binary disease outcome (e.g., disease positive or negative). However, many chronic disease outcomes, including the prognosis of patients with malignancy, are time dependent. Therefore, time-dependent ROC curve analysis has been introduced to evaluate the predictive power of assessment markers for time-dependent disease outcomes . No previous studies have used this approach to evaluate parameters of liver function in terms of their association with survival in patients with unresectable HCC who received lenvatinib therapy. In this study, we used time-dependent ROC analysis to show that the ALBI score was superior to the Child–Pugh score in terms of predicting overall survival up to 2 years after the start of lenvatinib therapy in patients with unresectable HCC.
The main limitations of this study are its hospital-based subject population and retrospective nature. Although the study included a large number of patients with unresectable HCC from multiple centers in Japan, future prospective studies with community-based populations are warranted. An additional limitation was that the study only enrolled patients with unresectable HCC who were treated with lenvatinib. Future studies of patients with HCC should include those who receive atezolizumab plus bevacizumab, a recently approved, first-line, systemic combination therapy, as well as those who receive lenvatinib.
In conclusion, the mALBI grade is a new, simple, objective parameter that was a better predictor of survival in HCC patients who received lenvatinib therapy than the Child–Pugh classification, even among individuals with good liver function as defined by a Child–Pugh score of 5. Further studies in other populations are warranted to confirm these findings.