Liver resection remains the most effective treatment currently for patients with hepatocellular carcinoma, but the long-term prognosis after hepatectomy for HCC is still unsatisfactory due to a high intrahepatic recurrence rate1,9. Our study demonstrated that the ALBI grade at the first year post-operation predicts the prognosis of HCC patients after liver resection. The ALBI grade has currently been proven as an objective, evidence-based tool for assessing liver function8,10,11. It has also been proposed as a tool to predict the OS among HCC patients after curative liver resection8,12,13. The studies conducted were based on the baseline or pre-operative ALBI grade. Consistent with previous reports, our study also demonstrated that a high grade preoperative ALBI grade correlates with poor OS, but not with HCC recurrence.
In the present study, 57% (301/525) of patients were classified as grade I, and the other patients were classified as grade II (43%, 224/525). The liver-related survival rate of the group with ALBI grade I was higher than that of the group with grade II (p = 0.035). Since liver function can change over time after liver resection, it is uncertain whether the pre-operative ALBI grade is better than the post-operative ALBI grade. We found that the ALBI grade at one year after hepatectomy was an independent predictor for HCC recurrence and OS. The liver function after liver resection is an important element for outcomes, and the ALBI grade has been proposed and validated for the assessment of liver function and failure.
In this study, we chose the first year after resection as our second time to evaluate the impact of ALBI grade after resection. If we chose a later second time, such as the second or third year after resection, there might be more patients with recurrent HCC before the second time who would be excluded from the RSF analysis. In contrast, if we chose an earlier time, such as the third or sixth month after resection, the liver function might not be recovering completely. Second, Chen et al.14 evaluated the liver regeneration by serial abdominal CT and revealed complete regeneration took about one year. Previous studies also indicated liver regeneration wound continue up to one year after hepatectomy15,16,17,18,19,20. Therefore, we chose the time point of the assessment of post-OP ALBI at one year after resection for comparison.
Based on the results of this study, we recommend using the ALBI grade at the first year post-operation as a significant predictor and checking it routinely in HCC patients after liver resection to predict recurrence and OS. In the future, a prospective study is needed to check serial serum data, including albumin and bilirubin levels, to get the serial ALBI grade after HCC resection to evaluate the precise time to check ALBI grade for HCC recurrence prediction.
Liver function may be influenced by numerous factors, such as tumor burden, reserved liver volume, nutritional status, and post-operative complications. The ALBI grade is determined with albumin and bilirubin. Theoretically, liver function should be recovered after HCC resection. However, in the present study, there were 28 patients with ALBI grade deterioration and 65 patients with ALBI grades II and III after one year of surgery. The pre-operative ALBI grade and post-operative ALBI grade at one year had statistically significant correlation (p < 0.05) (Table S2), but the multivariate analysis indicated that the ALBI grade after liver resection, not the pre-operative ALB grade, was an independent risk factor for RFS and liver-related survival. Hence, we supposed that the pre-operative ALBI grade is affected by the tumor burden, resulting in minimizing the predictive effect. After HCC resection, the post-operative ALBI grade can reflect the environment of the liver exactly to provide more reliable predictive value for RFS and OS without tumor burden. In addition, basic researches showed that albumin suppresses the proliferation and growth of HCC cell through the modulation of AFP or effects on growth-controlling kinases21,22. The inhibitory role of albumin on HCC growth may explain why a high ALBI grade occurs and contribute to the recurrence HCC. But, the exact mechanism between liver function, as indicated by the ALBI grade, and tumor recurrence remains unclear and need further study.
It is an unexpected result that only 50.8% of patients in ALBI grade II had cirrhosis. We might explain this phenomenon is due to multiple factors, such as tumor, nutrition, and comorbidity, such as sarcopenia, not only by liver cirrhosis. By this view, ALBI grade is a useful index for pre-operative evaluation. Furthermore, we found that after curative resection, around 70% of patients with pre-operative ALBI grade II improved their ALBI grade (Table S3). Therefore, we suppose that the preoperative ALBI grade might be partially affected by the tumor. Previous studies indicates that hypoalbuminemia is associated with new cancer diagnosis23 and advanced cancers24. Hence, cancers reduce circulating albumin due to metabolic and vascular effect of tumor and may cause hypoalbuminemia25. After tumor resection, the post-operative ALBI grade can reflect the environment of the liver exactly to provide a more reliable predictive effect in RFS and OS without tumor burden. Therefore, we can conclude that the post-operative ALBI grade is much more important and useful than the pre-operative ALBI grade.
A previous study indicated that the ALBI grade has a significant better performance in predicting the outcomes of HCC patients after liver resection than the Child-Pugh classification26. The Child-Pugh classification was designed to evaluate the prognosis and outcome of cirrhotic patients. It is now the most widely used method to assess the preserved liver function in HCC patients for further systematic management of HCC9,27. However, whether the Child-Pugh classification is appropriate for evaluating the liver function in HCC patients remains to be determined due to patients in the same Child-Pugh classification could be separated into different ALBI grade and have survival difference with the wide range of hepatic reserve within a single Child-Pugh classification. Furthermore, the evaluation of ascites and encephalopathy is highly subjective and may greatly reduce the accuracy of the assessment. In the present study, the majority (96%) of early HCC patients were Child-Pugh class A. In contrast, with the classification of the ALBI grade, 220 (43.7%) patients and 283 (56.3%) patients were stratified into ALBI grades I and II, respectively. Although, the mean ALBI score increases with higher Child Pugh score in our study and the distribution has linear trend (p = 0.004). (Figure S2) The areas under the receiver operating characteristic curve (AUCs) of the ALBI grades for postoperative recurrence and mortality are significantly higher than that of the Child-Pugh classification. This result is compatible with previous studies. In the future, HCC management should seriously consider integrating the ALBI grade into the stratification of hepatic function among patients with resectable HCC.
With regard to anti-HBV therapy, previous studies showed that nucleoside analogue treatment would reduce the recurrence of HCC after tumor resection28,29. However, some studies indicated the opposite findings30. In our current study, there was no association between HBV treatment, survival and recurrence free survival after hepatectomy. However, the result is not very solid because of the diversity and complexity of antiviral treatment within our study cohort. The National Health Insurance in Taiwan covers the treatment of HBV, but patients with hepatocellular carcinoma are not supported only when patients had liver cirrhosis with serum HBV DNA > 2000 IU/mL. As a result, many patients are treated with self-paid nucleos(t)ide analogues(NAs), which leads to poor compliance. Furthermore, in the earlier era of HBV treatment with lamivudine and adefovir, HBV DNA measurements were not very popular in clinical practice, which induced virological resistance without early detection and the change of drugs. Hence, the evidence is too weak to conclude that the usage of nucleos(t)ide analogues(NAs) is not associated with RFS and OS. However, we have still seen better trends of RFS and OS in more recent times (2009-2016) compared with the early era (2001-2008), although the changes in either one are not significant (Figure S1). Furthermore, there is no statistically significance in RFS and OS by different NAs (Figure S3).
Aside from the ALBI grade, we also showed that age, DM, AFP, platelet count, and liver cirrhosis are important predictors of HCC recurrence. Furthermore, age, DM, AFP, and TNM stage were independent risk factors for OS. This is consistent with the results of previous studies in which patient factors (age, DM, and platelet count)31,32,33, liver background factors (liver cirrhosis)34, and tumor factors (TNM stage, and AFP)35 contributed to the outcomes of HCC patients.
In the present study, there are 253 patients with recurrence, 19 patients received hepatectomy, 81 patients received radiofrequency ablation (RFA), 114 patients underwent transcatheter arterial chemoembolization (TACE), 4 patients received TACE and RFA concomitantly, 6 patients received percutaneous ethanol injection (PEI), 14 patient received systemic treatment (target therapy or palliative chemotherapy), 15 patients chose hospice care. The ALBI grade at recurrence might affect the choice of treatment and have different prognosis. In our study, different treatment strategies have diverse ALBI grade distribution. In hospice group, ALBI grade III is up to 41.7%. (Figure S4) The overall survival result revealed those who received resection or RFA had better outcomes than patients receive TACE then follows with TACE/RFA, PEI and the group who received systemic treatment or hospice care.(Figure S5 and Table S1) Plans of retreatment is based on tumor size, numbers, lymph nodes involvement and liver function reservation once recurrence. Therefore, if we can detect the recurrence earlier with preserved liver function, the following treatment plan and the outcome will be better. Post-operative ALBI grade provides the evaluation of liver reservation and would be a useful model for early prediction of HCC recurrence.
There are some limitations in our study. First, the information and data are retrospectively collected from medical records. Some patients didn’t return to our hospital for further follow-up or even died after the operation. Therefore, some important data was insufficient, such as complete serum bilirubin and albumin levels. The precise time of ALBI grade for prognosis evaluation needs prospective study for further assessment. Second, referral bias could not be completely avoided due to all patients in our study cohort were treated at a tertiary medical center. In addition, although we indicated that ALBI grade variation after hepatectomy contributes significantly to the accuracy of OS prediction, the generalizability of the change in ALBI grade requires further analyses to evaluate its survival impact.
In summary, our present study demonstrated that the post-operative ALBI grade at one year after resection is a valuable serum index for assessing the recurrence and survival of HCC patients undergoing hepatectomy. Nevertheless, further researches are needed before applying ALBI grade into daily practice.