Albumin - bilirubin (ALBI) versus Child-Turcotte-Pugh (CTP) in prognosis of HCC after stereotactic body radiation therapy

Background Child-Turcotte-Pugh (CTP) score extensively used to assess hepatic function, predicting postoperative outcome of hepatocellular carcinoma (HCC) patients. Lately, the albumin–bilirubin (ALBI) grade has been identified to be a predictor of overall survival of HCC patients. In this investigation, we compared the pre-SBRT ALBI and CTP scores with the prognosis of patients with HCC. Methods This cohort study included 594 HCC patients who treated with SBRT. Overall survival (OS) rates were measured from treatment date to death date or last follow-up. We compared ALBI score with the CTP score in predicting long-term survival. Results The average follow-up time was 21 months (1 to 82 months). The CTP and ALBI ratings have discriminatory for long-term survival across the groups. CTP class was significantly related to OS, with a median OS of 29.9 months in CTP-A, 11.5 in CTP-B (P < 0.0001). ALBI grade is also significantly related to OS, with a median OS of 53.0 months in ALBI-1, 19.5 months in ALBI-2, and 6.5 months in ALBI-3(P < 0.0001). Within CTP-A class, CTP score-A5/A6 and ALBI grade has a similar predictive power (all P < 0.001). However, both CTP score and ALBI grade have no predictive power in CTP ≥ B7 class (all P>0.05). Conclusions To assess liver dysfunction in HCC patients before SBRT, traditional CTP classification is a necessary but imperfect tool for assessing HCC liver injury. The ALBI score is a more objective, discriminatory and evidence-based approach in CTP-A groups, and need to be validated in CTP ≥ B7 class.


Introduction
Hepatic function / dysfunction is closely related to the progression of hepatocellular carcinoma (HCC) and are a key determinant. To assess the severity of liver function/ dysfunction, the Child-Pugh (CTP) classification has been widely used. Many HCC staging systems, such as Barcelona Clinic Liver Cancer (BCLC) staging system [1], use CTP classification as an indicator for hepatic disease severity. However, the CTP classification not only includes objective biosynthetic parameters such as circulating albumin, bilirubin and coagulation characteristics, but also more subjective parameters such as the presence and severity of ascites and encephalopathy. The clinical evaluation of ascites and encephalopathy may be affected by the lack of reproducibility among clinicians. To overcome these limitations, albumin-bilirubin (ALBI) grade is an objective method of assessing hepatic dysfunction based on albumin and bilirubin levels and has been proposed as an alternative to the CTP rating [2]. More and more studies have validated the predictive accuracy of ALBI classification for multi-region cohorts of different stage HCC and for patients undergoing different treatment, such as liver resection, radiofrequency ablation, transarterial chemoembolization and Sorafenib [3][4][5][6][7][8][9][10][11].
With the progress of radiation technology, stereotactic body radiation therapy (SBRT), recommended as category 2B for HCC in the version of the National Comprehensive Cancer (NCCN), has become an alternative treatment of HCC in clinical practice worldwide [12]. In this study, we predicted the long-term survival of 594 patients of HCC treated with SBRT by externally validating and comparing the ability of ALBI and CTP grading.

Patients
From January 1, 2011 to December 31, 2016, 657 primary liver cancer patients were treated with SBRT. Before any form of definitive treatment, we comprehensively recorded baseline demographics, tumor burden, serum biochemistry, and severity of liver disease. Twenty-nine cases of intrahepatic cholangiocarcinoma, 15 cases for which complete data were lacking, and 19 cases that were lost to follow-up were excluded. All of 594 patients were retrospectively enrolled in this study. Survival of the enrolled patients was re-evaluated 1 month after SBRT and subsequently at every 3 or 6 months. Contrast-enhanced CT and/or MRI was compared at each follow-up. In addition, serum albumin, bilirubin, prothrombin time, alkaline phosphatase, hepatic AST and ALT, and alpha-fetoprotein level have been routinely examined in clinic.

SBRT
Three or 4 gold markers of 0.8 mm in diameter were inserted into tumor tissue or the surrounding area of a tumor. Gross tumor volume (GTV) was delineated with visible lesion based on CT and/or MRI were performed 1 week later. GTV was established by 0-5 mm to cover the planning target volume (PTV). SBRT were using with CyberKnife® (Accuray Inc., Sunnyvale, CA, USA) for a few continuous days.
According to the volume of liver and various dose-volume constraints for the organs at risk, different radiation doses and fractions were recommended [13][14][15][16]. For the liver, VS15 was > 700 mL and/or V15 was < 1/3 absolute normal liver volume. SBRT doses were further optimized according to CTP score and V15 and VS10 (Table 1) [16]. For GTVs closed central porta of liver or gastrointestinal tract, more than 4 fractions were recommended. For the kidneys, the V15 was < 1/3 total volume. Similarly, for the duodenum, stomach, and small bowel, the maximum doses to 1 mL (D1 mL) were < 15Gy in 1-2 fractions or < 25 Gy in more than 3 fractions. For the spinal cord, the D1 mL was < 10 Gy in 1-2 fractions or < 15 Gy in more than 3 fractions.

Statistical analysis
All statistical analyses were undertaken with SPSS® version 23.0 (SPSS, Inc., Chicago, IL, USA) and Stata 15.0 (IBM, New York, NY, USA). Overall survival (OS) was defined from the date of SBRT until the date of death or last follow-up. A Kaplan-Meier curve with log-rank test was used to estimate the OS rates for different groups and Gehan-Breslow-Wilcoxon test was applied for the comparison of survival curves. Statistical significance was identified as p value < 0.05.

Baseline characteristics
Demographic and clinical features of the HCC patients were summarized in Table 2. This study included 511 men and 83 women. There were 479 (80.6%) patients of CTP-A, 108 (18.2%) of CTP-B and 7(1.2%) of CTP-C. CTP-A patients included 219 of ALBI-1 and 262 of ALBI-2 patients. There were 2 of ALBL-1, 84 of ALBI-2 and 22 of ALBI-3 patients in the CTP-B group. CTP-C consisted of 1 of ALBI-2 and 6 of ALBI-3.
Both CTP score with ALBI grade have the similar predictive power in CTP class a group For CTP-A population, A significant difference in OS was observed between CTP-A5 and A6, with a median OS of 51.0 months and 16.2 months (log-rank, P < 0.0001, Fig. 2a), respectively. For ALBI grade, ALBI − 1 patients had a significantly longer survival than that of ALBI − 2, with a median OS of 55.0 months and 21.9 months, respectively (log-rank, P = 0.0007, Fig. 2b).
Both CTP score with ALBI grade have no predictive power in CTP ≥ B7 group For the CTP B7-B9 population, no significant change was observed in OS between in CTP scores, respectively (P = 0.6834, Fig. 3a). ALBI grade has no predictive power in this group, but the curves of ALBI grade tend to separate (P = 0.4035, Fig. 3b).

Discussion
The key issue in predicting HCC outcomes is the liver function reserve. The traditional CTP rating system is an alternate for the severity of cirrhosis in patients with HCC. Previous studies with smaller sample tried to assess the ALBI grade for patients treated with SBRT, but lack of long-term outcome [17][18][19]. In this larger sample study of SBRT for HCC, we found that both CTP and ALBI grade have 3 separate curves for long-term survival post-SBRT. In CTP-A population, there was similar predictive power between CTP and ALBI scoring system. But there was no significant change between CTP-B and CTP-C groups based on CTP classification system and ALBI grade. The results in CTP ≥ B7 group need to be validated by larger sample study. CTP classification semi-quantitative assessment included five common clinical and laboratory indicators and they are ascites, degree of hepatic encephalopathy, coagulation, serum albumin, bilirubin levels. CTP scores are commonly used in patients with cirrhosis to determine prognosis. It is subject to equal weighting of 5 parameters and any cut-off value. In addition, clinical assessment of ascites and hepatic encephalopathy may be subjective and difficult to be consistently scored by different evaluators. The ALBI score system was recently developed to assess hepatic functional reserve in HCC patients. The results of albumin and bilirubin can be readily obtained as a routine blood test, so both scores are completely objective measures of liver dysfunction. More and more studies have validated the predictive accuracy of ALBI classification for multi-region cohorts of different stage HCC and for patients undergoing different treatment, such as liver resection, radiofrequency ablation, transarterial chemoembolization and Sorafenib [3][4][5][6][7][8][9][10][11]. We confirmed that both CTP and ALBI systems were able to prognose HCC patients into three groups, and the application of ALBI was also verified in hepatocellular carcinoma with SBRT.
SBRT can target the tumor area more accurately. Hepatic SBRT is increasingly used in clinic. Our previous studies showed that CTP-B was significantly associated with worse OS in small (longest diameter ≤ 5 cm) HCC group [14]. We further compared long-term survival after SBRT with liver resection for small HCC with CTP-A cirrhosis, the 5-year OS was 70.0% in the SBRT group and 64.4% in the liver resection group [13]. In current study of SBRT for HCC without differentiation of tumor size and staging, the 5-year OS was 41.4% in CTP-A groups and 49.9% in ALBI-1 groups. The long-term survival data may support the clinical application of SBRT in future.
The limitations of our study are: 1. referral bias may exist in CTP ≥ B7 in this study. The number of patients with CP-B was 108 but the number of patients with CP-C was only seven. These differences among the groups was too large to achieve any statistical significance. The results need to be validated by other research groups; 2. This study is a single-center retrospective study conducted in hepatitis B endemic areas in China, whether these dosimetric data are fully applicable to patients with other risk factors for HCC is unclear.

Conclusions
CTP assessment of HCC liver function reserve is commonly used with semi-quantitative assessment. We recommend that the ALBI grading is an alternative assessment of liver function in HCC treated with SBRT in CTP-A groups. This method is objective, discriminatory and evidence-based, with more clinical feasibility and superior prognosis, especially for patients with minimal liver dysfunction and patients receiving more active intervention. Applying these objective models to the current HCC staging system to further improve its predict ability is critical.