Fibro-Scan versus Child-Pugh Score for the Assessment of Liver Function and Treatment Outcome in Hepatocellular Carcinoma Patients Treated with Sorafenib or Intervention Therapy

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and ranks as the fifth most common cancer worldwide. HCC is categorized as an advanced cancer when vascular invasion and/or extrahepatic spread are present [1]. Patients with non-advanced HCC exhibit favorable survival outcomes if they receive timely and appropriate management. Unfortunately, owing to the asymptomatic nature of the tumor in its early stages, HCC is typically diagnosed at an advanced stage, where curative treatments are limited [2].

Over the last few years, major progress has been made regarding systemic therapy for advanced HCC. Sorafenib, a multi-tyrosine kinase inhibitor, gained FDA approval for the treatment of advanced HCC after showing survival benefits [3, 4].Prognostic evaluation before initiating any form of treatment is essential for HCC management. 

It is worth noting that liver cirrhosis is a common comorbidity among HCC patients, underscoring the significance of liver function status as a crucial prognostic indicator. The primary clinical prognostic factors utilized in the Barcelona Clinic Liver Cancer (BCLC) staging system to ascertain the natural progression of HCC include tumor burden, liver function, and overall health status. Liver function is typically evaluated using the Child–Turcott-Pugh (CTP) classification system. However, in the most recent update of this staging system, the CTP score has been eliminated as a tool for assessing liver function [5, 6]. Various elastography techniques have been used as effective noninvasive tools for staging fibrosis, diagnosing liver cirrhosis, and evaluating liver status [7-9]. 

This study aimed to evaluate the effectiveness of liver stiffness (LS) measurement versus CTP scoring in predicting outcomes and post-treatment hepatic decompensation in cirrhosis-related HCC patients receiving sorafenib treatment or other intervention treatment, providing valuable insights into post-intervention prognosis and risk factors for disease progression.

METHODS

Patients` recruitment and assessment:

This study was conducted at the Tropical Medicine and Medical Oncology departments of Zagazig University Hospitals and involved 116 patients with cirrhosis-related advanced HCC between March 2021 and January 2023. The eligibility criteria included patients with (1) cirrhosis-related HCC confirmed by the specific imaging criteria, (2) preserved liver functions, and (3) no prior systemic or intervention therapy for HCC. Twelve patients did not have successful LS measurements because of ascites or morbid obesity. Four patients were lost to the follow-up.  Therefore, 100 patients were included in this study.

Before active treatment initiation, the patients underwent a thorough evaluation, including history, clinical examination, laboratory investigations, viral markers, and radiological studies. The CTP score was calculated based on its specific parameters to assess liver function. Liver stiffness was measured using transient elastography (FibroScan Echosens). Patients with HCC were treated using either microwave ablation (MWA), transarterial chemoembolization (TACE), or sorafenib, according to the multidisciplinary team's decision. Patients were treated with 400 mg sorafenib twice daily until either disease regression or the occurrence of adverse events. If sorafenib side effects occurred, the dose was reduced or stopped according to the severity of adverse events.

LS measurements were performed for all patients within one week before therapy or intervention one month after intervention therapy, and 3 months after sorafenib treatment. LS was measured by transient elastography after 6 hours of fasting. An M-sized probe transducer was used in this study. The results were measured in Kilo Pascals (kPa). A median of 10 valid measurements was approved [10].

Post-intervention assessment:

Post-intervention assessment focused on the prognostic value of LS measurement in predicting liver decompensation and HCC progression, compared with the CTP score. The study also analyzed the risk factors for post-intervention liver decompensation and HCC progression or regression. Patients were followed up for hepatic insufficiency post-therapy and HCC status, correlating LS measurements with CTP scoring. Multiphasic liver computed tomography (CT) was regularly performed to monitor treatment responses.

Statistical analysis:

Data collected were statistically analyzed using SPSS 26.0 (SPSS Inc., Chicago, IL, USA). The paired samples t-test, Wilcoxon ranked signed test, and Chi-square test were used for data analysis. The validity of LS measurement and CTP score was tested using ROC curve analysis. Statistical significance was set at P < 0.05.

RESULTS

The present study included 100 patients with advanced HCC and compensated cirrhosis, with a mean age of 56.3 years (range: 45-69 years). About two-thirds of the cases (70%) were male, 30% were diabetic, and 12% were hypertensive Serology tests revealed that 98 patients have positive HCV antibodies, 16% of the cases were positive for HBsAg, and only 2% were positive for HBc Ab. Approximately 44% of the patients were on sorafenib therapy at a dosage of 800 mg/day, while 28% were on a dose of 400 mg/day. Hand and foot rashes were observed in 44% of the cases as a side effect of sorafenib, and diarrhea was reported in 36%.        

Liver injury after sorafenib

Regarding liver function, there was a significant increase in the mean values of both bilirubin and ALT levels and a significant decrease in mean albumin levels after therapy compared to baseline values. In terms of complete blood counts, there was a significant decrease in neutrophil and platelet counts after therapy, whereas no significant change was observed in total WBC counts. Additionally, the median INR values significantly increased after therapy. The median value of creatinine after therapy was 1 (range: 1-2), and the median hemoglobin value was 10.5 (range: 9.1-11.5).

Pathological characteristics of HCCs

Triphasic CT abdomen revealed that more than half of the diagnosed tumors (56%) were multiple. Portal vein thrombosis was found in 58% of cases, lymph node metastasis in 34%, and distant metastasis in 22%. Bone metastasis was observed in 10% of cases, both pulmonary and lung metastases in 8%, and paraspinal metastases in 2%. There was a decrease in the median AFP level after therapy.

Prognostic indicators

There was no statistically significant difference in the CTP scores before and after therapy. The majority of patients (88%) had a CTP score of A before treatment. More than half of the patients (54%) retained a CTP score of A, 20 % had a score of B, and 26 % had a score of C. Only 14 % of patients had mild ascites before therapy. Post-therapy, mild ascites developed in 22 % of patients, moderate ascites in 28 %, and marked ascites in only two cases.

The means of LS measurements before and after sorafenib therapy were 16.1±4.83 kPa and 15.99±5.93 kPa, respectively and the range was between 6.5 and 28.5 kPa. There were no statistically significant differences in the LS measurements or fibrosis stages before and after therapy (Table 1).

Treatment outcome

As shown in Table 2, more than half of the cases (60%) showed regression (48% partial regression and 12% complete regression), whereas 40% showed progression (34% complete progression and 6% stationary course).

There was a statistically significant difference when comparing between outcome and fibrosis stages before and after therapy as before therapy, with nearly 87.5 % of stage F2 patients showing regression, about 66.7 % of stage F3 patients showing regression, and half of F4 stage patients showing regression. After therapy, approximately 83.3 % of stage F2 and F3 patients showed regression, and 36 % of F4 stage patients showed regression (Table 3).

Table 4 shows a statistically significant difference in outcomes and CTP scores before and after therapy. Before therapy, nearly 63.6 % of CTP A patients and 33.3 % of CTP B patients showed regression. After therapy, approximately 96.3 % of CTP A patients and 40 % of CTP B patients showed regression.

ROC curve analysis was performed to test the predictive value of LS measurement in HCC patients treated with sorafenib or intervention therapy for liver function after systemic treatment or intervention therapy. The cut-off level for LS measurements before therapy was 17.75 kPa, with a sensitivity of 73.3%, specificity of 65%, positive predictive value (PPV) of 76%, negative predictive value (NPV) of 62%, and accuracy of 70% (Table 5) (Fig. 1).

Table 6 shows that analysis by the ROC curve was performed to test the predictive value of sorafenib or intervention therapy in hepatocellular carcinoma patients regarding CTP score. The CTP score before therapy had a sensitivity of 93.3%, specificity of 20%, PPV of 63.6%, NPV of 66.7%, and accuracy of 64%. The CTP score after therapy had a sensitivity of 86.7%, specificity of 95%, PPV of 96.3%, NPV of 82.6%, and accuracy of 90% (Fig. 2).