Prospective evaluation of combining three biomarkers and image tools for early detection of hepatocellular carcinoma: an interim analysis

Abstract

Background and aims: Early detection of hepatocellular carcinoma (HCC) is critically important for the improvement of prognosis. Although combining AFP and ultrasonography (US) are the standard modalities for surveillance of HCC, combining other tumor biomarkers such as PIVKA-II or AFP L3 with AFP is currently suggested to improve the detection rates of HCC. However, prospective evaluation of combinations of such biomarkers has been rarely performed. The present study aimed to confirm the utility of combination of biomarkers and imaging modalities for early detection of HCC inpatients with liver cirrhosis.

Method: Patients with histologically or clinically confirmed liver cirrhosis were enrolled at 14 tertiary hospitals in Korea. Patients with elevated AFP (>20 ng/ml), hepatic nodule ≥1 cm by US or liver CT, or Child-Pugh score ≥11 points were excluded. HCC surveillance using AFP, AFP L3, PIVKA-II, and US were performed every 6 months. In addition, liver CT was scanned every 12 months.

Results: A total of 2810 patients/year were followed-up prospectively. Among them, HCC developed in 56 patients. Under this intensive surveillance program, most of HCCs detected were at early stage (50/56 were BCLC stage 0 or A, 48/56 were TNM stage 1, 54/56 were modified UICC stage1 or 2) and the mean size of HCCs was 1.8 cm (1.3–2.6). The sensitivity of the biomarkers was 42.9% for AFP, 48.2% for AFP L3, 39.3% for PIVKA-II, 59.0% for combination of the three markers when the sensitivity was set to be ≥90%; Three-combination was the highest and the AFP L3 was the next. We assessed the area under the receiver operating curves (AUROC) for one, two, and three combination of the biomarkers such as AFP (0.598), AFP+AFP L3 (0.646), AFP+PIVKA-II (0.664), and AFP+AFPL3+PIVKA-II (0.688), and found that the three combination was the best. In addition, when incorporated the three biomarkers into GALAD (Gender, Age, L3, AFP, and DCP [= PIVKA-II]) score, the AUROC was 0.778, which is the better. The AUROC improved by adding US (0.820) or liver CT (0.864) on combination of three biomarkers.

Conclusion: For early detection of HCCs, a combination of three biomarkers (AFP, AFP L3, PIVKA-II) or GALAD score was shown to be useful in this prospective evaluation. Adding imaging modalities improved the performance further.