GASTROENTEROLOGY 2010;138:493–502 심 재 준 월요 저널

Background HCC (hepatocellular carcinoma) –The 3 rd most common cause of cancer-related death –Poor survival rate: 5-year survival < 10% in USA –Late detection: most patients (>2/3) in advanced state Known risk factors for HCC (HCV, HBV, cirrhosis) –For early detection  curative treatments  survival –Surveillance of high risk group is recommended

Background II Surveillance for HCC –The lack of reliable biomarkers –AFP (α-Fetoprotein): low sensitivity, low specificity AASLD (2005): not recommend AFP but ultrasound alone –Abdominal ultrasound Operator dependent, in cirrhotics, in obese patients Des-γ-carboxy prothrombin (DCP) –PIVKA II (Prothrombin induced by vitamin K absence)

Background III Results from the HALT-C study –Baseline AFP (>20 ng/ml) Cirrhosis, in women, and black patients –Peginterferon + ribavirin  decreased AFP level Baseline biomarker at the time of HCC diagnosis  serial change of biomarkers before HCC diagnosis?

Aims 1.Demographics and liver histology  AFP and DCP? 2.Maintenance peginterferon  AFP and DCP? 3.Accuracy of the biomarkers during 12 months before HCC diagnosis? 4.Increase in AFP or suspicious nodule on ultrasound occurred earlier?

Subjects and Methods The HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial – The hepatitis C patients who failed to respond (SVR) to combination therapy (Peg-IFN + Ribavirin) – Randomized to maintenance therapy with Peg-IFN (90 μg/wk) or no treatment for 3.5 years –Imaging study (6, 12 mo), AFP level every 3 mo –Diagnosis of HCC: definite vs. presumed –Early HCC: single, < 3 cm, no vascular invasion, no metastasis

Subjects and Methods Nested case-control study –39 HCC cases (33 definite [32 histologically], 6 presumed) –For each case, 2 controls without HCC selected –Blood samples at the time of HCC diagnosis and month -3, - 6, -9, and -12

Early HCC: 24 cases (61.5%)

(1) Demographics and liver histology  baseline AFP and DCP? Cirrhosis –Both AFP and DCP were higher (p < ) –AFP: 23.6 ± 36.4 vs ± 22.7 ng/mL –DCP: 48.8 ± vs ± 85.3 mAU/mL Sex –AFP: higher in women than in men (19.6 ± 29.7 vs ± 29.5 ng/mL, p = ) –DCP: higher in men than in women (44.5 ± vs ± 25.8 mAU/mL, p = 0.002) Race –AFP: higher in black patients than in white (23.1 ± 29.4 vs ± 28.7 ng/mL, p < ) –DCP: higher in white patients than in black (43.9 ± vs ± 21.9 mAU/mL, p = )

(2) Maintenance peginterferon  AFP and DCP? DCP: gradually increased among the both groups –Treated patients: 36.6  53.1 mAU/mL –Untreated patients: 35.4  50.8 mAU/mL (p = 0.65) AFP: remained lower –Treated patients: 17.1  15.7 ng/mL –Untreated patients: 17.1  19.0 ng/mL (p = 0.046)

(3) Changes in AFP values 37 ± ± ± ± 34.2

(3) Changes in DCP values 79.1 ± ± ± ± 13.1

(4) Accuracy of the biomarkers during 12 months before HCC diagnosis?

(5) AFP vs. ultrasound as the first indication of HCC Early HCC (24 cases) A suspicious nodule on US (14 cases, 58.4%) Increased AFP, negative US (5 cases, 20.8%) 1.13      30 A suspicious nodule on CT or MRI, negative US, AFP doubling in 1 patient (5 cases, 20.8%)

Summary This nested case-control study (1)DCP was not superior to AFP in the early detection of HCC in patients with advanced hepatitis C (2)AFP, DCP, the combination of two makers: not sufficiently accurate for HCC surveillance (3)Increasing AFP  may be helpful to early diagnosis (4)DCP and AFP are complementary

Conclusions Biomarkers are needed to complement ultrasound in the detection of early HCC, but neither DCP nor AFP is optimal.

AFP …