Page 190 - Read Online

Page 2 of 11 Nakamura et al. Hepatoma Res 2019;5:16 I http://dx.doi.org/10.20517/2394-5079.2019.06

hepatectomy or radio-frequency ablation. We calculated the annual incidence of HCC recurrence after DAA therapy and
identified the risk factors for HCC recurrence using Cox regression models.

Results: The median age was 74 years old, and a sustained virological response was achieved by 288 patients. The
3-year-overall survival rate was 95.4% in a median follow-up period of 855 days. HCC recurred in 135 patients. The
1-, 2- and 3-year recurrence rates were 18.3%, 38.8% and 55.4%, respectively. A multivariate analysis revealed that the
following factors were associated with HCC recurrence: multiple tumors at the first HCC treatment [hazard ratio (HR)
= 2.21; 95%CI: 1.41-3.49], a history of multiple treatments for HCC (HR = 1.97; 95%CI: 1.28-3.02), and α-fetoprotein
(AFP-L3) ≥ 10% at the initiation of DAA therapy (HR = 4.74; 95%CI: 2.10-10.7).

Conclusion: Among patients treated with DAAs after the curative treatment of HCC, multiple tumors at the first HCC
treatment, multiple prior HCC treatments and a high AFP-L3 level before DAA therapy were associated with recurrence,
and the rate of recurrence was comparable to that before the DAA era.

Keywords: Hepatocellular carcinoma, hepatitis C virus, direct-acting antiviral, recurrence

INTRODUCTION
Worldwide, primary liver cancer is the second and sixth leading cause of cancer mortality in men and women,
[3]
[1,2]
respectively . The most frequent cause of HCC is liver cirrhosis due to HCV infection .
DAA therapy have made it possible for most patients with HCV infection to achieve a sustained virological response,
even if they cannot tolerate interferon-based therapy. The introduction of DAA therapy is expected to improve the
prognosis of patients with liver cirrhosis due to HCV infection, and it is also expected that the recurrence rate will
decrease in patients after HCC treatment. However, recent studies have suggested that DAA therapy might increase
[4,5]
[4]
the risk of HCC recurrence . For example, a Spanish multicenter study reported by Reig et al. warned that DAA
therapy may increase the risk of HCC recurrence. In their paper, 16/58 (27.6%) patients who received DAA therapy
after HCC treatment experienced tumor recurrence after a median follow-up period of 5.7 months. Subsequently,
several studies reporting contradictory findings have been published [6-15] .

Although DAAs have been demonstrated to lower carcinogenicity in patients without a history of HCC
treatment [8,16] , the effect of DAAs for preventing recurrence after HCC treatment has not been proven. In this
study, we investigated the outcomes of HCC patients who received DAA therapy after curative treatment with
hepatectomy or radio-frequency ablation (RFA) in a multicenter collaborative study and attempted to elucidate the
effect of DAAs on recurrence.

METHODS
Patients
We performed a multicenter, retrospective cohort analysis of HCC patients who had previously been treated
with hepatectomy or RFA and who received anti-HCV treatment with DAAs between September 2014 and
July 2016. In this study, 312 consecutive patients were enrolled: 224 (71.8%) and 88 (28.2%) patients received
RFA and hepatectomy before DAA treatment, respectively. A flowchart of the patient selection is shown in the
Supplementary Figure 1.

All patients were diagnosed as cancer-free prior to DAA treatment based on triple-phase multidetector computed
tomography (CT), dynamic contrast-enhanced magnetic resonance imaging (MRI) or ultrasonography (US). We
confirmed the cancer-free status at least with two imaging modalities. The study protocol conformed to the ethical