Digestive Diseases and Sciences

, Volume 57, Issue 4, pp 1092–1101

Effect of Previous Interferon Treatment on Outcome After Curative Treatment for Hepatitis C Virus-Related Hepatocellular Carcinoma

Authors

  • Hirokazu Miyatake
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Yoshiyuki Kobayashi
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Shin-ichiro Nakamura
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Hideki Ohnishi
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Kenji Kuwaki
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Junichi Toshimori
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Hiroaki Hagihara
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Kazuhiro Nouso
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
  • Kazuhide Yamamoto
    • Department of Gastroenterology and HepatologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Original Article

DOI: 10.1007/s10620-011-1934-1

Cite this article as:
Miyatake, H., Kobayashi, Y., Iwasaki, Y. et al. Dig Dis Sci (2012) 57: 1092. doi:10.1007/s10620-011-1934-1

Abstract

Background and Aims

Treatment of chronic hepatitis C virus (HCV) infection with interferon (IFN) prevents the development of hepatocellular carcinoma (HCC). The purpose of this study was to clarify the effect of previous IFN treatment before the development of HCC on recurrence and survival in HCV-related HCC patients.

Methods

Three hundred ninety-five patients who underwent curative treatment for HCV-related HCC were enrolled. Of these, 124 had received IFN treatment before the development of HCC (17 achieved sustained virological response [SVR group] and 107 did not [non-SVR group]), whereas 271 patients had never received IFN treatment (IFN-untreated group). The first and second recurrence and survival rates in these patient groups were statistically analyzed.

Results

The first HCC recurrence rate was similar among patient groups. In contrast, the second HCC recurrence rate was significantly lower in the SVR group than in the non-SVR group (p = 0.003) and the IFN-untreated group (p = 0.006). In multivariate analysis, platelet count (p = 0.033) and number of tumors (p = 0.001) were associated with the first HCC recurrence, while SVR (p = 0.002) was the only factor associated with the second HCC recurrence. The survival rate was higher in the SVR group than in non-SVR and IFN-untreated groups, and SVR to previous IFN treatment was an independent factor associated with better survival (p < 0.001).

Conclusions

SVR to previous IFN treatment before the development of HCV-related HCC was associated with lower risk of the second recurrence of HCC and better survival.

Keywords

Hepatocellular carcinomaHepatitis C virusPrevious interferon therapyRecurrenceSurvival

Introduction

Chronic hepatitis and cirrhosis following hepatitis C virus (HCV) infection are major risk factors for hepatocellular carcinoma (HCC) [13]. Particular risk factors for developing HCV-related HCC in patients are advanced stage fibrosis, male gender, older age, heavy drinking, and high serum alanine aminotransferase (ALT) levels [4, 5]. Interferon (IFN) therapy improves hepatic inflammation and inhibits the progression of hepatic fibrosis [6]. Furthermore, treating patients with IFN with chronic HCV infection can prevent the development of HCC, particularly in patients with sustained virological response (SVR) to IFN therapy [713]. In contrast, HCC is liable to frequently recur even after curative therapy primarily because of its multicentric occurrence, leading to a poor prognosis [1419]. The recurrence rate after resection of HCV-related HCC is higher in patients with HCV viremia than in those without it [20]. It has been reported that IFN therapy after resection or ablation of HCC reduces recurrence and improves prognosis in patients with HCV-related HCC [2128]. However, no complete investigation has been performed of the possible effect of IFN therapy before HCC development on the outcome of curative treatment for HCV-related HCC particularly in relation to the response to IFN treatment. Only a few relevant studies involving limited number of patients with previous IFN therapy are available [2932].

The purpose of this study was to clarify the effect of previous IFN treatment before the development of HCV-related HCC on recurrence and prognosis after curative treatment of HCC in a large cohort of patients.

Patients and Methods

Patients

Between 1995 and 2006, 733 consecutive patients with HCC positive for HCV antibody and HCV RNA were diagnosed at Okayama University Hospital. Three hundred thirty-eight patients who did not receive curative treatment for HCC or undergo IFN therapy after the development of HCC were excluded from the study (Fig. 1). Inclusion criteria were as follows: (1) no evidence of HCC before consulting the Okayama University Hospital, (2) absence of hepatitis B surface antigen, (3) absence of co-existing liver diseases such as autoimmune hepatitis or primary biliary cirrhosis, and (4) absence of a history of alcohol abuse.
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-011-1934-1/MediaObjects/10620_2011_1934_Fig1_HTML.gif
Fig. 1

Schematic presentation of patients with HCV-related hepatocellular carcinoma (HCC). Patients with HCV-related HCC who were diagnosed at Okayama University Hospital were classified into three groups according to their previous IFN treatment and response to that treatment. One hundred twenty-four patients had received IFN treatment before the development of HCC (IFN-treated group) and the remaining 271 had not (IFN-untreated group). Patients who had undergone IFN treatment before the development of HCC were further classified according to their response into a sustained virological response (SVR) group or a non-SVR group. Patients were regularly screened for HCC

HCV infection was diagnosed on the basis of identification of anti-HCV antibodies using the first, second, or third enzyme-linked immunosorbent assays (Ortho Diagnostics, Tokyo, Japan). HCV RNA was identified by reverse transcription-polymerase chain reaction (RT-PCR) [33].

HCC was suspected on the basis of several imaging methods, including abdominal ultrasonography (US), dynamic computed tomography (CT), magnetic resonance imaging, and angiography. Diagnosis of HCC was confirmed by needle biopsy, by surgically resected tumor specimens, or by typical radiological findings on hepatic angiography or dynamic CT.

The study was conducted in accordance with the Helsinki Declaration and approved by the Ethical Committee of the institution.

Treatment

Of the 395 patients receiving curative treatment of HCC, 103 were treated with surgical resection and 292 with percutaneous tumor ablation (PTA) [3437], that is, percutaneous ethanol injection therapy (PEIT) (n = 116), percutaneous microwave coagulation therapy (PMCT) (n = 11), or radiofrequency ablation (RFA) (n = 165). There were no patients who underwent liver transplantation or other modes of HCC treatment. The choice between surgical resection and PTA were determined according to the extent of tumor and hepatic functional reserve as assessed by Child’s classification [38]. If the liver tumor consisted of fewer than three nodules that were less than 3 cm in diameter, patients were indicated for PTA. When a patient was indicated for both surgery and PTA, the modality of treatment was determined by patient choice after obtaining fully informed consent. PEIT was carried out under US guidance using a 15- or 20-cm-long needle (21 gauge) (Hakko, Chikuma, Japan) [35], PMCT was performed under US guidance using a 15-cm-long guide needle (14 gauge) according to the procedure described previously [37], and RFA was executed under US guidance using a 15- or 20-cm-long guide needle (16 gauge) (Tyco Healthcare Japan, Tokyo, Japan) [36]. PTA was repeated until complete necrosis of all HCC lesions was confirmed by dynamic CT. Treatment of HCC was considered curative, when no viable HCC lesions were detected on dynamic CT 3 months after completion of the treatment.

Of the 395 patients receiving curative treatment for HCC, 124 had received either human lymphoblastoid IFN, recombinant IFN-alpha 2a, or recombinant IFN-alpha 2b monotherapy for chronic HCV infection before the development of HCC (IFN-treated group), whereas 271 had not (IFN-untreated group) (Fig. 1). Patients received 6 million units of IFN by intramuscular injection three times weekly for 24 weeks as outpatients. If patients could not tolerate this dose, the IFN dose was reduced to 3 million units. SVR was defined as HCV RNA (as determined by RT-PCR; detection limit, 102 copies/ml) negativity for over 6 months after the termination of IFN therapy. SVR was achieved in 17 of the 124 patients (SVR group) and the remaining 107 were regarded as non-SVR (non-SVR group) (Fig. 1).

Follow-up of Patients

Patients attended a monthly medical consultation at the Okayama University Hospital outpatient clinic. Blood biochemical markers, including α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), were measured every 1–2 months; US was performed every 2–3 months, and dynamic CT was performed every 6 months. If HCC recurrence was suspected, further imaging examinations including dynamic CT, magnetic resonance imaging, abdominal angiography, or US-guided tumor biopsy were performed to confirm the diagnosis.

New HCC foci as well as local recurrent nodules at tumor, node, metastasis (TNM) stage I, II, and III, were mainly treated by a second course of PTA; local recurrent nodules at TNM stage IV were treated with transarterial chemoembolization or chemotherapy. Further development of HCC and survival of patients (tumor recurrence rate and survival rate) were analyzed in relation to the time interval after treatment of HCC.

Statistical Analysis

Statistical analysis was performed using JMP statistical discovery software, version 8.0 (SAS Institute Inc., Cary, NC). Differences between two groups were evaluated using the unpaired Student’s t test or the Mann–Whitney U test. The Chi-square test or the Fisher’s exact probability test was used to compare categorical data. Cumulative incidence curves were determined with the Kaplan–Meier method, and the differences between patient groups were assessed using the logrank test. Possible risk factors for recurrence of HCC and survival included both IFN-related variables and variables at the development and recurrence of HCC (age, total bilirubin level, albumin level, prothrombin time, ALT level, platelet count, number of tumors, largest tumor size, AFP level, and DCP level). Tumor associated variables, number of tumors and size of largest tumor, were transformed into categorical data consisting of two ordinal numbers by the median value. Variables exhibiting p values less than 0.10 in univariate analysis were subjected to a stepwise Cox proportional hazards regression analysis. A risk ratio with a 95% confidence interval was denoted for each analysis. p values less than 0.05 were considered statistically significant.

Results

Demographic and clinical characteristics of patients at the development of HCC are shown in Table 1. The patient group comprised 260 men and 135 women (73 men and 51 women in the IFN-treated group), and median age was 58 years (65 years in the IFN-treated group). Of the 395 patients (80%), 317 were classified as Child–Pugh stage A. Significant differences were observed between IFN-treated and untreated patients in sex, age, albumin level, and size of largest tumor. On the other hand, significant differences were observed between IFN-treated patients with SVR and non-SVR in albumin level, prothrombin time, ALT level, platelet count, Child–Pugh stage, and initial treatment of HCC. This indicated better hepatic functional reserve in SVR patients than in non-SVR patients.
Table 1

Demographic and clinical characteristics of patients with HCV-related HCC

Groups

IFN-treated

IFN-untreated (n = 271)

pa

pb

SVR (n = 17)

Non-SVR (n = 107)

Characteristics

 Sex (men/women), n

13/4

60/47

187/84

0.049

0.112

 Age (years)

63 (52–71)

65 (46–82)

67 (33–85)

0.018

0.061

Laboratory data

 Total bilirubin (mg/dl)

0.74 (0.40–1.29)

0.85 (0.36–3.28)

0.91 (0.16–4.13)

0.194

0.171

 Albumin (g/dl)

4.4 (3.7–4.8)

3.7 (2.5–4.8)

3.6 (2.2–4.7)

<0.001

<0.001

 Prothrombin time (%)

93 (70–121)

85 (47–142)

85 (40–145)

0.355

0.023

 ALT (IU/l)

22 (10–54)

55 (12–198)

60 (14–201)

0.058

<0.001

 Platelet count (×104/μl)

16.6 (8.4–30.3)

9.2 (2.8–37.2)

10.1 (3.2–31.9)

0.980

<0.001

 Child–Pugh stage (A/B/C), n

17/0/0

87/20/0

213/54/4

0.236

0.049

Tumor-related variables

 Number of tumors (single/multiple), n

15/2

76/31

192/79

0.603

0.136

 Size of largest tumor (mm)

20 (8–40)

18 (10–53)

20 (9–74)

0.033

0.942

 AFP (ng/ml)

13 (1.9–25,716)

24 (1.7–3,480)

20 (0.6–54,535)

0.956

0.297

 DCP (mAU/ml)

34 (1–35,000)

46 (10–56,000)

46 (1–66,700)

0.294

0.195

Initial treatment of HCC

 PTA/surgical resection, n

6/11

79/28

207/64

0.100

0.002

Laboratory data and tumor-related variables are at the development of HCC. Continuous variables are given as medians with ranges

HCV hepatitis C virus, HCC hepatocellular carcinoma, IFN interferon, SVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, DCP des-γ-carboxy prothrombin, PTA percutaneous tumor ablation

aIFN-treated versus IFN-untreated

bSVR versus non-SVR

The median follow-up period after curative treatment of HCC for patients with and without IFN treatment was 3.8 years and 3.5 years, respectively. In the IFN-treated group, patients underwent IFN therapy 7.2 (0.8–17.4) (median and range) years before development of HCC. Of the 395 patients, 277 (70%) had recurrence of HCC during a median follow-up period of 2.1 (1.8–2.4) years [including 86 of 124 IFN-treated patients (69%)]. Of the 168 patients receiving curative treatment for the first recurrence of HCC, 113 (67%) had a second HCC recurrence during a median follow-up period of 1.3 (1.0–1.4) years [including 38 of 59 IFN-treated patients (64%)] (Fig. 1).

HCC Recurrence Rates

The rates of the first and second HCC recurrence after curative treatment of primary HCC in each treatment group are shown in Fig. 2. In the IFN-treated group, 86 patients (10 with SVR and 76 with non-SVR) had the first HCC recurrence and 38 (four with SVR and 34 with non-SVR) had the second HCC recurrence during the follow-up period. The average times to the first and second HCC recurrence were 632 and 1,069 days, 661 and 401 days, and 666 and 428 days in SVR, non-SVR, and IFN-untreated groups, respectively. The rates of the first recurrence at 2 years in SVR, non-SVR, and IFN-untreated groups were 36, 47, and 48%, respectively. The differences between these rates were not statistically significant (p = 0.410) (Fig. 2a). However, the rates of the second HCC recurrence at 2 years were significantly lower in the SVR group than in the non-SVR group (10 vs. 69%, p = 0.003) and in the IFN-untreated group (10 vs. 70%, p = 0.006) (Fig. 2b). There was no significant difference in the second HCC recurrence rates between non-SVR and IFN-untreated groups (p = 0.441). In multivariate analysis, platelet count (p = 0.033) and number of tumors (p = 0.001) were independent factors associated with the first recurrence of HCC (Table 2), whereas SVR to previous IFN therapy (p = 0.002) was the only factor associated with lower risk for the second recurrence of HCC (Table 3).
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-011-1934-1/MediaObjects/10620_2011_1934_Fig2_HTML.gif
Fig. 2

Cumulative first (a, n = 395) and second (b, n = 168) HCC recurrence rates in patients with curative treatment of HCC according to the previous IFN treatment and response to the treatment. The first HCC recurrence rates were similar among SVR, non-SVR, and IFN-untreated groups (a). However, the second HCC recurrence rate in the SVR group at 2 years after HCC treatment was significantly lower than that in the non-SVR group (10 vs. 69%, p = 0.003) and the IFN-untreated group (10 vs. 70%, p = 0.006) (b)

Table 2

Risk factors for the first recurrence of HCC (n = 395)

Variable

Univariate analysis

Multivariate analysis

Odds ratio (95% CI)

p

Odds ratio (95% CI)

p

Sex (male)

1.17 (0.91–1.51)

0.229

 

IFN-related variables

 IFN-untreated

1

   

 Non-SVR

1.07 (0.82–1.39)

0.623

 

 SVR

0.68 (0.34–1.22)

0.209

 

Variables at the development of HCC

 Age (≥60 years)

1.13 (0.84–1.56)

0.434

 

 Total bilirubin (≥1.0 mg/dl)

1.07 (0.83–1.37)

0.579

 

 Albumin (<3.5 g/dl)

1.34 (1.04–1.71)

0.022

1.24 (0.95–1.61)

0.108

 Prothrombin time (<70%)

1.07 (0.79–1.43)

0.664

 

 ALT (≥40 IU/l)

1.09 (0.83–1.43)

0.542

 

 Platelet count(<10 × 104/μl)

1.37 (1.08–1.75)

0.009

1.34 (1.04–1.75)

0.026

Tumor-related variables

 Number of tumors (multiple vs. single)

1.66 (1.27–2.15)

<0.001

1.63 (1.24–2.14)

0.001

 Size of largest tumor (≥20 mm)

1.24 (0.98–1.57)

0.074

1.22 (0.94–1.59)

0.140

 AFP (≥100 ng/ml)

1.45 (1.07–1.92)

0.016

1.30 (0.96–1.74)

0.093

 DCP (≥40 mAU/ml)

1.33 (1.02–1.75)

0.034

1.11 (0.85–1.44)

0.448

Initial treatment of HCC

 PTA/surgical resection

1.09 (0.84–1.43)

0.530

 

HCC hepatocellular carcinoma, IFN interferon, SVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, DCP des-γ-carboxy prothrombin, PTA percutaneous tumor ablation, CI confidence interval

Table 3

Risk factors for the second recurrence of HCC (n = 168)

Variable

Univariate analysis

Multivariate analysis

Odds ratio (95% CI)

p

Odds ratio (95% CI)

p

Sex (male)

1.07 (0.73–1.61)

0.719

 

IFN-related variables

 IFN-untreated

1

 

1

 

 Non-SVR

1.17 (0.77–1.74)

0.447

1.09 (0.68–1.72)

0.718

 SVR

0.27 (0.08–0.65)

0.002

0.10 (0.01–0.50)

0.002

Variables at the development of HCC

 Age (≥60 years)

1.50 (0.91–2.61)

0.115

 

 Total bilirubin (≥1.0 mg/dl)

1.08 (0.72–1.60)

0.701

 

 Albumin (<3.5 g/dl)

1.04 (0.68–1.57)

0.847

 

 Prothrombin time (<70%)

1.18 (0.70–1.89)

0.529

 

 ALT (≥40 IU/l)

1.30 (0.86–2.01)

0.220

 

 Platelet count (<10 × 104/μl)

1.00 (0.69–1.47)

0.984

 

 Number of tumors (multiple vs. single)

1.57 (1.04–2.32)

0.033

1.51 (0.93–2.42)

0.098

 Size of largest tumor (≥20 mm)

0.91 (0.63–1.32)

0.613

 

 AFP (≥100 ng/ml)

0.65 (0.38–1.06)

0.084

0.77 (0.39–1.39)

0.391

 DCP (≥40 mAU/ml)

0.81 (0.54–1.23)

0.331

 

Initial treatment of HCC

 PTA/surgical resection

1.12 (0.75–1.69)

0.595

 

Variables at the first recurrence of HCC

 Age (≥60 years)

0.97 (0.46–2.39)

0.950

  

 Total bilirubin (≥1.0 mg/dl)

0.94 (0.59–1.46)

0.785

 

 Albumin (<3.5 g/dl)

1.67 (1.06–2.61)

0.029

1.47 (0.90–2.36)

0.125

 Prothrombin time (<70%)

1.24 (0.60–2.30)

0.531

 

 ALT (≥40 IU/l)

1.49 (0.95–2.40)

0.083

1.21 (0.75–2.01)

0.452

 Platelet count (<10 × 104/μl)

1.13 (0.74–1.73)

0.573

 

 Number of tumors (multiple vs. single)

2.09 (1.37–3.13)

<0.001

1.47 (0.91–2.34)

0.112

 Size of largest tumor (≥20 mm)

0.96 (0.62–1.45)

0.840

 

 AFP (≥100 ng/ml)

0.72 (0.32–1.41)

0.355

 

 DCP (≥40 mAU/ml)

1.05 (0.67–1.63)

0.842

 

HCC hepatocellular carcinoma, IFN interferon, SVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, DCP des-γ-carboxy prothrombin, PTA percutaneous tumor ablation, CI confidence interval

Overall Survival

Survival rates after curative treatment of primary HCC in each group are shown in Fig. 3. A tendency was observed toward a higher survival rate in the IFN-treated group than in the IFN-untreated group but it was not significant (p = 0.053) (Fig. 3a). In contrast, survival rates at 5 years were higher in the SVR group (100%) than in non-SVR (73%) and IFN-untreated groups (62%) (p = 0.004) (Fig. 3b). No significant difference was observed in the survival rates between non-SVR and IFN-untreated groups (p = 0.450). In multivariate analysis, SVR to previous IFN therapy (p < 0.001), albumin level (p = 0.006), number of tumors (p = 0.007), and AFP level (p = 0.046) were independent factors associated with overall death after curative treatment of primary HCC (Table 4).
https://static-content.springer.com/image/art%3A10.1007%2Fs10620-011-1934-1/MediaObjects/10620_2011_1934_Fig3_HTML.gif
Fig. 3

Overall survival rates of HCV-related HCC patients (n = 395) according to their previous IFN treatment before development of HCC (a) and their response to the treatment (b). A tendency was observed toward a higher survival rate in the IFN-treated group than in the IFN-untreated group but it was not significant (p = 0.053) (a). On the other hand, the survival rate of the SVR group was significantly higher than those of non-SVR and IFN-untreated groups (p = 0.004) (b)

Table 4

Analysis of factors associated with overall death after curative treatment for primary HCC (n = 395)

Variable

Univariate analysis

Multivariate analysis

Odds ratio (95% CI)

p

Odds ratio (95% CI)

p

Sex (male)

1.02 (0.73–1.44)

0.911

 

IFN-related variables

 IFN-untreated

1

 

1

 

 Non-SVR

0.86 (0.59–1.24)

0.445

1.05 (0.71–1.54)

0.794

 SVR

<0.01 (0–0.17)

<0.001

<0.01 (0–0.26)

<0.001

Variables at the development of HCC

 Age (≥60 years)

1.06 (0.72–1.63)

0.773

 

 Total bilirubin (≥1.0 mg/dl)

1.45 (1.04–2.01)

0.028

1.21 (0.82–1.76)

0.332

 Albumin (<3.5 g/dl)

2.07 (1.49–2.89)

<0.001

1.70 (1.16–2.49)

0.007

 Prothrombin time (<70%)

1.44 (0.99–2.06)

0.059

0.97 (0.65–1.43)

0.874

 ALT (≥40 IU/L)

1.12 (0.78–1.67)

0.531

 

 Platelet count (<10 × 104 μl)

1.72 (1.23–2.41)

0.001

1.35 (0.93–1.96)

0.118

Tumor-related variables

 Number of tumors (multiple vs. single)

1.59 (1.10–2.26)

0.014

1.71 (1.16–2.46)

0.007

 Size of largest tumor (≥20 mm)

1.15 (0.83–1.60)

0.395

 

 AFP (≥100 ng/ml)

1.71 (1.17–2.45)

0.006

1.50 (1.00–2.18)

0.047

 DCP (≥40 mAU/ml)

1.33 (0.91–1.98)

0.145

 

Initial treatment of HCC

 PTA/surgical resection

1.69 (1.16–2.53)

0.006

1.03 (0.68–1.60)

0.882

HCC hepatocellular carcinoma, IFN interferon, SVR sustained virological response, ALT alanine aminotransferase, AFP α-fetoprotein, DCP des-γ-carboxy prothrombin, PTA percutaneous tumor ablation, CI confidence interval

Discussion

In the present study, we have demonstrated that patients with SVR to previous IFN treatment before development of HCC showed lower risk for the second recurrence of HCC and better survival compared to patients with non-SVR to previous IFN treatment or IFN-untreated patients. Several studies have demonstrated that IFN therapy reduces the risk of HCC development among chronic hepatitis C patients. On the other hand, a few reports are available on the influence of previous IFN therapy before the development of HCC on patient outcomes after curative treatment of HCV-related HCC. It was initially reported that HCV-related HCC patients who received IFN therapy before development of HCC showed lower recurrence rates and better survival rates, independent of response to IFN therapy, compared to those without previous IFN therapy [29, 30]. It has recently been reported that patients showing biochemical response, with or without SVR to previous IFN therapy, showed higher tumor-free survival rates after surgery than those without such a response to IFN or those without previous IFN therapy [31, 32]. In these previous reports, a biochemical response as well as SVR to previous IFN therapy was associated with favorable outcome, demonstrating the importance of response to previous IFN therapy for the outcome after surgery of HCV-related HCC.

However, in the present study, patients with non-SVR showed similar recurrence and survival rates as IFN-untreated patients. Furthermore, no difference was observed in the recurrence and survival rates among non-SVR patients with and without biochemical response to previous IFN therapy (data not shown). In fact, only patients with SVR to previous IFN therapy showed better outcome than those with non-SVR or IFN-untreated patients. Therefore, the present data indicate that SVR but not biochemical response without SVR to previous IFN treatment is a predictor of favorable outcome in patients who have developed HCC.

The reason for the difference between the present and previous studies in the outcome of non-SVR patients with biochemical response to previous IFN therapy is currently unknown. In patients with HCV-related chronic hepatitis and cirrhosis, who received IFN therapy and showed normalization of ALT levels, suppression of primary HCC development and better survival rates have been independently demonstrated of eradication of HCV infection by the IFN therapy [10, 11, 13, 39]. However, this suppression observed for primary carcinogenesis in non-SVR patients with biochemical response to IFN therapy does not appear to be the case for secondary carcinogenesis in the present study. The period after IFN therapy was much longer in the present study than in the previous reports on primary carcinogenesis. The IFN therapy had preceded to the HCC development, that should have required long incubation after the termination of IFN treatment, and in the present study the observation of HCC recurrence and survival started with the curative treatment of the primary HCC. In patients who had sustained biochemical response but had not eradicated HCV infection, we and others demonstrated that platelet count transiently increases following IFN therapy but decrease over the following 3 years after the termination of IFN therapy. On the other hand, in patients with SVR an increase followed by persistence in platelet counts was observed [40, 41]. These observations suggest the progression of fibrosis during a longer incubation period after IFN therapy, even in the non-SVR patients with biochemical response to the therapy. Therefore, the suppressive effect of IFN therapy on development of HCC may not persist beyond the development of primary HCC particularly in these patients.

It has also been demonstrated that HCV core transgenic mice can develop HCC without apparent hepatitis [42]. Therefore, besides active hepatitis, which involves persistent hepatocyte death and regeneration, and should result in both genetic and epigenetic disorders as well as increased oxidative stress, the presence and persistence of HCV infection and viral products such as core protein may themselves play an important role in the development of HCC in non-SVR patients with biochemical response. Thus, patients with SVR who had eradicated HCV infection should have a lower incidence of HCC recurrence and higher survival rates than non-SVR patients with biochemical response.

In the present study, patients with SVR showed a better overall survival rate than other groups. However, although patients with SVR showed lower rates of the second HCC recurrence, this was not the case for the first HCC recurrence. Although both SVR and non-SVR groups have a carcinogenic background during the development of primary HCC, the carcinogenic potential in SVR patients may be gradually attenuated because of the eradication of HCV infection, whereas it may increase in those with non-SVR because of persistence of HCV infection and relapse of hepatitis, finally leading to progression of fibrosis over a longer period. However, a substantial time may be required before differences between patients with and without SVR become apparent, and these differences eventually become significant in the second recurrence of HCC.

It should also be noted that IFN-treated patients enrolled in the present and previous studies are a selected cohort, since the incidence rates of HCC development in patients treated with IFN should be lower than in those untreated with IFN [13]. This is particularly the case for patients with SVR to previous IFN treatment, whose risk for development of HCC is less than one fifth of that for IFN-untreated patients [13]. Reported risk factors for HCC development in patients who received IFN therapy include advanced fibrosis, lower platelet count, advanced age, male gender, and regular drinking [8, 9, 12, 13, 43]. Therefore, in the present study, HCC patients who received IFN therapy before the development of HCC may have demonstrated many of these characteristics, making them more prone to develop HCC than those not developing HCC after IFN therapy and not included in this study. Furthermore, it has been suggested that cirrhotic patients who develop primary HCC may already be at a “carcinogenic stage” and have a higher potential to develop intrahepatic multicentric carcinogenesis than those without HCC [15]. Patients who have already developed HCC may have background features such as greater age and impaired liver function because of more advanced fibrosis. Therefore, the observed recurrence and survival rates in the present study are those of selected patients who were already at the carcinogenic stage, and are thus biased in comparison to previous observations on primary prevention of HCC development in patients who had received IFN therapy. Recently, Imai et al. reported that an inhibitory effect of IFN therapy on development of HCC in older patients was limited to patients with SVR [44]. This also supports the notion that patients already at a carcinogenic stage or with risk factors associated with HCC development, such as greater age or advanced fibrosis, require eradication of HCV infection in order to achieve a significantly better prognosis.

The present observation highlights the importance of eradication of HCV in order to prevent HCC recurrence and to achieve better survival in this patient group. Plenty of reports are available that demonstrated the favorable effect of IFN therapy on the recurrence of HCC and survival particularly in patients who achieved SVR [2128]. Therefore, re-treatment with more potent IFN therapies, such as combination therapy of PEGylated IFN plus ribavirin [45], should be recommended for patients who previously underwent IFN treatment without achieving SVR.

The present study has limitations as it is retrospective in nature, and thus, patients enrolled were biased in favor of experience of IFN treatment, and also HCC patients with previous IFN treatment were a selected population from a large cohort of patients who had undergone IFN treatment. Also, information on the histological data that may have influence on the outcome of HCC patients was not available in the present study. Further prospective studies are required to address these issues.

In conclusion, the present study demonstrated that patients with SVR to IFN treatment before the development of HCV-related HCC showed lower second HCC recurrence rates and higher survival rates than those with non-SVR to previous IFN treatment or IFN-untreated patients. Therefore, treatment with potent antiviral therapy is recommended for patients in the latter groups in order to suppress recurrence and improve survival by eradicating HCV infection.

Acknowledgments

The authors thank Dr. Kenji Miyoshi and Dr. Shota Iwadou for contribution to this study.

Copyright information

© Springer Science+Business Media, LLC 2011