ORIGINAL ARTICLE
Antiviral Therapy in Patients With Chronic Hepatitis C-related Hepatocellular Carcinoma Responding to Palliative Treatment Jung-Hwan Yu, MD, PhD, Ja Kyung Kim, MD, PhD, Kwan Sik Lee, MD, PhD, and Jung Il Lee, MD, PhD
Background/Aim: Advances in hepatitis C virus (HCV) treatment offer high sustained virologic response rates with minimal side-effects. However, benefits of eradicating HCV in hepatocellular carcinoma (HCC) patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that responded to the palliative HCC treatment to speculate whether treating HCV would be beneficial in these patients. Materials and Methods: In this retrospective cohort study, the medical records of 97 patients that showed complete or partial response to the initial HCC treatment were included. Results: Receiving HCV treatment [hazard ratio (HR), 0.244; 95% confidence interval (CI), 0.075-0.788; P = 0.018] increased the survival, whereas partial response to the initial HCC treatment (HR, 1.795; 95% CI, 1.071-3.008; P = 0.026) and increased Child-Turcotte-Pugh score (HR, 2.017; 95% CI, 1.196-3.403; P = 0.009) reduced the survival. From 97 patients, 16 patients were eventually treated for HCV. The mean time from the last HCC therapy to HCV treatment was 16.9 ± 13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). Among the HCV-treated patients 3 patients had HCC recurred. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P = 0.032). Conclusions: Although treating HCV in HCC patient that undergo noncurative HCC treatment is still debatable, this study results carefully suggest that HCV-related HCC patients that responded to the initial HCC palliative treatment might benefit from HCV treatment. Key Words: antiviral therapy, hepatitis C virus, hepatocellular carcinoma, radiotherapy, transhepatic arterial chemoembolization
(J Clin Gastroenterol 2017;00:000–000)
S
uccessful hepatitis C virus (HCV) eradication may offer valuable benefits including decrease or elimination of liver inflammation, reduction in the rate of liver fibrosis progression as well as amelioration of extrahepatic symptoms. In addition, studies demonstrated that HCV treatment and the achievement
Received for publication January 11, 2017; accepted July 25, 2017. From the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4015192). The authors declare that they have nothing to disclose. Address correspondence to: Jung Il Lee, MD, PhD, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea (e-mail: mdflorence @yuhs.ac). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MCG.0000000000000923
of sustained virologic response (SVR) in patients with advanced liver disease decreased hepatocellular carcinoma (HCC) and other liver-related mortality.1–6 Therefore, HCV treatment is recommended for virtually all patients with chronic HCV infection. However, patients with short-life expectancies that cannot be remediated by HCV treatment may not be recommended for HCV treatment and treating patients with uncertain life expectancies due to complicated liver disease,7 such as HCC, is under controversy. Several studies reported the benefit of antiviral therapy after curative treatment in both hepatitis B virus (HBV) and HCV-related HCC. In patients with HBV-related HCC that received curative treatment including liver resection and an ablation therapy, studies suggested that treating patients with nucleoside analog (NA) would decrease HCC recurrence and increased overall survival.8–14 In cases with HBV-related HCC patients receiving palliative treatment such as transhepatic arterial chemoembolization (TACE), studies support NA treatment based on the results that showed increased overall survival in NA-treated group.15–17 In contrast, relatively few studies with limited numbers of patients exist investigating the benefits of antiviral therapy in HCV-related HCC patients. Several studies suggested that interferon (IFN)-based treatment would reduce HCC recurrence and increase overall survival after curative treatment.18–20 Evidences on the impact of HCV treatment in patients with HCV-related HCC that were put under palliative treatment such as TACE are very few. From a study of 11 patients with SVR after IFN treatment, that experienced either TACE or nonsurgical ablation therapy, survival rate was higher compared with that of HCV-untreated patients.21 The reason for the rarity of evidences on HCVrelated HCC patients might be due to higher incidence of adverse effects and relatively low SVR rates after IFN-based treatment. Recently, with introduction of IFN-free direct acting antivirals (DAAs), higher SVR rates and minimal side-effects are expected. However, benefits of eradicating HCV in HCC patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that showed complete (CR) or partial response (PR) to the initial noncurative therapy to speculate whether treating HCV would be beneficial even in patients that were not candidates for curative treatment such as surgical liver resection or nonsurgical ablation therapy.
MATERIALS AND METHODS Patient Selection In this retrospective cohort study, the medical records of patients diagnosed and treated for HCV-related HCC,
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and seen at Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea from January 2004 to 2016 were reviewed. This study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board (3-2016-0238). Among 181 patients with HCV-related HCC, 16 patients had HCV treated before the diagnosis of HCC. From 165 HCV-related HCC patients whose HCV infection had never been treated, 23 patients that received curative treatment such as liver resection, local ablation therapy or liver transplantation were excluded. Among 142 patients that received noncurative treatment, 97 patients that showed CR or PR to the initial HCC treatment. These patients were confirmed to be positive for HCV RNA at the diagnosis of HCC, had neither evidences of HBV infection nor other potential causes of chronic liver disease such as excessive alcohol abuse or autoimmune liver diseases. HCC was diagnosed either histologically or clinically. The clinical diagnosis consisted of having typical radiologic findings of hyperattenuation in the arterial phase and washout in the late phase using either dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in patients with chronic liver disease .22 Those that could not be diagnosed as HCC clinically might undergo liver biopsy for histologic diagnosis.
HCC Treatment and Follow-up Treatment of HCC patients was performed after an extensive discussion among experts in different specialists including hepatologists, surgeons, radiologists, oncologists, and radiation oncologists. Treatment responses were evaluated based on imaging studies that were obtained at 1 to 3 months after the initiation of the treatment, according to modified Response Evaluation Criteria in Solid Tumors (mRECIST).23 The patients were regularly followed-up. Liver function tests, α-fetoprotein (AFP) measurements were done every 1 to 3 months. Liver fibrosis stage was evaluated by calculating fibrosis-4 (FIB-4) index as previously described24 at the time of HCC diagnosis and at the last follow-up. For those patients censored due to liver-related mortality, FIB-4 index was calculated based on liver function test results estimated at least 1 month before the event of death. Dynamic CT was regularly performed with the interval no > 6 months. All patients were followed until the time of death or for at least 6 months. When a new lesion was detected by abdominal CT, evaluation for HCC recurrence was performed. When the liver CT showed compatible findings with HCC with accompanied AFP elevation, recurrence was diagnosed. However, if vascular pattern was not typical on liver CT, liver MRI and/or hepatic angiogram was performed. When the nodule showed atypical pattern on all the imaging studies, the nodule was followed-up with the interval no longer than 3 months. In case of elevated AFP without evidence of newly appeared lesion on CT, MRI, and/or hepatic angiography was performed.
Antiviral Therapy Among 97 patients with either PR or CR to HCC treatment, 16 patients eventually received antiviral therapy for HCC. All 16 patients had at least 3 months of remission period after HCC treatment. Patients were treated with either pegylated interferon (Peg-IFN) and weight-based ribavirin or combination of DAAs. SVR was defined as last HCV-RNA test being negative at 12 weeks after the completion of HCV treatment for
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those treated with DAAs and negative at 24 weeks after the treatment for patients underwent Peg-IFN–based treatment as previously described.25
Statistical Analyses Statistical analyses were performed using IBM SPSS version 23. Overall survival was evaluated using the KaplanMeier method. Survival was compared with the log-rank test. Factors predicting survival were analyzed using Cox proportional hazard model. Variables with P < 0.1 in univariable analysis were included in the multivariable model. These models were considered using conditional selection procedures. Hazard ratios (HRs) were presented with 95% confidence interval (CI). P < 0.05 was considered significant for multivariate analysis.
RESULTS Patient Characteristics The clinical characteristics of patients included in the analysis are summarized in Table 1. These patients had positive serum HCV RNA, and had no experience of HCV treatment before HCC diagnosis. They showed either PR or CR to the initial HCC treatment, according to mRECIST. The initial treatment modality included noncurative therapy such as TACE, intra-arterial chemoinfusion therapy, or external radiation therapy alone or in combination of different modalities. When demographic findings of HCC patients treated for HCV after HCC diagnosis were compared with those that did not receive HCV treatment, the Model for EndStage Liver Disease (MELD) score,26 the Child-TurcottePugh (CTP) score27 and FIB-4 index24 during follow-up showed statistically significant differences. Those who received HCV antiviral therapy after HCC treatment had better liver function before HCV treatment and during the follow-up after treatment.
Factors Associated With Overall Survival Among HCC patients with currently replicating HCV RNA, those showed at least PR to the initial HCC treatment, factors associated with overall survival were evaluated. After univariable and multivariable analysis, higher CTP score at HCC diagnosis (HR, 2.017; 95% CI, 1.1963.403; P = 0.009), partially responding to the initial treatment, rather than complete treatment response (HR, 01.795; 95% CI, 1.071-3.008; P = 0.026), increased the risk, and receiving HCV treatment (HR, 0.244; 95% CI, 0.075-0.788; P = 0.018) decreased the risk resulting in increased survival rate (Table 2).
HCV Treatment After HCC Diagnosis, Overall Survival, and Time to HCC Progression After HCV Treatment From 97 HCC patients with PR or CR to the initial HCC treatment, 16 patients eventually underwent antiviral therapy against HCV. Clinical background and HCV treatment regimens are described in Table 3. These patients had HCV treatment initiated at least 3 months after HCC treatment. The median time from HCC diagnosis to initiation of HCV treatment was 14.5 months (range, 3 to 97 mo). The mean time from the last HCC therapy to initiation of HCV treatment was 16.9 ± 13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). All but 1 patient achieved SVR (93.8%).
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TABLE 1. Characteristics of the Study Patients
Factors
HCV Untreated (N = 81)
Follow-up [median (range)] 100 (4-440) (wk) Age (y) [n (%)] < 60 18 (22.2) ≥ 60 63 (77.8) Gender (M:F) 57:24 Log10HCVRNA [n (%)] (IU/mL)‡ 3.25 73 (90.1) MELD Score, initial 10.14 ± 3.32 (mean ± SD)¶ CTP Score, initial [n (%)] A 44 (54.3) B 37 (45.7) Mode of HCC treatment [n (%)] TACE 79 (97.5) Others 2 (2.5) Response to the initial HCC treatment [n (%)]# PR — CR —
TABLE 2. Factors Associated With Overall Survival in HCV-related HCC Patients that Received Palliative Therapy Without Previous HCV Treatment
HCV Treated (N = 16)†
P
117 (4-520)
0.796 0.214
6 (37.5) 10 (62.5) 10:6
0.562 0.744
12 (75.0) 4 (25.0) 0.164 10 (62.5) 5 (31.2) 1 (6.3) 0 (0.0) 1.000 14 (87.5) 2 (12.5) 0.062 13 (81.3) 1 (12.5) 1.000 10 (62.5) 6 (37.5) 0 (0.0)
1.000 0.179
10 (62.5) 4 (25.0) 2 (12.5) 0 (0.0) 0.684 1 (6.2) 15 (93.8)
0.003*
7 (43.8) 9 (56.3) 8.38 ± 1.99 0.008* 0.046* 13 (81.3) 3 (18.8) 0.421 15 (93.8) 1 (6.3) 0.158 32 (34.8) 60 (65.2)
†HCV treatment performed after diagnosis of HCC. ‡HCV RNA in IU/mL, evaluated at HCC diagnosis, is expressed in 10Log. §T stage, evaluated at initial HCC diagnosis was estimated according to modified Union for International Cancer Control staging classification. ∥FIB-4 index at follow-up was calculated based on the parameters at the last follow-up. ¶MELD score at HCC diagnosis. #Response to the initial treatment was evaluated according to modified RECIST. *P < 0.05 are considered to be significant and presented in bold, italic forms. AFP indicates α-fetoprotein; CR, complete response; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; MELD, model for end-stage liver disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumor; TACE, transarterial chemoembolization.
Univariate
Multivariate
Factors
P*
Hazard Ratio (95% CI )
P*
Gender (Male Sex) Age (< 60 vs. ≥ 60) (y) Log10HCVRNA ≤6 >6 HCV genotype HCV treatment AFP ( ≥ 200) (ng/mL) Tumor size ( ≤ 5 vs. > 5) (cm) Tumor number (single vs. multiple) Vascular invasion T stage* Mode of HCC treatment† TACE Others Response to the initial HCC treatment‡ CR PR Existence of liver cirrhosis CTP score, initial§ A B FIB-4 index, at diagnosis ≤ 3.25 > 3.25 FIB-4 Index, at followup∥ ≤ 3.25 > 3.25
0.218 0.954 0.705
— — —
— — —
0.767 0.003* 0.218 0.773
— — 0.244 (0.075-0.788) 0.018* — — — —
0.527
—
—
0.383 0.069* 0.586
— — —
— — —
0.005*
—
0.026*
0.053* 0.000* 0.657 0.244
1 1.795 (1.071-3.008) — — — 0.009* 1 2.017 (1.196-3.403) — — —
—
*HCC stage was evaluated according to modified Union for International Cancer Control stage. †Mode of HCC palliative treatment included TACE and other mode of treatment such as radiotherapy or current chemoradiotherapy. ‡Response to the initial treatment was evaluated according to mRECIST. §CTP score calculated at HCC diagnosis before HCC treatment. ∥FIB-4 index at follow-up was calculated based on the parameters at the last follow-up. *P < 0.05 are considered to be significant and presented in bold, italic forms. AFP indicates α-fetoprotein; CI, confidence interval; CR, complete response; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; mRECIST, modified Response Evaluation Criteria in Solid Tumor; PR, partial response; TACE, transarterial chemoembolization. *P < 0.05 are considered to be significant.
All the patients had FIB-4 index > 3.25, which indicates advanced liver fibrosis with 98.2% specificity.24 Three patients had FIB-4 index decreased below 3.25 after HCV treatment, although 13/16 (81.3%) patients had the absolute FIB-4 index value decreased after the treatment. Among the HCC patients that failed to receive HCV treatment, 59 patients died. Of 59 patients, 30 patients had HCC-related mortality, 20 patients had liver cirrhosisrelated mortality although HCC showed stable disease, and 7 patients had unidentified cause of death. In contrast, from 16 patients that received HCV treatment, 3 patients died due to progression of HCC. No liver cirrhosis-related mortality
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4 Initial Modified Union Platelet Initial Duration From Last Age BCLC for International count CTP Initial HCC HCC Treatment to Patient (y) Staging Cancer Control (X103/m3) Score Treatment HCV Treatment (mo) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
50 65 63 60 71 51 58 53 61 66 68 69 76 55 46 68
B A A A A B B A A B B A B B B A
1 1 2 1 2 2 1 3 2 3 1 1 1 1 1 1
70 110 103 84 119 112 103 86 104 100 68 81 42 130 61 147
1 1 1 1 1 1 1 1 1 1 1 2 1 1 2 2
TACE TACE TACE TACE TACE Radiotherapy TACE TACE TACE TACE TACE TACE TACE TACE TACE TACE
39 14 16 45 40 3 5 12 3 6 2 10 27 20 15 14
HCV Treatment Regimen PEG/RBV* DAK/ASU† PEG/RBV DAK/ASU DAK/ASU PEG/RBV PEG/RBV PEG/RBV DAK/ASU DAK/ASU DAK/ASU PEG/RBV DAK/ASU PEG/RBV HARVONI‡ SOF/RBV§
HCC Recur HCV After HCV Genotype SVR Treatment 3 1b 2 1b 1b 2 1b 2 1b 1b 1b 2 1b 2 1b 2
Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
No No Yes No No No Yes No No No No No No No No Yes
Follow-up After HCV Treatment (mo) 47 8 13 10 9 34 31 3 14 13 5 35 10 9 4 3
FIB-4 FIB-4 Index, at Index, at HCC FollowDiagnosis up 10.86 9.24 5.89 5.35 7.11 4.79 12.47 6.98 3.37 3.89 9.89 11.68 10.46 2.85 11.68 6.33
6.52 6.67 15.09 4.87 5.80 1.36 3.53 8.08 4.17 2.90 13.18 4.30 10.44 2.78 3.82 3.08
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*HCV treatment regimen consists of PEG interferon with RBV combination therapy for 24 weeks in genotype 2 and 48 weeks in genotype 1. †HCV treatment regimen consists of daily daclatasvir 60 mg and asunaprevir 200 mg for 24 weeks in genotype 1b. ‡HCV treatment regimen consists of daily sofosbuvir (400 mg)/ledipasvir (90 mg) for 12 weeks in genotype 1. §HCV treatment regimen consists of daily sofosbuvir 400 mg in combination with RBV for 12 weeks in genotype 2. ASU indicates asunaprevir; BCLC, indicates Barcelona clinic liver cancer; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; DAK, daclatasvir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PEG, pegylated; RBV, ribavirin; SVR, sustained virologic response; TACE, transarterial chemoembolization.
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TABLE 3. Characteristics of the 16 Patients With HCV Treatment After HCC Diagnosis
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was noticed in this group of patients. The overall survival was significantly higher in patients treated for HCV compared with that in patients without HCV treatment (P = 0.003) (Fig. 1). The medians for survival time were 95.5 (95% CI, 63.3-127.6) months for HCV-treated patients and 44.8 ± 4.0 (95% CI, 36.9-52.6) months for HCV-untreated patients, respectively. Among the patients that received HCV treatment, 3 patients had HCC recurred after HCV treatment. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P = 0.032) (Fig. 2).
DISCUSSION This study evaluated factors for survival in HCVrelated HCC patients that responded to the initial HCC treatment which could be classified as noncurative. The results suggest that treating HCV infection might be beneficial for the survival even in patients that received noncurative treatment and possess high probability of HCC recurrence, as long as the tumor responded to the therapy. Although previous studies reported that achieving SVR after HCV treatment might be beneficial for the survival by decreasing liver-related mortality including that from HCC,1–6 effectiveness of HCV treatment in HCC patients whose disease tends to recur very frequently, is still under debate. Majority of the HCV-related HCC patients may not be suitable for the curative HCC treatment such as liver resection or local ablation therapy. However, these patients may still respond to noncurative treatment such as TACE, and role of HCV treatment in these patients needs to be evaluated. The benefits of treating underlying liver disease in HCC patients after the curative treatment has been extensively investigated in HBV-related HCC patients.8,9,28 In addition several studies on HBV-related HCC patients that receive TACE, the treatment modality classified as a palliative treatment, reported improved overall survival and disease-free survival in these
FIGURE 1. Overall survival after palliative treatment of HCC according to HCV treatment. All the patients had responded to HCC treatment either completely or partially. Patients treated for HCV had at least 3 months of HCC remission period after HCC treatment. Patients treated for HCV (n = 16, dashed line) had significantly higher overall survival rates compared with those that were not treated for HCV (n = 91, solid line) (P = 0.003). HCC indicates hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.
FIGURE 2. Probability of HCC progression after HCV treatment. Patients treated for HCV (n = 16, dashed line) had significantly reduced probability of HCC progression after HCV treatment compared with those that were not treated for HCV (n = 81, solid line) (P = 0.0032). HCC indicates hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.
patients.16,17 In contrast, evidences pertaining HCV treatment in HCV-related HCC patients are far less numerous as eradicating HCV before DAA era was less successful with many side-effects. Small number of studies are on HCV-related HCC patients that received curative treatment. The study results suggested that HCV treatment might reduce HCC recurrence and increase overall survival in patients that receive curative treatment.18–20 However, only a small number of patients are candidates for curative treatment and majority of the patients receive treatment other than surgical resection or local ablation therapy.29 Treating HCV in patients that are not suitable for curative treatment but still have controllable HCC with other noncurative means of therapy need to be studied to assess the benefits and rationale for HCV treatment. Furthermore, with introduction of DAAs, treating HCV patients with comorbidity including HCC becomes feasible without much treatment-related side-effects. However, a recent study raised a suspicion that DAA might have increased the recurrence of HCC after the treatment.30 Another study opposing this suggestion has also been published.31 In our study, 3 from 16 patients had HCC recurred after HCV treatment. All 3 patients received Peg-IFN–based treatment. Although none of patients that received DAA (n = 9) had HCC recurred, follow-up period was relatively shorter in these patient compared with those that received Peg-IFN–based treatment. The median time of follow-up in DAA administered patients was 9 months (range, 3 to 14 mo) when that in PegIFN–treated patients was 31 months (range, 3 to 47 mo). Future studies are expected to settle this important dispute. In addition, cost-effectiveness of DAA-based treatment in patients that may not undergo curative treatment should be investigated as well. The current study has several limitations. First, the number of the patients that received antiviral therapy after HCC treatment is very small. Second, among 16 patients treated with noncurative treatment, 8 patients had Barcelona clinic liver cancer stage A HCC that would have been treated by a curative treatment such as liver resection or radiofrequency ablation. The main reason that these patients could not receive curative therapy was accompanying portal hypertension that results in CTP score beyond A or thrombocytopenia. These are
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prognostic factors frequently hindering surgical treatment of HCC. Although the HCC treatment guidelines recommend these patients to receive liver transplantation, they failed to undergo transplantation due to organ shortage in this country. Instead, patients included in this study received noncurative treatment, and responded partially or completely to the treatment so as to have at least 3 months of HCC remission period before HCV treatment. The reasonable HCC remission period before the initiation of HCV treatment may need to be studied in the future. Third, patients that received HCV treatment after HCC management had lower MELD and CTP score suggesting more spared liver function which might have affected improved survival. However, multivariate analysis still indicated HCV treatment as an important factor for survival, and further studies with larger study sample sizes would be able to validate the result of this study. Regardless of these limitations including the small number of patients with retrospective nature of the study, this study offers the possible benefits from HCV treatment in HCC patients whose tumor is controllable with noncurative means. This suggestion need to be verified by larger number of patients, and detailed qualifications for HCV treatment including the duration of HCC remission period in patients that receive noncurative treatment should further be investigated.
12. 13.
14.
15.
16. 17.
18. 19.
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Antiviral Therapy in Patients With Chronic Hepatitis C-related Hepatocellular Carcinoma Responding to Palliative Treatment Jung-Hwan Yu, MD, PhD, Ja Kyung Kim, MD, PhD, Kwan Sik Lee, MD, PhD, and Jung Il Lee, MD, PhD
Background/Aim: Advances in hepatitis C virus (HCV) treatment offer high sustained virologic response rates with minimal side-effects. However, benefits of eradicating HCV in hepatocellular carcinoma (HCC) patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that responded to the palliative HCC treatment to speculate whether treating HCV would be beneficial in these patients. Materials and Methods: In this retrospective cohort study, the medical records of 97 patients that showed complete or partial response to the initial HCC treatment were included. Results: Receiving HCV treatment [hazard ratio (HR), 0.244; 95% confidence interval (CI), 0.075-0.788; P = 0.018] increased the survival, whereas partial response to the initial HCC treatment (HR, 1.795; 95% CI, 1.071-3.008; P = 0.026) and increased Child-Turcotte-Pugh score (HR, 2.017; 95% CI, 1.196-3.403; P = 0.009) reduced the survival. From 97 patients, 16 patients were eventually treated for HCV. The mean time from the last HCC therapy to HCV treatment was 16.9 ± 13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). Among the HCV-treated patients 3 patients had HCC recurred. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P = 0.032). Conclusions: Although treating HCV in HCC patient that undergo noncurative HCC treatment is still debatable, this study results carefully suggest that HCV-related HCC patients that responded to the initial HCC palliative treatment might benefit from HCV treatment. Key Words: antiviral therapy, hepatitis C virus, hepatocellular carcinoma, radiotherapy, transhepatic arterial chemoembolization
(J Clin Gastroenterol 2017;00:000–000)
S
uccessful hepatitis C virus (HCV) eradication may offer valuable benefits including decrease or elimination of liver inflammation, reduction in the rate of liver fibrosis progression as well as amelioration of extrahepatic symptoms. In addition, studies demonstrated that HCV treatment and the achievement
Received for publication January 11, 2017; accepted July 25, 2017. From the Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4015192). The authors declare that they have nothing to disclose. Address correspondence to: Jung Il Lee, MD, PhD, Department of Internal Medicine, Yonsei University College of Medicine, 211 Eonjuro, Gangnam-gu, Seoul 135-720, Republic of Korea (e-mail: mdflorence @yuhs.ac). Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MCG.0000000000000923
of sustained virologic response (SVR) in patients with advanced liver disease decreased hepatocellular carcinoma (HCC) and other liver-related mortality.1–6 Therefore, HCV treatment is recommended for virtually all patients with chronic HCV infection. However, patients with short-life expectancies that cannot be remediated by HCV treatment may not be recommended for HCV treatment and treating patients with uncertain life expectancies due to complicated liver disease,7 such as HCC, is under controversy. Several studies reported the benefit of antiviral therapy after curative treatment in both hepatitis B virus (HBV) and HCV-related HCC. In patients with HBV-related HCC that received curative treatment including liver resection and an ablation therapy, studies suggested that treating patients with nucleoside analog (NA) would decrease HCC recurrence and increased overall survival.8–14 In cases with HBV-related HCC patients receiving palliative treatment such as transhepatic arterial chemoembolization (TACE), studies support NA treatment based on the results that showed increased overall survival in NA-treated group.15–17 In contrast, relatively few studies with limited numbers of patients exist investigating the benefits of antiviral therapy in HCV-related HCC patients. Several studies suggested that interferon (IFN)-based treatment would reduce HCC recurrence and increase overall survival after curative treatment.18–20 Evidences on the impact of HCV treatment in patients with HCV-related HCC that were put under palliative treatment such as TACE are very few. From a study of 11 patients with SVR after IFN treatment, that experienced either TACE or nonsurgical ablation therapy, survival rate was higher compared with that of HCV-untreated patients.21 The reason for the rarity of evidences on HCVrelated HCC patients might be due to higher incidence of adverse effects and relatively low SVR rates after IFN-based treatment. Recently, with introduction of IFN-free direct acting antivirals (DAAs), higher SVR rates and minimal side-effects are expected. However, benefits of eradicating HCV in HCC patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that showed complete (CR) or partial response (PR) to the initial noncurative therapy to speculate whether treating HCV would be beneficial even in patients that were not candidates for curative treatment such as surgical liver resection or nonsurgical ablation therapy.
MATERIALS AND METHODS Patient Selection In this retrospective cohort study, the medical records of patients diagnosed and treated for HCV-related HCC,
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and seen at Yonsei University College of Medicine, Gangnam Severance Hospital, Seoul, Republic of Korea from January 2004 to 2016 were reviewed. This study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Institutional Review Board (3-2016-0238). Among 181 patients with HCV-related HCC, 16 patients had HCV treated before the diagnosis of HCC. From 165 HCV-related HCC patients whose HCV infection had never been treated, 23 patients that received curative treatment such as liver resection, local ablation therapy or liver transplantation were excluded. Among 142 patients that received noncurative treatment, 97 patients that showed CR or PR to the initial HCC treatment. These patients were confirmed to be positive for HCV RNA at the diagnosis of HCC, had neither evidences of HBV infection nor other potential causes of chronic liver disease such as excessive alcohol abuse or autoimmune liver diseases. HCC was diagnosed either histologically or clinically. The clinical diagnosis consisted of having typical radiologic findings of hyperattenuation in the arterial phase and washout in the late phase using either dynamic contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) in patients with chronic liver disease .22 Those that could not be diagnosed as HCC clinically might undergo liver biopsy for histologic diagnosis.
HCC Treatment and Follow-up Treatment of HCC patients was performed after an extensive discussion among experts in different specialists including hepatologists, surgeons, radiologists, oncologists, and radiation oncologists. Treatment responses were evaluated based on imaging studies that were obtained at 1 to 3 months after the initiation of the treatment, according to modified Response Evaluation Criteria in Solid Tumors (mRECIST).23 The patients were regularly followed-up. Liver function tests, α-fetoprotein (AFP) measurements were done every 1 to 3 months. Liver fibrosis stage was evaluated by calculating fibrosis-4 (FIB-4) index as previously described24 at the time of HCC diagnosis and at the last follow-up. For those patients censored due to liver-related mortality, FIB-4 index was calculated based on liver function test results estimated at least 1 month before the event of death. Dynamic CT was regularly performed with the interval no > 6 months. All patients were followed until the time of death or for at least 6 months. When a new lesion was detected by abdominal CT, evaluation for HCC recurrence was performed. When the liver CT showed compatible findings with HCC with accompanied AFP elevation, recurrence was diagnosed. However, if vascular pattern was not typical on liver CT, liver MRI and/or hepatic angiogram was performed. When the nodule showed atypical pattern on all the imaging studies, the nodule was followed-up with the interval no longer than 3 months. In case of elevated AFP without evidence of newly appeared lesion on CT, MRI, and/or hepatic angiography was performed.
Antiviral Therapy Among 97 patients with either PR or CR to HCC treatment, 16 patients eventually received antiviral therapy for HCC. All 16 patients had at least 3 months of remission period after HCC treatment. Patients were treated with either pegylated interferon (Peg-IFN) and weight-based ribavirin or combination of DAAs. SVR was defined as last HCV-RNA test being negative at 12 weeks after the completion of HCV treatment for
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those treated with DAAs and negative at 24 weeks after the treatment for patients underwent Peg-IFN–based treatment as previously described.25
Statistical Analyses Statistical analyses were performed using IBM SPSS version 23. Overall survival was evaluated using the KaplanMeier method. Survival was compared with the log-rank test. Factors predicting survival were analyzed using Cox proportional hazard model. Variables with P < 0.1 in univariable analysis were included in the multivariable model. These models were considered using conditional selection procedures. Hazard ratios (HRs) were presented with 95% confidence interval (CI). P < 0.05 was considered significant for multivariate analysis.
RESULTS Patient Characteristics The clinical characteristics of patients included in the analysis are summarized in Table 1. These patients had positive serum HCV RNA, and had no experience of HCV treatment before HCC diagnosis. They showed either PR or CR to the initial HCC treatment, according to mRECIST. The initial treatment modality included noncurative therapy such as TACE, intra-arterial chemoinfusion therapy, or external radiation therapy alone or in combination of different modalities. When demographic findings of HCC patients treated for HCV after HCC diagnosis were compared with those that did not receive HCV treatment, the Model for EndStage Liver Disease (MELD) score,26 the Child-TurcottePugh (CTP) score27 and FIB-4 index24 during follow-up showed statistically significant differences. Those who received HCV antiviral therapy after HCC treatment had better liver function before HCV treatment and during the follow-up after treatment.
Factors Associated With Overall Survival Among HCC patients with currently replicating HCV RNA, those showed at least PR to the initial HCC treatment, factors associated with overall survival were evaluated. After univariable and multivariable analysis, higher CTP score at HCC diagnosis (HR, 2.017; 95% CI, 1.1963.403; P = 0.009), partially responding to the initial treatment, rather than complete treatment response (HR, 01.795; 95% CI, 1.071-3.008; P = 0.026), increased the risk, and receiving HCV treatment (HR, 0.244; 95% CI, 0.075-0.788; P = 0.018) decreased the risk resulting in increased survival rate (Table 2).
HCV Treatment After HCC Diagnosis, Overall Survival, and Time to HCC Progression After HCV Treatment From 97 HCC patients with PR or CR to the initial HCC treatment, 16 patients eventually underwent antiviral therapy against HCV. Clinical background and HCV treatment regimens are described in Table 3. These patients had HCV treatment initiated at least 3 months after HCC treatment. The median time from HCC diagnosis to initiation of HCV treatment was 14.5 months (range, 3 to 97 mo). The mean time from the last HCC therapy to initiation of HCV treatment was 16.9 ± 13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). All but 1 patient achieved SVR (93.8%).
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TABLE 1. Characteristics of the Study Patients
Factors
HCV Untreated (N = 81)
Follow-up [median (range)] 100 (4-440) (wk) Age (y) [n (%)] < 60 18 (22.2) ≥ 60 63 (77.8) Gender (M:F) 57:24 Log10HCVRNA [n (%)] (IU/mL)‡ 3.25 73 (90.1) MELD Score, initial 10.14 ± 3.32 (mean ± SD)¶ CTP Score, initial [n (%)] A 44 (54.3) B 37 (45.7) Mode of HCC treatment [n (%)] TACE 79 (97.5) Others 2 (2.5) Response to the initial HCC treatment [n (%)]# PR — CR —
TABLE 2. Factors Associated With Overall Survival in HCV-related HCC Patients that Received Palliative Therapy Without Previous HCV Treatment
HCV Treated (N = 16)†
P
117 (4-520)
0.796 0.214
6 (37.5) 10 (62.5) 10:6
0.562 0.744
12 (75.0) 4 (25.0) 0.164 10 (62.5) 5 (31.2) 1 (6.3) 0 (0.0) 1.000 14 (87.5) 2 (12.5) 0.062 13 (81.3) 1 (12.5) 1.000 10 (62.5) 6 (37.5) 0 (0.0)
1.000 0.179
10 (62.5) 4 (25.0) 2 (12.5) 0 (0.0) 0.684 1 (6.2) 15 (93.8)
0.003*
7 (43.8) 9 (56.3) 8.38 ± 1.99 0.008* 0.046* 13 (81.3) 3 (18.8) 0.421 15 (93.8) 1 (6.3) 0.158 32 (34.8) 60 (65.2)
†HCV treatment performed after diagnosis of HCC. ‡HCV RNA in IU/mL, evaluated at HCC diagnosis, is expressed in 10Log. §T stage, evaluated at initial HCC diagnosis was estimated according to modified Union for International Cancer Control staging classification. ∥FIB-4 index at follow-up was calculated based on the parameters at the last follow-up. ¶MELD score at HCC diagnosis. #Response to the initial treatment was evaluated according to modified RECIST. *P < 0.05 are considered to be significant and presented in bold, italic forms. AFP indicates α-fetoprotein; CR, complete response; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; F, female; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; M, male; MELD, model for end-stage liver disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumor; TACE, transarterial chemoembolization.
Univariate
Multivariate
Factors
P*
Hazard Ratio (95% CI )
P*
Gender (Male Sex) Age (< 60 vs. ≥ 60) (y) Log10HCVRNA ≤6 >6 HCV genotype HCV treatment AFP ( ≥ 200) (ng/mL) Tumor size ( ≤ 5 vs. > 5) (cm) Tumor number (single vs. multiple) Vascular invasion T stage* Mode of HCC treatment† TACE Others Response to the initial HCC treatment‡ CR PR Existence of liver cirrhosis CTP score, initial§ A B FIB-4 index, at diagnosis ≤ 3.25 > 3.25 FIB-4 Index, at followup∥ ≤ 3.25 > 3.25
0.218 0.954 0.705
— — —
— — —
0.767 0.003* 0.218 0.773
— — 0.244 (0.075-0.788) 0.018* — — — —
0.527
—
—
0.383 0.069* 0.586
— — —
— — —
0.005*
—
0.026*
0.053* 0.000* 0.657 0.244
1 1.795 (1.071-3.008) — — — 0.009* 1 2.017 (1.196-3.403) — — —
—
*HCC stage was evaluated according to modified Union for International Cancer Control stage. †Mode of HCC palliative treatment included TACE and other mode of treatment such as radiotherapy or current chemoradiotherapy. ‡Response to the initial treatment was evaluated according to mRECIST. §CTP score calculated at HCC diagnosis before HCC treatment. ∥FIB-4 index at follow-up was calculated based on the parameters at the last follow-up. *P < 0.05 are considered to be significant and presented in bold, italic forms. AFP indicates α-fetoprotein; CI, confidence interval; CR, complete response; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; mRECIST, modified Response Evaluation Criteria in Solid Tumor; PR, partial response; TACE, transarterial chemoembolization. *P < 0.05 are considered to be significant.
All the patients had FIB-4 index > 3.25, which indicates advanced liver fibrosis with 98.2% specificity.24 Three patients had FIB-4 index decreased below 3.25 after HCV treatment, although 13/16 (81.3%) patients had the absolute FIB-4 index value decreased after the treatment. Among the HCC patients that failed to receive HCV treatment, 59 patients died. Of 59 patients, 30 patients had HCC-related mortality, 20 patients had liver cirrhosisrelated mortality although HCC showed stable disease, and 7 patients had unidentified cause of death. In contrast, from 16 patients that received HCV treatment, 3 patients died due to progression of HCC. No liver cirrhosis-related mortality
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4 Initial Modified Union Platelet Initial Duration From Last Age BCLC for International count CTP Initial HCC HCC Treatment to Patient (y) Staging Cancer Control (X103/m3) Score Treatment HCV Treatment (mo) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
50 65 63 60 71 51 58 53 61 66 68 69 76 55 46 68
B A A A A B B A A B B A B B B A
1 1 2 1 2 2 1 3 2 3 1 1 1 1 1 1
70 110 103 84 119 112 103 86 104 100 68 81 42 130 61 147
1 1 1 1 1 1 1 1 1 1 1 2 1 1 2 2
TACE TACE TACE TACE TACE Radiotherapy TACE TACE TACE TACE TACE TACE TACE TACE TACE TACE
39 14 16 45 40 3 5 12 3 6 2 10 27 20 15 14
HCV Treatment Regimen PEG/RBV* DAK/ASU† PEG/RBV DAK/ASU DAK/ASU PEG/RBV PEG/RBV PEG/RBV DAK/ASU DAK/ASU DAK/ASU PEG/RBV DAK/ASU PEG/RBV HARVONI‡ SOF/RBV§
HCC Recur HCV After HCV Genotype SVR Treatment 3 1b 2 1b 1b 2 1b 2 1b 1b 1b 2 1b 2 1b 2
Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
No No Yes No No No Yes No No No No No No No No Yes
Follow-up After HCV Treatment (mo) 47 8 13 10 9 34 31 3 14 13 5 35 10 9 4 3
FIB-4 FIB-4 Index, at Index, at HCC FollowDiagnosis up 10.86 9.24 5.89 5.35 7.11 4.79 12.47 6.98 3.37 3.89 9.89 11.68 10.46 2.85 11.68 6.33
6.52 6.67 15.09 4.87 5.80 1.36 3.53 8.08 4.17 2.90 13.18 4.30 10.44 2.78 3.82 3.08
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*HCV treatment regimen consists of PEG interferon with RBV combination therapy for 24 weeks in genotype 2 and 48 weeks in genotype 1. †HCV treatment regimen consists of daily daclatasvir 60 mg and asunaprevir 200 mg for 24 weeks in genotype 1b. ‡HCV treatment regimen consists of daily sofosbuvir (400 mg)/ledipasvir (90 mg) for 12 weeks in genotype 1. §HCV treatment regimen consists of daily sofosbuvir 400 mg in combination with RBV for 12 weeks in genotype 2. ASU indicates asunaprevir; BCLC, indicates Barcelona clinic liver cancer; CTP, Child-Turcotte-Pugh classification of the severity of cirrhosis; DAK, daclatasvir; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; PEG, pegylated; RBV, ribavirin; SVR, sustained virologic response; TACE, transarterial chemoembolization.
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TABLE 3. Characteristics of the 16 Patients With HCV Treatment After HCC Diagnosis
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was noticed in this group of patients. The overall survival was significantly higher in patients treated for HCV compared with that in patients without HCV treatment (P = 0.003) (Fig. 1). The medians for survival time were 95.5 (95% CI, 63.3-127.6) months for HCV-treated patients and 44.8 ± 4.0 (95% CI, 36.9-52.6) months for HCV-untreated patients, respectively. Among the patients that received HCV treatment, 3 patients had HCC recurred after HCV treatment. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P = 0.032) (Fig. 2).
DISCUSSION This study evaluated factors for survival in HCVrelated HCC patients that responded to the initial HCC treatment which could be classified as noncurative. The results suggest that treating HCV infection might be beneficial for the survival even in patients that received noncurative treatment and possess high probability of HCC recurrence, as long as the tumor responded to the therapy. Although previous studies reported that achieving SVR after HCV treatment might be beneficial for the survival by decreasing liver-related mortality including that from HCC,1–6 effectiveness of HCV treatment in HCC patients whose disease tends to recur very frequently, is still under debate. Majority of the HCV-related HCC patients may not be suitable for the curative HCC treatment such as liver resection or local ablation therapy. However, these patients may still respond to noncurative treatment such as TACE, and role of HCV treatment in these patients needs to be evaluated. The benefits of treating underlying liver disease in HCC patients after the curative treatment has been extensively investigated in HBV-related HCC patients.8,9,28 In addition several studies on HBV-related HCC patients that receive TACE, the treatment modality classified as a palliative treatment, reported improved overall survival and disease-free survival in these
FIGURE 1. Overall survival after palliative treatment of HCC according to HCV treatment. All the patients had responded to HCC treatment either completely or partially. Patients treated for HCV had at least 3 months of HCC remission period after HCC treatment. Patients treated for HCV (n = 16, dashed line) had significantly higher overall survival rates compared with those that were not treated for HCV (n = 91, solid line) (P = 0.003). HCC indicates hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.
FIGURE 2. Probability of HCC progression after HCV treatment. Patients treated for HCV (n = 16, dashed line) had significantly reduced probability of HCC progression after HCV treatment compared with those that were not treated for HCV (n = 81, solid line) (P = 0.0032). HCC indicates hepatocellular carcinoma; HCV, hepatitis C virus; Tx, treatment.
patients.16,17 In contrast, evidences pertaining HCV treatment in HCV-related HCC patients are far less numerous as eradicating HCV before DAA era was less successful with many side-effects. Small number of studies are on HCV-related HCC patients that received curative treatment. The study results suggested that HCV treatment might reduce HCC recurrence and increase overall survival in patients that receive curative treatment.18–20 However, only a small number of patients are candidates for curative treatment and majority of the patients receive treatment other than surgical resection or local ablation therapy.29 Treating HCV in patients that are not suitable for curative treatment but still have controllable HCC with other noncurative means of therapy need to be studied to assess the benefits and rationale for HCV treatment. Furthermore, with introduction of DAAs, treating HCV patients with comorbidity including HCC becomes feasible without much treatment-related side-effects. However, a recent study raised a suspicion that DAA might have increased the recurrence of HCC after the treatment.30 Another study opposing this suggestion has also been published.31 In our study, 3 from 16 patients had HCC recurred after HCV treatment. All 3 patients received Peg-IFN–based treatment. Although none of patients that received DAA (n = 9) had HCC recurred, follow-up period was relatively shorter in these patient compared with those that received Peg-IFN–based treatment. The median time of follow-up in DAA administered patients was 9 months (range, 3 to 14 mo) when that in PegIFN–treated patients was 31 months (range, 3 to 47 mo). Future studies are expected to settle this important dispute. In addition, cost-effectiveness of DAA-based treatment in patients that may not undergo curative treatment should be investigated as well. The current study has several limitations. First, the number of the patients that received antiviral therapy after HCC treatment is very small. Second, among 16 patients treated with noncurative treatment, 8 patients had Barcelona clinic liver cancer stage A HCC that would have been treated by a curative treatment such as liver resection or radiofrequency ablation. The main reason that these patients could not receive curative therapy was accompanying portal hypertension that results in CTP score beyond A or thrombocytopenia. These are
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prognostic factors frequently hindering surgical treatment of HCC. Although the HCC treatment guidelines recommend these patients to receive liver transplantation, they failed to undergo transplantation due to organ shortage in this country. Instead, patients included in this study received noncurative treatment, and responded partially or completely to the treatment so as to have at least 3 months of HCC remission period before HCV treatment. The reasonable HCC remission period before the initiation of HCV treatment may need to be studied in the future. Third, patients that received HCV treatment after HCC management had lower MELD and CTP score suggesting more spared liver function which might have affected improved survival. However, multivariate analysis still indicated HCV treatment as an important factor for survival, and further studies with larger study sample sizes would be able to validate the result of this study. Regardless of these limitations including the small number of patients with retrospective nature of the study, this study offers the possible benefits from HCV treatment in HCC patients whose tumor is controllable with noncurative means. This suggestion need to be verified by larger number of patients, and detailed qualifications for HCV treatment including the duration of HCC remission period in patients that receive noncurative treatment should further be investigated.
12. 13.
14.
15.
16. 17.
18. 19.
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