427
Recent Advances in the Prevention of Hepatocellular Carcinoma Recurrence Ann-Lii Cheng, MD, PhD1,2,3
Ronnie T. P. Poon, FRCS, PhD4
1 Departments of Oncology, National Taiwan University Hospital,
Taipei, Taiwan 2 Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
Address for correspondence Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan (e-mail: [email protected]).
Semin Liver Dis 2014;34:427–434.
Abstract Keywords
► hepatocellular carcinoma ► prevention ► recurrence ► hepatitis B virus ► hepatitis C virus ► antiviral
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Earlystage HCC can be curatively treated, but the recurrence rate remains high. To date, adjuvant treatments have not proven effective in preventing HCC recurrence after curative treatment. Although early studies explored the potential of vitamin K2, retinoid, chemotherapy, and recently, sorafenib, none of the studies reported successful outcomes. Several new lines of evidence have emerged to support the use of novel antiviral agents for preventing the recurrence of virus-related HCC after curative treatment. In this review, the authors provide a thorough overview of the various adjuvant treatments that have been attempted or are being considered for trial.
Hepatocellular carcinoma (HCC) is one of the most common cancers and leading causes of malignancy-related deaths worldwide.1 Early-stage HCC can be treated with curative therapies, such as surgery and ablation. However, despite the advances in surgical techniques and ablation technologies, the 5-year survival rate remains unsatisfactory and the 5-year recurrence rate is around 70%.2–4 Strategies to prevent HCC recurrence are, therefore, crucial. In this article we review the recent advances in the use of contemporary antiviral agents and molecular-targeted therapies to prevent HCC recurrence after curative treatment.
Historic Studies Involving Adjuvant Therapy Previous preclinical studies suggested that vitamin K2 or its analogs may induce cell cycle arrest and inhibit HCC cell growth.5,6 Thereafter, several small clinical trials were conducted to evaluate the postoperative use of vitamin K2 in patients with HCC, but the results were inconsistent.7–11 A large-scale, randomized, placebo-controlled trial that en-
Issue Theme Hepatocellular Carcinoma: Current Evidence and Future Research; Guest Editor, Jordi Bruix, MD
rolled 548 patients was recently published by Yoshida et al. The results showed that vitamin K2 did not prevent recurrence or improve survival in HCC patients who underwent curative resection or ablation.12 Although the results of a meta-analysis suggested that vitamin K2 may reduce the 1-year recurrence rate, the conclusion should be interpreted with caution.13 Retinoids are considered chemopreventive.14 A small randomized control trial reported that oral administration of peretinoin, an acyclic retinoid, for 12 months prevented the development of a second primary HCC and improved the overall survival of HCC patients who underwent curative surgery or percutaneous ethanol injections.15–17 A recent, randomized, double-blinded, large-scale trial testing peretinoin (600 mg/day and 300 mg/day) against placebo was conducted by the Japanese Peretinoin Study Group.18 Only HCV patients with newly diagnosed or first recurrence HCC were enrolled; however, the primary endpoint, demonstration of the superiority of peretinoin (300 and 600 mg/day) over the placebo in terms of recurrence-free survival, was not met.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1394141. ISSN 0272-8087.
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Li-Chun Lu, MD1,2
Seminars in Liver Disease
Vol. 34
Phase III RCT
Okita et al; Japan/201418
No. 4/2014
HBV predominant
Phase II RCT
Xia et al; China/201021
RCT
Chung et al; Singapore/ 201323
HBV predominant
Resection
Resection
Resection
Resection
Resection
Resection or ablation
Resection or ablation
Resection or ablation
Local treatment
51/52
22/21
30/30
79/80
51/57
127/126/124
45/44
181/182/185
Patients
Control/ I-131-Lipiodol
Control / I-131-Lipiodol
Placebo/Xeloda
Control/UFT
Control/epirubicinbased regimens
Placebo/peretinoin (300 mg/d)/peretinoin (600 mg/d)
Placebo/Polyprenoic acid (600 mg/d)
Placebo/VK2 (45 mg/d)/VK2 (90 mg/d)
Adjuvant treatment
RFS (HR ¼ 0.75; 95% CI 0.46–1.23; p ¼ 0.25)
Median DFS: 13.6 m/57.2 m (p ¼ 0.037)
Median TTR: 20.0 m/40.0 m (p ¼ 0.046)
3, 5 y RFS: 37%, 29%/41%, 29% (p ¼ 0.87)
3, 5 y DFS: 42.2%, 25.7%/36.8%, 27.6%
RFS: combined peretinoin group vs. placebo (p ¼ 0.434)
Incident of treatment failure: 49%/27% (p ¼ 0.04)
Median DFS: 540 d/ 541 days (combined VK2 groups)
Primary end point
OS (HR ¼ 0.88; 95% CI 0.51–1.51; p ¼ 0.64)
3 y OS: 46.3%/86.4% (p ¼ 0.039)
5 y OS: 39.8%/62.5% (p ¼ 0.216)
3, 5 y OS: 92%, 73%/90%, 58% (p ¼ 0.08)
OS: better in control group (p ¼ 0.022)
1, 3 y RFS: 66.0%, 29.3%/63.6%, 24.9%/71.9%, 43.7%
2nd primary tumor: 44%/16% (p ¼ 0.004)
1 y DFS: 69.8%/64.9% (combined VK2 groups)
Other end point
Terminated early due to perceived treatment benefit
Advanced recurrence: significantly more frequent in the UFT group than in the control group
Worse DFS and OS in cirrhotic patients receiving chemotherapy
600 mg-group vs. placebo: better RFS at 2 y (HR: 0.27)
Significant OS difference in the follow-up studies16,17
Terminated early
Note
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Abbreviations: CI, confidence interval; DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; TTR, time to recurrence; UFT, uracil-tegafur; VK2, vitamin K2.
RCT
Lau et al; Hong Kong/ 199922
HBV predominant
HCV predominant
Phase II RCT
Hasegawa et al; Japan/200620
Transarterial I-131-Lipiodol
HCV predominant
Combination of 3 phase II RCTs
Ono et al; Japan/200119
All HCV
HCV predominant
HCV predominant
Etiology
Prevention of HCC Recurrence
Chemotherapy
Phase II RCT
Phase II/III RCT
Study type
Muto et al; Japan/199615
Retinoids
Yoshida et al; Japan/201112
Vitamin K2
Study/y
Table 1 Prior studies of adjuvant therapy to prevent hepatocellular carcinoma recurrence
428 Lu et al.
Prevention of HCC Recurrence
Sorafenib and Other Molecular-Targeted Agents Sorafenib, a multikinase inhibitor that targets Raf kinase and vascular endothelial growth factor receptor-2, is the standard treatment for advanced HCC.24,25 A phase III, randomized, double-blind, placebo-controlled study of sorafenib as an adjuvant treatment for HCC after surgical resection or local ablation (STORM trial) enrolled 1,114 patients randomized to receive either sorafenib or placebo for 4 years or until tumor recurrence. The study group recently announced that neither its primary end point, recurrence-free survival, secondary end points, time to recurrence, nor overall survival were met.26 Heparanase is associated with tumor growth and angiogenesis via degrading heparan sulfate, an extracellular matrix proteoglycan.27 PI-88 is a heparan sulfate mimetic that inhibits heparanase and may have anticancer activity.28 A multicenter, phase II, randomized trial in Taiwan evaluated two different doses of PI-88 (250 mg/d and 160 mg/d) for 36 weeks.29 The preliminary results showed marginally better recurrence-free rates in the 160 mg/d arm than in the untreated control arm (p ¼ 0.07).30 Because of a high dropout rate in the 250 mg/d arm, the 160 mg/d dose was later selected for further exploration in a randomized, placebocontrolled, phase III trial (PATRON trial, NCT01402908). The study has completed accrual and the results will be available in the near future. Thalidomide has antitumor activity resulting from its antiangiogenic and immunomodulatory effects. Several single-arm, phase II studies have shown that thalidomide has
429
modest activity in patients with advanced HCC.30–32 In a pilot, randomized, phase II study of thalidomide as an adjuvant therapy, 42 HCC patients underwent curative hepatic resection and were randomized to receive either thalidomide (200 mg/d) or placebo for 1 year.33 The thalidomide arm showed a trend toward an improved 2-year disease-free survival rate (65% vs. 33.3% in the placebo arm; p ¼ 0.06). The study results were limited by the relatively small sample size and short follow-up period. ►Table 2 provides details of sorafenib and other molecular-targeted agents for prevention of hepatocellular carcinoma recurrence.
Conventional Interferon-Based Therapy in HBV and/or HCV-Related Hepatocellular Carcinoma Interferon (IFN) has antiviral, immunomodulatory, and antiproliferative activities. Before the emergence of modern antiviral and anticancer therapies, conventional IFN was extensively tested for the treatment and prevention of HCC. In the adjuvant setting, the results of conventional IFN therapy have been inconsistent, although some meta-analyses have suggested that adjuvant IFN therapy improved both recurrence-free survival and overall survival.34–36 In general, the evidence for adjuvant IFN therapy prevention of hepatitis B virus- (HBV-) related HCC was not promising.37–39 However, some subgroups may benefit from the treatment. For example, low expression of miR-26 and high expression of RIG-I were reported to predict better responses to IFN therapy.40,41 Whether these findings translate into better responses to adjuvant IFN remains to be explored. Compared with HBV, hepatitis C virus (HCV) is more responsive to conventional IFN therapy. Interferon reduces the risk of HCC development more significantly in patients with chronic HCV infection than it does for those with chronic HBV infection.42 In a randomized control trial performed in Japan, 49 patients with HCV-related HCC were administered IFN-α after complete ethanol ablation. Among the treated patients, 14 (29%) demonstrated sustained antiviral responses. Compared with the 25 patients who did not receive adjuvant IFN-α, the rates of first recurrence were similar, but the rates of second and third recurrence were lower in those receiving adjuvant IFN-α.43 In an Italian, randomized control trial for patients with HCV-related HCC, adjuvant IFN-α did not affect overall recurrence. However, among patients who were adherent to the treatment, adjuvant IFN-α reduced late recurrence in the pure HCV subgroup.44 ►Table 3 gives an overview of conventional INF-based adjuvant therapy in HBV- and/or HCV-related hepatocellular carcinoma.
Nucleos(t)ide Analogs in HBV-Related Hepatocellular Carcinoma High HBV viral load is associated with an increased incidence of HBV-related HCC recurrence after curative resection.45–47 Compared with IFN, oral nucleos(t)ide analogs are generally Seminars in Liver Disease
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Adjuvant systemic chemotherapy is a common strategy for preventing postoperative recurrence of malignant tumors; however, evidence of success in HCC patients is lacking. A meta-analysis evaluating adjuvant chemotherapy with epirubicin alone or in combination with oral 5-fluorouracil, showed disappointing results.19 Another randomized control trial by Hasegawa et al. compared uracil-tegafur treatment for 1 year with surgery alone, and failed to report significant improvements in recurrence-free survival or overall survival.20 In a relatively small randomized control trial, performed in China, postoperative adjuvant capecitabine delayed the recurrence of HCC after curative resection.21 However, a large-scale and well-designed randomized control trial is needed to confirm these results. Transarterial radioactive iodine in Lipiodol (I-131-Lipiodol) has been shown to reduce recurrence in a single-center randomized controlled trial involving 43 patients from Hong Kong.22 However, the study was terminated prematurely before initial plan of proposed patient number due to perceived benefit of the treatment, giving rise to a possibility of type 2 error. Subsequently, a more recent multi-center randomized controlled trial in Singapore including a larger sample size of 103 patients failed to demonstrate any significant improvement in recurrence-free or overall survival.23 ►Table 1 provides an overview of prior studies of adjuvant therapy to prevent HCC recurrence.
Lu et al.
Prevention of HCC Recurrence
Lu et al.
Table 2 Sorafenib and other molecular targeted agents for prevention of hepatocellular carcinoma recurrence Study/y
Study type
Etiology
Local treatment
Patients
Adjuvant treatment
Primary end point
Other end point
Phase III RCT
HBV predominant
Resection or ablation
558/556
Placebo/ sorafenib
Median RFS: 33.8 m/33.4 m (HR, 0.940; p ¼ 0.26)
Median OS: NR (HR, 0.995; p ¼ 0.48)
Liu et al; Taiwan/ 200929
Phase II RCT
HBV predominant
Resection
58/56/54
Control/PI-88 (160 mg/d)/ PI-88 (250 mg/d)
Recurrence-free rate: 50%/63%/ 41% (control vs. 160 mg/d group, p ¼ 0.07)
TTR: 24 w vs. 47 w in control vs. 160 mg-group, respectively (at 36th percentile), p ¼ 0.13
PATRON; global trial/ 2014 (active, not recruiting)
Phase III RCT
Mixed
Resection
Around 519 (1:1 randomization)
Placebo/PI-88
DFS
TTR
Phase II RCT
HBV predominant
Resection
21/21
Placebo/ thalidomide (200 mg/d)
2 y DFS: 33.3%/ 65.0% (p ¼ 0.06)
2 y OS: 85.7% 84.2% (p ¼ 0.94)
Sorafenib STORM; global trial/201426 PI-88
Thalidomide Ho et al; Taiwan/ 201133
Abbreviations: DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; NR, not reached; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; TTR, time to recurrence.
more tolerable and more potent for controlling HBV infections. Five nucleos(t)ide analogs, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, are currently available. Earlier studies using lamivudine and adefovir in HBV carriers
reported a decrease in HCC development (secondary prevention).48–51 In the setting of recurrence prevention, after curative therapies (tertiary prevention), several retrospective cohort
Table 3 Conventional interferon-based adjuvant therapy in hepatitis B virus- and/or hepatitis C virus-related hepatocellular carcinoma Study/y
Study type
Etiology
Local treatment
Patients
Adjuvant treatment
Primary end point
Other end point
Sun et al; China/ 200637
Phase II/III RCT
HBV
Resection
118/118
Control/IFN
Median DFS: 17.7 m/31.2 m (p ¼ 0.1425)
Median OS: 38.8 m/63.8 m (p ¼ 0.0003)
Lo et al; Hong Kong/ 200739
Phase II RCT
HBV predominant
Resection
40/40
Control/IFN
DFS: no significant difference (p ¼ 0.311)
1, 3, 5 y OS: 85%, 70%, 61%/ 97%. 79%, 79% (p ¼ 0.137)
Chen et al; Taiwan/ 201238
Phase III RCT
HBV predominant
Resection
135/133
Control/IFN
Median RFS: 48.6 m/42.2 m (p ¼ 0.828)
Median OS: NR (p ¼ 0.863)
Shiratori et al; Japan/ 200343
Phase II RCT
HCV
Ablation
25/49
Control/IFN
1, 3, 5 y recurrence rates: 24%, 76%, 92%/ 24%, 69%, 80%
1, 3, 5 y survival rates: 96%, 84%, 48%/98%, 82%, 68%
Mazzaferro et al; Italy/ 200644
Phase II RCT
HCV
Resection
74/76
Control/IFN
3, 5 y RFS: 37.1%, 5.8%/ 42.8%, 24.3% (p ¼ 0.499)
3, 5 y DSS: 69.0%, 52.4%/77.3%, 63.6% (p ¼ 0.471)
Abbreviations: DFS, disease-free survival; DSS, disease-specific survival; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NR, not reached; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival. Seminars in Liver Disease
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studies and meta-analyses have suggested that adjuvant treatment with nucleos(t)ide analogs reduces HBV-related HCC recurrence and improves overall survival.52–55 A nationwide study from Taiwan investigated a large cohort of HBVrelated HCC patients who underwent curative liver resection.54 The risk of tumor recurrence was compared between the treatment cohort (n ¼ 518, receiving postoperative administration of lamivudine, entecavir, or telbivudine for at least 90 days) and the untreated cohort (n ¼ 4051). The treatment cohort had a significantly lower 6-year HCC recurrence rate (45.6% vs. the untreated cohort, 54.6%; p < 0.001) and lower 6-year overall mortality (29.0% vs. the untreated cohort, 42.4%; p < 0.001). Multivariate analysis confirmed that postoperative nucleos(t)ide analog use was associated with a 33% reduction in HCC recurrence. A prospective study in China involved 180 patients randomly assigned to the nucleos(t)ide analog group (receiving postoperative lamivudine, adefovir, or entecavir) or to a control group.56 Among the 163 patients analyzed, those who received nucleos(t)ide analogs had better 2-year recurrence-free survival and 2-year overall survival than those in the control group; the survival benefits were maintained at 4 years. Notably, nucleos(t)ide analog use even reduced HCC recurrence in those with a low HBV virus load. Although this study was prospective in nature, imbalances with regard to several clinicopathologic factors between the two study groups were found. Specifically, patients in the control group had a higher proportion of incomplete or no tumor encapsulation, poor differentiation, and increased serum α-fetoprotein.56 Direct comparisons between different nucleos(t)ide analogs for the prevention of HCC are not available. In a retrospective, propensity score-adjusted study, Hosaka et al reported that entecavir was more efficacious than lamivudine for preventing the development of HCC in HBV carriers with cirrhosis.57 In a retrospective study by Huang et al, postoper-
Lu et al.
ative nucleos(t)ide analog (lamivudine, adefovir, or entecavir) use was associated with a marginal 3-year disease-free survival benefit (43.7% vs. 31.8% in the group without nucleos[t]ide analogs; p ¼ 0.056) in patients with high HBV loads. Again, the 3-year disease-free survival in the entecavir group was significantly better than that in the lamivudine and adefovir groups.58 In a Korean, single-center study, 134 newly diagnosed patients were curatively treated; those who received adjuvant therapy with entecavir had a significantly lower risk of HCC recurrence than the untreated patients (odds ratio [OR], 0.077; p ¼ 0.016) or those treated with other nucleos(t)ide analogs (OR, 0.145; p ¼ 0.012).59 ►Table 4 details the nucleos(t)ide analogs for prevention of hepatitis B virus-related hepatocellular carcinoma recurrence.
Novel Antiviral Agents for HCV-Related Hepatocellular Carcinoma Persistent HCV viremia has been associated with higher recurrence rates after resection of HCV-related HCC. In a study by Shindoh et al, 370 patients underwent curative surgery for HCV-related HCC and were divided into low and high viral load groups. The 5-year recurrence-free survival rate was 36.1% in the low viral load group and 12.4% in the high viral load group (p < 0.001); the respective 5-year overall survivals were 76.65% and 57.7% (p < 0.001).60 The current standard regimen for chronic HCV infection, peg-IFN plus ribavirin, can achieve a sustained virologic response in 40% to 75% of treated patients, depending on the HCV genotypes.61,62 In a nationwide cohort study from Taiwan, this regimen was shown to significantly reduce both HCC recurrence and mortality after 5 years of follow-up.63 The landscape of HCV treatment has been rapidly evolving with the development of various direct-acting antiviral
Table 4 Nucleos(t)ide analogs for prevention of hepatitis B virus-related hepatocellular carcinoma recurrence Study/y
Study type
Local treatment
Patients
Adjuvant treatment
Major end point
Other end point
Chuma et al; Japan/200952
RS
Resection or ablation
64/20
Control/NAs
Recurrence incidence: control vs. NAs, HR: 2.57 (p ¼ 0.005)
Recurrence incidence in control group: high vs. low HBV DNA level, HR: 2.67 (p ¼ 0.007)
Chan et al; Hong Kong/201153
RS
Resection
94/42
Control/NAs
1, 3, 5 y DFS: 48.9%, 33.8%, 33.8%/66.5%, 51.4%, 51.4% (p ¼ 0.05)
1, 3, 5 y OS: 76.5%, 47.5%, 43.5%/88.1%, 79.1% 71.2% (p ¼ 0.005)
Wu et al; Taiwan/201254
RS
Resection
4051/518
Control/NAs
6 y recurrence rates: 54.6%/45.6% (p < 0.001)
6 y overall mortality rates: 42.4%/29.0% (p < 0.001)
Yin et al; China/201356
RCT
Resection
82/81
Control/NAs
2, 4 y RFS: 19.5%, 12.1%/55.6%, 37.3% (p < 0.001)
2, 4 y OS: 62.2%, 47.4%/93.8%, 86.4% (p < 0.001)
Lee et al; Korea/201259
CS
Resection or ablation
57/39/38
Control/other NA/entecavir
Risk of recurrence: entecavir vs. control, OR: 0.077 (p ¼ 0.016)
Risk of recurrence: entecavir vs. other NA, OR: 0.145 (p ¼ 0.012)
Abbreviations: CS, cohort study; DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; NA, nucleos(t)ide analog; OR, odds ratio; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; RS, retrospective study. Seminars in Liver Disease
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Prevention of HCC Recurrence
Prevention of HCC Recurrence
Lu et al.
agents (DAAs).64 Interferon-free therapies involving different DAA-containing regimens have dramatically increased viral clearance rates.65–67 Although too early to extrapolate the viral clearance rates to secondary or even tertiary prevention of HCV-related HCC, these novel antiviral agents may be reasonably expected to play crucial roles in these regards.
Prevention of Early Recurrence Using Effective Antiviral Therapy—What Do the Data Show? Hepatocellular carcinoma recurrence after curative therapy has been classified as early (within 2 years of curative therapy) or late (> 2 years after curative therapy).68,69 Early recurrence has been attributed to undetected micrometastasis and is associated with both tumor and surgical factors, such as large tumor size, macroscopic vascular invasion, multinodularity, and close resection margins. Late recurrence, on the other hand, has been attributed to de novo second primary tumor development and is associated with host factors, such as background liver diseases, hepatitis virus load, and cirrhosis status. One may expect that effective antiviral therapies may only reduce late HCC recurrence as demonstrated by Mazzaferro et al using adjuvant IFN therapy in HCV-related HCC.44 However, according to the aforementioned Taiwanese nationwide cohort study and the randomized control trial in China, nucleos (t)ide analogs significantly reduce HBV-related HCC recurrence as early as a few months after curative resection (i.e., reducing early recurrence),54,56 indicating that direct suppression of either micrometastases or small undetected second primary tumors is possible using effective antiviral therapy. For HCV-related HCC, peg-IFN plus ribavirin also reduced early recurrence within 1 year (1-year recurrence rates: 16.2% and 24.5% in the treated and untreated groups, respectively; p ¼ 0.005) in another Taiwanese nationwide cohort study.63 These results were unexpected and the potential mechanisms need to be explored. The HBx protein was reported to be rarely detected in most resected HCCs.70 However, in a recent study published by Huang et al, the hepatitis B core antigen (HBcAg) and mutant S gene were detected more frequently in small HCC tumors than in large ones,71 suggesting that small, undetected, postoperative, residual tumors may contain viruses, and that their growth may remain under the influence of viral molecules. The freely replicative form of HBV was also isolated from these HBcAg-positive tumors. The mutant S gene was also shown to have transformation activity.71 Additionally, the growth of small tumors or unresected micrometastases may be fostered by inflammation within the microenvironment. Nucleos(t)ide analogs suppress inflammation and may thereby suppress early recurrence. All these hypotheses require future testing.
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References 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global
cancer statistics. CA Cancer J Clin 2011;61(2):69–90 2 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet
2012;379(9822):1245–1255 3 Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis
4
5
6
7
8
9
10
11
12
13
14
For hepatitis virus-related HCC, the current evidence suggests that novel antiviral agents may reduce HCC recurrence after Seminars in Liver Disease
curative treatment. However, which subgroups of patients will benefit most and which regimens will be most cost effective remains unclear. In addition, for patients who have received nucleos(t)ide analogs before curative treatment of HBV-related HCC, the efficacy of adding other adjuvant agents is unclear. For HCV-related HCC, IFN-free, novel DAA-containing regimens for secondary or tertiary prevention are attractive and warrant further investigation. Accordingly, for clinical trials exploring adjuvant/chemopreventive agents, clear patient stratification should be recommended. In addition to effective antiviral therapies for hepatitis virusrelated HCC, biomarker-based enrichment and strategy for studies of adjuvant therapy by molecular-targeted agents is needed.
No. 4/2014
15
after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 2000;18(5):1094–1101 Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005; 25(2):181–200 Kuriyama S, Hitomi M, Yoshiji H, et al. Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules. Int J Oncol 2005;27(2):505–511 Ozaki I, Zhang H, Mizuta T, et al. Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res 2007;13(7):2236–2245 Mizuta T, Ozaki I, Eguchi Y, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer 2006;106(4):867–872 Hotta N, Ayada M, Sato K, et al. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007;54(79):2073–2077 Kakizaki S, Sohara N, Sato K, et al. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol 2007; 22(4):518–522 Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51(2):315–321 Ishizuka M, Kubota K, Shimoda M, et al. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res 2012;32(12):5415–5420 Yoshida H, Shiratori Y, Kudo M, et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011;54(2): 532–540 Zhong JH, Mo XS, Xiang BD, et al. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS ONE 2013;8(3):e58082 Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc 1979;38(11):2528–2534 Muto Y, Moriwaki H, Ninomiya M, et al; Hepatoma Prevention Study Group. Prevention of second primary tumors by an acyclic
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interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010;52(6): 889–894 Singal AK, Freeman DH Jr, Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010;32(7):851–858 Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Müllhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009;96(9):975–981 Sun HC, Tang ZY, Wang L, et al. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006;132(7):458–465 Chen LT, Chen MF, Li LA, et al; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, National Health Research Institutes, Zhunan, Taiwan. Long-term results of a randomized, observationcontrolled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012;255(1): 8–17 Lo CM, Liu CL, Chan SC, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007;245(6):831–842 Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009;361(15): 1437–1447 Hou J, Zhou Y, Zheng Y, et al. Hepatic RIG-I predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell 2014;25(1):49–63 International Interferon-alpha Hepatocellular Carcinoma Study Group. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 1998;351(9115):1535–1539 Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003; 138(4):299–306 Mazzaferro V, Romito R, Schiavo M, et al; HCC Italian Task Force. Prevention of hepatocellular carcinoma recurrence with alphainterferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6):1543–1554 Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol 2008; 103(7):1663–1673 Qu LS, Jin F, Huang XW, Shen XZ. High hepatitis B viral load predicts recurrence of small hepatocellular carcinoma after curative resection. J Gastrointest Surg 2010;14(7):1111–1120 Sohn W, Paik YH, Kim JM, et al. HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma. Ann Surg Oncol 2014; 21(7):2429–2435 Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351(15): 1521–1531 Matsumoto A, Tanaka E, Rokuhara A, et al; Inuyama Hepatitis Study Group. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res 2005;32(3):173–184 Eun JR, Lee HJ, Kim TN, Lee KS. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease. J Hepatol 2010;53(1):118–125
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retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med 1996;334(24):1561–1567 Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 1999;340(13):1046–1047 Takai K, Okuno M, Yasuda I, et al. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 2005;48(1):39–45 Okita K, Izumi N, Matsui O, et al; Peretinoin Study Group. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol 2014 Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer 2001; 91(12):2378–2385 Hasegawa K, Takayama T, Ijichi M, et al. Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 2006;44(4):891–895 Xia Y, Qiu Y, Li J, et al. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17(12):3137–3144 Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999;353(9155):797–801 Chung AY, Ooi LL, Machin D, et al. Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg 2013; 37(6):1356–1361 Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378–390 Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10(1):25–34 Bruix J, Takayama T, Mazzaferro V, et al. STORM: a phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC). J Clin Oncol 2014;32(5S):4006 Yang Y, Macleod V, Miao HQ, et al. Heparanase enhances syndecan1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 2007;282(18):13326–13333 Ferro V, Dredge K, Liu L, et al. PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 2007; 33(5):557–568 Liu CJ, Lee PH, Lin DY, et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 2009;50(5):958–968 Hsu C, Chen CN, Chen LT, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65(3): 242–249 Lin AY, Brophy N, Fisher GA, et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005;103(1):119–125 Patt YZ, Hassan MM, Lozano RD, et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005;103(4):749–755 Ho MC, Hu RH, Ho CM, Chen CN, Chang KJ, Lee PH. A randomized pilot phase II study of thalidomide as adjuvant therapy in patient with high recurrence risk hepatocellular carcinoma. Paper presented at: The International Liver Congress; April 1, 2011; Berlin, Germany
Lu et al.
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Lu et al.
51 Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of
52
53
54
55
56
57
58
59
60
hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 2005;42(1):121–129 Chuma M, Hige S, Kamiyama T, et al. The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J Gastroenterol 2009;44(9):991–999 Chan AC, Chok KS, Yuen WK, et al. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg 2011;146(6): 675–681 Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection. JAMA 2012; 308(18):1906–1914 Wong JS, Wong GL, Tsoi KK, et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011;33(10):1104–1112 Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 2013;31(29):3647–3655 Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58(1): 98–107 Huang G, Yang Y, Shen F, et al. Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load. Ann Surg Oncol 2013;20(5): 1482–1490 Lee DH, Lee JH, Cho Y, et al. Entecavir treatment significantly reduces the risk of hepatocellular carcinoma recurrence in patients with chronic hepatitis B. Paper presented at: The American Association for the Study of Liver Disease; November 10, 2012; Boston, MA Shindoh J, Hasegawa K, Matsuyama Y, et al. Low hepatitis C viral load predicts better long-term outcomes in patients undergoing
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70
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resection of hepatocellular carcinoma irrespective of serologic eradication of hepatitis C virus. J Clin Oncol 2013;31(6):766–773 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361(6):580–593 Hadziyannis SJ, Sette H Jr, Morgan TR, et al; PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5): 346–355 Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology 2013;58(1): 150–157 Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med 2013;368(20):1907–1917 Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370(3): 211–221 Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370(20):1879–1888 Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973–1982 Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38(2):200–207 Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009;51(5):890–897 Hsia CC, Nakashima Y, Tabor E. Deletion mutants of the hepatitis B virus X gene in human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;241(3):726–729 Huang SF, Chen YT, Lee WC, et al. Identification of transforming hepatitis B virus S gene nonsense mutations derived from freely replicative viruses in hepatocellular carcinoma. PLoS ONE 2014; 9(2):e89753
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Recent Advances in the Prevention of Hepatocellular Carcinoma Recurrence Ann-Lii Cheng, MD, PhD1,2,3
Ronnie T. P. Poon, FRCS, PhD4
1 Departments of Oncology, National Taiwan University Hospital,
Taipei, Taiwan 2 Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 4 Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
Address for correspondence Ann-Lii Cheng, MD, PhD, Department of Oncology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 10002, Taiwan (e-mail: [email protected]).
Semin Liver Dis 2014;34:427–434.
Abstract Keywords
► hepatocellular carcinoma ► prevention ► recurrence ► hepatitis B virus ► hepatitis C virus ► antiviral
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Earlystage HCC can be curatively treated, but the recurrence rate remains high. To date, adjuvant treatments have not proven effective in preventing HCC recurrence after curative treatment. Although early studies explored the potential of vitamin K2, retinoid, chemotherapy, and recently, sorafenib, none of the studies reported successful outcomes. Several new lines of evidence have emerged to support the use of novel antiviral agents for preventing the recurrence of virus-related HCC after curative treatment. In this review, the authors provide a thorough overview of the various adjuvant treatments that have been attempted or are being considered for trial.
Hepatocellular carcinoma (HCC) is one of the most common cancers and leading causes of malignancy-related deaths worldwide.1 Early-stage HCC can be treated with curative therapies, such as surgery and ablation. However, despite the advances in surgical techniques and ablation technologies, the 5-year survival rate remains unsatisfactory and the 5-year recurrence rate is around 70%.2–4 Strategies to prevent HCC recurrence are, therefore, crucial. In this article we review the recent advances in the use of contemporary antiviral agents and molecular-targeted therapies to prevent HCC recurrence after curative treatment.
Historic Studies Involving Adjuvant Therapy Previous preclinical studies suggested that vitamin K2 or its analogs may induce cell cycle arrest and inhibit HCC cell growth.5,6 Thereafter, several small clinical trials were conducted to evaluate the postoperative use of vitamin K2 in patients with HCC, but the results were inconsistent.7–11 A large-scale, randomized, placebo-controlled trial that en-
Issue Theme Hepatocellular Carcinoma: Current Evidence and Future Research; Guest Editor, Jordi Bruix, MD
rolled 548 patients was recently published by Yoshida et al. The results showed that vitamin K2 did not prevent recurrence or improve survival in HCC patients who underwent curative resection or ablation.12 Although the results of a meta-analysis suggested that vitamin K2 may reduce the 1-year recurrence rate, the conclusion should be interpreted with caution.13 Retinoids are considered chemopreventive.14 A small randomized control trial reported that oral administration of peretinoin, an acyclic retinoid, for 12 months prevented the development of a second primary HCC and improved the overall survival of HCC patients who underwent curative surgery or percutaneous ethanol injections.15–17 A recent, randomized, double-blinded, large-scale trial testing peretinoin (600 mg/day and 300 mg/day) against placebo was conducted by the Japanese Peretinoin Study Group.18 Only HCV patients with newly diagnosed or first recurrence HCC were enrolled; however, the primary endpoint, demonstration of the superiority of peretinoin (300 and 600 mg/day) over the placebo in terms of recurrence-free survival, was not met.
Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1394141. ISSN 0272-8087.
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Li-Chun Lu, MD1,2
Seminars in Liver Disease
Vol. 34
Phase III RCT
Okita et al; Japan/201418
No. 4/2014
HBV predominant
Phase II RCT
Xia et al; China/201021
RCT
Chung et al; Singapore/ 201323
HBV predominant
Resection
Resection
Resection
Resection
Resection
Resection or ablation
Resection or ablation
Resection or ablation
Local treatment
51/52
22/21
30/30
79/80
51/57
127/126/124
45/44
181/182/185
Patients
Control/ I-131-Lipiodol
Control / I-131-Lipiodol
Placebo/Xeloda
Control/UFT
Control/epirubicinbased regimens
Placebo/peretinoin (300 mg/d)/peretinoin (600 mg/d)
Placebo/Polyprenoic acid (600 mg/d)
Placebo/VK2 (45 mg/d)/VK2 (90 mg/d)
Adjuvant treatment
RFS (HR ¼ 0.75; 95% CI 0.46–1.23; p ¼ 0.25)
Median DFS: 13.6 m/57.2 m (p ¼ 0.037)
Median TTR: 20.0 m/40.0 m (p ¼ 0.046)
3, 5 y RFS: 37%, 29%/41%, 29% (p ¼ 0.87)
3, 5 y DFS: 42.2%, 25.7%/36.8%, 27.6%
RFS: combined peretinoin group vs. placebo (p ¼ 0.434)
Incident of treatment failure: 49%/27% (p ¼ 0.04)
Median DFS: 540 d/ 541 days (combined VK2 groups)
Primary end point
OS (HR ¼ 0.88; 95% CI 0.51–1.51; p ¼ 0.64)
3 y OS: 46.3%/86.4% (p ¼ 0.039)
5 y OS: 39.8%/62.5% (p ¼ 0.216)
3, 5 y OS: 92%, 73%/90%, 58% (p ¼ 0.08)
OS: better in control group (p ¼ 0.022)
1, 3 y RFS: 66.0%, 29.3%/63.6%, 24.9%/71.9%, 43.7%
2nd primary tumor: 44%/16% (p ¼ 0.004)
1 y DFS: 69.8%/64.9% (combined VK2 groups)
Other end point
Terminated early due to perceived treatment benefit
Advanced recurrence: significantly more frequent in the UFT group than in the control group
Worse DFS and OS in cirrhotic patients receiving chemotherapy
600 mg-group vs. placebo: better RFS at 2 y (HR: 0.27)
Significant OS difference in the follow-up studies16,17
Terminated early
Note
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Abbreviations: CI, confidence interval; DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; TTR, time to recurrence; UFT, uracil-tegafur; VK2, vitamin K2.
RCT
Lau et al; Hong Kong/ 199922
HBV predominant
HCV predominant
Phase II RCT
Hasegawa et al; Japan/200620
Transarterial I-131-Lipiodol
HCV predominant
Combination of 3 phase II RCTs
Ono et al; Japan/200119
All HCV
HCV predominant
HCV predominant
Etiology
Prevention of HCC Recurrence
Chemotherapy
Phase II RCT
Phase II/III RCT
Study type
Muto et al; Japan/199615
Retinoids
Yoshida et al; Japan/201112
Vitamin K2
Study/y
Table 1 Prior studies of adjuvant therapy to prevent hepatocellular carcinoma recurrence
428 Lu et al.
Prevention of HCC Recurrence
Sorafenib and Other Molecular-Targeted Agents Sorafenib, a multikinase inhibitor that targets Raf kinase and vascular endothelial growth factor receptor-2, is the standard treatment for advanced HCC.24,25 A phase III, randomized, double-blind, placebo-controlled study of sorafenib as an adjuvant treatment for HCC after surgical resection or local ablation (STORM trial) enrolled 1,114 patients randomized to receive either sorafenib or placebo for 4 years or until tumor recurrence. The study group recently announced that neither its primary end point, recurrence-free survival, secondary end points, time to recurrence, nor overall survival were met.26 Heparanase is associated with tumor growth and angiogenesis via degrading heparan sulfate, an extracellular matrix proteoglycan.27 PI-88 is a heparan sulfate mimetic that inhibits heparanase and may have anticancer activity.28 A multicenter, phase II, randomized trial in Taiwan evaluated two different doses of PI-88 (250 mg/d and 160 mg/d) for 36 weeks.29 The preliminary results showed marginally better recurrence-free rates in the 160 mg/d arm than in the untreated control arm (p ¼ 0.07).30 Because of a high dropout rate in the 250 mg/d arm, the 160 mg/d dose was later selected for further exploration in a randomized, placebocontrolled, phase III trial (PATRON trial, NCT01402908). The study has completed accrual and the results will be available in the near future. Thalidomide has antitumor activity resulting from its antiangiogenic and immunomodulatory effects. Several single-arm, phase II studies have shown that thalidomide has
429
modest activity in patients with advanced HCC.30–32 In a pilot, randomized, phase II study of thalidomide as an adjuvant therapy, 42 HCC patients underwent curative hepatic resection and were randomized to receive either thalidomide (200 mg/d) or placebo for 1 year.33 The thalidomide arm showed a trend toward an improved 2-year disease-free survival rate (65% vs. 33.3% in the placebo arm; p ¼ 0.06). The study results were limited by the relatively small sample size and short follow-up period. ►Table 2 provides details of sorafenib and other molecular-targeted agents for prevention of hepatocellular carcinoma recurrence.
Conventional Interferon-Based Therapy in HBV and/or HCV-Related Hepatocellular Carcinoma Interferon (IFN) has antiviral, immunomodulatory, and antiproliferative activities. Before the emergence of modern antiviral and anticancer therapies, conventional IFN was extensively tested for the treatment and prevention of HCC. In the adjuvant setting, the results of conventional IFN therapy have been inconsistent, although some meta-analyses have suggested that adjuvant IFN therapy improved both recurrence-free survival and overall survival.34–36 In general, the evidence for adjuvant IFN therapy prevention of hepatitis B virus- (HBV-) related HCC was not promising.37–39 However, some subgroups may benefit from the treatment. For example, low expression of miR-26 and high expression of RIG-I were reported to predict better responses to IFN therapy.40,41 Whether these findings translate into better responses to adjuvant IFN remains to be explored. Compared with HBV, hepatitis C virus (HCV) is more responsive to conventional IFN therapy. Interferon reduces the risk of HCC development more significantly in patients with chronic HCV infection than it does for those with chronic HBV infection.42 In a randomized control trial performed in Japan, 49 patients with HCV-related HCC were administered IFN-α after complete ethanol ablation. Among the treated patients, 14 (29%) demonstrated sustained antiviral responses. Compared with the 25 patients who did not receive adjuvant IFN-α, the rates of first recurrence were similar, but the rates of second and third recurrence were lower in those receiving adjuvant IFN-α.43 In an Italian, randomized control trial for patients with HCV-related HCC, adjuvant IFN-α did not affect overall recurrence. However, among patients who were adherent to the treatment, adjuvant IFN-α reduced late recurrence in the pure HCV subgroup.44 ►Table 3 gives an overview of conventional INF-based adjuvant therapy in HBV- and/or HCV-related hepatocellular carcinoma.
Nucleos(t)ide Analogs in HBV-Related Hepatocellular Carcinoma High HBV viral load is associated with an increased incidence of HBV-related HCC recurrence after curative resection.45–47 Compared with IFN, oral nucleos(t)ide analogs are generally Seminars in Liver Disease
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Adjuvant systemic chemotherapy is a common strategy for preventing postoperative recurrence of malignant tumors; however, evidence of success in HCC patients is lacking. A meta-analysis evaluating adjuvant chemotherapy with epirubicin alone or in combination with oral 5-fluorouracil, showed disappointing results.19 Another randomized control trial by Hasegawa et al. compared uracil-tegafur treatment for 1 year with surgery alone, and failed to report significant improvements in recurrence-free survival or overall survival.20 In a relatively small randomized control trial, performed in China, postoperative adjuvant capecitabine delayed the recurrence of HCC after curative resection.21 However, a large-scale and well-designed randomized control trial is needed to confirm these results. Transarterial radioactive iodine in Lipiodol (I-131-Lipiodol) has been shown to reduce recurrence in a single-center randomized controlled trial involving 43 patients from Hong Kong.22 However, the study was terminated prematurely before initial plan of proposed patient number due to perceived benefit of the treatment, giving rise to a possibility of type 2 error. Subsequently, a more recent multi-center randomized controlled trial in Singapore including a larger sample size of 103 patients failed to demonstrate any significant improvement in recurrence-free or overall survival.23 ►Table 1 provides an overview of prior studies of adjuvant therapy to prevent HCC recurrence.
Lu et al.
Prevention of HCC Recurrence
Lu et al.
Table 2 Sorafenib and other molecular targeted agents for prevention of hepatocellular carcinoma recurrence Study/y
Study type
Etiology
Local treatment
Patients
Adjuvant treatment
Primary end point
Other end point
Phase III RCT
HBV predominant
Resection or ablation
558/556
Placebo/ sorafenib
Median RFS: 33.8 m/33.4 m (HR, 0.940; p ¼ 0.26)
Median OS: NR (HR, 0.995; p ¼ 0.48)
Liu et al; Taiwan/ 200929
Phase II RCT
HBV predominant
Resection
58/56/54
Control/PI-88 (160 mg/d)/ PI-88 (250 mg/d)
Recurrence-free rate: 50%/63%/ 41% (control vs. 160 mg/d group, p ¼ 0.07)
TTR: 24 w vs. 47 w in control vs. 160 mg-group, respectively (at 36th percentile), p ¼ 0.13
PATRON; global trial/ 2014 (active, not recruiting)
Phase III RCT
Mixed
Resection
Around 519 (1:1 randomization)
Placebo/PI-88
DFS
TTR
Phase II RCT
HBV predominant
Resection
21/21
Placebo/ thalidomide (200 mg/d)
2 y DFS: 33.3%/ 65.0% (p ¼ 0.06)
2 y OS: 85.7% 84.2% (p ¼ 0.94)
Sorafenib STORM; global trial/201426 PI-88
Thalidomide Ho et al; Taiwan/ 201133
Abbreviations: DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; NR, not reached; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; TTR, time to recurrence.
more tolerable and more potent for controlling HBV infections. Five nucleos(t)ide analogs, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, are currently available. Earlier studies using lamivudine and adefovir in HBV carriers
reported a decrease in HCC development (secondary prevention).48–51 In the setting of recurrence prevention, after curative therapies (tertiary prevention), several retrospective cohort
Table 3 Conventional interferon-based adjuvant therapy in hepatitis B virus- and/or hepatitis C virus-related hepatocellular carcinoma Study/y
Study type
Etiology
Local treatment
Patients
Adjuvant treatment
Primary end point
Other end point
Sun et al; China/ 200637
Phase II/III RCT
HBV
Resection
118/118
Control/IFN
Median DFS: 17.7 m/31.2 m (p ¼ 0.1425)
Median OS: 38.8 m/63.8 m (p ¼ 0.0003)
Lo et al; Hong Kong/ 200739
Phase II RCT
HBV predominant
Resection
40/40
Control/IFN
DFS: no significant difference (p ¼ 0.311)
1, 3, 5 y OS: 85%, 70%, 61%/ 97%. 79%, 79% (p ¼ 0.137)
Chen et al; Taiwan/ 201238
Phase III RCT
HBV predominant
Resection
135/133
Control/IFN
Median RFS: 48.6 m/42.2 m (p ¼ 0.828)
Median OS: NR (p ¼ 0.863)
Shiratori et al; Japan/ 200343
Phase II RCT
HCV
Ablation
25/49
Control/IFN
1, 3, 5 y recurrence rates: 24%, 76%, 92%/ 24%, 69%, 80%
1, 3, 5 y survival rates: 96%, 84%, 48%/98%, 82%, 68%
Mazzaferro et al; Italy/ 200644
Phase II RCT
HCV
Resection
74/76
Control/IFN
3, 5 y RFS: 37.1%, 5.8%/ 42.8%, 24.3% (p ¼ 0.499)
3, 5 y DSS: 69.0%, 52.4%/77.3%, 63.6% (p ¼ 0.471)
Abbreviations: DFS, disease-free survival; DSS, disease-specific survival; HBV, hepatitis B virus; HCV, hepatitis C virus; IFN, interferon; NR, not reached; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival. Seminars in Liver Disease
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studies and meta-analyses have suggested that adjuvant treatment with nucleos(t)ide analogs reduces HBV-related HCC recurrence and improves overall survival.52–55 A nationwide study from Taiwan investigated a large cohort of HBVrelated HCC patients who underwent curative liver resection.54 The risk of tumor recurrence was compared between the treatment cohort (n ¼ 518, receiving postoperative administration of lamivudine, entecavir, or telbivudine for at least 90 days) and the untreated cohort (n ¼ 4051). The treatment cohort had a significantly lower 6-year HCC recurrence rate (45.6% vs. the untreated cohort, 54.6%; p < 0.001) and lower 6-year overall mortality (29.0% vs. the untreated cohort, 42.4%; p < 0.001). Multivariate analysis confirmed that postoperative nucleos(t)ide analog use was associated with a 33% reduction in HCC recurrence. A prospective study in China involved 180 patients randomly assigned to the nucleos(t)ide analog group (receiving postoperative lamivudine, adefovir, or entecavir) or to a control group.56 Among the 163 patients analyzed, those who received nucleos(t)ide analogs had better 2-year recurrence-free survival and 2-year overall survival than those in the control group; the survival benefits were maintained at 4 years. Notably, nucleos(t)ide analog use even reduced HCC recurrence in those with a low HBV virus load. Although this study was prospective in nature, imbalances with regard to several clinicopathologic factors between the two study groups were found. Specifically, patients in the control group had a higher proportion of incomplete or no tumor encapsulation, poor differentiation, and increased serum α-fetoprotein.56 Direct comparisons between different nucleos(t)ide analogs for the prevention of HCC are not available. In a retrospective, propensity score-adjusted study, Hosaka et al reported that entecavir was more efficacious than lamivudine for preventing the development of HCC in HBV carriers with cirrhosis.57 In a retrospective study by Huang et al, postoper-
Lu et al.
ative nucleos(t)ide analog (lamivudine, adefovir, or entecavir) use was associated with a marginal 3-year disease-free survival benefit (43.7% vs. 31.8% in the group without nucleos[t]ide analogs; p ¼ 0.056) in patients with high HBV loads. Again, the 3-year disease-free survival in the entecavir group was significantly better than that in the lamivudine and adefovir groups.58 In a Korean, single-center study, 134 newly diagnosed patients were curatively treated; those who received adjuvant therapy with entecavir had a significantly lower risk of HCC recurrence than the untreated patients (odds ratio [OR], 0.077; p ¼ 0.016) or those treated with other nucleos(t)ide analogs (OR, 0.145; p ¼ 0.012).59 ►Table 4 details the nucleos(t)ide analogs for prevention of hepatitis B virus-related hepatocellular carcinoma recurrence.
Novel Antiviral Agents for HCV-Related Hepatocellular Carcinoma Persistent HCV viremia has been associated with higher recurrence rates after resection of HCV-related HCC. In a study by Shindoh et al, 370 patients underwent curative surgery for HCV-related HCC and were divided into low and high viral load groups. The 5-year recurrence-free survival rate was 36.1% in the low viral load group and 12.4% in the high viral load group (p < 0.001); the respective 5-year overall survivals were 76.65% and 57.7% (p < 0.001).60 The current standard regimen for chronic HCV infection, peg-IFN plus ribavirin, can achieve a sustained virologic response in 40% to 75% of treated patients, depending on the HCV genotypes.61,62 In a nationwide cohort study from Taiwan, this regimen was shown to significantly reduce both HCC recurrence and mortality after 5 years of follow-up.63 The landscape of HCV treatment has been rapidly evolving with the development of various direct-acting antiviral
Table 4 Nucleos(t)ide analogs for prevention of hepatitis B virus-related hepatocellular carcinoma recurrence Study/y
Study type
Local treatment
Patients
Adjuvant treatment
Major end point
Other end point
Chuma et al; Japan/200952
RS
Resection or ablation
64/20
Control/NAs
Recurrence incidence: control vs. NAs, HR: 2.57 (p ¼ 0.005)
Recurrence incidence in control group: high vs. low HBV DNA level, HR: 2.67 (p ¼ 0.007)
Chan et al; Hong Kong/201153
RS
Resection
94/42
Control/NAs
1, 3, 5 y DFS: 48.9%, 33.8%, 33.8%/66.5%, 51.4%, 51.4% (p ¼ 0.05)
1, 3, 5 y OS: 76.5%, 47.5%, 43.5%/88.1%, 79.1% 71.2% (p ¼ 0.005)
Wu et al; Taiwan/201254
RS
Resection
4051/518
Control/NAs
6 y recurrence rates: 54.6%/45.6% (p < 0.001)
6 y overall mortality rates: 42.4%/29.0% (p < 0.001)
Yin et al; China/201356
RCT
Resection
82/81
Control/NAs
2, 4 y RFS: 19.5%, 12.1%/55.6%, 37.3% (p < 0.001)
2, 4 y OS: 62.2%, 47.4%/93.8%, 86.4% (p < 0.001)
Lee et al; Korea/201259
CS
Resection or ablation
57/39/38
Control/other NA/entecavir
Risk of recurrence: entecavir vs. control, OR: 0.077 (p ¼ 0.016)
Risk of recurrence: entecavir vs. other NA, OR: 0.145 (p ¼ 0.012)
Abbreviations: CS, cohort study; DFS, disease-free survival; HBV, hepatitis B virus; HR, hazard ratio; NA, nucleos(t)ide analog; OR, odds ratio; OS, overall survival; RCT, randomized controlled trial; RFS, recurrence-free survival; RS, retrospective study. Seminars in Liver Disease
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Prevention of HCC Recurrence
Prevention of HCC Recurrence
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agents (DAAs).64 Interferon-free therapies involving different DAA-containing regimens have dramatically increased viral clearance rates.65–67 Although too early to extrapolate the viral clearance rates to secondary or even tertiary prevention of HCV-related HCC, these novel antiviral agents may be reasonably expected to play crucial roles in these regards.
Prevention of Early Recurrence Using Effective Antiviral Therapy—What Do the Data Show? Hepatocellular carcinoma recurrence after curative therapy has been classified as early (within 2 years of curative therapy) or late (> 2 years after curative therapy).68,69 Early recurrence has been attributed to undetected micrometastasis and is associated with both tumor and surgical factors, such as large tumor size, macroscopic vascular invasion, multinodularity, and close resection margins. Late recurrence, on the other hand, has been attributed to de novo second primary tumor development and is associated with host factors, such as background liver diseases, hepatitis virus load, and cirrhosis status. One may expect that effective antiviral therapies may only reduce late HCC recurrence as demonstrated by Mazzaferro et al using adjuvant IFN therapy in HCV-related HCC.44 However, according to the aforementioned Taiwanese nationwide cohort study and the randomized control trial in China, nucleos (t)ide analogs significantly reduce HBV-related HCC recurrence as early as a few months after curative resection (i.e., reducing early recurrence),54,56 indicating that direct suppression of either micrometastases or small undetected second primary tumors is possible using effective antiviral therapy. For HCV-related HCC, peg-IFN plus ribavirin also reduced early recurrence within 1 year (1-year recurrence rates: 16.2% and 24.5% in the treated and untreated groups, respectively; p ¼ 0.005) in another Taiwanese nationwide cohort study.63 These results were unexpected and the potential mechanisms need to be explored. The HBx protein was reported to be rarely detected in most resected HCCs.70 However, in a recent study published by Huang et al, the hepatitis B core antigen (HBcAg) and mutant S gene were detected more frequently in small HCC tumors than in large ones,71 suggesting that small, undetected, postoperative, residual tumors may contain viruses, and that their growth may remain under the influence of viral molecules. The freely replicative form of HBV was also isolated from these HBcAg-positive tumors. The mutant S gene was also shown to have transformation activity.71 Additionally, the growth of small tumors or unresected micrometastases may be fostered by inflammation within the microenvironment. Nucleos(t)ide analogs suppress inflammation and may thereby suppress early recurrence. All these hypotheses require future testing.
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References 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global
cancer statistics. CA Cancer J Clin 2011;61(2):69–90 2 Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet
2012;379(9822):1245–1255 3 Poon RT, Fan ST, Lo CM, Liu CL, Ng IO, Wong J. Long-term prognosis
4
5
6
7
8
9
10
11
12
13
14
For hepatitis virus-related HCC, the current evidence suggests that novel antiviral agents may reduce HCC recurrence after Seminars in Liver Disease
curative treatment. However, which subgroups of patients will benefit most and which regimens will be most cost effective remains unclear. In addition, for patients who have received nucleos(t)ide analogs before curative treatment of HBV-related HCC, the efficacy of adding other adjuvant agents is unclear. For HCV-related HCC, IFN-free, novel DAA-containing regimens for secondary or tertiary prevention are attractive and warrant further investigation. Accordingly, for clinical trials exploring adjuvant/chemopreventive agents, clear patient stratification should be recommended. In addition to effective antiviral therapies for hepatitis virusrelated HCC, biomarker-based enrichment and strategy for studies of adjuvant therapy by molecular-targeted agents is needed.
No. 4/2014
15
after resection of hepatocellular carcinoma associated with hepatitis B-related cirrhosis. J Clin Oncol 2000;18(5):1094–1101 Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis 2005; 25(2):181–200 Kuriyama S, Hitomi M, Yoshiji H, et al. Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules. Int J Oncol 2005;27(2):505–511 Ozaki I, Zhang H, Mizuta T, et al. Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation. Clin Cancer Res 2007;13(7):2236–2245 Mizuta T, Ozaki I, Eguchi Y, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer 2006;106(4):867–872 Hotta N, Ayada M, Sato K, et al. Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Hepatogastroenterology 2007;54(79):2073–2077 Kakizaki S, Sohara N, Sato K, et al. Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection. J Gastroenterol Hepatol 2007; 22(4):518–522 Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol 2009; 51(2):315–321 Ishizuka M, Kubota K, Shimoda M, et al. Effect of menatetrenone, a vitamin k2 analog, on recurrence of hepatocellular carcinoma after surgical resection: a prospective randomized controlled trial. Anticancer Res 2012;32(12):5415–5420 Yoshida H, Shiratori Y, Kudo M, et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology 2011;54(2): 532–540 Zhong JH, Mo XS, Xiang BD, et al. Postoperative use of the chemopreventive vitamin K2 analog in patients with hepatocellular carcinoma. PLoS ONE 2013;8(3):e58082 Sporn MB, Newton DL. Chemoprevention of cancer with retinoids. Fed Proc 1979;38(11):2528–2534 Muto Y, Moriwaki H, Ninomiya M, et al; Hepatoma Prevention Study Group. Prevention of second primary tumors by an acyclic
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
432
Prevention of HCC Recurrence
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
433
34 Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
interferon therapy after curative therapy for hepatocellular carcinoma (HCC): a meta-regression approach. J Hepatol 2010;52(6): 889–894 Singal AK, Freeman DH Jr, Anand BS. Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma. Aliment Pharmacol Ther 2010;32(7):851–858 Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Müllhaupt B, Clavien PA. Systematic review and meta-analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis. Br J Surg 2009;96(9):975–981 Sun HC, Tang ZY, Wang L, et al. Postoperative interferon alpha treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol 2006;132(7):458–465 Chen LT, Chen MF, Li LA, et al; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, National Health Research Institutes, Zhunan, Taiwan. Long-term results of a randomized, observationcontrolled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg 2012;255(1): 8–17 Lo CM, Liu CL, Chan SC, et al. A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg 2007;245(6):831–842 Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to interferon in liver cancer. N Engl J Med 2009;361(15): 1437–1447 Hou J, Zhou Y, Zheng Y, et al. Hepatic RIG-I predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell 2014;25(1):49–63 International Interferon-alpha Hepatocellular Carcinoma Study Group. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 1998;351(9115):1535–1539 Shiratori Y, Shiina S, Teratani T, et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003; 138(4):299–306 Mazzaferro V, Romito R, Schiavo M, et al; HCC Italian Task Force. Prevention of hepatocellular carcinoma recurrence with alphainterferon after liver resection in HCV cirrhosis. Hepatology 2006; 44(6):1543–1554 Hung IF, Poon RT, Lai CL, Fung J, Fan ST, Yuen MF. Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection. Am J Gastroenterol 2008; 103(7):1663–1673 Qu LS, Jin F, Huang XW, Shen XZ. High hepatitis B viral load predicts recurrence of small hepatocellular carcinoma after curative resection. J Gastrointest Surg 2010;14(7):1111–1120 Sohn W, Paik YH, Kim JM, et al. HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma. Ann Surg Oncol 2014; 21(7):2429–2435 Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351(15): 1521–1531 Matsumoto A, Tanaka E, Rokuhara A, et al; Inuyama Hepatitis Study Group. Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res 2005;32(3):173–184 Eun JR, Lee HJ, Kim TN, Lee KS. Risk assessment for the development of hepatocellular carcinoma: according to on-treatment viral response during long-term lamivudine therapy in hepatitis B virus-related liver disease. J Hepatol 2010;53(1):118–125
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This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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retinoid, polyprenoic acid, in patients with hepatocellular carcinoma. N Engl J Med 1996;334(24):1561–1567 Muto Y, Moriwaki H, Saito A. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. N Engl J Med 1999;340(13):1046–1047 Takai K, Okuno M, Yasuda I, et al. Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma. Updated analysis of the long-term follow-up data. Intervirology 2005;48(1):39–45 Okita K, Izumi N, Matsui O, et al; Peretinoin Study Group. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol 2014 Ono T, Yamanoi A, Nazmy El Assal O, Kohno H, Nagasue N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: metaanalysis of three randomized controlled trials. Cancer 2001; 91(12):2378–2385 Hasegawa K, Takayama T, Ijichi M, et al. Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology 2006;44(4):891–895 Xia Y, Qiu Y, Li J, et al. Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol 2010; 17(12):3137–3144 Lau WY, Leung TW, Ho SK, et al. Adjuvant intra-arterial iodine131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999;353(9155):797–801 Chung AY, Ooi LL, Machin D, et al. Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg 2013; 37(6):1356–1361 Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378–390 Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10(1):25–34 Bruix J, Takayama T, Mazzaferro V, et al. STORM: a phase III randomized, double-blind, placebo-controlled trial of adjuvant sorafenib after resection or ablation to prevent recurrence of hepatocellular carcinoma (HCC). J Clin Oncol 2014;32(5S):4006 Yang Y, Macleod V, Miao HQ, et al. Heparanase enhances syndecan1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem 2007;282(18):13326–13333 Ferro V, Dredge K, Liu L, et al. PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost 2007; 33(5):557–568 Liu CJ, Lee PH, Lin DY, et al. Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage. J Hepatol 2009;50(5):958–968 Hsu C, Chen CN, Chen LT, et al. Low-dose thalidomide treatment for advanced hepatocellular carcinoma. Oncology 2003;65(3): 242–249 Lin AY, Brophy N, Fisher GA, et al. Phase II study of thalidomide in patients with unresectable hepatocellular carcinoma. Cancer 2005;103(1):119–125 Patt YZ, Hassan MM, Lozano RD, et al. Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial. Cancer 2005;103(4):749–755 Ho MC, Hu RH, Ho CM, Chen CN, Chang KJ, Lee PH. A randomized pilot phase II study of thalidomide as adjuvant therapy in patient with high recurrence risk hepatocellular carcinoma. Paper presented at: The International Liver Congress; April 1, 2011; Berlin, Germany
Lu et al.
Prevention of HCC Recurrence
Lu et al.
51 Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of
52
53
54
55
56
57
58
59
60
hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 2005;42(1):121–129 Chuma M, Hige S, Kamiyama T, et al. The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma. J Gastroenterol 2009;44(9):991–999 Chan AC, Chok KS, Yuen WK, et al. Impact of antiviral therapy on the survival of patients after major hepatectomy for hepatitis B virus-related hepatocellular carcinoma. Arch Surg 2011;146(6): 675–681 Wu CY, Chen YJ, Ho HJ, et al. Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection. JAMA 2012; 308(18):1906–1914 Wong JS, Wong GL, Tsoi KK, et al. Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma. Aliment Pharmacol Ther 2011;33(10):1104–1112 Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study. J Clin Oncol 2013;31(29):3647–3655 Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58(1): 98–107 Huang G, Yang Y, Shen F, et al. Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load. Ann Surg Oncol 2013;20(5): 1482–1490 Lee DH, Lee JH, Cho Y, et al. Entecavir treatment significantly reduces the risk of hepatocellular carcinoma recurrence in patients with chronic hepatitis B. Paper presented at: The American Association for the Study of Liver Disease; November 10, 2012; Boston, MA Shindoh J, Hasegawa K, Matsuyama Y, et al. Low hepatitis C viral load predicts better long-term outcomes in patients undergoing
Seminars in Liver Disease
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No. 4/2014
61
62
63
64 65
66
67
68
69
70
71
resection of hepatocellular carcinoma irrespective of serologic eradication of hepatitis C virus. J Clin Oncol 2013;31(6):766–773 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009;361(6):580–593 Hadziyannis SJ, Sette H Jr, Morgan TR, et al; PEGASYS International Study Group. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140(5): 346–355 Hsu YC, Ho HJ, Wu MS, Lin JT, Wu CY. Postoperative peg-interferon plus ribavirin is associated with reduced recurrence of hepatitis C virus-related hepatocellular carcinoma. Hepatology 2013;58(1): 150–157 Liang TJ, Ghany MG. Current and future therapies for hepatitis C virus infection. N Engl J Med 2013;368(20):1907–1917 Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al; AI444040 Study Group. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370(3): 211–221 Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370(20):1879–1888 Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014;370(21):1973–1982 Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 2003;38(2):200–207 Wu JC, Huang YH, Chau GY, et al. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol 2009;51(5):890–897 Hsia CC, Nakashima Y, Tabor E. Deletion mutants of the hepatitis B virus X gene in human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;241(3):726–729 Huang SF, Chen YT, Lee WC, et al. Identification of transforming hepatitis B virus S gene nonsense mutations derived from freely replicative viruses in hepatocellular carcinoma. PLoS ONE 2014; 9(2):e89753
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
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