Journal of Liver Cancer

Volume 16(1); March 2016

Review Articles

Treatments Other than Sorafenib for Patients with Advanced Hepatocellular Carcinoma: Do Seon Song, Si Hyun Bae; J Liver Cancer. 2016;16(1):1-6. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.1

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Sorafenib is the standard treatment for advanced hepatocellular carcinoma according to the Barcelona Clinic Liver Cancer staging system. However, because of its unsatisfactory efficacy, adverse effects, and high cost, the use of sorafenib is limited, and other treatment modalities are required. Recent studies reported that treatment modalities other than sorafenib, such as hepatic arterial infusion chemotherapy and transarterial radioembolization, showed comparable or better response rates and survival rates than sorafenib. In this review, treatment modalities that could be used as alternatives to sorafenib will be discussed. (J Liver Cancer 2016;16:1-6)

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Phase I Radiation Dose-Escalation Study to Investigate the Dose-Limiting Toxicity of Concurrent Intra-Arterial Chemotherapy for Unresectable Hepatocellular Carcinoma
Yeona Cho, Jun Won Kim, Ja Kyung Kim, Kwan Sik Lee, Jung Il Lee, Hyun Woong Lee, Kwang-Hun Lee, Seung-Moon Joo, Jin Hong Lim, Ik Jae Lee
Cancers.2020; 12(6): 1612. CrossRef

Evaluation of the Outcome after Transarterial Chemoembolization; Refinement of Barcelona Clinic Liver Cancer Stage-B from Eastern Point of View: Namiki Izumi; J Liver Cancer. 2016;16(1):7-11. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.7

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Abstract PDF: Transarterial chemoembolization (TACE) is recommended as the first line treatment option for the patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), however, treatment strategy and evaluation of effects after TACE has not been fully established. Recently, sub-stage of BCLC stage B has been proposed and validated, but it should be validated including a large number of the patients and its refinement should be discussed. We have validated the sub-stage of BCLC stage B (B1-B4) by comparing overall survival after TACE, and there was no statistically significant difference in overall survival after TACE between B1 and B2. After excluding the patients with Child-Pugh point 7 from B1, the overall survival was significantly better than that of B2. Therefore, up-to-seven criteria is shown to be a reliable tool for the treatment strategy in the patients with intermediate stage of HCC. Refinement of sub-stage of BCLC stage B has been proposed by some other institutes, and it is important to establish novel treatment strategy for the patients with BCLC stage B after TACE to improve the prognosis of the patients after TACE, and to define the best timing for conversion to sorafenib or liver transplantation should be discussed. (J Liver Cancer 2016;16:7-11)

Experience and Expectation for Molecular Target Therapy in Hepatocellular Carcinoma: Do Young Kim; J Liver Cancer. 2016;16(1):12-16. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.12

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Abstract PDF: Sorafenib, the first-approved molecular targeted agent (MTA), is actively used in patients with advanced hepatocellular carcinoma (HCC) worldwide. Accumulating experiences suggest that the efficacy of this drug is modest and the adverse events are not minimal, although those are manageable. Given that newer drugs targeting various molecules involved in hepatocarcinogenesis have been failed to show efficacy compared with sorafenib, the perspectives regarding development of novel MTA appear to be gloomy. Nonetherless, it is necessary to maximize the efficacy of sorafenib by combining this drug with locoregional therapies and by finding biomarkers predicting the outcomes of patients treated with sorafenib. A series of data indicate that combining sorafenib and locoregional therapies including transarterial chemoemolization could improve patients outcome. Unfortunately, there has been no biomarkers identified which could predict the response to sorafenib. Global investigation of therapeutic decisions in HCC and of its treatment with sorafeNib (GIDEON) is a global, non-interventional, observational study to evaluate the safety and efficacy of sorafenib, particularly in patients with Child-Pugh B. The final report of GIDEON study is going to be published soon, and the Korean GIDEON data suggest that sorafenib in patients with decreased liver function might be safe and effective as in patients with Child-Pugh A. The way to conquer HCC using molecular approach is still long and the era of immune-oncology seems to get started. (Journal of Liver Cancer 2016;16:12-16)

Original Articles

Subclassification of Hepatocellular Carcinoma with Barcelona Clinic Liver Cancer Intermediate Stage: Hye Won Lee, Seung Up Kim, Jun Yong Park, Do Young Kim, Snag Hoon Ahn, Kwang-Hyub Han, Beom Kyung Kim; J Liver Cancer. 2016;16(1):17-22. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.17

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Abstract PDF: Background/Aims
Hepatocellular carcinoma (HCC) with Barcelona Clinic Liver Cancer (BCLC) intermediate stage includes a highly heterogeneous population. Here, we aimed to subclassify hepatocellular carcinoma with BCLC intermediate stage for better prognostification.
Methods
Between 2003 and 2008, 325 patients who were newly diagnosed as HCC with BCLC intermediate stage were considered eligible. Tumor factor and liver function were used for sub-classification. Overall survival (OS) was analyzed using Kaplan-Meier method with a comparison by log-rank test.
Results
A total of 325 patients with intermediate stage HCC were analyzed. Patients with tumor size ≥7 cm, tumor number ≥4 and Child-Pugh class B had the worse OS compared to those with tumor size <7 cm, tumor number <4 and Child-pugh class A, respectively (all P<0.05). These three variables affected the OS independently from multivariate Cox regression analysis (all P<0.05). So, using these three variables, patients were finally sub-classified as those with fulfilling none of three factors (B-a), one of three factors (B-b), two of three factors (B-c) and all of three factors (B-d) with the median OS of 39.2, 20.6, 12.0 and 8.3 months with statistical significances (all P<0.05 between B-a and B-b, between B-b and B-c, and between B-c and B-d), respectively.
Conclusions
Sub-classification of HCC with BCLC intermediate stage may be useful in not only prognostification but also guidance of treatment strategies. (J Liver Cancer 2016;16:17-22)

Survival Benefit of Antiviral Agents for Hepatocellular Carcinoma Patients Treated with Sorafenib: Jeong Han Kim, Hyung Min Yu, Yong Hwang, Soon Young Ko, Won Hyeok Choe, So Young Kwon; J Liver Cancer. 2016;16(1):23-30. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.23

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Abstract PDF: Background/Aims
Nucleos(t)ide analogues (NAs) help reduce the recurrence rate after the curative treatment of hepatitis B related hepatocellular carcinoma (HCC). Sorafenib has been shown to improve survival of advanced HCC patients. Whether antiviral therapy with NAs could help such patients is unknown. Our aim is to investigate the usefulness of antiviral therapy for advanced-stage HCC treated with sorafenib.
Methods
We performed a retrospective cohort study in advanced-stage HCC patients treated with sorafenib between June 2007 and December 2013. Patients in group A (the nonantiviral therapy group) were treated with sorafenib alone. Those in group B (the antiviral therapy group) were treated with sorafenib and NAs. Progression-free survival (PS) and overall survival (OS) were compared between these two groups.
Results
Finally, 23 patients in group A and 40 patients in group B were enrolled in the study. The mean number of days of treatment with sorafenib was 79 (34-231) days and 96 (33-449) days for group A and B, respectively (P=0.286). The mean PS of group A and B was 97 (14-449) days and 51 (0-461) days, respectively (P=0.068). The OS was 154 (44-741) days in group A and 138 (30-1,025) days in group B (P=0.665). PS and OS showed no significant difference between the two groups.
Conclusions
This study shows that there was no significant survival gain of using antiviral therapy in patients with advanced-stage HCC treated with sorafenib. In consideration of costeffectiveness, antiviral therapy may be not mandatory. (J Liver Cancer 2016;16:23-30)

Confirmation of HIF-1α Independent Pathway in the Progression of HepG2 Cells by Hypoxic Condition: Sang Woo Lee, Jae Uk Chong, Seon Ok Min, Kyung Sik Kim; J Liver Cancer. 2016;16(1):31-37. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.31

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Abstract PDF: Background/Aims
When hepatocellular carcinoma (HCC) is exposed to hypoxic condition, HIF-1α is activated and results in angiogenesis and increased tumor burden. Although inhibition of HIF-1α may reduce tumor growth, there are some limitations to control tumor growth completely. For a more effective therapy for HCC, we investigated HIF-1α independent pathway related tumor growth with angiogenesis.
Methods
We cultured HepG2 cells (HCC cell line) in both normoxia and hypoxia conditions. These cells were divided into three groups: a echinomycin treated group, a echinomycin and quinazoline treated group and a control group without any treatments. Growth morphologies of cells were observed with a microscope after 24 hours. Immunocytochemistry assay was done to detect the angiogenesis during inhibition of HIF-1α and/or NF-κB in hypoxia condition, and compared with results in normoxia condition.
Results
In normoxia, the expression of HIF-1α on tumor growth was not found. In hypoxia, inhibition of HIF-1α reduced the tumor growth compared to the control group. But, inhibition of both HIF-1α and NF-κB did not show apparent reduction of tumor growth as shown in HIF- 1α only group.
Conclusions
Signaling pathways related to cancer cell growth exist through a vast network. Inhibition of one target molecule may result in over-expression of other molecules related to the tumor growth. For an effective therapy in blocking of the tumor growth, more comprehensive understanding of the network related to signaling pathways on tumor growth is necessary. (J Liver Cancer 2016;16:31-37)

Case Reports

Long Term Survival in Patient with Hepatocellular Carcinoma after Surgical Resection of Brain Metastasis: A Case Report: Jeong-Ho Lee, Hyung-Min Yu, Sung-Bum Cho; J Liver Cancer. 2016;16(1):38-41. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.38

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Abstract PDF: Brain metastasis is a rare condition of extraheptaic metastases in hepatocellular carcinoma (HCC). Patients with hepatocellular carcinoma and brain metastasis have rapidly worsened neurologic signs and symptoms, therefore it is regarded to oncologic emergency. Current recommended treatments for brain metastasis are surgical resection or gamma-knife surgery with/without whole brain radiation therapy (RT). However, patients with brain metastasis have a very poor prognosis after adequate treatment. Here, we report a 62-year-old man with HCC and brain metastasis who had long term survival after surgical resection and whole brain RT. (J Liver Cancer 2016;16:38-41)

A Case of Rapid Progressive Extrahepatic Metastasis of Hepatocellular Carcinoma after Surgical Resection for Huge Single Mass: Eun Sun Jang, Haeryoung Kim, Young Rok Choi, Jai Young Cho, Yoo-Seok Yoon, Ho-Seong Han, Ji Hyun Kim, Jin-Wook Kim, Sook-Hyang Jeong; J Liver Cancer. 2016;16(1):42-46. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.42

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Abstract PDF: Hepatocellular carcinoma (HCC) shows a poor prognosis with high recurrence rate even after surgical resection. To improve prognosis of HCC patient, regular surveillance for high-risk group is recommended, but cost-benefit of the surveillance under 40 years old Asian male with hepatitis B infection is unclear. We share a 39-year-old male case which showed early recurrence and rapid extrahepatic metastasis after surgical resection for single huge HCC. Based on the pathologic finding, this case was diagnosed with ‘stemness’-related markerexpressing HCC. Further molecular classification for HCC could be beneficial to estimate individual risk for HCC recurrence and to predict prognosis.

Complete Response of Single Nodular Large Hepatocellular Carcinoma with Pulmonary Metastasis by Sequential Transarterial Chemoembolization and Sorafenib: A Case Report: Gi-Hyun Kim, Hyung-Min Yu, Chae-June Lim, Sung-Bum Cho; J Liver Cancer. 2016;16(1):47-51. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.47

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Abstract PDF: Current guidelines recommend sorafenib as the first-line molecular target agent for advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis and unresectable HCC. Sorafenib was reported to show survival benefit for patients with advanced HCC. However, complete response is extremely rare in patients treated with sorafenib. Here, we report a 52-year-old man with advanced HCC and pulmonary metastasis who showed complete response by sequential transarterial chemoembolization and continuous sorafenib. Complete response was sustained for 53-month until now.

A Case of Complete Response by Multidisciplinary Management in a Patient with Solitary Bone Metastasis after Curative Resection of Hepatocellular Carcinoma: Seawon Hwang, Hyun Yang, Hae Lim Lee, Jeong Won Jang, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon; J Liver Cancer. 2016;16(1):52-56. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.52

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Abstract PDF: Despite recent advances in the treatment of hepatocellular carcinoma (HCC), the prognosis of patients with extrahepatic metastasis from HCC still remains dismal. The current study presents a case of HCC that was metastatic to the pelvis and describes successful treatment with multidisciplinary approach to the skeletal metastasis. The patient was a 67-year-old male who presented with right pelvic pain 28 months following right hepatectomy for HCC. Computed tomography and magnetic resonance imaging indicated a solitary bone metastasis without intrahepatic recurrence. Complete response was achieved with multidisciplinary management including sorafenib, transarterial embolization, surgery to remove the metastatic mass and radiotherapy after surgery. A post-operative follow-up 15 months later found that the patient remained in good health with maintained complete response. This case suggests that a multidisciplinary approach can achieve long-term cancer-free survival and prolonged life expectancy beyond palliative care for patients with solitary bone metastasis after curative surgery for HCC.

Regression of Advanced Hepatocellular Carcinoma with Lung Metastasis in Response to Sorafenib: Dae-ha Kim, Gee ho Min, Dong-won Lee, Ke Ryun Ahn, Ji Hye Kim, Snag-Jun Suh, Young Kul Jung, Hyung Joon Yim; J Liver Cancer. 2016;16(1):57-62. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.57

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Abstract PDF: Sorafenib is a multi-targeted tyrosine kinase inhibitor that inhibits Raf kinase and the vascular endothelial growth factor receptor intracellular kinase pathway and is the first agent to demonstrate a statistically significant improvement in overall survival for patients with advanced hepatocellular carcinoma (HCC). However, there were few cases of partial or complete response reported in the previous studies. We herein report a case of dramatic partial response in a patient who had advanced HCC with multiple lung metastasis and portal vein thrombosis treated with sorafenib.

A Case of Complete Remission in Patient with Extrahepatic Metastasis after Curative Resection of Hepatocellular Carcinoma by Radiotherapy, Lung Resection and Systemic Chemotherapy: Yeong Jin Kim, Hye won Lee, Ji Hoon Lee, Jin Sil Sung, Do Young Kim; J Liver Cancer. 2016;16(1):63-66. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.63

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Abstract PDF: Surgical resection is mainstay treatment of hepatocellular carcinoma (HCC). However, its prognosis is poor, because of the high incidence of HCC recurrence (cumulative 5-year HCC recurrence rate of 70-80%). The most common site of HCC recurrence is the remnant liver, and extrahepatic recurrence occurs in 6.7-13.5% of patients. Because the tumor characteristics in extrahepatic recurrence are usually multiple and aggressive, the optimal treatment modality has not yet been determined. We report a case of complete remission and long term survival over 60 months in patient with extrahepatic metastasis after curative resection of HCC by aggressive treatment, which include lung resection for lung metastasis, radiotherapy for mediastinal lymph node metastasis, and systemic chemotherapy.

Retraction: A Case of Rapid Progression of Hepatocellular Carcinoma after Radiofrequency Ablation: Keol Lee, Geum-Youn Gwak, Yong-Han Paik, Moon Seok Choi, Joon Hyeok Lee, Kwang Cheol Koh, Seung Woon Paik, Dong Hyun Sinn; J Liver Cancer. 2016;16(1):67-67. Published online March 31, 2016; DOI: https://doi.org/10.17998/jlc.16.1.67

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Abstract PDF: This paper (“A case of rapid progression of hepatocellular carcinoma after radiofrequency ablation” by Lee K, et al from Journal of Liver Cancer 2015;15(2):118-121) has been retracted because of the several figures (Fig. 1A, Fig. 3A, and Fig. 4) of the paper1 were identical to those of the previous published original article2 without agreement of the copyright holder. The authors informed that they will take full responsibility for this unintended duplicate publication of figures caused by lack of communication, and wish to apologize to readers of the journal for any convenience. To preserve scientific integrity, Journal of Liver Cancer agreed with the authors that this paper be retracted.

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