Drug Discoveries & Therapeutics. 2013; 7(4):137-143.

137

Review DOI: 10.5582/ddt.2013.v7.4.137

Adjuvant therapy for hepatocellular carcinoma: Current situation
and prospects
Zhigang Wang, Guofeng Zhang, Jiacheng Wu, Mingku Jia*
Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The Second Affiliated Hospital of Jilin University, Changchun,
Jilin, China.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of Research on Cancer, approximately 670,000 new cases
the most common malignancies worldwide, accounting of HCC develop per year (1), making it the fifth most
for 90% of primary liver cancers, and its incidence common cancer and the third most common cause of
is still increasing. While the curative treatment for cancer related death worldwide. The risk factors for HCC
HCC is surgical resection and liver transplantation, include infection with HBV or HCV, aflatoxin B1 intake,
most patients are in advanced stage, and lose the alcohol consumption, non-alcoholic fatty liver disease
chance of surgery. Other palliative treatments include (NAFLD), and some hereditary diseases, including
radiofrequency ablation, transarterial embolization, hereditary hemochromatosis (2). Most HCC cases occur
chemotherapy, and radiotherapy. Although there are in Eastern Asia and sub-Saharan Africa, while low rate
so many treatments, the prognosis of HCC is still very areas are found in North America, northern Europe and
poor. A major obstacle for the treatment for HCC is Australia (3,4). Generally, only less than 30-40% of HCC
the high frequency of tumor recurrence even after patients are eligible for potentially curative therapies
curative resection and liver transplantation. Since HCC including surgical resection and transplantation because
is frequently resistant to conventional chemotherapy patients are often diagnosed at an advanced stage, losing
and radiotherapy, clinical development of novel the surgery opportunity (5,6). For other patients with
therapeutic agents against HCC has begun in earnest. unresectable HCC, transarterial chemoembolization
Thus far, a series of adjuvant therapies for HCC have (TACE) offers a definite survival benefit, although its
emerged, including small molecular target agents, use is often limited by the presence of vascular invasion
monocolonal antibodies, microRNA, and Chinese or extrahepatic spread (7,8). Systemic therapies are
herbal medicine. Some agents such as sorafenib have consequently indicated for a substantial portion of
shown an advantage in prolonging the overall survival patients with advanced HCC. There had been no proven
time, and has been approved by FDA for the treatment effective systemic therapy for patients with advanced
of advanced HCC. In this article we review the current HCC until sorafenib showed a survival benefit in
situation and prospects of adjuvant therapies for HCC. such patients in two randomized controlled trials (the
Sorafenib HCC Assessment Randomized Protocol
Keywords: Hepatocellular carcinoma (HCC), adjuvant (SHARP), and Efficacy and Safety of Sorafenib in
therapy, molecular targeted therapy, micro RNA (miRNA), Patients in the Asia-Pacific Region with Advanced
Chinese herbal medicine Hepatocellular Carcinoma: a Phase III Randomized,
Double-blind, Placebo-controlled Trial (AP)) (9,10). And
now more and more adjuvant treatments have been used
in the clinic, including small molecular target agents,
1. Introduction monocolonal antibodies, and Chinese herbal medicine.
Some of these treatments have shown superiority to
Hepatocellular carcinoma (HCC) is the most common conventional chemotherapy, but all of these did not
liver cancer, accounting for 90% of primary liver reach an ideal objective. In this review we will keep
cancers. According to the International Agency for the focus on the current situation and prospect of those
adjuvant therapies and the combination of them with
other treatments such as percutaneous ablation, TACE,
*Address correspondence to:
conventional chemotherapy, and radiotherapy.
Dr. Mingku Jia, Hepato-Biliary-Pancreatic Surgery
Division, Department of Surgery, The Second Affiliated
Hospital of Jilin University, Changchun, Jilin 130041, 2. Signal pathway in HCC
China.
E-mail: flybirdgang@hotail.com The key signal transduction pathways that have been

www.ddtjournal.com

8 months in tested and control group. suggesting that the combined treatment of sorafenib and radiotherapy was feasible (12). SHARP and AP.7 months (SHARP) and 6.75 months 25-28 AZD6244 Preclinical MEK-ERK --. and the VEGFR can be inhibited by sorafenib. Sorafenib is a multikinase inhibitor. 23 TSU-68 Phase II VEGFR-2 13. linifanib. cederanib. the overall survival times were 10. Wnt/β-catenin. BAY43-9006) is currently the most promising molecular targeting drug for HCC. and linifanib. and bevacizumab. The two trials demonstrated that sorafenib is effective in prolonging median survival and time-to- progression in patients with advanced HCC.7 months 31. We have generalized the resistance to apoptosis. c-Met can be inhibited deleted on chromosome ten (PTEN)/Akt/mammalian by tivantinib and forentinib. 7(4):137-143.34 Tivantinib Phase II c-Met 7. And mTOR can be inhibited 1). Small molecular agents for HCC Agent Stage of development Target Overall survial time Reference Sorafenib FDA approved VEGFR/PDGFR-β/Flt-3 /c-Kit 10. sunitinib. sorafenib. molecules in these signal pathways. the stimulation relationships between signal pathways and molecule targeted agents in Figure 1 and Table 1. in the treatment of HCC than doxorubicin (13). and c-Kit.30 Linifanib Phase II VEGF/PDGFR 9.1. but all of them did not reach ideal results. Scientists have strived to combine sorafenib with other treatments. platelet-derived that have been approved have an effect to inhibit critical growth factor (PDGF)/PDGF receptor (PDGFR).7 months 10-13 Sunitinib FDA approved PDGF/VEGF/kIt/Flt/cSF-1/RET-receptor 9. Small molecular target agents 3. invasiveness and metastasis. Ras/Raf/mitogen-extracellular activated protein kinase vatalanib. FGFR kinase (PI3K)/phosphatase and the tensin homologue can be inhibited by brivanib. 3. which in addition to targeting Raf kinases also inhibits VEGFR-2/-3. cederanib.5 months (AP). insulin.7 months and 7. For example. Inhibiting mediated by epidermal growth factor (EGF)/EGF some of the targets of the signal pathways may exhibit receptor (EGFR).ddtjournal. Some agents (VEGF)/VEGF receptor (VEGFR). Sorafenib plus Figure 1. i) Sorafenib combined with radiotherapy: The median overall survival time was 15. kinase (MEK)/extracellular signal-regulated kinase PDGFR can be inhibited by regorafenib.2 months 36 www. (ERK). like growth factor (IGF)/IGF receptor (IGFR).138 Drug Discoveries & Therapeutics. respectively.com .32 Regorafenib Phase II VEGFR1-3/TIE2 13. and phosphatidylinositol-3. 2013. Table 1. Signal pathways in hepatocytes and the targets doxorubicin appears to be well tolerated and more effective of molecular target drugs.3 months 14-17 Brivinib Phase III EGF/FGFR 9. PDGFR-β.8 months 33. respectively. sorafenib has been approved by the United States (US) Food and Drug Administration (FDA) for the treatment of patients with advanced HCC (10. implicated in the pathogenesis of HCC include those of angiogenesis. cell proliferation. ii) Sorafenib combined with doxorubicin: The disease control rate for 16 evaluable patients was 69% and 40% in tested and control group.11). 29. Sorafenib Sorafenib (Nexavar. sunitinib. On the basis of two large randomized phase III studies. RAF can be inhibited by target of rapamycin (mTOR) signaling pathways (Figure sorafenib and regorafen. Flt- 3.1 months 24 Erlotinib Phase II EGFR 10. vatalanib. vascular endothelial growth factor an inhibitory effect on tumor progression.2 months 18-22 Foretinib Preclinical HGF/VEGF --. Activation of these pathways will eventually lead to by sorafenib andregorafen.

Brivanib has a single ERK pathway by AZD6244 enhanced the anti-tumor asymmetric center derived from a secondary alcohol (19). control benefit in HCC (25).2 months observed in the phase II study of sorafenib in and PDGFR.17). but the median overall survival was similar to Linifanib (ABT-869) is a selective inhibitor of VEGFR 9. TSU-68 of sunitinib using different methods.7 months observed advanced HCC patients received oral linifanib at a daily in the SHARP study. the median overall survival was 10.75 off treatment).8. Commonly observed advanced HCC. giving erlotinib is well tolerated and has a modest disease- an overall objective response rate of 2. sub-G1 component of the cell cycle in the Hep3B cell line (15). Flt3. and (iii) sorafenib plus AZD6244.8%) that were possibly related (26-28). MEK-ERK pathway in patients with advanced HCC (29). encouraging results in patients with advanced HCC. the trial did not proceed to the second stage. 13.5.1. sunitinib moderately inhibited proliferation of the c-Kit.3. In this trial. In a preclinical trial Huh7.3%). 10.7% (95% CI 0. 2013. In a preclinical trial families. disease stabilization duration. Erlotinib as the best response achieved. Brivanib is a dual inhibitor of VEGFR and fibroblast (ii) AZD6244.9. cSF1. On the basis of these results. but further phase III AZD6244 is an oral tyrosine kinase inhibitor of the clinical trials are needed. Drug Discoveries & Therapeutics.5. in a phase I/ Cancer Research (SAKK) and Swiss Association for the II trial.ddtjournal. 7(4):137-143.5. PDGFR. neutropenia (9 of 37. There were four deaths Current results may help to guide future HCC studies among the 37 patients (10. kit.2.6. and anemia (4 of 37.8%). and Tie-2. AZD6244 suggested that sunitinib is a promising molecular agent with continuous oral administration. PDGFR. The result demonstrated that one (2. In other three phase II 14.7%) months. and RET-receptor. In this trial. and Erlotinib (Tarceva. Melville. the estimated progression-free rate at www. patient- derived HCC xenografts were treated with (i) sorafenib. and 9.8%). showing that the (14 of 37. USA) is an orally active.2).com . Linifanib manageable safety profile in patients with advanced HCC (20-22). Results growth factor receptor (FGFR) that are implicated in showed that pharmacological inhibition of the MEK/ the pathogenesis of HCC (18). One is 'Continuous Sunitinib Treatment in Patients with Advanced TSU-68 is an inhibitor of VEGFR-2. Phase II Study'. the median overall survival was 10. 10. potent selective respectively. The median PFS duration. 13 (35%) of 37 patients achieved studies of erlotinibin plus bevacizumab in patients with stable disease for over 3 months. followed by 2 weeks phase I/II trial. A preclinical trial combining AZD6244 with sorafenib 3.1 months.5%). 13. and Hepatocellular Carcinoma: A Swiss Group for Clinical FGFR. Results of this study indicated that single-agent patient experienced a confirmed partial response. Brivinib tested the effect of AZD6244. dose of 25 mg/kg. OSI-774. These two trials 3. and kinase inhibitor that targets members of the hepatocyte it can thereby impair tumor proliferation.7. the median overall survival was 13. patients received continuous safety profile in patients with advanced HCC (24). overall survival was 10 months. effect of sorafenib in both orthotopic and ectopic models Three phase II open-label studies showed that the median of HCC (30). In addition. A phase II study showed that when patients with advanced HCC and 10. and increased the S-phase and the patient-derived HCC xenograft models (23). VEGF1. Erlotinib inhibits EGF-dependent proliferation Carcinoma: an Open-label.7 grade 3 and 4 adverse events included thrombocytopenia months. overall survival time were 1. The other one was 'Safety and Efficacy inhibitor of the EGFR/HER-1-related tyrosine kinase of Sunitinib in Patients with Advanced Hepatocellular enzyme.5 months.3 months. NY. hand-foot syndrome (4 of 37. GSK1363089) is a small-molecule and β.5 mg daily). to treatment (16.3. 1. with additional inhibitory activity toward AXL. asthenia combination of bevacizumab with erlotinib achieved (5 of 37. sunitinib treatment (37. time to progression. 139 3. OSI Pharmaceuticals. Foretinib Sunitinib is a multikinase inhibitor that targets PDGF α Foretinib (XL880. 37. There were two phase II trials to test the effect 3. In a sunitinib (50 mg/day for 4 weeks.4. of cancer cells at submicromolar concentrations and Patients were treated with repeated cycles of oral blocks cell-cycle progression in the G1 phase. 2. 24. upregulated p53 in the p53-wild-type foretinib demonstrated significant antitumor activities in cell line SK-hep-1. and 9. Multicentre.7 months.8%). Flt-3. Sunitinib 3. Study of the Liver (SASL) Multicenter Phase II Trial showing promising preliminary efficacy and a high (SAKK 77/06)'. In patients with advanced HCC.5 cell line. pathological growth factor (HGF) and VEGF receptor tyrosine kinase angiogenesis and metastasis (14). Results demonstrated one complete response and a 40% rate of stable disease 3. Brivanib as first-line therapy demonstrates promising antitumor activity and a 3.

2. It showed characteristics. Tivantinib (ARQ 197) is a selective oral inhibitor of Phase I study results showed that the GPC3-derived c-Met (35). In a phase II study.46 Bevacizumab plus rapamycin Phase I VEGF --. proteoglycans that are attached to the cell surface by a in patients with advanced HCC that has progressed glycosyl-phosphatidylinositol anchor.9 months 45 www. PDGFR and FGFR). perhaps because it inhibits both VEGF and broad spectrum activity against several experimental EGF. has a distinct iv) Combining bevacizumab with capecitabine. and oncogenic kinases. Some regimens achieved promising results. oncogenesis (e. Regorafenib with erlotinib. They regulate the following first-line treatment with sorafenib. several studies revealed that the 4. miRNA-29C. factors with their respective signaling receptors.7 months. The result of all the treatments are shown in Table tumors (33). demonstrated it extended the time to progression of the result showed that either linifanib or rapamycin could HCC xenografts in mouse models and significantly significantly reduce tumor burden. such as miRNA-503. including: i) Combining bevacizumab 3.140 Drug Discoveries & Therapeutics.43 Bevacizumab capecitabine and oxaliplation Phase II VEGF 9. 9. miRNA-22. VEGFR1-3 and TIE2).10. 4. In two phase II treatment reduced tumors to the lowest volume. It is approved for treatment clinically active in patients with advanced HCC (31).com .9. Monocolonal antibodies expression of miRNA is deregulated in human HCC in comparison with matched non-neoplastic tissue. Glypicans are was 13. angiogenesis (e. A controlled phase II study showed that peptide vaccine was well tolerated (48). a sorafenib analog. bevacizumab showed good clinical and biologic was significantly better than single agent treatment.8 months 44 Bevacizumab plus capecitabine Phase II VEGF 5. In recent years. a second-line treatment of patients with advanced HCC and well-compensated liver cirrhosis. iii) Combining bevacizumab with TACE. Most of these miRNAs are downregulated Bevacizumab is a humanized recombinant monoclonal in HCC.8%. The effect and target of bevacizumab combined with other drug Combination Phase Target OS reference Bevacizumab plus erlotinib Phase II VEGF and EGF 15. The median overall survival was 7. Micro RNA (miRNA) patients with c-Met-high expression tumors (36).42. RET. Therefore. the median overall survival was antibody that binds all isoforms of circulating VEGF-A. This regulation is based on the ability of glypicans may overcome resistance to sorafenib remains to be to stimulate or inhibit the interaction of these growth investigated in future studies (34). 7(4):137-143. of several advanced solid tumors. including potent inhibition of several that bevacizumab combined with erlotinib has the angiogenic. The present study suggests that. it still had a vaccination was well-tolerated (49). activity. including can be beneficial. bevacizumab with other drugs. particularly for 5.45. In addition some studies treated with the combination treatment of ABT-869 and have examined the efficacies of treatments combining rapamycin (32).46).2 target for the treatment of HCC. GPC3 is a good promising result. ii) Combining bevacizumab with rapamycin. c-kit. 16 weeks was 31. and v) biochemical kinase inhibition profile and pharmacologic Combining bevacizumab with oxaliplation. stromal.1. regorafenib signaling activity of several growth factors. Regorafenib targets kinases involved in 2 (39-43. and longest OS. Another when tivantinib (ARQ 197) was used in patients who phase I study also showed that GPC3-derived peptide had received previous sorafenib treatment. and wild-type and V600-mutated 4. Preclinical studies When combined with rapamycin in a preclinical study.8 month 41. and studies. suggesting that single-agent linifanib was the main ligand of VEGFR. this glypican is not detected in normal and cirrhotic liver. 40 Bevacizumab plus TACE Phase II VEGF 10. median overall survival GPC3 is a member of the glypican family.g. while combination decreased microvessel density (37). tivantinib could provide an option for investigation. Glypican-3 (GPC3) BRAF) and the tumor microenvironment (e.g.8 months. 2013.6 month 39. indicating that it is a hopeful molecular agent These results suggested that HCC could potentially be for advanced HCC (38). or in benign hepatic lesions (47). The mechanism by which regorafenib Wnts. Table 2. It has been clearly established that whereas GPC3 is expressed 3. Bebacizumab These miRNAs were most likely involved in liver tumorigenesis. Regorafenib. but it still needs further months. Tivantinib by most HCCs.ddtjournal.g.

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