Targeting Vascular Endothelial Growth Factor in Treatment of Hepatocellular Carcinoma

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Systemic antiangiogenesis therapies offer hope for liver cancer / Science Source
Systemic antiangiogenesis therapies offer hope for liver cancer / Science Source

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is associated with poor prognosis and high mortality.1 It is largely asymptomatic until later stages, with fewer than 30% of patients eligible for resection because of the advanced stage of disease at diagnosis.2,3

Effective systemic treatment is needed to help improve survival rates, which is currently estimated to be 26% at 5 years in the United States.4

Age-adjusted HCC rates have tripled since the 1980s; the age at diagnosis has also shifted to a younger generation, with the greatest proportional increase among persons ranging from 45 to 60 years of age.1 In the United States, where an estimated two in three persons infected with the hepatitis C virus (HCV) were born between 1945 and 1964, 50% to 60% of patients who currently have HCC are chronic hepatitis C virus (HCV) carriers. HCV-related HCC has seen the largest proportional increase and is expected to continue rising over the next few decades.1

Rationale for Angiogenesis Inhibition

As in other arenas of oncology, targeted therapies are of great interest in treating HCC. These tumors develop in a step-wise fashion, where overactivation of the Raf/MEK/ERK mitogen-activated pathway appears to be crucial in tumor development.5 Raf/MEK/ERK can be activated through several mechanisms, including mutations in Raf, overexpression of growth factors, and hepatitis virus–related mechanisms. Once activated, this pathway stimulates proliferation and growth through vascular endothelial growth factor (VEGF)–mediated angiogenesis in a lengthy carcinogenic process that may take as long as 30 years before tumor development.5,6

HCC is a well-vascularized tumor that requires VEGF for growth and progression, which is present at higher levels at later disease stages. Its role in clinical outcome is underscored by the finding that higher VEGF levels following locoregional treatment correlate with poor prognosis.6,7 VEGF is more likely to be overexpressed in HCV-related HCC than in hepatitis B virus (HBV)–associated disease, with clinical implications for VEGF-targeted treatments in different populations.8

Systemic Therapies Targeting Hepatocellular Carcinoma

Sorafenib (Nexavar®) has been shown to be an effective systemic therapy for advanced HCC in patients with preserved liver function (Child-Pugh class A), particularly those with alcohol- or HCV-related cancer. Survival, however, is shorter for patients with HBV-related disease or Child-Pugh class B liver function.3 Due to its multiple antitumor effects, such as induction of apoptosis and inhibition of Raf kinases, VEGF receptors (VEGFR-2, VEGFR-3), platelet-derived growth factor-beta, and KIT,  sorafenib is approved for advanced, nonresectable HCC.

As monotherapy, sorafenib has demonstrated small but significant improvements compared with placebo in overall survival (OS; 2.3-2.8 months), time to progression (TTP; 1.4-2.7 months), and disease control rates (DCR; 11%-19%). Sorafenib combined with doxorubicin prolonged OS (13.7 vs. 6.5 months), TTP, and DCR (62% vs. 29%) compared with doxorubicin alone without adding significant toxicity.5 In clinical trials, sorafenib appears to be more effective in HCV- than HBV-associated HCC.5,7

Dermatologic toxicity, in particular hand-foot syndrome (HFS), is an issue, as are high rates of discontinuation due to adverse events (20%-38%) and loss of efficacy over time. Grade 3 HFS occurred at a rate of 8% in a pivotal phase 3 trial (SHARP) and 8.9% in a meta-analysis of sorafenib studies. There is also a potential for bleeding events. Poorer response rates and higher toxicity are seen in populations in Asia, where HBV-related disease is predominant and HCC rates, overall, are the highest in the world.7

Bevacizumab (Avastin®), a potent VEGF inhibitor, has been studied as monotherapy and in combination with other therapies for HCC. As monotherapy, bevacizumab is active and well tolerated, producing partial responses (PRs) in 14% of patients and DCR in 56%. In a 2012 French study, 12-month progression-free survival (PFS) with bevacizumab was 7% and 12-month OS was 30%.

With 27 months' follow-up, median PFS was 3 months and median OS was 8 months.9 When bevacizumab was combined with capecitabine/oxaliplatin or gemcitabine/oxaliplatin, no complete responses (CRs) were achieved; PR rates, on the other hand, were 20% and 18% and DCR rates were 77.5% and 42%, respectively.10

Bevacizumab also has been studied in combination with erlotinib to treat HCC. In clinical trials with heterogenous populations, results have been equivocal, with responses similar to that of erlotinib monotherapy, but lower than achieved with bevacizumab alone. In HCV-associated HCC, poor response may result from HCV activation of the Raf/MEK/ERK pathway, undermining the antitumor effect of bevacizumab.10-12 A systematic review of phase 2 bevacizumab trials in HCC found no unexpected toxicities associated with treatment.10 While not superior to sorafenib, bevacizumab may offer an alternative to patients resistant to or intolerant of sorafenib.

A combined treatment regimen of bevacizumab and sorafenib was studied in a phase 1 study of 17 patients with advanced or metastatic HCC; one PR was achieved and 10 patients experienced stable disease. A phase 2 study of combined bevacizumab and sorafenib is ongoing.13 

Looking to the Future: Latest Research in Antiangiogenesis       

Phase 1 or 2 trials with several other antiangiogenesis agents have also been reported.6 Ramucirumab, a VEGFR-2 inhibitor, showed activity in a phase 2 study, producing a DCR of 50% as first-line treatment in patients with HCC who had preserved liver function (Child-Pugh class A). The REACH study, a phase 3 trial with patients who experienced treatment failure with sorafenib is ongoing.7,14

Linifanib (ABT-869) is a multi-targeted VEGFR/PDGFR inhibitor. In a phase 2 study, where most of the 44 patients were Asian and 61% of patients had HBV-associated disease, the objective response rate was 9.1%, TTP was 3.7 months, and median OS was 9.7 months. Response and survival were higher when patients with Child-Pugh class A liver function were analyzed separately. Grade 3/4 toxicities noted were hypertension and fatigue. Linifanib is now being studied in a phase 3 trial as first-line treatment compared with sorafenib.7,15

Disappointments have also occurred. Vandetanib, a dual inhibitor of VEGFR/EGFR, produced insignificant trends in PFS and OS and did not differ from placebo in a phase 2 trial.16 Brivanib, a dual inhibitor of FGF/VEGF, delayed progression versus sorafenib in preclinical studies with a low incidence of grade 3/4 toxicities, but in phase 3 studies failed to prolong OS versus placebo in patients who experienced treatment failure with sorafenib or versus sorafenib in treatment-naive patients.7,14,17 A phase 3 trial with sunitinib, a dual EGFR/VEGF inhibitor approved for renal cell carcinoma and gastrointestinal stromal tumors was discontinued due to high toxicity in patients with HCC.7


Advanced HCC requiring systemic therapy remains a daunting clinical challenge. Sorafenib has become a standard of care for the patient population of HCC that have a Child Pugh class A score and those with HCV etiology.3 Results of several studies with bevacizumab suggest it may offer an alternative for patients with advanced HCC who experience treatment failure with sorafenib, or who cannot tolerate it; however, more investigation is needed.

Ramucirumab and linifanib, two newer antiangiogenesis agents, have shown promising results in phase 2 studies, and phase 3 studies are underway. However, experience with sunitinib and brivinib, both of which held promise before producing disappointing results in phase 3 studies, suggests that, until well-designed, larger trials are completed, enthusiasm should. Further research will better determine how management of patients with HCC can be improved over time.


1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2-12;142(6):1264-1273.

2. Mulder K. Koski S, Scarfe A, Chu Q, King K, Spratlin J. Antiangiogenic agents in advanced gastrointestinal malignancies: past, present, and a novel future. Oncotarget. 2010;1(7):515-529.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary cancers. Version 1.2013. Accessed July 3, 2013.

4. Maluccio M, Covey A. Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012;62:394-399.

5. Xie B, Wang DH, Spechler SJ. Sorafenib for the treatment of hepatocellular carcinoma: a systematic review. Dig Dis Sci. 2012;57(5):1122-1129.

6. Cervello M, McCubrey JA, Cusimano A, Lampiasi N, Azzolina A, Montalto G. Targeted therapy for hepatocellular carcinoma on the horizon. Oncotarget. 2012;3(3):236-260.

7. Frenette C, Gish R. Targeted systemic therapies for hepatocellular carcinoma: clinical perspectives, challenges and implications. World J Gastroenterol. 2012;18(6):498-506.

8. Shao YY, Hsieh M-S, Huang C-Y, et al. Vascular endothelial growth factor expression in hepatitis C virus-related advanced hepatocellular carcinoma compared with hepatitis B virus-related advanced HCC.  J Clin Oncol. 2013;31(Suppl):Abstract 4115.

9. Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist. 2012;17:1063-1072.

10. Fang P, Hu J, Cheng Z, et al. Efficacy and safety of bevacizumab for the treatment of advanced hepatocellular carcinoma: a systematic review of phase II trials. PLoS One. 2012;7(12):e49717

11. Philip PA, Mahoney MR, Holen KD, et al. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012;118:2424-2430.

12. Govindarajan R, Siegel E, Makhoul I, Williamson S. Bevacizumab and erlotinib in previously untreated hepatocellular carcinoma. Am J Clin Oncol. 2013;36(3):24-257.

13. Hubbard JM, Alberts SR, Loui WS, et al. Phase 1 evaluation of sorafenib and bevacizumab as first-line therapy in hepatocellular cancer: North Central Cancer Treatment Group trial N0745. J Clin Oncol. 2011;29(Suppl):Abstract 4116.

14. Zhu AX. New agents on the horizon in hepatocellular carcinoma. Ther Adv Med Oncol. 2013;5(1):41-50.

15. Toh HC, Chen PJ, Carr BI, et al. Phase 2 trial of linifanib (ABT-869) in patients with hepatocellular carcinoma. Cancer. 2013;119(2):380-387.

16. Hsu C, Yang TS, Huo TI, et al. Vandetanib in patients with inoperable hepatocellular carcinoma: phase II randomized, double-blind, placebo-controlled study. J Hepatol. 2012;56(5):1097-1103.

17. BRISK-FL study with investigational compound brivanib in hepatocellular carcinoma does not meet overall survival primary endpoint.  Accessed July 6, 2013.

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