Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2013 Mar 13.
Published in final edited form as: Dig Dis Sci. 2012 Mar 27;57(5):1122–1129. doi: 10.1007/s10620-012-2136-1

Sorafenib for the Treatment of Hepatocellular Carcinoma: A Systematic Review

Bingru Xie 1, David H Wang 1, Stuart Jon Spechler 1
PMCID: PMC3596114  NIHMSID: NIHMS430705  PMID: 22451120

Abstract

Background

Sorafenib, a drug that inhibits Raf serine/threonine kinases mediating cell proliferation and receptor tyrosine kinases involved in angiogenesis, is approved for the treatment of advanced hepatocellular carcinoma (HCC).

Aims

To explore the efficacy and safety of sorafenib for treating advanced HCC, and to identify clinical factors that might influence that efficacy and safety.

Methods

We conducted a systematic review using PRISMA guidelines to identify prospective studies on sorafenib used alone or in combination with systemic and/or locoregional anti-tumor therapies for treating advanced HCC.

Results

We identified 21 prospective trials of sorafenib treatment alone (7) or combined with other treatments (14). In randomized, placebo-controlled trials, sorafenib prolonged overall survival (OS) by 2.3 to 2.8 months, extended the time to tumor progression (TTP) by 1.4 to 2.7 months, and increased the disease control rate (DCR) by 11% to 19%. Studies with the highest percentage of hepatitis B patients showed the lowest OS and DCRs. Most studies described major side effects (diarrhea, fatigue and hand-foot syndrome) in <15% of patients, with higher rates in patients with advanced cirrhosis and those treated in combination with 5-FU drugs.

Conclusions

Sorafenib provides statistically significant, but clinically modest, improvements in OS, TTP and DCR. Patients with hepatitis B appear to have a poorer response than those with hepatitis C. The frequency of hand-foot syndrome appears to be higher when sorafenib is used in advanced cirrhosis and combined with 5-FU drugs. It is not clear that sorafenib combined with other treatments is more effective than sorafenib alone.

Keywords: sorafenib, hepatocellular carcinoma, cirrhosis, transarterial chemoembolization, systematic review

Background

Worldwide, liver cancer is the sixth most common malignancy and the third most common cause of cancer-related deaths.1 Hepatocellular carcinoma (HCC) accounts for 85% to 90% of all primary hepatic malignancies. 2, 3 Cirrhosis is the major risk factor for HCC, and 60% to 80% of these tumors arise in the setting of cirrhosis. The major chronic liver diseases underlying the development of cirrhosis and HCC include chronic viral hepatitis (B and C), non-alcoholic steatohepatitis, and alcoholic liver disease. In the United States, the incidence of HCC has increased from 1.4 cases per 100,000 in 1976–1980 to approximately 5 cases per 100,000 in 2003–2006. 4–6 A major factor underlying this rising incidence of HCC in Americans is the increased frequency of hepatitis C infection acquired in the 1960s and 1970s due to intravenous drug use, sexual contacts, and blood transfusion in the era prior to the availability of serologic tests for the hepatitis C. 7

HCC develops in a stepwise process that involves activation of oncogenes and inactivation of tumor suppressor genes through genetic and epigenetic alterations that develop in the setting of chronic hepatitis and cirrhosis. Alterations that cause over-activation of the Raf/MEK/ERK mitogen-activated protein (MAP) kinase signaling pathway appear to be particularly important in the development of HCC. 8–10 The MAP kinases are serine/threonine protein kinases that normally regulate a number of important cellular activities, such as proliferation and apoptosis. Abnormalities in cellular proliferation and apoptosis are key physiologic hallmarks of malignancy.

The Raf/MEK/ERK pathway can be over-activated through a variety of mechanisms including oncogenic mutations in the upstream Ras gene 11; over-expression of growth factors [e.g. platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF)] and their receptor tyrosine kinases that induce Raf activation; stimulation by the hepatitis B virus protein X (HBx) and PreS2-activator large surface protein; and stimulation by hepatitis C virus core proteins via signaling intermediates.12–14 Once the Raf/MEK/ERK pathway is activated, it can increase cell proliferation and survival directly, and can indirectly stimulate angiogenesis by increasing the production of VEGF and PDGF. 15 (Figure 1) These processes are required for tumor growth and, thus, the molecular components of the Raf/MEK/ERK signaling pathway are potential therapeutic targets for HCC. 16

Figure 1.

Figure 1

Open in a new tab

Sorafenib targets cell proliferation, apoptosis and angiogenesis. Red Xs indicate inhibition by sorafenib. Black arrows/lines indicate established pathways. Pink arrows/lines indicate proposed pathways affected by sorafenib. In tumor cells, sorafenib blocks the Raf/MEK/ERK pathway and induces apoptosis by inhibiting Raf isoforms. Sorafenib also appears to induce apoptosis through mechanisms independent of the Raf/MEK/ERK pathway including inhibition of eIF4E phosphorylation, and downregulation of Mcl-1. In vascular endothelial cells, sorafenib inhibits receptor tyrosine kinases involved in angiogenesis including VEGFR and PDGFR.

Sorafenib is a biaryl urea that blocks the Raf/MEK/ERK pathway by inhibiting Raf serine/threonine kinase isoforms (e.g. Raf-1, B-Raf). In addition, sorafenib also inhibits the upstream receptor tyrosine kinases that play important roles in angiogenesis including VEGFR-2, VEGFR-3, PDGFR-beta and Kit. Thus, sorafenib can induce tumor cell death and inhibit angiogenesis. Sorafenib also has been shown to induce apoptosis in several tumor cell lines through mechanisms that are not well established. 16, 17 Proposed mechanisms include inhibition of phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which (when phosphorylated) mediates the up-regulation of a number of oncogenic proteins, and the downregulation of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein. Both inhibition of eIF4E phosphorylation and loss of Mcl-1 have been documented in association with sorafenib-induced apoptosis, independent of the drug’s effects on the MEK/ERK pathway.18 The pro-apoptotic activity of sorafenib can be enhanced significantly by the addition of certain chemotherapeutic agents (e.g. gemcitabine) and by agents that inhibit signal transduction pathways (e.g. sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR) pathway). 19, 20 These observations suggest that the combination of sorafenib with chemotherapeutic agents or signal transduction inhibitors might have better anti-tumor activity than any of these agents given alone. 21

Sorafenib is the first FDA-approved systemic therapy for patients with advanced HCC not amenable to treatment by surgical resection or liver transplantation. In clinical practice, sorafenib generally is not given until such patients have failed to respond to locoregional therapies such as transcatheter arterial chemoembolization (TACE). A number of prospective clinical trials have assessed the anti-HCC effects of sorafenib alone, sorafenib with systemic chemotherapy, and sorafenib with locoregional therapy. We have conducted a systematic review of these studies to answer the following questions: (1) what is the efficacy of sorafenib in treating advanced HCC using overall survival, time to tumor progression and disease control rate as evaluating parameters? (2) What is the safety of sorafenib treatment using the rate of major (Grade 3 or 4) side effects as the evaluation parameter? (3) Does the efficacy of sorafenib treatment vary depending on gender, age, stage of cirrhosis, and etiology of the underlying liver disease (especially hepatitis B and hepatitis C)? (4) What sorafenib combined therapies have been assessed in prospective clinical trials? (5) Are there advantages of sorafenib combined treatment over sorafenib alone?

Material and Methods

Search Strategy

We followed the PRISMA recommendations for systematic literature analysis.22 We performed computer–based searches of the PubMed database 23 and the ISI Web of Science database 24 for clinical trials in original articles or conference abstracts between January 2000 and November 2011. We searched using combinations of the following terms: “sorafenib” or “nexavor” and “hepatocellular carcinoma” or “HCC” in the title or abstract fields. Clinical trials published in English were identified. We screened each abstract resulting from these searches for eligibility. We also examined reference lists of each selected original article or conference abstract and protocol registration system of clinical trials 25 to identify additional articles that might meet our eligibility requirements. Any discrepancies among reviewers were resolved by consensus discussion.

Selection of clinical trials

Article selection was determined a priori using the following inclusion criteria: (i) only adults were included in the clinical trial; (ii) only patients with advanced HCC were included; (iii) the study used sorafenib alone or sorafenib-based therapy combined with one or more other treatments (systemic or locoregional therapy). We excluded: (i) review articles, (ii) editorials; (iii) letters to the editor (iv) retrospective studies; (v) research protocols; (vi) duplicated records; (vii) sub-analyses of the same clinical trial; (viii) preliminary results if the final study results had been published; (ix) interim reports if the final results had been published; (x) studies including patients with other malignancies besides HCC.

Data abstraction

For the sorafenib treatment alone clinical trials, the following data were extracted from each report: publication type (original article or conference abstract) ; phase of the clinical trial; number of patients; percentage of men; median age of study participants; percentage of patients with Child Pugh score A, B or C; percentage of patients with hepatitis B or hepatitis C; overall survival (OS); time to tumor progression (TTP); disease control rate (DCR); and frequency of the three major adverse effects of sorafenib (hand-foot syndrome, diarrhea and fatigue). Extracted information for the sorafenib combined with other treatment clinical trials included all of the information extracted for the sorafenib alone trials plus information on the combined treatment regimen.

Results

Systematic Review Flow

The flow chart of the systematic review is shown in Figure 2. Our initial search yielded 133 articles including 14 from PUBMED and 119 from ISI Web of Science, clinical trial registry and relevant references. Ultimately, 21 prospective clinical trials were chosen for review including 7 of sorafenib treatment alone and 14 of sorafenib plus other treatments; sorafenib was combined with systemic chemotherapy in 9 trials and with locoregional therapy in the other 5 trials.

Figure 2.

Figure 2

Open in a new tab

Trial selection flow

Studies on Sorafenib-Alone Treatment

The 7 sorafenib-alone trials, which included a total of 1,072 patients, are summarized in Table 1. Two reports described phase 3 randomized, placebo-controlled clinical trials,26, 27 three described phase 2 trials 28–30 and two described phase 1 trials31, 32. The percentage of male patients ranged from 71% 28 to 100% 32. Median age ranged from 5127 to 72 years29. Among the five trials providing precise OS and TTP data 26–28, 30, 31, OS ranged from 5 30 to 15.6 months 31 and TTP ranged from 3 30 to 5.5 months 26 in the patients who received sorafenib. All seven reports described DCRs, which ranged from 26 % 30 to 82%31. All seven reports described major (grade 3 or 4) adverse events [hand-foot-syndrome (HFS), diarrhea and fatigue], with wide variations in frequency among reports. In patients who received sorafenib, the frequency of HFS ranged from 3% 26 to 27%31, diarrhea ranged from 0% 31 to 82% 32, and fatigue ranged from 0% 31 to 91% 31

Table 1.

Trials of treatment with sorafenib alone

Ref. Phase of trial No. of patients Male (%) Median age (years) CPS (A/B/C %) Etiology (HBV/HCV %) OS (months) TTP (months) DCR (%) AE (HFS/diarrhea/fatigue %)
[26] 3 (RPC) Sor 299 87 65 95/5/0 19/29 10.7 5.5 43 3/1/3
Pl 303 87 66 98/2/0 18/27 7.9 2.8 32 0.3/1/0.6
[27] 3 (RPC) Sor 150 85 51 97/3/0 71/11 6.5 2.8 35 11/6/3
Pl 76 87 52 97/3/0 78/4 4.2 1.4 16 0/1/0
[28] 2 137 71 69 72/28/0 17/48 9.2 4.2 36 5/8/10
[29] 2 16 88 72 NR NR >15 >3 64 6/6/6
[30] 2 51 88 56 71/26/3 90/6 5.0 3.0 26 16/20/8a
[31] 1 27 93 70 48/52/0 15/74 15.6 4.9 82 27/0/0
[32] 1 13 100 64 92/NR/NR 0/23 >2 NR 62 18/82/91a
Open in a new tab

AE, adverse effects grade 3/4; CPS, Child–Pugh score; DCR, disease control rate; HFS, hand–foot syndrome; OS, overall survival; Pl, placebo; RPC, randomized placebo-controlled; Sor, sorafenib; TTP, time to tumor progression; NR, not reported

a

Adverse effects of all grades

The SHARP and Asian-Pacific26, 27 studies were the two highest quality reports (phase 3 randomized, placebo-controlled trials). The large majority of patients in both studies had Child A cirrhosis (95% and 97%), but the frequency of hepatitis B infection was considerably higher in the Asian-Pacific trial (71% vs. 19%). For the sorafenib and placebo groups in the SHARP trial, the OS was 10.7 vs. 7.9 months (P<0.05) and the TTP was 5.5 vs. 2.8 months (P<0.05), respectively26. For the sorafenib and placebo groups in the Asian-Pacific trial, the OS was 6.5 vs. 4.2 months and the TTP was 2.8 months vs. 1.4 months, respectively27.

Among the six studies that provided data on Child-Pugh scores26–28, 30–32, most patients had Child A cirrhosis. The frequency of Child B patients ranged from 3% 27 to 52% 31, and only one study included any patients (two) with Child C cirrhosis 30. It appears that the development of HFS may be more frequent in patients with Child B cirrhosis. For example, the study with highest percentage of Child B patients (52%) also had the highest rate of HFS (27%) 31 among these seven trials. However, the large, phase II trial by Abou-Alfa et al., in which 28% of the total study population of 137 patients had Child B cirrhosis, had a relatively low frequency of HFS (5%).28

It appears that hepatitis B infection might adversely influence the response to sorafenib. The studies with the highest percentages of patients with hepatitis B also showed the lowest OS and DCRs. For example, the Honkong trial30, which had the highest percentage of hepatitis B patients (90%), described the lowest OS (5 months) and DCR (26%). In contrast, the Japanese trial, in which 74% of patients had hepatitis C, had the longest OS (15.6 months) and the highest DCR (82%)31.

Among 7 studies on sorafenib-alone that provided data on OS, 3 (43%) described an OS that clearly was >10 months. Among 6 studies on sorafenib-alone that provided data on TTP, none described a TTP >6 months. Among 7 studies on sorafenib-alone that provided data on DCR, 3 (43%) described a DCR >60%.

In summary, the seven studies summarized in Table 1 show that sorafenib-alone treatment results in statistically significant, but clinically modest, improvements in OS, TTP and DCR in patient populations comprised primarily of men under age 70 who have advanced HCC with Child A cirrhosis. Very few data are available on the effects of sorafenib in women, in patients older than age 70 years and in patients with advanced cirrhosis. Patients with hepatitis B appear to have a poorer response to sorafenib-alone treatment than patients with hepatitis C, and side effects of sorafenib are frequent, especially in patients with advanced cirrhosis.

Studies on Sorafenib Combined with Other Treatments

The 14 studies on sorafenib combined with other treatments, which included a total of 470 patients, are summarized in Table 2. Ten studies were Phase 2 trials 33–41, Pawlik, 3 were phase 1 trials 42–44 and one was a phase 1/2 trial 45. Nine studies used sorafenib combined with other systemic therapies33–39, 42, 43, and 5 used sorafenib combined with locoregional therapies.40, 41, 44, 45 Pawlik Most of the reports are relatively small case series describing preliminary results, and complete data on patient populations and outcomes often are not provided. Nevertheless, the patient populations appear similar to those of the sorafenib-alone trials, comprising predominantly men under age 70 who have advanced HCC with Child A cirrhosis. OS ranged from 7.4 months38 to 13.7 months 37, TTP ranged from 3.7 months 38 to 7.6 months 34, and DCRs ranged from 48% 34 to 100 % 41. There was only one randomized, controlled trial37 in which patients received doxorubicin plus sorafenib or doxorubicin plus placebo. Compared to the 49 patients who received doxorubicin plus placebo, the 47 patients treated with doxorubicin and sorafenib had significantly better OS (13.7 vs. 6.5 months), TTP (6.4 vs. 2.8 months) and DCR (62% vs. 29%). Generally, the frequency of side effects described in these studies is similar to that for patients treated with sorafenib alone. However, the frequency of hand-foot syndrome was especially high in a study in which sorafenib was combined with 5-FU (55%)34, and another in which sorafenib was combined with oxaliplatin and the 5-FU pro-drug capecitabine (73%) 36. In one study in which sorafenib was combined with tegafur (another 5-FU pro-drug), however, the frequency of hand-foot syndrome was only 9% 38.

Table 2.

Trials of sorafenib combined with other treatment

Ref. Phase of trial Regimen No. of patients Male (%) Median age (years) CPS (A/B/C %) Etiology (HBV/HCV %) OS (months) TTP (months) DCR (%) AE (HFS/diarrhea/fatigue %)
[36] 2 (RPC) Dox ? Sor 47 66 66 100/0/0 NR 13.7 6.4 62 6/11/6
Dox ? Pl 49 86 65 96/4/0 NR 6.5 2.8 29 0/8/6
[33] 2 Oct ? Sor 50 86 NR 78/22/0 68/22 11.0 7.0 78 2/5/2
[34] 2 5FU ? Sor 38 84 68 92/8/0 NR 12.2 7.6 48 55/13/NR
[35] 2 Mit-c ? Sor 22 NR NR NR NR NR NR 77 NR
[35] 2 Cap ? Oxa ? Sor 51 NR 58 98/NR/NR 84/NR 10.2 7.1 75 73/69/NR
[37] 2 TU ? Sor 53 89 57 100/0/0 72/25 7.4 3.7 57 9/2/15
[38] 2 Cis ? Gem ? Sor 11 77 67 NR NR NR NR 63 13/13/NR
[39] 2 TACE ? Sor 38 NR NR NR NR NR NR NR 20 Overall
[40] 2 TACE ? Dox ? Sor 19 NR 65 95/NR/NR NR NR NR 100 NR
[45] 2 TACE ? DEB ? Sor 35 74 63 89/11/0 6/37 NR NR 95 21/0/36
[44] 1 and 2 TACE ? Sor 12 83 71 92/8/0 NR NR NR 58 58 Overall
[42] 1 AVE1642 ? Sor 13 77 70 100/0/0 NR NR NR 77 NR
[41] 1 Dox ? Sor 18 94 56 NR NR NR NR 69 11/17/22
[43] 1 TACE ? Sor 14 78 64 93/7/0 0/29 NR NR NR 21/7/NR
Open in a new tab

AE, adverse effects; Cap, capecitabine; Cis, cisplatin; CPS, Child–Pugh score; DCR, disease control rate; DEB, doxorubicin-elutingbeads; Dox, doxirubicin; Gem, gemcitabine; HFS, hand–foot syndrome; Mit-c, mitomycin-c; Oct, octreotide; OS, overall survival; Oxa, oxaliplatin; Pl, placebo; RPC, randomized placebo-controlled; Sor, sorafenib; TTP, time to tumor progress; TU, tegafur/uracil; NR not reported

Among 5 studies on sorafenib combined with other treatments that provided data on OS, 4 (80%) described an OS that was >10 months. Among 5 studies on sorafenib combined with other treatments that provided data on TTP, 4 (80%) described a TTP >6 months. Among 11 studies on sorafenib combined with other treatments that provided data on DCR, 8 (73%) described a DCR >60%.

In summary, studies of sorafenib combined with other treatments have patient populations similar to those of sorafenib-alone studies (i.e. they are comprised primarily of men under age 70 who have advanced HCC with Child A cirrhosis). The number of patients included in each study generally is considerably smaller than that of the sorafenib-alone studies. Overall, reports on sorafenib combined with other treatments describe better OS, TTP and DCR than those described in reports on sorafenib alone, but the studies are not directly comparable. The combination of sorafenib with other agents does not appear to result in inordinate toxicity, but hand-foot syndrome appears to be especially frequent when sorafenib is combined with 5-FU or some of its derivatives.

Discussion

This systematic review shows that sorafenib treatment results in statistically significant, but clinically modest, improvements in OS, TTP and DCR in patient populations comprised predominantly of men under age 70 with advanced HCC and Child A cirrhosis. In two randomized, placebo-controlled trials, sorafenib treatment prolonged OS by 2.3 to 2.8 months (from 4.2 to 6.5 months in one study 27, and from 7.9 to 10.7 months in the other 26), extended the TTP by 1.4 to 2.7 months (from 1.4 to 2.8 months in one study 27, and from 2.8 to 5.5 months in the other 26), and increased the DCR by 11% to 19% (from 16% to 35% in one study 27, and from 32% to 43% in the other 26). Uncontrolled studies of sorafenib alone have described an OS as long as 15.6 months and a DCR as high as 82% but, with no control group, the contribution of sorafenib to these outcomes is not clear.

The most frequently described side effects of sorafenib are diarrhea, fatigue and hand-foot syndrome (palmoplantar erythrodysesthesia), a troublesome condition characterized by painful, erythematous, blistering patches and plaques that involve the palms and soles of the feet primarily. Hand-foot syndrome has been associated with a number of antineoplastic agents, especially 5-fluoruracil (5-FU) and its derivatives, and the pathogenesis is not understood46. In most of the reports included in this systematic review, major side effects of sorafenib were described in fewer than 15% of patients. However, the frequency of adverse events varied widely among studies, with some reports describing major side effects in more than 90% of cases. Our review suggests that advanced cirrhosis might predispose to the development of hand-foot syndrome with sorafenib treatment. The study of sorafenib-alone treatment that had the highest percentage of patients with Child B cirrhosis (52%) also had the highest rate of hand-foot syndrome (27%) 31. However, most studies included too few patients with advanced cirrhosis (i.e. Child B and C) to establish this association. Our review also suggests that hand-foot syndrome might be especially likely when sorafenib is combined with 5-FU or some of its derivatives. The frequency of hand-foot syndrome was 55% in a study in which sorafenib was combined with 5-FU 34, and 73% in a study in which sorafenib was combined with oxaliplatin and capecitabine, a pro-drug that is enzymatically converted to 5-FU36. However, the frequency of hand-foot syndrome was not inordinately high (9%) in one study in which sorafenib was combined with tegafur, another 5-FU pro-drug38.

It is not possible to establish meaningful conclusions on the safety and efficacy of sorafenib for the treatment of HCC in women, the elderly, and patients with advanced cirrhosis (Child B and C). The large majority of patients included in the reports identified by our systematic review were men under the age of 70 who had HCC associated with Child A cirrhosis. Our systematic review does suggest that patients with hepatitis B infection might have a poorer response to sorafenib treatment than patients with hepatitis C. The trial with the highest percentage of hepatitis B patients (90%) described the lowest OS (5 months) and DCR (26%)30, whereas the trial with the highest percentage of hepatitis C patients (74%) had the longest OS (15.6 months) and the highest DCR (82%) 31. Further studies that directly compare the response to sorafenib in patients who have HCC associated with hepatitis B and C are needed to establish this relationship.

Prospective studies on the treatment of HCC have evaluated the safety and efficacy of sorafenib combined with a number of systemic chemotherapeutic agents including the anthracycline antibiotic doxorubicin, pyrimidine analogues (5-FU, capecitabine, tegafur/uracil, gemcitabine), DNA crosslinking agents (mitomycin c, cisplatin, oxaliplatin), octreotide, and AVE1642 (a humanized monoclonal antibody that binds the insulin-like growth factor 1 receptor). In addition, prospective studies have evaluated sorafenib combined with TACE, in which a chemotherapeutic agent mixed with embolic material is administered through a catheter positioned in branches of the hepatic artery that supply the HCC. TACE creates a hypoxic environment for the residual tumor cells (Chan, 2002). This hypoxia stimulates those surviving cells to express VEGF, which can lead to neovascularization and reestablishment of the tumor’s blood supply (Shweiki, 1992) (Li, 2003) (Lee, 2002). Thus, an anti-angiogenesis agent like sorafenib, which can inhibit VEGF receptors, seems like a good choice for combination with TACE.

In general, the reports on sorafenib combined with other treatments summarized in Table 3 describe better OS, TTP and DCR than those described in reports on sorafenib alone. However, all but one of the studies on sorafenib combined with other treatments are relatively small and uncontrolled case series, and it is not appropriate to compare the results of these studies directly with those of the sorafenib-alone studies. The only published randomized, controlled trial of combined treatment found that patients who received doxorubicin and sorafenib had significantly better OS (13.7 vs. 6.5 months), TTP (6.4 vs. 2.8 months) and DCR (62% vs. 29%) than those treated with doxorubicin and placebo. This shows that sorafenib plus doxorubicin is better than doxorubicin alone, but does not establish that combination therapy is better than sorafenib alone. Well designed, placebo controlled studies in this area are sorely needed.

Acknowledgments

This work was supported by the Office of Medical Research, Department of Veterans Affairs and the National Institutes of Health (R01-CA134571)

Footnotes

There is no financial or personal interest to report.

References

  • 1.Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108. doi: 10.3322/canjclin.55.2.74. [DOI] [PubMed] [Google Scholar]
  • 2.Pons-Renedo F, Llovet JM. Hepatocellular carcinoma: a clinical update. MedGenMed. 2003;5:11. [PubMed] [Google Scholar]
  • 3.Cancer Facts & Figures 2010. American Cancer Society; Atlanta, Geogia: 2010. [Google Scholar]
  • 4.El-Serag HB. Epidemiology of hepatocellular carcinoma in USA. Hepatol Res. 2007;37 (Suppl 2):S88–94. doi: 10.1111/j.1872-034X.2007.00168.x. [DOI] [PubMed] [Google Scholar]
  • 5.El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817–23. doi: 10.7326/0003-4819-139-10-200311180-00009. [DOI] [PubMed] [Google Scholar]
  • 6.El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–50. doi: 10.1056/NEJM199903113401001. [DOI] [PubMed] [Google Scholar]
  • 7.NHANES III data. 2008 http://www.cdc.gov/NCIDOD/Diseases/hepatitis/c/plan/HCV_infection.htm.
  • 8.Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130:1117–28. doi: 10.1053/j.gastro.2006.01.006. [DOI] [PubMed] [Google Scholar]
  • 9.Marotta F, Vangieri B, Cecere A, et al. The pathogenesis of hepatocellular carcinoma is multifactorial event. Novel immunological treatment in prospect. Clin Ter. 2004;155:187–99. [PubMed] [Google Scholar]
  • 10.Avila MA, Berasain C, Sangro B, et al. New therapies for hepatocellular carcinoma. Oncogene. 2006;25:3866–84. doi: 10.1038/sj.onc.1209550. [DOI] [PubMed] [Google Scholar]
  • 11.Goodsell DS. The molecular perspective: the ras oncogene. Oncologist. 1999;4:263–4. [PubMed] [Google Scholar]
  • 12.Stockl L, Berting A, Malkowski B, et al. Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression. Oncogene. 2003;22:2604–10. doi: 10.1038/sj.onc.1206320. [DOI] [PubMed] [Google Scholar]
  • 13.Giambartolomei S, Covone F, Levrero M, et al. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the Hepatitis C Virus (HCV) core protein. Oncogene. 2001;20:2606–10. doi: 10.1038/sj.onc.1204372. [DOI] [PubMed] [Google Scholar]
  • 14.Shimotohno K, Watashi K, Tsuchihara K, et al. Hepatitis C virus and its roles in cell proliferation. J Gastroenterol. 2002;37 (Suppl 13):50–4. doi: 10.1007/BF02990100. [DOI] [PubMed] [Google Scholar]
  • 15.Gollob JA, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006;33:392–406. doi: 10.1053/j.seminoncol.2006.04.002. [DOI] [PubMed] [Google Scholar]
  • 16.Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109. doi: 10.1158/0008-5472.CAN-04-1443. [DOI] [PubMed] [Google Scholar]
  • 17.Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–40. doi: 10.1158/1535-7163.MCT-08-0013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Rahmani M, Davis EM, Bauer C, et al. Apoptosis induced by the kinase inhibitor BAY 43–9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280:35217–27. doi: 10.1074/jbc.M506551200. [DOI] [PubMed] [Google Scholar]
  • 19.Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43–9006. Oncogene. 2005;24:6861–9. doi: 10.1038/sj.onc.1208841. [DOI] [PubMed] [Google Scholar]
  • 20.Molhoek KR, Griesemann H, Shu J, et al. Human melanoma cytolysis by combined inhibition of mammalian target of rapamycin and vascular endothelial growth factor/vascular endothelial growth factor receptor-2. Cancer Res. 2008;68:4392–7. doi: 10.1158/0008-5472.CAN-07-5844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Takimoto CH, Awada A. Safety and anti-tumor activity of sorafenib (Nexavar) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol. 2008;61:535–48. doi: 10.1007/s00280-007-0639-9. [DOI] [PubMed] [Google Scholar]
  • 22.Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.http://www.ncbi.nlm.nih.gov/pubmed.
  • 24.http://www.isiknowledge.com.
  • 25.https://register.clinicaltrials.gov/.
  • 26.Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90. doi: 10.1056/NEJMoa0708857. [DOI] [PubMed] [Google Scholar]
  • 27.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;10:25–34. doi: 10.1016/S1470-2045(08)70285-7. [DOI] [PubMed] [Google Scholar]
  • 28.Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293–300. doi: 10.1200/JCO.2005.01.3441. [DOI] [PubMed] [Google Scholar]
  • 29.Massa ESC, et al. Efficacy, safety and impact on quality of life of a treatment with sorafenib in elderly cancer patients with advanced hepatocellular carcinoma. Result of a phase II study. Annals of Oncology. 2009;20 (Suppl 8):s65. [Google Scholar]
  • 30.Yau T, Chan P, Ng KK, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer. 2009;115:428–36. doi: 10.1002/cncr.24029. [DOI] [PubMed] [Google Scholar]
  • 31.Furuse J, Ishii H, Nakachi K, et al. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci. 2008;99:159–65. doi: 10.1111/j.1349-7006.2007.00648.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Castroagudin JFME, et al. Shor-term efficacy and safety of treatment of advanced hepatocellular carcinoma with sorafenib. Journal of Hepatology. 2008;48(362 Suppl 2):s141–s142. [Google Scholar]
  • 33.Prete SD, Montella L, Caraglia M, et al. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR study. Cancer Chemother Pharmacol. 2010;66:837–44. doi: 10.1007/s00280-009-1226-z. [DOI] [PubMed] [Google Scholar]
  • 34.Petrini ILM, et al. A phase II trial of sorafenib in combination with 5-fluorouracil continuous infusion in patients with advanced hepatocellular carcinoma: preliminary data. Journal of clinical oncology. 2009;27(15 Suppl):4592. [Google Scholar]
  • 35.Gianluca DML, et al. Prospective phase II study of combination sorafenib plus mitomycin-c in the treatment of advanced hepatocellular carcinoma. Annals of Oncology. 2009;63(Suppl 8):20. [Google Scholar]
  • 36.Yau TCP, et al. Phase II trial of sorafenib with capecitabine and oxaliplatin (SECOX) in patients with locally advanced or metastatic hepatocellular carcinoma. EJC supplements. 2009;7(3):20–21. [Google Scholar]
  • 37.Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154–60. doi: 10.1001/jama.2010.1672. [DOI] [PubMed] [Google Scholar]
  • 38.Hsu CH, Shen YC, Lin ZZ, et al. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol. 2010;53:126–31. doi: 10.1016/j.jhep.2010.01.035. [DOI] [PubMed] [Google Scholar]
  • 39.Giuliana FAR, et al. Sorafenib plus cisplatin and gemcitabine in the treatment of advanced hepatocellular carcinoma: a phase II study by the Grupo Oncologico Dell’Italia Meridonale. (PROT. GOIM 2705) Cancer treatment reviews. 2010;36(4 Suppl):S96. [Google Scholar]
  • 40.Erhardt AKF, et al. First-in-men demonstration of sorafenib pluse TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial) Hepatology. 2009;50(4 Suppl):1080A. [Google Scholar]
  • 41.Reyes DKAN, et al. Phase II trial of sorafenib wit hdoxirubicin eluting bead-transarterial chemoembolization (DEB-TACE) for patients with hepatocellular carcinoma: interim safety and efficacy analysis. Hepatology. 2009;50(6):6A–7A. LB9. [Google Scholar]
  • 42.Richly H, Schultheis B, Adamietz IA, et al. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial. Eur J Cancer. 2009;45:579–87. doi: 10.1016/j.ejca.2008.10.039. [DOI] [PubMed] [Google Scholar]
  • 43.Faivre SFL, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of AVE 1642, a human monoclonal antibody inhibiting the insulin-like grouth factor-1 receptor (IGF-1R/CD221), administered as single agent and in combination with sorafinib as first line therapy in patients with advanced hepatocellular carcinoma. Hepatology. 2010;52(4 Suppl S):466A, 288. [Google Scholar]
  • 44.Dufour JF, Hoppe H, Heim MH, et al. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist. 2010;15:1198–204. doi: 10.1634/theoncologist.2010-0180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Pinter MSW, et al. An interim safety analysis of sorafenib plus transarterial chemoembolization in hepatocellular carcinoma- A phase I/II pilot study (SORATACE-1 trial) Hepatology. 2010;52(4 Suppl):1157A, 1759. [Google Scholar]
  • 46.Yang CH, Lin WC, Chuang CK, et al. Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol. 2008;158:592–6. doi: 10.1111/j.1365-2133.2007.08357.x. [DOI] [PubMed] [Google Scholar]

RESOURCES