Sorafenib in treatment of patients with advanced hepatocellular carcinoma:a systematic review

Shanghai,China

Introduction

Liver cancer is the second most frequent cause of cancer death in men and the sixth leading cause of cancer death in women.[1]Among primary liver cancers,hepatocellular carcinoma (HCC) represents the major histological subtype,accounting for 70%-85% of the total liver cancer burden worldwide.[2]The prognosis for patients with HCC is dismal.[3,4]Up to the present,the 5-year survival rate of 60%-70% can be achieved in well-selected HCC patients after surgical or locoregional procedures,which are only suitable to 30%-40% of all patients at early stages.[4]Although patients with unresectable HCC can receive other palliative treatments such as transcatheter arterial chemoembolization(TACE),three-dimensional conformal radiotherapy,and cytotoxic chemotherapy,the therapeutic effect is limited.[5]Exploring new agents with better efficacy and safety is important in the treatment of patients with advanced HCC.

Recently,molecular targeted therapies have created an encouraging trend in the management of HCC.[6]Sorafenib,a molecular targeted therapeutic agent,was the first drug approved for the treatment of patients with unresectable HCC by the Food and Drug Administration of the USA.[7]Sorafenib,acting as a multi-kinase inhibitor,targets both cell surface tyrosine kinase receptors and downstream intracellular serine/threonine kinases in the Ras/MAPK cascade.[8-10]These kinases play key roles in tumor cell proliferation,apoptosis,and tumor angiogenesis.[8,9]

Although sorafenib has been reported to improve the overall survival (OS) of patients with advanced HCC,[11-13]the short improved survival time (about 3-6 months) and high expenditure for the drug made clinicians more careful to use sorafenib in treating advanced HCC.As a newly approved agent for treating advanced HCC,a meta-analysis is necessary to assess the true efficacy and safety of sorafenib for patients with advanced HCC.There has been a meta-analysis of sorafenib for advanced HCC,which was considered to be the first published meta-analysis of randomized trials of sorafenib versus placebo therapy in treating advanced HCC.[14]But two of the three included studies were published in the form of an abstract,which might provide no guarantee for data integrity and veracity.Meanwhile,this meta-analysis did not assess the effect of sorafenib on specific subgroups.As there were only three randomized controlled trials (RCTs)for sorafenib treatment,[11-13]the results from phase II single-arm clinical trials might be useful and should not be overlooked.[15-17]Based on these clinical data,we conducted a meta-analysis to access the true value of sorafenib in advanced HCC patients and explore the specific subgroups for sorafenib treatment and its toxicities,which might improve the efficacy and safety of sorafenib for HCC treatment.

Methods

Data collection

The aim of this meta-analysis was to include all available data from clinical trials of sorafenib in the treatment of advanced HCC.A computer-based systematic search of PubMed (MEDLINE),Embase,and Web of Knowledge-SCI expanded from January 2005 to June 2011 with"sorafenib" and "advanced hepatocellular carcinoma" as search terms was performed for possible clinical trials.We also searched Web of Knowledge (CPCI-S) and the 2010 American Society of Clinical Oncology meeting conference for more information.

Study selection

Trials that met the following criteria were chosen for analysis:RCTs,single-arm trials with available data,retrospective studies,and patients with advanced HCC who received no systemic treatment.Additionally,the sorafenib or sorafenib-based (sorafenib combined with other agent) therapy should be contained in the research group,while placebo or placebo-based (placebo with the same agent that combined with sorafenib in the research group) therapy should be contained in the control group.Studies were independently selected by four researchers(Zhang X,Yang XR,Huang XW and Zhou J).

Quality assessment

The quality of selected RCTs was assessed according to the criteria presented in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.0; Chapter 8).[18]Details include sequence generation,allocation concealment,blinding of participants,personnel and outcome assessors,addressing incomplete outcome data,and ensuring absence of selective reporting and other sources of bias.

Data extraction

Study characteristics,patient details,total number of patients in each trial,hazard ratios (HR) and their 95% confidence intervals (CI) for OS and time to progression (TTP),rates of partial response (PR),rates of toxicity effects,and details of subgroup analysis were extracted.If a single-arm trial was included,the placebo or placebo-containing group from a well matched RCT would be introduced as the control arm.New HRs for OS and TTP were estimated by entering data that were directly extracted from Kaplan-Meier curves to spreadsheets in Microsoft Excel designed by Tierney et al.[19]We also contacted authors of some undergoing studies for data updates and statistical details.

Statistical analysis

As presented in most trials,OS and TTP were considered to be primary outcomes of this metaanalysis.Pooled HRs were calculated using a generic inverse variance method while data were entered on a log scale.During the process of calculation,the variance of ln[HR] was calculated using the method reported by Parmar et al.[20]The odds ratio (OR) was used as the effect size of the PR while the risk ratio (RR) was used for toxicity assessment,and both were estimated using the Mantel-Haenszel test.Begg's rank-correlation method was introduced to assess possible publication bias.[21]Statistical heterogeneity among trials was tested using the Chi-square test.An alpha value of 0.10 was deemed to indicate heterogeneity among the trials.The degree of heterogeneity for each analysis was represented as I2values.Fixed-effect models were used in all analyses unless heterogeneity existed (P＜0.1 or I2＞50%).P values less than 0.05 were considered to be significant and all reported P values were two-sided.All statistical calculations were performed using the Cochrane Collaboration's software Review Manager (version 5.0).

Results

Trials included

Our search strategies led to 1283 results from the published reports.After reviewing each publication,we identified 13 original reports that met our criteria,including RCTs,[11-13]single-arm phase II studies,[15-17]study protocols or conference abstracts.[22-28]Seven reports were excluded because they were ongoing studies or abstracts with no available data for our analysis.[22-28]Finally,three RCTs[11-13]and three single-arm phase II trials[15-17]with a total patient number of 1164 were included in the present meta-analysis (Fig.1).According to the eligibility criteria of included trials,the study population consisted of patients with advanced-stage(unresectable or metastatic) HCC,as confirmed by pathological analysis.Characteristics of these trials and quality assessment of RCTs are summarized in Tables 1 and 2.As a newly approved drug,only a few clinical trials presented useful data.Meanwhile,three phase II single-arm studies presented meaningful results with treatment of sorafenib; thus,discarding these data would be unwise.To make these single-arm trials[15-17]analyzable,we introduced the placebo or placebocontaining group from three RCTs[11-13]as the control arm of these trials.The matching principle was based on patient region distribution,close sample size and similareligibility criteria of patient characteristics (Table 3).

Fig.1.Flow chart of study identification,rejection and selection in the meta-analysis.

Table 1.The patients' characteristics of included clinical trials

Table 2.The quality assessment of three included randomized controlled trials

Table 3.Details of manually created controlled trials for three single-arm trials

Effect of sorafenib treatment on OS,TTP and PR

Based on the intention-to-treat population,the efficacy of sorafenib or sorafenib-based therapy was commonly demonstrated with OS and TTP in the three RCTs and three single-arm trials.

The pooled HR for OS in the three RCTs performed by our analysis was 0.66 (95% CI:0.56-0.78; P＜0.00001;I2=0%),representing a 34% reduction in the risk of death in patients treated with sorafenib or sorafenibbased therapy (Fig.2A).When we explored the pooled HR for the three single-arm trials,we obtained a similar result (HR=0.69; 95% CI:0.56-0.84; P=0.0002; I2=38%;Fig.2B).The Begg's test revealed no publication bias.

Regarding TTP,the pooled HR of the three RCTs was 0.57 (95% CI:0.47-0.68; P＜0.00001; I2=0%),indicating a 43% reduction in the risk of disease progression in patients treated with sorafenib or the sorafenib-based method (Fig.3A).The pooled HR for TTP from the three single-arm trials was 0.64 (95% CI:0.52-0.78; P＜0.00001; I2=0%; Fig.3B) The Begg's test also showed no publication bias.

Fig.2.A:Forest plot of hazard ratio (HR) for overall survival (OS)from three randomized controlled trials (RCTs).Compared with placebo group,sorafenib significantly prolong the overall survival(HR=0.66,P＜0.0001).It includes combined HR calculated using general inverse variancefixed effects as well as the evaluation for heterogeneity (I2).Horizontal lines represent 95% confidence interval (95% CI).Red boxes indicate the HR point estimate,and their areas are proportional to the weight of the studies.The black diamond represents the summary estimate.The unbroken vertical line is at the null value (HR=1.0); B:Forest plot of HR for OS from three combined single-arm trials.The pooled HR is 0.69(P=0.0002).

Fig.3.A:Forest plot of HR for time to progression (TTP) from three RCTs.The pooled HR is 0.57 (P＜0.00001) which indicates a 43% reduction in the risk of disease progression in patients treated with sorafenib or sorafenib contained therapy; B:Forest plot of HR for TTP from three combined single-arm trials.The pooled HR is 0.64 (P＜0.00001).

A PR was demonstrated in all six trials.According to the Response Evaluation Criteria in Solid Tumors(RECIST),[29]PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions with radiological assessment,taking as reference the baseline sum diameter.Based on the three RCTs,the pooled OR value was 2.96.However,with a P value of 0.06,the result only showed a propensity for a PR (95%CI:0.96-9.15; I2=0%; Fig.4A).We also investigated the pooled OR value for the three single-arm trials and the pooled OR was 3.56 (95% CI:1.22-10.39; P=0.02;I2=0%; Fig.4B).Similarly,the Begg's test indicated no existence of publication bias.

Subgroup analysis of two phase III RCTs

To identify the efficacy of sorafenib treatment in specific subpopulations,the studies with completed subgroups information (the SHARP trial[11]and the Asia-Pacific trial[12]) were enrolled for further investigation.Subgroup exploratory analyses of OS and HRs in patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status,the presence or absence of macroscopic vascular invasion(MVI) or extrahepatic spread,and baseline levels of alanine aminotransferase/aspartate aminotransferase(ALT/AST),alpha-fetoprotein (AFP),and bilirubin.HRs and their 95% CIs were directly extracted from the original studies[11,12]and a subsequently published abstract.[30]For the total population,sorafenib was an effective treatment for advanced HCC.We tested the efficacy of sorafenib in subgroups and found that sorafenib was an effective treatment irrespective of ECOG performance status,MVI,and ALT/AST ratio.Interestingly,a limited therapeutic effect of sorafenib was found in patients with an extrahepatic spread,with a normal AFP level,or with an elevated level of serum bilirubin (Table 4).

Fig.4.A:Forest plot of odds ratio (OR) for partial response (PR)from three RCTs.It includes combined OR calculated using Mantel-Haenszel fixed effects as well as the evaluation for heterogeneity(I2).Horizontal lines represent 95% CI.Blue boxes indicate the OR point estimate,and their areas are proportional to the weight of the studies.The black diamond represents the summary estimate.The unbroken vertical line is at the null value (OR=1.0).The pooled OR based on three RCTs is 2.96 (P=0.06).This result yielded no statistical significance; B:Forest plot of OR for PR from three combined single-arm trials.The pooled OR is 3.56 (P=0.02).

Adverse events

All six trials included multiple adverse events after sorafenib treatment.Among them,two trials[15,17]were excluded in the toxicity analysis because the adverse events could not be determined to be caused by sorafenib or other agents (5- fluorouracil and octreotide).Thus,the other four trials were used for analysis of adverse events.[11-13,16]Results of grade 3/4 and all grade adverse events are presented in Table 5.

Regarding grades 3 and 4 adverse events,all four trials reported data of hand-foot skin reaction,fatigue,rash/desquamation,diarrhea,and nausea.Data of hypertension were not available in two trials.[13-16]Data of anorexia were not available in two trials.[12,13]Data of bleeding were not available in another two trials.[12,16]

Regarding all grade adverse events,data of alopecia,rash/desquamation,nausea,HFSR,fatigue,anorexia,and diarrhea were not available in one trial.[13]Data of hypertension were not available in one trial.[16]Data of vomiting were not available in two trials.[12,13]Dataof liver dysfunction were not available in another two trials.[13,16]

Table 4.Subgroup analysis based on the SHARP trial and the Asia-Pacific trial

Table 5.The toxicity effects of sorafenib in advanced HCC patients

Compared with placebo-based therapy,sorafenibbased therapy significantly increased the risk of grades 3 and 4 HFSR,diarrhea,fatigue,and rash/desquamation(Table 5).Concerning all grade adverse events,only liver dysfunction showed no statistical significance (Table 5).The heterogeneity test yielded no statistical significance in analysis of the toxic events.

Discussion

It has been reported that sorafenib could prolong the median progression-free survival time for about 3 months in patients with advanced clear-cell renal-cell carcinoma.[31]The promising antitumor activity of sorafenib has pushed forward its use in the treatment of advanced HCC.Now,sorafenib has become the standard first-line treatment for patients with advanced HCC because of its survival benefits compared with placebo or placebo-based therapy in three RCTs.[11-13]More and more studies[25,26]are underway to assess optimal combinations with sorafenib such as TACE or radiofrequency ablation as well as sequencing of treatment modalities to maximize patient outcome.However,high cost and the modest efficacy of sorafenib have prohibited its widespread use for such patients in societies with limited resources,particularly in those developing countries with restrictive coverage for certain pharmaceuticals from national health insurance systems.Thus,we conducted a meta-analysis to reevalue the efficacy and safety of sorafenib in patients with advanced HCC and to identify the efficacy of sorafenib treatment in specific subpopulations.Based on three published RCTs,the results of the present meta-analysis indicated that sorafenib or sorafenib-containing therapy significantly improved OS and prolonged TTP.For the limited data and lack of analyzable RCTs,we also enrolled three uncontrolled phase II trials in our metaanalysis.[15-17]We found that the results from the metaanalysis of single-arm trials did not change for OS and TTP.Neither the Begg's funnel plot for publication bias nor the heterogeneity test yielded a significant result.

An interesting finding in this meta-analysis was that sorafenib had limited effect in patients with extrahepatic spread (with:P=0.13 vs without:P＜0.0001),with normal AFP level (normal:P=0.15 vs elevated:P=0.0006),and with elevated serum bilirubin level (elevated:P=0.06 vs normal:P=0.0009).Under the background of the high cost of sorafenib and its limited use in society with limited resources,these results suggested that more reasonable administration of sorafenib be adopted during clinical practice to tailor a more cost-effective sorafenib therapeutic strategy.Although this finding was already presented with statistical significance in the two included trials[11,12]respectively,the results of meta-analysis can present a more precise,objective and credible outcome based on different studies.

Extrahepatic spread is one of the worst prognostic factors for advanced HCC patients.Although the role of sorafenib in patients with or without extrahepatic spread has been verified in both phase III RCTs,[11,12]there is limited space for patients with extrahepatic spread to gain further survival benefit because of high tumor burden.A phase II study has also signified high tumor load in advanced HCC patients that renders the patients refractory to sorafenib treatment.[32]

The elevation of AFP usually occurs in hepatocyte regeneration and hepatocarcinogenesis.[33]With a high serum level of AFP,the tumor is in a more aggressive state,which indicates vigorous tumor cell proliferation and differentiation.The anti-proliferation effect of sorafenib indicates that patients with elevated AFP are more sensitive to sorafenib treatment.On the other hand,AFP is similar to albumin making it possible that function as a carrier for several ligands including various drugs.[33]We assume that the elevation of AFP facilitates the absorption and distribution of sorafenib,thus enhancing the efficiency of the drug in the treatment.Therefore,HCC patients with elevated AFP might be more suitable for sorafenib treatment.

Sorafenib is less effective in patients with an elevated bilirubin level,which might be correlated with poor liver function of advanced HCC patients who are not tolerable to the toxicity of sorafenib.

The side-effects associated with sorafenib are mostly mild to moderate.The present study mainly analyzed grade 3/4 side effects,and significant differences were found in HFSR,diarrhea,fatigue,and rash or desquamation,which are commonly seen in 33%-38%of patients.[34]Among them,HFSR was considered to be the most frequently encountered adverse event in sorafenib-based therapy with an RR value of 25.32.HFSR,which is localized and magnified in the areas of trauma or friction (e.g.,palms,soles,and elbows),where affected vessels andfibroblasts cannot be repaired after daily use,would lead to in flammation.This may be largely due to inhibition of one or a combination of vascular endothelial growth factor receptor,plateletderived growth factor receptor,c-KIT tyrosine kinase,and Fms-like tyrosine kinase-3 by sorafenib.[35]Treatment of HFSR with moisturizers,shock absorbers,corticosteroids,and urea has been recommended.[36-38]In addition,diarrhea,fatigue,and rash or desquamation should not be overlooked.

In conclusion,our meta-analysis showed that sorafenib had a statistically significant and clinically relevant extension of life in patients with advanced HCC.The subgroup analysis discovered that sorafenib was less effective in patients with extrahepatic spread,with a normal AFP level,and an elevated level of serum bilirubin.However,this finding was mainly based on statistical analysis with adjustment of other prognostic factors.Thus it needs to be further validated in future studies.Toxicity analysis suggested that clinicians pay more attention to HFSR,diarrhea,fatigue,and rash or desquamation that commonly occur in sorafenib-based therapy.

Contributors:ZX proposed the study.ZX,YXR and HXW contributed equally to this work.ZX,YXR and HXW performed research and wrote the first draft.ZX,YXR and WWM collected and analyzed the data.All authors contributed to the design and interpretation of the study and to further drafts.ZJ is the guarantor.

Funding:This study was supported by grants from the National Natural Science Foundation of China (30700815,30972949 and 81000927),Shanghai Key-Tech Research & Development Program(09411951700),Program for Shanghai Excellent Subject Leaders(10XD1401200),and the Research Fund for the Doctoral Program of Higher Education of China (20100071120064)

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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