Introduction

Hepatocellular carcinoma (HCC) is one of the most common forms of cancer worldwide and is particularly present in some Asian countries due to the high prevalence of hepatitis B virus infection [1, 2]. Approximately 30 % of patients present with advanced or unresectable HCC, and consequently the mortality rate for HCC is high [3, 4].

Due to the high rates of advanced disease, palliative treatment, aimed at increasing the length of survival after diagnosis, is a very important component of managing HCC [5]. A number of therapies are used to treat advanced HCC such as transarterial chemoembolization (TACE), radiation, systematic chemotherapy, portal vein stent, surgical resection, percutaneous ethanol injection, I-125 implantation, laser ablation, and conservative treatment [6–12]. Currently, there is no consensus regarding a common treatment strategy for patients with advanced HCC [13].

TACE, which delivers chemotherapy to the tumor location, is considered the standard treatment for unresectable HCC and has been demonstrated to provide a modest survival benefit [14, 15]. However, failure of TACE therapy is common, and studies have found that this may, in part, result from cellular adaptation to hypoxia resulting from the chemotherapy by neoangiogenesis [16]. Vascular endothelial growth factor (VEGF) plays an important role in promoting neoangiogenesis [16–18]. Sorafenib, an antiangiogenic drug that inhibits the VEGF signaling pathway, is indicated for the treatment of patients with unresectable HCC [19].

The use of sorafenib with TACE in treating advanced HCC has been actively studied, although the findings have been inconsistent [20]. Hence, the effectiveness of the combined use of sorafenib and TACE in HCC, especially in the majority of patients with more advanced disease, is not well understood. This systematic review and meta-analysis aimed to analyze the safety and efficacy of sorafenib combined with TACE in treating unresectable HCC.

Materials and methods

Search strategy

This meta-analysis was conducted in accordance with the PRISMA guidelines [21]. MEDLINE, the Cochrane Library, EMBASE, and the ISI Web of Knowledge were searched (until 31 December 2013) using combinations of the following keywords: hepatocellular carcinoma/HCC/hepatoma, sorafenib and chemoembolization transarterial chemoembolization/TACE. Randomized controlled trial studies that evaluated patients who had diagnoses of HCC and received treatment with sorafenib combined with TACE were included. The included studies provided numerical information about the specified primary or secondary outcomes (see below). Studies not published in English were excluded. Letters, commentaries, editorials, and case reports were also excluded. Potential studies were reviewed by two independent reviewers, and a third reviewer was consulted if there was uncertainty regarding eligibility.

Data extraction

The following information was extracted from studies that met the inclusion criteria: the name of the first author, year of publication, study design, patient demographics, key clinical characteristics (tumor stage, performance status, rate of viral hepatitis infection, chemoembolization treatment regimen), survival outcomes, tumor responses, and adverse events. Two independent reviewers extracted the data, and a third reviewer was used to solve any discrepancies.

Quality assessment

The Delphi list was used to assess the quality of the randomized controlled trials [22]. The Newcastle-Ottawa scale was used to assess the quality of the nonrandomized controlled study [23].

Statistical analysis

The primary outcome measure was time to progression (TTP), and the secondary outcomes measures were overall survival (OS) and adverse events.

The hazard ratio (HR) with 95 % confidence interval (CI) was calculated for TTP and OS among patients treated with TACE + sorafenib compared to those with TACE + placebo or TACE only. Because adverse events are rare, the Peto odds ratio (OR) with 95 % CI was calculated for the adverse event outcomes [22]. An HR/OR <1 indicated TACE + sorafenib was favored. Because the number of studies included in the meta-analysis was small, the heterogeneity tests may have had low statistical power [23]. Tests for heterogeneity are often underpowered, and random-effects models are routinely used [24]. The National Research Council report recommends the use of random-effects approaches for meta-analysis and the exploration of sources of variation in study results [25]. Combined HRs were calculated, and a two-sided p value <0.05 was considered to indicate statistical significance. Sensitivity analysis was performed for primary outcomes based on the leave-one-out approach. All statistical analyses were performed using the Comprehensive Meta-Analysis statistical software, version 2.0 (Biostat, Englewood, NJ, USA).

We did not evaluate publication bias as the number of studies included in the meta-analysis was too small to assess for publication bias using a funnel plot [26].

Results

Literature search

After the initial search and removal of duplicates, a total of 96 articles were identified for screening (Fig. 1). Of these, 75 were subsequently excluded for not being relevant. Ten additional studies were eliminated because the intervention studied did not involve TACE (n = 9) or only reported a study protocol (n = 1). Five studies were included in the systematic review [26–31].

Fig. 1
figure 1

Flowchart of study selection

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Study characteristics

The 5 studies included 899 patients with unresectable HCC, with 400 patients treated with TACE + sorafenib and 499 treated with TACE + placebo or TACE alone. The four studies in the meta-analysis [27, 28, 29, 31] included 809 patients (n = 355 for sorafenib + TACE and n = 454 for TACE + placebo or TACE alone). The total number of patients in each of the 5 studies ranged from 43 to 458. The mean age across the studies ranged from 49 to 73 years, and most patients were male (Table 1). For both treatment groups, the most common BCLC stages were B (intermediated stage) and C (advanced stage); most patients had a Child-Pugh class A tumor and ECOG score of 0–1 (Table 1). The chemobolization and dose of sorafenib varied across the studies (Table 2).

Table 1 Characteristics of included studies in the meta-analysis and systematic review
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Table 2 Summary of study participants and study outcomes
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The median TTP time ranged from 5.4 to 9.2 and 3.7 to 4.9 months for patients with TACE + sorafenib and those with TACE + placebo or TACE alone, respectively. The median OS time ranged from 7.5 to 29.7 and 5.1 to 18.3 months for patients with TACE + sorafenib and those with TACE + placebo or TACE alone, respectively.

Safety

Meta-analysis

Time to progression—primary outcome

The study of Qu et al. [26] was excluded from the meta-analysis of TTP because it did not provide point estimates and 95 % CIs for HR regarding TTP; hence, three [27, 29, 31] studies were used for the meta-analysis. Because of the small number of studies included, a random-effects model was used. Patients treated with TACE + sorafenib had better prognoses in terms of TTP compared to those with TACE + placebo or TACE alone; HRs ranged from 0.40 to 0.87, with the combined HR = 0.61 (95 % CI 0.39–0.95, p = 0.031) (Fig. 2).

Fig. 2
figure 2

Meta-analysis for treatment effects of sorafenib in combination with TACE on progression-free survival in patients with unresectable hepatocellular carcinoma

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Overall survival—secondary outcome

Only three [27, 29, 31] of the four studies provided the point estimate (HR) and 95 % CI for OS. The combined HR revealed that the OS did not significantly differ between patients treated with TACE + sorafenib and those with TACE + placebo or TACE alone (combined HR 0.79, 95 % CI 0.54–1.16, p = 0.235) (Fig. 3).

Fig. 3
figure 3

Meta-analysis for treatment effects of sorafenib in combination with TACE on overall survival in patients with unresectable hepatocellular carcinoma

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Adverse effects—secondary outcome

The summary of adverse events is shown in Table 3. We classified the adverse events according to Common Terminology Criteria for Adverse Events (version 4.03) [32]. The most frequent adverse events across the studies associated with TACE + sorafenib treatment were hand-foot skin reactions, diarrhea and hypertension). The individual and overall adverse events for the included studies are presented in a Forest plot in Fig. 4. Random-effects models for rates of hand-foot skin reaction, diarrhea and hypertension were used. Patients treated with TACE + sorafenib had a higher frequency of hand-foot skin reactions, diarrhea and hypertension compared to those with TACE + placebo or TACE alone (all p < 0.05).

Table 3 Summary of adverse events
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Fig. 4
figure 4

Sensitivity analysis for treatment effects of sorafenib in combination with TACE on progression-free survival by the leave-one-out approach

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Sensitivity analysis

We performed sensitivity analyses for TTP, OS, and rates of adverse events in which the data analyzed after each study was removed in turn (Table 4). Removal of the study of Sansonno et al. [28] or Bai et al. [29] caused the pooled HR for TTP to become nonsignificant. These findings suggest that these two studies overly impacted the combined findings. For OS, the results differed when Kudo et al. [27] was removed; the pooled HR for OS became significant, suggesting this study may have overly influenced the findings. For rates of diarrhea and hypertension, the results differed when Kudo et al. [27] was removed; the pooled Peto OR became nonsignificant, suggesting this study may have overly influenced the findings. However, the magnitude of the combined estimate for hand-foot skin reactions did not vary markedly with the removal of the studies, indicating these findings are robust.

Table 4 Sensitivity analysis for treatment effects of sorafenib in combination with TACE
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Quality assessment of studies with two treatment arms

The quality of the data was evaluated for the two included studies that were randomized control trials using the Delphi list [27, 28]. The study of Kudo et al. [27] received 8 points and of Sansonno et al. [28] 7 points, indicating the data were of good quality. A risk for detection bias was present because the outcome assessors in both studies were not blinded. The Sansonno et al. [28] study also did not include an intention-to-treat analysis. The quality of the Bai et al. [29], Muhammad et al. [30] and Qu et al. [26] studies, which were non-randomized, was evaluated using the Newcastle-Ottawa scale. The Bai et al. data were considered of high quality as they received a score of 9. Muhammad et al. and Qu et al. received a score of 6 because they may have had selection bias as they did not explain the selection of participants.

Discussion

This meta-analysis evaluated the efficacy of TACE alone or TACE + sorafenib in treating patients with advanced HCC. We found that the addition of sorafenib to TACE improved TTP but not OS. The common adverse events associated with TACE + sorafenib treatment were fatigue, diarrhea, nausea, hand-foot skin reactions, alopecia, rash, and hypertension.

Several recent meta-analyses have also evaluated the use of TACE + sorafenib in treating patients with unresectable HCC [5, 33–35]. Yang et al. included 6 studies that together had 1181 patients [35]. Similar to our findings, they found that the pooled HR for the randomized control trials for OS did not reach statistical significance. However, when they also included retrospective studies, they found the HR did reach statistical significance for the TACE + sorafenib treatment (HR 0.64; 95 % CI 0.43–0.97). Yang et al. also evaluated time to progression (TTP) and response to treatments. They found that TACE + sorafenib resulted in longer TTP and better response to treatment than TACE alone. Also similar to our findings and those of Yang et al., the meta-analysis of Liu et al. [32] found that TACE + sorafenib did not benefit OS [33]. Their analysis included seven comparative studies. The HR for OS was 0.81 (p = 0.061). Similar to Yang et al., they did find that TACE + sorafenib benefited TTP (HR 0.76; p < 0.001).

In contrast to our findings and those of Yang et al. and Liu et al., the meta-analysis of Fu et al. [33] found a benefit in survival with the addition of sorafenib to TACE [34]. Fu et al. included 9 studies in their meta-analysis with 900 patients. They found TACE + sorafenib significantly reduced 6-month and 1-year mortality (p ≤ 0.007) but did not decrease 2-year mortality (p = 0.46) compared with TACE alone. In contrast to our analysis, they did not find a benefit of adding sorafenib to TACE for the 6-month TTP (p = 0.06). However, they did find that the objective response ratio (p = 0.008) and clinical benefit ratio (p < 0.0001) favored the combination therapy. Similar to Fu et al., a meta-analysis by Zhang et al. [34] found TACE + sorafenib improved OS (HR = 0.65; p = 0.007) [35]. Zhang et al. included seven comparative studies. They also found TACE + sorafenib improved TTP (HR 0.68; p = 0.003) and ORR (HR 1.06; p = 0.021).

In the four prior meta-analyses the incidence of adverse events was higher in the TACE + sorafenib group than in the TACE alone group [33–35]. Similar to our findings, the other meta-analyses found that common adverse events associated with TACE + sorafenib were hand-foot skin reactions, diarrhea, hypertension, rash, and fatigue.

The difference across the meta-analyses likely reflects the different studies included and different methods of analyses. The findings of all the meta-analyses, including our own, are limited by the small number of included studies (range 4–9 comparative studies). Regardless, all the studies indicate that TACE + sorafenib may bring a benefit to patients with unresectable HCC compared to TACE alone. Our study was also limited by the high heterogeneity among the studies used in the meta-anlaysis and the fact that the pooled HR for TTP was not significant when either the study of Sansone et al. [28] or Bai et al. [29] was removed. Of the three studies included in the OS analysis, only Kudo et al. [27] found the TTP not to be significantly different between TACE + sorafenib and TACE alone [29]. However, in the study of Kudo et al., [27] sorafenib was given 1–3 months following embolization. Kudo et al. [27] speculate that the reason for the OS finding may reflect the delay in starting sorafenib after TACE and/or the lower daily dose of sorafenib (200 mg twice daily used in their study vs. 400 mg twice daily in the other trials) [6]. Consistent with this, subgroup analysis indicated that several factors might affect TTP including the age, treatment lag, treatment duration, number of prior TACE courses, and administration dose [27]. Another limitation of our analysis was not all the included studies in the meta-analysis were randomized controlled trials, and we did not take into consideration differences in clinical characteristics across the studies such as Child-Pugh stage, HBV or HCV infection, dose of sorafenib, treatment length of sorafenib, and concurrent chemoembolization (doxorubicin, mitomycin, etc.). Finally, there were differences across the studies in the definition of complete response. One study defined complete response (CR) using the mRECIST criteria [30]; another defined CR using the RECIST criteria [29]. Kudo et al. [27] defined CR as 100 % tumor necrosis or shrinkage, and Sansonno et al. [28] defined it as the absence of contrast enhancement within the original tumor. According to BCLC, many of the patients in our study had intermediate HCC; the inclusion criteria for the studies selected for patients diagnosed unresectable HCC with Child-Pugh class A or B, ECOG 0–1, and limitations of tumor size. Patients with intermediate HCC represent a heterogeneous population with different liver functions and tumor burdens. It is possible that TACE was effective in a subgroup of this population and that some patients may have benefited from other treatments.

In summary, our meta-analysis found that TACE + sorafenib can improve TTP. We did not find the combined therapy improved OS. Additional randomized controlled studies are necessary to further investigate the clinical benefit of TACE + sorafenib in treating advanced HCC.