Hepatic Re-resection Versus Transarterial Chemoembolization for the Treatment of Recurrent Hepatocellular Carcinoma after Initial Resection : a Systematic Review and Meta-analysis

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. Surgical resection is a curative treatment option of early HCC (Bruix and Sherman, 2011; 2012). However, the recurrence of HCC after surgical resection is very frequent with a 5-year incidence of >70% (Franco et al., 1990; Belghiti et al., 1991; Shirabe et al., 1991; Okada et al., 1994; Adachi et al., 1995; Balsells et al., 1996; Fong et al., 1999; Poon et al., 2001; Ercolani et al., 2003; Minagawa et al., 2003), which negatively influences the outcomes. Until now, there is no consensus regarding the management of recurrent HCC (Bruix and Sherman, 2011; 2012). Salvage liver transplantation is a promising treatment option of recurrent HCC (Majno et al., 2000; Poon et al., 2002; Sala et al., 2004; Hu et al., 2005; Hu et al., 2012; Wu et al., 2012; Liang et al., 2014). However, liver transplantation is largely restricted by the donor shortage. Re-resection and transarterial chemoembolization (TACE) represent two additional treatment options. Re-resection can provide


Introduction
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death.Surgical resection is a curative treatment option of early HCC (Bruix and Sherman, 2011;2012).However, the recurrence of HCC after surgical resection is very frequent with a 5-year incidence of >70% (Franco et al., 1990;Belghiti et al., 1991;Shirabe et al., 1991;Okada et al., 1994;Adachi et al., 1995;Balsells et al., 1996;Fong et al., 1999;Poon et al., 2001;Ercolani et al., 2003;Minagawa et al., 2003), which negatively influences the outcomes.Until now, there is no consensus regarding the management of recurrent HCC (Bruix and Sherman, 2011;2012).Salvage liver transplantation is a promising treatment option of recurrent HCC (Majno et al., 2000;Poon et al., 2002;Sala et al., 2004;Hu et al., 2005;Hu et al., 2012;Wu et al., 2012;Liang et al., 2014).However, liver transplantation is largely restricted by the donor shortage.Re-resection and transarterial chemoembolization (TACE) represent two additional treatment options.Re-resection can provide RESEARCH ARTICLE Hepatic Re-resection Versus Transarterial Chemoembolization for the Treatment of Recurrent Hepatocellular Carcinoma after Initial Resection: a Systematic Review and Meta-analysis Di-Ya Wang 1& , Lei Liu 2& , Xing-Shun Qi 3& *, Chun-Ping Su 4 , Xue Chen 3 , Xu Liu 3 , Jiang Chen 3 , Hong-Yu Li 3 , Xiao-Zhong Guo 3 * a relatively good outcome of recurrent HCC in selected patients with solitary tumor, although it is compromised by reduced liver volume and presence of liver cirrhosis.By comparison, TACE is employed in patients with multiple tumors.Considering that the appropriate selection of treatment options is very important to improve the prognosis, we have conducted a systematic review and meta-analysis of observational studies to compare the post-recurrence survival of hepatic re-resection versus TACE for the treatment of recurrent HCC after initial resection.

Materials and Methods
This work was registered with PROSPERO (registration number: CRD42015017798).

Study selection
The inclusion criteria should be as follows.
Participants: patients with recurrent HCC.Interventions: hepatic resection and TACE as retreatment modalities.
Outcomes: overall survival after HCC recurrence.
The exclusion criteria should be as follows.
1) Duplicate papers among databases and redundant publications.
8) TACE before and after hepatic resection.9) Comparison between hepatic resection versus TACE for the initial treatment of HCC.10) Comparison between hepatic resection versus TACE for the treatment of spontaneous rupture of HCC. 11) No separate data in the hepatic resection or TACE group.
12) No detailed data regarding the survival rate in the hepatic resection or TACE group.
13) No detailed data regarding the number of observed patients in the hepatic resection or TACE group.
If two or more papers by the same study team had the overlapping data, only one paper with more adequate data and/or a longer enrollment period would be included.

Data extraction
The following data were extracted: the first author, publication year, publication form, region, enrollment period, study design, study population, follow-up time, eligibility criteria, treatment selection criteria, number of cases with recurrent HCC in different groups, and post-recurrence survival rates.Post-recurrence survival was defined as the interval between tumor recurrence and death.If the post-recurrence survival was not reported, we attempted to extract the interval between re-treatment and death.However, we did not extract the interval between initial treatment and death.If only Kaplan-Meier curves were presented, we extracted the cumulative 1-, 2-, 3-, and/or 5-year survival rates by using the Distance Tool in the Measurements menu of Foxit PDF Reader software version 5.4.4.1023 (Foxit Cooperation, California, USA).This software was freely downloaded.

Study quality
The Newcastle-Ottawa Scale (NOS) is a well-known tool for assessing the quality of non-randomized studies.However, we should acknowledge that our study population and study objectives should be more specific (i.e., recurrent HCC and post-recurrence survival).
According to the NOS, we developed the following questions that were more appropriate for the present systematic review.1) Were the patients consecutively enrolled and prospectively followed?
2) Was the age at the time of HCC recurrence statistically similar between the two groups?
3) Was the gender at the time of HCC recurrence statistically similar between the two groups?4) Was the Child-Pugh score/class or MELD score at the time of HCC recurrence statistically similar between the two groups?5) Were the diameter and number of tumor at the time of HCC recurrence statistically similar between the two groups?
6) Was the recurrent region of HCC clearly reported?7) Was the initial treatment modality of HCC clearly reported?8) Were the criteria for treatment selection of recurrent HCC homogeneous between the two groups?9) Was the follow-up time clearly reported?If the answers to 7-9 questions were "Yes", the study would be considered to be of high quality.If the answers to 4-6 questions were "Yes", the study would be considered to be of moderate quality.Otherwise, it would be considered to be of poor quality.

Meta analysis
First, we calculated log(hazard ratio [HR]) with standard error by using a calculation sheet which was developed by Matthew Sydes and Jayne Tierney (Tierney et al., 2007).Then, HRs with 95% confidence intervals (CIs) were pooled by using a random-effects model.A P value of <0.05 was considered statistically significant.Heterogeneity between studies was assessed by using the I 2 statistic (I 2 > 50% was considered as having substantial heterogeneity) and the Chi-square test (P<0.10 was considered to represent significant statistical heterogeneity).Funnel plots were performed to evaluate the publication bias.Subgroup analyses were performed according to the countries.Sensitivity analyses were performed in the following conditions: 1) the studies which clearly reported the recurrent regions of HCC; 2) the studies which were of moderate-or high-quality; 3) the studies which were published in the full-text form; and 4) the studies which were published after 2005.All metaanalyses were conducted by using the statistical package Review Manager version 5.1.6(Copenhagen, The Nordic Cochrane Center, The Cochrane Collaboration, 2011).

Study characteristics
Study characteristics were summarized in Table 1.Four and eight studies were performed in China and Japan, respectively.All of the included studies clearly reported that hepatic resection was the initial treatment option of HCC.Nine studies evaluated the outcomes of intrahepatic recurrent HCC, and another three studies did not report the recurrent regions of HCC.Eleven studies evaluated the interval between tumor recurrence and death, and another one study evaluated the interval between initial treatment and death.Criteria for patient selection and treatment selection were summarized in Supplementary Table 1 and 2, respectively.

Study quality
Five and seven studies were of moderate and poor quality, respectively (Supplementary Table 3).No study was of high quality.

Sensitivity analyses
In all sensitivity analyses, the post-recurrence survival remained statistically significantly higher in hepatic reresection group than in TACE group (Supplementary Figures 1-4).

Discussion
To the best of our knowledge, this study might be the first systematic review and meta-analysis to compare the post-recurrence survival between patients undergoing hepatic re-resection and TACE.This study had several strengths.1) The search strategy was extensive via the three major databases.2) No publication language was restricted, because our review authors were skilled at Chinese, English, and Japanese languages.Two papers were published in Japanese.One paper was published in Chinese.
3) The study quality was strictly evaluated.We developed a total of nine questions to assess the study quality, which were more specific to the objectives of our study.They included four major categories, such as patient enrollment, comparability of patient characteristics, comparability of treatment selection, and follow-up work.4) Subgroup and sensitivity analyses were performed to confirm the reliability of our findings.
The overall analysis suggested that hepatic re-resection had a significantly better post-recurrence survival than TACE.Notably, a relatively narrow CI might suggest a stable benefit of hepatic re-resection.The statistically significant heterogeneity should not be neglected.As we took a close look at the individual data, two included studies showed a very similar survival between the two groups (HR was equal to 1) (Lee et al., 1995;Taniai et al., 2012), but the remaining ten studies supported a better survival in hepatic re-resection group (HR was beyond 1) (Shimamura et al., 1994;Imaoka et al., 1995;Ueno et al., 2009;Yang et al., 2009;Hirokawa et al., 2011;Umeda et al., 2011;Ho et al., 2012;Yamamoto et al., 2013;Takemura et al., 2014;Wang et al., 2014).In addition, the subgroup analysis confirmed the statistically significance regardless of China or Japan.The sensitivity analyses were largely consistent with the overall analysis.These findings suggested that hepatic re-resection might be an optimal choice of therapy for recurrent HCC and that TACE might be an alternative treatment option if hepatic re-resection was unavailable or infeasible.
Patterns of tumor recurrence in HCC cases primarily include intrahepatic and extrahepatic regions.In a majority of included studies (75%, 9/12), only intrahepatic recurrence of HCC without extrahepatic involvement was considered as the target population.However, we had to acknowledge that the other patient characteristics were not well-matched between hepatic re-resection and TACE groups.Only two studies had statistically similar Child-Pugh score or class between the two groups (Ueno et al., 2009;Hirokawa et al., 2011).Only three studies had statistically similar tumor size and number between the two groups (Ueno et al., 2009;Hirokawa et al., 2011;Wang et al., 2014).In addition, none of included studies employed any random allocation methods.Only one retrospective study clearly reported that the treatment selection criteria were the same between the two groups (i.e., both resection and TACE were employed in patients with resectable HCC) (Lee et al., 1995).In the remaining studies, the patients with small and solitary HCC nodule are more likely to undergo surgical resection; by comparison, the patients with multiple HCC nodules are more likely to undergo TACE.Thus, we would like to emphasize that the potential bias in the selection of patients and treatment options might lead to an imbalance in the comparison of survival results between the two different treatment options.Therefore, our findings should be cautiously interpreted.
In conclusion, Generally, a systematic review of available data is helpful to clarify the current knowledge regarding the management of recurrent HCC and is necessary to guide the study design in future.Based on the present systematic review and meta-analysis, we found a statistically significant survival benefit of hepatic re-resection over TACE for recurrent HCC after initial resection.However, we could not draw any strong recommendations because these published data were of low quality.Further randomized controlled trials were warranted to avoid the potential bias of treatment selection and to achieve a definitive conclusion.