Liver transplantation versus liver resection for hepatocellular carcinoma: a meta-analysis

Xin-Sen Xu, Chang Liu, Kai Qu, Yan-Zhou Song, Peng Zhang and Yue-Lang Zhang

Liver transplantation versus liver resection for hepatocellular carcinoma: a meta-analysis

Xin-Sen Xu, Chang Liu, Kai Qu, Yan-Zhou Song, Peng Zhang and Yue-Lang ZhangXi'an, China

BACKGROUND:Liver transplantation (LT) and liver resection (LR) are currently considered the standard treatment of patients with hepatocellular carcinoma (HCC). However, the outcomes of LT and LR are still inconclusive.

DATA SOURCES:MEDLINE, EMBASE, and Cochrane Library were searched for relevant studies. Surgical safety indices such as treatment-related morbidity and mortality, and efficacy indices such as overall and tumor-free survival outcomes were evaluated. Weighted mean differences and odds ratios (ORs) were calculated using a random-effects model.

RESULTS:Seventeen studies were included in this metaanalysis. LT achieved significantly higher rates of surgeryrelated morbidity (OR=1.47; 95% CI: 1.02-2.13) and mortality (OR=2.12; 95% CI: 1.11-4.05). Likewise, the 1-year survival rate was lower in LT (OR=0.86; 95% CI: 0.61-1.20). However, the 3-and 5-year survival rates were significantly higher in LT than in LR and the ORs were 1.12 (95% CI: 0.96-1.30) in 3 years and 1.84 (95% CI: 1.49-2.28) in 5 years. Furthermore, the tumorfree survival rate in LT was significantly higher than that in LR in 1, 3, 5 years after surgery, with the ORs of 1.72 (95% CI: 1.24-2.41), 3.75 (95% CI: 2.94-4.78) and 5.64 (95% CI: 4.35-7.31), respectively.

CONCLUSIONS:One-year morbidity and mortality are higher in LT than in LR for patients with HCC. However, long-term survival and tumor-free survival rates are higher in patients treated with LT than those treated with LR.

(Hepatobiliary Pancreat Dis Int 2014;13:234-241)

hepatocellular carcinoma;

liver transplantation;

hepatectomy

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and as a result of the spread of HBV and HCV infection during the past century, its incidence will further increase in the future in both Asian and Western countries.[1,2]Liver transplantation (LT) and liver resection (LR) have been considered potential curative treatments because they achieve a higher rate of complete response in properly selected candidates compared with other adjunctive treatments such as percutaneous radiofrequency ablation and alcohol injection.[3]For patients with compensated (Child-Pugh class A) cirrhosis, LR used to be the mainstay of treatment, especially in Asia. For early HCC associated with severe cirrhosis (Child-Pugh classes B and C), LT is universally accepted to be the first choice.[3,4]Theoretically speaking, to compare the pros and cons of LT and LR, the researchers need to design a randomized clinical trial (RCT) and the patients enrolled should be completely comparable, such as those who have good liver function and the tumors are within the Milan criteria. However, the current status is whether LT or LR is chosen depends on the patient's clinical status, such as Child-Pugh classes, tumor size and number, etc.[5,6]Due to these limitations, there are no RCTs to compare LT with LR so far. Besides the Milan criteria which include: solitary tumor ≤5 cm in diameter or 2 or 3 tumor nodules with the largest diameter ≤3 cm, absence of macroscopic vascular invasion and extrahepatic metastasis, there are other expanded criteria, such as the widely used Hangzhou criteria in China (total tumor diameter ≤8 cm; or total tumor diameter ≥8 cm, with histopathologic grade I or II and preoperative AFP level≤400 ng/mL). Again, no RCT is available to compare LT and LR for those patients within the Hangzhou criteria. These lead to an intense debate on whether LR or LT is the treatment of choice for such patients.[7,8]

Although a number of retrospective studies have compared the prognosis of HCC patients who underwent LT and LR, the results are inconsistent.[9]The present study was to resolve the uncertainty by meta-analysis and to compare LT and LR for HCC. Our specific aims are: 1) to analyze the surgery safety by comparing the surgery-related morbidity and mortality among the studies; 2) to estimate the 1-, 3- and 5-year overall survival rates and tumor-free survival rates among HCC patients receiving LT or LR; and 3) to evaluate the overall potency of LT and LR by analyzing the surgery safety and long-term survival.

Methods

Literature search

The primary sources of the relevant literature were from MEDLINE, EMBASE and Cochrane Library between January 1, 1990 and March 1, 2012. The search key words are: hepatocellular carcinoma, liver resection, liver transplantation, comparative study, and combinations of them, as well as liver cancer, primary liver carcinoma, hepatectomy, resection, hepatic resection and transplantation. The "related articles" were used to broaden our search. References of selected articles were also examined to find relevant studies. Only articles in English were included.

Inclusion and exclusion criteria

Studies included had to have a comparison of patients who had undergone LT or LR for HCC and a clear documentation of patients' demographics and tumor characteristics, and had to have records of one or more of the outcomes of interest.

The exclusion criteria were as follows: 1) Data were impossible to conduct statistical analyses; 2) A series of articles from the same author or institution that contained significant overlap of patient data; only the most recently published study containing the most updated data was included.

Data extraction

Data of all variables and outcomes of interest were extracted independently by three investigators (QK, SYZ and ZP). When the survival rates were unavailable to extract directly through the main text, yet the article provided the results in the form of Kaplan-Meier survival curves, the specific data were extracted from the curves with the help of Enguage software. Discrepancies among reviewers were infrequent (overall interobserver variation of ＜10%) and were resolved by discussion and consensus.

Outcomes

Surgery safety parameters were evaluated including surgery-related morbidity (e.g., hepatic hemorrhage, biliary leakage, postoperative ascites, liver failure, and infection) and mortality. Efficacy outcomes of LT and LR included the 1-, 3- and 5-year overall survival rates and 1-, 3- and 5-year tumor-free survival rates. The quality of studies was evaluated using the modified Newcastle-Ottawa Scale with appropriate changes made to reflect the needs of this study.[10,11]The maximum numbers of stars in the selection, comparability, and outcome categories were 3, 4, and 2, respectively.

Statistical analysis

Statistical analyses were made using Review Manager statistical software, version 5.1 (Cochrane Collaboration 2011, Nordic Cochrane Centre, Copenhagen). We analyzed dichotomous variables using estimation of odds ratios (ORs) with 95% confidence intervals (CIs). Pooled estimates of 1-, 3- and 5-year survival rates were calculated using random-effects model after applying sample weights according to the sample size, because this method is preferable in surgical meta-analyses to account for heterogeneity in surgical technique among centers. Heterogeneity was assessed by using theI2statistics, which describes the proportion of variance across studies not due to chance.I2＜25% andI2＞40% reflect small and large inconsistency, respectively.[12]According to some recent literatures, funnel plots were not applied to explore the publication bias, given the limitations and potential misleading results of these graphs.[13]Sensitivity analyses were conducted to explore statistical heterogeneity by using the following subgroups: 1) studies published between January 2005 and March 2012; 2) studies containing more than 100 patients in each group; and 3) studies of high comparability quality with 2 or more stars.

Results

Eligible studies

The initial literature search retrieved 1241 relevant articles, among which, 1109 articles were excluded because these studies were either not for discussion of LT versus LR or not for humans; 95 were because these were reviews, updates, or the data in the papers were not comparative, 4 were because of insufficient data,[14-17]and another 6 were because the same authors or institutions that contained significant overlap of patient data which had already been included in other studies.[18-23]Consequently, 27 articles published between January 1, 1990 and March 1, 2012 were included in this meta-analysis (Fig. 1).[5,6,24-48]

All studies were retrospective analysis. Methodologicalquality scores ranged from 3 to 7 stars on a scale of 0 to 9 (Table 1). With regard to the quality of the studies, 10 articles with the quality of less than 1 star were excluded from the meta-analysis,[24,27,37-39,41,42,45-47]which resulted in 17 studies included in the end (Fig. 1).[5,6,25,26,28-36,40,43,44,48]Of the 17 included articles, 10 were published before 2005, and the other 7 after 2005. There were a total of 1515 patients in the LT group and 2723 in the LR group. The patients with HCC in each study ranged from 27 to 1197. Characteristics of arms (LT and LR) included in the meta-analysis were detailed in Table 1.

Surgery-related morbidity

Five studies reported postoperative morbidity.[6,26,28,30,48]Overall, postoperative morbidity (complications) was observed in 49% of patients treated by LT and 39% by LR, and the postoperative morbidity was higher in LT than that in LR (OR=1.47; 95% CI: 1.02-2.13). The heterogeneity of studies was acceptable (I2=22%;P=0.27) (Table 2).

Fig. 1.Search strategy flow diagram of study selection and inclusion.

Table 1.Summary of characteristics and quality of selected studies

Surgery-related mortality

Eleven studies reported perioperative mortality (30-day after surgery) (Table 2).[5,6,26,28,30-33,35,36,48]Sixty-six patients died in the LT group and 33 in the LR group. The OR was significantly higher in the LT group (OR=2.12; 95% CI: 1.11-4.05) with acceptable heterogenerity (I2=33%;P=0.14) (Table 2).

Survival analysis

Selected studies reported data on overall survival and tumor-free survival in different time intervals. Available data were used to calculate ORs of 1-, 3-, 5-year overall survival rates and tumor-free survival rates. At 1, 3, and 5 years, pooled-analyses showed that the overall survival rates were 83%, 69%, 63% in the LT group and 88%, 72%, 58% in the LR group respectively, with significant heterogeneity (Table 2). Pooled-analyses on tumor-free survival rates at 1, 3, and 5 years showed 85%, 75%, and 71% in the LT group and 79%, 53%, and 41% in the LR group respectively, again, with significant heterogeneity at 1 and 5 years (Table 2). Furthermore, meta-analysis showed a difference in favor of LR in the early stage (1 year), but implied a significant preference to LT in the long run (3 and 5 years) (Table 2). The tumor-free survival rates showed that LT outweighed LR at all the 1-, 3- and 5-year intervals (Fig. 2, Table 2).

Sensitivity analysis

The overall survival and tumor-free survival rates were affected by surgical skills and patient baseline conditions. In a separate analysis of studies published after 2005,[5,25,26,28-31]the ORs and weighted mean differences did not change except the 1-year overall survival rate that LT outweighed LR (OR=1.14; 95% CI: 0.72-1.80;I2=29%) (Table 3). We then conducted the pooled analysis of the 1-year overall survival rate of the studies published before 2005 (OR=0.69; 95% CI: 0.47-1.03;I2=49%), and compared the ORs of LT vs LR after 2005 and before 2005 (OR=1.14, OR=0.69; respectively). The results indicated an increasing advantage of LT over LR in the 1-year overall survival.

Another separate analysis of studies containing more than 100 patients in each group was made to evaluate whether larger centers with more experiences would have significantly different results.[28,29,32,35]This analysis demonstrated that the data from the larger centers weresimilar to the overall results in all cases (Table 3). Only the OR of 3-year overall survival rate was in favor of LR (OR=0.91; 95% CI: 0.73-1.15; I2=59%). In terms of highquality studies, those with a score of 2 stars or greater in comparability of the Newcastle-Ottawa Scale were also separately analyzed.[5,6,28,34,36,40]It turned out that it had the same direction of effect but with acceptable heterogeneity (Table 3). Considering that comparability of the LT and LR patients would have significant impact on survival outcomes, the subgroup analysis of the higher quality studies provided more convincing results that although with a lower 1-year overall survival rate, which might be due to the higher surgery-related morbidity and mortality, LT far outweighed LR in the long-term survival.

Table 2.Results of meta-analysis comparing LT with LR in efficacy and safety

Fig. 2.Difference of survival rates between LT and LR of the selected studies.A: 5-year overall survival rates;B: 5-year tumorfree survival rates.

Table 3.Meta-analysis of the survival parameters comparing LT with LR in the subgroups

Discussion

The results of this meta-analysis suggest that LT is superior to LR in terms of long-term survival and tumor-free survival rates for HCC patients. However, the higher rate of adverse perioperative events displayed is something that has to be considered with the quality of the donor liver, infection, immune rejection, immune deficiency and the experiences and skills of the institutions implementing the surgeries. According to recent guidelines, for patients with compensated (Child-Pugh class A) cirrhosis, LR used to be the mainstay of treatment, whereas for patients associated with severe cirrhosis (Child-Pugh classes B and C), LT has emerged as a real competitor to LR in clinical practice.[3,4]However, to date, the survival of LT versus that of LR for patients with HCC is controversial. Llovet et al[3]discussed the opinion on the role of resection and transplantation for HCC and concluded that LR maybe a more appropriate surgical treatment for patients with small (＜5 cm) solitary HCC with well-preserved synthetic function (Child-Pugh class A) and normal portal pressure (hepatic venous pressure gradient, HVPG＜10 mmHg). However, they did not analyze the published articles regarding the LT versus LR for patients with HCC. A similar meta-analysis[49]demonstrate that LT in HCC patients results in increased late disease-free and overall survival when compared with LR. However, the benefit of LT is offset by higher short-term mortality, donor organ availability, and long transplant wait times associated with more patient deaths. Unfortunately, this meta-analysis included only the 9 articles published between 2000 and 2012. In our study, we analyzed all the 27 articles published between 1990 and 2012, and 17 articles were included. Therefore, our analysis is more comprehensive and more convincing. Similarly, Dhir et al[50]also made a meta-analysis about LT versus LR for patients with HCC, revealing a survival advantage for transplantation in these patients. Interestingly, they focused on the analysis of patients with early HCC, indicating HCC falling within the Milan criteria with well-compensated cirrhosis. Moreover, they put an extra emphasis on the intention-to-treat patients, which had never been systematically analyzed. However, this restriction limited the number of selected articles to 10, and even decreased to 6 when making the subgroup analysis of early HCC patients and intention-to-treat patients, respectively. Another defect brought along with the limited articles for analysis was that only reported in these articles was the 5-year overall survival, which was chosen as the indicator for the prognosis of HCC, and that no 1-, 3-year or recurrence-free data were available. As to our meta-analysis, we selected 17 articles through strict screening, and provided the prognostic data on 1-, 3-, 5-year overall survival and tumor-free survival as well as the data on the safety of surgery. Although we did not include the early HCC and intention-to-treat analysis, we focused the issue on a different aspect, that LT versus LR from a more general perspective.

In accordance with Rahman's results, a significant benefit in LT vs LR in long-term survival and tumorfree survival was observed in our study. Interestingly enough, though the data on 1-year overall survival indicate a superiority of LR, which is in accordance with the low surgery-related morbidity and mortality, the advantage of LT over LR in survival increases with time. Indeed, at 5-year there is a higher survival rate of 5% for the LT group. In addition, the rates of survival found in the LR and LT groups are comparable to those reported in prior studies on patients with HCC of similar characteristics.[49,51]The improved survival can be explained by the fact that, as this study confirms, LT is superior to LR in leaving a clear surgical margin and tumor control, as demonstrated by its obviously greater tumor-free survival rate. In our study, the ORs of LT vs LR in the 1-, 3-, 5-year tumor-free survival rates were 1.72, 3.75, and 5.64, respectively. Hence we conclude that LT is able to treat HCC and its underlying oncogenic liver diseases.[52,53]

The general conditions of patients with HCC would significantly influence their survival. The subgroup analysis of the higher quality studies showed that although the lower 1-year overall survival rate might be due to the higher surgery-related morbidity and mortality, LT far outweighed LR in the longterm survival. Clinically, estimates of their relative effectiveness must at least be based on similar patient populations to avoid selection bias. These findings seemto be highly significant, and although the number of studies is limited, the absence of patient differences as Child-Pugh grade of liver function, tumor size and tumor numbers between the groups highlights the possible benefits of LT itself. Similarly, several studies have studied transplantation eligible patients, i.e., patients meeting the Milan criteria for transplantation underwent resection rather than transplantation.[46,54]Such transplantation eligible patients undergoing resection had a 5-year survival rate of 70%, which was comparable with that after LT, which to some extent was contradictory to our results.

In our study, although the data were limited, available evidences indicated that LT has a higher surgery-related morbidity and mortality. The overall rate of surgery-related morbidity was 49% in the LT group, which was higher than 39% in the LR group. Furthermore, it is important to emphasize the high degree of consistency in studies, which something may increase the strength of the results. In addition, the rates of perioperative complications of LT in this study are comparable to the published.[55]While these rates may lead to an increase in mortality, it should be taken into account that although LT has been a popular therapy for HCC in clinical settings, the safety of transplant surgery itself is lower than LR. Here, we must point out that some of the morbidity and mortality observed could be partly due to the immature transplant experiences in some institutions and the inappropriate indications in choosing the right patients for transplantation.[56]Even both resection and transplantation may be performed safely, resection has the additional advantage of delaying need and risks associated with immune suppression, which include toxicities, infectious complications, and post-transplantationde novoneoplasm.[57]

Last but not least, LT would face some health resource-related problems, such as donor liver resource and cost-effectiveness. When transplantation is analyzed according to an intention-to-treat analysis, the loss of patients (dropouts) from the transplant waiting list due to death or the appearance of contraindications may significantly diminish the long-term survival. Studies[29,58,59]reported that a waiting time of about 4 months or more is the estimated transition point at which the benefit of transplantation relative to surgical resection may begin to wane. On the other hand, LT is more expensive than LR, with mean direct costs showing a significant positive difference not balanced by a significant better impact on the 1- and 3-year overall survival rates. Consequently, to date there is no evidence supporting a better costeffectiveness ratio for LT from a social perspective.[60]

Since its advent in the late 1980s and the early 1990s, living donor LT has been performed widely in countries like Japan, Korea and India. Living donor LT has emerged as a way to expand the donor pool and may produce a drastic change in the role of LT for HCC. It decreases the waiting time and dropout rate of HCC patients from the LT waiting list.[61]However, the main issue limiting this option is a finite mortality and morbidity among the donors despite strictest precautions. Living donor LT is warranted if the waiting time for a liver graft is expected to exceed 7 months.[62,63]In addition, the use of living donor LT for patients that exceed the Milan criteria remains controversial.[64,65]From the donor's perspective, living donor LT does carry a risk of morbidity and mortality. Although the outcome of donor operation continues to improve in experienced centers, reports about donor deaths are not rare. The intra-operative and postoperative complications of donors in the reported series vary from 9% to 67%.[66]A survey[55]indicated that by the end of the first year, almost half of donors had minor symptoms. Studies[55,67]on living donors indicated that regeneration to the pre-resection volume is less than complete even after 2.5 years of follow-up. Lack of vigilance and loosening of acceptance criteria are the major reasons for the mortality of donors. To avoid further donor death, transplant surgeons should serve as gatekeepers in preventing unjustified and risky donor operations.

In conclusion, while LT ideally addresses both malignancy and underlying liver disease which prolong the long-term survival and tumor-free survival, resection offers patients minimal surgery-related morbidity and mortality without limitation of organ availability.

Acknowledgements:We thank Drs. Ji-Chao Wei, Lei Zhou, Fan-Di Meng and Rui-Tao Wang from First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University for giving many helpful suggestions for the design of this research.

Contributors:XXS and LC designed the research. XXS and QK wrote the paper. QK, SYZ and ZP collected and analyzed the data. ZYL revised the paper. LC is the guarantor.

Funding:This study was supported by grants from the National Natural Science Foundation of China (30872482 and 81072051).

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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Received March 10, 2013

Accepted after revision August 25, 2013

Author Affiliations: Department of Hepatobiliary Surgery (Xu XS, Liu C, Qu K, Song YZ and Zhang P) and Department of Radiology (Zhang YL), First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China

Chang Liu, MD, PhD, Department of Hepatobiliary Surgery, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710061, China (Tel: 86-29-85323900; Fax: 86-29-82654746; Email: liuchangdoctor@163.com)

? 2014, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(14)60037-0

Published online March 27, 2014.