Role Of Liver Resection And Salvage Liver Transplantation In The Treatment Of Hepatocellular Carcinoma:Analysis And Progress

Background:A large number of hepatitis B virus (HBV) infected patients exist in China, which results in the high prevalence of hepatocellular carcinoma (HCC). Liver transplantation (LT) has been accepted as the optimal treatment of choice for the patients with HCC. However, the donor organ shortage and the exponentially increasing number of patients on the waiting list have limited its application. Several literatures have proposed salvage liver transplantation (SLT), namely providing patients with HCC with liver resection (LR) first and when HCC recurs the secondary liver transplantation being offered, as an alternative way of treatment to solve this contradiction. This strategy has established liver resection as the first line therapy for HCC, and can prolong the waiting time for the donor liver. Yet, the results of SLT are debating. Some key issues remain to be identified through clinical trials based on large samples. Experts in the field of liver transplantation from all over the world have proposed37key recommendations for liver transplantation for HCC on international consensus conference held in December,2010 in Zurich, Switzerland, among which SLT ranks the16th. Of note, it pointed out that SLT should be verified urgently by evidenced based medical trials of high levels, which was published on The Lancet, one of the four most famous journals in the world (The Lancet,2011,2045(11):70175-9). Specifically focused on the issue of liver resection and SLT for treatment of HCC, the aim of this study is to access the factors that influence this strategy and verify the effectiveness and safety of SLT through evidence based medical research including uni-center, multi-center, and meta analysis to provide theoretical and evidence based proof for the clinical practice.Materials and Methods:(1) A retrospective study examined clinical data of262patients from the Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine. A total of118patients were clinically considered as resectable patients. The remaining144patients were clinically unresectable. Statistical analysis was performed in SPSS15.0for Windows to access the relationship between a positive family history of liver cancer or HBV infection and the operative resectability of HCC in the Chinese population.(2) A retrospective study examined clinical data of40patients from June2001to June2009who received SLT at the Liver Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine. A total of19patients fulfilled Hangzhou criteria and21exceeded Hangzhou criteria. Kaplan-Meier curves were used to compare survival rates.(3) A retrospective study examined data from the China Liver Transplant Registry (CLTR) for6,975transplants performed in76liver transplantation centers all around China from January1999to December2009. A total of6,087patients underwent primary liver transplantation (PLT) and888patients underwent SLT for recurrence. Living donor liver transplantation (LDLT) was performed in389patients, while6,586patients underwent deceased donor liver transplantation (DDLT). Clinical characteristics of SLT after primary liver resection and PLT were analyzed and Kaplan-Meier curves were used to compare survival rates.(4) A systematic review screened eligible studies from2,799references and meta-analysis evaluated the survival rate and the risk of postoperative complication incidences of SLT recipients.(5) Data collected by CLTR containing all the transplants performed in86liver transplantation centers all around China from January1999to December2010were examined. A total of7,658patients were included, with7,162HBV associated HCC (HBV-HCC) cases and496HCV associated HCC (HCV-HCC) cases. PLT was performed in6,627patients while1,031patients underwent SLT. Clinical characteristics of HBV-HCC and HCV-HCC were analyzed and Kaplan-Meier curves were used to compare survival rates.(6) A retrospective cohort study based on the Scientific Registry of Transplant Recipients (SRTR) examined16,682adult (≥18years) recipients with definite hepatitis B or hepatitis C receiving a first isolated liver transplantation between January2002and January2010. A total of5,983patients were diagnosed as HBV-HCC or HCV-HCC or HBV and HCV coinfection associated HCC. Kaplan-Meier methods were used to calculate patient survival rates and Cox proportional hazard models were used to estimate the effect of hepatitis virus infection related HCC. Results:(1) A family history of HBV infection is significantly associated with the resectability of HCC (AOR=2.332;95%CI,1.051-5.177). There was also has a significant association between the first degree relatives infected with HBV and the resectability of HCC (AOR=2.334;95%CI,1.050-5.190), especially a patient's sibling having a history of HBV infection is significantly related to the resectability of HCC (AOR=2.727;95%CI,1.092-6.808).(2) For those patients who received SLT fulfilling Hangzhou criteria, the1-,3-,5-year survival rates were100%,86.7%,80.0%, retrospectively, which were much better for patients exceeding Hangzhou criteria. Similar results were observed for the desease-free survival rates. No statistical significance was revealed between patients fulfilling Hangzhou criteria (n=19) and patients fulfilling Milan criteria (n=15) according to comparison of survival and disease-free survival. Within Hangzhou criteria, there is no statistical significant difference of comparable survival and disease-free survival between patients undergoing SLT and those undergoing PLT.(3) Among the6,975patients, the1-year,3-year, and5-year overall survival of SLT recipients was similar to that of PLT recipients:73.00%,51.77%, and45.84%vs.74.49%,55.10%, and48.81%, respectively (P=0.260). The1-year,3-year and5-year disease-free survival of SLT recipients was inferior to that of PLT recipients:64.79%,45.57%, and37.78%vs.66.39%,50.39%, and43.50%, respectively (P=0.048). Similar survival results were observed for SLT and PLT within both the LDLT and DDLT recipients who met Hangzhou criteria.Within the SLT group,the1-year,3-year,and5-year overall survival for LDLT and DDLT recipients who met Hangzhou criteria was similar:93.33％,74.67％,and74.67％vs.80.13％,62.10％,and54.18％(P=0.281),as was the disease-free survival:84.85％,62.85％,and62.85％vs.70.54％,53.94％,and43.57％(P=0.462).(4)Meta-analysis results indicated no statistically significant difference in terms of overall survival rate between SLT and PLT with1,3,5-year pooled relative risk(RR)0.99(95％CI,0.90-1.08,P=0.740),0.97(95％CI,0.84-1.11,P=0.651),0.94(95％CI,0.81-1.10,P=0.446),respectively. With respect to postoperative complications between SLT and PLT,the incidence of sepsis,biliary complication and acute rejection showed no statistically significant difference except for bleeding,of which RR was2.60(95％CI,1.49-4.54,P=0.001).(5)Among the7,658patients,no differences existed in overall,tumor-free and recurrence-free survival rates between HBV-HCC and HCV-HCC patients who met Hangzhou criteria in SLT group,at86.61％,72.42％,68.69％, compared with72.73％,60.61％,60.61％(P=0.188),and71.16％,55.23％,48.88％,compared with72.73％,60.61％,60.61％(P=0.920),and85.46％,70.37％,67.68％,compared with72.73％,60.61％,60.61％(P=0.230), respectively. For PLT group within Hangzhou criteria, the survival of HBV-HCC patients was higher than that of HCV-HCC patients.Within HBV-HCC group and HCV-HCC group,the survival of PLT and SLT recipients who met Hangzhou criteria was all similar.(6) In HCC group,HBV subgroup had the highest post-transplant survival rate:92％1-year survival,82％3一year survival and73％5-year survival,being superior to patient survival rates in HCV subgroup,88％1-year survival, 73%3-year survival,64%5-year survival (P<0.001), and no difference was found between HBV subgroup and coinfection subgroup (85%1-year survival,73%3-year survival and70%5-year survival, P=0.122), respectively. With the HBV as reference, HCV recipients had a remarkably higher risk of patient survival (hazard ratio,1.577;95%CI,1.314-1.893).Conclusions:A family history of HBV infection is associated with the resectability of HCC which indicates a reduced opportunity to receive curative liver resection. This will help guide us greatly to perform liver resection in the clinical practice. On the other hand, Hangzhou criteria can be applicable to SLT in patients with recurrent HCC after liver resection. Within Hangzhou criteria, SLT has a similar survival to that of PLT, indicating that SLT is acceptable for patients with recurrent HCC after liver resection. Given the limited organ donor pool, SLT can be considered as an alternative way of treatment. HCV infected patients had statistically worse survival than those with HBV infection after liver transplantation for HCC. These findings may provide some evidence in prioritizing selection of candidates who are diagnosed as HCC with chronic HBV or HCV infection for liver transplantation, whereas patients with either HBV infection or HCV infection receiving SLT for HCC can gain similar survival to those who receive PLT.