Results of salvage liver transplantation

Transcription

1 Liver International ISSN LIVER TRANSPLANTATION Results of salvage liver transplantation Gian Piero Guerrini 1, Giorgio E. Gerunda 2, Roberto Montalti 1, Roberto Ballarin 1, Nicola Cautero 1, Nicola De Ruvo 1, Mario Spaggiari 1 and Fabrizio Di Benedetto 1 1 Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, Department of Surgery and Transplantation, University of Modena and Reggio Emilia, Modena, Italy 2 General Surgery Unit, Department of Surgery and Transplantation, University of Modena and Reggio Emilia, Modena, Italy Keywords hepatocellular carcinoma liver resection liver transplantation outcome of liver transplantation salvage liver transplantation Correspondence Gian Piero Guerrini, MD, PhD, Hepato- Pancreato-Biliary Surgery and Liver Transplantation Unit, University Hospital of Modena, Del pozzo 71, Modena, Italy Tel: Fax: guerrinigp@yahoo.it Received 20 October 2013 Accepted 5 February 2014 DOI: /liv Liver Int. 2014: 34: e96 e104 Abstract Background & Aims: Salvage liver transplantation (SLT) is an attractive sequential strategy which combines liver resection (LR) for hepatocellular carcinoma (HCC), followed by liver transplant (LT) in the event of HCC recurrence or progressive liver deterioration. To compare the long-term results of SLT with primary liver transplant (PLT). Methods: Between 2000 and 2011, 125 patients (72 transplantable) underwent LR and 226 underwent LT in our unit. The outcome of SLT was analysed in a two-step fashion: firstly, SLT (n = 28) was compared with PLT (n = 198), secondly an intention-to-treat analysis was performed on all transplantable HCC patients who underwent LR (LRT group = 72) compared to PLT (n = 198). Results: The five-year overall survival (OS) was 65.4% vs. 49.2% (P = 0.63), and diseasefree survival (DFS) was 89.7% vs. 80.6% (P = 0.31) for PLT and SLT respectively. Predictive factors for DFS after LT included HCC total diameter [hazard ratio (HR) 1.29 P = 0.003], alpha-foetoprotein (HR P < 0.001) and number of HCC nodules (HR P = 0.035), whereas viral hepatitis C positivity (HR P = 0.03) and outside Up-to-seven criteria (HR P < 0.001) were negative independent prediction factors of OS. Intention-to-treat analysis showed that OS at 5 years was improved in PLT vs. LRT (LRT n = 72 including SLT plus LR group) and was 69.4% vs. 42.2% (P < 0.004), with an additional increase in DFS (89.2% vs. 54.5% respectively P < 0.001). Conclusion: Salvage liver transplantation is a safe treatment strategy, as it does not impair long-term survival. At intentionto-treat analysis, PLT showed improved survival compared with LRT. Liver transplantation (LT) represents the ideal treatment for early hepatocellular carcinoma (HCC) as it removes the tumour and also resolves the underlying liver disease. In fact, LT offers the patient survival that reaches 70% at 5 years, and disease-free survival (DFS) of 90% at 5 years: a valid oncological treatment (1 3). Before the introduction of Milan criteria, the results of liver transplant for HCC were rather disappointing (4). As transplant has become the victim of its own success, because of organ shortage the risk of drop-out for tumour progression and the deterioration of the patients clinical conditions constitute an important problem (5 8). Alternative curative treatments that do not unnecessarily compromise the subsequent transplant include: transcutaneous ablation, transarterial chemioembolization (TACE) and liver resection (LR) that are practicable with a low-operating risk (9 14). Sorafenib should be considered for advanced HCC with an eye on complete or partial remission (15). An improved staging of the patient with early HCC based on an accurate evaluation of hepatic function and portal pressure associated with refining of the surgical and anaesthetic techniques has given results of survival up to 70% at 5 years in selected patients after LR for HCC (16, 17). These data have reopened the debate on the surgical treatment of HCC in patients with a small HCC and preserved liver function (18 20). In recent years, some authors have proposed LR as the front-line treatment for HCC for patients with compensated hepatic cirrhosis, offering a subsequent transplant for patients who developed limited hepatic recurrence or in the event of deterioration of hepatic function (21 25). Initial LR of HCC as a primary therapy, in patients who otherwise could have been transplanted, offers a good quality of life and is less demanding than LT. The strategy of LR followed by salvage transplant (SLT) potentially offers an advantage with respect to liver transplant: a therapy with good long-term survival, immunosuppression-free and the theoretical possibility of saving the organ to transplant in a patient who needs one (26 28). e John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

2 Guerrini et al. SLT: Modena s experience However, SLT is based on the pre-supposition that the recurrence of HCC after hepatic resection is still found in those shared limits of transplantability. This is unfortunately not always true and various authors have emphasized that the histological characteristics analysed on the specimen removed after the hepatic resection can help to stratify the population in high- and low-risk groups. It must also be emphasized that half of the patients had a devastating recurrence which precluded the subsequent transplant (29, 30). There are few clinical studies documenting salvage LT as a viable treatment in patients who underwent LR prior to LT for HCC. The aim of this study was to evaluate the feasibility and viability of a strategy of primary resection with secondary LT for HCC on cirrhosis according to intentionto-treat analysis. Materials and methods From January 2000 to November 2011, 351 patients with HCC documented by two imaging studies, including triple-phase computed tomography (CT) and/or magnetic resonance imaging showing both early hyperenhancement and delayed hypoenhancement (washout) in accordance with the Practice Guidelines for Management of HCC (American Association for the Study of the Liver Disease) (31), underwent hepatic resection (n = 125) or liver transplant (n = 226). Hepatic resection was indicated when the patients had one or two tumour nodules, preserved hepatic function (Child Pugh A or MELD score <9), no portal hypertension (PLT > l/ml or HVPG < 10 mmhg) and absence of macro-vascular tumour invasion. However, over time our indications for hepatic resection were changed by the implementation of the indocyanine green retention test (IGC-15 test). Based on this test, patients with slightly compromised liver function (Child B) were treated with minor hepatic resection (segmentectomy) (32). All the resections had intent to cure; the resection R0 was defined with a surgical margin of tumour >1 mm. In this group of patients, 53 (42.4%) were considered not transplantable because of their age >65 years, a tumour with diameter >6 cm or tumours with multifocal disease (up to 3 nodules and >4 cm) in accordance with the criteria used for the selection for transplant in the same period. The remaining 72 patients (57.6%) were potentially transplantable; however, because of organ shortage, hepatic resection treatment represented the first choice. This constituted the LR transplantable group (LRT group n = 72). After LR, follow-up included alpha-foetoprotein and an ultrasound every 3 months, and a thoracic-abdominal CT scan every 6 months for the first 2 years, and then annually. The therapeutic strategy adopted was to consider the transplant as salvage for those patients who had developed a hepatic recurrence or presented with irreversible hepatic failure post-resection. Among the 72 potentially transplantable patients, 28 were subsequently transplanted: 22 for tumour recurrence, four for deterioration of hepatic function and two for high risk of recurrence. A total of 198 patients transplanted for HCC over the study period were selected according to the following criteria: age <65 years, no lymph node metastasis or extrahepatic spread, no macroscopic vascular invasion, no history of malignant neoplastic pathologies in the previous 5 years, HCC fulfilling Milan Criteria and, from 2009, Up-to-seven criteria (33). The main indications for liver transplant generally depended on the technical impossibility of resecting the tumour or the decompensated hepatic function. In the last 5 years, patients with HCC outside the Milan criteria were not discarded from the transplant program, but were started on a program of down-staging with loco-regional ablative techniques. The patients who responded positively to this down-staging treatment were assessed by a commission of multidisciplinary experts, comprising oncologists and radiologists, for approval for re-enlistment. Because of the criteria adopted for selection, the study population comprised 72 patients in the LRT group and 198 in the LT group of the 226 transplanted in the study period. The therapeutic strategy of the SLT was analysed in two ways: 1 Salvage transplant (SLT group n = 28 patients) was compared with PLT for HCC (LT group n = 198) to evaluate the outcome and operating risk of these patients. The survival in every group was calculated from the time of transplant. 2 On an intention-to-treat basis, the LR transplantable group (LRT group which included SLT, n =72 patients) was compared with PLT for HCC (LT group n = 198) to evaluate the outcome of this strategy treatment. Continuous variables in each group were compared by independent sample t-test and Mann Whitney for two groups. Categorical parameters were compared using Fischer s exact test. On intention-to-treat analysis, survival time in each group started at the time of the procedure for those who underwent LR and at the time of listing for those who were considered for LT first. Survival rates were calculated according to the Kaplan Meier method and compared using the log rank test. The univariate and multivariate analyses were done to characterize predictive factors for post-transplant survival. Recipient and tumour variables were entered into univariate analysis and multivariate analysis for overall survival and DFS using the Cox proportional hazard regression model. The disease-free survival was calculated considering patients who developed recurrence of HCC after LT or LR. The logistic regression model was applied to investigate predictors of HCC recurrence beyond Milan Criteria John Wiley & Sons A/S. Published by John Wiley & Sons Ltd e97

3 SLT: Modena s experience Guerrini et al. All co-variates with P < 0.2 in the univariate analysis were included in a multivariate Cox regression analysis by forward stepwise method. Results are expressed as means with SD. P values of 0.05 or less were considered statistically significant. All the analyses were carried out using SPSS 14.0 for Windows (release 14.0; SPSS, Chicago, IL, USA). Results Primary liver transplantation vs. salvage liver transplantation Salvage liver transplantation group at the time of resection In the SLT group (n = 28) at the time of hepatic resection, the main aetiology was HCV-related hepatitis (n = 13), followed by HBV infection (n = 7), HBV- HDV coinfection (n = 3), alcohol (n = 2) and nonalcoholic steato-hepatitis (NASH, n = 3). The median MELD score was 8.5 ± 2 and the number of Child A patients was slightly greater than B patients (17 Child A vs. 11 Child B). Major hepatic resections were eight right hepatectomies and minor resection were five left lateral sectionectomies and 15 anatomical resections (segmentectomies), using a transabdominal approach in all cases. The mean number of tumour nodules was 1.14 ± 0.3 (82.1% of the patients n = 23 had a single nodule), the mean of diameter of the tumour was 5.5 ± 3.1 cm and alphafoetoprotein levels were 188 ± 500 ng/ml respectively. On histological examination, six patients (21.4%) did not meet Milan criteria, and three (10.7%) of them could not be considered as fulfilling the Up-to-seven criteria. The mean time from resection to transplantation was 33 ± 11 months. Clinical and biological characteristics of the tumour in the salvage liver transplantation group and primary liver transplantation group at the time of transplantation The demographic characteristics of patients who underwent PLT or SLT are represented in Table 1. The mean duration of follow-up was 44.2 ± 34.9 months. No significant difference between the two groups was observed regarding clinical variables, aetiology, D-MELD, including the total ischaemia time and the ReOLT rate. As regards the biological characteristics of the tumour in the two study groups, only the number and the total diameter of the HCC were statistically higher in the LT group (Table 2). Moreover, in the LT patient group, treatment of the tumour included TACE and RFA as bridging to the transplant in 73.3% (n = 145), while in 67.8% (n = 19) the treatment included TACE plus RFA in the SLT patient group. In this last group, the waiting time on the list was statistically higher, an average of 21 ± 17 months vs. 15 ± 13 months (P = 0.03). Table 1. The demographic characteristics of the study population PLT (n = 198) SLT (n = 28) P value Age (years) 56 ± 7 56± MELD 16 ± 7 12± Donor (age) 61.3 ± ± D-MELD ± ± Sex (male) 168 (84.8%) 27 (96.4%) Aetiology (%) Cholestatic 17 (8.6) 0.40 Alcohol 20 (10.1) 2 (7.1) HCV 119 (60.1) 13 (46.4) HBV 42 (21.2) 10 (35.7) Metabolic 3 (10.7) Child (%) A 77 (38.9) 17 (60.7) 0.05 B 76 (38.4) 9 (32.2) C 45 (22.7) 2 (7.1) Tx type (%) DDLT 186 (93.9) 27 (96.4) 0.5 LDLT 12 (6.1) 1 (3.6) Re-LT (%) No 189 (95.5) 26 (92.9) 0.55 Yes 9 (4.5) 2 (7.1) Waiting list time months 15.1 ± ± Numeric variables are expressed as mean ± SD, qualitative variables are expressed as count and percentage. DDLT, deceased donor liver transplant; HBV, viral hepatitis B; HCV, viral hepatitis C; LDLT, living donor liver transplant; MELD, model for end stage liver disease; PLT, primary liver transplant; SLT, salvage liver transplantation. Overall and disease-free survival Perioperative mortality ( 1 month post-transplant) was 3.5% in the PLT group (n = 7) and 7.1% (n = 2) in the SLT group P = In this last group, the two deaths that occurred were a case of primary nonfunction (PNF) and an invasive form of aspergillosis, while in the PLT group, three deaths were caused by PNF, three by sepsis and one by multiorgan failure. One-, three- and five year overall survival and DFS rates in the PLT and SLT groups are shown in Figs 1 and 2. In the entire cohort of patients, the predictive factors for DFS after LT at Cox regression analysis included HCC total diameter [hazards ratio (HR) 1.29 (95% CI interval), range , P = 0.003], alpha-foetoprotein (HR 1.002, range , P < 0.001) and number of HCC nodules (HR 1.317, range , P = 0.035), whereas HCV positivity (HR range P = 0.03) and outside Up-to-seven criteria (HR 2.652, range , P < 0.001) were negative independent prediction factors of overall posttransplant survival (Table 3). Complications During the operation, the two groups showed no differences in terms of amount of transfused erythrocytes e John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

4 Guerrini et al. SLT: Modena s experience Table 2. Tumour characteristics of the study population PLT (n = 198) SLT (n = 28) P value HCC no. of nodules 2.34 ± ± HCC total diameter, cm 4.1 ± ± Milan criteria Out 65 (32.8%) 6 (21.4%) 0.22 Up-to-seven criteria Out 37 (18.6%) 4 (14.8%) 0.57 Satellitosis Yes 39 (19.6%) 7 (25%) 0.53 Grading G (60.1%) 23 (82.1%) 0.28 G (39.8%) 5 (17.9%) Necrosis Yes 43 (21.7%) 6 (21.4%) 0.98 HCC treatment Yes 145 (73.5%) 19 (67.8%) 0.36 Tace Yes 115 (58.1%) 19 (67.8%) 0.22 RFA Yes 62 (31.3%) 7 (25%) 0.49 Microvascular invasion Yes 24 (12.1%) 2 (7.1%) 0.48 AFP, ng/ml ± ± Recurrence 17 (8.5%) 4 (14.2%) 0.33 Numeric variables are expressed as mean ± SD, qualitative variables are expressed as count and percentage. AFP, a-foetoprotein; HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; PLT, primary liver transplant; SLT, salvage liver transplantation; TACE, transarterial chemoembolization. (1876 ml in the SLT group vs ml in the LT group), or of plasma (705 ml vs. 822 ml). Ischaemia times were very similar: warm ischaemia of 39.4 min in the SLT group vs. 45 min in the LT group (P = ns). On the other hand, the operating time in the SLT group was significantly longer compared to the PLT group (596 ± 122 min vs. 504 ± 109 min, P = 0.01). Significant perioperative complications consisted of two cases of portal thrombosis in the SLT group. Liver resection transplantable group vs. primary liver transplantation Clinical and biological characteristics of the tumour in LR and LT In the liver resection transplantable group (LRT that also comprises the Salvage transplantation group), the most frequent associated cause of HCC was correlated with HCV infection, followed by HBV and metabolic diseases (haemochromatosis and NASH), while in the LT group, in addition to the above causes, cholestatic pathologies were also found. The status of hepatic function in the PLT group was decidedly more compromised with respect to the LRT group; in fact the mean MELD score was 16 vs. 8 (P = 0.001), the Child Pugh class B and C was 60% vs. 11% P < (Table 4). Regarding the tumour characteristics observed, the average number of HCC nodules was greater in the PLT Overall survival 1.0 Probability of survival % Log-rank test P = NS PLT SLT PLT-censored SLT-censored Months Primary liver transplantation = 198 pts Salvage liver transplantation = 28 pts 1 year % 3 years % 5 years % P 81.4 (36 pts) 69.8 (56) 65.4 (60) (4) 66.4 (7) 49.2 (9) Fig. 1. Overall survival primary liver transplant vs. salvage liver transplantation John Wiley & Sons A/S. Published by John Wiley & Sons Ltd e99

5 SLT: Modena s experience Guerrini et al. Disease free survival Probability of survival % Log-rank test P = NS PLT SLT PLT-censored SLT-censored Months Primary liver transplantation = 198 pts Salvage liver transplantation = 28 pts 1 year % 3 years % 5 years % P 94.1 (1) 89.7 (17) 89.7 (17) (1) 80.6 (4) 80.6 (4) Fig. 2. Disease-free survival primary liver transplant vs. salvage liver transplantation. Table 3. Multivariate analysis COX regression of the entire population of HCC-transplanted patients salvage liver transplantation + primary liver transplantation HR 95% CI for HR Lower Upper P value Disease-free survival AFP, ng/ml <0.001 HCC no. of nodules HCC total diameter Overall survival HCV hepatitis (yes) Outside Up-to-seven criteria (yes) <0.001 HCC, hepatocellular carcinoma, HCV, viral hepatitis C; HR, hazard ratio. group (2.3 ± 1.9) than in the LRT group (1.2 ± 0.5), the total diameter of the HCC nodules was greater in the LT group (4.1 ± 3.1 cm) than in the LRT group (3.4 ± 1.7 cm), whereas the rate of microvascular invasion was increased in the LTR group (15.2%) compared with the LT group (12.1% P = 0.01). The other tumour variables did not differ between the two groups (Table 4). The mean follow-up was 44.3 ± 11.2 months. In the LRT group, a recurrence rate of 62.5% (n = 45) was observed, vs. 8.6% in LT (n = 17) P < Of the 45 patients with tumour recurrence, 22 patients subsequently underwent salvage transplant and the transplant rate for recurrence was 49%. Overall and disease-free survival Figures 3 and 4 illustrate one-, three- and five-year overall survival and DFS rates in the LRT group and in the PLT group, according to the intention-to-treat analysis. Univariate and multivariate analyses of overall and DFS based on a model of intention-to-treat were performed in all the HCC transplantable groups, both the LRT group and those patients with PLT. Variables analysed included treatment type (SLT vs. LR and PL vs. LR), aetiology, MELD score, Child A vs. Child B and C age, sex, number of HCC nodules, tumour diameter, microvascular invasion, grading G1 2 vs. G3 4, alphafoetoprotein, Up-to seven criteria In vs. Out. Predictor factors of overall survival were Modality of treatment (P < 0.001), where SLT had better survival compared with LRT (HR 0.278, range , P < 0.001); PLT vs. LRT (HR 0.512, range , P = ns), and outside Up-to-seven criteria (HR 2 range P = 0.021). For DFS, independent predictor factors were Modality of treatment P < (SLT vs. LRT: HR range P < ; PLT vs. LRT: HR 0.042, range P < ), outside Up-to-seven criteria (HR 4, range , P = 0.014) and HCC diameter (HR 1.32, range , P < ) (Table 5). On intention-to-treat analysis, the risks of recurrence beyond Milan criteria in all the LTR groups at logistic multivariate regression analysis were: number of HCC nodules (HR 4.15, range , P < ) and alphafoetoprotein (HR 1.001, range , P = 0.004). e John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

6 Guerrini et al. SLT: Modena s experience Table 4. Clinical and biological characteristics of the tumour in the LRT and PLT groups Discussion LRT group (n = 72) PLT group (n = 198) P value Sex Male 64 (88.8%) 168 (84.8%) 0.39 Age Mean ± SD 56.4 ± ± Aetiology HCV 41 (56.9%) 119 (60.1%) 0.57 HBV 19 (26.3%) 42 (21.2%) Cholestatic 17 (8.6%) Alcohol 7 20 (10.1%) Metabolic 5 (9.7%) Child A 64 (88.8%) 77 (38.8%) <0.001 B 8 (11.2%) 76 (38.4%) C 45 (22.7%) MELD Mean ± SD 8.9 ± ± Grading G (66.1%) 119 (60.1%) 0.34 G (33.9%) 79 (38.9%) HCC satellitosis Yes 13 (18%) 39 (19.7%) 0.98 Microvascular invasion Yes 11 (15.2%) 24 (12.1%) 0.01 HCC no. of nodules Mean ± SD 1.2 ± ± 1.9 <0.001 HCC total diameter Mean ± SD 3.4 ± ± AFP Mean ± SD ± ± Recurrence Yes 45 (62.5%) 17 (8.6%) <0.001 AFP, alpha-foetoprotein; HBV, viral hepatitis B; HCV, viral hepatitis C; LRT, liver resection transplantable; PLT, primary liver transplant. Of the treatments proposed for dealing with early HCC on cirrhosis, LT remains the best treatment as it removes the tumour radically, treats the underlying hepatic disease and cures the physiopathological consequences of the cirrhosis (8, 34). Two problems of notable importance limit the indiscriminate application of LT to all patients: the ever increasing lack of organs and the drop-out from the waiting list because of tumour progression. However, hepatic resection for HCC has achieved remarkable results in terms of long-term survival, thanks to the improvement in surgical techniques, careful perioperative anaesthetic management and early diagnosis. Currently, hepatic resection for a small HCC is associated with a five-year overall survival of 70%, comparable with that of liver transplant. An alternative strategy has been proposed in the management of HCC that entails hepatic resection as the first treatment, followed by the salvage transplant in the event of tumour recurrence or deterioration of hepatic function. This therapeutic strategy was initially researched by Majno et al. on a theoretical Markov-decision model and is based on three assumptions: a short waiting list <12 months, a post-resection recurrence in 60% of cases still eligible for transplant, a survival rate similar to that of primary transplant (25). In our study, the patients who underwent LR had a perioperative mortality rate of 4.1% in line with the results reported in the literature by specialized centres. Of the 72 patients who underwent hepatic resection, 45 (62.5%) developed a hepatic recurrence at follow-up; 22 patients underwent successful salvage transplant, while in 23 patients transplant was not indicated because the recurrence was outside the Milan criteria, or for age limits. As the net rate of transplantability was 49%, the strategy to transplant a patient for post-resection recurrence was theoretically valid but it was applicable in only half of our patients. Regarding the results published by the Hong-Kong group, in which a cohort of 135 patients underwent hepatic resection for HCC within Milan criteria, 53 patients had a hepatic recurrence still considered eligible for salvage transplantation, our data seem to be nearer to those recently published by the French group (23, 35). Our intention-to-treat analysis demonstrated two pre-operative variables as being predictive of recurrence outside Milan criteria in the patients who underwent LR: number of HCC nodules and alpha-foetoprotein. The effort to search for prognostic factors to stratify the patients for risk of recurrence is a much needed requirement in the scientific community, since preoperative risk factors have so far demonstrated little sensitivity. Hepatic resection, on the other hand, offers the advantage of being able to give an accurate histological analysis, estimating the tumour stage, grading and the microvascular invasion, all universally recognized prognostic elements of poor outcomes (36, 37). In fact, in our study, two patients who underwent hepatic resection were directed to liver transplant (de principe) in the absence of histologically documented tumour recurrence because of histological factors considered to be of higher recurrence risk. In agreement with the Barcelona group, at the end of the follow-up none of these patients developed a posttransplant recurrence (30). Fucks et al. (27) recently demonstrated that tumour recurrence outside Milan criteria post-resection is an expected event when associated with three unfavourable histological factors, while patients with only one or two risk factors had an odds ratio of recurrence of 20%. One disadvantage of LR with respect to transplantation is that the diseased liver remains, with a consequent high risk of developing an intrahepatic recurrence. Two types of recurrence can occur after hepatic resection: the so-called early form and the late form (de novo recurrence) (38, 39). When this last form occurs more than 2 years after the resective treatment, it seems to have 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd e101

7 SLT: Modena s experience Guerrini et al. Overall survival intention-to-treat Probability of survival % Log rank test < LR +SLT PLT LR + PLTcensored PLT-censored Months Primary liver transplantation group = 198 pts Liver resection transplantable group = 72 pts 1 year % 3 years % 5 years % P 91.8 (16) 75.7 (46) 69.4 (56) < (7) 71 (16) 42.2 (22) Fig. 3. Intention-to-treat overall survival primary liver transplant vs. salvage liver transplantation. 100 Disease free-survival intention to-trea analys Probability of survival % Log rank test < LR+SLT PLT LR+SLT-censored PLT censored Months Primary liver transplantation group = 198 pts Liver resection transplantable group = 72 pts 1 year % 3 years % 5 years % P 93.4 (11) 89.2 (17) 89.2 (17) < (12) 67.8 (29) 54.5 (45) Fig. 4. Intention-to-treat disease-free survival primary liver transplant vs. salvage liver transplantation. e John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

8 Guerrini et al. SLT: Modena s experience Table 5. Multivariate analysis of transplantable HCC patients: overall, disease-free survival and risk of recurrence Disease-free survival Modality of treatment: LRT-SLT-LT Hazard ratio LRT* reference group 95% CI for HR Lower Upper P value < SLT vs. LRT < PLT vs. LRT < Up-to-seven criteria (outside) HCC diameter, cm < Overall survival Modality of LRT* <0.001 treatment: LRT-SLT-LT reference group SLT vs. LRT <0.001 PLT vs. LRT Up-to-seven criteria (outside) Risk of recurrence beyond Milan criteria (in LRT group) HCC no. of nodules < AFP, ng/ml AFP, alpha-foetoprotein; HCC, hepatocellular carcinoma; HCV, viral hepatitis C; HR, hazard ratio; LRT, liver resection transplantable; PLT, primary liver transplant; SLT, salvage liver transplantation. various pathogeneses and can be interpreted by the presence of dysplasia on the remaining diseased liver. The early recurrence rate, instead, seems to diminish after anatomical hepatic resection (segmental) since the recurrence could be caused by an invasion of the portal branches from the segmented portion. Several studies have demonstrated a better DFS of anatomical hepatic resection vs. non-anatomical resection of HCC (40, 41). Another argument frequently discussed is whether transplant after hepatic resection can be technically more complex. Portal hypertension and the presence of adhesions certainly make the transplant more demanding. However, we did not observe an increase in complications in the SLT group with respect to the PLT group, although the duration of the operation was longer in the first group. Perioperative mortality, on the other hand, did not differ between the two groups. This demonstrates that the complexity of the technical intervention does not translate into an increase in mortality and post-operative morbidity (23). In our study, we observed that the DFS and overall survival of the SLT group was lower than in the PLT group, although not statistically significant. Our results do not seem to be in line with those of the French group of Adam et al. (42) in which the patients who underwent SLT had a five-year survival <40%. Moreover, LR before transplant turned out to be negative predictive variable of post-transplant survival in their analysis. Although in our multivariate analysis LR before transplant was not a negative prognostic factor for DFS post-transplant, we must consider that a type-ii b error would occur because of a restricted number of patients in the SLT group. Hepatic resection should be considered the front-line treatment for early HCC in patients with residual hepatic function. The data provided by the histological analysis of the tumour are currently the most useful means of grading patients for high risk post-resection recurrence. We nevertheless still await future genetic markers to characterize and predict the biological aggressiveness of the tumour. In conclusion, salvage transplant for tumour recurrence or deterioration of hepatic function is feasible and practicable and does not increase the risk of post-operative mortality. This strategy is applicable only in half the patients with potentially transplantable HCC. Although SLT achieves good survival post-transplantation, on intention-to-treat analysis the outcome of SLT is still inferior to PLT. Acknowledgements The authors have no grant, financial support for this paper. Conflict of interest: The authors do not have any disclosures to report. References 1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365: Adam R, McMaster P, O Grady JG, et al. Evolution of liver transplantation in Europe: report of the European Liver Transplant Registry. Liver Transpl 2003; 9: Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35: Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: Abrams P, Marsh JW. Current approach to hepatocellular carcinoma. Surg Clin North Am 2010; 90: Yao FY, Bass NM, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: lessons from the first year under the model of end-stage liver disease (MELD) organ allocation policy. Liver Transpl 2004; 10: Bismuth H, Majno PE, Adam R. Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 1999; 19: Guerrini GP, Pleguezuelo M, Maimone S, et al. Impact of tips preliver transplantation for the outcome posttransplantation. Am J Transplant 2009; 9: Capussotti L, Ferrero A, Vigano L, Polastri R, Tabone M. Liver resection for HCC with cirrhosis: surgical perspectives out of EASL/AASLD guidelines. Eur J Surg Oncol 2009; 35: Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005; 42: Belghiti J, Carr BI, Greig PD, Lencioni R, Poon RT. Treatment before liver transplantation for HCC. Ann Surg Oncol 2008; 15: John Wiley & Sons A/S. Published by John Wiley & Sons Ltd e103

9 SLT: Modena s experience Guerrini et al. 12. Di Bisceglie AM. Pretransplant treatments for hepatocellular carcinoma: do they improve outcomes? Liver Transpl 2005; 11(11 Suppl. 2): S Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation. Liver Transpl 2005; 11: Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006; 243: Kim HY, Park JW. Molecularly targeted therapies for hepatocellular carcinoma: sorafenib as a stepping stone. Dig Dis 2011; 29: Belghiti J, Hiramatsu K, Benoist S, et al. Seven hundred forty-seven hepatectomies in the 1990s: an update to evaluate the actual risk of liver resection. J Am Coll Surg 2000; 191: Poon RT, Fan ST, Lo CM, et al. Improving survival results after resection of hepatocellular carcinoma: a prospective study of 377 patients over 10 years. Ann Surg 2001; 234: Margarit C, Escartin A, Castells L, et al. Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class A patients with cirrhosis who are eligible for liver transplantation. Liver Transpl 2005; 11: Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30: Sapisochin G, Castells L, Dopazo C, et al. Single HCC in cirrhotic patients: liver resection or liver transplantation? Long-term outcome according to an intention-to-treat basis. Ann Surg Oncol 2013; 20: Adam R, Azoulay D. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy? Ann Surg 2005; 241: Del GM, Ercolani G, Ravaioli M, et al. Liver transplantation for recurrent hepatocellular carcinoma on cirrhosis after liver resection: University of Bologna experience. Am J Transplant 2008; 8: Belghiti J, Cortes A, Abdalla EK, et al. Resection prior to liver transplantation for hepatocellular carcinoma. Ann Surg 2003; 238: Hu RH, Ho MC, Wu YM, Yu SC, Lee PH. Feasibility of salvage liver transplantation for patients with recurrent hepatocellular carcinoma. Clin Transplant 2005; 19: Majno PE, Sarasin FP, Mentha G, Hadengue A. Primary liver resection and salvage transplantation or primary liver transplantation in patients with single, small hepatocellular carcinoma and preserved liver function: an outcomeoriented decision analysis. Hepatology 2000; 31: Dhir M, Lyden ER, Smith LM, Are C. Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 2012; 14: Fuks D, Dokmak S, Paradis V, et al. Benefit of initial resection of hepatocellular carcinoma followed by transplantation in case of recurrence: an intention-to-treat analysis. Hepatology 2012; 55: Hu Z, Wang W, Li Z, Ye S, Zheng SS. Recipient outcomes of salvage liver transplantation versus primary liver transplantation: a systematic review and meta-analysis. Liver Transpl 2012; 18: Poon RT, Fan ST. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy? Ann Surg 2004; 240: Sala M, Fuster J, Llovet JM, et al. High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: an indication for salvage liver transplantation. Liver Transpl 2004; 10: Tan CH, Low SC, Thng CH. APASL and AASLD consensus guidelines on imaging diagnosis of hepatocellular carcinoma: a Review. Int J Hepatol 2011; 2011: Imamura H, Sano K, Sugawara Y, Kokudo N, Makuuchi M. Assessment of hepatic reserve for indication of hepatic resection: decision tree incorporating indocyanine green test. J Hepatobiliary Pancreat Surg 2005; 12: Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009; 10: Washburn K, Halff G. Hepatocellular carcinoma and liver transplantation. Curr Opin Organ Transplant 2011; 16: Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 2002; 235: Ercolani G, Grazi GL, Ravaioli M, et al. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg 2003; 237: Cillo U, Vitale A, Bassanello M, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg 2004; 239: Grazi GL, Cescon M, Ravaioli M, et al. Liver resection for hepatocellular carcinoma in cirrhotics and noncirrhotics. Evaluation of clinicopathologic features and comparison of risk factors for long-term survival and tumour recurrence in a single centre. Aliment Pharmacol Ther 2003; 17 (Suppl. 2): Yang T, Zhang J, Lu JH, et al. Risk factors influencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases. World J Surg 2011; 35: Yamazaki O, Matsuyama M, Horii K, et al. Comparison of the outcomes between anatomical resection and limited resection for single hepatocellular carcinomas no larger than 5 cm in diameter: a single-center study. J Hepatobiliary Pancreat Sci 2010; 17: Zhou Y, Xu D, Wu L, Li B. Meta-analysis of anatomic resection versus nonanatomic resection for hepatocellular carcinoma. Langenbecks Arch Surg 2011; 396: Adam R, Azoulay D, Castaing D, et al. Liver resection as a bridge to transplantation for hepatocellular carcinoma on cirrhosis: a reasonable strategy? Ann Surg 2003; 238: e John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

10 本文献由 学霸图书馆 - 文献云下载 收集自网络, 仅供学习交流使用 学霸图书馆 ( 是一个 整合众多图书馆数据库资源, 提供一站式文献检索和下载服务 的 24 小时在线不限 IP 图书馆 图书馆致力于便利 促进学习与科研, 提供最强文献下载服务 图书馆导航 : 图书馆首页文献云下载图书馆入口外文数据库大全疑难文献辅助工具