Recurrence-free survival after liver transplantation for small hepatocellular carcinoma

Abstract Recurrence-free survival (RFS) in patients with small hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) was analyzed. From 1988 until 1996, 725 OLTs were performed in 669 patients. In 52 adults, HCC was confirmed histologically. OLT was limited to patients with small (<5 cm) HCC with a maximum number of three nodules. Actuarial survival for these 52 patients at 1 and 5 years is 88% and 71%. RFS was defined as time until death without recurrence, time until follow up with a diagnosis of recurrence, or, in patients without recurrence, time of last follow up. Overall, the 5-year RFS was 60%. Five-year RFS was less for bilobar compared to unilobar tumors (36% vs 70%), less for stage IVa tumors (UICC) compared to stage I-III tumors (17% vs 71%), and less for multiple compared to solitary tumors (54% vs 67%). In conclusion, potential cure may be achieved in more than 50% of all transplanted patients.     

Adjuvant chemotherapy improves survival after liver transplantation for hepatocellular carcinoma.

OBJECTIVE: The aim of this study was to evaluate the effect of postoperative adjuvant chemotherapy on the recurrence rate and survival of patients after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Historically, liver transplantation for HCC has yielded poor long-term survival. Multimodality therapy has been initiated in an effort to improve survival statistics. METHODS: Twenty-five patients were placed on 6 months of intravenous fluorouracil, doxorubicin, and cisplatin after OLT. Risk factors, recurrence rates, and survival rates were analyzed and compared with historic controls. RESULTS: Overall long-term survival in the protocol patients was 46% at 3 years, improved over our historic controls of 5.8% at 3 years (p = 0.0001). Overall recurrence rate was 20% (n = 4). Possible risk factors, such as tumor size, vascular invasion, multifocality, capsular invasion, and tumor differentiation, were not found to be significantly predictive of survival. Three patients with long-term, disease-free survival had tumors > 5 cm. Side effects from chemotherapy were common, but rarely severe. CONCLUSIONS: This study suggests that adjuvant chemotherapy after transplantation for HCC can provide long-term cure and may improve survival, even in patients with stage III and IV disease.     

Hepatitis C virus infection with hepatocellular carcinoma: not a controversial indication for liver transplantation

BACKGROUND: The association of hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection has been identified as a potential contraindication for orthotopic liver transplantation (LT) because of lower survival rate compared with other indications. AIM: Evaluate the outcome of patients with and without HCC and cirrhosis with and without chronic HCV infection undergoing transplantation. Determine the postLT HCC recurrence rate and frequency of de novo postLT HCC. PATIENTS AND METHODS: United Network for Organ Sharing (UNOS) data was collected from January 1998 to December 2002. Cohort included 17,968 patients (11,552 M; 6,416 F) with a mean age of 51 (18-87) years. Four groups were established: HCV (n = 7,079), HCC (n = 611), HCV+HCC (n = 1,078), and no HCV/no HCC (n = 9,200). The overall survival rate was calculated at 24 and 48 months postLT. RESULTS: Patient survival at 24 months and 48 months was 84% and 75% for HCV, 84% and 68% for HCC, 78% and 72% for HCV+HCC, and 85% and 80% for no HCV/no HCC, respectively. Survival at 48 months among the two groups was not significantly different (NS). Further analysis of these groups revealed a statistically significant advantage in survival at 48 months postLT for the no HCV/no HCC group when compared with the HCV group.(P < 0.05) The reported rate of postLT HCC recurrence and de novo postLT HCC was 3.3% and 0.05%, respectively. CONCLUSION: In this large cohort of U.S. patients, HCC does not have an impact on the survival of LT patients infected with HCV.     

Survival after liver transplantation for hepatocellular carcinoma

BACKGROUND: Selection criteria for patients with hepatocellular carcinoma (HCC) suitable for liver transplantation (LT) include tumor size and number and vascular invasion. There has been a recent trend to expand the transplant criteria for HCC. We reviewed our experience to determine survival following LT based on tumor characteristics. METHODS: A retrospective analysis was performed on 72 patients with HCC who underwent LT between 1985 and July 2002. The Milan criteria were applied for LT candidacy for HCCs that were deemed unresectable from anatomical considerations and/or the severity of underlying cirrhosis. Patients were divided into four groups: group 1: patients with known HCC who satisfied the selection criteria (n = 22); group 2: patients with known HCC that exceeded the criteria (n = 17); group 3: patients with incidental HCC found at pathological examination of the explant (n = 33); group 4: contemporary LT recipients without HCC (n = 935). RESULTS: In the known HCC group, the interval between listing as status 2 and transplantation was 72.2 +/- 133.6 days (median 23 days). Three-year patient survival was 80.2% in group 1, 35.8% in group 2, 63.2% in group 3, and 81.5% in group 4. In group 2 patients, the tumors were significantly larger, had more nodules, and were more often bilobar. In group 3, five (15%) exceeded the criteria mainly because of tumor size and four patients died within 3 years post-LT (three from tumor recurrence). CONCLUSION: Liver transplantation for HCC yields acceptable survival in early-stage tumors, particularly if transplanted soon after listing. Long-term survival was inferior in patients with multiple tumors and tumors that were greater than 5 cm in diameter.     

Impact of pretransplantation transarterial chemoembolization on survival and recurrence after liver transplantation for hepatocellular carcinoma.

The actual impact of transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma (HCC) on patient survival and HCC recurrence is not known. Between 1985 and 1998, 479 patients with HCC in 14 French centers were evaluated for LT. Among these 479 patients, this case-control study included 100 patients who received transarterial chemoembolization before LT (TACE group) and 100 control patients who did not receive chemoembolization (no-TACE group). Patients and controls were matched for the pre-LT tumor characteristics, the period of transplantation, the time spent on the waiting list, and pre- and posttransplantation treatments. Kaplan-Meier estimates were calculated 5 years after LT and were compared with the log-rank test. The mean waiting time before LT was 4.2 +/- 3.2 months in the TACE group and 4.3 +/- 4.4 months in the no-TACE group. The median number of TACE procedures was 1 (range: 1-12). Demographic data, median alpha-fetoprotein level (21.6 ng/mL and 22.0 ng/mL, respectively), and pre- and post-LT morphologic characteristics of the tumors did not differ in the TACE and no-TACE groups. Overall 5-year survival was 59.4% with TACE and 59.3% without TACE (ns). Survival rates did not differ significantly between the two groups with respect to the time on the waiting list, the tumor diameter, or the type of TACE (selective or nonselective). In the TACE group, 30 patients had tumor necrosis > or =80% on the liver explant with a 5-year survival rate of 63.2%, compared with 54.2% among their matched controls (P = 0.9). In conclusion, with a mean waiting period of 4.2 months and 1 TACE procedure, pre-LT TACE does not influence post-LT overall survival and disease-free survival.     

肝癌肝移植术后复发机制及其防治

原发性肝癌是位列中国第二位的恶性肿瘤,全世界每年新发肝癌的一半以上在我国[1].近年来,肝移植在我国发展迅速,技术日臻成熟,肝移植亦已成为治疗肝癌的一个重要手段,目前肝癌肝移植约占我国每年开展肝移植的30%～40%,比例较国外明显偏高[2].     

Hepatitis C virus is independently associated with increased insulin resistance after liver transplantation

BACKGROUND AND AIMS: There is a strong epidemiologic association between diabetes mellitus (DM) and hepatitis C virus (HCV) infection. However, the pathogenetic basis for this association has not been established. We sought to evaluate the association between insulin resistance (IR), beta-cell dysfunction, and HCV among orthotopic liver transplant (OLT) recipients. METHODS: We performed a cross sectional analysis comparing 39 HCV(+) with 60 HCV(-) OLT recipients. IR and beta-cell function were calculated using validated measures and were correlated with clinical variables. RESULTS: By multivariate analysis of the entire cohort, HCV infection and body mass index (BMI) were independent predictors of IR (P =0.04 and 0.0006, respectively). HCV infection was associated with 35% increase in IR. Because the model used to calculate IR was derived from nondiabetic subjects, we performed additional analysis of patients who did not meet criteria for diabetes at the time of their study evaluation. In this analysis, HCV(+) subjects had greater fasting insulin and homeostasis model assessment (HOMA) IR (15.3 mu U/mL and 3.8) compared with HCV(-) patients (10.7 mu U/mL and 2.5) (P =0.03, 0.03). There was no difference in beta-cell function or hepatic insulin extraction between the HCV (+) and (-) groups. HCV (P =0.0005), BMI (P <0.0001), and high high-density lipoprotein (P =0.039) were the only independent predictors of IR. The presence of HCV infection and a 10-fold increase in HCV RNA were associated with a 62% and 8% increase in IR, respectively. CONCLUSIONS: HCV is independently associated with increased IR after OLT. These findings provide a possible pathogenetic basis for the association of DM with HCV.     

Recurrence of hepatocellular carcinoma after liver transplantation

Outcome after liver transplantation (OLT) clearly depends on recurrence of hepatocellular carcinoma (HCC). After recurrence, patient outcome will depend on the time and site of appearance. The aim of this study was to analyze the therapeutic implications of tumor recurrence behavior. From October 1988 to December 2005, 685 patients received OLT, including 202 due to HCC (32%). We analyzed 28 recurrences (15.2%) among 184 patients who survived at least 3 months (minimum follow-up 1 year). According to the time of recurrence, we divided the patients into early recurrence (ER < 12 months; n = 9; 32.1%) and late recurrence (LR > 12 months n = 19; 67.9%). Actuarial survivals at 1, 5, and 10 years were 82%, 65%, and 50% and disease-free survival, 80%, 58%, and 46%, respectively. Risk factors for recurrence were: vascular invasion (P < .01), bad differentiation (P < .01), and previous hepatectomy (P < .05). After OLT, ER presented at: 5.7 ± 2.3 months (range 3-10) vs 33.5 ± 24.3 months (range 12-103) for LR P < .001). Survival postrecurrence (SPR) was shorter: 3.1 ± 2.4 (range 1-8) months vs 16.4 ± 14.2 (range 1-5) months (P < .001). Treatment was offered to one ER (11%) and to eight LR (47.1%; P < .05), achieving in these cases longer SPR: 20.1 ± 14 vs 6.9 ± 9 months (P < .05).The most common sites of recurrence were liver (n = 7), lung (n = 7), bone (n = 5), adrenal gland (n = 2), peritoneum (n = 2), lymph node (n = 2), skin (n = 2) or cerebral (n = 1). Early recurrences showed short survivals; no treatment could be offered to these patients. Liver recurrence appeared early. In contrast, most lung recurrences appeared later with the possibility of treatment and longer SPR. Bone recurrence appeared later, usually associated with other locations. Treatment was paliative and prognosis was worse. Skin and lymph node recurrences can be treated curatively with prolonged survival. In conclusion, HCC recurrence was difficult to treat curatively and was only prevented by employing restricted criteria.     

Predictors of post-recurrence survival in hepatocellular carcinoma patients following liver transplantation: Systematic review and meta-analysis

BackgroundData on predictors of post-recurrence survival (PRS) of recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT) have not been reviewed and analysed systematically. We aimed to systematically analyse all published data on the predictors for PRS.MethodsIn accordance with PRISMA and MOOSE guidelines, online search of PubMed and EMBASE databases was done for all reports that evaluate the predictors of PRS based on multivariate analyses. Cumulative analyses of hazard ratios (HRs) and their corresponding 95% CIs were conducted to assess the potential predictors of PRS.ResultsTwenty-three studies met the inclusion criteria. Among the 11,868 patients involved, 1921 (16%) had HCC recurrence within a median time of 16 months. The following were recurrence and tumour-related predictors: time to recurrence (<1 year; HR: 1.97; p < 0.001), AFP level at recurrence(≥100 ng/ml; HR: 1.82; p < 0.001), multiple recurrence (HR: 1.22; p < 0.001), bone recurrence (HR: 2.10; p < 0.001), poor differentiation (HR: 1.52; p < 0.001), intrahepatic recurrence (HR: 0.91; p = 0.03), extrahepatic recurrence (HR: 1.87; p < 0.001), Milan criteria at LT (HR: 1.34; p < 0.001), microvascular invasion (HR: 1.59; p < 0.001), multiorgan recurrence (HR: 1.28; p < 0.001), and recurrent HCV infection (HR: 1.21; p < 0.001). The treatment-related predictors were as follows: surgical resection (HR: 0.33; p < 0.001), mTOR inhibitors (HR: 0.63; p < 0.001), sorafenib (HR: 1.00; p = 0.01), palliative treatment (HR: 3.07; p < 0.001), RFA (HR: 0.47; p < 0.001), and radiotherapy (HR: 1.19; p < 0.001).ConclusionsSystematic evaluation of these predictors could guide surgeons to design risk-adapted algorithms for the management of post-LT HCC recurrence to construct reliable predictive models and to design future prospective studies or clinical trials.     

补救性肝移植的疗效

目的探讨补救陛肝移植的适应证及其临床疗效。方法回顾性分析2003年10月至2006年3月中山大学附属第三医院35例肝癌肝切除术后行肝移植患者的临床资料。比较补救性肝移植组（19例）和超补救性肝移植组（16例）患者的手术情况、术后并发症及预后等指标。计数和计量资料分别采用X^2和t检验,非正态分布采用秩和检验,Kaplan-Meier法进行生存分析,生存率的比较采用Log-rank检验。结果补救性肝移植组和超补救性肝移植组患者的无肝期、冷缺血时间、手术时间、术中出血量、术中输注红细胞量、术中输注新鲜冰冻血浆量、肝移植并发症发生率、再移植率分别为（32±9）rain、（8．0±2．1）h、（7．6±1．5）h、2300ml、8U、23U、6／19、2／19和（34±7）min、（7．4±2．3）h、（7．4±2．0）h、2750ml、12U、20U、4／16、1／16,两组比较,差异无统计学意义（t=0．726,-0．804,-0．366,Z=-0．348,-0．549,-0．149,）（X^2=0．184,0．203,P〉0．05）。补救性肝移植组和超补救性肝移植组患者围术期死亡率、术后肿瘤复发率分别为0、2／19和4／16、9／16,两组比较,差异有统计学意义（X^2=5．363,8．426,P〈0．05）。补救性肝移植组和超补救性肝移植组患者1、3、5年累积生存率分别为100％、84％、84％和75％、33％、33％;1、3、5年无瘤生存率分别为100％、89％、89％和48％、29％、19％,两组比较,差异有统计学意义（X^2=11．58,19．31,P〈0．05）。结论补救性肝移植是肝癌治疗过程中的一种有效策略,米兰标准是目前补救性肝移植的最佳适应证。     

Salvage living donor liver transplantation after prior liver resection for hepatocellular carcinoma.

Salvage liver transplantation has been performed for recurrent hepatocellular carcinoma (HCC) or deterioration of liver function after primary liver resection. Because prior liver resection per se is an unfavorable condition for living donor liver transplantation (LDLT), we assessed the technical feasibility of LDLT after prior hepatectomy, and we compared the outcome of salvage LDLT with that of primary LDLT in HCC patients. Of 342 patients with HCC, 17 (5%) underwent salvage LDLT, with 5 having undergone prior major liver resection and 12 prior minor resection. During salvage LDLT, 12 patients received right lobe grafts, 3 received left lobe grafts, and 2 received dual grafts. There was 1 incident (5.9%) of perioperative mortality. Recipient operation time was not prolonged in patients undergoing salvage LDLT, but bleeding complications occurred more frequently than in patients undergoing primary LDLT. Overall survival rates after salvage LDLT were similar to those after primary LDLT, especially when the extent of recurrent tumor was within the Milan criteria. These results indicate that every combination of prior hepatectomy and living donor liver graft is feasible for patients undergoing salvage LDLT, and the acceptable extent of HCC for salvage LDLT is equivalent to that for primary LDLT.     

以西罗莫司为主的免疫抑制方案在肝癌肝移植受者中的应用

目的 探讨肝癌肝移植受者术后采用以西罗莫司联合两剂激素为主的免疫抑制方案的安全性和有效性.方法 2004年3月至2006年10月间,共为92例超出米兰标准的中晚期肝癌患者施行了肝移植.其中89例纳入研究.前54例患者采用以他克莫司为主的免疫抑制方案,后35例患者采用以西罗莫司为主的新免疫抑制方案.术后对两组受者均进行了随访.随访时检测受者的肝肾功能、血糖和血脂水平等生化指标,监测受者感染、急性排斥反应、肿瘤复发、存活率及药物副作用等表现,并对两组免疫抑制方案的效果进行了分析和比较.结果 两组间1年肿瘤复发率、3个月内感染发牛率、术后1个月高血糖发生率及术后1年肾功能损害和高脂血症发生率的比较,差异均有统计学意义(P<0.05);其它指标的比较,无显著性差异.结论 肝癌肝移植受者采用以西罗莫司联合两剂激素为主的免疫抑制方案是安全和有效的.该方案在有效抑制排斥反应的同时可显著降低受者的肿瘤复发率,还可减少感染发生率、高血糖及.肾功能损害,但增加了高脂血症发生率.     

Pediatric liver transplantation for primary hepatocellular carcinoma associated with hepatitis virus infection

We report two cases of early primary hepatocellular carcinoma (PHC) in children, after probable maternal transmission of hepatitis B, that were treated with orthotopic liver transplantation (OLT). Both children were 8.5 years old and had elevated levels of serum alpha-fetoprotein. The diagnosis of PHC was made at 8 years and confirmed histologically. Serum hepatitis B surface antigen (HBs Ag) was detected in the mothers and suggested vertical transmission. An attempt at complete liver tumor resection failed, leading to OLT. In order to prevent recurrence of the hepatitis B virus (HBV) infection, hepatitis B immunoprophylaxis was used. Two years after OLT, one child presented with recurrent HBV infection. No tumor recurrence was observed at follow-up in either of the patients. From these two cases we conclude that (1) HBV infection may play an important causal role in PHC in children, with an even shorter incubation period than that in adults; (2) close follow-up is needed for children who are HBs Ag-positive carriers; and (3) liver transplantation should be proposed early after the diagnosis of PHC, when tumor resection is not feasible.     

Liver transplantation for hepatocellular carcinoma: prognostic factors associated long-term survival

Abstract  Between December 1985 and February 1995, 260 orthotopic liver transplantations (OLTX) were performed on 238 patients at Niguarda Hospital. Sixty-three patients had hepatocellular carcinoma (HCC); in 13 of the patients HCC was incidental. All patients had negative lymph nodes. According to the Child classification, 13 patients were Child A, 30 Child B, and 18 Child C. According to the TNM classification, 11 patients were stage I, 22 stage II, 15 stage III, and 15 stage IVa. Pre-OLTX chemoem-bolization was performed on 25 patients. The perioperative mortality rate was 27 % (17 patients). Overall survival and disease-free actuarial survival rates at 1, 3, and 5 years were 94 %, 76 %, 76 %, and 83 %, 75 %, 75 %, respectively. Survival curves were compared for 16 different variables. No difference was observed for all parameters analyzed except tumor site, TNM stage, pre-OLTX AFP levels and vascular infiltration. These results seem to demonstrate that the OLTX for un-resectable HCC can be considered in specifically selected cases as the treatment of choice. An adequate tumor staging is also necessary for a better patient selection in order to increase survival.