Liver resection versus liver transplantation for hepatocellular carcinoma within Milan criteria: a meta-analysis of 18,421 patients

BackgroundOutcomes after liver resection (LR) and liver transplantation (LT) for hepatocellular carcinoma (HCC) are heterogenous and may vary by region, over time periods and disease burden. We aimed to compare overall survival (OS) and disease-free survival (DFS) between LT versus LR for HCC within the Milan criteria.MethodsTwo authors independently searched Medline and Embase databases for studies comparing survival after LT and LR for patients with HCC meeting the Milan criteria. Meta-analyses and metaregression were conducted using random-effects models.ResultsWe screened 2,278 studies and included 35 studies with 18,421 patients. LR was associated with poorer OS [hazard ratio (HR) =1.44; 95% confidence interval (CI): 1.14–1.81; P<0.01] and DFS (HR =2.71; 95% CI: 2.23–3.28; P<0.01) compared to LT, with similar findings among intention-to-treat (ITT) studies. In uninodular disease, OS in LR was comparable to LT (P=0.13) but DFS remained poorer (HR =2.95; 95% CI: 2.30–3.79; P<0.01). By region, LR had poorer OS versus LT in North America and Europe (P≤0.01), but not Asia (P=0.25). LR had inferior survival versus LT in studies completed before 2010 (P=0.01), but not after 2010 (P=0.12). Cohorts that underwent enhanced surveillance had comparable OS after LT and LR (P=0.33), but cohorts undergoing usual surveillance had worse OS after LR (HR =1.95; 95% CI: 1.24–3.07; P<0.01).ConclusionsMortality after LR for HCC is nearly 50% higher compared to LT. Survival between LR and LT were similar in uninodular disease. The risk of recurrence after LR is threefold that of LT.     

Selection of patients of hepatocellular carcinoma beyond the Milan criteria for liver transplantation

The Milan criteria have been proven to be reliable and easily applicable in selection of patients with small unresectable hepatocellular carcinomas for liver transplantation. It has been repeatedly shown that patients who met these criteria had a 5-year survival of over 70% after transplantation. Such a result is remarkably good for an otherwise incurable malignancy. The main disadvantage of this set of criteria is that it is rather restrictive. Following it religiously denies transplantation to many patients who have tumor stage slightly more advanced.There have been many attempts to extend the criteria to include tumors with larger sizes (as in the UCSF criteria) or with a larger number (as in the Kyoto criteria). Alpha-fetoprotein and PIVKA-II, two biological markers in more aggressive tumors, have also been employed in the selection of patients, and biopsies have been used by the University of Toronto to determine tumor aggressiveness before deciding on transplantation. Patients with tumors beyond the Milan criteria yet not of a high grade have been accepted for transplantation and their survival is comparable to that of transplant recipients who were within the Milan criteria. Preoperative dual-tracer (¹¹C-acetate and FDG) positron emission tomography has been used to determine tumor grade, and transarterial chemoembolization has been used to downstage tumors, rendering them meeting the Milan criteria. Patients with downstaged tumors have excellent survival after transplantation. Partial response to chemical treatment is a reflection of less aggressive tumor behavior.Careful selection of patients beyond the Milan criteria with the aid of serum tumor marker assay, positron emission tomography or tumor biopsy allows transplanting more patients without compromising survival. The use of liver grafts either from the deceased or from living donors could thus be justified.Key Words: Hepatocellular carcinoma, liver transplantation, Milan     

Liver transplantation is an alternative treatment of hepatocellular carcinoma beyond the Milan criteria

Background

The decision to perform liver transplantation (LT) or liver resection (LR) for patients with hepatocellular carcinoma (HCC) who are beyond the Milan criteria remains controversial.

Methods

We retrospectively analyzed outcome data for 179 patients with HCC beyond the Milan criteria who were treated with LR (n = 135) or LT (n = 44). Univariate and multivariate Cox proportional hazard models were established. Kaplan-Meier survival curves were generated, and a log-rank test was performed to compare group survival status.

Results

Patients who underwent LR group were significantly older, had a lower TNM stage, and were more likely to have unilateral disease and noncirrhotic liver. Significantly more patients in the LR group had recurrence (53.3% vs 29.5%) or died (61.5% vs 43.2%) than patients in the LT group. Recurrence-free survival rates were 11.9% for the LR group and 61.5% for the LT group. The median overall survival duration showed no statistically difference between the LR group (28.0 months) and the LT group (50.0 months).

Conclusions

LT may be the better choice for patients with HCC beyond the Milan criteria.     

Liver transplantation for acute liver failure: the Hungarian experience

Acute liver failure (ALF) counts for 9%-11% of activity in leading liver transplant programs. We have summarized the Hungarian Liver Transplant Program experience for ALF among 412 consecutive orthotopic liver transplantations (OLTs). All OLTs were performed without an extended international donor background. The proportion of ALF among the indications for OLT was lower (5.8% vs 9%) and early mortality higher than the European Liver Transplant Registry (1 year cumulative patients survival is 70% in ELTR vs 60% in the HU LT Program). The waiting time for a donor was longer than expected in the Eurotransplant community. Regarding postoperative complications, there was a higher incidence of initial poor function, bacterial infection, sepsis, and multiorgan failure. We conclude that ALF can be managed with reasonable results but requires an extended donor pool with an integrated international network to improve postoperative morbidity and mortality.     

Liver transplantation for hepatocellular carcinoma: Comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria

We previously proposed modified staging criteria for predicting acceptable outcome after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). These were solitary tumor ≤6.5 cm, or three or fewer nodules with the largest lesion ≤4.5 cm and total tumor diameter ≤8 cm, without gross vascular invasion (University of California, San Francisco [UCSF] criteria). In this study, we further evaluated the performance of the Milan criteria (solitary tumor ≤5 cm, or three or fewer lesions none >3 cm), the UCSF criteria, and the Pittsburgh modified tumor-node-metastasis (TNM) criteria. Pathologic HCC staging according to each set of criteria was performed in 70 patients. The difference in survival when comparing 24 patients with HCC exceeding Milan criteria versus 46 patients meeting Milan criteria did not reach statistical significance (HR, 2.0; P = .12). Using our definition for acceptable 2-year survival to be ≥70%, the 14 patients (20%) meeting UCSF criteria but exceeding Milan criteria had a 2-year survival of 86% (95% CI, 54% to 96%). Survival for Pittsburgh stage I, II, and IIIA patients as a group was significantly better than for stages IIIB and IVA patients combined (HR, 4.2; P = .007), and similar to survival for patients meeting UCSF criteria. Advanced tumor exceeding UCSF criteria served reasonably well as a surrogate marker for poorly differentiated grade and microvascular invasion. In conclusion, our analyses suggest that UCSF criteria better predict acceptable posttransplant outcome than Milan criteria. UCSF criteria confer a different advantage over Pittsburgh criteria, which require information on microvascular invasion that is difficult to ascertain preoperatively without the attendant risk of biopsy. (Liver Transpl 2002;8:765-774.)     

超出Milan标准肝癌肝移植患者术后预防性化疗的价值

目的 探讨超出Milan标准肝癌肝移植患者术后预防性化疗的价值.方法 回顾性分析2001年4月至2007年7月243例超出Milan标准肝癌肌移植患者的临床资料,其中预防性化疗162例,未化疗81例.结果 预防性化疗与未化疗患者术后1、3年生存率(78.5%、63.7%和56.6%、39.1%)以及无瘤生存率(76.8%、52.5%和69.3%、64.7%)比较差异无统计学意义(X2=3.084,0.444,P>0.05).Cox风险比例分析显示,对无大血管侵犯的肝癌肝移植患者,术后足否化疗不是影响生存率的独立因素;对有大血管侵犯的肝癌肝移植患者,术后是否化疗是影响生存率的独立因素.结论 对于超出Milan标准且伴有大血管侵犯的肝癌肝移植患者,术后早期预防性化疗可以延缓肿瘤复发,明显提高疗效.     

Comparative evaluation of expanded criteria for patients with hepatocellular carcinoma beyond the Milan criteria undergoing living-related donor liver transplantation

Shirabe K, Taketomi A, Morita K, Soejima Y, Uchiyama H, Kayashima H, Ninomiya M, Toshima T, Maehara Y. Comparative evaluation of expanded criteria for patients with hepatocellular carcinoma beyond the Milan criteria undergoing living‐related donor liver transplantation.
Clin Transplant 2011: 25: E491–E498. © 2011 John Wiley & Sons A/S. Abstract: Objective: To clarify the predictive impact of expanded criteria for liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) in 54 patients with HCC beyond the Milan criteria (MC) from a series of 109 consecutive living‐related donor liver transplantation (LDLT) recipients with HCC. Methods: Among 54 patients with HCC exceeding the MC, the predictive values for HCC recurrence within expanded criteria comprising the UCSF, Tokyo, Kyoto, Kyushu University (based on the tumor size and des‐gamma carboxy prothrombin level) and Up‐to‐seven criteria were compared using univariate and multivariate analyses. The histological characteristics of HCC were compared among these extended criteria. Results: All five criteria were significant predictors for recurrence‐free survival after univariate analyses. The Kyushu University criteria were the most powerful predictive criteria for HCC recurrence after multivariate analyses. The incidence of microvascular invasion and poorly differentiated HCC was significantly higher in patients with HCC exceeding the Kyushu University criteria than in those with HCC within the criteria. Conclusions: Compared with the other expanded criteria, the Kyushu University criteria may be useful to eliminate LT candidates at very high risk of HCC recurrence. The Kyushu University criteria were useful to evaluate LT candidates with HCC.     

索拉非尼预防超米兰标准肝癌患者肝移植术后复发

目的 观察超米兰标准的肝癌患者在肝移植术后应用索拉非尼预防肿瘤复发的效果.方法 将2008年3月至2010年6月30例行肝移植手术的超米兰标准肝癌患者分为两组,每组各15例.实验组:口服索拉非尼400 mg,bid.对照组:口服卡培他滨1500 mg,bid,每个疗程服用14d后休息2周.术后18个月两组未复发者均停止用药,治疗过程中出现复发者则维持原剂量直至患者不宜再继续服药.出现严重不良反应者减量或停药.结果 实验组1年复发率为53.3％,对照组86.6％,2组比较差异有统计学意义(x2=3.968,P＜0.05).实验组1年生存率为93.3％,对照组46.6％,组间比较差异有统计学意义(x2=7.777,P＜0.05).实验组的生存期为7～28个月,平均(24.6±1.7)个月,对照组的生存期为5～34个月,平均(16.4±2.7)个月,实验组患者的生存时间长于对照组,差异有统计学意义(x2=7.154,P＜0.05).实验组及对照组的毒副反应大部分为Ⅰ～Ⅱ级,其中实验组发生腹泻、手足综合征的机会较对照组高.结论 超米兰标准的肝癌患者在肝移植术后预防应用索拉非尼可能会减少或推迟肝癌复发,延长患者的生存期,药物的大部分不良反应患者可以耐受.     

肝切除和肝移植治疗符合米兰标准肝癌患者的疗效比较

目的 探讨肝切除术和肝移植治疗符合米兰标准肝癌患者的疗效.方法 回顾性分析2002年7月至2009年2月南京军区福州总医院行肝切除术和肝移植治疗121例符合米兰标准且合并肝硬化、肝功能为Child A级的原发性肝癌患者的临床资料,其中89例行肝癌切除术的患者作为肝切除术组;32例行肝移植的患者作为肝移植组.两组患者在年龄、性别、肝硬化病因、肿瘤最大直径、肿瘤数目、微血管侵犯、微小卫星灶、肿瘤分化程度方面比较,差异无统计学意义.对两组患者资料进行回顾性比较分析,Kaplan-Meier法计算生存时间,Log-rank分析生存曲线之间的差别,COX比例风险模型单因素、多因素分析影响预后的因素.结果 中位随访时间37个月,肝切除术组患者1、3、5年生存率分别为86％、63％、44％,肝移植组患者1、3、5年生存率分别为87％、70％、62％,两组总体生存率比较,差异无统计学意义(x2=1.092,P＞0.05);肝切除术组患者1、3、5年无瘤生存率分别为68％、44％、26％,肝移植组患者1、3、5年无瘤生存率分别为80％、65％、52％,两组总体无瘤生存率比较,差异有统计学意义(x2=4.712,P＜0.05).单因素分析结果显示:微血管侵犯、微小卫星灶与生存显著相关(Wald=9.625,7.340,P＜0.05);多因素分析结果显示:微血管侵犯是影响生存的独立危险因素(Wald=5.008,P＜0.05).结论 对于符合米兰标准的肝癌患者行肝切除术和肝移植比较总体生存率无明显差异,但肝移植术后患者无瘤生存率高于肝切除术;微血管侵犯是影响患者生存的独立危险因素.     

Expanded criteria for hepatocellular carcinoma and liver transplantation

In this study, we evaluated our early results of liver transplantation for hepatocellular carcinoma. Between January 2003 and June 2006, 26 patients (4 women and 22 men; age, 1.1-65 years) with preoperatively diagnosed or incidental hepatocellular carcinoma (HCC) underwent liver transplantation at our center. Inclusion criteria (independent of tumor size and number of tumor nodules) were no invasion of major vascular structure and no evidence of extrahepatic disease. In 13 of the patients, tumors were beyond the Milan criteria. At this writing, with a mean follow-up of 16.5 months (range, 1-31 months), all patients are doing well with excellent graft function. The longest survival is 2.5 years, and our patient survival rate is 100%. There has been only one tumor recurrence that was 4 months after liver transplantation. Liver transplantation provides long patient and disease-free survival, even in patients with HCC that exceeds the Milan criteria.     

Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria.

The selection criteria in liver transplantation for HCC are a matter of debate. We reviewed our series, comparing two periods: before and after 1996, when we started to apply the Milan criteria. The study population was composed of patients with a preoperative diagnosis of HCC, confirmed by the pathological report and with a survival of >1 year. Preoperative staging as revealed by radiological imagining was distinguished from postoperative data, including the variable of tumor volume. After 1996 tumor recurrences significantly decreased (6 out of 15 cases, 40% vs. 3 out of 48, 6.3%, P < .005) and 5-year patient survival improved (42% vs. 83%, P < .005). Not meeting the Milan criteria was significantly related to higher recurrence rate (37.5% vs. 12.7%, P < .05) and to lower 5-year patient survival (38% vs. 78%, P < .005%) in the preoperative analysis, but not in the postoperative one. The alfa-fetoprotein level of more than 30 ng/dL and the preoperative tumor volume of more than 28 cm3 predicted HCC recurrences in the univariate and mutivariate analysis (P < .005 and P < .05, respectively). The ROC curve showed a linear correlation between preoperative tumor volume and HCC recurrence. Milan criteria significantly reduced tumor recurrences after liver transplantation, improving long-term survival. In conclusion, the efficacy of tumor selection criteria must be analyzed with the use of preoperative data, to avoid bias of the postoperative evaluation. Tumor volume and alfa-fetoprotein level may improve the selection of patients.     

Expanded criteria for hepatocellular carcinoma and liver transplantation

In this study, we evaluated our early results of liver transplantation for hepatocellular carcinoma (HCC). Between January 2004 and June 2006, 26 patients (4 females, 22 males; aged 1.1-65 years) with preoperatively diagnosed or incidental HCC underwent liver transplantation at our center. Inclusion criteria (independent of tumor size and number of tumor nodules) were no invasion of major vascular structures and no evidence of extrahepatic disease. In 13 of the patients, tumors were beyond the Milan criteria. At this writing, at a mean follow-up of 16.5 months (range, 1-31 months), all patients were doing well with excellent graft function. The longest survival is 2.5 years, and our patient survival rate is 100%. There has been only 1 tumor recurrence, which occurred 4 months after liver transplantation. In conclusion, liver transplantation provides long patient and disease-free survival, even in patients with HCC that exceeds the Milan criteria.     

Locoregional treatments before liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry

Locoregional treatment while on the waiting list for liver transplantation (Ltx) for hepatocellular carcinoma (HCC) has been shown to improve survival. However, the effect of treatment type has not been investigated. We investigate the effect of locoregional treatment type on survival after Ltx for HCC. We investigated patients registered in the European Liver Transplant Registry database using multivariate Cox regression survival analysis. Information on locoregional therapy was registered for 4978 of 23 124 patients and was associated with improved overall survival [hazard ratio (HR) 0.84 (0.73–0.96)] and HCC‐specific survival [HR 0.76 (0.59–0.98)]. Radiofrequency ablation (RFA) was the one monotherapy associated with improved overall survival [HR 0.51 (0.40–0.65)]. In addition, the combination of RFA and transarterial chemoembolization also improved survival [HR 0.74 (0.55–0.99)]. Adjusting for factors related to prognosis, disease severity, and tumor aggressiveness, RFA was highly beneficial for overall and HCC‐specific survival. The effect may represent a selection of patients with favorable tumor biology; however, the treatment may be effective per se by halting tumor progression. Clinicaltrials.gov number: NCT02995096.     

Liver transplantation for hepatocellular carcinoma: our experience from 1986

Currently liver transplantation is the treatment of choice for early hepatocellular carcinoma and end-stage liver disease. We analyzed our experience to identify factors that could be used to select patients who will benefit from liver transplantation. PATIENTS AND METHODS: From April 1986 to December 2001, 71 (8.7%) of 816 LT performed in our institution, were for patients with hepatocellular carcinoma. In 25 patients the tumor was observed incidental by (35.2%). All patients had liver cirrhosis, most due to hepatitis C related (35) or alcoholic (14) diseases. Before liver transplantation, chemoembolization was performed in 18 patients (25.4%). RESULTS: Bilateral involvement was present in seven patients. Eight patients showed macroscopic vascular invasion, and eight others showed satellite nodules. Most patients were stage TNM II (29) and IVa (16). Overall 1-, 3-, and 5-year survival were 79.3%, 61%, and 50.3% with recurrence-free survivals of 74.6%, 57.5%, and 49%, respectively. With a mean follow-up of 42 months, 12 patients (19%) developed recurrence and 29 patients died (only 11 due to recurrence). Stage TNM IVa, macroscopic vascular invasion, and the presence of satellite nodules significantly affected overall survival and recurrence-free survival rates and histologic differentiation and bilateral involvement only recurrence-free survival. Patients with solitary tumors less than 5 cm or no more than three nodules smaller than 3 cm showed better recurrence-free survival and lower recurrence rates. DISCUSSION: In our experience, liver transplantation proffers good recurrence-free survival and low recurrence rates among patients with limited tumor extension. The most important prognostic factor was macroscopic vascular invasion.     

Liver transplantation for hepatocellular carcinoma: experience at an Australian transplantation unit

The author experienced 11 cases of orthotopic liver transplantation (LTx) for hepatocellular carcinoma (HCC) in Sydney, Australia, series. LTx was selected in 5 cases for the treatment of HCC and in 6 for terminal liver failure. Three patients had new lesions, which were not detected on preoperative imaging, and 5 had vascular or extrahepatic infiltrations. Two patients with hepatitis C had recurrence of hepatitis at an early stage. Two had tumor recurrence, one of which had 7 lesions with invasion to the vessels and bare area. Thus some problems remain in LTx for HCC, including the recurrence of hepatitis in hepatitis C and tumor recurrence in cases with high-risk factors based on the pathologic findings.     

关于肝移植治疗肝癌的受者选择标准与肝癌分期标准的商榷

肝细胞癌(HCC,以下简称"肝癌")是最常见的原发性肝癌,全世界每年新发患者达60万人,其中约34万人(约占55 %)在于中国,在肝癌的临床诊治上,中国理应占有举足轻重的地位.通过老一代肝脏外科学家如吴孟超、汤钊猷等的卓越努力下,我国在肝癌的诊治上已在国际上取得一席之地.     

超出米兰标准的原发性肝癌肝移植术后化疗对患者存活和肿瘤复发率的影响

目的 探讨超出米兰标准的原发性肝癌肝移植术后化疗对患者存活时间及肿瘤复发率的影响。方法 2002年7月至2004年12月间对46例超出米兰标准的原发性肝癌患者行原位肝移植，其中44例患者接受术后化疗，分析术后化疗患者的临床资料，观察化疗后的不良反应，统计患者肝移植术后的存活率及肿瘤复发率，比较术前是否存在癌栓以及术后是否化疗对存活率和肿瘤复发率的影响。结果 44例患者在化疗过程中均出现不同程度的胃肠道反应；16例患者出现肝功能损害，经停药、调整免疫抑制剂用量及使用护肝药后恢复；7例患者出现白细胞减少，采用粒细胞集落刺激因子类药物治疗后恢复正常。肝移植术后化疗的患者存活超过1年的有22例，1年存活率为47．8％，最长存活至今已有30个月。26例患者在1年内肿瘤复发，1年复发率为59．1％。术前有癌栓的患者术后肿瘤复发率明显高于无癌栓的患者，存活率明显低于无癌栓的患者。肝移植术后化疗的患者与术后未化疗的患者相比，存活率升高，肿瘤复发率降低。结论 超出米兰标准的原发性肝癌患者肝移植术后化疗可提高生存率，减少肿瘤复发的可能。肝移植术后辅助性化疗是安全、可行的，且患者可以耐受。