【EASL2013】口头报告之肝细胞癌篇

liver411

Abstract 1

A RANDOMISED CONTROLLED TRIAL OF MELOXICAM, A COX-2 INHIBITOR, TO PREVENT HEPATOCELLULAR CARCINOMA RECURRENCE AFTER INITIAL CURATIVE TREATMENT

Background and Aims: Because the recurrence rate of hepatocellular carcinoma (HCC) is high, even after curative treatments such as hepatic resection and microwave ablation,chemopreventive agents that can effectively suppress HCC recurrence are required. Cyclooxygenase-2 (COX-2) was recently found to be overexpressed in HCC. Therefore, COX-2 inhibitors may offer a chemopreventive therapy for HCC. This randomised controlled trial (RCT) investigated the potential for meloxicam, a clinically used COX-2 inhibitor, to prevent HCC recurrence after initial curative treatment.

Methods: 232 consecutive patients underwent hepatic resection and/or microwave ablation as initial therapy for HCC at our institute between July 2008 and April 2011. 8 patients were excluded because of poor renal function, history of non-steroidal antiinflammatory drug-related ulceration, or multiple cancers. The remaining 224 patients were randomised to a control group (CG;n = 113) or a meloxicam group (MG; n = 111). As 7 patients in the CG received meloxicam after the RCT, 106 patients who did not receive meloxicam were analysed as the true control group(TCG). 30 patients in the meloxicam group discontinued meloxicam because of a decline in renal function, gastric ulceration, and poor compliance, so 111 patients were analysed as the true meloxicam group (TMG). The overall survival (OS) and disease-free survival(DFS) rates were determined.

Results: The 1-, 2-, and 3-year OS rates were 96.2%/98.2%,89.5%/90.3%, and 83.8%/85.2% in CG/MG, respectively (P = 0.7447). The corresponding DFS rates were 88.9%/88.0%, 70.6%/73.8%, and 59.3%/42.7% (P = 0.4539). Intent-to-treat analysis showed no differences in OS or DFS between the GC and GM groups. Among patients with good liver function (Child–Pugh class A), per-protocol analysis showed that the 1-, 2-, and 3-year OS rates for the TMG (n = 70)/TCG (n = 82) were 98.5%/968.8%, 96.0%/95.2%, and 96.0%/91.3% (P = 0.3201), respectively, while the corresponding DFS rates were 97.0%/87.4%, 87.4%/77.4%, and 73.4%/48.7% (P = 0.0160). DFS was significantly different between the TMG and TCG. There were no significant differences in OS or DFS in other patient groups, including those with Child–Pugh class B or hepatitis C virus infection.

Conclusion: Administration of the COX-2 inhibitor meloxicam may suppress HCC recurrence after initial curative treatments in patients with good liver function (Child–Pugh class A).

liver411

Abstract 2

A NOVEL MODEL OF PRIORITY ASSESSMENT FOR PATIENTS WITH AND WITHOUT HEPATOCELLULAR CARCINOMA ON A COMMON LIVER TRANSPLANT WAITING LIST: A MULTICENTRE, COHORT STUDY

一个用于评估肝移植等待列表中终末期肝病患者移植优先级的新型模型：一项多中心的队列研究

Background: Liver transplantation (LT) priority assessment strictly based on 3-months dropout estimation creates both an unbalance between patients with and without hepatocellular carcinoma(HCC), and penalizes post LT outcomes. The aim of this study was to describe an alternative model able to re-establish allocation equity between HCC and no-HCC patients using 5-year transplant benefit as the common endpoint.

Methods: We enrolled consecutive adult patients with chronic end-stage liver disease entering the waiting list (WL) for LT (WL group = 2697) and undergoing LT (LT group = 1702) during the period 2004–2009 in the North Italian Transplant program area. Two independent multivariable regressions (WL and LT models) were created to measure the prognostic power of model for end stage liver disease (MELD) in patients with and without HCC. The models were also adjusted for the following covariates: recipient age, sex, and aetiology, re-transplant, donor age. For the WL model we used competing risk multivariable analysis. Hazard ratio (HR, 95% confidence intervals) were finally included in a Markov model to calculate 5-year survival benefit in different subgroups.

Results: WL competing risk model: MELD significantly predicted survival in both HCC (1.075, 1.043–1.110) and non-HCC (1.061, 1.053–1.080) patients.

LT Cox model: MELD significantly predicted survival in both HCC(1.042, 1.007–1.075) and non-HCC (1.038, 1.018–1.058) patients.

Benefit model: the survival benefit of LT at each MELD point was higher in HCC than non-HCC patients.

Using two-way sensitive analysis we calculated the following benefit MELD (bMELD) equation: bMELD = 9.16 +1.32·MELD in HCC patients with MELD score ≤22; bMELD = 40 for HCC patients with MELD >22.

Conclusion: We obtained a new bMELD score to weigh the priorities of HCC and non-HCC on a common waiting list.

背景：严格地基于3个月内候选者等待列表进行肝移植优先级的评估，造成了肝癌肝移植候选者和非肝癌肝移植候选者之间的不平衡，并且影响肝移植受体预后。此项研究旨在介绍一种基于肝移植后五年受益为观察点的新型模型，对候选者进行再次评估，使肝癌和非肝癌患者之间的分配更加平等。

方法：我们连续性选取了2004～2009年北意大利移植中心的慢性终末期肝病成年患者作为研究对象，其中进入肝移植等待名单的有2697例，最终接受移植的有1702例，通过两个独立的多变量回归统计模型（移植等待患者和接受移植患者）来检测此预后模型对于肝癌患者或非肝癌患者的评估能力。通过以下一些协变量来进行调整：受体年龄、性别、病因、再次移植、供体年龄。对于等待患者模型我们通过竞争风险多变量进行分析，利用马尔可夫模型里的风险比（95%置信区间）计算不同组别的5年生存受益情况。

结果：移植等待的竞争风险模型：MELD评分（终末期肝病模型）可以预测肝癌患者（1.075，[1.043～1.110]）和非肝癌患者（1.061，[1.053-1.080]）的生存率。移植的回归模型：MELD评分（终末期肝病模型）可以预测肝癌患者（1.042，[1.007～1.075]）和非肝癌患者（1.038，[1.018～1.058]）的生存率。受益模型：在每一个MELD评分点上，肝癌组的移植后生存受益都显著高于非肝癌组。利用双向敏感分析，我们统计出以下受益MELD（bMELD）公式：bMELD=9.16+1.32×MELD（HCC患者MELD≤22）；bMELD=40（HCC患者MELD>22）。

结论：我们获得了一种新型的用来衡量肝癌和非肝癌患者优先级的评分模型（受益终末期肝病模型）。

liver411

Abstract 3

CLINICAL VALIDATION OF A SUB-STAGING PROPOSAL OF PATIENTS WITH INTERMEDIATE HCC (BCLC-B)

Background and Aims: The intermediate stage of BCLC staging system for hepatocellular carcinoma (HCC) comprises patients with Child–Pugh A and B, with a single unresectable HCC >5cm or >3 HCC regardless of size, or 2–3 HCC >3 cm, without extrahepatic spread or vascular invasion and with performance status ECOG 0. Prognosis is likely highly variable within the intermediate stage. For this reason and to tailor treatment allocation, a sub-staging of BCLC-B has been recently proposed by Bolondi et al. based on literature and expert opinion as reported in the following table, adding in greater detail tumor burden (IN or OUT of the Up-toseven criterion) and Child–Pugh score (A5 to B9). Since no validation of the prognostic capability of this new substaging system exists, this study aims to validate its prognostic capacity in a large italian database (ITALICA).

Methods: 391 patients, included in the already existing ITA.LI.CA. (Italian Liver Cancer) database, update end 2008, affected by HCC in BCLC-B stage, were divided in four subgroups (B1-B4) according to the sub-classification. The survival of each group was assessed and compared using Kaplan–Meier method and log-rank test, after a follow-up of 60 months.

Results: Number of patients in BCLCsubsgroups was B1 = 162,B2 = 136, B3 = 28, B4 = 65. Each stage was associated with different median overall survival (p < 0.0001 among groups), namely B1 = 34m, B2 = 24m, B3 = 15m, B4 = 12 months. The 5y survival were:B1 = 39.5%; B2 = 32.4%; B3 = 10.7%; B4 = 13.8% (p<0.001).

Conclusions: The new substaging proposal of intermediate patients according to up-to-seven criteria and specific Child–Pugh numeric score is able to refine prognostic prediction capacity in the intermediate HCC stage.

liver411

Abstract 4

URINARY METABOLIC PROFILE DISCRIMINATES HEPATOCELLULAR CARCINOMA BETTER THAN SERUM ALPHA FETOPROTEIN IN WEST AFRICANS

Background and Aims: Although effective therapies for hepatocellular carcinoma (HCC) exist, current screening tools(serum alpha fetoprotein [AFP]) have low sensitivity and specificity. We have published preliminary data demonstrating the performance of urinary metabolites in HCC diagnosis. We aimed to validate and further characterise urinary metabolites for screening HCC in West Africa.

Methods: Urine samples were collected from 4 subject groups, at two sites in West Africa on the case–control platform of PROLIFICA,“Prevention of Liver Fibrosis and Carcinoma in Africa” as follows: patients with HCC (n = 65), cirrhosis (Cir, n = 36), non-cirrhotic liver disease (DC, n = 110) and healthy controls (NC, n = 91). HCC patients were diagnosed using EASL guidelines. Nuclear magnetic resonance(NMR) spectroscopy was utilised to acquire one-dimensional (1D) spectral data from the urine samples, using a standard 1D NMR pulse sequence with presaturation of the water peak. Spectral data were analysed using both unsupervised principal components analysis (PCA), and supervised orthogonal partial least squares discriminant analysis (OPLS-DA), using MATLAB v 7.0 and SIMCA v 13.0. The diagnostic accuracy of metabolic profiles as well as individual metabolites to discriminate HCC from Cir, DC and NC were examined using Area under the Receiver Operating Characteristic (AUROC) curves.

Results: Multivariate analyses of urinary NMR spectra showed a distinct profile for urine of patients with HCC compared to Cir, DC and NC with sensitivity (95% CI)/specificity (95% CI) of 87% (76–94)/81% (63–93), 86% (74–94)/93% (87–97) and 97% (89–100)/99% (94–100) respectively; which outperformed serum AFP(cut-off=20 ng/mL) that differentiated HCC from these groups by 79% (58–93)/53% (28–77), 75% (53–90)/75% (63–85) and 76% (55–91)/100% (59–100) respectively. The metabolites that were significantly increased (p < 0.001) in HCC patients compared to all groups of control were methionine, acetylcarnitine, carnitine, 2-oxoglutarate, indole-3-acetate, and creatine; whereas creatinine was significantly lower in HCC than controls. Citrate, 4-cresol sulfate and trimethylamine N-oxide were also significantly lower in HCC compared to NC. Urinary metabolite panel performed better than AFP in discriminating HCC from other non-HCC liver conditions {AUROC: HCC vs. DC (both sexes); metabolites [0.96] vs. AFP [0.85], p = 0.018; HCC vs. Cir (men); metabolites [0.92] vs. AFP [0.64],p = 0.028}.

Conclusions: Our findings validate urinary metabolic profiling as a potential screening tool for HCC, with superior diagnostic accuracy to serum AFP.

liver411

Abstract 5

DEVELOPMENT OF A SCORING SYSTEM TO PREDICT RISK OF HEPATOCELLULAR CARCINOMA IN A COHORT OF PATIENTS WITH CIRRHOSIS

Background and Aims: Current guidelines recommend biannual screening imaging for all cirrhotic patients. However, the risk of HCC varies considerably for different groups of cirrhotic patients, making risk stratification difficult. The current study aims to develop a scoring system to predict 5- and 10-year risk of HCC among a large cohort of cirrhotic patients.

Methods: Retrospective review was conducted on a cohort of cirrhotic patients followed over a 10-year period (January 2000 –December 2009) to determine the time to diagnosis of HCC. Risk factors for HCC were determined using Cox Proportional Hazards regression. For each risk factor, HCC incidence was evaluated using the Kaplan–Meier method and appropriate threshold values were determined. Based on the Hazard Ratio (HR) for HCC in the multivariable (MV) Cox regression model, each variable was assigned a point value. The sum of all point categories was used to estimate the risk of HCC.

Results: 2229 patients with cirrhosis (62% male) were identified with median follow-up of 5.6 years (Range 0.5–19.7). 374 patients were diagnosed with HCC. The etiology of cirrhosis was: HBV (20%),HCV (43%), Autoimmune (AIH, PBC, PSC – 12%), Steatohepatitis (NAFLD, Alcohol – 16%) and Other (9%). By MV stepwise Cox regression, age, sex, etiology of cirrhosis and AST-Platelet Ratio Index (APRI) were significantly associated with development of HCC. Points were assigned for each covariate in proportion to the HR from the MV model: Age (60 (8)); Sex (Female(0), Male (5)); Etiology (Autoimmune (0), Other (3), Steatohepatitis(6), HCV (9), HBV (12)), APRI (4 (8). The sum of points for each variable determined HCC risk (Figure 1). No patients with a combined score of 32 points had an HCC incidence of 48% by 10 years (p < 0.0001).

Conclusions: Using a combination of routine laboratory and clinical measures (age, gender, APRI, etiology), a risk score was developed to accurately distinguish cirrhotic patients with low, intermediate and high risk for HCC development.

liver411

Abstract 6

INCIDENCE AND PREDICTIVE FACTORS OF HEPATOCELLULAR CARCINOMA AND COMPLICATIONS IN HBV- OR HCV-RELATED COMPENSATED CIRRHOSIS. A MULTICENTER PROSPECTIVE COHORT IN 1653 PATIENTS (ANRS CO12 CirVir)

HBV/HCV相关的代偿性肝硬化患者发生肝癌及相关并发症的发病率和预测因子：一项涉及1653患者的多中心前瞻性队列研究

Background and Aims: The aim of this cohort was to assess the incidence and predictive factors of complications,mainly hepatocellular carcinoma (HCC) in HBV- or HCV-related compensated cirrhosis.

Methods: This study involved 35 French centres. Inclusion criteria were histologically proven HCV- or HBV-related cirrhosis, Child–Pugh A, no previous hepatic complication including HCC. Patients were prospectively screened for HCC. A sequential biobank was collected at inclusion and annually.

Results: A total of 1653 eligible patients were consecutively enrolled from March 2006 to June 2012, of whom 31 HCV-HBV coinfections were excluded from this analysis. Of the 1622 patients[mean age 56 yrs, males 67%; HCV 1306, HBV 316], alcohol consumption and metabolic syndrome were more frequent in HCV than HBV patients: 30.7% vs 9.8% (P < 0.0001) and 16.8% vs 8.6% (P = 0.0002), respectively. Based on a median follow-up of 30 months, liver nodule(s) occurred in 343 patients, diagnosed as HCC in 108 (2-yr cumulative incidence, cumI: 4.3%) and cholangiocarcinoma in 2. The cumulative incidence of HCC was higher in HCV than in HBV patients (2-yr cumI: 4.6% vs. 2.9%), though non-significantly (P = 0.06). Other hepatic complications occurred more frequently in HCV than HBV patients (2-yr cumI: 10.4% vs. 3.5%, P = 0.0003). Eighty deaths occurred, more frequently in HCV than in HBV patients (2-yr OS: 99.6% vs. 97.2%, P = 0.0003),attributable to liver disease in 36 (45%) and to extra-hepatic causes in 44 (55%). Viral control was obtained in 370 HCV (28.3%) and 223 (71%) HBV patients. In multivariate analyses, predictive factors of HCC were low platelet count (HR = 1.007 [95% CI: 1.002–1.01], P = 0.008) and esophageal varices (HR = 1.69 [95% CI: 1.02–2.8],P = 0.04).

Conclusion: Early results of this prospective cohort are:

a. only 31% of detected liver nodules were confirmed as primary liver cancer;

b. complications were more frequent in HCV than HBV patients in whom viral infection control was higher;

c. after a follow-up of 2.5 yrs, non liver-related mortality still concerned more than one half of deaths.

This multicenter cohort constitutes the backbone permitting precise study of HCC and other complications of cirrhosis, particularly through subsequent follow-up and nested studies exploiting high quality clinical data and biobank.

背景及目的：此研究主要目的是评估HBV/HCV相关的代偿性肝硬化患者肝癌和相关并发症的发病率和预测因子。

方法：该研究涉及35个法国的研究中心，入选标准为病理证实HCV/HBV相关的肝硬化，Child-Pugh评分A级，未发生肝细胞性肝癌等并发症。患者进行肝癌的前瞻性筛查，每年这些病人资料都会被收集在生物标本库中。

结果：2006年3月至2012年6月，我们总共纳入了符合标准的1653例患者，其中包含了31例同时感染HCV/HBV的患者。在1622例患者中，（平均年龄56岁，男性占67%，HCV感染1306例，HBV感染316例），在丙型肝炎患者中，酒精性成瘾及代谢综合征较乙型肝炎患者常见，（酒精性成瘾30.7% vs. 9.8%，P<0.0001；代谢综合征16.8% vs. 8.6%，P=0.0002）。中位随访期为30个月，343例患者出现肝硬化结节，并且有108例最终被诊断为肝细胞性肝癌（2年累积发病率为4.3%），有2例被诊断为胆管细胞癌。丙型肝炎患者的肝细胞性肝癌发病率高于乙型肝炎患者（2年累积发病率4.6% vs. 2.9%），尽管没有显著性差异（P=0.06）。其他肝脏并发症在丙型肝炎中均较乙型肝炎容易发生（2年累积发病率10.4% vs. 3.5%， P=0.0003）。丙型肝炎患者的死亡率亦高于乙型肝炎患者（2年总生存期：99.6% vs. 97.2%， P=0.0003），在80例死亡患者中，死于肝脏疾病的有36例（45%），肝外性疾病的44例（55%），370例的丙型肝炎患者及233乙型肝炎患者接受了抗病毒治疗。在多变量分析中，肝癌发生的预测因子有低血小板计数（HR=1.007，95%CI：1.002～1.01，P=0.008）及食管静脉曲张（HR=1.69，95%CI：1.02～2.8，P=0.04）。

结论：这个前瞻性队列研究的初步结果是：A. 只有31％的肝脏结节最终被证实为原发性肝癌；B. 相比较于乙型肝炎病毒滴度高的患者，丙型肝炎患者的并发症发生率更高；C. 随访2.5年，非肝脏相关性死亡仍然占据半数以上。这个多中心队列研究准确的分析了肝癌的发病率和肝硬化并发症的发生率，特别是通过后期的长期随访和嵌套的研究会有更高质量的临床数据和生物样本库。

liver411

Abstract 7

A PROSPECTIVE RANDOMIZED TRIAL COMPARING HDR-BRACHYTHERAPY AND TRANSARTERIAL CHEMOEMBOLIZATION IN HEPATOCELLULAR CARCINOMA

一项前瞻性随机试验：高清图像引导下的近距离放射治疗和肝动脉栓塞化疗治疗肝细胞肝癌的疗效比较

Aim: To compare image-guided HDR-brachytherapy (BT) with transarterial chemoembolization (TACE) in intermediate and advanced stage hepatocellular carcinoma.

Design: Single-center randomized controlled trial. Material and Methods: In this single-center randomized controlled trial 75 patients were allocated to either BT (n = 38) or TACE (n = 37). Eligibility criteria included BCLC A-C, Child Pugh ≤9 points, no PVT ipsilaterally, number of lesions ≤5. Primary endpoint was time to untreatable progression (TTUP) by the allocated method. Secondary endpoints included time to progression (TTP), overall survival (OS) and adverse events. BT as well as TACE could be performed repeatedly if necessary until the primary endpoint was reached. BT was conducted applying Iridium192 and 15Gy minimum dose enclosing the clinical target volume. Selective TACE employed a standardized mixture of Cisplatin, Doxorubicin and Lipiodol. Cross over was allowed after the primary endpoint was reached or in case of technical failure. Subsequent treatments were not restricted in both groups. Imaging, clinical and paraclinical follow up were performed every three months.

Results: Mean patient age was 69.9 and 67.1 years (BT/TACE group, respectively). 26 patients were classified as BCLC A (BT/TACE: 12/14), 40 patients as BCLC B (20/20), 9 patients as BCLC C (6/3). Median TTUP was 25.1 and 12.6 months (BT and TACE group, respectively). Median time to progression (TTP) was 13.0 and 5.7 months (BT and TACE group, respectively). These differences were significant (p 0.05).

Conclusion: TTUP and TTP were significantly longer in the BTgroup as compared to TACE. Failed demonstration of improved OS may be attributed to the cross-over design as well as to the low patient number. These data suggest BT should be further validated for possible inclusion in future HCC treatment concepts.

目的：比较高清图像引导下的近距离放射治疗（BT）和肝动脉栓塞化疗（TACE）对中晚期肝细胞性肝癌治疗效果。

材料和方法：在这个单中心随机控制研究实验中，有75例患者纳入研究，其中BT（n=38）和TACE（n=37），纳入标准为巴塞罗那标准（BCLC）A～C、Child Pugh≤9分、无同侧静脉癌栓（PVT）、病灶数少于5个，初步的终止观察点是患者疾病进展至无法治疗的时间（TTUP），其次的终止观察点是疾病进展时间（TTP）、总体生存率和不良事件。BT和TACE都能够多次在患者身上重复使用，直到患者达到初级终止观察点。BT疗法应用铱192及15Gy最小量去治疗靶器官。选择性的TACE则使用顺铂、阿霉素和碘油作为治疗药物。假如患者达到初级终止评分或者在技术失败的情况下，可以采取交叉疗法过渡，后续的治疗不会限制在这两个组里，影像检查、临床性的及亚临床性的观察每三个月进行一次。

结果：BT组与TACE组的患者平均年龄为69.9岁和67.1岁，符合BCLC A的有26例患者（BT/TACE：12/14），符合BCLC B的有40例（20/20），符合BCLC C的有9例（6/3），BT/TACE组的TTUP中位数时间是25.1个月和12.6个月（P<0.05），TTP中位数时间是13.0个月和5.7个月（BT/TACE组，P0.05）

结论：BT组的TTUP和TTP时间显著长于TACE组，总体存活时间比较没有统计学差异归结于交叉设计或者患者病例数偏少。以上研究数据提示，未来BT纳入肝癌治疗规范还需要进一步的理论验证

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