VIENNA (EGMN) – Sirolimus-based immunosuppression appears to provide a unique survival advantage over other immunosuppression regimens that are employed after liver transplantation for unresectable hepatocellular carcinoma, a large registry experience indicates.

“I think the use of sirolimus should be promoted in hepatocellular carcinoma patients who have undergone liver transplantation because of this specific anticancer immunosuppression and adjuvant therapy effect. I’m wondering whether the time has not come to revise the [U.S. Food and Drug Association’s] black box warning currently preventing the use of sirolimus after liver transplant,” Dr. Christian Toso said at the annual International Liver Congress sponsored by the European Association for the Study of the Liver.

In another observational study presented at the congress, the use of mycophenolate mofetil following liver transplantation for indications other than hepatocellular carcinoma (HCC) was associated with significantly improved 1-year graft patency.

Sirolimus Boosts 5-Year Survival

Dr. Toso and his coworkers analyzed survival rates in 2,491 adults who underwent liver transplantation for HCC, and 12,167 others with liver transplantation for other indications. All underwent the surgery in 2002-2009 and participated in the U.S. Scientific Registry of Transplant Recipients. All subjects remained on stable immunosuppression for at least 6 months after transplantation.

The most frequently used immunosuppressive agents were tacrolimus, mycophenolate mofetil, and corticosteroids. Sirolimus, antithymocyte globulin, induction therapy with a humanized monoclonal anti-CD25 antibody, and cyclosporine were each employed in about 10% or fewer of organ recipients.

Patient survival at 5 years post transplant in the HCC group was significantly better in organ recipients who were on sirolimus than in those on nonsirolimus immunosuppression. (See box.) The only other agents associated with a survival advantage were the anti-CD25 antibodies daclizumab and basiliximab, according to Dr. Toso, a transplant surgeon at the University of Geneva.

In a multivariate regression analysis adjusted for age; disease severity as reflected in the MELD (Model for End-Stage Liver Disease) score; year of transplant; pretransplant HCC therapy; total tumor volume; and serum alpha fetoprotein level, the sirolimus-based maintenance immunosuppression was associated with a 47% improvement in survival, compared with nonsirolimus regimens. Induction anti-CD25 antibody therapy was associated with a 36% survival advantage. Both were statistically significant.

To learn whether sirolimus improved survival in all liver transplant recipients or had a specific anticancer effect that was limited to those undergoing transplant for HCC, the investigators also analyzed survival rates in the 12,167 registry patients with non-HCC indications. In this large group, sirolimus showed a nonsignificant trend for worse survival than did nonsirolimus-based immunosuppression.

The only drug that significantly affected survival in a multivariate analysis was cyclosporine, which was associated with a 30% increase in mortality. However, the registry experience also shows that cyclosporine has been utilized much less frequently in recent years, Dr. Toso noted.

Possible mechanisms for sirolimus’ survival advantage post transplantation for HCC include the drug’s previously described antiproliferative effect on tumor cells and its inhibitory effects on a number of growth factors, according to the surgeon.

“But I’d like to point out that the activity of sirolimus is more related to a cytostatic effect than a cytotoxic effect. So I would expect that the rate of growth of an HCC recurrence will be slower in a patient treated with sirolimus, but I’m not sure that sirolimus will prevent recurrence or kill a preexisting tumor,” he continued.

In response to audience questions, Dr. Toso said that he would favor waiting several weeks post transplant before starting sirolimus, mainly because of early increased risks of delayed wound healing and incisional hernia rather than the more remote risk of hepatic artery thrombosis that is emphasized in the drug’s black box warning.

“I would strongly advise using sirolimus in HCC patients, but I would also advise not starting it right away. Wait a few weeks,” he said.

Less Graft Failure Risk With Mycophenolate Mofetil

In a separate presentation, Dr. Mario Angelico provided an interim analysis of data from the Italian Liver Match study which showed that the inclusion of mycophenolate mofetil in posttransplant immunosuppression was associated with a highly significant 45% reduction in the risk of graft failure at 1 year.

The Liver Match study is an ongoing Italian nationwide study designed primarily to examine the effect of donor matching on patient outcomes. But because decisions regarding immunosuppression post liver transplant are based largely on experiences compiled at individual transplant centers rather than on evidence-based medicine, the Liver Match investigators decided to try to determine whether their data pointed to a best immunosuppressive option.

The interim analysis involved 1,177 adults who underwent liver transplantation for non-HCC indications at 20 Italian centers during 2007-2008. One-third of them received mycophenolate mofetil, which in 94% of cases was added to calcineurin inhibitor therapy. In most cases, mycophenolate mofetil was brought in as a calcineurin inhibitor–sparing agent or to improve renal function. In all, 60% of patients on mycophenolate mofetil started the drug within the first 4 weeks post transplant. Once patients were placed on the drug, they typically remained on it indefinitely.

Graft survival at 1 year was 90.5% in patients who were on mycophenolate mofetil, which was significantly better than the 80.9% rate in patients on immunosuppressive regimens that did not include the drug. This was true despite the fact that patients who received mycophenolate mofetil had significantly worse liver disease, as evidenced by their higher MELD scores at transplantation. The mycophenolate mofetil–associated graft survival benefit was significant in patients on less than the median 1,000 mg/day dosage, as well as in those patients taking more.

In a multivariate regression analysis adjusted for numerous donor, recipient, perioperative, and postoperative factors, immunosuppression with mycophenolate mofetil was independently associated with a 45% reduction in the risk of graft failure at 1 year. The benefit was significant regardless of whether patients were hepatitis C positive or negative, although the benefit was greater in the 540-patient HCV-positive cohort, said Dr. Angelico of the University of Rome Tor Vergata.

Mycophenolate mofetil has demonstrated antifibrotic effects in in vitro studies showing that the drug inhibits type 1 collagen expression and fibroblast migration. This might explain the clinical benefit seen in the Liver Match study. The drug also has in vitro antiviral activity against HCV, he added.

The Liver Match study is supported by the Italian National Transplant Center and the Italian Association for Study of the Liver. Dr. Angelico disclosed that he has no financial interests relevant to the study. Similarly, Dr. Toso disclosed that he has no financial conflicts with regard to his study.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

维也纳(EGMN) ——一项大规模注册研究显示，无法手术的肝细胞癌患者在肝脏移植术后采用以西罗莫司为基础的免疫抑制治疗方案，可获得较其他免疫抑制方案更长的生存时间。

 

Christian Toso博士在欧洲肝病研究学会主办的国际肝病年会上称：“我认为，应让更多接受肝移植的肝细胞癌(HCC)患者应用西罗莫司，后者具有独特的抗癌免疫抑制作用和其他辅助治疗功能。我一直在想，当前修订(美国食品药品管理局)有关‘肝移植术后防止使用西罗莫司’黑框警告的时机是否仍未到来。”

 

会上报告的另一项观察研究结果显示，非HCC患者肝移植术后应用麦考酚酸酯治疗可显著提高1年移植血管通畅率。

 

西罗莫司可提高5年生存率

 

Toso博士及其合作者分析了2,491名因HCC而进行肝移植的成年患者，以及12,167名因其他适应证而行肝移植患者的生存率。所有患者均在2002~2009年接受手术治疗，并在美国器官移植受者科学登记系统中进行了登记。所有研究对象在术后至少接受6个月稳定的免疫抑制治疗。

 

最常用的免疫抑制剂包括他克莫司、麦考酚酸酯和皮质类固醇。而西罗莫司、抗胸腺细胞球蛋白、人化抗CD25单克隆抗体诱导治疗以及环孢霉素中每种药物仅在10%或更少的器官移植受者治疗方案中应用。

 

Toso 博士是日内瓦大学的移植外科医生。根据他的研究，HCC组中，接受西罗莫司治疗的器官受者移植后5年生存率较接受非西罗莫司免疫抑制治疗者有显著提高。而其他可提高生存率的药物仅有抗CD25抗体达克珠单抗和巴利昔单抗。

 

对年龄、以MELD(终末期肝病模型)评分反映的疾病严重程度、移植年限、移植前HCC治疗情况、肿瘤总体积和血清甲胎蛋白水平进行校正后，多因素回归分析结果显示，与非西罗莫司免疫抑制治疗方案相比，以西罗莫司为基础的免疫抑制治疗可将生存期提高47%。抗CD25抗体诱导治疗可将生存期提高36%。二者均有统计学意义。

 

西罗莫司是对所有肝移植受者有提高生存期的作用，还是仅对因HCC而行肝移植的患者有特殊的抗癌作用？为解答此问题，研究者还分析了12,167名非HCC而进行肝移植的登记患者的生存率。在这一大组病例中，与非西罗莫司为基础的免疫移植治疗相比，西罗莫司并未显示出缩短生存期的显著趋势。

 

多因素分析显示，唯一对生存期有不良影响的药物是环孢霉素，其使病死率增加30%。不过，Toso博士指出，这项注册研究还显示，近年来应用环孢霉素的患者比例已大幅减少。

 

根据Toso博士的报告，西罗莫司延长因HCC接受移植患者术后生存期的可能机制包括抗肿瘤细胞增殖作用以及对多种生长因子的抑制作用。

 

 “需要指出的是，与细胞毒作用相比，西罗莫司的活性与抑制细胞生长更相关。因此，我期望应用西罗莫司治疗的患者HCC复发的生长率更慢，但我并不确定西罗莫司可预防复发或杀死已存在的肿瘤。”

 

在回答参会者提问时，Toso博士指出，建议在行移植术几周后再应用西罗莫司，因为该药的黑框警告中强调，与肝动脉血栓形成这一更远期的危险相比，过早应用该药更可能会增加伤口延迟愈合和出现切口疝的危险性。

 

他说：“我强烈建议HCC患者应用西罗莫司，但不必马上使用。可以等上几个星期。”

 

麦考酚酸酯可减少移植失败的危险性

 

在会议的一个分会场上，Mario Angelico博士报告了一项对意大利肝脏配对研究数据进行的期中分析。结果显示，移植术后应用麦考酚酸酯在内的免疫抑制治疗可非常显著地减少高达45%的1年移植失败的危险性。

 

肝脏配对研究是一项正在进行的意大利全国性研究，其主要目的是探讨与患者指标相匹配的供体的影响。但因在决定患者肝移植术后免疫抑制治疗方案时很大程度上是基于每个移植中心各自的经验，而非循证医学，故研究者试图确定通过他们的研究数据是否能找到最佳的免疫抑制治疗方案。

 

该期中分析所涉及的1,177例非HCC成人患者来自意大利20个移植中心，均在2007~2008年接受肝移植手术。其中1/3患者接受麦考酚酸酯治疗，这些患者中有94%增加钙调磷酸酶抑制剂治疗。在大多数病例中，麦考酚酸酯作为钙调磷酸酶抑制剂的节约剂或用于提高肾脏功能。所有病例中，60%的患者在移植术后最初4周内开始应用麦考酚酸酯。一旦患者使用该药，他们一般会长期使用。

 

应用麦考酚酸酯治疗的患者1年移植肝脏生存率达90.5%，而所用免疫抑制方案中不包括该药的患者1年移植肝脏生存率仅为80.9%，二者差异显著。更有甚者，接受麦考酚酸酯治疗的患者肝病病情严重得多，他们在接受移植时MELD评分均较高。与麦考酚酸酯相关的移植肝脏生存收益在日均用药量少于1,000mg的患者中明显，在用药量更多的患者中亦有表现。

 

对多种供体、受体、围手术期及术后因素进行校正后，多因素回归分析显示，应用麦考酚酸酯进行免疫抑制治疗是1年移植物失败风险减少45%的独立相关因素。罗马托威尔伽塔大学的Angelico博士还指出，这一收益相当显著，虽然在540名丙型肝炎病毒阳性患者中表现更为明显，但与患者是否患有丙型肝炎无关。

 

麦考酚酸酯在体外实验中显示出具有抗纤维化作用，表现为可抑制1型胶原表达和成纤维细胞迁移。这可能可以解释其在肝脏配对研究中显示的临床收益。该药物还在体外实验中表现出对丙型肝炎病毒具有抗病毒作用。

 

肝脏配对研究由意大利国家移植中心和意大利肝病研究学会提供支持。Angelico博士声称，他无与该研究相关的经济利益关系。同样，Toso博士声称，他无与其研究相关的经济利益冲突。

 

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