University Hospital Regensburg, Department of Surgery, Regensburg, Germany.
BMC Cancer. 2010 May 11;10:190. doi: 10.1186/1471-2407-10-190.
The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
METHODS/DESIGN: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.
If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.
Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).
哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂具有潜在的抗癌作用，目前正受到广泛研究。然而，迄今为止，很少有随机临床试验（RCT）能够在纯肿瘤学环境中证明抗肿瘤作用，目前，在免疫抑制移植受者这种高恶性风险人群中，也没有报告任何针对肿瘤终点的 RCT。有趣的是，由于 mTOR 抑制剂既有免疫抑制作用又有抗癌作用，因此它们有可能同时预防免疫性移植物丢失和肿瘤发展。因此，我们设计了一项前瞻性 RCT，以确定雷帕霉素（mTOR 抑制剂）是否可以改善移植前诊断为 HCC 的肝移植（LT）受者的 HCC 无复发生存。
方法/设计：该研究是一项开放标签、随机的 RCT，比较了接受 LT 治疗 HCC 的患者中含雷帕霉素和不含 mTOR 抑制剂的免疫抑制方案。在 LT 后 4-6 周内，对组织学确诊 HCC 的患者进行分组；一组维持中心特异性无 mTOR 抑制剂的免疫抑制方案，另一组在前 4-6 周内维持中心特异性无 mTOR 抑制剂的免疫抑制方案，然后开始使用雷帕霉素。计划进行 21/2 年的招募阶段，随访 5 年，以 HCC 无复发生存作为主要终点。我们的假设是，研究第二组中使用雷帕霉素将改善 HCC 无复发生存。该研究是由雷根斯堡大学医院赞助的非商业性研究者发起的试验（IIT），并得到欧洲肝脏和肠道移植协会的认可；欧洲、加拿大和澳大利亚的 13 个国家参与了该研究。
如果我们的假设是正确的，即 mTOR 抑制可以减少 HCC 肿瘤生长，同时提供免疫抑制以保护肝移植免受排斥，那么患者在移植后 HCC 复发方面应该会遇到更少的问题，因此他们可以预期更长和更好的生活质量。如果结果为阳性，可能会改变 LT 患者 HCC 移植后免疫抑制治疗的标准。
在 http://www.clinicaltrials.gov 上注册：NCT00355862（EudraCT 编号：2005-005362-36）。
