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.     

Expanded criteria for liver transplantation in patients with hepatocellular carcinoma

INTRODUCTION: Liver transplantation is the only curative treatment for patients with cirrhosis and unresectable hepatocellular carcinoma (HCC) without extrahepatic dissemination. Since criteria for transplantation in HCC are controversial, we evaluated our early results of liver transplantation for unresectable HCC. MATERIALS AND METHODS: Three women and 14 men (age range, 1.1 to 64 years) with preoperatively diagnosed or incidentally discovered HCC underwent liver transplantation. Six grafts were obtained from cadaveric donors, and each of the remaining 11 grafts from a living related donor. Criteria for participation, independent of tumor size and number of tumor nodules, were no invasion of major vascular structure and no evidence of extrahepatic disease. In nine patients, tumors were beyond the Milan criteria. Twelve patients (86.7%) received tacrolimus and 2 (13.30%), rapamycin monotherapy with early withdrawal of corticosteroid therapy. Two patients underwent neoadjuvant chemoembolization before transplantation; none received adjuvant chemotherapy. Seven patients with hepatitis B virus infection underwent antiviral prophylaxis with antibody to hepatitis B surface antigens and lamivudine. RESULTS: During follow-up (range, 1 to 17 months), all patients exhibited excellent graft function. Imaging studies revealed no evidence of tumor recurrence and no elevation of alpha fetoprotein or carcinoembryonic antigen levels. DISCUSSION: Low-dose immunosuppressive therapy and expanded criteria for liver transplantation in patients with HCC, especially when donation from a living related donor is possible, appear to inhibit disease recurrence and improve outcomes.     

扩大肝癌肝移植适应证的探索

目的 评价不同入选标准对肝癌肝移植适应证的范围及其对预后的影响,探索扩大肝癌肝移植适应证的可行性.方法 回顾分析北京大学第三医院81例长期随访的肝癌肝移植患者,Kaplan-Meier法计算依Milan、UCSF及Pittsburgh标准入选的肝癌病例数及肝移植术后生存率,观察不同标准的临床应用价值.对可能降低术后生存率的危险因素行单因素及多因素分析,依据主要危险因素建立人选标准模型.结果 81例患者中符合Milan标准者19例,1、2、3年累计生存率分别为87.7%、87.7%及52.6%,无瘤生存率为88.9%、72.7%及72.7%;符合UCSF标准者26例,1、2、3年累计生存率分别为87.2%、80.5%及55.2%,无瘤生存率为84.1%、68.4%及68.4%.新的人选标准为:单发肿瘤直径≤8 cm;多发肿瘤数目≤3个,其中最大肿瘤直径≤6 cm,且所有肿瘤直径总和≤10 cm.81例患者中符合新标准者41例,术后1、2、3年累计生存率分别为89.0%、81.8%及71.8%;1、2、3年无瘤生存率分别为81.9%、72.4%及72.4%.此41例术后累计生存率及无瘤生存率与符合Milan标准的19例及符合UCSF标准的26例比较,差异无统计学意义.41例入选病例与40例排除病例比较,累计生存率及无瘤生存率比较,差异均有统计学意义(P＜0.05).结论 适当扩大肝癌肝移植适应证并不降低术后生存率,新标准具有可行性.     

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.     

努力提高肝细胞癌的肝移植治疗效果——肝移植治疗肝癌时的受者选择标准和围手术期辅助治疗

肝细胞癌(以下简称"肝癌")是严重威胁人类健康的恶性肿瘤,全球每年新发肝癌约626 000例,因肝癌死亡598 000例.我国是肝癌高发地区,每年新发肝癌约344 000例,约占全球新发病例的55 %,在我国恶性肿瘤所致死亡中,肝癌是第2大死亡原因[1].     

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     

Extended criteria for living donor liver transplantation in patients with advanced hepatocellular carcinoma

Background

The purpose of this study was to evaluate the possibility of expanding the selection criteria in living donor liver transplantation (LDLT) to treat hepatocellular carcinoma (HCC).

Methods

From October 2000 to December 2010, we retrospectively analyzed 71 patients who had undergone LDLT beyond the Milan criteria (MC), among the entire cohort of 199 HCC patients. We evaluated the tumor biology as well as overall and disease-free survival (DFS), seeking to identify risk factors for recurrence. The median follow-up was 37 months (range 5-124).

Results

Among the 71 patients beyond the MC were 18 recurrences and 30 deaths. Their 5-year overall and DFS rates were 52.3% and 67.7%, respectively. On multivariate analysis, tumor diameter, tumor number, and E-S grade significantly influenced overall and DFS. According to our new criteria (size ≤7 cm, number ≤7), 86% of our patients would be included compared with 64% using MC. Five-year DFS and overall survival rates according to our criteria were comparable with the MC: 86.8% and 72.3% versus 86.8% and 73.4%, respectively.

Conclusion

Our criteria appear to achieve useful cut-off values beyond the MC.     

不同肝癌肝移植标准受者预后分析

目的分析不同肝癌肝移植标准受者预后情况,评价不同标准之间的差异。 方法回顾性分析2013年1月至2017年12月首都医科大学附属北京朝阳医院原发性肝癌肝移植受者的临床资料,比较不同肝癌肝移植标准受者的预后情况。采用单因素方差分析比较不同肝癌肝移植标准受者年龄、手术时间、无肝期时间和肿瘤最大直径,采用秩和检验比较AFP、终末期肝病模型评分和出血量。采用Kaplan-Meier法绘制生存曲线,采用Log-Rank检验比较生存率。采用卡方检验比较Child分级、肿瘤分化程度等指标。P<0.05为差异有统计学意义。 结果根据肝移植术后病理结果,115例肝癌肝移植受者中符合米兰标准43例;符合美国加州大学旧金山分校(UCSF)标准49例,较米兰标准扩大14.0%;符合杭州标准91例,较米兰标准扩大111.6%,较UCSF标准扩大85.7%。截至2017年12月,115例受者平均随访(19±17)个月,中位生存时间41.5个月(1.0～57.0个月)。除肿瘤最大直径和肿瘤数目外,3组不同肝癌肝移植标准受者均具有可比性(P均>0.05)。不同肝癌肝移植受者术后1～4年总体和和无瘤生存曲线差异均无统计学意义(P均>0.05)。 结论相较于米兰标准和UCSF标准而言,杭州标准安全地扩大了肝癌肝移植适用范围,使更多的原发性肝癌患者受益。     

Living-donor liver transplantation for hepatocellular carcinoma

Transplant surgeons have long dreamed of achieving a complete cure for hepatocellular carcinoma (HCC) by replacing the liver with a new graft. Although the early results of liver transplantation for HCC were disappointing, with 5-year survival less than 40%, improved results in patients who met the so-called Milan criteria rekindled the enthusiasm for the treatment of HCC with liver transplantation. Furthermore, the recent development of living-donor liver transplantation in adults has allowed timely grafting for HCC patients and tentative expansion of the criteria for transplant candidacy in patients with HCC — although such expansion is fraught with controversy. Identification of a noninvasive marker that could predict the biological behavior as well as the prognosis of HCC would indeed be a major breakthrough.     

肝脏移植治疗原发性肝癌20例报告

目的　探讨原位肝移植技术在治疗原发性肝癌中的地位和疗效。　方法　对1993年4月至2000年6月中山医科大学器官移植中心进行的20例原位肝移植术治疗原发性肝癌临床资料进行回顾性研究。其中大肝癌14例（直径＞5cm）,小肝癌6例（直径≤5cm）。　结果　大肝癌组肝移植术后平均存活6.5个月,肝癌复发率为71%(10/14);小肝癌组移植术后1、2年存活率分别为83％(5/6)和67%（4/6）,肝癌复发率为17%(1/6),两组肝癌复发率的差异有显著意义(P＜0.05)。　结论肝移植对肝癌单发,直径小于或等于5cm,无血管侵犯的小肝癌有良好的疗效;对部分病例选择适当的大肝癌患者可获得较好的姑息疗效;肝移植围手术期辅助化学药物治疗可能会减少肝癌复发。     

肝癌肝移植适应证标准——验证及再思考

对不同的原发性肝细胞癌(肝癌)肝移植适应证标准进行评价与验证.方法 2001年至2007年上海七家肝移植中心施行的肝癌肝移植病例共948例,采用Kaplan-Meier法分析符合米兰标准、加利福尼亚标准和上海复旦标准的肝癌肝移植患者的术后4年总体生存率及无复发生存率,并作比较.结果符合米兰标准(369例)、加利福尼亚标准(470例)和上海复旦标准(554例)的患者的术后4年总体生存率及无复发生存率分别为65.8%和74.1%、66.0%和73.6%、63.9%和70.4%.三种标准的总体生存率及无复发生存率比较差异无统计学意义(均为P>0.05).与符合米兰标准的病例相比,超出米兰标准但符合上海复旦标准的185例,其术后4年生存率及无复发生存率分别为61.5%、65.0%,比较差异亦无统计学意义(均为P>0.05).结论 上海复旦标准适度扩大了肝癌肝移植适应证范围且生存率满意,可能更符合中国国情.     

肝细胞癌肝移植适应证选择的疗效评估

目的:总结肝癌肝移植不同标准适应证的疗效,探讨影响预后的因素.方法:回顾性分析2002年6月至2007年6月96例肝细胞癌肝移植病例,其中符合米兰(Milan)标准者29例,符合加利福尼亚(UCSF)标准者41例,超过UCSF标准者55例.采用Kaplan-Meier法统计分析不同病例入选标准对肝癌肝移植术后生存率及无瘤生存率的影响,并进行Log-rank和Cox多元回归分析.结果:Milan和UCSF标准内影响长期生存的因素包括肿瘤分化、肿瘤部位、镜下癌栓和TNM分期.Milan标准组术后1、2、3、4年总体生存率分别为92.5%、79.6%、79.6%及53.0%,无瘤生存率分别为90.2%、79.3%、76.3%及51.7%;UCSF标准组术后1、2、3、4年总体生存率分别为92.4%、80.9%、73.0及51.1%,无瘤生存率分别为90.2%、79.8%、71.7%及50.2%;超过UCSF标准组术后1、2、3、4年总体生存率分别为66.3%、39.8%、26.5%及15.9%,无瘤生存率分别为64.4%、31.5%、15.8%及15.8%.Milan、UCSF标准组生存率和无瘤生存率与超过UCSF标准组比较有显著差异(P<0.01),Milan标准组与UCSF标准组间生存率和无瘤生存率无显著差异(P>0.05).结论:与Milan标准相比,UCSF标准显著扩大了肝癌肝移植的适应证范围,更符合作为选择肝癌肝移植病人的标准.     

Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma.

An increasing number of patients with hepatocellular carcinoma (HCC) are undergoing evaluation for listing for liver transplantation. Criteria for selection require ongoing review for suitability. A consecutive series of 40 patients with HCC within the standard Milan criteria (single tumors n = 19 < 5 cm, or up to 3 tumors < 3 cm) and beyond (Extended Criteria; single tumors n = 21 < 7.5 cm, multiple tumors < 5 cm) underwent liver transplant with a sirolimus-based immunosuppressive protocol designed to minimize exposure to calcineurin inhibitors and steroids. At 44.3 +/- 19.3 months (mean +/- standard deviation) follow-up, 1- and 4-year survivals (Kaplan-Meier) are 94.1 +/- 5.7% and 87.4 +/- 9.3%, in the Milan group, respectively, and 90.5 +/- 6.4% and 82.9 +/- 9.3% in the Extended Criteria group, respectively. Five patients died during follow-up, only 1 from recurrent HCC. Five tumor recurrences have occurred at median 17 (mean 22 +/- 17) months posttransplant, 1 in the Milan group and 4 in the Extended Criteria group. Median survival in the patients with recurrent tumor is 42 months (mean 45 +/- 25), and the median postrecurrence survival is 15.5 months (mean 23 +/- 16). The rate of patients who were alive and free of tumor at 1 and 4 years is 94.1 +/- 5.7% and 81.1 +/- 9.9%, respectively, in the Milan group and is 90.5 +/- 6.4% and 76.8 +/- 10.5%, respectively, in the Extended Criteria group. Five patients had sirolimus discontinued for toxicity, while 24 of 35 surviving patients have sirolimus monotherapy immunosuppression. In conclusion, the Milan criteria for liver transplantation in the presence of HCC can be carefully extended without compromising outcomes. This sirolimus based immunosuppression protocol appears to have beneficial effects on tumor recurrence and survival with an acceptable rate of rejection and toxicity.     

Expanded criteria donors for kidney transplantation

The shortage of deceased donor kidneys for transplantation continues to restrict the full application of this lifesaving procedure to all who might benefit. Increasing reliance on donors with characteristics previously thought to be unsuitable for use in transplantation has led to questions about graft outcomes for recipients of such organs. Careful definition of the expanded criteria donor (ECD) for kidney has facilitated modifications of national organ allocation policy that are designed to increase procurement, improve use, decrease cold ischemia time, and lead to improved outcome. The effects of these policy changes in the United States have been studied recently and are reviewed here. In addition, the impact of ECD kidney transplantation on mortality risk among candidates awaiting deceased donor renal transplantation is examined. Further studies of ECD organs and their recipients are needed to optimize the use of these scarce resources.     

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.     

Living donor liver transplantation for hepatocellular carcinoma

Background

Liver transplantation is a widely accepted modality in the treatment of hepatocellular carcinoma (HCC). In our center, patients with HCC limited to the liver without macrovascular invasion are accepted as candidates for living donor liver transplantation (LDLT). The aim of this study was to describe the patient characteristics and outcomes at a single institution to analyze the impact of our criteria on the survival of HCC patients.

Patients and Methods

We reviewed the medical records of all HCC (n = 105) patients who underwent liver transplantation in our institution. We excluded deaths in the early postoperative period and deceased donor liver transplantation (DDLT) patients, leaving 74 subjects (65 males and 9 female). Their median age was 53 years (range, 19-69). Univariate Kaplan-Meier and multivariate Cox proportional hazards models were used to analyze overall and disease-free survivals.

Results

Thirty-two (43%) patients were within the Milan criteria, and 42 (57%) exceeded them. One- and 2-year overall survival rates for patients within versus exceeding the Milan criteria were 72% versus 68% and 61% versus 58%, respectively. One- and 2-year disease-free survival rates for patients within versus exceeding the Milan criteria were 72% versus 68% and 60% versus 55%, respectively (P > .05). Tumor recurrence rates for patients within versus exceeding the Milan criteria were 0% versus 36%, respectively (P = .0002). Alpha-fetoprotein level was the only predictor of overall survival; alpha-fetoprotein level and tumor differentiation were predictors of disease-free survival.

Conclusion

Although higher recurrence rates have been observed among patients exceeding the Milan criteria, LDLT is the only treatment option for the patients in countries with limited sources of cadaveric organs. As a general principle, we believe that the use of cadaveric donor liver grafts is not suitable for patients who exceed these criteria.