Liver transplantation for hepatocellular carcinoma

The role of liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) has evolved over the past two decades, and transplantation has become one of the few curative treatment modalities for patients with HCC. Early results were poor, but the current restrictive selection criteria can yield excellent results. This review will discuss recent issues in the field, including (1) factors affecting the recurrence of HCC after LT; (2) the effect of downstaging HCC before LT, including transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA); and (3) living-donor versus deceased-donor liver transplantation for HCC patients. The most important factors that have been described to affect LT survival include the tumor size, vascular invasion, and the degree of tumor differentiation. Recently, tumor markers, including alpha-fetoprotein and des-gamma carboxy prothrombin, were reported as predictors of HCC recurrence after LT. Furthermore, the experience accumulated with locoregional therapies such as TACE and RFA as bridging procedures to LT, along with the reduced waiting time under the HCC-adjusted MELD (model for endstage liver disease) system for organ allocation has led to improved outcomes. With the recent advances in adult living-donor liver transplantation (LDLT), there may be a marked change in the role of liver transplantation for hepatic malignancies, in particular for HCC.     

Liver transplantation for hepatocellular carcinoma

OBJECTIVE: To analyze patient and tumor characteristics that influence patient survival to select patients who would most benefit from liver transplantation. SUMMARY BACKGROUND DATA: The selection of patients with hepatocellular carcinoma (HCC) for liver transplantation remains controversial. METHODS: One hundred twelve patients with nonfibrolamellar HCC who underwent a liver transplant from 1985 to 2000 were reviewed. Survival was calculated using the Kaplan-Meier method, with differences in outcome assessed using the log-rank procedure. Multivariate analysis was then performed using a Cox regression model. RESULTS: Overall patient survival rates were 78%, 63%, and 57% at 1, 3, and 5 years, respectively. Patients infected with the hepatitis B virus had a worse 5-year survival than those who were not (43% vs. 64%), with most deaths being attributed to recurrent hepatitis B. However, patients with hepatitis B virus who underwent more recent transplants using antiviral therapy fared as well as those who were negative for the virus, showing a 5-year survival rate of 77%. Patients with vascular invasion by tumor had a worse 5-year survival than patients without vascular invasion (33% vs. 68%). Vascular invasion, tumor size greater than 5 cm, and poorly differentiated tumor grade were predictors of tumor recurrence by univariate analysis; however, only vascular invasion remained significant on multivariate analysis: the rate of tumor recurrence at 5 years was 65% in patients with vascular invasion and only 4% for patients without vascular invasion. CONCLUSIONS: For well-selected patients with HCC, liver transplantation in the current era can achieve equivalent results to transplantation for nonmalignant indications. Vascular invasion is an indicator of high risk of tumor recurrence but is difficult to detect before transplantation.     

Liver transplantation for hepatocellular carcinoma

Total hepatectomy plus liver transplantation was performed on 105 patients considered unsuitable for liver resection. Postoperative 5-year actuarial survivals correlated with the pathologic stage of the tumor: stage I 75%, stage II 68%, stage III 52,1%, and stage IVA 11%. The overall 5-year survival for all patients was 36%. Nodal disease, bilobar tumor, and macroscopic venous invasion were significant poor-prognosis features. In addition, 12 patients with pT4N1M0 lesions (also stage IVA) had hepatectomy plus more extensive en bloc regional resection (Whipple procedure or cluster resection) plus transplantation in an effort to prevent local recurrence. Only 2 of these 12 patients (16.7%) are alive and free of disease after 2 years. Seven patients (58%) have died from tumor recurrence usually originating from distant metastases an average of 10.6 months after transplantation. Successful transplantation for hepatoma depends on screening programs to identify early stage disease. Successful outcome of transplantation for late stage disease, which includes most of the patients in our series, awaits the development of neoadjuvant therapy to control distant microscopic metastases, which are almost certainly present though not apparent at the time of transplantation.

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Resumen Se practicó hepatectomía total y trasplante de hígado en 105 pacientes considerados inadecuados para resección hepática. La supervivencia actuarial a 5 años correlacionó bien con el estado patológico del tumor: estado I-75%; estado II-68%; estado III-52.1% y estado IV-A-11%, en tanto que la sobrevida global a cinco años para la totalidad de los pacientes fue 36%. Extensión ganglionar, tumor bilobar e invasión venosa macroscópica demostraron ser características de mal pronóstico. Además, 12 pacientes con lesiones pT4N1M0 (también estado IV-A) fueron sometidos a hepatectomía y más amplia resección regional en bloque (operación de Whipple o resecciones amplias) y trasplante, en un esfuerzo por prevenir recurrencias locales. Sólo 2 pacientes (16.7%) se encuentran vivos y libres de enfermedad a los 2 años de seguimiento. Siete pacientes (59%) han muerto por recurrencia tumoral, usualmente originaria en metástasis distantes, a los 10.6 meses (promedio) luego del trasplante. El trasplante exitoso por hepatoma depende de programas de tamizaje orientados a identificar la enfermedad en sus estados iniciales. El éxito del trasplante por enfermedad avanzada, situación en que se encontraba la mayoría de los pacientes en nuestra serie, espera el desarrollo de terapia neoadyuvante para el control de las metástasis microscópicas que casi con seguridad están presentes, aunque no aparentes, en el momento del trasplante.

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Résumé L'hépatectomie totale suivie de transplantation a été réalisée chez 105 patients considérés comme de mauvais candidats à la résection pour carcinome hépatocellulaire. La survie actuarielle à 5 ans par rapport au stade anatomopathologique de la tumeur était de 75% pour le stade I, de 68% pour le stade II, de 52.1% pour le stade III et de 11% pour le stade IV-A alors que la survie globale à 5 ans était de 36%. L'envahissement ganglionnaire, une tumeur occupant plus de deux lobes et un envahissement veineux macroscopique ont été des facteurs de mauvais pronostic. Douze patients ayant une lésion pT4N1M0 (stage IV-A) ont eu une hépatectomie associée à une résection en bloc plus étendue (duodénopancréatectomie ou résection en cluster) suivie de transplantation en vue de prévenir les récidives locales. Seulement deux patients (16.7%) sont en vie et sans maladie à deux ans. Sept patients (59%) sont morts d'une récidive tumorale dont l'origine était essentiellement des métastases à distance survenues en moyenne 10.6 mois après la transplantation. La réussite de la transplantation pour carcinome hépatocellulaire dépend de la qualité des programmes de détection pour identifier la maladie à son début. Le succès de la transplantation pour une tumeur évoluée, ce qui était le cas pour la plupart des malades dans notre série, dépend du développement d'un traitement néoadjuvant efficace pour contrôler les métastases microscopiques à distance qui sont très certainement présentes mais non apparentes lors de la transplantation.

     

Liver transplantation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has been a major reason for liver transplantation (LT). Globally, LT for HCC is performed on the basis of the Milan criteria, and if performed within those criteria, then the outcome is not different from that of LT performed for other primary diseases. On the other hand, the scope of the Milan criteria covers only early-stage HCC, and many HCC patients do not meet the criteria even at the time of diagnosis. Therefore, over the last decade, efforts have been made to perform LT for patients whose clinical characteristics lie outside the Milan criteria. In Japan, more than 99% of LTs are living donor LTs (LDLTs) and more than 15% of LTs are performed in patients with HCC. The 1- and 3-year actual survival rates of LDLT for HCC in Japan are 82 and 79%, respectively. Efforts to extend the Milan criteria have also been made in Japan. To improve the outcome of LT for HCC, pre- and postoperative management of hepatitis B and hepatitis C, and immunosuppressant specific for this type of LT are still crucial issues. In this review, we provide an overview of current outcome, efforts to extend the Milan criteria, control of viral hepatitis, and immunosuppression for LT in patients with HCC.     

Liver transplantation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is considered an aggressive tumor with mean survival estimated between 6 and 20 months. Hepatitis B and C are the most common etiologies. Pathological, laboratory and radiologic imaging all aid in diagnosis but much controversy exists in the utilization of any given modality. Many treatment options exist for management of HCC, each has its own limitation. Liver transplantation offers the most reasonable expectation for curative treatment while simultaneously removing the burden of the diseased liver. Still, advancements in the field have thus far not yet matched its potential, although new immunosuppressive and chemotherapy regimen may allow transplantation to push the envelope once again.Key Words: Hepatocellular carcinoma, heptatoma, liver transplantation     

Liver transplantation in hepatocellular carcinoma

Liver transplantation is one option of surgical treatment for cirrhotic patients with hepatocellular carcinoma, it not only treats the malignancy but also the underlying disease. After an initial period of disappointing results, mainly due to lack of adequate selection, survival nowadays is similar to that obtained by cirrhotic patients without tumor. Currently the scarcity of donors is the main limitation in the treatment of this type of patients. Increased time on the waiting list does compromise the results if they are analyzed in an intention-to-treat basis. Adjuvant therapy on the waiting list (ethanol injection, chemoembolization, surgery, etc.) or the use of marginal grafts in order to increase the donor pool may be some alternatives to overcome this deficit. The development of adult living donor liver transplantation has proved to be a good alternative in this type of patients even if they do not fulfill the conventional criteria.     

Liver transplantation for patients with hepatocellular carcinoma

BACKGROUND: Liver transplantation (LT) has been advocated as a salvage treatment for unresectable hepatocellular carcinoma (HCC). Selection criteria still need to be developed in Taiwan. OBJECTIVES: The purpose of our study was to assess the clinical findings and outcome of cirrhotic patients with HCC undergoing liver transplantation. METHODS: Our study consisted of 13 HCC patients who underwent liver transplantation during October 1996 to March 2003. The medical records and pathologic reports were analyzed retrospectively. RESULTS: Overall survival rates at 1 and 3 years were 86% and 61%, respectively. HCC recurrences occurred in three patients, one of whom is still alive with HCC recurrence 2 years after LT. The other two patients died of HCC recurrence 1 and 2 years after LT, respectively. Pretransplant alpha-fetoprotein (AFP) levels of >200 ng/mL were noted in all three patients with HCC recurrence. In contrast, only one of the ten patients without HCC recurrence had pretransplant AFP >200 ng/mL (P = .003). Four patients did not meet Milan criteria, two of whom had HCC recurrence. However, the other two patients with microscopic vascular invasion survived and were free of HCC. The only one patient, who had histologic grade 4 HCC, died of recurrence, although his tumor was AJCC stage 1. CONCLUSIONS: High AFP level is a risk factor for HCC recurrence after LT. In addition to Milan criteria, histologic tumor grading should be considered in patient selection. Microscopic vascular invasion may not affect the outcome of the patients with early HCC.     

Liver transplantation in hepatocellular carcinoma

The initial enthusiasm for orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) soon vanished as early recurrences appeared [3, 5, 6]. OLT in HCC remains a controversial issue. We evaluated the efficacy of preoperative studies to select No-Mo patients and determined whether pT stage and histopathological grade (G) have a prognostic significance. A group of 25 patients, all previously thoroughly studied to rule out extrahepatic disease, underwent OLT for HCC. All patients were pNo after pathological study and none of the six patients who died in the postoperative period showed extrahepatic dissemination at necropsy (pMo). The recurrence rate was 43%. The 2 and 5 years actuarial survival was 62% and 43% respectively. The pT and G were not prognostic factors for long-term survival. We think that HCC is still a good indication for OLT because almost 50% of patients have good survival prospects.     

Liver transplantation for recurrent hepatocellular carcinoma in Europe

Abstract. Background: Patient death after liver resection for hepatocellular carcinoma in cirrhosis is caused by tumor recurrence as well as by complications of cirrhosis. Liver transplantation represents the only simultaneous treatment of tumor and primary liver disease. Certain criteria regarding the number (up to three) and size (up to 5 cm) of tumor nodules have to be observed in order to ensure a low risk of extrahepatic spread or vascular infiltration. Liver transplantation, as treatment for recurrent hepatocellular carcinoma, has to observe the same rules. Only few patients have undergone liver transplantation for recurrent hepatocellular carcinoma in cirrhosis. The reason for this restraint is not fully evident. Poor survival rates after liver transplantation as therapy for advanced hepatocellular carcinoma in the 1980s and an increasing shortage of donor grafts are certainly two factors. Methods: We report on two cases from our experience and review the European literature. Results: Outcome in a few selected patients has been rather favorable, despite varying approaches. Conclusions: The only conclusion that can be drawn is that tumor control by liver transplantation is possible in individual patients suffering from recurrent hepatocellular carcinoma. Adult living donor liver transplantation is one way to overcome graft shortage. Other strategies, for example, salvage transplantation, are presented. Received: April 20, 2001 / Accepted: May 11, 2001     

肝脏移植对23例肝细胞性肝癌的治疗价值研究

目的进一步探讨肝细胞性肝癌肝移植治疗的疗效 ,评价其应用价值。方法对 1999年 2月～ 2 0 0 2年 3月连续实施的 95例肝移植中的 2 3例肝细胞肝癌患者进行随访和回顾性分析 ,探讨肝细胞性肝癌临床病理学因素对肝移植术后生存率和肝癌复发的影响。结果本组肝细胞性肝癌总的复发率为 6 5 % (15 /2 3) ,6个月、12个月的无癌生存率分别为 75 %、5 8%。多元分析表明 ,肝细胞性肝癌的直径与它的复发率有相关性 (P =0 0 2 4 ) ,而其他的临床病理学因素未显示有统计学意义(Wald =5 113,P =0 0 2 4 )。而年龄、性别、癌灶数目、门静脉癌栓形成、TNM分期、术前AFP水平、术前治疗、合并肝硬化等病理学因素则在统计学上未显示有显著意义 (P >0 0 5 )。结论大肝癌是肝移植的相对禁忌证 ,而小肝癌是肝移植的良好适应证     

Liver transplantation for hepatocellular carcinoma in cirrhotic patients

A consecutive series of 88 patients underwent transplantation for hepatocellular carcinoma with cirrhosis over a 7-year period. Liver transplantation was indicated because of the tumor in 75 cases (85.2%); tumor was an incidental finding in 13 cases (14.8%). One patient was retransplanted due to primary nonfunction. The perioperative mortality was 4.5%. Tumor recurrence was observed in seven patients (7.95%) with incidental tumor recurrence in one case. As in patients with known primary liver tumors pretransplant, a thorough follow-up is advisable to establish an early diagnosis of recurrence. The actuarial survival for nonincidental hepatocellular carcinoma at 1, 3, and 5 year was 92%, 77%, and 75%, respectively. The differences in actuarial survival between hepatitis C negative and positive hepatocellular carcinoma were not significant (log-rank test P=.27), though there was a clear improvement in results (94%, 85%, and 78% vs 90%, 71%, and 71%), at 1, 3, and 5 years meaning that HCV infection is an important prognostic factor. Although transplantation for HCC has the advantages of removing the tumor and the cirrhotic liver, it remains a controversial topic. In our experience patients showing lesions less than 5 cm or three or fewer lesions experience an equivalent survival to transplanted patients who do not have cancer.     

原发性肝癌肝切除术后复发患者的肝移植治疗

目的观察肝移植治疗原发性肝癌肝切除术后复发患者的疗效。方法回顾性分析11例原发性肝癌肝切除术后复发接受经典原位肝移植治疗的受者的临床资料,观察移植效果。结果在围手术期,1例术后发生移植肝功能不全和凝血功能障碍并发肾功能衰竭死亡;1例术后出现急性胰腺炎,给予生长抑素治疗10d缓解;2例发生急性排斥反应,行大剂量甲泼尼龙冲击治疗3d逆转。10例受者顺利出院。出院后,3例分别于术后第5个月、第7个月、第19个月死于肝癌复发,1、2年受者存活率分别为72．7％（8／11）和63．6％（7／11）,至今最长存活的1例已达4年余。获长期存活的受者肝癌肝切除术前原发病均为小肝癌,肝切除术后复发行肝移植时肝癌均符合Milan标准。结论小肝癌行肝癌肝切除术后应密切随访,如发现肝癌复发且符合Milan标准可考虑行肝移植治疗,患者仍有可能获较长时间生存。     

Liver transplantation for hepatocellular carcinoma: an Asian perspective

Liver transplantation is an established treatment modality for patients with hepatocellular carcinoma (HCC), creating a potential for disease-free, long-term survival. In Asia, due to a severe shortage of donors, resection remains the treatment of choice for patients with HCC and good liver functional reserve. The use of marginal donors, split liver grafts and grafts from living donors are potential solutions that are best performed in experienced liver transplant centres to ensure an optimal outcome. Ethical issues relating to living donor liver transplantation have yet to be fully addressed. The roles of therapies to limit tumour progression during the waiting period, such as transarterial chemoembolization, need to be further investigated in the setting of a prospective trial and their benefits better defined.