Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a systematic review

Background and Aim: Surgery is the standard treatment option for hepatocellular carcinoma (HCC) meeting the Milan criteria, defined as single HCC ≤ 5 cm in maximum diameter or up to three nodules ≤ 3 cm. However, favorable survival outcomes have also been reported for these HCCs following radiofrequency ablation (RFA). Methods: We performed a systematic review to compare the results of hepatic resection and percutaneous RFA as a primary treatment option of HCC meeting the Milan criteria. Studies were identified by searching MEDLINE on PubMed, the Cochrane Library database and CANCERLIT using appropriate key words. Results: In all six identified observational studies, there were no statistically significant differences in overall survival rates between the two treatment modalities. The results of two randomized trials are controversial, while the power of these randomized trials is too limited to reach a reliable conclusion. In practice, the choice of treatment between surgery and RFA largely depends on the relationship between the local recurrence and perioperative mortality rates of HCC patients. Following RFA, local recurrence rates are low when a minimal safety margin ≥ 4–5 mm is achieved. A previous simulation study of overall survival for very early stage HCC, defined as an asymptomatic solitary small HCC ≤ 2 cm, showed that primary RFA with a 9% local recurrence rate is comparable to surgical resection with a 3% operative mortality rate. Conclusion: Acquisition of a sufficient safety margin seems to be a critical factor before recommending wider application of RFA as primary treatment for HCCs that meet the Milan criteria.     

Liver transplantation for hepatocellular carcinoma

Hepatocellular carcinoma can only be cured by physical removal or destruction of the tumor before it has spread. This can be accomplished by the ablation of the tumor, surgical resection of the tumor-bearing liver, or by liver transplantation. Ablation and resection can only be performed in patients who will be left with sufficient liver volume to sustain normal hepatic function. Unfortunately, the same disease that caused the HCC also limits the amount of parenchymal loss that can be tolerated by the patient. Liver transplantation is an appealing treatment option because it has the potential to cure patient of both the cancer and the predisposinig liver disease. Excellent survival rates are possible in patients with early HCC who receive a transplant, but dismal results are seen when patients with advanced tumors are transplanted.Wide criteria for transplant allow for more patients to be cured of HCC, but this comes at the expense of a greater overall recurrence rate. The acceptable recurrence rate is not a concrete number, but this is a function of donor organ availability. A 50% cure rate is viewed as an excellent outcome for many accepted cancer operations; however, in the case of transplant for HCC, this would represent a poor use of the scarce donor resource when the same liver offers a 70% 5-year survival rate to a non-HCC patient. These issues and methods retarding tumor progression while on the transplant waiting list are reviewed herein.     

Radiofrequency ablation therapy for hepatocellular carcinoma in elderly patients

Background and Aim: With the aging of society, the number of elderly patients with hepatocellular carcinoma (HCC) has been increasing in Japan. The Government of Japan defines elderly as being over 65 and has divided the elderly into two stages: the first elderly stage (< 75 years old) and the second elderly stage (≥ 75). We investigated the efficacy and safety of radiofrequency ablation therapy (RFA) in patients in the second elderly stage in comparison with other HCC patients, retrospectively. Methods: Two hundred six patients with HCC, who were within the Milan criteria, with low‐grade performance status (0 or 1) and a Child‐Pugh classification of A or B were enrolled. All were treated with RFA from January 2000 to December 2008 as an initial therapy and were divided into elderly HCC group (e‐HCC group; ≥ 75, n = 63) and non e‐HCC group (< 75, n = 143), and their clinical data and survival rates were compared. Results: Age and the level of protein induced by vitamin K absence or antagonist (PIVKA‐II) were higher in the e‐HCC group as compared with the non e‐HCC group (78.3 ± 3.2 vs 64.2 ± 7.5 years, 676.3 ± 2643.7 vs 142.4 ± 442.2 mAU/mL: P < 0.01, respectively). There were no significant differences for Child‐Pugh class, tumor node metastasis stage, and Japan Integrated Stage score and in survival rates after 3, and 5 years between the groups (e‐HCC group: 82.5% and 49.7%, respectively; non e‐HCC group: 78.3% and 57.5%, respectively). There were no severe complications in the e‐HCC group. Conclusions: Elderly HCC patients, who have good performance status, should be treated in the same manner and with the same strategy as young HCC patients.     

Living donor liver transplantation in hepatocellular carcinoma beyond the Milan criteria

Background/Aims: In patients with hepatocellular carcinoma (HCC) exceeding the Milan criteria, the recurrence rate after liver transplantation is over 50%. We investigated pretransplant factor(s) that could predict recurrence after living donor liver transplantation (LDLT) in patients with HCC exceeding the Milan criteria. Methods: Pre‐operative imaging showed that, of the 111 HCC patients who underwent LDLT between June 1995 and January 2006, 37 exceeded the Milan criteria. Clinical factors before LDLT were evaluated. Results: The 1‐ and 3‐year cumulative recurrence rates were 35 and 55% respectively. Pretransplant risk factors for HCC recurrence were large tumour size (>6 cm, P=0.001), tumour exposed to the liver surface (P=0.014) and progressive disease after pretransplant treatment (P=0.038). The 2‐year HCC recurrence rates in patients with 0, 1, 2 and 3 factors were 0% (0/4), 9% (1/16), 80% (8/10) and 100% (7/7) respectively (P<0.001). The 2‐year survival rate was significantly higher in patients with 0 or 1 factor than in patients with two or more factors (P=0.022). Conclusions: In patients with HCC exceeding the Milan criteria, the three pretransplant factors that may be useful for identifying those with high HCC recurrence potential after LDLT are tumour size >6 cm, progressive disease after pretransplant treatment and tumour exposed to the liver surface.     

Percutaneous ablation for small hepatocellular carcinoma

Hepatocellular carcinoma is increasingly detected at small size, usually 5 cm or smaller in diameter. For small hepatocellular carcinoma, percutaneous ablation is a potentially curative treatment. Ethanol injection is able to achieve a complete response of 70–80% and a 5-year survival of 40–60% in the treatment of hepatocellular carcinoma of 3 cm or less. Radiofrequency ablation has emerged as the more powerful alternative method. Randomized controlled trials show that radiofrequency ablation offers a higher complete response at fewer treatment sessions and better survival compared with ethanol injection. Microwave ablation has been demonstrated to be equivalent to radiofrequency ablation in both local efficacy and long-term outcome. Laser ablation is mainly applied in clinical settings in Europe. Nowadays, percutaneous ablation is commonly accepted as the best option for patients with small hepatocellular carcinoma who are not candidates for surgical resection or liver transplantation. However, whether it can compete with surgery as the first-line treatment has long been debated. There are some retrospective studies and only a few randomized controlled trials to compare the two modalities. The currently available data are not robust enough to draw a solid conclusion. This review article provides an overview of the current status of percutaneous ablation in management of small hepatocellular carcinoma and also focuses on comparison with surgical resection.     

Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma

Aim: To generate a new score with improved accuracy compared with Milan criteria to select patients. Patients: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut‐off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). Results: Multivariate analysis identified three predictors of 5‐year tumour‐free survival: tumour differentiation (P=0.02), diameter (P<0.0001) and number of nodules (P=0.04). A cut‐off value of 4 was derived from the AUROC of the final score. Five‐year tumour‐free survival was 60.2 ± 3.1% in patients with as score <4 and 36.4 ± 4.7% in individuals with a score ≥4, P<0.0001. In the validation cohort, 5‐year tumour‐free survival was 82.8 ± 3.6% (score <4) and 50.0 ± 10.7% (score ≥4), P=0.0003. In patients with a score <4, there was no significant difference in 5‐year tumour‐free survival between Milan+ and Milan? patients, either in cohort 1 or 2. Five‐year tumour‐free survival of Milan? patients was significantly better in individuals with a score <4 compared with those with a score ≥4, both in cohort 1 (61.5 ± 9.1 vs 31.4 ± 4.6%, P=0.009) and in cohort 2 (P=0.02). Conclusion: A novel score taking into account tumour differentiation shows higher accuracy than Milan criteria in predicting 5‐year tumour‐free survival following liver transplantation for HCC. Prospective studies should validate these findings.     

Percutaneous microwave and radiofrequency ablation for hepatocellular carcinoma: a retrospective comparative study

Background Percutaneous microwave ablation and radiofrequency ablation are two commonly used modalities for the treatment of hepatocellular carcinoma; however, comparisons of them have not been documented adequately. Methods Of 102 patients with biopsy-proved hepatocellular carcinoma, 49 (98 nodules) were treated percutaneously with microwave ablation and 53 (72 nodules) with radiofrequency ablation. The local tumor control, complications related to treatment, and long-term results of the two modalities were compared retrospectively. Results The complete ablation rates were 94.9% (93/98) using microwave ablation vs 93.1% (67/72) using radiofrequency ablation (P = 0.75), and no significant differences were found either in the ablation of tumors of 3.0 cm or less (P = 1.00) or in those of more than 3.0 cm (P = 1.00) between the two modalities. The local recurrence rates were 11.8% (11/93) using microwave ablation vs 20.9% (14/67) using radiofrequency ablation (P = 0.12), and there were no significant differences between the two modalities either in tumors of 3.0 cm or less (P = 0.36) or in those of more than 3.0 cm (P = 0.82). The rates of major complications associated with microwave ablation and radiofrequency ablation were 8.2% (4/49) vs 5.7% (3/53; P = 0.71). The disease-free survival rates in the microwave ablation group were 45.9%, 26.9%, 26.9%, and 13.4% at 1, 2, 3, and 4 years, respectively, and those in the radiofrequency ablation group were 37.2%, 20.7%, and 15.5% at 1, 2 and 3 years, respectively (P = 0.53). The 1-, 2-, 3-, and 4-year cumulative survival rates for patients who underwent microwave ablation were 81.6%, 61.2%, 50.5%, and 36.8%, respectively, and for patients who underwent radiofrequency ablation the rates were 71.7%, 47.2%, 37.6%, and 24.2%, respectively (P = 0.12). Conclusions Percutaneous microwave ablation and radiofrequency ablation are both effective methods in treating hepatocellular carcinomas. The local tumor control, complications related to treatment, and long-term survivals were equivalent for the two modalities.     

肝细胞癌射频消融术前肝脏功能评估的意义

肝脏功能是影响肝细胞癌（HCC）射频消融（RFA）治疗效果及预后的重要因素,应在治疗前进行全面评估。总结了Child-Turcotte-Pugh（CTP）评分、终末期肝病模型（MELD）、凝血酶原时间（PT）及其活动度（PTA）、血小板（PLT）、血清白蛋白（Alb）、胆红素（Bil）及HBV DNA水平等评估手段对预测消融后并发症及生存情况的价值,明确了术前肝脏功能评价的意义。     

高龄原发性肝癌射频治疗疗效分析

目的观察高龄原发性肝细胞癌(HCC)患者射频消融治疗(RFA)疗效及RFA对肝功能及生命质量的影响.方法超声引导RFA治疗的225例HCC患者为本文研究对象;非老年组(年龄≤60岁)109例;老年组(年龄＞60岁)116例中,年龄≥70岁者50例,52.6%(61人)合并其他疾病.治疗前两组病灶大小,肝功能分级均无显著差异.比较两组RFA疗效、生存期、生存率、生命质量变化及对肝功能的影响.结果两组消融成功率,局部肿瘤进展率均无明显差异.平均生存期非老年组为(43.31±3.16)个月,老年组为(41.07±2.50)个月,两组无统计学差异.老年组RFA治疗前后生命质量得分无显著差异;治疗后,老年组社会功能领域得分高于非老年组,两组生命质量总得分及其他领域得分均无显著差异.两组患者治疗前与治疗后1个月的谷丙转氨酶、谷草转氨酶、总胆红素水平均无明显差异.结论RFA对不适合手术治疗的高龄HCC患者,可获得良好疗效,并保持患者较高的生命质量;对高龄患者可作为首选治疗方法之一.     

Expanded criteria for liver transplantation in patients with hepatocellular carcinoma

Following the seminal publication by the group from Milan, Italy using a restrictive set of criteria for orthotopic liver transplantation in patients with hepatocellular carcinoma to limit the risk for tumor recurrence, excellent 5-year patient survival of greater than 70% after liver transplantation has been reported from many centers using criteria similar to or slightly exceeding the Milan criteria (single lesion of ≤5 cm, or 2–3 lesions of ≤3 cm). The growing experience and success of orthotopic liver transplantation for HCC have also fueled controversies related to expansion of conventional criteria for cadaveric or living-donor liver transplantation based on tumor size and number. The limitations of imaging studies, exemplified by tumor under-staging in up to 25% of patients,have been a major concern for liberalizing the current criteria for liver transplantation. The University of California, San Francisco criteria (single lesion of ≤6.5 cm, or 2–3 lesions of ≤4.5 cm with a total tumor diameter ≤8 cm) have been independently tested in several studies, and undergone prospective evaluation based on preoperative imaging. This article provides an in-depth review of published data on expansion of current criteria for liver transplantation.     

Surgical dilemma: liver resection or liver transplantation for hepatocellular carcinoma and cirrhosis. Intention-to-treat analysis in patients within and outwith Milan criteria

Background:

The optimal role of surgery in the management of hepatocellular carcinoma (HCC) is in continuous evolution.

Objective:

The objective of this study was to analyse survival rates after liver resection (LR) and orthotopic liver transplantation (OLT) for HCC within and outwith Milan criteria in an intention-to-treat analysis.

Methods:

During 1997–2007, 179 patients with cirrhosis and HCC either underwent LR (n= 60) or were listed for OLT (n= 119). Patients with incidental HCC after OLT, preoperative macrovascular invasion before LR, non-cirrhosis and Child–Pugh class C cirrhosis prior to OLT were eliminated, leaving 51 patients primarily treated with LR and 106 patients listed for primary OLT (84 of whom were transplanted) to be included in this analysis. A total of 66 patients fell outwith Milan criteria (26 LR, 40 OLT) and 91 continued to meet Milan criteria (25 LR, 66 OLT).

Results:

The median length of follow-up was 26 months. The mean waiting time for OLT was 7 months. During that time, 21 patients were removed from the waiting list as a result of tumour progression. Probabilities of dropout were 2% and 13% at 6 and 12 months, respectively, for patients within Milan criteria, and 34% and 57% at 6 and 12 months, respectively, for patients outwith Milan criteria (P < 0.01). Tumour size >3 cm was found to be the independent factor associated with dropout (hazard ratio [HR] 6.0). Postoperative survival was slightly higher after OLT, but this was not statistically significant (64% for OLT vs. 57% for LR). Overall survival from time of listing for OLT or LR did not differ between the two groups (P= 0.9); for patients within Milan criteria, 1- and 4-year survival rates after LR were 88% and 61%, respectively, compared with 92% and 62%, respectively, after OLT (P= 0.54). For patients outwith Milan criteria, 1- and 4-year survival rates after LR were 69% and 54%, respectively, compared with 65% and 40%, respectively, after OLT (P= 0.42). Tumour size >3 cm was again found to be an independent factor for poor outcome (HR 2.4) in the intention-to-treat analysis.

Conclusions:

Survival rates for patients with HCC are similar in LR and OLT. Liver resection can potentially decrease the dropout rate and serve as a bridge for future salvage LT, particularly in patients with tumours >3 cm.     

Japanese experience in ablation therapies for hepatocellular carcinoma

In the treatment of hepatocellular carcinoma, only 20–30% of patients are candidates for surgery. Still worse, even after curative surgical resection, 80% of patients develop recurrence within 5 years. Thus, various non-surgical therapies have developed. Among them, image-guided local ablation therapies, such as percutaneous ethanol injection, microwave coagulation and radiofrequency ablation, have been widely used for small hepatocellular carcinoma, because they are potentially curative, minimally invasive and easily repeatable. Percutaneous ethanol injection was a standard therapy. However, there has been a drastic shift from ethanol injection to radiofrequency ablation in recent years. In Japan, 1500 institutes have already introduced radiofrequency ablation in the treatment of liver tumors and the cool-tip electrode system has an 80% share of the market. Radiofrequency ablation can achieve complete tumor necrosis in most cases.Long-term survival seems considerably good, and complications are not frequent in radiofrequency ablation. Randomized controlled trials have proved that radiofrequency ablation is superior to ethanol injection in the treatment of small hepatocellular carcinoma from the viewpoint of, not only treatment response, but also long-term survival. Radiofrequency ablation seems feasible, efficacious and considerably safe. Radiofrequency ablation will be more widely performed in the treatment of primary and metastatic liver tumors in Japan.     

Radiofrequency ablation vs surgical resection in elderly patients with hepatocellular carcinoma in Milan criteria

BACKGROUNDSurgical resection and radiofrequency ablation (RFA) represent two possible strategy in treatment of hepatocellular carcinoma (HCC) in Milan criteria.AIMTo evaluate short- and long-term outcome in elderly patients (> 70 years) with HCC in Milan criteria, which underwent liver resection (LR) or RFA.METHODSThe study included 594 patients with HCC in Milan criteria (429 in LR group and 165 in RFA group) managed in 10 European centers. Statistical analysis was performed using the Kaplan-Meier method before and after propensity score matching (PSM) and Cox regression.RESULTSAfter PSM, we compared 136 patients in the LR group with 136 patients in the RFA group. Overall survival at 1, 3, and 5 years was 91%, 80%, and 76% in the LR group and 97%, 67%, and 41% in the RFA group respectively (P = 0.001). Disease-free survival at 1, 3, and 5 years was 84%, 60% and 44% for the LR group, and 63%, 36%, and 25% for the RFA group (P = 0.001).Postoperative Clavien-Dindo III-IV complications were lower in the RFA group (1% vs 11%, P = 0.001) in association with a shorter length of stay (2 d vs 7 d, P = 0.001).In multivariate analysis, Model for End-stage Liver Disease (MELD) score (> 10) [odds ratio (OR) = 1.89], increased value of international normalized ratio (> 1.3) (OR = 1.60), treatment with radiofrequency (OR = 1.46) ,and multiple nodules (OR = 1.19) were independent predictors of a poor overall survival while a high MELD score (> 10) (OR = 1.51) and radiofrequency (OR = 1.37) were independent factors associated with a higher recurrence rate.CONCLUSIONDespite a longer length of stay and a higher rate of severe postoperative complications, surgery provided better results in long-term oncological outcomes as compared to ablation in elderly patients (> 70 years) with HCC in Milan criteria.     

Laparoscopic repair of iatrogenic diaphragmatic hernia following radiofrequency ablation for hepatocellular carcinoma

Radiofrequency ablation (RFA) is commonly used for treating unresectable hepatic malignancies. Some commonly associated complications of RFA include fever, symptomatic pleural effusion, abscess, hepatoma and hepatic insufficiency. Here, we report a case of diaphragmatic hernia in a patient following RFA for hepatic malignancy with cirrhosis.