Efficacy and safety of radiofrequency ablation versus laparoscopic hepatectomy for small hepatocellular carcinoma: A protocol for a randomized controlled trial

Background:Hepatocellular carcinoma (HCC) is one of the most common type of malignant tumors in adults, and is the most common cause of death in people with cirrhosis. Both laparoscopic hepatectomy (LH) and radiofrequency ablation (RFA) are radical treatments for small HCC. However, there is no international standard for the treatment of small HCC, and it is still controversial to choose LH or RFA in treating small HCC. We try to carry out a randomized, controlled, prospective study to compare the the short-term and long-term effects and safety of LH versus RFA in the treatment of small HCC.Methods:This study is a single-center, evaluator-blinded, randomized, controlled clinical trial (RCT). The patients will be randomly divided into RFA group and LH group in a 1:1 ratio according to a computer-generated randomization list. Postoperative complications rates, Alpha fetoprotein (AFP), hospital stay, 1, 2, 3-year overall survival (OS) rates, disease-free survival (DFS) rates and all possible adverse events will be recorded. Statistical analyses will be performed with SPSS v22.0 software.Conclusions:The study will compare the the short-term and long-term effects and safety of LH versus RFA in the treatment of small HCC.OSF Registration number:doi: 10.17605/OSF.IO/HNX2T     

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.     

Hepatocellular carcinoma: new options for image-guided ablation

Image-guided percutaneous ablation is currently accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when transplantation and resection are precluded. Several methods for chemical or thermal tumor destruction have been developed and tested clinically during the past two decades. The seminal technique used for local treatment of HCC has been percutaneous ethanol injection (PEI). Several studies have provided indirect evidence that PEI improves the natural history of nonsurgical patients with early-stage HCC. Its major limitation is the high rate of local recurrence. Radiofrequency (RF) ablation has been the most widely assessed alternative to PEI. Five randomized controlled trials have shown that RF ablation achieves more effective and reproducible tumor destruction than PEI, leading to a better local control of the disease. As a result, RF ablation has been established as the primary ablative modality. The value of newer thermal and non-thermal methods for local tumor treatment, such as microwave ablation, irreversible electroporation (IRE), and light activated drug therapy, should be investigated in the setting of randomized controlled trials.     

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.     

Outcome of transarterial chemoembolization monotherapy, and in combination with percutaneous ethanol injection, or radiofrequency ablation therapy for hepatocellular carcinoma

Aim:  Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
Methods:  The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
Results:  The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
Conclusions:  The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.     

Radiofrequency ablation,PEIT, and TACE for hepatocellular carcinoma

At detection or over time, hepatocellular carcinoma (HCC) is multicentric in origin, against a background of chronic hepatic disease at different stages. Orthotopic liver transplantation (OLT) is the only therapy able to definitely cure both diseases. When OLT is not feasible, all other options can be only palliative. Owing to the multicentricity, surgical resection may be one possible option at the initial detection in selected patients, whereas percutaneous interventional techniques (percutaneous ethanol injection [PEI], radiofrequency ablation [RFA], selected transcatheter arterial chemoembolization [TACE]) are the options more often used. The range of their indications is becoming wider. Although it is understood that partial resection assures the greatest local control, the survival rates after surgery are roughly comparable with those obtained with PEI. The explanation for this result reflects a balance among the advantages and disadvantages of the two therapies. PEI survival curves are better than curves of resected patients who present with adverse prognostic factors, and this means that a better selection of the patients for surgery is needed. An open question remains the choice among percutaneous techniques. In our department we currently use RFA in most patients but consider PEI and selected TACE complementary, and use them according to the features of the disease and the response.     

Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial.

BACKGROUND: Transcatheter arterial embolization (TAE) may reduce the risk of hepatocellular carcinoma (HCC) recurrence when performed before percutaneous tumor ablation (PTA), either percutaneous ethanol injection therapy (PEIT) or radiofrequency ablation (RFA). We conducted a randomized, controlled trial comparing the use of TAE combined with percutaneous ethanol injection therapy (TAE/PEIT) to the use of PEIT only to assess the effects on HCC recurrence and survival. We continued the study after the introduction of RFA and compared TAE combined with RFA (TAE/RFA) with RFA only. METHODS: Between March 1997 and April 2001, 42 HCC patients were enrolled who satisfied the following inclusion criteria: (1) uninodular HCC as determined by angiography under computed tomography, (2) arterial hypervascularity, and (3) no prior history of HCC treatment. Twenty-two patients were treated with TAE/PTA (PEIT, 12; RFA, 10) and 20 patients with PTA only (PEIT, 14; RFA, 6). RESULTS: There were four cases of local recurrence in the PTA-only group and none in the TAE/PTA group (P=0.043). The four patients with local recurrence were treated with PEIT. None of the patients treated with RFA showed local recurrence. The effect of TAE on overall recurrence was not significant (P=0.4179). In the multivariate analysis, prior TAE was not significant for survival (P=0.514). CONCLUSIONS: TAE has a limited use in suppressing local recurrence when performed before PEIT but not before RFA.     

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.     

Local injection therapy for hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world and ranks the third most common cause of cancer-related death. Surgical resection, liver transplantation and percutaneous ablation are generally considered the only curative treatment for early stage HCC. Besides the limitations of insufficient organ donors and a long waiting time for liver transplantation, however, resection is applied only to patients with good hepatic reserve and localized tumors, with a resectability of 30%. DATA SOURCES: Local ablation therapy, which is minimally invasive but contributes to the significant improvement of survival in patients with unresectable tumor, hasbeen widely used in treating small HCC. Among the techniques of local therapy, percutaneous ethanol injection (PEI) with a complete response in 80% of HCCs less than 3 cm has been accepted as an alternative to surgery in patients with small HCC. Moreover, percutaneous hepatic quantified ethanol injection (PHQEI) or PEI according to the standard criteria has been confirmed to benefit patients with HCC, especially when quantified ethanol is given at a short interval (QESI, the interval was 2-3 days). RESULT: Several limitations related to local percutaneous methods may result in incomplete therapeutic effect in case of larger HCC nodules (>3 cm). CONCLUSION: The combined use of different methods according to the clinical status of patients or tumors may be essential to the effective treatment of HCC.     

Radiofrequency ablation versus surgical resection for single nodule hepatocellular carcinoma: Long-term outcomes

Background. Radiofrequency ablation (RFA) has been increasingly utilized for treatment of hepatocellular carcinoma (HCC). Long-term results of RFA, especially in comparison to surgical resection, have not been well described.Methods. Eighty-seven patients with single nodule HCC underwent surgical resection (N=47) or RFA (N=40) during a 9-year period. RFA was performed for 36 unresectable disease and 4 surgical refusals. Each group was further divided based on tumor size for analysis; Group 1: resection, ≤5 cm (N=18), Group 2: RFA, ≤5 cm (N=26), Group 3: resection, >5 cm (N=29) and Group 4: RFA, >5 cm (N=14). Follow-up ranged from 2 to 72 months (median 16 months). Patients'' characteristics, local recurrences and overall and disease-free survivals were compared.Results. Patients who underwent RFA were older (69 versus 60, p=0.0006), had more advanced Child-Pugh class and TNM stage (p=0.0002 and p=0.016, respectively), and had smaller tumors (4.6 versus 7.4 cm, p=0.0032). Local recurrence rates were 2% for resection and 10% for RFA (p=0.12). These local and other recurrences were subsequently treated with multimodal therapies as indicated. The median overall and disease-free survivals were equivalent both between Groups 1 and 2 (49 versus 51 months, p=0.44, 36 versus 22 months, p=0.84), and Groups 3 and 4 (47 versus 463 months, p=0.94, 28 versus 20 months, p=0.67).Discussion. Although the groups were not truly comparable, this retrospective study suggests that RFA may offer similar long-term results to surgical resection for single nodule HCC when combined with multimodal treatments.     

Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm

BACKGROUND & AIMS: The aim of this study was to compare the clinical outcome of percutaneous radiofrequency (RF) ablation, conventional percutaneous ethanol injection (PEI), and higher-dose PEI in treating hepatocellular carcinoma (HCC) 4 cm or less. METHODS: A total of 157 patients with 186 HCCs 4 cm or less were randomly assigned to 3 groups (52 patients in the conventional PEI group, 53 in the higher-dose PEI group, and 52 in the RF group). Clinical outcomes in terms of complete tumor necrosis, overall survival, local tumor progression, additional new tumors, and cancer-free survival were compared across 3 groups. RESULTS: The rate of complete tumor necrosis was 88% in the conventional PEI group, 92% in the higher-dose PEI group, and 96% in the RF group. Significantly fewer sessions were required to achieve complete tumor necrosis in the RF group than in the other 2 groups (P < .01). The local tumor progression rate was lowest in the RF group (vs the conventional PEI group, P = .012; vs the higher-dose PEI group, P = .037). The overall survival rate was highest in the RF group (vs the conventional PEI group, P = .014; vs the higher-dose PEI group, P = .023). The cancer-free survival rate was highest in the RF group (vs the conventional PEI group, P = .019; vs the higher-dose PEI group, P = .024). Multivariate analysis determined that tumor size, tumor differentiation, and the method of treatment (RF vs both methods of PEI) were significant factors in relation to local tumor progression, overall survival, and cancer-free survival. CONCLUSIONS: The results show that RF ablation yielded better clinical outcomes than conventional and higher-dose PEI in treating HCC 4 cm or less.     

Evidence-based medicine in the treatment of hepatocellular carcinoma

The incidence of hepatocellular carcinoma is increasing worldwide. Diagnosis at early stage is crucial to allow the application of curative treatments, that are the sole hope to increase their life expectancy. Surgical resection and liver transplantation are considered the first line options for early tumors, although there is no agreement on which is the best treatment approach. Resection achieves excellent results in patients with single tumors, absence of portal hypertension and normal bilirubin, but is limited by the high recurrence rate. Liver transplantation also achieves excellent results in patients with single tumors smaller than 5 cm or even three nodules smaller than 3 cm. However, this procedure is hampered by the shortage of donors and the increasing waiting times that have reduced their intention-to-treat outcomes. Treatment while waiting for a donor is controversial, but radical antitumoral therapies seem cost-effective in long waiting times. Percutaneous therapies are reserved for patients with single non-surgical tumors. More than 60 randomized clinical trials have been published to assess treatments for patients with advanced tumors, but there is no definitive evidence of survival benefits. A recent randomized trial reported that chemoembolization may benefit HCC patients in terms of survival, but additional studies to confirm this data are recommended.     

Management of inoperable hepatocellular carcinoma

Abstract   Hepatocellular carcinoma (HCC) is a common and difficult-to-treat malignant tumor. Surgical interventions are feasible in only a small proportion of patients, and non-surgical therapy has been frequently administered to patients with inoperable HCC. Various modalities of loco-regional therapy have gained much interest during the past decade. Among them, transarterial chemoembolization (TACE), percutaneous injection of ethanol (PEI) or acetic acid (PAI), radiofrequency ablation (RFA) and microwave coagulation therapy (MCT) are effective treatment options. TACE can target multiple hypervascular tumors but has the potential risk of inducing hepatic or renal failure. PEI is a well-established method for small (< 3 cm) HCC, and PAI has the advantage over PEI as being more effective with fewer treatment sessions. RFA has excellent tumor ablation ability, and has been extended to treat medium- or large-sized HCC. However, the overall complication rate may be higher than previously assumed. MCT is similar to RFA in its clinical application and adverse effects. Although combination therapy often achieves a higher response rate, the side-effects may also be additive. Other therapies, such as injection of hot saline or yttrium-90 microspheres, interstitial laser photocoagulation and cryoablation are seldom used nowadays. Thalidomide may be useful in a minority of HCC patients, whereas radiotherapy, chemotherapy and tamoxifen are generally ineffective. In conclusion, although long-term survival in patients with inoperable HCC is possible in selected patients, the overall prognosis remains unsatisfactory, especially in those with aggressive tumor behavior. Newer antitumor therapy with better treatment efficacy is urgently needed. Information of the design for a more comprehensive approach using the existing therapeutic options may help refine the treatment strategy.