Focus
Authors: Daniel Shouval
Journal: Journal of Hepatology (2012)

A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinomaJournal of HepatologyVol. 57Issue 4PreviewThe aim of this study was to compare the efficacy of radiofrequency ablation (RFA) with surgical resection (RES) in the treatment of small hepatocellular carcinoma (HCC). Full-Text PDF The incidence of hepatocellular carcinoma (HCC) has been rising worldwide in the past decade. During this period, major progress has been achieved in understanding the pathophysiology, natural history, diagnosis, staging and treatment of HCC as reflected in the two recently updated guidelines of the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver [1Bruix J. Sherman M. Management of hepatocellular carcinoma: an update.Hepatology. 2011; 53: 1020-1045Crossref PubMed Scopus (6722) Google Scholar, 2European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43.Google Scholar]. Both documents consider surgical resection for small solitary tumors as a first-line treatment option in patients with cirrhosis and well preserved liver function, and an hepatic vein pressure <10 mmHg (or platelet count >100,000/mm3). This recommendation requires specific standards of care including updated surgical techniques, an expected 5-year survival rate of ∼60%, and a perioperative mortality of 2–3% [[2]European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43.Google Scholar]. In addition, liver transplantation is considered to be a first-line treatment for patients meeting the Milan criteria who are not suitable for resection. Local ablation with radiofrequency (RFA) and until recently, percutaneous alcohol injection (PEI), have been considered a standard of care for patients with BCLC 0-A tumors not suitable for surgery [[2]European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43.Google Scholar]. Three independent meta-analyses including 5 randomized controlled trials (RCT) have provided evidence for enhanced local control and increased survival benefits in patients treated by RFA as compared to PEI [[2]European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908–43.Google Scholar]. This advantage was established despite a marginally higher rate of major complications associated with RFA at 4% as compared to 2.7% for PEI. The best results were reported for RFA-treated patients with tumors <2 cm in diameter who had 5-year survival rates ranging from 40% to 70%. However, RFA has also been shown to provide a survival benefit in patients with tumors >2 cm but <5 cm, as compared to PEI. Consequently RFA has progressively replaced PEI for patients with small HCC who are not candidates for surgery. Yet, no consensus has been reached so far whether percutaneous RFA can replace surgical resection as first-line treatment for small tumors. Two RCTs provided conflicting evidence regarding the benefits of RFA versus surgical resection. On the one hand, the results from one RCT suggest a benefit for surgery over RFA in patients who met the Milan criteria followed for up to 5 years [[3]Huang J. Yan L. Cheng Z. Wu H. Du L. Wang J. et al.A randomized trial comparing radiofrequency ablation and surgical resection for HCC conforming to the Milan criteria.Ann Surg. 2010; 252: 903-912Crossref PubMed Scopus (630) Google Scholar]. On the other hand, the other RCT did not identify a significant difference in survival between RFA and surgery in patients with solitary HCC and a diameter up to 5 cm followed for 4 years [[4]Chen M.S. Li J.Q. Zheng Y. Guo R.P. Liang H.H. Zhang Y.Q. et al.A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma.Ann Surg. 2006; 243: 321-328Crossref PubMed Scopus (1180) Google Scholar]. In the present issue of the Journal, Dr. Kai Feng and co-workers report the result of a third RCT, comparing survival and recurrence-free survival between percutaneous RFA and open surgical resection. The study cohort consisted of 168 Chinese patients with small HCC up to a diameter of 4 cm and not more than two nodules, selected from 2537 admitted patients [[5]Feng K. Yan J. Li X. Xia F. Ma K. Wang S. et al.A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.J Hepatol. 2012; 57: 794-802Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar]. Patients were randomized to one of the groups in a non-blinded manner, with stratification according to tumor diameter below or above 2 cm but <4 cm. The baseline characteristics of the randomized patients are shown in Table 1 of whom the majority (121 patients) had hepatitis B virus infection [[5]Feng K. Yan J. Li X. Xia F. Ma K. Wang S. et al.A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma.J Hepatol. 2012; 57: 794-802Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar]. The primary observation of this study revealed a comparable survival rate between the RFA and the surgical resection group, with an excellent safety record for both groups, and no mortality. The 1-, 2- and 3-year survival rates were 93.1%, 83.1%, 67.2% as compared to 96.0%, 87.6%, 74.8% for the RFA and surgical groups respectively. The recurrence-free survival rates were similar but somewhat lower although statistically not significant for the RFA treated group as compared to the surgical group. During the 3-year follow-up, 42% and 32% of the RFA and surgical groups respectively, had tumor recurrence. Multivariate analysis revealed that two risk factors, namely decreased hepatic function, as measured by indocyanine green, and presence of two nodules in different hepatic segments were associated with a poorer prognosis. Furthermore, tumor recurrence as a result of incomplete ablation appears to be more frequent in RFA recipients as compared to surgery when an HCC nodule is subcapsular or is adjacent to the gall bladder or the diaphragm. Comments: The main results of this study suggest that survival rates and recurrence-free survival rates obtained by single RFA treatment are comparable to open surgical resection in a subgroup of HCC patients with tumor diameter <4 cm selected from a large cohort of over 2500 patients. The study results do not provide unequivocal evidence for superiority of one modality over the other. Therefore, the debate regarding the advantage of surgery over RFA or vice versa for small HCC remains unresolved. A recent retrospective national survey conducted in Japan - which reviewed the mortality rates among 54,145 HCC patients who underwent hepatectomy, RFA or transarterial embolization (TAE) - confirmed the continuous improvement in the safety of these procedures [[6]Sato M, Tateishi R, Yasunaga H, Horiguchi H, Yoshida H, Matsuda S, et al. Mortality and morbidity of hepatectomy, radiofrequency ablation, and embolization for hepatocellular carcinoma: a national survey of 54,145 patients. J Gastroenterol 2012. http://dx.doi.org/10.1007/s00535-012-0569-0.Google Scholar]. The overall mortality rates in these patients, irrespective of tumor characteristics, were 0.3% for RFA treated patients, 1.0% in TAE treated patients and 2.6% in those who underwent hepatectomy. Thus, regardless of the pros and cons of RFA versus surgical resection, the study results of Kai Feng et al. reaffirm the efficacy of RFA in patients with small HCC (<4 cm) who prefer local ablation over surgery. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.