Is surgical resection still the treatment of choice for early hepatocellular carcinoma?

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, and in North America is one of only a few malignancies with an increasing incidence in recent years. Screening is recommended for all patients with cirrhosis, and for certain chronic carriers of hepatitis B, in hopes that HCC can be diagnosed at an early stage where curative therapy can be offered [1]. The Barcelona Clinic Liver Cancer (BCLC) staging system has been recommended by the American Association for the Study of the Liver (AASLD) because it accounts for liver function, extent of tumor and patient performance status, and it links these factors to specific therapies [1]. In the BCLC algorithm, surgical resection has been recommended for patients with very early stage HCC (BCLC stage 0) who have small tumors (<2 cm), well preserved liver function [Child-Turcotte-Pugh (CTP) class A] and good performance status (PS1⁄4 0). Patients with early stage cancer (BCLC stage A) who have a single tumor or three tumors each <3 cm, should be offered surgical resection if they have a normal bilirubin and no evidence of portal hypertension. Liver transplantation is recommended for patients with a single tumor 5 cm or three tumors each <3 cm in who impaired liver function precludes the ability to perform surgical resection [1]. The best outcomes and lowest recurrence rates have been reported following liver transplantation, but the limited supply of donor livers precludes its broad applicability. Resection of HCC is associated with 5-year survivals of 40–70% [1], and the excellent long-term outcomes with resection therefore represent a ‘‘gold standard. ’’ But resection is not without risks, with major complications occurring in about 20% and mortality rates up to 4% commonly reported. Therefore, given the ‘‘costs’’ of resection (in terms of safety, hospitalization, and prolonged convalescence), it may be time to reconsider the role of a less invasive approach such as thermal ablation, particularly in patients with very limited disease. Radiofrequency ablation (RFA) is perhaps the most widely employed thermal ablative technique. Until recently, RFA was primarily indicated in patients with HCC in whom resection (or transplantation) was not feasible. RFAwas therefore typically applied in patients in poor general medical condition or with poor hepatic functional reserve. However, given the less invasive nature of RFA, the lower morbidity and the lower costs associated with the procedure, some have questioned whether resection remains the treatment of choice for early HCC [2]. The experience of Livraghi et al. [2] with RFA on 218 patients with HCC 2 cm provides data to support that position. In that series, a 97.2% complete ablation rate was reported after a median follow-up of 31 months. Only six patients required salvage therapy with percutaneous ethanol injection (PEI), transarterial chemoembolization (TACE), or surgical resection. Importantly, in a subgroup of 100 patients, who would have otherwise been candidates for surgical resection, a 5-year survival of 68.5% was demonstrated [2]. In this issue, Tashiro et al. [3] present additional data that incite reconsideration of the role of RFA in the treatment of early HCC. They report on a retrospective analysis of a single center experience with surgical resection versus RFA for patients with early stage HCC ( 3 tumors, all of which were 3 cm). A group of 199 patients who underwent surgical resection was compared with 87 patients who had RFA, of which 69 subjects had a combination of TACE followed by RFA.With a mean follow-up of nearly 3 years, Tashiro et al. did not see a difference in overall survival or disease-free survival between the two groups. This recapitulated the observations made in the Livraghi study, where a subgroup of patients with CTP class A cirrhosis and a small ( 2 cm) single HCC had long-term survivals following RFA similar to what has been reported following surgical resection [2]. What makes the series reported by Tashiro et al. unique is that the majority of patients (79%) in the RFA group received TACE with cisplatinum and Lipiodol an average of 3 days before the RFA. Therefore, unlike the Livraghi experience, the present study was a comparison of combination therapy (TACEþRFA) to surgical resection. There is emerging evidence that the combination of TACE and ablative techniques is superior to ablation alone. A recent metaanalysis of randomized controlled trials (RCTs) confirmed that combination therapy was superior for larger HCC treated with PEI; however, sensitivity analysis demonstrated no benefit of the combination of TACEþRFA over RFA alone for small HCCs [4]. In the present study, as is the case in most retrospective studies, the surgery and RFA groups were not equally matched in factors that are known to be associated with survival [3]. The hepatic resection group included tumors which were significantly larger and more likely to be multiple, both of which are recognized as risk factors for recurrence as they correlate with the risk of microvascular invasion. The resection group also had a trend toward higher levels of alfa-fetoprotein (AFP) and had significantly higher levels of des-U-carboxy-prothrombin (DCP) compared to the RFA group. These tumor markers have predicted risk of recurrence following surgery in other series. Conversely, the RFA group was more likely to have worse liver function with significantly higher ICG retention rates and more patients with CTP class B cirrhosis (17% vs. 9%, P1⁄4 0.06). The importance of liver function on prognosis, is highlighted in the series