Liver resection versus radiofrequency ablation in the treatment of cirrhotic patients with hepatocellular carcinoma

Terni, Italy

Liver resection versus radiofrequency ablation in the treatment of cirrhotic patients with hepatocellular carcinoma

Amilcare Parisi, Jacopo Desiderio, Stefano Trastulli, Elisa Castellani, Rosario Pasquale, Roberto Cirocchi, Carlo Boselli and Giuseppe Noya

Terni, Italy

BACKGROUND:Hepatocellular carcinoma is the most common type of primary liver tumor and its incidence is increasing worldwide. The study aimed to compare patients subjected to liver resection or radiofrequency ablation.

METHODS:One hundred and forty cirrhotic patients in stage A or B of Child-Pugh with single nodular or multinodular hepatocellular carcinoma were included in this retrospective study. Among them, 87 underwent surgical resection, and 53 underwent percutaneous radiofrequency ablation. Patient characteristics, survival, and recurrence-free survival were analyzed.

RESULTS:Recurrence-free survival was longer in the resection group in comparison to the radiofrequency group with a median recurrence-free time of 36 versus 26 months, respectively (P=0.01, HR=1.52, 95% CI: 1.05-2.25). In the resection group, median survival was 46 months, with the 1-, 3- and 5-year survival rates of 89.7%, 72.4% and 40.2%. In the radiofrequency group, median survival was 32 months, with the 1-, 3- and 5-year survival rates of 83.0%, 43.4% and 22.6% (P<0.01).

CONCLUSIONS:Surgical resection improves the overall survival and recurrence-free survival in comparison with radiofrequency ablation. New evidences are needed to def i ne the real role of the percutaneous technique as an alternative to surgery.

(Hepatobiliary Pancreat Dis Int 2013;12:270-277)

hepatocellular carcinoma; liver resection; radiofrequency ablation

Introduction

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor (90%) and its incidence is increasing worldwide.[1,2]Cirrhosis is the most important recognized risk factor for development of HCC and an association between HCC and cirrhosis is indeed found from 80% to 95% of cases.[3]Among the etiologic agents, hepatitis B and C viruses are the leading causes of liver cancer with a risk of 50% and 55%, respectively. The risk is also increased by 40% in heavy alcohol users.[4]In presence of this combination, cancer treatment requires an assessment not only of tumoral stage, but also of the underlying chronic liver disease.[5]

Surgery, when possible, is the best therapeutic approach.[6]It includes resection or liver transplantation, but these options can be carried out only in about 30% of all patients.[7]In presence of cirrhosis, liver transplantation is regarded as the treatment of choice, since it simultaneously removes both the tumor and the associated liver disease, but the lack of donors and specif i c selection criteria (Milan criteria) restricts transplanting opportunities.[8,9]Liver resection should take into account tumor characteristics at diagnosis, but also liver functional reserve.[10]

Currently, some percutaneous treatments such as radiofrequency ablation (RFA) have been shown to be feasible and effective in increasing survival in patients whose clinical conditions and tumor location do not allow access to surgical management.[11,12]Rare studies[13-25]have evaluated the results of treatment withRFA, by comparing it to liver resection. Our objective was to compare results and prognosis in patients subjected to liver resection or RFA through a retrospective analysis on the database of specialized centers.

Methods

A total of 140 patients with HCC on cirrhosis have been treated either with liver resection or RFA and subsequently underwent follow-up at St. Maria Hospital in Terni and St. Maria della Misericordia Hospital in Perugia. All the procedures in the resection group were performed by general surgeons with ten years of experience in hepatic surgery before the study was started. Percutaneous radiofrequency treatment was performed by interventional gastroenterologists with 4 years of experience before the study.

In this retrospective investigation, adult patients with liver cirrhosis from different etiologies (alcohol, HBV, HCV) in stage A or B of Child-Pugh and with single nodular or multinodular (up to 3 HCCs) macroscopic conf i guration[26]measuring ≤6 cm were included. There were no previous liver resections in both groups, and patients who had undergone liver transplantation after initial treatment were excluded. Portal vein thrombosis, arterioportal fi stula, metastatic disease and decompensated liver cirrhosis were considered as contraindications for the execution of such treatments.[27]

The diagnosis of cirrhosis was made according to clinical, laboratory and instrumental criteria. Sonographic criteria, in particular, included irregular hepatic margins, left lobe and/or caudate lobe hypertrophy, and abnormal liver parenchymal texture (coarse echopattern). These criteria were combined with portal hypertension parameters such as increased portal vein caliber with reverse fl ow, splenomegaly, ascites, presence of vascular collateral circles and umbilical vein patency, allowing to achieve high sensitivity values.[28]

Afterwards, we assessed cirrhosis severity, following the Child-Pugh score, and thus considering 5 different parameters: total bilirubin, albumin, prothrombin time, presence of ascites and encephalopathy. Cirrhosis has been classif i ed into stage A with a Child-Pugh score between 5 and 6, stage B with a score of 7 through 9 and stage C with a score of 10 to 15.[29,30]

Patients with a Child-Pugh C chronic liver disease were not included in the series. For them, therapeutic procedures reported are impracticable, and thereby these patients have been directed to supportive treatment.

Diagnosis of HCC was based on non-invasive fi ndings or histopathology, according to the European Association for Study of the Liver (EASL) consensus conference criteria.[31]Nodules more than 2 cm in diameter were characterized as HCC, whenever presenting the typical hallmark, hypervascularization in the arterial phase with washout in the portal venous or delayed phases, in two different imaging techniques including 4-phase multidetector CT scan and/or dynamic Gadolinium based contrast-enhanced MRI (DCE-MRI) and/or contrast enhanced sonography (CES) with second generation agents, or in case of positivity of just one technique with AFP >400 ng/mL.

For nodules of less than 2 cm in diameter, when diagnosis of HCC could not be based on non-invasive criteria or AFP levels, we proceeded to biopsy-proven pathological conf i rmation.

Surgical procedure (Fig. 1) was taken into account depending on lesions location and remnant liver volume (RLV) evaluation.[7]This selection was performed using a thorough analysis of imaging when we considered total liver volume (TLV), hepatic volume to be resected (HVR), and tumor size (TS), respectively. We proceeded, case by case, to calculate the estimated rate of functional parenchyma to be resected: (HVR-TS)/TLV, and overall estimated rate of remnant functional liver parenchyma: RLV/(TLV-TS).[32,33]

Patients in whom hepatectomy would have resulted in the loss of more than 50% of functional liver parenchyma volume were excluded from surgical treatment.

Fig. 1.Liver resection in cirrhotic patients at our institution.

Types of performed resections included: 12 wedgeresections, 46 segmentectomies, 18 bisegmentectomies, and 11 major resections (≥3 segments). At histological examination, all of them were found to have tumor-free resection margins.

The RFA group showed no general contraindications to surgery, but resection would have entailed for patients an excessive parenchymal sacrif i ce with consequent risk of postoperative liver failure. All RFAs were performed percutaneously via ultrasound guided approach (Fig. 2).[34]An expandable, electrode-needle type probe, connected to a radiofrequency generator (RITA Medical System, Mountain View, CA, USA) was used.

The Starburst XL, 5-cm ablation catheter was used to treat tumors less than 5 cm and the Starburst Xli, 7-cm ablation catheter to treat tumors larger than 5 cm.

Post-treatment monitoring was performed by CES on the second postoperative day to highlight the possible presence of residual tumor activity. Final control on treatment radicality was performed 30 days apart, through spiral CT with contrast medium. Treatment eff i cacy was evaluated according to the WHO criteria, in which complete tumor response is def i ned as the absence of arterial enhancement within or at the periphery of treated lesions.[35]

To verify eventual recurrent disease, patients have been subjected to control by bimonthly clinic visit, AFP level measurement, and CT scan every 6 months. Patients with intrahepatic recurrence were then evaluated for new treatments with ablative therapies (single RFA,n=18; multiple RFA,n=22), transarterial chemoembolization (TACE,n=27), combined treatments (RFA+TACE,n=21) or surgery (resection,n=15).

Overall survival was calculated from the day of surgery or RFA to the day of death or to the most recent follow-up visit. Recurrence-free survival (RFS) was calculated from the day of surgery or RFA to the followup visit with evidence of tumor recurrence.

Statistical analysis

The data of the patients were analyzed with a statistical computer software (MedCalc Software Version 12.2.1). Patient characteristics such as gender, age, etiology of cirrhosis, Child-Pugh class, and number and size of lesions were compared in the two treatment arms using the Chi-square test for categorical variables and Student'sttest for continuous variables. Overall survival and RFS analyses were performed using the Kaplan-Meier method. Comparisons between different groups were made using the log-rank test. Moreover, hazard ratio (HR) was determined with a conf i dence interval (CI) of 95%. APvalue <0.05 was considered statistically signif i cant.

Fig. 2.Radiofrequency percutaneous ablation in a cirrhotic patient through ultrasound guide.

Table 1.Characteristics of patients enrolled in the study

Results

Subjects

During the study period, 87 patients were treated with liver resection, 53 underwent RFA. There were no signif i cant differences in patient characteristics in the two groups (Table 1). Different variables are considered in the treatment of HCC patients with cirrhosis. Table 2 shows the analysis of patients with a single HCC ≤3 cm in Child-Pugh B, multiple HCCs >3 cm in Child-Pugh A, and multiple HCCs >3 cm in Child-Pugh B.

Tumor location

Tumor location was characterized according toCouinaud's subdivision of the liver into segments (Table 3). Tumor location appeared to play a role in treating multiple tumors involving several liver segments at the same time. Surgical treatment proved to be more radical and advantageous for a long-term survival. The surgically treated patients with multiple lesions involving the segments of the left hepatic lobe had anaverage survival of 44 vs 25 months in the RFA group (P=0.0004, HR=3.42, 95% CI: 1.31-8.90), while those with the lesions located in the right lobe treated by resection had an average survival of 42 vs 20 months (P=0.04, HR=2.29, 95% CI: 0.84-6.20).

Table 2.Analysis of survival

Table 3.Single and multiple HCC location according to Couinaud's subdivision

Treatment mortality and morbidity

In the resection group, no perioperative mortality was observed. After resection, the following complications occurred: ascites (8 patients), hepatic failure (3), hemoperitoneum (4), and biliary fi stula (2).

No mortality was observed after RFA. Issues related to radiofrequency treatment were negligible, and this allowed for rapid discharge of patients (1-2 days of mean hospital stay). In fact, only minor complications occurred in this group, such as pain (14.6%) and fever (17.1%).

Follow-up and recurrence-free survival

The mean follow-up of the resection group was 43.1 months (range 6-60) and the median RFS in this group was 36 months (95% CI: 32-48), with the 1-, 3- and 5-year RFS rates of 86.2%, 56.3% and 17.2%, respectively.

In the RFA group, the mean follow-up time was 31.5 months (range 4-60) and the median RFS was 26 months (95% CI: 14-32) with the 1-, 3- and 5-year RFS rates of 67.9%, 26.4% and 15.1%, respectively. In the comparison, signif i cant values show RFS longer in the resection group than in the RFA group (P=0.01, HR=1.52, 95% CI: 1.05-2.25) (Fig. 3A).

Survival

The median survival time in the resection group was 46 months (95% CI: 40-60 months), with the 1-, 3- and 5-year survival rates (SRs) of 89.7%, 72.4% and 40.2% respectively.

Median survival time in the RFA group was 32 months (95% CI: 23-38) with the 1-, 3- and 5-year SRs of 83.0%, 43.4% and 22.6%, respectively. The overall survival was signif i cantly longer in the resection group (P=0.001) (Fig. 3B).

In Child-Pugh A patients, the median survival time was 52 months in the resection group and 32 months in the RFA group (Fig. 3C). In Child-Pugh B patients, resection was advantageous (HR=1.65) although it was not signif i cant in the present analysis (P=0.14) (Fig. 3D). Excellent results were obtained in multiple surgically treated lesions as compared with RFA treated ones (HR=2.92,P=0.0001) (Fig. 3E). But in the treatment of a single HCC (Fig. 3F), no signif i cant differences were observed between the two groups (HR 1.48,P=0.16), especially when it was associated with Child-PughA disease (HR=1.12,P=0.75). Survival analysis of patients with HCC <3 cm showed a MST of 52 months in the resection group vs 34 months in the RFA group (HR=2.10,P=0.01) (Fig. 3G). Subgroup survival analysis of patients with single or multiple HCCs <3 cm in Child-Pugh A or B chronic liver disease conf i rmed longer MST for the resection group, but the difference was not statistically signif i cant unless for Child-Pugh A patients with multiple HCCs ≤3 cm, who displayed a clear advantage for resection. This subgroup consisted of a small sample size with a broad CI (HR=3.25, 95% CI: 1.00-10.53,P=0.002). In patients with HCC >3 cm, their survival was longer in the resection group, with a median survival of 40 months compared with 30 months of the RFA group(HR=1.73,P=0.03) (Fig. 3H). In patients with a single HCC>3 cm and Child-Pugh A, the results of surgical resection were similar to those of radiofrequency, but there was no signif i cant difference (HR=1.07, 95% CI: 0.48-2.38,P=0.8). Subgroup analysis for patients with a single HCC >3 cm of Child-Pugh B showed an advantage for the resection group (HR=2.88, 95% CI: 1.04-7.97,P=0.02).

Fig. 3.Kaplan-Meier curves of recurrence-free survival (A), overall survival (months) (B), survival (months) for HCC in Child-Pugh A (C), survival (months) for HCC in Child-Pugh B (D), survival (months) for multinodular HCC (E), survival (months) for single nodular HCC (F), survival (months) for HCC ≤3 cm (G), and survival (months) for HCC >3 cm (H).

Discussion

Management of HCC associated with cirrhosis involves several specialities.[36]It is essential to consider not only the tumor characteristics, but also the accurate estimate of liver function with the aid of imaging to correctly select candidates for resection. The risk of incorrect staging of associated cirrhosis may result in postoperative liver failure, followed by chronic decompensated cirrhosis.[37]

Liver resection in cirrhotic patients has long been debated and limited by the high mortality and morbidity associated with chronic liver disease.[38]Liver transplantation is regarded as the treatment of choice, with best results in terms of long-term survival, but this option is only feasible in a small number of patients because of the shortage of donors.[39]However, current progresses in liver resection techniques and in postoperative assistance have improved the resection results in terms of operative risk and long-term survival.[37,40]

Indications for resection depend on the size, number and location of lesions as well as the estimation of RLV. The best candidates are patients with a single peripheral lesion, which permits the preservation of more than 50% of RLV.[7]

Tumor location is a basic assessment parameter, indeed. With regard to peripheral lesions, no matter how bulky, resection may be performed with a curative intent and anatomically, without compromising a large parenchymal volume. In contrast, a small central lesion (<3 cm) may require the sacrif i ce of a signif i cantly greater parenchymal volume, with risk of postoperative liver failure, so as to render RFA preferable.

Several percutaneous procedures have been suggested to treat HCC; however in recent years RFA has achieved a large consent because of its eff i cacy in determining tumor necrosis, tolerability, low risk of periprocedural complications and mortality, and short hospital stay.[41]

Studies[13,15,21,23]compared RFA and other local ablative therapies with surgical resection. Retrospective studies have highlighted that surgical resection provides the best results of overall survival and RFS. But there are different views about it. Nishikawa et al[25]found that in patients with HCC <3 cm, there was no signif i cant difference between two treatment groups in terms ofoverall survival and RFS. They concluded that RFA is effective as resection in the treatment of single and small HCC, and is less invasive than surgery. Therefore, RFA could be the fi rst treatment of choice for single and small HCC.

Huang et al[16]reported that in treating Child-Pugh A cirrhotic patients with solitary HCC larger than 3 cm but less than 5 cm, or with two or three lesions each less than 5 cm, surgical resection provides a better survival than RFA. In treating Child-Pugh A cirrhotic patients with solitary HCC <3 cm, RFA has been a comparable RFS to surgical resection. Moreover Chen's prospective randomized trial[42]on the role of percutaneous local ablative therapy suggests that RFA and surgery have similar results in terms of overall survival and RFS for single HCC <5 cm.

Several centers specializing in the treatment of HCC, including our institute, have introduced laparoscopic surgery as an approach to perform both RFA and liver resection.

Laparoscopic radiofrequency ablation (LRFA) has been widely used in clinical practice for a decade[43]and is indicated for superf i cial lesions located on the upper or lower surface of the liver, subdiaphragmatic lesions, or lesions in the proximity of the gallbladder and bile duct, near the gastrointestinal tract or the heart.[44]

LRFA offers a direct view of the procedure, which allows easy positioning of the RF needle and performance of intraoperative high-frequency ultrasound, which aids the identif i cation of the margins of tumor to be treated and other small lesions which may have been missed during the preoperative investigation.

This approach is useful for selected patients and for particularly risky lesions which are to be treated percutaneously. However, we hold that this is a complementary approach and not a replacement for percutaneous treatment, given the greater invasiveness of the procedure, the administration of general anesthesia, and the complications associated with laparoscopic surgery.

Regarding the use of mini-invasive surgery, a recent meta-analysis by Li[45]compared laparoscopic with open liver resection in the treatment of HCC, including 10 studies with a total of 627 patients. The results revealed less intraoperative blood loss, shorter hospital stays, and fewer postoperative complications with laparoscopy, while there were no signif i cant differences in radicality and recurrence.

The conclusions of this meta-analysis appear to be limited by the absence of randomized and prospective studies in the literature. For this reason, the analysis only reports on retrospective studies conducted on small patient samples: in total, only 244 patients underwent laparoscopic surgery. Furthermore, although the perioperative data conf i rm the advantages associated with a mini-invasive approach, the data relative to the long-term oncological outcomes are still insuff i cient. It should also be emphasized that the cases reported in the laparoscopic group are segmentectomies or subsegmentectomies located in segments II-III, IV, and VI. Therefore, from an analysis of the current literature, we hold that a mini-invasive approach to surgery for HCC is feasible, but only in selected patients, and it may be indicated for superf i cial or peripheral lesions located away from major blood vessels.

The present study describes our experience in liver resection vs RFA in the treatment of HCC, and the observed short- and long-term outcomes, arising from a strict follow-up. The study shows the superior results of surgery compared with RFA in regard to overall survival (Fig. 3B). In particular, the difference is sharply evident in the long term. One year after treatment, the surgery resection of resection group compared with RFA group was 89.7% vs 83.0%, but at 3 and 5 years, this discrepancy was found to be 72.4% vs 43.4% and 40.2% vs 22.7%, respectively.

Subgroup analysis revealed that surgery showed better results than RFA in Child-Pugh A patients, with an improved MST (52 vs 38 months), whereas in Child-Pugh B patients the difference in survival was not clear (34 vs 28 months,P=0.13).

For patients with HCC >3 cm, a decreased survival rate was noted in both groups, especially in the RFA group (40 vs 30 months). In this case, hepatectomy is preferable whenever possible because its decontamination of small peritumoral satellites and microvascular invasion.

Surgical treatment of HCC is related to the type of resection to be performed. In fact, anatomical resection allows for the removal of the portal area of the lesion and is the most appropriate treatment. However, this issue is controversial. Although some studies[46,47]have reported a signif i cant increase in overall survival and in RFS, others have not conf i rmed these benef i ts.[48]In cirrhotic patients with borderline liver function, it is diff i cult to meet the criteria of anatomical resection, and the preservation of the parenchyma may become the dominant factor. In these cases it is preferable to choose a non-anatomical resection (wedge) with a margin of at least 1 cm. In our study, the anatomical resection was performed in 86.2% of the reported cases, while wedge resection was carried out for individual small lesions in patients with a dysmorphic liver and portal hypertension, for whom it was necessary to preserve the liver parenchyma as far as possible. A study reported that in these cases radio-frequency may have comparableresults to surgical resection.[21]The data we analyzed do not clarify this issue; however wedge resection is superior to RFA (median survival time: 43 vs 36 months, RFS: 36 vs 26 months). Thus we agree with the Abu-Hilal study[13]on the treatment of small unifocal HCCs which shows that RFA should be considered as an acceptable alternative when surgery is not possible and not in patients who simply have a smaller tumor. In order to clarify the issue, new studies and randomized controlled trials are necessary to compare resection with RFA in the treatment of unifocal HCCs.

The limitations of this study are inherent from a retrospective study, for which the data were gathered in a clinical context in order to compare two different treatments. The study is based on a limited number of patients and presents differences in the absolute values for the two treatments. However, the groups prove to be quite homogeneous in terms of characteristics of the patients. Furthermore, if a comparison is made between this paper and other studies[13,15,20,23]with a follow-up of over 3 years at other centers, the number of patients enrolled is not different signif i cantly from that in our study.

In conclusion, this retrospective analysis shows a difference in long-term survival between the two treatments. The advantage of surgery was more evident for HCC<3 cm and solitary lesions. Therefore, resection depending on surgical treatment feasibility and on impairment degree of hepatic parenchyma should be considered the treatment of choice. However, for patients who do not fall into this category, RFA can be considered an effective method for controlling disease progression.

It is diff i cult to carry out studies on treatment of HCC associated with cirrhosis, since tumor characteristics should be considered along with chronic liver disease features. There are many disputes, contradictory data from different trials and debates on this topic. In the literature, studies comparing the results of resection with RFA are still few, and new evidences are needed to def i ne the real role of the percutaneous technique as an alternative to surgery.

Acknowledgement:We thank Dr. Mariano Quartini, Director of Department of Hepatology and Gastroenterology, St. Maria Hospital, Terni, Italy for his help in data analysis and approval of fi nal version of the work.

Contributors:PA and NG proposed the study. DJ analyzed the data and wrote the fi rst draft. All authors contributed to the design and interpretation of the study and to further drafts. DJ is the guarantor.

Funding:None.

Ethical approval:Not needed.

Competing interest:No benef i ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received July 15, 2012

Accepted after revision October 5, 2012

AuthorAff i liations:Department of Digestive Surgery and Liver Unit, St. Maria Hospital, Terni, Italy (Parisi A, Desiderio J, Trastulli S and Pasquale R); Department of General and Oncologic Surgery, University of Perugia, St. Maria della Misericordia Hospital, Perugia, Italy (Castellani E, Boselli C and Noya G); Department of General and Urgent Surgery, University of Perugia, Terni, Italy (Cirocchi R)

Jacopo Desiderio, MD, Department of Digestive Surgery and Liver Unit, St. Maria Hospital, Via Tristano di Joannuccio 1, Terni 05100, Italy (Email: djdesi85@hotmail.it)

© 2013, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(13)60044-2