Abstract
Background/Aim: The impact of radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) on survival in patients with small hepatocellular carcinoma (HCC) is unclear. We compared their efficacy in cirrhotics with single HCC ≤2 cm. Patients and Methods: Two hundred forty-four cirrhotics with single HCC ≤2 cm treated with PEI (108 cases) or RFA (136 cases) were enrolled in the study. Eighty-one patients in each group were selected for propensity score matching analysis. Results: The five-year survival was not significantly different (64.7% in PEI and 72.9% in RFA group) but the 5-year recurrence (73.3% in PEI and 49% in RFA group, p=0.023) and local tumor progression (49% in PEI and 30.1% in RFA group, p=0.018) were higher in the PEI group. Conclusion: PEI and RFA are equally effective in treating HCCs smaller than 2 cm in terms of 5-year survival, despite higher cumulative and local recurrence rates, in patients treated with PEI.
- Hepatocellular carcinoma
- liver cirrhosis
- percutaneous ethanol injection
- radiofrequency ablation
- overall survival
- tumor recurrence
Surveillance programs based on liver ultrasound (US) at 6-month intervals and serum alpha-fetoprotein (AFP) testing are required in cirrhotic patients for early cancer detection (1). According to the Barcelona Clinic Liver Cancer (BCLC) staging system for HCC (2), the best curative treatments of single nodules up to 2 cm and well-compensated cirrhosis (BCLC Stage 0, very early HCC) are resection and percutaneous ablation, which offer a median 5-year survival of 40-70% (3).
Percutaneous ethanol injection (PEI) was the first ablation treatment used in clinical practice and several studies demonstrated complete necrosis in 70-80% cases of small HCC (4, 5) with a 5-year survival rate higher than 60% in patients with single tumor up to 3 cm in size (5-7). At the end of the 1990s, radiofrequency ablation (RFA) was introduced in clinical practice and, compared to PEI, showed advantages in terms of tumor necrosis rate (93-100% vs. 66-100%), 3-year survival (63-81% vs. 48-67%) and local tumor progression rate (LTP) (8-14% vs. 22-34%) in the treatment of HCCs up to 4 cm (8-12). In the 2012 EASL guidelines for HCC management, RFA was recommended as the main ablative therapy for tumors less than 5 cm; however, for tumors up to 2 cm, the outcome benefits of PEI and RFA appeared to be similar, as both techniques achieved complete response in more than 90% of the cases (3). Indeed, few studies have compared the long-term effectiveness of the two aforementioned ablative techniques in this population with conflicting results. No significant difference in terms of survival was found in a single-Center prospective study comparing RFA and PEI in patients with a single HCC no more than 3 cm in size and in a sub-group of patients with HCC smaller than 2 cm (13). A better 5-year survival for patients treated with RFA compared to patients who underwent PEI has been recently shown in a retrospective series including 1,036 patients. This result was confirmed in a sub-group of 526 patients with single or multiple HCC ≤2 cm but the authors did not specify the number of patients with single tumor and did not apply the propensity score matching in the survival analysis (14). A recent meta-analysis regarding RFA, PEI and percutaneous acetic acid injection, found no significant differences between PEI and RFA in terms of survival and LTP in the sub-group of patients with HCC ≤2 cm (15). Thus, the aim of the present study was to compare the efficacy of RFA and PEI with regard to survival and HCC recurrence using the propensity score matching in a large retrospective series of cirrhotics with single HCC smaller than 2 cm.
Patients and Methods
Patients. The present retrospective analysis, performed in 7 Italian liver Centers, included patients who underwent PEI or RFA and fulfilled the following criteria: (i) single HCC nodule ≤2 cm in size; (ii) liver cirrhosis Class A or B according to Child-Pugh staging system; (iii) absence of HCC extrahepatic or vascular spread; (iv) complete necrosis 1 month after treatment. Most cases of HCC were diagnosed during a 6-month interval screening program for early diagnosis of HCC based on abdominal US and serum AFP measurement. All patients gave informed written consent and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki.
After US detection of a nodule suspicious for HCC, all patients underwent contrast enhanced abdomen computed tomography (CT) and/or magnetic resonance imaging (MRI). The HCC diagnosis was based on the guidelines in place at the time of enrollment (7, 16, 17). Based on these criteria, between January 1988 and December 2011, 108 patients treated with PEI and 136 treated with RFA were enrolled.
All patients were excluded from surgical resection for 1 or more of the following reasons: severe portal hypertension, lesion location or severe comorbidities that made surgery unfeasible and patient refusal. Ablation-related major complications included any clinical event requiring therapeutic intervention or an extended hospital stay (18). All the remaining complications were defined as minor.
The ablation's effectiveness was assessed 1 month after ablation using dynamic CT/MRI; the detection of a non-enhancing area at the tumor site larger than the pre-treatment tumor suggested complete ablation, whereas the presence of tumor arterial enhancement indicated partial ablation; in such cases, the ablation was repeated until complete necrosis was achieved.
Follow-up. All patients underwent post-treatment follow-up, including serum assay of AFP level and liver US study every 3 months that ended at patient death, last visit or liver transplantation. LTP was diagnosed when neoplastic viable tissue reappeared within 2 cm from the ablation site. All other cases of intrahepatic recurrence were defined as non-local, while extrahepatic recurrence included all HCC lesions detected outside the liver. Each recurrent HCC lesion was managed according to treatment guidelines available at the time of diagnosis (16, 19).
Statistical analysis. Distributions of continuous variables were analyzed for parametric distribution by the Kolmogorov-Smirnov test and the Mann-Whitney test was applied in all cases to analyze differences between subgroups. Categorical variables were tested with the two-sided Fisher exact test. Patient survival and recurrence rate were computed from the day of the procedure until death or first evidence of any tumor relapse, respectively, or until the last follow-up visit (censored). Survival and recurrence rates were estimated with the Kaplan-Meier method (univariate analysis) and compared using the log-rank test.
In order to account for confounding factors that could affect the analysis, we firstly performed a Cox proportional hazard model including variables with a p-value <0.1 and the primary exposure variable (PEI versus RFA); the results were expressed as hazard ratios (HR) with 95% confidence intervals (CI). The second step was to create a one-to-one match using a propensity score generated from a logistic regression model that had the primary exposure variable as dependent variable and variables that were significantly different for the two treatment arms as independent variables. The analyses in this matched sample were all paired. Results with p-values <0.05 were considered significant. Because p-values can be biased by population size, results from the propensity score match were also reported as effect sizes: values <|.1| indicated very small differences, between |.1| and |.3| indicated small differences, between |.3| and |.5| indicated moderate differences and >|.5| indicated large differences. Data were analyzed with the IBM SPSS Statistics Release 20.0 (http://www-01.ibm.com/software/analytics/spss/products/statistics/index.html)
Results
The demographic and clinical data of the 244 patients (108 in the PEI group and 136 in the RFA group) are summarized in Table I. Significant differences included higher prevalence of male sex and hepatitis B surface antigen positivity, higher size of HCC nodule, lower AFP level and lower prevalence of mixed cirrhosis etiology in the PEI group. The 15 patients with mild ascites who underwent PEI or RFA had been successfully treated with diuretics before HCC treatment. A pre-treatment histological assessment of the tumor was available for 54 PEI patients (50%) and for 59 RFA patients (43.4%); thus, because of the low number of histological evaluations available, it was not possible to use these data for statistical analyses.
In the RFA group, 74 (54.4%) patients were treated with an internally-cooled needle and 62 (45.6%) were treated with a multihook expandable needle; complete ablation was achieved in 81 patients (59.6%) with a single session and in 55 patients (40.4%) with 2 or more sessions. Among PEI patients, complete ablation was achieved after 3.1±1.5 sessions (range=1-8 sessions). No case of perioperative mortality was observed in either group. Major complications occurred in 4 patients treated with RFA (2.9%, 2 tense ascites, 1 pleural effusion, 1 hemobilia) and in 2 patients treated with PEI (1.9%, 1 hemobilia, 1 portal vein thrombosis) (p=0.585).
Demographic and clinical characteristics of the enrolled patients.
Survival and tumor recurrence analysis. The median follow-up was 27 months in the PEI group (range=2-189) and 34 months in the RFA group (range, 6-111; p=0.180). During follow-up, 26 patients (24.1%) in the PEI group and 43 patients in the RFA group (31.6%) died. Twenty-two patients (31.9%) died because of tumor progression, whereas the cause of death in the remaining patients was liver function failure (28 cases, 40.6%) or non-liver-related disease (19 cases, 27.5%).
Overall survival in the whole population at 1, 3 and 5 years was 97.4%, 79.6% and 63.1%, respectively. The 1-, 3- and 5-year survival rates were 97%, 83.3% and 64.6% in the PEI group and 97.7%, 77.1%, and 62.3% in the RFA group (p=0.163) (Figure 1A). Intrahepatic recurrence of HCC was observed in 30 patients (27.8%) treated with PEI and in 46 patients (33.8%) who underwent RFA (p=0.311). LTP, observed in 27 patients (25%) submitted to PEI and in 28 patients (20.6%) treated with RFA (p=0.413), was mostly diagnosed within the first 2 follow-up years (77.8% in the PEI group and 71.4% in the RFA group) and was effectively treated in 96.3% of cases, using PEI, RFA or transarterial chemoembolization. The cumulative 1-, 3- and 5-year tumor recurrence rates were 16.1%, 61.4% and 71.4% in the PEI group and 20.4%, 47.7% and 57.4% in the RFA group (p=0.278) (Figure 1B). Three patients in the RFA group showed extrahepatic HCC spread at 20, 24 and 29 months from treatment. For the whole cohort, the treatment applied did not affect survival and the only pre-treatment parameters, independently and negatively linked to survival at multivariate analysis, were older age (HR=1.04 95% CI) (1.01-1.08) and previous presence of ascites (HR=8.21 95% CI=3.21-21.03). None of the pre-treatment parameters was linked to tumor recurrence (Table II). Moreover, the impact of tumor recurrence on overall survival was evaluated. Tumor recurrence did not affect survival in the overall population (p=0.892) and in patients treated with PEI (p=0.166) or RFA (p=0.274).
Survival and tumor recurrence analysis after propensity score matching. Eighty-one patients were matched in each group and the baseline clinical and demographic characteristics were well-balanced (Table III). The mean follow-up was 45±34 months in the PEI group and 44±25 months in the RFA group (p=0.726).
After matching, the overall survival rates at 1, 3 and 5 years were 96.1 %, 83.4% and 64.7% in the PEI group and 96.2%, 87.5% and 72.9% in the RFA group (p=0.688) (Figure 1C). HCC recurrence was observed in 46 (42.6%) patients who underwent PEI and in 33 (24.3%) patients who underwent RFA (p=0.049). Tumor recurrence rates at 1, 3 and 5 years were significantly different: 20.4%, 63.9% and 73.3% in the PEI group and 17.8%, 42.4% and 49% in the RFA group (p=0.023) (Figure 1D). Moreover, LTP rates at 1, 3 and 5 years were significantly higher in the PEI group (18.1%, 44.3% and 49%) than in the RFA group (7%, 24.7% and 30.1%; p=0.018) (Figure 2A). No significant differences were observed with regard to non-local intrahepatic recurrence (9.3%, 48.9% and 62.1% for the PEI group and 17.8%, 38.9% and 41.3% for the RFA group; p=0.420) (Figure 2B). Univariate and multivariate analysis showed that among the pre-treatment parameters, only mild ascites were significantly associated with overall survival (p=0.001), whereas PEI treatment was the only factor significantly linked to tumor recurrence (p=0.020) (Table IV).
Survival and tumor recurrence curves of patients treated with percutaneous ethanol injection (PEI) or radiofrequency ablation (RFA). Survival rates before (A) and after (C) matching were not significantly different in the two treatement groups. Tumor recurrence rates were not different for the whole population (B), but were significantly higher in the PEI group after matching (D).
Discussion
Our multi-center survey of cirrhotics which mainly had Child-Pugh scores of Class A with single HCCs up to 2 cm shows that 3- and 5-year survival rates are not significantly different between patients treated with PEI or RFA (83.4% and 64.7% in the PEI group and 87.5% and 72.9 % in the RFA group) after propensity score matching. These results are similar to those obtained from most retrospective cohort studies, including BCLC Stage 0 patients treated with either of the two ablation techniques. Indeed, 5-year survival rates, ranging between 54% and 78.3% for patients treated with PEI (5, 20-22) and between 55% and 83.3% for patients treated with RFA (23-25), have been reported so far. Therefore, we can confirm that both PEI and RFA provide excellent and comparable medium-term survival in BCLC Stage 0 patients.
After matching, local tumor progression appeared to be significantly higher in the PEI group compared to the RFA group (A); non-local intrahepatic recurrence did not differ significantly between the groups (B).
After propensity score matching, the HCC recurrence rates at 3 and 5 years were significantly higher in the PEI (63.9% and 73.3%) than in the RFA group (42.4% and 49%). We believe that this result is mainly caused by the significantly higher rate of LTP in patients treated with PEI, that arises from RFA's superior local ablation effect (8, 9). Indeed, the effectiveness of PEI-induced tumor ablation is less predictable than RFA-induced ablation, even in HCCs up to 2 cm in size, and this is due to the inhomogeneous diffusion of ethanol within the nodule because of the presence of fibrous septa and the better effectiveness of thermal ablation in the treatment of extracapsular invasion or satellitosis. Indeed, the occurrence of satellitosis has been reported in as much as 12% of patients with single HCC up to 2 cm treated with surgical resection (26).
In our cohort, neither local nor distant recurrence negatively affected survival in the whole population. Our group has previously shown that LTP does not negatively affect survival in a large cohort of patients with single HCC <3 cm treated with RFA (27). This finding may be related to the timely and effective treatment of the locally recurrent tumor. The absence of a significant impact on survival of non-local intrahepatic recurrence is more difficult to explain. Similar data were previously reported by Kim et al. who found that extrahepatic, but not intrahepatic, HCC recurrence negatively impacted survival in a large series of 1,305 patients with very early or early HCC treated with RFA (28). Possible explanations for this result in our population may be the relatively short mean follow-up period in a series of HCC patients treated in a very early phase of the tumor's natural history, as well as the efficient program of early diagnosis and treatment of non-local intrahepatic recurrences using a multi-disciplinary approach. Furthermore, it should not be overlooked that most patients were compensated cirrhotics in the seventh decade of life and that progression of HCC was the cause of death only in 31.9% of the whole cohort, whereas, among the remaining patients, death was caused by liver function failure without HCC progression or by extrahepatic comorbidities.
This study has some limitations. Firstly, this is a retrospective survey with all its inherent limits. Secondly, only 46.3% of the patients had a histological diagnosis of HCC before treatment; however, all patients without biopsy assessment received a pre-treatment non-invasive imaging diagnosis of HCC according to the guidelines in effect at the time of enrollment. Thirdly, the prolonged enrollment period and the multicenter nature of the study could be additional sources of bias leading to time- and recruiting center-related variability in pre-treatment staging and post-treatment effectiveness assessment.
Overall survival and tumor recurrence prognostic factors.
Comparison of the demographic and clinical characteristics of patients after propensity match analysis.
In conclusion, PEI and RFA are equally effective for treating HCCs smaller than 2 cm in terms of 5-year survival but local and cumulative HCC recurrences are significantly higher in patients who undergo PEI. Therefore, RFA should be considered the standard treatment, whereas PEI should be reserved to patients with severely-impaired clotting parameters or with HCC nodule located superficially close to the abdomen wall or in a site that would be dangerous for thermal ablation, such as near the gallbladder, major bile ducts or bowel loops, or decreasing the effectiveness of RFA-induced thermal ablation, such as close to large intrahepatic vessels. Lastly, a rigorous cost-effectiveness analysis concerning the best therapeutic approach for this subgroup of patients is of crucial importance to curb the increasing economic costs of health care.
Overall survival and tumor recurrence prognostic factors after propensity match analysis.
Footnotes
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Disclosure
All Authors read and approved the final manuscript. The Authors do not have any conflict of interest in connection with the submitted manuscript.
- Received August 16, 2014.
- Revision received September 17, 2014.
- Accepted September 24, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
