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Hepatocellular Carcinoma Treated with Radiofrequency Ablation with or without Ethanol Injection: A Prospective Randomized Trial¹

¹ From the Department of Hepatobiliary Surgery, Cancer Centre of Sun Yat-Sen University, 651 Dongfeng Rd East, Guangzhou 510060, China (Y.J.Z., H.H.L., M.S.C., R.P.G., J.Q.L., Y.Z., Y.Q.Z.); State Key Laboratory of Oncology in Southern China, Guangzhou, China (Y.J.Z., M.S.C., R.P.G., J.Q.L., Y.Z., Y.Q.Z.); and Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China (W.Y.L.). Received May 11, 2006; revision requested July 11; revision received August 28; accepted September 28; final version accepted January 2, 2007. Supported by a grant of Sciences and Technology Committee of Guangdong Province, 2002 China and Sciences and Technology Committee of Guangzhou City, China. Address correspondence to M.S.C. (e-mail: Chminsh{at}mail.sysu.edu.cn).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 
Purpose: To prospectively evaluate whether use of combined radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) results in better survival compared with use of RFA alone in patients with hepatocellular carcinoma.

Materials and Methods: This study was local ethical committee approved; all patients gave written informed consent. One hundred thirty-three patients were randomly assigned to undergo RFA-PEI (n = 66; 57 men, nine women; mean age, 53.3 years; age range, 32–73 years) or RFA alone (n = 67; 58 men, nine women; mean age, 52.2 years; age range, 33–74 years). Patients with viable tumors at computed tomography (CT) 4 weeks after treatment received additional treatment. Overall survival rates were calculated and 3-year survival rates were compared with life-table and Mantel-Haenszel analyses, respectively. Survival curves were constructed and compared by using Kaplan-Meier and log-rank tests, respectively. The relative prognostic significance of variables in predicting overall survival and the time to tumor recurrence or metastasis were assessed with multivariate Cox proportional hazards regression and logistic regression analyses, respectively.

Results: One-, 2-, 3-, 4-, and 5-year overall survival rates were 95.4%, 89.2%, 75.8%, 63.3%, and 49.3%, respectively, with RFA-PEI and 89.6%, 68.7%, 58.4%, 50.3%, and 35.9%, respectively, with RFA alone. The survival curve for the RFA-PEI group was significantly better than that for the RFA-only group (P = .04). The survival curve for the RFA-PEI group was better than that for the RFA-only group with 3.1–5.0-cm tumors (P = .03) but not for those with 3.0 cm or smaller (P = .44) or 5.1–7.0-cm (P = .70) tumors. Overall tumor recurrence was lower with RFA-PEI (23 patients) than with RFA alone (33 patients, nonsignificant difference). Local recurrence was significantly lower with RFA-PEI (four patients) than with RFA alone (14 patients, P = .012). Tumor diameter proved to be the only significant prognostic factor for overall recurrence and intrahepatic recurrence. Treatment type and tumor size were significant prognostic factors for local recurrence.

Conclusion: RFA-PEI facilitated better local tumor control and long-term survival compared with RFA alone.

© RSNA, 2007

	INTRODUCTION

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According to the 2005 American Association for the Study of Liver Disease guidelines for hepatocellular carcinoma (HCC) (1), (a) surgical resection can be offered to patients with solitary lesions if they do not have cirrhosis or if they have cirrhosis with well-preserved liver function, (b) liver transplantation is an effective option for patients with solitary lesions 5 cm in diameter or smaller or for those with up to three lesions smaller than 3 cm in diameter, and (c) local ablation is a safe and effective therapy for patients who cannot undergo resection or as a palliative treatment before transplantation. However, surgical resection is the treatment of choice for only about 5% of patients in the western hemisphere and for 40% of Asian patients (2,3), and liver transplantation is limited owing to donor shortage and the long list of patients waiting for donors (1,4).

Among the various local percutaneous ablative therapies, radiofrequency ablation (RFA) has attracted the greatest interest because of its effectiveness and safety in the treatment of small (5.0-cm) HCCs, with a 3-year survival rate of 62%–68%, a treatment-associated morbidity rate of 0%–12%, and a treatment-related mortality rate of 0%–1% (5–10). Prospective randomized trials (11,12) have revealed that RFA yields higher rates of complete tumor necrosis with fewer numbers of treatment sessions and better survival compared with percutaneous ethanol injection (PEI). However, the complete tumor necrosis rate with RFA for tumors larger than 5 cm is less favorable (13), and the local recurrence rate can be as high as 20%, even for HCCs smaller than 3.5 cm (14). Thus, to improve RFA results, the ablation zone needs to be extended so that larger tumors can be treated and local recurrences of smaller tumors after treatment can be decreased.

PEI is also an effective treatment that has been widely used in patients with HCC (15). We hypothesized that use of combined RFA and PEI (RFA-PEI) might result in better patient survival compared with use of RFA alone. Thus, the purpose of our study was to prospectively evaluate whether use of RFA-PEI results in better survival outcomes than does RFA alone in patients with HCC.

	MATERIALS AND METHODS

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This study was approved by the ethical committee of the Cancer Centre of Sun Yat-Sen University and was designed according to the CONSORT (Consolidated Standards of Reporting Trials) guidelines. All patients gave written informed consent before beginning the study and being randomly assigned to treatment groups.

Between October 2000 and December 2003, 133 patients with HCC were randomly assigned to undergo RFA-PEI (n = 66) or RFA alone (n = 67). During this period, 2507 patients with HCC were hospitalized in our facility (Cancer Centre of Sun Yat-Sen University). The diagnosis of HCC was based on the diagnostic criteria of the European Association for the Study of the Liver (16). A diagnosis of HCC was made when two different imaging examinations revealed the typical features of HCC in a patient with an elevated -fetoprotein level (400 ng/mL) (n = 37) or when there was a cytologic or histologic diagnosis of HCC (n = 96).

Inclusion criteria for this study were as follows: (a) age 18–75 years and refusal to undergo surgery; (b) a solitary HCC 7.0 cm in diameter or smaller or multiple (up to three) HCCs 3.0 cm in diameter or smaller; (c) lesions visible at ultrasonography (US), with an acceptable and safe path between the lesion and the skin seen on the US scan; (d) no extrahepatic metastasis; (e) no imaging evidence of tumor invasion into the major portal or hepatic vein branches; (f) no history of encephalopathy, ascites refractory to diuretics, or variceal bleeding; (g) a platelet count of more than 40 000 cells per cubic millimeter; and (h) no previous treatment for HCC except liver resection. All 133 study subjects were patients, from the total group of 2507 hospitalized patients with HCC, who met all of our inclusion criteria.

A research nurse randomly assigned the patients to treatment groups by using random numbers generated from a computer in a central registry and then further grouped them according to tumor size (3.0, 3.1–5.0, and 5.1–7.0 cm). Each patient's treatment group assignment was concealed from the interventional radiologist until before the treatment. In addition, patients were all blinded to treatment assignment.

Overall Treatment Procedure
RFA-PEI or RFA alone was performed with real-time US guidance (EUB-2000; Hitachi Medical Systems, Tokyo, Japan) by a single interventional radiologist (M.S.C.), who had 11 years of experience in interventional therapy at the start of the study in October 2000. The patients were placed in the supine position. A local anesthetic, 1% lidocaine, was injected from the insertion point on the skin to the peritoneum, along the planned puncture track. The skin was incised with a small lancet, and the needle was advanced to the chosen area. Conscious analgesic sedation with intravenous fentanyl citrate and droperidol was induced before the procedure (RFA-PEI or RFA alone).

After the treatment, the patients underwent medical observation. A single intravenous 750-mg dose of cefuroxime sodium (Zinacef; GlaxoSmithKline, London, England) was administered before the procedure. Major complications were defined as those that, if left untreated, threatened the patient's life, led to substantial morbidity and/or disability, or lengthened the patient's hospital stay (8). All other complications were considered to be minor. Pain was graded as absent or mild if the patient did not require analgesics and moderate or severe if analgesics were necessary to relieve pain. The medical observation, determination of complications, and grading of pain were performed by two authors (Y.Z., H.H.L.), and any disagreements were settled by means of consultation (with M.S.C.).

RFA-PEI and RFA-only Procedures
For RFA, we used a commercially available system (RF 2000; Radio Therapeutics, Mountain View, Calif) and a needle electrode with a 15-gauge insulated cannula that had 10 hook-shaped expandable electrode tines with a diameter of 3.5 cm at expansion (LeVeen; Radio Therapeutics). Chiba needles (21-gauge, 150 mm; Top, Tokyo, Japan) were used for PEI.

First, the 15-gauge RFA needle was inserted into the tumor. Then, the Chiba needle was placed immediately adjacent to the radiofrequency needle but not through the guiding needle. Absolute alcohol was slowly injected, first into the portion of the tumor farthest away from the skin puncture site and then into the rest of the tumor. Particular attention was paid to inject the parts of the tumor where the RFA was likely to be incomplete, such as the subcapsular region and areas near large vessels or the gallbladder. The needle was then slowly withdrawn. The amount of ethanol injected into the tumors was determined according to the size of the tumors and was always kept below the estimated volume of the tumors (V): V = (4/3)·[(r + 0.5)³], where r is the tumor radius, in centimeters. The mean volume of ethanol used was 11.2 mL ± 0.8 (standard deviation) (range, 3–40 mL). The injection of ethanol was stopped if resistance was felt.

RFA was performed 1 minute after PEI. After the 10 tines of the electrode were deployed, the radiofrequency generator was activated and initiated with 10 W of power, and the power was increased 10 W per minute to 90 W. Radiofrequency energy was applied until there was a marked increase in impedance or until 15 minutes had elapsed. If a marked increase in impedance was not achieved, a second application of radiofrequency energy was performed. No more than three RFAs were performed during a treatment session. For tumors 3.0 cm or smaller, a single ablation was performed. For tumors larger than 3.0 cm, multiple overlapping ablations, as described by Chen et al (17), were performed. The first ablation was performed at the location farthest away from the skin puncture site. After the ablation was completed, the electrode tines were retracted and the needle was withdrawn and deployed to the second predetermined location. Then, the electrode tines were re-expanded and the radiofrequency generator was reactivated. This process was repeated until the entire lesion was adequately covered. During RFA, a hyperechoic area around the electrode tip was observed at US monitoring. The aim of the treatment was to have this hyperechoic area encompass a region larger than 1 cm around the HCC. At the end of the procedure, the generator was reactivated for ablation of the needle track to prevent bleeding. The PEI needle track did not require ablation. RFA alone was performed in the same manner but without insertion of the Chiba needle or injection of ethanol.

Follow-up Protocol
Dual-phase spiral computed tomography (CT) was performed 4 weeks after treatment. Thereafter, the patients were followed up every 2 months for the first 2 years. At each follow-up visit, blood tests—including liver function and serum -fetoprotein tests—were performed. Chest radiography was performed every 6 months. After the first 2 years, follow-up examinations were performed once every 3 months. This study was censored on March 1, 2006.

At spiral CT 4 weeks after treatment, residual viable tumor tissue was considered to be present if enhancing areas were seen within the tumor on either arterial phase or portal venous phase images. Depending on the initial random treatment assignment, RFA-PEI or RFA alone was repeated. Magnetic resonance (MR) imaging was performed if there was uncertainty at CT as to whether residual viable tumor tissue was present. Between October 2000 and December 2004, all CT examinations were performed by using the same multi–detector row CT scanner (CT-TWIN; Philips Medical Systems, Best, the Netherlands) at 120 kV and 250 mA for the sequential acquisition of 8-mm-thick sections. Since January 2005, all CT examinations have been performed by using another spiral CT scanner (Brilliance 16; Philips Medical Systems) with the same technical parameters.

MR imaging was performed by using a 1.5-T MR unit (CVi; GE Medical Systems, Milwaukee, Wis) for the sequential acquisition of 5–8-mm-thick sections. Nonenhanced breath-hold T1-weighted gradient-echo (120/1.5 [repetition time msec/echo time msec], 80° flip angle, 320 x 224 matrix, 1–2-mm intersection gap) and respiratory-triggered fat-saturated T2-weighted fast spin-echo (4000–6000/102–108, four signals acquired, 384 x 224 matrix, 1–2-mm intersection gap) pulse sequences were performed. Contrast material–enhanced T1-weighted breath-hold gradient-echo images were acquired in the transverse plane with and without fat saturation by using the same technical parameters used to perform the nonenhanced sequences. An intravenous contrast agent (gadodiamide, Omniscan; Nycomed Amersham, Princeton, NJ) was used to perform the dynamic contrast-enhanced MR examinations.

All images were interpreted by four radiologists in our radiology department, who had 10, 12, 12, and 16 years of experience in image diagnosis at the start of the study. All radiologists were blinded to the patients' treatment assignments.

The primary end point was overall survival, the secondary end point was recurrence-free survival, and the tertiary end point was side effects of treatment. Survival time was defined as the interval between the first treatment and either death or last follow-up visit. Tumor recurrence included local recurrence, intrahepatic recurrence, and extrahepatic metastasis (6). In terms of outcomes after complete tumor ablation was achieved, local recurrence was defined as the development of tumor staining at the margins on follow-up CT and/or MR images, intrahepatic recurrence was defined as the development of a separate new lesion in the liver more than 2.0 cm away from the primary lesion on these images, and extrahepatic metastasis was defined as a metastatic lesion outside the liver on these images.

For patients with local or intrahepatic recurrence who still met the study inclusion criteria at follow-up, either RFA alone or RFA-PEI—depending on the initial treatment assignment—was repeated. Patients with findings outside the inclusion criteria at follow-up were treated with either transcatheter arterial chemoembolization or supportive care according to their tumor type, liver function, and general medical condition. For extrahepatic metastasis, supportive care was given.

Sample Size and Statistical Analyses
We used death due to HCC at 2 years after treatment as the outcome measure for estimation of the sample size. With RFA alone, we estimated that 30% of patients would die of HCC on the basis of previously published data (6–10,17,18) and our clinical experience. With RFA-PEI, we estimated that 10% of patients would die of HCC on the basis of the results of our pilot study. Two-sided testing with 80% power at a significance level of 5% revealed that the minimum sample size needed to detect a significant difference was 60 patients in each treatment group. Thus, we randomly assigned 133 patients to either of the two treatment groups in this study.

The statistical analyses were performed by using SPSS 10.0 software (SPSS, Chicago, Ill). Comparisons between the two groups were performed by using the Student t test for continuous data and the ² test for categorical data. Overall survival rates were calculated by using the life-table method, and 3-year survival rates were compared by using the Mantel-Haenszel test. Survival curves were constructed by using the Kaplan-Meier method and were compared by using the log-rank test. The relative prognostic significance of the variables in predicting the overall survival rate and the time to tumor recurrence or metastasis were assessed by using multivariate Cox proportional hazards regression analysis and logistic regression analysis, respectively. Results are reported as means ± standard deviations. All statistical tests were two sided, and P < .05 was considered to indicate a significant difference. All analyses were performed on an intention-to-treat basis, and all patients received the treatment randomly assigned to them.

	RESULTS

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Patient Groups
There were no significant differences in demographic data between the two treatment groups (66 patients in the RFA-PEI group, 67 patients in the RFA-only group) (Fig 1, Table 1). The predominant cause of HCC in our study was hepatitis B viral infection (in 126 patients); hepatitis C viral infection (in seven patients) was the other cause. In the RFA-PEI group, 60 patients were followed up for 1 year; 55 patients, for 2 years; 30 patients, for 3 years; 11 patients, for 4 years; and three patients, for 5 years (Table 2). In the RFA-only group, 59 patients were followed up for 1 year; 47 patients, for 2 years; 26 patients, for 3 years; 11 patients, for 4 years; and two patients, for 5 years (Table 2). Mean follow-up periods were 35.5 months ± 14.3 (range, 2.2–62.9 months) and 32.2 months ± 15.7 (range, 2.2–61.5 months) for the RFA-PEI and RFA-only groups, respectively (Table 1).

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1: Patient flow diagram for the intention-to-treat analyses. TACE = transcatheter arterial chemoembolization.

There were no procedure-related mortalities or major complications. Pain and fever were the most commonly seen complications. Twenty patients in the RFA-PEI group compared with 16 in the RFA-only group had moderate or severe pain. Slightly more patients in the RFA-PEI group (n = 26) than in the RFA-only group (n = 14) had a fever.

Survival
The 1-, 2-, 3-, 4-, and 5-year overall survival rates were 95.4%, 89.2%, 75.8%, 63.3%, and 49.3%, respectively, for the RFA-PEI group and 89.6%, 68.7%, 58.4%, 50.3%, and 35.9%, respectively, for the RFA-only group. Mantel-Haenszel testing revealed that 3-year (P = .01) and 5-year (P = .03) overall survival rates for the RFA-PEI group were significantly better than those for the RFA-only group. The survival curve for the RFA-PEI group was significantly better than that for the RFA-only group (P = .04, log-rank test) (Fig 2).

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Cumulative (Cum) survival curves for patients treated with RFA-PEI or RFA only. Curves for (a) overall survival, (b) survival for patients with tumors 3.0 cm or smaller, (c) survival for patients with tumors 3.1–5.0 cm, and (d) survival for patients with tumors 5.1–7.0 cm are illustrated.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Cumulative (Cum) survival curves for patients treated with RFA-PEI or RFA only. Curves for (a) overall survival, (b) survival for patients with tumors 3.0 cm or smaller, (c) survival for patients with tumors 3.1–5.0 cm, and (d) survival for patients with tumors 5.1–7.0 cm are illustrated.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2c: Cumulative (Cum) survival curves for patients treated with RFA-PEI or RFA only. Curves for (a) overall survival, (b) survival for patients with tumors 3.0 cm or smaller, (c) survival for patients with tumors 3.1–5.0 cm, and (d) survival for patients with tumors 5.1–7.0 cm are illustrated.

View larger version (11K): [in this window] [in a new window] [Download PPT slide]   Figure 2d: Cumulative (Cum) survival curves for patients treated with RFA-PEI or RFA only. Curves for (a) overall survival, (b) survival for patients with tumors 3.0 cm or smaller, (c) survival for patients with tumors 3.1–5.0 cm, and (d) survival for patients with tumors 5.1–7.0 cm are illustrated.

Multivariate Cox proportional hazards regression analysis revealed patient sex, tumor diameter, and treatment group to be significant prognostic factors of overall survival after treatment (Table 3): Patients who were female, patients with small tumors, and patients in the RFA-PEI group had better survival.

	DISCUSSION

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However, the therapeutic effect of RFA decreases as the tumor size increases. Livraghi et al (19) reported RFA-induced complete tumor necrosis rates of 90%, 71%, and 45%, respectively, for tumors smaller than 3.0 cm, tumors 3.0–5.0 cm, and tumors larger than 5.0 cm, respectively. In a study of 126 RFA-treated HCCs with a mean diameter of 5.4 cm (range, 3.1–9.5 cm), a complete tumor necrosis rate as low as 48% was reported (13). Currently available RFA systems produce ablation zones 3.0–5.0 cm in diameter (4,5). It is generally accepted that the safety margin of ablation for small HCCs is at least 1.0 cm (2,20), so it is not surprising that RFA results for tumors larger than 3.0 cm are still unsatisfactory.

An increased ablation zone and decreased tumor recurrence are key to improving the results of RFA in the treatment of tumors larger than 3.0 cm. There have been attempts to perform transcatheter arterial chemoembolization, transarterial embolization, balloon occlusion of the hepatic artery, and saline infusion during RFA in an effort to increase the thermal ablation zone (21–23). However, the results of these treatments have not been completely satisfactory. In our study, we combined RFA with PEI to treat HCCs larger than 3.0 cm. Watanabe et al (24) and Kurokohchi et al (25) reported that with use of combined RFA and PEI, the ablative zone could be increased in both in vivo and ex vivo studies. Favorable RFA-PEI results have been obtained, especially for tumors that were difficult to treat with RFA. Goldberg et al (26) confirmed this observation by using a R3230 rat tumor model. As far as we know, the long-term clinical results of RFA-PEI compared with those of RFA have not been reported.

In our study, the overall survival rates with RFA-PEI were significantly better than those with RFA only. However, at subgroup analyses, use of RFA-PEI improved the overall survivals of only those patients with 3.1–5.0-cm tumors—not those of patients with tumors 3.0 cm or smaller or those of patients with 5.1–7.0-cm tumors. Evidence in the medical literature indicates that RFA is very effective for treatment of tumors 3.0 cm or smaller: A complete tumor necrosis rate of 90% and survivals comparable to those after surgery have been reported (5,9,19). Because RFA is very effective in the treatment of HCCs 3 cm or smaller, it was difficult to further improve the results by adding PEI. Our study results indicate that tumors larger than 5.0 cm are too large to be treated adequately with percutaneous local ablation.

Multivariate Cox analysis revealed patient sex, tumor diameter, and treatment group as significant prognostic factors for overall survival. To our knowledge, sex had not been previously reported as a prognostic factor for survival. In our study, however, the number of female patients recruited was small—nine in each group, for a total of only 18 female patients.

Tumor recurrence is the main reason for failed RFA (5,7,14). Local recurrence rates as high as 20% have been reported, even for HCCs 3.5 cm or smaller (14). In our previous study, patients with HCC had many micrometastases up to 1.0 cm away from the main tumor, even with encapsulated tumors 3.0 cm or smaller (27). Thus, a clear safety margin of 1.0 cm is important not only for liver resection but also for local ablative therapy. Local recurrence occurs when the administered treatment does not yield adequate safety margins. Results of in vivo and ex vivo experiments (24,25) have shown that RFA-PEI yields a larger ablative zone than does RFA, and, thus, RFA-PEI treatment of small HCCs can result in decreased local recurrence. Our results show that use of RFA-PEI facilitates significant decreases in local recurrence but not in intrahepatic recurrence or extrahepatic metastasis. In addition, our logistic regression analysis revealed treatment type and tumor diameter to be significant factors for local recurrence, suggesting that use of RFA-PEI, compared with use of RFA only, led to improved local control of HCC but not to decreased intrahepatic recurrence or decreased extrahepatic metastasis.

Although more patients in the RFA-PEI group had moderate or severe pain (20 vs 16 in RFA-only group) and fever (26 vs 14 in RFA-only group), this treatment was found to be as safe as RFA alone. No mortalities or serious procedure-related complications resulted from the use of RFA-PEI in either our study or other investigations (24–26).

There were limitations in our study. First, only 18 female patients (nine in each treatment group), compared with 115 male patients, were recruited in our study. Second, the predominant cause of HCC in our study population (in 126 patients) was hepatitis B viral infection, which is different from the predominant causes of HCC in Japan (hepatitis C viral infection) and Europe (hepatitis C viral infection and alcohol abuse). Third, the follow-up period was limited: Only five patients were followed up for more than 4 years.

In conclusion, results of this prospective randomized study show that the combined use of RFA and PEI was more effective than the use of RFA alone in terms of both local tumor recurrence and long-term survival for patients with HCC.

	ADVANCES IN KNOWLEDGE

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• In this prospective randomized trial, overall survival for the radiofrequency ablation (RFA)-percutaneous ethanol injection (PEI) group was significantly better than that for the RFA-only group (P = .04).
  
• At subgroup analyses, overall survival was significantly better for patients in the RFA-PEI group with 3.1–5.0-cm tumors (P = .03) but not for those with tumors 3.0 cm or smaller or those with 5.1–7.0-cm tumors. Local recurrence was also significantly lower in the RFA-PEI group (P = .01).
  
• Logistic regression analysis revealed tumor diameter as the only significant prognostic factor for overall (P = .01) and intrahepatic (P = .002) recurrence.
  
• Logistic regression analysis revealed treatment group (P = .01) and tumor diameter (P = .01) as significant prognostic factors for local recurrence.
  

	IMPLICATIONS FOR PATIENT CARE

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• Our study results indicate that radiofrequency ablation (RFA)-percutaneous ethanol injection (PEI) is a more appropriate choice for the treatment of 3.1–5.0-cm tumors, which if treated with RFA alone may have incomplete necrosis or high local recurrence.
  
• RFA-PEI can be a substitute treatment for tumors that are difficult to treat with RFA alone, especially tumors near large vessels or organs; ethanol can be injected into the parts of the tumor where the RFA is likely to be incomplete.
  
• RFA-PEI can also be used in combination with other methods such as transcatheter arterial chemoembolization and surgery.
  

	ACKNOWLEDGMENTS

 
The authors thank Chao-Mei Ruan, MD, Lei Zheng, MD, Chuang-Miao Xie, MD, and Yun-Xian Mo, MD, for support in image interpretation and Su-Mei Cao, MD, for help in statistical analysis.

	FOOTNOTES

 

Abbreviations: HCC = hepatocellular carcinoma • PEI = percutaneous ethanol injection • RFA = radiofrequency ablation

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, Y.J.Z., M.S.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; clinical studies, all authors; statistical analysis, all authors; and manuscript editing, all authors

	References

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