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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 819-823

Comparative study of radiofrequency ablation combined with either percutaneous ethanol injection or percutaneous acetic acid injection in the management of hepatocellular carcinoma


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Radiology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission16-Dec-2018
Date of Decision04-Feb-2019
Date of Acceptance10-Feb-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Haytham M Azab
Shiekh Zayed 12588, Giza Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_408_18

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  Abstract 


Objective
The objective of this study was to compare radiofrequency ablation (RFA) plus percutaneous ethanol injection with RFA plus percutaneous acetic acid injection in hepatocellular carcinoma (HCC) treatment in patients having single focal lesions more than 5 cm and up to 7 cm in diameter.
Background
RFA has proved its effectiveness and safety between various local ablative therapies. Acetic acid, which has the ability to penetrate cells with the property of extracting collagen and dissolving lipids, has a stronger killing effect on hepatocytes than ethanol.
Patients and methods
This prospective study was carried out from April 2014 to January 2017; it included 60 patients with compensated HCC who had a single lesion more than 5 cm and up to 7 cm in diameter; they were Child A. The patients were selected according to the triphasic computed tomography scanning characteristics of HCC. They were randomly allocated into two groups: group I was ablated for one setting of RFA, followed by percutaneous ethanol injection in the same setting. Group II was ablated by one setting of RFA with two overlaps to decrease the size of the unablated areas, followed by percutaneous acetic acid injection in the same setting.
Results
Evaluation of the response to ablation 1 month later using triphasic computed tomography showed significant better responses in group II compared with group I (83.3 vs. 60%). The response 3 months later was not changed significantly compared with the response after 1 month.
Conclusion
Combined techniques give the best results for management of HCCs in comparison with individual techniques. Acetic acid-enhanced RFA is a very effective method of HCC ablation.

Keywords: hepatocellular carcinoma, percutaneous acetic acid injection and radiofrequency ablation, percutaneous ethanol injection


How to cite this article:
Nouh MA, El Sharkawy MK, El Deeb GS, Badawy AM, Azab HM. Comparative study of radiofrequency ablation combined with either percutaneous ethanol injection or percutaneous acetic acid injection in the management of hepatocellular carcinoma. Menoufia Med J 2020;33:819-23

How to cite this URL:
Nouh MA, El Sharkawy MK, El Deeb GS, Badawy AM, Azab HM. Comparative study of radiofrequency ablation combined with either percutaneous ethanol injection or percutaneous acetic acid injection in the management of hepatocellular carcinoma. Menoufia Med J [serial online] 2020 [cited 2020 Oct 29];33:819-23. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/819/296689




  Introduction Top


Hepatocellular carcinoma (HCC) is the fifth most common neoplasm globally and the second most common cause of cancer-related death according to the WHO. The predomination of liver cancer is greater than 2:1 in the male to female ratio. In 2012, almost 83% of the estimated 782 000 HCC cases had been shown to be in less developed regions. East, South Asia, and sub-Saharan Africa are the regions of highest incidence, whereas, in Southern Europe and North America, are the regions of intermediate incidence, whereas Northern Europe and South-Central Asia are the regions of lowest incidence [1]. Hepatitis C virus (HCV) and hepatitis B virus (HBV) are the most common precipitating factors in HCC development. HCV has affected around 12% of the Egyptian population, leading to cirrhosis in about 20%. In such patients, HCC develops in about 15% of the cases [2]. To decide the appropriate therapeutic choice, the accurate diagnosis of neoplastic lesions by one or more of the imaging modalities is mandatory. This imaging workup has two purposes: lesion characterization and cancer staging [3]. Often, once HCC has been detected, it is difficult to treat due to chemoresistance, multicentric incidence and underlying poor hepatic reserve, which itself leads to a high mortality rate [4]. Surgery offers the only real chance of cure, but the majority have an unresectable disease because of tumor stage or liver cirrhosis [5]. Local ablation is a safe and effective therapy for patients who cannot undergo resection or as a palliative treatment before transplantation [2]. Among the various local percutaneous ablative therapies, RFA has attracted the greatest interest because of its effectiveness and safety in the treatment of small HCCs, with a 62–68% 3-year survival rate and related morbidity and mortality rates of 0–12 and 0–1%, respectively. Although less favorable results of complete tumor necrosis rate with RFA occurs in tumors larger than 5 cm in diameter, the local recurrence rate can be as high as 20% even for HCCs less than 3.5 cm in diameter [6]. 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 [7]. Acetic acid, which has the ability to penetrate cells with the property of extracting collagen and dissolving lipids, has a stronger killing effect on hepatocytes than ethanol [8]. Percutaneous ethanol injection (PEI) is also effective in ablating small tumors [9]. The aim of this study was to evaluate and compare two percutaneous combined therapies, RFA plus PEI and RFA plus percutaneous acetic acid injection (PAI) in HCC treatment in patients having single focal lesions more than 5 cm and up to 7 cm in diameter.


  Patients and Methods Top


This prospective study was carried out on 60 patients with compensated HCC who had a single lesion more than 5 cm and up to 7 cm in diameter; they were Child A according to Child–Pugh classification. Their ages ranged from 46 to 77 years. They were managed at the RFA Unit of Tropical Medicine Department, Al-Azhar University Hospital, from April 2014 to January 2017. Ethical approval was taken for conducting this study, and written consents were obtained. The patients were selected according to the triphasic computed tomography (CT) scanning characteristics of HCC (early uptake of the dye in the arterial and rapid washout in venous and delayed phases) using the GE-16MS (Siemens Healthcare GmbH, Henkestr, Erlangen, Germany) triphasic CT machine. They were randomly allocated into two groups: group I included 30 patients who were candidates for one setting of RFA (RITA 1500X RF generator and RITA StarBurst XL; RITA Medical Systems, Mountain View, California, USA), followed by PEI in the same setting. Their mean age was 60.7. Group II included 30 patients. They were ablated by one setting of RFA with two overlaps to decrease the size of the remaining unablated areas, followed by PAI in the same setting. Their mean age was 58.1. According to the lesion size, each group was subdivided into two subgroups: group A, which included 15 patients who had lesions 5.1–6 cm in maximum diameter, and group B, which included 15 patients who had lesions 6.1–7 cm in maximum diameter. All patients were subjected to preprocedure workup including full history, thorough clinical examination and detailed investigations including complete blood picture, liver function tests, serum α-fetoprotein (AFP) and viral hepatitis markers. This was followed by performing triphasic CT scanning and AFP (human AFP ELISA kit, Parkway Lane, Suite, Peachtree Corners, GA) 1 and 3 months later. The results were compared to decide whether one regimen was better than the other.

Statistical analysis

Data were analyzed using statistical program for social science, version 20.0 (IBM Corp., IBM SPSS Statistics for Windows, Armonk, NY). Quantitative data were expressed as mean ± SD. Qualitative data were expressed as frequency and percentage. The following tests were carried out: Independent-samples t-test of significance was used when comparing the two means, χ2-test of significance was used to compare proportions between two qualitative parameters and P value. P value less than 0.05 was considered significant, P value less than 0.001 was considered as highly significant, and P value more than 0.05 was considered insignificant.


  Results Top


This study was conducted on 60 patients having single focal HCC, ranging from 5.1 to 7 cm in diameter. The mean age of the patients was 60.30. It was 60.70 for GI and 58.16 for GII. They were 51 (85%) males and 9 (15%) females. GI composed of 26 males (86.7%) and 4 females (13.3%). GII composed of 25 males (83.3%) and 5 females (16.7%). The studied patients included 13 smokers (22%) as 6 (20%) in GI and 7 (23.3%) in GII. No significant statistical difference was detected between the two groups. HCV Ab was positive in 54 (90%) patients, 26 (86.7%) for GI and 28 (93.3%) for GII. HBs Ag was positive in one patient in GI. Combined infection was seen in 3 (10%) patients of GI and 2 (6.7%) patients of GII [Table 1] with no significant statistical difference was detected between the two groups regarding the etiology. AFP was positive in 44 (73.3%) patients, 23 (76.6%) in GI and 21 (70%) in GII. The difference was not statistically significant between the two groups. When AFP levels were compared after one month of ablation a significant drop was observed. However, no further drop was noted 3 months later [Table 2]. Evaluation of the response one month later using triphasic CT showed significant better responses in GII compared to GI (83.3% vs 60%) with P value <0.05. The response 3 months later was not changed significantly compared to the response after one month of the procedure (56.7% in GI and 80% in GII) [Table 3]. When the groups were subdivided into two subgroups A and B. Subgroups GI A showed better results when compared to GI B (66.7% vs 53.3%). However, this did not reach a significant value after 1 month of ablation (P >0.05). This was also observed 3 months later [Table 4]. Comparing subgroups GII A to GII B better results were in favor to GII A. However, it did not reach a significant value (P <0.05). Comparing subgroups GI A to GII A (66.7% vs 86.6%) significantly better response was noted in GII A. Comparing subgroups GI B to GII B (46.6 vs 73.3%) significantly better response was observed in GII B [Table 5]. The Complications reported were abdominal pain and fever. This was noted in 63.3% of patients, 60% in GI and 66.7% in GII. The difference was not statistically significant. Fever was observed in 26.6% of patients, 23.3% for GI and 30% for GII. The difference was also no statistically significant [Table 6]. The results indicate significantly better responses when acetic acid was combined to RFA.
Table 1: Demographic features and prevalence of hepatitis C virus antibody and hepatitis B virus surface antigen among the studied groups

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Table 2: Comparison between α-fetoprotein prevalence and values before treatment and 1 and 3 months after treatment (cutoff value 200 ng/ml)

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Table 3: Comparison between two procedures for hepatocellular carcinoma ablation in two groups of patients with lesions 5.1-7 cm in maximum diameter based on triphasic computed tomography 1 and 3 months after ablation as well as the comparison between both groups in postprocedural complications

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Table 4: Comparison of two procedures for hepatocellular carcinoma ablation in subgroups of patients with lesions 5.1-6 cm and subgroups of patients with lesions 6.1-7 in maximum diameter based on triphasic computed tomography after 3 months

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Table 5: Comparison of the response between the two subgroups of group I after 1 and 3 months

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Table 6: Comparison of the response between the two subgroups of group II after 1 and 3 months

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  Discussion Top


This study was conducted on 60 HCC patients to test the effectiveness of two modalities on large lesions, 5.1–7 cm in the largest diameter. All the patients were Child A, and this was a part of the inclusion criteria to achieve high success rate with the least complications. Male individuals were predominant with a ratio of 5.7: 1. This ratio is similar to that reported by Sherlock and Dooley [10] who pronounced male predominance of HCC throughout the world, on the order of 4: 1 in low incidence areas and up to 9: 1 in high incidence areas. This ratio could be explained by hormonal factors such as high testosterone level in male individuals and methoxyestradiol in female individuals [11]. The mean age was 60.3 ± 8.6, and this was slightly higher than some Egyptian studies carried out by Azab et al. [12], Salama et al.[13], and El-Kady et al.[14], probably because of the selection of patients, as the previous studies included patients with smaller lesions up to 5 cm compared with our study, in which longer time was needed by the lesions to develop larger sizes. The mean age was slightly lower than the results of the Japanese and Italian patients in the studies conducted by Omata et al. [15] and Livraghi et al. [16], respectively. El-Zayadi et al. [17] reported that the average age of HCC patients was 60 years, as was found in the study of Badawi and Michael [18]. The earlier age among Egyptians could be explained by the early age of acquisition of viral hepatitis (HCV and HBV) due to several factors that can transmit infection among the population, such as, injections, circumcision, and tattooing without proper sterilization [19].

In this study, AFP was positive in 73% of patients. In the follow-up period, the number of positive patients dropped to 20 and 15% 1 and 3 months later, respectively. This was in agreement with Poon et al. [20] who stated that not all HCCs secrete AFP and that ∼30% of the patients had normal AFP levels. In this study, the postprocedural complications were mild, which included abdominal pain in 18 (60%) and 20 (66.7%) and fever in seven (23.3%) and nine (30%) patients in groups I and II, respectively. There was no significant statistical difference with regard to complications in the two modalities in this study. Other complications including hematemesis and ascites were not observed. Livraghi et al. [16] reported hemothorax (2%) due to damage of an intercostal vessel along the needle track, intraperitoneal bleeding, hemobilia and mild cholecystitis. Livraghi et al. [21] reported complications such as segmental bile duct injury and multiorgan failure. In another study by Azab et al. [2], two major complications including massive bleeding from the liver capsule and death were reported. However, both complications seemed largely attributable to surgeon error rather than to the RFA procedure itself. Complete ablation was achieved in 43 (71.6%) of all (60) patients: 18 (60%) in group I compared with 25 (83.3%) of group II, after 3 months, as confirmed by triphasic CT with contrast. The difference was statically significant, denoting better penetration of acetic acid, as it destroys the fibrous septa present in the HCC. When the studied patients were classified into subgroups A (5.1–6 cm) and B (6.1–7 cm), ablation was significantly better in group II A than group I A (86.6 vs. 66.7%) and in group II B than group I B (80 vs. 46.7%), denoting that, when acetic acid was added to RFA, ablation was better than when ethyl alcohol was added, indicating better diffusion to the unablated zones of the HCCs. There are few studies concerning combination therapies for large tumors; PAI alone was compared with RFA alone with medium and large-sized tumors; acetic acid showed comparable results (76 vs. 73.7%) in a study conducted by El-Kady et al., [22]. Moreover, the current results are similar to Livraghi et al. [21] who conducted the first study in which the effectiveness of RFA in the treatment of HCCs 3.1–8.0 cm in diameter by means of a predominantly surgical approach was evaluated specifically. He demonstrated an overall complete ablation rate of 91% for HCCs 3.1–8.0 cm in diameter and 93% for HCCs 3.1–5 cm. He assumed that radical ablation of large tumors is difficult to achieve percutaneously, even with repeated sessions. In the study conducted by El-Kady et al. [22], PAI alone was used for medium and large-sized tumors, which ablated 76% of the lesions. When PAI was compared with PEI in tumors up to 6 cm in diameter, ablation was achieved in 86.7 and 66.7%, respectively [5]. Combined therapies in smaller tumors up to 5 cm gave better results than in large tumors. In one study conducted by El-Sayed et al. [23] using RFA plus PEI, 97% of 33 lesions were ablated. In one study using RFA plus PAI ablation of large tumors (5–8 cm) conducted by Okoda [8], ablation was achieved in 46.6% compared with 20% using PAI alone. In another study using RFA plus PAI conducted by El-Sayed [23], ablation was achieved in 90% in lesions less than 5 cm. Our results showed the superiority of RFA plus PAI combination for large tumors (>5 cm and up to 7 cm in diameter). Acetic acid has the ability to penetrate cells, with the property of extracting collagen and dissolving lipids, and has a stronger killing effect on hepatocytes than ethanol, as reported by Okoda [8]. However, more studies are needed to evaluate different combinations and frequencies of sessions on larger series of patients.


  Conclusion Top


Ablation of inoperable large HCC 5.1–7 cm can be performed with combined techniques (RFA plus PAI or RFA plus PEI). However, while using the overlapping technique, RFA plus PAI was superior in complete ablation of lesions than RFA plus PEI.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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