Menoufia Medical Journal

ORIGINAL ARTICLE
Year
: 2018  |  Volume : 31  |  Issue : 2  |  Page : 487--493

Primary assessment of radiofrequency ablation combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma, a comparative study with traditional transarterial chemoembolization


Mohammed S Abd Allah1, Mohamed S Eldin El Zawawi1, Osama L El Abd2, Mohamed K Abd El-Mageed1,  
1 Department of Radiology, Faculty of Medicine, Menoufiya University, Shibin Al Kawm, Egypt
2 Department of Radiology, National Liver Institute, Menoufiya University, Shibin Al Kawm, Egypt

Correspondence Address:
Mohamed K Abd El-Mageed
Radiology Department, Faculty of Medicine, Menoufia University, Shibin Al Kawm
Egypt

Abstract

Objectives This study aimed to evaluate the role and efficacy of combined transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) in the management of patients with large unresectable hepatocellular carcinoma (HCC) in comparison with traditional TACE alone. Background Surgery is still the treatment of choice for patients with HCC when diagnosed at an early stage. Unfortunately, most HCCs are diagnosed at intermediate or advanced stages. RFA is an alternative to partial hepatectomy for early HCC less than 3 cm. TACE is classified as palliative therapy in patients with intermediate-stage HCC. However, neither TACE nor RFA can result in adequate control of large-sized HCCs. Sequential application of TACE and RFA is increasingly being used in the treatment of medium-sized or large-sized HCC to overcome the limitations of each technique. Patients and methods This prospective study included 40 patients (men/women ratio: 31/9) who had a large unresectable HCC (<5 cm in maximum diameter). Patients were divided into two groups: the first group was treated with combined therapy (TACE–RFA) whereas the second group was treated with traditional TACE. Finally, the therapeutic response was evaluated by 1-month postprocedure triphasic computed tomography. Results The 1-month postprocedure triphasic computed tomography indicated that a complete response was achieved in 19/20 patients in group I and 8/20 patients in group II, whereas a partial response was achieved in 1/20 patients in group I and 10/20 patients in group II. A stable disease was observed in 2/20 patients in group II alone. Finally, no evidence of disease progression could be observed in both groups. Conclusion Combined therapy TACE–RFA is superior to TACE alone in achieving better therapeutic effects for patients with large unresectable HCC.



How to cite this article:
Abd Allah MS, Eldin El Zawawi MS, El Abd OL, Abd El-Mageed MK. Primary assessment of radiofrequency ablation combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma, a comparative study with traditional transarterial chemoembolization.Menoufia Med J 2018;31:487-493


How to cite this URL:
Abd Allah MS, Eldin El Zawawi MS, El Abd OL, Abd El-Mageed MK. Primary assessment of radiofrequency ablation combined with transarterial chemoembolization for the treatment of hepatocellular carcinoma, a comparative study with traditional transarterial chemoembolization. Menoufia Med J [serial online] 2018 [cited 2020 Apr 7 ];31:487-493
Available from: http://www.mmj.eg.net/text.asp?2018/31/2/487/239720


Full Text



 Introduction



Hepato cellular carcinoma (HCC) is the sixth most common cancer in the world and the third cause of cancer death [1],[2],[3],[4],[5]. In Egypt, liver and bladder cancers represent 44% of cancers in men, whereas breast and liver cancers represent 45% of cancers in women [6].

HCC is not sensitive to radiotherapy or chemotherapy; therefore, surgery is still the treatment of choice for early stages. Unfortunately, only 30% of patients benefit from curative therapies as most HCCs are diagnosed at intermediate or advanced stages [1].

Radiofrequency ablation (RFA) and transcatheter arterial chemoembolization (TACE) are minimally invasive options that may achieve the pertinent balance in successful tumor eradication and maximal preservation of liver function [3].

Nowadays, RFA is generally recognized as a curative treatment alternative to partial hepatectomy for early HCC less than 3 cm in diameter [7]. TACE prolongs survival in patients with compensated liver disease and intermediate-stage HCC. However, this procedure is not curative [8]. Therefore, neither TACE nor RFA can result in adequate control of medium or large HCC.

The combination of TACE and RFA is, therefore, increasingly being used in the treatment of medium or large HCC to induce large areas of coagulative necrosis without any possibility of revascularization [4].

This study aimed to evaluate the efficacy of TACE, followed by RFA in the management of patients with large unresectable hepatocellular carcinoma.

 Patients and Methods



Ethical consideration

Written informed consent was obtained from all participants. The patients were informed that they had the right to refuse participation.

Patients

This study was carried out from April 2014 to March 2015 at the Radiology Department of the National Liver Institute of Menofyia University.

The study included forty patients, 31 (77.5%) men and nine (22.5%) women, ranging in age from 49 to 62 years; these patients had a large unresectable HCC <5 cm in maximum diameter) with Child Pugh classification (A or B).

The patients were divided into two groups according to treatment modality. Group I included 20 HCC patients who underwent TACE, followed by RFA (TACE–RFA) within 4 weeks, with 18 (90%) patients with single tumor sizes of 5–7 cm and two (10%) patients with single tumor sizes of 7–9 cm. Group II included 20 HCC patients who underwent TACE only as a control group, with 14 (70%) patients with single tumor sizes of 5–7 cm and six (30%) patients with single tumor sizes of 7–9 cm [Figure 1], [Figure 2], [Figure 3].{Figure 1}{Figure 2}{Figure 3}

Inclusion criteria included patients with accurate proof of solitary irresectable HCC of more than 5 cm in diameter with Child–Pugh class A or B.

The exclusion criteria were patients with Child–Pugh class C, patients with multinodular focal lesions, extra hepatic spread, patients with radiologic evidence of vascular invasion, patients with marked bleeding diathesis, and patients who had contraindications to the chemoembolizing drugs used.

All patients were categorized according to the Barcelona-Clinic liver cancer Staging System of HCC, performance status of liver functionality, and Child–Pugh scores [9].

Procedures

All of the patients enrolled were subjected to tests of complete blood count, alanine transaminase (ALT), aspartate transaminase (AST), serum albumin, serum bilirubin, serum creatinine, prothrombin time and international normalized ratio, hepatitis markers (HCVAb, HBsAg), α-fetoprotein (AFP), abdominal ultrasonography, and abdominal triphasic computed tomography (CT) study.

In 1-month post-treatment follow-up studies, all patients were subjected to the following evaluation measures: assessment of history and full clinical examination, determination of prothrombin concentration, serum albumin level, serum total and direct bilirubin, AST and ALT levels, AFP level, and triphasic multidetector CT scan of the liver.

Classification of response was performed according to the modified Response Evaluation Criteria in Solid Tumors (m-RECIST) criteria taking into account enhancement of viable tumor tissue without taking into consideration changes in tumor volume as follows: complete response (CR): disappearance of any intratumoral enhancement in all target lesions; partial response (PR): at least a 30% decrease in the sum of the diameter of viable (arterial phase enhancement) target lesions; progressive disease (PD): at least 20% increase in the sum of the diameters of viable target lesions; and stable disease (SD): does not qualify for CR/PR or PD [8].

Using percutaneous endovascular techniques, TACE was performed by selective catheterization of the hepatic segmental arteries nourishing the lesions using a 5-F Cobra catheter (Ruby line angiography catheter, 5 Fr, 80 cm; Biotech Corporation, Taiwan 8F., No.156, Chien-Kang Rd., Taipei) with a 3-F coaxial microcatheter (2.9 F; Terumo Corporation, Tokyo, Japan). The cytotoxic mixture was prepared by mixing 50 mg adriamycin powder (Doxorubicin; Pfizer, 235 East 42nd Street New York, NY 10017) with 10 ml of saline and 10 ml of oily contrast (Lipiodol Ultrafluide, Laboratoire Guerbet, Aulnay, Sous-Bois, France). Then, it was injected slowly, followed by embolization by small pieces of gel foam particles.

Percutaneous radiofrequency ablation was performed under ultrasound guidance after administration of general anesthesia. RITA (RITA Medical Systems, Mountain View, California, USA) expandable-type electrodes were used. These electrodes had multiple thin curved monopolar electrodes extending from the central cannula (18–14 G). Radiofrequency emanates from each of these hooks, resulting in increased coagulation.

Statistical analysis

Sample size calculation for an interventional case–control study

The sample size required to achieve the set objectives at a 90% confidence level was calculated using the formula for calculating the sample size for an interventional case–control study:

[INLINE:1]

Where Zα is the standard normal deviate in α-probability from a normal distribution curve and Zβ is the standard normal deviate in β-probability from a normal distribution curve.

[INLINE:2]

Where p 1 is the expected event in the control group, from a previous study in the literature and p 2 is the expected event in the treatment group, from previous studies in the literature

[INLINE:3]

Zα and Zβ from normal distribution curves are 1.96 and 0.842, respectively, p 1 and p 2 from a previous study are 13 and 57%, respectively, and δ is 44%. Application of the above formula yields a sample size of 20 patients.

[INLINE:4]

Therefore, we chose 20 patients f or each group.

The collected data were statistically analyzed using the program SPSS (Statistical Package for Social Sciences, software version 16.0; Released 2007. Chicago, SPSS Inc., USA). Quantitative data were expressed as mean and standard deviation and analyzed using the student t-test for the comparison of two groups of normally distributed variables and the Mann–Whitney U-test for non-normally distributed variables. Qualitative data were expressed as number and percentage and analyzed using the χ2-test. All these tests were used as tests of significance at P less than 0.05: no significance at P greater than 0.05 and highly significant at P less than 0.001.

 Results



Both groups were matched with respect to age and sex. Comparison between both groups in the different scoring systems showed no statistically significant difference (P > 0.05). There were 15 (75%) Child–Pugh class A and five (25%) class B patients in the TACE-RFA group versus 14 (70%) and six (30%) patients in the TACE-only group [Table 1]. Performance status grades of 0 were present in 14 (70%) and six (30%) patients with grade 1 in the TACE-RFA group versus 15 (75%) and five (25%) patients in the TACE-only group [Table 2].{Table 1}{Table 2}

There was a statistically insignificant difference in the Child–Pugh class as well as the performance status of both groups before and 1 month after the procedure (P > 0.05) [Table 1] and [Table 2].

There was a statistically significant difference in ALT and AST levels in both groups before and 1 month after the procedure (P < 0.05), whereas there was a statistically insignificant difference in the results of other lab investigations (P > 0.05) [Table 3] and [Table 4].{Table 3}{Table 4}

There was a statistically significant difference between the studied groups in the incidence of immediate post-procedure pain (P < 0.05), whereas there was a statistically insignificant difference in the incidence of fever and vomiting (P > 0.05) [Table 5].{Table 5}

There was a statistically insignificant difference between the studied groups in the incidence of 1-month postprocedure complications (P > 0.05) [Table 6].{Table 6}

There was a statistically significant difference between the studied groups in the preprocedure and 1-month postprocedure level of alpha fetoprotein level (P < 0.05) [Table 7].{Table 7}

There was a statistically significant difference between the studied groups in tumor response to treatment according to the modified RECIST criteria (P < 0.05) [Table 8]. Complete response achieved in 19/20 patients of group I and 8/20 patients of group II, whereas partial response was achieved in 1/20 patients of group I and 10/20 patients of group II. Stable disease was observed in 2/20 patients of group II alone. Finally, no evidence of disease progression could be observed in both groups.{Table 8}

 Discussion



TACE and RFA were introduced successfully as new combined therapy for the treatment of unresectable (intermediate or large HCC). The aim of its use are aiming to gain most of their benefits and overcoming their own limitations without affection of the proper hepatic reserve for already compromised cirrhotic patients.

In our study, there was no statistically significant difference between the studied groups in age and sex distribution. This is to ensure that there was no difference between both groups in age and sex. This was consistent with El Dorry et al. [10], who reported that both groups were matched with respect to age and sex.

In our study, there was no statistically significant difference between both groups in baseline Child–Pugh classification stage. This was also to ensure that there was no difference between both groups in the hepatic functional reserve. This was consistent with El Dorry et al. [10], who reported that both groups were matched with respect to child class.

In our study, there was a statistically insignificant difference in group I as well as in group II patients in preprocedure and 1-month postprocedure Child–Pugh classification. These results run parallel with the results of the study published by Cheng et al. [11], who found no significant difference in patients in preprocedure and postprocedure Child–Pugh classification.

In our study, there was a statistically insignificant difference between the studied groups in 1-month postprocedure liver function tests. However, statistical analysis of laboratory studies of both groups showed a statistically significant difference in ALT, AST before, and 1 month after the procedure (P < 0.05). These results were in agreement with those of Cheng et al. [11], who found that most patients had increased serum alanine aminotransferase and aspartate aminotransferase levels, considering it as a common finding after TACE sessions because of induced liver tissue necrosis and release of these enzymes. This was not in agreement with a previous study by Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire [12], who considered liver failure after TACE as a major limitation to survival benefit as it occurred in more than 50% of patients because the mean levels of SGOT and SGPT increased to 600–1200 U/l in serious cases.

In our study, there was no significant difference in the performance status of both groups before and 1 month after the procedure as 44% of patients shifted from a PST score of 1-0 after 1 month of the combined therapy whereas 4% of patients shifted from a PST of 0-1 after TACE only. This was not in agreement with El Dorry et al. [10], who reported that there was an improvement in the performance status of many patients following RFA–TACE therapy as 44% of patients shifted from a PST score of 1-0 after 1 month of the combined therapy, whereas 4% of patients shifted from a PST of 0-1 after TACE only. Sacco et al. [13] reported that there was worsening of clinical status in patients after TACE only.

In our study, in terms of immediate postprocedure minor complications, there was a statistically significant difference between both groups in fever and abdominal pain, whereas there was a statistically insignificant difference between both groups in fever and vomiting. This was in agreement with El Dorry et al. [10], who reported that immediate postprocedure complications affected 68% combined group patients, whereas 72% of the patients in the TACE group were affected. This was not in agreement with Takaki et al. [14], who reported that immediate postprocedure complications were observed in 3% of patients after combined TACE–RFA therapy.

In our study, no significant major complications were reported 1 month after combined TACE–RFA or after TACE alone. This was in agreement with El Dorry et al. [10], who reported that no major complications were encountered after combined therapy or after TACE only. Peng et. al. [15] also reported that there were no treatment-related deaths. Our results were not in agreement with Chen et al. [7], who reported a complication rate of 2.5% (14 of 565 procedures) in their study, which included incidences of five hemorrhages, one colon perforation, five injuries of adjacent structures, two bile leakages, and one skin burn. The large sample size could explain the high incidence rate of these complications in comparison with the small sample size in our study.

In our study, statistical analysis of serum AFP values before and after treatment showed that there was a statistically significant decrease in its levels (P < 0.05) in both groups. This was in agreement with Riaz et al. [16], who concluded that AFP response observed after locoregional therapy should be considered an ancillary method of assessing tumor response.

In our study, the 1-month postprocedure triphasic CT showed a significantly higher complete response and no significant local tumoral progression with the use of the combined technique in comparison with traditional TACE. A complete response was achieved in 19 patients of group I (95% of the total group) and eight patients of group II (40% of the total group). These results are in agreement with Veltri et al. [17], who had treated nonearly HCCs patients with TACE, followed by RFA, with a complete response achieved for 66.7% of the lesions. These results were also consistent with those of El Dorry et al. [10], who reported that CR was achieved after 1 month in 100 and 84% of patients in the combined RFA–TACE and TACE-alone groups, respectively. This was also in agreement with Yamakado et al. [18], who reported that CR was achieved in 79.9 and 92.5% of HCC patients after combined (TACE–RFA) and RFA therapy, respectively. These results were not in agreement with Wang et al. [19], who showed that CR was achieved in only 6% of large-sized HCCs (>5 cm) after (TACE–RFA) therapy.

From the above results, on comparing combined TACE and RFA and TACE alone, it was found that combined TACE and RFA is more effective in achieving local control of the treated target lesions. The difference in the complete response rate between combined TACE and RFA and TACE alone could be accounted for by the difference in the mechanism of the two treatments, and the effectiveness of combined TACE and RFA in achieving a decrease in heat dispersion by blood flow occlusion in the tumor region and, therefore, to increase the size of the necrosis area induced by RFA.

The present study may had a bias that the patients were followed up with CT and therefore residual or recurrent lesions that might be masked by lipiodol accumulated within the treated tumors.

The present study also had some limitations. The sample size was small, but it was large enough to prove the concept. The postprocedure follow-up was also short, and long-term efficacy and survival need to be studied further. Finally, we determined efficacy only on the basis of angiographic and CT imaging, without a postoperative pathological examination. These limitations can be easily avoided in larger, longer, and better-funded studies.

 Conclusion



Combined therapy TACE–RFA is superior to TACE alone in achieving a better therapeutic effect for patients with large unresectable hepatocellular carcinoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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