Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol–ethanol mixture

Adel M El Wakeel; Mohammed S El Warraky; Tarek F Abd Ella; May S El Safty

doi:10.4103/1110-2098.192426

ORIGINAL ARTICLE

Year : 2016 | Volume : 29 | Issue : 2 | Page : 285-290

Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol–ethanol mixture

Adel M El Wakeel¹, Mohammed S El Warraky¹, Tarek F Abd Ella², May S El Safty³
¹ Department of Diagnostic Radiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
² Department of Diagnostic Radiology and Interventional, National Liver Institution, Menoufia University, Menoufia, Egypt
³ Department of Diagnostic Radiology, El Menashowy Hospital, Egypt

Date of Submission	15-Mar-2014
Date of Acceptance	02-Jun-2014
Date of Web Publication	18-Oct-2016

Correspondence Address:
May S El Safty
Omar Ibn Abd El Aziz, Tanta, 31511
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/1110-2098.192426

Abstract

Objective:
The aim of the study was to determine the safety and effectiveness of transarterial embolization ablation (TEA) of hepatocellular carcinoma (HCC) with a lipiodol–ethanol mixture.
Background:
TEA is a new treatment strategy for HCC, and some researchers have reported its effectiveness in HCC.
Patients and methods:
This study was a prospective cohort study conducted at the National Liver Institute and Faculty of Medicine, Menoufia University, and included 40 patients having unresectable HCCs. At 3 and 6 months after TEA, triphasic computed tomography was performed, and tumor responses were assessed using a modified version of Response Evaluation Criteria in Solid Tumor (mRECIST).
Results:
Every case was treated. At 3 and 6 months after embolization, contrast computed tomography showed no enhancing lesions.
a-Fetoprotein levels were significantly reduced (12.18 ± 15.67) at 6 months after treatment. The partial and complete responses of tumors were 12.5 and 87.5%, respectively, 6 months after treatment. The overall survival rate was 90%.
Conclusion:
TEA is an effective therapy for patients with unresectable HCC.

Keywords: hepatocellular carcinoma, lipiodol–ethanol mixture, transarterial ethanol ablation

How to cite this article:
El Wakeel AM, El Warraky MS, Abd Ella TF, El Safty MS. Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol–ethanol mixture. Menoufia Med J 2016;29:285-90

How to cite this URL:
El Wakeel AM, El Warraky MS, Abd Ella TF, El Safty MS. Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol–ethanol mixture. Menoufia Med J [serial online] 2016 [cited 2023 Oct 3];29:285-90. Available from: http://www.mmj.eg.net/text.asp?2016/29/2/285/192426

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide and the third most common cause of tumor-related death ^[1],[2],[3]. HCC is not sensitive to radiotherapy or chemotherapy. Therefore, surgery is still the treatment of choice. Unfortunately, fewer than 30% of patients with HCC benefit from surgical resection because of unfavorable tumor location, stage or extent of disease, limited liver functional reserve, or high operative risk ^[4],[5]. Minimally invasive thermal ablation, a new form of treatment for HCC, achieves complete responses in more than 80% of tumors smaller than 3 cm in diameter. However, in tumors of 3–5 cm diameter, the complete response rate is only 50% ^[6]. Therefore, ablation is not recommended for tumors larger than 5 cm. HCC is a hypervascular tumor that receives mostly hepatic arterial blood ^[7]. Since its introduction by Yamada et al. ^[8],[9] in the 1980s, transcatheter arterial chemoembolization (TACE) has been widely used to treat patients with inoperable liver tumors. The theoretical basis of TACE for treating HCC is that chemotherapeutic agents mixed with embolic material and injected into the hepatic artery will embolize the arteries that supply the tumor and kill the tumor cells ^[8],[9]. However, Liu et al. ^[7] have also have reported that many HCC tumors, especially those larger than 5 cm in diameter, receive blood from both the hepatic artery and the portal vein. Therefore, TACE must be administered more than once, and tumor necrosis might still be incomplete ^{[10],[11],[12]}. More recently, drug-containing beads have been evolved and have proved to have greater survival benefit, although they are expensive ^[2].

Percutaneous ethanol injections have been used to treat unresectable small HCC tumors ^[3]. Ethanol produces permanent microcirculatory embolization that inhibits tumor growth by denaturing protein, coagulating platelets, and dehydrating vascular endothelial cells in tumors, and can kill tumor cells ^[14],[15].

Transarterial embolization ablation (TEA) started to be used to treat HCC with lipiodol–ethanol mixture (LEM), similar to that for renal tumors ^{[16],[17],[18]}. Theoretically, compared with TACE, TEA has the following potential advantages:

LEM can permanently embolize tumor-feeding vessels that come from the hepatic artery and portal vein [15, 17, 19]; therefore, TEA might have a stronger antitumor effect compared with TACE ^[15],[17].
After TACE, tumor and peritumoral normal tissues become ischemic and hypoxic and secrete angiogenic substances that provide new conditions for tumor proliferation and recurrence ^[20],[21], whereas TEA with the fluid LEM leads to infarction of the entire tumor and of the peritumoral normal liver tissue without collateral circulation ^[0].
Finally, embolization of tumor vessels by LEM helps ethanol diffuse into the tumor tissue cells [18,22–26].

The formulation of the LEM used in this study consisted of a decreased proportion of ethanol to 33% by volume. On the basis of the study by Yamada et al. ^[8], a LEM with a reduced ethanol composition has been shown to be associated with a diminished degree of endothelial damage of the arterial feeder vessel of the tumor, which facilitates effective delivery of the mixture to the tumor vasculature. Previous studies had reported that lipiodol–ethanol treatment was found to be safe and effective for the treatment of HCC, especially for small lesions in patients with Child–Pugh class A disease ^[13],[14].

The purpose of this study was to evaluate the safety and efficacy of patients treated by TEA using a LEM with the proportion of ethanol 33% by volume.

Patients and Methods

This study included 40 patients with unresectable HCC with 48 lesions treated by transarterial embolization using a LEM. Inclusion criteria included Child A and B score, unsuitability for radiofrequency ablation, refusal of or contraindication to surgical resection, Eastern Cooperative Oncology Group (ECOG) performance status 2 or less, creatinine less than 2 mg/dl, serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase less than 270 IU/l, tumor burden less than 50% of the liver volume, and hypervascularity of the lesion as evaluated on triphasic computed tomography (CT) ([Figure 1] and [Figure 2]) or digital subtraction angiography.

Figure 1: Triphasic computed tomography demonstrated rounded exophyetic lesion in segment showing contrast enhancement in the arterial phase and portovenous phase and washout in the delayed phase

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Figure 2: Angiogram during and after embolization: celiac angiogram (a). Left hepatic angiogram showing tumor blush (b). Angiogram after embolization (c). Lipiodol and ethanol retention in the focal lesion (d)

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The demographic data of these patients are shown in [Table 1].

Table 1: Demographic data of the studied hepatocellular carcinoma patients

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Treatment protocol

After infiltration of a local analgesic, the Seldinger technique was used to gain access to the aorta through femoral artery puncture.

A 5 Fr vascular sheath was placed into the common femoral artery over a 0.035 inch guidewire. Under fluoroscopic guidance, the 5-Fr Cobra catheter (Cordis, 2201 Rosecrans Ave. El Segundo, CA 90245) was advanced into the aorta. Angiographic study of the superior mesenteric artery, celiac trunk, and common hepatic artery was performed to identify all of the vessels feeding the HCC nodule and to assess patency of the portal vein. The arterial branches feeding the tumor were selectively cannulated by a microcatheter to proceed with transcatheter arterial embolization and to ensure better preservation of the surrounding nontumoral liver tissue.

LEM formulation was prepared by drawing 6 ml of lipiodol (equivalent to ethiodol; ethyl ester of fatty acid of poppy seed oil; contains 37% by weight of iodine) and 3 ml of absolute ethanol (99.9% ethyl alcohol) into 10-ml syringes, which were vigorously shaken with forward and backward motion for 20 cycles until a clear champagne-like homogeneous solution was formed. The mixture was prepared within 5 min just before its administration.

The volume of LEM to be delivered was not decided in advance and was dependent on the amount of uptake by tumor vasculature. The upper limit of total volume of LEM to be delivered in one treatment session was set at 60 ml to limit the dose of ethanol to 20 ml. When necessary, 50 mg fentanyl and 2–3 mg midazolam were given for pain relief.

Follow-up was performed at 3 and 6 months after embolization by a-fetoprotein (AFP) and triphasic CT.

Results

The transarterial treatments with LEM were technically successful in all patients. The mean ± SD LEM volume was 16.9 ± 3.9 ml and the range was from 8 to 45 ml. The maximum total dose of LEM was 55 ml. Regarding the number of treatment sessions, 34 patients underwent one treatment session and six patients underwent two sessions, with an overall 46 sessions for the 40 patients ([Table 1]). Procedure-related mortality was 0%. Postembolization syndrome occurred after six (13.04%) of the 46 procedures. Acute hepatic decompensation occurred after six (13.04%) procedures: in two patients with Child B and in one patient with Child A. Ascites represented the most common manifestation and occurred alone after five of the six procedures. Jaundice and ascites occurred after one procedure. Two (5%) patients recovered completely 6 weeks after treatment. One patient did not recover but did not die ([Table 2]). There was a highly significant decrease in serum AFP levels 6 months after (12.18 ± 15.67 ng/ml) compared with before TAE-LEM (808.11 ± 545.14 ng/ml) (P < 0.001) ([Table 3]).

Table 2: Descriptive table shows frequency and percentages of different complications after 1 month

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Table 3: Means and SD values of a-fetoprotein level recorded 6 months after treatment and their significance to the pretreatment values

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Three months after treatment, ([Figure 3]) the lesions were classified as complete response (n = 44; 91.67%) and partial response (n = 4; 8.3%). One of them had extralesional intrahepatic disease; the other three patients with partial response were subjected to two additional sessions of embolizations. For extralesional intrahepatic disease, the HCC lesion was in segment 8 and measured 3 cm in diameter. This lesion was subjected to radio-frequency ablation.

Imaging 6 months after the procedure ([Figure 4]) demonstrated two additional lesions with partial response in six (12.5%) lesions, whereas a complete response was seen in 42 (87.5%) lesions ([Table 4]).

Table 4: The tumor response according to the modified version of response evaluation criteria in solid tumor criteria at 3 and 6 months

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Figure 3: Follow-up triphasic computed tomography (after 3 months) demonstrating adequate embolization. No enhancement in the arterial phase. Portal phase and delayed phase displayed adequate embolization and no washout

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Figure 4: Follow-up triphasic computed tomography (after 6 months) demonstrated adequate embolization. No enhancement in the arterial phase. Portal phase and delayed phase displayed adequate embolization and no washout

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The overall 3- and 6-month survival rates were 100 and 90%, respectively. Thirty-six (90%) patients survived until the end of the study (after 6 months).

Discussion

TACE has become an important palliative treatment for patients with inoperable HCC ^{[5],[11],[12],[27],[28]}. Embolization of tumor-feeding arteries also prolong the exposure and concentration of tumor drugs and chemotherapeutic agents in the tumor microvascular bed, rather than allowing the drugs to reach the systemic circulation, which would reduce their effectiveness ^[5],[8],[9].

Kan et al. ^[5] performed superselective transcatheter arterial embolization with LEM, with 75% by volume of absolute ethanol, in the treatment of HCC lesions smaller than 5 cm with a prominent feeding artery, and found it a safe treatment for small nodular HCC that causes total or subtotal necrosis of the tumor and thickening of the capsule ^[5]. Ito et al. ^[9] reported that interarterial injection of 50% by volume of absolute ethanol was effective for achieving hemostasis of ruptured HCC and to prevent impending rupture of HCC ^[9].

In our study, instead of using a LEM with a high proportion of absolute ethanol by volume, the formulation of lipiodol–ethanol consisted of a decreased proportion of ethanol to 33% by volume. On the basis of the study by Kan et al. ^[9], a LEM with a reduced ethanol composition has been shown to be associated with a diminished degree of endothelial damage of the arterial feeder vessel of the tumor, which facilitates effective delivery of the mixture to the tumor vasculature. The findings of the present study were in keeping with those of two previous studies of lipiodol–ethanol treatment performed with a similar protocol ^[13],[14] in which lipiodol–ethanol treatment was found to be safe and effective for the treatment of HCC, especially for small lesions in patients with Child–Pugh class A disease.

Regarding the dose of LEM, the mean ± SD LEM volume was 16.9 ± 3.9 ml and the range was from 8 to 45 ml. According to Yu et al. ^[0], the total dose of LEM for each treatment session was limited to 60 ml to reduce the risk of potential adverse effects on the pulmonary circulation. Excessive LEM not trapped in the tumor vasculature will be drained through hepatic veins to the right heart and subsequently the pulmonary artery, where lipiodol will be trapped in pulmonary arterioles and eventually cleared by macrophages. Ethanol can cause vasoconstriction of pulmonary arterioles and resultant pulmonary hypertension. In the present study, we excluded cases with an arterioportal shunt and an arteriovenous shunt, and superselective catheterization of arterial tumor feeder vessels was adopted. The majority of the administered LEM was trapped in the tumor vasculature. It was found that 60 ml of LEM, which consists of 40 ml lipiodol and 20 ml ethanol, does not cause pulmonary or cardiac complications. Lipiodol was not detected in the lungs of our 40 patients on follow-up CT.

As shown in our study, the postembolization syndrome occurred much less commonly with TEA with lipiodol and ethanol. Post-treatment fever was predominant and occurred in 13.04% of 46 procedures. Acute hepatic decompensation occurred in 13.04% of the procedures and in 7.5% of patients, and irreversible decompensation occurred in 2.5% of patients. No other adverse effects of TACE occurred in the present study. There were no biliary complications. Prophylactic antibiotics were given to all patients and no liver abscesses were recorded. Reduction in the incidence of postembolization syndrome could be related to the absence of gelatin sponge embolization in TACE and selective embolization through tumor feeder vessels.

Regarding the efficacy of TAE, we selected parameters including laboratory response (decrease in AFP level), imaging response [according to modified version of Response Evaluation Criteria in Solid Tumor (mRECIST)], and clinical response (survival analysis).

In our study, serum baseline AFP level ranged between 52 and 10 000 ng/ml with a mean of 808.11 ± 545.14 ng/ml. Analysis of AFP values before and after treatment showed that there was a highly significant reduction in its levels during the follow-up period, being maximal at the end of 3 months (P < 0.001). The reduction in the AFP level is consequent to tumor necrosis induced by treatment because the AFP level is a good tumor marker for monitoring the effect of treatment in patients with HCC.

Regarding tumor response, the assessment of change in tumor dimension based on WHO criteria may not truly reflect tumor response to transcatheter embolization or local ablation in solid tumors such as HCC. This is because a mass of dead tissue always remains even after complete killing of tumor cells in the tumor mass, and it may take years for the dead tissue mass to be completely resolved. Instead of WHO criteria, we used mRECIST criteria that reflect the actual practical course of HCC after treatment. These criteria depend on evaluating the residual and recurrence active tissue plus the diameter of the target tumor. The high effectiveness and potency of TEA with lipiodol and ethanol in the local eradication of HCC were reflected by the sustained lipiodol retention inside the tumor tissue seen on CT. At 3 months, the complete and partial responses were achieved in 91.6 and 8.3% of 48 lesions, respectively. At 6 months, the complete and partial responses were achieved in 87.5 and 12.5% of 48 lesions, respectively.

Regarding overall survival, of the 40 patients studied, 4 died during the 6 months of follow-up with a survival rate of 90%. The cause of death was liver cell failure in two patients and hepatic encephalopathy in other two patients, and we considered the underlying cirrhosis responsible for mortality in those patients.

Conflicts of interest

There are no conflicts of interest.[30]

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