Transarterial Ethanol Ablation for Unresectable Hepatocellular Carcinoma

Abstract: Transarterial ethanol ablation (TEA) has been compared to transarterial chemoembolization  (TACE) in randomized controlled trials and found to be associated with better tumor response in hepatocellular carcinoma (HCC). These results suggest TEA is a promising transarterial therapy that may be better than TACE for HCC.

Key words: transarterial ethanol ablation, transarterial chemoembolization, hepatocellular carcinoma

______________________________

Hepatocellular carcinoma (HCC), one of the most commonly occurring solid malignancies globally, has tripled in incidence in the last 2 decades in United States,¹ and it remains endemic in Asia and Africa,² so much so that it is diagnosed in half a million of people annually worldwide.³ Transarterial therapy has been playing an important role for patients with multifocal or large intrahepatic lesions not eligible for surgical resection, transplantation, or local ablative therapy.⁴ There are various options for transarterial therapy including lipiodol-based transarterial chemoembolization (TACE), bland embolization,⁵ radioembolization,⁶ drug-eluting bead with doxorubicin (DEB-DOX),⁷ and transarterial ethanol ablation (TEA).^8-11 TACE is the only therapy of these that has been proven to have survival benefit vs best supportive care in randomized controlled trials (RCTs).^12-14 Currently it remains the standard of care for transarterial therapy for unresectable HCC, and it serves as a benchmark against which other transarterial options should be compared. Compared to TACE, DEB-DOX has been shown in RCTs to be associated with less liver and systemic toxicity and better objective tumor response in patients with more advanced disease (52.4% vs 34.7%, P=.038),⁷ however, the study failed to show a difference in objective tumor response in the whole group. Transarterial ethanol ablation has also been compared to TACE in RCTs and found to be associated with better tumor response in terms of complete response, longer time to intralesional progression, and longer survival free from intralesional progression.¹⁵ The complete response rate on a lesion basis was persistently and significantly higher in the transarterial ethanol ablation arm at 3 months (70.5% vs 51.3%, P=.012) and 6 months (72.2% vs 53.9%, P=.012). The median time to progression and progression free survival for intralesional progression were longer in the TEA arm, (TTP 34.6 months vs 26.05 months, P=.028); PFS 14.8 months vs 9.3 months, P=.029). These results suggest TEA is a promising transarterial therapy that may be better than TACE for HCC.

The Formulation

Lipiodol-ethanol mixture formulation is prepared by drawing 2 mL of lipiodol (equivalent to ethiodol; ethyl ester of fatty acid of poppy seed oil; contains 37% by weight of iodine) and 1 mL of absolute ethanol (99.9% ethyl alcohol; Quantum Chemical Corporation) into 3-mL syringes, which are vigorously shaken with forward and backward motion for 20 cycles until a clear champagne-like homogeneous solution is formed. The mixture is prepared in less than 5 minutes just before its administration.

Mechanism of Action

Transarterial ethanol ablation is a hybrid of bland embolization and chemical ablation. Utilizing a liquid agent of lipiodol-ethanol mixture consisting of 33% ethanol by volume, TEA offers complete and long-lasting embolization of both the arterioles and portal venules supplying the tumor.^16-18 The component of ethanol very likely offers synergistic effect to embolization and causes tumor ablation.¹¹ 

Selection Criteria 

Patients who fulfill the following criteria could be accepted for treatment: Child-Pugh A or B cirrhosis, ECOG performance score 2 or below, massive expansive tumor type, total tumor mass <50% liver volume, tumor size ≤15cm in largest dimension, tumor number ≤5, no concurrent ischemic heart disease or heart failure, serum creatinine level ≤180 umol/L, serum total bilirubin level <50 umol/L, serum albumin level ≥25g/L, and INR ≤1.5. Transarterial ethanol ablation is contraindicated if there is biliary obstruction not amenable to percutaneous drainage, Child-Pugh C cirrhosis, history of hepatic encephalopathy, intractable ascites not controllable by medical therapy, extrahepatic metastasis, infiltrative or diffuse tumor, tumor number >5, thrombosis of target hepatic artery, partial or complete thrombosis of the main portal vein, tumor invasion of portal branch of contralateral lobe, hepatic vein tumor thrombus, significant arterioportal venous shunt, or significant arterial-hepatic venous shunt.

Treatment Procedures

Prophylactic antibiotic is not mandatory. It is important for the treatment to be delivered in a tumor-selective manner without affecting the normal liver, to minimize liver toxicity. The aim of the treatment procedure was to fill the tumor vasculature completely with the lipiodol-ethanol mixture. The volume of lipiodol-ethanol mixture to be delivered was not decided in advance and was dependent on the amount of uptake by tumor vasculature. We aim to identify all arterial feeders to tumors and catheterize them one after the other with a microcatheter to segmental or subsegmental level for delivery of the lipiodol-ethanol mixture. The agents are delivered under fluoroscopic control to prevent backflow, with an aim to completely fill up the vasculature of all tumors, at a rate of 0.5 mL/min to 6 mL/min until there is filling of portal venules. The completeness of treatment to a tumor is confirmed with cone-beam CT by assessing the degree of coverage of lipiodol to the tumor. Lignocaine 1% up to 5mL given intraarterially at individual tumor feeders within a minute before lipiodol-ethanol mixture administration is usually effective for analgesia. When necessary, 50 microgram fentanyl and 2–3 mg midazolam are given for pain relief and sedation. The maximum total volume of lipiodol-ethanol mixture to be delivered in one treatment session is 60mL.¹⁰ Further treatment sessions are given when there is CT evidence of residual or recurrent disease within the treated tumors or occurrence of new hepatic tumors. There is no upper limit on the number of further treatment sessions. Further treatment is contraindicated when there is CT evidence of progressive tumor growth within the treated tumors, CT evidence of vascular invasion or extrahepatic metastasis, or deterioration in liver function or patient condition meeting the exclusion criteria for patient selection. 

Treatment Toxicity

Treatment-related death has not occurred in published studies. Incidence of new onset of liver function derangements of grade ≥3, INR >1.2, and ascites following treatment are not common and usually reversible within 2 weeks. The majority of abdominal pain is of grade 1 severity, according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 2.0. Cardiac ischemia, hepatitis reactivation, liver abscess, cholecystitis, and post-treatment tumor rupture have not occurred. Respiratory decompensation due to intralesional arteriovenous shunting occurred rarely (3%, 3 out of 186 patients). The condition was associated with relatively large tumors that were treated with a relatively large dose. The patients presented acutely with oxygen desaturation and shortness of breath. Chest radiograph showed miliary pulmonary shadows on the same day and small pleural effusion subsequently. Radiographic signs subsided completely in 1 week. The patients recovered completely within 10 days after treatment with oxygen and steroids. Alcohol intoxication presenting with transient confusion and drowsiness occurred rarely (0.5%, one out of 186 patients). 

Conclusion

Transarterial ethanol ablation is an effective transarterial treatment option for local control of unresectable HCC, and it is well tolerated and reasonably safe if delivered in an appropriate manner.

Editor’s note: Disclosure: The author has completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Yu reports no related disclosures.

Manuscript received March 13, 2015; manuscript accepted July 1, 2015. 

Address for correspondence: Simon Yu, MD, The Chinese University of Hong Kong, Department of Imaging and Interventional Radiology, Hong Kong. Email: simonyu@cuhk.edu.hk

Suggested citation: Yu S. Transarterial ethanol ablation for unresectable hepatocellular carcinoma. Intervent Oncol 360. 2015;3(8):E93-E97.

References

1. Surveillance, Epidemiology, and End Results (SEER) Program. SEER Stat database: incidence — SEER 9 Regs research data, Nov 2009 Sub (1973-2007). Bethesda, MD: National Cancer Institute, April 2010.

2. World Health Organization International Agency for Research on Cancer. GLOBOCAN 2008. https://globocan.iarc.fr

3. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, version 1.0. International Agency for Research on Cancer CancerBase no. 5. Lyon, France: IARC Press, 2001.

4. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118-1127.

5. Maluccio MA, Covey AM, Porat LB, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008:19(6):862-869. 

6. Sato KT, Lewandowski RJ, Mulcahy MF, et al. Unresectable chemorefractory liver metastases: radioembolization with 90Y microspheres—safety, efficacy and survival. Radiology. 2008;247(2):507-515.

7. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41-52.

8. Cheng Y, Kan Z, Chen C, et al. Efficacy and safety of preoperative lobar or segmental ablation via transarterial administration of ethiodol and ethanol mixture for treatment of hepatocellular carcinoma: clinical study. World J Surg. 2000; 24(7):844-850.

9. Cheung YC, Ko SF, Ng SH, Chan SC, Cheng YF. Survival outcome of lobar or segmental transcatheter arterial embolization with ethanol-lipiodol mixture in treating hepatocellular carcinoma. World J Gastroenterol. 2005;11(18):2792-2795.

10. Yu SCH, Hui EP, Wong J, et al. Transarterial ethanol ablation of hepatocellular carcinoma with lipiodol–ethanol mixture: phase II study. J Vasc Interv Radiol. 2008;19(1):95-103.

11. Yu SCH, Hui JWY, Hui EP, et al. Embolization efficacy and treatment effectiveness of transarterial therapy for unresectable hepatocellular carcinoma: a case-controlled comparison of transarterial ethanol ablation with lipiodol-ethanol mixture versus transcatheter arterial chemoembolization. J Vasc Interv Radiol. 2009;20(3):352-359.

12. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation vs symptomatic treatment in patients with unresectable HCC: a randomised controlled trial. Lancet. 2002;359(9319):1734-1739.

13. Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable HCC. Hepatology. 2002;35(5):1164-1171.

14. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology. 2004;127(Suppl 1):S179-S188.

15. Yu SC, Hui JW, Hui EP, et al. Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization. Radiology. 2014;270(2):607-620.

16. Kan Z, Ivancev K, Lunderquist A. Peribiliary plexa-important pathways for shunting of iodized oil and silicon rubber solution from the hepatic artery to the portal vein: an experimental study in rats. Invest Radiol. 1994;29(7):671-676.

17. Kan Z, Wallace S. Transcatheter liver lobar ablation: an experimental trial in an animal model. Eur Radiol. 1997;7(7):1071-1075.

18. Yu SCH, Chan CT. Investigative radiology transarterial ethanol ablation of cirrhotic liver with lipiodol-ethanol mixture: Safety and efficacy study in rats. Invest Radiol. 2006;41(8):609-617.