Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less

S-M Lin; C-J Lin; C-C Lin; C-W Hsu; Y-C Chen

doi:10.1136/gut.2004.045203

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Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less

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Complications of radiofrequency ablation in hepatocellular cancer: what about "exoplosive spread"?
Fabio Farinati
Published on: 18 April 2016
Complication Rates of Ablation Therapies for HCC: a Difficult Comparison with an Easy Solution
Vincenzo Arienti
Published on: 18 April 2016

Published on: 18 April 2016
Complications of radiofrequency ablation in hepatocellular cancer: what about "exoplosive spread"?
- Fabio Farinati, Associate Professor of Gastroenterology
- Other Contributors:
  C.Angonese, A.Baldan, U.Cillo, A.DAlessandro, M.De Antoni, M.De Giorgio, A.Masotto, D.Marino, M.Massani, M.Mazzucco, E.Miola, D.Neri, D.Paccagnella, G.Pivetta G, L.Tommasi, F.Tremolada, A.Tufano, G.Zanus
Dear Sir,
Surgery (resection or transplantation) is the first treatment choice for early HCC, but unfortunately it is feasible only in a minority of patients.[1] Local percutaneous ablation has therefore dramatically increase in importance and radio-frequency thermal ablation (RFTA) has showed in recent reports global or disease-free survivals better than those reported for percutaneous ethanol injection (PEI).[2] The...
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Dear Sir,
Surgery (resection or transplantation) is the first treatment choice for early HCC, but unfortunately it is feasible only in a minority of patients.[1] Local percutaneous ablation has therefore dramatically increase in importance and radio-frequency thermal ablation (RFTA) has showed in recent reports global or disease-free survivals better than those reported for percutaneous ethanol injection (PEI).[2] The recent reports in GUT apparently also supports a superiority, albeit small, of RFTA on PEI or acetic acid injection in a randomised prospective controlled study.[3] Nevertheless, not all agree on RFTA efficacy [4], major complications are described [5], with an incidence rate of major complications significantly higher than in the ethanol or acetic acid injection procedures.[3]
We are carrying out a multicentre prospective study on efficiency and complications of RFTA in HCC in North-East Italy with 399 HCC patients having being recruited and a centralized radiological assessment.
Overall, 133 patients (33%) experienced some complication, 5 of which were severe (1.3%), with 2 casualties (0.5%) one being procedure-related, in relation to an intestinal perforation and the second being a cerebral infarction.
Last, but definitely not least, some author has reported rapid intra-hepatic progression after RFTA [6,7], a fact that in our minds, deserve special attention. We therefore would like to document 9 cases of rapid, unexpected spread of HCC after RFTA observed in our multicentric study, The nine cases (2.3% of the series) are hereby reported: 8 males and 1 female, etiology was HCV in 6 and HBV in 3, 6 had complete response at the CT scanning performed after 1 month, 2 90% and 1 70%, 1 nodule was treated in 7 cases and 2 in 2, the size ranging from 1,8 to 4,6 cm (all patients had CT scanning prior to the procedure). Grading was G1 in all instances and AFP values were normal in 4 cases. New lesions were:
1. satellites + controlateral HCC at 1 month;
2. three x 3 cm nodes at 3 months;
3. multifocality at 4 months;
4. 3 nodes at 1 month;
5. multiple, up to 6 cm at 3 months;
6. multiple at 1 month;
7. thirteen nodes at 5 months;
8. 1 8 cm node at 6 months
9. multifocality at 5 months.
This rapid unexplained and biologically unclear progression of HCC following RFTA treatment is most unusual considering the natural history of the disease. It could be prompted by increased intra-tumoural pressure with intravascular spread, seeding due to artero-venus fistula or to the expandable hooks needles. Suggested risk factors have been high AFP levels, location near major portal branches and poor tumour differentiation.[5,6] Also, increased liver concentrations of growth factors (TGF-ALFA and BETA-FGF) have been documented in rat liver after thermal coagulation, with increased HCC growth.[8]
Our data show that side effects are relatively frequent following RFTA, with a mortality rate lower than 1% but still present. Our series additionally confirm that “explosive HCC spread” may occur after RFTA, in our experience with no correlation with AFP, differentiation and location of the tumour, and frequently even after total ablation.
Why do these patients develop this severe, (dramatic if observed in patients in the waiting list for OLTx!)[9] and unexpected complication, what is its prevalence, whether we can identify patients at risk is open to a discussion that we think should be exhaustive before abandoning PEI as obsolete and considering RFTA as the treatment of early disease not eligible for surgery. Let’s wait for the end of the honey-moon effect of this new procedure!
References
1. Christians K K, Pitt H A, Rilling WS , Franco J, Quiroz FA, Adams MB, Wallace JR, Quebbeman EJ. Hepatocellular carcinoma: Multi-modality management. Surgery 2001; 130 (4): 554-560
2. Lencioni R, Cioni D, Crocetti L, Bartolozzi C. Percutaneous ablation of hepatocellular carcinoma: state-of-the-art. Liver Transpl. 2004 Feb;10(2 Suppl 1):S91-7.
3. Lin SM, Lin CJ, Lin CC, HSU CW, Chen YC. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005; 54: 1151-6.
4. Mazzaferro V, Battiston C, Perrone S, Pulvirenti A, Regalia E, Romito R, Sarli D, Schiavo M, Garbagnati F, Marchiano A, Spreafico C, Camerini T, Mariani L, Miceli R, Andreola S.. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg. 2004;240:900-9.
5. De Baère T, Risse O, Kuoch V, Domain C, Sengel C, Smayra T, Gamal El Din M, Letoublon C, Elias D. Adverse Event During Radiofrequency Treatment of 582 Hepatic Tumours. AJR 2003; 181: 695-700
6. Ruzzante A, De Manzoni G, Molfetta M, Pachera S, Genco B, Donataccio M, Guglielmi A. Rapid progression of hepatocellular carcinoma after Radiofrequency Ablation. World J Gastroenterol 2004; 10(8) 1137-1140
7. Nicoli N, Casaril A, Hilal MA, Mangiante G, Marchiori L, Ciola M, Invernizzi L, Campagnaro T, Mansueto G. A case of rapid intrahepatic dissemination of hepatocellular carcinoma after radiofrequency thermal ablation. Am J Surg. 2004 Aug;188(2):165-7.
8. Ohno T, Kawano K, Yokoyama H, Tahara K, Sasaki A, Aramaky M, Kitano S. Microwave coagulation therapy accelerates growth of cancer in rat liver. Journal of Hepatology 2002; 36: 774-779
9. Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, Burra P, Fagiuoli S, Farinati F, Rugge M, D'Amico DF. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carcinoma. Ann Surg. 2004 Feb;239(2):150-9.
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Conflict of Interest:
None declared.
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Published on: 18 April 2016
Complication Rates of Ablation Therapies for HCC: a Difficult Comparison with an Easy Solution
- Vincenzo Arienti, Chief of Internal Medicine
- Other Contributors:
  Stefano Pretolani
Dear Editor,
we read the recent debate from Taipei on which is the best image- guided ablation therapy for Hepatocellular Carcinoma (HCC) by Lin et al (1,2) and Huo et al (3), that represents a interesting topic for hepatologists and gastroenterologists.
The papers by Lin et al stated that to treat HCC radiofrequency (RFA) was superior to percutaneous ethanol injection (PEI) and percutaneous acetic acid...
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Dear Editor,
we read the recent debate from Taipei on which is the best image- guided ablation therapy for Hepatocellular Carcinoma (HCC) by Lin et al (1,2) and Huo et al (3), that represents a interesting topic for hepatologists and gastroenterologists.
The papers by Lin et al stated that to treat HCC radiofrequency (RFA) was superior to percutaneous ethanol injection (PEI) and percutaneous acetic acid injection (PAI) with respect to local recurrence, overall survival and cancer free survival, but RFA also caused more major complications. By the contrary Huo stresses that PEI may still be a preferred ablation method for small HCC considering that the complication rate of RFA may be higher than previously assumed. In fact the rate of death occurring with the two techniques is higher for RFA (0.3-0.5%) than PEI (0.09%) (4,5). Moreover Huo reinforces his point of view by emphasizing that RFA is affected by a higher mortality (risk ratio of 10.6 -fold) if the death rate is calculated on the basis of number of sessions of treatment (4,5). The letter of Huo shows that a lack of standardization persists in reporting results of ablation therapies. This is due to the use of non-uniform terms and different parameters to calculate the rate of complications.
Although the recent publication of the International Working Group on Image-guided Tumor Ablation (6) has standardized terminology, thus facilitating the communication between investigators and improving comparison of the results of different ultrasound-guided treatments, some doubts remain on which denominator should be used for the rate of complications: number of patients, of sessions, of ablations or of tumors?
As far as mortality is concerned, it is clear that death should be reported on a per-patient basis. If instead we indicate the number of sessions as the denominator, as reported in the letter by Huo, then the technique which employs a higher number of sessions to achieve ablation obviously has a lower rate of complications, and this is particularly true when we compare PEI with RFA. As regards treatment-related morbidity, i.e. major (not death) and minor complications as defined by SIR classification (7), it is more appropriate, in our opinion, to divide the number of complications by the number of ablated nodules (i.e. cured).
Unlike the number of sessions, ablations or tumors, the number of ablated nodules represents the main objective for all ablation techniques and only by using this parameter can we truly compare the incidence of complications that occur after RFA, PEI or other image-guided tumor ablation therapies.
In conclusion, we suggest using a sole parameter as the denominator, i.e. the number of ablated nodules, since the future for prevention and therapy for HCC will rest on comparative prospective studies based on dedicated databases (8).
References
1) Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, prercutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 2005;54:1151-1156.
2) Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency ablation improves prognosis comparerd with with ethanol injection for hepatocellular carcinoma ¡Ü 4 cm. Gastroenterology 2004;127:1714-1723.
3) Huo TI, Lee SD, Wu JC. Ethanol injection versus radiofrequency ablation for hepatocellular carcinoma: which is better? Gastroenterology 2005 Mar;128(3):806-7
4) Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio- frequency ablation: complications encountered in a multicenter study. Radiology 2003 Feb;226(2):441-51.
5) Di Stasi M, Buscarini L, Livraghi T, Giorgio A, Salmi A, De Sio I, Brunello F, Solmi L, Caturelli E, Magnolfi F, Caremani M, Filice C. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J Gastroenterol 1997 Nov;32(11):1168-73.
6) Goldberg SN, Grassi CJ, Cardella JF, et al. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005;235:728-739.
7) Sacks D, McClenny TE, Cardella JF, Lewis CA, et al. Society of Interventional Radiology clinical practice guidelines. J Vasc Interv Radiol 2003;14:S199-S202.
8) Hoofnagle JH. Hepatocellular carcinoma: summary and recommendations. Gastroenterology 2004 Nov;127(5 Suppl 1):S319-23. Review.
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Conflict of Interest:
None declared.
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