Title Page
© 2017 The Authors. Published by the British Institute of Radiology Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma in cirrhosis: analysis of complications in a single center over 20 years. Antonio Giorgio MD1,2 , Maria Gabriella Merola MD2, Luca Montesarchio MD2, Francesca Merola MD2, Pietro Gatti MD2, Carmine Coppola MD2, Valentina Giorgio MD2, Giorgio Calisti MD2. Interventional Ultrasound Unit, D. Cotugno Hospital, Naples –Italy Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno – Italy
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There are not conflicts of interest.
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Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma in cirrhosis: analysis of complications in a single center over 20 years.
Abstract
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Objectives
To report on our 20 years’ experience on complications after Radiofrequency Ablation (RFA) of
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Hepatocellular Carcinoma (HCC) in cirrhotic patients.
Methods: From 1994 to 2014, 1787 RFA procedures were performed percutaneously in 1162 cirrhotic patients
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(852 Child A and 310 Child B) with HCC nodules (1.2-7cm), PT>50%, platelet count of 50.000mm3 and total
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Bilirubin ranging from 0,80 to 4.5mg/dl. In 67 patients RFA was performed on both intraparenchymal HCC nodule and tumor thrombus extended in the main portal vein and/or its branches.
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Results
4 patients (0,3%) died after RFA. 39 patients (3.2 %) changed in Child's Class: 26 out of 28 Child A cirrhotic
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patients changed to Child B and 2 changed to Child C class; 11 Child B patients changed to Child C class. At
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multivariate analysis, total bilirubin pre-RFA was the only independent risk factor for impairment of liver function and death. Complications were haemoperitneum, abscess and intrahepatic hematoma.
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Conclusions
RFA of HCC in cirrhotic patients is safe, even in case of invasion of the portal venous system.
2.5 mg/dl.
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Functional liver reserve should be strictly monitored, mainly when pre-RFA total bilirubin value is superior to
The study was approved by our Institutional Review Board.
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Advances in knowledge
Total bilirubin value more than 2.5 mg/dl represents the main marker of functional liver reserve that predicts
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decompensation of liver cirrhosis in patients undergoing RFA for HCC.
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Introduction
Recently several percutaneous ablation techniques, such as Radiofrequency ablation (RFA), Microwave ablation (MWA), Cryoablation and Laser-induced interstitial thermotherapy (LITT), are imployed in treatment of HCC in cirrhosis [1,2,3].
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Percutaneous radiofrequency ablation (RFA) has gained great popularity in the treatment of HCC in cirrhosis [4,5,6]. Several studies have shown its efficacy and high reproducibility elsewhere [7]. In fact, all practice guidelines for management of HCC in cirrhosis include RFA in the treatment of HCC in BCLC stage A [8,9,10]. Compared with percutaneous ethanol injection (PEI), the first percutaneous ablation procedure that was used for the treatment of HCC [11], RFA was shown to achieve better 3-year survival rates in patients whit HCC
nodules up to 3 cm [11,12]. Even in nodules larger than 3 cm, RFA induces larger volume of necrosis compared to ethanol injection [8]. The problem of both PEI and RFA is the fact that HCC arises in the setting of liver cirrhosis [13]. Although the effect of RFA is local, several complications (either major or minor) have been reported [14].
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Mortality can be observed after RFA and other major complications, such as hemorrhage, abscess formation or decompensation of liver cirrhosis or had been described [15, 16]. One of the major problems encountered
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in the clinical setting of percutaneous ablation of HCC in cirrhosis is the impairment of liver function of patients who underwent RFA. Being minimally invasive compared to surgery, percutaneous ablation
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techniques for HCC are generally safe and well-tolerated. Complications of RFA can range from the common
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post-ablation syndrome, characterized by flu-like symptoms developing within the first 24–48 hours after the
cirrhosis, the risk of liver decompensation needs to be considered.
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procedure, to life-threatening hemorrhage [17]. Furthermore, when RFA is performed in the setting of liver
Therefore the aim of the present study was to investigate the rate and patterns of complications following RFA
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for HCC treatment in our center over a period of 20 years, with special emphasis on impairment of liver
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function and their risk factors.
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Materials and Method
We retrospectively reviewed the case notes of 1162 consecutive cirrhotic patients (57-86 years), affected by
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liver cirrhosis ( 852 Child A and 310 Child B ) and superimposed HCC who underwent 1787 percutaneous RFA procedures under ultrasound guidance at our Institution from April 1994 to March 2014. Table 1 reports the demographic and clinical characteristics pre-RFA of our patients.
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The indications to perform RFA were the following:
- patients with HCC not suitable for liver resection or liver transplantation or refusing surgery
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- Child A or B class of cirrhosis;
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- presence of one nodule up to 7 cm in diameter or maximum 4 nodules with the largest lesser or equal to 5
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Patients were excluded when: - platelet count was < 50.000 mm3; - PT < 50% ;
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- total bilirubin > 4.5 mg/dl; - presence of more than 4 noduleswith the largest one > 5cm. The pre-RFA total bilirubin limit of 4.5 mg/dl and the 7 cm limit of maximum diameter of nodule were chosen on the basis of our previous experience with percutaneous ethanol injection, according to our previous reported data [18,19]. Presence of ascites was not an exclusion criteria (59 patients presented with mild ascites before RFA).
Patients with neoplastic invasion of a segmental or sub-segmental portal vessel or presence of main portal vein tumor thrombus (MPVTT- patients n=67; 5,7%) were also treated. In such cases, percutaneous RFA was performed en bloc on both and the segmental or sub-segmental portal vessel or on both the HCC nodule and MPVTT [20]
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Diagnosis of HCC was made using percutaneous US guided biopsy and/or elevated AFP (> 400ng/dl) and or
enhanced CT and or enhanced MRI. Diagnosis of PVTT was made using US- guided Fine Needle Biopsy in
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all cases [20].
During the study period, we used three different RFA devices: hooks electrode needle (RITA Medical System,
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Angiodynamics; Latham, NY, USA) in 270 cases from 1994 to 1998; perfused electrode needle (Berthold,
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Enlarghen, Germany from 1999 to 2002 and from 2003 RF medical company; Seul, South Korea) in 1041 cases and cold perfused electrode needle (Covidien Italia spa; Segrate, Milan, Italy) in 476 cases from 2009.
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Perfused electrode-needle was used when the nodule’s size was lesser or equal to 2.5cm. Cold perfused electrode needle was employed in case of nodule’s size larger than 2.5 cm. In patients with MPVTT RFA was
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performed as described elsewhere [20]. All ablation procedures were performed by a single experienced
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operator.
Unless complications occurred, patients were discharged from hospital the day after the procedure following
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clinical examination, routine biochemical tests (WBC, LFTs including coagulation profile and U&Es) and abdominal US exam. A 30 days enhanced CT/and or MRI was schedule for evaluation of efficacy of the
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procedure. In all patients hospital stay was recorded.
The study was approved by our Institutional Review Board and all patients gave their informed written consent. Statistical analysis. Values are expressed as mean ± standard deviation. Twelve risk factors (age, sex, albumin level, INR value, platelet count, pre RFA total bilirubin, Child’s Class
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of cirrhosis, number of nodules, size of nodules, number of needle insertions, type of electrode needle and time of experience from starting RFA to perform RFA) for development of complications were evaluated by
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univariate analysis using Cox regression tests. If multiple risk factors were shown to be significant by this test,
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multivariate analysis was performed using Cox regression tests to identify independent prognostic factors for complications. All statistical analyses were performed using the SPSS 15.0 statistical software (SPSS Inc.,
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Chicago, IL, United States). All reported P-values were 2-sided. P < 0.05 was considered statistically significant.
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Results
Mortality.
During the entire period of the study 4 deaths (0.3%) were observed. Three patients (0.2%) died from hemorrhagic events: two patients (one Child A and one Child B, respectively) died from haemoperitoneum while one Child B patient died from haemothorax. The two patients who died from haemoperitoneum had no ascites before RFA. Impairment of liver function and death occurred in a Child
B patient (0.1%). Both haemoperitoneum patients died within 24 hours after RFA for hypovolemic shock, while the patient with haemothorax died 21 days after RFA for multi-organ failure.
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The patient died from liver failure had a nodule of 3.4 cm in diameter and a pre-RFA bilirubin of 2.7 mg/dl; soon after the procedure a continuous increase of total bilirubin up to 54 mg/dl was observed (Fig. 1) and death
occurred on day 25 after RFA. After day 9, the patient showed a constant decrease of PT, INR and on day 22
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hepatic coma developed.
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No deaths were observed in patients treated with RFA for both the intraparenchymal HCC nodule and PVTT.
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All haemorragic events after RFA were observed for lesions located in the 5th and 6th segments.
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There was no correlation between the early operator experience and the haemorragic events after RFA because many of the haemorragic events were observed during the last period of the study. The compensation of liver
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cirrhosis was observed omegeneously during all the period of the study.
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Morbidity.
During 1 month period of follow-up after RFA changes in Child‘s class of cirrhosis were observed in 39 patients (3.2%) due to liver decompensation (i.e ascites and/or jaundice and/or decreasing INR).
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26 out of 28 Child A cirrhotics changed to child B; 2 out of 28 Child A cirrhotics changed to Child C. 11 Child B cirrhotics changed to Child’s C class.
On univariate analysis, pre RFA total bilirubin > 2.5 mg/dl, size of nodules, number of nodules and number of needle-electrode insertions were independent risk factors for liver decompensation. At multivariate analysis,
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total bilirubin before RFA > 2.5 mg/dl was the only independent risk factor for impairment of liver function
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and death (OR = 1.556; 95%CI: 1.827-2.965; P= 0.028).
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analysis.
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Table 2 reports pre-RFA significant variable for liver decompensation in the univariate and multivariate
No correlation was found between the type of the needle electrode employed and mortality and morbidity rates neither between complications and time from starting RFA. Figure 1 reports the trend of total bilirubin level in 59 patients who showed increase of bilirubin after RFA.
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In two patients (0.2 %), liver abscess formation and sepsis developed; they were successfully treated with percutaneous sonography-guided needle (18-gauge) aspiration and antibiotic therapy. One cirrhotic patient had intrahepatic hematoma and another one had subcutaneous cellulitis along the electrode needle path: all lesions healed spontaneously. In case of complications, the hospitalization ranged from 4 to 60 days (mean: 12 days ± 9). There was a statistical significant difference between the hospital stay of patients with and without complications.
Outcome. The rate of necrosis was evaluated on the imaging characteristics of enhanced CT and /or MRI, also in patients with multiple nodules.
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Complete necrosis was 87-100% in nodules 3cm (mean 95%); 72-95% in nodules 5 cm (mean 83%); and 60-77% in nodules 7cm (mean 59%). Post-procedural sonography and follow-up CT showed local recurrence of tumor in 10% of patients at five years while intrahepatic recurrences, in different segments of the liver, were
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observed in 76% of patients at five years.
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The outcome in relation to each associated complication was as follows:
with medical therapy and ascites disappeared after 5-13 days (mean 8 days);
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- 25 out 39 patients with decompensation of liver cirrhosis presented with ascites after RFA; they were treated
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- 19 out 39 patients with decompensation of liver cirrhosis presented with ascites and jaundice after RFA; they were treated with medical therapy and complications disappeared after 10-28 days (mean 14 days);
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- 18 out 39 patients with decompensation of liver cirrhosis presented with ascites, jaundice and increased INR
showed liver recompensation after 12-34 days (18 days).
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after RFA; they were treated with medical therapy: one of these patients died, while the remained patients
aspiration and healed within 17 days.
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The two patients with liver abscess formation were treated with antibiotic therapy and US- guided needle
The intrahaepatic haematoma healed spontaneously within 15 days.
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The patient with subcutaneous cellulitis had antibiotic therapy and healed completely within 10 days. The patient with haemothorax died. There were no cutaneous burning, no biliary injury, no vascular injury and no fistula. We have seven tumor seeding as subcutaneous nodules (2-3 cm in diameter) and all nodules were
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Discussion
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removed surgically.
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Mortality and morbidity rates of our series are in line with those reported by other authors worldwide [13,14]. Two recent reviews specifically evaluated mortality and major complications rates in, respectively,
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9531 [21] and 13844 [22] patients who underwent RF. Both these studies reported a 0,15% pooled mortality rates. In our series mortality rate was 0.3%. In the Bertot’s series the pooled proportion rate of major complications was 3.29%, with a range of 2.4-4.28 [21]. The incidence of major complications in our center
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was 1.99%. Therefore, also for such complications, the results of our single center does not differ from the recent data of the literature. But, in addition, over the hemorrhagic or abscess complications after RFA, that was similar in our and other’s studies, our series has better focused on the findings occurring in case of decompensation of liver cirrhosis after RFA. In fact, although hemorrhagic events remain the main cause of mortality (3 out of 4 deaths) also in our experience, impairment of liver function was found as the most frequent major complication that occurred and that had a great impact in clinical setting.
With regard to liver function, changes in Child’s Class of cirrhosis was observed in 38 of our patients (3.2 %). These changes in Child’s Class occurred in both Class A patients and, not surprisingly, also in Class B patients. According to our experience, Child B patients are more suitable to develop acute on chronic liver failure: in fact, 11 Child B patients changed to Child C class and only one of these died. Moreover, also patients in Child
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Class A of cirrhosis can change to Child B (26 cases) or (only 2 cases) to Child C Class.
In our experience, the best parameter that can predict a poor prognosis is the total bilirubin value before RFA.
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In our series, in the first days following RFA, a slight increase of the total bilirubin value can be observed.
This increase usually returns to pre-RFA values within 15-30 days, as shown in Fig 1: the peak in bilirubin
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levels increasing in our series was observed around day 15 after the procedure (Fig 1). If total bilirubin value
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does not decrease within a few days after having reached the peak (around day 15) or if it continues to increase further, there seems to be an high chance of progression to liver failure.
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The rate of other major complications, such as abscess or hematoma, is in line with other researchers’ experience.
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Our study has some limitations, firstly it’s a retrospective study and, secondly, there were no comparison
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among the different types of ablation.
In conclusion, RFA of HCC in cirrhotic patients can be considered safe, even in case of advanced disease,
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such as in HCC with PVTT.
Despite hemorrhagic events remain the main cause of death, special care should be taken in the evaluation of
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residual hepatic reserve to avoid liver failure, which can lead to increased morbidity, prolonged hospitalization
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and, in some cases, to increased mortality as well.
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References
1. Slotta JE, Kollmar O, Ellenrieder V, et al. Hepatocellular carcinoma: Surgeon's view on latest findings and
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future perspectives. World J Hepatol. 2015; 7: 1168–1183.
2. Seinstra BA, van Delden OM, van Erpecum KJ, et al. Minimally invasive image-guided therapy for
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inoperable hepatocellular carcinoma: What is the evidence today? Insights Imaging. 2010 Jul; 1: 167–181.
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3. Qian J, Feng GS, Vogl T. Combined interventional therapies of hepatocellular carcinoma. World J
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Gastroenterol. 2003; 9: 1885–1891.
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4. Giorgio A. Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma on Cirrhosis: State of the Art and Future Perspectives. Recent Pat Anticancer Drug Discov. 2010; 5:69-76.
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5. Gao J, Wang SH, Ding XM, et al. Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less
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as first line treatment. World J Gastroenterol. 2015; 21:5287-94.
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6. Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular
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carcinoma: a systematic review. Ann Surg. 2009; 249:20-5.
7. Kang TW, Rhim H. Recent Advances in Tumor Ablation for Hepatocellular Carcinoma. Liver Cancer. 2015; 4:176-87.
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2011; 53:1020-22.
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8. Bruix J, Sherman M. AASLD - Management of Hepatocellular Carcinoma: An Update. HEPATOLOGY
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9. European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellularcarcinoma.J Hepatol.
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2012; 56:908-43.
10. Kudo M, Izumi N, Kokudo N, et al. HCC Expert Panel of Japan Society of Hepatology.Management of
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hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.Dig Dis. 2011; 29:339-64.
11. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197:101-8.
12. Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009; 104:514-24.
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13. Flemming JA, Yang JD, Vittinghoff E, Kim WR, Terrault NA. Risk prediction of hepatocellular carcinoma
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in patients with cirrhosis: the ADRESS-HCC risk model. Cancer 2014; 120:3485-93.
14. Kwon HJ, Kim PN, Byun JH, et al. Various complications of percutaneous radiofrequency ablation for
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hepatic tumors: radiologic findings and technical tips. ActaRadiol. 2014; 55:1082-92.
15. Ding J, Jing X, Liu J, et al. Complications of thermal ablation of hepatic tumours: comparison of
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radiofrequency and microwave ablative techniques. ClinRadiol. 2013; 68:608-15.
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16. Kwon HJ, Kim PN, Byun JH, et al. Various complications of percutaneous radiofrequency ablation for
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hepatic tumors: radiologic findings and technical tips. Acta Radiol. 2014; 55:1082-92.
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Semin Intervent Radiol 2014; 31:138-48.
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17. Kim KR, Thomas S. Complications of image-guided thermal ablation of liver and kidney neoplasms.
18. Giorgio A, Tarantino L, Francica G, et al. Percutaneous ethanol injection under sonographic guidance of hepatocellular carcinoma in compensated and decompensated cirrhotic patients. J Ultrasound
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Med. 1992 ;11:587-95.
19. Giorgio A , Tarantino L, Mariniello N, et al. Percutaneous ethanol injection of hepatocellular carcinoma in
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cirrhosis: can indications be extended?; Radiology 1992; 183-195.
20. Giorgio A, Di Sarno A, de Stefano G, et al. Hepatocellular carcinoma with cirrhosis: are patients with
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neoplastic main portal vein invasion eligible for percutaneous radiofrequency ablation of both the nodule and the portal venous tumor thrombus?AJR Am J Roentgenol. 2009; 193:948 54.
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21. Bertot LC, Sato M, Tateishi R, Yoshida H, Koike K. Mortality and complication rates of percutaneous ablative techniques for the treatment of liver tumors: a systematic review.EurRadiol. 2011; 21:2584-96.
22. Lahat E, Eshkenazy R, Zendel A, et al. Complications after percutaneous ablation of liver tumors: a systematic review. HepatobiliarySurgNutr. 2014; 3:317-23.
Figures Fig.1: Trend of bilirubin levels after RFA of 59 patients who presented with increase of bilirubin after
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procedure.
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Click here to download Figure FIGURA 1 copia.tif
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Figure 1
Table
Table 1: Demographic and clinical characteristics of our patients.
57- 86 years (mean 72 ± 6 )
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Age
882 males (75,9%)
Sex
852 (73,3%)
Child B
310 (26,7%)
Diameter of HCC nodules
1.2 to 7 cm (mean 2.9 ± 0.7)
Number of HCC nodules
1-4 ( mean 1.9 mean ± 0.7)
Total bilirubin
0.80 - 4.5 mg/dl (mean 1.6 ± 0.4)
International Normalized Ratio (INR)
1.4-1.01 (mean 1.06 ± 0.149)
Platelet count
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Child A
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310 females (24,1%)
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50.000 -129-000 mm3 (mean 81.000 ± 8.35)
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Table 2: Pre-RFA significant variable for liver decompensation in the univariate and multivariate analysis. Univariate analysis
Multivariate analysis
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Variables
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Age ( 65 years) sex (males), yes/no albumin level (3gr/dl) INR value (1.2) platelet count (60.000) total bilirubin (2.5) Child (class A/B) number of nodules (1/>1) size of nodules (3cm) number of needle insertions (1/>1) type of electrode needle (number of procedures used 500) time of experience (5 years)
OR (95%CI)
1.139 (0.737-1.725) 0.984 (0.539-1.758) 0.998 (0.745-1.333) 0.998 (0.745-1.333) 1.069 (0.560-2.029) 3.029 (1.633-5.598) 0.979 (0.483-2.771) 1.43 (0.753-1.742) 1.164 (0.754-1.763) 2.874 (1.891-4.457) 1.033 (0.575-2.045)
P value
0.949 0.988 0.997 0.997 0.850 0.004 0.939 0.033 0.04 0.018 0.893
0.598 (0.225-1.423) 0.342
OR (95%CI)
1.556 (1.827-2.965)
P value
0.028
© 2017 The Authors. Published by the British Institute of Radiology Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma in cirrhosis: analysis of complications in a single center over 20 years. Antonio Giorgio MD1,2 , Maria Gabriella Merola MD2, Luca Montesarchio MD2, Francesca Merola MD2, Pietro Gatti MD2, Carmine Coppola MD2, Valentina Giorgio MD2, Giorgio Calisti MD2. Interventional Ultrasound Unit, D. Cotugno Hospital, Naples –Italy Interventional Ultrasound Unit, Tortorella Clinical Institute, Salerno – Italy
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There are not conflicts of interest.
Revised Manuscript - Clean
Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma in cirrhosis: analysis of complications in a single center over 20 years.
Abstract
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Objectives
To report on our 20 years’ experience on complications after Radiofrequency Ablation (RFA) of
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Hepatocellular Carcinoma (HCC) in cirrhotic patients.
Methods: From 1994 to 2014, 1787 RFA procedures were performed percutaneously in 1162 cirrhotic patients
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(852 Child A and 310 Child B) with HCC nodules (1.2-7cm), PT>50%, platelet count of 50.000mm3 and total
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Bilirubin ranging from 0,80 to 4.5mg/dl. In 67 patients RFA was performed on both intraparenchymal HCC nodule and tumor thrombus extended in the main portal vein and/or its branches.
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Results
4 patients (0,3%) died after RFA. 39 patients (3.2 %) changed in Child's Class: 26 out of 28 Child A cirrhotic
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patients changed to Child B and 2 changed to Child C class; 11 Child B patients changed to Child C class. At
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multivariate analysis, total bilirubin pre-RFA was the only independent risk factor for impairment of liver function and death. Complications were haemoperitneum, abscess and intrahepatic hematoma.
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Conclusions
RFA of HCC in cirrhotic patients is safe, even in case of invasion of the portal venous system.
2.5 mg/dl.
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Functional liver reserve should be strictly monitored, mainly when pre-RFA total bilirubin value is superior to
The study was approved by our Institutional Review Board.
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Advances in knowledge
Total bilirubin value more than 2.5 mg/dl represents the main marker of functional liver reserve that predicts
N
C
decompensation of liver cirrhosis in patients undergoing RFA for HCC.
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Introduction
Recently several percutaneous ablation techniques, such as Radiofrequency ablation (RFA), Microwave ablation (MWA), Cryoablation and Laser-induced interstitial thermotherapy (LITT), are imployed in treatment of HCC in cirrhosis [1,2,3].
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Percutaneous radiofrequency ablation (RFA) has gained great popularity in the treatment of HCC in cirrhosis [4,5,6]. Several studies have shown its efficacy and high reproducibility elsewhere [7]. In fact, all practice guidelines for management of HCC in cirrhosis include RFA in the treatment of HCC in BCLC stage A [8,9,10]. Compared with percutaneous ethanol injection (PEI), the first percutaneous ablation procedure that was used for the treatment of HCC [11], RFA was shown to achieve better 3-year survival rates in patients whit HCC
nodules up to 3 cm [11,12]. Even in nodules larger than 3 cm, RFA induces larger volume of necrosis compared to ethanol injection [8]. The problem of both PEI and RFA is the fact that HCC arises in the setting of liver cirrhosis [13]. Although the effect of RFA is local, several complications (either major or minor) have been reported [14].
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Mortality can be observed after RFA and other major complications, such as hemorrhage, abscess formation or decompensation of liver cirrhosis or had been described [15, 16]. One of the major problems encountered
O
in the clinical setting of percutaneous ablation of HCC in cirrhosis is the impairment of liver function of patients who underwent RFA. Being minimally invasive compared to surgery, percutaneous ablation
O
techniques for HCC are generally safe and well-tolerated. Complications of RFA can range from the common
R
post-ablation syndrome, characterized by flu-like symptoms developing within the first 24–48 hours after the
cirrhosis, the risk of liver decompensation needs to be considered.
P
procedure, to life-threatening hemorrhage [17]. Furthermore, when RFA is performed in the setting of liver
Therefore the aim of the present study was to investigate the rate and patterns of complications following RFA
D
for HCC treatment in our center over a period of 20 years, with special emphasis on impairment of liver
E
function and their risk factors.
C T
Materials and Method
We retrospectively reviewed the case notes of 1162 consecutive cirrhotic patients (57-86 years), affected by
R R E
liver cirrhosis ( 852 Child A and 310 Child B ) and superimposed HCC who underwent 1787 percutaneous RFA procedures under ultrasound guidance at our Institution from April 1994 to March 2014. Table 1 reports the demographic and clinical characteristics pre-RFA of our patients.
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The indications to perform RFA were the following:
- patients with HCC not suitable for liver resection or liver transplantation or refusing surgery
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- Child A or B class of cirrhosis;
cm.
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- presence of one nodule up to 7 cm in diameter or maximum 4 nodules with the largest lesser or equal to 5
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Patients were excluded when: - platelet count was < 50.000 mm3; - PT < 50% ;
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- total bilirubin > 4.5 mg/dl; - presence of more than 4 noduleswith the largest one > 5cm. The pre-RFA total bilirubin limit of 4.5 mg/dl and the 7 cm limit of maximum diameter of nodule were chosen on the basis of our previous experience with percutaneous ethanol injection, according to our previous reported data [18,19]. Presence of ascites was not an exclusion criteria (59 patients presented with mild ascites before RFA).
Patients with neoplastic invasion of a segmental or sub-segmental portal vessel or presence of main portal vein tumor thrombus (MPVTT- patients n=67; 5,7%) were also treated. In such cases, percutaneous RFA was performed en bloc on both and the segmental or sub-segmental portal vessel or on both the HCC nodule and MPVTT [20]
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Diagnosis of HCC was made using percutaneous US guided biopsy and/or elevated AFP (> 400ng/dl) and or
enhanced CT and or enhanced MRI. Diagnosis of PVTT was made using US- guided Fine Needle Biopsy in
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all cases [20].
During the study period, we used three different RFA devices: hooks electrode needle (RITA Medical System,
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Angiodynamics; Latham, NY, USA) in 270 cases from 1994 to 1998; perfused electrode needle (Berthold,
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Enlarghen, Germany from 1999 to 2002 and from 2003 RF medical company; Seul, South Korea) in 1041 cases and cold perfused electrode needle (Covidien Italia spa; Segrate, Milan, Italy) in 476 cases from 2009.
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Perfused electrode-needle was used when the nodule’s size was lesser or equal to 2.5cm. Cold perfused electrode needle was employed in case of nodule’s size larger than 2.5 cm. In patients with MPVTT RFA was
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performed as described elsewhere [20]. All ablation procedures were performed by a single experienced
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operator.
Unless complications occurred, patients were discharged from hospital the day after the procedure following
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clinical examination, routine biochemical tests (WBC, LFTs including coagulation profile and U&Es) and abdominal US exam. A 30 days enhanced CT/and or MRI was schedule for evaluation of efficacy of the
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procedure. In all patients hospital stay was recorded.
The study was approved by our Institutional Review Board and all patients gave their informed written consent. Statistical analysis. Values are expressed as mean ± standard deviation. Twelve risk factors (age, sex, albumin level, INR value, platelet count, pre RFA total bilirubin, Child’s Class
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of cirrhosis, number of nodules, size of nodules, number of needle insertions, type of electrode needle and time of experience from starting RFA to perform RFA) for development of complications were evaluated by
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univariate analysis using Cox regression tests. If multiple risk factors were shown to be significant by this test,
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multivariate analysis was performed using Cox regression tests to identify independent prognostic factors for complications. All statistical analyses were performed using the SPSS 15.0 statistical software (SPSS Inc.,
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Chicago, IL, United States). All reported P-values were 2-sided. P < 0.05 was considered statistically significant.
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Results
Mortality.
During the entire period of the study 4 deaths (0.3%) were observed. Three patients (0.2%) died from hemorrhagic events: two patients (one Child A and one Child B, respectively) died from haemoperitoneum while one Child B patient died from haemothorax. The two patients who died from haemoperitoneum had no ascites before RFA. Impairment of liver function and death occurred in a Child
B patient (0.1%). Both haemoperitoneum patients died within 24 hours after RFA for hypovolemic shock, while the patient with haemothorax died 21 days after RFA for multi-organ failure.
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The patient died from liver failure had a nodule of 3.4 cm in diameter and a pre-RFA bilirubin of 2.7 mg/dl; soon after the procedure a continuous increase of total bilirubin up to 54 mg/dl was observed (Fig. 1) and death
occurred on day 25 after RFA. After day 9, the patient showed a constant decrease of PT, INR and on day 22
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hepatic coma developed.
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No deaths were observed in patients treated with RFA for both the intraparenchymal HCC nodule and PVTT.
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All haemorragic events after RFA were observed for lesions located in the 5th and 6th segments.
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There was no correlation between the early operator experience and the haemorragic events after RFA because many of the haemorragic events were observed during the last period of the study. The compensation of liver
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cirrhosis was observed omegeneously during all the period of the study.
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Morbidity.
During 1 month period of follow-up after RFA changes in Child‘s class of cirrhosis were observed in 39 patients (3.2%) due to liver decompensation (i.e ascites and/or jaundice and/or decreasing INR).
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26 out of 28 Child A cirrhotics changed to child B; 2 out of 28 Child A cirrhotics changed to Child C. 11 Child B cirrhotics changed to Child’s C class.
On univariate analysis, pre RFA total bilirubin > 2.5 mg/dl, size of nodules, number of nodules and number of needle-electrode insertions were independent risk factors for liver decompensation. At multivariate analysis,
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total bilirubin before RFA > 2.5 mg/dl was the only independent risk factor for impairment of liver function
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and death (OR = 1.556; 95%CI: 1.827-2.965; P= 0.028).
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analysis.
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Table 2 reports pre-RFA significant variable for liver decompensation in the univariate and multivariate
No correlation was found between the type of the needle electrode employed and mortality and morbidity rates neither between complications and time from starting RFA. Figure 1 reports the trend of total bilirubin level in 59 patients who showed increase of bilirubin after RFA.
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In two patients (0.2 %), liver abscess formation and sepsis developed; they were successfully treated with percutaneous sonography-guided needle (18-gauge) aspiration and antibiotic therapy. One cirrhotic patient had intrahepatic hematoma and another one had subcutaneous cellulitis along the electrode needle path: all lesions healed spontaneously. In case of complications, the hospitalization ranged from 4 to 60 days (mean: 12 days ± 9). There was a statistical significant difference between the hospital stay of patients with and without complications.
Outcome. The rate of necrosis was evaluated on the imaging characteristics of enhanced CT and /or MRI, also in patients with multiple nodules.
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Complete necrosis was 87-100% in nodules 3cm (mean 95%); 72-95% in nodules 5 cm (mean 83%); and 60-77% in nodules 7cm (mean 59%). Post-procedural sonography and follow-up CT showed local recurrence of tumor in 10% of patients at five years while intrahepatic recurrences, in different segments of the liver, were
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observed in 76% of patients at five years.
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The outcome in relation to each associated complication was as follows:
with medical therapy and ascites disappeared after 5-13 days (mean 8 days);
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- 25 out 39 patients with decompensation of liver cirrhosis presented with ascites after RFA; they were treated
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- 19 out 39 patients with decompensation of liver cirrhosis presented with ascites and jaundice after RFA; they were treated with medical therapy and complications disappeared after 10-28 days (mean 14 days);
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- 18 out 39 patients with decompensation of liver cirrhosis presented with ascites, jaundice and increased INR
showed liver recompensation after 12-34 days (18 days).
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after RFA; they were treated with medical therapy: one of these patients died, while the remained patients
aspiration and healed within 17 days.
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The two patients with liver abscess formation were treated with antibiotic therapy and US- guided needle
The intrahaepatic haematoma healed spontaneously within 15 days.
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The patient with subcutaneous cellulitis had antibiotic therapy and healed completely within 10 days. The patient with haemothorax died. There were no cutaneous burning, no biliary injury, no vascular injury and no fistula. We have seven tumor seeding as subcutaneous nodules (2-3 cm in diameter) and all nodules were
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Discussion
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removed surgically.
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Mortality and morbidity rates of our series are in line with those reported by other authors worldwide [13,14]. Two recent reviews specifically evaluated mortality and major complications rates in, respectively,
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9531 [21] and 13844 [22] patients who underwent RF. Both these studies reported a 0,15% pooled mortality rates. In our series mortality rate was 0.3%. In the Bertot’s series the pooled proportion rate of major complications was 3.29%, with a range of 2.4-4.28 [21]. The incidence of major complications in our center
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was 1.99%. Therefore, also for such complications, the results of our single center does not differ from the recent data of the literature. But, in addition, over the hemorrhagic or abscess complications after RFA, that was similar in our and other’s studies, our series has better focused on the findings occurring in case of decompensation of liver cirrhosis after RFA. In fact, although hemorrhagic events remain the main cause of mortality (3 out of 4 deaths) also in our experience, impairment of liver function was found as the most frequent major complication that occurred and that had a great impact in clinical setting.
With regard to liver function, changes in Child’s Class of cirrhosis was observed in 38 of our patients (3.2 %). These changes in Child’s Class occurred in both Class A patients and, not surprisingly, also in Class B patients. According to our experience, Child B patients are more suitable to develop acute on chronic liver failure: in fact, 11 Child B patients changed to Child C class and only one of these died. Moreover, also patients in Child
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Class A of cirrhosis can change to Child B (26 cases) or (only 2 cases) to Child C Class.
In our experience, the best parameter that can predict a poor prognosis is the total bilirubin value before RFA.
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In our series, in the first days following RFA, a slight increase of the total bilirubin value can be observed.
This increase usually returns to pre-RFA values within 15-30 days, as shown in Fig 1: the peak in bilirubin
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levels increasing in our series was observed around day 15 after the procedure (Fig 1). If total bilirubin value
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does not decrease within a few days after having reached the peak (around day 15) or if it continues to increase further, there seems to be an high chance of progression to liver failure.
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The rate of other major complications, such as abscess or hematoma, is in line with other researchers’ experience.
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Our study has some limitations, firstly it’s a retrospective study and, secondly, there were no comparison
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among the different types of ablation.
In conclusion, RFA of HCC in cirrhotic patients can be considered safe, even in case of advanced disease,
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such as in HCC with PVTT.
Despite hemorrhagic events remain the main cause of death, special care should be taken in the evaluation of
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residual hepatic reserve to avoid liver failure, which can lead to increased morbidity, prolonged hospitalization
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and, in some cases, to increased mortality as well.
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References
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future perspectives. World J Hepatol. 2015; 7: 1168–1183.
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inoperable hepatocellular carcinoma: What is the evidence today? Insights Imaging. 2010 Jul; 1: 167–181.
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3. Qian J, Feng GS, Vogl T. Combined interventional therapies of hepatocellular carcinoma. World J
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Gastroenterol. 2003; 9: 1885–1891.
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4. Giorgio A. Percutaneous Radiofrequency Ablation of Hepatocellular Carcinoma on Cirrhosis: State of the Art and Future Perspectives. Recent Pat Anticancer Drug Discov. 2010; 5:69-76.
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5. Gao J, Wang SH, Ding XM, et al. Radiofrequency ablation for single hepatocellular carcinoma 3 cm or less
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as first line treatment. World J Gastroenterol. 2015; 21:5287-94.
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6. Lau WY, Lai EC. The current role of radiofrequency ablation in the management of hepatocellular
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carcinoma: a systematic review. Ann Surg. 2009; 249:20-5.
7. Kang TW, Rhim H. Recent Advances in Tumor Ablation for Hepatocellular Carcinoma. Liver Cancer. 2015; 4:176-87.
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2011; 53:1020-22.
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8. Bruix J, Sherman M. AASLD - Management of Hepatocellular Carcinoma: An Update. HEPATOLOGY
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9. European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellularcarcinoma.J Hepatol.
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2012; 56:908-43.
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hepatocellular carcinoma in Japan: Consensus-Based Clinical Practice Guidelines proposed by the Japan Society of Hepatology (JSH) 2010 updated version.Dig Dis. 2011; 29:339-64.
11. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197:101-8.
12. Orlando A, Leandro G, Olivo M, Andriulli A, Cottone M. Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials. Am J Gastroenterol. 2009; 104:514-24.
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13. Flemming JA, Yang JD, Vittinghoff E, Kim WR, Terrault NA. Risk prediction of hepatocellular carcinoma
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in patients with cirrhosis: the ADRESS-HCC risk model. Cancer 2014; 120:3485-93.
14. Kwon HJ, Kim PN, Byun JH, et al. Various complications of percutaneous radiofrequency ablation for
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hepatic tumors: radiologic findings and technical tips. ActaRadiol. 2014; 55:1082-92.
15. Ding J, Jing X, Liu J, et al. Complications of thermal ablation of hepatic tumours: comparison of
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radiofrequency and microwave ablative techniques. ClinRadiol. 2013; 68:608-15.
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16. Kwon HJ, Kim PN, Byun JH, et al. Various complications of percutaneous radiofrequency ablation for
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hepatic tumors: radiologic findings and technical tips. Acta Radiol. 2014; 55:1082-92.
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Semin Intervent Radiol 2014; 31:138-48.
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17. Kim KR, Thomas S. Complications of image-guided thermal ablation of liver and kidney neoplasms.
18. Giorgio A, Tarantino L, Francica G, et al. Percutaneous ethanol injection under sonographic guidance of hepatocellular carcinoma in compensated and decompensated cirrhotic patients. J Ultrasound
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Med. 1992 ;11:587-95.
19. Giorgio A , Tarantino L, Mariniello N, et al. Percutaneous ethanol injection of hepatocellular carcinoma in
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cirrhosis: can indications be extended?; Radiology 1992; 183-195.
20. Giorgio A, Di Sarno A, de Stefano G, et al. Hepatocellular carcinoma with cirrhosis: are patients with
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neoplastic main portal vein invasion eligible for percutaneous radiofrequency ablation of both the nodule and the portal venous tumor thrombus?AJR Am J Roentgenol. 2009; 193:948 54.
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21. Bertot LC, Sato M, Tateishi R, Yoshida H, Koike K. Mortality and complication rates of percutaneous ablative techniques for the treatment of liver tumors: a systematic review.EurRadiol. 2011; 21:2584-96.
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Figures Fig.1: Trend of bilirubin levels after RFA of 59 patients who presented with increase of bilirubin after
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procedure.
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Click here to download Figure FIGURA 1 copia.tif
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Figure 1
Table
Table 1: Demographic and clinical characteristics of our patients.
57- 86 years (mean 72 ± 6 )
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Age
882 males (75,9%)
Sex
852 (73,3%)
Child B
310 (26,7%)
Diameter of HCC nodules
1.2 to 7 cm (mean 2.9 ± 0.7)
Number of HCC nodules
1-4 ( mean 1.9 mean ± 0.7)
Total bilirubin
0.80 - 4.5 mg/dl (mean 1.6 ± 0.4)
International Normalized Ratio (INR)
1.4-1.01 (mean 1.06 ± 0.149)
Platelet count
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Child A
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310 females (24,1%)
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50.000 -129-000 mm3 (mean 81.000 ± 8.35)
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Table 2: Pre-RFA significant variable for liver decompensation in the univariate and multivariate analysis. Univariate analysis
Multivariate analysis
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Variables
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Age ( 65 years) sex (males), yes/no albumin level (3gr/dl) INR value (1.2) platelet count (60.000) total bilirubin (2.5) Child (class A/B) number of nodules (1/>1) size of nodules (3cm) number of needle insertions (1/>1) type of electrode needle (number of procedures used 500) time of experience (5 years)
OR (95%CI)
1.139 (0.737-1.725) 0.984 (0.539-1.758) 0.998 (0.745-1.333) 0.998 (0.745-1.333) 1.069 (0.560-2.029) 3.029 (1.633-5.598) 0.979 (0.483-2.771) 1.43 (0.753-1.742) 1.164 (0.754-1.763) 2.874 (1.891-4.457) 1.033 (0.575-2.045)
P value
0.949 0.988 0.997 0.997 0.850 0.004 0.939 0.033 0.04 0.018 0.893
0.598 (0.225-1.423) 0.342
OR (95%CI)
1.556 (1.827-2.965)
P value
0.028
