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Radiofrequency ablation plus drug-eluting beads transcatheter arterial chemoembolization for the treatment of single large hepatocellular carcinoma
Digestive and Liver Disease 47 (2015) 242–248
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Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Liver, Pancreas and Biliary Tract
Radiofrequency ablation plus drug-eluting beads transcatheter arterial chemoembolization for the treatment of single large hepatocellular carcinoma Roberto Iezzi a,e,∗ , Maurizio Pompili b,e , Michele Fabio La Torre a,e , Maria Chiara Campanale b,e , Martina Montagna b,e , Antonio Saviano b,e , Valentina Cesario b,e , Massimo Siciliano b,e , Eleonora Annicchiarico b,e , Salvatore Agnes c,e , Felice Giuliante d,e , Antonio Grieco b,e , Gian Lodovico Rapaccini b,e , Anna Maria De Gaetano a,e , Antonio Gasbarrini b,e , Lorenzo Bonomo a,e , on behalf of the HepatoCATT Study Group for the Multidisciplinary Management of HCC a
Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital – Catholic University, Rome, Italy Department of Internal Medicine, “A. Gemelli” Hospital – Catholic University, Rome, Italy c Department of Surgery, Division of Organ Transplantation, “A. Gemelli” Hospital – Catholic University, Rome, Italy d Department of Surgery, Hepatobiliary Surgery Unit, “A. Gemelli” Hospital – Catholic University, Rome, Italy e Division of Medical Oncology, “A. Gemelli” Hospital – Catholic University, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 26 September 2014 Accepted 10 December 2014 Available online 13 December 2014 Keywords: Ablation Chemoembolization Combined therapy HCC RFA
a b s t r a c t Background: Our aim was to evaluate the effectiveness of the single-step combined therapy with radiofrequency ablation and drug-eluting beads transarterial chemoembolization in single hepatocellular carcinoma (HCC) larger than 3 cm. Secondary aim was to compare the results with those obtained in a matched population treated with drug-eluting beads transarterial chemoembolization alone. Methods: 40 consecutive cirrhotic patients with single HCC were prospectively enrolled and treated. Twenty-three patients had tumours between 3 and 5 cm (Group A), and 17 larger than 5 cm (Group B). Twenty cirrhotic patients with single HCC treated only with chemoembolization formed the control group. Results: Complete response at 1 month was achieved in 32/40 tumours (80%). During follow-up, complete response was maintained in 25 patients (25/40, 62.5%), and this rate was higher in Group A (69.6% vs 53%, p = 0.008). The group treated with combined therapy showed a significantly lower 2-year recurrence (48.1% vs 78.2%, p < 0.001) and significantly higher survival (91.1% vs 60.6%, p = 0.004) than the group treated with chemoembolization alone. Conclusions: Balloon-occluded-radiofrequency ablation plus drug-eluting beads transarterial chemoembolization is an effective treatment of HCC larger than 3 cm not amenable to surgical resection, providing better results than transarterial chemoembolization alone. The best results are achieved in tumours up to 5 cm. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Despite the implementation of screening programmes for early diagnosis, about half of the cirrhotic patients still present with
∗ Corresponding author at: Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital – Catholic University, L.go A Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30154977; fax: +39 06 35501928. E-mail addresses: [email protected], [email protected] (R. Iezzi).
single large hepatocellular carcinomas (HCC) at diagnosis, and only 30% of them benefit from curative therapies [1–4]. Resection may provide excellent long-term results in these patients [5]. However, in patients who are not good surgical candidates, radiofrequency ablation (RFA) is not a good treatment option as the better results are achieved in tumours up to 3 cm large [6]; furthermore, studies performed on explanted livers obtained from patients treated with RFA before transplantation show that the rate of complete necrosis ranges between 13% and 43% in tumours larger than 3 cm [7]. On the other hand, despite transarterial chemoembolization
http://dx.doi.org/10.1016/j.dld.2014.12.007 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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(TACE) is the current standard of care for patients with large HCC not amenable to surgery, a sustained complete response (CR) is achieved in only 27–35% of cases [8]. An improvement in TACE technique has been attained after the introduction of drug-eluting beads (DEB-TACE): these particles are able to bind and then elute doxorubicin in a predictable manner, thus allowing a more standardized approach and less drug-related toxicity [9]. However, even though DEB-TACE induces extensive tumour necrosis in more than 70% of tumours, less than 20% of the patients achieve a CR [10–12]. The main goal of the research in this field should be to increase the number of patients with single HCC larger than 3 cm suitable for non-surgical curative treatment; for these patients, a reasonable approach is to combine therapies with possible synergistic effects. Recent studies show that combined therapy with RFA and TACE could be more effective than TACE or RFA alone in local disease control and survival improvement, but it is not clear how the lesion’s size affects the follow-up response [13–15]. Therefore, the primary aim of this study was to evaluate the effectiveness of the single-step combined therapy with RFA and DEB-TACE in single HCC ≥3 cm. The secondary aim was to compare the results with those obtained in a matched population treated with DEB-TACE alone. 2. Materials and methods 2.1. Study design/study population A prospective single-centre pilot study was carried out to test a new single-step combined therapy of HCC with RFA of the lesion followed by selective DEB-TACE. Requirements for inclusion were: (a) single HCC larger than 3 cm; (b) liver cirrhosis classified as Child–Pugh score A5–6 or B7; (c) no vascular invasion or extrahepatic metastases; (d) no previous treatment of HCC. The exclusion criteria were: (a) Child–Pugh score B ≥8 or class C; (b) platelet count <40,000/L and/or international normalized ratio >1.5; (c) serum creatinine levels >2.0 mg/dL; (d) diuretic resistant ascites. All patients had been excluded from surgical resection due to one or more of the following reasons: severe portal hypertension (defined as presence of oesophageal varices ≥ F2 or gastric varices, and/or splenomegaly with platelet count <100,000/mL, and/or previous ascites successfully treated with diuretics), surgery unfeasible or hazardous due to lesion’s location or concurrent severe comorbidities, and refusal of surgery. The diagnosis of cirrhosis was established by means of histological and/or clinical findings (laboratory parameters, ultrasound [US] and/or computed tomography [CT] signs). The ethical conduct of the study was approved by our Institutional Review Board, and the study was performed in agreement with the 1990 Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from all patients. 2.2. Pre-treatment work-up Within 2 weeks before treatment, all patients underwent physical examination, laboratory tests, and imaging studies with diagnostic and staging purposes, including liver US, radionuclide bone scan, contrast-enhanced chest and abdominal CT performed with a multiphasic protocol (flow-rate: 4 mL/s; unenhanced, arterial, portal and late phases; slice thickness: 0.625-mm) using a 64-multidetector-row CT scanner (Lightspeed VCT, GE Medical Systems). According to the guidelines in force at the time of enrolment, the diagnosis of HCC was made in the presence of a nodule detectable on US and showing the typical features of HCC on contrast-enhanced CT (hypervascular in arterial phase with washout in portal-venous phase) [16]. Eventual parasitic vascular
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supplies of the lesion were evaluated on pre-treatment contrastenhanced CT. 2.3. Treatment All combined treatments were performed in a single-step approach by the same interventional radiologist, using antibiotic prophylaxis, patient monitoring, and anaesthesiological assistance. An hepatic artery angiography was performed through a right common femoral approach to map liver vascular anatomy, as well as to check for arteriovenous shunts, and identify the arterial tumour supply. A 0.014-inch guide wire (Choice, Boston Scientific, USA) was advanced into the segmental hepatic artery feeding the lesion, enabling an optimal guidance of the low-profile monorail PTAballoon (4–5 × 20 mm, Muso, Terumo, Tokyo, Japan). RFA was then performed using US guidance with the patient under sedation with Fentanyl citrate (0.1–0.2 mg, Phentanest; Daiichi Sankyo, Tokyo, Japan) and local anaesthesia. An internally cooled electrode with a 3-cm exposed tip (Cool-Tip RF Ablation System, Covidien, Valleylab, USA) was introduced into the nodule, and the occlusion balloon in the hepatic artery was filled with a mixture of saline solution and contrast material. The RF generator was activated, and the power needed to maintain a temperature of 90–115 ◦ C at the exposed tip was delivered for 12 min. At the end of the procedure, the electrode was withdrawn, the occlusion balloon was deflated, and the immediate results were evaluated with angiography. After RFA, DEB-TACE was performed. The time elapsed between RFA completion and DEB-TACE performance was less than 5 min. A superselective chemoembolization of the lesion was performed using a coaxial technique and placing a 2.7-Fr microcatheter (Progreat; Terumo, Tokyo, Japan) in the distal segmental hepatic artery feeding the HCC. Slow injection of the 100–300 m DC-Bead (Terumo, Tokyo, Japan) loaded with Epirubicin (Farmorubicin® 50 mg powder) followed until the complete intended dose was administered and slow flow was observed. 2.4. Post-treatment and follow-up studies Perioperative morbidity and mortality included major/minor complications and death occurring within 7 days from treatment. A major complication was defined as an event that engenders substantial morbidity and disability, requires an increased level of care, or substantially lengthens hospital stay. All other complications were considered minor [17]. The endpoint of combined treatment was the disappearance of tumour enhancement at hepatic arteriography performed immediately after chemoembolization. The multiphasic CT study was performed one month after the procedure and then every 3 months both to evaluate the treatment result at the level of the target lesion using m-RECIST criteria [18], and to detect the occurrence of new lesions. CR was defined as the absence of enhancing tissue and a non-enhancing area at the tumour site larger than that of the tumour pre-treatment. In case of partial response (PR) of the target lesion, another session of combined treatment or TACE was performed; specifically, a combined treatment was preferred in case of nodular residual tumour larger than 3 cm. Local tumour progression (LTP) was defined as the appearance of nodular, irregular enhancement around or within the treated area in tumours previously assessed as completely necrotic. Intrahepatic distant recurrence (IDR) was defined as the appearance of new HCCs in the untreated liver or extrahepatic sites. All the patients with relapsing or progressive tumours were treated with the best possible options (combined therapy, percutaneous ethanol injection, RFA, TACE, or supportive care), depending on tumour staging, liver function assessment, and patient’s clinical condition.
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2.5. Control group The results from patients who underwent combined treatment were compared to those of a control group of cirrhotic patients with unifocal HCC, and without ascites, that were treated with DEBTACE alone during the period 2008–2012 (DEB-TACE group). These patients did not undergo DEB-TACE + RFA either because they were treated before the start of the present study or because RFA was judged unfeasible due to tumour location or inadequate clotting parameters (platelet count <40,000/L and/or international normalized ratio >1.5). 2.6. Statistical analysis Continuous variables were tested for normality using the Kolmogorov–Smirnov test and were reported as mean ± standard deviation. Comparisons between groups were performed using the Student’s t-test for continuous variables and the Chi-square or Fisher exact test for categorical data. Both for patients with CR and PR, the follow-up data regarding survival and IDR were estimated from the first treatment date, whereas follow-up data concerning LTP were calculated from the achievement of short-term CR. Follow-up ended at the last follow-up visit or death, or at the time of liver transplantation. The cumulative LTP, HCC recurrence, and overall survival rates were estimated with the Kaplan–Meier method and compared using the log-rank test. P values were considered significant if they were less than 0.05. Data were analysed with IBM SPSS Statistic release 20.0 and SAS software (SAS Institute Inc, USA). 3. Results 3.1. RFA + DEB-TACE group 3.1.1. Study population Between November 2010 and June 2012, 40 consecutive cirrhotic patients with single HCC larger than 3 cm were enrolled. The main features of patients and tumours are reported in Table 1. Mean HCC diameter was 4.7 ± 1.1 cm (range 3.2–7.5 cm); according to the HCC size, the patients were further divided in Group A
(23 patients with HCC ≤5 cm, mean diameter 3.9 ± 0.5 cm, range 3.2–5.0 cm) and Group B (17 patients with HCC >5.0 cm, mean diameter 5.7 ± 0.7 cm, range 5.2–7.5 cm). Besides tumour size, no significant differences were found between these two groups (Table 1). 3.1.2. Intraprocedural/early post-treatment results Technical success was achieved in all patients. Hepatic angiography at the end of the combined therapy showed a complete disappearance of the tumour vasculature and/or tumour stain in all cases. A mean procedural time of 68 ± 12 min was recorded and no major complications occurred. Minor complications were subcapsular haematoma (1 patient, 2.5%), serum level of transaminases increased compared to basal value (14 patients, 35%), and transient cholecystitis (2 patients, 5%). No complications related to the use of the balloon-occlusion technique were recorded; in particular, no arterial tears and rupture or flow-limiting dissection and segmental hepatic artery thrombosis occurred. None of the patients experienced a worsening of Child–Pugh score at 1-month followup. 3.1.3. Short-term results At 1-month CT, based on the m-RECIST criteria, a CR was achieved in 32/40 (80%) patients, whereas a PR was obtained in the remaining 8 patients (residual tumour <30% in 6 patients, and 30–50% in 2 patients). In group A, CR and PR were achieved in 20/23 (87%) and 3/23 (13%) tumours, respectively. In group B, CR and PR were reached in 12/17 (70.6%) and 5/17 (29.4%) tumours, respectively. When comparing CR rates, the difference between Group A and B was significant (p = 0.009). According to the 1-month CT results, a repeated locoregional treatment was performed in 8 patients (3 in Group A and 5 in Group B) to achieve complete necrosis. A DEB-TACE session was performed in all 3 patients of Group A and in 4 patients of Group B, whereas a repeated combined treatment was performed in the remaining patient of Group B, who presented with an eccentric nodular residual tumour of 3.1 cm in size. To obtain a complete necrosis, a total number of 48 procedures were needed (41 combined treatments and 7 TACE procedures) and a mean number of
Table 1 Demographic, clinical and hematochemical features of patients treated with radiofrequency ablation plus drug-eluting beads transarterial chemoembolization (total population, Group A, Group B) and transarterial chemoembolization only, respectively. Numbers in brackets are percent rates. Patients treated with RFA + DEB-TACE
N Male Age (years) Cirrhosis aetiology Hepatitis B Hepatitis C Alcohol-related Cryptogenic Mean HCC size (cm) HCC size >5 cm Child–Pugh Class B7 Severe portal hypertension Total bilirubin (mg/dL) ≤ 1.0 Albumin (g/dL) > 3.5 ALT (IU/L) ≤ 40 AFP (ng/mL) ≤ 20 Mean follow up (months)
p*
p**
Patients treated with DEB-TACE N (%)
17 11 (64.7) 67.9 ± 5.6
0.601 0.839
20 16 (80) 70.5 ± 5.8
0.121 0.141
3 (17.6) 11 (64.7) 1 (5.9) 2 (11.8) 5.7 ± 0.7 NA 7 (41.2) 11 (64.7) 9 (52.9) 8 (47.1) 3 (17.6) 7 (41.2) 23 ± 7
0.471 0.184 0.373 1.000 <0.001 NA 0.896 0.746 0.091 0.554 1.000 0.676 0.844
3 (15) 10 (50) 5 (25) 2 (10) 4.2 ± 1.7 6 (30) 3 (15) 15 (75%) 11 (55) 13 (65) 12 (60) 13 (65) 24 ± 17
0.375 0.855 0.155 0.422 0.251 0.348 0.050 0.550 0.344 0.357 0.001 0.144 1.000
Total N (%)
Group A N (%)
Group B N (%)
40 24 (60) 68.2 ± 6.1
23 13 (56.5) 68.3 ± 6.6
10 (25) 21 (52.5) 5 (12.5) 4 (10) 4.7 ± 1.1 17 (42.5) 16 (40) 27 (67.5%) 27 (67.5) 21 (52.5) 7 (17.5) 18 (45) 24 ± 8
7 (30.4) 10 (43.5) 4 (17.4) 2 (8.7) 3.9 ± 0.5 NA 9 (39.2) 16 (69.6) 18 (78.3) 13 (56.5) 4 (17.4) 11 (47.8) 24 ± 9
RFA, radiofrequency ablation; DEB-TACE, drug eluting beads-transarterial chemoembolization; HCC, hepatocellular carcinoma; NA, not applicable; ALT, alanine aminotransferase; AFP, alphafetoprotein. * RFA + DEB-TACE (total population) vs DEB-TACE. ** RFA + DEB-TACE: Group A vs Group B.
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Fig. 1. A single large hepatocellular carcinoma in VIII hepatic segment (4.5 cm in diameter) was confirmed on selective digital subtraction angiography (a). Radiofrequency ablation electrode was placed into the lesion under ultrasound-guidance (b) and the radiofrequency ablation generator was activated during balloon-occlusion (circle in b) of the tumour arterial supply. Angiographic image performed after radiofrequency ablation showed the immediate result with a complete central devascularized area and peripheral reactive hyperemia (c). After radiofrequency ablation, a superselective chemoembolization of the lesion demonstrated complete devascularization of the lesion (d).
1.13 and 1.3 procedures per patient were performed in Group A and Group B, respectively (Fig. 1).
in Group A, and 94.1% and 84.7% in Group B. Also in this case, the difference between Group A and B was not significant (p = 0.389).
3.1.4. Long-term results During follow-up a CR was maintained in 25 patients (25/40, 62.5%). Specifically, at the time of last response assessment, in Group A (mean follow-up: 24 ± 8 months) a CR was still present in 16/23 patients (69.6%) (Fig. 2); among these 16 patients, two underwent liver transplantation 4 and 8 months after treatment and showed complete necrosis of the tumours at explant analysis. On the other hand, in Group B (mean follow-up: 23 ± 7 months) a long-term CR was observed in 9/17 patients (53%) (p = 0.008). At the time of censoring, 15 patients (37.5%) showed HCC recurrence; of these, 7 were in group A (30.4%) and 8 in group B (47%). In Group A, 3 LTP (two treated with percutaneous ethanol injection, the other with one session of DEB-TACE) and 4 IDR (two treated with RFA, the other two with one session of DEB-TACE) were observed. In Group B, 5 LTP (two treated with percutaneous ethanol injection, the other three with one session of DEB-TACE) and 3 IDR (one treated with RFA, the other two with one session of DEB-TACE) were detected. Both the 1 and 2-year LTP cumulative rates (5.6% and 22.5% vs 18.1% and 40.3%) and 1 and 2-year cumulative HCC recurrence rates (19.2% and 39.2% vs 30.7% and 59.6%) were lower in Group A than in Group B, despite these differences did not reach statistical significance (p = 0.214 and 0.337, respectively) (Fig. 3). Three patients (4%) died because of neoplastic disease progression (one in Group A and two in Group B). The cumulative 1 and 2-year overall survival rates were 94.7% and 91.1% in the whole population, 92.5% and 92.5%
3.2. DEB-TACE group 3.2.1. Study population In the control group, 20 cirrhotic patients with single HCC treated with DEB-TACE were enrolled. Mean HCC diameter was 4.2 cm (range 2.5–8.0 cm), and a mean procedural time of 51 ± 10 min was recorded. No significant differences were found between the two groups in terms of mean procedural time (68 ± 12 min vs 51 ± 10 min; p = 0.120). The characteristics of these patients are summarized in Table 1. Besides the significant lower serum level of alanine-aminotransferase, they did not show any other significant difference when compared with the RFA + DEBTACE group.
3.2.2. Short-term results On 1-month CT, based on the m-RECIST criteria, CR and PR were achieved in 8/20 (40%) and 12/20 (60%) patients, respectively. Compared with the DEB-TACE + RFA Group, the rate of patients achieving a short-term CR was significantly lower (p < 0.001). In patients with PR, a repeated TACE was performed in 7 cases; four patients achieved complete necrosis, while the remaining 3 underwent further procedures including percutaneous ethanol injection, TACE, and RFA. Concerning the remaining 5 patients with PR, 2 were treated with sorafenib, 1 with percutaneous ethanol injection, 1
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Fig. 2. Axial contrast-enhanced computed tomographic images before combined treatment showed a right lobe hepatocellular carcinoma of 4.5 cm in size (a: arterial phase; b: late-phase). At 1-year follow-up, computed tomographic images displayed a complete necrosis of the lesion without local tumour progression (c: arterial phase; d: late-phase).
Fig. 3. Cumulative local tumour progression (A) and tumour recurrence (B) rates in patients treated with drug-eluting beads transarterial chemoembolization plus radiofrequency ablation: Groups A and B. HCC, hepatocellular carcinoma.
with resective surgery and 1 did not undergo any treatment due to liver function failure. 3.2.3. Long-term results During follow-up (mean duration: 24 ± 17 months), CR was maintained in 4/20 patients (20%), and this rate was significantly lower than that achieved in the RFA + DEB-TACE Group (p < 0.001). At the time of censoring, a total of 16 patients (76%) showed HCC recurrence: 8 showed both LTP and IDR recurrence, 6 showed only LTP recurrence, and 2 showed only IDR recurrence. Seven patients died (33%) because of neoplastic disease progression or
liver function failure. Compared to the RFA + DEB-TACE Group, the DEB-TACE Group showed significantly higher 1 and 2-year HCC recurrence rates (45.5% and 78.2% vs 24.3% and 48.1%, p < 0.001), and significantly lower 1 and 2-year overall survival rates (67.4% and 60.6% vs 94.7% and 91.1%, p 0.004) (Fig. 4).
4. Discussion A few recent studies suggest that combined therapy with RFA and TACE could be superior to TACE or RFA alone in the treatment
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Fig. 4. Cumulative overall survival (A) and recurrence rates (B) in patients treated with radiofrequency ablation plus drug-eluting beads transarterial chemoembolization and transarterial chemoembolization only, respectively. DEB-TACE, drug eluting beads transarterial chemoembolization; RFA, radiofrequency ablation; TACE: transarterial chemoembolization.
of large HCC [13–15]. Balloon occlusion of the tumour arterial supply increases the area of coagulation necrosis obtained with RFA by reducing arterial blood flow and minimizing heat loss [19,20]. On the other hand, by performing TACE after RFA it is possible to obtain some sustained anticancer effect from the sublethal heating created by RFA in the area surrounding the lethal heating zone. In detail, the chemotherapeutic agent could be concentrated in the peripheral residual viable neoplastic tissue, characterized by both increased drug delivery, due to the heating-related reactive hyperemia, and reduced cell resistance to the drug, due to the previous exposure to sublethal heating [21]. Based on this theoretical background of a synergistic effect of RFA and DEB-TACE, our combined approach could enhance both the thermal damage and the cytotoxic injury without increasing the procedural time [22,23]. Indeed, in our study the mean duration of RFA + DEB-TACE did not differ significantly from that of DEB-TACE alone (68 ± 12 min vs 51 ± 10 min; p = 0.120). This study shows that balloon-occluded RFA followed by DEBTACE is effective in achieving prolonged local disease control in single HCC >3 cm; in fact, we showed a sustained CR in 62.5% of treated lesions, a 2-year cumulative HCC recurrence rate of 48.1%, and an overall survival rate of 91.1%, significantly better than that achieved in a comparable control group of patients treated with DEB-TACE alone. It is worth noting that these promising results were obtained in a single-step procedure and that the benefit of combined therapy was not offset by any important side effect or worsening of liver function as none of our patients experienced an increased Child–Pugh score at 1 month after treatment. It is well known that TACE alone may require treatment repetition and that this may injury the non-cancerous cirrhotic liver tissue. As a matter of fact, drug-related toxicity may be a major limitation of TACE regimens, as previous studies reported to occur in more than 30% of patients [24]. Tumour size is a significant prognostic factor associated with the maintenance of local disease control. In particular, the rate of sustained CR was significantly higher in Group A than in Group B (69.6% vs 53.0%). The former group also showed a trend towards lower cumulative 2-year LTP and HCC recurrence rates, both of which did not reach statistical significance probably due to the limited number of patients enrolled and the relatively short follow-up period. We think that the combined approach allows a sustained control in the majority of HCCs ≤5 cm. On the other hand, in patients with lesions >5 cm, we obtained in most cases a large necrotic area, and a sustained CR was achieved in about half of the cases with a mean
of only 1.3 procedures per patient. This implies a potential reduction of the therapeutic procedures’ number and, consequently, of the risk of liver function failure; in addition, this could explain the absence of significant differences in overall survival rates between the two groups. Finally, we think that the combined therapy is also promising as an effective bridging treatment to liver transplantation, as 2 patients with HCC <5 cm showed complete tumour necrosis at explant histological assessment. The main limitation of this pilot study is the small number of patients enrolled. Further investigations with larger patient populations and longer follow-up periods are warranted. In addition, the possible better effectiveness of the combined therapy with respect to conventional TACE or DEB-TACE alone, as well as its role as a bridge-to-transplant therapy, should be proven in prospective randomized studies. In conclusion, our study demonstrates that single-step balloonoccluded-RFA plus DEB-TACE is a safe and effective treatment of unifocal HCC larger than 3 cm detected in compensated cirrhotic patients and not amenable to surgical treatment. The combined treatment seems to provide better results than DEB-TACE alone. Tumour size is an important factor associated with sustained HCC control, as a significantly higher rate of long-term CR was observed in patients with lesions smaller than 5 cm.
Conflict of interest None declared.
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Liver, Pancreas and Biliary Tract
Radiofrequency ablation plus drug-eluting beads transcatheter arterial chemoembolization for the treatment of single large hepatocellular carcinoma Roberto Iezzi a,e,∗ , Maurizio Pompili b,e , Michele Fabio La Torre a,e , Maria Chiara Campanale b,e , Martina Montagna b,e , Antonio Saviano b,e , Valentina Cesario b,e , Massimo Siciliano b,e , Eleonora Annicchiarico b,e , Salvatore Agnes c,e , Felice Giuliante d,e , Antonio Grieco b,e , Gian Lodovico Rapaccini b,e , Anna Maria De Gaetano a,e , Antonio Gasbarrini b,e , Lorenzo Bonomo a,e , on behalf of the HepatoCATT Study Group for the Multidisciplinary Management of HCC a
Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital – Catholic University, Rome, Italy Department of Internal Medicine, “A. Gemelli” Hospital – Catholic University, Rome, Italy c Department of Surgery, Division of Organ Transplantation, “A. Gemelli” Hospital – Catholic University, Rome, Italy d Department of Surgery, Hepatobiliary Surgery Unit, “A. Gemelli” Hospital – Catholic University, Rome, Italy e Division of Medical Oncology, “A. Gemelli” Hospital – Catholic University, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 26 September 2014 Accepted 10 December 2014 Available online 13 December 2014 Keywords: Ablation Chemoembolization Combined therapy HCC RFA
a b s t r a c t Background: Our aim was to evaluate the effectiveness of the single-step combined therapy with radiofrequency ablation and drug-eluting beads transarterial chemoembolization in single hepatocellular carcinoma (HCC) larger than 3 cm. Secondary aim was to compare the results with those obtained in a matched population treated with drug-eluting beads transarterial chemoembolization alone. Methods: 40 consecutive cirrhotic patients with single HCC were prospectively enrolled and treated. Twenty-three patients had tumours between 3 and 5 cm (Group A), and 17 larger than 5 cm (Group B). Twenty cirrhotic patients with single HCC treated only with chemoembolization formed the control group. Results: Complete response at 1 month was achieved in 32/40 tumours (80%). During follow-up, complete response was maintained in 25 patients (25/40, 62.5%), and this rate was higher in Group A (69.6% vs 53%, p = 0.008). The group treated with combined therapy showed a significantly lower 2-year recurrence (48.1% vs 78.2%, p < 0.001) and significantly higher survival (91.1% vs 60.6%, p = 0.004) than the group treated with chemoembolization alone. Conclusions: Balloon-occluded-radiofrequency ablation plus drug-eluting beads transarterial chemoembolization is an effective treatment of HCC larger than 3 cm not amenable to surgical resection, providing better results than transarterial chemoembolization alone. The best results are achieved in tumours up to 5 cm. © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Despite the implementation of screening programmes for early diagnosis, about half of the cirrhotic patients still present with
∗ Corresponding author at: Department of Bioimaging and Radiological Sciences, Institute of Radiology, “A. Gemelli” Hospital – Catholic University, L.go A Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30154977; fax: +39 06 35501928. E-mail addresses: [email protected], [email protected] (R. Iezzi).
single large hepatocellular carcinomas (HCC) at diagnosis, and only 30% of them benefit from curative therapies [1–4]. Resection may provide excellent long-term results in these patients [5]. However, in patients who are not good surgical candidates, radiofrequency ablation (RFA) is not a good treatment option as the better results are achieved in tumours up to 3 cm large [6]; furthermore, studies performed on explanted livers obtained from patients treated with RFA before transplantation show that the rate of complete necrosis ranges between 13% and 43% in tumours larger than 3 cm [7]. On the other hand, despite transarterial chemoembolization
http://dx.doi.org/10.1016/j.dld.2014.12.007 1590-8658/© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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(TACE) is the current standard of care for patients with large HCC not amenable to surgery, a sustained complete response (CR) is achieved in only 27–35% of cases [8]. An improvement in TACE technique has been attained after the introduction of drug-eluting beads (DEB-TACE): these particles are able to bind and then elute doxorubicin in a predictable manner, thus allowing a more standardized approach and less drug-related toxicity [9]. However, even though DEB-TACE induces extensive tumour necrosis in more than 70% of tumours, less than 20% of the patients achieve a CR [10–12]. The main goal of the research in this field should be to increase the number of patients with single HCC larger than 3 cm suitable for non-surgical curative treatment; for these patients, a reasonable approach is to combine therapies with possible synergistic effects. Recent studies show that combined therapy with RFA and TACE could be more effective than TACE or RFA alone in local disease control and survival improvement, but it is not clear how the lesion’s size affects the follow-up response [13–15]. Therefore, the primary aim of this study was to evaluate the effectiveness of the single-step combined therapy with RFA and DEB-TACE in single HCC ≥3 cm. The secondary aim was to compare the results with those obtained in a matched population treated with DEB-TACE alone. 2. Materials and methods 2.1. Study design/study population A prospective single-centre pilot study was carried out to test a new single-step combined therapy of HCC with RFA of the lesion followed by selective DEB-TACE. Requirements for inclusion were: (a) single HCC larger than 3 cm; (b) liver cirrhosis classified as Child–Pugh score A5–6 or B7; (c) no vascular invasion or extrahepatic metastases; (d) no previous treatment of HCC. The exclusion criteria were: (a) Child–Pugh score B ≥8 or class C; (b) platelet count <40,000/L and/or international normalized ratio >1.5; (c) serum creatinine levels >2.0 mg/dL; (d) diuretic resistant ascites. All patients had been excluded from surgical resection due to one or more of the following reasons: severe portal hypertension (defined as presence of oesophageal varices ≥ F2 or gastric varices, and/or splenomegaly with platelet count <100,000/mL, and/or previous ascites successfully treated with diuretics), surgery unfeasible or hazardous due to lesion’s location or concurrent severe comorbidities, and refusal of surgery. The diagnosis of cirrhosis was established by means of histological and/or clinical findings (laboratory parameters, ultrasound [US] and/or computed tomography [CT] signs). The ethical conduct of the study was approved by our Institutional Review Board, and the study was performed in agreement with the 1990 Declaration of Helsinki and subsequent amendments. Written informed consent was obtained from all patients. 2.2. Pre-treatment work-up Within 2 weeks before treatment, all patients underwent physical examination, laboratory tests, and imaging studies with diagnostic and staging purposes, including liver US, radionuclide bone scan, contrast-enhanced chest and abdominal CT performed with a multiphasic protocol (flow-rate: 4 mL/s; unenhanced, arterial, portal and late phases; slice thickness: 0.625-mm) using a 64-multidetector-row CT scanner (Lightspeed VCT, GE Medical Systems). According to the guidelines in force at the time of enrolment, the diagnosis of HCC was made in the presence of a nodule detectable on US and showing the typical features of HCC on contrast-enhanced CT (hypervascular in arterial phase with washout in portal-venous phase) [16]. Eventual parasitic vascular
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supplies of the lesion were evaluated on pre-treatment contrastenhanced CT. 2.3. Treatment All combined treatments were performed in a single-step approach by the same interventional radiologist, using antibiotic prophylaxis, patient monitoring, and anaesthesiological assistance. An hepatic artery angiography was performed through a right common femoral approach to map liver vascular anatomy, as well as to check for arteriovenous shunts, and identify the arterial tumour supply. A 0.014-inch guide wire (Choice, Boston Scientific, USA) was advanced into the segmental hepatic artery feeding the lesion, enabling an optimal guidance of the low-profile monorail PTAballoon (4–5 × 20 mm, Muso, Terumo, Tokyo, Japan). RFA was then performed using US guidance with the patient under sedation with Fentanyl citrate (0.1–0.2 mg, Phentanest; Daiichi Sankyo, Tokyo, Japan) and local anaesthesia. An internally cooled electrode with a 3-cm exposed tip (Cool-Tip RF Ablation System, Covidien, Valleylab, USA) was introduced into the nodule, and the occlusion balloon in the hepatic artery was filled with a mixture of saline solution and contrast material. The RF generator was activated, and the power needed to maintain a temperature of 90–115 ◦ C at the exposed tip was delivered for 12 min. At the end of the procedure, the electrode was withdrawn, the occlusion balloon was deflated, and the immediate results were evaluated with angiography. After RFA, DEB-TACE was performed. The time elapsed between RFA completion and DEB-TACE performance was less than 5 min. A superselective chemoembolization of the lesion was performed using a coaxial technique and placing a 2.7-Fr microcatheter (Progreat; Terumo, Tokyo, Japan) in the distal segmental hepatic artery feeding the HCC. Slow injection of the 100–300 m DC-Bead (Terumo, Tokyo, Japan) loaded with Epirubicin (Farmorubicin® 50 mg powder) followed until the complete intended dose was administered and slow flow was observed. 2.4. Post-treatment and follow-up studies Perioperative morbidity and mortality included major/minor complications and death occurring within 7 days from treatment. A major complication was defined as an event that engenders substantial morbidity and disability, requires an increased level of care, or substantially lengthens hospital stay. All other complications were considered minor [17]. The endpoint of combined treatment was the disappearance of tumour enhancement at hepatic arteriography performed immediately after chemoembolization. The multiphasic CT study was performed one month after the procedure and then every 3 months both to evaluate the treatment result at the level of the target lesion using m-RECIST criteria [18], and to detect the occurrence of new lesions. CR was defined as the absence of enhancing tissue and a non-enhancing area at the tumour site larger than that of the tumour pre-treatment. In case of partial response (PR) of the target lesion, another session of combined treatment or TACE was performed; specifically, a combined treatment was preferred in case of nodular residual tumour larger than 3 cm. Local tumour progression (LTP) was defined as the appearance of nodular, irregular enhancement around or within the treated area in tumours previously assessed as completely necrotic. Intrahepatic distant recurrence (IDR) was defined as the appearance of new HCCs in the untreated liver or extrahepatic sites. All the patients with relapsing or progressive tumours were treated with the best possible options (combined therapy, percutaneous ethanol injection, RFA, TACE, or supportive care), depending on tumour staging, liver function assessment, and patient’s clinical condition.
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2.5. Control group The results from patients who underwent combined treatment were compared to those of a control group of cirrhotic patients with unifocal HCC, and without ascites, that were treated with DEBTACE alone during the period 2008–2012 (DEB-TACE group). These patients did not undergo DEB-TACE + RFA either because they were treated before the start of the present study or because RFA was judged unfeasible due to tumour location or inadequate clotting parameters (platelet count <40,000/L and/or international normalized ratio >1.5). 2.6. Statistical analysis Continuous variables were tested for normality using the Kolmogorov–Smirnov test and were reported as mean ± standard deviation. Comparisons between groups were performed using the Student’s t-test for continuous variables and the Chi-square or Fisher exact test for categorical data. Both for patients with CR and PR, the follow-up data regarding survival and IDR were estimated from the first treatment date, whereas follow-up data concerning LTP were calculated from the achievement of short-term CR. Follow-up ended at the last follow-up visit or death, or at the time of liver transplantation. The cumulative LTP, HCC recurrence, and overall survival rates were estimated with the Kaplan–Meier method and compared using the log-rank test. P values were considered significant if they were less than 0.05. Data were analysed with IBM SPSS Statistic release 20.0 and SAS software (SAS Institute Inc, USA). 3. Results 3.1. RFA + DEB-TACE group 3.1.1. Study population Between November 2010 and June 2012, 40 consecutive cirrhotic patients with single HCC larger than 3 cm were enrolled. The main features of patients and tumours are reported in Table 1. Mean HCC diameter was 4.7 ± 1.1 cm (range 3.2–7.5 cm); according to the HCC size, the patients were further divided in Group A
(23 patients with HCC ≤5 cm, mean diameter 3.9 ± 0.5 cm, range 3.2–5.0 cm) and Group B (17 patients with HCC >5.0 cm, mean diameter 5.7 ± 0.7 cm, range 5.2–7.5 cm). Besides tumour size, no significant differences were found between these two groups (Table 1). 3.1.2. Intraprocedural/early post-treatment results Technical success was achieved in all patients. Hepatic angiography at the end of the combined therapy showed a complete disappearance of the tumour vasculature and/or tumour stain in all cases. A mean procedural time of 68 ± 12 min was recorded and no major complications occurred. Minor complications were subcapsular haematoma (1 patient, 2.5%), serum level of transaminases increased compared to basal value (14 patients, 35%), and transient cholecystitis (2 patients, 5%). No complications related to the use of the balloon-occlusion technique were recorded; in particular, no arterial tears and rupture or flow-limiting dissection and segmental hepatic artery thrombosis occurred. None of the patients experienced a worsening of Child–Pugh score at 1-month followup. 3.1.3. Short-term results At 1-month CT, based on the m-RECIST criteria, a CR was achieved in 32/40 (80%) patients, whereas a PR was obtained in the remaining 8 patients (residual tumour <30% in 6 patients, and 30–50% in 2 patients). In group A, CR and PR were achieved in 20/23 (87%) and 3/23 (13%) tumours, respectively. In group B, CR and PR were reached in 12/17 (70.6%) and 5/17 (29.4%) tumours, respectively. When comparing CR rates, the difference between Group A and B was significant (p = 0.009). According to the 1-month CT results, a repeated locoregional treatment was performed in 8 patients (3 in Group A and 5 in Group B) to achieve complete necrosis. A DEB-TACE session was performed in all 3 patients of Group A and in 4 patients of Group B, whereas a repeated combined treatment was performed in the remaining patient of Group B, who presented with an eccentric nodular residual tumour of 3.1 cm in size. To obtain a complete necrosis, a total number of 48 procedures were needed (41 combined treatments and 7 TACE procedures) and a mean number of
Table 1 Demographic, clinical and hematochemical features of patients treated with radiofrequency ablation plus drug-eluting beads transarterial chemoembolization (total population, Group A, Group B) and transarterial chemoembolization only, respectively. Numbers in brackets are percent rates. Patients treated with RFA + DEB-TACE
N Male Age (years) Cirrhosis aetiology Hepatitis B Hepatitis C Alcohol-related Cryptogenic Mean HCC size (cm) HCC size >5 cm Child–Pugh Class B7 Severe portal hypertension Total bilirubin (mg/dL) ≤ 1.0 Albumin (g/dL) > 3.5 ALT (IU/L) ≤ 40 AFP (ng/mL) ≤ 20 Mean follow up (months)
p*
p**
Patients treated with DEB-TACE N (%)
17 11 (64.7) 67.9 ± 5.6
0.601 0.839
20 16 (80) 70.5 ± 5.8
0.121 0.141
3 (17.6) 11 (64.7) 1 (5.9) 2 (11.8) 5.7 ± 0.7 NA 7 (41.2) 11 (64.7) 9 (52.9) 8 (47.1) 3 (17.6) 7 (41.2) 23 ± 7
0.471 0.184 0.373 1.000 <0.001 NA 0.896 0.746 0.091 0.554 1.000 0.676 0.844
3 (15) 10 (50) 5 (25) 2 (10) 4.2 ± 1.7 6 (30) 3 (15) 15 (75%) 11 (55) 13 (65) 12 (60) 13 (65) 24 ± 17
0.375 0.855 0.155 0.422 0.251 0.348 0.050 0.550 0.344 0.357 0.001 0.144 1.000
Total N (%)
Group A N (%)
Group B N (%)
40 24 (60) 68.2 ± 6.1
23 13 (56.5) 68.3 ± 6.6
10 (25) 21 (52.5) 5 (12.5) 4 (10) 4.7 ± 1.1 17 (42.5) 16 (40) 27 (67.5%) 27 (67.5) 21 (52.5) 7 (17.5) 18 (45) 24 ± 8
7 (30.4) 10 (43.5) 4 (17.4) 2 (8.7) 3.9 ± 0.5 NA 9 (39.2) 16 (69.6) 18 (78.3) 13 (56.5) 4 (17.4) 11 (47.8) 24 ± 9
RFA, radiofrequency ablation; DEB-TACE, drug eluting beads-transarterial chemoembolization; HCC, hepatocellular carcinoma; NA, not applicable; ALT, alanine aminotransferase; AFP, alphafetoprotein. * RFA + DEB-TACE (total population) vs DEB-TACE. ** RFA + DEB-TACE: Group A vs Group B.
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Fig. 1. A single large hepatocellular carcinoma in VIII hepatic segment (4.5 cm in diameter) was confirmed on selective digital subtraction angiography (a). Radiofrequency ablation electrode was placed into the lesion under ultrasound-guidance (b) and the radiofrequency ablation generator was activated during balloon-occlusion (circle in b) of the tumour arterial supply. Angiographic image performed after radiofrequency ablation showed the immediate result with a complete central devascularized area and peripheral reactive hyperemia (c). After radiofrequency ablation, a superselective chemoembolization of the lesion demonstrated complete devascularization of the lesion (d).
1.13 and 1.3 procedures per patient were performed in Group A and Group B, respectively (Fig. 1).
in Group A, and 94.1% and 84.7% in Group B. Also in this case, the difference between Group A and B was not significant (p = 0.389).
3.1.4. Long-term results During follow-up a CR was maintained in 25 patients (25/40, 62.5%). Specifically, at the time of last response assessment, in Group A (mean follow-up: 24 ± 8 months) a CR was still present in 16/23 patients (69.6%) (Fig. 2); among these 16 patients, two underwent liver transplantation 4 and 8 months after treatment and showed complete necrosis of the tumours at explant analysis. On the other hand, in Group B (mean follow-up: 23 ± 7 months) a long-term CR was observed in 9/17 patients (53%) (p = 0.008). At the time of censoring, 15 patients (37.5%) showed HCC recurrence; of these, 7 were in group A (30.4%) and 8 in group B (47%). In Group A, 3 LTP (two treated with percutaneous ethanol injection, the other with one session of DEB-TACE) and 4 IDR (two treated with RFA, the other two with one session of DEB-TACE) were observed. In Group B, 5 LTP (two treated with percutaneous ethanol injection, the other three with one session of DEB-TACE) and 3 IDR (one treated with RFA, the other two with one session of DEB-TACE) were detected. Both the 1 and 2-year LTP cumulative rates (5.6% and 22.5% vs 18.1% and 40.3%) and 1 and 2-year cumulative HCC recurrence rates (19.2% and 39.2% vs 30.7% and 59.6%) were lower in Group A than in Group B, despite these differences did not reach statistical significance (p = 0.214 and 0.337, respectively) (Fig. 3). Three patients (4%) died because of neoplastic disease progression (one in Group A and two in Group B). The cumulative 1 and 2-year overall survival rates were 94.7% and 91.1% in the whole population, 92.5% and 92.5%
3.2. DEB-TACE group 3.2.1. Study population In the control group, 20 cirrhotic patients with single HCC treated with DEB-TACE were enrolled. Mean HCC diameter was 4.2 cm (range 2.5–8.0 cm), and a mean procedural time of 51 ± 10 min was recorded. No significant differences were found between the two groups in terms of mean procedural time (68 ± 12 min vs 51 ± 10 min; p = 0.120). The characteristics of these patients are summarized in Table 1. Besides the significant lower serum level of alanine-aminotransferase, they did not show any other significant difference when compared with the RFA + DEBTACE group.
3.2.2. Short-term results On 1-month CT, based on the m-RECIST criteria, CR and PR were achieved in 8/20 (40%) and 12/20 (60%) patients, respectively. Compared with the DEB-TACE + RFA Group, the rate of patients achieving a short-term CR was significantly lower (p < 0.001). In patients with PR, a repeated TACE was performed in 7 cases; four patients achieved complete necrosis, while the remaining 3 underwent further procedures including percutaneous ethanol injection, TACE, and RFA. Concerning the remaining 5 patients with PR, 2 were treated with sorafenib, 1 with percutaneous ethanol injection, 1
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Fig. 2. Axial contrast-enhanced computed tomographic images before combined treatment showed a right lobe hepatocellular carcinoma of 4.5 cm in size (a: arterial phase; b: late-phase). At 1-year follow-up, computed tomographic images displayed a complete necrosis of the lesion without local tumour progression (c: arterial phase; d: late-phase).
Fig. 3. Cumulative local tumour progression (A) and tumour recurrence (B) rates in patients treated with drug-eluting beads transarterial chemoembolization plus radiofrequency ablation: Groups A and B. HCC, hepatocellular carcinoma.
with resective surgery and 1 did not undergo any treatment due to liver function failure. 3.2.3. Long-term results During follow-up (mean duration: 24 ± 17 months), CR was maintained in 4/20 patients (20%), and this rate was significantly lower than that achieved in the RFA + DEB-TACE Group (p < 0.001). At the time of censoring, a total of 16 patients (76%) showed HCC recurrence: 8 showed both LTP and IDR recurrence, 6 showed only LTP recurrence, and 2 showed only IDR recurrence. Seven patients died (33%) because of neoplastic disease progression or
liver function failure. Compared to the RFA + DEB-TACE Group, the DEB-TACE Group showed significantly higher 1 and 2-year HCC recurrence rates (45.5% and 78.2% vs 24.3% and 48.1%, p < 0.001), and significantly lower 1 and 2-year overall survival rates (67.4% and 60.6% vs 94.7% and 91.1%, p 0.004) (Fig. 4).
4. Discussion A few recent studies suggest that combined therapy with RFA and TACE could be superior to TACE or RFA alone in the treatment
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Fig. 4. Cumulative overall survival (A) and recurrence rates (B) in patients treated with radiofrequency ablation plus drug-eluting beads transarterial chemoembolization and transarterial chemoembolization only, respectively. DEB-TACE, drug eluting beads transarterial chemoembolization; RFA, radiofrequency ablation; TACE: transarterial chemoembolization.
of large HCC [13–15]. Balloon occlusion of the tumour arterial supply increases the area of coagulation necrosis obtained with RFA by reducing arterial blood flow and minimizing heat loss [19,20]. On the other hand, by performing TACE after RFA it is possible to obtain some sustained anticancer effect from the sublethal heating created by RFA in the area surrounding the lethal heating zone. In detail, the chemotherapeutic agent could be concentrated in the peripheral residual viable neoplastic tissue, characterized by both increased drug delivery, due to the heating-related reactive hyperemia, and reduced cell resistance to the drug, due to the previous exposure to sublethal heating [21]. Based on this theoretical background of a synergistic effect of RFA and DEB-TACE, our combined approach could enhance both the thermal damage and the cytotoxic injury without increasing the procedural time [22,23]. Indeed, in our study the mean duration of RFA + DEB-TACE did not differ significantly from that of DEB-TACE alone (68 ± 12 min vs 51 ± 10 min; p = 0.120). This study shows that balloon-occluded RFA followed by DEBTACE is effective in achieving prolonged local disease control in single HCC >3 cm; in fact, we showed a sustained CR in 62.5% of treated lesions, a 2-year cumulative HCC recurrence rate of 48.1%, and an overall survival rate of 91.1%, significantly better than that achieved in a comparable control group of patients treated with DEB-TACE alone. It is worth noting that these promising results were obtained in a single-step procedure and that the benefit of combined therapy was not offset by any important side effect or worsening of liver function as none of our patients experienced an increased Child–Pugh score at 1 month after treatment. It is well known that TACE alone may require treatment repetition and that this may injury the non-cancerous cirrhotic liver tissue. As a matter of fact, drug-related toxicity may be a major limitation of TACE regimens, as previous studies reported to occur in more than 30% of patients [24]. Tumour size is a significant prognostic factor associated with the maintenance of local disease control. In particular, the rate of sustained CR was significantly higher in Group A than in Group B (69.6% vs 53.0%). The former group also showed a trend towards lower cumulative 2-year LTP and HCC recurrence rates, both of which did not reach statistical significance probably due to the limited number of patients enrolled and the relatively short follow-up period. We think that the combined approach allows a sustained control in the majority of HCCs ≤5 cm. On the other hand, in patients with lesions >5 cm, we obtained in most cases a large necrotic area, and a sustained CR was achieved in about half of the cases with a mean
of only 1.3 procedures per patient. This implies a potential reduction of the therapeutic procedures’ number and, consequently, of the risk of liver function failure; in addition, this could explain the absence of significant differences in overall survival rates between the two groups. Finally, we think that the combined therapy is also promising as an effective bridging treatment to liver transplantation, as 2 patients with HCC <5 cm showed complete tumour necrosis at explant histological assessment. The main limitation of this pilot study is the small number of patients enrolled. Further investigations with larger patient populations and longer follow-up periods are warranted. In addition, the possible better effectiveness of the combined therapy with respect to conventional TACE or DEB-TACE alone, as well as its role as a bridge-to-transplant therapy, should be proven in prospective randomized studies. In conclusion, our study demonstrates that single-step balloonoccluded-RFA plus DEB-TACE is a safe and effective treatment of unifocal HCC larger than 3 cm detected in compensated cirrhotic patients and not amenable to surgical treatment. The combined treatment seems to provide better results than DEB-TACE alone. Tumour size is an important factor associated with sustained HCC control, as a significantly higher rate of long-term CR was observed in patients with lesions smaller than 5 cm.
Conflict of interest None declared.
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