Comparison of no-touch multi-bipolar vs. monopolar radiofrequency ablation for small HCC

Accepted Manuscript Comparison of NoTouch MultiBipolar vs. Monopolar radiofrequency ablation for small HCC Arnaud Hocquelet, Christophe Aubé, Agnès Rode, Victoire Cartier, Olivier Sutter, Anne Frederique Manichon, Jérome Boursier, Gisèle N’kontchou, Philippe Merle, Jean-Frédéric Blanc, Hervé Trillaud, Olivier Seror PII: DOI: Reference:

S0168-8278(16)30334-8 http://dx.doi.org/10.1016/j.jhep.2016.07.010 JHEPAT 6186

To appear in:

Journal of Hepatology

Received Date: Revised Date: Accepted Date:

14 April 2016 4 July 2016 4 July 2016

Please cite this article as: Hocquelet, A., Aubé, C., Rode, A., Cartier, V., Sutter, O., Manichon, A.F., Boursier, J., N’kontchou, G., Merle, P., Blanc, J-F., Trillaud, H., Seror, O., Comparison of NoTouch MultiBipolar vs. Monopolar radiofrequency ablation for small HCC, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep. 2016.07.010

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Comparison of NoTouch MultiBipolar vs. Monopolar radiofrequency ablation for small HCC

Authors: Arnaud Hocquelet 1,2, MD, [email protected] Christophe Aubé 3,4, MD, PhD, [email protected] Agnès Rode 5, MD, [email protected] Victoire Cartier 3, MD, [email protected] Olivier Sutter 6,7, MD, [email protected] Anne Frederique Manichon 5, MD, [email protected] Jérome Boursier 4,8, MD, [email protected] Gisèle N’kontchou 9, MD, [email protected] Philippe Merle10, MD, PhD, [email protected] Jean-Frédéric Blanc 11, MD, PhD, [email protected] Hervé Trillaud1,2, MD, PhD, [email protected] Olivier Seror6,7,12, MD, PhD, [email protected]

1

Affiliations: 1 Service

de radiologie de l’Hôpital Haut-lévêque, CHU de Bordeaux, avenue Magellan,

33600 Pessac, France 2

EA IMOTION (Imagerie moléculaire et thérapies innovantes en oncologie) Université

de Bordeaux, 146 rue Leo Saignat, Case 127, 33076 Bordeaux, France 3 Département 4

de radiologie, CHU d’Angers, LUNAM université, 49933 Angers, France

Laboratoire HIFIH, UPRES 3859, LUNAM université, université d’Angers, 49045

Angers, France 5

service d'imagerie médicale, hôpital de la Croix Rousse, Lyon

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Service de Radiologie de l’Hôpital Jean Verdier, Hôpitaux universitaires Paris-Seine-

Saint-Denis, Assistance publique Hôpitaux de Paris, Bondy, France 7 Unité

de Formation et de Recherche Santé Médecine et Biologie humaine, Université

Paris 13, Communauté d’Universités et Etablissements Sorbonne Paris Cité, Paris, France 8 Service

de gastroenterologie et hépatologie, LUNAM université, CHU d’Angers, 49933

Angers, France 9

Service d’Hepatologie de l’Hôpital Jean Verdier, Hôpitaux universitaires Paris-Seine-

Saint-Denis, Assistance publique Hôpitaux de Paris, Bondy, France 10 service

d’hépatologie, hôpital de la Croix Rousse, Lyon

11Service

d’hépatologie de l’Hôpital Haut-lévêque, CHU de Bordeaux, avenue Magellan,

33600 Pessac, France 12

Unité mixte de Recherche 1162, Génomique fonctionnelle des Tumeurs solides,

Institut National de la Santé et de la Recherche médicale, Paris, France

2

Corresponding author: Hocquelet Arnaud, [email protected] +33621110379 Hopital Haut-Lévêque, centre medico-chirurgical de Magellan, Avenue Magellan 33600 Pessac

Keywords: Hepatocellular carcinoma; Radiofrequency ablation; NoTouch multibipolar RFA; Monopolar RFA; Tumor recurrence; coarsened exact matching

Abbreviations: HCC: Hepatocellular carcinoma RFA: Radiofrequency ablation LTP: Local Tumor Progression MonoRFA; Monopolar Radiofrequency Ablation NTmnpRFA: NoTouch MultiBipolar Radiofrequency Ablation MRI: Magnetic Resonance Imaging CT: Computed Tomography CEM: Coarsened Exact Matching AFP: AlphaFetoprotein

Electronic word count: 4782

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Number of figures and tables: 4 tables and 4 Figures with additional 5 tables as supplementary files Conflict of interest statement: Olivier Seror: Activities related to the present article: none to disclose. Activities not related to the present article: has received personal fees and non-financial support from Bayer Healthcare, Angio- dynamics, and Olympus Surgical. Other relationships: none to disclose. All other authors: None to disclose

Financial support: None

Authors contributions: Concept and design: AH, CA, AR, HT, OS Experiments and procedures: All authors Writing of article: AH, CA, AR, HT, OS Statistical analysis: AH

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Abstract Background & Aims The primary aim of this study was to compare the rate of global radiofrequency ablation (RFA) failure between monopolar RFA (MonoRFA) versus NoTouch MultiBipolar RFA (NTmbpRFA) for small hepatocellular carcinoma (HCC) ≤5cm in cirrhotic patients. Methods A total of 362 cirrhotic patients were included retrospectively across 4 French centres (181 per treatment group). Global RFA failure (primary RFA failure or local tumor progression) was analysed using the Kaplan Meier method after coarsened exact matching. Cox regression models were used to identify factors associated with global RF failure and overall survival (OS). Results Patients were well-matched according tumour size (≤30/>30mm); Tumour number (one/several); Tumour location (subcapsular and near large vessel); Serum AFP (<10; 10-100; >100ng/ml); Child-Pugh score (A/B) and platelet count (30mm and HCC near large vessel were independent factors associated with global RFA failure. Five-year OS was 37.2% following MonoRFA versus 46.4% following NTmbpRFA P=0.378. Conclusions This large multicentre case-matched study showed that NTmbpRF provided better primary RF success and sustained local tumor response without increasing severe complications rates, for HCC≤5cm.

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Lay summary: Using NoTouch MultiBipolar radiofrequency ablation for hepatocellular carcinoma ≤5cm provide better sustained local tumor control compared to monopolar radiofrequency ablation

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Introduction Percutaneous thermal ablative techniques are recognized as curative for early-stage hepatocellular carcinoma (HCC)[1,2]. Radiofrequency ablation (RFA) is the most widely used technique with significant literature available, including several reports on long-term outcomes. The major drawback of RFA is local tumour progression (LTP)[3] due to untreated satellite nodules [4] or primary treatment failure[5]; both being directly linked to tumor size[5–8]. Conventional intratumourous monopolar techniques provide only limited necrotic volume[9] that can lead to insufficient treatment margins or inhomogeneous necrotic volume[10], even when overlapping techniques are used[11]. Consequently, LTP rates after monopolar RFA have been reported to be as high as 27% at 5 years[7]. RFA devices thus need to be improved and multibipolar RFA has been developed to increase the maximal ablative volume[12], providing more homogeneous necrosis with a higher rate of pathological complete necrosis in preliminary reports[10]. Furthermore, multibipolar RFA could be performed in no-touch intention. The No Touch technique is performed by inserting multiples electrodes around the periphery of the tumour and activating them sequentially to perform ablation with a sufficient peritumoural margin and avoid direct puncture of the tumor [13]. Although very encouraging results have been reported after treatment of small HCC with multibipolar RFA [8,13–15], the monopolar technique remains by far the most frequently used technique worldwide. The aim of this work was thus to compare the local efficacy of monopolar RFA (MonoRFA) versus NoTouch Multipolar RFA (NTmbpRFA) for the curative treatment of small HCC (≤5cm) in a large multicentre case-matched study.

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Patients and Methods Study design and Patient selection This retrospective study was approved by the institutional ethics review board in each participating centre. Informed consent was not required for this retrospective study. From each prospectively-maintained database at the four centres (University hospitals of Angers, Bondy, Bordeaux and Lyon) in which monopolar and multibipolar RFA technologies were available, we selected 596 consecutive cirrhotic patients with single HCC ≤ 5cm, or fewer than three nodules all <3 cm, without extrahepatic metastasis (Milan criteria) who were treated by first-line RFA from January 2004 to December 2013 according to the decision of local tumour boards. Additional criteria were: (i) First occurrence of HCC; (ii) treated by monopolar RFA device or by multipolar RFA device using NoTouch multibipolar RFA technique; (iii) Child-Pugh A or B; (v) no other cancer. Exclusion criteria were: (i) treatment with multipolar RFA devices with intra-tumoral puncture; (ii) lost-to-follow-up before the first imaging control; and (iii) patients included in the clinical trial ARMCENVIN (NCT01008657). All patients were input into a combined database, and patients were matched in two groups according to the ablative technique: MonoRFA or NTmbpRFA. Tree hundred sixty-two patients were included after matching, 181 in each group, MonoRFA vs. NTmbpRFA (Figure 1). Matching was performed using coarsened exact matching, controlling for Child-Pugh level, Platelet count, serum AFP, tumour size, tumour number, subcapsular location and near large vessel location (further details in statistical section).

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Diagnosis and Staging of HCC All patients were cirrhotic. Cirrhosis was diagnosed via liver biopsy for 209 (57.7%) patients and via liver stiffness, imaging and blood sample for the remaining 153 (42.3%) patients. HCC diagnosis was pathologically proven for 191 (52.3%) patients and based on noninvasive criteria of the European Association for the Study of the Liver[2] for the remaining 171 (47.2%) patients. Radiofrequency ablation All RFA procedures were performed percutaneously under general anaesthesia. Real-time ultrasound (US) was chosen as the first-line guidance modality (n=348; 96.1%). When this was not possible, computed tomography (CT) guidance was used in 14 cases (3.9%) procedures. Eight senior interventional radiologists (at least five years of experience at the beginning of the study) performed RFA using one of the following devices: monopolar expandable Boston LeVeen™ needles (RF 3000 Boston Scientific Corporate®); RITA, StarBurst XL (Angiodynamics®); Cool-tip™ RFA system (Covidien®); or multipolar internally cooled-tip CelonProSurge™ (CelonPOWER System OLYMPUS Medical®). The device was chosen based on the operator’s expertise. From 2004 to 2006 all patients were treated with monopolar devices. In 2006 one center began to use exclusively NTmbpRFA, whereas the 3 remained centers began progressively to use NTmbpRFA. At the beginning, NTmbpRFA was used for medium size HCC (3-5cm) and for subcapsular HCC. Then, considering the clinical results observed in each center, the utilization of NTmbpRFA progressively increased year by year in each center. Therefore, each RFA was feasible with both technics (mono or multibipolar). Considering the technical advantages of NTmbpRFA for subcapsular HCC and HCC near large vessels (see discussion), the switch from monopolar to NTmbpRFA was faster in these specific tumor locations. Thermal ablations with monopolar RFA devices were performed according to the

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manufacturer’s instructions. NTmbpRFAmultibipolar RF ablations were performed as previously described by Seror et al[13]. Track ablation was systematically performed during needle(s) withdrawal for both techniques. Technical differences between NTmbpRFAand MonoRFA are illustrated in figure 2.

Patient follow-up Treatment efficacy was assessed four to six weeks after the RF procedure, by triphasic contrast-enhanced magnetic resonance imaging (MRI) (or computed tomography (CT) in case of contraindication), all read by radiologists expert in hepatology imaging. Complete tumor ablation was defined as a hypoattenuating, nonenhancing area at the tumor site during both the arterial and the portal venous phases. Discontinuous, focal, or nodular enhancement persistent after RF at the tumor site was considered to be residual viable tumor and thus incomplete treatment. In this last case, a second RF ablation was performed if the patient still complied with the criteria of indication. Once the treatment was considered complete, after a single RF procedure or two, the patient was followed-up by MRI every three months for two years and then every six months. Study endpoints and definitions of terminology The primary endpoint was the rate of global RF failure [8], defined as primary RF failure or local tumour progression (LTP) during follow-up, compared between the two groups (MonoRFA versus NTmbpRFA). Primary RF failure was defined as incomplete treatment after two initial RF sessions or local progression after an incomplete first RF session precluding further RF. LTP was defined as the appearance of tumour foci at the edge of the ablation zone, after at least one contrast-enhanced follow-up study had documented adequate ablation and an absence of viable tissue in the target tumour and surrounding ablation margin

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by using imaging criteria. This term applies regardless of when tumor foci were discovered either early or late in the course of imaging follow-up [3]. We also recorded whether the tumour was adjacent to large vessels (portal or sus-hepatic veins > 3mm)[16]. Secondary endpoints were the comparison of (i) major complication using the society of interventional imaging [17] and the Clavien-Dindo classification[18]; (ii) intra-hepatic distant recurrence rates and (iii) overall survival. Statistical analysis Coarsened exact matching: To control for selection bias and provide a more accurate matching on prognostic factors rather than using only a propensity score we used one-to-one coarsened exact matching (CEM)[19]. CEM methods specify how covariates differ across groups before matching, instead of merely taking those differences as a post-matching result as in propensity score. CEM was performed using seven categorized variables potentially associated with local tumor progression: Tumor size (≤30mm versus >30mm); Tumor number (one versus several); Tumour location, subcapsular (or not) and near large vessel (>3mm) (or not); Serum AFP (categorized in three groups: <10 ng/ml; 10-100 ng/ml; >100ng/ml); ChildPugh score (A or B) and platelet count (< or ≥100G/L). Analysis: Qualitative variables are expressed as percentages and quantitative variables as median with 1 st and 3 rd quartiles in brackets unless otherwise specified. They were compared using two tailed t-test or Mann-Whitney U test, according to data distribution. Percentages were compared using the chi- squared test or Fisher’s exact test. A patient was considered lost-to-follow-up if last information available was older than 6 months with a total follow-up duration <5 years. To estimate OS time to last follow-up evaluation or death was measured from the date of treatment. Patients with liver transplantation were censored at the date of transplantation.

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To identify factors associated with Global RF failure, patients with primary RF failure were censored at the first imaging control date. First, we performed a univariate Cox model reporting Hazard Ratios (HR) and their 95% confidence intervals (95%CI) for several variables: Age; Sex (Male); Non-viral hepatitis (vs.viral); Child B score (vs. A); Platelet count <100G/L (vs. ≥100G/L); Alpha-fetoprotein >100 ng/ml (vs. ≤100 ng/ml); Tumour size >3cm (vs. ≤3cm); Multiple nodules (vs. single nodule); Tumour near large vessel (vs. not); sub-capsular tumour (vs. not); Monopolar RFA (vs. NoTouch multibipolar RFA). Then, variables with a P value <0.10 were introduced in a multivariate Cox model. The same procedure was used to identify predictive factors of distant recurrences and overall survival. To identify factor associated with major complication, logistic regression was used. A P-value <0.05 was considered as significant. Statistical analyses were performed with Stata 13. Results Patient characteristics and follow-up After matching, 362 patients were selected, 181 in each treatment group (MonoRFA group or NTmbpRFA group) (figure 1). As shown in Table 1, patients were well matched across both groups according to Child-Pugh score, tumor size, number and location; serum AFP and platelet count strata. No differences were recorded for other variables such as age, sex and cirrhosis aetiology. RF devices used according to tumor size are summarized in supplementary table 1. The mean (SD) and median (1 st-3 rd quartile) follow-up durations were: 3.2 (2.0) years and 3.0 (1.57-4.63) years. Forty-seven patients were transplanted (12.9%), 27 in the MonoRFA group (14.9%) and 20 in the NTmbpRFA group (11%), P=0.274. The mean (SD) and median (1st3 rd quartile) time to transplantation were 2.1 (1.8) years and 1.42 (1.0-2.9) years. Causes of liver transplantations were Hepatocellular insufficiency for 7 (26%) MonoRFA and 7 (35%)

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NTmbpRFA patients and HCC for 20 (74%) MonoRFA and 13 (65%) NTmbpRFA patients, P=0.501. At 5-years follow-up, 20 (5.5%) patients were lost-to follow-up: 12 in the MonoRFA group and 8 in the NTmbpRFA group. The mean (range) and median (1 st-3rd quartile) follow-up duration of these lost-to-follow-up patients were: 2.3 (0.56-4.7) years and 2.2 (0.83-3.30) years. Primary radiofrequency ablation failure and local tumour progression The global RF failure rate was higher after MonoRFA (52/181; 28.7%) than after NTmbpRFA (13/181; 7.1%), P<0.001. Details of global RF failures, primary RF failure and LTP according to tumor size are presented in Table 2. Following the first RF session a second RFA session were performed for 11 patients in the MonoRFA group leading to three complete treatments. Additionally, two patients without complete responses after the first RFA were treated by transarterial chemoembolization due to multifocal local progression, precluding subsequent RFA treatment. In the NTmbpRFA group, six patients had a second RFA treatment, which was complete for all patients. The primary RF failure rate was higher using MonoRFA than NTmbpRFA, occuring for 10/181 patients (5.52%) treated by MonoRFA versus none in NTmbpRFA group (P=0.002). The LTP rate in the MonoRFA group was 24.6% (42/171) versus 7.2% (13/181) in the NTmbpRFA group (P<0.001). LTP following NTmbpRFA was significantly lower than MonoRFA for each tumour size (Table 2). The 5-years cumulative global RF failure rates did not differ between MonoRFA and NTmbpRFA according to tumor number, 35.6% and 7.9% respectively for single HCC, P<0.0001 and 41.1% versus 14.08, P=0.04 for multiple HCC.

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Predictive factors of global radiofrequency failure In the multivariate Cox model 3 variables were identified as independent risk factors of global RF failure (table 3): MonoRFA HR=4.631 (95% CI: 2.52-8.53); Tumour size>30mm HR=2.349 (1.38-3.99) and HCC near large vessel with HR=2.019 (1.10-3.73). The cumulative rates of global RF failure at 1, 3 and 5 years were respectively 13.3%, 31% and 36.7% for MonoRFA versus 0.02%, 7.9% and 9.2% for NTmbpRFA, P<0.001 (figure 3). Among the 48 HCC near large vessels, 13 (27%) global RF failures were recorded, 10/24 (42%) in the MonoRFA group (3 primary RF failures and 7 LTP) versus 3/24 (12.5%) in the NTmbpRFA group (0 primary RF failure and 3 LTP). In this subgroup of patients the corresponding 5-year cumulative failure rate was 51.5% for MonoRFA versus 15% for the NTmbpRFA group (P=0.021). Among the 44 sub-capsular HCC, 9 global RF failures were recorded, 7/22 (32%) in the MonoRFA (0 primary RF failure and 7 LTP) group versus 2/22 (9%) in the NTmbpRFA group (0 primary RF failure and 2 LTP). In this subgroup of patients, the corresponding 5year cumulative failure rate was 41% for MonoRFA versus 15% for the NTmbpRFA group (P=0.207). Splitting multivariate analysis according to RFA techniques (either MonoRFA or NTmbpRFA; data not shown), HCC near large vessels and tumor size>30mm were associated with global RF failure only for the MonoRFA group (P=0.046 and P=0.001 respectively). No associations were found in the NTmbpRFA group (variables not retained in multivariate analysis). Furthermore, no differences were found between the different MonoRFA devices for global RF failures (P=0.126 by log-rank test and P=0.141 by Cox-regression) Complications The rate of major complications according to the SIR classification did not differ between the two treatment groups, 7.2% (P=1) (see table 4). Although not significant (P=0.054) the rate

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of complication over Clavien-Dindo grade 3a (meaning that required surgery or intensive care unit or death) was higher after NTmbpRFA (4.4%; 8/181) than after MonoRFA (1.1%; 2/181). In the MonoRFA group one patient needed selective hepatic artery embolization and one required surgery to place a chest tube for major haemothorax. In the NTmbpRFA group, one patient died following severe acute liver failure, 2 patients required surgery for diaphragmatic hernia, and 1 patient was liver transplanted because of liver failure linked to severe haemobilia despite percutaneous biliary-drainage. The complication rate associated with liver failure did not differ between the two groups (n=6; 3.3% for both; P=1). In multivariate logistic regression (supplementary table 2) only Child B classification was associated with higher risk of major complication (SIR classification) with Odds ratio: 4.625 (95%CI 1.96-10.89). Overall survival and distant recurrence One hundred eighty nine patients died, 104/181 (57.5%) in the MonoRFA group and 85/181 (47%) in the NTmbpRFA group (P=0.046). Causes of death were: HCC progression for 65/181 patients (34.4%); liver failure for 50/181 patients (26.5%); sepsis for 18/181 patients (9.5%); other cancer for 12/181 patients (6.3%); no-liver or cancer related death for 33/181 patients (17.5%), treatment related death for 1/181 (0.5%) and unknown for 10/181 patients (5.3%). Causes of death did no differ between the two treatment groups (P=0.203) (causes of death according to MonoRFA or NTmbpRFA are detailed in supplementary table 3). At the date of death, among the 124 patients for whom death was not assigned to HCC progression, (73 in the MonoRFA and 51 in the NTmbpRFA group), 76 had no detectable tumours - 41 in the MonoRFA group (56.2%) versus 35 in NTmbpRFA(68.6%), P=0.161. The 3- and 5-year OS rates were 63.5% and 37.2% following MonoRFA versus 64.5% and 46.4% following NTmbpRFA, P=0.964 and P=0.378 (figure 4). In the multivariate Cox

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model (supplementary table 4), Child-Pugh B (HZ=1.706 {1.125-2.587}) was the only independent risk factor associated with OS. On the date of the study’s end-point, among the 126 patients alive without transplantation (50 in MonoRFA and 76 in NTmbpRFA group), 93 had no detectable tumours - 32 in the MonoRFA group (64%) versus 61 in the NTmbpRFA group (80.3%), P=0.042. The 3- and 5year cumulative distant-recurrence rates were 58.5% and 72.8% following MonoRFA versus 56.6% and 67.5% following NTmbpRFA, P=0.328. In the multivariate Cox model (supplementary table 5), only multiple tumours (HR=1.501 {1.086 -2.074}) was associated with intra-hepatic distant recurrence.

Discussion In this large multicentre case-matched study NTmbpRFA offered a better primary RFA success rate and better sustained local tumour control than Monopolar RFA for HCC≤5cm. These results are further supported by the multivariate analysis, which highlighted MonoRFA as an independent prognostic factor of global RF failure. Considering the group of HCC>3cm and ≤5cm, the better results of NTmbpRFA compared to MonoRFA, both in terms of less primary RF failure and low LTP rates, are not surprising and have been reported in previous preliminary studies[8,10,14,15]. This pattern can be explained by the limitation of MonoRFA techniques to produce large and homogeneous histopathological necrosis (for all monopolar techniques). A recent report [10] demonstrated 50% complete necrosis (on explanted livers) for HCC≤3cm using MonoRFA, while using NTmbpRFA it climbed to almost 90%. NTmbpRFA deposits higher energy and thanks to the sequential activation in bipolar mode of each possible pair’s combination of applicators a reliable and extended necrosis volume can be obtained without probe repositioning.

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NTmbpRFA for smaller tumours (HCC≤3cm), also improved local tumour control significantly compared with monoRFA. This result was less expected as MonoRFA, the most popular ablative technique used worldwide, is regarded as a reliable technology for inducing complete ablation of HCC including sufficient safety margins[7,20–23]. Using MonoRFA we found a 4% primary RF failure rate (6/149) with 20% LTP, in agreement with the multicentre study of Pompili et al.[22], whereas we found no primary RF failure and 6.7% LTP using NTmbpRFA. In addition to the standard limitations of the MonoRFA technique previously described, an additional explanation can be offered, in that to be curative, ablation must exceed the macroscopic boundaries of the nodule and ideally provide 2cm safety margins[4]. NTmbpRFA consists in inserting needles into the periphery of the tumour to produce centripetal energy in contrast to the centrifugal radiating energy ablation technique of MonoRFA[13]. Thus the maximum amount of energy is actively deposited in the margin conversely to monopolar devices that induce ablation of the margin at the end stage of the procedure by passive rapidly-decreasing energy diffusion from the centre to the periphery. A further explanation may be that placing probes at the tumor periphery leads to vessel coagulation around the tumour thus limiting the intra-tumoural perfusion effect, providing a more homogeneous necrosis. The NoTouch approach is particularly interesting for the treatment of subcapsular nodules, which are contraindicated for direct puncture (with the use of a monopolar expandable needle for example), because of possible tumoral tract seeding[24]. Finally NoTouch ablation does not increase intratumoural pressure and does not require several repositionings (required to achieve satisfying margins with MonoRFA) decreasing the risk of transvessel tumour spread and thus theoretically decreasing the occurrence of local tumor progression [25,26]. Another point of interest is the lower rate of RF failure in patients with HCC near large vessels when treated by NTmbpRFA(12.5% versus 50% in MonoRFA group) confirming a

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trend observed in previous studies [10,13]. Probe placing near vessels is easier with straight probes as in NTmbpRFA than with expandable needles thus improving ablation targeting. We believe this to be the explanation of this result because in our series most MonoRFA needles used for HCC near vessels (92%; 22/24) were expandable needles. In addition, the placement of one of the needles close to the tumor part near a large vessel deposited a high amount of energy in this location, reducing the impact of the heat-sink effect. On a technical level, NTmbpRFA is usually considered to be more demanding than MonoRFA. NTmbpRFA requires the insertion of several roughly parallel needles outside the tumor that could be challenging under US-guidance. We also observed a definite learning curve for No Touch, more so than for monoRFA. However, for a trained operator NTmbpRFA is more feasible and safe than some ablations performed with monoRFA which needs to be complete, and requires electrodes repositioning after a first cycle of energy deposition that partially or totally hides the targeted tumour in echogenic shadow. In addition, more advanced guidance tools now available such as fusion imaging, cone beam CT or MRI allow precise needles insertion even in challenging situations. The rate of major complications according to the SIR classification did not differ between both groups (7.2%) but seems higher than previous reports (<3%)[7,21,22,27]. This higher rate is mainly explained by the different terminology, SIR classification in our study versus equivalent to Clavien-Dindo surgical classification in other studies. According to the ClavienDindo classification the rate of major complication after monopolar RFA was close to other publications (<2%) and was higher after NTmbpRFA (4.4%). Indeed most of the severe complications requiring surgery or intensive care, or leading to death were after NTmbpRFA treatment. It thus appears that placing several probes increases the risk of puncture complications and the larger ablative area could lead to more collateral damages (as illustrated by the two diaphragmatic hernia). However the rate of liver failure-related

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complications did not differ between the two groups, but most patients were Child A (86.1%). Child B status was the only predictor of complication in our study, that could also explaine the higher rate of major complication compared to previous publications that studied only Child A patients with single HCC versus 17% Child B and 20% multiple tumours in our population. Therefore Child score must be taken into account before performing ablations over large areas to avoid liver failure using NTmbpRFA[8,13]. An other way to explain the higher rate of complications in our study is the size of HCC treated (≤5cm) here versus <3cm for Pompili et al[22] and <2cm for Livraghi et al[21]. Larger HCCs required larger ablative volumes and exposed to higher risk of complication as shown in table 4. To circumvent the limitations of the MonoRF technique, techniques other than NTmbpRFA have been proposed. Microwave ablation or combination of RFA and trans-arterial chemoembolization (TACE) are frequently used to treat HCC>3cm or near vessels. Similar to MonoRFA, microwave ablation involves a centrifugal distribution of energy. Previous studies have reported a similar LTP rate to NTmbpRFA for HCC near large vessels (13.5%)[28] but a higher rate for HCC>3cm, with LTP of 20%[29] versus 9.3% for NTmbpRFA(3/32). The potential advantage to combine RFA and TACE in treating small HCC remains to be confirmed. For HCC>3cm, the combination of RFA and TACE provides a lower LTP rate than MonoRF, but the range of LTP rates reported is large, from 6% to 42%[30,31]. Further, the association of RFA and TACE provides varying necrotic volumes and the technique is still debated with regards to which treatment should precede the other and the optimal time between the treatments. Furthermore, combined RFA-TACE treatment adds the limitations and complications of endovascular interventions, leading to X-ray exposure for both the patient and the radiologist and it is time consuming. In our results, despite the significant better local sustained tumor control offered by NTmbpRFA compared to MonoRFA, no significant differences were found for OS or intra-

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hepatic distant recurrence. However, 5-years OS was lower by 10% using NTmbpRFA and the number of patients tumour-free at the end of the study was significantly different between the two groups, with fewer in NTmbpRFA. In addition, reducing the occurrence of LTP is important for patient management, as this decreases the overall number of treatments per patient, consequently improving their quality of life. The main limitation of our study is its retrospective non-randomized design and the second is the choice of a monopolar or multibipolar technique that was based on each centre’s experience (as shown in the flow-chart) and not on strict and clear criteria. Although randomized trial is the gold standard to compare two treatments, its implantation for interventional procedures are often hampered by several logistic concerns like the multiplicity and the heterogeneity of technologies used routinely in clinical centres. Thus retrospective comparison of patients’ outcome appears as the most convenient method to assess in first attempt the value of different interventional procedures resting on the use of specific devices. Obviously randomized trials are still needed to address remnant open questions beyond the clinical equipoise principle [32,33]. Thus, a randomized trial is underway to compare multibipolar RFA using the “No-Touch” versus the “Touch” technic (NCT01008657). Furthermore, coarsened exact matching was used to counter for both of these limitations, allowing us to match patients according to several categorized variables, with each pair of matched patients belonging to the same strata of each variable used in the matching model. As such, the main bias induced by these limitations should be avoided. In conclusion, this large multicentre case-matched study showed that NTmbpRFA provided better primary RF success rates and sustained local tumour response without increasing severe complications rates comparing to MonoRFA, for HCC>3cm but also for HCC≤3cm. Consequently,

NTmbpRFA could be proposed as the standard RF ablative technique for

treatment of HCC≤5cm.

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Acknowledgements: The authors thank Dr Lebigot Jerome, Dr Panteleimon Papadopoulos and Dr Laumonier Hervé for their work. The authors thank Pippa McKelvie-Sebileau for medical editorial services.

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Figures Figure 1: Flow-chart About the 596 patients who met the inclusions criteria, 362 were matched (181 patients in each treatment group). NTmbpRF= NoTouch mulitiBipolar radiofrequency; * The clinical trial is ARMCENVIN (ClinicalTrials.gov Identifier: NCT01008657).

Figure 2: Illustration of the differences between the different radiofrequency devices. There is three main types of radiofrequency devices: (a) NoTouch multibipolar RFA; (b) Intra-tumourous monopolar RFA using a multi-prong expandable electrode; and (c) Intratumourous monopolar RFA using a straight electrode.

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Figure 3: Comparison of global radiofrequency failure between monopolar group (N=181) and NoTouch multiBipolar group (N=181). Global radiofrequency failure includes primary radiofrequency failure and local tumour progression. The cumulative rates of global RF failure at 1, 3 and 5 years were respectively 13.3%, 31% and 36.7% for MonoRFA versus 0.02%, 7.9% and 9.2% for NTmbpRFA, P<0.001. Figure 4: Comparison of overall survival between monopolar group (N=181) and NoTouch multiBipolar group (N=181). The 3- and 5-year overall survival rates were 63.5% and 37.2% following monopolar radiofrequency versus 64.5% and 46.4% following NoTouch MultiBipolar radiofrequency, P=0.964 and P=0.378

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Age in years (SD) Male Cirrhosis aetiologies -Non-viral hepatitis -Viral Hepatitis -Mixed Child-Pugh A Platelet Count ≤100G/L Alphafetoprotein serum level (categorized) <10 ng/ml 10-100 ng/ml >100 ng/ml Mean tumour size in mm (SD)≤30mm >30mm Multiple tumours Subcapsular tumour Tumour near large vessel

Monopolar RFA NoTouch multibipolar N=181 (%) RFA N=181 (%) 64 (10) 65 (9) 149 (82.3) 144 (79.5)

P value

0.110 0.503 0.196

103 (57) 66 (36) 12 (7) 156 (86.1) 72 (40)

98 (54) 61 (34) 22 (12) 156 (86.1) 72 (40)

122 (67.4) 52 (28.7) 7 (3.9)

122 (67.4) 52 (28.7) 7 (3.9)

24(8)

25(8)

0.279

149 (82.3) 32 (17.7) 36 (19.9) 22 (12.1) 24 (13.2)

149 (82.3) 32 (17.7) 36 (19.9) 22 (12.1) 24 (13.2)

1

1 1 1

1 1 1

TABLES Table 1: Baseline characteristics of patients treated either by monopolar or NoTouch multibipolar radiofrequency ablation.

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Table 2: Global radiofrequency (RF) failure, Primary RF failure and local tumour progression according to tumour size and RFA technique. <20mm n(%) RF Primary RF Failure LTP* Global RF Failure

20-30 mm n(%)

31-40 mm n(%)

>40mm n(%)

MonoRF n=47

NTmbp n=39

P

MonoRF n=102

NTmbp n=110

P

MonoRF n=25

NTmbp n=24

P

MonoRF n=7

NTmbp n=8

P

0

0

NA

6 (5.9)

0

0.011

3 (12)

0

0.235

1 (14)

0

0.467

10 (21)

1 (2.6)

0.019

19 (20)

9 (8.4)

0.024

8 (36)

2 (8)

0.032

5 (83)

1 (12.5)

0.026

10 (21)

1 (2.5)

0.01

25 (25)

9 (8.2)

0.001

11 (44)

2 (8.3)

0.008

6 (86)

1 (12.5)

0.01

*For LTP % were calculated for patients with initial complete response. Global RF failure= Primary RF failure + LTP Abb: LTP = Local tumour progression; RF= Radiofrequency; MonoRF= Monopolar RF; NTmbp= NoTouch multibipolar RF.

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Table 3: Predictive factors of global RF failure (LTP and primary treatment failure)

Variable

Univariate analysis P

Hazard ratio

Multivariate analysis Step

P

(95%CI) Age (years)

0.327

Hazard ratio (95%CI)

1.012 (0.9871.038)

Sex (Male) (%)

0.354

Non-Viral hepatitis

0.765

1.394 (0.6892.819) 0.884 (0.3941.983)

Child B

0.218

Platelet count <100G/L

0.456

AFP>100 ng/ml

0.930

HCC>3cm

0.004

Multiple nodules

0.409

0.529 (0.1921.456) 0.822(0.492-1.375) 1.041 (0.4182.594) 2.189 (1.2923.709)

2

0.002

2.349 (1.3833.990)

1.275 (0.7162.272)

HCC near large vessel

0.066

1.769 (0.963-

3

3.249) Subcapsular HCC

0.867

0.024

2.019 (1.0953.725)

1.062 (0.5252.147)

Monopolar radiofrequency

<0.001 4.424 (2.4078.129)

1

<0.001 4.631 (2.5158.526)

Abb: RF= Radiofrequency; AFP= alphafetoprotein; HCC= Hepatocellular carcinoma

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Table 4: Major complications according to the society of interventional radiology classification

Society of interventional Radiology classification Grade C

Grade D

Treatment group MonoRFA NTmbpRFA

4 Ascites 1 Encephalopathy 1 Acute gout 1 Sepsis 1 Esophageal varices rupture 2 Liver abcess 1 Haemothorax

3 Sepsis

3 Liver failure

1 haemobilia with liver failure 3 ascite

1 Active Bleeding 2 diaphragmatic hernia

Grade F

1 Severe sepsis none

1 Death following liver failure

Abb: RF= Radiofrequency; MonoRFA= Monopolar RF; NTmbpRFA= NoTouch multibipolar RF.

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NoTouch Mul*Bipolar RFA -No tumoral puncture -Ac*ve margin abla*on -Reliable abla*ve volume -Low heat-sink effect

Monopolar RFA -Direct tumoral puncture -Passive margin abla*on -Variable abla*ve volume -heat-sink effect

Major complica*on rate = 4.4%

Major complica*on rate = 1.1%