Liver International ISSN 1478-3223

CLINICAL STUDIES

Pilot study for a new bipolar radiofrequency ablation/aspirator device in the management of primary and secondary liver cancers
Dimitris Zacharoulis1, Shirin E. Khorsandi2, Petr Vavra2,3, Jan Dostalik3, Giuseppe Navarra4, Joanna P. Nicholls2,5, Long R. Jiao2 and Nagy A. Habib2,5
1 Department of Surgery, University Hospital of Larissa, Larissa, Greece 2 Department of Biosurgery and Surgical Technology, Imperial College London, Hammersmith Hospital, London, UK 3 Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic 4 Department of Surgical Sciences, University of Messina, Messina, Italy 5 EMcision Ltd, London, UK

Keywords bipolar liver cancer radiofrequency

Correspondence Prof. Nagy A. Habib, Department of Biosurgery and Surgical Technology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK Tel: 144 20 8383 8574 Fax: 144 20 8383 3212 e-mail: nagy.habib@imperial.ac.uk Received 6 May 2008 Accepted 19 September 2008 DOI:10.1111/j.1478-3231.2008.01910.x

Abstract Background: In the US, the thermal ablation workload for cancer involving the liver is predicted to more than double in the next 5 years, emphasising the need to develop and improve the current technology. Study Design: A multicentre nonrandomised prospective clinical trial (NCT00514930) was undertaken, to assess the efcacy and safety of a new bipolar radiofrequency ablation/aspirator device, in the treatment of primary and secondary cancers of the liver. Results: A total of 34 lesions in 16 patients were ablated at laparotomy and followed up at 4 weeks. The mean diameter of lesion before ablation was 3.2 2.22 (range 110) cm, the mean volume aspirated during ablation was 9.25 7.3 (range 025) ml and the mean operative time was 145.95 40.7 (range 60215) min. There was one major complication of a pleural effusion, which required drainage. The mean length of stay was 8 3.2 (range 314) days. In 11 patients, the ablated tumour was resected. On histological assessment, there was no evidence of viable cancer at the tumour edge. On follow-up computed tomography, the ablation zone fully encompassed the targeted tumour and there were no local complications related to ablation. Conclusion: Initial analysis of the data from this small cohort, with only a short-term follow-up, shows this device to be safe and effective.

Cancer has now overtaken cardiovascular disease as the leading cause of death. Globally, cancer deaths are predicted to increase, with nine million people estimated to die from cancer in 2015 and 11.4 million estimated to die in 2030 (1). The liver is second only to lymph nodes as a site for metastatic disease, (2) with the incidence of hepatocellular carcinoma (HCC) predicted to increase throughout the 21st century (3). Therefore, it is necessary to develop safe and effective treatment strategies for primary and secondary malignancies of the liver. Surgical resection has emerged as the standard of care for colorectal and neuroendocrine liver metastases. The survival gains from resection have led to this approach being assessed in noncolorectal nonneuroendocrine liver metastases as well, while in HCC, treatments that can offer long-term cure in selected patients are resection or transplantation. However, limited numbers of patients, approximately 1020%, are ever deemed suitable for resection (47), the tumour being unresectable on the grounds of extensive hepatic involvement, unfavourable localisation in relationship with bile duct/blood vessel,

extrahepatic spread, comorbidity or a limited liver reserve (volume/synthetic). Faced with this reality, there have been numerous innovations in the development of alternative therapeutic approaches, for example percutaneous ethanol injection; transarterial chemoembolisation; selective internal radiation therapy using 90Yttrium resin-microspheres; and cryoablation, and in the last decade there has been a major interest in using heat to destroy tumours, for example radiofrequency (RF), laser and microwave energies. It is expected that the total number of thermal ablation procedures performed in the US will grow from an estimated 47 600 in 2005 to 135 500 procedures in 2010 (8), emphasising the need to develop and improve current technologies. We and others have advocated the use of RF energy for the ablation of liver tumours when surgery is inappropriate (9, 10). This has been of major benet for the patient. However, the technology is still being developed. Many devices (Valleylab, Boulder, CO, USA; Angiodynamics, Queensbury, NY, USA; Boston Scientic Inc., Natick, MA, USA) are monopolar, which present risks of
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collateral damage to adjacent organs, skin burn at the grounding pad site and unpredictable current pathways reducing the area of ablation (11, 12). But other groups, like us, are exploring the feasibility of using bipolar RF devices to ablate liver tumours (13, 14). Another potential problem arising from ablation is the intermittent discharge of vapour and uid during a procedure, and this may lead to recurrence around the diaphragm through contamination of the peritoneal cavity, or by promoting intraparenchymal spread (1517). From the literature, it is difcult to determine the nature of spread after RF ablation because the pattern of recurrence or spread may be related to the natural history of the disease as is the case for HCC or from initial incomplete ablation with the larger tumours, rather than directly being related to the spume produced during ablation. In order to address these limitations, we have designed a new bipolar RF aspirator/ablation device that allows the surgeon or the radiologist to ablate and aspirate simultaneously. In this paper, we present our preliminary results from a pilot clinical study, which assesses the safety and efcacy of this new device, in the treatment of primary and secondary cancers of the liver.
Methods Patients

Before commencement of this multicentre prospective clinical trial (NCT00514930), local ethical approval or permission from a new devices committee was obtained for participating clinical sites. The Declaration of Helsinki was adhered to throughout. Eligible patients had cancer isolated to the liver, with no evidence of extrahepatic disease. The suitability for ablation alone or ablation, followed by resection was decided upon at a multidisciplinary team meeting, taking into consideration the patients tness, underlying liver synthetic function and anatomical distribution of disease within the liver. Informed consent was obtained from all the participating patients. Study patients underwent a helical computed tomography (CT) scan with contrast of the chest and abdomen 40 days before RF ablation/aspirator treatment. A full pre-operative assessment (history, clinical examination and relevant investigations) was completed. Data collected on each patient included tumour details (tumour type, size, location and number), and the tness of the patient was assessed using the American Society of Anaesthesiology classication.
Description of device and operative procedure

The novel RF ablation/aspirator device (Hexablate, EMcision Ltd, London, UK) consists of a ring of six electrodes with a central electrode having a dual role as an aspiration channel and an active electrode. The electrodes are made of stainless steel. The outer electrodes have
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a diameter of 1.5 mm. Marker bands are electrochemically etched, 1 cm apart along the electrode shaft, to indicate the depth of tissue penetration. The active tip of all electrodes is 4 cm, the outer ring of electrodes is spaced 10 mm apart and the outer electrodes are 8.25 mm apart from the central electrode. The electrodes are not internally cooled; through the central electrode, normal saline was run to keep the aspiration channel patent during the procedure. On repeat application, the electrodes were manually cleaned between each application. In order to prevent carbonisation, a programme was used where coagulation was controlled by impedance. The central electrode was designed to aspirate water vapour, fatty uids, coagulated blood and tissue mass from the centre of the tumour during the heating process. Suction was achieved via an array of perforations along the shaft of the central electrode. Three alternative handsets have been developed: one for percutaneous use, one for use at open surgery and one for laparoscopic surgery. For this study, the Hexablate handset for open surgical procedures was used throughout. The RF generators used were either the Radionics Cosman Coagulator CC-1 (Radionics Cosman Coagulator, Burlington, MA, USA) or the RITA, RF 1500 (RITA Model 1500X RF, Angiodynamics, Queensbury, NY, USA). Under general anaesthesia, the liver was mobilised; mobilisation was limited to the lobe in which the tumour was located. Dissection of the hilus or the hepatic vein conuence was not performed. Intra-operative ultrasound (IOUS) was performed to conrm disease distribution and to assist with device deployment. The Pringle manoeuvre was not used. Like any other RF device, Hexablate cannot be used to ablate tumours around major structures (vessels or ducts) that need to be preserved. Therefore, it performs best in supercial tumours and its usefulness is limited in deep-seated tumours. Antibiotic prophylaxis consisted of intravenous Cefuroxime (1.5 g) and Metronidazole (500 g), given at induction, and then 8 and 16 h later. For tumours o 2 cm in diameter, the device was introduced into the liver so that the central needle of the device was centralised on the deposit. For tumours larger than 2 cm, the device was applied several times on the periphery of the lesion, starting at the deepest part of the tumour, in order to ablate the circumference of the tumour. Once the periphery of the tumour had been ablated, multiple applications were applied to the central core of the tumour (Fig. 1). IOUS was performed to monitor ablation and in the cases of HCC, IOUS with contrast (SonoVues, Bracco Diagnostics, Milan, Italy) was used. Throughout ablation, the aspiration channel was open to remove tumour spume, uid and debris through the channel of the central needle. In addition to its role of aspiration, the design of the handset allows the channel of the central needle to be used as a delivery channel. For the present clinical series, the central needle channel was purely used as an irrigation channel in order to ensure patency of the aspiration needle.

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The RF generator was activated in the bipolar mode. The outer ring of the electrodes was activated at 80 W for 90 s and the inner electrode was activated at 40 W for 30 s. The outer ring of the needles was initially activated for peripheral circumference ablation, with the electrical current active between the outer six needles only, to produce ablation of the outer zone with liquefaction of the central zone, which could then be aspirated by the central needle. When impedance had increased by 10% over baseline, ablation was stopped. After ablation produced by the outer ring of needles was complete, the central needle was then activated at half the wattage that was used for the outer zone ablation, with the current running from the outer ring needles to the central needle, thereby completing ablation of the central core of tumour,

resulting in a 3 3 cm cylinder of ablation (Fig. 2). The total activation time required to produce this cylinder of ablation was 2 min. At the end of ablation of a given tumour, the aspiration uid from the central needle was sent for cytology. The lesions selected for treatment were all initially ablated with Hexablate. When technically possible, the ablated lesion was resected, and a histological assessment of the effectiveness of Hexablate was then undertaken. In the cases where resection of the ablated tumour was performed, a surgical scalpel was used to cut through the zone of coagulated normal liver parenchyma, which surrounded the tumour following ablation. A surgical margin of 1 cm was aimed for. Any technical or clinical complications related to the immediate use of the device were recorded. Patients were assessed clinically at 4 weeks and had a baseline follow-up CT scan at 2 weeks. Images were analysed for evidence of local complications relating to ablation and to check whether the ablation zone fully encompassed the tumour. To assess the effectiveness of RF ablation, the recommendations by the International Working Group on ImageGuided Tumor Ablation were used (18). Long-term follow-up was performed to continue with a repeat CT scan at 3 months and then according to routine local practice.
Results Patient demographics and tumour characteristics

Fig. 1. Intra-operative photograph of Hexablate being used in an open operation to ablate the outer edge of an intrahepatic cholangiocarcinoma. The purpose of the white dome shape in the centre of the device is to keep the electrodes in alignment and to prevent any crossing of the electrodes and consequent short circuiting.

In total, 17 Hexablate treatments were performed in 16 patients and followed up at 4 weeks after discharge. Table 1 summarises the clinicopathological characteristics of patients. In all cases, a pre-operative CT scan did not demonstrate any evidence of extrahepatic disease. In three cases IOUS demonstrated disease within the liver, which had not been seen on pre-operative CT. Eight (50%) of the livers were chemonaive. Four patients had undergone

Fig. 2. (a) Contrast (SonoVues)-enhanced ultrasound of a hepatocellular deposit before ablation showing blood ow in the tumour neovasculature. (b) Contrast (SonoVues)-enhanced ultrasound of a hepatocellular deposit after ablation showing no blood ow in the tumour.

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Table 1. Summary of patients (n = 16) clinicopathological details and segmental distribution of deposits ablated (n = 34) Patient characteristics (n = 16) Age median (range) years Gender Male Female ASA 1 2 3 Tumour type Metastatic Colorectal Breast Pancreatic adenocarcinoma Primary Hepatocellular carcinoma Intrahepatic cholangiocarcinoma Segmental location of deposit (n = 34) II III IV V VI VII VIII 66 (5081) years 8 8 3 8 5

9 1 1 4 1 2 5 4 4 5 6 8

decision was based on there being insufcient liver reserve and in one case the patient was deemed medically unt for a formal liver resection. In the ve patients with insufcient liver reserve, three had bilobar disease and two were Child B cirrhotics with HCC, whose predicted future liver remnant would have been insufcient (o 40%). In the remaining 11 patients, surgical resection after ablation of the target lesion was performed. Nonanatomical resection in the form of metastasectomy was the most common procedure. One patient had a left lateral segmentectomy, two patients had a one-segment metastectomy, ve patients had a two-segment metastectomy and in the remaining three patients a four-segment metastectomy was performed. The only technical issue during the use of Hexablate was that midway through one procedure, the aspirator channel blocked. However, this did not alter the procedure undertaken or lead to the device being exchanged for an alternative.
Mortality and morbidity

The majority of the deposits ablated were supercial and not adjacent ( 1 cm) to major structures such as blood vessel or bile duct. o ASA, American Society of Anaesthesiology.

previous therapeutic interventions on the liver. Two patients had prior percutaneous RF ablation (one of whom had RF ablation on three previous occasions). One patient had a prior surgical resection (an open wedge resection of segments III and VII plus RF ablation to segment IV). The fourth patient had a planned staged treatment with Hexablate, where wedge resections were initially performed and 12 weeks later ablation was performed for a residual large solitary deposit.
Surgical procedures and perioperative outcome

No patient required a blood transfusion during their inpatient stay. There were three post-operative complications: one wound infection and two pleural effusions. One pleural effusion was managed conservatively and the other required a percutaneous drainage. There were no cases of post-ablation syndrome. Therefore, major complications occurred in one patient (5.8%) and minor complications occurred in two patients (11.7%). The mean length of stay was 8 3.2 (range 314) days. There were no re-admissions and there were no 30-day deaths.
Follow-up and review of cytology, histology and computed tomography scan

Seventeen Hexablate treatment sessions were performed in an open operation. In total, 34 lesions were ablated in 16 patients. The mean number of lesions ablated per patient was 2 (range 16). Table 1 summarises the segmental distribution of the lesions ablated. The mean diameter of lesion before ablation was 3.2 2.22 (range 110) cm, the mean volume aspirated during ablation was 9.25 7.3 (range 025) ml and the mean operative time was 145.95 40.7 (range 60215) min. The mean number of applications of Hexablate to the treated tumours was 2.64 1.84 (range 19), and so as the tumour increased in size multiple applications were required. In six patients, the decision not to undertake surgical resection after ablation was made; in ve cases, this
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At the 4-week post-operative review, all patients were clinically well. Cytological assessment of the aspirate obtained during ablation with Hexablate was performed in eight patients. In all these cases, malignant cells were demonstrated in the aspirate (Fig. 3). Histological assessment of the resected lesions after ablation was performed in 11 cases to determine the effectiveness of Hexablate (18). In the resected specimens, there was no evidence of viable cancer at the tumour edge and coagulative necrosis was found throughout the ablated tumour. In all lesions, satisfactory ablation had been produced; on average, 90% of the target tumour volume had been coagulated, and when lesions o 3 cm were considered alone, complete ablation (100% coagulative necrosis) was consistently observed (Fig. 4). In all cases, the CT scan at 2 weeks after discharge showed no local complications related to ablation or resection. In the cases where only ablation had been performed, the CT demonstrated that the ablation zone (18) produced by the application of Hexablate had fully encompassed the target tumour (Fig. 5).

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Fig. 3. Haematoxylin and eosin stain ( 40) of Hexablate aspirate from colorectal liver metastases, showing the presence of malignant cells in the aspirate.

Fig. 4. Haematoxylin and eosin stain ( 10) of hepatocellular deposit after ablation with Hexablate, showing extensive necrosis of the tumour.

Fig. 5. (a) Computed tomography showing 7 5 5 cm colorectal metastases in the right liver lobe; the tumour periphery has a high density (7580 HU) because of the presence of feeding blood vessels (white arrows). To deal with the posterior aspect of the tumour, ultrasound guidance and the hand were used to position Hexablate into an optimal position. (b) After nine Hexablate applications, complete necrosis has been achieved. The tumour is now characterised by a homogeneous low density (2535 HU) both centrally and peripherally.

Discussion

For patients with malignant disease of the liver that have been deemed inoperable, alternative therapies to improve long-term survival are being developed. One of the emerging modalities that has emerged is the use of local ablation techniques. The technology and the benet of its use are still being optimised and evaluated. Reports from the literature suggest that judicious use of local ablation can offer patients a survival benet (19). Radiofrequency energy is emerging as an effective and safe way to ablate tumours. However, the present technology, which often uses monopolar RF, has limitations. Reported problems associated with the use of monopolar

RF include collateral damage to adjacent organs, skin injury at the site of the grounding pad and the risk of uncontrolled current pathways leading to a reduction in the area of ablation (11, 12, 20). Another complication that can arise with tumour ablation, irrespective of whether monopolar or bipolar energy is used, is the occurrence of infection within the ablated area, leading to abscess formation and tumour smoke, which may contribute to local (intraparenchymal or intra-abdominal) and systemic spread of disease (1517). The design of Hexablate attempted to address some of these issues by using bipolar energy and incorporating an aspirator channel into the handset.
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Although this is an early report in a small series of patients, the results suggest that the Hexablate handset is safe and may be an effective way to ablate liver tumours, with the use of bipolar RF eliminating the risk of collateral damage, which is inherent with the use of monopolar RF. The Hexablate handset designed for use in an open operation produces a 3 3 cm ablation, with a vertical axis up to 3 cm; therefore, multiple applications will be required for larger lesions. Additionally, the array of needles and mode of use where a sequential ow of electrical current runs from the outer ring of needle electrodes to the inner needle appears to produce effective ablation with no evidence of viable cancer at the periphery of the ablated tumour. The aim of incorporating an aspirator channel into the design of the Hexablate handset was to eliminate the tumour spume, which a number of groups have described and associated with local and intraparenchymal spread of tumour after RF treatment. Other potential gains from an aspirator channel could be a reduction in the systemic effects from RF by reducing the amount of debris and uid after ablation. In the reported series, there were no cases of post-ablation syndrome reported, despite some tumours being left in situ after ablation. The impact of an aspiration channel in controlling tumour spume, which, on aspirate cytology, contains viable cancer cells, may hold promise in reducing the recurrence rates after ablation. However, to conrm this, a long-term follow-up in a larger cohort of patients will need to be undertaken to determine whether aspiration has a signicant effect or whether other factors such as ablation of the electrode track or a subcapsular location of the ablated tumour are the main determinants of recurrence after ablation. Another concept described in the technique of applying Hexablate to large cancers of the liver is the priority given to focusing initial ablation therapy on the periphery of the tumour, before moving to ablate the tumour centrally. It has been recognised by a number of groups that when RF ablation treatment fails, recurrences tend to occur at the outer edge of the tumour (21, 22). The interface between normal liver parenchyma and the cancer has a unique micro-environment and ill-understood cellular interactions, which is gaining attention as a possible explanation for treatment failure after chemotherapy or surgical resection/ablation (2325). The periphery of the tumour may be cancers twilight zone and perhaps be the area where cancer stem cells reside and survive after chemotherapy, whereas the central zone contains somatic cancer cells that are chemosensitive. Whether the strategy of ablating the outer edge of the tumour, before moving to treat the central component of the tumour, has any impact on patterns of recurrence can only be answered when long-term follow-up data in a larger cohort of patients become available. In summary, the short-term results presented for this novel RF ablation/aspirator probe illustrate the evolution of bipolar RF technology and the development of an
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innovative approach to the management of unresectable cancers of the liver. These initial data show this approach to ablation to be effective and safe.

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