Hexablate-Liver International 2009

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C L I N I C A L S T U D I E S

Pilot study fora newbipolar radiofrequencyablation/aspiratordevice inthemanagementofprimaryandsecondary 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 CollegeLondon, Hammersmith Hospital, Du Cane

Road, London W12 0NN, UK

Tel: 144 20 8383 8574

Fax: 144 20 8383 3212

e-mail: [email protected]

Received 6 May 2008

Accepted 19 September 2008

DOI:10.1111/j.1478-3231.2008.01910.x

AbstractBackground: In the US, the thermal ablation workload for cancer involving theliver is predicted to more than double in the next 5 years, emphasising theneed to develop and improve the current technology. Study Design: A multi-centre nonrandomised prospective clinical trial (NCT00514930) was under-taken, to assess the efficacy and safety of a new bipolar radiofrequency

ablation/aspirator device, in the treatment of primary and secondary cancersof the liver. Results: A total of 34 lesions in 16 patients were ablated atlaparotomy and followed up at 4 weeks. The mean diameter of lesion beforeablation was 3.2Æ 2.22 (range 1–10) cm, the mean volume aspirated duringablation was 9.25Æ 7.3 (range 0–25) ml and the mean operative time was145.95Æ 40.7 (range 60–215) min. There was one major complication of apleural effusion, which required drainage. The mean length of stay was 8 Æ 3.2(range 3–14) days. In 11 patients, the ablated tumour was resected. Onhistological assessment, there was no evidence of viable cancer at the tumouredge. On follow-up computed tomography, the ablation zone fully encom-passed the targeted tumour and there were no local complications related toablation. Conclusion: Initial analysis of the data from this small cohort, withonly a short-term follow-up, shows this device to be safe and effective.

Cancer has now overtaken cardiovascular disease as theleading cause of death. Globally, cancer deaths arepredicted to increase, with nine million people estimatedto die from cancer in 2015 and 11.4 million estimatedto die in 2030 (1). The liver is second only to lymphnodes as a site for metastatic disease, (2) with theincidence of hepatocellular carcinoma (HCC) predictedto increase throughout the 21st century (3). Therefore, itis necessary to develop safe and effective treatmentstrategies for primary and secondary malignancies of theliver.

Surgical resection has emerged as the standard of carefor colorectal and neuroendocrine liver metastases. Thesurvival gains from resection have led to this approachbeing assessed in noncolorectal nonneuroendocrine livermetastases as well, while in HCC, treatments that canoffer long-term cure in selected patients are resection ortransplantation. However, limited numbers of patients,approximately 10–20%, are ever deemed suitable forresection (4–7), the tumour being unresectable on thegrounds of extensive hepatic involvement, unfavourablelocalisation in relationship with bile duct/blood vessel,

extrahepatic spread, comorbidity or a limited liver re-serve (volume/synthetic).

Faced with this reality, there have been numerousinnovations in the development of alternative therapeuticapproaches, for example percutaneous ethanol injection;transarterial chemoembolisation; selective internal radia-tion therapy using 90Yttrium resin-microspheres; andcryoablation, and in the last decade there has been a majorinterest in using heat to destroy tumours, for exampleradiofrequency (RF), laser and microwave energies. It isexpected that the total number of thermal ablationprocedures performed in the US will grow from anestimated 47 600 in 2005 to 135 500 procedures in 2010(8), emphasising the need to develop and improve currenttechnologies.

We and others have advocated the use of RF energy forthe ablation of liver tumours when surgery is inappropri-ate (9, 10). This has been of major benefit for the patient.However, the technology is still being developed. Many devices (Valleylab, Boulder, CO, USA; Angiodynamics,Queensbury, NY, USA; Boston Scientific Inc., Natick,MA, USA) are monopolar, which present risks of

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Liver International ISSN 1478-3223

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collateral damage to adjacent organs, skin burn at thegrounding pad site and unpredictable current pathwaysreducing the area of ablation (11, 12). But other groups,like us, are exploring the feasibility of using bipolar RFdevices to ablate liver tumours (13, 14).

Another potential problem arising from ablation is theintermittent discharge of vapour and fluid during a

procedure, and this may lead to recurrence around thediaphragm through contamination of the peritonealcavity, or by promoting intraparenchymal spread(15–17). From the literature, it is difficult to determinethe nature of spread after RF ablation because the patternof recurrence or spread may be related to the naturalhistory of the disease as is the case for HCC or frominitial incomplete ablation with the larger tumours,rather than directly being related to the spume producedduring ablation.

In order to address these limitations, we have designeda new bipolar RF aspirator/ablation device that allows thesurgeon or the radiologist to ablate and aspirate simulta-

neously. In this paper, we present our preliminary resultsfrom a pilot clinical study, which assesses the safety andefficacy of this new device, in the treatment of primary and secondary cancers of the liver.

Methods

Patients

Before commencement of this multicentre prospectiveclinical trial (NCT00514930), local ethical approval orpermission from a new devices committee was obtainedfor participating clinical sites. The Declaration of Helsin-ki was adhered to throughout. Eligible patients hadcancer isolated to the liver, with no evidence of extra-

hepatic disease. The suitability for ablation alone orablation, followed by resection was decided upon at amultidisciplinary team meeting, taking into considera-tion the patient’s fitness, underlying liver synthetic func-tion and anatomical distribution of disease within theliver. Informed consent was obtained from all the parti-cipating patients.

Study patients underwent a helical computed tomo-graphy (CT) scan with contrast of the chest and abdomen40 days before RF ablation/aspirator treatment. A fullpre-operative assessment (history, clinical examinationand relevant investigations) was completed. Data col-lected on each patient included tumour details (tumour

type, size, location and number), and the fitness of thepatient was assessed using the American Society of Anaesthesiology classification.

Description of device and operative procedure

The novel RF ablation/aspirator device (Hexablate, EM-cision Ltd, London, UK) consists of a ring of six electro-des with a central electrode having a dual role as anaspiration channel and an active electrode. The electro-des are made of stainless steel. The outer electrodes have

a diameter of 1.5 mm. Marker bands are electrochemi-cally etched, 1 cm apart along the electrode shaft, toindicate the depth of tissue penetration. The active tipof all electrodes is 4 cm, the outer ring of electrodes isspaced 10 mm apart and the outer electrodes are 8.25 mmapart from the central electrode. The electrodes are notinternally cooled; through the central electrode, normal

saline was run to keep the aspiration channel patentduring the procedure. On repeat application, the electro-des were manually cleaned between each application. Inorder to prevent carbonisation, a programme was usedwhere coagulation was controlled by impedance.

The central electrode was designed to aspirate watervapour, fatty fluids, coagulated blood and tissue massfrom the centre of the tumour during the heatingprocess. Suction was achieved via an array of perforationsalong the shaft of the central electrode. Three alternativehandsets have been developed: one for percutaneous use,one for use at open surgery and one for laparoscopicsurgery. For this study, the Hexablate handset for open

surgical procedures was used throughout. The RF gen-erators used were either the Radionics Cosman Coagu-lator 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 tumourwas located. Dissection of the hilus or the hepatic veinconfluence was not performed. Intra-operative ultrasound(IOUS) was performed to confirm disease distributionand to assist with device deployment. The Pringle man-oeuvre was not used. Like any other RF device, Hexablatecannot be used to ablate tumours around major structures(vessels or ducts) that need to be preserved. Therefore, it

performs best in superficial tumours and its usefulness islimited in deep-seated tumours. Antibiotic prophylaxisconsisted of intravenous Cefuroxime (1.5 g) and Metroni-dazole (500 g), given at induction, and then 8 and 16 hlater.

For tumours o 2 cm in diameter, the device wasintroduced into the liver so that the central needle of thedevice was centralised on the deposit. For tumours largerthan 2 cm, the device was applied several times on theperiphery of the lesion, starting at the deepest part of thetumour, in order to ablate the circumference of thetumour. Once the periphery of the tumour had beenablated, multiple applications were applied to the centralcore of the tumour (Fig. 1). IOUS was performedto monitor ablation and in the cases of HCC, IOUS withcontrast (SonoVues, Bracco Diagnostics, Milan, Italy)was used. Throughout ablation, the aspiration channelwas open to remove tumour spume, fluid and debristhrough the channel of the central needle. In addition toits role of aspiration, the design of the handset allows thechannel of the central needle to be used as a delivery channel. For the present clinical series, the central needlechannel was purely used as an irrigation channel in orderto ensure patency of the aspiration needle.

Liver International (2009)c 2009 The Authors. Journal compilation c 2009 Blackwell Publishing Ltd 825

Zacharoulis et al . A new bipolar RF ablation/aspirator device



The RF generator was activated in the bipolar mode.The outer ring of the electrodes was activated at 80 W for90 s and the inner electrode was activated at 40 W for30 s. The outer ring of the needles was initially activatedfor peripheral circumference ablation, with the electricalcurrent active between the outer six needles only, toproduce ablation of the outer zone with liquefaction of

the central zone, which could then be aspirated by thecentral needle. When impedance had increased by 10%over baseline, ablation was stopped. After ablation pro-duced by the outer ring of needles was complete, thecentral needle was then activated at half the wattage thatwas used for the outer zone ablation, with the currentrunning from the outer ring needles to the central needle,thereby completing ablation of the central core of tumour,

resulting in a 3Â 3 cm cylinder of ablation (Fig. 2). Thetotal activation time required to produce this cylinder of ablation was 2 min. At the end of ablation of a giventumour, the aspiration fluid from the central needle wassent for cytology. The lesions selected for treatment wereall initially ablated with Hexablate. When technically possible, the ablated lesion was resected, and a histological

assessment of the effectiveness of Hexablate was thenundertaken. In the cases where resection of the ablatedtumour was performed, a surgical scalpel was used to cutthrough the zone of coagulated normal liver parenchyma,which surrounded the tumour following ablation. Asurgical margin of 1 cm was aimed for.

Any technical or clinical complications related to theimmediate use of the device were recorded. Patients wereassessed clinically at 4 weeks and had a baseline follow-upCT 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 recommen-

dations by the International Working Group on Image-Guided Tumor Ablation were used (18). Long-termfollow-up was performed to continue with a repeat CTscan at 3 months and then according to routine localpractice.

Results

Patient demographics and tumour characteristics

In total, 17 Hexablate treatments were performed in 16patients and followed up at 4 weeks after discharge. Table1 summarises the clinicopathological characteristics of patients.

In all cases, a pre-operative CT scan did not demon-strate any evidence of extrahepatic disease. In three casesIOUS demonstrated disease within the liver, which hadnot been seen on pre-operative CT. Eight (50%) of thelivers were chemonaive. Four patients had undergone

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.

Fig. 2. (a) Contrast (SonoVues)-enhanced ultrasound of a hepatocellular deposit before ablation showing blood flow in the tumour

neovasculature. (b) Contrast (SonoVues)-enhanced ultrasound of a hepatocellulardeposit after ablation showing no blood flow in the tumour.



A new bipolar RF ablation/aspirator device Zacharoulis et al .



previous therapeutic interventions on the liver. Twopatients had prior percutaneous RF ablation (one of whom had RF ablation on three previous occasions). One

patient had a prior surgical resection (an open wedgeresection of segments III and VII plus RF ablation tosegment IV). The fourth patient had a planned stagedtreatment with Hexablate, where wedge resections wereinitially performed and 12 weeks later ablation wasperformed for a residual large solitary deposit.

Surgical procedures and perioperative outcome

Seventeen Hexablate treatment sessions were performedin an open operation. In total, 34 lesions were ablated in16 patients. The mean number of lesions ablated perpatient was 2 (range 1–6). Table 1 summarises thesegmental distribution of the lesions ablated. The meandiameter of lesion before ablation was 3.2Æ 2.22 (range1–10) cm, the mean volume aspirated during ablationwas 9.25Æ 7.3 (range 0–25) ml and the mean operativetime was 145.95Æ 40.7 (range 60–215) min. The meannumber of applications of Hexablate to the treatedtumours was 2.64Æ 1.84 (range 1–9), and so as thetumour increased in size multiple applications wererequired.

In six patients, the decision not to undertake surgicalresection after ablation was made; in five cases, this

decision was based on there being insufficient liver reserveand in one case the patient was deemed medically unfit fora formal liver resection. In the five patients with insuffi-cient liver reserve, three had bilobar disease and two wereChild B cirrhotics with HCC, whose predicted future liverremnant would have been insufficient (o 40%). In theremaining 11 patients, surgical resection after ablation of

the target lesion was performed. Nonanatomical resectionin the form of metastasectomy was the most commonprocedure. One patient had a left lateral segmentectomy,two patients had a one-segment metastectomy, five pa-tients had a two-segment metastectomy and in the re-maining three patients a four-segment metastectomy wasperformed.

The only technical issue during the use of Hexablatewas that midway through one procedure, the aspiratorchannel blocked. However, this did not alter the proce-dure undertaken or lead to the device being exchangedfor an alternative.

Mortality and morbidity

No patient required a blood transfusion during theirinpatient stay. There were three post-operative complica-tions: one wound infection and two pleural effusions. Onepleural effusion was managed conservatively and the otherrequired a percutaneous drainage. There were no cases of post-ablation syndrome. Therefore, major complicationsoccurred in one patient (5.8%) and minor complicationsoccurred in two patients (11.7%). The mean length of stay was 8Æ 3.2 (range 3–14) days. There were no re-admis-sions and there were no 30-day deaths.

Follow-up and review of cytology, histology andcomputed tomography scan

At the 4-week post-operative review, all patients wereclinically well. Cytological assessment of the aspirateobtained during ablation with Hexablate was performedin eight patients. In all these cases, malignant cells weredemonstrated in the aspirate (Fig. 3). Histological assess-ment of the resected lesions after ablation was performedin 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 necrosiswas found throughout the ablated tumour. In all lesions,satisfactory ablation had been produced; on average, 90%of the target tumour volume had been coagulated, andwhen lesions o 3 cm were considered alone, completeablation (100% coagulative necrosis) was consistently observed (Fig. 4).

In all cases, the CT scan at 2 weeks after dischargeshowed no local complications related to ablation orresection. In the cases where only ablation had beenperformed, the CT demonstrated that the ablation zone(18) produced by the application of Hexablate had fully encompassed the target tumour (Fig. 5).

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 66 (50–81) years

Gender

Male 8

Female 8ASA

1 3

2 8

3 5

Tumour type

Metastatic

Colorectal 9

Breast 1

Pancreatic adenocarcinoma 1

Primary

Hepatocellular carcinoma 4

Intrahepatic cholangiocarcinoma 1

Segmental location of deposit (n =34)

II 2

III 5IV 4

V 4

VI 5

VII 6

VIII 8

The majority of the deposits ablated were superficial and not adjacent

(o1 cm) to major structures such as blood vessel or bile duct.

ASA, American Society of Anaesthesiology.





Discussion

For patients with malignant disease of the liver that havebeen deemed inoperable, alternative therapies to improvelong-term survival are being developed. One of the emer-ging modalities that has emerged is the use of localablation techniques. The technology and the benefit of itsuse are still being optimised and evaluated. Reports fromthe literature suggest that judicious use of local ablationcan offer patients a survival benefit (19).

Radiofrequency energy is emerging as an effective andsafe way to ablate tumours. However, the present tech-nology, which often uses monopolar RF, has limitations.Reported problems associated with the use of monopolar

RF include collateral damage to adjacent organs, skininjury 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 complicationthat can arise with tumour ablation, irrespective of whether monopolar or bipolar energy is used, is theoccurrence of infection within the ablated area, leading toabscess formation and tumour ‘smoke’, which may con-tribute to local (intraparenchymal or intra-abdominal)and systemic spread of disease (15–17). The design of Hexablate attempted to address some of these issues by using bipolar energy and incorporating an aspiratorchannel into the handset.

Fig. 4. Haematoxylin and eosin stain (Â10) of hepatocellular

deposit after ablation with Hexablate, showing extensive necrosis of

the tumour.

Fig. 3. Haematoxylin and eosin stain (Â40) of Hexablate aspirate

from colorectal liver metastases, showing the presence of malignant

cells in the aspirate.

Fig. 5. (a) Computed tomography showing 7Â5Â5 cm colorectal metastases in the right liver lobe; the tumour periphery has a high density

(75–80HU) 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 (25–35 HU) both centrally and peripherally.






Although this is an early report in a small series of patients, the results suggest that the Hexablate handset issafe 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 usein an open operation produces a 3Â 3 cm ablation, with

a vertical axis up to 3 cm; therefore, multiple applicationswill be required for larger lesions. Additionally, the array of needles and mode of use where a sequential flow of electrical current runs from the outer ring of needleelectrodes to the inner needle appears to produce effec-tive ablation with no evidence of viable cancer at theperiphery of the ablated tumour.

The aim of incorporating an aspirator channel into thedesign of the Hexablate handset was to eliminate thetumour spume, which a number of groups have de-scribed and associated with local and intraparenchymalspread of tumour after RF treatment. Other potentialgains from an aspirator channel could be a reduction in

the systemic effects from RF by reducing the amount of debris and fluid 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 controllingtumour spume, which, on aspirate cytology, containsviable cancer cells, may hold promise in reducing therecurrence rates after ablation. However, to confirm this,a long-term follow-up in a larger cohort of patients willneed to be undertaken to determine whether aspirationhas a significant effect or whether other factors such asablation of the electrode track or a subcapsular locationof the ablated tumour are the main determinants of recurrence after ablation.

Another concept described in the technique of apply-ing Hexablate to large cancers of the liver is the priority given to focusing initial ablation therapy on the periph-ery of the tumour, before moving to ablate the tumourcentrally. It has been recognised by a number of groupsthat when RF ablation treatment fails, recurrences tendto occur at the outer edge of the tumour (21, 22). Theinterface between normal liver parenchyma and thecancer has a unique micro-environment and ill-under-stood cellular interactions, which is gaining attention as apossible explanation for treatment failure after che-motherapy or surgical resection/ablation (23–25). Theperiphery of the tumour may be cancer’s ‘twilight zone’and perhaps be the area where cancer stem cells resideand survive after chemotherapy, whereas the central zonecontains somatic cancer cells that are chemosensitive.Whether the strategy of ablating the outer edge of thetumour, before moving to treat the central component of the tumour, has any impact on patterns of recurrence canonly be answered when long-term follow-up data in alarger cohort of patients become available.

In summary, the short-term results presented for thisnovel RF ablation/aspirator probe illustrate the evolutionof bipolar RF technology and the development of an

innovative approach to the management of unresectablecancers of the liver. These initial data show this approachto ablation to be effective and safe.

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