Additional Papers on Irreversible Electroporation for Treating Pancreatic Cancer

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NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of irreversible electroporation for treating pancreatic cancer

Treating pancreatic cancer using bursts of electricity Irreversible electroporation is a process that uses electrical pulses to kill cancer cells. It is applied directly to a pancreatic cancer tumour through special needles. The main difference between this procedure and thermal techniques for destroying tumours is that it does not produce extreme heat or cold. This means that it may cause less damage to healthy surrounding tissues than some other procedures. Introduction

The National Institute for Health and Clinical Excellence (NICE) has prepared this overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared

This overview was prepared in May 2012 and updated in September 2012. Procedure name

Irreversible electroporation for treating pancreatic cancer

Specialist societies

British Society of Interventional Radiology The Great Britain and Ireland Hepato-Pancreato-Biliary Association The Royal College of Radiologists.

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Description

Indications and current treatment

Pancreatic cancer is relatively uncommon. In 2008, there were 8085 newly diagnosed cases of pancreatic cancer in the UK. The condition tends to affect people aged between 50 and 80 years.

Pancreatic cancers are divided into 2 main groups, exocrine and endocrine tumours. Exocrine tumours start in the exocrine cells, which make digestive enzymes. Over 95% of pancreatic cancers are classified as exocrine tumours and about 90% of these are pancreatic ductal adenocarcinomas. Endocrine tumours (also called neuroendocrine tumours) start in the hormone-producing cells and account for less than 5% of all pancreatic cancers. Pancreatic cancer tends to develop silently, causing few symptoms until the disease is well advanced.

As potentially curative surgery is seldom an option, most patients can be offered only palliative treatment to relieve their symptoms, and outcomes remain poor. Palliative stenting of the bile duct and duodenum can be used to control complications of pancreatic cancer such as jaundice and gastric outlet obstruction. Other treatment options include palliative chemotherapy and radiotherapy. These can be used to reduce the size of an inoperable tumour so it becomes operable, but this is rare.

The aim of irreversible electroporation (IRE) is to destroy cancerous cells by subjecting them to a series of short electrical pulses using high-voltage direct current. This creates multiple holes in the cell membrane, irreversibly damaging the cell’s homeostasis mechanisms and leading to cell death. IRE is a non-thermal cell-destruction technique which is claimed to allow targeted destruction of cancerous cells with less damage to surrounding supporting connective tissue (such as nearby blood vessels and nerves) than other types of treatment.).

What the procedure involves

The procedure is performed with the patient under general anaesthesia. A neuromuscular blocking agent is essential to prevent uncontrolled severe muscle contractions caused by the electric current. Bipolar or unipolar electrode needles are introduced percutaneously (or by open surgical or laparoscopic approaches) and guided into place in and adjacent to the tumour using imaging guidance (either computed tomography [CT] or, less commonly, ultrasound). The distance between the electrodes is confirmed by imaging to ensure that the electrodes are correctly placed parallel to one another and that sufficient current flow would be generated to ensure IRE.

Each ablation cycle consists of pulses of high-voltage direct current delivered in groups (of about 10) with a brief time for recharging between groups (a cycle is usually completed in less than 2 minutes). Electrodes may be repositioned under imaging guidance to extend the zone of electroporation

IP overview: Irreversible electroporation for treating pancreatic cancer Page 2 of 23 IP 1023 [IPG442] until the entire tumour and an appropriate margin have been ablated. The number of ablations is determined by the volume of the target tumour. When the ablation procedure is completed, further imaging may be carried out to confirm satisfactory ablation. Total procedure time has been reported to range from 2.5 to 4.5 hours.

Cardiac synchronisation is used to time delivery of the electrical pulse within the refractory period of the heart cycle, minimising the risk of arrhythmias. Precautions should be taken for patients with implantable electrical devices. Ablation of lesions in the vicinity of implanted electronic devices or implanted devices with metal parts should be avoided. It is important to ensure that interventions (such as a defibrillator) and people trained to treat cardiac arrhythmias are available. Literature review

Rapid review of literature

The medical literature was searched to identify studies and reviews relevant to irreversible electroporation for treating pancreatic cancer. Searches were conducted of the following databases, covering the period from their commencement to 27 September 2012: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion.

The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved.

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Table 1 Inclusion criteria for identification of relevant studies Characteristic Criteria Publication type Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patient Patients with pancreatic cancer. Intervention/test Irreversible electroporation. Outcome Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Language Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base.

List of studies included in the overview

This overview is based on 241 patients from 1 case series1, 1 case report2 and 6 conference abstracts3-8.

Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A.

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Table 2 Summary of key efficacy and safety findings on irreversible electroporation for treating pancreatic cancer Abbreviations used: AJCC, American Joint Committee on Cancer; CI, confidence interval; CT, computed tomography; ICU, intensive care unit ; IRE, irreversible electroporation; mcg, microgram; MRI, magnetic resonance imaging; PET, positron emission tomography; RFA, radiofrequency ablation; US, ultrasound Study details Key efficacy findings Key safety findings Comments

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Abbreviations used: AJCC, American Joint Committee on Cancer; CI, confidence interval; CT, computed tomography; ICU, intensive care unit ; IRE, irreversible electroporation; mcg, microgram; MRI, magnetic resonance imaging; PET, positron emission tomography; RFA, radiofrequency ablation; US, ultrasound Study details Key efficacy findings Key safety findings Comments Martin R (2012)1 Number of patients analysed: 27 Death (<90 days) Follow-up issues: Case series Technical success 1 death occurred 70 days after IRE (related to a Imaging was performed at USA All patients underwent successful IRE. partial portal vein thrombus because of oedema time of discharge or within after ablation). Before IRE, the patient was noted two weeks of IRE Recruitment period: 2009–2011 At 90-day follow-up for all patients, there was 100% to have partial portal vein thrombosis, which had treatment, then at 3 month ablation success with no evidence of local Study population: Patients with been stable for 4 months without anticoagulation. intervals. occurrence. Ablation success was defined as ability advanced, unresectable pancreatic At 45 days after IRE the patient presented with Study design issues: adenocarcinoma. Fifteen had to deliver planned therapy in the operative room and worsening ascites, hepatic and renal failure and Primary objective; to pancreatic head lesions, 12 had lesions no evidence of residual tumour recurrence. A treaded with anticoagulation. evaluate safety and efficacy in the body/neck of the pancreas, 85% combination of CT, MRI and PET scanning was used After 90 day follow-up, there were 17 of IRE in locally advanced had undergone previous chemotherapy to evaluate local recurrence. complications (graded from 1–5) reported in 33% pancreatic cancer. and/or radiation therapy. Median time (9/27) patients. Locally advanced pancreatic from diagnosis to IRE was 6.6 months. Changes in narcotic use and pain score cancer was defined n=27 (IRE alone (n=19) or in th Pre-IRE Post-IRE p a according to 7 AJCC combination with left sided or a Complications n Grade (90 days) value staging system and pancreatic head resection (n=8) Haematologic 3 1,2,2 described as arterial Median 75 (50– 25 (0–75) 0.03 Age: median 61 years Ileus 1 2 encasement of either celiac fentanyl 150) b axis, superior mesenteric Sex: 52% male Bile leak 2 3,4 dose artery or both. Patient selection criteria: Patients with mcg/day Portal vein 2 5,2 c Complications were locally advanced, unresectable (range) thrombosis pancreatic adenocarcinoma. Patients prospectively graded from with borderline resectable lesions were Median 5 (3–9) 3 (0–6) 0.04 Deep venous 2 2,2 1-5:Grade1 required excluded from study. pain thrombosis supportive care or oral score medications; Grade 2 Pulmonary 2 3,3 required IV medication or (range) Renal failure 1 3 Technique: Under general anaesthesia parenteral nutrition; Grade 3 aIt is unclear if this p value is comparing baseline with with deep paralysis to avoid twitching, Ascities 1 3 required ICU admission or 90 days 26 patients had an open approach, and Wound infection 3 2,2,2 non-invasive procedures; 1 patient was treated percutaneously. Grade 4 required major re- IRE (Nanoknife (Angiodyanmics) was operation or involved For patients with more than 1 complication, the delivered by 4 probes, capable of chronic disability; Grade 5 complication with the highest severity was delivering a minimum of 90 pulses. Postoperative death within High definition ultrasound imaging was assigned. a 90 days of intervention used intraoperatively to demonstrate possible device related complications in 4 Total pre-procedure narcotic precise needle placement and patients use was normalised to total

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Angiodynamics. Partial support for the c1 patient died. Another patient developed (non- soft tissue ablation registry has come fatal) portal vein thrombosis with ascites needing Study population issues: from an unrestricted educational grant paracentesis and subsequent oral aldactone. No from Angiodynamics. All other authors evidence of recurrence at 6 months. had nothing to declare. Additional procedures were performed;

All patients had non-clinically relevant elevation of gastrojejunostomy, lipase and amylase, which peaked at 48 hours hepaticojejunostomy and post procedure, returning to normal after 72 hours partial gastrectomy.

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Abbreviations used: AJCC, American Joint Committee on Cancer; CI, confidence interval; CT, computed tomography; ICU, intensive care unit ; IRE, irreversible electroporation; mcg, microgram; MRI, magnetic resonance imaging; PET, positron emission tomography; RFA, radiofrequency ablation; US, ultrasound Study details Key efficacy findings Key safety findings Comments Bagla S (2011)2 Evidence of residual tumour/disease progression Pain Study population issues: Case report or recurrence At 2-week clinical follow-up, the patient had mild, This is a case report of a USA An absence of enhancement within the expected intermittent pain, without fatigue, fever, or other single patient. ablation zone was demonstrated when contrast- symptoms. Recruitment period: not reported enhanced MRI was performed within 24 hours of Other issues: Study population: a patient with each ablation and at 30 days after the second It was unclear if liver Preservation of adjacent vasculature surgically unresectable stage III ablation. metastasis, which occurred (tumour/node/metastasis stages, Vasculature within the ablation zone, specifically after IRE treatment, was Serum cancer antigen 19-9 levels decreased from T4N0M0) pancreatic adenocarcinoma. the splenic artery and superior mesenteric artery, due to distal seeding as a 1500 U/mL to 404 U/mL at 30 days and 407 U/mL at Patient did not have metastatic disease remained patent and unchanged from its transhepatic approach to 90 days after the ablation procedure. before treatment with IRE. preoperative appearance. needle placement was n =1 patient (2 ablative sessions) A mild peripheral ring of enhanced uptake was used during the first IRE Age: 76 demonstrated 3 months after diagnosis when ablative session. If the liver PET/CT imaging was performed. Although there was metastasis had occurred Sex: male no evidence of residual tumour or ‘nodal’ disease, a because of distal seeding, Patient selection criteria: a patient 1.5-cm liver metastasis was also identified on the 3- this could be a safety diagnosed with stage III unresectable month PET/CT scan. Liver metastasis was treated finding. However, no pancreatic cancer secondary to successfully with percutaneous RFA because the judgment can be made vascular invasion was referred for lesion was isolated from large vasculature. without further evidence. percutaneous IRE after he refused Chemotherapy with gemcitabine was then initiated. It was unclear if the chemotherapy or radiation. chemotherapy with 2 months after the RFA, and 6 months after the Technique: the patient received IRE gemcitabine was indicated diagnosis, MRI of the abdomen demonstrated no for the management of the ablation, using Nanoknife evidence of disease progression or recurrence. The pancreatic cancer or for (AngioDynamics, NY), on 2 separate cancer antigen 19-9 level decreased to 236 U/mL at liver metastasis. However, occasions, 2 weeks apart. The first 6 months. ablative session targeted the central NICE technology appraisal and lateral aspect of the tumour and guidance 25 on the procedure is performed under US gemcitabine states: guidance. CT imaging with contrast ‘Gemcitabine may be medium was performed to evaluate considered as a treatment needle position relative to vessels and option for patients with to measure interprobe distance. All advanced or metastatic probes had 1 cm of electrode exposure, adenocarcinoma of the and 1 probe was placed by using a pancreas and a Karnofsky transhepatic approach. All pulses were performance score of 50 or administered in the absolute refractory more, where first line

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USA Study design issues: Recruitment period: 2010–11 Information was only Study population: Patients with locally available from a conference advanced pancreatic adenocarcinoma. abstract, which gave limited All patients had prior chemotherapy details of study design. and 7 patients had prior radiation. This is a retrospective study n =8 patients to evaluate the technical Median age: 53 years (range 51–72) feasibility and clinical safety Sex: not reported of IRE. Patient selection criteria: records of patients with biopsy-proven pancreatic cancer who underwent percutaneous IRE ablation were examined. Technique: IRE was performed percutaneously. Follow-up: up to 10 months in 1 patient and ongoing in 3 patients. 2 patients were lost to follow-up. Conflict of interest/source of funding: not reported

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One pancreatic fistula occurred after distal Study population: patients with resection. There was no evidence of significant unresectable pancreatic cancer pancreatitis or fistula formation in any other N=16 (13 had in situ ablation of tumour patients. and 3 margin treatment with distal resection)

Age: not reported Sex: not reported Patient selection criteria: all lesions were chosen because of proximity/involvement of vascular, biliary or visceral structures. Technique: ablations were performed under ultrasound guidance. Mean follow-up: 9 months Conflict of interest/source of funding: not reported

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Age: not reported Study population issues: Sex: not reported Study recruited and Patient selection criteria: all lesions reported patients with were chosen because of different tumours of the proximity/involvement of vascular, liver, kidney, lung and biliary or visceral structures. pancreas. Only 2 patients in Technique: ablations were performed this case series had under ultrasound guidance. pancreatic tumours. Mean follow-up: 9 months Conflict of interest/source of funding: not reported

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Technique: IRE was performed with the safety events. patients under general anaesthesia One patient returned 4 days post-procedure with using cardiac synchronisation. tachycardia, which resolved spontaneously. Follow-up: not reported Hospital readmission Conflict of interest/source of funding: not reported Readmission rate within 30 days after discharge =2.0%.

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Efficacy

Evidence of residual tumour/disease progression or recurrence A case series of 27 patients reported 100% ablation success with no evidence of local occurrence (assessed using imaging) at 90-day follow-up. Ablation success was defined as ability to deliver planned therapy in the operative room and no evidence of residual tumour recurrence at 3-month interval follow up1.

A case report of a patient with surgically unresectable stage III pancreatic adenocarcinoma, who received 2 consecutive IRE ablative sessions 2 weeks apart, reported no evidence of residual tumour or ‘nodal’ disease on 3-month positron emission tomography (PET) or CT scans2. A 1.5-cm liver metastasis was identified, which was treated successfully with percutaneous radiofrequency ablation. Chemotherapy with gemcitabine was then started. Magnetic resonance imaging (MRI) of the abdomen showed no evidence of disease progression or recurrence 6 months after the pancreatic cancer diagnosis.

Safety

Pancreatitis Pancreatitis was reported in 1 patient in the case series of 8 patients3,4. The patient recovered completely (no further details given).

Partial splenic infarction Partial splenic infarction was reported during 1 percutaneous IRE ablation in a case series of 4 patients5. No treatment was needed.

Portal vein thrombosis Portal vein thrombosis was reported in 2 patients in the case series of 27 patients. This resulted in death in 1 patient 70 days after the procedure (related to progression of portal vein thrombus likely because of oedema after ablation). The other patient developed portal vein thrombosis with ascites (needing paracentesis and subsequent oral aldactone), with no evidence of recurrence at 6 months after the procedure1.

Renal failure Renal failure was reported in 1 patient in the case series of 27 patients (needing admission into an intensive care unit or non-invasive procedure)1.

Bile leak Bile leak (classified as a device-related complication) was reported in 2 patients in the case series of 27 patients. 1 patient developed a leak 5 days after the

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Pancreatic fistula Pancreatic fistula occurred after distal resection in 1 patient (no further details) in a case series of 16 patients6.

Transient ascites Transient ascites was reported in 1 patient in a case series of 29 patients with tumours in the liver, kidney, lung and pancreas (no further details given)6. It was not stated if the patient was treated for lesions in the pancreas.

Pain Mild, intermittent pain, without fatigue, fever or other symptoms, was reported at 2-week follow-up in the single case report2.

Hypertension Another adverse event attributed to the procedure was transient intraprocedural hypertension5.

Validity and generalisability of the studies

Only 1 case series and 1 case report were identified that had been published as full peer-reviewed articles1,2. Six conference abstracts3-8 have been included in accordance with the Interventional Procedures Programme methods guide, which states that data on safety may be considered by the Committee regardless of their source and publication status. It is difficult to assess the quality of these studies and the validity of the assessment measures used. Three conference abstracts included patients with either primary or secondary cancer in multiple sites (liver, lung, pelvis, kidney and pancreas); however, outcomes were not reported separately most of the time so it was not possible to identify safety findings specifically for pancreatic cancer. There are no long-term or comparative data.

Existing assessments of this procedure

There were no published assessments from other organisations identified at the time of the literature search.

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Related NICE guidance

Below is the NICE guidance related to this procedure. Appendix B gives details of the recommendations made in the guidance listed.

Technology appraisals

Guidance on the use of gemcitabine for the treatment of pancreatic cancer. NICE technology appraisal guidance 25 (2001). Available from http://guidance.nice.org.uk/TA25

Specialist Advisers’ opinions

Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and does not represent the view of the society.

Dr Antony Goode (British Society of Interventional Radiology), Dr Andrew Smith and Mr Mark Taylor (The Great Britain and Ireland Hepato-Pancreato-Biliary Association), and Professor Edward Leen (The Royal College of Radiologists).

One Specialist Adviser has performed this procedure at least once and 3 have never performed it. Two Specialist Advisers consider the procedure to be definitely novel and of uncertain safety and efficacy; 1 considered it to be the first in a new class of procedure; 1 considered it to be a minor variation on an existing procedure. Comparator: Whipple’s (pyrolus preserving pancreaticoduodenectomy) surgery, portal vein resection and reconstruction, palliative chemotherapy with or without radiotherapy (stereotactic) and radiofrequency ablation. Theoretical adverse events include cardiac arrhythmias (atrial fibrillation), damage to major arteries or veins, bowel injury (stomach, duodenum, small and large bowel), acute pancreatitis, pancreatic leak or fistula, sepsis, infection or abscess, and haemorrhage. Adverse events reported in the literature include cardiac arrhythmias (ventricular and atrial), non-target organ damage (reported in studies of the use of IRE for non-pancreatic cancer but the Specialist Adviser stated that adverse effects could potentially be expected whatever the target organ), pancreatitis, pneumothorax, hyperkalaemia, raised amylase and lipase post- procedure, neurapraxia and pain post-treatment. Key efficacy outcomes include increase in overall and relapse-free patient survival, local tumour control, tumour response and improvement of response rates when used in combination with established therapies. The Specialist Advisers noted that there is currently too little data on efficacy of this procedure and long-term outcome is uncertain.

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One Specialist Adviser stated that radiological or hepato-pancreato-biliary surgical training with skill for imaging guidance using CT and ultrasound is needed. Another Specialist Adviser stated that training would include accurate needle placement, use of the machine to generate the current, understanding of the process and follow-up needed for patients having this procedure, and a clear understanding of the likely complications. One Specialist Adviser noted that dedicated units, machines and associated probes are needed for treatment. Other facilities needed include CT and ultrasound machines. One Specialist Adviser thought that the procedure will have a moderate impact on the NHS and that the speed of diffusion will be slow. Two Specialist Advisers thought that the procedure will have a minor impact on the NHS. One Specialist Adviser stated that it may widen the group of patients with pancreatic cancer who can be offered locoregional treatment. The Specialist Adviser stated that if the procedure proves to be safe and effective, it was likely that it would eventually be performed in all hepatobiliary surgery centres. Patient Commentators’ opinions

NICE’s Patient and Public Involvement Programme was unable to gather patient commentary for this procedure.

Issues for consideration by IPAC

Future trials: NCT01369420 NanoKnife low energy direct current (LEDC) system in subjects with locally advanced unresectable pancreatic cancer: location: Italy; type: single group open-label assignment; estimated enrolment: 5 patients; estimated study completion date: May 2012.

Register: The soft tissue ablation registry (STAR), USA collects data on patients treated by IRE for liver, pancreas, lung, prostate and kidney tumours, as well as other soft tissue tumours.

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References

1. Martin II RCG, McFarland K, Ellis S et al. (2012) Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. Journal of the American College of Surgeons 215 (3) 361-9.

2. Bagla S and Papadouris D (2012) Percutaneous irreversible electroporation of surgically unresectable pancreatic cancer: a case report. Journal of Vascular and Interventional Radiology 23 (1): 142–5

3. Narayanan G, Arora G, Barbery KJ et al. (2012) Downstaging locally advanced pancreatic adenocarcinoma (LAPC) with vascular encasement using percutaneous irreversible electroporation (IRE). Journal of Vascular and Interventional Radiology Vol. 23 No. 3 March, 2012 pS6-S7

4. Hosein PJ, Barbery KJ, Perez-Rojas E et al. (2012) Initial experience using percutaneous irreversible electroporation (IRE) in the treatment of locally advanced pancreatic adenocarcinoma (LAPC) with vascular encasement. Journal of Clinical Oncology, 2012 Gastrointestinal Cancers Symposium. Vol 30, No 4_suppl (February 1 Supplement), 2012: 291

5. Bagla S, Papadouris D and Van Breda A (2012) Percutaneous irreversible electroporation (IRE) of surgically unresectable pancreatic carcinoma: single center safety experience. Journal of Vascular and Interventional Radiology Vol. 23, Issue 3, Supplement, p S54

6. Watkins K, Bao, P. (2012) Initial experience with irreversible electroporation in the management of unresectable pancreatic cancer. HPB.Conference: 10th World Congress of the International Hepato- Pancreato-Biliary Association Paris France.Conference Publication: (var.pagings).14: 89-90

7. Ali NS, Cohn S and Raofi V (2012) Single center experience with irreversible electroporation for liver and pancreas tumor ablation [abstract]. HPB. Conference: 12th Annual Americas Hepato-Pancreato-Biliary Congress Miami Beach, FL United States. Conference Start: 20120307 Conference End: 20120311. Conference Publication: (var.pagings).14 (p 2)

8. Hays D, Robbins KV, Goodwin WJ et al. (2011) Single center, multiuser experience and safety of 50 irreversible electroporation (IRE) ablations. Journal of Vascular and Interventional Radiology 22 (3 Suppl.): S80–1

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Appendix A: Additional papers on irreversible electroporation for treating pancreatic cancer

There were no additional papers identified.

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Appendix B: Related NICE guidance for irreversible electroporation for treating pancreatic cancer Guidance Recommendations Technology appraisals Guidance on the use of gemcitabine for the treatment of pancreatic cancer. NICE technology appraisal 25 (2001)

1.1 Gemcitabine may be considered as a treatment option for patients with advanced or metastatic adenocarcinoma of the pancreas and a Karnofsky performance score of 50 or more, where first line chemotherapy is to be used.

1.2 Gemcitabine is not recommended for patients who are suitable for potentially curative surgery, or patients with a Karnofsky (see Appendix D) score of less than 50.

1.3 There is insufficient evidence to support the use of gemcitabine as a second line treatment in patients with pancreatic adenocarcinoma.

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Appendix C: Literature search for irreversible electroporation for treating pancreatic cancer

Databases Date Version/files searched Cochrane Database of Systematic 27/09/2012 September 2012 Reviews – CDSR (Cochrane Library) Database of Abstracts of Reviews 27/09/2012 September 2012 of Effects – DARE (CRD website) HTA database (CRD website) 27/09/2012 September 2012 Cochrane Central Database of 27/09/2012 September 2012 Controlled Trials – CENTRAL (Cochrane Library) MEDLINE (Ovid) 27/09/2012 1946 to September Week 2 2012 MEDLINE In-Process (Ovid) 27/09/2012 September 25, 2012 EMBASE (Ovid) 27/09/2012 1974 to 2012 Week 38 CINAHL (NLH Search 2.0 or 27/09/2012 N/A EBSCOhost) JournalTOCS 27/09/2012 N/A

The following search strategy was used to identify papers in MEDLINE. A similar strategy was used to identify papers in other databases.

1 Electroporation/ 5060

2 Electric Stimulation/ 102592

3 exp Nanotechnology/ 22097

4 nanoknife.tw. 4

5 (irrevers* adj3 (electropor* or electro-por* or electropermeab* or electro-permeab*)).tw. 105

6 (electric* adj3 (field* or stimul* or pulse* or cell? or membrane* or pore?)).tw. 66429

7 Electric Stimulation Therapy/ 15435

8 IRE.tw. 972

9 LEDC.tw. 4

10 Electrochemotherapy/ 195

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11 electrochemo*.tw. 302

12 Ablation Techniques/ 452

13 ((tissue* or tumor* or tumour*) adj3 ablat*).tw. 4105

14 (bipolar adj3 (puls? or electrod* or mode?)).tw. 2863

15 or/1-14 182550

16 exp Pancreatic Neoplasms/ 48676

((pancrea* or neuroendocrin* or ductal*) adj3 (adenoma*or Neoplasm* or Cancer* or 17 Metastas* or Carcinoma* or Adenocarcinom* or Tumour* or Tumor* or Malignan* or Lump* 52378 or Masses* or Sarcoma*)).tw.

((islet cell or islet-cell or island cell) adj3 (adenoma* or Neoplasm* or Cancer* or 18 Metastas* or Carcinoma* or Adenocarcinom* or Tumour* or Tumor* or Malignan* or Lump* 2151 or Masses* or Sarcoma*)).tw.

19 Adenoma, Islet Cell/ 4390

20 Islet Cell Carcinoma/ 286

21 Somatostatinoma/ 283

22 somatostatinoma*.tw. 297

23 nesidioblastoma*.tw. 37

24 or/16-23 71451

25 15 and 24 178

26 animals/ not humans/ 3620832

27 25 not 26 153

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