Pancreatic adenocarcinoma has the highest mortality rate of all solid cancers and is the fourth leading cause of cancer death in Western countries (1,2); the outcome remains poor with an overall 5-year survival of less than 5% with no significant improvement over the last 50 years. Surgical resection offers the potential for cure, but less than 20% of patients are suitable and the median survival remains under 2 years and the 5-year survival ranging 11–21% (3,4). In the majority who present with metastatic (MPC) or inoperable locally advanced (LAPC) disease, the median survival ranges from 6–16 months. Considerable efforts have been made over the last decade to identify more effective systemic treatments (5-7). Unfortunately, most clinical trials have not shown any survival advantage for newer therapies including antiangiogenic approaches (8,9).
Local approaches for LAPC such as radiofrequency ablation appear promising, but being thermal-based and limited with significant risk of injury to adjacent blood vessels, gastrointestinal tract perforation and pancreatitis. Combining chemotherapy with RFA has been tried with results similar to CRT (10,11).
A more recent ablative technology, Irreversible Electroporation (IRE) is a non-thermal technique using ultra-short strong electrical fields to create permanent lethal nanopores in the cell membrane, disrupting cellular homeostasis and leading to apoptosis. The main advantage of IRE is in the conservation of blood vessel and bowel walls’ integrity. There are early reports of improved survival following percutaneous or intra-operative IRE-ablation in LAPC (12,13).
We assessed the safety and efficacy of percutaneous IRE integration in consecutive patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) undergoing chemotherapy.
A retrospective analysis of patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) undergoing chemotherapy, treated with IRE-ablation, was performed. IRE-ablation was undertaken in a single centre with chemotherapy delivered at multiple referring hospitals. Exemption was granted by the internal review board as data review was retrospective (The Princess Grace Hospital, Reg: FV11042016). Data management was conducted within the requirements of the Data Protection Act. From the database of 75 consecutive patients with pancreatic carcinoma which remained stable after chemotherapy were treated with IRE between April 2011 and July 2016; LAPC tumours measured less than 5 cm and regional lymph nodes (number <3 with suspected involvement) measured less than 3 cm each. All cancers were ductal adenocarcinomas confirmed by biopsy or FNA. Patients had a minimum of 3 months of a standard first-line chemotherapy as dictated suitable by the referring oncologist (Table 1). All had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, coagulation and platelet profile suitable for an interventional procedure; all had shown evidence of initial disease control after chemotherapy (stability/response by RECIST criteria).
All patients underwent contrast-enhanced computed-tomography (CT) of the chest and abdomen to assess the size, location and extension of the pancreatic carcinoma and to evaluate the degree of involvement of the adjacent vessels, common bile duct, duodenum/stomach and adjacent nodal metastases. CT/positron emission tomography (CT-PET) imaging was used if there was any doubt, to determine the extent of nodal disease. Contrast-enhanced magnetic resonance imaging (MRI) scans were carried out in select cases for more accurate staging.
NanoKnife™ (AngioDynamics®, NY, USA) was used to carry out the IRE percutaneously using CT guidance, 2–7 days before or after the chemotherapy cycle, without interrupting standard-of-care chemotherapy as deemed safe by the referring oncologist. IRE was delivered by a generator supplying low-energy direct current at very high voltages (up to 3,000 V) (14,15). Two IRE 19-gauge monopolar needles spaced at 2 cm (with 2.5 cm exposure lengths) are positioned in parallel in the target tumour. An AccuSync (AccuSync Medical Research Corporation, Milford, CT) device was used to synchronize with the R wave of the electrocardiogram to deliver the planned 90 electrical pulses at a pulse-length of 70 µsec leading to an electrical current ranging 20–40 Amperes. The 2 electrodes were positioned in multiple overlapping axial planes serially to cover the whole tumoral volume (including a safety ablation-margin of 3–5 mm). Under GA and respiratory suspension following neuromuscular blockade, the needles were inserted percutaneously with no incision using a planned trajectory avoiding visceral and vessels walls. Prophylactic intravenous antibiotic (usually cefuroxime and/or metronidazole) was administered during the procedure. Subsequently 10 mL of Bupivacaine (50 mg) was instilled in the retro-crural space using a Chiba needle. For those with nodal metastases, the latter were ablated during the same session as the pancreatic carcinoma.
All patients were admitted overnight post-IRE. Complications were reported and scored retrospectively using NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE). They were discharged the following morning. A follow-up contrast-enhanced CT scan of the abdomen was carried out before discharge in some cases to exclude sub-clinical adverse events.
Patients were followed up in the clinic within 2 weeks to assess toxicity and safety of proceeding with their planned chemotherapy, by the referring oncologist. Repeat CT scans of the chest and abdomen were performed two/three monthly after IRE. Post-IRE follow-up CT-PET scans were performed in some patients.
Normally distributed variables are reported as percentage, mean and standard deviation (SD). Non-parametric variables are described as median and range. Kaplan-Meier curves were used to estimate the survival rate probability as median estimate [95% confidence interval (CI): lower – upper bound]. Survival was calculated from the time of IRE treatment and each patient was censored up to the time of last follow-up. Statistical analyses were performed using SPSS® software 22 (IBM corporation, Armonk, NY, USA).
Seventy-five consecutive patients with disease control for unresectable locally advanced pancreatic carcinoma using IRE were analysed retrospectively. Patient demography and characteristics are summarised in Table 1. Prior to IRE, all LAPC were deemed unresectable at MDT review, except six patients who had previously failed an attempt at radical surgery. Everyone had chemotherapy before IRE [median duration: 4 (range, 3–6) months] and after IRE. Forty-three percent received FOLFIRINOX chemotherapy and the remainder received gemcitabine alone or gemcitabine-based combinations. Four patients had prior radical radiation therapy to the pancreas. At diagnosis and the time of IRE, major vascular invasion was noted with 52% involving the coeliac axis (CA) alone, 19% with superior mesenteric artery (SMA) alone, 12% with CA & SMA combined, 6% with SMA & superior mesenteric vein (SMV) combined, and 11% with CA/SMA + portal vein & SMV combined. The average duration of the IRE-ablation (measured from planning CT completion under GA to withdrawal of the IRE and Chiba needles) was 32 (range, 25–40) minutes.
The 7-day mortality and morbidity after IRE-ablation was 0% and 25% respectively (Table 2). Twelve hours after the IRE-ablation, 3 patients (4%) had CT evidence of small self-contained bleed as a result of needle puncture requiring no intervention. Suspected IRE-ablation related adverse events and grades are shown in Table 2, as per CTCAEs. Five patients developed sepsis at 3 months following liver ablation and one patient had a reported perforated stomach at 5 months post-IRE which was unrelated to IRE.
The median follow-up of the patients was 11.7 (range, 3–45) months. CT scans at 2–3 months after IRE-ablation showed a partial response of the treated pancreas mass (RECIST) in 31%; stable disease in 66% and local progression in 3%. Four of the patients with LAPC responded and down-staged to undergo Whipples operation, but one failed to proceed to resection, due to presence of peritoneal seedlings at laparotomy. However, the other 3 had complete R0 (pathological margin free of tumour) resections. Overall 38% of patients developed recurrent disease over 2 years with 25% in the liver, 10% in the peritoneum and 3% in the laparotomy cutaneous scar. The median change in the ratio of post IRE CA19-9 to Pre-IRE CA19-9 was 80% (range, 20–445%).
This is the largest series of IRE of unresectable pancreatic carcinoma carried out percutaneously to date. Whilst the main limitation is the retrospective nature, potentially leading to selection bias and variability of consistency of data, the overall survival (OS) of LAPC, as a non-variable end-point is encouraging. Selection bias was minimised by assessing a consecutive series. Patients who were progressing on treatment prior to referral were excluded; these are invariably poor candidates for consolidative or locally ablative treatments.
The results confirm the safety of IRE-ablation in previously studies (12,15-19). To date there has been no mortality directly attributed to the procedure using the percutaneous approach. Of the 43 patients undergoing 50 sessions of IRE ablation of the pancreatic carcinoma, Venkat and colleagues reported the complications of abdominal pain (23%), pancreatitis (14%), haematoma (16%), 1 case each (2%) of spontaneous pneumothorax, duodenal stenosis, portal vein thrombosis and sepsis (18). In the PANFIRE study of 25 LAPC cases, 11 patients developed gastrointestinal grade-I/II adverse events, 9 developed grade-III complications (2 pancreatitis, 3 biliary obstruction requiring stenting, 1 cholangitis requiring percutaneous drainage, 1 high grade SMA stenosis) and 2 grade-IV adverse events (1 pancreatitis and 1 bleeding from duodenal ulcer) (19). These complications might be explained by the larger tumour size in the cohort and possibly being more locally invasive. In our series, we reported 21% symptomatic cases of abdominal pain and nausea (1 patient required extended admission of 2 days) mostly of grade 1 and 2 toxicity and 3% asymptomatic (3 small haematoma requiring no intervention) cases within the first 7 days’ post-IRE ablation (Table 2). Delayed adverse events rate occurred in 9% (6 grade 4 and 3 grade 1) and we did not observe any symptomatic pancreatitis.
The alternative approach of intra-operative (open) IRE of LAPC has been reported before percutaneous IRE was developed (20-22). In the latest study with intra-operative IRE ablation of LAPC alone, 54 patients (36%) developed 100 complications (mostly of low grade toxicity) and of these the most common were gastrointestinal in origin in 70% of patients and 28% developed infection (23). There was 2% mortality within the 90-day follow-up with one patient bleeding from duodenal ulcer at day-55, one of liver failure at day-45 and another from pulmonary embolism on day-50 after IRE-ablation. There was no pancreatic-related complication, no leak or pancreatitis, as in our percutaneous cohort.
Outcome data from the Miami group on 43 patients treated with IRE percutaneously, following multiple treatments, showed a median OS of 14.5 months from the date of the IRE for those with LAPC (n=30) compared with 8.6 months for those with MPC (n=13); 95% had received pre-IRE chemotherapy and 44% received post-IRE chemotherapy (20). There was no reported PFS data. In the PANFIRE study, the median time to local progression after percutaneous IRE was 12 months (95% CI: 8–16 months). The median OS was 11 months from IRE (95% CI: 9–13 months) and 17 months from diagnosis (95% CI: 10–24 months). However, only 52% of those patients had received chemotherapy prior to IRE and tumour sizes were on the larger size for any ablative technique (the median size of 4 cm). The largest series of 200 intraoperative (open) IRE-ablated LAPC patients showed a median PFS of 12.4 months, distant PFS of 16.8 months and median OS of 24.9 months from time of diagnosis and a range of 18 to 23 months from day of IRE-ablation (23).
Similarly, our data from the day of percutaneous IRE of LAPC patients, the median PFS and OS were 15 and 27 months respectively (and 30 months from time of diagnosis). These are remarkably similar across different studies. Whilst none of these studies are randomised, multi-centred or controlled, there appears to be some consistency of data, and a possible survival benefit from IRE with acceptable morbidity irrespective of the method used (percutaneously or intra-operatively). Of note is the fact that our percutaneous non-invasive approach allowed for shorter procedural duration (32 vs. 195 minutes), reduced in-patient stay (1 vs. 6 days) and fewer IRE needles used (2 vs. 4), which would translate into lower costs, improved health economics and patient convenience.
The clinical utility of local radical chemo-radiotherapy (CRT) remains controversial. It may have a selective consolidating role after chemotherapy induction in those who have initial disease control (potentially allowing for a chemotherapy free-interval). A recent international phase-III study (LAP 07), showed no significant benefit in either the median PFS or OS comparing the addition of CRT versus chemotherapy alone in patients with inoperable LAPC (24). These outcomes are similar to the UK multicenter SCALOP study where the best median OS was 15.2 months (25). However, radical chemoradiotherapy is usually delivered over a seven-week period with at least 25 hospital-visits for treatment; re-admission due to toxicities and prolonged fatigue is common. Four of our IRE-treated LAPC patients had active disease by CT-PET following chemoradiotherapy and went on to have IRE-ablation successfully. Intriguingly, 4 IRE-treated LAPC patients were downstaged to resectability, when this had not been achieved prior to IRE with any prior treatment strategy. Similarly, 2 of 30 LAPC patients from the Miami study went on to have surgery after IRE ablation with R0 resection (18).
The data suggest that the integration of IRE-ablation within systemic chemotherapy is safe and potentially effective with improved survival for those patients with inoperable pancreatic carcinoma. These data provide a compelling argument to assess IRE plus chemotherapy against current standards of care in inoperable pancreatic cancer, within a prospective randomized phase III clinical trial.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: Exemption was granted by the internal review board of The Princess Grace Hospital (Reg: FV11042016) as data review was retrospective.
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