Pancreatic Irreversible Electroporation: An Alternative to Pancreatic Metastasectomy?

Abstract: In the presence of metastatic disease, the 5-year overall survival drops from 74% to approximately 8% in patients with renal cell carcinoma. Solitary metastases to the pancreas are uncommon, as disease is more often found in the lung, liver, or bone. Surgical metastasectomy has been shown to improve overall survival, but it is accompanied by significant morbidity. In cases that are not amenable to surgery, thermal ablative techniques have been employed with elevated complication rates given sensitive nature of structures adjacent to the tumor. Irreversible electroporation (IRE) has been shown to be safe and effective in treating pancreatic cancer and may provide a viable alternative when surgical options cannot be pursued. Presented here is a patient with renal cell carcinoma who developed a biopsy-proven solitary metastasis to pancreas 3 years after left nephrectomy. He elected management with IRE. This was complicated by pancreatitis, which resolved after supportive care and an extended hospital stay. There was evidence of local recurrence after 8 months, which was treated with IRE again. The patient was free of disease 18 months from the original intervention.  

Key words: irreversible electroporation, pancreatic cancer, renal cell carcinoma

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Irreversible electroporation (IRE) has been demonstrated to be safe and effective in the management of pancreatic cancer. The delivery of electrical pulses results in the formation of nanopores in the cell membrane, while preserving the extracellular matrix, thus minimizing thermal injury to vital structures and maintaining patency of adjacent vessels. In nonsurgical candidates with metastatic disease to the pancreas, IRE is a viable alternative over thermal modalities in which high complication rates are reported.

Case Presentation

A 47-year-old white male with a history of renal cell carcinoma (RCC) was referred to the interventional oncology service for locoregional therapy to manage a 2 cm lesion in the
head of the pancreas. The 0.9 cm x 1.0 cm x 2.0 cm enhancing lesion in the head of the pancreas was discovered on a follow-up MRI 3 years after left nephrectomy was performed for a 9 cm conventional RCC Fuhrman grade 3 confined to the kidney (Figure 1). Endoscopic ultrasound (EUS) guided biopsy revealed abnormal cells of epithelial origin consistent with RCC. Tumor cells were positive for renal cell common antigen (RCA). His lymph node resection during the nephrectomy was negative. After surgery, the patient declined adjuvant chemotherapy. 

The patient was a very active individual with young children; his ECOG performance status  was 0. Treatment options for the solitary renal cell metastasis to the pancreas offered included targeted vascular endothelial growth factor (VEGF) receptor therapy (bevicizumab), a cytokine (interleukin), or a Whipple procedure. He declined chemotherapy and surgery favoring a minimally invasive approach. After consultation and discussion with his referring oncologist, off-label use of irreversible electroporation (IRE) to percutaneously ablate the lesion was elected (Figure 2). 

Procedure

After intubation, triple-phase computed tomography (CT) was performed and the lesion measured 1.2 cm x 1.1 cm x 2.0 cm. Under CT guidance, three IRE probes (NanoKnife IRE device, AngioDynamics) were advanced in a triangular configuration around the lesion with one probe cranial to and two probes on either side of the lesion. The probes were exposed to 1.5 cm. After initial treatment the needles were pulled back 1 cm and a second ablation was performed. An immediate post-procedure scan showed a very small hematoma anterior to the pancreatic head that resolved on a follow-up CT scan. At 4 months there was no evidence of local recurrence by imaging (Figure 3). His hospital stay was complicated by mild pancreatitis, which was managed conservatively in the hospital for 3 days post procedure. 

Follow-up

On a follow-up magnetic resonance imaging (MRI), 8 months after the first IRE procedure, a new 5 mm x 4 mm x 5 mm focus of enhancement was seen in the pancreatic head (Figure 4). Given concern for local recurrence he sought retreatment. He declined surgery favoring IRE ablation.

Three IRE probes were placed in a triangular configuration around the lesion. They were exposed to 1.5 cm. Immediate post procedure scan did not reveal any enhancement (Figure 5).

In the post-operative period, he again developed pancreatitis, which was marked by pain and elevated lipase (>6,000 U/L) and amylase (2,490 U/L), which resolved with conservative management. Soft tissue attenuation in the surrounding mesentery was noted. These inflammatory changes were still seen in follow-up imaging 2 months later (Figure 6). A subsequent scan in 5 months demonstrated resolution of the inflammation, and no residual enhancement in the pancreatic head to suggest local recurrence (Figure 7). He currently is undergoing routine surveillance with his oncologist and in our clinic. It has been 18 months from the first intervention. 

Discussion

The incidence of kidney cancer in the United States, which includes renal cell carcinoma and transitional cell cancer, is projected to be 65,150 people with an estimated 13,680 deaths in 2013.¹ The 5-year survival rate is 71% and as high as 91% when diagnosed at a local stage.¹ As in this case for primary RCC, surgical resection is the preferred treatment modality. Despite good margins, up to half of patients post resection develop recurrence later in life, thus close clinical follow-up and surveillance imaging guidelines have been adopted.^2,3 

In the presence of metastatic disease, the median survival drops to 10 months.⁴ Renal cell cancer commonly metastasizes to lung, liver, and bone. Solitary metastases to the pancreas are uncommon. At autopsy, reported incidence of pancreatic metastases in advanced disease from RCC varies from 1.6% to 11%.⁴ Metastatic disease accounts for less than 2% of pancreatic malignancies.⁵ 

Renal cell carcinoma is very resistant to chemotherapy. In the past, cytokines such as interleukin-2 or Interferon (IFN) alpha were used as a first-line agent with median survival of 12 months and a 5-year survival less than 10%.⁴ Sunitinib, a multitargeted tyrosine kinase inhibitor, was shown to be more effective in randomized control studies as was the addition of bevicizumab, an anti-VEGF, to IFN. Median overall survival in patients with metastatic clear-cell RCC receiving sunitinib has shown to be 26.4 months.⁵ Adverse events that have been reported included hypertension, fatigue, diarrhea, and hand-foot syndrome. For patients with a poor prognosis, mammalian target of rapamycin (mTOR) pathway inhibitors such as temsirolimus have shown survival benefit.⁴

Pancreatic metastectomy has shown improved survival particularly in the setting of renal cell cancer metastases with 5-year survival rates reported between 51.8% and 100%.^6,7 Surgical options depending on location include pancreaticoduodenectomy, distal pancreatectomy which can include an en bloc splenectomy, and total pancreatectomy. Reported complications include delayed gastric emptying, abscess formation, bacteremia, hemorrhage, pancreatic fistula, bile leak, aspiration, and cardiac arrest.^4,7 

Radiation therapy has been reported in small case series (i.e., 4 patients) to establish local control of disease.⁸ Currently, guidelines suggest adding radiation therapy to induce symptomatic relief. It may be investigated as a treatment option in patients with diabetes mellitus, advanced age, or a poor performance status who are not surgical candidates.⁴

Thermal modalities have been investigated in treatment of pancreatic cancer. Girelli et al evaluated ultrasound-guided radiofrequency ablation (RFA) during laparotomy in 50 patients with locally advanced pancreatic cancer and deemed the procedure feasible, but reported a complication rate of 24%.⁹ Elias et al treated 2 patients with metastatic RCC to the pancreas with RFA during laparotomy; both of which developed severe complications including necrotizing pancreatitis.¹⁰ Carrafiello et al reported on the feasibility of microwave ablation (MWA) on 10 patients with locally advanced pancreatic cancer within the head (5 from a surgical and 5 from a percutaneous approach) with complications including on incidence of pseudocyst formation and another of a pseudoaneurysm formation of the gastroduodenal artery.¹¹ These series highlight the risk of thermal injury both to the adjacent vascular structure and to the pancreatic parenchyma itself.

Nonthermal modalities for ablation such as cryoablation and IRE show more promise. The former was evaluated in a retrospective review by Li et al as a palliative technique along with bypass surgery in 68 patients and reported complications including delayed gastric emptying (25 patients), pancreatic fistula (5 patients), biliary fistula (2 patients) and gastrointestinal hemorrhage (3 patients).¹² Niu et al reported a much safer experience in a review of 32 patients treated with percutaneous cryoablation without any of the aforementioned serious complications, and a median survival of 12.6 months.¹³

Irreversible electroporation has been shown to be feasible and safe in locally advanced pancreatic cancer.^14,15 Narayanan et al demonstrated this in a series of 14 patients by percutaneous approach under CT guidance.¹⁴ One patient had an anesthesia-related pneumothorax and another mild pancreatitis. The patients with the best survival benefit were downstaged to allow resection. Irreversible electroporation from a surgical approach was deemed to have an improved overall survival of 20 months in comparison with standard chemotherapy by Martin et al.¹⁵ 

Technical considerations in creating an IRE volume in the pancreas are related to probe position. Probes should be oriented parallel to each other encompassing the lesion. The probes should be no less than 1cm and no greater than 2cm apart. When the probes are exposed to greater lengths than 1.5cm in the pancreas, high voltages are experienced.

Whether this approach may improve survival in metastatic disease to the pancreas is yet to be determined. In this case, however, the patient was able to maintain his quality of life by undergoing a minimally invasive procedure. The procedures were complicated by pancreatitis likely due to the fact that the small lesions were surrounded by a large volume of normal pancreas. To date, there is no evidence of disease progression. In our experience in patients who are unable to or are unwilling to undergo surgery, IRE is a safe and effective option.

References

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12. Li J, Chen X, Yang H, et al. Tumour cryoablation combined with palliative bypass surgery in the treatment of unresectable pancreatic cancer: a retrospective study of 142 patients. Postgrad Med J. 2011;87(1024)89-95.
13. Niu L, He L, Zhou L, et al. Percutaneous ultrasonography and computed tomography guided pancreatic cryoablation: Feasibility and safety assessment. Cryobiology. 2012;65(3):301-307.
14. Narayanan G, Hosein PJ, Arora G, et al. Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Intervent Radiol. 2013; 23(12):1613-1621.
15. Martin RC 2nd, McFarland K, Ellis S, Velanovich V. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol. 2013;20(Suppl 3):S443-S449.

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Editor’s note: Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Narayanan reports consultancy to Angiodynamics and Dr. Venkat reports no disclosures related to the content herein.

Manuscript submitted December 15, 2014; final version accepted February 1, 2015. 

Address for correspondence: Shree R. Venkat, MD, University of Miami-Miller School of Medicine. Email: vshree@med.miami.edu

Suggested citation: Venkat SR, Narayanan G. Pancreatic irreversible electroporation: an alternative to pancreatic metastasectomy? Intervent Oncol 360. 2015;3(4):E36-E43.