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Irreversible electroporation: A novel pancreatic cancer therapy
Curr Probl Cancer 37 (2013) 262–265
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Irreversible electroporation: A novel pancreatic cancer therapy Matthew J. Weiss, MD, Christopher L. Wolfgang, MD, PhD, FACS
Background Approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) are identified yearly in the United States. Surgical resection offers the only chance for cure with 5-year survival rates approaching 20%. However, only 80% of patients are candidates for a potentially curative resection because of metastatic disease (50%) or locally advanced tumors (30%). Perhaps more than any other stage of pancreatic cancer, patients with stage III locally advanced or unresectable tumors derive the most benefit from a multidisciplinary team approach. A typical treatment regimen begins with systemic therapy to control micrometastatic disease followed by radiation for local control. At each step of treatment, the surgeon is involved in assessing the resectability. Unfortunately, “downstaging” is estimated to occur in only 10%-15% of patients, and despite multimodality therapy, the median survival remains only 8-12 months.1 As such, locally advanced pancreatic cancer presents a difficult problem for the multidisciplinary team. Patients with locally advanced, albeit unresectable disease, should theoretically benefit from maximal local therapy. However, currently, there are very few treatment options for aggressive localized therapy in these patients. In highly selected cases, aggressive operations such as pancreatectomy with en bloc resection of the celiac axis can be performed, but these types of operations are only possible in few patients. Until recently, modest improvements in the prognosis and quality of life for locally advanced PDAC have focused on systemic chemotherapy and radiation therapy. Recently, several reports have described the technique and the outcome of ablative techniques for locally advanced PDAC. This article focuses on irreversible electroporation (IRE), which is a novel method for focal tumor ablation in the pancreas. Until recently, locoregional cancer therapies focused on the application of thermal energy for tissue destruction, such as radiofrequency ablation, microwave ablation, and cryoablation. Although effective in other organs such as the liver or kidney, these technologies lack safety and efficacy in the pancreas owing to the risk of thermal damage to adjacent structures and significant thermal dissipation from large adjacent blood vessels. IRE applies short, high-voltage pulses to the tissue to permeabilize cell membranes and induce cellular apoptosis.2-4 As IRE relies on apoptosis to induce cell death, structures formed by proteins such as vascular elastin and collagenous structures are not damaged, which should lead to preservation of blood vessel scaffolding. In addition, as IRE is nonthermal, there should be no heat-cold sink effect. Both are 0147-0272/$ - see front matter & 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.currproblcancer.2013.10.002
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essential if IRE gains traction in the treatment of PDAC. It is essential to note that the use of IRE for destruction of the pancreatic tumor is in its infancy, and the few published reports focus on safety; the efficacy of this technology still requires further study with long-term follow-up. Safety The application of IRE technology to PDAC represents a unique dilemma. First, the pancreas is a retroperitoneal structure that is intimately associated with multiple vital blood vessels and the bile duct, all of which need to be preserved. Second, the pancreas is a gland that is susceptible to autodigestive pancreatitis and pancreatic fistulae formation, which can be devastating, lifethreatening complications for patients. Using a swine model, Bower et al5 reported that IRE of the pancreas was well tolerated with rapid resolution of clinically mild pancreatitis and preserved vascular structures. However, peer-reviewed data on the use of IRE for destruction of the pancreatic tumor in humans are scarce. A dual-institution pilot evaluation of 27 patients undergoing IRE of the pancreas for locally advanced tumors revealed that all patients had non–clinically significant elevations in their serum amylase and lipase levels that returned to normal within 72 hours, and there seemed to be acceptable morbidity (33%) and mortality (3.7%).6 In this study, 19 patients had IRE performed in situ and 8 underwent margin augmentation. There was only 1 death at 70 days after IRE related to progression of a preexisting portal vein thrombosis. This pilot study demonstrates that IRE for locally advanced pancreatic adenocarcinoma appears safe with acceptable toxicity.
Efficacy The first application of IRE to human pancreatic tumors began ca 2009. As a result, data on the efficacy of this new technology are relatively limited. Martin et al7 published an update on their multi-institutional experience of 54 patients undergoing IRE in 2012. In this study, propensity-matched comparison with standard chemotherapy or chemoradiation therapy was performed and suggested an improvement in local progression-free survival (14 vs 6 months, P ¼ 0.01), distant progression-free survival (15 vs 9 months, P ¼ 0.02), and overall survival (20 vs 13 months, P ¼ 0.03).7 In addition, it appeared that IRE of locally advanced tumors achieved greater local palliation compared with standard treatments, although no quality of life scores were included. A randomized trial is necessary before definite conclusions can be drawn, but these results are encouraging.
Patient selection Locally advanced pancreatic cancer has a 5-year survival rate o 5% and has great room for improvement. For patients with localized disease, the potential for improved survival by effective tumor ablation is significant. As IRE is a local therapy, selecting for tumors that are locally aggressive in the absence of metastatic disease seems the most appropriate. Currently, we offer IRE to patients with locally advanced disease who have already exhausted traditional systemic (chemotherapy) and local therapy (radiation therapy) options and continue to remain free of distant metastatic disease. Patients need to be in adequate health to endure an open laparotomy and be free of preexisting cardiac conduction abnormalities. Metallic biliary stents interfere with the electrical current and usually need to be removed if they are going to be within the electroporation field but are not an absolute contraindication. Technique Our center began selectively using IRE for locally advanced pancreatic tumors in 2012, and to date, we have performed 7 electroporations (unpublished data). Two of these electroporations
264
M.J. Weiss, C.L. Wolfgang / Curr Probl Cancer 37 (2013) 262–265
Fig. 1. (A) Contrast-enhanced computer tomography image in arterial phase of a biopsy-proven pancreatic neck adenocarcinoma demonstrating celiac trunk encasement. Note the presence of the fiducials that were used for targeting preoperative stereotactic body radiation therapy before surgical exploration. Patient underwent an in situ irreversible electroporation owing to extensive medical comorbidities prohibiting celiac resection. (B) Contrast-enhanced computer tomography image in arterial phase of a biopsy-proven uncinate process pancreatic adenocarcinoma demonstrating superior mesenteric artery (SMA) encasement. Patient underwent a pancreaticoduodenectomy with negative pathologic margins and SMA margin augmentation with irreversible electroporation.
have been performed in situ (Fig 1A) and 5 for margin augmentation (Fig 1B) in combination with a resection. Our current selection criteria include patients with locally advanced stage III pancreatic cancer who have already been treated with standard chemoradiation therapy for 4 4 months and have no evidence of metastatic disease. We begin with a diagnostic laparoscopy to confirm that no metastatic disease is present. A midline laparotomy is performed and a surgical resection is attempted. If resection is feasible with at least an R1 margin, then we go ahead with the resection with IRE margin augmentation. If a negative margin does not appear possible, then we perform an in situ IRE (Fig 2). The decision to proceed with IRE margin augmentation vs an in situ electroporation is at the discretion of the surgeon and is based on the location of the tumor, intraoperative assessment, previous therapy, patient comorbidities, and patient wishes.
Fig. 2. In situ irreversible electroporation of a pancreatic adenocarcinoma. Three probes are placed around the tumor that is encasing the superior mesenteric vein causing complete occlusion plus superior mesenteric artery involvement. (Color version of figure is available online.)
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We believe that given the anatomical location of the pancreas and close proximity to major vascular structures, an open technique is safer and more accurate for probe placement. Each probe is a 19-gauge needle with depth markings and an echogenic tip and adjustable active exposure length. Based on the size and location of the tumor, we select the number of probes (26) and exposure (0.5-4 cm). Under ultrasound guidance, probes are placed around the zone to be electroporated with adequate spacing (0.5-2 cm). After confirming the distance of the electrodes by ultrasound, the IRE device is synchronized to the R-wave (nonconduction phase) of the electrocardiography and complete muscle paralysis is confirmed by anesthesia using the trainof-four test (0/4 twitches). The surgeon then delivers the energy and monitors the ablation with ultrasound. Further investigation The adaptation of IRE for pancreatic tumor therapy appears safe but the efficacy remains in the early evaluation phase. Current retrospective data on IRE for locally advanced tumors suffer from selection bias, and long-term follow-up is still unavailable. A multi-institutional prospective trial comparing this technique to traditional chemoradiation therapy is necessary before this therapy is universally adopted. Appropriate end points for such a trial should focus on safety, overall survival, and quality of life. References 1. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009;27:2269–77. 2. Al-Sakere B, Andre F, Bernat C, et al. Tumor ablation with irreversible electroporation. PloS One 2007;2:e1135. 3. Edd JF, Horowitz L, Davalos RV, et al. In vivo results of a new focal tissue ablation technique: irreversible electroporation. IEEE Trans Biomed Eng 2006;53:1409–15. 4. Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng 2005;33:223–31. 5. Bower M, Sherwood L, Li Y, et al. Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. J Surg Oncol 2011;104:22–8. 6. Martin RC 2nd, McFarland K, Ellis S, et al. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg 2012;215:361–9. 7. Martin RC 2nd, McFarland K, Ellis S, et al. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol 2012.
Contents lists available at ScienceDirect
Curr Probl Cancer journal homepage: www.elsevier.com/locate/cpcancer
Irreversible electroporation: A novel pancreatic cancer therapy Matthew J. Weiss, MD, Christopher L. Wolfgang, MD, PhD, FACS
Background Approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) are identified yearly in the United States. Surgical resection offers the only chance for cure with 5-year survival rates approaching 20%. However, only 80% of patients are candidates for a potentially curative resection because of metastatic disease (50%) or locally advanced tumors (30%). Perhaps more than any other stage of pancreatic cancer, patients with stage III locally advanced or unresectable tumors derive the most benefit from a multidisciplinary team approach. A typical treatment regimen begins with systemic therapy to control micrometastatic disease followed by radiation for local control. At each step of treatment, the surgeon is involved in assessing the resectability. Unfortunately, “downstaging” is estimated to occur in only 10%-15% of patients, and despite multimodality therapy, the median survival remains only 8-12 months.1 As such, locally advanced pancreatic cancer presents a difficult problem for the multidisciplinary team. Patients with locally advanced, albeit unresectable disease, should theoretically benefit from maximal local therapy. However, currently, there are very few treatment options for aggressive localized therapy in these patients. In highly selected cases, aggressive operations such as pancreatectomy with en bloc resection of the celiac axis can be performed, but these types of operations are only possible in few patients. Until recently, modest improvements in the prognosis and quality of life for locally advanced PDAC have focused on systemic chemotherapy and radiation therapy. Recently, several reports have described the technique and the outcome of ablative techniques for locally advanced PDAC. This article focuses on irreversible electroporation (IRE), which is a novel method for focal tumor ablation in the pancreas. Until recently, locoregional cancer therapies focused on the application of thermal energy for tissue destruction, such as radiofrequency ablation, microwave ablation, and cryoablation. Although effective in other organs such as the liver or kidney, these technologies lack safety and efficacy in the pancreas owing to the risk of thermal damage to adjacent structures and significant thermal dissipation from large adjacent blood vessels. IRE applies short, high-voltage pulses to the tissue to permeabilize cell membranes and induce cellular apoptosis.2-4 As IRE relies on apoptosis to induce cell death, structures formed by proteins such as vascular elastin and collagenous structures are not damaged, which should lead to preservation of blood vessel scaffolding. In addition, as IRE is nonthermal, there should be no heat-cold sink effect. Both are 0147-0272/$ - see front matter & 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.currproblcancer.2013.10.002
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essential if IRE gains traction in the treatment of PDAC. It is essential to note that the use of IRE for destruction of the pancreatic tumor is in its infancy, and the few published reports focus on safety; the efficacy of this technology still requires further study with long-term follow-up. Safety The application of IRE technology to PDAC represents a unique dilemma. First, the pancreas is a retroperitoneal structure that is intimately associated with multiple vital blood vessels and the bile duct, all of which need to be preserved. Second, the pancreas is a gland that is susceptible to autodigestive pancreatitis and pancreatic fistulae formation, which can be devastating, lifethreatening complications for patients. Using a swine model, Bower et al5 reported that IRE of the pancreas was well tolerated with rapid resolution of clinically mild pancreatitis and preserved vascular structures. However, peer-reviewed data on the use of IRE for destruction of the pancreatic tumor in humans are scarce. A dual-institution pilot evaluation of 27 patients undergoing IRE of the pancreas for locally advanced tumors revealed that all patients had non–clinically significant elevations in their serum amylase and lipase levels that returned to normal within 72 hours, and there seemed to be acceptable morbidity (33%) and mortality (3.7%).6 In this study, 19 patients had IRE performed in situ and 8 underwent margin augmentation. There was only 1 death at 70 days after IRE related to progression of a preexisting portal vein thrombosis. This pilot study demonstrates that IRE for locally advanced pancreatic adenocarcinoma appears safe with acceptable toxicity.
Efficacy The first application of IRE to human pancreatic tumors began ca 2009. As a result, data on the efficacy of this new technology are relatively limited. Martin et al7 published an update on their multi-institutional experience of 54 patients undergoing IRE in 2012. In this study, propensity-matched comparison with standard chemotherapy or chemoradiation therapy was performed and suggested an improvement in local progression-free survival (14 vs 6 months, P ¼ 0.01), distant progression-free survival (15 vs 9 months, P ¼ 0.02), and overall survival (20 vs 13 months, P ¼ 0.03).7 In addition, it appeared that IRE of locally advanced tumors achieved greater local palliation compared with standard treatments, although no quality of life scores were included. A randomized trial is necessary before definite conclusions can be drawn, but these results are encouraging.
Patient selection Locally advanced pancreatic cancer has a 5-year survival rate o 5% and has great room for improvement. For patients with localized disease, the potential for improved survival by effective tumor ablation is significant. As IRE is a local therapy, selecting for tumors that are locally aggressive in the absence of metastatic disease seems the most appropriate. Currently, we offer IRE to patients with locally advanced disease who have already exhausted traditional systemic (chemotherapy) and local therapy (radiation therapy) options and continue to remain free of distant metastatic disease. Patients need to be in adequate health to endure an open laparotomy and be free of preexisting cardiac conduction abnormalities. Metallic biliary stents interfere with the electrical current and usually need to be removed if they are going to be within the electroporation field but are not an absolute contraindication. Technique Our center began selectively using IRE for locally advanced pancreatic tumors in 2012, and to date, we have performed 7 electroporations (unpublished data). Two of these electroporations
264
M.J. Weiss, C.L. Wolfgang / Curr Probl Cancer 37 (2013) 262–265
Fig. 1. (A) Contrast-enhanced computer tomography image in arterial phase of a biopsy-proven pancreatic neck adenocarcinoma demonstrating celiac trunk encasement. Note the presence of the fiducials that were used for targeting preoperative stereotactic body radiation therapy before surgical exploration. Patient underwent an in situ irreversible electroporation owing to extensive medical comorbidities prohibiting celiac resection. (B) Contrast-enhanced computer tomography image in arterial phase of a biopsy-proven uncinate process pancreatic adenocarcinoma demonstrating superior mesenteric artery (SMA) encasement. Patient underwent a pancreaticoduodenectomy with negative pathologic margins and SMA margin augmentation with irreversible electroporation.
have been performed in situ (Fig 1A) and 5 for margin augmentation (Fig 1B) in combination with a resection. Our current selection criteria include patients with locally advanced stage III pancreatic cancer who have already been treated with standard chemoradiation therapy for 4 4 months and have no evidence of metastatic disease. We begin with a diagnostic laparoscopy to confirm that no metastatic disease is present. A midline laparotomy is performed and a surgical resection is attempted. If resection is feasible with at least an R1 margin, then we go ahead with the resection with IRE margin augmentation. If a negative margin does not appear possible, then we perform an in situ IRE (Fig 2). The decision to proceed with IRE margin augmentation vs an in situ electroporation is at the discretion of the surgeon and is based on the location of the tumor, intraoperative assessment, previous therapy, patient comorbidities, and patient wishes.
Fig. 2. In situ irreversible electroporation of a pancreatic adenocarcinoma. Three probes are placed around the tumor that is encasing the superior mesenteric vein causing complete occlusion plus superior mesenteric artery involvement. (Color version of figure is available online.)
M.J. Weiss, C.L. Wolfgang / Curr Probl Cancer 37 (2013) 262–265
265
We believe that given the anatomical location of the pancreas and close proximity to major vascular structures, an open technique is safer and more accurate for probe placement. Each probe is a 19-gauge needle with depth markings and an echogenic tip and adjustable active exposure length. Based on the size and location of the tumor, we select the number of probes (26) and exposure (0.5-4 cm). Under ultrasound guidance, probes are placed around the zone to be electroporated with adequate spacing (0.5-2 cm). After confirming the distance of the electrodes by ultrasound, the IRE device is synchronized to the R-wave (nonconduction phase) of the electrocardiography and complete muscle paralysis is confirmed by anesthesia using the trainof-four test (0/4 twitches). The surgeon then delivers the energy and monitors the ablation with ultrasound. Further investigation The adaptation of IRE for pancreatic tumor therapy appears safe but the efficacy remains in the early evaluation phase. Current retrospective data on IRE for locally advanced tumors suffer from selection bias, and long-term follow-up is still unavailable. A multi-institutional prospective trial comparing this technique to traditional chemoradiation therapy is necessary before this therapy is universally adopted. Appropriate end points for such a trial should focus on safety, overall survival, and quality of life. References 1. Huguet F, Girard N, Guerche CS, et al. Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 2009;27:2269–77. 2. Al-Sakere B, Andre F, Bernat C, et al. Tumor ablation with irreversible electroporation. PloS One 2007;2:e1135. 3. Edd JF, Horowitz L, Davalos RV, et al. In vivo results of a new focal tissue ablation technique: irreversible electroporation. IEEE Trans Biomed Eng 2006;53:1409–15. 4. Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng 2005;33:223–31. 5. Bower M, Sherwood L, Li Y, et al. Irreversible electroporation of the pancreas: definitive local therapy without systemic effects. J Surg Oncol 2011;104:22–8. 6. Martin RC 2nd, McFarland K, Ellis S, et al. Irreversible electroporation therapy in the management of locally advanced pancreatic adenocarcinoma. J Am Coll Surg 2012;215:361–9. 7. Martin RC 2nd, McFarland K, Ellis S, et al. Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol 2012.