- Email: [email protected]
Irreversible electroporation for locally advanced pancreatic cancer
+Model
ARTICLE IN PRESS
DIII-873; No. of Pages 8
Diagnostic and Interventional Imaging (2016) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
Irreversible electroporation for locally advanced pancreatic cancer J.-P. Tasu a,∗, G. Vesselle a, G. Herpe a, J.-P. Richer b,c, S. Boucecbi a, S. Vélasco a, M. Carretier c, B. Debeane d, D. Tougeron e a
Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France b Laboratory of Simulations and Anatomy Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France c Abdominal Surgery Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France d Anaesthesiology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France e Abdominal Oncology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
KEYWORDS Irreversible electroporation; Pancreas; Pancreatic adenocarcinoma; Cancer; Interventional radiology
Abstract Pancreatic adenocarcinoma is one of the solid cancers associated with the poorest prognosis; the only curative treatment remains surgical resection but in most cases, this treatment is not possible because of distant metastasis or local extension. Irreversible electroporation is a new tumor ablation technique, which provides cellular apoptosis without any thermal coagulation effect. This technique helps preserve the ducts, vessels or nerves located in the treatment area. This article reviews the current knowledge regarding the use of electroporation for the treatment of pancreatic adenocarcinoma. © 2016 Published by Elsevier Masson SAS on behalf of Editions franc ¸aises de radiologie.
∗ Corresponding author at: Département d’imagerie diagnostique, fonctionnelle et thérapeutique, CHU de Poitiers, rue de la Milétrie, 86000 Poitiers France. E-mail address: [email protected] (J.-P. Tasu).
http://dx.doi.org/10.1016/j.diii.2016.10.001 2211-5684/© 2016 Published by Elsevier Masson SAS on behalf of Editions franc ¸aises de radiologie.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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Ninety-five percent of pancreatic cancers are adenocarcinomas. The diagnosis is still usually made at a late stage when the patient present abdominal pain, jaundice or deterioration in general health. Consequently, at the time of diagnosis, only 15% of patients have surgically resectable disease whereas 85% of patients have a locally advanced or metastatic disease and are therefore beyond the reach of surgery. For those patients who are not amenable to surgical resection, the 5-year-survival rate falls to less than 5%. For patients who can be operated, the 5-year-survival rate is around 20%. Whilst everyone understands the concept of metastatic disease, locally advanced disease is more specific to the pancreas. Considering the retroperitoneal situation of the pancreatic gland, the tumor tends to spread quickly the superior mesenteric and/or hepatic artery and/or coeliac trunk and/or junction of the mesenteric and portal vessels. In this situation, the only treatment option is a combination of chemotherapy with gemcitabine or folfirinox, palliative surgery (biliary and gastric shunting) and/or radiotherapy. In view of the limited treatment options, irreversible electroporation (IE) has recently been proposed to treat locally advanced pancreatic cancer [1]. IE has been around for over 30 years [2] when it was initially used to destroy microorganisms or introduce drugs into cells in in vitro cell cultures. It has more recently emerged as an effective method to destroy tissue [3]. Above all, however, IE can destroy cells located into a target area wherein collagen architecture of the vascular, biliary or neuronal structures is preserved. [4]. This article reviews the current knowledge about the use of electroporation to treat pancreatic adenocarcinoma.
Mechanisms of cell death from electroporation IE uses very high voltage current, maximum 3,000 volts, delivered in microseconds (70 to 80 microsecs) pulses. These ultrashort electrical pulses create multiple microscopic holes within the cell membrane resulting in irreversible cell damage due to interference with homeostatic mechanisms [5]. Apoptosis does not occur immediately but only after a few days. The method is therefore completely different from thermal ablation techniques producing heat (radiofrequency or microwave) or cold (cryotherapy); indeed, IE does not cause coagulation necrosis [6,7]. A summary of
Table 1
the major differences between thermal and electroporation methods are shown in Table 1. Histologically, early changes occur in the target tissue as early as 30 minutes although the macroscopic changes are slower. Normal tissue regenerates after several weeks and the collagen structures preserved by IE are used as ‘‘guides’’ for endothelial or duct cells restoring a normal ductal or vascular architecture over a few weeks. This has been clearly shown in a mouse model of pancreatic cancer [8] and confirmed on a pig model [9].
Practical aspects of treatment The aim of treatment is to surround the tumor with two to six needles [10]. The number of needles chosen depends on the size and shape of the target lesion. The distance between each needle should not be over 2.5 cm and not under 1 cm and all of the needles must be positioned in parallel. It is occasionally difficult to correctly placed needles, which requires previous experience with ablation techniques, and if possible with multipolar techniques. A precise guidance method is also recommended and in our view, CT achieves this better than ultrasound although there are numerous descriptions of ultrasound guidance in the literature. The other purpose of guidance is to avoid puncturing at risk organs although a transgastric or transhepatic approach may be used as the needles are thin (22 Gauge). In terms of vascular structures, the manufacturer recommends the needle be positioned at least 2 mm away from large vessels in order to avoid any risk of damage and the risks of burns as it has been shown that the temperature may reach 62.8 ◦ C in a radius of approximately 0.5 cm around the needle tip. Treatment can be delivered in different approaches. Surgical groups commonly prefer a peroperative approach, which allows to check the peritoneal cavity and to exclude possible carcinomatosis. This approach also has the advantage of allowing the needles to be positioned parallel to the mesenteric vessel which is the best approach in cases of mesenteric involvement. A percutaneous approach has also been proposed, which has two major advantages of being less invasive and enabling CT guidance. By this way, correct needle positioning can cause real difficulties and it could be sometimes more difficult to position needles along the axis of the mesenteric vessels. It also does not allow a peritoneal cavity assessment. All of the procedures need to be carried out under general anesthesia, synchronized with an electrocardiogram and under total muscle relaxation [11]. The size of the
Main differences between thermal ablation methods and irreversible electroporation (IE).
Effects
Hyperthermia methods (RF and MW)
IE
Target tissue damage Protein damage Connective tissue Nerves and vessels Heat sink effecta
Coagulation necrosis Yes Coagulation Coagulation Variable
Cell membrane No No Theoretically not coagulated No
RF: radiofrequency; MW: microwave. a The Heat sink effect describes a reduction in temperature due to vascular cooling (at 37 ◦ C) in the treatment area, potentially reducing the effectiveness of treatment.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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Irreversible electroporation for locally advanced pancreatic cancer voltage used carries a risk of muscle contractions if the muscles are not totally relaxed. Similarly, the current must be delivered during cardiac diastole to avoid any interaction with myocardial contraction and possible dysrhythmias. The contraindications of the technique are therefore arrhythmias, heart failure and active coronary disease. Electroporation has not been shown to cause cerebral stimulation but epilepsy is still a contraindication in principle. In addition, IE also cannot be used on the pancreas in patients with a metal, particularly biliary, stent because of the risk of electric arcing between the needle and the metal of the stent. Delivery of the IE current is monitored by the generator, which measures tissue electrical conductivity during treatment. The treatment time depends on the number of electrodes positioned, heart rate and possibly on a need to reposition the needles in order to increase target volume. Regardless of the protocol commonly used, the procedure takes at least two hours. After IE, gas is commonly seen in the treatment area due to local electrolysis (separation between hydrogen from oxygen from water molecules). A hypointense lesion has been described on MRI sixty minutes after electroporation and may represent the ablated area. A fall in positron emission tomography uptake has been described a month after the procedure [12]. Clinically, patients classically experience abdominal pains for 1 to 3 days after treatment due to an acute slight pancreatitis with small laboratory changes but occasionally, cases of clinical moderate acute pancreatitis may occur [13]. More severe complications have been described, including mesenteric or portal thrombosis, pancreatic fistula, a biliary leak, duodenal or transverse colon perforation or hemorrhage from the superior mesenteric artery. Regardless of these complications or their severity, these are minor compared to the complication rate with pancreatic surgery, particularly involving the duodenum and neck of pancreas. The overall complication rate is reported to be 13% regardless of technique: approximately 15% for the peroperative approach and 9% for the percutaneous approach. Overall mortality is estimated to be 2%: 3% for the peroperative approach and 0% for the percutaneous approach. Deaths are
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due mostly to the risk of duodenal or pancreatic rupture or portal vein thrombosis [12].
Clinical indication and results IE is currently used to treat tumors which are not accessible to a conventional ablation technique because of the risk of side effects. It has been assessed on small non-randomized cohorts in liver, kidney and prostate cancer [13—16]. In pancreatic cancer, IE has been tested on patients with locally advanced stage III non-surgical lesions involving the head, body or tail of the pancreas. Several authors have also described the use of IE to increase surgical resection margins [17] or as adjuvant treatment [18]. Its major indication for the pancreas, however, is still in borderline or locally advanced tumors without metastatic spread [19—21]. It is particularly important to carry out a liver MRI before IE in order to be sure that the patient does not have any liver lesions. Some groups also propose 3 months of chemotherapy prior to treatment, which excludes rapid growth of remote metastases [22—24]. The initial results have been obtained from case studies or small series [17,25]. The largest study which has currently been published is the study conducted by Martin et al. which described a multicenter series of 200 cases [26] and reported increased survival in the group treated with electroporation compared to a control group treated with chemotherapy (20 months compared to 13 months), which is similar to survival in patients treated surgically. Nineteen percent of these patients in this study developed a complication, median severity grade II and two patients died as a result of treatment. This study does however have its limitations: the inclusion criteria were not precisely defined and both the patients and treatments given were not consistent. Nevertheless, it is the largest published series and does appear to be extremely promising. One single prospective trial, the IRECAP trial, is currently open in France and is including patients with locally advanced disease. The primary endpoint of this trial is the R0 resection rate. The case of a female patient treated is illustrated in Figs. 1—5.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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Figure 1. Initial tumor assessment. The lesion spreads the origin of the hepatic artery (a) and its junction with the spleno-mesenteric artery, which leads to vascular stenosis (b) (arrows); c: invasion of the hepatic vascular pedicle (arrows); d, e and f show VRT volume reconstructions showing the vascular relationships with the tumor; d: mass (arrow) and adjacent anatomical structures; e: stenosis of the spleno-mesaraic junction; f: reconstruction of the portal stenosis. The staging assessment (not shown) was negative (normal liver MRI and chest and pelvic CT). The tumor was therefore classified as locally advanced.
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Figure 2. After 3 months of chemotherapy by folfirinox, computed tomography (CT) showed a stable disease. Electroporation was carried out in order to treat the local vascular extension which was not accessible to surgery; a: two electrodes positioned in the lower part of the tumor extension. Two other electrodes were positioned higher up to surround the junction of the spleno-mesenteric and hepatic arteries (b: sagittal oblique MRP reconstruction showing the position of the 4 needles around the target area); c: the post-procedure CT scans: gas (arrow) due to electrolysis is present in the electroporation area.
Figure 3. CT scan performed at 1 day showing extensive inflammation around the treatment area. The patient developed abdominal pain (score 4 out of 10) and serum lipase was 3.5 times the upper limit of normal, consistent with acute pancreatitis. She recovered without treatment over 3 days.
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Figure 4. CT scan performed at 1 month showing that the stenosis of the spleno-mesenteric junction is stable overall (a). Note persistence of tissue around the common hepatic artery. It is difficult to know whether or not this is viable tumor tissue (b, arrows).
Figure 5. The patient underwent surgery with cephalic duodenopancreatectomy 4 months after the electroporation procedure. The initial vascular invasion was left in situ and the perivascular biopsies taken during the procedure were negative for adenocarcinoma. The resection was classified as R1 on the specimen (microscopic residual disease). The decision was taken to give six months of chemotherapy with folfirinox. The figure shows the check 24 months after electroporation. The infiltration of the common hepatic artery is still present (a) (arrow) and was interpreted as being stable compared to the checks at 12 and 18 months. Lung nodules (b) have appeared on a repeat examination at 24 months and are interpreted as lung secondary nodules (arrows), classifying the disease as progressive.
Conclusion
Clinical case
Electroporation is bringing new hopes in the treatment of non-metastatic locally advanced pancreatic cancer. Most of the studies on efficacy and safety of this method are based on non-randomized series but have shown that electroporation is promising in terms of overall patient survival. It is, nevertheless, an expensive technique with risks of complications and an associated mortality rate of 1%. It therefore still needs to be validated in large, randomized, prospective series.
A 55-year-old man with hypercholesterolemia presented with painless jaundice. Final diagnosis was a pancreatic adenocarcinoma with invasion of the main hepatic artery and portal vein over a length of approximately 3 cm. A metal stent was inserted to treat the jaundice and the patient’s case was presented to the gastroenterology multidisciplinary team meeting. You are asked for your opinion.
Take-home messages • Irreversible electroporation causes cellular apoptosis by interfering with intracellular electrolyte balance by opening several holes in the cell membranes and therefore cannot be considered as a thermal coagulation technique. • The initial results of irreversible electroporation for the treatment of pancreatic cancer are promising. • Electroporation is a new tumor ablation technique, which needs further evaluation.
Questions 1. A chest, abdominal and pelvic CT is normal apart from the pancreatic mass. Which imaging investigation is essential in order to classify the disease as nonmetastatic? A. Bone scintigraphy. B. Cerebral MRI. C. Hepatic contrast ultrasound. D. Hepatic MRI. E. Choline PET-CT.
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Irreversible electroporation for locally advanced pancreatic cancer 2. The patient asks you for electroporation as he has read on the Internet that it is beneficial. What would you say to him as a response about this treatment? A. It is a new technique which has not been validated scientifically. B. The treatment should ideally be given in a research trial. C. All oncology centers are equipped with the technique in France. D. It is fully reimbursed in France because of the patent’s long-term benefits. E. Electroporation can be replaced by microwave ablation in this situation. 3. Which of the statements below about irreversible electroporation are true? A. It is a thermal ablation technique. B. It is a technique which preserves the vessel, duct and nerve structures. C. Treatment requires a single needle to be inserted. D. Cardiac dysrhythmias are a contraindication to the technique. E. Electroporation can be carried out under local anesthesia. 4. What is the contraindication to possible IE in this patient? A. Hypercholesterolemia. B. Arterial hypertension. C. The metal biliary stent. D. The persistent jaundice. E. Involvement of 3 cm along the portal vein.
Answers (1) D. Ten percent of patients without a visible liver lesion on a chest, abdominal and pelvic CT have secondary liver lesions. (2) A, B. (3) B, D. (4) C. There is a risk of electric arcing and therefore, of burns between the needle and the stent. The stent therefore needs to be removed, if possible, before any treatment. If the stent is not removable, the treatment by IR should be contraindicated.
Acknowledgements The authors would like to thank Mr Michel Rousseau (angiodynamics) for his useful support during each procedure of Electroporation.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Rombouts SJ, Vogel JA, van Santvoort HC, van Lienden KP, van Hillegersberg R, Busch OR, et al. Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg 2015;102:182—93.
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[2] Sugar IP, Neumann E. Stochastic model for electric fieldinduced membrane pores: electroporation. Biophys Chem 1984;19:211—25. [3] Davalos RV, Mir IL, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng 2005;33:223—31. [4] Heger M, van der Wal AC, Storm G, van Gemert MJ. Potential therapeutic benefits stemming from the thermal nature of irreversible electroporation of solid cancers. Hepatobiliary Pancreat Dis Int 2015;14:331—3. [5] Petrishia A, Sasikala M. Molecular simulation of cell membrane deformation by picosecond intense electric pulse. J Membr Biol 2015;248:1015—20. [6] Seror O. Ablative therapies: advantages and disadvantages of radiofrequency, cryotherapy, microwave and electroporation methods, or how to choose the right method for an individual patient? Diagn Interv Imaging 2015;96:617—24. [7] Yarmush ML, Golberg A, Sersa G, Kotnik T, Miklavcic D. Electroporation-based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng 2014;16:295—320. [8] Philips P, Li Y, Li S, St Hill CR, Martin RC. Efficacy of irreversible electroporation in human pancreatic adenocarcinoma: advanced murine model. Mol Ther Methods Clin Dev 2015;2:15001. [9] Fritz S, Sommer CM, Vollherbst D, Wachter MF, Longerich T, Sachsenmeier M, et al. Irreversible electroporation of the pancreas is feasible and safe in a porcine survival model. Pancreas 2015;44:791—8. [10] Scheffer HJ, Melenhorst MC, Vogel JA, van Tilborg AA, Nielsen K, Kazemier G, et al. Percutaneous irreversible electroporation of locally advanced pancreatic carcinoma using the dorsal approach: a case report. Cardiovasc Intervent Radiol 2015;38:760—5. [11] Martin RC, Schwartz E, Adams J, Farah I, Derhake BM. Intraoperative anesthesia management in patients undergoing surgical irreversible electroporation of the pancreas, liver, kidney, and retroperitoneal tumors. Anesth Pain Med 2015;5:e22786. [12] Wagstaff PG, Buijs M, van den Bos W, de Bruin DM, Zondervan PJ, de la Rosette JJ, et al. Irreversible electroporation: state of the art. Onco Targets Ther 2016;9:2437—46. [13] Wagstaff PG, de Bruin DM, Zondervan PJ, Savci Heijink CD, Engelbrecht MR, van Delden OM, et al. The efficacy and safety of irreversible electroporation for the ablation of renal masses: a prospective, human, in vivo study protocol. BMC Cancer 2015;15:165. [14] Wendler JJ, Ganzer R, Hadaschik B, Blana A, Henkel T, Kohrmann KU, et al. Irreversible electroporation: current value for focal treatment of prostate cancer. Urologe A 2015;54:854—62. [15] Trimmer CK, Khosla A, Morgan M, Stephenson SL, Ozayar A, Cadeddu JA. Minimally invasive percutaneous treatment of small renal tumors with irreversible electroporation: a singlecenter experience. J Vasc Interv Radiol 2015;26:1465—71. [16] Sugimoto K, Moriyasu F, Kobayashi Y, Saito K, Takeuchi H, Ogawa S, et al. Irreversible electroporation for nonthermal tumor ablation in patients with hepatocellular carcinoma: initial clinical experience in Japan. Jpn J Radiol 2015;33:424—32. [17] Paiella S, Butturini G, Frigerio I, Salvia R, Armatura G, Bacchion M, et al. Safety and feasibility of irreversible electroporation (IRE) in patients with locally advanced pancreatic cancer: results of a prospective study. Dig Surg 2015;32:90—7. [18] Belfiore MP, Ronza FM, Romano F, Ianniello GP, De Lucia G, Gallo C, et al. Percutaneous CT-guided irreversible electroporation followed by chemotherapy as a novel neoadjuvant protocol in locally advanced pancreatic cancer: our preliminary experience. Int J Surg 2015;21:S34—9. [19] Lambert L, Horejs J, Krska Z, Hoskovec D, Petruzelka L, Krechler T, et al. Treatment of locally advanced pancreatic cancer
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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by percutaneous and intraoperative irreversible electroporation: general hospital cancer center experience. Neoplasma 2016;63:269—73. Martin RC. Irreversible electroporation of locally advanced pancreatic neck/body adenocarcinoma. J Gastrointest Oncol 2015;6:329—35. Weiss MJ, Wolfgang CL. Irreversible electroporation: a novel therapy for stage III pancreatic cancer. Adv Surg 2014;48:253—8. Martin RC. Use of irreversible electroporation in unresectable pancreatic cancer. Hepatobiliary Surg Nutr 2015;4:211—5. Paiella S, Salvia R, Ramera M, Girelli R, Frigerio I, Giardino A, et al. Local ablative strategies for ductal pancreatic cancer
(radiofrequency ablation, irreversible electroporation): a review. Gastroenterol Res Pract 2016;2016:4508376. [24] Linecker M, Pfammatter T, Kambakamba P, DeOliveira ML. Ablation strategies for locally advanced pancreatic cancer. Dig Surg 2016;33:351—9. [25] Trueba-Arguinarena FJ, de Prado-Otero DS, Poves-Alvarez R. Pancreatic adenocarcinoma treated with irreversible electroporation case report: first experience and outcome. Medicine (Baltimore) 2015;94:e946. [26] Martin RC, Kwon D, Chalikonda S, Sellers M, Kotz E, Scoggins C, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg 2015;262:486—94.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
ARTICLE IN PRESS
DIII-873; No. of Pages 8
Diagnostic and Interventional Imaging (2016) xxx, xxx—xxx
CONTINUING EDUCATION PROGRAM: FOCUS. . .
Irreversible electroporation for locally advanced pancreatic cancer J.-P. Tasu a,∗, G. Vesselle a, G. Herpe a, J.-P. Richer b,c, S. Boucecbi a, S. Vélasco a, M. Carretier c, B. Debeane d, D. Tougeron e a
Department of Imaging, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France b Laboratory of Simulations and Anatomy Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France c Abdominal Surgery Department, University of Poitiers, rue de la Milétrie, 86000 Poitiers, France d Anaesthesiology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France e Abdominal Oncology Department, University Hospital of Poitiers, rue de la Milétrie, 86000 Poitiers, France
KEYWORDS Irreversible electroporation; Pancreas; Pancreatic adenocarcinoma; Cancer; Interventional radiology
Abstract Pancreatic adenocarcinoma is one of the solid cancers associated with the poorest prognosis; the only curative treatment remains surgical resection but in most cases, this treatment is not possible because of distant metastasis or local extension. Irreversible electroporation is a new tumor ablation technique, which provides cellular apoptosis without any thermal coagulation effect. This technique helps preserve the ducts, vessels or nerves located in the treatment area. This article reviews the current knowledge regarding the use of electroporation for the treatment of pancreatic adenocarcinoma. © 2016 Published by Elsevier Masson SAS on behalf of Editions franc ¸aises de radiologie.
∗ Corresponding author at: Département d’imagerie diagnostique, fonctionnelle et thérapeutique, CHU de Poitiers, rue de la Milétrie, 86000 Poitiers France. E-mail address: [email protected] (J.-P. Tasu).
http://dx.doi.org/10.1016/j.diii.2016.10.001 2211-5684/© 2016 Published by Elsevier Masson SAS on behalf of Editions franc ¸aises de radiologie.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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Ninety-five percent of pancreatic cancers are adenocarcinomas. The diagnosis is still usually made at a late stage when the patient present abdominal pain, jaundice or deterioration in general health. Consequently, at the time of diagnosis, only 15% of patients have surgically resectable disease whereas 85% of patients have a locally advanced or metastatic disease and are therefore beyond the reach of surgery. For those patients who are not amenable to surgical resection, the 5-year-survival rate falls to less than 5%. For patients who can be operated, the 5-year-survival rate is around 20%. Whilst everyone understands the concept of metastatic disease, locally advanced disease is more specific to the pancreas. Considering the retroperitoneal situation of the pancreatic gland, the tumor tends to spread quickly the superior mesenteric and/or hepatic artery and/or coeliac trunk and/or junction of the mesenteric and portal vessels. In this situation, the only treatment option is a combination of chemotherapy with gemcitabine or folfirinox, palliative surgery (biliary and gastric shunting) and/or radiotherapy. In view of the limited treatment options, irreversible electroporation (IE) has recently been proposed to treat locally advanced pancreatic cancer [1]. IE has been around for over 30 years [2] when it was initially used to destroy microorganisms or introduce drugs into cells in in vitro cell cultures. It has more recently emerged as an effective method to destroy tissue [3]. Above all, however, IE can destroy cells located into a target area wherein collagen architecture of the vascular, biliary or neuronal structures is preserved. [4]. This article reviews the current knowledge about the use of electroporation to treat pancreatic adenocarcinoma.
Mechanisms of cell death from electroporation IE uses very high voltage current, maximum 3,000 volts, delivered in microseconds (70 to 80 microsecs) pulses. These ultrashort electrical pulses create multiple microscopic holes within the cell membrane resulting in irreversible cell damage due to interference with homeostatic mechanisms [5]. Apoptosis does not occur immediately but only after a few days. The method is therefore completely different from thermal ablation techniques producing heat (radiofrequency or microwave) or cold (cryotherapy); indeed, IE does not cause coagulation necrosis [6,7]. A summary of
Table 1
the major differences between thermal and electroporation methods are shown in Table 1. Histologically, early changes occur in the target tissue as early as 30 minutes although the macroscopic changes are slower. Normal tissue regenerates after several weeks and the collagen structures preserved by IE are used as ‘‘guides’’ for endothelial or duct cells restoring a normal ductal or vascular architecture over a few weeks. This has been clearly shown in a mouse model of pancreatic cancer [8] and confirmed on a pig model [9].
Practical aspects of treatment The aim of treatment is to surround the tumor with two to six needles [10]. The number of needles chosen depends on the size and shape of the target lesion. The distance between each needle should not be over 2.5 cm and not under 1 cm and all of the needles must be positioned in parallel. It is occasionally difficult to correctly placed needles, which requires previous experience with ablation techniques, and if possible with multipolar techniques. A precise guidance method is also recommended and in our view, CT achieves this better than ultrasound although there are numerous descriptions of ultrasound guidance in the literature. The other purpose of guidance is to avoid puncturing at risk organs although a transgastric or transhepatic approach may be used as the needles are thin (22 Gauge). In terms of vascular structures, the manufacturer recommends the needle be positioned at least 2 mm away from large vessels in order to avoid any risk of damage and the risks of burns as it has been shown that the temperature may reach 62.8 ◦ C in a radius of approximately 0.5 cm around the needle tip. Treatment can be delivered in different approaches. Surgical groups commonly prefer a peroperative approach, which allows to check the peritoneal cavity and to exclude possible carcinomatosis. This approach also has the advantage of allowing the needles to be positioned parallel to the mesenteric vessel which is the best approach in cases of mesenteric involvement. A percutaneous approach has also been proposed, which has two major advantages of being less invasive and enabling CT guidance. By this way, correct needle positioning can cause real difficulties and it could be sometimes more difficult to position needles along the axis of the mesenteric vessels. It also does not allow a peritoneal cavity assessment. All of the procedures need to be carried out under general anesthesia, synchronized with an electrocardiogram and under total muscle relaxation [11]. The size of the
Main differences between thermal ablation methods and irreversible electroporation (IE).
Effects
Hyperthermia methods (RF and MW)
IE
Target tissue damage Protein damage Connective tissue Nerves and vessels Heat sink effecta
Coagulation necrosis Yes Coagulation Coagulation Variable
Cell membrane No No Theoretically not coagulated No
RF: radiofrequency; MW: microwave. a The Heat sink effect describes a reduction in temperature due to vascular cooling (at 37 ◦ C) in the treatment area, potentially reducing the effectiveness of treatment.
Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001
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Irreversible electroporation for locally advanced pancreatic cancer voltage used carries a risk of muscle contractions if the muscles are not totally relaxed. Similarly, the current must be delivered during cardiac diastole to avoid any interaction with myocardial contraction and possible dysrhythmias. The contraindications of the technique are therefore arrhythmias, heart failure and active coronary disease. Electroporation has not been shown to cause cerebral stimulation but epilepsy is still a contraindication in principle. In addition, IE also cannot be used on the pancreas in patients with a metal, particularly biliary, stent because of the risk of electric arcing between the needle and the metal of the stent. Delivery of the IE current is monitored by the generator, which measures tissue electrical conductivity during treatment. The treatment time depends on the number of electrodes positioned, heart rate and possibly on a need to reposition the needles in order to increase target volume. Regardless of the protocol commonly used, the procedure takes at least two hours. After IE, gas is commonly seen in the treatment area due to local electrolysis (separation between hydrogen from oxygen from water molecules). A hypointense lesion has been described on MRI sixty minutes after electroporation and may represent the ablated area. A fall in positron emission tomography uptake has been described a month after the procedure [12]. Clinically, patients classically experience abdominal pains for 1 to 3 days after treatment due to an acute slight pancreatitis with small laboratory changes but occasionally, cases of clinical moderate acute pancreatitis may occur [13]. More severe complications have been described, including mesenteric or portal thrombosis, pancreatic fistula, a biliary leak, duodenal or transverse colon perforation or hemorrhage from the superior mesenteric artery. Regardless of these complications or their severity, these are minor compared to the complication rate with pancreatic surgery, particularly involving the duodenum and neck of pancreas. The overall complication rate is reported to be 13% regardless of technique: approximately 15% for the peroperative approach and 9% for the percutaneous approach. Overall mortality is estimated to be 2%: 3% for the peroperative approach and 0% for the percutaneous approach. Deaths are
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due mostly to the risk of duodenal or pancreatic rupture or portal vein thrombosis [12].
Clinical indication and results IE is currently used to treat tumors which are not accessible to a conventional ablation technique because of the risk of side effects. It has been assessed on small non-randomized cohorts in liver, kidney and prostate cancer [13—16]. In pancreatic cancer, IE has been tested on patients with locally advanced stage III non-surgical lesions involving the head, body or tail of the pancreas. Several authors have also described the use of IE to increase surgical resection margins [17] or as adjuvant treatment [18]. Its major indication for the pancreas, however, is still in borderline or locally advanced tumors without metastatic spread [19—21]. It is particularly important to carry out a liver MRI before IE in order to be sure that the patient does not have any liver lesions. Some groups also propose 3 months of chemotherapy prior to treatment, which excludes rapid growth of remote metastases [22—24]. The initial results have been obtained from case studies or small series [17,25]. The largest study which has currently been published is the study conducted by Martin et al. which described a multicenter series of 200 cases [26] and reported increased survival in the group treated with electroporation compared to a control group treated with chemotherapy (20 months compared to 13 months), which is similar to survival in patients treated surgically. Nineteen percent of these patients in this study developed a complication, median severity grade II and two patients died as a result of treatment. This study does however have its limitations: the inclusion criteria were not precisely defined and both the patients and treatments given were not consistent. Nevertheless, it is the largest published series and does appear to be extremely promising. One single prospective trial, the IRECAP trial, is currently open in France and is including patients with locally advanced disease. The primary endpoint of this trial is the R0 resection rate. The case of a female patient treated is illustrated in Figs. 1—5.
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Figure 1. Initial tumor assessment. The lesion spreads the origin of the hepatic artery (a) and its junction with the spleno-mesenteric artery, which leads to vascular stenosis (b) (arrows); c: invasion of the hepatic vascular pedicle (arrows); d, e and f show VRT volume reconstructions showing the vascular relationships with the tumor; d: mass (arrow) and adjacent anatomical structures; e: stenosis of the spleno-mesaraic junction; f: reconstruction of the portal stenosis. The staging assessment (not shown) was negative (normal liver MRI and chest and pelvic CT). The tumor was therefore classified as locally advanced.
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Figure 2. After 3 months of chemotherapy by folfirinox, computed tomography (CT) showed a stable disease. Electroporation was carried out in order to treat the local vascular extension which was not accessible to surgery; a: two electrodes positioned in the lower part of the tumor extension. Two other electrodes were positioned higher up to surround the junction of the spleno-mesenteric and hepatic arteries (b: sagittal oblique MRP reconstruction showing the position of the 4 needles around the target area); c: the post-procedure CT scans: gas (arrow) due to electrolysis is present in the electroporation area.
Figure 3. CT scan performed at 1 day showing extensive inflammation around the treatment area. The patient developed abdominal pain (score 4 out of 10) and serum lipase was 3.5 times the upper limit of normal, consistent with acute pancreatitis. She recovered without treatment over 3 days.
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Figure 4. CT scan performed at 1 month showing that the stenosis of the spleno-mesenteric junction is stable overall (a). Note persistence of tissue around the common hepatic artery. It is difficult to know whether or not this is viable tumor tissue (b, arrows).
Figure 5. The patient underwent surgery with cephalic duodenopancreatectomy 4 months after the electroporation procedure. The initial vascular invasion was left in situ and the perivascular biopsies taken during the procedure were negative for adenocarcinoma. The resection was classified as R1 on the specimen (microscopic residual disease). The decision was taken to give six months of chemotherapy with folfirinox. The figure shows the check 24 months after electroporation. The infiltration of the common hepatic artery is still present (a) (arrow) and was interpreted as being stable compared to the checks at 12 and 18 months. Lung nodules (b) have appeared on a repeat examination at 24 months and are interpreted as lung secondary nodules (arrows), classifying the disease as progressive.
Conclusion
Clinical case
Electroporation is bringing new hopes in the treatment of non-metastatic locally advanced pancreatic cancer. Most of the studies on efficacy and safety of this method are based on non-randomized series but have shown that electroporation is promising in terms of overall patient survival. It is, nevertheless, an expensive technique with risks of complications and an associated mortality rate of 1%. It therefore still needs to be validated in large, randomized, prospective series.
A 55-year-old man with hypercholesterolemia presented with painless jaundice. Final diagnosis was a pancreatic adenocarcinoma with invasion of the main hepatic artery and portal vein over a length of approximately 3 cm. A metal stent was inserted to treat the jaundice and the patient’s case was presented to the gastroenterology multidisciplinary team meeting. You are asked for your opinion.
Take-home messages • Irreversible electroporation causes cellular apoptosis by interfering with intracellular electrolyte balance by opening several holes in the cell membranes and therefore cannot be considered as a thermal coagulation technique. • The initial results of irreversible electroporation for the treatment of pancreatic cancer are promising. • Electroporation is a new tumor ablation technique, which needs further evaluation.
Questions 1. A chest, abdominal and pelvic CT is normal apart from the pancreatic mass. Which imaging investigation is essential in order to classify the disease as nonmetastatic? A. Bone scintigraphy. B. Cerebral MRI. C. Hepatic contrast ultrasound. D. Hepatic MRI. E. Choline PET-CT.
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Irreversible electroporation for locally advanced pancreatic cancer 2. The patient asks you for electroporation as he has read on the Internet that it is beneficial. What would you say to him as a response about this treatment? A. It is a new technique which has not been validated scientifically. B. The treatment should ideally be given in a research trial. C. All oncology centers are equipped with the technique in France. D. It is fully reimbursed in France because of the patent’s long-term benefits. E. Electroporation can be replaced by microwave ablation in this situation. 3. Which of the statements below about irreversible electroporation are true? A. It is a thermal ablation technique. B. It is a technique which preserves the vessel, duct and nerve structures. C. Treatment requires a single needle to be inserted. D. Cardiac dysrhythmias are a contraindication to the technique. E. Electroporation can be carried out under local anesthesia. 4. What is the contraindication to possible IE in this patient? A. Hypercholesterolemia. B. Arterial hypertension. C. The metal biliary stent. D. The persistent jaundice. E. Involvement of 3 cm along the portal vein.
Answers (1) D. Ten percent of patients without a visible liver lesion on a chest, abdominal and pelvic CT have secondary liver lesions. (2) A, B. (3) B, D. (4) C. There is a risk of electric arcing and therefore, of burns between the needle and the stent. The stent therefore needs to be removed, if possible, before any treatment. If the stent is not removable, the treatment by IR should be contraindicated.
Acknowledgements The authors would like to thank Mr Michel Rousseau (angiodynamics) for his useful support during each procedure of Electroporation.
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Tasu J-P, et al. Irreversible electroporation for locally advanced pancreatic cancer. Diagnostic and Interventional Imaging (2016), http://dx.doi.org/10.1016/j.diii.2016.10.001