Cardiovasc Intervent Radiol DOI 10.1007/s00270-014-0950-x
CASE REPORT
Percutaneous Irreversible Electroporation of Locally Advanced Pancreatic Carcinoma Using the Dorsal Approach: A Case Report Hester J. Scheffer • Marleen C. A. M. Melenhorst • Jantien A. Vogel • Aukje A. J. M. van Tilborg • Karin Nielsen • Geert Kazemier • Martijn R. Meijerink
Received: 8 May 2014 / Accepted: 9 June 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2014
Abstract Irreversible electroporation (IRE) is a novel image-guided ablation technique that is increasingly used to treat locally advanced pancreatic carcinoma (LAPC). We describe a 67-year-old male patient with a 5 cm stage III pancreatic tumor who was referred for IRE. Because the ventral approach for electrode placement was considered dangerous due to vicinity of the tumor to collateral vessels and duodenum, the dorsal approach was chosen. Under CTguidance, six electrodes were advanced in the tumor, approaching paravertebrally alongside the aorta and inferior vena cava. Ablation was performed without complications. This case describes that when ventral electrode
H. J. Scheffer (&) M. C. A. M. Melenhorst A. A. J. M. van Tilborg M. R. Meijerink Department of Radiology and Nuclear Medicine, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands e-mail: [email protected] M. C. A. M. Melenhorst e-mail: [email protected] A. A. J. M. van Tilborg e-mail: [email protected] M. R. Meijerink e-mail: [email protected] J. A. Vogel Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected] K. Nielsen G. Kazemier Department of Surgery, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands e-mail: [email protected] G. Kazemier e-mail: [email protected]
placement for pancreatic IRE is impaired, the dorsal approach could be considered alternatively. Keywords Irreversible electroporation (IRE) Electroporation/methods Pancreatic cancer/ pancreatic neoplasms Tumor ablation/percutaneous Ablation Techniques/adverse effects
Introduction Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. It has a dismal prognosis, with a 5-year survival rate of 6 % and a case-fatality rate among the highest of any malignancy. Unfortunately, at the time of diagnosis only 15–20 % of patients are eligible for surgical resection with curative intent. Forty percent have locally advanced pancreatic carcinoma (LAPC) (stage III; AJCC TNM Staging System for Pancreatic Cancer). For these patients, chemotherapy or chemoradiation with palliative intent is the treatment of choice, leading to a modest increase in survival and improved quality of life. However, with a median survival of 6–11 months, the prognosis remains extremely poor [1]. The past two decades, image-guided tumor ablation has received substantial attention when surgical options are precluded. The aim of pancreatic ablation is cytoreduction, leading to better symptom palliation, improved quality-of-life and prolonged survival. However, due to the vulnerability of pancreatic tissue and its vicinity to critical structures, local treatment in this area risks pancreatitis and injury of duodenum, vessels and common bile duct. Thermal ablation using radiofrequency or microwave ablation to treat LAPC is therefore associated with a high complication rate, but without a clear benefit in survival [2].
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Recently, irreversible electroporation (IRE) has been introduced as a novel ablation technique. With IRE, multiple short, high-voltage electrical pulses are delivered to malignant tissue. The electrical pulses destabilize the existing cellular membrane potential and lead to the formation of ‘nano-pores’ in the lipid bilayer, irreversibly damaging the cell’s homeostatic mechanism which ultimately leads to cell death through apoptosis [3]. IRE only affects the membranes of living cells, whilst preserving the extracellular matrix constituents that are responsible for the patency of major vascular and ductal structures and other vulnerable tissues, without the generation of heat [4]. With these characteristics, IRE may be suitable to treat LAPC. Several studies have investigated the safety and efficacy of open as well as percutaneous IRE using the ventral approach for this indication. Although results are still preliminary, the technique seems to be tolerated well and early results of efficacy appear promising [5–7]. The shortest pathway and therefore the most commonly used route for CT-guided ablation of lesions in the pancreatic head is the ventral, or anterior, approach. However, in certain cases it can be extremely challenging to reach the desired position for all electrodes without having to traverse overlying intestinal, ductal and vascular structures. In this case the conventional ventral epigastric approach of needle placement can be complicated and concerns about the safety of the procedure arise. Here, we present a case of percutaneous IRE for LAPC using the dorsal approach for electrode placement.
Case Report A 67-year-old male patient presented with intermittent abdominal pain. Computed tomography (CT) imaging showed a 5.0 9 5.0 9 4.2 cm mass in the head and corpus of the pancreas with [180° encasement of the celiac axis, splenic and hepatic artery, and abutment of the superior mesenteric artery of 180°. The main portal vein was completely obliterated, which had led to extensive collateral vessel formation ventrally from the tumor (Fig. 1A, B). The tumor was also located in proximity to the duodenum. There were no signs of lymph nodal or metastatic spread. A transgastric biopsy of the lesion confirmed the diagnosis pancreatic adenocarcinoma. Due to the vascular encasement the tumor was considered surgically incurable (stage III). The patient was referred to our center for irreversible electroporation of the lesion as part of the prospective PANFIRE-study (clinicaltrials.gov registration number NCT01939665) and gave written informed consent. Given the vicinity of the tumor to the common bile duct, a plastic retrievable biliary endoprosthesis was placed via endoscopic retrograde cholangiopancreaticography as a
123
precautionary and protective measure prior to the procedure. Because of the extensive network of portal collaterals that had developed anteriorly from the tumor and its vicinity to the duodenum, ventral needle placement was considered to be associated with a substantial risk of damaging these structures. Therefore, we opted for a dorsal approach for needle placement. The patient was put under general anesthesia in the prone position. A contrast-enhanced (CE) CT scan (Sensation 64 slice MDCT, Siemens, Erlangen, Germany) in the arterial (triggered) and portal venous phase (70 s after contrast injection) was made to determine the threedimensional measurements of the tumor and its proximity to other structures. Size and shape, including a 5 mm margin, determines the number and configuration of the electrodes, which must cover the full extent of the tumor. The distance between electrode pairs should be 20 mm (±5 mm), which is considered the most effective treatment distance at which the ablation zone has an oval shape [8]. A total of six monopolar needle electrodes (NanoKnife, AngioDynamics, Latham, New York) were advanced into the central part and in the outer border of the cranial and caudal part of the tumor, approaching paravertebrally alongside the aorta and inferior vena cava under CTguidance (Fig. 1C and Fig. 2). Due to the necessity to place the needles on either side of the vertebral column, exact parallel positioning of all electrode pairs was not feasible. The active working length of the electrodes was set at 2 cm. Eight vectors for pulse delivery were chosen (Fig. 3A, C). All pulses were delivered in the absolute refractory period of the heart with use of electrocardiographic synchronization (Accusync, Model 72, Milford, Connecticut) to avoid the induction of cardiac arrhythmias and with deep muscle paralysis using additional rocuronium to prevent generalized muscle contractions. First, ten test pulses of 1500 V/cm with a pulse length of 90 lsec were delivered for each electrode pair to verify the delivered current, which must lie between 20–40 Amps. Subsequently, 80 treatment pulses were delivered along each vector. High current between electrodes 3 and 5 led to energy shutdown twice. With adjustment of the voltage and pulse length to 70 lsec the ablation was continued successfully. After a 2 cm pullback of all needles, an overlapping ablation was performed with use of the similar protocol. To cover the lateral parts of the tumor, the most cranial and caudal electrodes (electrodes 1 and 5) were repositioned to the lateral left and right tumor border approaching from the left paravertebral region. Next, another series of 90 pulses between four electrode pairs (Fig. 2 and Fig. 3A) was delivered. Mean delivered current of all electrodes was 35 Amps (SD 5.7). After removal of all needles, CECT showed a spastic but patent hepatic and splenic artery. There were no signs for early complications
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Fig. 1 A Axial contrast enhanced (CE) CT image of the pancreatic tumor prior to IRE with collateral vessels anteriorly (arrow). B Axial CE MRI image (T1 with fat suppression) of the tumor which appears slightly hypovascular compared to normal pancreatic tissue. C Axial CT image of two electrodes placed alongside the vertebral column. D Coronal view of fused CT series depicting all electrode positions before and after needle reposition. Close proximity of the duodenum
(D) to the tumor. E Axial CECT image obtained ten minutes after IRE demonstrating air within the ablated area but no complications. F Axial CE MRI image (T1 with fat suppression) with a typical ablation zone showing a non-enhancing center and a peripheral enhancing rim. G Axial CECT image 2 weeks after IRE showing a hypodense tumor center. H Axial CE MRI (T1 with fat suppression) 2 weeks post IRE depicting shrinkage of the ablation zone
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Fig. 2 3D image with electrodes placed within the tumor. Pink electrodes representing electrode position during the first ablation. Orange electrodes representing repositioned electrode 1 and 5 prior to the second ablation (marked with *). Biliary endoprosthesis in the common bile duct in situ (long arrow). Prominent pancreatic duct due to tumor obstruction (short arrow)
(Fig. 1E). The patient awakened uneventfully in the recovery unit and was transferred to the ward. The next day contrast enhanced magnetic resonance imaging (CE MRI) showed a typical ablation zone with a non-enhancing center and a peripheral hyperintense reactive rim (Fig. 1F). There was a moderate increase in lipase (from 11 to 86 U/L) and amylase (from 24 to 112 U/L) that normalized to 15 U/L and 20 U/L on the third day, respectively. Pain was managed well with oral acetaminophen and tramadol and continuous intravenous morphine and ketamine. On the fourth day post-IRE the patient was discharged with oral acetaminophen, tramadol and oxycodone. During the next two weeks he experienced moderate intermittent abdominal pain, loss of appetite and a subfebrile temperature (up to 38 °C). After 2 weeks, CT and MRI showed a decreased size of the ablated area with a hypovascular center and no signs of complications (Fig. 1G, H). In the following weeks the pain significantly decreased and the patient was able to reduce his pain medication to half the amount of what he was using prior to the treatment. At 3 months, the ablated area had further decreased in size. The patient resumed his normal daily activities and remains in followup.
Discussion The advantage of percutaneous ablation over ablation during laparotomy is the less invasive nature, which generally implies a lower risk for complications and faster recovery. However, using the ventral approach, intervening
123
structures like stomach and intestines can obstruct access to the lesions, which requires transgression of the gastrointestinal tract. Acute pancreatitis is an uncommon but severe complication of pancreatic biopsy. Because bowel transgression can potentially contaminate a sterile biopsy procedure, it is best avoided to preclude even a small risk of infection or leakage of bile and pancreatic juices [9]. In their series of 184 pancreatic biopsies Mueller et al. [10] found an 8 % risk of pancreatitis after transintestinal biopsy as opposed to a 1.3 % risk after normal biopsy. With IRE, multiple electrodes are inserted in the pancreas and remain in situ for a substantial period of time, so the risk of bowel transgression leading to pancreatitis and infection of the ablation zone can be considered higher. Another issue that can preclude the ventral approach is preexisting portal vein thrombosis with subsequent formation of collateral circulation vessels. Although uncommon, major hemorrhage with pancreatic biopsy resulting from the inadvertent puncture of mesenteric or pancreatic vessels has been reported [11]. To overcome abovementioned difficulties, alternative routes for pancreatic biopsies such as the transhepatic and transsplenic approach, have been reported [12]. Posterior transcaval and paracaval biopsy have also been investigated and have proven relatively safe [9]. In our case, we considered the posterior approach to have the lowest risk of complications. To the best of our knowledge, this approach for pancreatic IRE has not been previously described. Although the vertebrae impeded exact parallel positioning of the electrodes, we eventually succeeded to place all needles in the desired position with the required interelectrode distances and to properly deliver all planned pulses within the desired current range. The maximum allowed angulation as advised by the manufacturer is 20°, since beyond this angle the strength and distribution of the electric field could become unreliable. However, whether exceeding this angle can truly result in a less effective ablation has not been investigated. For the electrode pairs that were placed on the ipsilateral side of the vertebral column the largest angulation was 22°. To cover the full extent of the tumor, ablation was also performed between electrode pairs that traversed the spine on either side, with the midpoint of the active tips in a crossed position (Fig. 3B). The maximum angulation for these pairs was 62°. In clinical practice, a slight deviation from exact parallel electrode placement is common. It could be argued that as long as the distance between two electrodes remains between the required 1.5–2.5 cm over the entire length of the active tips, this should result in effective ablation. Still, validation of the consequence of out-of-plane electrode placement on the strength and distribution of the electric field is of great importance and should be a focus of future research on IRE.
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach Fig. 3 A Coronal view of fused CT series demonstrating all electrode pairs during the first (pink lines) and second ablation (orange lines) in proximity to the duodenum (D). B Electrode pair originating from either side of the spine, with the midpoint of the active tips in a crossed position. C Table with electrode pairs and corresponding distances and angles. Ablation between electrode 2 and 5 was not considered essential (distance 3.0 cm) since no tumor tissue was expected in this region
Current published data on safety and feasibility of IRE for LAPC is limited. One study investigating open IRE for locally advanced pancreatic tumors in patients who had undergone standard induction chemotherapy for a minimum of 4 months did show greater local palliation and potential improved overall survival (20 vs. 11 months, P = .03) compared to standard chemoradiation or chemotherapy regimens [6]. Percutaneous pancreatic IRE also seems relatively safe and feasible with the important additional benefit of providing a less invasive treatment option. The largest series has been reported by Narayanan et al. [7] who performed 14 procedures using the percutaneous ventral approach. No major (CTCAE grade C3) complications were observed and three minor complications occurred (pneumothorax, subcutaneous hematoma and mild pancreatitis). The observed palliation of pain after pancreatic IRE may be explained by a reduction of tumor load, diminishing pain caused by tumor obstruction or celiac plexus invasion. Theoretically, given the vicinity of the celiac plexus to pancreatic head tumors, the treatment may also induce a temporary or permanent celiac plexus block, which may further contribute to reduced pain perception. This would be a desirable side effect of the treatment.
Our imaging findings post-IRE are in concordance with the available literature, which describes that 24 h after IRE, T1-weighted CE MRI of the ablated region typically shows a non-enhancing center, surrounded by a hyper-intense reactive rim [13]. The radiologic ablation zone measurements show a high correlation with the histologically confirmed ablation zone in a study on IRE in rodent liver (P \ .001 for both T1- and T2-weighted measurements) [14] and could therefore be used as an indication for complete or incomplete ablation and for follow-up evaluation of clinical outcome. The increased uptake of contrast at the periphery of the ablated region may be due to an initial inflammatory response increasing metabolic activity at the targeted region as the cellular debris is removed from the targeted site. However, whether all tumor cells in this region have truly been destroyed must become evident during follow-up. In the hours after IRE, a margin of reversibly electroporated tissue exists between the ablation zone and the untreated tissue, where the electrical field strength remained below the critical threshold. The cell membranes of the cells in this zone are temporarily permeable during this period, allowing drugs such as chemotherapeutics to travel freely into the cells. Reversible electroporation has been
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
used for decades to promote the uptake of chemotherapy into the cell, a process known as electrochemotherapy. Capitalizing on this principle, the addition of systemic chemotherapy immediately after IRE could potentially eradicate marginal reversibly electroporated tumor cells, which would improve treatment effect [15]. This approach warrants further study and may contribute to the multidisciplinary treatment approach of cancer in the near future. In conclusion, this case report describes a technically successful IRE procedure of a locally advanced pancreatic carcinoma using the dorsal approach. This case illustrates that if a pancreatic tumor is enclosed by organs or vessels which impedes ventral needle placement, clinicians could consider alternative routes for needle placement, such as the dorsal approach. Conflict of interest Hester J Scheffer, Marleen CAM Melenhorst, Jantien A Vogel, Aukje AJM van Tilborg, Karin Nielsen, Geert Kazemier and Martijn R Meijerink have no conflicts of interest to declare.
References 1. Huguet F, Girard N, Se´blain-El Guerche C et al (2009) Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 27: 2269–2277 2. Pezzilli R, Serra C, Ricci C et al (2011) Radiofrequency ablation for advanced ductal panctreatic carcinoma. Is this approach beneficial for our patients? A systematic review. Pancreas 40: 163–165 3. Lee EW, Chen C, Prieto VE et al (2010) Advanced hepatic ablation technique for creating complete cell death: irreversible electroporation. Radiology 255:426–433
123
4. Lee EW, Thai S, Kee ST (2010) Irreversible electroporation: a novel image-guided cancer therapy. Gut Liver 4(Suppl 1):S99– S104 5. Scheffer HJ, Nielsen K, de Jong MC, et al. (2014) Irreversible Electroporation for Nonthermal Tumor Ablation in the Clinical Setting: A Systematic Review of Safety and Efficacy. J Vasc Interv Radiol 1–15 6. Martin RCG, McFarland K, Ellis S, Velanovich V (2012) Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol 20:S443– S449 7. Narayanan G, Hosein PJ, Arora G et al (2012) Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Interv Radiol 23: 1613–1621 8. Ball C, Thomson KR, Kavnoudias H (2010) Irreversible electroporation: a new challenge in ‘‘out of operating theater’’ anesthesia. Anesth Analg 110:1305–1309 9. Gupta S, Ahrar K, Morello Fa et al (2002) Masses in or around the pancreatic head: CT-guided coaxial fine-needle aspiration biopsy with a posterior transcaval approach. Radiology 222:63–69 10. Mueller PA, Miketic LM, Simeone JF et al (1988) Severe acute percutaneous pancreas pancreatitis after biopsy of the pancreas. Am J Roentgenol 43:84–85 11. Tillou a, Schwartz MR, Jordan PH (1996) Percutaneous needle biopsy of the pancreas: when should it be performed? World J Surg 20:283–6; discussion 287 12. Brandt KR, Charboneau JW, Stephens DH et al (1993) CT- and US-guided biopsy of the pancreas. Radiology 187:99–104 13. Neal RE II, Cheung W, Kavnoudias H, Thomson KR (2012) Spectrum of imaging and characteristics for liver tumors treated with irreversible electroporation. J Biomed Sci Engin 2012:11–15 14. Zhang Y, Guo Y, Ragin AB et al (2010) Mr imaging to assess immediate response to irreversible electroporation for targeted ablation of liver tissues: preclinical feasibility studies in a rodent model. Radiology 256:424–432 15. Charpentier KP (2012) Irreversible electroporation for the ablation of liver tumors: are we there yet? Arch Surg 147:1053–1061
CASE REPORT
Percutaneous Irreversible Electroporation of Locally Advanced Pancreatic Carcinoma Using the Dorsal Approach: A Case Report Hester J. Scheffer • Marleen C. A. M. Melenhorst • Jantien A. Vogel • Aukje A. J. M. van Tilborg • Karin Nielsen • Geert Kazemier • Martijn R. Meijerink
Received: 8 May 2014 / Accepted: 9 June 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2014
Abstract Irreversible electroporation (IRE) is a novel image-guided ablation technique that is increasingly used to treat locally advanced pancreatic carcinoma (LAPC). We describe a 67-year-old male patient with a 5 cm stage III pancreatic tumor who was referred for IRE. Because the ventral approach for electrode placement was considered dangerous due to vicinity of the tumor to collateral vessels and duodenum, the dorsal approach was chosen. Under CTguidance, six electrodes were advanced in the tumor, approaching paravertebrally alongside the aorta and inferior vena cava. Ablation was performed without complications. This case describes that when ventral electrode
H. J. Scheffer (&) M. C. A. M. Melenhorst A. A. J. M. van Tilborg M. R. Meijerink Department of Radiology and Nuclear Medicine, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands e-mail: [email protected] M. C. A. M. Melenhorst e-mail: [email protected] A. A. J. M. van Tilborg e-mail: [email protected] M. R. Meijerink e-mail: [email protected] J. A. Vogel Department of Surgery, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands e-mail: [email protected] K. Nielsen G. Kazemier Department of Surgery, VU University Medical Center, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands e-mail: [email protected] G. Kazemier e-mail: [email protected]
placement for pancreatic IRE is impaired, the dorsal approach could be considered alternatively. Keywords Irreversible electroporation (IRE) Electroporation/methods Pancreatic cancer/ pancreatic neoplasms Tumor ablation/percutaneous Ablation Techniques/adverse effects
Introduction Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death. It has a dismal prognosis, with a 5-year survival rate of 6 % and a case-fatality rate among the highest of any malignancy. Unfortunately, at the time of diagnosis only 15–20 % of patients are eligible for surgical resection with curative intent. Forty percent have locally advanced pancreatic carcinoma (LAPC) (stage III; AJCC TNM Staging System for Pancreatic Cancer). For these patients, chemotherapy or chemoradiation with palliative intent is the treatment of choice, leading to a modest increase in survival and improved quality of life. However, with a median survival of 6–11 months, the prognosis remains extremely poor [1]. The past two decades, image-guided tumor ablation has received substantial attention when surgical options are precluded. The aim of pancreatic ablation is cytoreduction, leading to better symptom palliation, improved quality-of-life and prolonged survival. However, due to the vulnerability of pancreatic tissue and its vicinity to critical structures, local treatment in this area risks pancreatitis and injury of duodenum, vessels and common bile duct. Thermal ablation using radiofrequency or microwave ablation to treat LAPC is therefore associated with a high complication rate, but without a clear benefit in survival [2].
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Recently, irreversible electroporation (IRE) has been introduced as a novel ablation technique. With IRE, multiple short, high-voltage electrical pulses are delivered to malignant tissue. The electrical pulses destabilize the existing cellular membrane potential and lead to the formation of ‘nano-pores’ in the lipid bilayer, irreversibly damaging the cell’s homeostatic mechanism which ultimately leads to cell death through apoptosis [3]. IRE only affects the membranes of living cells, whilst preserving the extracellular matrix constituents that are responsible for the patency of major vascular and ductal structures and other vulnerable tissues, without the generation of heat [4]. With these characteristics, IRE may be suitable to treat LAPC. Several studies have investigated the safety and efficacy of open as well as percutaneous IRE using the ventral approach for this indication. Although results are still preliminary, the technique seems to be tolerated well and early results of efficacy appear promising [5–7]. The shortest pathway and therefore the most commonly used route for CT-guided ablation of lesions in the pancreatic head is the ventral, or anterior, approach. However, in certain cases it can be extremely challenging to reach the desired position for all electrodes without having to traverse overlying intestinal, ductal and vascular structures. In this case the conventional ventral epigastric approach of needle placement can be complicated and concerns about the safety of the procedure arise. Here, we present a case of percutaneous IRE for LAPC using the dorsal approach for electrode placement.
Case Report A 67-year-old male patient presented with intermittent abdominal pain. Computed tomography (CT) imaging showed a 5.0 9 5.0 9 4.2 cm mass in the head and corpus of the pancreas with [180° encasement of the celiac axis, splenic and hepatic artery, and abutment of the superior mesenteric artery of 180°. The main portal vein was completely obliterated, which had led to extensive collateral vessel formation ventrally from the tumor (Fig. 1A, B). The tumor was also located in proximity to the duodenum. There were no signs of lymph nodal or metastatic spread. A transgastric biopsy of the lesion confirmed the diagnosis pancreatic adenocarcinoma. Due to the vascular encasement the tumor was considered surgically incurable (stage III). The patient was referred to our center for irreversible electroporation of the lesion as part of the prospective PANFIRE-study (clinicaltrials.gov registration number NCT01939665) and gave written informed consent. Given the vicinity of the tumor to the common bile duct, a plastic retrievable biliary endoprosthesis was placed via endoscopic retrograde cholangiopancreaticography as a
123
precautionary and protective measure prior to the procedure. Because of the extensive network of portal collaterals that had developed anteriorly from the tumor and its vicinity to the duodenum, ventral needle placement was considered to be associated with a substantial risk of damaging these structures. Therefore, we opted for a dorsal approach for needle placement. The patient was put under general anesthesia in the prone position. A contrast-enhanced (CE) CT scan (Sensation 64 slice MDCT, Siemens, Erlangen, Germany) in the arterial (triggered) and portal venous phase (70 s after contrast injection) was made to determine the threedimensional measurements of the tumor and its proximity to other structures. Size and shape, including a 5 mm margin, determines the number and configuration of the electrodes, which must cover the full extent of the tumor. The distance between electrode pairs should be 20 mm (±5 mm), which is considered the most effective treatment distance at which the ablation zone has an oval shape [8]. A total of six monopolar needle electrodes (NanoKnife, AngioDynamics, Latham, New York) were advanced into the central part and in the outer border of the cranial and caudal part of the tumor, approaching paravertebrally alongside the aorta and inferior vena cava under CTguidance (Fig. 1C and Fig. 2). Due to the necessity to place the needles on either side of the vertebral column, exact parallel positioning of all electrode pairs was not feasible. The active working length of the electrodes was set at 2 cm. Eight vectors for pulse delivery were chosen (Fig. 3A, C). All pulses were delivered in the absolute refractory period of the heart with use of electrocardiographic synchronization (Accusync, Model 72, Milford, Connecticut) to avoid the induction of cardiac arrhythmias and with deep muscle paralysis using additional rocuronium to prevent generalized muscle contractions. First, ten test pulses of 1500 V/cm with a pulse length of 90 lsec were delivered for each electrode pair to verify the delivered current, which must lie between 20–40 Amps. Subsequently, 80 treatment pulses were delivered along each vector. High current between electrodes 3 and 5 led to energy shutdown twice. With adjustment of the voltage and pulse length to 70 lsec the ablation was continued successfully. After a 2 cm pullback of all needles, an overlapping ablation was performed with use of the similar protocol. To cover the lateral parts of the tumor, the most cranial and caudal electrodes (electrodes 1 and 5) were repositioned to the lateral left and right tumor border approaching from the left paravertebral region. Next, another series of 90 pulses between four electrode pairs (Fig. 2 and Fig. 3A) was delivered. Mean delivered current of all electrodes was 35 Amps (SD 5.7). After removal of all needles, CECT showed a spastic but patent hepatic and splenic artery. There were no signs for early complications
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Fig. 1 A Axial contrast enhanced (CE) CT image of the pancreatic tumor prior to IRE with collateral vessels anteriorly (arrow). B Axial CE MRI image (T1 with fat suppression) of the tumor which appears slightly hypovascular compared to normal pancreatic tissue. C Axial CT image of two electrodes placed alongside the vertebral column. D Coronal view of fused CT series depicting all electrode positions before and after needle reposition. Close proximity of the duodenum
(D) to the tumor. E Axial CECT image obtained ten minutes after IRE demonstrating air within the ablated area but no complications. F Axial CE MRI image (T1 with fat suppression) with a typical ablation zone showing a non-enhancing center and a peripheral enhancing rim. G Axial CECT image 2 weeks after IRE showing a hypodense tumor center. H Axial CE MRI (T1 with fat suppression) 2 weeks post IRE depicting shrinkage of the ablation zone
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
Fig. 2 3D image with electrodes placed within the tumor. Pink electrodes representing electrode position during the first ablation. Orange electrodes representing repositioned electrode 1 and 5 prior to the second ablation (marked with *). Biliary endoprosthesis in the common bile duct in situ (long arrow). Prominent pancreatic duct due to tumor obstruction (short arrow)
(Fig. 1E). The patient awakened uneventfully in the recovery unit and was transferred to the ward. The next day contrast enhanced magnetic resonance imaging (CE MRI) showed a typical ablation zone with a non-enhancing center and a peripheral hyperintense reactive rim (Fig. 1F). There was a moderate increase in lipase (from 11 to 86 U/L) and amylase (from 24 to 112 U/L) that normalized to 15 U/L and 20 U/L on the third day, respectively. Pain was managed well with oral acetaminophen and tramadol and continuous intravenous morphine and ketamine. On the fourth day post-IRE the patient was discharged with oral acetaminophen, tramadol and oxycodone. During the next two weeks he experienced moderate intermittent abdominal pain, loss of appetite and a subfebrile temperature (up to 38 °C). After 2 weeks, CT and MRI showed a decreased size of the ablated area with a hypovascular center and no signs of complications (Fig. 1G, H). In the following weeks the pain significantly decreased and the patient was able to reduce his pain medication to half the amount of what he was using prior to the treatment. At 3 months, the ablated area had further decreased in size. The patient resumed his normal daily activities and remains in followup.
Discussion The advantage of percutaneous ablation over ablation during laparotomy is the less invasive nature, which generally implies a lower risk for complications and faster recovery. However, using the ventral approach, intervening
123
structures like stomach and intestines can obstruct access to the lesions, which requires transgression of the gastrointestinal tract. Acute pancreatitis is an uncommon but severe complication of pancreatic biopsy. Because bowel transgression can potentially contaminate a sterile biopsy procedure, it is best avoided to preclude even a small risk of infection or leakage of bile and pancreatic juices [9]. In their series of 184 pancreatic biopsies Mueller et al. [10] found an 8 % risk of pancreatitis after transintestinal biopsy as opposed to a 1.3 % risk after normal biopsy. With IRE, multiple electrodes are inserted in the pancreas and remain in situ for a substantial period of time, so the risk of bowel transgression leading to pancreatitis and infection of the ablation zone can be considered higher. Another issue that can preclude the ventral approach is preexisting portal vein thrombosis with subsequent formation of collateral circulation vessels. Although uncommon, major hemorrhage with pancreatic biopsy resulting from the inadvertent puncture of mesenteric or pancreatic vessels has been reported [11]. To overcome abovementioned difficulties, alternative routes for pancreatic biopsies such as the transhepatic and transsplenic approach, have been reported [12]. Posterior transcaval and paracaval biopsy have also been investigated and have proven relatively safe [9]. In our case, we considered the posterior approach to have the lowest risk of complications. To the best of our knowledge, this approach for pancreatic IRE has not been previously described. Although the vertebrae impeded exact parallel positioning of the electrodes, we eventually succeeded to place all needles in the desired position with the required interelectrode distances and to properly deliver all planned pulses within the desired current range. The maximum allowed angulation as advised by the manufacturer is 20°, since beyond this angle the strength and distribution of the electric field could become unreliable. However, whether exceeding this angle can truly result in a less effective ablation has not been investigated. For the electrode pairs that were placed on the ipsilateral side of the vertebral column the largest angulation was 22°. To cover the full extent of the tumor, ablation was also performed between electrode pairs that traversed the spine on either side, with the midpoint of the active tips in a crossed position (Fig. 3B). The maximum angulation for these pairs was 62°. In clinical practice, a slight deviation from exact parallel electrode placement is common. It could be argued that as long as the distance between two electrodes remains between the required 1.5–2.5 cm over the entire length of the active tips, this should result in effective ablation. Still, validation of the consequence of out-of-plane electrode placement on the strength and distribution of the electric field is of great importance and should be a focus of future research on IRE.
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach Fig. 3 A Coronal view of fused CT series demonstrating all electrode pairs during the first (pink lines) and second ablation (orange lines) in proximity to the duodenum (D). B Electrode pair originating from either side of the spine, with the midpoint of the active tips in a crossed position. C Table with electrode pairs and corresponding distances and angles. Ablation between electrode 2 and 5 was not considered essential (distance 3.0 cm) since no tumor tissue was expected in this region
Current published data on safety and feasibility of IRE for LAPC is limited. One study investigating open IRE for locally advanced pancreatic tumors in patients who had undergone standard induction chemotherapy for a minimum of 4 months did show greater local palliation and potential improved overall survival (20 vs. 11 months, P = .03) compared to standard chemoradiation or chemotherapy regimens [6]. Percutaneous pancreatic IRE also seems relatively safe and feasible with the important additional benefit of providing a less invasive treatment option. The largest series has been reported by Narayanan et al. [7] who performed 14 procedures using the percutaneous ventral approach. No major (CTCAE grade C3) complications were observed and three minor complications occurred (pneumothorax, subcutaneous hematoma and mild pancreatitis). The observed palliation of pain after pancreatic IRE may be explained by a reduction of tumor load, diminishing pain caused by tumor obstruction or celiac plexus invasion. Theoretically, given the vicinity of the celiac plexus to pancreatic head tumors, the treatment may also induce a temporary or permanent celiac plexus block, which may further contribute to reduced pain perception. This would be a desirable side effect of the treatment.
Our imaging findings post-IRE are in concordance with the available literature, which describes that 24 h after IRE, T1-weighted CE MRI of the ablated region typically shows a non-enhancing center, surrounded by a hyper-intense reactive rim [13]. The radiologic ablation zone measurements show a high correlation with the histologically confirmed ablation zone in a study on IRE in rodent liver (P \ .001 for both T1- and T2-weighted measurements) [14] and could therefore be used as an indication for complete or incomplete ablation and for follow-up evaluation of clinical outcome. The increased uptake of contrast at the periphery of the ablated region may be due to an initial inflammatory response increasing metabolic activity at the targeted region as the cellular debris is removed from the targeted site. However, whether all tumor cells in this region have truly been destroyed must become evident during follow-up. In the hours after IRE, a margin of reversibly electroporated tissue exists between the ablation zone and the untreated tissue, where the electrical field strength remained below the critical threshold. The cell membranes of the cells in this zone are temporarily permeable during this period, allowing drugs such as chemotherapeutics to travel freely into the cells. Reversible electroporation has been
123
H. J. Scheffer et al.: IRE For LAPC: The Dorsal Approach
used for decades to promote the uptake of chemotherapy into the cell, a process known as electrochemotherapy. Capitalizing on this principle, the addition of systemic chemotherapy immediately after IRE could potentially eradicate marginal reversibly electroporated tumor cells, which would improve treatment effect [15]. This approach warrants further study and may contribute to the multidisciplinary treatment approach of cancer in the near future. In conclusion, this case report describes a technically successful IRE procedure of a locally advanced pancreatic carcinoma using the dorsal approach. This case illustrates that if a pancreatic tumor is enclosed by organs or vessels which impedes ventral needle placement, clinicians could consider alternative routes for needle placement, such as the dorsal approach. Conflict of interest Hester J Scheffer, Marleen CAM Melenhorst, Jantien A Vogel, Aukje AJM van Tilborg, Karin Nielsen, Geert Kazemier and Martijn R Meijerink have no conflicts of interest to declare.
References 1. Huguet F, Girard N, Se´blain-El Guerche C et al (2009) Chemoradiotherapy in the management of locally advanced pancreatic carcinoma: a qualitative systematic review. J Clin Oncol 27: 2269–2277 2. Pezzilli R, Serra C, Ricci C et al (2011) Radiofrequency ablation for advanced ductal panctreatic carcinoma. Is this approach beneficial for our patients? A systematic review. Pancreas 40: 163–165 3. Lee EW, Chen C, Prieto VE et al (2010) Advanced hepatic ablation technique for creating complete cell death: irreversible electroporation. Radiology 255:426–433
123
4. Lee EW, Thai S, Kee ST (2010) Irreversible electroporation: a novel image-guided cancer therapy. Gut Liver 4(Suppl 1):S99– S104 5. Scheffer HJ, Nielsen K, de Jong MC, et al. (2014) Irreversible Electroporation for Nonthermal Tumor Ablation in the Clinical Setting: A Systematic Review of Safety and Efficacy. J Vasc Interv Radiol 1–15 6. Martin RCG, McFarland K, Ellis S, Velanovich V (2012) Irreversible electroporation in locally advanced pancreatic cancer: potential improved overall survival. Ann Surg Oncol 20:S443– S449 7. Narayanan G, Hosein PJ, Arora G et al (2012) Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Interv Radiol 23: 1613–1621 8. Ball C, Thomson KR, Kavnoudias H (2010) Irreversible electroporation: a new challenge in ‘‘out of operating theater’’ anesthesia. Anesth Analg 110:1305–1309 9. Gupta S, Ahrar K, Morello Fa et al (2002) Masses in or around the pancreatic head: CT-guided coaxial fine-needle aspiration biopsy with a posterior transcaval approach. Radiology 222:63–69 10. Mueller PA, Miketic LM, Simeone JF et al (1988) Severe acute percutaneous pancreas pancreatitis after biopsy of the pancreas. Am J Roentgenol 43:84–85 11. Tillou a, Schwartz MR, Jordan PH (1996) Percutaneous needle biopsy of the pancreas: when should it be performed? World J Surg 20:283–6; discussion 287 12. Brandt KR, Charboneau JW, Stephens DH et al (1993) CT- and US-guided biopsy of the pancreas. Radiology 187:99–104 13. Neal RE II, Cheung W, Kavnoudias H, Thomson KR (2012) Spectrum of imaging and characteristics for liver tumors treated with irreversible electroporation. J Biomed Sci Engin 2012:11–15 14. Zhang Y, Guo Y, Ragin AB et al (2010) Mr imaging to assess immediate response to irreversible electroporation for targeted ablation of liver tissues: preclinical feasibility studies in a rodent model. Radiology 256:424–432 15. Charpentier KP (2012) Irreversible electroporation for the ablation of liver tumors: are we there yet? Arch Surg 147:1053–1061
