**3. Technique of IRE**

vessels [21, 32]. For the above-cited reasons, IRE is a very attractive local ablation method in pancreatic cancer, given the inherent proximity of the pancreas to vital vascular structures as

However, IRE cannot be applied under any circumstances given that several contraindications for its use exist. The presence of metallic material in close proximity to the placed IRE needles (e.g., metallic biliary stent that is not removable) is a relative contraindication for IRE, given that the conductivity of the metal could potentiate the minimal thermal effect of it. Even more importantly, the presence of metal can distract, respectively, and derivate the electrical current used in IRE, rendering prediction of the ablation zone impossible. Hence the effect of IRE is potentially dangerous [33, 34]. Also, a tumor size >5 cm is generally seen as a contraindication, given that the volume of the ablation zone of a tumor exceeding this size is technically difficult to achieve [21]. Additionally, IRE is contraindicated in patients with certain cardiac arrhythmias, and patients with pacemakers should be evaluated by a cardiologist prior to IRE, as the high-voltage electric current applied can itself provocate potentially serious arrhythmias [32]. To avoid such complications in ablations at the level of the pancreas, the electrical pulses are applied during the complete refractory phase of the heart (50 ms after the R wave). To achieve the coordination of the IRE pulses and the heart rhythm of the patient, the IRE device is synchronized with the patient's ECG. Furthermore, application of IRE is not recommended in patients having a history of epi-

lepsy or recent myocardial infarction. No data exist about the use of IRE in pregnancy.

IRE has first been established as a complementary local therapy in conjunction with chemotherapy for patients with locally advanced pancreatic cancer, which is not amenable to surgical resection [30]. In situations where surgical resection seems too risky (e.g., a tumor encapsulating the superior mesenteric artery), IRE has shown to be a safe and valuable treatment alternative. Standalone IRE without surgical resection of the primary tumor is called "in situ" IRE. Its primary aim is to achieve maximal local tumor control. As in thermal ablative strategies, there is currently no randomized data available that look at oncological outcomes of (radio-) chemotherapy and IRE compared to (radio-) chemotherapy alone. However, there is encouraging evidence that suggests a relevant improvement of overall survival in patients with in situ IRE after induction chemotherapy/(radio-) chemotherapy [2, 35]. A propensity-matched score analysis by Martin et al. showed a survival benefit of induction chemotherapy and/or radiation followed by IRE compared to (radio-) chemotherapy alone. The additional treatment with IRE showed a prolongation of local progression free survival from 6 to 14 months, distant progression free survival from 9 to 15 months and overall survival from 13 to 20 months [35]. Another study analyzing 200 patients with locally advanced pancreatic cancer, either undergoing in situ IRE or margin accentuation IRE after an induction chemotherapy/(radio-)chemotherapy showed an encouraging median overall survival of 24.9 months and local recurrence rates of only 3% [36]. These results indicate that local tumor control with IRE is achievable and has a significant positive effect on patients with locally advanced pancreatic cancer. However, the interpretation of data on long-term oncological outcomes after IRE is still difficult, given that the studies available are of substantial heterogeneity and mostly lacking direct control groups. Additionally, most studies were not primarily designed to demonstrate oncological efficacy of the procedure but rather aimed to demonstrate safety and efficacy of the IRE procedure itself [2]. Some authors emphasize

well as the bile and pancreatic duct.

102 Advances in Pancreatic Cancer

*2.2.2. IRE in locally advanced pancreatic cancer*

#### **3.1. General considerations**

As mentioned earlier, all eligible patients for in situ IRE with locally advanced pancreatic cancer have to complete at least 3 months of neoadjuvant (radio-) chemotherapy, mainly to avoid local IRE treatment in patients with metastatic disease. This said, restaging after finishing induction treatment is crucial and should be performed with major diligence. Noteworthy is the usually absent "radiographic response" in pancreatic imaging after neoadjuvant

therapy—consensus is therefore to proceed to in situ IRE unless imaging shows local disease progression or newly observed distant metastases [2, 35, 36].

In case restaging confirms the presence of locally advanced pancreatic adenocarcinoma, every patient should be discussed at an interdisciplinary tumor board including medical oncologists, radiation oncologists, radiologists, pathologists and surgical oncologists. If tumor response is achieved and the lesion can be downstaged to borderline resectable disease, patients should be considered for surgical resection with margin-accentuation IRE (see part 4). In cases of stable disease without development of distant metastases and a maximal tumor diameter of <5 cm, patients can be planned for in situ IRE.

#### **3.2. Practice of IRE**

#### *3.2.1. Open approach*

Technically, there are different ways to apply IRE to a target lesion. Practice in our institution is at the moment the "classical" open abdominal approach. An upper midline or transverse incision is performed followed by a meticulous abdominal exploration looking for occult metastatic disease. IRE needles are then placed under ultrasound guidance covering the suspected tumor area. At least two unipolar probes are needed to deliver the high-voltage current. Parallel orientation of the needles is of utmost importance, with ideally a distance of about 2 cm between each needle pair (**Figures 4** and **5**).

*3.2.2. Minimal-invasive approach*

sound guidance [46].

*3.2.3. Percutaneous approach*

settings exist.

IRE may also be applied in the setting of minimally invasive surgery under laparoscopic ultra-

**Figure 5.** Intraoperative needle positioning under ultrasound guidance. In this example the two needle tips (red arrows)

Irreversible Electroporation in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75737 105

Additionally, surgical interventions like hepaticojejunostomy or gastroenterostomy, which have the potential to improve the quality of life in patients suffering from locally advanced pancreatic adenocarcinoma, can be performed during the same intervention in patients

Several groups have gained experience in the percutaneous application of IRE supported by different imaging modalities. Narayanan et al. reported a series of 50 patients with CT-guided percutaneous IRE. The procedure was technically feasible in all patients. A median overall survival of 27 months from the time of diagnosis and 14 months from the time of IRE was reported, which is comparable to the oncological outcomes observed in open IRE [47]. Another group around Mansson performed IRE under ultrasound guidance. Of the 24 patients, all treatments were completed using ultrasound guidance only [48]. The case series presented are small, but the data suggest that the percutaneous approach is technically feasible and generally safe [47, 48]. A potential drawback of the percutaneous approach is the lack of visual assessment of the peritoneal cavity. Small liver/peritoneal lesions can be missed and patients with potential metastatic disease might be "locally overtreated," given that at present no data for application of IRE in metastatic

receiving IRE by either an open or a laparoscopic approach.

are placed to the left and right of the superior mesenteric artery (\*).

A maximum of six probes can be inserted at the same time [43]. During the IRE procedure itself, full neuromuscular relaxation has to be guaranteed as the high voltages transmitted by the electrodes can produce significant muscular contractions [44]. If successful ablation was performed at one site, needle pull-back can be repeated as many times as needed with performance of the treatment at another level in order to cover the full desired ablation volume. Early imaging documentation of the success of IRE treatment is not possible, given the unspecific postoperative changes. As such, control imaging by CT-scan is not recommended before 3 months after IRE, as the images can be altered by ongoing edema following electroporation [45].

**Figure 4.** (a and b) Parallel placement of two needles at the distance of 2 cm for an IRE treatment around the common hepatic artery.

**Figure 5.** Intraoperative needle positioning under ultrasound guidance. In this example the two needle tips (red arrows) are placed to the left and right of the superior mesenteric artery (\*).

#### *3.2.2. Minimal-invasive approach*

IRE may also be applied in the setting of minimally invasive surgery under laparoscopic ultrasound guidance [46].

Additionally, surgical interventions like hepaticojejunostomy or gastroenterostomy, which have the potential to improve the quality of life in patients suffering from locally advanced pancreatic adenocarcinoma, can be performed during the same intervention in patients receiving IRE by either an open or a laparoscopic approach.

#### *3.2.3. Percutaneous approach*

**Figure 4.** (a and b) Parallel placement of two needles at the distance of 2 cm for an IRE treatment around the common

therapy—consensus is therefore to proceed to in situ IRE unless imaging shows local disease

In case restaging confirms the presence of locally advanced pancreatic adenocarcinoma, every patient should be discussed at an interdisciplinary tumor board including medical oncologists, radiation oncologists, radiologists, pathologists and surgical oncologists. If tumor response is achieved and the lesion can be downstaged to borderline resectable disease, patients should be considered for surgical resection with margin-accentuation IRE (see part 4). In cases of stable disease without development of distant metastases and a maximal tumor diameter of

Technically, there are different ways to apply IRE to a target lesion. Practice in our institution is at the moment the "classical" open abdominal approach. An upper midline or transverse incision is performed followed by a meticulous abdominal exploration looking for occult metastatic disease. IRE needles are then placed under ultrasound guidance covering the suspected tumor area. At least two unipolar probes are needed to deliver the high-voltage current. Parallel orientation of the needles is of utmost importance, with ideally a distance of about 2 cm between each

A maximum of six probes can be inserted at the same time [43]. During the IRE procedure itself, full neuromuscular relaxation has to be guaranteed as the high voltages transmitted by the electrodes can produce significant muscular contractions [44]. If successful ablation was performed at one site, needle pull-back can be repeated as many times as needed with performance of the treatment at another level in order to cover the full desired ablation volume. Early imaging documentation of the success of IRE treatment is not possible, given the unspecific postoperative changes. As such, control imaging by CT-scan is not recommended before 3 months after IRE, as

the images can be altered by ongoing edema following electroporation [45].

progression or newly observed distant metastases [2, 35, 36].

<5 cm, patients can be planned for in situ IRE.

**3.2. Practice of IRE**

104 Advances in Pancreatic Cancer

*3.2.1. Open approach*

needle pair (**Figures 4** and **5**).

hepatic artery.

Several groups have gained experience in the percutaneous application of IRE supported by different imaging modalities. Narayanan et al. reported a series of 50 patients with CT-guided percutaneous IRE. The procedure was technically feasible in all patients. A median overall survival of 27 months from the time of diagnosis and 14 months from the time of IRE was reported, which is comparable to the oncological outcomes observed in open IRE [47]. Another group around Mansson performed IRE under ultrasound guidance. Of the 24 patients, all treatments were completed using ultrasound guidance only [48]. The case series presented are small, but the data suggest that the percutaneous approach is technically feasible and generally safe [47, 48]. A potential drawback of the percutaneous approach is the lack of visual assessment of the peritoneal cavity. Small liver/peritoneal lesions can be missed and patients with potential metastatic disease might be "locally overtreated," given that at present no data for application of IRE in metastatic settings exist.

#### **3.3. Potential complications of IRE**

Despite its nonthermal technique, also IRE is associated with potential complications. In the so far largest population from Martin et al. consisting of 200 patients treated with IRE, a total rate of 37% adverse events were recorded along with a mortality rate of 2%. The most common adverse events reported were pancreatic leak, pancreatitis and duodenal ulcer formation. Also, less frequently vascular complications (such as hepatic arterial thrombosis or mesenteric/portal vein thrombosis) and liver dysfunction/failure have been observed [36]. A group from Scandinavia analyzed the so-far gained IRE experience in a recent review including 10 studies comprising 446 patients in total (304 patients treated with open IRE and 142 patients treated percutaneously). A total of nine fatalities (2%) were recorded, while overall complication rate was summarized to be 35% [37]. It has to be kept in mind that complications after open IRE are challenging to interpret, as in many cases, patients had major gastrointestinal surgery in addition to their IRE treatment. However, whereas most complications seemed self-limited, there have been several reports on severe complications in open IRE such as portal vein thrombosis, pancreatic fistula and pancreatitis. Overall complications following percutaneous IRE vary from 0 to 20% in the different study groups. In the abovementioned population of 50 patients from Narayanan et al., most patients described postinterventional abdominal pain, 10 patients (20%) were reported to have a severe complication, but no IRErelated deaths occurred [47].

## **4. Navigated IRE**

An additional, novel technology is the so-called navigated IRE. One of the most critical and difficult steps of IRE is the correct positioning of the needles in accurate depth and perfect parallelism. If IRE is performed in an open fashion, the placement of the needles is normally controlled under ultrasound guidance. However, given the complex anatomical situation around the pancreas, 3D reconstructions based on preoperative imaging can provide the surgeon with a better topologic understanding of the patient's specific anatomy. Those reconstructions can nowadays be transferred to planning tools and even be used intraoperatively as navigational help. It has been shown that the ability to plan procedures on these image data and visualize them during the surgery holds significant value as different surgical strategies can be evaluated on the 3D models preoperatively and can be used as additional patientspecific information throughout the surgery (**Figure 6**) [49, 50].

In 2005, Grenacher et al. discussed the role of computer-assisted surgery (CAS) in the field of liver and pancreas surgery [51]. Up to then, CAS was well established in surgical procedures related to orthopedics and neurosurgery, but the advantage of transferring the knowledge to soft tissue applications was insufficiently studied. However, advances in computer science nowadays enable intraoperative navigation in hepato-pancreato-biliary surgery. Using the CAScination® system, the real world can be linked to tThe virtual scene, either by using landmarks on the surface of the organs or by using ultrasound to mark internal structures like tumors or bifurcations of vessels [52]. The surgical instruments are then equipped with mark-

**Figure 7.** Demonstration of equipment for navigated IRE: touch screen (red arrow); infra red detection device (black arrow); metal spheres required for real-time instrument tracking consisting of instrument and ultrasound (white arrow).

**Figure 6.** 3D reconstruction showing the arteries (red), veins (blue), tumor of the pancreatic body (yellow), duodenum

Irreversible Electroporation in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75737 107

(green) and the pancreas (light green).

A specific solution for IRE treatment of the pancreas has been implemented, which provides the surgeon with the possibility to preoperatively verify the needle placement based on given constraints like parallelism and spacing between the needles [53]. The aim of this novel technique in IRE would be the placement of the needles under live CAS-guidance according to the preoperatively defined plan. Nevertheless, further improvements of the intraoperative navigation

ers, which can be detected by an optical tracking system in real time (**Figure 7**).

**3.3. Potential complications of IRE**

106 Advances in Pancreatic Cancer

related deaths occurred [47].

**4. Navigated IRE**

Despite its nonthermal technique, also IRE is associated with potential complications. In the so far largest population from Martin et al. consisting of 200 patients treated with IRE, a total rate of 37% adverse events were recorded along with a mortality rate of 2%. The most common adverse events reported were pancreatic leak, pancreatitis and duodenal ulcer formation. Also, less frequently vascular complications (such as hepatic arterial thrombosis or mesenteric/portal vein thrombosis) and liver dysfunction/failure have been observed [36]. A group from Scandinavia analyzed the so-far gained IRE experience in a recent review including 10 studies comprising 446 patients in total (304 patients treated with open IRE and 142 patients treated percutaneously). A total of nine fatalities (2%) were recorded, while overall complication rate was summarized to be 35% [37]. It has to be kept in mind that complications after open IRE are challenging to interpret, as in many cases, patients had major gastrointestinal surgery in addition to their IRE treatment. However, whereas most complications seemed self-limited, there have been several reports on severe complications in open IRE such as portal vein thrombosis, pancreatic fistula and pancreatitis. Overall complications following percutaneous IRE vary from 0 to 20% in the different study groups. In the abovementioned population of 50 patients from Narayanan et al., most patients described postinterventional abdominal pain, 10 patients (20%) were reported to have a severe complication, but no IRE-

An additional, novel technology is the so-called navigated IRE. One of the most critical and difficult steps of IRE is the correct positioning of the needles in accurate depth and perfect parallelism. If IRE is performed in an open fashion, the placement of the needles is normally controlled under ultrasound guidance. However, given the complex anatomical situation around the pancreas, 3D reconstructions based on preoperative imaging can provide the surgeon with a better topologic understanding of the patient's specific anatomy. Those reconstructions can nowadays be transferred to planning tools and even be used intraoperatively as navigational help. It has been shown that the ability to plan procedures on these image data and visualize them during the surgery holds significant value as different surgical strategies can be evaluated on the 3D models preoperatively and can be used as additional patient-

In 2005, Grenacher et al. discussed the role of computer-assisted surgery (CAS) in the field of liver and pancreas surgery [51]. Up to then, CAS was well established in surgical procedures related to orthopedics and neurosurgery, but the advantage of transferring the knowledge to soft tissue applications was insufficiently studied. However, advances in computer science nowadays enable intraoperative navigation in hepato-pancreato-biliary surgery. Using the CAScination® system, the real world can be linked to tThe virtual scene, either by using landmarks on the surface of the organs or by using ultrasound to mark internal structures like

specific information throughout the surgery (**Figure 6**) [49, 50].

**Figure 6.** 3D reconstruction showing the arteries (red), veins (blue), tumor of the pancreatic body (yellow), duodenum (green) and the pancreas (light green).

**Figure 7.** Demonstration of equipment for navigated IRE: touch screen (red arrow); infra red detection device (black arrow); metal spheres required for real-time instrument tracking consisting of instrument and ultrasound (white arrow).

tumors or bifurcations of vessels [52]. The surgical instruments are then equipped with markers, which can be detected by an optical tracking system in real time (**Figure 7**).

A specific solution for IRE treatment of the pancreas has been implemented, which provides the surgeon with the possibility to preoperatively verify the needle placement based on given constraints like parallelism and spacing between the needles [53]. The aim of this novel technique in IRE would be the placement of the needles under live CAS-guidance according to the preoperatively defined plan. Nevertheless, further improvements of the intraoperative navigation

research is definitely needed to assess the independent effect of margin accentuation IRE on

Irreversible Electroporation in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75737 109

Pancreatic cancer remains a highly lethal disease. Especially patients with locally advanced pancreatic cancer usually face a discouraging prognosis with limited treatment options. The local ablative therapy with IRE is a valuable additional treatment modality, which, looking at present evidence, seems to have the potential to improve disease-specific and overall survival among patients with this dreadful disease. IRE is technically feasible and generally safe in its open and minimal-invasive access. It can either be applied as in situ IRE in unresectable cases or as a complementary treatment to surgery in borderline resectable patients in order to improve the percentage of true R0 resections. Despite being now an accepted and increasingly applied therapy, there are still a lot of open questions regarding the use of IRE. Future efforts should aim toward the establishment of standard treatment protocols for IRE, in order to make its potential benefit available to more patients suffering from pancreatic adenocarcinoma.

Melanie Holzgang, Benjamin Eigl, Suna Erdem, Beat Gloor and Mathias Worni\*

lcancer.2017.10.006. [Epub ahead of print] Review. PMID: 29153290

Department of Visceral Surgery and Medicine, University Clinic of Bern, Inselspital, Bern,

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: A Cancer Journal for Clinicians.

[2] O'Kane GM, Knox JJ. Locally advanced pancreatic cancer: An emerging entity. Current Problems in Cancer. 2017 Nov 16. pii: S0147-0272(17)30106-X. DOI: 10.1016/j.currprob-

\*Address all correspondence to: mathias.worni@insel.ch

local recurrence rates and overall survival.

**6. Conclusions**

**Conflict of interest**

None.

**Author details**

Switzerland

**References**

2017;**67**:7-30

The authors declare no conflict of interest.

**Notes/thanks/other declarations**

**Figure 8.** Preoperative 3D planning of an in situ IRE with 4 needles in a patient with locally advanced pancreatic cancer.

tools are required before they can be implemented to clinical routine and will be tackled by our team in the near future (**Figure 8**).
