**2. Local ablative strategies**

#### **2.1. Thermal local ablative strategies**

Radiofrequency (RFA) and microwave ablation (MWA) have been used in an attempt to achieve local control among patients with locally advanced pancreatic cancer. Both treatments generate thermal energy by a high-frequency alternating current, which is delivered to the cancerous tissue by one or more needle electrodes. The created high local temperature at the tip of the electrodes leads to cell death by coagulative necrosis and protein denaturation [21, 22]. RFA has been used with success in the setting of unresectable tumors in multiple solid organs (liver, lung, kidney, brain, breast, prostate, bone, adrenal glands, spleen) [22]. Over the last years, it has also been deployed in the palliative setting of locally advanced pancreatic cancer. However, RFA in patients with pancreatic adenocarcinoma has not been widely accepted because of considerable morbidity and mortality rates [19]. The high complication rate was thought to be due to thermal injury to the multiple delicate structures (bile duct, pancreatic duct, duodenum, vital vessels)

surrounding the pancreas. By adjusting the administered temperature from 105 to 90°C for 5 min' length, complications in recent patient cohorts treated by RFA were substantially reduced [20]. Still, gastrointestinal hemorrhages, acute pancreatitis, pancreatic/biliary fistulas, duodenal injury and portal vein thrombosis are regularly reported in the literature [19]. A systematic review from 2014 cited an RFA-related morbidity ranging from 10 to 37% and an RFA-related mortality from 0 to 19% [23]. Another important downside of thermal ablative therapies is the so-called "heat-sink effect." During the ablation process, adjacent blood vessels are "cooling the tissue down" leading to an insufficient temperature in the immediate proximity of the vessels, where therefore efficient cell death cannot be induced [24]. Given the anatomical complexity of the pancreatic region and bearing the abovementioned aspects in mind, it is self-evident that the application of thermal ablative therapy in locally advanced pancreatic cancer is delicate. It is at this state unknown whether RFA should be combined with chemo- and/or radiotherapy as a standard treatment. A retrospective analysis of patients with locally advanced pancreatic cancer with short induction chemotherapy and RFA compared to a patient group with RFA did not show a difference in early disease progression or overall survival [25]. While there is no evidence from randomized controlled trials regarding the oncological outcome of RFA in locally advanced disease, several case series show a significantly increased median overall survival in patients where RFA was part of the treatment concept [26, 27].

MWA is less prone to the heat-sink effect compared to RFA and is therefore more suitable for application closer to large vessels. Similar to RFA, no randomized data using MWA in locally advanced pancreatic cancer are available [28]. Given the heterogeneous reports of MWA and RFA, direct comparisons between the two techniques in regard of long-term survival are currently not available. However, based on published evidence, MWA seems to lead to less postoperative pain and decreased ablation time with similar results in morbidity and mortality compared to RFA [29]. However, at present, MWA is still studied less extensively than RFA [30, 31].

#### **2.2. Irreversible electroporation**

#### *2.2.1. Introduction to IRE*

and often implies arterial resection associated with high perioperative morbidity and mortality [8–11]. A timely meta-analysis by Mollberg et al. assessed the impact of arterial resection on perioperative outcomes among patients undergoing pancreatic resection. They showed that perioperative morbidity and mortality was, with 53 and 12%, significantly higher for patients with arterial resection compared to around 25–30 and 6% reported for pancreatoduodenectomies, not requiring arterial reconstruction, respectively [12–14]. In summary, given the high perioperative risk and its limited impact on survival, arterial resection can at present not be justified as a standard procedure in the treatment of pancreatic cancer [2, 10]. Accordingly, the current treatment recommendations for patients with locally advanced pancreatic cancer are chemo- and/or radiotherapy, which achieve a median overall survival of 9–13 months on average [2]. There is notably a difference in the standard treatment regimens according to the geographic location; most patients in the USA with locally advanced pancreatic cancer are currently undergoing combined chemoradiotherapy, whereas patients in the Europe are usually treated with chemotherapy alone. Recent advances in chemotherapy allow to downstage certain patients with locally advanced disease, making a surgical resection of some tumors possible [15, 16]. Patients treated with neoadjuvant chemotherapy followed by surgical resection can achieve similar survival rates like patients diagnosed in a resectable or borderline resectable state. It is estimated that in select patient cohorts, up to one-third of patients initially judged as non-resectable can be converted into a resectable state by neoadjuvant chemotherapy. However, the neoadjuvant regimen is still debated and is not internationally accepted yet as standard of

Given that patients with locally advanced disease have a poor prognosis despite multimodal therapy, additional treatment alternatives are desperately needed. In the group of locally advanced pancreatic cancer, the tumor is confined to the location of origin without evidence of distant spread—rendering local therapy an attractive additional treatment option. As such, loco-regional therapies including radiofrequency ablation (RFA), microwave ablation (MWA) and irreversible electroporation (IRE) have gained increased attention in the treatment of locally

Radiofrequency (RFA) and microwave ablation (MWA) have been used in an attempt to achieve local control among patients with locally advanced pancreatic cancer. Both treatments generate thermal energy by a high-frequency alternating current, which is delivered to the cancerous tissue by one or more needle electrodes. The created high local temperature at the tip of the electrodes leads to cell death by coagulative necrosis and protein denaturation [21, 22]. RFA has been used with success in the setting of unresectable tumors in multiple solid organs (liver, lung, kidney, brain, breast, prostate, bone, adrenal glands, spleen) [22]. Over the last years, it has also been deployed in the palliative setting of locally advanced pancreatic cancer. However, RFA in patients with pancreatic adenocarcinoma has not been widely accepted because of considerable morbidity and mortality rates [19]. The high complication rate was thought to be due to thermal injury to the multiple delicate structures (bile duct, pancreatic duct, duodenum, vital vessels)

advanced pancreatic adenocarcinoma over the last years [19, 20].

**2. Local ablative strategies**

**2.1. Thermal local ablative strategies**

care [17, 18].

100 Advances in Pancreatic Cancer

Irreversible electroporation (IRE) is an emerging ablative modality that gained enormous interest over the last years. In contrast to the abovementioned thermal ablative strategies, IRE leads to cell death mainly through a nonthermal technique. In IRE, high voltage (maximum of 3000 V) electrical pulses of 70–90 μs duration are applied through a minimum of two electrodes positioned next to or into the target neoplastic tissue. The thus created electrical field leads to a disruption of the cell membrane's lipophilic bilayer by formation of nanoscale micropores. This damage to the cell membrane eventually leads to a collapse of intracellular homeostasis and an activation of apoptotic pathways, finally resulting in cell death. The distinct advantage of this technique compared to thermal ablative strategies is the preservation of structural components like collagen and elastin as thermal damage does only occur in the very close proximity to the ablation needles depending on pulse length, exposure of the needle tips, delivered energy, distance between the electrodes and underlying tissue. Another advantage of IRE compared to thermal ablative modalities is its nonexisting "heat sink effect," which means that the efficiency of IRE will not be reduced in proximity to large 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 well as the bile and pancreatic duct.

the possible impact of neoadjuvant chemotherapy over the direct effect of IRE given that the specific impact of IRE has not yet been demonstrated. However, Gillen et al. found a median overall survival of 22 months in patients with locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and if possible subsequent pancreatic resection [17]. These survival outcomes are still slightly worse than the ones of the 200 patients documented by Martin et al. in his cohort undergoing in situ IRE/margin accentuation IRE with pancreatic resection. IRE thus seems to add some additional benefit that systemic chemotherapy cannot provide, most probably by its local field of action. This observation has led to the hypothesis that the resection margin in pancreatic cancer deserves further investigation, as IRE might contribute to better overall survival by achieving more "true" R0 resections (see Chapter 4) [37]. Additional studies focusing on overall survival are certainly needed to further investigate the potential of IRE in improving the outcomes of

Irreversible Electroporation in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75737 103

**2.3. Induction therapy in locally advanced pancreatic cancer before in situ IRE**

At present, in situ IRE is mainly recommended in combination with upfront chemotherapy or (radio-) chemotherapy for at least 3 months. This does not only allow a "test for time" to get familiar with the biology of the patients underlying tumor, but also avoids local treatment with in situ IRE among patients with metastatic disease. Several induction treatment regimens have been suggested while so far no specific data are available, which favor one regimen over the other. Gemcitabine-based chemotherapy and/or radiotherapy is an option; however, more recent studies show beneficial results with the more aggressive FOLFIRINOX regimen as initial therapy [38–40]. Given the significant toxicity of FOLFIRINOX, a modified regimen has been suggested, where the 5-FU bolus is left out [15]. An alternative chemotherapy regimen often used in advanced pancreatic cancer and also in the setting of induction therapy before IRE is the combination of gemcitabine and Nab-paclitaxel [41]. Further studies assessing the best inductive treatment before IRE are needed before any general recommendation can be given. Whatever induction therapy is used, it must be followed by restaging investigations. While there is no standard algorithm recommended, we perform a 3-phase contrast enhanced pancreas protocol computer tomography including the chest, to exclude pulmonary metastases and to plan the IRE procedure in detail. High quality CT-scans allow for sound judgment of tumor vessel relationships. In addition, given that diffusion MRI of the liver has shown to outperform CT-scans in regard of detection of liver metastases, all patients will undergo this

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

patients with locally advanced pancreatic cancer.

imaging tool prior to surgical exploration [42].

**3. Technique of IRE**

**3.1. General considerations**

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

#### *2.2.2. IRE in locally advanced pancreatic cancer*

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 the possible impact of neoadjuvant chemotherapy over the direct effect of IRE given that the specific impact of IRE has not yet been demonstrated. However, Gillen et al. found a median overall survival of 22 months in patients with locally advanced pancreatic cancer treated with neoadjuvant chemotherapy and if possible subsequent pancreatic resection [17]. These survival outcomes are still slightly worse than the ones of the 200 patients documented by Martin et al. in his cohort undergoing in situ IRE/margin accentuation IRE with pancreatic resection. IRE thus seems to add some additional benefit that systemic chemotherapy cannot provide, most probably by its local field of action. This observation has led to the hypothesis that the resection margin in pancreatic cancer deserves further investigation, as IRE might contribute to better overall survival by achieving more "true" R0 resections (see Chapter 4) [37]. Additional studies focusing on overall survival are certainly needed to further investigate the potential of IRE in improving the outcomes of patients with locally advanced pancreatic cancer.

#### **2.3. Induction therapy in locally advanced pancreatic cancer before in situ IRE**

At present, in situ IRE is mainly recommended in combination with upfront chemotherapy or (radio-) chemotherapy for at least 3 months. This does not only allow a "test for time" to get familiar with the biology of the patients underlying tumor, but also avoids local treatment with in situ IRE among patients with metastatic disease. Several induction treatment regimens have been suggested while so far no specific data are available, which favor one regimen over the other. Gemcitabine-based chemotherapy and/or radiotherapy is an option; however, more recent studies show beneficial results with the more aggressive FOLFIRINOX regimen as initial therapy [38–40]. Given the significant toxicity of FOLFIRINOX, a modified regimen has been suggested, where the 5-FU bolus is left out [15]. An alternative chemotherapy regimen often used in advanced pancreatic cancer and also in the setting of induction therapy before IRE is the combination of gemcitabine and Nab-paclitaxel [41]. Further studies assessing the best inductive treatment before IRE are needed before any general recommendation can be given.

Whatever induction therapy is used, it must be followed by restaging investigations. While there is no standard algorithm recommended, we perform a 3-phase contrast enhanced pancreas protocol computer tomography including the chest, to exclude pulmonary metastases and to plan the IRE procedure in detail. High quality CT-scans allow for sound judgment of tumor vessel relationships. In addition, given that diffusion MRI of the liver has shown to outperform CT-scans in regard of detection of liver metastases, all patients will undergo this imaging tool prior to surgical exploration [42].
