Locally Advanced Pancreatic Cancer: A Review of Local Ablative Therapies

Pancreatic cancer is typically characterized by its aggressive tumor growth and dismal prognosis. Approximately 30% of patients with pancreatic cancer present with locally advanced disease, broadly defined as having a tumor-to-artery interface >180°, having an unreconstructable portal vein or superior mesenteric vein and no signs of metastatic disease. These patients are currently designated to palliative systemic chemotherapy, though median overall survival remains poor (approximately 11 months). Therefore, several innovative local therapies have been investigated as new treatment options for locally advanced pancreatic cancer (LAPC). This article provides an overview of available data with regard to morbidity and oncological outcome of novel local therapies for LAPC.


Introduction
Pancreatic adenocarcinoma is one of the most aggressive forms of cancer and is projected to arise as the second leading cause of cancer-related deaths in Europe and the United States by 2030 [1]. The prognosis has hardly improved over the past two decades and remains dismal, with an overall 5-year survival rate of approximately 8% [2,3]. Surgical resection is the only treatment option with the potential for long-term survival and cure. Even after potential curative resection, most patients will eventually have recurrent disease, resulting in a 5-year survival of only 20% [4]. Because early symptoms are often vague and mild, roughly 30% of patients with pancreatic cancer present with locally advanced pancreatic carcinoma (LAPC) and approximately 50% with metastatic disease (mPC) [5].
Systemic chemotherapy is considered the standard of care for patients with LAPC (AJCC stage III) and mPC (AJCC stage IV) [6]. The FOLFIRINOX regimen (combination chemotherapy using fluorouracil, leucovorin (folinic acid), irinotecan, and oxaliplatin) has emerged over the last years as a therapy that improves survival (median overall survival (OS) 11.1 months for FOLFIRINOX vs. 6.8 months for gemcitabine for mPC), at the cost of a greater concomitant toxicity [7]. International medical oncology guidelines extrapolate these results and hence recommend the use of FOLFIRINOX as the standard of care for mPC and for LAPC patients with a good performance status and no major comorbidities [4,8,9].
Considering the poor survival of LAPC patients, a lot of research from the last decade focused on combining systemic chemotherapy with local ablative therapies, such as radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, irreversible electroporation (IRE), stereotactic body radiation therapy (SBRT), iodine-125 seed implantation, high-intensity focused ultrasound (HIFU), and photodynamic therapy (PDT). The ablative techniques all share the mutual goal to achieve local tumor control, as this likely impacts quality-of-life and survival.

Microwave Ablation (MWA)
Currently available data on microwave ablation for LAPC is limited. Lygidakis et al. studied the feasibility, safety, and efficacy of MWA in 15 patients with histologically proven LAPC [27]. In all patients, partial necrosis was achieved whilst no major procedure-related morbidity or mortality occurred. Carrafiello and colleagues retrospectively reviewed ten patients treated with percutaneous (n = 5) or laparotomic (n = 5) MWA [11]. The 9-month and 1-year local tumor progression rates per new response evaluation criteria in solid tumours (RECIST 1.1) were 37.5% (3/8) and 62.5% (5/8), respectively [28]. In 20% of the patients, minor complications were registered. Two grade 3 or more complications were registered: pancreatitis (grade 3; n = 1) and pseudoaneurysm of the gastroduodenal artery (grade 4; n = 1).

Cryoablation
Two studies compared cryoablation plus palliative bypass surgery (PBC group) to bypass surgery alone (PB group) [29,30]. Although both studies found tumor mass shrinkage in the PBC group, OS was not significantly different from the patients in the PB group (350 days versus 257 days, p = 0.124; 5 months versus 4 months, p > 0.05). The postoperative complication rate in the study from Li et al. was not significantly different between the two groups, except for delayed gastric emptying, which was higher in the PBC group (35.7% in PBC group vs. 5.3% in PB group) [29]. Main postoperative complications included pancreatic or biliary leakage, GI bleeding or obstruction, delayed gastric emptying, infection or intra-abdominal bleeding [29,30].

Iodine-125 Seed Implantation
Two studies from Wang et al. treated a total of 28 patients (who were considered unresectable) during laparotomy with 125 I seed implantation [62,63]. Median irradiation dose was 120 Gy (range 60-163 Gy). Seven patients received an additional 35-50 Gy external beam radiotherapy (EBRT) and ten patients received 2-10 cycles of adjuvant chemotherapy. The overall local control rate was 87.5% (n = 24), median OS 10.1 months. In the majority of patient pain relief was classified as good or medium (94.1%). Adverse events included a chylous fistula (n = 1), gastric ulcer (n = 1), radiation enteritis (n = 2), and transient fever (n = 10). In two patients, seeds migrated to the liver, however without any side effects.
Xu et al. investigated the combination of 125 I seed implantation with cryosurgery in 49 patients with LAPC, of which 12 patients had hepatic metastases [64,65]. Seeds were implanted during cryosurgery in 35 patients, or 3-9 days after cryosurgery in 14 patients. Twenty patients received additional (1-4 cycles) chemotherapy. After a median follow-up (FU) of 18 months, the median survival was 16.2 months. The majority of patients experienced abdominal pain (n = 34) and/or fever (n = 26). Other adverse events included acute pancreatitis (n = 6), increased amylase levels (n = 25), abdominal bleeding (n = 3), pulmonary infection (n = 3), myocardial infarction (n = 1) and cerebral infarction (n = 1). Iodine-125 seed implantation has also been investigated in combination with RFA by Zou et al. [66]. Twenty-four patients with stage III pancreatic cancer, identified during laparotomy, were treated with intraoperative RFA plus seed implantation. Pain scores decreased significantly after the operation (p < 0.05). The median OS was 19 months. One patient experienced acute pancreatitis, which was related to the RFA procedure.

Photodynamic Therapy (PDT)
One study, performed by Huggett et al., was published investigating PDT for patients with LAPC [82]. An earlier study from the same group studied the photosensitizer meso-tetrahydroxyphenyl chlorin (mTHPC), however, this study also included patients with stage 1 and 2 pancreatic cancer, whilst data for stage III pancreatic cancer could not be extracted separately [83]. The study from Huggett et al. used the photosensitizer verteporfin in 15 patients treated for LAPC, with a median tumor size of 4.0 cm [82]. One and three months after IRE, 11 and 6, respectively, out of 13 patients had stable disease. The median OS after PDT was 8.8 months and from diagnosis 15.5 months. Adverse events included mild to moderate pain (n = 3), transient increase in amylase levels (n = 1), mild diarrhea (n = 1), persistent steatorrhea (n = 1), and subclinical inflammatory changes on computed tomography (CT) (n = 2).

Electrochemotherapy (ECT)
Experience with ECT for LAPC is limited. Granata et al. investigated the safety and feasibility of ECT in 13 patients with LAPC [84]. No electrochemotherapy-related serious adverse events occurred. A transient, self-limiting supraventricular arrhythmia was detected in one patient. In four patients, delayed gastric emptying occurred, however without clinical significant symptoms. Other complications included: pleural effusion, ascites, and splenic infarction without thrombosis of the splenic vessels. The same research group also published an article regarding early radiological assessment of LAPC treated with ECT, elaborating the cohort to 19 patients [84,85]. One patient died within 48 h after treatment with ECT because of a complication, which has not been discussed in detail. No significant reduction of largest diameter by CT scan and magnetic resonance imaging (MRI) was observed. According to RECIST criteria, all patients showed stable disease using MRI, while on CT imaging one patient showed progressive disease. According to Choi criteria, all patients were considered in partial response. Using functional MR derived parameters, a significant reduction of viable tumor tissue was observed.

Discussion
This study presents an overview of the available literature on local ablative therapies for LAPC. The most data was available for RFA, SBRT, IRE and HIFU. The main shortcoming affecting all techniques is the lack of randomized controlled trials determining the (additional) value of local ablative technique above systemic palliative chemotherapy alone. The comparative analysis of treatment options is also hampered by the fact that until recently there was no globally accepted standard of care for LAPC [86] Potential selection biases, such as the lack of consensus regarding resectability criteria and the heterogeneous use of (neo-)adjuvant chemo(radio)therapy plus consequential timing of the ablative procedure, further impede a reliable assessment [21,[86][87][88]. Since protracted courses of neo-adjuvant therapy will exclude patients with early disease progression from receiving ablative therapy, the OS for the ablated group will likely increase given the biologically favorable nature of the tumor. Nonetheless the reported OS, especially after SBRT and IRE, remains promising. Besides the goal to achieve local tumor control, downstaging to resectable disease has also been reported after local ablative therapies as SBRT and IRE (see Tables 3 and 4). Although the number of patients that were able to undergo resection is low, local ablative therapies can create curative potential for patients who were actually designated to palliative therapy only.
All local therapies described in this article have their own distinct advantages and disadvantages (Table 5). Although the survival benefit of adding traditional fractionated external-beam radiotherapy to chemotherapy regimens remains controversial [14][15][16], SBRT allows for limited fractions, decreased toxicity, and more promising survival outcomes (median OS reaching 20 months; Figure 1) [56,89,90]. Furthermore, patients can be treated in the outpatient setting because the technique is minimally invasive, with the exception of the need to implant fiducials [89]. The latter may be overcome by MRI-guided radiation therapy [91]. This technique continuously images soft-tissue during radiation treatment, allowing for accurate alignment of the tumor to the treatment beams, and does not require fiducials [91]. Physicians should be aware of the risk of late complications (i.e., >3 months after SBRT) and the inability of retreatment in the case of local failure. The literature on SBRT is heterogeneous with regards to delivered radiation doses and fractions, which confounds the comparison of SBRT to other local ablative therapies [90].   Similar to SBRT, HIFU does not require needle placement. Although the number of articles on HIFU for LAPC is relatively high, the number of patients per series was limited and the majority focused on pain relief without reporting oncological outcomes [92]. Pain can effectively be relieved by HIFU in 78.6-87.5% of patients, albeit at the cost of major skin burns (grade 2 or 3) and/or subcutaneous fat sclerosis, [31,35,36,39].
Due to the anatomical location of pancreatic cancer, RFA in the pancreas is associated with a high morbidity and mortality, since heating can seriously damage critical blood vessels, bile ducts and gastro-intestinal structures [93]. For this reason RFA has been largely abandoned, with the exception of one group who advocates the use of a large safety margin to these critical structures. Hence the primary aim of the technique is cytoreduction [22,87]. The continuous cooling caused by nearby blood vessels may further negatively impact the effect of RFA (heat-sink effect) [93]. On the other hand, RFA is relatively easily applicable, has a superior availability, and low costs. Pancreatic RFA is mostly performed during open laparotomy, which has the advantage of the exploration of the peritoneal cavity to identify unsuspected disease and therefore withhold patients from unnecessary treatment with RFA. Although the percutaneous approach may be more suitable to palliate patients, only one study investigated this approach [24].
Similar to thermal ablation, IRE can also be performed during open laparotomy or percutaneously. IRE has the theoretical advantage that the goal is to radically ablate the entire macroscopically visible tumor and hence achieve local tumor control. Since the working mechanism of IRE is based on the destruction of cellular membranes, whilst preserving the extracellular matrix, blood vessels and bile ducts remain intact [93]. Moreover, since the working mechanism is not based on thermal energy, IRE is not affected by the heat-sink effect [93]. These two characteristics make the use of pulsed electrical fields a promising technique for LAPC. These statements seem to be supported by the OS found in literature (range 15.3-27.0 months; Figure 1) [94]. However, IRE is known to have a high learning curve and literature is heterogeneous with regards to the electrical settings used for the procedure [95]. This latter problem is currently being addressed by an international Delphi consensus study, aiming for a uniform applied protocol. The morbidity and mortality rates reported in the more recent prospective series seem to be higher than those from earlier retrospective reports, especially for the open approach [77].
The other techniques discussed in this review, i.e., PDT, MWA, cryoablation, ECT, and iodine-125 seed implantation, all proved feasible in the treatment of LAPC patients. However, the data is too limited to draw any hard conclusions with regards to safety and efficacy.

PDT
Preservation of connective tissues, maintaining the mechanical integrity of critical structures, such as intestines and blood vessels.
Limited data for pancreatic cancer.

Future Perspectives
As stated before, the main shortcoming of all local therapies is the lack of randomized controlled trials, comparing the additional value of local therapy over systemic chemotherapy. The currently ongoing CROSSFIRE-trial (ClinicalTrials.gov number NCT02791503), is a randomized controlled phase III trial comparing the outcome of FOLFIRINOX plus IRE with FOLFIRINOX plus MR-guided SBRT on OS for patients with LAPC. The PELICAN-trial (Dutch Trial Register number NTR5517), is another ongoing randomized controlled trial that compares the outcome on OS for patients with LAPC treated with FOLFIRINOX or gemcitabine plus RFA to treatment with chemotherapy only. The randomized phase III trial, organized by the Stanford University, aims to determine the additional value of SBRT over FOLFIRINOX alone (ClinicalTrials.gov number NCT01926197). These trials will hopefully further define the exact role of local therapies for patients with LAPC.
The current focus of several studies is the immunogenic potential of local ablative therapies. After the destruction of the tumor with a local ablative technique, antigen presenting cells (APCs) infiltrate the ablation zone [98]. These APCs then activate the immune system, specifically helper and cytotoxic T cells [98]. This may induce a so-called 'abscopal effect', referring to the phenomenon where localized treatment of the primary tumor induces a forceful immune response, targeting occult distant micrometastases, potentially prolonging tumor control and survival [99]. Besides the activation of the immune response, small studies also have shown a decrease of immunosuppressive cells after treatment with local ablative techniques [96]. Combining local ablative techniques with immunotherapy may potentially boost the immune system to suppress pancreatic cancer [97]. Another direction for future studies on LAPC is the correlation of treatment effectiveness or survival with genetic alterations. There are four commonly known mutated genes in pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4 [3]. Studies of precursor lesions found KRAS mutations to be one of the earliest alterations in pancreatic tumorigenesis, along with CDKN2A [3,[100][101][102]. In contrast, the inactivation of SMAD4 and TP53 were found in advanced pancreatic intraepithelial neoplasias grade 3 and invasive carcinomas [102]. A recent study from Paiella et al. showed patients with pancreatic cancer with a SMAD4 loss had a poorer prognosis after RFA [26]. In the future, it may be possible to identify subgroups of patients who will and will not benefit from local therapies.
Also currently investigated, though not addressed in this paper, are oncolytic viruses [103,104]. Viruses are designed with biological specificity to infect cancerous cells preferentially [104]. The direct working mechanism is overwhelming viral infection and lysis, which releases additional viral particles to infect neighboring cells and distant metastases [104]. Viral infections can also activate the immune system and aid the immune system to recognize and attack malignancies [104]. For instance, in the randomized phase II trial performed by Noonan et al., pelareorep (reolysin) was added to treatment with chemotherapy (carboplatin and paclitaxel) [103]. Pelareorep has cytotoxic effects on malignant cells with an activated RAS signaling pathway, due to mutations in the RAS proto-oncogene [103]. No survival benefit was found for patients treated with pelareorep, which could be due to a neutralized effect in the context of other (unknown) mutations. Although patients receiving pelareorep did not experience a survival benefit, a number of immune biomarkers were found that were associated with an improved disease control rate or progression free survival [103].

Conclusions
In conclusion, this review gives an overview of the currently available ablative techniques for the treatment of patients with LAPC, with their distinct advantages and disadvantages. Although the safety profile is generally defined as good, major adverse events can occur and even mortality has been reported for all techniques. In the absence of randomized controlled trials, high-quality evidence for any survival benefit over chemotherapy alone is lacking. Only one series, comparing IRE plus chemotherapy to chemotherapy alone, has used case matching and multivariate analysis to compare two historical cohorts [70]. Although OS was superior in the IRE group, several confounders remain. Nonetheless, the promising survival, especially for studies employing SBRT and IRE, warrant the setup of randomized controlled phase II and III trials to compare the available local ablative therapies and to assess the additive value of local therapy over chemotherapy alone.