Treatment strategies and clinical outcomes in consecutive patients with locally advanced pancreatic cancer: A multicenter prospective cohort.

INTRODUCTION: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC. MATERIALS AND METHODS: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy. RESULTS: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34). CONCLUSION: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice.

Computed tomography findings after radiofrequency ablation in locally advanced pancreatic cancer.

PURPOSE: The purpose of the study was to provide a systematic evaluation of the computed tomography(CT) findings after radiofrequency ablation (RFA) in locally advanced pancreatic cancer(LAPC). METHODS: Eighteen patients with intra-operative RFA-treated LAPC were included in a prospective case series. All CT-scans performed prior to RFA and 1 week and 3 months of post-RFA, according to standard regimen, were assessed by two radiologists in consensus, using standardized radiological scoring lists. RESULTS: 51 CT-scans were assessed. One week after RFA, the ablation zone was visible in all patients as a (partially) sharply defined (83%), heterogeneous area (94%). At 3 months of follow-up, the ablation zone was completely invaded by tumor in 67% of patients and still present, but decreased in 33%. In two patients (11%), local thrombosis and/or occlusion of the superior mesenteric vein occurred. The occlusions persisted without clinical consequences and the thrombosis disappeared. A peripancreatic fluid collection was visible 1 week after RFA in 3 patients, wherein the ablation zone extended ventrally outside of the pancreas. CONCLUSIONS: Directly after RFA for LAPC, a well-defined ablation zone is visible on CT-imaging. This ablation zone is usually replaced by tumor ingrowth after 3 months. Moreover, the ablation zone regularly included vascular structures, with rare asymptomatic venous occlusion or thrombosis and without adverse effects on arteries.

Clinical and pathological outcomes after irreversible electroporation of the pancreas using two parallel plate electrodes: a porcine model.

BACKGROUND: Irreversible electroporation (IRE) by inserting needles around the tumor as treatment for locally advanced pancreatic cancer entails several disadvantages, such as incomplete ablation due to field inhomogeneity, technical difficulties in needle placement and a risk of pancreatic fistula development. This experimental study evaluates outcomes of IRE using paddles in a porcine model. METHODS: Six healthy pigs underwent laparotomy and were treated with 2 separate ablations (in head and tail of the pancreas). Follow-up consisted of clinical and laboratory parameters and contrast-enhanced computed tomography (ceCT) imaging. After 2 weeks, pancreatoduodenectomy was performed for histology and the pigs were terminated. RESULTS: All animals survived 14 days. None of the animals developed signs of infection or significant abdominal distention. Serum amylase and lipase peaked at day 1 postoperatively in all pigs, but normalized without signs of pancreatitis. On ceCT-imaging the ablation zone was visible as an ill-defined, hypodense lesion. No abscesses, cysts or ascites were seen. Histology showed a homogenous fibrotic lesion in all pigs. CONCLUSION: IRE ablation of healthy porcine pancreatic tissue using two plate electrodes is feasible and safe and creates a homogeneous fibrotic lesion. IRE-paddles should be tested on pancreatic adenocarcinoma to determine the effect in cancer tissue.

Induction Chemotherapy Followed by Resection or Irreversible Electroporation in Locally Advanced Pancreatic Cancer (IMPALA): A Prospective Cohort Study.

BACKGROUND: Following induction chemotherapy, both resection or irreversible electroporation (IRE) may further improve survival in patients with locally advanced pancreatic cancer (LAPC). However, prospective studies combining these strategies are currently lacking, and available studies only report on subgroups that completed treatment. This study aimed to determine the applicability and outcomes of resection and IRE in patients with nonprogressive LAPC after induction chemotherapy. METHODS: This was a prospective, single-center cohort study in consecutive patients with LAPC (September 2013 to March 2015). All patients were offered 3 months of induction chemotherapy (FOLFIRINOX or gemcitabine depending on performance status), followed by exploratory laparotomy for resection or IRE in patients with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 nonprogressive, IRE-eligible tumors. RESULTS: Of 132 patients with LAPC, 70% (n = 93) started with chemotherapy (46% [n = 61] FOLFIRINOX). After 3 months, 59 patients (64%) had nonprogressive disease, of whom 36 (27% of the entire cohort) underwent explorative laparotomy, resulting in 14 resections (11% of the entire cohort, 39% of the explored patients) and 15 IREs (11% of the entire cohort, 42% of the explored patients). After laparotomy, 44% (n = 16) of patients had Clavien-Dindo grade 3 or higher complications, and 90-day all-cause mortality was 11% (n = 4). With a median follow-up of 24 months, median overall survival after resection, IRE, and for all patients with nonprogressive disease without resection/IRE (n = 30) was 34, 16, and 15 months, respectively. The resection rate in 61 patients receiving FOLFIRINOX treatment was 20%. CONCLUSION: Induction chemotherapy followed by IRE or resection in nonprogressive LAPC led to resection or IRE in 22% of all-comers, with promising survival rates after resection but no apparent benefit of IRE, despite considerable morbidity. Registered at Netherlands Trial Register (NTR4230).

Irreversible Electroporation of the Pancreas Using Parallel Plate Electrodes in a Porcine Model: A Feasibility Study.

BACKGROUND: Irreversible electroporation (IRE) with needle electrodes is being explored as treatment option in locally advanced pancreatic cancer. Several studies have shown promising results with IRE needles, positioned around the tumor to achieve tumor ablation. Disadvantages are the technical difficulties for needle placement, the time needed to achieve tumor ablation, the risk of needle track seeding and most important the possible occurrence of postoperative pancreatic fistula via the needle tracks. The aim of this experimental study was to evaluate the feasibility of a new IRE-technique using two parallel plate electrodes, in a porcine model. METHODS: Twelve healthy pigs underwent laparotomy. The pancreas was mobilized to enable positioning of the paddles. A standard monophasic external cardiac defibrillator was used to perform an ablation in 3 separate parts of the pancreas; either a single application of 50 or 100J or a serial application of 4x50J. After 6 hours, pancreatectomy was performed for histology and pigs were terminated. RESULTS: Histology showed necrosis of pancreatic parenchyma with neutrophil influx in 5/12, 11/12 and 12/12 of the ablated areas at 50, 100, and 4x50J respectively. The electric current density threshold to achieve necrosis was 4.3, 5.1 and 3.4 A/cm2 respectively. The ablation threshold was significantly lower for the serial compared to the single applications (p = 0.003). The content of the ablated areas differed between the applications: areas treated with a single application of 50 J often contained vital areas without obvious necrosis, whereas half of the sections treated with 100 J showed small islands of normal looking cells surrounded by necrosis, while all sections receiving 4x 50 J showed a homogeneous necrotic lesion. CONCLUSION: Pancreatic tissue can be successfully ablated using two parallel paddles around the tissue. A serial application of 4x50J was most effective in creating a homogeneous necrotic lesion.

Systematic review on the treatment of isolated local recurrence of pancreatic cancer after surgery; re-resection, chemoradiotherapy and SBRT.

BACKGROUND: The majority of patients who have undergone a pancreatic resection for pancreatic cancer develop disease recurrence within two years. In around 30% of these patients, isolated local recurrence (ILR) is found. The aim of this study was to systematically review treatment options for this subgroup of patients. METHODS: A systematic search was performed in PubMed, Embase and the Cochrane Library. Studies reporting on the treatment of ILR after initial curative-intent resection of primary pancreatic cancer were included. Primary endpoints were morbidity, mortality and survival after ILR treatment. RESULTS: After screening 1152 studies, 18 studies reporting on 313 patients undergoing treatment for ILR were included. Treatment options for ILR included surgical re-resection (8 studies, 100 patients), chemoradiotherapy (7 studies, 153 patients) and stereotactic body radiation therapy (SBRT) (4 studies, 60 patients). Morbidity and mortality were reported for re-resection (29% and 1%, respectively), chemoradiotherapy (54% and 0%) and SBRT (3% and 1%). Most patients had a prolonged disease-free interval before recurrence. Median survival after treatment of ILR of up to 32, 19 and 16 months was reported for re-resection, chemoradiotherapy and SBRT, respectively. CONCLUSION: In selected patients, treatment of ILR following pancreatic resection for pancreatic cancer seems safe, feasible and associated with relatively good survival.

Recent Advances in Pancreatic Cancer Surgery of Relevance to the Practicing Pathologist.

Recent advances in pancreatic surgery have the potential to improve outcomes for patients with pancreatic cancer. We address 3 new, trending topics in pancreatic surgery that are of relevance to the pathologist. First, increasing awareness of the prognostic impact of intraoperatively detected extraregional and regional lymph node metastases and the international consensus definition on lymph node sampling and reporting. Second, neoadjuvant chemotherapy, which is capable of changing 10% to 20% of initially unresectable, to resectable disease. Third, in patients who remain unresectable following neoadjuvant chemotherapy, local ablative therapies may change indications for treatment and improve outcomes.

Systematic Review of Resection Rates and Clinical Outcomes After FOLFIRINOX-Based Treatment in Patients with Locally Advanced Pancreatic Cancer.

BACKGROUND: FOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with locally advanced pancreatic cancer (LAPC). Furthermore, it may downstage a proportion of LAPC into (borderline) resectable disease, however data are lacking. This review assessed outcomes after FOLFIRINOX-based therapy in LAPC. METHODS: The PubMed, EMBASE and Cochrane library databases were systematically searched for studies published to 31 August 2015. Primary outcome was the (R0) resection rate. RESULTS: Fourteen studies involving 365 patients with LAPC were included; three studies administered a modified FOLFIRINOX regimen. Of all patients, 57 % (n = 208) received radiotherapy. The pooled resection rate was 28 % (n = 103, 77 % R0), with a perioperative mortality of 3 % (n = 2), and median overall survival ranged from 8.9 to 25.0 months. Survival data after resection were scarce, with only one study reporting a median overall survival of 24.9 months in 28 patients. A complete pathologic response was found in 6 of 85 (7 %) resected specimens. Dose reductions were described in up to 65 % of patients, grade 3-4 toxicity occurred in 23 % (n = 51) of patients, and 2 % (n = 5) had to discontinue treatment. Data of patients treated solely with FOLFIRINOX, without additional radiotherapy, were available from 292 patients: resection rate was 12 % (n = 29, 70 % R0), with 15.7 months median overall survival and 19 % (n = 34) grade 3-4 toxicity. CONCLUSIONS: Outcomes after FOLFIRINOX-based therapy in patients with LAPC seem very promising but further prospective studies are needed, especially with regard to survival after resection.