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Pancreatic Cancer Interventional Oncology

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Pancreatic Cancer Interventional  Oncology

INTRODUCTION

INTERVENTIONAL ONCOLOGY

While surgical resection remains the only curative therapy for pancreatic cancer, 80% to 90% of patients present with unresectable tumors. While systemic chemotherapy and radiation therapy are optional treatment approaches for these individuals, the use of needle-guided ablation techniques such as radiofrequency ablation (RFA), cryoablation, microwave ablation (MWA) or irreversible electroporation (IRE) have emerged as treatment for individuals who are not candidates for the surgical management of pancreatic cancer. These interventional image-guided procedures provide minimally invasive alternatives for select patients with tumors located in inaccessible locations.

Interventional Oncology Procedures for Pancreatic Cancer

Percutaneous ablative techniques include both thermal and non-thermal approaches. Thermal approaches include heat-based procedures (radiofrequency and microwave ablation) and cold-based procedures (cryoablation). Thermal ablative techniques have been shown to be effective in the local treatment of tumors and are associated with a low recurrence rate. Irreversible electroporation is currently the only non-thermal ablative approach. As a result of the pancreas having a number of delicate structures and its anatomical location being near critical organs and structures such as the duodenum, common bile duct, splenic vessels, portal vein and abdominal aorta, ablative techniques must be used with caution and precision to avoid treatment complications. Currently available ablative techniques are described below.

Radiofrequency ablation (RFA)

A minimally invasive procedure that uses electrical energy and heat to destroy cancer cells. A needle or needles are inserted through the skin into the cancer tissue and an alternating current via one or more needle produces heat that causes coagulation necrosis and subsequent cell death. While RFA is a simple, repeatable, standardized, lower risk procedure, it is limited by only having a small area of effectiveness since electrical impedance develops as the tissue boils and becomes charred. This insulates the tissue from the electrical signal and results in an effective area of only a few millimeters. Despite widespread availability, there is limited data on RFA’s benefits in pancreatic cancer. A literature review of the sue of RFA for ed the oncological outcomes locally advanced pancreatic cancer reported overall survival (OS) ranging from 19 to 25.6 months with the use of RFA as second line treatment after chemotherapy associated with longer survival.2 The Pancreatic Locally advanced Irresectable Cancer Ablation in the Netherlands (PELICAN) trial (NCT03690323) is an ongoing study designed to study the effect of RFA after 2 months of chemotherapy with either four cycles of FOLFIRINOX or two cycles of nab-paclitaxel/gemcitabine compared to current standard treatment of palliative chemotherapy in patients with locally advanced pancreatic cancer.

Microwave ablation (MWA)

Uses high frequency microwave energy to heat and kill cancer cells. A thin probe containing an antenna which emits microwaves is into the tumor. The probe produces intense heat that destroys tumor tissue via coagulation necrosis, often within 10 minutes. Microwave ablation has a number of advantages over RFA including more predictable ablation volumes, more precise margins, shorter time to reaching lethal temperatures aster heating over a larger area, shorter procedure time, no need for a grounding pad, resistance to the heat sink effect, and less pain. Data on the use of MWA for pancreatic adenocarcinomas is limited with most studies reporting on tumor progression but not overall survival. While there are reports demonstrating technical success with both laparoscopic and percutaneous MWA approaches for the treatment of locally advanced pancreatic cancer with a 3 month local tumor recurrence rate of 10% and a complication rate of approximately 15% (compared to a complication rate of 40% with RFA), these studies have included only a limited number of patients.3-5 The use of MWA in combination with the immune checkpoint inhibitors durvalumab and tremelimumab in the treatment of locally unresectable advanced pancreatic cancer (NCT04156087).

Cryoablation

Cryoablation causes rapid cooling of the target tissue, resulting in intracellular ice crystal formation that destroys organelle and cell membranes and induces membrane pore formation that disrupts the electrochemical gradient. Cellular tonicity is also disturbed, causing lethal transmembrane fluid shifts. If these changes do not cause immediate cell death, they often initiate apoptosis. The ability to visualize ice ball formation, the edge of which marks the 0°C isotherm, in cryoablation on several imaging modalities is a particular benefit.

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Similar to MWA, there are only a limited number of smaller studies have been conducted which assess the use of percutaneous cryoablation to treat pancreatic tumors.6,7 An initial study of 32 patients with Stages II, III and IV pancreatic cancer and tumors measuring 2 to 11 cm reported a clinically benefit response for 84.4% of patients with a survival time of 15.9 months.6 OS at 6-, 12- and 24-months was 82.8%, 54.7%, and 27.3% respectively. Most patients also experienced a greater than 50% reduction in pain scores. Improvement in pain scores following the use of cryoablation to treat pancreatic tumors has also been reported in a more recent small patient series.7 This analgesic effect associated with cryoablation suggest it possible utility for the palliative treatment of locally advanced pancreatic cancer.

Irreversible electroporation (IRE)

IRE is a nonthermal ablation technique that induces cell death by disrupting the electric potential gradient across cell membranes, leading to the formation of permanent nanopores through the plasma membrane, altering cellular transport and ultimately cell homeostasis. The procedure involves the delivery of a series of high voltage direct current electrical pulses between two or more electrodes placed within a target area surrounding the tumor. Since IRE is primarily non-thermal, it resists the resist the heat-sink phenomenon in which high blood flow in vasculature near ablation targets thermoregulate tissue and mitigate ablative effects in tissue that plagues thermal ablation. IRE also spares vascular, ductal, and connective tissues within its ablation zone and can produce more defined ablation borders than other ablative approaches. The procedure can be performed percutaneously, laparoscopically, or via an open approach with two or more electrodes (up to a maximum of six) placed in or around the tumor.

There is a growing body of evidence supporting the use of IRE for the treatment of borderline resectable and unresectable pancreatic tumors.8-10 The largest of these studies, a 200-patient, multicenter registry of patients with stage 3 pancreatic cancer treated with IRE via an open surgical approach, reported a median OS of 24.9 months and a median local progression free interval of 10.7 months.11 Recently reported results from a multicenter registry which included 152 patients with locally advanced pancreatic cancer treated with IRE via an open approach at 6 different institutions reported a median OS, progression-free survival (PFS), and time to progression (TTP) from diagnosis were 30.7 months, 22.8 months, and 27.3 months, respectively.12 Narayanan et al. reported median OS following percutaneous IRE treatment was 14.2 months for 50 patients with locally advanced pancreatic cancer.13 Multivariate analysis indicated patients with tumors ≤3 cm had significantly longer median OS than patients with tumors >3 cm (16.2 vs. 9.9 months from time of IRE; p = 0.031). More recently, Ruarus et al. reported the results of the Phase II multicenter PANFIRE II study which prospectively enrolled 50 patients treated with CT-guided percutaneous IRE.14 The median OS from diagnosis for patients with LAPC was 17 months. For patients with local recurrence, the median OS was 16 months from the diagnosis of recurrence and 9 months from IRE treatment. Major complications (grade 3 or higher) have been reported in approximately 21% to 34% of patients treated with IRE.10,14 This includes the development of portal vein thrombosis, pancreatic fistulae, pancreatitis and hematomas.15 The ongoing multicenter, prospective, observational DIRECT study (NCT03899649) is designed to provide real-world data demonstrating the clinical utility and safety of the use of IRE in combination with chemotherapy in patients with Stage 3 pancreatic adenocarcinoma.

References

  1. 1. Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol. 2019;10:10–27.
  2. Ruarus A, Vroomen L, Puijk R, et al. Locally Advanced Pancreatic Cancer: A Review of Local Ablative Therapies. Cancers (Basel) 2018;10:16.
  3. Vogl TJ, Panahi B, Albrecht MH, Naguib NNN, Nour-Eldin NA, Gruber-Rouh T, Thompson ZM, Basten LM. Microwave ablation of pancreatic tumors. Minim Invasive Ther Allied Technol. 2018 Feb;27(1):33-40. doi: 10.1080/13645706.2017.1420664.
  4. Carrafiello G, Ierardi AM, Fontana F, Petrillo M, Floridi C, Lucchina N, Cuffari S, Dionigi G, Rotondo A, Fugazzola C. Microwave ablation of pancreatic head cancer: safety and efficacy. J Vasc Interv Radiol. 2013 Oct;24(10):1513-20. doi: 10.1016/j.jvir.2013.07.005.
  5. Ierardi AM, Biondetti P, Coppola A, Fumarola EM, Biasina AM, Alessio Angileri S, Carrafiello G. Percutaneous microwave thermosphere ablation of pancreatic tumours. Gland Surg. 2018 Apr;7(2):59-66. doi: 10.21037/gs.2017.11.05.
  6. Niu L, He L, Zhou L, et al. Percutaneous ultrasonography and computed tomography guided pancreatic cryoablation: feasibility and safety assessment. Cryobiology 2012;65:301-7.
  7. Wu Y, Gu Y, Zhang B, et al. Laparoscopic ultrasonography-guided cryoablation of locally advanced pancreatic cancer: a preliminary report. Jpn J Radiol 2022;40:86-9
  8. Lafranceschina S, Brunetti O, Delvecchio A, Conticchio M, Ammendola M, Currò G, et al. Systematic review of irreversible electroporation role in management of locally advanced pancreatic cancer. Cancers (Basel). 2019;11:1718. https://doi.org/10.3390/cancers11111718
  9. Ansari D, Kristoffersson S, Andersson R, Bergenfeldt M. The role of irreversible electroporation (IRE) for locally advanced pancreatic cancer: A systematic review of safety and efficacy. Scand J Gastroenterol. 2017;52:1165-1171. https://doi.org/10.1080/00365521.2017.1346705.
  10. Moris D, Machairas N, Tsilimigras DI, Prodromidou A, Ejaz A, Weiss M, et al. Systematic review of surgical and percutaneous irreversible electroporation in the treatment of locally advanced pancreatic cancer. Ann Surg Oncol. 2019;26:1657-1668. https://doi.org/10.1245/s10434-019-07261-7.
  11. Martin RC 2nd, Kwon D, Chalikonda S, Sellers M, Kotz E, Scoggins C, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. 2015;262:486‐494. https://doi.org/10.1097/SLA.0000000000001441
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