The CROSSFIRE Study of Irreversible Electroporation for Pancreatic Cancer: Can IRE Improve Survival?

Irreversible electroporation (IRE) is a promising new ablation technique to fight pancreatic cancer. Cell death is achieved by delivering high-voltage pulses. The CROSSFIRE trial is an international phase 3, multicenter, randomized controlled trial comparing the effect of sterotactic ablative body radiotherapy (SABR) to percutaneous IRE after neoadjuvant FOLFIRINOX in patients with locally advanced pancreatic cancer. Primary participating centers are the VU University Medical Center (Amsterdam, the Netherlands) and the Miami Miller School of Medicine (Miami, Florida, USA).

Pancreatic adenocarcinoma is one of the most aggressive forms of cancer, with an increasing global incidence. The overall 2-year survival rate is less than 10% and has hardly improved over the past 2 decades. For nonmetastatic patients, the only opportunity for cure is complete surgical resection of the primary tumor. Unfortunately, because of the generally late presentation of the disease, only 10% to 12% of patients are candidates for surgical (curative) resection. Up to 40% of patients present with locally advanced pancreatic cancer (LAPC, AJCC stage III), for which median overall survival is approximately 1 year. Currently there is no consensus on how to manage LAPC.

Palliative chemotherapy using gemcitabine has demonstrated a median overall survival of 9.2 months to 11.7 months for patients with LAPC. Although potentially more effective regimens have become available, most studies have focused on patients with metastatic disease. A recent advancement in systemic therapy is FOLFIRINOX (fluorouracil, folinic acid, oxaliplatin, and irinotecan), which resulted in a significant improvement in overall survival of patients with metastatic disease.¹

Traditionally, trials using radiotherapy include the use of conventional external beam radiation (EBRT). This technique uses large radiation fields that inevitably deliver a high percentage of the radiation dose to surrounding critical structures. An advancement in radiation therapy is SABR, which can deliver higher doses of radiation more precisely to the tumor because of the rapid dose fall-off beyond the treated volumes. This limits the dose delivered to normal bowel, resulting in decreased toxicity and dose escalation to the tumor. In total, 16 studies (including 391 patients) investigated the effects of SABR for patients with LAPC.² No study group randomized patients between treatment arms. Complication rates varied from 0% to 25% and included gastroparesis, gastrointestinal bleeding, ulcers, anorexia, nausea/vomiting, and thrombosis of the superior mesenteric vein or inferior vena cava. No SABR-related mortality was reported. Median overall survival ranged from 6.2 months to 24 months.

Although 2 decades ago, image-guided tumor ablation techniques were still in their infancy, today many different ablation techniques have substantially improved curative treatment possibilities for numerous types of localized cancer in many different organs. Different non-surgical thermal ablation techniques (cryoablation, radiofrequency ablation [RFA], high-intensity focused ultrasound [HIFU], laser-ablation and microwave ablation [MWA]) have been investigated to improve survival for patients with LAPC.^2,3 However, ablative therapies are limited due to the risk of thermal damage to nearby vital structures, association with high complication rate (28% to 40%), and high mortality rate (7.5%).³ Also, the so-called “heat-sink” effect, in which tumor cells near to large vessels are prevented from adequate heating due to blood flow cooling the adjacent tissue, can lead to incomplete ablation. This effect is another drawback in the performance of thermal ablation in LAPC, because major vessels typically surround the tumor.

Irreversible electroporation is a new, image-guided tumor ablation technique that takes advantage of the electric potential gradient that exists across cell membranes. The application of an electric field across a cell alters the cellular transmembrane potential. By reaching a sufficiently high voltage, the phospholipid bilayer structure of the cell membrane is permanently disrupted, inducing apoptosis and cell death. 

Tumors in contact with vessels can be treated with IRE without compromising the vessels or resulting in heat sink because its effectiveness relies on electrical energy. This makes IRE a very attractive option in patients with LAPC. Besides inducing local tumor destruction, IRE may also induce a systemic immune response (the “abscopal effect”).⁴ While the exact mechanism of the abscopal effect following local ablation has not been definitively demonstrated, it likely involves the induction of tumor-specific immunity through the activity of dendritic cells.

Five clinical studies were published regarding IRE in LAPC.^3,5,6 The overall complication rate was 57% for all patients (open 60%, percutaneous 27%), of which 13% were related to the IRE procedure (open 14%, percutaneous 9%). Overall and IRE-related mortality rates were 4% and 2% respectively. Morbidity related to the IRE procedure consisted mainly of duodenal leakage, pancreatic leakage, bile leakage and (progression of) portal vein thrombosis. Martin et al, in a study of 200 patients, suggested prolonged overall survival by 9 months (24.9 months).⁵ The IRE procedure was performed after unresectability had been confirmed during exploratory laparotomy, and was given in addition to standard treatment (palliative bypass when indicated, and adjuvant chemotherapy). 

Our research team recently finished the inclusion of the PANFIRE-I safety study (25 patients). Overall, the complication rate was acceptable with no mortality and 2 reversible grade IV complications. Preliminary results suggest prolonged progression-free survival (PFS) and overall survival.

There is a growing body of literature to suggest a beneficial role for combining local tumor destruction with systemic chemotherapy. The rationale for neoadjuvant FOLFIRINOX for patients with LAPC is to select patients who will most likely benefit from local tumor ablation; neoadjuvant therapies provide insight into the biology of the disease and can spare patients who progress or develop distant metastases during treatment. Additionally, neoadjuvant therapies have the potential to downstage the pancreatic tumor to resectable disease.

The CROSSFIRE phase 3 multicenter, randomized controlled trial will compare the effect of percutaneous IRE (experimental arm) to SABR (control arm) after neoadjuvant FOLFIRINOX (6 cycles). Prior to randomization, computed tomography imaging is performed to assess the effect of chemotherapy. 

In cases of metastatic disease, local tumor progression >5 cm, or resectable disease, patients will be excluded (drop-out). Patients who remain unresectable are randomized to undergo either percutaneous IRE or SABR. If patients that have been allocated to the SABR arm show local recurrence, the primary endpoint of progression is reached. If they still meet the inclusion criteria, a crossover to IRE is allowed. Also, a crossover to SABR is allowed after local failure of IRE (Figure 1).

The hypothesis of the study is that treatment with IRE will achieve better symptom palliation and local tumor control as compared to SABR. The primary outcome will be PFS with local progression free survival (LPFS), overall survival, safety/toxicity, quality of life, immunomodulation, tumor marker CA-19.9, and total direct and indirect costs as secondary outcomes. The study is scheduled to start including patients in early 2016.

Editor’s note: This article first appeared in the Synergy Daily conference newspaper, available to attendees of the Synergy Miami interventional oncology meeting in November 2015. This article did not undergo peer review. The authors report no disclosures. 

Suggested citation: Vroomen L, Scheffer H, Narayanan G, Meijerink M. The CROSSFIRE study of irreversible electroporation for pancreatic cancer: can IRE improve survival? Articles from the official show daily for Synergy 2015. Intervent Oncol 360. 2015;3(12):E151-E154.

References

1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.

2. Rombouts SJ, Vogel JA, van Santvoort HC. Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. Br J Surg. 2015;102(3):182-193.

3. Scheffer HJ, Nielsen K, de Jong MC, et al. Irreversible electroporation for nonthermal tumor ablation in the clinical setting: a systematic review of safety and efficacy. J Vasc Interv Radiol. 2014;25(7):997-1011.

4. Sideras K, Braat H, Kwekkeboom J, et al. Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies. Cancer Treat Rev. 2014;40(4):513-522. 

5. Martin RC 2nd, Kwon D, Chalikonda S, et al. Treatment of 200 locally advanced (stage III) pancreatic adenocarcinoma patients with irreversible electroporation: safety and efficacy. Ann Surg. 2015;262(3):486-494.

6. Narayanan G, Hosein PJ, Arora G, et al. Percutaneous irreversible electroporation for downstaging and control of unresectable pancreatic adenocarcinoma. J Vasc Interv Radiol. 2012;23(12):1613-1621.