To irradiate or electroporate: how should we ablate pancreatic cancer?
Editorial Commentary

To irradiate or electroporate: how should we ablate pancreatic cancer?

John Michael Bryant1, Justyn Nakashima1, Vaseem Khatri1, Mokenge Malafa2, Jessica Frakes1, Sarah Hoffe1,2

1Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Correspondence to: John Michael Bryant, MD. Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Email: john.bryant@moffitt.org.

Comment on: Timmer FEF, Geboers B, Ruarus AH, et al. MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): a single-centre, open-label, randomised phase 2 trial. Lancet Gastroenterol Hepatol 2024;9:448-59.

Keywords: Pancreatic cancer; irreversible electroporation (IRE); locally advanced pancreatic adenocarcinoma (LAPC); stereotactic body radiation therapy (SBRT); stereotactic ablative body radiation therapy (SABR therapy)

Received: 17 December 2024; Accepted: 24 March 2025; Published online: 17 April 2025.

doi: 10.21037/tgh-24-164

Introduction

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with limited advances in curative treatments over the past several decades (1). Despite improvements in systemic therapies such as FOLFIRINOX and gemcitabine-based regimens, the prognosis for patients with unresectable pancreatic cancer remains dire, with median overall survival (OS) ranging from 6 to 14 months depending on treatment intensity.

For patients with upfront unresectable PDAC, more aggressive therapeutic strategies often hinge on a combination of systemic therapy and locally ablative modalities that aim to improve local tumor control while mitigating systemic disease progression. Among these, radiation-based approaches and non-thermal ablative techniques have garnered significant attention for their ability to precisely target these deeply set tumors that are adjacent to critical structures.

Stereotactic ablative body radiation (SABR) therapy and its advanced iteration, stereotactic magnetic resonance imaging (MRI)-guided adaptive radiation therapy (SMART) (2,3), leverage precise image guidance (and daily adaptive planning in the case of SMART) to safely deliver high biologically effective doses (BED) to pancreatic tumors (4,5). These techniques offer enhanced tumor control while sparing nearby radiosensitive tissues, such as the duodenum and stomach. On the other hand, irreversible electroporation (IRE), a novel non-thermal ablative technique, uses high-voltage electrical pulses to disrupt cellular membranes, inducing apoptosis and necrosis while preserving the structural integrity of adjacent vasculature and ducts. This unique mechanism makes IRE particularly attractive for tumors in anatomically complex regions (6-9).

Both modalities show promise in enhancing local control and improving outcomes for patients with unresectable pancreatic cancer (4,6). However, their distinct mechanisms of action, potential synergies with systemic therapies, and comparative efficacy remain areas of active investigation (10,11). The recently published CROSSFIRE trial (12) represents a pivotal effort to elucidate these dynamics, directly comparing the outcomes of radiotherapy and IRE in the management of locally advanced pancreatic cancer (LAPC). This commentary critically examines the findings of the CROSSFIRE trial, evaluating its implications for locally ablative treatment strategies and their integration into the broader multimodal therapeutic landscape for PDAC.

SMART and IRE in unresectable pancreatic cancer

SMART and IRE have emerged as innovative locally ablative modalities in the treatment of unresectable pancreatic cancer, each offering unique advantages tailored to the challenges of this aggressive disease. SMART integrates high-dose precision radiation with the imaging benefits of MRI (13,14), enabling accurate tumor targeting in proximity to critical structures. Its capacity for real-time adaptive planning addresses daily anatomical changes, ensuring optimal tumor coverage while reducing radiation exposure to adjacent normal tissues (15). Clinical evidence highlights the efficacy of SMART in the management of upfront unresectable pancreatic cancer, with reported 1-year local control rates >80% (16,17). Median OS for patients treated with SMART spans 14 to 18 months, reflecting its potential to extend survival in this difficult-to-treat population (4,16). Additionally, SMART is associated with a favorable toxicity profile, with rates of grade 3 or higher gastrointestinal toxicities consistently below 10% (5,17), even in medically frail patient populations (18). Despite these advances, challenges such as the need for specialized infrastructure, prolonged treatment times, and high operational costs remain barriers to widespread implementation.

In contrast, IRE has emerged as a novel non-thermal ablative technique for the treatment of unresectable pancreatic cancer, offering distinct advantages for tumors located near critical anatomical structures. By delivering high-voltage electrical pulses, IRE disrupts cellular integrity while preserving the extracellular matrix and the structural integrity of nearby vasculature and ducts, making it particularly well-suited for anatomically challenging cases. Clinical evidence supports the efficacy of IRE, with reported median OS ranging from 15 to 27 months in patients with LAPC (6,19,20). Additionally, IRE has demonstrated durable local control rates exceeding 70% at 1 year in select patient populations (6,19,20). Beyond its local effects, IRE’s ability to induce immunogenic cell death introduces the potential for synergistic interactions with systemic therapies, such as immune checkpoint inhibitors (ICIs), representing an exciting frontier in multimodal treatment strategies (21). However, the technique is highly operator-dependent, requiring precise electrode placement and specialized expertise to minimize the risk of complications such as pancreatitis or vascular thrombosis. Furthermore, IRE requires general anesthesia, restricting its use to patients who are medically eligible for surgery.

Both modalities have demonstrated encouraging clinical outcomes. As evidence continues to accrue, these approaches may play pivotal roles in multimodal treatment strategies, addressing the dual challenges of local and systemic disease progression in PDAC. The CROSSFIRE trial represents a landmark effort to directly compare these two innovative approaches—SMART and IRE—evaluating their relative efficacy and safety in the management of LAPC.

Clinical implications

The CROSSFIRE trial provides a comparative investigation into MRI-guided stereotactic ablative body radiotherapy and computed tomography (CT)-guided IRE for LAPC (12). This randomized phase II trial enrolled 68 patients who had undergone 3–8 cycles of FOLFIRINOX chemotherapy (CHT) and were deemed non-metastatic. Patients were assigned to receive either SMART (referred to as MRI-guided SABR in the trial), delivered as 40 Gy in 5 fractions (BED10 =72 Gy with an α/β=10) on non-consecutive days, or CT-guided IRE under general anesthesia. The trial’s primary endpoint was OS, with secondary endpoints including progression-free survival (PFS), toxicity, and quality-of-life outcomes (12).

The median OS from randomization was 16.1 months [95% confidence interval (CI): 12.1–19.4] for the SMART cohort and 12.5 months (95% CI: 10.9–17.0) for the IRE group, though this difference did not reach statistical significance [hazard ratio (HR), 1.39; 95% CI: 0.84–2.30; P=0.21] (12). Interestingly, distant PFS was significantly better in the IRE cohort, with a hazard ratio of 0.42 (95% CI: 0.19–0.94; P=0.03), highlighting a potential systemic benefit associated with IRE. However, these results must be interpreted with caution. Differences in the number of neoadjuvant CHT cycles between groups raised concerns about potential confounding effects (22), though further analysis indicated no significant impact of cycle number on PFS outcomes (23). Moreover, the side effect profiles and invasiveness of these treatments diverge significantly. Grade 3–5 adverse events deemed possibly or likely treatment related were more frequent in the IRE group (22%) compared to the SMART group (6%) (P=0.07), and IRE required general anesthesia and hospitalization, whereas SMART was delivered in five outpatient sessions with shorter procedural times (12). Ultimately, the trial was stopped early for futility, with a conditional probability of only 13% to demonstrate superiority for either modality (12).

The CROSSFIRE trial demonstrated results that are similar to other reported prospective LAPC SMART studies (Table 1). In the SMART trial, a single-arm phase II study of 136 patients with borderline resectable pancreatic cancer (BRPC) or LAPC treated with SMART of 50 Gy in 5 daily fractions (BED10 =100 Gy with an α/β=10), the median OS from diagnosis was 22.8 months (95% CI: 20.4–25.1) (4). In contrast, the SMART arm in CROSSFIRE showed a median OS from diagnosis was 21.4 months (95% CI: 17.5 to 24.2). The SMART trial also reported a 2-year OS of 53.6%, with 34.6% of patients proceeding to surgical resection after radiation. However, surgery significantly improved survival in SMART (HR, 0.218; 95% CI: 0.104–0.454; P<0.001) (4), a treatment option absent in the CROSSFIRE protocol. Additionally, the IRE CROSSFIRE arm demonstrated an OS of 18.2 months (14.8 to 22.9), comparable to 17 months (95% CI: 15–19) in PANFIRE-2, which included 50 patients with LAPC or local recurrence (6) (Table 1). Adverse event profiles varied across the trials. In CROSSFIRE, grade 3–5 toxicity rates were 16% for SABR and 25% for IRE. By comparison, SMART reported a late grade ≥3 toxicity rate of 5.3%, while PANFIRE-2 documented an overall complication rate of 58% with IRE, reflecting the procedure’s invasiveness.

Table 1

Comparison of outcomes across CROSSFIRE trial and largest single arm IRE and SMART trials

Characteristics SMART Trial (single arm) CROSSFIRE Trial: SMART arm CROSSFIRE Trial: IRE arm PANFIRE-2 Trial (single arm)
Accrual location United States, Israel, Italy Amsterdam, Netherlands Amsterdam, Netherlands Amsterdam, Netherlands
n 136 32 32 50
Trial design Multi-center, prospective, phase II Single-center, phase II, superiority trial Single-center, phase II, superiority trial Multi-center, prospective, phase II
Resectability/stage BRPC (43.4%) or LAPC (56.5%) per institutional definition Unresectable (per NCCN), stage III, T4, LAPC Unresectable (per NCCN), stage III, T4, LAPC Unresectable LAPC, stage III (n=40)
Isolated local recurrence post-surgery (n=10)
Neoadjuvant therapy ≥3 months of any induction CHT ≥3 cycles of FOLFIRINOX ≥3 cycles of FOLFIRINOX FOLFIRINOX (n=28), gemcitabine +/− nab-paclitaxel (n=4), CAPOX (n=2), surgery (n=11)
No prior pancreatic surgeries No prior pancreatic surgeries
Maximum diameter N/A 5 cm 5 cm 5 cm
Performance status ECOG 0–1 WHO performance status 0–1 WHO performance status 0–1 N/A
Randomization N/A 1:1 1:1 N/A
Treatment modality MRI-guided RT (0.35 T) MRI-guided RT (0.35 T) Percutaneous approach with CT arteriography Percutaneous approach with CT guidance
Tumor location in head/uncinate process/neck 70.6% 79% 82% 71%
PTV expansion 3 mm 3 mm N/A N/A
Radiation dose and fractionation (BED10) 50 Gy in 5 daily fractions (100 Gy) 40 Gy in 5 non-consecutive daily fractions (72 Gy) N/A N/A
Electrode placement N/A N/A 5 mm tumor-free margin 5 mm tumor-free margin
Current N/A N/A 20–40 A 20–40 A
Pulses N/A N/A 90 90
Median needle electrodes N/A N/A 4 6
Median electrode pairs N/A N/A 6 9
Adjuvant therapy CHT (24.3%) and/or surgery (34.6%) (at discretion of physician) CHT for 12 cycles (at discretion of patient & physician) CHT for 12 cycles (at discretion of patient & physician) N/A
Primary endpoint Acute grade ≥3 GI toxicity definitely related to SMART OS from randomization OS from randomization Median OS from diagnosis
Median follow up, months 22.9 from Dx, 14.2 from SMART 13 13 N/A
Median OS, months 22.8 months from Dx, 14.2 months from SMART 16.1 months from randomization, 21.4 months from Dx 12.5 from randomization, 18.2 from Dx LAPC: 10 from IRE, 17 from Dx
Those treated with neoadjuvant FOLFIRINOX: 9 from IRE
Locally recurrent: 9 from IRE, 16 from Dx
Median local PFS from treatment, months N/A 17.9 10.2 10
Median distant PFS from treatment, months ~13* 8.5 13.2 11
Grade 3+ AE** Acute: 12 (8.8%) 5 (16%) 8 (25%) 21 (42%)
Late: 21 (16.1%)
Grade 5 AE** Acute: 2 (1.5%) 1 (3%) 1 (3%) 2 (4%)
Late: 1 (0.8%)

*, estimated from Kaplan-Meier curve. **, all reported adverse events (i.e., including events that may not be directly related to the locally ablative intervention). AE, adverse event; BRPC, borderline resectable pancreatic cancer; BED10, biologically effective dose with α/β=10; CAPOX, capecitabine and oxaliplatin; CHT, chemotherapy; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; FOLFIRINOX, folinic acid, fluorouracil, irinotecan, and oxaliplatin; GI, gastrointestinal; IRE, irreversible electroporation; LAPC, locally advanced pancreatic cancer; MRI, magnetic resonance imaging; N/A, not applicable; NCCN, National Comprehensive Cancer Network; OS, overall survival; PFS, progression-free survival; PTV, planning target volume; RT, radiation therapy; SMART, stereotactic magnetic resonance-guided adaptive radiation therapy; WHO, World Health Organization.

The contrasting results of these trials emphasize the importance of aligning treatment choice with patient characteristics and institutional expertise. SMART’s non-invasive nature and lower toxicity profile make it preferable for frail patients or those unable to undergo invasive procedures. Conversely, IRE’s apparent improvement in distant failure rate may be related to its ability to simulate a strong immune response.

The CROSSFIRE trial provides a strong foundation for future research. It underscores the need for larger, multicenter trials to validate these results and explores the potential for combining these modalities with systemic therapies. For instance, both modalities may synergize with checkpoint inhibitors. Ultimately, the CROSSFIRE trial reflects the complexity of managing LAPC and the ongoing evolution of locally ablative therapies. While neither modality emerged as definitively superior, the trial contributes to a growing body of evidence that will inform personalized treatment strategies and the design of future trials. By addressing key questions about safety, efficacy, and feasibility, CROSSFIRE sets the stage for further advancements in the fight against this challenging disease.

Future directions

The findings of the CROSSFIRE trial, alongside advancements in locally ablative therapies, underscore critical opportunities for improving outcomes in LAPC. As systemic therapies evolve, integrating locally ablative modalities into multimodal treatment strategies holds significant promise.

One promising avenue is the combination of locally ablative therapies with systemic immunotherapy. The immunomodulatory effects of SABR and IRE, including their ability to enhance antigen presentation and induce immunogenic cell death, suggest they could synergistically prime the tumor microenvironment (TME) for ICIs. Preclinical studies demonstrate that IRE induces T-cell infiltration, reduces immunosuppressive cell populations, and enhances antigenicity in pancreatic tumors, effectively converting the immunologically “cold” TME into a more immune-responsive “hot” state (10). Similarly, SABR has been shown to stimulate systemic T-cell activation and enhance immune-mediated anti-tumor responses in preclinical models (24), making it a logical partner for ICIs. The ongoing phase 1 trial exploring a multistrike approach to LAPC combines SABR, IRE, and pembrolizumab, leveraging evolutionary oncology principles to optimize timing and sequencing of these therapies (25). This protocol integrates CHT and SMART as the first strike, followed by IRE to prime the TME, creating a window for ICIs to induce sustained systemic immune activation. This approach aims to capitalize on the transient immune-permissive state induced by IRE and SABR, potentially achieving durable responses by targeting residual tumor cells resistant to first-line therapies.

Biomarker-guided patient selection is another critical area for future research in LAPC. Biomarkers such as circulating tumor DNA (ctDNA), T-cell receptor clonality, and radiomic signatures could help identify patients most likely to benefit from specific ablative therapies or combinations. The integration of these biomarkers into clinical practice could improve personalized treatment strategies, reduce unnecessary toxicity, and enhance therapeutic efficacy.

Conclusions

The CROSSFIRE trial underscores the potential of SMART and IRE as complementary approaches for managing LAPC. While neither emerged as definitively superior, their distinct mechanisms and benefits highlight opportunities for further exploration. Combining these modalities into a unified treatment strategy offers a promising avenue for future research, leveraging the precision of SMART and the unique immunogenic potential of IRE. By building on the findings of CROSSFIRE and designing innovative trials to evaluate these combinations, we can advance the therapeutic landscape for this challenging disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-164/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-164/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/tgh-24-164
Cite this article as: Bryant JM, Nakashima J, Khatri V, Malafa M, Frakes J, Hoffe S. To irradiate or electroporate: how should we ablate pancreatic cancer? Transl Gastroenterol Hepatol 2025;10:19.

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