A SMART-er approach to upfront unresectable pancreatic adenocarcinoma

Introduction

Pancreatic ductal adenocarcinoma (PDAC) presents one of the most formidable challenges in oncology. Most patients present with advanced unresectable disease that is associated with dismal survival rates (1). For many patients, particularly the elderly or those with significant comorbidities, therapeutic choices are limited, often reduced to palliative care (2). Traditional radiotherapy, while beneficial to some extent, is hampered by the proximity of critical gastrointestinal (GI) structures, which limits the delivery of doses necessary for effective tumor control (3).

Advances in radiotherapy techniques have sought to address this limitation by delivering high-dose radiation in a more precise and conformal manner, enabling dose escalation without exceeding normal tissue constraints (4). Dose escalation is associated with improved local control and survival outcomes in PDAC, particularly biologically effective doses with an α/β of 10 (BED₁₀) ≥70 (3) to 100 Gy (4). While the fractionation schedule (e.g., 5 vs. 15 vs. 25 fractions) may vary based on institutional practice and patient-specific considerations, the underlying principle remains the same: the total BED must reach an ablative threshold to optimize outcomes. As such, stereotactic body radiation therapy (SBRT) emerged as a more precise approach, allowing for higher doses over fewer fractions (5). However, even conventional computed tomography (CT)-based SBRT is limited by the challenge of accurately targeting the tumor while sparing surrounding healthy tissue (6,7). One known but rare complication in the use of SBRT is the risk of GI bleeding and/or vascular complications. Rates of GI bleeding vary by radiation delivery modality, with SBRT in the modern era reporting rates ranging from 4% to 11% (8).

The evolution of radiation therapy, particularly with the advent of stereotactic magnetic resonance-guided adaptive radiotherapy (SMART), heralds a new era in the treatment of this lethal disease (9). The phase II multi-institutional SMART trial exemplifies the potential of this technology to redefine the management of PDAC (10,11), offering a beacon of hope, especially for patients with inoperable disease. The recently published Danish phase II confirms many of the benefits seen with SMART for patients with locally advanced PDAC (LAPC) (12). Our commentary delves into the implications of these findings within the broader context of pancreatic cancer treatment, exploring how this new technology could reshape the therapeutic landscape for patients with PDAC.

The advent of daily magnetic resonance-guided radiotherapy (MRgRT)

The development of MRgRT for pancreatic cancer has marked a significant leap forward, transitioning from early cobalt-based systems to the more sophisticated combination magnetic resonance linear accelerator (MRL) technology (9). The initial commercially available MRgRT units utilized a tri-⁶⁰Co system (13,14). The subsequent shift to linac-based systems, exemplified by the integration of the 6 MV flattening filter-free (FFF) linac in the MRIdian system (13) and the 7 MV FFF linac in the Elekta Unity (15), represented a critical evolution. These linac-based magnetic resonance-guided linear accelerators (MRLs) provided higher energy beams, enabling more precise and potent radiation doses while maintaining the benefits of magnetic resonance imaging (MRI)-guidance.

The ViewRay MRIdian and Elekta Unity systems have been at the forefront of this technological advancement, with the MRIdian offering a low-field 0.345 T MRI and the Unity utilizing a conventional 1.5 T MRI. Each system presents distinct advantages; the MRIdian’s lower field strength reduces geometric distortions, enhancing real-time tumor tracking and automatic beam gating—features integral to its success in adaptive radiotherapy (16). In contrast, the Elekta Unity’s higher field strength allows for superior image quality and the potential for multiparametric imaging (17), which could further refine treatment planning and delivery. The global adoption of these systems has been significant, with over 112 units installed worldwide by the end of 2022, collectively performing tens of thousands of treatments and contributing to the expanding body of evidence supporting MRgRT (9).

Advantages of daily MRgRT in pancreatic cancer

The integration of MRI into radiotherapy through MRgRT offers several distinct advantages over traditional CT-guided approaches, particularly in the context of treating pancreatic cancer (10,11,18-22). A significant benefit is the superior soft tissue contrast that MRI provides compared to CT imaging. This enhanced visualization is crucial for pancreatic tumors, which are located near highly radiosensitive organs such as the duodenum, stomach, and bowel (23). These structures present substantial challenges in radiation therapy due to the difficulty in precisely delineating the tumor-tissue interfaces on CT scans. MRgRT’s enhanced imaging capabilities allow for more accurate identification of these critical structures, reducing the risk of inadvertent radiation exposure. Of note, recent data demonstrated that daily CT-based adaptive therapy has a favorable toxicity profile when treated to 40 Gy in 5 fractions (24), whereas MRgRT can be safely dose escalated to 50 Gy in 5 fractions (10).

Furthermore, MRgRT’s real-time tumor tracking and direct tumor gating offer advantages for pancreatic tumors, which are subject to respiratory motion. The use of MRI CINE in MRgRT enables continuous visualization of the tumor throughout the breathing cycle, allowing for precise delivery of radiation with smaller treatment margins. This approach obviates the need for larger internal target volumes (ITVs) typically required to account for tumor motion, thereby sparing more healthy tissue and reducing the likelihood of treatment-related toxicities. These features make MRgRT an exceptionally valuable tool in the management of pancreatic cancer, where the margin for error is exceedingly narrow (18).

One of the key advancements brought by linac-based MRgRT systems in the treatment of pancreatic cancer is the ability to perform daily adaptive radiotherapy. This technique allows for the modification of treatment plans based on daily imaging. The daily adaptive workflow expands the therapeutic window in several ways (25). In addition to adjusting the dose based upon daily anatomic variation, this workflow allows for daily feathering dose as each plan has a unique beam weighting and enables the treating physician to adjust coverage based upon their knowledge of prior plan coverage (25). This increased therapeutic window is especially useful in pancreatic cancer, where the tumor’s proximity to sensitive structures like the duodenum, stomach, and bowel has historically constrained the effectiveness of radiation therapy (3). By adapting to daily changes in tumor size, shape, and position, MRgRT can deliver higher doses to the tumor with greater precision, thus improving local control and potentially enhancing survival outcomes.

SMART in pancreatic cancer

The early work in MRgRT for pancreatic cancer laid the groundwork for what would become an essential tool in oncological treatment. Foundational studies, such as those conducted by Rudra et al., demonstrated that MRgRT could safely escalate radiation doses (18). Critically, it was shown that the higher doses that were safely achievable with adaptive MRgRT were associated with improvements in survival (18), supporting prior data that demonstrated a correlation with dose and survival (3). However, an important difference is that patients treated with adaptive MRgRT were not excluded from treatment due to the proximity of nearby radiosensitive structures, significantly increasing the potential patient pool that could benefit from dose-escalated therapy (22,26). An early phase I trial exploring MRL-based therapy for GI tumors by Henke et al. confirmed the improved safety profile (22). Additional early reports of higher dose escalation to a BED₁₀ of 100 Gy with 50 Gy in 5 fractions on MRLs continued to demonstrate excellent disease control and toxicity profiles (19,23).

The phase II SMART trial conducted at the Odense University Hospital in Odense, Denmark by Weisz Ejlsmark et al. was recently published in the Radiotherapy and Oncology journal (12) (Table 1). This trial was designed as a single-arm single-institution study that enrolled 28 patients with histologically confirmed LAPC between August 2018 and March 2022. This trial adds more prospective data for the use of SMART in LAPC, along with the also recently published SMART trial, a multi-institutional phase II study conducted across several centers in the United States between January 2019 and January 2022 (10). Two important distinctions are that the Danish study only included patients with LAPC and was performed on a 1.5 T MRL, whereas the U.S.-based SMART trial included patients with both borderline resectable pancreatic cancer (BRPC) and LAPC and was performed on a 0.35 T MRL.

One of the key inclusion criteria in the Danish trial was that all patients must have received at least two months of combination chemotherapy, with no evidence of disease progression before enrollment (12). This requirement was crucial in selecting patients who would benefit the most from a locally ablative modality, like SBRT. The primary endpoint of the trial was the resection rate, a clever endpoint given that surgical resection remains the only potential path to a cure in LAPC. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and treatment-related adverse events. The first 4 patients had CT-based SBRT, with the rest undergoing SMART on a 1.5 T MRL. SMART was performed with doses of either 50 Gy in five fractions or 60 Gy in 8 fractions, with the choice dependent on the size and location of the tumor.

The median time from diagnosis to the initiation of SBRT was 6.0 months (12). All but one patient received induction chemotherapy with FOLFIRINOX (67%) and gemcitabine-based (33%) therapies. The treatment was administered over a median duration of 8 days, with most patients receiving 50 Gy in 5 fractions (93%). Twenty-six patients (93.%) completed the planned SBRT regimen, with the two discontinuations being attributed to factors unrelated to the radiation therapy. With a median follow-up of 28.3 months, the study reported a median PFS of 7.8 months, a median OS of 16.5 months from the time of inclusion, and a median OS of 20.8 months from diagnosis. These results are in line with prior reported median OS for patients with PDAC tumors treated with SMART, such as Chuong et al., which reported a median OS of 22.8 months (10), and Rudra et al., which found a median OS of approximately 24 months in their high-dose cohort (18). Notably, six patients were still alive at the time of the final analysis, with five of them showing no evidence of active disease (12). Six patients experienced grade 3 treatment-related adverse events. There was one grade 4 event of duodenal perforation that occurred in a patient treated with CT-based SBRT rather than MR-guided therapy. The authors noted that the perforation was likely due to tumor progression rather than the radiation treatment itself, although the etiology could not be definitively determined. Overall, the study’s toxicity profile was consistent with previous reports, reaffirming the safety of SMART in this patient population.

We applaud Weisz Ejlsmark et al. for the successful completion of their phase II trial and especially for their primary endpoint choice of resection rate. Successful surgical resection remains the only curative option for patients with localized PDAC and its importance cannot be understated. Critically, patients with LAPC who have undergone multimodality preoperative therapy and successful surgery have a median OS that ranges from 35–58 months, in line with rates for patients with upfront resectable PDAC (27,28). Therefore, when delivering ablative RT for patients with LAPC, a delicate balance between disease control and toxicity must be maintained. Any toxicities that could potentially delay or make a patient medically inoperable despite the tumor itself converting to a resectable status are likely to impact their survival in addition to quality of life.

Six patients (21%) had surgery in the Danish trial, with four of the six resected patients achieving an R0 resection status. The median OS for patients who underwent resection from the time of diagnosis was 27.7 months. These findings align with the outcomes reported in the SMART trial by Chuong et al., where patients who underwent surgical resection after MR-guided SBRT had a 2-year OS rate of approximately 67% (10). Similarly, we reported a 2-year OS rate of 82% for patients who were able to proceed to surgery following SMART at our center (21). These results underscore the critical role of surgery as a critical component of long-term survival in this patient population. The median time from SBRT to resection was 2.9 months in the Danish trial, which is slightly longer as compared to the length reported in the studies by Chuong et al. and our single institution experience, where the times from RT to resection were 55 and 50 days, respectively. It is not reported as to whether any of the toxicities associated with SMART contributed to the longer time or if it reflects a difference in the surgical approach to preoperative ablative radiotherapy. However, surgical morbidity post ablative SMART was not significantly increased as none of the patients experienced any treatment-related adverse events after one month, in line with prior data (12,21).

Future directions

Looking ahead, further research is needed to refine the use of SMART in PDAC. Long-term studies will be essential to fully understand the potential of this technology and to optimize its use in combination with other treatments, such as irreversible electroporation (IRE) and immunotherapy. A phase I trial looking at the combination of SMART with IRE and immune checkpoint inhibitor therapy, entitled “Irreversible Electroporation & Pembro Immunotherapy in Locally Advanced Pancreatic Cancer” is active and enrolling at our center (#NCT06378047). This novel treatment paradigm is based on an evolutionary dynamics model and is the first to adapt insights from Anthropocene extinction events into treating PDAC with the aim of inducing permanent changes within the tumor microenvironment. Additionally, building on the promising early reports of ablative radiotherapy for upfront unresectable cases, there is an increasing effort to investigate ablative dose radiotherapy in a randomized, prospective setting following neoadjuvant chemotherapy.

Conclusions

The ongoing evolution of SMART represents a significant advancement in the treatment of upfront unresectable PDAC, offering new avenues for patients who traditionally had few viable options. Data continues to support the excellent safety profile and disease control outcomes of SMART. SMART has demonstrated the potential to widen the therapeutic window of radiation therapy in pancreatic cancer. While challenges remain in optimizing this technology, the consistency of results across multiple studies underscores the importance of further research and clinical trials to refine and expand the use of SMART. As we look forward to the outcomes of ongoing trials like LAP-ABLATE and others combining SMART with novel therapies, SMART holds promise for significantly altering the therapeutic landscape for pancreatic cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-186/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-186/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/.

References

1. Howlader N, Noone AM, Krapcho M, et al. editors. SEER Cancer Statistics Review, 1975–2017. Bethesda, MD: National Cancer Institute; 2020.
2. Higuera O, Ghanem I, Nasimi R, et al. Management of pancreatic cancer in the elderly. World J Gastroenterol 2016;22:764-75. [Crossref] [PubMed]
3. Krishnan S, Chadha AS, Suh Y, et al. Focal Radiation Therapy Dose Escalation Improves Overall Survival in Locally Advanced Pancreatic Cancer Patients Receiving Induction Chemotherapy and Consolidative Chemoradiation. Int J Radiat Oncol Biol Phys 2016;94:755-65. [Crossref] [PubMed]
4. Reyngold M, O'Reilly EM, Varghese AM, et al. Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer. JAMA Oncol 2021;7:735-8. [Crossref] [PubMed]
5. Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 2005;76:48-53. [Crossref] [PubMed]
6. Shouman MA, Fuchs F, Walter F, et al. Stereotactic body radiotherapy for pancreatic cancer - A systematic review of prospective data. Clin Transl Radiat Oncol 2024;45:100738. [Crossref] [PubMed]
7. Noel CE, Parikh PJ, Spencer CR, et al. Comparison of onboard low-field magnetic resonance imaging versus onboard computed tomography for anatomy visualization in radiotherapy. Acta Oncol 2015;54:1474-82. [Crossref] [PubMed]
8. Petrelli F, Comito T, Ghidini A, et al. Stereotactic Body Radiation Therapy for Locally Advanced Pancreatic Cancer: A Systematic Review and Pooled Analysis of 19 Trials. Int J Radiat Oncol Biol Phys 2017;97:313-22. [Crossref] [PubMed]
9. Bryant JM, Weygand J, Keit E, et al. Stereotactic Magnetic Resonance-Guided Adaptive and Non-Adaptive Radiotherapy on Combination MR-Linear Accelerators: Current Practice and Future Directions. Cancers (Basel) 2023;15:2081. [Crossref] [PubMed]
10. Chuong MD, Lee P, Low DA, et al. Stereotactic MR-guided on-table adaptive radiation therapy (SMART) for borderline resectable and locally advanced pancreatic cancer: A multi-center, open-label phase 2 study. Radiother Oncol 2024;191:110064. [Crossref] [PubMed]
11. Parikh PJ, Lee P, Low DA, et al. A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer. Int J Radiat Oncol Biol Phys 2023;117:799-808. [Crossref] [PubMed]
12. Weisz Ejlsmark M, Bahij R, Schytte T, et al. Adaptive MRI-guided stereotactic body radiation therapy for locally advanced pancreatic cancer - A phase II study. Radiother Oncol 2024;197:110347. [Crossref] [PubMed]
13. Ménard C, van der Heide UA. Introduction: Magnetic resonance imaging comes of age in radiation oncology. Semin Radiat Oncol 2014;24:149-50. [Crossref] [PubMed]
14. Mutic S, Dempsey JF. The ViewRay system: magnetic resonance-guided and controlled radiotherapy. Semin Radiat Oncol 2014;24:196-9. [Crossref] [PubMed]
15. Lagendijk JJ, Raaymakers BW, van Vulpen M. The magnetic resonance imaging-linac system. Semin Radiat Oncol 2014;24:207-9. [Crossref] [PubMed]
16. Weygand J, Fuller CD, Ibbott GS, et al. Spatial Precision in Magnetic Resonance Imaging-Guided Radiation Therapy: The Role of Geometric Distortion. Int J Radiat Oncol Biol Phys 2016;95:1304-16. [Crossref] [PubMed]
17. Ghadimi DJ, Vahdani AM, Karimi H, et al. Deep Learning-Based Techniques in Glioma Brain Tumor Segmentation Using Multi-Parametric MRI: A Review on Clinical Applications and Future Outlooks. J Magn Reson Imaging 2025;61:1094-109. [Crossref] [PubMed]
18. Rudra S, Jiang N, Rosenberg SA, et al. Using adaptive magnetic resonance image-guided radiation therapy for treatment of inoperable pancreatic cancer. Cancer Med 2019;8:2123-32. [Crossref] [PubMed]
19. Hassanzadeh C, Rudra S, Bommireddy A, et al. Ablative Five-Fraction Stereotactic Body Radiation Therapy for Inoperable Pancreatic Cancer Using Online MR-Guided Adaptation. Adv Radiat Oncol 2021;6:100506. [Crossref] [PubMed]
20. Bryant JM, Palm RF, Herrera R, et al. Multi-Institutional Outcomes of Patients Aged 75 years and Older With Pancreatic Ductal Adenocarcinoma Treated With 5-Fraction Ablative Stereotactic Magnetic Resonance Image-Guided Adaptive Radiation Therapy (A-SMART). Cancer Control 2023;30:10732748221150228. [Crossref] [PubMed]
21. Bryant JM, Palm RF, Liveringhouse C, et al. Surgical and Pathologic Outcomes of Pancreatic Adenocarcinoma (PA) After Preoperative Ablative Stereotactic Magnetic Resonance Image Guided Adaptive Radiation Therapy (A-SMART). Adv Radiat Oncol 2022;7:101045. [Crossref] [PubMed]
22. Henke L, Kashani R, Robinson C, et al. Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen. Radiother Oncol 2018;126:519-26. [Crossref] [PubMed]
23. Chuong MD, Bryant J, Mittauer KE, et al. Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy With On-Table Adaptive Replanning and Elective Nodal Irradiation for Inoperable Pancreas Cancer. Pract Radiat Oncol 2021;11:134-47. [Crossref] [PubMed]
24. Lee A, Pasetsky J, Lavrova E, et al. CT-guided online adaptive stereotactic body radiotherapy for pancreas ductal adenocarcinoma: Dosimetric and initial clinical experience. Clin Transl Radiat Oncol 2024;48:100813. [Crossref] [PubMed]
25. Bryant JM, Cruz-Chamorro RJ, Gan A, et al. Structure-specific rigid dose accumulation dosimetric analysis of ablative stereotactic MRI-guided adaptive radiation therapy in ultracentral lung lesions. Commun Med (Lond) 2024;4:96. [Crossref] [PubMed]
26. Sim AJ, Hoffe SE, Latifi K, et al. A Practical Workflow for Magnetic Resonance-Guided Stereotactic Body Radiation Therapy to the Pancreas. Pract Radiat Oncol 2023;13:e45-53. [Crossref] [PubMed]
27. Gemenetzis G, Groot VP, Blair AB, et al. Survival in Locally Advanced Pancreatic Cancer After Neoadjuvant Therapy and Surgical Resection. Ann Surg 2019;270:340-7. [Crossref] [PubMed]
28. Truty MJ, Kendrick ML, Nagorney DM, et al. Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer. Ann Surg 2021;273:341-9. [Crossref] [PubMed]