Preoperative Stereotactic Radiotherapy to Prevent Pancreatic Fistula in High-Risk Patients Undergoing Pancreatoduodenectomy (FIBROPANC): Prospective Multicentre Phase II Single-Arm Trial

Anesthesiology Oncology Gastroenterology Medicine Hepatobiliary System
pancreatic fistula stereotactic radiotherapy pancreatoduodenectomy high-risk patients fibrosis safety efficacy

Pancreaticoduodenectomy is a common surgery for treating tumors of the pancreas and surrounding organs, but postoperative pancreatic fistula (POPF) is one of its major complications, especially in high-risk patients, where the incidence of POPF can be as high as 50%. POPF not only increases hospitalization time and medical costs but can also lead to severe infections, bleeding, and even death. Despite recent improvements in surgical techniques and postoperative management, the incidence of POPF has not significantly decreased. Therefore, finding effective preventive measures has become a focus of clinical research.

Previous studies have shown that preoperative chemoradiotherapy can significantly reduce the incidence of POPF in pancreatic cancer patients, which may be related to radiation-induced fibrosis. Fibrosis can increase the hardness of pancreatic tissue, thereby reducing the risk of tearing during surgery. However, for non-pancreatic cancer patients, the application of preoperative chemoradiotherapy lacks clear indications. Based on this, researchers hypothesized that a single preoperative dose of stereotactic body radiotherapy (SBRT) might reduce the incidence of POPF in high-risk patients by inducing local fibrosis.

Source of the Paper

This study was conducted by multiple researchers from the Dutch Pancreatic Cancer Group, with primary authors including Leonoor V. Wismans, Tessa E. Hendriks, and others, from several medical institutions in the Netherlands, such as Erasmus MC University Medical Center Rotterdam and Amsterdam UMC. The study was published in 2025 in the British Journal of Surgery (BJS) under the title “Preoperative stereotactic radiotherapy to prevent pancreatic fistula in high-risk patients undergoing pancreatoduodenectomy (FIBROPANC): prospective multicentre phase II single-arm trial.”

Research Process

Study Design and Participants

This study was a prospective, multicenter, single-arm phase II clinical trial aimed at evaluating the safety, feasibility, and efficacy of a single preoperative dose of SBRT in high-risk patients undergoing pancreaticoduodenectomy. The study included patients at high risk of POPF due to non-pancreatic ductal adenocarcinoma, with main inclusion criteria such as a main pancreatic duct diameter ≤3 mm, WHO performance status ≤2, and age ≥18 years. Exclusion criteria included chronic pancreatitis and benign tumors. The study was divided into a safety and feasibility assessment phase and an efficacy evaluation phase.

Intervention

All enrolled patients received a single 12 Gy dose of SBRT before pancreaticoduodenectomy, with the target area being the pancreatic neck (future resection site). Radiotherapy was delivered using MRI-guided SBRT or the CyberKnife system, with some patients receiving endoscopic ultrasound (EUS)-guided pancreatic fiducial markers. Surgery was performed at least 4 weeks after radiotherapy to ensure the formation of fibrosis.

Primary Endpoints

The primary endpoints of the study included safety (≤15% grade 3–5 toxicity), feasibility (significant changes in pancreatic tissue hardness), and efficacy (a 15% reduction in POPF incidence compared to a control group that did not receive SBRT). Safety was assessed by recording radiotherapy-related adverse events, feasibility was measured using a durometer to assess pancreatic tissue hardness, and efficacy was evaluated by comparing POPF incidence.

Secondary Endpoints

Secondary endpoints included the assessment of tissue fibrosis (collagen density) and the incidence of other postoperative complications. Collagen density was quantified using picrosirius red staining and digital pathology analysis.

Main Results

Safety

A total of 38 patients were enrolled, with 33 (87%) completing the study protocol. The safety endpoint was met, with only 1 patient (2.6%) experiencing grade 3 toxicity (acute pancreatitis) related to radiotherapy. Other adverse events were mild and did not require medical intervention.

Feasibility

Durometer measurements showed that pancreatic tissue hardness significantly increased after radiotherapy (median hardness 47 vs. 37 Shore OO units, p < 0.001). Collagen density analysis also revealed that the collagen density of irradiated tissue was significantly higher than that of non-irradiated tissue (6.1% vs. 4.6%, p = 0.003).

Efficacy

Among patients who received SBRT, 57.6% developed grade B/C POPF, while the incidence of POPF in the control group that did not receive SBRT was 34% (p = 0.011). This indicates that SBRT did not significantly reduce the incidence of POPF and may even have increased the risk of POPF.

Conclusion and Significance

This study is the first to evaluate the application of a single preoperative dose of SBRT in high-risk patients undergoing pancreaticoduodenectomy. The results show that SBRT is safe and can increase pancreatic tissue hardness and fibrosis but did not significantly reduce the incidence of POPF. This outcome may be related to factors such as radiation dose and the interval between radiotherapy and surgery. Future research could explore higher radiation doses or longer intervals after radiotherapy to further assess the potential value of SBRT.

Highlights of the Study

  1. Innovation: First evaluation of the preventive effect of preoperative SBRT in high-risk non-pancreatic cancer patients.
  2. Methodology: Use of a durometer and collagen density analysis to objectively assess changes in pancreatic tissue, providing reliable tools for future research.
  3. Clinical Significance: Although SBRT did not significantly reduce the incidence of POPF, its safety and enhancement of tissue hardness lay the foundation for future research.

Other Valuable Information

The study also found that some patients developed mild pancreatitis after radiotherapy, suggesting that radiotherapy may induce certain inflammatory responses in pancreatic tissue. Additionally, the research team suggested that future studies should combine other interventions, such as improved surgical techniques or postoperative management, to further reduce the incidence of POPF.

Through this study, we not only gained insights into the application of preoperative SBRT in high-risk patients but also provided important references and directions for future research.