Can preoperative radiotherapy reduce the risk of postoperative pancreatic fistula after pancreatoduodenectomy?

Postoperative pancreatic fistula (POPF) continues to represent a major challenge for pancreatic surgeons worldwide and is a source of significant perioperative morbidity and mortality after pancreatoduodenectomy (PD) (1). Both patient (i.e., body mass index) and gland-related (i.e., pancreatic texture and pancreatic duct width) risk factors for POPF are well established and have been incorporated into preoperative risk scores [e.g., alternative fistula risk score (aFRS) and Birmingham risk scores] (2,3). These factors are generally considered to be non-modifiable, whilst there is a lack of evidence that potentially modifiable factors can reduce POPF (e.g., anastomotic technique, pancreatic duct stent or somatostatin analogues) (4). By contrast, the impact of surgeon experience on POPF rates has not been widely studied in the literature (5). For the past decade, the Dutch Pancreatic Cancer Group (DPCG) has been leaders in the field of pancreatic surgery research and has undertaken several practice-changing clinical trials in this space (6-9). Based on their observation that preoperative chemoradiotherapy was associated with reduced POPF rates (10), DPCG hypothesized that preoperative stereotactic body radiotherapy (SBRT) may induce pancreatic fibrosis and thereby reduce the incidence of clinically relevant (CR)-POPF in high-risk patients (11).

Wismans et al. conducted a prospective multicentre phase II single-arm trial, which included 38 patients who were considered high-risk of POPF after PD based on non-pancreatic cancer indications for surgery [e.g., cholangiocarcinoma, duodenal cancer, intraductal papillary mucinous neoplasm (IPMN), neuroendocrine tumours (NET)] and non-dilated main pancreatic duct (11). Preoperatively, patients were administered a single dose of SBRT targeted at the expected location of the future pancreatic anastomosis (i.e., pancreatic neck/proximal body) and underwent PD approximately four weeks later. Preoperative SBRT was associated with acceptable toxicity and resulted in a significant increase in pancreatic ‘firmness’ as measured by durometry. However, surgeon assessment of ‘firmness’ at the time of PD indicated that the SBRT had not significantly altered the pancreatic tissue in the majority of patients (85%), and there was an absence of pancreatic fibrosis on pathological assessment in 63% of patients. Moreover, surgeons did not find that the technical difficulty of surgery was increased due to SBRT, and no patients required portal vein resection despite SBRT targeting the pancreatic neck. Considering that the incidence of CR-POPF in this study was significantly higher than a historical control group (57% vs. 34%, P=0.011), one may reasonably conclude that SBRT was either ineffective or potentially harmful in terms of increased POPF risk.

The authors must be commended on exploring a very interesting and novel approach aimed at reducing POPF after PD. The fact that 86% of screened patients were included in this trial is remarkable and a testament to the value placed on clinical research in DPCG participating centres. Given that pancreatic texture is considered to be an important factor in POPF, the authors’ hypothesis that preoperative SBRT may be beneficial was entirely reasonable. The authors have acknowledged that five weeks between SBRT and surgery may have been an insufficient time for clinically significant fibrosis to have developed, or alternatively it is possible that a single dose of SBRT was inadequate. Other risk factors for POPF (e.g., pancreatic duct width) are not affected by SBRT, which may also explain why there was no reduction in POPF rates. The authors included patients with non-pancreatic cancer indications for surgery and non-dilated pancreatic ducts in this study, but it would have been informative to present objective data on preoperative fistula risk scores in the cohort.

This study highlights an important limitation of the ISGPF classification of POPF (12), which can only be applied retrospectively and POPF grade is affected by variation in practice between surgeons and/or centres (e.g., use of intraoperative drains and drain removal policies). In the study by Wismans et al. (11), intraoperative drains were not placed in 45% of patients. Given the lack of any evidence that PD can be safely undertaken without drain placement in high-risk patients (13,14), the authors’ decision not to place intraoperative drains in a significant proportion of high-risk patients could be questioned. It is very likely that the need for postoperative radiological drainage of POPF-related fluid collections was more frequent in patients without intraoperative drains, and this may have converted some patients into grade B3 clinically relevant POPFs, who otherwise may have had biochemical leaks (if intraoperative drains had been placed). Given that CR-POPF is the most appropriate primary outcome, routine intraoperative drain placement for all high-risk patients should be considered for future studies on this topic, to prevent artificial inflation of CR-POPF due to variations in drain policy.

Limitations of the study by Wismans et al. (11) should also be considered when interpreting its findings. Despite being a prospective study, it is not a randomised controlled trial to provide high level comparative evidence. Moreover, radiation therapy is not a treatment indicated for non-cancer conditions and the likelihood of its application in the standard of care setting is low. Furthermore, considering the follow-up period, the long-term safety profile of radiation therapy in the selected patients has not been demonstrated.

As a direction for future research, it is worthwhile to note that the available evidence synthesis surrounding neoadjuvant chemoradiotherapy indicates that the risk of CR-POPF in patients who received such treatment before pancreatectomy is around 9.1% (15). Whether or not the radiation therapy contributed to this relatively lower rate of CR-POPF in pancreatic cancer patients remains unknown and may require future research.

In summary, the study by Wismans et al. (11) has reported a novel application for stereotactic radiotherapy to induce pancreatic fibrosis and potentially reduce the risk of POPF in high-risk patients undergoing PD. Although a conclusive answer to the research question posed in this study was not forthcoming, future studies with modifications in the study design could be justified.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-45/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.

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