Does neoadjuvant therapy reduce pancreatic fistula after pancreatoduodenectomy and distal pancreatectomy?—a systematic review and meta-analysis

Introduction

Pancreatic cancer is a growing global health concern, with approximately half a million patients being newly diagnosed annually (1-3). The prognosis for pancreatic cancer remains dismal, with a median survival of only 6–12 months with chemotherapy alone (4). Surgery offers the only potential for cure, increasing median survival to 55 months when followed by chemotherapy (5).

In pancreatoduodenectomy (Whipple procedure), the pancreatojejunostomy is often considered the Achilles’ heel due to its potential for complications. The incidence of postoperative pancreatic fistula (POPF) varies but can reach up to 30%, posing a serious risk to patients’ recovery, quality of life, and long-term outcomes (6,7). POPF after pancreatoduodenectomy is a major cause of mortality, with rates potentially reaching 8% (8). Similarly, morbidity after distal pancreatectomy for left-sided pancreatic cancers is also primarily attributed to POPF, which can occur at rates comparable to those observed after the Whipple procedure (7).

In the case of borderline resectable and locally advanced pancreatic cancer, upfront surgery (UPS) rarely achieves local tumor control and presents with poor outcomes. Neoadjuvant chemotherapy can significantly alter this course. In contrast, neoadjuvant treatment in resectable pancreatic cancer remains debated (9-11). With the increasing use of neoadjuvant therapy (NAT) in pancreatic cancer, surgeons have observed changes in the consistency of the pancreas during surgery. Pancreatic texture is a well-established risk factor for POPF (7). This observation has led to investigations into the potential impact of NAT on POPF development. However, the definition of POPF itself has undergone recent revisions. In 2005, the International Study Group of Pancreatic Fistula (ISGPF) proposed a standardized definition to facilitate comparisons among researchers (12). After 11 years in use, this classification was updated in 2016 based on accumulated experience (6). However, this update presents a challenge for comparing published outcomes across different eras, underscoring the need for a comprehensive analysis to clarify the relationship between NAT and POPF formation.

Herein, we present a meta-analysis on the impact of NAT on fistula development after pancreatic resection using current POPF definitions. We present this article in accordance with the PRISMA reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-121/rc). (13)

Methods

Search strategy and study selection

The study protocol was registered with PROSPERO (registration No. CRD42023435035). The work has been reported in line with AMSTAR (Assessing the methodological quality of systematic reviews) Guidelines (14). A comprehensive literature search was performed using the following electronic databases: PubMed/MEDLINE, Scopus, Embase, and the Cochrane Central Register of Controlled Trials. The search strategy employed a combination of keywords and Medical Subject Headings (MeSH) terms related to NAT, pancreatic fistula, pancreatectomy, pancreatoduodenectomy, and distal pancreatectomy. The search strategy was limited for studies since 2016 due to change in fistula definition. The updated final search was conducted in September 2024. Additionally, the reference lists of relevant articles were manually screened to identify any potentially eligible studies missed by the database searches. Studies were included if they met the following criteria:

• Reported the impact of NAT on POPF formation after pancreatoduodenectomy or distal pancreatectomy;
• Used the 2016 ISGPF definition for POPF;
• Were published as full-text articles in peer-reviewed journals;
• Studies published in the English language.

Studies were excluded if they:

• Included fewer than 10 patients;
• Were case reports, conference abstracts, editorials, or letters to the editor;
• Did not report data on POPF occurrence;
• Animal studies;
• No stratification or clear identification of patients with total pancreatectomies.

Data extraction and quality assessment

Two independent reviewers (S.H. and V.L.L.) screened the titles and abstracts of all identified citations. Full-text articles of potentially eligible studies were retrieved, and those meeting the inclusion criteria were selected for data extraction. Any disagreements between reviewers were resolved through discussion and consensus. For complex issues, the senior author was consulted to ensure a consensus.

Data extracted from each study included:

• Study characteristics (e.g., year of publication, study design, country);
• Patient demographics (e.g., age, sex);
• Type of NAT;
• Surgical procedure performed;
• Incidence of POPF (using the 2016 ISGPF definition);
• Pancreatic texture (if reported);
• Main pancreatic duct size (if reported).

The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies (15).

Data synthesis and statistical analysis

The meta-analysis was performed using R. A random-effects model was used to pool the data, given the anticipated heterogeneity between studies. The primary outcome, pancreatic fistula formation, was analyzed as a dichotomous variable, and the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. Initially, we analyzed the overall impact of NAT on POPF formation across all types of pancreatic resection included in the meta-analysis, excluding total pancreatectomy. In a subsequent step, we performed subgroup analyses to evaluate POPF formation separately for Whipple procedure and distal pancreatectomy. Further outcomes, including pancreatic texture and main pancreatic duct size, were also analyzed. Heterogeneity across studies was assessed using the I² statistic, with values interpreted according to the Cochrane Handbook (16). Artificial intelligence was used for language editing.

Results

Literature search results and study characteristics

Our systematic literature search initially identified 1,206 studies. After removing duplicates, 1,120 studies remained. Through manual searching of reference lists, an additional 57 studies were identified. Ultimately, 30 studies, encompassing 22,048 patients, met the inclusion criteria and were included in the final meta-analysis (17-41), with additional eligible studies (42-46). The detailed study selection process, including reasons for inclusion and exclusion, is presented in Figure 1 (provide an updated PRISMA flow diagram).

Figure 1 PRISMA flow diagram. ISGPF, International Study Group of Pancreatic Fistula; NAT, neoadjuvant therapy; POPF, postoperative pancreatic fistula; UPS, upfront surgery.

Of the included studies, 24 were comparative studies, directly comparing the rate of POPF in patients who received NAT with those who did not. The remaining 6 studies were single-arm cohorts evaluating POPF rates in patients following NAT. All studies included patients with pancreatic ductal adenocarcinoma in the NAT group, while 6 studies also included a small number of patients with other pancreatic tumors (such as neuroendocrine tumors or ampullary cancers) in the UPS group. In the included studies, radiotherapy was administered in minority of patients in conjunction with neoadjuvant chemotherapy. Chemotherapy regimens varied, with FOLFIRINOX and gemcitabine based being the most common regimen. All included studies were retrospective in design. A summary of the study characteristics, including risk of bias assessment using the NOS, is provided in Table 1.

Does NAT reduce the risk of pancreatic fistula?

Data comparing POPF rates in patients who received NAT versus those who underwent UPS were available in 24 studies. The analyzed data includes both Whipple procedure and distal pancreatectomy. The pooled analysis of these comparative studies demonstrated a significantly lower POPF rate in the NAT group (RR, 0.56; 95% CI: 0.46–0.70; P<0.01). However, there was statistically significant moderate heterogeneity among the studies (I² =47%, P<0.01), indicating some variability in the effect size across the included studies.

In addition to the comparative studies, we analyzed data from single-arm studies reporting POPF rates. Among patients who received NAT, the pooled POPF rate was 9% (95% CI: 7–12%). In contrast, the pooled POPF rate for patients undergoing upfront surgical resection was 16% (95% CI: 13–20%).

Do POPF rates differ after Whipple?

Next, we performed a subgroup analysis to evaluate the impact of NAT on POPF rates after Whipple procedure. Data for this analysis were available from 16 studies. The pooled analysis of these comparative studies demonstrated a significantly lower POPF rate in the NAT group (RR, 0.44; 95% CI: 0.38–0.52; P<0.01; heterogeneity I²=8%, P=0.36) (Figure 2). Analysis of single-arm studies showed a POPF rate of 7% (95% CI: 5–9%) in patients who received NAT prior to pancreatoduodenectomy. In contrast, the pooled POPF rate for patients undergoing upfront surgical resection was 16% (95% CI: 12–20%).

Figure 2 Fistula rate after pancreatic head resection. CI, confidence interval; RR, risk ratio.

To isolate the effect of chemotherapy on POPF, we conducted a further subgroup analysis including only studies that reported on patients who received neoadjuvant chemotherapy alone, without radiotherapy. This analysis was limited to 4 studies, as most studies included a small number of patients who received neoadjuvant chemotherapy with the addition of radiotherapy. In this analysis, neoadjuvant chemotherapy alone was also associated with a significant reduction in POPF rate compared to UPS (RR, 0.45; 95% CI: 0.23–0.84; P=0.01; heterogeneity I²=0, P=0.60). Due to the limited available data, an analysis comparing the effects of radiochemotherapy versus chemotherapy alone or UPS was not feasible.

We conducted a similar analysis to assess the impact of NAT on POPF rates after distal pancreatectomy. Results are provided in an Appendix 1 with a brief discussion.

How does POPF reduction after NAT impact other outcomes in Whipple procedure?

Since there was no significant difference in POPF development after distal pancreatectomy, we focused this analysis on patients who underwent Whipple procedure. First, we analyzed the total complication rate. This analysis revealed no significant difference in the total complication rate between patients who received NAT and those who did not (RR 1.08; 95% CI: 0.87–1.34; P=0.50). Similarly, there was no significant difference in 90-day mortality rate between the two groups (RR 1.07; 95% CI: 0.50–2.30; P=0.90; heterogeneity I²=45%, P=0.12). It is worth noting that both mortality and morbidity analyses included only 5 studies, as other studies had to be excluded due to mixed reporting, which may have limited the power of these analyses.

Analysis of hospital stay also showed no significant difference between patients who received NAT and those who did not [mean difference (MD) −0.83; 95% CI: −1.8 to 0.13; P<0.09; I²=95%, P<0.001].

Do NAT and UPS groups differ in other fistula risk factors?

There was a significant association between NAT and the occurrence of a harder pancreatic gland texture (RR, 1.27; 95% CI: 1.23–1.32; Z=14.7; P<0.001; heterogeneity I²=0%, P=0.50). In studies reporting pancreatic duct size, there was no significant difference in duct size between the NAT and UPS groups (MD 0.58; 95% CI: −3.1 to 4.2; P=0.60; I²=99%, P<0.001). Similarly, there was no significant difference in BMI between the NAT and UPS groups (MD 0.30; 95% CI: −0.5 to 1.2; P=0.40; I²=98%, P<0.001). However, there was a significant difference in age between the two groups, with patients receiving NAT being slightly younger on average (MD −0.60; 95% CI: −1.0 to −0.17; P=0.01; I²=98%, P<0.001).

Discussion

This systematic review and meta-analysis highlighted that the POPF rate after Whipple procedure is significantly reduced when NAT is administered. This finding has important implications for the management of pancreatic cancer, particularly in the context of multimodal treatment approaches.

NAT has become a standard approach for locally advanced and borderline resectable pancreatic cancer (9,11,47). While several randomized controlled trials have investigated NAT in resectable pancreatic cancer, its role in this setting is still evolving and is not yet considered a standard of care (11,47). Despite the ongoing debate, this meta-analysis indicates that NAT reduces POPF rates after Whipple procedure, offering a clear benefit in this context. It is well known that the presence of POPF can delay the start of adjuvant treatment, which can, in turn, negatively affect long-term survival outcomes. A harder pancreatic texture is associated with lower POPF rates in Whipple procedures, and this reduction in POPF is likely to positively influence long-term outcomes by facilitating timely adjuvant therapy and reducing complications.

Given that clinically relevant POPF rates can reach 30%, the ability of NAT to reduce POPF, as demonstrated in this meta-analysis, represents a significant added benefit in pancreatic cancer care (6,7). This finding highlights the importance of understanding how NAT alters pancreatic texture, as a harder pancreas is associated with lower POPF rates. Several mechanisms have been proposed (48). To understand these mechanisms, it is important to consider the composition of pancreatic tissue, which consists of acinar parenchyma with fatty and fibrotic tissue in between (48). Neoadjuvant treatment can alter this balance, leading to a firmer pancreatic texture. The degree of change is positively correlated with the number of chemotherapy cycles administered, suggesting a dose-dependent effect (48).

Indeed, acinar cell-rich pancreatic remnants are associated with increased POPF after Whipple procedure, and NAT reduces POPF while simultaneously increasing fibrotic tissue content (48,49). However, the exact mechanism by which NAT increases fibrosis while reducing acinar parenchyma remains unclear. One proposed mechanism is the rearrangement of the pancreatic parenchyma during chemotherapy, leading to a reduction in acinar cells and an increase in the proportion of fibrotic tissue (34). A direct (toxic) effect of chemotherapy on acinar cells is also plausible. Another theory suggests that longer-term obstruction of the pancreatic duct causes fibrosis and atrophy of both exocrine and endocrine components of the pancreas, including acinar cells (50). It is plausible that tumor size and the resulting compression of the pancreatic duct play a role in this process.

One might consider that radiotherapy could have influenced the outcomes, as it was applied, although in a minority of patients, in many included studies and often reported together with chemotherapy. Moreover, fibrosis is typically observed after radiotherapy. To clarify this point, we conducted a subgroup analysis that included only studies where chemotherapy alone was administered. Although only 4 studies could be included in this analysis, the results supported the statement that chemotherapy alone, even without radiotherapy, can induce structural changes leading to a harder pancreas and, consequently, a lower POPF rate. However, it is crucial to acknowledge that radiation and chemotherapy impact tissue through distinct biological pathways. Furthermore, due to the limited number of studies exclusively reporting chemotherapy only data, this subgroup analysis lacked sufficient statistical power to definitively isolate the effect of chemotherapy alone or to robustly compare its impact relative to chemoradiotherapy or mixed neoadjuvant strategies. These results appear contradictory to a previous study by Wismans et al., where only radiotherapy was claimed to reduce the POPF rate in multivariate analysis, but not chemotherapy alone (51). However, several methodological points raise questions about this conclusion. First, the study groups significantly differed in relevant parameters, including resectability, texture, and others. Second, the fistula rate was low in both the radiochemotherapy and chemotherapy groups (2% vs. 4%). Third, the hard pancreas rate was high in both groups compared to UPS. In such a scenario, the validity of conclusions based on multivariate analysis is questionable.

An appropriately designed study directly comparing radiochemotherapy versus chemotherapy alone could clarify the impact of radiotherapy on both POPF rates and oncologic outcomes. However, the recent findings from the A021501 phase 2 randomized clinical trial, which compared neoadjuvant mFOLFIRINOX versus mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable pancreatic cancer, may make conducting such studies challenging (52). This trial reported a median overall survival of 29.8 months in the chemotherapy group and 17.1 months in the chemoradiotherapy group (52). Although the chemoradiotherapy arm was terminated prematurely after interim analysis, these results raise concerns about the potential negative impact of prolonged waiting during additional radiotherapy on survival.

While our meta-analysis demonstrates a significant reduction in POPF following pancreatoduodenectomy preceded by NAT, the broader clinical impact of this treatment strategy extends to significant effects on oncological staging parameters, particularly lymph node (LN) status. Compared to UPS, where LN metastases are common, NAT is associated with a markedly lower rate of LN positivity at resection, a reduced median number of involved nodes, and a lower LN ratio (LNR) (53). This apparent downstaging effect suggests neoadjuvant treatment may alter lymphatic metastatic patterns, potentially through a “sterilizing” effect on micrometastases or established nodal disease, a concept supported by histological evidence of tumor regression within nodes in some patients (53). Despite this reduction in overall nodal burden, residual LN positivity (ypN⁺) after NAT remains a powerful negative prognostic factor (54). Consequently, accurate pathological LN evaluation is critical post-treatment, potentially identifying patients who might benefit most from subsequent adjuvant therapy (54). However, assessing the true pathological stage after NAT presents unique challenges; treatment-induced fibrosis can complicate surgical dissection and lymphadenectomy (55), although total LN yields may not significantly differ from UPS cohorts (53). Moreover, the prognostic applicability of standard American Joint Committee on Cancer (AJCC) staging criteria, particularly size-based T-staging, has been questioned in the post-neoadjuvant setting, leading to proposals for modified systems incorporating factors like extrapancreatic extension (54). Understanding these alterations is crucial, especially when considering baseline metastatic patterns observed in UPS, where stations 13 and 14 are most frequently involved (56). Therefore, NAT exerts complex effects, influencing both pancreatic parenchymal texture and the locoregional lymphatic environment.

Several significant limitations inherent to this meta-analysis warrant careful consideration. Primarily, the analysis is based predominantly on data from non-randomized, retrospective cohort studies. This reliance on observational data introduces a potential for significant bias, including selection bias (related to why patients received neoadjuvant vs. UPS, often linked to disease stage), confounding variables (which may not be fully adjusted for across studies), and information bias in data reporting. Furthermore, a potential limitation arises from the observed baseline clinically relevant POPF rates in our pooled analysis, which appear lower than those reported in some large prospective randomised controlled trials (RCTs) (e.g., DISPACT trial reporting ~35–40%) (57). This discrepancy might stem from variability in the application of the 2016 ISGPS definition across different studies included in our meta-analysis. Specifically, challenges in consistently distinguishing biochemical leaks from grade B POPF could potentially lead to an underestimation of the true clinically relevant POPF incidence in some cohorts. While our meta-analysis relies on the reported data adhering to the 2016 definition within the included studies, such potential underestimation of baseline clinically relevant POPF rates could influence the precise magnitude of the relative risk reduction calculated for NAT. Readers should consider this potential variability when interpreting the results.

Finally, we would like to address the implications of this study for future research and clinical practice. Advances in magnetic resonance imaging now allow for the prediction of pancreatic texture before surgery (58). This raises the possibility of personalizing treatment strategies based on pancreatic texture, potentially using NAT to modify texture in patients with a soft pancreas and thereby reducing postoperative complications. However, the application of this approach is not straightforward, as the current paradigm involves UPS for resectable pancreatic cancer and NAT for borderline resectable or locally advanced disease (11,47). The potential risk of tumor progression during NAT in resectable cases creates a dilemma for this personalized approach. However, recent advances in personalized and targeted therapies offer hope for overcoming this challenge. As our understanding of tumor biology and treatment response improves, it may become possible to predict which patients will respond to NAT and which are at higher risk of progression (59). By identifying patients with resectable tumors who are unlikely to experience disease progression during NAT, we can potentially expand the use of this approach to those with a soft pancreas, leading to lower POPF rates and improved surgical outcomes. This personalized approach could potentially lead to a paradigm shift in the management of resectable pancreatic cancer, allowing for tailored treatment strategies that optimize both oncologic and surgical outcomes. It is important to note that this concept currently applies only to pancreatic ductal adenocarcinoma, as NAT is not typically considered for other pancreatic tumors such as neuroendocrine tumors or ampullary cancers.

Conclusions

This meta-analysis indicates that NAT reduces POPF after pancreatoduodenectomy. This reduction, likely due to altered pancreatic texture, could improve surgical outcomes, especially in patients with a soft pancreas. However, accurately predicting tumor response to NAT is crucial to avoid potential disease progression in resectable pancreatic cancer. Advances in personalized medicine offer hope for tailoring treatment strategies based on individual patient characteristics, ultimately minimizing complications and maximizing outcomes.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-121/rc

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-121/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-121/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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