Pancreatic adenocarcinoma (PDAC) remains a devastating disease with an extremely poor prognosis (1). The 5-year overall survival (OS) rate in the United Kingdom (UK) is approximately 7% and has not improved significantly in the past 30 years (2). Furthermore, there is a 17% increase in the incidence of PDAC cases at the same time period (3) resulting to more than 10,000 new diagnoses annually in the UK. In patients with non-metastatic PDAC, margin-negative (R0) surgical resection of the primary tumour is the primary therapeutic approach to achieve long-term survival (4, 5). Advancements in surgical quality and perioperative care and the introduction of more efficient perioperative systemic treatment have further improved patient outcomes (6, 7).

The paradigm of surgical management is shifting in patients with borderline resectable (BR) and locally advanced (LA) PDAC. Several classification systems in the literature define BR and LA-PDAC (8–10) focusing on variable degrees of vessel involvement by the tumour; yet the presence of different staging systems results in evolving definitions and a nuanced distinction between them (11). In BR-PDAC, the introduction of neoadjuvant/induction systemic treatment (NAT) was based on its potential advantages: addressing occult micrometastatic disease in the preoperative setting, avoiding unnecessary surgery in tumours with aggressive biology, increasing the likelihood of R0 resection, and improving delivery rates of systemic treatment. Recent prospective trials have demonstrated a potential benefit in overall survival in patients with BR-PDAC who underwent NAT (12, 13), and emerging data suggest potential future practice changes.

In the UK, the National Institute for Health and Care Excellence (NICE) pancreatic cancer guidelines recommend surgery for resectable cancer and advise the utilisation of NAT in resectable and BR-PDAC only as part of clinical trials (14). However, trial availability varies over time and patient recruitment can often be challenging. Therefore, it appears to be presently unclear what treatment pathways are chosen by the various specialist pancreatic surgical teams within the UK. A previous prospective audit on diagnostic pathways in PDAC (RICOCHET) demonstrated wide variations in practice and indicated the need for clinical pathway optimisation (15). The present study aims to further characterize variations in surgical management of patients with non-metastatic PDAC in specialised centres across the UK, assess and investigate differences in practice, and determine potential parameters for pathway standardisation.

Within the study period, approximately 120 individual emails were sent to candidate participants, excluding reminder communications. In total, 65 eligible participants completed the survey, accounting approximately for 58% of all estimated HPB consultants in the UK and representing 27 of the 28 national referral centres. The median completion rate of the survey was 94.6% and all responses were included in the final analysis. The majority of the participants practise in academic institutions (n= 55) and 21 surgeons are also performing liver and/or pancreas transplantation. Regarding geographical distribution, 72% of the responders were based in England (n=47), 23% in Scotland (n=15), 3% in Wales (n=2), and 2% in Northern Ireland (n=1). According to the predetermined volume-based stratification, 14 surgeons practise in standard-volume (22%), 20 in high-volume (31%), and 31 in very high-volume institutions (48%).

All participants stated that MDT meetings are conducted in their respective institutions for evaluation and management of PDAC patients ( Table 1 ). Most MDT meetings utilise the National Comprehensive Cancer Network (NCCN) guidelines for assessment of tumour resectability (19) (69%); surgeons from very high-volume centres reported increased adherence to the NCCN guidelines compared to standard-volume institutions (p=0.036). Interestingly, 14% of participants replied that they do not utilise a dedicated resectability classification system. Additionally, in the vast majority of cases MDT reports are presented as free text and only 3% of participants mentioned outcome reporting in a pre-drafted template. Most surgeons find useful the application of a universal resectability classification system nationally (62%) and approximately half of them support the standardisation of MDT reporting across the UK.

Surgeon preferences on the management of non-metastatic PDAC are available in Tables 1 , 2 . For upfront resectable PDAC, 65% of participants would never offer NAT in patients with performance status of 0-1, even in the presence of high CA19-9 levels (86%). Surgeons who supported the utilisation of NAT in resectable PDAC would offer it in patients with increased risk of positive margin (R1) resection due to contact of the tumour with the portal/superior mesenteric complex (n=13), or within a clinical trial (n=3).

Participants practising in very high-volume institutions for pancreatic surgery performed statistically significantly more vascular resections in pancreatectomies compared to ones in standard or high-volume centres (p<0.001). In BR and LA-PDAC, no differences were identified between surgeons regarding preferred technique for vascular reconstruction. Similarly, the importance of radiological involvement of regional vascular structures by the tumour was equally distributed: in veins length of involved segment and presence of cavernous transformation, and in arteries degree of circumferential involvement and presence of narrowing appear to be more significant in preoperative assessment ( Table 2 ). Figure 1 demonstrates the distribution of upfront surgical resection, NAT, and declaration of unresectability based on different degrees of venous and arterial involvement between participants in the three volume-based tiers ( Figure 1 ; baseline histogram available in Supplementary File 2 ). Surgeons in high-volume centres were less likely to offer upfront resection in patients with tumours with any degree of vessel involvement compared to surgeons in the other two tiers. Additionally, surgeons in standard-volume institutions offered NAT in fewer cases and declared more patients unresectable, especially in the presence of cavernous transformation or encasement of the superior mesenteric artery (>180° involvement). Despite management variations, statistically significant differences were not identified between the three tiers.

The rationale for this study was to assess and define variations in surgical practice and to our knowledge is the first to provide an insight into the landscape of current surgical management of non-metastatic PDAC in the UK. The replies collected from this survey represent the majority of surgeons who perform pancreatic resections nationally and demonstrate significant variability in therapeutic approach and decision-making, both in inter-, and intra-institutional level. These differences were more prominent in the management of BR-PDAC and LA-PDAC, primarily in terms of anatomic criteria for resectability of the primary tumour.

The highest rate of agreement among the responders was observed in the management of patients with resectable PDAC; approximately 90% advocate for upfront surgery and adjuvant systemic treatment. Traditionally, surgical resection of primary pancreatic tumours without vessel involvement is the treatment of choice in eligible patients (21) and is recommended by national and international guidelines (22). Moreover, “fast-track” clinical pathways can facilitate prompt patient access to surgery and result in higher resection rates and improved outcomes (23). Although postoperative complications can delay the administration of systemic treatment (24, 25), recent advancements in chemotherapy (6, 7) have had a significant impact in recurrence-free and overall survival rates (26).

However in this survey, treatment of patients with resectable PDAC was not significantly affected by high CA19-9 levels or poor patient performance status (PS) (27). More specifically, 86% and 51% of surgeons would offer upfront resection in patients with CA19-9 >1000U/ml or PS ≥2, respectively. CA19-9 is currently the only available biomarker in clinical practice for PDAC and despite mediocre sensitivity and specificity, high values are suggestive of aggressive tumour biology (28) and have been associated with early disease recurrence (29). The study of biological behaviour in PDAC gradually introduced further criteria for resectability beyond anatomic considerations (11, 30) aiming at the improvement of recurrence rates and overall survival. Since optimal outcomes in PDAC are observed when a combination of local and systemic treatment is provided, the concept of NAT in resectable PDAC was developed with two objectives in mind: 1. test tumour biology and better select patients who are eligible for surgery, and 2. increase the percentage of patients who received chemotherapy. Retrospective studies on NAT in resectable PDAC have demonstrated increased rates in delivery of intended systemic therapy (31), and the recent SWOG S1505 trial showed that this is a feasible approach that needs to be investigated further (32). In this study, less than 10% of participants from high and very high-volume institutions would routinely offer this approach and only within a clinical trial, as suggested by the NICE guidelines.

Limited variation was identified in the management of BR-PDAC, since the majority of surgeons support utilisation of NAT and surgical exploration. The concept of preoperative chemotherapy and chemoradiation in BR-PDAC was developed under the prism of vessel involvement by the tumour and increased probability of R1 resection with a subsequent effect on patient survival (4, 33). Even though the percentage of patients who eventually undergo surgical resection may be lower, the recent prospective PREOPANC and ESPAC-5F trials demonstrated improved tumour response and a survival benefit with NAT and surgery (12, 13), indicating a paradigm shift in the surgical management of these patients.

Advancements in surgical techniques, perioperative care, and systemic treatment options have significantly improved outcomes in patients with LA-PDAC. Recent retrospective series have demonstrated that surgical resection in LA-PDAC post induction therapy is feasible (34–36) and has a direct impact on patient survival (37, 38). However, most of the current practice is based on observational data and therefore, the lack of consensus in LA-PDAC management shown in this study is not surprising. Participants expressed different opinions regarding time and regimen of induction therapy, most likely based on single-centre retrospective data. These results coincide with differing views regarding number of chemotherapy cycles, or any survival benefit in utilisation of radiation therapy in the preoperative setting (39, 40).

Since tumour response to induction therapy in LA-PDAC is evaluated almost exclusively based on imaging, anatomic criteria are primarily utilised by surgeons to assess resectability and reconstructability. This combination of subjective radiological evaluation and low specificity and sensitivity of imaging modalities (41) can explain the limited role of surgery in LA-PDAC demonstrated in this study. The role of CT/PET has been previously investigated regarding assessment of resectability and has proven to provide an advantage in identifying active disease versus fibrosis, especially after neoadjuvant treatment (42). Another important factor appears to be the limited exposure to complex vascular reconstruction: participants from standard-volume hospitals performed significantly smaller number of vein resections and subsequently were more likely to declare a locally advanced tumour as unresectable, and vice versa. However, almost all surgeons in this study would declare a tumour unresectable intraoperatively if arterial involvement were identified, particularly of the superior mesenteric artery. Arterial resection and reconstruction in PDAC have been previously reported in very selective cases (43), but is characterised by high rates of postoperative complications and questionable survival benefit (44).

The variability in the assessment of patients with PDAC shown in this study indicates that the decision-making process is a combination of guideline utilisation, surgical skills, and individual experience within an MDT setting. Previous studies have reported differences in MDT outcomes between institutions and deviations in assessment of resectability or tumour response (45–47), extending beyond classification systems. This study further underlines that these differences are essentially present on an intra-institutional level and illustrates the necessity for standardisation of MDT reporting, which is also supported by the majority of participants.

This study has several important limitations. Firstly, even though response rate was >50%, the sample size was relatively small (n=65) making identification of statistically significant differences problematic. Additionally, the survey was eponymous and therefore research bias that may have affected the responses (Hawthorne effect) was introduced. Limited information regarding previous exposure of participating surgeons to the management of BR-DPAC and LA-PDAC post neoadjuvant therapy were also available. Most importantly, it remains unclear if the demonstrated differences in management translate into differences in patient outcomes, since they were not the scope of this study. Lastly, this study was primarily performed before the ongoing COVID-19 pandemic, which has significantly affected the management of PDAC patients and is expected to have significant effect on resection rates and survival (48, 49).

Following previous reports (15), the present study shows wide variations in the surgical management of non-metastatic PDAC across the UK. Even though pancreatic surgery is centralised in high-volume centres, a need for creation of a nationwide patient outcome database is underlined. This will allow identification and standardisation of optimal clinical pathways via audit processes within the NHS, similar to the National Surgical Quality Improvement Program in the United States and the British Transplantation Society in the United Kingdom, aiming primarily at the complex management of patients with BR and LA-PDAC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

All authors have contributed equally to this manuscript in terms of data acquisition and analysis, and manuscript preparation and refinement.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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