Advanced pancreatic neuroendocrine neoplasia (pNEN): complex diseases with therapeutic challenges

For rare disease such as pancreatic neuroendocrine tumors (pNETs), unmet surgical needs and grey area in their management are numerous. The 2024 consensus meeting of the European Society of Endocrine Surgeons (ESES) (1) provides recommendations and new insights on the surgical management of advanced pancreatic neuroendocrine neoplasia (pNEN), including locally advanced pNET, pNET with synchronous distant metastasis, and high-grade pNEN (i.e., G3 pNET and neuroendocrine carcinoma). Seven key questions were assessed, with recommendations based on a systematic literature review of 61 studies and subsequently validated through voting at the ESES annual conference, using a five-point Likert score. Figure 1 summarizes the main results of this ESES consensus for each question and compares them to current available international guidelines (2-5).

Figure 1 Summary of the current recommendations on the 7 questions raised by the ESES 2024. In italics is an excerpt from the recommendation that addresses the question asked. ESMO, European Society for Medical Oncology; NANETS, North American Neuroendocrine Tumor Society; ENETS, European Neuroendocrine Tumour Society; NCCN, National Comprehensive Cancer Network; ESES, European Society of Endocrine Surgeons; pNET, pancreatic neuroendocrine tumor; pNEC, pancreatic neuroendocrine carcinoma.

First, the ESES developed recommendations on the surgical management of what can be called “locally advanced” pNET, by analogy with pancreatic ductal adenocarcinoma. In surgical series, vascular invasion occurs in 17% to 20% of pNETs cases, primarily affecting the venous porto-mesenteric axis. The ESES recommends that venous invasion should not contraindicate curative intent R0 surgery. Indeed, in over 30% of cases, no vascular resection is ultimately required since, unlike pancreatic ductal adenocarcinoma, pNETs seldom invade the vascular wall, enabling sharp dissection with R0/R1 resection. Moreover, if venous resection is necessary, it does not appear to increase the risk of severe morbidity or mortality and is associated with acceptable overall and recurrence-free survival rates, independent of other prognostic factors, in high-volume centers. Notably, venous involvement often results from tumoral thrombus, removable with venotomy or minimal venous resection, rarely necessitating complex reconstruction. Similar safety is nowadays observed in portal vein resections performed for pancreatic ductal adenocarcinoma, especially at high-volume centers with well-selected patients, though often conducted in older, more fragile, or sarcopenic patients (6). Additionally, this recommendation reaffirms the critical role of high-quality, multi-modality preoperative imaging to accurately assess tumor-vascular relationships, enhancing surgical planning and anticipation of vascular resection needs.

A similar recommendation is suggested by the ESES for multivisceral resection, reported in 7% to 39% of cases in surgical series. Their position stands out from other guidelines, where the role of multivisceral resection is more debated or absent. However, the heterogeneity in definitions of multivisceral resection (en-bloc resection? Combined liver resection? Splenectomy? Number of organs resected?) requires cautious interpretation of published results. Furthermore, although the impact of multivisceral resection on morbidity appears minimal in the articles that contributed to this recommendation, extensive multivisceral resection negatively affects postoperative outcomes and patient quality of life. The question is less about whether multivisceral resection is technically or oncologically feasible, and more about the extent a surgeon should pursue to maintain an appropriate benefit-risk balance for the patient. This is particularly relevant, as multivisceral resection primarily aims to achieve an R0 resection. However, there is no data supporting that more aggressive resection to obtain wider surgical margins is justified for pNETs. The concern lies more with the biological and genetic aggressiveness of the lesion and its risk of dissemination than with the resection margins. Additionally, 14% of voters expressed a neutral opinion on the benefits of multivisceral resection. Finally, it should be noted that for these advanced tumors, an associated cholecystectomy is strongly recommended due to the significant risk of postoperative treatment with somatostatin analogues. Given the expected long-term survival of patients even with “locally advanced” pNET and the numerous available medical treatments, preserving postoperative quality of life should remain a major concern.

For non-metastatic unresectable pNET, tumor downstaging to enable surgical resection is the ultimate goal. The ESES suggests using neoadjuvant peptide receptor radionuclide therapy (PRRT), such as 177Lu-DOTATATE, or chemotherapy, with or without radiotherapy. Literature shows a RECIST partial response in 49% patients and an R0 resection in 68% of cases operated on after neoadjuvant treatment. However, due to the low evidence level in published studies and the heterogeneity in indications and treatment protocols, this recommendation is limited, with 11% of voters not supporting it. Although the oncological results appear slightly better after PRRT, no comparative data with chemotherapy exists to recommend a specific neoadjuvant treatment. Notably, PRRT efficacy depends on somatostatin receptor expression in pNET, which diminishes as the tumor becomes more aggressive and poorly differentiated.

Second, the ESES made two recommendations concerning primary tumor management in cases with liver metastases, which is crucial since approximately 45% of pNET patients present with metastases at diagnosis (7). For those with synchronous resectable liver metastases, the ESES recommends resection of both primary and metastatic lesions, either staged or combined. It should be noted that metastases are always “many more than what we think” or seen on preoperative imaging exams (8). This observation raises two fundamental question: the importance of achieving the most accurate possible tumor and metastatic staging, as well as the definition of resectability in hepatic metastasis in pNET. We should never forget that “Biology is king, patient’s selection is queen, and surgical technic only prince/princess”. Conversely, for unresectable liver metastases, the collective decision-making approach appears more cautious, suggesting a case-by-case analysis, carefully balancing risks and benefits. The evidence levels here remain very low, though there is a slight trend favoring debulking strategies, especially combining surgical resection with PRRT (9). Three key factors guide this personalized approach. First, the location of pNET within the pancreas is critical. Indeed, a pNET in the pancreatic head requiring pancreaticoduodenectomy with biliodigestive anastomosis would contraindicate hepatic arterial embolization or chemoembolization due to the increased risk of biliary abscess (10), representing a strong contraindication in such cases. Secondly, beyond a possible oncological benefit, surgical debulking may be an endocrine necessity for functional pNETs with inadequate secretory syndrome control via medical treatment, however, this situation is becoming exceptional given current medical armamentarium. As the ESES meeting noted, the role of liver transplantation remains debated, though literature and guidelines support it for selected patients with low-aggressiveness tumors, particularly functional pNETs with isolated, unresectable liver metastases. Lastly, how to manage patients with both hepatic and extra-hepatic metastases remain controversial. While the ESES recommendation does not address such question, most surgeons avoid surgery when extra-hepatic lesions are present (5,7), though other guidelines support it (2).

Finally, the ESES issued recommendations for high-grade pNENs, which encompass Grade 3 (G3) well-differentiated pNET and poorly differentiated neuroendocrine carcinoma (pNEC). The ESES suggests that surgical resection may be relevant for localized G3 pNET, while its role in pNEC remains unclear. This conclusion aligns with current recommendations for G3 pNET, while opinions vary on pNECs. Of note, the distinction between G3 pNET and pNEC was introduced only with the 2017 World Health Organization (WHO) classification. Despite recognized biological aggressiveness, therapeutic urgency, and limited published data, this recommendation applies to a small subset of patients, as NEC account for 5% of NENs (previously including G3 NETs) and only less than 10% are diagnosed without distant metastatic spread. It does not seem unreasonable to consider surgery after neoadjuvant treatment for these very aggressive lesions in highly selected patients.

Overall, this ESES guideline highlights the significant challenges involved in managing pNENs, particularly advanced cases, where the rarity of these neoplasms implies low evidence-based recommendations, which may explain differences across consensus guidelines (Figure 1), justifying the development of ambitious international prospective research projects. Currently, 101 interventional studies are registered as ongoing on clinicaltrial.gov, aiming to provide additional insights to the ESES guidelines on medical and surgical strategies on advanced pNEN. Additionally, it emphasizes the importance of surgery as the cornerstone of curative management for pNETs and the only potential hope of prolonged survival. Nevertheless, morbidity and mortality associated with pancreatic surgery are substantial, and the benefit-risk balance must always be carefully weighted to avoid imposing a heavy, quality-of-life-impacting intervention on a patient for minimal oncological benefit. Finally, two points should be emphasized: first, while this BJS article is authored solely by surgeons, it is important to recognize that managing this disease inherently requires a multidisciplinary approach, also involving pathologists, endocrinologists, radiologists, nuclear medicine specialists, gastroenterologists, and oncologists. Second, while this ESES consensus meeting may appear to overlap or potentially conflict with the 2023 European Neuroendocrine Tumour Society (ENETS) guidance papers (3,4), we believe that enhanced collaboration between international societies would be highly beneficial in achieving collegial thinking and recommendations, while setting aside corporate or national distinctions.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2024-643/coif). L.d.M. received institutional research grants from Ipsen and Esteve, and personal consulting fees from AAA/Novartis and Esteve. The other 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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