Surgical management of small intestinal neuroendocrine tumours

Gastroenteropancreatic neuroendocrine neoplasms (NENs) originate from neuroendocrine cells across the body; they are increasing in incidence and prevalence, as documented across several regions1–3. The most frequent sites of NENs include the small intestine and the pancreas. The prevalence of small intestinal NENs was most recently estimated at 45 per 100 000 people and that of pancreas NENs at 35 per 100 000 people compared with 10 per 100 000 people for pancreatic adenocarcinoma for example3,4. As a result, most surgeons will encounter gastroenteropancreatic NENs in their practice. The management of gastroenteropancreatic NENs, including work-up, diagnosis, staging, and treatment, varies based on the specific site of the primary tumour. NENs include neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs); NETs are well-differentiated malignancies while NECs are poorly differentiated and present with more aggressive behaviour5. This article will focus on NETs. Small intestinal neuroendocrine tumours (SI-NETs) have different biology compared with other epithelial cancers and, hence, have different considerations for management than most other gastrointestinal cancers. Three features of SI-NETs drive these considerations: prolonged survival, endocrine hypersecretion, and fibrosis within the tumour environment. Prolonged survival is often observed, even in patients with locally advanced or widely metastatic disease2,3. Both endocrine hypersecretion and fibrosis (desmoplastic reaction) can contribute to deteriorating quality of life over the course of disease via systemic endocrine syndrome and locoregional complications6–8. As such, oncological control must be pursued along with preservation of intestinal function and quality of life. To do so, multidisciplinary care involving several disciplines is critical to devise tailored management plans. Despite the prevalence of SI-NETs in surgical practice, the operative management of SI-NETs lacks standardization. Decision-making and recommendations are informed largely by retrospective, single-centre (often single-surgeon) series. Compared with systemic therapy for NETs, surgical evidence is sparse and heterogeneous. Indeed, the field overall has advanced rapidly, particularly in biomarker discovery, imaging, and systemic therapy, but surgical strategies have remained largely unchanged. This contrast underscores the opportunity for better evidence and innovation in the operative care of patients with SI-NETs. This article aims to provide insights into existing clinical dilemmas in the surgical care of patients with SI-NETs as well as current and future directions. Rather than attempt to provide an exhaustive review of SI-NETs, it focuses on key clinical challenges that commonly arise in practice and areas where evidence is evolving and likely to influence surgical management. To undertake this overview, experts within the different domains of management of SI-NETs were selected by two BJS Editors. All those selected had a significant record of high-quality publications within the fields of interest. Once a list of expert authors was compiled, it was then approved by the BJS Editorial Team and, of those invited, all agreed to take part in this BJS Commission. The authors were also asked to include ‘future experts’ at a senior trainee or early consultant level, to compliment the authorship group. Authors were then split into seven groups, each tasked with providing a detailed contemporary review of certain key aspects of the management of SI-NETs. By selecting an international group of experts, the aim was to formulate a balanced and collaborative analysis that represents SI-NET practice, globally. Primary tumour resection of an asymptomatic SI-NET with unresectable stage IV disease remains controversial. While retrospective studies have suggested potential benefits in overall survival (OS) and prevention of future complications, these must be weighed against the risks of surgical morbidity, even if those risks are generally considered acceptably low9,10. The lack of definitive prospective data continues to fuel uncertainty. Any potential oncological or symptom-related benefits must be balanced against the risk of perioperative complications, as a surgical intervention may expose otherwise asymptomatic patients with a long life expectancy (despite malignancy) to unnecessary morbidity. Primary tumour resection may benefit the patient in two ways: help them live longer and/or better. Multiple retrospective studies have demonstrated an association between primary tumour resection and improved survival of unresectable stage IV patients. These mainly include population-based studies using the National Cancer Database, the Surveillance, Epidemiology and End Results (SEER) Registry, and the California Cancer Registry11–16. Appropriate statistical techniques were performed to attempt to control for confounding, but the nature of these databases plus the inherent selection bias in surgical decision-making make it hard to confidently attribute the improved survival to primary tumour resection. Other population-based studies have demonstrated no association between primary tumour resection and survival17,18. One of the more novel studies took advantage of a natural experiment whereby one centre (Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands) adopted a policy of primary tumour resection for all patients while another (Aintree University Hospital (AUH), Liverpool, UK) only performed primary tumour resection for symptoms19. While this study was not a randomized trial, the retrospective analysis of patients treated from 2000 to 2018 relied on thoughtful statistical analysis and provided important insight. Overall, 93 patients with asymptomatic stage IV SI-NETs were treated at NKI (78% upfront primary tumour resection) and 52 patients at AUH (8% upfront primary tumour resection). In the AUH cohort, 19% for a of survival was at NKI at AUH significant in was also primary tumour resection with tumour of that primary tumour resection to improved survival a randomized to the for no survival This was for a more a of only the incidence of SI-NETs and the prolonged survival of patients with SI-NETs, a is to be if the of improved survival remains or to primary tumour resection may to better locoregional disease the risk of or the prolonged life expectancy of patients with SI-NETs, even those with stage IV is a long of for the primary SI-NET to and quality of life. population-based study from a of for all patients with stage IV SI-NETs. also that upfront primary tumour resection was with and small to the clinical of primary tumour resection in unresectable stage IV SI-NETs is the that patients are The prevalence of asymptomatic SI-NET primary tumours is stage IV SI-NET patients in only had no or study of surgical patients in also in they their on diagnosis, to the nature and of the In for patients for in the of unresectable primary tumour resection and disease is generally to future and for This underscores the of early and surgical even metastatic disease to the clinical The current for all patients with stage IV SI-NETs is for by a multidisciplinary with including a and that be primary tumour even in the of and for patients with unresectable metastatic This is by from international across the This is most likely to gastrointestinal that patients may have with and over future locoregional complications, and to improved While a randomized be collaborative as the of for the of prospective data on including complications, quality of and patients can benefit from primary tumour even those with unresectable as it likely future and complications, and may be in multidisciplinary with even patients as this be for NETs. are but are to in and prolonged patient present and challenges from or of patients with SI-NETs have often or The of is and by tumour primary and overall disease While an a to to as and patients may survival with aggressive the for on diagnosis, patient and of surgical and systemic and is the and of in NETs may be is critical for between NETs and poorly differentiated The and be in to potential review by an is of the small intestine is of tumour include the and the Cancer Both are for and patient selection in but the is for and detailed of disease in the of of disease and are for and risk than or for NETs but may if are or are to the small intestine with as and may but lack and are tumour is an for disease therapy for NETs on tumour and no evidence systemic therapy for are by for systemic therapy for advanced while therapy and may be considered for and is to against NETs. 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