Version May 2024
INTRODUCTION — Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that are thought to arise from neuroendocrine cells and their precursors located throughout the body. These tumors are characterized by variable but most often indolent biologic behavior. They are also classically characterized by their ability to secrete peptides resulting in distinctive hormonal syndromes.
Classification and nomenclature — Neuroendocrine neoplasms can arise at different sites within the body and are classified according to their histologic features. While there are differences in terminology and grading depending on site of origin, all commonly used classification systems reflect a basic separation between more indolent, well-differentiated NETs (which in the digestive system were previously referred to as carcinoid tumors and pancreatic neuroendocrine [islet cell] tumors) and far more aggressive, poorly differentiated neuroendocrine carcinomas (which behave clinically more like small cell carcinoma of the lung). (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Classification and nomenclature'.)
This topic review will cover local treatment options for patients with well-differentiated metastatic gastroenteropancreatic NETs. Systemic treatment options to control tumor growth and/or symptoms of hormone hypersecretion from gastroenteropancreatic NETs and the treatment of poorly differentiated neuroendocrine carcinomas are discussed elsewhere, as are the clinical presentation, imaging, and biochemical monitoring for patients with advanced gastroenteropancreatic NETs; pathology and classification of gastroenteropancreatic NETs; clinical features of NETs; diagnosis of carcinoid syndrome and tumor localization; treatment of early stage NETs; lung NETs; localization and treatment of pancreatic NETs; evaluation and management of NETs of unknown primary site; management of symptoms of the carcinoid syndrome; carcinoid heart disease; and functioning pancreatic NETs:
●(See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Carcinoid heart disease".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
●(See "Insulinoma".)
●(See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)
●(See "Glucagonoma and the glucagonoma syndrome".)
●(See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)
●(See "VIPoma: Clinical manifestations, diagnosis, and management".)
NATURAL HISTORY AND TREATMENT OPTIONS — NETs are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Clinical behavior and prognosis correlate closely with histologic differentiation and grade. The World Health Organization (WHO) classifies well-differentiated gastroenteropancreatic NETs into low-grade (G1), intermediate-grade (G2), and high-grade (G3) categories based on histologic appearance and proliferative rate (as assessed by mitotic count and/or Ki-67 labeling index) (table 1) [1]. Poorly differentiated neuroendocrine carcinomas are high-grade neoplasms that can be further classified as small cell or large cell type neuroendocrine carcinomas. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification'.)
Among patients with G1 or G2 histology and distant disease, survival is highly variable and can depend on other factors, including primary tumor location. As an example, among patients with advanced NETs, outcome is worst for patients with lung and colon (other than cecum) primaries (median survival 17 and 7 months, respectively) and is most favorable for tumors arising in the jejunum, ileum, and cecum (median survival 55 to 65 months) [2]. This wide difference in natural history complicates the comparative assessment of benefit from individual therapies.
Patients with metastases from a gastroenteropancreatic NET may become symptomatic from hormone hypersecretion rather than from tumor bulk. Approximately 10 to 30 percent of pancreatic NETs secrete hormones resulting in clinical syndromes; additionally, patients with midgut (small bowel or appendiceal) NETs may develop carcinoid syndrome, typically after development of hepatic metastases and entry of vasoactive substances, such as serotonin, into the systemic circulation. (See "Clinical features of carcinoid syndrome" and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
Symptoms of hormonal excess from functional NETs can often be well controlled with somatostatin analogs, such as octreotide or lanreotide. Similarly, somatostatin analogs, molecularly "targeted" therapies, and cytotoxic chemotherapy may be beneficial in controlling tumor growth. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)
In patients with limited metastases, however, local options can also be considered. The following sections will discuss local treatment options to control symptoms and tumor growth. Systemic options are discussed in detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)
OVERVIEW OF THE APPROACH TO LOCAL TREATMENT — For initial management of patients with hepatic metastases from gastrointestinal or pancreatic NETs in whom complete resection is possible, surgery is appropriate in the absence of extrahepatic metastases, diffuse bilobar involvement, or compromised liver function, particularly for low-volume or symptomatic disease and low-grade tumors. The benefit of surgical debulking in patients with incompletely resectable metastatic NETs is controversial and not universally accepted. (See 'Surgical resection' below.)
Another point of controversy is whether the primary site should be resected in patients with metastatic disease. For most malignancies, there is little rationale to resect the primary site when widespread, unresectable metastases are present. In patients with NETs, however, resection of the primary may be beneficial if the primary site is causing symptoms, even in the setting of metastatic disease, given the sometimes prolonged survival of such patients. Additionally, if the primary and liver metastases are both amenable to potentially curative resection, surgery should be performed. On the other hand, the benefit of resecting asymptomatic small bowel primary sites in patients with unresectable metastatic disease has not been clearly established. (See 'Management of the primary tumor in patients with metastatic disease' below.)
The role of ablation (radiofrequency ablation [RFA], cryoablation, microwave ablation) in the therapeutic management of small (<3 cm) neuroendocrine liver metastases, particularly in patients who are eligible for resection, is undefined. Because the majority of patients present with multifocal and bilateral disease, ablation is most often used as an adjunct to surgical resection to allow local treatment of all disease when major hepatectomy alone might compromise residual liver function. (See 'Ablation' below.)
For symptomatic patients with hepatic-predominant, unresectable gastrointestinal or pancreatic NETs, transarterial therapy with hepatic arterial embolization, chemoembolization, or radioembolization is a potential alternative to medical therapy alone for symptom palliation. While many studies demonstrate successful control of symptoms related to hormone secretion or tumor bulk, survival benefits from transarterial therapy are less clear. (See 'Hepatic arterial embolization' below.)
Orthotopic liver transplantation is not currently a standard option for unresectable neuroendocrine liver metastases, and further investigation is needed to evaluate its benefits for patients with metastatic gastrointestinal and pancreatic NETs. (See 'Liver transplantation' below.)
HEPATIC-PREDOMINANT METASTATIC DISEASE — The majority of patients with advanced gastroenteropancreatic NETs have liver metastases. How to best manage patients with liver metastases from NETs is a complex issue requiring a multidisciplinary team approach, taking into account factors such as the extent and biology of disease, presence of tumor-related symptoms, and patient-related factors (such as age and performance status). The role of primary tumor resection in patients with metastatic disease is also discussed below. (See 'Management of the primary tumor in patients with metastatic disease' below.)
Surgical resection — For patients with liver metastases from a well-differentiated gastroenteropancreatic NET, surgical resection is an option in the absence of diffuse bilobar involvement, compromised liver function, or extrahepatic metastases. The presence of poorly differentiated neuroendocrine carcinoma is also usually a contraindication to resection. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Poorly differentiated NEC'.)
Resection of neuroendocrine liver metastases via anatomic hepatectomy or multiple nonanatomic "wedge" resections can be performed even with bilobar involvement, provided sufficient functional hepatic reserve is preserved, typically over 20 percent of total liver volume and the presence of two contiguous preserved liver segments. The ability of the liver to undergo compensatory hypertrophy is decreased by cirrhosis, hepatitis, or steatosis related to obesity.
A surgical approach to hepatic-predominant disease has traditionally been advised given the limited availability of systemic therapy and the relatively indolent nature of disease. Historical recommendations have supported resection if at least 90 percent of the tumor can be feasibly removed [3]. However, the precise method of measuring 90 percent debulking is not defined, and the precise amount of tumor burden that must be treated for benefit remains unclear. Furthermore, randomized studies comparing hepatic resection versus a nonsurgical approach have not been performed. Finally, the indolent nature of the disease and the potential for selection bias have complicated the assessment of the efficacy of a surgical approach to hepatic-predominant disease. Nonetheless, the long-term survival and symptomatic improvement reported in select populations of patients undergoing hepatic resection of neuroendocrine liver metastases compare favorably with outcomes with other management approaches for advanced NETs (table 2). A few of the largest series are described in detail:
●A large, early, single-institution series included 170 patients undergoing liver resection over a 20-year period [4]. Metastases were bilateral in the majority of patients, and most had hormonal symptoms. Symptom control was achieved in 96 percent of patients who presented with symptoms related to a functioning tumor; five-year symptom recurrence was 59 percent. Overall survival in the group was 61 and 35 percent at 5 and 10 years, respectively, with a median survival of 81 months. These outcomes compare favorably with historical controls [5,6]. Of note, recurrence rates were 84 and 95 percent at 5 and 10 years, respectively. Although nearly all patients developed a disease recurrence, surgery appeared to offer significant improvements in expected survival.
●Others report a lower rate of disease recurrence after hepatic resection, at least at five years [7-10]. As examples:
•A second series of 144 patients undergoing resection with or without ablation for neuroendocrine liver metastases over a 30-year period at a single institution described a median overall survival of 9.6 years, with 5- and 10-year survivals of 77 and 50 percent, respectively [8]. While nearly 50 percent of all patients developed a recurrence of liver disease, most were able to have further local treatment with repeat resection or ablation. The authors acknowledge the selected nature of the patients undergoing surgical resection, as this number represented only 25 percent of the patients with stage IV NETs seen at that institution in the same time frame.
•The largest published multi-institutional series of patients undergoing surgery for neuroendocrine liver metastases included 376 patients treated over a 24-year period across 10 hepatobiliary referral centers [7]. Most presented with bilobar disease, extrahepatic disease was present in 9 percent, and 22 percent of procedures included ablation as a component of the intervention. In the entire cohort, the disease-free survival rate at five years was 46 percent; overall survival was not reported. However, there was a tail to the disease-free survival curve beyond 10 years, suggesting that approximately 35 to 40 percent did not recur during this time frame. In multivariate analysis, the type of NET (pancreatic nonfunctional versus other), grade of tumor differentiation (moderately/poorly versus well), and extent of liver involvement were the only independent predictors of inferior disease-free survival.
Despite the apparent benefit of surgical resection in terms of symptom palliation and potentially increased survival, most series share a high recurrence rate, even with complete resection and microscopically negative margins. The high rate of intrahepatic recurrence is likely related to an underestimation of the true extent of disease burden with preoperative cross-sectional imaging. In a study comparing preoperative radiology findings with the pathologic review of resected neuroendocrine liver metastases, the extent of disease was underestimated by up to 50 percent, with many additional metastases <2 mm identified in the pathologic specimen that had not been visualized on preoperative imaging [9].
While surgical resection may benefit highly selected patients, the potential for selection bias in these series and the lack of randomized data have made it difficult to assess the long-term benefits of this approach as compared with less invasive treatment strategies. One report of a large prospective database of 649 patients with neuroendocrine liver metastases who were followed for a median follow-up of 44 months suggested that hepatic resection was associated with a highly favorable overall survival (90 percent at five years) compared with other local modalities, such as radiofrequency ablation (RFA; 84 percent) and chemoembolization (55 percent), but the potential for selection bias (ie, that surgery was only offered to those patients who had an inherently better tumor biology) complicates interpretation of the results [10].
Some authors have attempted to address confounding factors by using propensity index modeling to identify patients with common characteristics for comparative analyses [11,12]:
●As an example, one report compared outcomes in a series of 339 patients with neuroendocrine liver metastases undergoing surgical therapy versus 414 patients with neuroendocrine liver metastases undergoing intra-arterial therapy (IAT) [11]. Patients undergoing IAT had more hormonally functioning tumors, a greater proportion of tumors with synchronous presentation of liver metastases, more extrahepatic metastases, more bilateral disease, and a greater extent of hepatic involvement, and they less frequently had their primary tumor resected. In the unadjusted analysis, median and five-year survival were, not surprisingly, significantly better for patients undergoing surgery as compared with IAT. Propensity score matching was used to identify a group of patients with balanced clinicopathologic characteristics who were most likely to have been considered for either treatment. While survival was significantly better in the surgical group in the unadjusted analysis, the propensity-adjusted analysis suggested that surgery was associated with superior outcomes in patients with a low (<25 percent) hepatic disease burden and in those who were symptomatic and had >25 percent hepatic tumor involvement. There was no treatment-related difference in long-term outcome in asymptomatic patients with >25 percent hepatic tumor involvement.
●A similar statistical approach was applied to an analysis of 376 patients with neuroendocrine liver metastases from small intestinal NETs [12]. In this series, 103 patients undergoing hepatectomy or ablation were compared with 273 patients treated nonsurgically. Patients selected for surgery were less likely to have symptomatic disease, were less likely to have residual or unresected extrahepatic disease or nodal metastases, and had lower overall disease burden and lower grade tumors. In an unadjusted comparison, five-year overall survival was 78 percent after surgery or ablation versus 56 percent in controls. To account for selection bias, propensity score matching identified two groups, each with 72 patients, without significant differences in baseline features. The five-year overall survival was 74 percent in both the matched surgery/ablation and nonsurgically treated groups, suggesting that surgery may not be clearly superior to nonoperative therapy for many patients.
Taken together, these data support the view that although intrahepatic disease progression and recurrence rates are high, resection of neuroendocrine liver metastases can provide symptom control and has been associated with favorable long-term survival, with 10-year survival rates approaching 50 to 60 percent in some series [10]. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) recommend consideration of cytoreductive surgery or ablative therapy if near-complete treatment of tumor burden can be achieved [13].
For patients with carcinoid syndrome, octreotide should be readily available during any surgical procedure. (See 'Prevention and management of carcinoid crisis' below.)
Appropriate preoperative assessment and complications of hepatic resection are discussed in detail elsewhere. (See "Overview of hepatic resection".)
Nonsurgical liver-directed therapy
Ablation — Ablation can be used as a primary treatment modality for neuroendocrine liver metastases or as an adjunct to surgical resection. The most commonly used ablation technique is RFA, but other modalities, including cryoablation and microwave ablation, can be utilized. These procedures, which can be performed percutaneously, laparoscopically, or at the time of laparotomy, are less morbid than either hepatic resection or hepatic arterial embolization. However, because the zone of ablation is limited, ablative techniques may be applicable only to smaller lesions (typically ≤3 cm).
Many published reports of tumor ablation are small case studies of fewer than 40 patients [14-19]. The largest published series examining ablation for neuroendocrine liver metastases included 89 patients undergoing laparoscopic RFA [20]. The mean number of lesions treated per patient was six (range 1 to 16), with a mean lesion size of 3.6 cm (range 1 to 10 cm). There was one postoperative death and a 6 percent perioperative morbidity rate, most frequently related to hemorrhage. Among patients with hormonal symptoms (44 percent), significant or complete symptom relief occurred in 73 percent of patients when assessed one week postprocedure, and relief was sustained for a median of 14 months. At a median follow-up of 30 months, the median disease-free survival after the first RFA treatment was 16 months, with an overall survival of six years. Twenty-two percent of patients developed a local liver recurrence, and 59 percent developed extrahepatic disease. Multimodality treatment subsequently was used to control disease, including octreotide (30 percent), repeat RFA (27 percent), chemoembolization (7 percent), and chemotherapy (18 percent).
The role of ablation in the therapeutic management of small neuroendocrine liver metastases, particularly in patients who are eligible for resection, is undefined. Because the majority of patients present with multifocal and bilateral disease, a primary role for ablation may be as an adjunct to surgical resection to allow local treatment of all disease when major hepatectomy alone might compromise residual liver function. Ablation may also be particularly useful for patients with an intrahepatic disease recurrence in whom surgical options are limited due to prior hepatectomy. The combination of resection and ablation is a well-described strategy for a variety of malignancies. In the series reported by Mayo et al, 66 of 339 patients (19 percent) undergoing liver-directed therapy underwent a combination of resection and ablation at the initial surgical attempt. A smaller number of patients underwent a second liver-directed procedure (n = 46), with increasing use of ablation alone (7 of 46; 15.2 percent) or resection plus ablation (17 of 46; 37 percent) during the second procedure [21].
Hepatic arterial embolization — We suggest hepatic arterial embolization, chemoembolization, or radioembolization as an alternative to medical therapy alone as a palliative technique for symptomatic patients with hepatic-predominant unresectable gastrointestinal or pancreatic NETs.
Hepatic arterial embolization is frequently applied as a palliative technique in patients with a hepatic-predominant metastatic NET who are not candidates for surgical resection. It is based on the principle that tumors in the liver derive most of their blood supply from the hepatic artery, whereas healthy hepatocytes derive most of their blood supply from the portal vein.
Embolization can be performed via the infusion of gel foam powder into the hepatic artery through an angiography catheter (bland embolization) or in conjunction with chemotherapy (ie, doxorubicin, cisplatin, or streptozocin, or drug-eluting beads) administered via the hepatic artery (chemoembolization). A third embolization technique uses radioactive isotopes (eg, yttrium-90 [90-Y]) that are tagged to glass or resin microspheres and delivered selectively to the tumor via the hepatic artery.
Technique and outcomes — In the absence of randomized trials, we consider any of the three techniques (bland embolization, chemoembolization, or radioembolization) to be a reasonable approach for the palliation of patients with NETs and hepatic-predominant disease who are not candidates for surgical resection.
In uncontrolled studies, efficacy appears to be similar for the three techniques:
●The response rates associated with all of these techniques, as measured by either decreased hormone secretion, symptomatic benefit, or radiographic regression, are generally over 50 percent, even among patients with massive hepatic tumor burden [22-38]. While many studies demonstrate symptom control, survival benefits from transarterial therapy are less clear [25,27,39-43]. Comparisons between studies and between methods of transarterial therapy are frustrated by the heterogeneity of inclusion criteria and the wide range of techniques used.
●A year 2015 systematic review of 18 studies conducted by a multidisciplinary panel of experts examined the clinical efficacy and safety of hepatic arterial chemoembolization, bland embolization, and radioembolization for patients with neuroendocrine liver metastases [44]:
•Although patient heterogeneity and differences in embolic technique make comparisons between studies and modalities difficult, similar tumor response rates, survival, and symptom palliation were observed with all techniques.
•In 11 studies examining bland embolization or chemoembolization, objective radiologic response rates ranged from 11 to 100 percent. Median survival durations ranged between 18 and 80 months.
•In seven studies of radioembolization, objective radiologic response rates ranged from 22 to 71 percent. Reported median survival durations ranged between 22 and 70 months.
●In one of the largest reports of 81 patients undergoing bland embolization or chemoembolization for a gastrointestinal NET, the median response duration was 17 months, and progression-free survival (PFS) rates at one, two, and three years were 75, 35, and 11 percent [37].
A second series of 69 patients with a gastrointestinal NET and 54 with a pancreatic NET suggested better results for gastrointestinal NETs (response rate 67 versus 35 percent, median PFS 23 versus 16 months, and median overall survival 34 versus 23 months) [34]. The addition of chemotherapy to hepatic arterial embolization seemed to benefit pancreatic but not gastrointestinal NETs.
●Experience with 90-Y radioembolization in metastatic NETs has been growing [29-31,35,36,45]. In the largest series, reported by Kennedy et al, of 148 patients with unresectable liver metastases, 64 percent had an objective response [29]. Fatigue (7 percent) was the most common side effect.
As with other techniques, radioembolization has been reported to reduce symptoms in approximately one-half of patients with functioning tumors [31,35]. A single case report describes control of refractory hypoglycemia for three months following radioembolization of a metastatic malignant insulinoma [46].
Several publications have evaluated the incidence of hepatic toxicity with 90-Y radioembolization in patients with neuroendocrine liver metastases. Cases of radiation-induced hepatic fibrosis and cirrhosis developing over the course of several years have been reported [47-49].
Retrospective comparative studies of 90-Y radioembolization versus transarterial chemoembolization have come to variable conclusions as to whether either approach is superior, at least in part due to heterogeneous patient populations [50-53]. Randomized trials are needed.
●Concern has been raised as to the high incidence of biliary injury with transarterial chemoembolization using drug-eluting beads [54].
●Information is expected from the RETNET (Randomized Embolization Trial for NeuroEndocrine Tumor metastases to the liver) trial, a prospective, multicenter, randomized, controlled trial designed to determine the optimal embolotherapy technique for NET liver metastases (NCT02724540). In this trial, patients with progressive or symptomatic unresectable neuroendocrine liver metastases will be randomized to bland embolization or transarterial chemoembolization. An arm of this trial evaluating transarterial chemoembolization using drug-eluting beads has closed due to concerns regarding hepatic toxicity.
Regardless of the approach that is chosen, appropriate patient selection is important to minimize treatment- and disease-related adverse effects, which can include pain, nausea, fever, fatigue, and biochemical abnormalities (elevated liver enzymes) [55]. Importantly, the toxicity and safety of 90-Y radioembolization for patients who have undergone or may be candidates for future peptide receptor radionuclide therapy have not been established. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Lutetium-177 dotatate' and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Lutetium Lu-177 dotatate'.)
Contraindications and complications of transarterial therapies, which are similar whether the approach is being used for NETs or for hepatocellular cancer, are presented elsewhere. However, in contrast to hepatocellular cancer, the presence of extrahepatic disease is not a contraindication to transarterial embolization for NETs, particularly for highly symptomatic patients [33]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Radioembolization'.)
Prophylaxis for carcinoid crisis should also be considered prior to embolization in patients with carcinoid syndrome [56]. (See 'Prevention and management of carcinoid crisis' below.)
Liver transplantation — Orthotopic liver transplantation (OLT) is not currently a standard option for unresectable neuroendocrine liver metastases, and further investigation is needed to evaluate its benefits.
The number of patients with liver-isolated metastatic disease in whom OLT has been attempted is relatively small, and the role of OLT in patients with metastatic NETs is not yet established and remains controversial [57-62]. One of the largest reported series included 213 patients who underwent OLT for NETs in 35 centers in 11 European countries between 1982 and 2009 [63]. Perioperative mortality within three months of transplantation was 10 percent. At a median follow-up of 56 months, the one-, three-, and five-year overall survival rates were 81, 65, and 52 percent, respectively, while the corresponding disease-free survival rates were 65, 40, and 30 percent.
In a report from the United Network for Organ Sharing (UNOS) database, 150 transplants were performed for metastatic NETs between 1988 and 2008 [62], including 51 for gastrointestinal NETs, 29 for pancreatic NETs, and 70 for unspecified NETs. The one-, three-, and five-year survival rates for the 137 patients undergoing isolated OLT were 81, 65, and 49 percent, respectively, and there were no differences based on site of tumor origin.
While long-term recurrence-free survival may be obtained in a minority of patients, the majority of those undergoing OLT for metastatic NETs ultimately develop recurrent disease [57,64-66]. Strict selection of patients for transplantation is therefore critical. In a systematic literature review of liver transplantation for hepatic metastases from NETs (64 studies, 57 of which were single-center reports), recurrence rates ranged from 33 to 57 percent [66].
The limited availability of donor organs in many regions has also limited the widespread use of this procedure. In the United States, where allocation of donor organs for transplantation is based on the Model for End-Stage Liver Disease (MELD) as proscribed by the Organ Procurement Transplantation Network (OPTN)/UNOS, there are no MELD exception points for NETs like there are for hepatocellular cancer. (See "Liver transplantation for hepatocellular carcinoma", section on 'Requirements for listing and management while on the wait list'.)
However, guidance on MELD exception review is available from OPTN for patients with liver metastases from NETs, which is intended to be used by regional review boards to evaluate case requests for liver transplantation in these patients in order to promote consistent review of these patients throughout the country.
MANAGEMENT OF THE PRIMARY TUMOR IN PATIENTS WITH METASTATIC DISEASE
Small bowel primaries — We suggest resection for symptomatic small bowel primary sites and for asymptomatic primaries if both the primary site and liver metastases are amenable to complete or near-complete resection as noted above. The benefit of resecting asymptomatic small bowel primary sites in patients with unresectable metastatic disease has not been clearly established, and we suggest not pursuing this approach.
For most malignancies, there is little rationale to resect the primary site when widespread, unresectable metastases are present. In patients with small bowel NETs, however, resection of the primary may be beneficial if the primary site is causing symptoms, even in the setting of metastatic disease, given the sometimes prolonged survival of such patients. Additionally, if the primary and liver metastases are both amenable to potentially curative resection, surgery should be performed [4,67,68].
Small bowel NETs are often associated with desmoplasia and fibrosis, which can result in intermittent small bowel obstruction and, in some cases, bowel ischemia [69,70]. Surgical resection of the primary should therefore be considered in patients experiencing intermittent obstruction or abdominal discomfort thought to be related to the primary tumor, even in the presence of metastatic disease [71]. Mesenteric angioplasty or stenting could be an option in selected patients, although experience with this approach is limited [69]. (See "Chronic mesenteric ischemia", section on 'Revascularization'.)
While some have also advocated the routine resection of asymptomatic small bowel primary tumors in patients with unresectable metastatic disease, this practice remains controversial. Guidelines on the surgical management of small bowel NETs are available from the North American Neuroendocrine Tumor Society (NANETS), the European Neuroendocrine Tumor Society (ENETS), the National Comprehensive Cancer Network (NCCN), and the European Society for Medical Oncology (ESMO):
●The NANETS guidelines recommend that resection of the primary tumor be considered, when feasible, to relieve symptoms, to avoid future symptoms, and for a potential survival advantage [72]. However, they also point out that the benefits of removing an asymptomatic primary tumor are controversial, that clinical factors, including the extent of metastatic disease, need to be considered, and that the risks of resection need to be weighed against the potential benefits [72,73].
●The ENETS guidelines do not provide specific recommendations regarding resection of an asymptomatic primary small intestinal NET in the presence of unresectable liver metastases, but they do state that there may be a role for resection to prevent later complications and acknowledge that the lack of prospective trials does not allow firm conclusions on any potential survival benefit [74,75].
●The NCCN recommends that both the primary and metastases be resected if both are resectable and that resection also be considered for symptomatic primary tumors in the setting of metastatic disease, but provides no recommendation for patients with asymptomatic primary tumors and categorically unresectable metastatic disease [76].
●ESMO guidelines also endorse palliative resection of primary small intestinal NETs in advanced disease to prevent complications related to bowel obstruction or intestinal ischemia, also noting that there are contradictory data on the survival benefit of this approach [77].
Does resection prolong survival? — The available data on the survival benefits of resecting an asymptomatic primary are conflicting:
●At least two systematic reviews have concluded that there is at least a trend toward longer survival in patients who undergo resection of the primary tumor despite the presence of metastatic disease [78,79]. However, the retrospective nature of these studies makes the data difficult to interpret given the high potential for selection bias in patients taken to surgery compared with those who were not.
●A large retrospective cohort of 4076 patients with metastatic midgut NETs derived from the National Cancer Database also concluded that there was a survival benefit for resection of the primary tumor (hazard ratio for death for those with primary tumor resection versus without 0.63, 95% CI 0.51-0.78) [80].
●On the other hand, a survival benefit for primary tumor resection could not be shown in a cohort study from Sweden, which examined outcomes among 161 patients with metastatic small bowel NETs without abdominal symptoms who had prophylactic surgery within six months of diagnosis combined with oncologic treatment, compared with 202 similar patients who underwent nonsurgical treatment or delayed surgery as needed in combination with oncologic treatment [81]. Prophylactic primary tumor resection conferred no survival benefit compared with delayed surgery as needed, and patients undergoing prophylactic surgery needed more reoperations for intestinal obstruction compared with delayed surgery as needed (14 versus 3 percent).
Pancreatic neuroendocrine tumors — The benefit of resecting the primary tumor in patients with metastatic nonfunctioning pancreatic NETs is also controversial. In contrast to small bowel primaries, in most series, removal of the primary tumor has been associated with longer survival, even in the setting of unresectable metastatic disease. However, all of the experience comes from retrospective analyses, and it remains possible that the perceived survival benefit is the result of selection bias. The issue of resection of the primary tumor in patients with nonfunctioning pancreatic NETs is discussed in detail elsewhere. (See "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Candidates for resection' and "Surgical resection of sporadic pancreatic neuroendocrine tumors", section on 'Nonfunctional'.)
PREVENTION AND MANAGEMENT OF CARCINOID CRISIS — Carcinoid crisis is a life-threatening form of carcinoid syndrome that may be triggered by tumor manipulation (biopsy, palpation at the bedside or during surgery) or by anesthesia. It is less commonly reported after chemotherapy, hepatic arterial embolization, or radionuclide therapy, mostly in patients with extensive tumor bulk.
Carcinoid crisis results from the release of an overwhelming amount of biologically active compounds from the tumor (table 3). In addition to hemodynamic instability, symptoms include flushing, diarrhea, tachycardia, arrhythmias, bronchospasm, and altered mental status.
Recent studies have questioned the routine need for prophylactic preoperative octreotide in all patients with metastatic neuroendocrine tumors, particularly for those who are already receiving long-acting somatostatin analogs or do not have carcinoid syndrome. If prophylactic octreotide is not administered, it should be available intraoperatively for emergent intravenous use for patients with carcinoid syndrome who develop hemodynamic instability concerning for carcinoid crisis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●For initial management of patients with hepatic metastases from well-differentiated gastrointestinal or pancreatic neuroendocrine tumors (NETs) that can be completely resected, we suggest resection rather than medical therapy (Grade 2B). Resection is an appropriate treatment for liver metastases in the absence of extrahepatic metastases, diffuse bilobar involvement, or compromised liver function, particularly for low-volume or symptomatic disease and low-grade tumors. The benefits of surgical debulking in patients with incompletely resectable metastatic gastrointestinal or pancreatic NETs remain controversial, and this should be considered an investigational approach. (See 'Surgical resection' above.)
●We suggest resection for symptomatic small bowel primary sites and for asymptomatic primaries if both the primary site and liver metastases are amenable to potentially curative resection (Grade 2C). The benefit of resecting asymptomatic small bowel primary sites in patients with unresectable metastatic disease has not been clearly established, and we suggest not pursuing this approach (Grade 2C). (See 'Management of the primary tumor in patients with metastatic disease' above.)
●Recent studies have questioned the routine need for prophylactic preoperative octreotide in all patients with metastatic neuroendocrine tumors, particularly for those who are already receiving long-acting somatostatin analogs or do not have carcinoid syndrome. If prophylactic octreotide is not administered, it should be available intraoperatively for emergent intravenous use for patients with carcinoid syndrome who develop hemodynamic instability concerning for carcinoid crisis. This subject is addressed in detail elsewhere. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)
●Orthotopic liver transplantation (OLT) is not currently a standard option for unresectable neuroendocrine liver metastases, and further investigation is needed to evaluate its benefits for patients with metastatic gastrointestinal and pancreatic NETs. (See 'Liver transplantation' above.)
●We suggest hepatic arterial embolization, chemoembolization, or radioembolization as an alternative to medical therapy alone as a palliative technique for symptomatic patients with hepatic-predominant unresectable gastrointestinal or pancreatic NETs (Grade 2C). The toxicity and safety of yttrium-90 (90-Y) radioembolization for patients who have undergone or may be candidates for future peptide receptor radionuclide therapy have not been established. (See 'Hepatic arterial embolization' above.)
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