High-grade gastroenteropancreatic neuroendocrine neoplasms

INTRODUCTION — The classification and nomenclature of neuroendocrine neoplasms (NEN) arising in the pancreas and gastrointestinal (GI) tract have evolved over the last two decades. High-grade NEN of the GI tract and pancreas are a heterogeneous group of aggressive malignancies. Most are poorly differentiated high-grade neuroendocrine carcinomas (NEC) with a high propensity for distant metastases and an ominous prognosis, even when clinically localized. A subset are high grade by proliferative or mitotic rate but demonstrate well-differentiated histology (well-differentiated grade 3 [G3] neuroendocrine tumors [NET]) and have a prognosis that is midway between the high-grade poorly differentiated NEC and well-differentiated grade 2 NET, which are more indolent. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

This topic review will cover the epidemiology, clinical features, diagnosis, staging, prognosis, and treatment of high-grade gastroenteropancreatic (GEP) NEN. A more in-depth discussion of the pathology and classification of NEN arising in the digestive system; clinical characteristics, localization, and staging of GI tract NEN and pancreatic NEN; the presentation, prognosis, and biochemical monitoring of metastatic GEP NEN; treatment options, including both local therapies and systemic therapies, for well-differentiated metastatic GEP NET; and issues related to presentation, evaluation, and treatment of NEN of unknown primary site are presented elsewhere:

●(See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)

●(See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)

●(See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)

●(See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

●(See "Surgical resection of sporadic pancreatic neuroendocrine tumors".)

●(See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)

●(See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

●(See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

●(See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

●(See "Neuroendocrine neoplasms of unknown primary site".)

CLASSIFICATION AND BIOLOGIC BEHAVIOR — In 2006 and 2007, the European Neuroendocrine Tumor Society (ENETS) proposed a grading scheme for neuroendocrine neoplasms (NEN) of the digestive tract, which was later endorsed by the American Joint Committee on Cancer for its tumor, node, metastasis (TNM) staging classification. (See 'Staging system' below and "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

The 2010 World Health Organization (WHO) classification of tumors of the gastrointestinal (GI) tract, liver, and pancreas also endorsed the ENETS grading scheme for NEN of the digestive tract, separating well-differentiated neuroendocrine tumors (NET) into low-grade (grade 1 [G1]) and intermediate-grade (grade 2 [G2]) categories [1-3]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification'.)

The 2010 WHO classification equated poorly differentiated histology with high tumor grade; however, an increasing number of studies have challenged the assumption that poorly differentiated histology and high tumor grade are equivalent [4-10]. While it is true that nearly all poorly differentiated cancers have a high proliferation rate, not all grade 3 (G3) tumors are poorly differentiated. A subset of patients with NEN that appear histologically well differentiated is associated with Ki-67 proliferation indices >20 percent, usually in the 20 to 55 percent range [11,12]. The most recent 2019 WHO classification of NEN of the digestive system now recognizes a category of high-grade but well-differentiated GEP NEN (table 1) [13]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'High-grade, well-differentiated neoplasms'.)

Poorly differentiated neuroendocrine carcinomas — In general, all high-grade poorly differentiated GEP neuroendocrine carcinomas (NEC) have an aggressive natural history that is frequently characterized by early, widespread metastases. Patients who present with locoregional disease may be cured by aggressive therapy; however, many relapse, and then the overall prognosis is poor. Similar to their lung counterparts, GEP NEC have been traditionally divided into large cell and small cell subtypes based on the morphologic features of the individual tumor cells (see "Pathology of lung malignancies", section on 'Neuroendocrine tumors'):

●Small cell carcinoma was the first category described in both the lung and GI tract, and for this reason, most of the published literature on extrapulmonary poorly differentiated NEC (which can arise in sites other than the GI tract and pancreas) is focused on small cell carcinoma. (See "Small cell carcinoma of the bladder" and "Small cell neuroendocrine carcinoma of the cervix" and "Extrapulmonary small cell cancer".)

●By contrast, the large cell subtype [14-16], which seems to constitute approximately 60 percent of GEP NEC cases [17], has been less frequently reported [18]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Poorly differentiated neoplasms'.)

●Most series report no apparent difference in prognosis between the large cell and small cell subtypes of poorly differentiated GEP NEC [14,15,17-20]; however, data from one large Dutch cancer registry showed better survival for large cell subtypes of all stages [21].

Given some similarities, treatment paradigms for poorly differentiated extrapulmonary NEC, including those arising in the GI tract, have largely paralleled those established for small cell lung cancer (SCLC). (See "Limited-stage small cell lung cancer: Initial management" and "Extrapulmonary small cell cancer".)

However, there are differences, as SCLC is more strongly associated with smoking, brain metastases are more common, and objective response rates to platinum-based chemotherapy are generally higher [22-26]. There are also several differences in the mutational frequencies: GEP NEC seems to have a lower rate of mutations in the TP53 gene and alterations in expression of the RB1 gene than SCLC, and other genes are more frequently altered [27-29]. One-half of small cell pancreatic NEC have KRAS mutations, in contrast to SCLC where KRAS mutations are rarely found [28,30]. On the other hand, SCLC has a greater than 90 percent incidence of loss of RB1 gene function, compared with 60 percent in pancreatic small cell NEC. (See "Pathobiology and staging of small cell carcinoma of the lung" and "Limited-stage small cell lung cancer: Initial management".)

High-grade well-differentiated tumors — The distribution of NET G3 relative to poorly differentiated NEC is difficult to ascertain. The only prospective data come from the Pronet study, a one-year prospective epidemiologic study among French pathologists to assess the characteristics of newly diagnosed NEN, including a review of the diagnostic pathology [31]. Of the 1340 cases that were collected, 104 were G3, of which 21 (20 percent) were described by the participating pathologists as well or moderately differentiated.

There are differences in the presentation of NET G3 as compared with NEC, including primary tumor location, percentage with elevated tumor markers, uptake on somatostatin receptor scintigraphy, and Ki-67 index; these are outlined in the table (table 2) [7,10-12,31,32]. Given these characteristics, among patients newly diagnosed with a high-grade NEN, the possibility of a NET G3 should especially be considered when the Ki-67 index is between 20 and 55 percent, if somatostatin receptor imaging is positive, and when a pancreatic primary is present.

The clinical behavior of these tumors appears to differ from that of high-grade poorly differentiated NEC. Median survival of patients with NET G3 tumors is more than double that of patients with poorly differentiated high-grade neoplasms; in three studies, the differences were 40 versus 17 months, 32 versus 15 months, and, among cases with metastatic disease, 33 versus 11 months [7,33,34]. As such, the clinical behavior of NET G3 tumors appears to be in between poorly differentiated NEC and intermediate-grade (G2) well-differentiated NET [10].

These data underscore the importance of distinguishing between NET G3 and poorly differentiated NEC. Moreover, there are significant differences with respect to treatment response. Large retrospective analyses demonstrate that tumors with Ki-67 rates <55 percent respond poorly to the cisplatin/carboplatin-based regimens that are used for poorly differentiated NEC [35]. (See 'High-grade, well-differentiated tumors (NET G3)' below.)

EPIDEMIOLOGY AND RISK FACTORS — The incidence of high-grade GEP NEN is difficult to establish given the fact that many international cancer registries that include NEN do not collect information on tumor grade [21,36-39]. However, the available data indicate that high-grade neoplasms are very rare:

●In the Netherlands Cancer Registry, from 2000 to 2010, the annual incidence of GEP neuroendocrine carcinoma (NEC) was estimated to be 0.54 per 100,000 inhabitants. Large cell GEP NEC was twice as common as small cell GEP NEC (incidence of 0.36 versus 0.18 per 100,000 inhabitants) [21].

●In the United States, based upon data from the Surveillance, Epidemiology, and End Results (SEER) program, the incidence of colorectal NEC was 0.2 per 100,000 inhabitants [36]. In a separate analysis of over 162,000 cases of NEC reported to SEER between 1973 and 2012, the colon, rectum, and anal canal accounted for 41 percent of the NEC arising within the gastrointestinal tract, while the upper gastrointestinal tract and the pancreas accounted for 23 and 20 percent, respectively [17].

●In Norway, between 1993 and 2010, the incidence of high-grade pancreatic NEN was 0.04 per 100,000 population and stable over time [40].

In the last two decades, the incidence of high-grade GEP NEN seems to be increasing [17,21,41]. As an example, in the Netherlands Cancer Registry report, there was an increase in incidence of GEP NEC over the last two decades from 0.3 to 0.54 per 100,000 [21]. However, this trend is difficult to interpret since it has coincided with the changes in the nomenclature and classification of GEP NEC resulting in more awareness of the entity among pathologists, epidemiologists, and oncologists, and more precise classification [6,17]. (See 'Classification and biologic behavior' above.)

In most series, incidence rates are similar in males and females. However, at certain sites (ie, esophagus, stomach), there is a male predominance [42-44].

Risk factors — Risk factors for high-grade GEP NEN are not well elucidated. Some reports note an association with smoking, but not as tight an association as with small cell lung cancer [21,26,45]; more data are required to determine how tobacco exposure affects risk. Studies have also suggested a prior history of achalasia, gastroesophageal reflux disease, or Barrett metaplasia can be associated with esophageal NEC, while colonic adenomas and ulcerative colitis may similarly increase risk for colorectal NEC [45,46].

The presence of a well-differentiated GEP NET is not a defined risk factor for GEP NEC. It is believed that NEC generally do not arise from well-differentiated NET, since usually GEP NEC and NET are not found together on pathologic exam [6,45]. While low-grade NET often develop high proliferative activity during the course of metastatic disease and well-differentiated NET may have a morphologically apparent high-grade component [47], transformation from a well-differentiated NET into a truly poorly differentiated phenotype is uncommon [47]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'High-grade, well-differentiated neoplasms'.)

CLINICAL PRESENTATION — The presenting symptoms of high-grade (grade 3 [G3]) GEP NEN are quite variable and depend upon the site of the primary tumor and whether or not metastatic disease is present:

●Within the digestive tract, the most common primary tumor locations for neuroendocrine carcinoma (NEC) are the esophagus, stomach, pancreas, and large bowel (including the anal canal) [17,32,35,45,48-50]. (See "Extrapulmonary small cell cancer".)

Within the large bowel, the majority of lesions are distal; in a review of 75 cases, the most common site of origin was the rectum, followed by the cecum, sigmoid colon, transverse colon, and ascending colon (38, 27, 17, 12, and 6 percent, respectively) [46].

For well-differentiated neuroendocrine tumors (NET) G3, the primary tumor is most frequently located in the pancreas [7,10-12,31].

●Presenting symptoms may include both generalized systemic symptoms (such as anorexia, fatigue, and weight loss) and site-specific symptoms (such as focal pain, melena, hematochezia, dysphagia, nausea, emesis, bowel obstruction, or jaundice). If the initial clinical manifestations are due to locoregional disease, the presenting symptoms may be indistinguishable from other tumors arising in the same site. As an example, the symptoms of esophageal small cell carcinoma typically reflect the presence of a mass. When the tumor is localized, progressive dysphagia and indigestion are common complaints; weight loss and cachexia due to anorexia and decreased caloric intake may also be seen [51,52].

●Nearly all GEP NEC are nonsecretory [32,53-55].

●Given the aggressive nature of GEP NEC, most patients have metastatic disease at the time of presentation [18,32,55]. An analysis using Surveillance, Epidemiology, and End Results data of 2546 cases of GEP NEC G3 revealed that distant disease was present at initial diagnosis in 57 percent of cases [56]. The scarce data available for NET G3 suggest also a high percentage of metastatic disease (62 to 70 percent) at diagnosis [11,28,57]. Symptoms related to distant metastases may include right upper quadrant pain from liver metastases, bone pain, respiratory complaints, and rarely, central nervous system symptoms from brain metastases.

However, in contrast to pulmonary small cell lung cancer, the risk of brain metastases is lower [25,58,59].

DIAGNOSIS AND STAGING — The diagnosis of a high-grade GEP NEN requires histologic examination of tumor material from a biopsy or excised specimen. The diagnostic workup of a GEP neuroendocrine carcinoma (NEC) differs from the diagnostic evaluation of a well-differentiated neuroendocrine tumor (NET). The roles of both tumor markers (ie, serum chromogranin A [CgA], serum/urinary 5-hydroxyindoleacetic acid [5-HIAA]) and somatostatin receptor imaging are usually minor unless the patient is suspected of having or has a well-differentiated high-grade (grade 3 [G3]) NET. By contrast, positron emission tomography (PET) scanning using fluorodeoxyglucose (FDG-PET) is of greater utility with NEC.

Pathologic diagnosis — The hallmark of neuroendocrine cells is the production of abundant neurosecretory granules, as reflected in the strong and diffuse immunohistochemical expression of neuroendocrine markers such as synaptophysin and chromogranin. All neoplasms with neuroendocrine differentiation should be assessed for grade and extent of differentiation. Differentiation refers to the resemblance of the tumor histology to its normal counterparts, whereas grade describes the proliferative activity of the tumor, as measured by mitotic rate or Ki-67 rate (table 1). (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Morphology and immunohistochemistry'.)

●NEC versus G3 NET

•GEP NEC less closely resembles nonneoplastic neuroendocrine cells, having a more sheet-like or diffuse architecture, irregular nuclei, and less cytoplasmic granularity (figure 1). There are two distinct histologic entities: small cell and large cell NEC (figure 2) [13]. Small cell carcinomas are composed of small- to medium-sized, round to oval cells with scant cytoplasm and hyperchromatic nuclei with indistinct nucleoli. The large cell subtype is composed of large cells with vesicular nuclei showing prominent nucleoli and abundant eosinophilic cytoplasm. In both cases, the tumor cells grow in sheets, forming nest-like structures, often with large confluent areas of necrosis [60]. Perineural and vascular invasions are frequently observed.

By contrast, GEP NET G3 more closely resemble nonneoplastic neuroendocrine cells, with characteristic "organoid" arrangements of the tumor cells with solid/nesting, trabecular, gyriform or sometimes glandular patterns. The cells are relatively uniform, and they have round to oval nuclei, coarsely stippled chromatin, and finely granular cytoplasm.

Histologically, when a pathologist is assessing a high-grade NEN, morphologic features have not always been reliable in separating a well-differentiated NET from a poorly differentiated NEC. However, more recent data suggests that this organoid growth pattern, in conjunction with a capillary network in direct contact to tumor cells, and absence of desmoplastic stroma can help to separate NET G3 from NEC [34].

•There is no Ki-67 index cutoff within the G3 range (>20 percent) that sharply separates these two neoplasms; a high Ki-67 (>55 percent) usually points to NEC, but rates in the 20 to 55 percent range can be seen with either NET or NEC. On the other hand, a mitotic rate greater than 20 per 10 high-powered fields usually indicates a NEC, since most NET fall into the G3 range solely based on Ki-67 index. This subject is discussed in more detail elsewhere. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Issues related to assessing grade'.)

•Immunohistochemical staining may help with this distinction in difficult cases. (See 'Immunohistochemistry' below.)

●Mixed neuroendocrine/nonneuroendocrine neoplasms

•Some GEP NEC may contain nonneuroendocrine components, including adenocarcinoma, signet ring cell carcinoma, and more rarely, squamous cell cancer. If the neoplasm consists of a neuroendocrine component and a gland-forming component both exceeding 30 percent, the new 2019 World Health Organization (WHO) classification defines it as a mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) [61,62].

The origin of these mixed tumors is thought to be a totipotent stem cell present in the submucosa that can differentiate into various cell lines [51,63,64]. Clinical management of metastatic disease is controversial as there are only retrospective series with limited sample sizes. As a result, there is significant variability as to initial systemic treatment of metastatic MiNEN (ie, use of a NEC-type regimen [platinum/etoposide] versus an adenocarcinoma regimen [fluoropyrimidine backbone based on primary tumor site]) [65]. Some have suggested a NEC-type regimen for those with a high-grade MiNEN (G3 poorly differentiated NEC as the neuroendocrine component) and an adenocarcinoma-type regimen for all others who have a well-differentiated NEN component [66].

Immunohistochemistry — Immunohistochemical staining for synaptophysin and CgA is used to determine if a tumor has neuroendocrine features. Many GEP NEC will stain for both synaptophysin and CgA, but whereas synaptophysin is almost always positive, CgA may be only focally positive or negative [1,11,35,67]. Generally, the presence of a small cell histology defines a NEC, whereas for cases in which the histology is non-small cell, synaptophysin should be present in addition to a neuroendocrine morphology. The specificity and clinical utility of immunohistochemical staining for other neuroendocrine markers, such as neuron-specific enolase, protein gene product 9.5, and CD56, are uncertain [68] and they are not used.

Immunohistochemical staining may also be helpful for differentiating NEC from NET G3. As an example, pancreatic NET G3 show loss of DAXX and ATRX in roughly one-half of cases, similar to pancreatic NET grade 1 (G1) and grade 2 (G2), whereas loss of RB1 expression or abnormality of p53 expression supports a diagnosis of NEC [69]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'High-grade, well-differentiated neoplasms'.)

Radiographic studies — The diagnostic workup for a GEP NEN G3 is typically accomplished by cross-sectional imaging (contrast-enhanced computed tomography [CT] and/or magnetic resonance imaging scans), which typically include imaging of the chest, abdomen, and pelvis.

For NEC, we often perform integrated PET-CT scanning using fluorodeoxyglucose (FDG-PET/CT), which is positive in most cases (92 percent in one study [32]). FDG-PET/CT is especially useful for patients after radical surgery for apparently localized disease before start of adjuvant therapy, as many cases will have developed metastatic disease. Routine brain imaging in patients lacking neurologic symptoms is not recommended because GEP NEC are associated with a lower incidence of brain metastases than small cell lung cancer. (See 'Clinical presentation' above and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)

For patients with NEC, somatostatin receptor-based imaging (eg, with Ga-68 DOTATATE, Ga-68 DOTATOC, or Cu-64 DOTATATE integrated PET/CT) is usually not helpful; it is negative in over one-half of cases [32,70]. However, somatostatin receptor-based imaging, rather than FDG-PET scanning, is reasonable for NET G3. Two studies have directly compared somatostatin receptor imaging in G3 NET with that in NEC: in one study, imaging was positive in 88 percent of NET G3 versus 40 percent of NEC cases [11]; in the second analysis, imaging was positive in 87 percent of NET G3 versus 50 percent of NEC cases [71].

Tumor markers — Well-differentiated GEP NET have the capacity to make and secrete bioactive amines and peptides, both hormonal (eg, serotonin) and nonhormonal (eg, chromogranin A [CgA]). (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)

However, the role of serial assay of tumor markers such as CgA in GEP NEN G3 is not well established. Serum levels of CgA can be elevated in some patients, including those with NEC [11,32,35]. In one series of 253 patients with a GEP NEC, 46 percent had elevated levels of CgA at diagnosis [32]. However, it is not clear that radiographically assessed disease burden is paralleled by changes in the CgA, even if it is initially elevated. Given that radiographic scans usually show progression and response quite clearly in this disease, and the fact that conventional tumor markers such as CgA are rarely useful (even for low-grade NET), we do not routinely assay CgA before or during treatment in patients with NEN G3. Measurement of serum/urine levels of the serotonin metabolite 5-HIAA is not useful for high-grade NEN or NEC given the lack of serotonin secretion in these patients [35]. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Role of nonhormonal tumor markers in clinical practice' and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)'.)

Staging system — There is no universally agreed-upon staging system for GEP NEN G3:

●In 2006 and 2007, the European Neuroendocrine Tumor Society (ENETS) proposed a staging scheme similar to most other types of epithelial neoplasms for NEN of the digestive tract, which was accompanied by a histologic grading system that could be applied to all tumor stages [72,73]. The ENETS proposal stages poorly differentiated NEC in the same way as well-differentiated NET.

●The WHO has endorsed staging NEN of both the pancreas and tubular gastrointestinal tract using a tumor, node, metastasis (TNM)-based system as is used by the American Joint Committee on Cancer (AJCC) [74,75]. The current eighth edition of the combined AJCC/Union for International Cancer Control TNM staging manual, which reflects a modification of the ENETS proposal [76], includes separate TNM staging systems for well-differentiated NET of appendix, pancreas, stomach, small bowel/ampulla of Vater, and colorectal primary sites [77]. However, in contrast to the ENETS recommendation [72,73], poorly differentiated NEC are staged using the staging classifications for adenocarcinomas at the individual primary tumor sites, not as well-differentiated NET. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors" and "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)

Differential diagnosis — Well-differentiated GEP NET can usually be distinguished from poorly differentiated GEP NEC G3 by their morphologic appearance and lower proliferative indices (table 1). However, the histologic diagnosis of a poorly differentiated NEC needs to be supported by immunohistochemical evidence of neuroendocrine differentiation (ie, staining for chromogranin and/or synaptophysin) to avoid possible misdiagnosis with the more frequent poorly differentiated adenocarcinomas (including pancreatic acinar cell cancers [18]) and squamous cell carcinomas, or with lymphomas and mesenchymal neoplasms. (See 'Immunohistochemistry' above.)

Molecular testing — Some molecular markers may be relevant for treatment of metastatic disease:

●Deficient DNA mismatch repair (dMMR) has been found in 5 percent of GEP NEC, and these patients should be considered candidates for therapy with an immune checkpoint inhibitor [78]. On the other hand, tumor mutational burden (TMB) is generally low in NEC and NET G3 that have proficient MMR [78]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

●Mutations in BRAF are present up to 50 percent in colonic NEC [78], and BRAF inhibitors in combination with cetuximab are an option for these patients as long as they are RAS wild-type. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, BRAF mutated tumors'.)

TREATMENT AND PROGNOSIS

Poorly differentiated NEC — There is a general lack of data from prospective trials to guide clinical decision-making regarding treatment of GEP neuroendocrine carcinoma (NEC). Current treatment approaches are based primarily on retrospective reports and parallel recommendations for small cell lung cancer (SCLC). In general, many patients with GEP NEC have a poor prognosis with rapid disease progression, and there is a high proclivity for metastatic dissemination, even in the setting of clinically localized tumors. Surgery alone can be curative for localized disease, but multimodality treatment is recommended for most patients. GEP NEC are chemotherapy-responsive neoplasms, and platinum-based chemotherapy represents the backbone of treatment for both early and advanced-stage GEP NEC [6].

Overview of the approach to treatment — The following represents our general approach to treatment, which is outlined in the algorithm (algorithm 1):

●For patients with nonesophageal NEC who have early stage, potentially readily resectable tumors, we suggest surgical resection plus four to six cycles of adjuvant platinum-based chemotherapy (etoposide plus cisplatin or carboplatin). Carboplatin may be preferred for patients with contraindications to or poor tolerance of cisplatin. Chemotherapy is often given as neoadjuvant therapy. (See 'Localized disease' below.)

●For locoregionally advanced, but nonmetastatic nonesophageal NEC (eg, T3N1 or T4), we suggest multimodality treatment that includes platinum-based chemotherapy in all cases, individualization of the use of radiation therapy depending on location and risk of locoregional recurrence, as well as surgery when feasible. Given the aggressive nature of poorly differentiated NEC, preoperative (neoadjuvant) rather than postoperative (adjuvant) treatment may be considered unless surgery can be undertaken quickly with expectation of a reasonably fast recovery. (See 'Benefit of radiotherapy' below.)

●For apparently isolated locoregional esophageal primaries, chemoradiotherapy plus chemotherapy is preferred over surgery plus chemotherapy.

●Data on extrapulmonary NEC suggest a lower frequency of central nervous metastases than has been seen with pulmonary SCLC, and we suggest not pursuing prophylactic cranial irradiation for any patient with local or locoregional disease. (See 'Prophylactic cranial irradiation' below.)

●Patients with metastatic NEC should be referred rapidly for palliative chemotherapy given the aggressive nature of these tumors. Standard palliative chemotherapy consists of cisplatin or carboplatin combined with etoposide; an acceptable alternative is irinotecan plus cisplatin. (See 'Initial chemotherapy' below.)

The optimal duration of treatment is not established. We typically aim for at least four to six cycles of chemotherapy, but if a patient is still responding and tolerating treatment well, continuation of chemotherapy to at least maximal response is appropriate.

Localized disease — A minority of patients with a GEP NEC have apparently localized disease at presentation [32,71]. Treatment recommendations for such patients are not based on prospective data, and supporting evidence from retrospective studies is quite limited. Many of these studies enrolled a heterogeneous patient population that was not exclusively GEP NEC and instead investigated outcomes for a variety of extrapulmonary NEC [23,24,58,79,80]. However, patients with localized disease, five-year survival rates can be as high as 40 to 50 percent with combined surgery and systemic therapy [17]. Nonetheless, in this context, there is consensus that local therapy alone is rarely curative and that all patients, including those with limited disease, benefit from systemic chemotherapy [6,45,48,81-83]. (See "Extrapulmonary small cell cancer".)

Role of surgery — For patients with a NEC that is not in the esophagus, early stage, and potentially resectable, we suggest surgical resection in addition to systemic chemotherapy rather than chemotherapy alone. If surgery is being considered, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be performed prior to resection to exclude distant metastases. (See 'Radiographic studies' above.)

For locoregional therapy of apparently localized esophageal NEC, we suggest definitive chemoradiotherapy rather than surgery.

●Primary tumor not in the esophagus – The data supporting a benefit from resection come from retrospective reports noting that potentially curative surgery is an independent prognostic factor for better outcomes among patients undergoing multimodality therapy [17,41,67,84-92].

As an example, in a study based on data from the National Cancer Database between 2004 and 2016, included 2314 cases with stage I to III digestive tract NEC [93]. The overall median survival was 20.7 months, and the five-year survival rate was 29.2 percent. Significant differences in survival were noted according to site and morphology. Colon NEC had the longest median survival (28.5 months with 39.7 percent five-year survival), while gallbladder and biliary NEC (median 14.8 months with 20.9 percent five-year survival) had the shortest median survival. Small cell morphology was associated with worse median survival compared with large cells and other histologies (17.7 versus 22.3 months). Even in patients undergoing chemoradiation, surgery was the only prognostic variable that significantly affected survival in stages I to II disease (HR 0.63, 95% CI 0.44-0.91) and there was also a trend towards better survival with stage III disease that was not statistically significant (HR 0.77, 95% CI 0.59-1.01).

In general, radical surgery alone is not considered adequate therapy for G3 NEC, and the majority of patients should receive some form of adjuvant systemic therapy. (See 'Postoperative adjuvant chemotherapy' below.)

●Colorectal primary – For colorectal primary tumors, the benefit of surgery may depend on cell type. In a study of 502 colorectal NEC stage I to III, three-year survival after surgery versus no surgery was 40 versus 18 percent [41] Patients with localized non-small cell CRC NEC had better survival after surgery (median 21 versus 6 months), whereas those with small cell CRC NEC did not (median survival 18 versus 14 months).

●Esophageal primaries – One exception where surgery is generally not recommended, even for apparently isolated locoregional disease, is esophageal NEC, in which chemoradiotherapy plus chemotherapy is preferred over surgery plus chemotherapy. In a review of 127 patients with limited-stage small cell esophageal carcinoma, survival was superior for patients treated with radiation plus chemotherapy as compared with that for patients treated with surgery and chemotherapy (three-year overall survival 50 versus 24 percent) [82], and results seem especially poor after surgical treatment of stage III esophageal NEC [82,86].

Postoperative adjuvant chemotherapy — For most patients with apparently localized GEP NEC, we suggest adjuvant chemotherapy in conjunction with local therapy rather than local therapy alone. Following the paradigm established for limited-stage SCLC, for most patients we administer four to six cycles of platinum-based chemotherapy (etoposide plus either carboplatin or cisplatin). This approach is consistent with current treatment guidelines from the National Comprehensive Cancer Network, the North American Neuroendocrine Tumor Society (NANETS), and the European Neuroendocrine Tumor Society [81,83,94].

There is a lack of prospective data that have established the benefit from adjuvant platinum-based chemotherapy therapy in localized GEP NEC [89,95], and recommendations have been primarily extrapolated from the treatment paradigm for limited stage SCLC, in which the contribution of chemotherapy to long-term survival in early stage disease has been demonstrated in observational studies. (See "Limited-stage small cell lung cancer: Initial management", section on 'Overview of treatment and benefits'.)

Retrospective reports on adjuvant chemotherapy for localized GEP NEN G3 are difficult to interpret due to a probable selection bias of which patients received adjuvant treatment. Furthermore, contemporary retrospective studies show conflicting results and suggest that the benefit of adjuvant therapy might depend, in part, on the primary site. In three reports, adjuvant chemotherapy after surgery for colorectal NEC showed a survival benefit, whereas this was not found in a fourth series of patients with gastric NEC/MiNEN [96-99]. (See 'Pathologic diagnosis' above.)

The standard regimen is etoposide plus cisplatin or carboplatin. In our view, either carboplatin or cisplatin represents an acceptable choice. The available data in limited-stage SCLC suggest that carboplatin and cisplatin are equivalent in terms of overall survival, progression-free survival (PFS), and objective response rate, differing only in terms of toxicity [100]:

●Carboplatin is more likely to be associated with grade 3 to 4 hematologic toxicities.

●Cisplatin is more likely to be associated with nonhematologic toxicities, including nausea, vomiting, ototoxicity, neuropathy, and nephropathy.

Nevertheless, many clinicians, citing the curability of limited-stage SCLC and the greater experience with cisplatin/etoposide, consider cisplatin/etoposide to represent the standard of care for localized disease, reserving carboplatin for patients with a contraindication to or intolerance of cisplatin. (See "Limited-stage small cell lung cancer: Initial management", section on 'Preferred regimen: Etoposide plus cisplatin'.)

Benefit of radiotherapy — For both localized and locoregionally advanced esophageal GEP NEC, we suggest chemoradiotherapy plus chemotherapy rather than surgery followed by chemotherapy. (See 'Role of surgery' above.)

For locoregionally advanced nonmetastatic nonesophageal NEC (ie, T3N1 or T4, (see 'Staging system' above)), we suggest a multimodality approach that includes chemotherapy in all cases, individualization of the use of radiation therapy depending on location (eg, anorectum) and risk of locoregional recurrence, as well as surgery when feasible. Given the aggressive nature of NEC, we often use neoadjuvant rather than adjuvant RT; however, many cases of NEC are diagnosed after surgery. (See 'Integration of local therapy' below.)

The use of chemoradiotherapy for locally or locoregionally advanced NEC (T3 to T4 and/or lymph node involvement) using a platinum agent plus etoposide is based upon the treatment paradigm for limited-stage SCLC, in which the addition of thoracic radiation therapy to systemic chemotherapy results in a small, statistically significant improvement in survival compared with the use of chemotherapy alone, albeit with an increase in toxicity. (See "Limited-stage small cell lung cancer: Initial management", section on 'Benefit of RT'.)

Integration of local therapy — There are no prospective trials addressing how best to integrate local and systemic therapy into the treatment of localized or locoregional GEP NEC. We mainly agree with consensus-based guidelines from NANETS, which suggest the following approach [81]:

●Surgery followed by adjuvant chemotherapy (four to six cycles of a platinum agent with etoposide) for most early stage tumors (T1 to T2, N0). (See 'Staging system' above.)

●Adjuvant or neoadjuvant chemoradiation is reasonable if the risk of local recurrence is thought to be higher than average, depending upon the anatomic location of the tumor (eg, anorectum). However, distant recurrences are far more frequent than local recurrences, and these patients all need four to six cycles of systemic platinum-based chemotherapy as well.

●Chemoradiotherapy is also a reasonable option for locally or locoregionally advanced disease (T3 to T4 and/or lymph node involvement), using concurrent radiation therapy plus a platinum agent with etoposide. This treatment can be considered definitive or neoadjuvant, depending on whether surgical resection is feasible. All patients should receive four to six cycles of platinum-based chemotherapy in addition to chemoradiotherapy.

●A neoadjuvant approach to treatment with chemotherapy alone followed by surgery is an option for patients with localized nonesophageal tumors, especially if it is estimated that postoperative morbidity will be high and adjuvant treatment might be delayed.

Prophylactic cranial irradiation — Data on extrapulmonary poorly differentiated NEC suggest a lower frequency of central nervous metastases than seen with pulmonary SCLC, and we do not suggest prophylactic cranial irradiation for these patients in the absence of demonstrable brain metastases. (See 'Clinical presentation' above and "Prophylactic cranial irradiation for patients with small cell lung cancer".)

Metastatic disease — Systemic chemotherapy is the mainstay of care for individuals with metastatic NEC. Systemic chemotherapy is palliative, but can improve survival. In a retrospective review of 305 patients with advanced (301 metastatic) GEP NEC diagnosed at 12 Nordic hospitals during 2000 to 2009, median survival for those who received palliative chemotherapy was 11 months; for the 53 who did not receive chemotherapy, it was one month [35]. These data reflect, in part, worse baseline health in the group receiving best supportive care.

General approach — Our general approach to treatment of metastatic GEP NEC is as follows, as outlined in the algorithm (algorithm 1):

●Rapid referral for palliative chemotherapy is necessary given the aggressive nature of these tumors. For most patients, standard palliative chemotherapy consists of cisplatin or carboplatin combined with etoposide; an acceptable alternative is irinotecan plus cisplatin, but we generally prefer carboplatin or cisplatin plus etoposide. (See 'Initial chemotherapy' below.)

The optimal duration of treatment is not established. We typically aim for four to six cycles of therapy, but if a patient is still responding and tolerating treatment well, continuation of chemotherapy to at least maximal response is appropriate.

●Surgical metastasectomy is generally not recommended in the management of GEP NEC. However, selected patients may benefit from liver surgery; decision-making must be individualized. (See 'Role of metastasectomy' below.)

●Patients with platinum-sensitive disease may benefit from retreatment with cisplatin or carboplatin plus etoposide if relapse occurs at least three to six months after discontinuation of first-line treatment. While second-line regimens have not been evaluated rigorously, options include temozolomide-, fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens. (See 'Second-line chemotherapy' below.)

●Given limited treatment options in the platinum-refractory setting and the potential for sustained remission with immunotherapy, combination immunotherapy, particularly with ipilimumab and nivolumab is a reasonable option for GEP NEC for second-line treatment and beyond.

Initial chemotherapy — We suggest treatment of metastatic GEP NEC with a two-drug platinum-based regimen, generally cisplatin or carboplatin plus etoposide. This approach is consistent with all published guidelines for this disease [53,81,83,94,101,102]. An acceptable alternative is irinotecan plus cisplatin, although we generally prefer a platinum plus etoposide regimen. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for platinum-etoposide as choice of chemotherapy'.)

Most cases of metastatic GEP NEC are responsive to systemic platinum-based chemotherapy, but almost all patients eventually relapse and die of their disease. However, for the subgroup of colorectal primary NEC, results after platinum plus etoposide are poor with an immediate disease progression in 60 percent of cases [35].

The available data on outcomes from palliative chemotherapy come from retrospective data primarily including patients with metastatic disease. Most of the available data are with cisplatin or carboplatin plus etoposide; there are few comparative studies with other regimens.

Platinum plus etoposide — The benefits of platinum plus etoposide chemotherapy in metastatic GEP NEC can be illustrated by the following retrospective reports:

●In a large Nordic consortium retrospective study, cisplatin or carboplatin plus etoposide was prescribed for 252 patients with advanced GEP NEC [35]. The response rate was 31 percent, PFS was four months, and median survival was 11 months. No significant differences in outcomes were observed in patients treated with cisplatin versus carboplatin. A Ki-67 threshold of 55 percent was predictive of response to chemotherapy: tumors with Ki-67 <55 percent were much less responsive to platinum-based chemotherapy (response rate 15 versus 42 percent) but had a significantly longer survival (median overall survival 14 versus 10 months) compared with patients with higher Ki-67 levels (figure 3).

●In a series of 123 evaluable patients who received a platinum plus etoposide regimen for first-line treatment of metastatic NEC, 61 had an objective response (50 percent) and 29 others (23 percent) achieved stable disease as the best response [32]. Median PFS was 6.2 months and median overall survival was 11.6 months.

The optimal duration of treatment is not established. We typically aim for four to six cycles of therapy, but if a patient is still responding and tolerating treatment well, continuation of chemotherapy to at least maximal response is appropriate.

Is there benefit from adding an immune checkpoint inhibitor? — The addition of an immune checkpoint inhibitor targeting PD-1 or PD-L1 (eg, atezolizumab, durvalumab) to first-line chemotherapy has become a standard of care in SCLC based on phase III studies. Whether this strategy is appropriate for extrapulmonary NEC is not yet known and is the subject of a randomized phase II/III study sponsored by SWOG. Until information from that study is available, we suggest not pursuing this approach. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Preferred option: Immunotherapy plus platinum-etoposide'.)

Irinotecan-based regimens — We consider an irinotecan plus cisplatin doublet to be an acceptable alternative initial chemotherapy regimen in patients with metastatic GEP NEC, although for most patients we prefer carboplatin or cisplatin plus etoposide.

At least two studies have directly compared irinotecan/cisplatin versus etoposide/cisplatin, both of which concluded that neither regimen was superior [103,104]. In the randomized JCOG-1213 trial, which directly compared both regimens in 170 patients with chemotherapy-naïve recurrent or unresectable NEC arising from the gastrointestinal or hepatobiliary tract [104]. Median survival was not significantly better with etoposide/cisplatin (median 12.5 versus 10.9 months, HR 1.04, 95% CI 0.79-1.37), and PFS and objective response rates were similar. Grade 3 or 4 adverse events were more common with etoposide/cisplatin, especially neutropenia.

Role of metastasectomy — Surgical metastasectomy is generally not recommended in the management of GEP NEC [6]. However, selected patients may benefit from liver surgery [84,105]. In a Nordic registry, 32 cases of 840 (3.8 percent) GEP NEC patients had hepatic metastasectomy, with a five-year survival of 43 percent [105]. Factors for improved survival was Ki-67 <55 percent and receiving adjuvant chemotherapy. The decision to pursue surgery must be individualized.

Second-line chemotherapy — There are few data on second-line therapy (and no studies comparing chemotherapy with best supportive care), and a standard regimen has not been established. Patients who progress more than three months after discontinuation of first-line treatment may still be platinum sensitive. In the Nordic NEC study described above, retreatment with the same platinum-based regimen yielded a response rate of 15 percent, with another 27 percent achieving stable disease [35].

No standard cytotoxic chemotherapy regimen has been established beyond first-line treatment in platinum-refractory cases; however, several retrospective studies suggest that GEP NEC patients can benefit from further lines of chemotherapy after failure of platinum plus etoposide treatment [35,45,106-109]:

●Temozolomide-based chemotherapy – Temozolomide is commonly used in the second-line setting [45,106,107,110]. As an example, temozolomide was given with or without capecitabine and bevacizumab as second-line treatment after cisplatin-based chemotherapy in a cohort of 25 patients with GEP NEC [106]. The response rate was 33 percent, another nine patients had stable disease, and median overall survival was 22 months from time of diagnosis.

●Irinotecan-based regimens

•FOLFIRI – FOLFIRI is an option for patients with platinum-refractory NEC [111]. In a series of 19 platinum-resistant NEC patients treated with irinotecan plus short-term infusional fluorouracil plus leucovorin (FOLFIRI), the response rate was 31 percent and median PFS was four months [112]. In a second report of 72 patients receiving second- or third-or-more-line FOLFIRI after failing an initial platinum plus etoposide regimen (54 evaluable patients), there were 13 objective responders (24 percent) and the median PFS was 2.9 months [32].

•Liposomal irinotecan plus FU – A multicenter randomized phase II trial of 58 patients with poorly differentiated extrapulmonary NEC (69 percent GEP) who had prior cisplatin-based chemotherapy directly compared second-line liposomal irinotecan (70 mg/m² as free base) in combination with short-term infusional FU (2400 mg/m² plus leucovorin) every 14 days versus docetaxel monotherapy (75 mg/m² every 21 days) [113]. In a preliminary report presented at the 2022 annual ASCO meeting, response rates were similar (10.3 percent) and PFS was three versus two months and the six-month overall PFS rate (the primary endpoint) favored liposomal irinotecan (32 versus 15 percent) as did median overall survival (nine versus five months), with manageable toxicity. In our view, these results are premature, and cannot yet be used to inform clinical practice.

●Oxaliplatin-based chemotherapy – In a report of 17 evaluable patients with NEC (12 GEP) receiving oxaliplatin plus short-term infusional fluorouracil plus leucovorin (FOLFOX) after progression on cisplatin or carboplatin, five had a partial response (29 percent), while six others (33 percent) had stable disease [109]. PFS and overall survival were superior for patients with a Ki-67 <55 versus >55 percent (median PFS 6.2 versus 3.6 months and median overall survival 19.5 versus 8.5 months). In another series of 33 patients receiving second- or third-or-more-line FOLFOX after failing an initial platinum plus etoposide regimen (24 evaluable patients), there were four objective responders (16 percent) and the median PFS was 2.3 months [32].

Very limited experience with a combination regimen that includes oxaliplatin, irinotecan, and short-term infusional fluorouracil plus leucovorin (modified FOLFIRINOX) suggests some efficacy in pancreatic NEC [114].

●Topotecan-based chemotherapy – Topotecan is recommended in several guidelines extrapolating from data from studies of recurrent SCLC. (See "Treatment of refractory and relapsed small cell lung cancer", section on 'Topotecan'.)

Few data are available in GEP NEC. In a small retrospective study in which topotecan was given as second- to fourth-line treatment in 22 GEP NEC patients, the response rate was poor: 77 percent had immediate disease progression, 23 percent had stable disease, and median survival was only 3.2 months [115].

Immunotherapy — Immune checkpoint inhibitor immunotherapy that targets both programmed cell death-1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 checkpoints is a reasonable alternative to cytotoxic chemotherapy for second-line treatment and beyond in patients with platinum-refractory disease, although data are limited. Response rates are fairly low, but some patients can achieve long-term remission. Patients whose tumors have deficient mismatch repair (dMMR)/high levels of microsatellite instability (MSI-H) or high levels of tumor mutational burden (TMB; 10 to 15 mutations/megabase) are much more likely to benefit from immunotherapy. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Studies evaluating single-agent therapy with an immune checkpoint inhibitor targeting PD-1 have shown very low response rates [116-119]; however, trials of combined targeting of both PD-1 plus CTLA-4 have been more promising, with some patients achieving long-term disease control. Most of the data are in combined populations of NEC/NET G3:

●A prospective study of nivolumab plus ipilimumab in 19 patients with G3 NEN (median Ki-67 80 percent) reported an objective response rate of 26 percent and PFS two months [120]. One-third of patients were still progression-free at six months.

●A retrospective evaluation of 34 patients with G3 NEN (79 percent NEC, 21 GEP) treated with nivolumab and ipilimumab reported an objective response rate of 15 percent with PFS of only one month [121].

●A preliminary report of a prospective study of durvalumab plus tremelimumab in G3 NEN reported a response rate of 9 percent and 9 month survival was 36 percent among GEP NEN G3 patients [122,123].

●The NICENEC single-arm phase II trial studied first-line treatment with nivolumab combined with up to six cycles of carboplatin and etoposide followed by maintenance nivolumab in 38 patients with NEN G3 of GEP (82 percent) or unknown (18 percent) origin; 53 percent were poorly differentiated (NEC) [124]. Response rate was 50 percent, PFS was 5.7 months and 39 percent of patients were free of progression after six months. Understanding the true benefit of adding an immune checkpoint inhibitor to first-line chemotherapy compared with chemotherapy alone will require a randomized trial.

●Preliminary results are also available from the randomized phase II NIPINEC trial, in which 185 patients (93 GEP NEC, 92 lung NEC) with platinum-refractory disease were randomized between nivolumab alone or with ipilimumab [125]. The primary endpoint was objective response rate at eight weeks, which was achieved by a higher fraction with combined treatment (14.9 versus 7.2 percent); however, this did not translate into better median PFS (1.8 versus 1.9 months) or overall survival (7.2 versus 5.8 months).

Deficient mismatch repair (dMMR), the biologic footprint of which is MSI-H, is present in about 5 percent of GEP NEC cases, most frequently in colorectal primaries [29,126]. As dMMR/MSI-H seems to be an agnostic tumor marker for the benefit of checkpoint inhibitors, routine MSI or MMR testing is important for NEC, particularly of colorectal origin. Patients whose tumors have dMMR/MSI-H or high levels of TMB (>10/15 per megabase (see 'Immunotherapy' below)) are much more likely to benefit from early-line immunotherapy treatment using single-agent pembrolizumab. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

The role of first-line immunotherapy in unselected GEP NEC patients is uncertain. While addition of atezolizumab or durvalumab to platinum plus etoposide has been shown to modestly improve survival in patients with extensive stage SCLC unselected for PD-L1 overexpression, dMMR or high TMB, and this is now a standard approach to initial therapy, such data does not exist in GEP NEC. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for addition of immune checkpoint inhibitors to chemotherapy'.)

Given limited treatment options in the platinum-refractory setting and the potential for sustained remission with immunotherapy, the above results suggest that combination immunotherapy, particularly with ipilimumab plus nivolumab, is an option for GEP NEC for second-line therapy and beyond. However, it should be noted that interpretation of available data is often challenging, due to inclusion of multiple primary sites (including lung), frequent lack of information about dMMR status and TMB, and lack of detail about the type of G3 GEP NEN enrolled (well differentiated or poorly differentiated). For NET G3, we would generally reserve immunotherapy for patients who are refractory to several lines of systemic therapy. (See 'Immunotherapy' below.)

Other molecularly targeted treatments — Colorectal NEC frequently (up to 40 percent) has a BRAF mutation [122]. A combination of BRAF-inhibitor/EGFR-inhibitor/MEK-inhibitor has shown benefit in metastatic colorectal RAS wild-type but BRAF-mutant adenocarcinomas and in case reports of colorectal NEC [127]. Encorafenib with cetuximab has been approved for second-line treatment of BRAF V600e mutated metastatic colorectal cancer, and not limited to adenocarcinoma cases. We would consider the doublet regimen of cetuximab and encorafenib in BRAF v600e mutated NEC patients with platinum-refractory disease based upon the colorectal adenocarcinoma data. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, BRAF mutated tumors'.)

Prognosis — Prognosis for GEP NEC is poor for all stages of disease [6,17,18,21,35,56,128]:

●Within several retrospective series, median survival was approximately 38 months for localized disease, 16 months for regional disease, and 5 to 14 months for metastatic disease from the time of diagnosis [32,35,56].

●Similarly, in an analysis of data derived from the Surveillance, Epidemiology, and End Results database of the National Cancer Institute, the median survival for GEP NEC was 33.9 months with localized disease, 16.3 months with regional disease, and 5.2 months with distant disease [17]. Corresponding five-year survival rates were 42, 25.6, and 4.7 percent, and varied depending on primary tumor site and morphology (eg, better for large cell than small cell GEP NEN G3).

Long-term relapse-free survival is possible among patients with localized disease who are treated with multimodality therapy. In one large series of patients with stage I, II, or III GEP NEC derived from the National Cancer Database, five-year survival was approximately 30 percent, and was best in those with colonic primaries (five-year survival 40 percent) [93] Regardless of primary site, survival was better when surgery was a component of therapy as compared with nonsurgical management. (See 'Localized disease' above.)

Prognosis is worse for advanced disease:

●The Nordic NEC study retrospectively compared 252 patients with advanced GEP NEC treated with chemotherapy with 53 patients treated with best supportive care and found that overall survival was 11 months in the chemotherapy group and 1 month in the best supportive care group. These data reflect in part, however, worse baseline health in the group receiving best supportive care [35]. Two-year survival was 14 percent and three-year survival was 9.5 percent in the cohort receiving chemotherapy.

●Prognosis is especially poor for a large bowel primary site with advanced disease. Even with aggressive therapy that includes platinum-based systemic chemotherapy, there are only rare reports of long-term survivors [41,128-132]. In one review of 47 cases, the median survival was six months and only 15 percent were still alive at one year [130].

Baseline factors related to shorter survival in patients receiving chemotherapy include the following:

●Poor performance status (table 3) (performance status of 0, 1, and 2 corresponded with overall survival of 18, 12, and 5 months, respectively) [32,35,50,133].

●Higher proliferation rate [8,35,107,109,134]. In the Nordic NEC study, Ki-67 rate >55 percent was associated with a significantly worse overall survival of 10 versus 14 months (figure 3) [35]. However, this association has not been seen in other series [32], while others have used a higher Ki-67 cutoff (>80 percent) in prognostic modeling [133].

●Elevated lactate dehydrogenase and other tumor markers [32,35,50].

●Thrombocytosis [35].

●Primary tumor in the esophagus or large bowel compared with stomach and pancreas [35,50,135].

High-grade, well-differentiated tumors (NET G3) — A minority of GEP NEN G3, particularly those of pancreatic origin, have a Ki-67 index >20 percent but well-differentiated histology (neuroendocrine tumor [NET] G3). (See 'High-grade well-differentiated tumors' above.)

Overview of the approach to treatment — The best way to treat these patients is not established, and there are few data to support a specific strategy; our approach is outlined in the algorithm (algorithm 1), and described in more detail below:

●For patients with apparently localized potentially resectable disease, we suggest resection rather than nonoperative therapy. (See 'Localized disease' below.)

●Patients with advanced NET G3 often respond relatively poorly to platinum plus etoposide regimens, and platinum-based chemotherapy may not be the most appropriate first-line treatment. Eligible patients should be encouraged to enroll in therapeutic trials testing the benefits of specific regimens. Off protocol, regimens used in NET G2 (eg, temozolomide-based chemotherapy, sunitinib, and everolimus [136,137]) are all reasonable options. We generally prefer first-line temozolomide-based chemotherapy, but FOLFOX is another option [32,109,138,139]. We do not generally treat NET G3 patients with platinum-based first-line chemotherapy, unless the disease is exceptionally aggressive at outset. Platinum-based chemotherapy is a reasonable second-line approach at the time of disease progression. Another option for salvage therapy is immunotherapy with ipilimumab plus nivolumab; however, we would generally recommend this in unselected patients only after progression on several lines of treatment. (See 'Advanced disease' below.)

●Peptide receptor radioligand therapy (PRRT) using radiolabeled somatostatin analogs is also a reasonable option for GEP NET G3 with a high uptake on somatostatin receptor imaging. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Radiolabeled somatostatin analogs'.)

Localized disease — Although definitive data are scarce, surgery is appropriate for NET G3 patients with localized and locoregional disease, as it is for low (G1)- and intermediate-grade (G2) NET [84,85,140,141] (see 'Role of surgery' above). The role of adjuvant chemotherapy is unknown, and we do not suggest it for most patients [83].

Advanced disease — The most appropriate approach for patients with advanced NET G3 has not been established and requires clinical judgment that takes into account factors such as proliferative rate, disease burden, tumor location, pace of disease progression, and the results of somatostatin receptor imaging.

Role of liver-directed therapy — The role of liver-directed therapy for hepatic-predominant metastatic NET G3 is uncertain, as the available data are very limited. However, as with NET G2, some patients with limited, liver-isolated metastases may be appropriate candidates for hepatic metastasectomy or other nonsurgical liver-directed therapies. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease'.)

Chemotherapy — We suggest temozolomide-based chemotherapy for most patients, FOLFOX is another option. Despite the general paucity of data, we do not generally treat NET G3 patients with platinum-based first-line chemotherapy, unless the disease is exceptionally aggressive at outset.

In contrast to GEP NEC, multiple studies suggest relatively low response rates to platinum plus etoposide regimens in this population [7,11,28,34,35]:

●In a large retrospective study of 252 GEP NEN of all types, response rates to platinum plus etoposide were 42 percent in tumors with a Ki-67 index >55 percent versus 15 percent in tumors with a Ki-67 index <55 percent [35].

●In a series of 30 patients with NET G3 seen in a single institution over a 27-year period of time complete or partial responses to a cisplatin-based regimen were seen in two of eight cases (25 percent), and median PFS was only three months [138].

●In a second report of 125 patients with GEP NEN G3 treated with a platinum plus etoposide first-line chemotherapy regimen, the objective response rate for the 113 poorly differentiated NEC was higher than it was for the 12 NET G3 (35 versus 17 percent), as was the overall disease control rate (68 versus 33 percent), but the median overall survival was not reached in those with a NET G3, compared with 16.4 months with NEC [11].

However, the optimal treatment for patients with NET G3 is not established, since this population has been excluded from most prospective studies. Most retrospective series of platinum-based chemotherapy for NEN G3 are a mixture of NET G3 and NEC, and specific data on responses and outcomes for the NET G3 subgroup are scarce and based on a very small number of patients. Nevertheless, despite the general paucity of data, we do not generally treat NET G3 patients with platinum-based first-line chemotherapy, unless the disease is exceptionally aggressive at outset.

Temozolomide-based chemotherapy (eg, temozolomide plus capecitabine) is active in NET G3 [137,138]. Oxaliplatin-based regimens (eg, FOLFOX) are also active [32,109,138]. There are no comparator trials.

Additional information on chemotherapy responsiveness is expected from an ongoing randomized trial (ECOG-ACRIN EA2142) comparing initial capecitabine plus temozolomide with cisplatin plus etoposide in patients with GEP NEN G3, including those with GEP NET G3.

Somatostatin analogs and other targeted therapy — Some of these patients may benefit from other treatments used for GEP NET G2, including molecularly targeted therapy (eg, everolimus [134]), and somatostatin analogs (conventional or radiolabeled) if the tumor expresses somatostatin receptors (see 'Peptide receptor radioligand therapy' below). For patients with positive somatostatin receptor imaging and favorable tumor biology, a somatostatin analog could be considered, although data are lacking.

Peptide receptor radioligand therapy — PRRT using radiolabeled somatostatin analogs is a reasonable option for GEP NET G3 with a high uptake at all disease sites on somatostatin receptor imaging.

PRRT using radiolabeled somatostatin analogs is regularly used for low- or intermediate-grade NET with a high uptake on somatostatin receptor imaging. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Somatostatin receptor-expressing tumors' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Peptide receptor radioligand therapy'.)

There are evolving data on the efficacy of PRRT in high-grade NEN [70,142-145]. In the largest report, a retrospective cohort study at 12 centers in 149 patients with somatostatin receptor-expressing GEP NEN G3 (n = 89 for pancreatic primary tumor, n = 34 for GI primary tumor, n = 26 for unknown primary tumor, n = 60 for well differentiated, n = 62 for poorly differentiated, n = 9 for intermediate grade, n = 18 for grade not specified), PRRT was administered as first-line (n = 30), second-line (n = 62), or later-line treatment (n = 57) [143]. Of the 114 evaluable patients, 1 percent had a complete response, 41 percent had a partial response, 38 percent had stable disease, and 20 percent had progressive disease as the best response. In the entire cohort, median PFS was 14 months and overall survival was 29 months. Outcomes were better among those with lower proliferative levels (for Ki-67 21 to 54 versus ≥55 percent: PFS 16 versus 6 months and overall survival 31 versus 9 months). Outcomes were also better for those with well-differentiated (n = 60) as compared with poorly differentiated NEN (n = 62): PFS 19 versus 8 months (p <0.001) and overall survival 44 versus 19 months (p <0.001). Grade 3 or 4 hematologic or renal toxicity occurred in 17 percent of patients.

Notably, patients with GEP NEN G3 who have a discordant uptake pattern on PET imaging (ie, FDG-PET positive lesions without uptake on somatostatin receptor imaging) do not seem to benefit from PRRT [70].

Immunotherapy — Immune checkpoint inhibitor immunotherapy with combined ipilimumab plus nivolumab is also a reasonable option for later lines of systemic therapy. Although response rates are fairly low, some patients can achieve long-term remission. As noted above, most of the data are in combined populations with GEP NEC/NET G3. (See 'Immunotherapy' above.)

Prognosis — Survival of patients with GEP NET G3 is significantly better than that of patients with GEP NEC [7,11,18,34,57,71]. In one report of 166 patients with metastatic, thoracic or GEP NEN, median survival for patients with GEP NET G3 was 41 months, compared with 17 months for non-small cell GEP NEC [7].

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

●Definition, presentation, diagnosis, and staging

•High-grade (grade 3 [G3]) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are heterogeneous group. Most are poorly differentiated neuroendocrine carcinomas ([NEC] G3), with a propensity for distant metastases and an ominous prognosis, even when localized. A subset are G3 but well differentiated (neuroendocrine tumor [NET] G3), with a prognosis that is better than NEC G3 but worse than well-differentiated intermediate-grade (grade 2 [G2]) NET (table 1). (See 'Classification and biologic behavior' above.)

•The most common primary tumor locations for a NEC are the esophagus, stomach, pancreas, and large bowel, whereas NET G3 are mainly located in the pancreas. Presenting symptoms may be generalized or site specific. A clinical presentation due to secretion of specific peptide hormones or bioamines is extremely uncommon. (See 'Clinical presentation' above.)

•The diagnosis requires histologic examination of tumor morphology, immunohistochemical staining for markers of neuroendocrine differentiation, and determination of the proliferative rate with Ki-67 staining or mitotic index. (See 'Pathologic diagnosis' above.)

•Staging evaluation includes cross-sectional imaging of the chest, abdomen, and pelvis, and, in some cases, fluorodeoxyglucose-positron emission tomography (FDG-PET). Somatostatin receptor-based imaging, is reasonable for NET G3 or in cases where differentiation is uncertain. (See 'Radiographic studies' above.)

●Management of local and locoregional NEC

•For all patients with a NEC, we suggest platinum-containing chemotherapy in conjunction with locoregional therapy rather than locoregional therapy alone (Grade 2C). Often, chemotherapy is administered in the neoadjuvant setting prior to locoregional therapy. (See 'Postoperative adjuvant chemotherapy' above.)

The standard regimen is four to six cycles of etoposide plus either cisplatin or carboplatin. Carboplatin may be preferred for patients with contraindications to or poor tolerance of cisplatin. (See 'Localized disease' above.)

•Recommendations for locoregional therapy depend on tumor location:

-For patients with a localized potentially resectable NEC that is not in the esophagus, we suggest surgical resection plus platinum-based chemotherapy rather than chemotherapy alone (Grade 2C). We perform FDG-PET prior to resection to exclude distant metastases. (See 'Role of surgery' above.)

-For locoregionally advanced, nonmetastatic (eg, T3N1 or T4) NEC outside of the esophagus, we individualize the use of radiation therapy as a component of multimodality therapy (chemotherapy with or without surgery) depending on location and risk of locoregional recurrence. Given the aggressive nature of NEC, we often use neoadjuvant rather than adjuvant combined modality treatment; however, many cases are diagnosed only after surgical resection. (See 'Benefit of radiotherapy' above and 'Integration of local therapy' above.)

-For localized or locoregional esophageal NEC, we suggest concurrent chemoradiotherapy plus chemotherapy rather than surgery plus chemotherapy (Grade 2C). (See 'Role of surgery' above and 'Integration of local therapy' above.)

•Prophylactic cranial irradiation is not required. (See 'Prophylactic cranial irradiation' above.)

●Management of metastatic NEC – For most patients, we suggest standard palliative chemotherapy with cisplatin or carboplatin combined with etoposide (Grade 2C). Rapid referral is appropriate given the aggressive nature of these tumors. (See 'Initial chemotherapy' above.)

We aim for four to six cycles of therapy, but if a patient is still responding and tolerating treatment well continuation of chemotherapy to at least maximal response is appropriate.

The decision to pursue metastasectomy must be individualized. (See 'Role of metastasectomy' above.)

●Management of recurrent NEC – Patients may benefit from retreatment with platinum/etoposide if relapse occurs at least three to six months after discontinuation of first-line treatment. For patients with platinum-refractory disease, other options include temozolomide with or without capecitabine-, fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens and immunotherapy. Patients whose tumors have deficient mismatch repair are much more likely to benefit from immunotherapy than are unselected patients. (See 'Second-line chemotherapy' above and 'Immunotherapy' above.)

●Management of NET G3 – A minority of high-grade NEN, particularly those of pancreatic origin, have a Ki-67 index >20 percent but relatively well-differentiated histology (NET G3). Prognosis is better compared with NEC.(See 'High-grade, well-differentiated tumors (NET G3)' above.)

•For patients with apparently localized potentially resectable disease we suggest resection rather than nonoperative therapy (Grade 2C). For most patients we suggest not pursuing adjuvant chemotherapy (Grade 2C). (See 'Localized disease' above.)

•For most patients with unresectable and/or metastatic disease, we suggest temozolomide-based chemotherapy or FOLFOX (table 4) (Grade 2C). However, other therapies such as everolimus or a somatostatin analog (for somatostatin receptor positive disease) could be options for tumors with favorable tumor biology. We do not generally treat with platinum-based first-line chemotherapy, unless the disease is exceptionally aggressive at outset. (See 'Advanced disease' above.)

Peptide receptor radioligand therapy is also a reasonable option for those with somatostatin receptor expressing tumors. (See 'Peptide receptor radioligand therapy' above.)

The role of liver-directed therapy for hepatic-predominant NET G3 is uncertain, as the available data are very limited. However, as with NET G2, some patients with limited, liver-isolated metastases may be appropriate candidates for hepatic metastasectomy.