Version July 2025
INTRODUCTION —
Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies characterized by variable biologic behavior. The clinical behavior and prognosis of NENs correlate closely with the tumor's histologic differentiation and grade, as assessed by mitotic count and/or Ki-67 labeling index (table 1). NENs can also arise from many different sites since neuroendocrine cells are distributed throughout the body. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
The clinical presentation, diagnosis, and management of well-differentiated high-grade (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) will be presented here. Other related topics on the management of well-differentiated NETs are discussed separately.
●(See "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)
●(See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
●(See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
DEFINITION —
Gastroenteropancreatic neuroendocrine neoplasms (NENs) are classified by tumor differentiation status (well- versus poorly differentiated) and tumor grade (low-, intermediate-, or high-grade) based on criteria from the World Health Organization (WHO) (table 1) [1]. Tumor differentiation refers to the resemblance of the tumor histology to normal neuroendocrine cells, whereas tumor grade describes the proliferative activity of the tumor, as measured by mitotic rate and/or Ki-67 proliferative index (table 1). (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Classification and terminology'.)
Well-differentiated high-grade (G3) GEP NETs are NENs arising from the gastrointestinal (GI) tract or pancreas that are well-differentiated on histopathologic evaluation and also exhibit high tumor grade, typically due to a high Ki-67 proliferative index (greater than 20 percent; generally between 20 and 55 percent) (table 1). We prefer the term "NET G3" to designate a well-differentiated high-grade NET since NETs are, by definition, well-differentiated. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Well-differentiated high-grade (G3) NET'.)
Of note, NET G3 are distinct entities from poorly differentiated neuroendocrine carcinoma (NEC). In the WHO classification system, tumor grade is no longer equated with tumor differentiation since not all G3 NENs are poorly differentiated [2-7]. A NET G3 also has clinical behavior and prognosis that is somewhere between that of a well-differentiated G2 NET and an NEC [7]. (See 'Prognosis' below and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
EPIDEMIOLOGY —
NET G3 comprises 10 to 20 percent of high-grade digestive neuroendocrine neoplasms (NENs), with the pancreas being the most common primary site of origin [8-13]. However, the prevalence of these tumors may be underestimated in less contemporary studies performed prior to the World Health Organization (WHO) classification system recognizing well-differentiated NET G3 as a distinct entity from poorly differentiated neuroendocrine carcinomas (NECs) [11]. In addition, between 10 to 30 percent of NET G3 develops from a prior known low-grade (G1) or intermediate-grade (G2) NET [14]. Further details on the epidemiology of well-differentiated NETs are discussed separately. (See "Clinical characteristics of well-differentiated neuroendocrine tumors arising in the gastrointestinal and genitourinary tracts", section on 'Epidemiology'.)
CLINICAL PRESENTATION —
The clinical presentation of GEP NET G3 is variable and depends upon the primary tumor site and extent of disease. Most patients present with metastatic disease at diagnosis (up to 70 percent) [8,10,15].
Primary tumor site — For GEP NET G3, the pancreas is the most common primary tumor site of origin (45 to 65 percent), followed by the small bowel (17 percent) and the colon or stomach (3 to 4 percent each), with the remainder of cases originating from other anatomic sites in the gastrointestinal (GI) tract [5,7-9,11,16].
Clinical symptoms — Patients with NET G3 are typically symptomatic at Presentation [5,7,8,17]. Examples of common symptoms include (see "Clinical characteristics of well-differentiated neuroendocrine tumors arising in the gastrointestinal and genitourinary tracts"):
●Anorexia, fatigue, and weight loss.
●Pain at the primary tumor site or areas of metastatic disease (usually the liver).
●Anorexia, weight loss, nausea, jaundice, and diarrhea for pancreatic NET. (See "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Clinical presentation'.)
●Hematochezia and bowel obstruction for small bowel and colorectal NET.
●Abdominal pain and anemia for gastric NET.
Most well-differentiated GEP NET G3 are not functional (ie, hormone secreting) [5,7,8,17]. Rarely, some tumors in the small bowel may produce symptoms consistent with carcinoid syndrome (eg, flushing, diarrhea, or wheezing) whereas others in the pancreas may produce symptoms consistent with a functional pancreatic tumor (table 2). (See "Clinical features of carcinoid syndrome".)
DIAGNOSTIC EVALUATION
How is the tumor identified? — In general, tumors due to GEP NET G3 are initially identified on diagnostic studies, either incidentally or for disease-related symptoms. These include radiographic imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI] of the abdomen and pelvis) or endoscopic evaluation (eg, colonoscopy, upper endoscopy). These tumors are also usually detectable on somatostatin receptor (SSTR)-based imaging studies [5], although such studies are typically obtained after the diagnosis is confirmed on histopathology. (See 'Staging imaging' below.)
Tissue sampling (diagnosis) — The diagnosis of a GEP NET G3 is confirmed based on histopathologic evaluation of tumor tissue either from a biopsy or surgically excised specimen (picture 1).
These tumors are usually distinguished as neuroendocrine neoplasms (NENs) by their morphologic appearance and distinct immunohistochemistry patterns. Well-differentiated NET G3 are further differentiated from other forms of NEN (well-differentiated NET of low- or intermediate-grade and poorly differentiated neuroendocrine carcinoma [NEC]) by the extent of tumor differentiation and specific-tumor grade (table 1). These tumors are well-differentiated on histopathologic evaluation, but also exhibit high tumor grade, either with a high mitotic rate (greater than 20 per 2 mm2) and/or high Ki-67 proliferative index (greater than 20 percent). Most well-differentiated NET G3 fall into this category due to a Ki-67 proliferation index in the grade 3 (G3) range that is typically between 20 and 55 percent [8,16] rather than a high mitotic rate.
Tumors that are classified as well-differentiated NET G3 but have a Ki-67 index greater than 55 percent should be re-evaluated by a pathologist for the possibility that the tumor is an NEC. Likewise, tumors classified as NEC with a Ki-67 less than 55 percent should be re-evaluated by pathology, as they are frequently NET G3. Separating these two pathologic entities can be challenging in many cases, even among NET pathology experts [18]. Further details on the pathologic classification of these tumors are discussed separately. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'How to distinguish between NET G3 and NEC'.)
Staging imaging — For patients with a histologically confirmed diagnosis of GEP NET G3, staging imaging studies include:
●Contrast-enhanced CT of the chest, abdomen, and pelvis to assess the extent of systemic disease (with the abdominal CT performed using multiphase technique). (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Computed tomography'.)
●For patients with resectable disease, fluorodeoxyglucose-positron emission tomography (FDG-PET)-CT imaging can be obtained prior to surgery since most NET G3 are FDG-avid.
●SSTR-based imaging (ie, PET-CT or PET-MRI using gallium Ga-68 dotatate, gallium Ga-68 dotatoc [where available], or copper Cu-64 dotatate) to accurately detect GEP NET G3 since most such tumors express high levels of SSTRs (90 percent or more) [8,19]. Furthermore, SSTR-based imaging is important to decide if peptide receptor radionuclide therapy (PRRT) is a treatment option for the patient. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)
SSTR-based imaging can be used to clinically support the diagnosis of a NET G3 over an NEC. As an example, a tumor that is strongly and uniformly positive for somatostatin uptake on SSTR-based imaging is more likely to be a NET G3 than a NEC [8,19]. FDG-PET does not usually help to distinguish NET G3 from NEC as both entities are usually FDG-avid. NEC also have more of a predilection for primary sites other than the pancreas, such as the esophagus and large bowel. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Clinical presentation'.)
What is the role of tumor markers? — We do not routinely obtain chromogranin-A as part of the postdiagnostic evaluation of a GEP NET G3, which is variably secreted by these tumors [8,20,21]. In addition, imaging studies generally demonstrate treatment responses quite clearly in this disease, which are not always paralleled by changes in chromogranin-A even if it is elevated at diagnosis. We also do not routinely measure serum or urine levels of the serotonin metabolite 5-hydroxyindoleacetic acid given the lack of serotonin secretion in most high-grade NEN [20]. Further details on the clinical utility of tumor biomarkers in GEP NET are discussed separately. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)
Genetic counseling — Clinicians may offer the option of genetic counseling to younger patients with a pancreatic NET G3. Approximately 17 percent of patients with pancreatic NET have an associated hereditary condition, such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis 1, and tuberous sclerosis, or harbor pathogenic variants in BReast CAncer gene 1 (BRCA1) and 2 (BRCA2), among others [22]. However, NET G3 are less commonly associated with a hereditary condition compared with low-grade (G1) and intermediate-grade (G2) pancreatic NET. Germline pathogenic or highly likely pathogenic variants have been found in 9.5 percent of patients with NET G3 [23]. (See "Genetic counseling: Family history interpretation and risk assessment" and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical presentation and diagnosis of von Hippel-Lindau disease", section on 'Pancreatic neuroendocrine neoplasms'.)
STAGING SYSTEM —
Several staging systems are available for GEP NET G3.
AJCC TNM staging system — GEP NET can be staged using the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system, which is endorsed by the World Health Organization (WHO) [1]. Separate AJCC TNM staging systems are available for well-differentiated NET with primary sites as follows (see "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors" and "Classification, clinical presentation, diagnosis, and staging of pancreatic neuroendocrine neoplasms", section on 'Staging system'):
●Stomach (table 3)
●Pancreas (table 4)
●Duodenum and ampulla of Vater (table 5)
●Jejunum and ileum (table 6)
●Appendix (table 7)
●Colon and rectum (table 8)
ENETs staging system — The European Neuroendocrine Tumor Society (ENETS) has proposed a staging system that is similar to the AJCC TNM staging system [24,25].
MANAGEMENT OF LOCALIZED DISEASE
Surgical resection — Although data are limited for localized (Stage I to III) GEP NET G3 [26-29], we offer surgical resection followed by surveillance. We do not offer adjuvant chemotherapy as there are insufficient data to support this approach, and further clinical trials are necessary. The topic on surgical resection of GEP NET G3 is presented separately. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors" and "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)
MANAGEMENT OF METASTATIC DISEASE —
The management of advanced or metastatic GEP NET G3 is evolving. Clinical trial enrollment is encouraged, due to the rarity of the disease (https://clinicaltrials.gov).
Initial therapy
Selection of initial therapy — For advanced or metastatic GEP NET G3, selection of therapy is based upon somatostatin receptor (SSTR) expression status, symptom burden, and Ki-67 level, among other clinical factors.
●SSTR-positive disease – For patients with SSTR-positive disease and Ki-67 between 20 and 55 percent, our approach to initial management is as follows:
•Minimal tumor burden and no symptoms – For selected patients with minimal (extremely low) tumor burden and no symptoms, we suggest a somatostatin analog (SSA) either alone or in combination with peptide receptor radionuclide therapy (PRRT; using lutetium Lu-177 dotatate) rather than other systemic agents. Chemotherapy (either capecitabine plus temozolomide or FOLFOX) is also an appropriate alternative.
Although SSA monotherapy has a favorable toxicity profile, patients who select this approach must be advised about the limited evidence for its activity, undergo close surveillance, and transition to more active treatments upon disease progression (such as PRRT plus SSA for those without rapid disease progression). (See 'Somatostatin analogs' below.)
•Moderate tumor burden or symptoms – For patients with moderate tumor burden or symptoms, we suggest either PRRT (Lu-177 dotatate) plus an SSA; or chemotherapy (capecitabine plus temozolomide or FOLFOX) rather than other systemic agents. Either strategy is appropriate as both are highly effective treatments, but they have not been directly compared in randomized trials. (See 'Peptide receptor radionuclide therapy (initial therapy)' below and 'Chemotherapy' below.)
•Major tumor burden or symptoms – For patients with major tumor burden or symptoms, we suggest chemotherapy (capecitabine plus temozolomide or FOLFOX) rather than PRRT or other systemic agents since immediate treatment is necessary; chemotherapy has a relatively rapid onset of action, and it is typically easier to access and initiate than PRRT. However, PRRT plus an SSA is an appropriate alternative for patients who have immediate access to and prefer this regimen.
PRRT with Lu-177 dotatate is a highly active treatment in patients with SSTR-positive NET G3, based on data from a phase III trial (NETTER-2) that demonstrated a progression-free survival (PFS) benefit for PRRT plus SSA relative to SSA monotherapy [30,31]. While these results are impressive, it is debatable whether PRRT plus an SSA should be the preferred first-line standard of care treatment. In the NETTER-2 trial, PRRT plus SSA was compared to an increased dose of SSA alone (which is not the optimal initial treatment for all patients with NET G3) and not chemotherapy (which is a frequently used initial treatment for NET G3). Furthermore, it is not clear whether administering PRRT plus an SSA as first-line therapy is superior to administering it as later-line therapy, as retrospective studies also indicate clinical benefit when PRRT plus an SSA is administered after chemotherapy.
Issues that guide selecting between PRRT plus an SSA and chemotherapy include primary site (eg, pancreatic NET appear to be particularly responsive to chemotherapy compared with small bowel or colorectal NET); Ki-67 expression (eg, chemotherapy may be more appropriate for NET with a higher Ki-67 [eg, between 31 and 55 percent] versus those with a lower Ki-67 [eg, between 21 and 30 percent]); tumor growth rate (chemotherapy is preferred for tumors that grow more rapidly); symptom burden (chemotherapy has a relatively rapid onset of action, whereas PRRT plus an SSA can sometimes take up to one month to take effect); and access to treatment (eg, patients who need immediate treatment may be able to access and initiate chemotherapy more quickly than PRRT plus SSA).
●SSTR-negative disease – For patients with SSTR-negative disease and Ki-67 between 20 and 55 percent, we suggest initial chemotherapy with either capecitabine plus temozolomide or FOLFOX rather than other systemic agents. (See 'Chemotherapy' below.)
●High Ki-67 or rapidly progressive disease – Patients with Ki-67 greater than 55 percent or rapidly progressive disease (regardless of SSTR expression) are managed similarly to poorly differentiated neuroendocrine carcinoma (NEC), typically with initial platinum-based chemotherapy. Such tumors demonstrate aggressive clinical behavior that is more consistent with an NEC and may thus be more likely to respond to a similar management strategy. Whether the optimal chemotherapy regimen should be one used for gastrointestinal (GI; eg, FOLFOX) or thoracic (eg, carboplatin plus etoposide) cancer is unclear. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)
Peptide receptor radionuclide therapy (initial therapy) — In patients with advanced or metastatic, SSTR-positive GEP NET G3, peptide receptor radionuclide therapy (PRRT) combined with an SSA is one highly effective option for initial therapy. In a phase III trial (NETTER-2) of 226 patients with newly diagnosed high-grade G2 NET or NET G3, PRRT with Lu-177 dotatate plus an SSA (standard-dose octreotide) improved PFS compared with a high-dose SSA alone in patients with high-grade NET G2 or NET G3 (median 23 versus 9 months) [30]. In a subgroup analysis of the 79 patients with GEP NET G3, median Ki-67 was 30 percent, and most had a pancreatic (47 patients) or small intestinal (18 patients) primary tumor site [31]. Among patients with GEP NET G3, PRRT plus SSA also improved median PFS (22.2 versus 5.6 months, hazard ratio [HR] 0.27, 95% CI 0.15-0.49) and objective response rate (ORR; 48 versus 7 percent). Of note, the comparison intervention for the NETTER-2, an escalated dose of SSAs, is likely not the optimal treatment for NET G3. A randomized clinical trial (COMPOSE) in higher G2 and G3, SSTR-positive NET is ongoing and will compare PRRT to the clinician's choice of capecitabine plus temozolomide, FOLFOX, or everolimus.
Full results of NETTER-2 for the entire study population are discussed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Efficacy'.)
Chemotherapy
Capecitabine plus temozolomide — Capecitabine plus temozolomide is an option for initial therapy in advanced or metastatic GEP NET G3. In observational studies with data available for this population, capecitabine plus temozolomide demonstrated ORRs between 27 and 41 percent [11,32-36] and is associated with longer PFS relative to other regimens in the first-line setting [36,37]. Data also suggest more activity for this regimen in pancreatic NET than GI NET [33].
●Capecitabine plus temozolomide was evaluated in a retrospective analysis of 133 patients with unresectable or metastatic high-grade (G3) neuroendocrine neoplasm (NEN) [33]. In the subgroup of 64 patients with NET G3, the ORR was 41 percent and the median overall survival (OS) was 32 months, respectively. In the entire study population, compared with use as later-line therapy, initial therapy with capecitabine plus temozolomide was associated with longer time to treatment failure (median 8 versus 3 months), longer OS (median 41 versus 15 months), and higher ORR (51 versus 29 percent). Compared with GI NEN, pancreatic NET was associated with a longer time to treatment failure (median 6 months versus 2 months) and ORRs (41 versus 23 percent); OS was similar between the two subgroups.
●Similar ORRs were seen in a retrospective analysis of 308 patients with metastatic NET treated with capecitabine plus temozolomide [35]. Among the subgroup of 12 patients with GEP NET G3 who received capecitabine plus temozolomide as initial therapy, the ORR and disease control rates were 36 and 54 percent, respectively.
●In a retrospective analysis, initial therapy with capecitabine plus temozolomide was associated with longer PFS relative to other regimens such as FOLFOX and platinum plus etoposide (median PFS 12 versus 7 months) [36].
There are limited randomized trials evaluating capecitabine plus temozolomide in GEP NET G3. In preliminary results of a randomized phase II trial (ECOG-ACRIN EA2142) of 62 patients with advanced or metastatic GEP NET G3 or NEC, capecitabine plus temozolomide did not confer an OS benefit over cisplatin plus etoposide but had a better toxicity profile [38]. However, only one-third of the enrolled patients had NET G3, and the study was closed early to accrual due to futility.
FOLFOX — FOLFOX is an option for initial therapy in advanced or metastatic GEP NET G3. In observational studies, FOLFOX demonstrates ORRs between 25 and 56 percent [11,21,36,39]. There are no randomized trials evaluating FOLFOX in GEP NET G3.
As an example, a retrospective analysis of 136 patients with advanced NET G3 receiving various first-line systemic therapies included a subgroup of 39 patients who received FOLFOX. FOLFOX was associated with the highest ORR (56 percent) relative to platinum plus etoposide (35 percent) and capecitabine plus temozolomide (27 percent); median PFS with FOLFOX was seven months [36]. In a separate retrospective study, FOLFOX demonstrated an ORR of 25 percent and a median PFS of 13 months [11].
Everolimus plus temozolomide — A prospective phase II trial evaluated everolimus plus temozolomide in 37 patients with treatment-naïve metastatic high-grade GEP NEN with Ki-67 less than 55 percent [40]. In the subset of 26 patients with NET G3, this combination demonstrated a median PFS and OS of 13 and 31 months, respectively.
Somatostatin analogs — Selected patients with SSTR-positive NET G3 and very minimal tumor burden or symptoms may be candidates for initial therapy with a somatostatin analog (SSA) alone, which has modest efficacy but is generally well-tolerated. However, patients who are treated with an SSA must be advised about the limited evidence for its activity, have close surveillance, and transition to more active treatments upon disease progression.
There are limited data evaluating SSAs in NET G3 [41]. In a retrospective study on first- or second-line treatment for advanced GEP NET G3, PFS was the lowest with SSAs and platinum plus etoposide [37]. In a phase III trial (NETTER-2), high-dose octreotide monotherapy demonstrated a much inferior PFS compared to PRRT with Lu-177 dotatate [30,31].
Less-preferred options
Platinum plus etoposide — We do not typically use platinum (ie, cisplatin or carboplatin) plus etoposide for the initial management of advanced or metastatic GEP NET G3 between 20 and 55 percent. We reserve this approach for patients with Ki-67 greater than 55 percent or rapidly progressive disease at presentation using a similar approach to NEC. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)
In preliminary results from a clinical trial (NORDIC NEC-2) on high-grade GEP NEN, PFS and OS were shorter for patients with NET G3 who received initial therapy with platinum plus etoposide compared to those who received a temozolomide-based regimen [42].
Observational studies also suggest relatively low ORRs and short PFS with platinum plus etoposide in treatment-naïve NET G3 with Ki-67 less than 55 percent (ORRs of 15 to 25 percent) [5,8,15,18,20]. In a retrospective study on first- or second-line treatment for advanced digestive NET G3, platinum plus etoposide had shorter PFS than adenocarcinoma-like and alkylating chemotherapy [37]. However, this evidence is low quality due to heterogeneous patient populations and small numbers of patients with treatment-naïve NET G3.
Second- and later-line therapy
Selection of therapy — The optimal approach to second- and later-line therapy for advanced or metastatic GEP NET G3 is not established, as there are limited randomized trials to support one sequence of therapy over another. Treatment is individualized, and patients should generally be treated with regimens not previously received. Clinical trial enrollment is encouraged, where available (https://clinicaltrials.gov).
●Prior SSA alone – For patients who progress on an SSA therapy alone, we suggest either PRRT plus SSA or chemotherapy (either capecitabine plus temozolomide or FOLFOX) rather than other systemic agents.
●Prior PRRT plus SSA – For patients who progress on PRRT plus an SSA, we suggest chemotherapy (either capecitabine plus temozolomide or FOLFOX) rather than other systemic agents. Targeted agents (sunitinib for pancreatic primary tumors only, everolimus, or cabozantinib) are appropriate alternatives for those with more indolent disease progression.
●Prior chemotherapy, no prior PRRT – For patients with SSTR-positive disease who progress on chemotherapy and have not previously received PRRT, we suggest PRRT plus SSA rather than other systemic agents. (See 'Peptide receptor radionuclide therapy (second- and later-line therapy)' below.)
An appropriate alternative (regardless of tumor SSTR expression) is to administer a chemotherapy regimen not previously received (eg, FOLFOX for those who were initially treated with capecitabine plus temozolomide and vice-versa). Targeted agents (eg, sunitinib for pancreatic primary tumors only, everolimus, or cabozantinib) can be used for those with more indolent disease progression. (See 'Peptide receptor radionuclide therapy (second- and later-line therapy)' below and 'Molecularly targeted therapy' below.)
●Transformed disease and/or later-line therapy – Some patients can have a NET G3 that becomes more aggressive over time, loses SSTR expression, and, in rare cases, transforms to an NEC [43]. Such patients should be treated similarly to those with an NEC. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)
For patients who previously received either capecitabine plus temozolomide or PRRT plus an SSA and experience a more aggressive tumor transformation similar to an NEC, FOLFOX may also be an effective later-line treatment option due to the inclusion of a platinum (oxaliplatin) [44]. (See 'FOLFOX' above.)
Peptide receptor radionuclide therapy (second- and later-line therapy) — In retrospective studies of patients with GEP NET G3, second- or third-line treatment with peptide receptor radionuclide therapy (PRRT) plus an SSA demonstrated durable ORRs between 30 and 41 percent [45,46]. Median PFS was 11 to 16 months, and median OS was 22 to 46 months.
Molecularly targeted therapy — Molecularly targeted therapy can be used for second- and later-line therapy in patients with advanced or metastatic GEP NET G3 and indolent disease progression. Options include sunitinib (for pancreatic tumors only [47]), everolimus as a single agent [48] or in combination with temozolomide [40], or cabozantinib [49]. As studies evaluating these agents are limited in GEP NET G3, the use of some agents is extrapolated from the treatment of well-differentiated pancreatic or GEP NET of low- (G1) or intermediate- (G2) grade.
Sunitinib (pancreatic primary tumor) — The use of sunitinib as a second- or later-line option for metastatic pancreatic NET G3 is mainly extrapolated from the treatment of G1 and G2 pancreatic NET. In one study, among 10 patients with pancreatic NET G3 who were treated with sunitinib, the ORR was 60 percent, and one-year PFS was 40 percent [47]. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
Everolimus — The use of everolimus as a single agent as a second- or later-line option is also mainly extrapolated from the treatment of G1 and G2 GEP NET. In one study of 15 patients with pancreatic NET G3 who received everolimus (mainly as second-line therapy), median PFS was six months [48]. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Everolimus' and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
Cabozantinib — Cabozantinib can be used for second- and later-line therapy in patients with metastatic GEP NET G3. Data are as follows:
●Cabozantinib improved PFS in a double-blind, placebo-controlled phase III trial (CABINET) of 298 patients with advanced well- or moderately-differentiated NET of various primary sites (including GEP NET G3), who progressed on one or more prior therapies [49]. The study included a limited number of patients with G3 tumors (24 patients; 11 with pancreatic NET and 13 with extrapancreatic NET). While a subgroup analysis suggests that cabozantinib confers a PFS benefit in both pancreatic and extrapancreatic NET G3, a pooled analysis of both groups was not reported. Further details of this trial are discussed separately. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Cabozantinib' and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
●Cabozantinib was also evaluated in a single-arm phase II trial (CABONEN) of 32 patients with advanced, NET G3 with Ki-67 between 20 and 60 percent [50]. The primary tumor site was located either in the pancreas (47 percent), GI tract (25 percent), lung (9 percent), or other sites (19 percent). Most patients had progressed on prior therapy (70 percent). In preliminary results, cabozantinib demonstrated a disease control rate at six months of 64 percent and a median PFS of seven months.
Cabozantinib is approved by the United States Food and Drug Administration for the treatment of adult and pediatric patients 12 years of age and older with previously treated, unresectable, locally advanced or metastatic, well-differentiated pancreatic and extra-pancreatic NETs [51].
What is the role of immune checkpoint inhibitors? — There are limited data to support the use of immune checkpoint inhibitors (ICIs) in unselected patients with metastatic GEP NET G3. However, NET (particularly tumors of pancreatic origin) can transform over time after exposure to multiple lines of therapy [52]. In addition, some patients with NETs who are exposed to prior temozolomide may acquire a high-tumor mutational burden phenotype due to selection of mismatch repair-deficient clones [53]. Data suggest that such patients with transformed NET G3 may become sensitive to treatment with ICIs. The extent to which sensitivity to ICIs correlates with the level of tumor mutational burden is unclear. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Tumors with high mutational burden'.)
SPECIAL POPULATIONS
Limited liver-isolated metastases — Patients with limited, liver-isolated metastases may be appropriate candidates for hepatic metastasectomy [54]. The role of nonsurgical liver-directed therapy for metastatic GEP NET G3 with hepatic-dominant disease only is uncertain, as data are limited [55,56]. Liver transplantation is not an option since Ki-67 >10 percent is a contraindication. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease'.)
dMMR/MSI-H tumors — Among patients with advanced or metastatic GEP NET G3, deoxyribonucleic acid (DNA) mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors are very rare (<5 percent) [57]. Such patients may be offered initial therapy with immune checkpoint inhibitors (ICIs) such as pembrolizumab or dostarlimab. This approach is extrapolated from data in other treatment-refractory cancers that demonstrate durable treatment responses with these agents. (See "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Primary site-independent approaches'.)
PROGNOSIS —
GEP NET G3 seems to have a prognosis that is midway between that of an intermediate-grade (G2) NET and neuroendocrine carcinoma (NEC). Median overall survival (OS) for patients with metastatic disease has been reported to be between 19 to 45 months [5,8,10,11,17-19,40,58]. Studies consistently demonstrate better survival outcomes for metastatic GEP NET G3 compared with metastatic NEC [5,19,40].
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: Neuroendocrine neoplasms".)
SUMMARY AND RECOMMENDATIONS
●Definition – Well-differentiated high-grade (G3) gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are neuroendocrine neoplasms (NENs) arising from the gastrointestinal (GI) tract or pancreas that are well-differentiated and also exhibit high tumor grade, typically due to a high Ki-67 proliferative index (greater than 20 percent; generally between 20 and 55 percent) (table 1). We prefer the term "NET G3" to designate a well-differentiated high-grade NET. (See 'Definition' above and "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Well-differentiated high-grade (G3) NET'.)
●Clinical presentation – The pancreas is the most common primary tumor site of origin, followed by the small bowel and the colon or stomach. Common presenting symptoms include anorexia, fatigue, weight loss, and pain at the tumor site or areas of metastatic disease (usually the liver). (See 'Clinical presentation' above.)
●Diagnosis – In general, tumors are initially identified on diagnostic studies (eg, imaging or endoscopic studies), either incidentally or for disease-related symptoms. The diagnosis is typically confirmed based on histopathologic evaluation of tumor tissue, either from a biopsy or surgically excised specimen. (See 'Diagnostic evaluation' above.)
●Staging imaging – For patients with a histologically confirmed diagnosis, staging imaging studies include (see 'Staging imaging' above):
•Contrast-enhanced CT chest, abdomen (performed using multiphase technique), and pelvis to assess the extent of systemic disease.
•For patients with resectable disease, fluorodeoxyglucose positron emission tomography (FDG-PET)-CT imaging can be obtained prior to surgery.
•Somatostatin receptor (SSTR)-based imaging to accurately detect tumor and to decide if peptide receptor radionuclide therapy (PRRT) is a treatment option.
●Management of localized disease – For patients with localized (Stage I to III) NET G3, we offer surgical resection followed by surveillance. We do not offer adjuvant chemotherapy as there are insufficient data to support this approach, and further clinical trials are necessary. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors" and "Surgical resection of sporadic pancreatic neuroendocrine neoplasms".)
●Initial therapy for metastatic disease – For advanced or metastatic GEP NET G3, our approach to initial therapy is as follows. (See 'Selection of initial therapy' above.)
•SSTR-positive disease – For patients with SSTR-positive disease and Ki-67 between 20 and 55 percent:
-Minimal tumor burden and no symptoms – For select patients with minimal (extremely low) tumor burden and no symptoms, we suggest a somatostatin analog (SSA) either alone or in combination with PRRT (using Lutetium Lu-177 dotatate) rather than other systemic agents (Grade 2C). Chemotherapy (either capecitabine plus temozolomide or FOLFOX) is also an acceptable alternative. (See 'Peptide receptor radionuclide therapy (initial therapy)' above and 'Somatostatin analogs' above and 'Chemotherapy' above.)
Although SSA monotherapy has a favorable toxicity profile, patients who select this approach must be advised about the limited evidence for its activity, undergo close surveillance, and transition to more active treatments upon disease progression (such as PRRT plus SSA for those without rapid disease progression). (See 'Somatostatin analogs' above.)
-Moderate tumor burden or symptoms – For patients with moderate tumor burden or symptoms, we suggest either PRRT (using Lu-177 dotatate) plus an SSA; or chemotherapy (capecitabine plus temozolomide or FOLFOX) rather than other systemic agents (Grade 2C). Either strategy is appropriate as both are highly effective treatments, but they have not been directly compared in randomized trials. Issues that guide selecting between these therapies are discussed above. (See 'Selection of initial therapy' above and 'Peptide receptor radionuclide therapy (initial therapy)' above and 'Chemotherapy' above.)
-Major tumor burden or symptoms – For patients with major tumor burden or symptoms, we suggest chemotherapy (capecitabine plus temozolomide or FOLFOX) rather than PRRT or other systemic agents (Grade 2C) since immediate treatment is necessary, chemotherapy has a relatively rapid onset of action, and it is typically easier to access and initiate than PRRT. However, PRRT plus an SSA is an appropriate alternative for patients who have immediate access to and prefer this regimen. (See 'Peptide receptor radionuclide therapy (initial therapy)' above and 'Chemotherapy' above.)
•SSTR-negative disease – For patients with SSTR-negative disease and Ki-67 between 20 and 55 percent, we suggest initial chemotherapy with either capecitabine plus temozolomide or FOLFOX rather than other systemic agents (Grade 2C). (See 'Chemotherapy' above.)
•High Ki-67 or rapidly progressive disease – Patients with Ki-67 greater than 55 percent or rapidly progressive disease (regardless of SSTR expression) are managed similarly to poorly differentiated neuroendocrine carcinoma (NEC), typically with initial platinum-based chemotherapy. Such tumors demonstrate aggressive clinical behavior that is more consistent with an NEC and may thus be more likely to respond to a similar management strategy. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)
●Second- and later-line therapy for advanced or metastatic disease – The optimal approach to second- and later-line therapy for advanced or metastatic GEP NET G3 is not established. Treatment is individualized, and patients should generally be treated with regimens not previously received. Clinical trial enrollment is encouraged, where available. (See 'Second- and later-line therapy' above.)
•Prior SSA alone – For patients who progress on an SSA alone, we suggest either PRRT plus an SSA or chemotherapy (either capecitabine plus temozolomide or FOLFOX) rather than other systemic agents (Grade 2C). (See 'Selection of therapy' above.)
•Prior PRRT plus SSA – For patients who progress on PRRT plus an SSA, we suggest chemotherapy (either capecitabine plus temozolomide or FOLFOX) rather than other systemic agents (Grade 2C). Targeted agents (sunitinib for pancreatic primary tumors only, everolimus, or cabozantinib) are appropriate alternatives for those with more indolent disease progression. (See 'Selection of therapy' above.)
•Prior chemotherapy, no prior PRRT – For patients with SSTR-positive disease who progress on chemotherapy and have not previously received PRRT, we suggest PRRT plus an SSA rather than other systemic agents (Grade 2C). (See 'Peptide receptor radionuclide therapy (second- and later-line therapy)' above.)
An appropriate alternative (regardless of tumor SSTR expression) is to administer a chemotherapy regimen not previously received (eg, FOLFOX for those who were initially treated with capecitabine plus temozolomide and vice-versa). Targeted agents (eg, sunitinib for pancreatic primary tumors only, or everolimus, cabozantinib) can be used for those with more indolent disease progression. (See 'Chemotherapy' above and 'Molecularly targeted therapy' above.)
•Transformed disease – Patients whose tumors become more aggressive over time, lose SSTR expression, and in rare cases, transform to an NEC, should be treated similarly to those with an NEC. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Initial treatment of metastatic disease'.)
