Version July 2025
INTRODUCTION —
Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies characterized by variable biologic behavior. Clinical behavior and prognosis correlate closely with 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".)
This topic will discuss systemic therapy for advanced or metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors (GINETs) arising from sites other than the pancreas. The management of well-differentiated G1 and G2 pancreatic neuroendocrine tumors (NETs) and well-differentiated high-grade (G3) gastroenteropancreatic (GEP) NETs and other related topics on NENs are discussed separately.
●(See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
●(See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)
●(See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis".)
●(See "Thymic neuroendocrine neoplasms".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
CLASSIFICATION OF NEUROENDOCRINE NEOPLASMS
Primary tumor site — Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) that arise from the pancreas and are well-differentiated on histopathology are known as pancreatic neuroendocrine tumors (NETs) (table 2), whereas those that arise from the gastrointestinal (GI) tract and are well-differentiated are known as gastrointestinal NETs (GINETs) (table 1); the latter group does not include tumors arising from the pancreas. Although these tumors appear similar on routine histologic evaluation, well-differentiated GINETs and pancreatic NETs have different pathogenesis, prognosis, and management [1,2]. The treatment of well-differentiated pancreatic NETs is discussed separately. (See "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors" and "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)
Well-differentiated GINETs can originate in the foregut (stomach, proximal duodenum), midgut (small intestine, proximal colon), or hindgut (distal colon, rectum). The clinical behavior and prognosis of well-differentiated GINETs by primary tumor site are discussed separately. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Stage and site of origin'.)
Tumor differentiation and grade — GEP NENs are also classified by differentiation status (well- versus poorly-differentiated) and tumor grade, based on criteria from the World Health Organization (WHO) (table 1) [3]. The term "carcinoid" is no longer used to classify GEP NENs but is still used to describe a constellation of symptoms in patients with hormone-secreting NENs (ie, carcinoid syndrome). (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms" and "Clinical features of carcinoid syndrome".)
Well-differentiated GEP NETs are divided into three grade categories based on mitotic count and proliferative index (Ki-67) (table 1):
●Low-grade (G1)
●Intermediate-grade (G2)
●High-grade (G3)
Well-differentiated GEP NETs that are G1 have a better prognosis than those that are G2 [4,5]. Well-differentiated GEP NETs that are G3 demonstrate clinical behavior that is somewhere between well-differentiated GEP NETs that are G2 and poorly differentiated neuroendocrine carcinoma (NEC). Poorly differentiated GEP NEC is, by definition, classified as high grade; these tumors typically progress rapidly and have a poor prognosis. The treatment of well-differentiated G3 GEP NETs and poorly differentiated GEP NEC is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors" and "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
INITIAL THERAPY —
The management of locally advanced or metastatic well-differentiated low-grade (G1) or intermediate-grade (G2) gastrointestinal neuroendocrine tumors (GINETs) is evolving. Clinical trials enrollment is encouraged, where available, due to the rarity of this disease.
Potentially resectable disease — For patients with a metastatic well-differentiated G1 or G2 GINET and hepatic predominant disease that is potentially resectable, surgical resection can provide durable control of symptoms and tumor growth. Although most patients recur, even after a complete resection, we generally prefer metastasectomy over systemic therapy. Further details are discussed separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
Unresectable disease
Selection of therapy — For patients with a locally advanced or metastatic, well-differentiated G1 and G2 GINET that is unresectable, initial management is based upon patient symptoms, level of disease burden, and clinicopathologic characteristics of the tumor (algorithm 1).
●Asymptomatic disease with low tumor burden – For patients with asymptomatic disease and low tumor burden, we suggest surveillance rather than immediate systemic therapy. Although the natural history of disease can be variable, most well-differentiated GINETs are indolent, slow-growing tumors. Thus, surveillance allows the clinician to determine the pace of disease and to defer treatment (and its potential toxicities) until more compelling disease progression is documented.
We obtain surveillance imaging of the abdomen and pelvis with either contrast-enhanced computed tomography (CT) or gadolinium-enhanced magnetic resonance imaging (MRI), along with a CT of the chest with or without contrast at three and six months. The frequency of subsequent imaging is based on the pace of disease progression (eg, every six months for slowly progressive disease).
●Disease-related symptoms and/or high tumor burden – Patients with disease-related symptoms and/or high tumor burden warrant initiation of therapy to control tumor growth and disease-related symptoms. Our approach is as follows:
•SSTR-positive G1 to G2 disease – For patients with somatostatin-receptor (SSTR)-positive G1 to G2 disease, we suggest initial therapy with a long-acting somatostatin analog (SSA), which treats both tumor growth and symptoms related to carcinoid syndrome. Options include octreotide long-acting release (LAR) and lanreotide. (See 'SSAs (octreotide LAR and lanreotide)' below.)
For those with SSTR-positive G1 to lower G2 (Ki-67 of 3 to less than 10 percent) disease and unresectable, extensive and/or bulky hepatic predominant tumors, we also evaluate for the addition of liver-directed therapy with hepatic arterial embolization to the SSA, as this approach achieves additional disease control and can improve symptoms related to carcinoid syndrome. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
•SSTR-positive higher G2 disease – For most patients with SSTR-positive, higher G2 tumors (ie, Ki-67 between 10 to 20 percent) and extensive and/or bulky disease who desire an objective response or in whom there is concern regarding progression of the underlying disease, we suggest the addition of peptide-receptor radionuclide therapy (PRRT) using Lutetium Lu-177 dotatate to an SSA. This approach improved progression-free survival (PFS) and objective response rates (ORRs) compared to high-dose long-acting release octreotide in a phase III trial (NETTER-2) [6]. For patients with unresectable, extensive and/or bulky hepatic predominant disease, an alternative approach is liver-directed therapy with hepatic arterial embolization in combination with an SSA. (See 'Peptide receptor radionuclide therapy (initial therapy)' below and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
•SSTR-negative disease – For patients with advanced SSTR-negative disease, we suggest initial therapy with either everolimus or cabozantinib rather than an SSA or PRRT, as such patients are unlikely to achieve significant disease control from therapy that targets SSTRs. Some patients with tumors that lack uptake on SSTR imaging may be candidates for an SSA to control hormone-related symptoms, but tumor control is less certain. For patients with unresectable, extensive and/or bulky hepatic-predominant disease, an appropriate alternative is liver-directed therapy with hepatic arterial embolization. (See 'Everolimus' below and 'Cabozantinib' below.)
Determining somatostatin receptor expression — Somatostatin is a 14-amino acid peptide that inhibits the secretion of a broad range of hormones in vivo. Somatostatin and analogs of somatostatin (such as octreotide and lanreotide) act by binding to SSTRs, which are expressed on the cell surface of most (over 80 percent) of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) [7]. The ability of octreotide and lanreotide to inhibit peptides secretion from NET cells is mediated mainly through SSTR-2 and SSTR-5.
Tumor SSTR expression is determined by diagnostic imaging studies that use radiolabeled SSAs. The preferred imaging study is an SSTR positron emission tomography (PET)-CT or PET-MRI due to its high sensitivity for detecting SSTR expression, particularly for smaller volume disease. Appropriate SSTR-PET tracers include gallium Ga-68 dotatate, Ga-68 dotatoc (where available), or copper Cu-64 dotatate. Patients whose imaging studies demonstrate radiotracer uptake have SSTR-positive tumors and are most likely to benefit from SSAs and PRRT. Further details on SSTR-based imaging techniques are discussed separately.
SSAs (octreotide LAR and lanreotide) — For most patients with advanced or metastatic, well-differentiated G1 and G2, SSTR-positive GINET and high tumor burden and/or disease-related symptoms, initial therapy with a long-acting somatostatin analog (SSA) treats both tumor growth and symptoms related to carcinoid syndrome. Options include octreotide long-acting release (LAR) and lanreotide, which are highly effective treatments for well-differentiated GINETs.
Selection of agent and dosing — Octreotide LAR and lanreotide are first-generation SSAs that primarily target SSTR-2 and SSTR-5. SSAs control tumor growth via direct antiproliferative effects (eg, cell cycle inhibition and proapoptotic effects) and indirect antiproliferative effects (eg, inhibition of tumor angiogenesis and the release of trophic growth hormones) [8].
●Octreotide LAR – Octreotide LAR is given at a dose of 20 or 30 mg via gluteal intramuscular injection every four weeks.
●Lanreotide – Lanreotide is given at a dose of 120 mg via gluteal deep subcutaneous injection every four weeks.
Selection of therapy is based on provider and patient preference since both agents are acceptable, effective therapies for well-differentiated GI NETs. Both treatments can be delivered with minimal discomfort to the patient [9]. However, costs of lanreotide can be higher than octreotide [10].
Efficacy — SSAs are used to treat hormone-related symptoms associated with carcinoid syndrome. (See "Treatment of the carcinoid syndrome", section on 'Somatostatin-analog therapy'.)
In addition, SSAs also stabilize disease, control tumor growth, and improve PFS based on data from randomized trials [11-13]. It is not known whether SSAs also increase overall survival (OS), as well-differentiated GINETs have an excellent prognosis, and many patients with the disease live long lives. However, one study of patients with advanced NETs treated with SSAs suggested a correlation between PFS and OS [14]. Data for the available agents are as follows:
●Octreotide LAR – Octreotide was evaluated in a placebo-controlled phase III trial (PROMID) of 85 patients with treatment-naïve, unresectable or metastatic, well-differentiated midgut GINETs, most of whom (95 percent) had G1 disease. Patients were randomly assigned to either octreotide LAR (30 mg administered via intragluteal intramuscular injection monthly) or placebo until radiographically documented tumor progression. Relative to placebo, octreotide improved time to progression (TTP; median 14 versus 6 months, hazard ratio [HR] 0.34, 95% CI 0.20-0.59) and rates of stable disease at six months (67 versus 37 percent) [11]. The TTP benefit for octreotide LAR was seen both in patients with functional (ie, causing hormone-related symptoms) and nonfunctional tumors. In extended follow-up (median 96 months), OS was similar for octreotide relative to placebo (median OS 85 versus 84 months, HR 0.83, 95% CI 0.47-1.46) [15]. Health-related quality-of-life was similar between the two treatment arms. Octreotide LAR was well-tolerated; the most common toxicities were gastrointestinal (GI) (six patients), hematologic (six patients), and generalized (fatigue, fever; eight patients).
●Lanreotide – Lanreotide was evaluated in a placebo-controlled phase III trial (CLARINET) of 204 patients with advanced well-differentiated G1 or G2 nonfunctional, SSTR-positive GEP NETs, including both GINETs and pancreatic NETs [12]. Most patients (96 percent) had no tumor progression in the three to six months prior to study enrollment. Patients were randomly assigned to either lanreotide 120 mg via deep subcutaneous injection every four weeks for 96 weeks or placebo. At a median follow-up of 24 months, lanreotide improved PFS relative to placebo (median not reached versus 18 months, two-year PFS 65 versus 33 percent HR 0.47, 95% CI 0.30-0.73). PFS benefit was seen across all clinically relevant subgroups including tumor grade (G1 and G2), primary tumor site (midgut and pancreas), and hepatic tumor volume. OS was similar between the two treatment arms. The most common treatment-related toxicities for lanreotide were diarrhea (26 percent); abdominal pain (14 percent); cholelithiasis (10 percent); flatulence (8 percent); injection site pain, nausea, and vomiting (7 percent each); and headache, lethargy, and hyperglycemia (5 percent each).
Lanreotide is approved by the US Food and Drug Administration (FDA) for the treatment of patients with unresectable, well- or moderately differentiated, locally advanced or metastatic GEP NETs [16].
Toxicity — SSAs are usually well tolerated, and side effects are generally mild. Potential side effects include symptoms of pancreatic malabsorption, mild glucose intolerance, and gallstones. Further details are discussed separately. (See "Treatment of the carcinoid syndrome", section on 'Side effects'.)
Peptide receptor radionuclide therapy (initial therapy)
Lutetium Lu-177 dotatate — For patients with advanced unresectable or metastatic, SSTR-positive, well-differentiated higher G2 GINETs (Ki-67 between 10 and 20 percent) with extensive and/or bulky disease who desire an objective response or in whom there is concern regarding progression of the underlying extent of disease, we suggest initial therapy with PRRT using Lu-177 dotatate in combination with an SSA. In a randomized trial (NETTER-2), this approach improved PFS and tumor response compared with high-dose octreotide with an acceptable toxicity profile [6]. For those with unresectable, extensive and/or bulky hepatic predominant disease, an appropriate alternative is liver-directed therapy with hepatic arterial embolization in combination with an SSA. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
The use of PRRT for well-differentiated high-grade (G3) GEP NETs is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Peptide receptor radionuclide therapy (initial therapy)'.)
Eligibility criteria, dosing, and administration — Eligibility criteria for PRRT include positive tumor SSTR expression, sufficient bone marrow reserve (grade 1 to 2 hematologic toxicity is usually acceptable), creatinine clearance >50 mL/minute, Karnofsky performance status >50 (table 3), and expected survival greater than three months [17].
Lutetium Lu-177 dotatate is the most frequently used radiolabeled SSA for PRRT [18-28].
The recommended dose for Lu-177 dotatate with PRRT is 7.4 gigabecquerel (200 millicuries) as an intravenous infusion over 30 minutes every eight weeks for a total of four doses.
Long-acting SSAs should not be administered four weeks prior to each dose of Lu-177 dotatate. Of note, octreotide LAR was administered after each infusion of PRRT and continued after completion of PRRT in the NETTER-1 trial [29]; however, in patients with nonfunctional tumors (ie, not associated with hormone-related symptoms) whose disease has previously progressed on SSA therapy, the benefit of continuing SSA therapy in combination with and following PRRT has not been established. (See 'Should the SSA be continued?' below.)
Efficacy — In an open-label phase III trial (NETTER-2), 226 patients with newly diagnosed, SSTR-positive well-differentiated high G2 or G3 (Ki-67 ≥10 and ≤55 percent) GEP NET and no prior exposure to PRRT or systemic therapy were randomly assigned to PRRT with four cycles of Lu-177 dotatate plus standard-dose octreotide LAR (30 mg) every eight weeks or high-dose octreotide LAR (60 mg every four weeks) [6]. The primary tumor sites involved the pancreas (54 percent), small intestine (29 percent), or other GI sites (16 percent). The frequency of G2 and G3 disease was 65 and 35 percent, respectively. Patients who progressed on PRRT were allowed retreatment, and those who progressed on octreotide LAR alone were allowed to cross over to therapy with PRRT.
At a median follow-up of 23 months, PRRT with Lu-177 dotatate plus standard-dose octreotide LAR improved PFS (median PFS 23 versus 9 months, HR 0.28, 95% 0.18-0.42) and ORRs (43 versus 9 percent) compared with high-dose octreotide LAR. This PFS benefit was consistent across prespecified clinical subgroups including tumor grade (G2 [HR 0.31] versus G3 [HR 0.27]) and primary tumor site (pancreatic [HR 0.34] versus small intestine [HR 0.30] versus nonpancreatic [HR 0.23]).
Grade ≥3 toxicity was higher for PRRT plus octreotide LAR (16 versus 4 percent), including decreased lymphocyte count, increased gamma-glutamyl transpeptidase (GGT; 5 percent each), small intestinal obstruction, abdominal pain (3 percent each), and secondary hematologic malignancy (1 percent). All toxicities related to PRRT were consistent with its known safety profile. Time to deterioration in health-related quality-of-life was also similar between the two treatment arms. (See 'Toxicity and risks' below.)
Toxicity and risks — Other toxicities and risks associated with PRRT include radiation exposure, myelotoxicity, and kidney damage.
●Radiation-related issues – Following each cycle of PRRT, radiation activity persists at low levels for several weeks following therapy because of ongoing decay of the administered radionuclide [30]. While this activity is not harmful to others, it can be picked up by sensitive radiation detectors at international airports and border crossings [31]. Patients need to be provided with a card that they should always carry after each treatment course, detailing the treatment they have received.
●Myelotoxicity and therapy-related myeloid neoplasms – The most serious long-term toxicity associated with PRRT is irreversible myelotoxicity and therapy-related myeloid neoplasms. Therapy-related myeloid neoplasms (which include myelodysplastic syndrome [MDS], acute leukemia, myeloproliferative neoplasms [MPN], or any type of myeloid neoplasm) are associated with a poor prognosis. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Therapy-related myeloid neoplasms: Management and prognosis".)
Clinicians should closely monitor patients who receive PRRT with periodic complete blood counts (CBC) after PRRT [32]. We suggest obtaining a CBC with differential at least every six months and prompt referral to a hematologist if hematologic abnormalities are detected.
In patients who receive PRRT, studies suggest that the rate of MDS is approximately 2 to 4 percent and the rate of acute leukemia is less than 1 percent [33-39]. Other risk factors that may increase the risk of secondary MDS include advanced age, the presence of bone metastases, and heavy pretreatment, although there is controversy as to whether prior therapy with alkylating agents, such as temozolomide, increase risk [39].
●Kidney/glomerular damage – PRRT may result in kidney/glomerular damage. Kidney function can be monitored every three months for the first year, and every six months thereafter, if it remains within normal limits.
In an observational study of 209 patients treated with Lu-177 dotatate, the rates of grade 2 kidney toxicity (table 4) were low (1 percent) [40]. Following treatment, the average annual decrease in creatinine clearance was 3.4 percent, and no patient had an annual decrease in kidney function of >20 percent. No risk factors for kidney toxicity could be identified. In the NETTER-1 trial, in the small population in which it was measured, the mean change from baseline in creatinine clearance over five years was similar for patients treated with Lu-177 dotatate versus an SSA alone [33].
However, rates of kidney toxicity may be higher depending on the means of assessment. In an analysis of 74 patients with GEP NETs undergoing PRRT with Lu-177 dotatate, kidney function was measured over time using 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance to accurately assess glomerular filtration rate (GFR). The rate of slight kidney impairment (GFR loss >2 mL/minute/m2 per year) was 43 percent [41], but more severe kidney toxicity (grade ≥3, as assessed by serum creatinine) was rare (1.3 percent).
Other radionuclide analogs
●Yttrium-90 dotatoc – Yttrium-90 dotatoc is another available radionuclide used with PRRT that has been evaluated in metastatic GEP NETs [42]. However, it is less preferred to Lu-177 dotatate, which data suggest are more effective with less toxicity [24,43,44].
SECOND-LINE THERAPY —
For patients with an advanced or metastatic well-differentiated low-grade (G1) or intermediate-grade (G2) gastrointestinal neuroendocrine tumor (GINET) and disease progression, the approach to second- and later-line therapy depends upon prior treatments received.
Progressive hormone-related symptoms — Patients who have worsening symptoms of hormone secretion may benefit from escalation of the somatostatin analog (SSA), either by increasing the dose or more frequent administration. Refractory diarrhea may benefit from the addition of the oral serotonin inhibitor telotristat. Further details are discussed separately. (See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)
Hepatic predominant disease — For patients who progress on a long-acting SSA (with or without peptide receptor radionuclide therapy [PRRT]) and have hepatic predominant disease, including those with low-burden extrahepatic disease (ie, bones, peritoneum), treatment options include noncurative debulking surgery, in highly selected patients, or liver-directed therapy (transarterial, chemoembolization, or radioembolization). Further details are discussed separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)
Progressive metastases not limited to the liver
Selection of therapy — For patients with a well-differentiated G1 or G2 GINET and progressive systemic metastases not limited to the liver, the optimal sequencing of systemic therapy is not established [45-47]. Enrollment in clinical trials is encouraged, where available. Our approach to second-line therapy is as follows:
●Patients without prior treatment – For patients with tumor progression after a period of observation, we initiate therapy using the same initial treatment approach for those with disease-related symptoms and/or high tumor burden. (See 'Selection of therapy' above.)
●Prior SSA only – For patients with somatostatin-receptor (SSTR)-positive disease and tumor progression on SSA therapy alone, we suggest the addition of PRRT with Lu-177 dotatate rather than escalating the dose of the SSA or other systemic agents. For patients who are ineligible for PRRT or for those where PRRT is not the favored approach (eg, low-volume disease progression), appropriate alternatives include cabozantinib or everolimus. (See 'Peptide receptor radionuclide therapy (second-line therapy)' below.)
●Prior SSA and PRRT – For those with SSTR-positive disease and tumor progression following SSA therapy and PRRT who demonstrated an adequate initial response to PRRT (objective response or stable disease lasting for at least one year), options include switching to another systemic agent (eg, everolimus or cabozantinib) or a repeat course of PRRT plus SSA. (See 'Everolimus' below and 'Cabozantinib' below and 'Retreatment with PRRT' below.)
●Other therapies – For those with tumor progression within one year of PRRT, or those who are ineligible for PRRT, including those with SSTR-negative tumors, we suggest either everolimus or cabozantinib rather than other systemic therapies. If a patient has been on one of these agents, we opt for the other. (See 'Everolimus' below and 'Cabozantinib' below.)
Should the SSA be continued? — For patients with a functional GINET (ie, associated with hormone-secreting symptoms) who receive PRRT for progressive disease, we continue a long-acting somatostatin analog (SSA) during and after PRRT. This approach minimizes hormone secretion and is associated with improved progression-free survival (PFS) in both observational studies [48] and randomized trials (NETTER-1) [29].
Patients with a nonfunctional GINET who progress on a long-acting SSA and switch to another therapy should discontinue the SSA. Such patients are likely deriving minimal benefit from the SSA, and discontinuing it also avoids further potential toxicity. In the NETTER-1 trial, octreotide LAR was administered after each infusion of PRRT and continued after completion of PRRT [29]; however, in patients with nonfunctional tumors whose disease has previously progressed on SSA therapy, the benefit of continuing SSA therapy in combination with and following PRRT has not been established.
Peptide receptor radionuclide therapy (second-line therapy)
Lutetium Lu-177 dotatate — For patients with advanced unresectable or metastatic, SSTR-positive, well-differentiated G1 or G2 GINETs and tumor progression on an SSA alone, we suggest the addition of PRRT using Lu-177 dotatate to the SSA rather than other systemic agents. The use of PRRT for well-differentiated high-grade (G3) pancreatic neuroendocrine tumors (NETs) is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Peptide receptor radionuclide therapy (initial therapy)'.)
In an open-label phase III trial (NETTER-1), 230 adult patients with inoperable, SSTR-positive, well-differentiated G1 or G2 midgut NETs who progressed on octreotide long-acting release (LAR; 20 to 30 mg every three to four weeks) were randomly assigned to PRRT with four doses of Lu-177 dotatate plus standard-dose octreotide LAR (30 mg) every eight weeks or high-dose octreotide LAR (60 mg every four weeks) [29]. Patients randomly assigned to PRRT who completed therapy continued to receive standard-dose octreotide LAR (30 mg every four weeks). The frequency of G1 and G2 disease was 68 and 32 percent, respectively.
At a median follow-up of 30 months, compared with high-dose octreotide LAR, PRRT with Lu-177 dotatate plus standard-dose octreotide LAR improved PFS (median not reached versus eight months, hazard ratio [HR] 0.21, 95% CI 0.13-0.33) and objective response rate (ORR; 18 versus 3 percent). In extended follow-up (median of 76 months), PRRT with Lu-177 dotatate plus standard-dose octreotide LAR demonstrated a nonstatistically significant trend towards improved overall survival (OS; median 48 versus 36 months, HR 0.84, 95% CI 0.60-1.17) [33]. This finding is likely because patients on high-dose octreotide LAR with disease progression were allowed to cross over and receive therapy with PRRT.
Grade 3 or 4 toxicity rates were higher with Lu-177 dotatate relative to high-dose octreotide LAR (41 versus 33 percent) [29]. Common grade 3 to 4 toxicities with Lu-177 dotatate included nausea (4 percent) and vomiting (7 percent) thought to be due to the amino acid infusions administered during therapy to protect the kidneys, abdominal pain, and diarrhea (3 percent each). Grade 3 to 4 hematologic toxicities caused by irradiation of the bone marrow such as lymphopenia (9 percent), thrombocytopenia (2 percent), and leukopenia (1 percent). Nadir counts commonly occur four to six weeks after each infusion and resolve within eight weeks [34]. Two patients developed myelodysplastic syndrome (MDS), including one fatality. Lu-177 dotatate improved quality-of-life, including a longer time to deterioration in quality-of-life global health status, physical functioning, role functioning, fatigue, pain, diarrhea, disease-related worries, and body image [49]. (See 'Toxicity and risks' above.)
In preliminary results from an open-label phase II trial (NETTER-P), additional safety, pharmacokinetic, and dosimetry data for Lu-177 dotatate were evaluated in pediatric patients aged 12 years and older with SSTR-positive tumors, including four pediatric patients with gastroenteropancreatic (GEP) NETs [16]. Patients received Lu-177 dotatate at 7.4 gigabecquerel (200 millicurie) administered every eight weeks concurrently with the recommended amino acid solution. Adverse reactions observed in NETTER-P were similar to those observed in adults treated with Lu-177 dotatate. There was no clinically relevant difference in Lu-177 dotatate exposure in pediatric patients aged 13 to 16 years versus adult patients. The risks of radiation exposure associated with Lu-177 dotatate are greater in pediatric patients than in adult patients due to longer life expectancy.
Based on the results of the NETTER-1 trial as well as the NETTER-P trial, Lu-177 dotatate is approved by the US Food and Drug Administration (FDA) for the treatment of SSTR-positive GEP NETs in adults and pediatric patients 12 years and older, including foregut, midgut, and hindgut NETs [16].
The use of PRRT for well-differentiated G3 pancreatic NETs is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Peptide receptor radionuclide therapy (initial therapy)'.)
Retreatment with PRRT — Further treatments with peptide receptor radiotherapy (PRRT) using Lu-177 dotatate can be administered if the patient experiences tumor progression after a reasonable period of disease response or stability after an initial course of PRRT (typically defined as an objective response or stable disease for at least 12 months). Although the maximal tolerated dose has not been clearly established, a total cumulative radiation dose of approximately 1600 millicuries (eight courses of 200 millicuries each) is considered a reasonable lifetime limit at some institutions [50]. Further prospective randomized trials investigating retreatment with PRRT are necessary.
●A meta-analysis of 13 studies (nine retrospective cohort studies, three prospective single-arm trials, one abstract) reported retreatment outcomes from PRRT (Lu-177 dotatate or dotatoc with or without Yttrium-90 dotatate/dotatoc) [51]. Median PFS was 13 months, which was similar with Lu-177 therapy alone or in combination with PRRT with Yttrium-90. Median OS was 27 months, and the disease control rate was 71 percent. Safety profile with retreatment was comparable with that of initial Lu-177 PRRT, with grade 3 or 4 toxicity in only 5 percent of treated patients (mainly hematologic, one case of grade 3 or 4 kidney toxicity). In a pooled analysis of three studies of 229 patients that reported the incidence of secondary malignancies, there were only two cases of MDS and two cases of acute myeloid leukemia.
●In an observational series of 33 patients with progressive disease after initial benefit from regular therapy who were retreated with two additional Lu-177 dotatate cycles, the median time to progression (TTP) was approximately 17 months. There were no serious delayed adverse effects [52].
Everolimus — Everolimus, a mechanistic target of rapamycin (mTOR) inhibitor, is a treatment option for patients with a well-differentiated G1 and G2 GINET and progressive disease.
Based on initial data from phase II trials [53,54], everolimus was subsequently evaluated in several phase III trials:
●In a double-blind, placebo-controlled phase III trial (RADIANT-2), 429 patients with advanced low- or intermediate-grade GINETs, a history of carcinoid syndrome, and disease progression within the past 12 months were randomly assigned either everolimus 10 mg daily or placebo, in conjunction with octreotide LAR (30 mg intramuscularly every 28 days) [55,56]. Patients in the placebo arm who progressed were allowed to cross over and receive everolimus.
Relative to placebo plus octreotide, everolimus plus octreotide improved PFS (median 16.4 versus 11.3 months; HR 0.77, 95% CI 0.59-1) [55]. This result did not meet the prespecified criteria for statistical significance. However, there were several imbalances in baseline demographic and clinical characteristics of the patient populations, including more good performance status, primary lung tumors, elevated chromogranin-A levels, and previous use of chemotherapy in the everolimus plus octreotide arm. In a subsequent analysis, available in abstract form only, everolimus was associated with improved PFS after adjusting for randomization imbalances (HR 0.62, 95% CI 0.51-0.87) [56]. In extended follow-up, there was no difference in OS between the two treatment arms (median 29 versus 35 months, HR 1.17, 95% CI 0.92-1.49) [57].
●In another phase III trial (RADIANT-4), 302 patients with advanced, treatment-refractory, well-differentiated nonfunctional lung NETs or GINETs were randomly assigned to either everolimus 10 mg daily or placebo [58]. The most common primary tumor site was the lung (30 percent) followed by the ileum (24 percent) and the rectum (13 percent).
At a median follow-up of 21 months, relative to placebo, everolimus improved PFS (median 11 versus 3.9 months; HR 0.48, 95% CI 0.35-0.67) [58]. Everolimus also demonstrated a nonstatistically significant trend towards improved OS (HR 0.64, 95% CI 0.40-1.05). This was reconfirmed in extended follow-up at a median of 33 months (two-year OS 77 versus 62 percent, HR 0.73, 95% CI 0.48-1.11; data available in abstract form only) [59].Everolimus improved the disease control rate relative to placebo (81 versus 64 percent), with similar low ORRs (2 versus 1 percent).Common grade 3 or 4 toxicities for everolimus included diarrhea (7 percent), stomatitis (9 percent), and anemia (5 percent). Everolimus demonstrated similar health-related quality-of-life relative to placebo [60].
Everolimus is approved by the FDA for the treatment of adults with progressive, well-differentiated, nonfunctional NET of gastrointestinal (GI) tract origin with unresectable, locally advanced, or metastatic disease [16].
Cabozantinib — Cabozantinib, an oral multitargeted tyrosine kinase inhibitor, is a treatment option for patients with well-differentiated G1 or G2 GINET and progressive disease. Among other targets, cabozantinib blocks the vascular endothelial growth factor (VEGF) pathway, which is a key driver of angiogenesis in GINETs.
Based on data from a phase II study [61], cabozantinib was evaluated in a double-blind, placebo-controlled phase III trial (CABINET) of 298 patients with advanced well- or moderately differentiated NETs of varying primary sites (95 patients with pancreatic NET and 203 patients with extrapancreatic NET) who progressed on one or more prior therapies (everolimus, sunitinib, or Lu-177 dotatate) [62]. At a median follow-up of 10 months, among the 203 patients with extrapancreatic NET, cabozantinib improved PFS over placebo (median eight versus four months, HR 0.38, 95% CI 0.25-0.59). In subgroup analyses, PFS benefit for cabozantinib was seen in patients with G1 and G2 disease and those whose primary tumor sites were strictly gastrointestinal. ORRs in patients with extrapancreatic NET were higher with cabozantinib (5 versus 0 percent). At a median follow-up of 24 months, OS was similar between the treatment arms (median OS 22 versus 20 months, HR 0.86, 95% CI 0.56-1.31).
The treatment-related grade ≥3 toxicity rate was higher for cabozantinib than placebo (65 versus 27 percent). Toxicities for cabozantinib were consistent with its known safety profile, and no new safety signals were identified. The most common adverse events across all grades observed in patients with extrapancreatic NET receiving cabozantinib included elevation in aspartate aminotransferase (65 percent) or alanine aminotransferase (58 percent), fatigue (62 percent), diarrhea (56 percent), hypertension (53 percent). The most common grade 3 or higher adverse events included hypertension (21 percent), fatigue (13 percent), and diarrhea (11 percent). Overall health-related quality-of-life remained stable over time and was similar in patients receiving cabozantinib compared with placebo. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)
Cabozantinib is approved by the FDA 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 [16].
Further details on the efficacy of cabozantinib in patients with metastatic pancreatic NETs and high-grade (G3) gastroenteropancreatic NETs are discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Cabozantinib' and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
Less preferred therapies
●Dose-escalated SSA therapy – For patients who progress on standard doses of long-acting SSAs, dose escalation of the SSA is a less-preferred treatment option, as the benefits of this approach are not well established [63,64]. In a randomized trial (NETTER-1) of patients with progressive disease, dose-escalation of the SSA demonstrated inferior PFS compared to PRRT plus standard-dose SSAs [29]. This approach, however, is potentially an option for patients with indolent disease progression. (See 'Peptide receptor radionuclide therapy (second-line therapy)' above.)
●Chemotherapy – We do not use chemotherapy to treat advanced or metastatic well-differentiated G1 and G2 GINETs, as these agents have limited response rates, do not improve PFS in randomized trials, and are associated with increased toxicity. The use of chemotherapy for well-differentiated G3 NETs is discussed separately. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors", section on 'Management of metastatic disease'.)
Single-agent chemotherapy, such as fluorouracil, capecitabine [65], dacarbazine [66,67], oxaliplatin, temozolomide [68-70], and doxorubicin [71] have demonstrated limited ORRs in well-differentiated GINETs [65,66,72]. Other agents, such as taxanes, topotecan, and gemcitabine, are relatively inactive as single agents [73-76].
Studies have evaluated combination chemotherapy regimens in well-differentiated G1 and G2 GINETs including and streptozocin-based regimens [67,71,77], FOLFOX or CAPOX plus bevacizumab [78], capecitabine plus temozolomide [79-81], and capecitabine plus bevacizumab [82]. However, we do not use these regimens due to limited efficacy, concerns about toxicity, or the need for further confirmatory randomized trials.
●Surufatinib – Surufatinib, an antiangiogenic agent, improved PFS in a double-blind, placebo-controlled phase III trial (SANET-ep) of patients with progressive well-differentiated extrapancreatic NET [83]. Surufatinib is approved in China for the treatment of pancreatic and extrapancreatic NET but is otherwise not widely available.
●Interferon alfa – We do not use interferon alfa (IFNa) for the treatment of well-differentiated GINETs, either as a single agent or in combination with an SSA. IFNa can reduce hormone-related symptoms and stabilize disease in patients who progress on or are intolerant of SSAs [84-101]. However, the use of this agent is limited by its severe side effects [102] and the availability of other more effective and better tolerated therapies. Standard (nonpegylated) IFNa-2b is also not available, as the manufacturer has discontinued production.
INVESTIGATIONAL AGENTS —
Clinical trial enrollment is encouraged, where available, for patients with well-differentiated neuroendocrine tumors (NETs) due to the rarity of the disease (https://clinicaltrials.gov). Some investigational agents of interest include the following:
●Immunotherapy – The use of immune checkpoint inhibitors remains investigational for well-differentiated NETs, as these agents have minimal activity as single agents or in combination with other systemic agents [103-106].
●Antiangiogenic agents (except cabozantinib) – With the exception of cabozantinib, the use of other antiangiogenic agents for treatment-refractory well-differentiated gastrointestinal neuroendocrine tumors (GINETs) remains investigational. Antiangiogenic therapies, such as pazopanib [107], lenvatinib [108], and bevacizumab [98,109] have shown evidence of activity, primarily through disease stabilization. However, confirmatory trials have not been performed.
●Lanreotide plus everolimus – In preliminary results of a phase III trial (JCOG1901, STARTER-NET) of patients with unresectable or recurrent, nonfunctional low-grade (G1) or intermediate-grade (G2) gastroenteropancreatic (GEP) NETs, initial therapy with lanreotide plus everolimus improved progression-free survival (PFS) and objective response rates (ORRs) over everolimus alone, with similar overall survival (OS) [110]. The use of this combination remains investigational, as it has not been directly compared with a somatostatin analog (SSA) alone, which is more commonly used as initial therapy. Furthermore, the clinical applicability of this combination is unclear since the study did not include patients with prior SSA therapy.
●Targeted alpha therapy – Targeted alpha therapy (TAT) using agents such as Lead Pb-212 dotamtate [111,112], Actinium Ac-225 dotatoc [113], and Ac-225 dotatate [114] are being investigated in clinical trials of patients with somatostatin-receptor (SSTR)-positive NETs.
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
●General principles – Management is evolving for advanced or metastatic, well-differentiated low-grade (G1) or intermediate-grade (G2) gastrointestinal neuroendocrine tumors (GINETs) (table 1); these do not include tumors arising from the pancreas. Clinical trials enrollment is encouraged, where available, due to the rarity of this disease. (See 'Classification of neuroendocrine neoplasms' above.)
●Initial therapy for potentially resectable disease – For patients with hepatic predominant disease that is potentially resectable, surgical resection may provide durable control of symptoms and tumor growth. Although most patients recur, even after a complete resection, we generally prefer metastasectomy over systemic therapy. (See 'Potentially resectable disease' above and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)
●Initial therapy for unresectable disease – For patients with unresectable disease, initial management is based upon patient symptoms, level of disease burden, and clinicopathologic characteristics of the tumor (algorithm 1). (See 'Unresectable disease' above.)
•Asymptomatic with low tumor burden – For patients with asymptomatic, low-volume disease, we suggest surveillance rather than immediate systemic therapy (Grade 2C). (See 'Selection of therapy' above.)
•Disease-related symptoms and/or high tumor burden – For patients with disease-related symptoms and/or high tumor burden, selection of therapy is as follows (see 'Selection of therapy' above):
-Somatostatin-receptor (SSTR)-positive G1 to G2 disease – For patients with SSTR-positive G1 to G2 disease, we suggest initial therapy with a long-acting somatostatin analog (SSA) (Grade 2B), which treats both tumor growth and symptoms related to carcinoid syndrome. Options include octreotide long-acting release (LAR) and lanreotide. (See 'SSAs (octreotide LAR and lanreotide)' above.)
For those with SSTR-positive G1 to lower G2 (Ki-67 of 3 to less than 10 percent) disease and unresectable, extensive and/or bulky hepatic predominant tumors, we evaluate for the addition of initial liver-directed therapy with hepatic arterial embolization to the SSA, as this approach achieves additional disease control and can improve symptoms related to carcinoid syndrome. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)
-SSTR-positive higher G2 disease – For most patients with SSTR-positive, higher G2 tumors (Ki-67 between 10 to 20 percent) with extensive and/or bulky disease who desire an objective response or in whom there is concern regarding progression of the underlying extent of disease, we suggest the addition of peptide-receptor radionuclide therapy (PRRT) using Lutetium Lu-177 dotatate to an SSA (Grade 2B) as this approach improves progression-free survival (PFS) and objective response rates (ORRs). For those with unresectable, extensive and/or bulky hepatic-predominant disease, an appropriate alternative is liver-directed therapy with hepatic arterial embolization in combination with an SSA. (See 'Peptide receptor radionuclide therapy (initial therapy)' above.)
-SSTR-negative disease – For patients with SSTR-negative disease, we suggest initial therapy with either everolimus or cabozantinib rather than an SSA or PRRT (Grade 2C), as such patients are unlikely to achieve significant disease control from therapy that targets SSTRs. Some patients with tumors that lack uptake on SSTR imaging may be candidates for an SSA to control hormone-related symptoms, but tumor control is less certain. For patients with unresectable, extensive and/or bulky hepatic-predominant disease, an appropriate alternative is liver-directed therapy with hepatic arterial embolization. (See 'Everolimus' above and 'Cabozantinib' above.)
●Second-line therapy
•Management of progressive hormone-related symptoms – Patients who have worsening symptoms of hormone secretion may benefit from escalation of SSA. Refractory diarrhea may benefit from the addition of the oral serotonin inhibitor telotristat. (See "Treatment of the carcinoid syndrome".)
•Hepatic predominant disease – For patients who progress on a long-acting SSA (with or without PRRT) and have hepatic predominant disease, including those with low-burden extrahepatic metastases (ie, bone or peritoneal), treatment options include noncurative debulking surgery in highly selected patients or liver-directed therapy (hepatic arterial embolization, chemoembolization, or radioembolization). Further details are discussed separately. (See 'Hepatic predominant disease' above and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)
•Progressive metastases not limited to the liver – For patients with progressive systemic metastases not limited to the liver, our approach to second-line therapy is as follows (see 'Progressive metastases not limited to the liver' above):
-Patients without prior treatment – Patients with tumor progression after a period of observation should initiate therapy using the same treatment approach as those who initially presented with disease-related symptoms and/or high tumor burden. (See 'Selection of therapy' above.)
-Patients with prior SSA alone – For patients with SSTR-positive disease and tumor progression on SSA therapy alone, we suggest the addition of PRRT using Lu-177 dotatate to the SSA rather than other systemic agents (Grade 2C). For those who are ineligible for PRRT or for those where PRRT is not the favored approach (ie, low tumor burden), appropriate alternatives include cabozantinib or everolimus. (See 'Peptide receptor radionuclide therapy (second-line therapy)' above.)
-Patients with prior SSA and PRRT – For patients with SSTR-positive disease and tumor progression on SSA therapy and PRRT who demonstrated an adequate initial response to PRRT (ie, objective response or stable disease lasting for at least one year), options include either switching to another systemic regimen (eg, everolimus or cabozantinib) or a repeat course of PRRT plus SSA. (See 'Everolimus' above and 'Cabozantinib' above and 'Retreatment with PRRT' above.)
-Other patients – For patients with tumor progression within one year of PRRT, or those who are ineligible for PRRT, including those with SSTR-negative tumors, we suggest either everolimus or cabozantinib rather than other systemic therapies (Grade 2C). If a patient has been on one of these agents, we opt for the other. (See 'Everolimus' above and 'Cabozantinib' above.)
•Should the SSA be continued?
-For patients with a functional GINET (ie, associated with hormone-secreting symptoms) who receive PRRT for progressive disease, we continue a long-acting SSA, as this approach minimizes hormone secretion and is associated with improved PFS.
-Patients with a nonfunctional GINET who progress on a long-acting SSA and switch to another therapy should discontinue the SSA due to likely minimal benefit and to avoid further potential toxicity. In the NETTER-1 trial, octreotide LAR was continued during and following treatment with Lu-177 dotatate; however, in patients with nonfunctional tumors whose disease has previously progressed on SSA therapy, the benefit of continuing SSA therapy in combination with and following PRRT has not been established. (See 'Should the SSA be continued?' above.)
