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

INTRODUCTION — Neuroendocrine cells are distributed widely throughout the body, and neoplasms of these cells, which are termed neuroendocrine tumors (NETs), can arise at many sites.

NETs are a heterogeneous group of malignancies characterized by variable but most often indolent biologic behavior. Clinical behavior and prognosis correlate closely with histologic differentiation and grade, as assessed by mitotic count and/or Ki-67 labeling index (table 1) [1]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

Systemic treatment options to control tumor growth in patients with advanced or metastatic well-differentiated NETs arising in the gastrointestinal tract (gastrointestinal NETs [GINETs]) will be discussed in this topic review. Management of symptoms related to hormone hypersecretion, and systemic therapy options for pancreatic NETs and for poorly differentiated neuroendocrine carcinomas arising in the digestive tract are discussed elsewhere, as are local management options for well-differentiated metastatic gastroenteropancreatic NETs; the clinical presentation, imaging, biochemical monitoring, pathology, and classification of gastroenteropancreatic NETs; the clinical features of primary NETs; the diagnosis of carcinoid syndrome and tumor localization; the treatment of early stage NETs; bronchial NETs; thymic NETs; and the evaluation and management of NETs of unknown primary site:

●(See "Treatment of the carcinoid syndrome".)

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

●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

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

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

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

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

●(See "Diagnosis of carcinoid syndrome and tumor localization".)

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

●(See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis".)

●(See "Thymic neuroendocrine (carcinoid) tumors".)

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

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

CLASSIFICATION, BIOLOGIC BEHAVIOR, AND IMPLICATIONS FOR TREATMENT — The World Health Organization (WHO) classifies all gastroenteropancreatic neuroendocrine neoplasms based on differentiation status and grade. Well-differentiated gastroenteropancreatic neuroendocrine tumors (NETs) are divided into low-grade (G1), intermediate-grade (G2), and high-grade (G3) categories based on mitotic count and proliferative index (Ki-67) (table 1) [1]. Poorly differentiated neuroendocrine carcinomas (NEC) are considered high grade by definition. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on '2010 and 2019 World Health Organization classification'.)

●Well-differentiated NETs arising within the digestive system have been traditionally referred to as carcinoids when they arise within the tubular gastrointestinal tract and pancreatic NETs (islet cell tumors) when they arise in the pancreas or, in the case of gastrinoma, the proximal duodenum. GINETs and pancreatic NETs may have similar characteristics on routine histologic evaluation, but they have a different pathogenesis and biology [2]. Pancreatic NETs have a worse prognosis than GINETs [3,4] and respond differently to anticancer agents, with most agents demonstrating higher response rates among patients with pancreatic NETs than those with GINETs. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion".)

●G2 gastroenteropancreatic NETs have a worse prognosis than G1 tumors [4,5]. Although they are treated similarly at present, as new treatment modalities become available, it is likely that the histologic grade of a well-differentiated NET will affect the selection of appropriate treatment.

●There is a subset of well-differentiated tumors with a proliferative rate that places them in the high-grade category (G3 NET). These tumors have a clinical behavior that is between G2 NET and poorly differentiated neuroendocrine carcinoma. Management is discussed in detail elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)

●By contrast, poorly differentiated neuroendocrine carcinomas have a rapidly progressive clinical course and a poor prognosis. They are generally treated with platinum-based chemotherapy regimens. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Poorly differentiated NEC' and "Extensive-stage small cell lung cancer: Initial management".)

Among well-differentiated GINETs, site may also impact clinical behavior. As an example, among patients with metastatic well-differentiated NETs, survival, according to the Surveillance, Epidemiology, and End Results (SEER) registry data, varies according to primary site; it is worst for patients with lung and colon primaries (median survival for distant G1 or G2 disease 24 and 14 months, respectively) and is most favorable for tumors arising in the small intestine (median survival 103 months) [4]. This heterogeneity in clinical behavior complicates the comparative assessment of benefit from individual therapies. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stage and site of origin'.)

GENERAL APPROACH TO THE PATIENT — The majority of patients with advanced metastatic GINETs have liver metastases [6]. An approach to management is outlined in the algorithm (algorithm 1) and summarized below:

●Potentially resectable disease – For patients who have potentially resectable disease, resection may provide prolonged control of symptoms and tumor growth. Although the majority of patients recur, even after a complete resection, metastasectomy is generally preferred over medical therapy for patients with potentially resectable liver metastases. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

●Unresectable, symptomatic disease – For patients with unresectable symptomatic disease, initial therapy with a somatostatin analog is highly effective for controlling symptoms of the carcinoid syndrome and for control of tumor growth. (See "Treatment of the carcinoid syndrome".)

●Unresectable, asymptomatic disease – Initial therapy for asymptomatic patients with unresectable disease must be individualized. Therapeutic options in this situation include observation, particularly if tumor burden is limited, or initial therapy with a somatostatin analog, particularly if tumor burden is high. If an initial approach of observation is chosen, initiation of a somatostatin analog should be considered at time of progression. (See 'Somatostatin analogs' below.)

●Therapy for progression of hormone-related symptoms – Patients who have worsening symptoms of hormone secretion may benefit from escalation of somatostatin analog. Refractory diarrhea may benefit from the addition of the oral serotonin inhibitor telotristat. (See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)

●Therapy at progression – For patients with radiologic disease progression despite use of a somatostatin analog, locoregional therapeutic options for patients with hepatic predominant disease include noncurative debulking surgery (in highly selected patients), or nonsurgical liver-directed therapy (eg, transarterial bland embolization, chemoembolization, or radioembolization). (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic-predominant metastatic disease' and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Nonsurgical liver-directed therapy'.)

For patients with more widespread disease that is not eligible for liver-directed therapy, systemic therapy is appropriate. Options include peptide receptor radioligand therapy (eg, lutetium Lu-177 dotatate [¹⁷⁷Lu-Dotatate] [7]), for patients with somatostatin receptor (SSTR) positive disease, where available, or everolimus.

Randomized trials with head to head comparisons and studies evaluating the optimal sequencing of therapy have not been conducted. Meta-analyses have not been helpful:

•Interpretation of an attempted network meta-analysis to rank the relative efficacy and toxicity of a variety of systemic therapies for GINETs was limited due to variability in patient populations, variability in eligibility and response criteria, a lack of trials directly comparing active treatments, as well as unclear efficacy of the comparator arm in some cases (especially interferon) [8,9].

•A later Cochrane meta-analysis concluded that a range of effective therapies with different safety profiles is available for GINETs, and failed to support any particular therapy (or therapy combination) with respect to patient centered outcomes (overall survival, quality of life) [10].

Randomized trials comparing different systemic therapy options are desperately needed, and eligible patients should be encouraged to enroll in available trials, such as the COMPETE trial evaluating lutetium Lu-177 edotreotide with everolimus (NCT03049189). If trial participation is not available or desired, for patients with midgut NETs whose disease is highly avid on SSTR imaging, we suggest ¹⁷⁷Lu-Dotatate rather than everolimus, depending on availability, and patient preference. If the disease is not SSTR-expressing, we suggest everolimus. Several small molecule tyrosine kinase inhibitors-targeting angiogenesis have demonstrated activity against GINET, but are currently not approved for treatment. (See 'Lutetium Lu-177 dotatate' below and 'Molecularly targeted therapy' below.)

The value of cytotoxic chemotherapy for GINETs continues to be debated, and no specific regimen can be recommended. (See 'Molecularly targeted therapy' below and 'Somatostatin receptor-expressing tumors' below and 'Cytotoxic chemotherapy' below.)

The benefit of continuing therapy with a long-acting somatostatin analog in patients whose disease progress while receiving somatostatin analog therapy is not well defined. For patients with functional tumors (ie, associated with symptoms related to hormone secretion), we continue the somatostatin analog to minimize hormone secretion. For patients with nonfunctional tumors who experience unequivocal radiographic progression on a somatostatin analog and for whom treatment with everolimus or cytotoxic chemotherapy is planned, we would consider discontinuing the somatostatin analog. (See 'Should the somatostatin analog be continued?' below.)

The following sections will discuss the various systemic treatment options to control symptoms and tumor growth. Local treatment options are discussed in detail elsewhere. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion".)

SOMATOSTATIN ANALOGS

Efficacy and timing of octreotide and lanreotide — Somatostatin analogs, including octreotide and lanreotide, are highly effective in controlling the symptoms associated with carcinoid syndrome. In addition to controlling symptoms associated with hormone hypersecretion, somatostatin analogs have also been shown to control tumor growth. However, the optimal time to initiate treatment with a somatostatin analog in asymptomatic patients remains uncertain, given the variable natural history of disease and often indolent nature of well-differentiated NET. We suggest initiation of a somatostatin analog in patients with unresectable, asymptomatic, well-differentiated GINETs and a high tumor burden, an approach that is consistent with guidelines from the European Neuroendocrine Tumor Society [11], the North American Neuroendocrine Tumor Society [12], and the National Comprehensive Cancer Network (NCCN) [13]. For patients with asymptomatic, advanced, unresectable GINETs and small-volume disease, we suggest observation alone rather than early administration of a somatostatin analog. In such patients, we initiate somatostatin analog therapy if there is evidence of clinically meaningful tumor progression.

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 somatostatin receptors (SSTRs), which are expressed on the majority of NETs [14]. The ability of octreotide and lanreotide to inhibit the secretion of peptides from NET cells is mediated mainly through SSTR-2 and SSTR-5.

The presence of SSTRs can be determined by diagnostic imaging using a radiolabeled somatostatin analog (indium-111 [111-In] pentetreotide [OctreoScan] or PET using gallium [Ga]-68 DOTATATE or Ga-68 DOTATOC or copper [Cu]-64 DOTATATE). Because of the higher sensitivity of SSTR-PET, this is the preferred nuclear imaging option in certain clinical scenarios, particularly in patients with smaller tumor volume. In general, uptake of radiotracer by the tumor is predictive of a response to therapy with somatostatin analogs. However, in some cases (eg, miliary disease), diagnostic imaging may be negative even if SSTRs are present on the tumor. In such cases, a trial of somatostatin analog therapy can be considered even in the presence of a negative scan. (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

Somatostatin analogs, including octreotide and lanreotide, are highly effective in controlling the symptoms associated with carcinoid syndrome. (See "Treatment of the carcinoid syndrome", section on 'Somatostatin-analog therapy'.)

In addition to controlling symptoms associated with hormone hypersecretion, somatostatin analogs have also been shown to control tumor growth. Although past studies indicated that <10 percent of patients with advanced GINETs have objective tumor shrinkage with somatostatin analogs [15-26], more recent reports have demonstrated that in addition to an improvement in symptoms, treatment with somatostatin analogs can significantly delay disease progression [19,27,28]. Whether somatostatin analogs also increase overall survival (OS) is not yet known, although a correlation between progression-free survival (PFS) and OS in patients with advanced NET treated with single-agent somatostatin analog therapy has been shown [29].

Median duration of PFS and OS depend on several factors, including primary tumor location, Ki-67 percent, extent of liver metastases, presence of bone and/or peritoneal metastases, and the presence of symptoms when initiating treatment. A nomogram has been developed to estimate PFS in patients with well-differentiated gastroenteropancreatic NET based upon these and other factors [30].

At least two placebo-controlled trials have addressed the PFS and OS benefits of long-acting somatostatin analogs:

●In the PROMID trial, 85 patients with locally inoperable or metastatic midgut GINETs were randomly assigned to receive treatment with either long-acting octreotide (Sandostatin LAR 30 mg monthly) or placebo [19]. The median time to tumor progression was significantly longer with octreotide compared with placebo (14.3 versus 6 months), confirming an antitumor effect in this population. Patients with functionally active and inactive tumors appeared to have a similar benefit. In a later report, while a trend toward improved OS was observed in the patients randomized to receive octreotide, the number of patients in this study was relatively small, and the difference was not statistically significant [31].

●Further support for the antiproliferative effect of somatostatin analogs in patients with gastroenteropancreatic NETs was provided by the CLARINET trial, a randomized, placebo-controlled, phase III trial evaluating the antiproliferative effects of lanreotide in 204 patients with advanced well- or moderately differentiated, nonfunctioning, gastroenteropancreatic NETs, including both GINETs and pancreatic NETs [27]. Patients were randomly assigned to either 120 mg lanreotide depot (n = 101) or placebo (n = 103) every four weeks for 96 weeks or until progressive disease or death. The primary endpoint for the trial was PFS as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (table 2). Most patients (96 percent) had no tumor progression per RECIST criteria in the three to six months before randomization. Compared with placebo, there was a highly significant advantage in PFS with the use of lanreotide. At a time-point of two years following initiation of treatment, median PFS was not reached with lanreotide, compared with 18 months with placebo (hazard ratio for progression or death 0.47, 95% CI 0.30-0.73). Estimated rates of PFS at 24 months were 65 versus 33 percent, and there were no differences in quality of life or OS. The most common treatment related adverse effect was diarrhea (26 versus 9 percent with lanreotide and placebo, respectively). Based on these data, lanreotide has been approved in the United States for the treatment of patients with unresectable, well- or moderately differentiated, locally advanced, or metastatic gastroenteropancreatic NETs.

We typically initiate therapy with long-acting octreotide 20 or 30 mg every four weeks or lanreotide depot 120 mg every four weeks. Whether higher doses of a somatostatin analog provide higher rates of disease control is unclear. Three retrospective studies using either octreotide LAR (160 mg intramuscularly every 14 days for two months, then monthly) or lanreotide (750 to 15,000 mcg per day) demonstrated disease stabilization in 37 to 75 percent of patients [32-34]. However, the number of patients included in these studies was small (12 to 30), follow-up was short (≤12 months), and the number of objective responses was not higher than reported with conventional doses (3 to 5 percent).

The choice of octreotide LAR versus lanreotide should be based on patient preference. Although both drugs are equally acceptable and efficacious treatments for WDNETs, they differ substantially in cost [35]. While it was originally hypothesized that a deep subcutaneous injection of lanreotide might be less painful compared with intramuscular injection of octreotide LAR, a randomized trial specifically designed to assess patient experience and drug preference in 51 patients initiating therapy with a long-acting somatostatin analog concluded that there was minimal pain with either drug and no significant pain score difference between the two [36]. Of the 34 patients who indicated a drug preference, more than half had no preference, and among those who did, there was a trend toward favoring octreotide LAR, but the numbers were very small.

Dose-escalated therapy — Dose escalation of the somatostatin analog is an option at the time of initial disease progression on a long-acting somatostatin analog, but it is not our preferred option.

The benefits of escalating the dose and/or frequency of a somatostatin analog for disease control are not well established [37,38], and clinical practice is variable. Furthermore, how this strategy compares with other systemic treatments for disease control after progression on a long-acting somatostatin analog (eg, peptide receptor radioligand therapy) is not known. (See 'Somatostatin receptor-expressing tumors' below.)

Continuation after progression — The benefits of continuing somatostatin analog therapy following disease progression when a different antitumor therapy is being considered are not well defined. For patients with functional NETs, somatostatin analogs are typically continued to control hormone secretion and symptoms related to hormone hypersecretion. It is reasonable to discontinue somatostatin analog therapy in patients with nonfunctional NETs whose disease has unequivocally progressed on somatostatin analog therapy.

SOMATOSTATIN RECEPTOR-EXPRESSING TUMORS

Peptide receptor radioligand therapy

Radiolabeled somatostatin analogs — For most patients with GINETs and progressive disease despite a long-acting somatostatin analog and who have somatostatin receptor-positive disease with no underlying renal or hematologic insufficiency, we suggest peptide receptor radiotherapy (PRRT) using a radiolabeled somatostatin analog rather than molecularly targeted therapy. Although there are no comparator trials, and no consensus on the optimal timing for a trial of PRRT in this setting [39], we base this decision on the higher response rate, favorable toxicity profile, and ease of treatment of PRRT as compared with other alternatives.

Somatostatin receptor (SSTR) expression is determined by use of diagnostic imaging using radiolabeled somatostatin analogs (ie, SSTR-PET CT or SSTR-PET MRI). (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

There has been substantial interest in targeted radiation therapy using radiolabeled somatostatin analogs [40-50]. The most frequently used radionuclides for targeted radiation therapy include yttrium-90 (⁹⁰Y) and lutetium-177 (¹⁷⁷Lu), which differ from one another in terms of emitted particles, particle energy, and tissue penetration. In general, objective tumor response rates are up to 30 percent, and approximately one-third have symptomatic improvement. Long-term side effects include loss of renal function, pancytopenia, and myelodysplastic syndrome (MDS)/secondary acute leukemia. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Radiolabeled somatostatin analogs'.)

Most of the series reporting efficacy and toxicity with radiolabeled somatostatin analogs have included both pancreatic NETs and GINETs [46,51-53].

Yttrium-90 Dotatoc — The most extensive experience with ⁹⁰Y-DOTA-TOC (⁹⁰Y-Dotatoc) comes from a large single-institution series of 1109 patients with metastatic gastroenteropancreatic NETs and disease progression within 12 months of study entry, with visible tumor uptake on pretreatment SSTR scintigraphy [53]. After the initial dose, additional treatment cycles were withheld if there was tumor progression or permanent toxicity; otherwise, patients were offered retreatment; the specific interval was not specified. The median number of courses administered was two, range 1 to 10.

Overall, 378 patients (34 percent) had a "morphologic" response (defined as any measurable decrease in the sum of the longest diameters of all pretherapeutically detected tumor lesions by computed tomography [CT], magnetic resonance imaging [MRI], or ultrasound), 172 (15 percent) had a biochemical response (defined as any post-treatment decrease in a tumor marker that had demonstrated progression prior to enrollment), and 329 (29.7 percent) improved symptomatically. The median survival from diagnosis was 94.6 months. Longer survival correlated with responses by any of the above criteria. Transient grade 3 or 4 hematologic toxicities developed in 142 (12 percent), and loss of renal function was the main dose-limiting toxicity. In all, 103 patients (9 percent) had permanent grade 4 or 5 (fatal, n = 35) renal toxicity. Older age, low baseline glomerular filtration rate, and high kidney uptake score were associated with severe nephrotoxicity.

Lutetium Lu-177 dotatate — Increasing data suggest that ¹⁷⁷Lu-Dotatate outperforms ⁹⁰Y-Dotatoc, although randomized trials have not been undertaken [7,46,54,55].

The most compelling demonstration of benefit for ¹⁷⁷Lu-Dotatate in midgut GINETs was shown in the phase III international NETTER-1 trial, in which 230 patients with inoperable, somatostatin-receptor-positive midgut NETs who experienced progressive disease on standard doses of octreotide LAR (20 to 30 mg every three to four weeks) were randomly assigned to four doses of ¹⁷⁷Lu-Dotatate every eight weeks or octreotide LAR 60 mg every 28 days [7]. In the ¹⁷⁷Lu-Dotatate group, patients continued to receive supportive care with octreotide LAR, which was administered at a dose of 30 mg after each infusion of ¹⁷⁷Lu-Dotatate and then monthly after completion of all four treatments. The primary endpoint was progression-free survival (PFS). The estimated PFS rate at month 20 was significantly higher with ¹⁷⁷Lu-Dotatate (65.2 versus 10.8 percent); median PFS for octreotide LAR alone was 8.4 months, while it had not been reached in the ¹⁷⁷Lu-Dotatate group (with approximately 30 months of follow-up since initiation of treatment). The hazard ratio (HR) for PFS was 0.21 (95% CI 0.13-0.33). Among patients evaluable for radiographic response, ¹⁷⁷Lu-Dotatate was also associated with a significantly higher objective response rate (18 versus 3 percent).

Radiopharmaceutical therapy was well tolerated overall; serious adverse events that were considered related to treatment were more common with ¹⁷⁷Lu-Dotatate (9 versus 1 percent). The most common adverse event in the ¹⁷⁷Lu-Dotatate group was nausea (all grade, 59 percent; grade 3 or 4, four percent), thought to be due to the amino acid infusions administered during therapy to protect the kidneys. Hematologic toxicities (caused by irradiation of the bone marrow) included mostly mild degrees of thrombocytopenia (25 percent), lymphopenia (18 percent, grade 3 or 4 in 9 percent), anemia (14 percent), and leukopenia (10 percent). Nadir counts commonly occur four to six weeks after each infusion and resolve within eight weeks [56].

A subsequent report assessing the impact of treatment on quality of life concluded that time to deterioration in quality of life was significantly longer with ¹⁷⁷Lu-Dotatate compared with higher dose octreotide in several domains, including global health status, physical functioning, role functioning, fatigue, pain, diarrhea, disease-related worries, and body image [57]. The differences were clinically significant in global health status (median time to deterioration in quality of life 28.8 versus 6.1 months) and physical functioning (25.2 versus 11.5 months).

Long-term outcomes were addressed in a later analysis, five years after the last patient was randomized (median follow-up approximately 76 months in both groups) [58]. Notably, 12 percent of the 177 patients in the ¹⁷⁷Lu-Dotatate group received further PRRT whereas 41 of 114 patients in the control group (36 percent) had documented crossover to PRRT. The final overall survival (OS) in the intent to treat population was potentially clinically meaningful but not significantly different between the study groups (median 48 versus 36.3 months, HR 0.84, 95% CI 0.60-1.17), but this was likely impacted by crossover.

During the entry study, only 7 (6 percent) of 111 patients in the ¹⁷⁷Lu-Dotatate group had a grade 3 or worse treatment-related serious adverse event. Two developed myelodysplastic syndrome, one fatal, and the third patient had a grade 3 respiratory tract infection. There were no cases of acute myelogenous leukemia.

Largely based on the early data from the NETTER-1 trial, in January 2018, the US Food and Drug Administration approved ¹⁷⁷Lu-Dotatate for the treatment of somatostatin-receptor-positive gastroenteropancreatic NETs in adults [59]. The recommended dose is 7.4 GBq (200 millicuries) as an intravenous infusion over 30 minutes every eight weeks for a total of four doses [60]. The limitations of ¹⁷⁷Lu-Dotatate at present include the complexity of administration; the lack of trials comparing this agent with other systemic therapies, such as everolimus; and the lack of widespread availability.

The optimal selection of candidates for ¹⁷⁷Lu-Dotatate is not established. Guidelines from the European Neuroendocrine Tumor Society, which largely mirror the eligibility criteria for the NETTER-1 trial, are outlined in the table (table 3) [61]. We agree with these guidelines.

Risks

●Radiation-related issues – Following each treatment, radiation activity persists at low levels for several weeks following each treatment because of ongoing decay of the administered radionuclide [62]. While this activity is not harmful to others, it can be picked up by sensitive radiation detectors at international airports and border crossings [63]. Patients need to be provided with a card that they carry at all times 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, including MDS, acute leukemia, myeloproliferative neoplasms (MPN), or any type of myeloid neoplasm. The available data from studies with long-term follow-up suggest a rate of MDS of approximately 2.0 percent and a rate of acute leukemia of approximately 0.5 percent [56,58,64-67]:

•In a systematic review of 28 reports totaling 7334 patients who were treated with PRRT for a NET, the incidence of therapy-related myeloid neoplasms was variable, with a mean of 2.61 percent (standard deviation 4.38 percent) [67]. The median time of developing a treatment-related myeloid neoplasm was variable, but most were diagnosed after one year of completing PRRT. Information on prior radiotherapy or chemotherapy was mostly not reported, so risk factors could not be addressed.

•The incidence and course of any persistent hematologic dysfunction were addressed in a Dutch multicenter report that systematically followed 274 patients with gastroenteropancreatic NETs for at least five years following treatment with ¹⁷⁷Lu-Dotatate; the intended cumulative dose was 29.6 GBq (800 millicuries) [64]. Eleven patients (3.7 percent) had persistent hematologic dysfunction post-treatment; these included eight with a hematologic neoplasm (four MDS, one acute myeloid leukemia, one MPN, and two MDS/MPN) and three with bone marrow failure characterized by cytopenias and bone marrow aplasia. The median latency period was 41 months after the first PRRT cycle. No risk factors for persistent hematologic dysfunction could be identified.

•Rates may be higher in those who received concurrent chemotherapy [68]. As an example, in a long- term Australian study of 104 patients followed for a period of 68 months after enrolling on two clinical trials of ¹⁷⁷Lu-dotate with concurrent capecitabine with or without temozolomide, at a median follow-up of 68 months, seven patients (6.7 percent) developed of MDS/ acute leukemia, with a median time to onset of five years (range two to seven years) after PRRT. All but one case occurred after four years. Administering PRRT with concurrent chemotherapy is not recommended outside of a clinical trial.

Advanced age, the presence of bone metastases, and heavy pretreatment are reported to increase the risk of secondary myelodysplasia, although there is controversy as to whether prior treatment with alkylating agents, such as temozolomide, increases risk [69].

Given the risk and the poor prognosis after a diagnosis of therapy-related myeloid neoplasms, clinicians should closely monitor patients with periodic complete blood counts (CBC) after PRRT [70]. We suggest obtaining a CBC with differential at least every six months and prompt referral to a hematologist if abnormalities are detected. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Therapy-related myeloid neoplasms: Management and prognosis".)

●Glomerular damage – Renal radiation may result in glomerular damage. Rates of nephrotoxicity as assessed by increases in creatinine during therapy were low during therapy (1 percent, grade 2 (table 4) in another Dutch report of 209 patients treated with ¹⁷⁷Lu-Dotatate [71]. Following treatment, the average annual decrease in creatinine clearance was 3.4 percent, and no patient had an annual decrease in renal function of >20 percent. No risk factors for renal toxicity could be identified. In the NETTER-1 trial, described above, in the small population in which it was measured, the mean change from baseline in creatinine clearance over time was similar for both the ¹⁷⁷Lu-Dotatate and control groups (at five years, -21.6 mL/min [n = 11] versus -24.7 mL/min [n = 17]) [58].

However, rates of nephrotoxicity may be higher depending on the means of assessment. An analysis of kidney function over time using ^99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance to accurately assess glomerular filtration rate (GFR) in 74 consecutive patients with gastroenteropancreatic NETs undergoing PRRT with ¹⁷⁷Lu-Dotatate noted slight renal impairment (GFR loss >2 mL/min/m² per year) in 43 percent [72]. By contrast, there was only one case of grade 3 or worse nephrotoxicity as assessed by serum creatinine (table 4) (1.3 percent).

Should the somatostatin analog be continued? — For patients with a functional NET, we continue therapy with a somatostatin analog during and after PRRT. For patients with a nonfunctional NET, we typically continue therapy with the somatostatin analog, although we consider stopping it for a patient with a nonfunctional NET whose disease is progressing unequivocally on somatostatin analog therapy. This approach is consistent with guidelines from the European Society for Medical Oncology [73].

The added benefit of combining a long-acting somatostatin analog with PRRT and continuing a somatostatin analog as maintenance therapy compared with PRRT alone is not established. At least some data from a retrospective analysis of 168 patients treated at a single institution for unresectable gastroenteropancreatic NETs suggest that combined therapy is associated with significantly better median PFS (48 versus 27 months) and OS (91 versus 47 months) [74] compared with PRRT alone.

Retreatment — Further treatments with ¹⁷⁷Lu-Dotatate can be administered if patients experience progression after a reasonable period of disease response or stability (typically defined as greater than 12 months). The following data are available regarding efficacy and safety:

●In a series of 33 patients with progressive disease after initial benefit from regular therapy who were retreated with two additional ¹⁷⁷Lu-Dotatate cycles, the median time to progression was approximately 17 months, and there were no serious delayed adverse effects [75].

●A meta-analysis of 13 studies (nine retrospective cohort studies, three prospective single arm trials, one abstract that did not report the type of study) reported retreatment outcomes from PRRT (¹⁷⁷Lu-Dotatate or Dotatoc with or without ⁹⁰Y Dotatate/Dotatoc) [76]. The median PFS (seven studies, 414 patients) was 12.52 months (95% CI 9.82-15.22) and was similar with ¹⁷⁷Lu alone or in combination with ⁹⁰Y PRRT; median OS (two studies, 194 patients) was 26.78 months (95% CI 18.73-34.83), and the disease control rate (eight studies, 347 patients) was 71 percent (95% CI 66-75). The safety profile was comparable with that of initial ¹⁷⁷Lu PRRT, with grade 3 or 4 toxicity in only 5 percent of treated patients (mainly hematologic, one case of grade 3 or 4 renal toxicity). In a pooled analysis of studies reporting secondary malignancies (three studies, 229 patients), there were only two cases of MDS and two of acute myeloid leukemia.

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 [77].

Iobenguane I-131 — Iodine-131-labeled iobenguane (iobenguane I-131 [therapeutic], also known as metaiodobenzylguanidine [MIBG] or ¹³¹I-MIBG) has been licensed by regulatory authorities in some countries [78] and has been approved for treatment of pheochromocytoma/paraganglioma and neuroblastoma in the United States; however, in our view, its use for the treatment of GINETs remains investigational.

Iobenguane is a compound resembling norepinephrine that is accumulated by some NETs. Benefit has been suggested for patients with metastatic gastroenteropancreatic NETs who have evidence of iobenguane uptake, as determined by iobenguane I-123 (diagnostic) scanning [78-81]. In two separate retrospective series, biochemical (5-HIAA) responses were observed in 37 percent of patients with gastroenteropancreatic NETs treated with iobenguane I-131, and objective radiographic responses were noted in 15 and 28 percent, respectively [80,81]. In one report, symptomatic improvement was reported by 27 of 48 patients (56 percent) [81].

However, the benefit of iobenguane I-131 (therapeutic) was subsequently called into question in a nonrandomized comparison of outcomes with iobenguane I-131 in 30 patients with carcinoid syndrome or tumor symptoms (fever, pain) attributed to the NET versus unlabeled iobenguane in 20 patients with carcinoid syndrome who were not suitable for treatment with the radioactive compound [82]. The rate of symptom response was identical in both groups (60 percent), though symptom response was not accompanied by either a biochemical or radiographic response in any patient.

OTHER PATIENTS AND THOSE PROGRESSING AFTER PEPTIDE RECEPTOR RADIOTHERAPY

Molecularly targeted therapy — Molecularly targeted therapy for NETs include agents that target the vascular endothelial growth factor (VEGF) and everolimus, an inhibitor of the mechanistic (previously called mammalian) target of rapamycin (mTOR).

Everolimus — For patients with progressive GINETs who are not eligible for PRRT, everolimus is an option.

Everolimus inhibits mTOR, a threonine kinase that mediates downstream signaling in a number of pathways that are implicated in NET growth, including the VEGF and insulin-like growth factor (IGF) signaling pathways [83,84]. In addition, mTOR regulates angiogenesis by controlling the production of hypoxia inducible factor.

The benefit of everolimus for GINET has been evaluated in the following studies (table 5):

●In a phase II study of everolimus in conjunction with octreotide in 30 patients with advanced GINETs, partial responses were observed in 5 of 30 (17 percent) patients, but the median time to tumor progression was relatively short, under eight months [85].

Further support for antitumor activity of everolimus comes from a phase II trial in which 34 patients with radiologically progressing, locally advanced, recurrent, or metastatic but nonfunctioning NETs at a variety of sites, including the intestinal tract (n = 22), received everolimus 10 mg daily [86]. The best response was a partial response in three patients and stable disease in 28, for an overall disease control rate of 94 percent. The median progression-free survival (PFS) was 15.3 months, and the four-month PFS rate was 78 percent. The major grade 3 or 4 adverse events were thrombocytopenia (15 percent), hyperglycemia, stomatitis, and anemia (6 percent each).

●Two phase III trials have been conducted, both of which suggest benefit compared with long-acting octreotide alone or placebo:

•The RADIANT-2 trial randomly assigned 429 patients with advanced GINETs, a history of carcinoid syndrome, and radiologic disease progression in the preceding 12 months to octreotide LAR (30 mg intramuscularly every 28 days) with or without everolimus (10 mg daily) [87,88]. As assessed by central radiographic review, combined therapy was associated with a potentially clinically meaningful prolongation in median PFS, but it was only of borderline statistical significance (16.4 versus 11.3 months; hazard ratio [HR] for tumor progression 0.77, 95% CI 0.59-1.0). Imbalances between study groups were noted in important prognostic variables, including disease site and performance status, all of which favored the control group and could have affected the primary outcome results. A later analysis, presented at the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, found a significant PFS benefit for everolimus after adjusting for randomization imbalances (HR for progression 0.62, 95% CI 0.51-0.87, p = 0.003) [88].

In the final analysis, there was no significant difference in overall survival (OS) between the two groups (HR for death 1.17, 95% CI 0.92-1.49) [89]; however, patients who were randomly assigned to the placebo group were permitted to cross over to the active treatment group, potentially obscuring any meaningful survival benefit.

•The most definitive demonstration of benefit from everolimus comes from a phase III study in which 302 patients with advanced, nonfunctional lung or GINETs (most common sites: lung [30 percent], ileum [24 percent], and rectum [13 percent]) were randomly assigned to everolimus or placebo [90]. Everolimus was associated with a significant improvement in median PFS, the primary endpoint (11.0 versus 3.9 months; HR for progression 0.48, 95% CI 0.35-0.67). There was an overall objective response rate of 2 percent for everolimus compared with 1 percent for placebo, but the disease control rate was 81 percent for patients assigned to everolimus compared with 64 percent for placebo. Adverse events were mainly grade 1 or 2 and included stomatitis, diarrhea, peripheral edema, fatigue, and rash. Most frequent severe (grade 3 or 4) adverse events, which were more common with everolimus, were diarrhea (7 versus 2 percent), stomatitis (9 versus 0 percent), and anemia (5 versus 2 percent). In the second interim analysis of OS presented at the 2016 annual ASCO meeting, at a median follow-up of 33 months, everolimus was associated with a 27 percent reduction in the risk of death, but the difference was not statistically significant (HR 0.73, 95% CI 0.48-1.11, two-year survival 77 versus 62 percent) [91]. The benefits of everolimus were achieved while preserving overall quality of life [92].

Largely based upon these results, everolimus was approved in February 2016 by the US Food and Drug Administration for the treatment of adults with progressive, well-differentiated, nonfunctional NET of gastrointestinal tract origin with unresectable, locally advanced, or metastatic disease. (See 'General approach to the patient' above.)

Treatments targeting tumor angiogenesis — NETs are among the most highly vascular of solid tumors and frequently express the VEGF and its receptor (VEGFR), which are key drivers of angiogenesis. In preclinical models, disruption of these and other signaling pathways inhibits neuroendocrine cell growth. VEGF-targeting agents can be generally divided into two categories: antiangiogenic small molecular tyrosine kinase inhibitors (TKIs)and circulating VEGF inhibitors, of which the most commonly used is the anti-VEGF monoclonal antibody bevacizumab.

Several small-molecule TKIs that target angiogenesis, including sunitinib, sorafenib, pazopanib, lenvatinib, and cabozantinib, and surufatinib, have been evaluated in advanced GINETs in phase II trials (table 5). Response rates have been low, although all studies report a high rate of disease stabilization and potentially encouraging PFS durations. As examples:

●Pazopanib – Alliance A021202, a randomized phase II trial including 171 patients with progressive advanced nonpancreatic NET, demonstrated improvement in PFS with pazopanib versus placebo. The majority of patients (66 percent) had primary tumors originating in the small intestine. Median PFS in patients receiving pazopanib (n = 97) was 11.6 months compared with 8.5 months in those receiving placebo (n = 74, HR 0.53, p = 0.0005). There was no improvement in OS in patients randomized to receive placebo; however, crossover from placebo to pazopanib at the time of disease progression confounds interpretation of the OS endpoint. This is the first randomized study suggesting that the VEGF pathway is a valid target for treatment of well-differentiated nonpancreatic NET.

●Surufatinib – The SANET-ep trial, a randomized, double-blind, placebo-controlled phase III trial conducted in China that included 198 patients with progressive advanced nonpancreatic NET, demonstrated improvement in PFS with surufatinib versus placebo [93]. Nearly one-half of the enrolled patients had gastrointestinal primary tumors, most commonly arising in the rectum; fewer than 10 percent had small intestine primary tumors. Investigator-assessed median PFS was significantly higher with surufatinib (9.2 versus 3.8 months, HR 0.33, 95% CI 0.22-0.50). OS data were not mature at the time of the interim analysis; survival follow-up is ongoing. Surufatinib is commercially available only in China.

●Other TKIs – The phase II TALENT trial demonstrated modest antitumor activity (16 percent objective response rate, median PFS 15.9 months) for lenvatinib in patients with GINET after progression on a somatostatin analog [94]. An ongoing  (A021602) is evaluating the efficacy of cabozantinib compared with placebo for patients with advanced NETs, including GINET.

●Bevacizumab – Activity for the anti-VEGF monoclonal antibody bevacizumab was suggested in a phase II trial, in which 44 patients with advanced or metastatic GINETs on a stable dose of octreotide were randomly assigned to 18 weeks of bevacizumab or pegylated interferon alfa (IFNa)-2b (table 5) [95]. At disease progression or at the completion of 18 weeks of therapy (whichever came first), all patients received bevacizumab plus interferon. During the first 18 weeks of therapy, four (18 percent) of the bevacizumab-treated patients experienced radiographic partial responses, while 17 (77 percent) had stable disease. Furthermore, after 18 weeks, 95 percent of patients treated with octreotide plus bevacizumab remained progression-free compared with only 68 percent of those receiving octreotide plus IFNa-2b.

These results led to a large randomized trial comparing both approaches in 427 patients with advanced (unresectable or metastatic) NETs of the gastrointestinal tract and lung with progressive disease or other indicators of poor prognosis (table 5) [96]. Radiologic responses were more frequent among patients treated with bevacizumab (12 versus 4 percent), but median PFS (the primary endpoint as determined by central review) was not significantly different (16.6 versus 15.4 months).

A role for bevacizumab in combination with octreotide in the treatment of GINETs is not yet established. Results with bevacizumab in combination with capecitabine are discussed below. (See 'Capecitabine plus bevacizumab' below.)

Interferon — The role of interferon alfa (IFNa) in the modern treatment of advanced GINETs is uncertain. While IFNa is an option for patients with advanced GINETs who have worsening symptoms while on treatment with somatostatin analogs or who are intolerant of somatostatin analog therapy, widespread acceptance of this agent for the treatment of advanced GINETs has been limited by the potential for severe side effects.

Consensus guidelines from the North American Neuroendocrine Tumor Society (NANETS) do not recommend use of IFNa unless no other options are available, due to the relatively lower level of evidence supporting its use and its side effect profile [97]. Updated National Comprehensive Cancer Network (NCCN) guidelines no longer endorse the use of IFNa for patients with progressive metastases for whom there are no other treatment options [13]. Guidelines from the European Neuroendocrine Tumor Society (ENETS) include IFNa as a second-line therapy in refractory carcinoid syndrome and as an agent to consider as an antiproliferative option in midgut NETs for which limited therapy options exist [98]. We agree with these guidelines.

IFNa has been used as a treatment for advanced NETs for several decades. Interferon (IFN) receptors are expressed in neuroendocrine neoplasms [99]. IFNs can exert antitumor effects via stimulation of T cells, induction of cell cycle arrest, and/or inhibition of angiogenesis [100,101]. The ability of IFNa to control the secretion of tumor products led to its initial use in patients with carcinoid syndrome [102].

In large, retrospective series, low-dose IFNa reduces symptoms of hormonal hypersecretion in 40 to 70 percent of patients with GINETs and induces tumor stabilization in 20 to 40 percent [16,23,103-114]. As with somatostatin analogs, tumor regression is less common, although it is reported in up to 20 percent of patients in some studies [16,102,104,106-109,113].

The usual dose is 3 to 5 MU three times weekly [115]. IFNa is somewhat myelosuppressive, and the dose is often titrated in individual patients to achieve a total leukocyte count of 3000/microL.

Use of IFNa is limited by severe side effects, including fatigue, depression, myelosuppression, flu-like symptoms, weight loss, and alteration of thyroid function [116]. For better tolerability, pegylated IFN (80 to 150 mcg per week subcutaneously) may be considered for symptomatic patients who are refractory to somatostatin analogs and other forms of therapy (eg, everolimus) and who do not tolerate conventional IFNa, although the data in patients with NETs are quite limited [95,117] and pegylated IFN is not approved for this indication.

Interferon alfa plus a somatostatin analog — Relatively few prospective studies have evaluated IFN in combination with somatostatin analogs compared with somatostatin analogs alone, and the results are conflicting:

●In a prospective trial of 68 patients with liver metastases who were randomly assigned to initial therapy with octreotide (100 mcg twice daily, increased to 200 mcg three times daily for persistent carcinoid symptoms) alone or with IFNa, both treatments were equally effective at reducing urinary 5-hydroxyindoleacetic acid (5-HIAA) levels [118]. However, patients receiving combined therapy had a significantly reduced risk of tumor progression when compared with patients receiving octreotide alone, suggesting that the addition of IFN had a significant antitumor effect. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Urinary excretion of 5-HIAA'.)

●On the other hand, two other randomized trials have not demonstrated improvements in tumor response or time to radiologic disease progression with combined therapy as a first-line treatment for progressive GINETs:

•The comparable efficacy of lanreotide, IFNa, or combined therapy was evaluated in a prospective randomized trial involving 80 therapy-naive patients with documented progressive metastatic GINETs [23]. Objective partial response rates were comparably low in all three groups (4, 4, and 7 percent for lanreotide, IFN, and combined therapy, respectively), and the number of patients who achieved disease stabilization was not substantially higher with combined therapy (28, 26, and 18 percent for lanreotide, IFN, and the combination, respectively).

•Similar findings were noted in a second trial in which 109 patients with progressive metastatic GINETs were randomly assigned to octreotide with or without IFNa [119]. At 3, 6, and 12 months, rates of objective partial response were low (3, 2, and 6 percent, respectively) and similar with octreotide alone and plus IFNa. There were also no significant differences between the two groups in the rates of stable disease at the three time points, time to treatment failure, or long-term survival.

These studies, however, were likely underpowered to detect significant differences between the arms. Nevertheless, we suggest initiating therapy for symptomatic patients with a somatostatin analog alone rather than a combination of a somatostatin analog and IFNa. The combination of octreotide plus either IFNa or bevacizumab was evaluated in a large randomized study performed by the Southwest Oncology Group (SWOG) and the North American Intergroup (SWOG S0518). (See 'Treatments targeting tumor angiogenesis' above.)

Cytotoxic chemotherapy — The benefit of cytotoxic chemotherapy for advanced GINETs continues to be debated. In general, we do not consider that any cytotoxic chemotherapy regimen represents a standard approach for treatment of advanced low-grade well-differentiated GINETs. This position is consistent with published guidelines from the ENETS, NANETS, and European Society for Medical Oncology (ESMO) [11,12,73]. The use of chemotherapy for high-grade well-differentiated NETs is addressed in detail elsewhere. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)

However, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest that anticancer agents, such as capecitabine, dacarbazine, fluorouracil (FU), and temozolomide, can be considered in patients with progressive metastases from a GINET for whom there are no other treatment options, although they emphasize the rarity of objective radiologic responses and the lack of a demonstration of a PFS or OS benefit in robust clinical trials [13]. Regimens that have demonstrated evidence of activity in preliminary reports of phase II studies include oxaliplatin plus short-term infusional FU plus leucovorin (FOLFOX), and temozolomide plus capecitabine; however, in our view, confirmatory studies are needed to better define the activity of these regimens and to assess whether response may differ depending on primary site.

Among patients with well-differentiated GINETs, single-agent therapy with fluoropyrimidines, streptozocin, dacarbazine, and doxorubicin is associated with only modest response rates [120-122]. As an example, single agent capecitabine (1000 mg/m² twice daily for 14 days every three weeks) was studied in a small phase II trial of 19 patients with metastatic NETs (12 arising in the gut, one in ovary, and six unknown) [121]. Although there were no radiologic partial or complete responses, 13 (68 percent) achieved stable disease radiographically, which lasted >12 months in four patients; there were two patients with a >50 percent decrease in the tumor marker chromogranin A from baseline. Median PFS was 9.9 months, but median OS was 36.5 months. Other chemotherapeutic agents, such as the taxanes, topotecan, and gemcitabine, are relatively inactive as single agents [123-126].

Most studies in advanced GINETs have focused on streptozocin-based regimens (table 6):

●An early Eastern Cooperative Oncology Group (ECOG) trial randomly assigned 118 patients to streptozocin plus either FU or cyclophosphamide [127]. Response rates (objective radiographic tumor regression or decreased urinary 5-hydroxyindoleacetic acid [5-HIAA]) were similar (33 and 26 percent FU and cyclophosphamide, respectively), as was survival. Toxicity was prominent in both regimens.

●A subsequent ECOG trial increased the dosing interval between cycles of streptozocin/FU, comparing this regimen with doxorubicin alone [128]. Although this streptozocin/FU regimen was somewhat better tolerated than the one used in the earlier study, the response rate was similar to doxorubicin alone (22 versus 21 percent), as was survival. More recently, streptozocin/FU was compared with doxorubicin/FU in a randomized trial of 249 patients with advanced NETs [129]. The radiographic response rate was similar with the two regimens (16 percent each), although there was a slight, but statistically significant, median survival benefit associated with streptozocin/FU (24 versus 16 months). However, PFS was short (4.5 months), and over one-third of the patients receiving streptozocin developed mild to moderate renal toxicity.

The relatively modest response rates of these regimens, together with the reported toxicity, have led many to question their utility in the routine treatment of patients with advanced GINETs [11]. As such, they are rarely utilized in this setting.

Dacarbazine and temozolomide — In a Southwest Oncology Group (SWOG) study of 56 patients with metastatic GINETs receiving single agent dacarbazine, the overall tumor response rate was 16 percent [122]. Toxicity was a concern; 88 percent of patients reported nausea and/or vomiting. In another report of second-line dacarbazine following treatment with streptozocin/FU or doxorubicin/FU, the response rate was only 8 percent [129].

Temozolomide is an oral analog of dacarbazine that is generally better tolerated. Although temozolomide is active in pancreatic NETs, its single-agent activity appears more limited in GINETs. In a retrospective series that included 44 patients with GINETs, only one (2 percent) had an objective tumor response [130]. The majority of these patients had primary GINETs. By contrast, 18 of 53 (34 percent) patients with pancreatic NETs had an objective response to treatment with temozolomide.

Several reports have suggested that temozolomide may be active in some patients with bronchial or thymic NETs [131,132]. However, a phase II study of temozolomide plus bevacizumab reported no objective responses among 19 patients with advanced NETs, four of whom had bronchial NETs [133]. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Cytotoxic chemotherapy'.)

Small studies have suggested activity for the combination of temozolomide and capecitabine in some GINETs:

●In one retrospective study of 18 patients with metastatic, well-differentiated NETs, there was one complete radiographic response and one partial response among four patients with GINET. Notably, one of the responses was in a patient with a duodenal NET [134].

●In a report of preliminary results from a phase II trial of capecitabine plus temozolomide presented at the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, 4 of 12 patients with metastatic NETs originating in various sites were reported as having experienced partial responses [135]. However, the primary sites of these tumors were not reported, and the trial had not yet completed full accrual.

Larger, prospective studies are clearly needed to better assess the potential activity of temozolomide and capecitabine in GINETs and to assess whether activity may differ depending on primary tumor site.

Oxaliplatin-based regimens — Antitumor activity has been suggested for oxaliplatin-based combinations, although the total number of treated patients has been small. One combined analysis included data from two phase II trials totaling 76 patients with well-differentiated pancreatic NET (n = 28) or nonpancreatic NET (carcinoid cohort, n = 42), or poorly differentiated neuroendocrine carcinoma (n = 6) who were treated with oxaliplatin plus bevacizumab and either capecitabine (n = 40) or short-term infusional FU plus leucovorin (n = 36) [136]. Overall, FOLFOX plus bevacizumab resulted in an objective response in 3 of 22 patients in the carcinoid cohort (14 percent, median PFS 19.3 months). Oxaliplatin plus capecitabine and bevacizumab was associated with an objective response in 1 of 20 patients (5 percent) and a median PFS of 19.1 months in the carcinoid cohort.

While these regimens may have activity in GINETs, the data are too limited to draw any conclusions as to the relative contributions of a fluoropyrimidine, oxaliplatin, or bevacizumab.

Capecitabine plus bevacizumab — Activity for capecitabine in combination with bevacizumab was suggested in a multicenter phase II trial, in which 49 patients with progressive, metastatic GINETs (82 percent originating in small bowel, the remainder in the cecum, rectum, and stomach) received bevacizumab (7.5 mg/kg every three weeks) with capecitabine (1000 mg/m² twice daily days 1 to 14 every 21 days) [137]. The median treatment duration was 13.8 months. At 24 months maximum follow-up, the tumor control rate was 88 percent (partial response in 18 percent, stable disease in 70 percent), and the median PFS was 23.4 months. However, grade 3 or 4 treatment-related toxicity was experienced by 84 percent of patients, mainly digestive; 31 percent developed grade 3 or 4 hypertension.

Immunotherapy — Immune checkpoint inhibitors appear to have little activity as monotherapy for well-differentiated NET, and they are not indicated, unless in the context of a clinical trial. Early data suggest promise for combinations of immunotherapy with other immune modulating agents; however, future studies are needed to better define the role of such treatment strategies for well-differentiated gastrointestinal NET.

The role of immunotherapy with immune checkpoint inhibitors is just beginning to be studied in patients with well-differentiated NETs. Limited data suggest that anti-programmed cell death 1 (PD-1) antibodies have minimal activity as single-agent therapy:

●The efficacy of the anti-PD-1 antibody spartalizumab (PDR001) was evaluated in a multicenter phase II trial that enrolled 116 patients, including 33 with pancreatic NET, 32 with GINET, 30 with thoracic NET, and 21 with poorly differentiated gastroenteropancreatic neuroendocrine carcinoma (NEC) [138]. In a preliminary report presented at the 2018 ESMO meeting, the overall radiographic response rate was 7.4 percent among all well-differentiated NETs (pooled) but it was 0 percent in patients with GINET. However, the stable disease rate in patients with well-differentiated NET was 55.8 percent, and it was 59.4 percent in patients with GINET [139].

●Activity of pembrolizumab in patients with programmed cell death 1 ligand (PD-L1)-positive advanced NET was evaluated in the KEYNOTE-028 study, which enrolled 16 patients with pancreatic NET and 25 patients with a nonpancreatic NET of GI origin (n = 7), lung (n = 9), or other site (n = 9). Overall, three patients with nonpancreatic NETs (12 percent, 95% CI 3-31 percent) had objective responses; the stable disease rate in these patients was 60 percent (n = 15) [140]. Only one of the pancreatic NETs responded. (See "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Immunotherapy'.)

●The activity of pembrolizumab was also evaluated in the phase II KEYNOTE-158 trial, which included a cohort of 107 patients with well- and moderately differentiated NET whose disease had progressed or who were intolerant of one or more lines of standard therapy [141]. PD-L1 expression was present in 16 percent of patients. Primary sites of disease included the pancreas (n = 40), small intestine (n = 25), other gastrointestinal sites (n = 18), lung (n = 14), and other organs (n = 10). The overall response rate was low and included four partial responses (3.7 percent), and the median progression-free survival was 4.1 months. Partial responses were noted in three patients with pancreatic NET and in one with an unknown primary; all responding tumors were PD-L1 negative. Two of the responding patients had a sustained response approaching two years.

Trials are ongoing to evaluate checkpoint inhibitors in combination with other immunomodulatory agents, including VEGF pathway inhibitors [142,143]. As an example, a phase II trial evaluated the combination of the anti-PD-1 antibody atezolizumab, plus bevacizumab in patients with well-differentiated G1 to G2 pancreatic (and extrapancreatic (ep) NET [144]. Objective response was observed in 4 of 20 patients with pNETs (20 percent) and 3 of 20 patients with epNETs (15 percent). The PFS was 14.9 (95% CI 4.4-32.0) months and 14.2 (95% CI 10.2-19.6) months in these two cohorts, respectively. Eligible patients should be encouraged to enroll in these trials.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)

SUMMARY AND RECOMMENDATIONS

●Initial therapy

•Somatostatin analogs are highly effective in controlling the symptoms related to hormone secretion associated with advanced gastrointestinal neuroendocrine tumors (GINETs). In addition, somatostatin analogs have also been shown to control tumor growth. (See 'Somatostatin analogs' above.)

•We suggest initiating therapy with a somatostatin analog for patients who are not already on a somatostatin receptor (SSTR) analog for carcinoid syndrome and who have a high tumor burden (Grade 2B). (See "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

•For patients with metastatic disease that appears completely resectable in the absence of extrahepatic metastases, diffuse bilobar involvement, or compromised liver function, we suggest resection rather than medical therapy (Grade 2B). (See 'General approach to the patient' above and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

•For patients with asymptomatic, advanced, unresectable GINETs and small-volume disease, we suggest observation alone rather than early administration of a somatostatin analog (Grade 2B). (See 'Somatostatin analogs' above.)

●Progressive disease

•For patients with clinically meaningful tumor progression who are not already on a somatostatin analog, we suggest initiating treatment with a long-acting somatostatin analog (Grade 2B). (See 'Somatostatin analogs' above.)

•We suggest hepatic arterial embolization, chemoembolization, or radioembolization rather than medical therapy alone as a palliative technique for symptomatic patients with hepatic-predominant unresectable disease (Grade 2C). (See 'General approach to the patient' above and "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

•For most patients with GINETs and progressive disease despite a long-acting somatostatin analog who are not eligible for liver-directed therapy, and who do not have underlying renal or hematologic insufficiency, we suggest peptide receptor radiotherapy (PRRT) using a radiolabeled somatostatin receptor analog rather than molecularly targeted therapy (Grade 2C). Although there are no comparator trials, we base this decision on the higher response rate, favorable toxicity profile, and ease of treatment of PRRT. (See 'Radiolabeled somatostatin analogs' above.)

•For patients with progressive GINETs who are not eligible for PRRT, everolimus is an option. (See 'Everolimus' above.)

Small molecule tyrosine kinase inhibitors targeting angiogenesis have demonstrated activity in clinical trials, but are not currently approved for GINETs and remain investigational. (See 'Treatments targeting tumor angiogenesis' above.)

Decision making between these options should be individualized and based on treatment efficacy and the adverse effect profile.

•Dose escalation is an option at the time of initial disease progression on a long-acting somatostatin analog for patients with indolent disease, but it is not our preferred option. The benefits of escalating the dose and/or frequency of a somatostatin analog for disease control are not well established, and efficacy is better established for other options, such as PRRT or molecularly targeted therapy. (See 'Dose-escalated therapy' above.)

•The benefit of cytotoxic chemotherapy for advanced, low-grade GINETs continues to be debated. In general, we do not consider that any cytotoxic chemotherapy regimen represents a standard approach for treatment of advanced low-grade GINETs. This position is consistent with published guidelines from several expert groups. (See 'Cytotoxic chemotherapy' above.)

Specific recommendations for cytotoxic chemotherapy in patients with high-grade well-differentiated GINETs are provided separately. (See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'High-grade, well-differentiated tumors (NET G3)'.)