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Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion

Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion
Literature review current through: Jan 2024.
This topic last updated: Nov 23, 2022.

INTRODUCTION — Neuroendocrine cells are distributed widely throughout the body, and neuroendocrine neoplasms of these dispersed cells can arise at many sites. The classification and nomenclature of neuroendocrine neoplasms arising within the digestive system has evolved over the past two decades (see "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'):

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) [1]. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

Systemic treatment approaches to control tumor growth and symptoms related to hormone hypersecretion for patients with advanced or metastatic well-differentiated NET arising in the pancreas will be reviewed here. Systemic therapy options for patients with advanced or metastatic well-differentiated gastrointestinal tract NET (carcinoid) are discussed elsewhere, as are the clinical presentation, imaging, biochemical monitoring, pathology, and classification of gastroenteropancreatic NET; localization and treatment of pancreatic NET; evaluation and management of NET of unknown primary site; management of symptoms of functioning pancreatic NET; local management options to control tumor growth and symptoms of hormone excess for well-differentiated metastatic gastroenteropancreatic NET; and the evaluation and management of patients with high-grade gastroenteropancreatic neuroendocrine carcinoma.

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

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

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

(See "Insulinoma".)

(See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

(See "Glucagonoma and the glucagonoma syndrome".)

(See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)

(See "VIPoma: Clinical manifestations, diagnosis, and management".)

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

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

CLASSIFICATION AND BIOLOGIC BEHAVIOR — The World Health Organization (WHO) classifies all gastroenteropancreatic NENs 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 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'.)

As a group, well-differentiated gastroenteropancreatic NETs are generally indolent malignancies with a prolonged natural history. However, clinical behavior is heterogeneous, as evidenced by the following observations:

NETs arising in the tubular gastrointestinal tract and pancreas may have similar characteristics on routine histologic evaluation, but they have a different pathogenesis and biology [2]. Pancreatic NETs in general pursue a somewhat more aggressive course than do other gastrointestinal tract NETs [3], although, conversely, most systemic agents have been associated with higher response rates among patients with pancreatic NETs than in those with gastrointestinal NET. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

G2 gastroenteropancreatic NETs have a slightly worse prognosis than do G1 NETs [4]. Although they are classified and 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.

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".)

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

GENERAL APPROACH TO THE PATIENT — The majority of patients with advanced pancreatic NETs have liver metastases [5]. Most tumors (between 50 and 75 percent) are nonfunctioning and are not associated with a hormonal syndrome. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms", section on 'Clinical presentation'.)

Symptoms of hormone secretion – Patients with symptoms of hormone hypersecretion from a well-differentiated pancreatic NET should be managed with somatostatin analogs and other agents as appropriate to the specific syndrome. In general, initial therapy for insulinomas consists of carbohydrates and diazoxide, which directly inhibits the release of insulin from insulinoma cells. Careful monitoring is necessary in insulinoma patients when initiating therapy with somatostatin analogs, which may paradoxically worsen hypoglycemia due to decreased secretion of counterregulatory hormones. Everolimus can also be highly effective in improving glycemic control in patients with insulinoma. For patients with gastrinoma, high doses of oral proton pump inhibitors are the treatment of choice. Somatostatin analogs may be helpful for refractory cases. (See "Insulinoma" and "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

Potentially resectable disease – For patients who have potentially resectable metastatic disease, resection may provide prolonged control of symptoms and tumor growth. Although the majority of patients recur, even if resection is complete, 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 disease – Somatostatin analogs and the molecularly targeted agents everolimus and sunitinib have been shown to improve progression-free survival (PFS) duration relative to supportive care alone in patients with metastases from a nonfunctioning pancreatic NET. For patients with low-volume disease who are asymptomatic, we suggest waiting until disease progression or development of symptoms related to tumor bulk before beginning systemic therapy. For most patients with a metastatic pancreatic NET who are felt to require therapy, we suggest somatostatin analogs rather than a molecularly targeted agent as initial therapy because of the more favorable side effect profile. (See 'Benefits' below.)

Therapy at progression – If an initial approach of observation is chosen, initiation of a somatostatin analog should be considered at the time of progression.

For patients with radiologic disease progression despite use of a somatostatin analog at standard doses, therapeutic options for those with hepatic-predominant disease include noncurative surgical debulking and 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 'Surgical resection' 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 options include everolimus, sunitinib, cytotoxic chemotherapy, peptide receptor radioligand therapy (PRRT; eg, lutetium-177 [177Lu] dotatate, for somatostatin receptor-expressing tumors), or dose-escalated somatostatin analog therapy. Studies evaluating the optimal sequencing of therapy have not been conducted. Furthermore, interpretation of an attempted network meta-analysis to rank the relative efficacy and toxicity of a variety of systemic therapies for NETs is 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 (such as interferon) [6,7]. (See 'Molecularly targeted therapy' below and 'Cytotoxic chemotherapy' below and 'Peptide receptor radioligand therapy' below.)

A single randomized trial directly comparing PRRT with 177Lu dotatate versus sunitinib (NCT02230176) for progressive disease in 84 patients with no prior cytotoxic therapy, previous PRRT or TKI inhibitor therapy concluded that median PFS was significantly better with 177Lu dotatate [8]. This trial is discussed in more detail below. (See 'Efficacy versus other treatments' below.)

For most patients, we prefer participation in a clinical trial. Otherwise, there is no clear consensus on the appropriate sequencing of available therapies. If trial participation is not available or desired, the following represents our approach to treatment:

For patients who are highly symptomatic from tumor bulk or who have rapidly enlarging metastases, we suggest chemotherapy rather than molecularly targeted therapy or PRRT. For most patients, we suggest the combination of capecitabine and temozolomide (CAPTEM) rather than temozolomide alone. In the absence of comparative trials, the choice of CAPTEM over a streptozocin-containing regimen should be individualized, taking into account the convenience of oral rather than intravenous treatment, performance status, and the anticipated side effect profile of both combinations. (See 'Dacarbazine and temozolomide-based regimens' below.)

For patients with progressing somatostatin receptor-expressing tumors who are not highly symptomatic from tumor bulk and who do not have rapidly enlarging metastases, we suggest 177Lu dotatate rather than molecularly targeted therapy or chemotherapy. (See 'Lutetium-177 dotatate' below.)

The molecularly targeted agents everolimus and sunitinib improve PFS duration relative to supportive care alone in patients with metastases from a nonfunctioning pancreatic NET. These drugs represent an appropriate alternative to 177Lu dotatate for patients whose disease has progressed while receiving a somatostatin analog who do not have highly symptomatic disease or rapidly enlarging metastases, especially if not all tumors express somatostatin receptors. The choice of agent is often based on the expected side effect profile, which differs between these two agents. (See 'Sunitinib' below and 'Everolimus' below.)

Another option for patients with indolent disease after an initial response or a prolonged duration of stability with standard-dose somatostatin analog therapy is dose escalation of the somatostatin analog. (See 'Control of tumor growth' below.)

The benefit of continuing therapy with a standard-dose long-acting somatostatin analog in patients whose disease has progressed while receiving such therapy, and who are initiating other medical forms of therapy, is not well defined. For patients with nonfunctional tumors who experience unequivocal radiographic progression on a somatostatin analog and for whom a switch in therapy is planned, we would discontinue the somatostatin analog. For patients with functional tumors, we continue the somatostatin analog to minimize the effects of hormone secretion.

The following sections will discuss systemic treatment options to control symptoms related to tumor bulk, or hormone hypersecretion and tumor growth for well-differentiated pancreatic NETs. Local treatment options for gastroenteropancreatic NETs, including resection and liver-directed therapy (such as embolization), are discussed in detail elsewhere, as are systemic therapy for well-differentiated gastrointestinal tract NETs and treatment approaches for high-grade gastroenteropancreatic neuroendocrine carcinomas. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion" and "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth" and "High-grade gastroenteropancreatic neuroendocrine neoplasms".)

SOMATOSTATIN ANALOGS — 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 [9]. 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. Options include SSTR-PET CT or SSTR-PET MRI, with appropriate SSTR-PET tracers including gallium Ga-68 DOTATATE (Ga-68 DOTATATE), gallium Ga-68 DOTATOC (Ga-68 DOTATOC), or copper Cu-64 DOTATATE (Cu-64 DOTATATE). Octreotide SPECT/CT with Indium-111 [111-In] pentetreotide [OctreoScan] is an option if SSTR-PET CT is not available. The higher sensitivity of SSTR-PET makes this a preferred imaging modality, particularly in certain clinical situations such as 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'.)

Benefits

Patients with symptoms from hormone secretion — Patients with metastases from functioning pancreatic NETs (which account for 10 to 30 percent of all pancreatic NETs [10]) often become symptomatic from hormone hypersecretion rather than from tumor bulk. For those who have octreotide-avid disease, symptoms of hormonal excess can often be well controlled with somatostatin analogs.

In series that include patients with only pancreatic NETs or combined series of patients with functioning gastroenteropancreatic NETs (gastrointestinal NETs and pancreatic NETs), somatostatin analogs provide symptom control in over 60 percent [11-19]. However, symptomatic benefit is dose-related, and also differs according to the type of functioning NET:

Somatostatin analogs are highly effective in controlling the symptoms associated with VIPomas (watery diarrhea) and glucagonomas (especially improvement in the characteristic rash, necrolytic migratory erythema) [20,21]. (See "VIPoma: Clinical manifestations, diagnosis, and management" and "Glucagonoma and the glucagonoma syndrome".)

Efficacy has also been shown for somatostatinomas [22,23], although the effects are may be less dramatic than with VIPomas and glucagonomas. (See "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Somatostatin analogue'.)

Insulinomas and gastrinomas represent the most common types of functioning pancreatic NET, but the role of somatostatin analogs in controlling hormone-related symptoms is somewhat limited:

Efficacy of somatostatin analogs for insulinomas with hypoglycemia is unpredictable [24-29], and somatostatin analogs should be used with caution in this setting. Only approximately one-half of these tumors express SSTRs and derive benefit from such therapy. Furthermore, somatostatin analogs may paradoxically result in transient worsening of hypoglycemia, presumably due to simultaneous inhibition of glucagon secretion. In general, initial therapy for insulinomas often consists of dietary modification. Treatment with everolimus may improve glycemic control in patients with insulinoma. Treatment with diazoxide, which directly inhibits the release of insulin from insulinoma cells, is another option. (See "Insulinoma", section on 'Medical therapy to control symptomatic hypoglycemia'.)

The role of somatostatin analogs in patients with hormone-related symptoms from gastrinoma is also limited. High doses of oral proton pump inhibitors are the treatment of choice, as they are able to effectively control the hypergastrinemia-related gastric acid overproduction. Somatostatin analogs may be helpful in refractory cases. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

Currently available somatostatin analogs include octreotide and lanreotide. Highly symptomatic patients may be initiated on short-acting octreotide with rapid transition to a long-acting formulation and subsequent titration of dose to optimize symptom control while the LAR formulation is starting to take effect. However, a depot preparation (Sandostatin LAR) has largely eliminated the need for daily octreotide injections and is now considered a standard approach for symptomatic treatment of advanced NETs [30,31]. Many clinicians initiate therapy with the depot preparation for most patients and do not give an initial dose of short-acting octreotide. Sandostatin LAR is typically initiated at a dose of 20 mg IM monthly with gradual dose escalation as needed for optimal symptom control [32]. Patients may use additional short-acting octreotide for breakthrough symptoms while doses are being titrated; therapeutic levels of octreotide are not reached until 10 to 14 days after the initiation of the LAR injection.

Lanreotide, another long-acting somatostatin analog, can be administered once monthly using a deep subcutaneous injection and appears to have similar efficacy to octreotide [15-17].

Control of tumor growth — In addition to controlling symptoms associated with hormone hypersecretion, somatostatin analogs have also been shown to control tumor growth. Given the variable and sometimes indolent disease course of some pancreatic NETs, the optimal time to initiate treatment with a somatostatin analog in asymptomatic patients remains uncertain. We suggest initiation of a somatostatin analog in patients with unresectable, asymptomatic, well-differentiated pancreatic NET and a high tumor burden, an approach that is consistent with guidelines from the European Neuroendocrine Tumor Society (ENETS) [31], North American Neuroendocrine Society (NANETS) [33], and the National Comprehensive Cancer Network (NCCN) [34]. For patients with asymptomatic, advanced, unresectable pancreatic NET and small-volume disease, we suggest initial 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.

Past studies have indicated that few patients with advanced gastroenteropancreatic NET (<10 percent) have objective tumor shrinkage with somatostatin analogs [31,35-38], even when limited to subgroups with progressive disease at the time of treatment initiation [12-14,35,39-41]. However, more reports have demonstrated that, in addition to an improvement in symptoms, treatment with somatostatin analogs may be associated with disease stabilization and significant prolongation of progression-free survival (PFS) [42-44]. Whether somatostatin analogs also increase overall survival is not yet known, although a correlation between PFS and overall survival in patients with advanced NET treated with single-agent somatostatin analog therapy has been shown [45].

Median duration of PFS and overall survival depends 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 NETs based upon these and other factors [46].

The PROMID study, which was the first randomized study demonstrating an antiproliferative effect of somatostatin analogs in NET, included patients with metastatic small intestinal NET who were treated with octreotide LAR versus placebo [42]. Because the study was limited to patients with small intestinal NET, applicability of these results to patients with pancreatic NET was uncertain. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth".)

However, support for the antiproliferative effect of somatostatin analogs in pancreatic NET was provided by the phase III CLARINET trial, which compared lanreotide versus placebo in 204 patients with advanced well- or moderately differentiated, nonfunctioning gastroenteropancreatic NET, including both gastrointestinal NET and pancreatic NET (45 percent of all enrollees) [43]. Patients were randomly assigned to receive either 120 mg lanreotide Autogel (n = 101) or placebo (n = 103) every four weeks for 96 weeks or until progressive disease (PD) or death. The trial’s primary end point was PFS as determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria (table 2). All patients had avid disease on somatostatin-receptor scintigraphy. Most patients (96 percent) had no tumor progression by RECIST criteria in the three to six months before randomization; approximately one-half had pancreatic primary sites. 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 [HR] for progression or death 0.47; 95% CI 0.30-0.73). Estimated rates of 24-month PFS were 65 versus 33 percent. There were no significant differences in quality of life or overall survival. The most common treatment-related adverse effect was diarrhea (26 versus 9 percent in the lanreotide and placebo groups, respectively). Based upon 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 NET.

The mechanisms by which somatostatin analogs control tumor growth may result from direct antiproliferative effects, including cell cycle inhibition and pro-apoptotic effects, and indirect antiproliferative effects, including inhibition of tumor angiogenesis and the release of trophic growth hormones [47]. Octreotide LAR and lanreotide are first-generation agents that primarily target SSTR-2 and SSTR-5; benefit for the addition of the second-generation somatostatin analog pasireotide, which targets multiple SSTR subtypes, with greater binding affinity for SSTR-1, SSTR-3, and SSTR-5, and lower affinity for SSTR-2, could not be shown in a randomized phase II trial of everolimus with or without pasireotide [48].

Dose-escalated therapy — Dose escalation 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, and clinical practice is variable. At least some data suggest the potential for prolonged periods of stable disease when the dose intensity is increased (eg, by using higher than standard doses or reducing the dosing interval) after an initial period of long-acting somatostatin analog use [49,50]. However, whether this reflects indolent biology rather than an intrinsic dose-response relationship is not clear. 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 'Peptide receptor radioligand therapy' below.)

Choice of lanreotide versus octreotide LAR — The choice of octreotide LAR versus lanreotide should be based on patient preference. Although both drugs are equally acceptable and efficacious treatments for well-differentiated NETs, they differ substantially in cost [51]. 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 SSA concluded that there was minimal pain with either drug and no significant pain score difference between the two [52]. 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.

Side effects — Somatostatin analogs are usually well tolerated, and side effects are generally mild [53,54]. Approximately one-third of patients may have mild nausea, abdominal discomfort, bloating, loose stools, and fat malabsorption during the first weeks of therapy, after which time, symptoms tend to subside. Use of pancreatic enzyme supplements can ameliorate symptoms associated with pancreatic insufficiency. Mild glucose intolerance may occur due to transient inhibition of insulin secretion. Somatostatin analogs reduce postprandial gallbladder contractility and delay gallbladder emptying; up to 25 percent of patients develop asymptomatic gallstones or sludge within the first 18 months of therapy [54].

CYTOTOXIC CHEMOTHERAPY — Well-differentiated pancreatic NETs are clearly responsive to cytotoxic chemotherapy (table 3). For patients who are highly symptomatic from tumor bulk or who have rapidly enlarging metastases, we suggest chemotherapy rather than molecularly targeted therapy or a somatostatin analog because of the higher objective response rate. For most patients, we suggest the combination of capecitabine and temozolomide (CAPTEM) rather than temozolomide alone. In the absence of comparative trials, the choice of CAPTEM over a streptozocin-containing regimen should be individualized, taking into account the convenience of oral rather than intravenous treatment, performance status, and the anticipated side effect profile of both combinations.

Dacarbazine and temozolomide-based regimens — Dacarbazine is an alkylating agent (like streptozocin), with activity against pancreatic NET. In an Eastern Cooperative Oncology Group (ECOG) phase II trial of dacarbazine in 42 patients with advanced pancreatic islet cell carcinomas, the objective response rate was 33 percent [55]. As with streptozocin, the toxicity of dacarbazine-based regimens has limited their widespread use.

Temozolomide is a less toxic orally active analog of dacarbazine with activity in pancreatic NET [56]:

CAPTEM – Accumulating data support promising activity with temozolomide plus capecitabine (CAPTEM) in patients with pancreatic NET (table 3):

In a retrospective series of 143 patients who were treated with CAPTEM, the response rate was 54 percent [57].

Benefit of CAPTEM relative to temozolomide alone was shown in the phase II ECOG-American College of Radiology Imaging Network (ACRIN) study 2211, which randomly assigned 144 patients with unresectable or metastatic pancreatic NET (low-grade [n = 76] or intermediate-grade [n = 57]) and progressive disease within the past 12 months to temozolomide alone (200 mg/m2 daily on days 1 through 5 every 28 days) or capecitabine (750 mg/m2 twice daily on days 1 through 14) plus temozolomide (200 mg/m2 orally daily on days 10 through 14), also given in 28-day cycles [58]. On-protocol treatment was prespecified as 13 cycles, after which time patients could receive any treatment at investigator discretion.

At the first interim analysis, conducted in 2018, median progression-free survival (PFS), the primary endpoint, was significantly better with combined therapy(median follow-up 29 months, 22.7 versus 14.4 months, hazard ratio 0.58, 95% CI 0.36-0.93). In the final analysis, which was conducted in May 2021, there was a trend toward better median overall survival (58.7 versus 53.8 months, HR 0.82, 95% CI 0.51-1.33) with combined therapy, which was also associated with a higher objective response rates (40 versus 34 percent, p = 0.42), higher overall disease control rate (objective response plus stable disease; 84 versus 74 percent), and longer duration of response (16.6 versus 12.6 months). Of note, there was an imbalance in tumor grade between the treatment arms, with less grade 2 disease in the CAPTEM arm. Treatment-related grade 3 or 4 adverse effects were twice as common with combined therapy (44 versus 22 percent); the most common were neutropenia (13 versus 4 percent), nausea and vomiting (8 versus 0 percent), diarrhea (8 versus 0 percent), and fatigue (8 versus 1 percent).

Other temozolomide combinations – In prospective studies, temozolomide has been combined with other agents, including thalidomide, bevacizumab, or everolimus, with overall response rates of 24 to 45 percent (table 3) [59-61]. In these studies, temozolomide has generally been administered using a dose-intense regimen of 150 mg/m2 daily for seven days on an every-other-week schedule. Prophylaxis for Pneumocystis jirovecii pneumonia is recommended in light of the lymphopenia associated with long-term use of temozolomide according to this schedule. The relative contribution of temozolomide and the agent used in combination with it to the observed antitumor activity is unclear.

Role of MGMT expression — As has been noted in patients with glioblastoma, there appears to be a correlation between expression of methylguanine DNA methyltransferase (MGMT) and temozolomide responsiveness in advanced NET. MGMT is an enzyme that is responsible for DNA repair induced by alkylating agent chemotherapy. Cells with a lower amount of MGMT may be more sensitive to alkylating agents such as temozolomide. (See "Initial treatment and prognosis of IDH-wildtype glioblastoma in adults", section on 'MGMT methylation status'.)

In one study, of 21 patients treated with temozolomide-based regimens, none of the 16 with intact MGMT expression (including all 13 carcinoid tumors) responded to treatment, while four of the five patients whose tumors lacked MGMT expression (all with pancreatic NET) had a radiologic response [62].

A second larger retrospective series also reported an association between MGMT status and response to alkylating agents (including temozolomide, dacarbazine, and streptozotocin-based regimens) in patients with NET [63]. In this study, the association between MGMT status and response to alkylating agents was observed in patients with either gastrointestinal or pancreatic NET.

Additional data are now available from the phase II ECOG/ACRIN study 2211 [58], described above. (See 'Dacarbazine and temozolomide-based regimens' above.)

While the study was not designed to test MGMT as a predictive marker for response to temozolomide, MGMT deficiency (as detected by loss of immunohistochemical [IHC] protein expression or promoter methylation) was associated with a greater odds of response to treatment. As an example, the response rate to treatment with CAPTEM or temozolomide was 52 percent (33/63) in patients whose tumors had low MGMT expression, compared to 15 percent in patients whose tumors had a high MGMT expression (5/34). Similarly, among 50 patients treated with CAPTEM, the response rate was 57 percent in patients whose tumors had low MGMT expression (21/37), compared with 8 percent in those with high MGMT expression (1/13).

Of note, only seven of 57 cases tested had MGMT promoter methylation, while low expression by IHC was seen in 63 of 97 cases tested (including all cases with promoter methylation), suggesting that mechanisms other than promoter methylation are involved in MGMT downregulation in NETs. Interestingly, at least some data suggest that fluoropyrimidines such as capecitabine might synergize with temozolomide, perhaps by downregulating O6-methylguanine-DNA methyltransferase (MGMT) gene expression [64].

Confirmatory testing is needed to assess whether MGMT is a predictive biomarker of response to temozolomide-based therapy. In addition, variability in the techniques and criteria used to assess MGMT status preclude its current use as a routine clinical test to select patients for treatment with temozolomide, with or without capecitabine. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Dacarbazine and temozolomide'.)

Streptozocin combinations — Streptozocin-based combination therapy has been a historical treatment standard for patients with advanced pancreatic NET (table 3). Antitumor efficacy can be illustrated by the following data:

In an early randomized trial, streptozocin plus doxorubicin had a combined biochemical and radiologic response rate of 69 percent and a median survival of 2.2 years [65].

A retrospective analysis of 84 patients with either locally advanced or metastatic pancreatic NET treated with streptozocin, fluorouracil (FU), and doxorubicin and using current standard response criteria reported a 39 percent objective radiographic response rate and a median survival duration of 37 months [66].

Another retrospective analysis of 96 patients with pancreatic NETs treated with streptozocin plus FU reported an objective response rate of 43 percent, and an additional 41 percent had stable disease as the best response [67].

While streptozocin-based regimens are clearly active in patients with advanced pancreatic NETs, widespread use has been limited by a relatively cumbersome administration schedule and by concerns about toxicity, which can include myelosuppression, nausea, hair loss, and renal dysfunction [68].

Oxaliplatin-containing regimens — Reports suggest antitumor activity for some oxaliplatin-based regimens in pancreatic NET [69,70]:

A combined analysis of two phase II trials examining oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab in advanced NET suggests antitumor activity for these regimens. The analysis included a study examining the efficacy of oxaliplatin plus short term infusional FU and leucovorin (FOLFOX) with bevacizumab (n = 36) and another examining capecitabine in combination with oxaliplatin and bevacizumab (n = 40) [69]. The best overall responses based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria in 12 patients with pancreatic NET treated with FOLFOX-bevacizumab included 50 percent with a partial response and 50 percent with stable disease. The outcomes in 16 patients with pancreatic NET treated with capecitabine with oxaliplatin and bevacizumab were 18.8 percent with a partial response and 69 percent with stable disease.

The contribution of bevacizumab to these results is unclear; similar benefit has been shown with capecitabine plus oxaliplatin alone [70].

MOLECULARLY TARGETED THERAPY — For patients with advanced pancreatic NETs whose disease has progressed on a somatostatin analog and who are not symptomatic from tumor bulk that would benefit from cytoreduction, we suggest treatment with a molecularly targeted agent (everolimus or sunitinib).

Progress in the understanding of the molecular biology of pancreatic NETs has revealed elevated expression of several cellular growth factors and their receptors (including vascular endothelial growth factor [VEGF] and the VEGF receptor [VEGFR]), and involvement of the mammalian Target of Rapamycin (mTOR) in pancreatic neuroendocrine tumorigenesis [71-73]. Many receptors like VEGFR function as tyrosine kinases (TKs). The finding in preclinical models that disruption of VEGFR signaling pathways inhibits neuroendocrine cell growth has prompted a number of clinical trials evaluating small molecule TK inhibitors (eg, sunitinib, sorafenib, pazopanib, and cabozantinib) and monoclonal antibodies (MoAbs) that target VEGF in patients with advanced NET.

Studies have demonstrated antitumor activity associated with bevacizumab (an anti-VEGF MoAb), and several TK inhibitors that inhibit VEGFR, as well as the mTOR inhibitor everolimus. As has been seen with cytotoxic chemotherapy, these agents appear to be more active in pancreatic NET than in advanced gastrointestinal NET (carcinoid). (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Molecularly targeted therapy'.)

Small molecule antiangiogenic TK inhibitors

Sunitinib — Sunitinib is a multi-targeted tyrosine kinase (TK) inhibitor that has shown activity against a range of signaling pathways and growth factors/receptors including VEGFR 1, 2, and 3 as well as PDGFR alpha and beta, KIT, glial cell-line derived neurotrophic factor, RET, FMS-like tyrosine kinase-3 (FLT3), and colony-stimulating factor receptor (CSF-1R).

In an initial phase II trial, sunitinib (50 mg daily for four of every six weeks) was administered to 109 patients with advanced NET [74]. Of 61 patients with pancreatic NET, 11 (18 percent) had a partial response, and 68 percent had prolonged periods of stable disease; median time to tumor progression (TTP) was 7.7 months. Rates of symptom control for patients with functioning tumors and refractory symptoms were not reported.

Continuous administration of sunitinib (37.5 mg daily) was compared with placebo in a phase III trial of 171 patients with progressing pancreatic NET [75]. Accrual was stopped prematurely prior to the first preplanned interim efficacy analysis. Median progression-free survival (PFS) was significantly longer with sunitinib (11.4 versus 5.5 months). There were eight objective responses with sunitinib (versus none in the placebo group), two of which were complete. Hand-foot skin reaction and hypertension of any grade occurred in 23 and 26 percent of patients receiving sunitinib, respectively, and the most common grade 3 or 4 adverse events in this group were neutropenia (12 percent) and hypertension (10 percent). Despite these side effects, there were no differences in the quality-of-life index with sunitinib. Rates of symptom control for patients with functioning tumors and refractory symptoms were not reported. In a later report, median overall survival favored sunitinib (38.6 versus 29.1 months), but the difference was not statistically significant, potentially due to crossover from placebo to sunitinib in 69 percent of the control group [76].

Largely based upon these data, sunitinib was approved in the United States for the treatment of progressive, well-differentiated pancreatic NET in patients with unresectable, locally advanced, or metastatic disease. Side effects may include hypertension, proteinuria, and other forms of renal toxicity, arterial thromboembolism, left ventricular dysfunction, and clinical heart failure, thyroid dysfunction, bleeding, myelosuppression, hand-foot skin reaction, delayed wound healing, hepatotoxicity, and muscle wasting. These side effects and their management are discussed in detail elsewhere. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'VEGFR/PDGFR inhibitors' and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents".)

Although few data are available, sunitinib provided control of refractory symptoms due to tumor hormone production in two patients with VIPomas [77]. By contrast, blood glucose concentrations were not increased in a single patient treated with sunitinib for a functioning metastatic insulinoma [78]. Furthermore, worsening hypoglycemia in patients with insulinoma and development of hypoglycemia in patients with a previously nonfunctioning pancreatic NET related to hyperinsulinemia have been reported [78-80].

Sorafenib and pazopanib — Two other orally active antiangiogenic TK inhibitors, sorafenib and pazopanib, have demonstrated modest activity in pancreatic NET in phase II studies:

Sorafenib, which targets VEGFR-2 and PDGFR-beta, was evaluated in 43 patients with pancreatic NET [81]. In a preliminary analysis, responses were observed in 9 percent of the 41 evaluable patients.

Pazopanib, which targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha and beta, as well as KIT, was evaluated in a prospective study of 51 patients with advanced NET (29 with pancreatic NET and 22 with carcinoid) on stable doses of octreotide-LAR [82]. Patients received pazopanib at a dose of 800 mg daily. The response rate among patients with well-differentiated pancreatic NET was 22 percent.

Cabozantinib — Cabozantinib, which targets VEGFRs, MET, AXL, and RET, was evaluated in a prospective study of 61 patients with advanced NETs (20 pancreatic and 41 gastrointestinal NETs). Patients started at a dose of 60 mg of cabozantinib daily. In a preliminary report, the response rate was 15 percent for patients with pancreatic NETs, with an encouraging median PFS of 21.8 months [83]. The CABINET trial, a randomized placebo-controlled phase III study, is currently enrolling patients and will evaluate the efficacy of cabozantinib in patients with advanced pancreatic and gastrointestinal NETs after prior therapy with everolimus (NCT03375320).

Lenvatinib — Lenvatinib, which targets VEGFRs as well as fibroblast growth factor (FGF) receptors, was studied in the phase II TALENT trial of 111 patients with advanced NETs (55 pancreatic and 56 gastrointestinal) [84]. All of the pancreatic NET patients had progressed after being treated with a targeted agent (everolimus in 69 percent, sunitinib in 29 percent). The objective response rate was 44 percent for the pancreatic NETs, and the median duration of response was 19.9 months (range 8.4 to 30.8).

Surufatinib — The SANET-p trial, a randomized, double-blind, placebo-controlled phase III trial conducted in China that included 172 patients with progressive advanced pancreatic NET, demonstrated improvement in PFS with surufatinib versus placebo [85]. Investigator-assessed median PFS was 10.9 months in the surufatinib group versus 3.7 months in the placebo group (HR 0.49, 95% CI 0.32–0.76; p = 0.0011). Overall survival data was not mature at the time of the interim analysis; survival follow-up is ongoing. Surufatinib is not currently available or FDA approved in the United States [86].

mTOR inhibitors

Everolimus — Several nonrandomized studies have explored the activity of everolimus, with and without octreotide [87-89]. The activity of everolimus (10 mg daily) in pancreatic NET was initially explored in an international multicenter phase II trial of 160 patients, 45 of whom also received treatment with concurrent octreotide at the discretion of the investigators [87]. Median PFS was longer in patients who received octreotide plus everolimus compared with everolimus alone (17 versus 9.7 months), but whether the addition of octreotide contributed to the higher PFS is unclear since the study did not randomly assign patients to receive octreotide.

Everolimus monotherapy (10 mg daily) was compared with best supportive care alone in the placebo-controlled RADIANT-3 trial of 410 patients with advanced progressing pancreatic NET [90]. Everolimus was associated with a significant prolongation in median PFS (11 versus 4.6 months, hazard ratio [HR] for progression 0.35, 95% CI 0.27 to 0.45). There were confirmed objective partial responses (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] v1.0 (table 2)) in 5 percent of patients receiving everolimus versus 2 percent of the placebo group. Drug-related adverse events were mostly grade 1 or 2, and included stomatitis (64 versus 17 percent of the placebo group), rash (49 versus 10 percent), diarrhea (34 versus 10 percent), fatigue (31 versus 14 percent), and infections (23 versus 6 percent), predominantly of the upper respiratory tract. The most common grade 3 or 4 drug-related adverse events were stomatitis (7 percent), anemia (6 percent), and hyperglycemia (5 percent). In a later analysis, median survival favored everolimus (44 versus 37.7 months), but the difference was not statistically significant [91]. The high rate of crossover of patients from placebo to everolimus (85 percent) may have confounded the ability to detect a difference in overall survival.

Largely based upon these data, everolimus was approved in the United States for the treatment of progressive NET of pancreatic origin in patients with unresectable, locally advanced, or metastatic disease.

Everolimus causes hyperglycemia, particularly in those with preexisting hyperglycemia. In analysis of data from the RADIANT-3 trial described above, the frequency of severe (grade 3 or 4) hyperglycemia was higher in those with preexisting diabetes mellitus or baseline hyperglycemia (15 versus 3 percent in those without diabetes or baseline hyperglycemia) [92]. Interestingly, rates of grade 3 or 4 hyperglycemia were similar in those with glucagonoma versus those without glucagonoma (9.1 versus 7.8 percent). (See "Glucagonoma and the glucagonoma syndrome", section on 'Laboratory abnormalities'.)

Largely because of this effect, everolimus may be of particular value in patients with functioning insulinomas and refractory hypoglycemia [93-96]. In one report, four patients with malignant insulinoma and refractory hypoglycemia normalized their glucose levels during everolimus therapy; two had an objective antitumor response [93]. Clinical improvement in the other two patients who had stable disease as the best response suggests a possible direct effect of the drug on insulin production and/or release. (See "Insulinoma".)

Though rare, everolimus has been associated with serious, adverse events, including pneumonitis [96]; tolerance should be carefully monitored during therapy. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Everolimus'.)

Everolimus plus bevacizumab — Both VEGF pathway and mTOR inhibitors are active in pancreatic NET. The benefit of adding bevacizumab to everolimus was addressed in a phase II trial in which 150 patients with locally advanced or metastatic pancreatic NET were randomly assigned to everolimus alone (10 mg by mouth daily) or with concurrent bevacizumab (10 mg/kg IV every two weeks) [97]. Combination therapy was associated with significantly higher response rate (31 versus 12 percent) and superior PFS (16.7 versus 14 months), but no overall survival benefit. Combined therapy was also associated with higher rates of serious grade 3 or higher toxicity, including diarrhea (14 versus 3 percent), hyponatremia (11 versus 3 percent), and hypertension (41 versus 12 percent). Although the higher rate of treatment-related adverse events may limit the use of this combination, the results support the continued evaluation of VEGF pathway inhibitors in pancreatic NET.

Temsirolimus — In a phase II study of 37 patients with progressive NET treated with the mTOR inhibitor temsirolimus, only 1 of 15 patients with pancreatic NET had an objective response, but 67 percent attained disease control (which included stable disease for at least two months) [98]. Higher baseline tumor levels of mTOR predicted for better outcomes.

Encouraging early results were noted in a phase II trial of temsirolimus (25 mg IV weekly) plus the anti-VEGF monoclonal antibody bevacizumab (10 mg/kg every other week) in 56 patients with RECIST criteria progression within seven months of study entry [99]. A confirmed partial response was documented in 23 patients (41 percent), and 44 (79 percent) remained progression free at six months. The most common grade 3 or 4 toxic effects related to therapy were hypertension (21 percent), hyperglycemia (14 percent), fatigue (16 percent), neutropenia, and headache (7 percent each).

PEPTIDE RECEPTOR RADIOLIGAND THERAPY

Radiolabeled somatostatin analogs — For patients without rapidly progressive pancreatic NET that expresses somatostatin receptors (SSTRs), we suggest peptide receptor radioligand therapy (PRRT) using a radiolabeled somatostatin analog such as lutetium-177 (177Lu) dotatate, rather than molecularly targeted therapy or chemotherapy. However, the optimal sequencing of this agent with regard to other therapies is debated, and there is no consensus on this issue [100].

Traditional external beam radiotherapy is beneficial for patients with painful bone metastases but has little utility for the more common visceral metastases. There has been substantial interest, however, in targeted radiotherapy using systemic administration of radiolabeled somatostatin analogs [101-111]. The most frequently used radionuclides for targeted radiotherapy are yttrium-90 (90Y) and lutetium-177 (177Lu), which differ from one another in terms of emitted particles, particle energy, and tissue penetration [112-114].

Transarterial radioembolization (TARE) using 90Y-radiolabeled glass or starch microspheres is a different procedure that is a local ablative treatment administered via the hepatic artery. Use of TARE to treat advanced NETs is discussed elsewhere. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Technique and outcomes'.)

Most of the series reporting efficacy and toxicity with systemic administration of radiolabeled somatostatin analogs have included both pancreatic NET and gastrointestinal NET [112,113,115,116]. The following data will focus on pancreatic primary NETs, where possible.

Yttrium-90 dotatoc — The most extensive experience with 90Y dotatoc comes from a large single-institution series of 1109 patients with metastatic gastroenteropancreatic NET (primary in the pancreas in 342) and disease progression within 12 months of study entry, with visible tumor uptake on pretreatment SSTR scintigraphy [115]. 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 pre-therapeutically 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. In the subset of patients with pNET, there was great variability in the range of morphologic (20 to 75 percent), biochemical (zero to 40 percent), and clinical responses (zero to 60 percent), depending on tumor subtype and whether the tumor was functional or nonfunctional. Among the 295 nonfunctioning pNETs, the morphologic, biochemical, and clinical response rates were 49, 14, and 29 percent, respectively.

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-177 dotatate — At least some data suggest that 177Lu dotatate outperforms 90Y dotatoc [114]. In a registry-based series of 450 patients with pancreatic or gastrointestinal NET, 54 percent were treated with 177Lu dotatate alone, 17 percent were treated with 90Y dotatoc alone, and combined therapy was administered to 29 percent [114]. The median progression-free survival (PFS) for the entire group was 41 months (27 months with 90Y dotatoc alone, 40 months for 177Lu dotatate, and 50 months for combined therapy). The nonrandomized nature of this series precludes drawing conclusions regarding the relative efficacy of these approaches; however, long-term side effects of peptide receptor radioligand therapy (PRRT) may include loss of renal function, pancytopenia, and myelodysplastic syndrome, although rates of severe (grade 3 or worse) toxicity are reported to be low (1 percent or less) [114].

Efficacy results with 177Lu dotatate alone are available from the following reports:

In one series of 443 Dutch patients with gastroenteropancreatic or lung NET, the objective response rate was 39 percent, and an additional 43 percent had stable disease [117]. At a median follow-up of 78 months, median PFS was 29 months, median time to tumor progression was 36 months, and median overall survival was 63 months. Response rates were particularly high in pancreatic NET, ranging from 52 percent for nonfunctioning tumors to 62 percent for functioning gastrinomas, insulinomas, and VIPomas.

The safety analysis included 610 patients who had received a cumulative dose of at least 100 millicuries (3.7 gigabecquerels). Acute treatment-related toxicity included grade 3 or 4 thrombocytopenia in 5 percent, lymphopenia in 50 percent, and elevated aminotransferases in 3 percent. Long-term toxicity included acute leukemia in four patients (0.7 percent, three fatal) and myelodysplastic syndrome in nine (1.5 percent, five fatal). There was no therapy-related long-term renal or hepatic failure.

In a meta-analysis of 15 studies in combined populations of gastrointestinal and pancreatic NETs, totaling 872 patients with metastatic disease, the pooled objective response rate following a course of 177Lu dotatate was 28 percent (95% CI 21-35 percent), and the pooled disease control rate was 79 percent (95% CI 76-82 percent) [118]. Early adverse effects were minimal, including nausea, vomiting, fatigue, and hormonal disorders.

In addition to these data, among patients with advanced midgut NET, the benefits of 177Lu dotatate were shown in the NETTER-1 trial, which demonstrated significant improvement in objective response rate, PFS, and overall survival with 177Lu dotatate compared with high-dose long-acting octreotide in patients whose disease had progressed on standard-dose somatostatin analog therapy (median PFS not reached versus 18 months) [116]. All patients enrolled in this trial had an extrapancreatic primary site; these data are discussed in more detail elsewhere. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs'.)

Largely based on data from the NETTER-1 trial, in January 2018, the US Food and Drug Administration (FDA) approved 177Lu dotatate for the treatment of somatostatin-receptor-positive gastroenteropancreatic NET, including those arising in the pancreas [119]. The recommended dose is 7.4 gigabecquerels (200 millicuries) as an intravenous infusion over 30 minutes every eight weeks for a total of four doses [120].

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 4) [121]. We agree with these guidelines.

The limitations of 177Lu dotatate at present include the complexity of administration, the lack of trials comparing this agent with other systemic therapies, and the limited widespread availability.

Efficacy versus other treatments — There are few data comparing 177Lu dotatate versus other therapies for progressive disease.

A single randomized trial directly compared PRRT with 177Lu dotatate versus sunitinib for progressive disease in 84 patients with no prior cytotoxic therapy, previous PRRT or TKI inhibitor therapy [8]. Notably, 81 percent of patients had grade 2 or 3 tumors, and 37 percent had Ki-67 levels >10 percent. In a preliminary report presented at the 2022 ESMO cancer congress, at a median follow-up of 40 months, the primary end point, (PFS at 12 months) was twofold higher with 177Lu dotatate (81 versus 42 percent) and median PFS was also double that in the sunitinib arm (20.7 versus 11 months). Grade 3 or 4 events were reported less commonly with 177Lu dotatate (44 versus 63 percent).

In our view, while there remains no clear consensus on optimal sequencing of therapy, the higher rates of anti-tumor activity and better tolerability observed with 177Lu dotatate in patients with advanced somatostatin receptor-expressing pNET makes this a preferable initial to molecularly targeted therapy for appropriate patients, particularly those who are symptomatic from their disease.

Additional randomized trials comparing different systemic therapy approaches are needed to define the optimal sequence of available therapies, including chemotherapy, and eligible patients should be encouraged to enroll in available trials, such as the following:

A European phase III trial, SEQTOR, is comparing the efficacy and safety of chemotherapy (fluorouracil and streptozotocin) followed by everolimus versus everolimus followed by fluorouracil and streptozotocin in patients with advanced and progressive pancreatic NETs.

The phase III COMPETE trial is evaluating PRRT with 177Lu-edotreotide versus everolimus.

In addition, the randomized phase II Alliance A022001 trial is evaluating PRRT with 177Lu dotatate versus capecitabine plus temozolomide in patients with advanced pancreatic NETs (NCT05247905).

Long-term toxicity — The most serious long-term toxicity associated with PRRT is irreversible myelotoxicity and therapy-related myeloid neoplasms, including myelodysplastic syndrome, acute leukemia, myeloproliferative neoplasms, or any type of myeloid neoplasm. The available data from studies with long-term follow-up suggest a rate of myelodysplastic syndrome of approximately 2 percent and a rate of acute leukemia of approximately 0.5 percent.

Rates may be higher in those who received concurrent chemotherapy [122]. 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 dotatate with either concurrent capecitabine or capecitabine plus temozolomide, at a median follow-up of 68 months, seven patients (6.7 percent) developed MDS/acute leukemia, with a median time to onset of 5 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.

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 [123]. We suggest obtaining a CBC with differential at least every six months, and prompt referral to a hematologist if abnormalities are detected. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Risks'.)

Should the somatostatin analog be continued? — The added benefit of combining a long-acting somatostatin analog with PRRT compared with PRRT alone is not established. All patients in the NETTER-1 trial continued receiving the long-acting somatostatin analog during and after PRRT. 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 overall survival (91 versus 47 months) [124] compared with PRRT alone.

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 [125].

Iobenguane I-131 — Benefit also has been suggested for systemic radionuclide therapy using iodine-131-labeled iobenguane (iobenguane I-131) in individuals with metastatic gastroenteropancreatic NET whose tumors express the norepinephrine transporter and take up iobenguane, as determined by scintigraphy using radiolabeled iobenguane [126]. There are different iobenguane nuclides used for therapeutic and diagnostic purposes. Iobenguane I-131 (therapeutic) is also known as metaiodobenzylguanidine (MIBG or 131I-MIBG); iobenguane expression is demonstrated by uptake on iobenguane I-123 (diagnostic) scintigraphy. While iobenguane I-131 has been licensed by regulatory authorities in some countries and is approved in the United States for treatment of pheochromocytoma/paraganglioma and neuroblastoma, in our view, its use for the treatment of gastroenteropancreatic NET remains investigational.

Iobenguane is a compound resembling norepinephrine that is accumulated by some NETs. In retrospective series, biochemical responses were observed in 37 percent of patients with gastroenteropancreatic NET treated with iobenguane I-131, objective radiographic responses were noted in 28 percent, and symptomatic improvement was reported by 27 of 48 patients (56 percent) [127].

In another report, iobenguane I-131 (therapeutic) was "beneficial" in 73 percent of 20 patients with metastatic gastroenteropancreatic NETs (including eight with pancreatic NETs) [128]. Treatment was judged beneficial if clinical status improved, laboratory tests for secreting tumors improved by >20 percent, tumor progression was halted, the size of the most significant localization had decreased by >25 percent, and the dose of analgesic and cold somatostatin analog therapy could be lowered. Treatment was well tolerated, and only one patient had severe pancytopenia. Notably, at 12 months, 7 of the 14 responders were again symptomatic.

IMMUNOTHERAPY — Immune checkpoint inhibitors appear to have little activity as monotherapy, 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 NET.

The role of immunotherapy with immune checkpoint inhibitors has been evaluated in several studies including patients with well-differentiated NETs. Data suggest that anti-programmed cell death 1 (PD-1) antibodies have minimal activity as monotherapy [129]. As examples:

The efficacy of the anti-PD-1 antibody spartalizumab (PDR001) was evaluated in a phase II multicenter trial that enrolled 116 patients, including 33 with pancreatic NETs, 32 with gastrointestinal NETs, 30 with thoracic NETs, and 21 with poorly differentiated gastroenteropancreatic neuroendocrine carcinomas [130]. In a preliminary report presented at The 2018 European Society for Medical Oncology (ESMO) meeting, the clinical activity of spartalizumab was notable in patients with thoracic NETs (partial response rate 20 percent) but appeared marginal in other cohorts, including well-differentiated pancreatic NETs (partial response rate 3 percent, stable disease rate 55 percent).

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 NETs and 25 patients with gastrointestinal (n = 7), lung (n = 9), or other site (n = 9) NETs. Only one patient with a pancreatic NET had an objective response (6 percent); the stable disease rate in the 14 patients who were evaluable for response was 88 percent [131].

The relevance of PD-L1 expression as a predictive factor for response was called into question by 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 [132]. 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). There were only four partial responses (3.7 percent), and the median progression-free survival (PFS) 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 vascular endothelial growth factor (VEGF) pathway inhibitors [133-135]. 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 [133]. Objective response was observed in 4 of 20 patients with pNETs (20 percent) and 3/20 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.

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

SUMMARY AND RECOMMENDATIONS

Definition and categorization

Neuroendocrine precursor cells are distributed widely throughout the body, and neoplasms of these dispersed cells, which are termed neuroendocrine neoplasms (NENs), can arise at many sites.

The World Health Organization (WHO) classifies all gastroenteropancreatic NENs based on differentiation and grade. Grade is assigned into low-grade neuroendocrine tumors (NETs), intermediate-grade NETs, and high-grade neoplasms based on mitotic count and proliferative index (Ki-67) (table 1). Poorly differentiated neuroendocrine carcinomas are all 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'.)

Initial therapy

Most patients with symptoms of hormone hypersecretion from a pancreatic NET (pNET) other than insulinoma or gastrinoma should be managed with somatostatin analogs and other agents, as appropriate to the specific syndrome. (See 'Benefits' above and "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Somatostatin analogs' and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "Glucagonoma and the glucagonoma syndrome", section on 'General measures'.)

Because somatostatin analogs may worsen glycemic control in insulinoma, initial therapy for insulinomas ore often consists of dietary modifications, diazoxide, which directly inhibits the release of insulin from insulinoma cells, and everolimus, which improves glycemic control in patients with insulinoma. Specific recommendations are provided separately. (See "Insulinoma", section on 'Medical therapy to control symptomatic hypoglycemia'.)

For patients with gastrinoma, most of whom have peptic ulcer disease, high doses of oral proton pump inhibitors are the initial treatment of choice; somatostatin analogs are may be helpful for refractory cases. Specific recommendations are provided separately. (See "Management and prognosis of the Zollinger-Ellison syndrome (gastrinoma)".)

For patients with unresectable, asymptomatic, well-differentiated pNET and a high tumor burden, we suggest initiation of a long-acting somatostatin analog rather than observation (Grade 2B). For asymptomatic patients with low-volume disease, we suggest observation alone rather than early administration of a somatostatin analog (Grade 2C). In such patients, we initiate somatostatin analog therapy at the time of clinically meaningful disease progression. (See 'Control of tumor growth' above.)

For most patients with hepatic metastases that are resectable with curative intent, in the absence of extrahepatic metastases, diffuse bilobar involvement, or compromised liver function, resection is generally preferred rather than medical therapy. Specific recommendations are provided separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Surgical resection'.)

Progressive disease and/or symptomatic from tumor bulk

For patients who require therapy because of progressive disease or symptoms related to hormone production, and who are not already receiving treatment with a somatostatin analog, we suggest a long-acting somatostatin analog rather than a different form of medical therapy (Grade 2C). However, everolimus may be of particular value in patients with functioning insulinomas and refractory hypoglycemia because of its association with hyperglycemia. (See "Insulinoma", section on 'Medical therapy to control symptomatic hypoglycemia'.)

For those who are already receiving treatment with a somatostatin analog, options include cytotoxic chemotherapy, a molecularly targeted agent (everolimus or sunitinib), hepatic artery embolization for hepatic-predominant disease, or, for somatostatin receptor-expressing tumors, 177Lu Dotatate.

For patients who are highly symptomatic from tumor bulk and who have rapidly enlarging metastases, we suggest chemotherapy as an initial treatment because of the higher objective response rate compared with other approaches (Grade 2C). For most patients, we suggest the combination of capecitabine and temozolomide (CAPTEM) rather than temozolomide alone (Grade 2C). In the absence of comparative trials, the choice of CAPTEM over a streptozocin-containing regimen should be individualized, taking into account the convenience of oral rather than intravenous treatment, performance status, and anticipated side effect profiles. (See 'Streptozocin combinations' above and 'Dacarbazine and temozolomide-based regimens' above.)

Hepatic arterial embolization is a reasonable alternative approach to systemic therapy for patients with hepatic predominant, but unresectable disease, particularly those who are symptomatic. Specific recommendations are provided separately. (See "Metastatic gastroenteropancreatic neuroendocrine tumors: Local options to control tumor growth and symptoms of hormone hypersecretion", section on 'Hepatic arterial embolization'.)

While there remains no clear consensus on optimal sequencing of therapy, the higher rates of anti-tumor activity observed with 177Lu dotatate and CAPTEM in patients with advanced pNET make them preferred initial options rather than molecularly targeted therapy for most patients, particularly for those who are symptomatic from their disease. (See 'Efficacy versus other treatments' above.)

Another option for patients with indolent disease after an initial response or a prolonged duration of stability with standard-dose somatostatin analog therapy is dose escalation of the somatostatin analog, but this is not a preferred strategy. (See 'Control of tumor growth' above.)

  1. Klimstra DS, Kloppell G, La Rosa S, Rindi G. Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours: Digestive System Tumours, 5th ed, WHO Classification of Tumours Editorial Board (Ed), International Agency for Research on Cancer, Lyon 2019. p.16.
  2. Duerr EM, Chung DC. Molecular genetics of neuroendocrine tumors. Best Pract Res Clin Endocrinol Metab 2007; 21:1.
  3. Panzuto F, Nasoni S, Falconi M, et al. Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization. Endocr Relat Cancer 2005; 12:1083.
  4. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010; 39:707.
  5. Riihimäki M, Hemminki A, Sundquist K, et al. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer 2016; 139:2679.
  6. Kaderli RM, Spanjol M, Kollár A, et al. Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis. JAMA Oncol 2019; 5:480.
  7. Strosberg JR, Al-Toubah T, Cives M. Evaluating Risks and Benefits of Evolving Systemic Treatments of Neuroendocrine Tumors. JAMA Oncol 2019; 5:489.
  8. Baudin E, Walter TA, Beron A, et al. First multicentric randomized phase II trial investigating the antitumor efficacy of peptide receptor radionucleide therapy with <sup>177</sup>Lutetium-Octreotate (OCLU) in unresectable progressive neuroendocrine pancreatic tumor: Results of the OCLURANDOM trial (abstract). Annals of Oncology (2022) 33 (suppl_7): S410-S416. 10.1016/annonc/annonc1060. https://oncologypro.esmo.org/meeting-resources/esmo-congress/first-multicentric-randomized-phase-ii-trial-investigating-the-antitumor-efficacy-of-peptide-receptor-radionucleide-therapy-with-sup-177-sup-lute (Accessed on September 21, 2022).
  9. Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res 1990; 50:5969.
  10. Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008; 135:1469.
  11. Kvols LK, Buck M, Moertel CG, et al. Treatment of metastatic islet cell carcinoma with a somatostatin analogue (SMS 201-995). Ann Intern Med 1987; 107:162.
  12. Saltz L, Trochanowski B, Buckley M, et al. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer 1993; 72:244.
  13. Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut 1996; 38:430.
  14. di Bartolomeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996; 77:402.
  15. Eriksson B, Renstrup J, Imam H, Oberg K. High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects. Ann Oncol 1997; 8:1041.
  16. Tomassetti P, Migliori M, Gullo L. Slow-release lanreotide treatment in endocrine gastrointestinal tumors. Am J Gastroenterol 1998; 93:1468.
  17. Toumpanakis C, Caplin ME. Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. Semin Oncol 2013; 40:56.
  18. Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther 2010; 31:169.
  19. Panzuto F, Di Fonzo M, Iannicelli E, et al. Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma. Ann Oncol 2006; 17:461.
  20. Nikou GC, Toubanakis C, Nikolaou P, et al. VIPomas: an update in diagnosis and management in a series of 11 patients. Hepatogastroenterology 2005; 52:1259.
  21. Frankton S, Bloom SR. Gastrointestinal endocrine tumours. Glucagonomas. Baillieres Clin Gastroenterol 1996; 10:697.
  22. Angeletti S, Corleto VD, Schillaci O, et al. Use of the somatostatin analogue octreotide to localise and manage somatostatin-producing tumours. Gut 1998; 42:792.
  23. Soga J, Yakuwa Y. Somatostatinoma/inhibitory syndrome: a statistical evaluation of 173 reported cases as compared to other pancreatic endocrinomas. J Exp Clin Cancer Res 1999; 18:13.
  24. Romeo S, Milione M, Gatti A, et al. Complete clinical remission and disappearance of liver metastases after treatment with somatostatin analogue in a 40-year-old woman with a malignant insulinoma positive for somatostatin receptors type 2. Horm Res 2006; 65:120.
  25. Okamoto M, Kishimoto M, Takahashi Y, et al. A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections. Endocr J 2013; 60:951.
  26. Hirshberg B, Cochran C, Skarulis MC, et al. Malignant insulinoma: spectrum of unusual clinical features. Cancer 2005; 104:264.
  27. Healy ML, Dawson SJ, Murray RM, et al. Severe hypoglycaemia after long-acting octreotide in a patient with an unrecognized malignant insulinoma. Intern Med J 2007; 37:406.
  28. Stehouwer CD, Lems WF, Fischer HR, et al. Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol (Copenh) 1989; 121:34.
  29. Jawiarczyk A, Bolanowski M, Syrycka J, et al. Effective therapy of insulinoma by using long-acting somatostatin analogue. A case report and literature review. Exp Clin Endocrinol Diabetes 2012; 120:68.
  30. Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012; 61:6.
  31. Pavel M, Baudin E, Couvelard A, et al. ENETS Consensus Guidelines for the management of patients with liver and other distant metastases from neuroendocrine neoplasms of foregut, midgut, hindgut, and unknown primary. Neuroendocrinology 2012; 95:157.
  32. Rubin J, Ajani J, Schirmer W, et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999; 17:600.
  33. Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 2013; 42:557.
  34. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf (Accessed on July 25, 2023).
  35. Aparicio T, Ducreux M, Baudin E, et al. Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. Eur J Cancer 2001; 37:1014.
  36. Sidéris L, Dubé P, Rinke A. Antitumor effects of somatostatin analogs in neuroendocrine tumors. Oncologist 2012; 17:747.
  37. Strosberg J, Kvols L. Antiproliferative effect of somatostatin analogs in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol 2010; 16:2963.
  38. Verslype C, Carton S, Borbath I, et al. The antiproliferative effect of somatostatin analogs: clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours. Acta Gastroenterol Belg 2009; 72:54.
  39. Ricci S, Antonuzzo A, Galli L, et al. Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. Am J Clin Oncol 2000; 23:412.
  40. Ducreux M, Ruszniewski P, Chayvialle JA, et al. The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors. Am J Gastroenterol 2000; 95:3276.
  41. Bianchi A, De Marinis L, Fusco A, et al. The treatment of neuroendocrine tumors with long-acting somatostatin analogs: a single center experience with lanreotide autogel. J Endocrinol Invest 2011; 34:692.
  42. Rinke A, Müller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27:4656.
  43. Caplin ME, Pavel M, Ćwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371:224.
  44. Michael M, Garcia-Carbonero R, Weber MM, et al. The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review. Oncologist 2017; 22:272.
  45. Ter-Minassian M, Zhang S, Brooks NV, et al. Association Between Tumor Progression Endpoints and Overall Survival in Patients with Advanced Neuroendocrine Tumors. Oncologist 2017; 22:165.
  46. Carmona-Bayonas A, Jiménez-Fonseca P, Lamarca Á, et al. Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study. J Clin Oncol 2019; 37:2571.
  47. Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol 2006; 17:1733.
  48. Kulke MH, Ruszniewski P, Van Cutsem E, et al. A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. Ann Oncol 2017; 28:1309.
  49. Lamberti G, Faggiano A, Brighi N, et al. Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor. J Clin Endocrinol Metab 2020; 105.
  50. Pavel M, Ćwikła JB, Lombard-Bohas C, et al. Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results. Eur J Cancer 2021; 157:403.
  51. Ayyagari R, Neary M, Li S, et al. Comparing the Cost of Treatment with Octreotide Long-Acting Release versus Lanreotide in Patients with Metastatic Gastrointestinal Neuroendocrine Tumors. Am Health Drug Benefits 2017; 10:408.
  52. Raj N, Cruz E, O'Shaughnessy S, et al. A Randomized Trial Evaluating Patient Experience and Preference Between Octreotide Long-Acting Release and Lanreotide for Treatment of Well-Differentiated Neuroendocrine Tumors. JCO Oncol Pract 2022; 18:e1533.
  53. Lamberts SW, van der Lely AJ, de Herder WW, Hofland LJ. Octreotide. N Engl J Med 1996; 334:246.
  54. Newman CB, Melmed S, Snyder PJ, et al. Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study. J Clin Endocrinol Metab 1995; 80:2768.
  55. Ramanathan RK, Cnaan A, Hahn RG, et al. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Ann Oncol 2001; 12:1139.
  56. Stevens MF, Hickman JA, Langdon SP, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987; 47:5846.
  57. Cives M, Ghayouri M, Morse B, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer 2016; 23:759.
  58. Kunz PL, Graham NT, Catalano PJ, et al. Randomized Study of Temozolomide or Temozolomide and Capecitabine in Patients With Advanced Pancreatic Neuroendocrine Tumors (ECOG-ACRIN E2211). J Clin Oncol 2023; 41:1359.
  59. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006; 24:401.
  60. Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol 2012; 30:2963.
  61. Chan JA, Blaszkowsky L, Stuart K, et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer 2013; 119:3212.
  62. Kulke MH, Hornick JL, Frauenhoffer C, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 2009; 15:338.
  63. Walter T, van Brakel B, Vercherat C, et al. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer 2015; 112:523.
  64. Murakami J, Lee YJ, Kokeguchi S, et al. Depletion of O6-methylguanine-DNA methyltransferase by O6-benzylguanine enhances 5-FU cytotoxicity in colon and oral cancer cell lines. Oncol Rep 2007; 17:1461.
  65. Moertel CG, Lefkopoulo M, Lipsitz S, et al. Streptozocin-doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326:519.
  66. Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 2004; 22:4762.
  67. Dilz LM, Denecke T, Steffen IG, et al. Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. Eur J Cancer 2015; 51:1253.
  68. Krug S, Boch M, Daniel H, et al. Streptozocin-Based Chemotherapy in Patients with Advanced Neuroendocrine Neoplasms--Predictive and Prognostic Markers for Treatment Stratification. PLoS One 2015; 10:e0143822.
  69. Kunz PL, Balise RR, Fehrenbacher L, et al. Oxaliplatin-Fluoropyrimidine Chemotherapy Plus Bevacizumab in Advanced Neuroendocrine Tumors: An Analysis of 2 Phase II Trials. Pancreas 2016; 45:1394.
  70. Bajetta E, Catena L, Procopio G, et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemother Pharmacol 2007; 59:637.
  71. Oberg K, Casanovas O, Castaño JP, et al. Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res 2013; 19:2842.
  72. Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 2010; 28:245.
  73. Zhang J, Francois R, Iyer R, et al. Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst 2013; 105:1005.
  74. Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008; 26:3403.
  75. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:501.
  76. Faivre S, Niccoli P, Castellano D, et al. Sunitinib in Pancreatic Neuroendocrine Tumors: Updated Progression-Free Survival and Final Overall Survival From a Phase III Randomized Study. Ann Oncol 2016.
  77. de Mestier L, Walter T, Brixi H, et al. Sunitinib achieved fast and sustained control of VIPoma symptoms. Eur J Endocrinol 2015; 172:K1.
  78. Chen J, Wang C, Han J, et al. Therapeutic effect of sunitinib malate and its influence on blood glucose concentrations in a patient with metastatic insulinoma. Expert Rev Anticancer Ther 2013; 13:737.
  79. Fountas A, Tigas S, Giotaki Z, et al. Severe resistant hypoglycemia in a patient with a pancreatic neuroendocrine tumor on sunitinib treatment. Hormones (Athens) 2015; 14:438.
  80. Ohn JH, Kim YG, Lee SH, Jung HS. Transformation of nonfunctioning pancreatic neuroendocrine carcinoma cells into insulin producing cells after treatment with sunitinib. Endocrinol Metab (Seoul) 2013; 28:149.
  81. Raymond E, Hobday T, Castellano D, et al. Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. Cancer Metastasis Rev 2011; 30 Suppl 1:19.
  82. Phan AT, Halperin DM, Chan JA, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol 2015; 16:695.
  83. Chan JA, Faris JE, Murphy JE, et al. Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET). J Clin Oncol 2017; 35S: ASCO #228.
  84. Capdevila J, Fazio N, Lopez C, et al. Lenvatinib in Patients With Advanced Grade 1/2 Pancreatic and Gastrointestinal Neuroendocrine Tumors: Results of the Phase II TALENT Trial (GETNE1509). J Clin Oncol 2021; 39:2304.
  85. Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 2020; 21:1489.
  86. HUTCHMED Receives Complete Response Letter from the U.S. FDA for Surufatinib for the Treatment of Advanced Neuroendocrine Tumors. Available at: https://www.hutch-med.com/suru-fda-nda/ (Accessed on June 01, 2022).
  87. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 2010; 28:69.
  88. Oh DY, Kim TW, Park YS, et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer 2012; 118:6162.
  89. Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 2008; 26:4311.
  90. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:514.
  91. Yao JC, Pavel M, Lombard-Bohas C, et al. Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study. J Clin Oncol 2016.
  92. van der Veldt AA, Kleijn SA. Advances in pancreatic neuroendocrine tumor treatment. N Engl J Med 2011; 364:1873; author reply 1873.
  93. Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med 2009; 360:195.
  94. Fiebrich HB, Siemerink EJ, Brouwers AH, et al. Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues. Oncologist 2011; 16:783.
  95. Ong GS, Henley DE, Hurley D, et al. Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma. Eur J Endocrinol 2010; 162:1001.
  96. Bernard V, Lombard-Bohas C, Taquet MC, et al. Efficacy of everolimus in patients with metastatic insulinoma and refractory hypoglycemia. Eur J Endocrinol 2013; 168:665.
  97. Kulke MH, Ou FS, Niedzwiecki D, et al. Everolimus with or without bevacizumab in advanced pNET: CALGB 80701 (Alliance). Endocr Relat Cancer 2022; 29:335.
  98. Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer 2006; 95:1148.
  99. Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors. J Clin Oncol 2015; 33:1551.
  100. Hope TA, Pavel M, Bergsland EK. Neuroendocrine Tumors and Peptide Receptor Radionuclide Therapy: When Is the Right Time? J Clin Oncol 2022; 40:2818.
  101. McCarthy KE, Woltering EA, Espenan GD, et al. In situ radiotherapy with 111In-pentetreotide: initial observations and future directions. Cancer J Sci Am 1998; 4:94.
  102. Buscombe JR, Caplin ME, Hilson AJ. Long-term efficacy of high-activity 111in-pentetreotide therapy in patients with disseminated neuroendocrine tumors. J Nucl Med 2003; 44:1.
  103. Anthony LB, Woltering EA, Espenan GD, et al. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med 2002; 32:123.
  104. McStay MK, Maudgil D, Williams M, et al. Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy. Radiology 2005; 237:718.
  105. Waldherr C, Pless M, Maecke HR, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med 2002; 43:610.
  106. Kwekkeboom DJ, Bakker WH, Kam BL, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA(0),Tyr3]octreotate. Eur J Nucl Med Mol Imaging 2003; 30:417.
  107. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol 2008; 26:2124.
  108. Grozinsky-Glasberg S, Barak D, Fraenkel M, et al. Peptide receptor radioligand therapy is an effective treatment for the long-term stabilization of malignant gastrinomas. Cancer 2011; 117:1377.
  109. Wang SC, Parekh JR, Zuraek MB, et al. Identification of unknown primary tumors in patients with neuroendocrine liver metastases. Arch Surg 2010; 145:276.
  110. Villard L, Romer A, Marincek N, et al. Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers. J Clin Oncol 2012; 30:1100.
  111. Savelli G, Bertagna F, Franco F, et al. Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of 90Y-DOTA-D-Phe1-Tyr3 octreotide. Cancer 2012; 118:2915.
  112. Schillaci O, Corleto VD, Annibale B, et al. Single photon emission computed tomography procedure improves accuracy of somatostatin receptor scintigraphy in gastro-entero pancreatic tumours. Ital J Gastroenterol Hepatol 1999; 31 Suppl 2:S186.
  113. Gibril F, Reynolds JC, Doppman JL, et al. Somatostatin receptor scintigraphy: its sensitivity compared with that of other imaging methods in detecting primary and metastatic gastrinomas. A prospective study. Ann Intern Med 1996; 125:26.
  114. Hörsch D, Ezziddin S, Haug A, et al. Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up. Eur J Cancer 2016; 58:41.
  115. Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol 2011; 29:2416.
  116. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376:125.
  117. Brabander T, Van der Zwan WA, Teunissen JJ, et al. Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res 2017.
  118. Zhang J, Song Q, Cai L, et al. The efficacy of 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours: a systematic review and meta-analysis. J Cancer Res Clin Oncol 2020; 146:1533.
  119. FDA approval announcement for lutetium Lu 177 dotatate available online at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm (Accessed on January 29, 2018).
  120. Lutetium Lu 177 dotatate injection. United States Prescribing Information. US National Library of Medicine. http://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf?et_cid=39972490&et_rid=907466112&linkid=https%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2018%2f208700s000lbl.pdf (Accessed on January 29, 2018).
  121. Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology 2017; 105:295.
  122. Kennedy KR, Turner JH, MacDonald WBG, et al. Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy. Cancer 2022; 128:2182.
  123. Hope TA, Abbott A, Colucci K, et al. NANETS/SNMMI Procedure Standard for Somatostatin Receptor-Based Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE. J Nucl Med 2019; 60:937.
  124. Yordanova A, Wicharz MM, Mayer K, et al. The Role of Adding Somatostatin Analogues to Peptide Receptor Radionuclide Therapy as a Combination and Maintenance Therapy. Clin Cancer Res 2018; 24:4672.
  125. Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020; 31:844.
  126. Pandit-Taskar N, Modak S. Norepinephrine Transporter as a Target for Imaging and Therapy. J Nucl Med 2017; 58:39S.
  127. Nwosu AC, Jones L, Vora J, et al. Assessment of the efficacy and toxicity of (131)I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours. Br J Cancer 2008; 98:1053.
  128. Nguyen C, Faraggi M, Giraudet AL, et al. Long-term efficacy of radionuclide therapy in patients with disseminated neuroendocrine tumors uncontrolled by conventional therapy. J Nucl Med 2004; 45:1660.
  129. Bongiovanni A, Maiorano BA, Azzali I, et al. Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis. Pharmaceuticals (Basel) 2021; 14.
  130. Yao JC, Strosberg J, Fazio N, et al. Activity & safety of spartalizumab (PDR001) in patients (pts) with advanced neuroendocrine tumors (NET) of pancreatic (Pan), gastrointestinal (GI), or thoracic (T) origin, & gastroenteropancreatic neuroendocrine carcinoma (GEP NEC) who have progressed on prior treatment (Tx). Ann Oncol 2018; 29S: ESMO #viii467.
  131. Mehnert JM, Bergsland E, O'Neil BH, et al. Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. Cancer 2020; 126:3021.
  132. Strosberg J, Mizuno N, Doi T, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res 2020; 26:2124.
  133. Halperin DM, Liu S, Dasari A, et al. Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial. JAMA Oncol 2022; 8:904.
  134. Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC). Available at: https://clinicaltrials.gov/ct2/show/NCT02955069?term=02955069&rank=1.
  135. Study of Pembrolizumab With Lanreotide Depot for Gastroenteropancreatic Neuroendocrine Tumors (PLANET). Available at: https://clinicaltrials.gov/ct2/show/NCT03043664?term=03043664&rank=1.
Topic 90664 Version 62.0

References

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