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GEP NET Clinical Pearls
Clinical Pearls With Gastroenteropancreatic NET Care

Released: December 27, 2024

Expiration: December 26, 2025

Thor R. Halfdanarson
Thor R. Halfdanarson, MD
Jonathan Strosberg
Jonathan Strosberg, MD
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Key Takeaways
  • Somatostatin analogs are the typical first systemic therapy for GEP-NETs and primarily lead to disease stabilization. 177Lu-dotatate combined with a somatostatin analog is an option for patients with somatostatin receptor (SSTR)–positive higher-grade GEP-NETs (Ki-67 >10%).
  • 177Lu-dotatate is a second-line option for patients with SSTR-positive GEP-NETs and is the preferred second-line systemic option for most patients with a history of carcinoid syndrome/small bowel primary tumors.
  • Everolimus can be used as a second-line therapy, particularly in patients who do not qualify for 177Lu-dotatate.
  • Capecitabine/temozolomide (CAPTEM) is an active regimen for progressive pancreatic NETs and can be used in grade 3 NETs of different primary sites.

Jonathan Strosberg, MD:
Neuroendocrine tumors (NETs) are heterogeneous, with each primary site having its own unique characteristics, such as growth rate and propensity to metastasize. They are primarily distinguished as low grade, intermediate grade, or high grade based on either their mitotic rate or their Ki-67 proliferation index. It is important to distinguish well-differentiated NETs from poorly differentiated neuroendocrine carcinomas, which are biologically and clinically distinct. NETs that produce hormones are referred to as functional, and NETs that do not produce excessive hormones resulting in recognizable symptoms are called nonfunctional. In addition, the level of somatostatin receptor (SSTR) expression has important therapeutic implications.

In general, for local tumors, depending on the primary site, size, and level of invasiveness, standard treatment is endoscopic or surgical management. Advanced disease most often requires systemic treatment. However, liver-directed therapy has an important role in liver-dominant NETs. Surgery may also be considered, even in the setting of stage IV disease, either for debulking of metastases, most commonly in the liver, or for resection of the primary tumor, most commonly for small bowel NETs.

First-line treatments for well-differentiated gastroenteropancreatic (GEP)-NETs typically consist of somatostatin analogs (SSAs) because they are a low-risk treatment and very well tolerated. Although they do not shrink tumors significantly, they can stabilize the disease, sometimes for many years. In addition to providing tumor control, SSAs effectively control functional NET syndromes such as the carcinoid syndrome.

An important treatment modality for advanced NETs is peptide receptor radionuclide therapy (PRRT), which uses a radiolabeled SSA, linked to radionuclides such as lutetium-177 (177Lu), to target SSTR-expressing tumors. As mentioned above, the vast majority of well-differentiated NETs strongly expresses SSTRs.

After many years of single-arm and retrospective series, the phase III NETTER-1 study was developed to test whether PRRT with 177Lu-dotatate could significantly improve progression-free survival (PFS) in patients with advanced, progressive, small bowel NETs. Patients enrolled in this study had disease that had previously progressed during treatment with the SSA octreotide as long-acting repeatable (LAR) therapy and were randomized to receive 177Lu-dotatate plus best supportive care, including octreotide LAR, or high-dose octreotide LAR therapy. NETTER-1 showed significantly longer PFS in the 177Lu-dotatate group, with an HR of 0.21. Moreover, the median PFS had not yet been reached at the time of primary endpoint analysis. The objective response rate was 18% in the 177Lu-dotatate group. These results contributed to the approval of 177Lu-dotatate for use in adults with SSTR receptor–positive GEP-NETs.

PRRT with 177Lu-dotatate was also studied in the NETTER-P study, an ongoing, international, multicenter, open-label, single-arm study of 177Lu-dotatate in adolescent patients with locally advanced/inoperable or metastatic SSTR-positive GEP-NETs or pheochromocytoma/paraganglioma. Extrapolation of efficacy outcomes in the NETTER-1 study was also conducted ultimately leading to the approval of 177Lu-dotatate for pediatric patients ≥12 years of age with SSTR-positive GEP-NETs, including foregut, midgut, and hindgut NETs.

The recently published NETTER-2 trial tested 177Lu-dotatate (plus standard-dose octreotide LAR) compared with high-dose octreotide LAR as a first-line therapy in patients with advanced/metastatic GEP-NETs and a Ki-67 index of 10% to 55%. It demonstrated significantly better PFS (median of 22.8 months in the 177Lu-dotatate group vs 8.5 months in the control group; HR: 0.28). The objective response rate with 177Lu-dotatate in this population was 43%. Although this trial suggests that first-line 177Lu-dotatate may be appropriate in certain patients with relatively aggressive GEP-NETs, the impact on overall survival associated with this strategy is uncertain. 

Everolimus is another drug widely used in treating GEP-NETs. This mTOR inhibitor was tested in 3 phase III trials. The RADIANT 2 trial tested everolimus plus octreotide vs placebo plus octreotide in patients with advanced, progressive GEP and lung NETs and a history of carcinoid syndrome. In this population, consisting primarily of patients with small bowel NETs, PFS was not significantly better in the everolimus arm. The RADIANT 3 trial compared everolimus vs placebo in patients with progressive pancreatic NETs and demonstrated significantly longer PFS with everolimus: median PFS was 4.6 months with placebo vs 11 months with everolimus (HR: 0.35). In the RADIANT 4 trial, everolimus was compared with placebo in patients with nonfunctional GEP and lung NETs. Results in this trial were also positive, with a median PFS of 3.9 months with placebo vs 11 months with everolimus (HR: 0.48). As a result of these 3 studies, everolimus was approved as treatment for nonfunctional GEP and lung NETs as well as pancreatic NETs. Objective response rates with everolimus are low (<10%) and adverse effects include oral ulcers, hyperglycemia, pneumonitis, and increased risk of infection.

Sunitinib, an inhibitor of vascular endothelial growth factor receptors, was approved for treating progressive metastatic pancreatic NETs based on a randomized, placebo-controlled phase III trial showing longer median PFS: 5.5 months with placebo vs 11.4 months with sunitinib (HR: 0.42). These results were quite similar to findings from the everolimus RADIANT 3 study. Adverse effects of sunitinib included hypertension, palmar-plantar erythrodysesthesia, fatigue, and diarrhea.

Cytotoxic chemotherapy has an important role in treating metastatic pancreatic NETs, particularly in treating those with a high tumor burden or aggressive growth. Capecitabine plus temozolomide (CAPTEM) was compared with temozolomide monotherapy in patients with progressive grade 1 and 2 pancreatic NETs. Median PFS was 14.4 months with temozolomide vs 22.7 months with CAPTEM (HR: 0.58). The response rate with CAPTEM was 40%. Retrospective studies have demonstrated that CAPTEM is active in grade 3 GEP-NETs regardless of the primary site.

Thor Halfdanarson, MD:
How are these therapies sequenced in patients with metastatic, small bowel/midgut NETs? First is typically consideration of surgical cytoreduction and resection of the primary small bowel tumor to prevent obstruction, bleeding, and other complications. In many cases, cytoreductive surgery for hepatic metastases can be done at the same time as resection of the primary tumor; in some cases, patients may be observed without any systemic therapy following cytoreductive surgery. Not only does cytoreductive surgery seem to prolong survival, but it can also effectively control the symptoms of functional NET syndromes. However, patients who are not considered candidates for surgery are commonly treated with an SSA as first-line systemic therapy. Either octreotide or lanreotide is used in these cases to inhibit tumor growth and control hormonal syndromes. Typically treatment begins with SSAs because they are better tolerated than most oncology drugs and they strongly inhibit tumor growth and effectively control functional syndrome symptoms in many patients. Although the response rates are low, they have been shown to significantly prolong PFS based on data from the PROMID and CLARINET studies. 

At the time of disease progression, the next most common systemic therapy is 177Lu-dotatate. However, for patients with liver-dominant disease, healthcare providers commonly consider hepatic artery embolization, which includes various modalities such as chemoembolization, bland embolization, and radioembolization. The different hepatic artery embolization procedures have not been compared but they are being evaluated in an ongoing trial. Bland embolization is recommended for most patients needing embolization therapy. There are certain contraindications and risks associated with PRRT. Patients with heavy-burden peritoneal carcinomatosis have an increased risk of bowel obstruction with 177Lu-dotatate, so this is often considered a contraindication. Several studies have shown that this agent is associated with a 2% to 3% risk of developing treatment-related myelodysplastic syndrome or leukemia. There may also be a further increased risk for these secondary malignancies after prior cytotoxic chemotherapy.

Less commonly, everolimus is considered as a second-line therapy for patients who do not meet criteria for 177Lu-dotatate or liver embolization, or as a later line of treatment. However, everolimus can have significant and chronic effects on quality of life, effects that are of particular concern in older or frail patients, patients with underlying lung disease, and patients with underlying diabetes.

Cytotoxic chemotherapy is generally ineffective for small bowel NETs. CAPTEM or FOLFOX (folinic acid, fluorouracil, and oxaliplatin) may be considered as a last-resort treatment in rare cases of particularly high-grade or aggressive disease.

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