Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors

Publication Date: September 28, 2023
Last Updated: September 29, 2023

Treatment

I. General Recommendations for G1–G3 GEP-NETs

Recommendation 1.1

Selection of initial treatment options and sequencing of treatments following progression should consider patient and tumor characteristics such as hormone status, primary site, grade, extent and burden of disease, growth rate, comorbidities, and somatostatin receptor (SSTR) positivity, and should be discussed within a multidisciplinary team (MDT) when possible. (IC, B, L, S)
Notes:
  • While local therapy options are outside the scope of this systematic review and guideline, surgical cytoreduction (if feasible to achieve >70–90% reduction in tumor volume) or other types of liver-directed therapy (e.g., embolization) may be considered for patients with hepatic disease, and preferably should be discussed within the setting of an MDT.
  • In addition, while the use of somatostatin analogs (SSAs) for symptom management is outside the scope of these guidelines, SSAs are often used indefinitely in patients with functional NETs.
1048203

Recommendation 1.2

All treatment decisions should be guided by a shared decisionmaking approach involving the patient, considering patient values and preferences, potential benefit and risk of harm, and patient characteristics and circumstances, which could include factors such as comorbidities, performance status, geographic location, and access to care. (IC, B, L, S)
1048203

Recommendation 1.3

Patients should be assessed for SSTR positivity using SSTR positron emission tomography (PET) with 68Ga-DOTA-peptides or 64Cu-DOTATATE at baseline. (IC, B, L, S)
1048203

II. Systemic Therapy for Metastatic G1–G2 Gastrointestinal NETs (GI-NETs)

First-line Systemic Therapy for G1–G2 GI-NETs

Recommendation 2.1
SSAs (octreotide or lanreotide) are recommended for SSTR-positive and/or functional metastatic G1–G2 GI-NETs. (EB, B, L, W)
Qualifying statements:
  • Observation and surveillance with anatomic imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) every 3–6 months, with extension to 6–12 months for patients with consistently stable disease, can be considered for patients with low volume metastatic G1–G2 GI-NETs, and an absence of symptoms from tumor burden or a functional tumor. For patients with bone-dominant metastases, follow-up with SSTR-PET imaging is recommended, due to the limited sensitivity of anatomic imaging for these metastases.
  • Evidence supporting SSA use for tumor control is strongest in patients with low or low-intermediate grade SSTR-positive tumors (Ki-67 <10%).
1048203
Recommendation 2.2
In the less common circumstance of patients with SSTR-negative G1–G2 GI-NETs, everolimus may be considered as a systemic treatment option. (EB, B, L, W)
1048203

Second- or Later-line Systemic Therapy for G1–G2 GI-NETs

Recommendation 2.3
Peptide receptor radionuclide therapy (PRRT) is recommended for patients with SSTR-positive metastatic G1–G2 GI-NETs that have progressed following treatment with SSAs. (EB, B, M, W)
Qualifying statements:
  • In addition to PRRT, continuation of treatment with SSAs is recommended for functional tumors; there is insufficient efficacy data to suggest that SSAs should be continued in patients with non-functional tumors at disease progression.
  • Patients with low volume of metastases should weigh the potential benefits of PRRT with the potential risk of long-term bone marrow toxicities.
1048203
Recommendation 2.4
Everolimus is recommended for patients with non-functional metastatic G1–G2 GI-NETs that are SSTR-negative, or SSTR-positive for whom PRRT is not an option due to higher risk of hematologic toxicity. (EB, B, M, W)
Qualifying statement:
  • Although the evidence base for everolimus is in patients with non-functional tumors, this agent may also be considered as later-line therapy for functional tumors.
1048203

III. Systemic Therapy for Metastatic G1–G2 Pancreatic NETS (panNETs)

First-line Systemic Therapy for G1–G2 panNETs

Recommendation 3.1
SSAs (octreotide or lanreotide) are recommended for SSTR-positive and/or functional metastatic G1–G2 panNETs. (EB, B, L, W)
Qualifying statements:
  • Observation and regular anatomic imaging (CT or MRI) every 3–6 months, with extension to 6–12 months for patients with consistently stable disease, can be considered for patients with low volume metastatic G1–G2 panNETs, and an absence of symptoms from tumor burden or a functional tumor. For patients with bone-dominant metastases, follow-up with SSTR-PET imaging is recommended, due to the limited sensitivity of anatomic imaging for these metastases.
  • Evidence supporting SSA use for tumor control is strongest in patients with low or low-intermediate grade SSTR-positive tumors (Ki-67 <10%).
1048203
Recommendation 3.2
Chemotherapy (e.g., capecitabine and temozolomide [CAPTEM]) is recommended for patients with G1–G2 higher volume panNETs and/or symptoms related to tumor burden. (EB, B, L, W)
Qualifying statement:
  • In the rare circumstance of patients with higher volume panNETs and/or symptoms related to tumor burden who are not candidates for chemotherapy, PRRT for patients with SSTR-positive tumors, or sunitinib or everolimus are recommended.
1048203
Recommendation 3.3
Chemotherapy (e.g., CAPTEM), everolimus, or sunitinib may be offered to SSTR-negative patients with G1-G2 panNETs. (EB, B, L, W)
1048203

Second- or Later-line Systemic Therapy for G1–G2 panNETs

Recommendation 3.4
PRRT for SSTR-positive tumors, chemotherapy (e.g., CAPTEM), everolimus, or sunitinib are recommended as second or later-line therapy for patients with G1–G2 panNETs, with choice of therapy depending on patient characteristics and goals of treatment. (EB, B, M, W)
Note:
  • At this time, there is insufficient evidence to recommend a particular sequence of systemic therapy options following progression on SSAs for patients with G1–G2 panNETs; the order of options in Recommendation 3.4 is not intended to suggest a particular sequencing strategy.

Qualifying statements:
  • In addition to PRRT, continuation of treatment with SSAs is recommended for functional tumors; there is insufficient efficacy data to suggest that SSAs should be continued in patients with non-functional tumors at disease progression.
  • RCTs have not been published to date with PRRT in panNETs.
  • Patients with low volume of metastases should weigh the potential benefits of PRRT with the potential risk of long-term bone marrow toxicities.
  • Everolimus and sunitinib are cytostatic agents, and are associated with tumor stability, while chemotherapy and PRRT are associated with tumor response.
  • Comorbidities may be considered during selection of therapy; sunitinib is not recommended for patients with uncontrolled hypertension, and everolimus is not recommended for patients with uncontrolled diabetes.
1048203

IV. Systemic Therapy for G3 GEP-NETs

Recommendation 4.1

The range of systemic options outlined in previous recommendations for G1–G2 NETs may be recommended for well-differentiated G3 GEP-NETs. (IC, B/H, VL, W)
Note:
  • G3 GEP-NETs are a relatively newly defined category within neuroendocrine neoplasms, and include a wide Ki-67 proliferation index range (i.e., >20%). Several trials, as outlined in the full-text guidelinea are currently underway to inform specific therapy options, and may be used to inform recommendations for subpopulations of G3-NETs patients in the future.

Qualifying statements:
  • SSAs alone may be considered as first-line treatment in select cases (i.e., SSTR-positive, low volume of disease, low tumor-related symptom burden, less rapid rate of growth).
  • PRRT with or without SSAs is a potential treatment option for patients with SSTR-positive G3 GEP-NETs with characteristics such as less rapid rate of growth, and lower volume of disease who have progressed on SSAs alone.
  • Chemotherapy may be particularly effective for patients with characteristics such as higher proliferation index and/or mitotic rate, rapid rate of growth, and bulky disease. Evidence for cytotoxic chemotherapy is strongest for panNETs.
a Del Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol. 2023 Sept 29. doi:10.1200/JCO.23.01529
1048203

Recommendation Grading

Disclaimer

The information in this patient summary should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health.

Overview

Title

Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors

Authoring Organization

Publication Month/Year

September 28, 2023

Last Updated Month/Year

February 14, 2024

Document Type

Guideline

Country of Publication

US

Target Patient Population

Patients with advanced or metastatic well-differentiated G1-G3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including tumors arising in sites such as the pancreas, stomach, small intestine, colon, rectum, and appendix.

Target Provider Population

Oncologists, Nuclear Medicine

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Assessment and screening, Treatment

Diseases/Conditions (MeSH)

D009362 - Neoplasm Metastasis, D006528 - Carcinoma, Hepatocellular, D018278 - Carcinoma, Neuroendocrine, D018358 - Neuroendocrine Tumors, D008113 - Liver Neoplasms, D018323 - Hemangioendothelioma, Epithelioid, D018197 - Hepatoblastoma

Keywords

Neuroendocrine tumor, Neuroendocrine neoplasm, pancreatic neuroendocrine tumor, gastrointestinal neuroendocrine tumor, GEP-NETs

Source Citation

Del Rivero J, Perez K, Kennedy EB, et al. Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline. J Clin Oncol. 2023 Sept 29. doi:10.1200/JCO.23.01529

Supplemental Methodology Resources

Evidence Tables

Methodology

Number of Source Documents
83
Literature Search Start Date
January 1, 2005
Literature Search End Date
November 1, 2022