Material and methods

The recommendations presented in this document are the result of a comprehensive literature review and a structured consensus process based on the Delphi methodology. This Delphi initiative was conceived as a pragmatic, real-world, practice-oriented process aimed at harmonizing routine clinical management of PRRT across centers within a regional multidisciplinary network, rather than redefining indications or addressing investigational strategies. The expert panel comprised 10 specialists with recognized expertise in the management of neuroendocrine tumors, representing endocrinology (n = 3), nuclear medicine (n = 3), medical oncology (n = 3), and radiology (n = 1). All panelists were members of the GGNET.

Experts were selected among GGNET members based on predefined, objective eligibility criteria reflecting real-world clinical expertise in the management of neuroendocrine tumors and PRRT. Eligibility criteria included active involvement in multidisciplinary tumor boards managing NET patients, regular participation in clinical decision-making related to PRRT, and direct experience in the follow-up of patients treated with PRRT. Multidisciplinary representation and hands-on clinical experience were prioritized in panel selection, in line with the practice-oriented scope of the consensus. Participation in PRRT-related clinical trials, contribution to PRRT-relevant publications or guidelines, cumulative experience in PRRT administration, and annual clinical exposure to PRRT-treated patients were considered supportive indicators of expertise when applicable, but were not mandatory inclusion criteria.

A systematic literature search was conducted in PubMed, covering publications up to January 31, 2024. The search terms included: “management of NETs,” “treatment guidelines for NETs,” “PRRT in NETs,” “somatostatin receptor expression in NETs,” “evaluation of treatment with PRRT,” and “follow-up of patients with NETs.” National and international clinical guidelines, original studies, and previously published consensus documents were also reviewed. The results of this review were used to identify key domains of routine clinical practice and areas of variability relevant to PRRT delivery, which informed the development of the Delphi statements.

Based on this review, a structured questionnaire was designed, including statements on patient selection, treatment administration, response assessment, imaging, biomarker use, and follow-up after PRRT. The statements were generated by a multidisciplinary core group comprising one medical oncologist, one nuclear medicine physician, and one endocrinologist, who drafted the initial items based on clinical relevance and identified practice gaps. In February 2024, the questionnaire was distributed to all panelists, who responded individually and anonymously using a structured Likert scale.

A single-round Delphi survey was conducted. Consensus was predefined as agreement by at least 70% of panelists rating a statement as “agree” or “strongly agree.” Following completion of the survey, a structured face-to-face consensus meeting was held on March 18, 2024, with a duration of approximately three hours. During this meeting, all statements were discussed in detail to contextualize their clinical applicability and to address areas of disagreement.

Statements that did not initially reach the predefined consensus threshold were re-voted after discussion. No statements were reformulated, merged, or eliminated during the process, as the discussion focused on interpretation and practical implementation rather than modification of item content. An external company provided logistical support for the face-to-face meeting but did not participate in item generation, voting, or interpretation of the results.

The final recommendations and the level of agreement for each statement are summarized in Table 1. Detailed agreement percentages are reported for each statement, allowing both consensus and variability across items to be explicitly assessed.

Recommendations | Level of agreement
Patient selection | 1 | 2 | 3 | 4
Indications
Statement 1. Any patient with a well-differentiated, grade 1–3 (Ki67 ≤ 55%), SSTR-positive, progressive, unresectable or metastatic GEP-NET is a potential candidate for peptide receptor-targeted radionuclide therapy (PRRT) | 0 | 0 | 10% | 90%
Statement 2. PRRT should be assessed on a case-by-case basis in: |  |  |  | 
2.1: Bronchopulmonary or thymic NETs | 0 | 10% | 0 | 90%
2.2: Pheochromocytoma-paragangliomas | 0 | 0 | 10% | 90%
2.3: Other neoplasms with SSTR expression | 0 | 0 | 10% | 90%
Statement 3. The eligibility of a patient to receive PRRT should be discussed in a multidisciplinary committee | 0 | 0 | 0 | 100%
Somatostatin receptor expression
Statement 4. A patient is deemed a candidate for PRRT if lesions detected on morphological imaging tests have positive uptake on functional imaging with somatostatin analogues (PET-SSTR or scintigraphy) | 0 | 10% | 20% | 70%
Statement 5. A lesion is considered to be SSTR positive if its uptake is higher than that of the liver in the case of PET-SSTR or [111In]-pentetreotide or [99mTc]Tc-octreotide scintigraphy | 0 | 0 | 0 | 100%
Statement 6. PET-SSTR is considered the functional imaging test of choice for determining SSTR expression | 0 | 0 | 0 | 100%
Statement 7. If PET-SSTR is not accessible, the following alternatives are considered valid: |  |  |  | 
7.1. Referral of the patient to a center with PET-SSTR availability (preferred option was considered) | 0 | 0 | 0 | 100%
7.2. If the above was not possible: the performance of [111In]In-pentetreotide or [99mTc]Tc-octreotide scintigraphy | 0 | 0 | 30% | 70%
Statement 8. PET-SSTR may be considered in patients with previous negative [111In]In-pentetreotide or [99mTc]Tc-octreotide scintigraphy | 0 | 0 | 10% | 90%
Usefulness of [18F]-Fluorodeoxyglucose ([18F]-FDG) PET
Statement 9. The [18F]-FDG PET complements the information from the PET-SSTR, identifying tumor heterogeneity and optimizing the selection of patients who are candidates for PRRT | 0 | 10% | 0 | 90%
Statement 10. The performance of FDG-PET could be particularly useful in the following scenarios: |  |  |  | 
10.1. Discordance between imaging tests for SSTR and morphological imaging tests | 0 | 0 | 0 | 100%
10.2. Rapid clinical or radiological progression (< 6 months) to previous therapies administered | 0 | 0 | 0 | 100%
10.3. Well-differentiated grade 3 or high grade 2 NETs (Ki 67 > 5%) | 0 | 0 | 0 | 100%
Other parameters
Statement 11. Patients who are candidates for PRRT must be in good overall health and have adequate bone marrow reserve, kidney, and liver function | 0 | 0 | 30% | 70%
Statement 12. The risk–benefit ratio of PRRT administration should be assessed in patients with the following conditions: |  |  |  | 
12.1. Kidney failure (creatinine clearance less than 40 ml/min) | 0 | 0 | 10% | 90%
12.2. Low bone marrow reserve (leukocytes < 2 g × 109/L, Hb < 8 g/dL or platelets < 75 × 109/L) | 0 | 0 | 10% | 90%
12.3. Impaired liver function (bilirubin > 3 times normal, albumin < 3 g/dL or INR > 1.5) | 0 | 10% | 10% | 80%
12.4. Extensive peritoneal carcinomatosis | 0 | 0 | 10% | 90%
Statement 13. Close monitoring for myelotoxicity is recommended in high-risk patients: |  |  |  | 
13.1. Older than 70 years | 0 | 0 | 30% | 70%
13.2. Kidney failure (clearance 40–60 ml/min) | 0 | 0 | 10% | 90%
13.3. Presence of previous cytopenias | 0 | 0 | 0 | 100%
13.4. Extensive metastatic bone disease (> 50% of the skeleton) | 0 | 0 | 0 | 100%
13.5. Prior chemotherapy, especially with alkylating agents | 0 | 0 | 0 | 100%
13.6. Previous radiotherapy | 0 | 0 | 10% | 90%
Treatment
Statement 14. Laboratory tests (including at least CBC, kidney and liver function) should be performed 2 weeks before the first cycle, at 4 and 6 weeks after each cycle, and at 3, 6 and 12 months after completion of treatment | 0 | 0 | 10% | 90%
Statement 15. Routine mid-treatment morphological or functional imaging tests are not recommended. They should be considered in the following cases: |  |  |  | 
15.1. Clinical deterioration | 0 | 0 | 10% | 90%
15.2. Impaired liver function | 0 | 10% | 10% | 80%
15.3. Patients at high risk of progression (high grade, high tumor burden, rapid progression to previous lines…) | 0 | 10% | 0 | 90%
Response assessment and follow-up
Morphological imaging tests
Statement 16. Morphological imaging tests, including multiphasic thoracoabdomino-pelvic computed tomography (CT) and/or magnetic resonance imaging (MRI), represent the gold standard for response assessment and follow-up after PRRT | 0 | 10% | 10% | 80%
Statement 17. Response evaluation shall be performed using the RECIST 1.1 response evaluation criteria | 0 | 0 | 40% | 60%
Statement 18. Morphological imaging tests will be performed at 3 and 6 months after the end of PRRT and every 6 months thereafter | 0 | 0 | 10% | 90%
Statement 19. The frequency of morphological imaging may be modified according to patient-related factors and/or tumor aggressiveness | 0 | 0 | 0 | 100%
Functional imaging tests
Statement 20. Functional imaging for somatostatin receptors should be performed 9–12 months after completion of PRRT | 0 | 0 | 10% | 90%
Statement 21. It is not recommended to perform routine periodic somatostatin receptor imaging at follow-up after PRRT | 0 | 30% | 10% | 60%
Statement 22. Imaging for SSTR could be considered in follow-up after PRRT therapy in the following cases: |  |  |  | 
22.1. Clinical deterioration | 0 | 0 | 10% | 90%
22.2. Suspected progression on morphological imaging | 0 | 0 | 10% | 90%
22.3. Small primary tumors | 0 | 0 | 20% | 80%
22.4. Nodal, bone or infiltrative disease | 0 | 0 | 20% | 80%
Statement 23. Changes in PET-SSTR lesion avidity (SUV) should not be considered as the sole criterion for decision making in response assessment or follow-up | 0 | 0 | 10% | 90%
Statement 24. Periodic [18F]-FDG PET scans are not routinely recommended for follow-up after PRRT | 10% | 0 | 10% | 80%
Statement 25. [18F]-FDG PET could be useful: |  |  |  | 
25.1. To resolve discrepancies between morphological and functional imaging findings for SSTR | 0 | 0 | 10% | 90%
25.2. When tumor dedifferentiation is suspected | 0 | 0 | 0 | 100%
Statement 26. It is recommended that the same SSTR imaging modality should be used before and after PRRT |  |  | 20% | 80%
Circulating response biomarkers
Statement 27. The routine use of non-specific circulating biomarkers, such as chromogranin A, in response assessment and follow-up after PRRT is not recommended | 0 | 10% | 40% | 50%
Statement 28. The determination of 5-hydroxyindoleacetic acid (5-HIAA) in small bowel NETs with associated carcinoid syndrome may be useful | 0 | 0 | 0 | 100%
Statement 29. Determination of specific neuropeptides could be useful in case of functioning pancreatic NETs | 0 | 0 | 0 | 100%