New Italian Guidelines for Managing Advanced GEP-NENs: A Patient’s Guide to the 2024 Recommendations

Table of Contents

• Key Points
• What Are GEP-NENs?
• Why These Guidelines Matter
• How the Guidelines Were Developed
• The GRADE Approach: How Evidence Was Evaluated
• Key Recommendations: The 15 Clinical Questions
• Imaging and Diagnosis (Questions 1, 2, and 12)
• Treatment After Surgery (Question 3)
• First-Line Treatment for Advanced Tumors (Question 4)
• PRRT for Progressive Disease (Question 5)
• Chemotherapy for Poorly Differentiated Tumors (Questions 6–8)
• Chemotherapy for Pancreatic NETs (Question 9)
• Surgery and Locoregional Treatments (Questions 10, 11, and 13)
• Clinical Implications: What This Means for Patients
• Limitations of the Guidelines
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• Patients with GEP-NENs should be managed by experienced, multidisciplinary teams.
• [68Ga]Ga-DOTA-peptides PET-CT is strongly recommended over Octreoscan for staging GEP-NETs.
• SSA is strongly recommended as first-line therapy for advanced slow-growing, SSTR-2-positive GEP-NETs.
• PRRT with lutetium-177 oxodotreotide is strongly recommended for patients whose disease progresses on SSA.
• Chemotherapy for GEP-NEC typically uses platinum-based regimens; temozolomide-based options are considered for select Ki-67 ranges and pancreatic NETs.

What Are GEP-NENs?

Neuroendocrine neoplasms (NENs) are a broad family of rare tumors that arise from neuroendocrine cells — specialized cells that behave partly like nerve cells and partly like hormone-producing endocrine cells. These tumors are marked by significant biological and clinical diversity.

Some NENs grow very slowly and behave in an indolent, low-grade manner, while others are high-grade and carry a poor prognosis. The behavior of the tumor is closely tied to how differentiated (how similar to normal cells) it appears under a microscope:

• Well-differentiated tumors (neuroendocrine tumors, or NETs) tend to grow slowly and are generally less aggressive.
• Poorly differentiated neoplasms (neuroendocrine carcinomas, or NECs) grow quickly and are much more aggressive.

NENs can arise anywhere in the body, but they most frequently originate in the gastroenteropancreatic (GEP) tract — the stomach, intestines, and pancreas — and in the thorax (chest area). Because these cells can produce and secrete peptides and biogenic amines (chemical messengers), NENs are broadly divided into two categories:

• “Functioning” tumors, which release hormones that cause distinct clinical syndromes (such as excessive insulin or serotonin production).
• “Non-functioning” tumors, which do not cause such syndromes. Non-functioning tumors represent the most prevalent subgroup and are the focus of this guideline.

Although historically considered rare, the incidence of NENs has greatly increased over recent decades. This trend is due, at least in part, to improved disease awareness, wider use of large-scale screening programs, and advances in diagnostic tools. Interestingly, because of their often indolent nature, NENs are actually more prevalent than gastric and pancreatic adenocarcinomas combined, making them a greater public health concern than previously recognized.

Why These Guidelines Matter

In recent years, major advances have been made in understanding NEN epidemiology, classification, biology, diagnostics, and treatment. The therapeutic arsenal for advanced disease has expanded significantly — and with it, the complexity of choosing the right treatment.

Treatment selection must take into account many factors, including:

• Extent of the disease
• Growth rate (how quickly the tumor is progressing)
• Primary site (where the tumor started)
• Histological grade (how abnormal the cells look)
• Functional status (whether the tumor secretes hormones)
• Patient characteristics and overall health
• Treatment availability
• Potential side effects and safety profile of each therapy

Given this complexity, the guideline authors emphasize that managing GEP-NENs requires a coordinated multidisciplinary approach by experienced teams. No single specialist can navigate this landscape alone; oncologists, surgeons, pathologists, radiologists, nuclear medicine physicians, endocrinologists, and others must work together.

How the Guidelines Were Developed

The Italian Association of Medical Oncology (AIOM), in collaboration with the Italian Association for Neuroendocrine Tumors (ITANET) and several other Italian scientific societies, has produced evidence-based clinical practice guidelines for GEP-NENs since 2013. This 2024 version represents the latest update. Here is how the panel went about its work:

The Working Group

The NEN Guidelines Working Group was selected by an AIOM representative (appointed as Guideline Coordinator) together with the Chairs of the other collaborating scientific societies, many of whom are also affiliated with ITANET. Multidisciplinarity was a core criterion. The team included:

• Oncologists
• Gastroenterologists
• Pathologists
• Radiologists
• Radiotherapists
• Surgeons
• Endocrinologists
• Nuclear medicine physicians
• Methodologists (experts in research methodology)
• Patients affected by cancer

Before final publication on the AIOM website (www.aiom.it) and approval by the Italian National Health Institute (ISS), the guideline was reviewed by external reviewers from major Italian scientific societies, including the Italian Society of Gastroenterology and Endoscopy, the Italian Society of Radiotherapy and Clinical Oncology, the Italian Society of Nuclear Medicine, the Italian Society of Endocrinology, the Italian Society of Oncological Surgery, the Italian Society of Medical Radiology and Interventional Radiology, the Italian Society of Dermatology and Venereology, the Italian Society of Pathology, and the Italian Society for the Study of the Pancreas. The guideline is also published on the ITANET website (www.ita-net.org).

Developing Clinical Questions

The panel used the PICO framework (Population, Intervention, Comparison, Outcomes) to structure clinical questions. Working group members selected, prioritized, and voted on these questions based on clinical needs, then ranked them by relative importance. Outcomes were identified as either “critical” or “important” based on priority.

In total, the main NEN guideline includes 56 clinical questions. For this publication, the authors selected 15 of those 56 questions, all focused on the management of non-functioning advanced GEP-NENs.

Searching the Evidence

For each question, a systematic literature search was conducted in three major medical databases — PubMed, Embase, and the Cochrane Library — without language or date restrictions. Key articles were cross-referenced to ensure all relevant literature was identified. The full search strategy and PRISMA flowcharts (diagrams showing how studies were screened and selected) for each question are available in the supplementary material of the original article.

The search process prioritized systematic reviews and randomized controlled trials (RCTs), which provide the strongest evidence. When these were not available, non-randomized studies were considered. Narrative reviews and case reports were excluded.

The GRADE Approach: How Evidence Was Evaluated

The guidelines used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach to assess the certainty of evidence. GRADE evaluation examines five main domains:

1. Study limitations — flaws in study design or conduct
2. Imprecision — wide confidence intervals or small sample sizes
3. Indirectness — evidence that doesn’t directly address the question
4. Inconsistency — conflicting results across studies
5. Publication bias — studies with negative results not being published

Based on study design, the certainty level starts at a pre-specified level (high for randomized controlled trials). If limitations are found in one or more of the five domains, the certainty can be downgraded. The final judgment is expressed as one of four levels:

• High — High confidence that the estimated effect is similar to the true effect.
• Moderate — Moderate confidence, but with limited possibility that the effect is substantially different.
• Low — Limited probability that the estimated effect matches the true effect, with high possibility it could be substantially different.
• Very low — Very limited probability that the estimate matches the true effect, with very high possibility of substantial difference.

How Recommendations Were Made

For benefit/harm balance, panel members voted on one of four options: in favor of the comparison, probably in favor of the comparison, probably in favor of the intervention, or in favor of the intervention. They also voted on the strength of the recommendation, choosing among:

• Strong in favor
• Conditional in favor
• Conditional against
• Strong against the intervention

According to the GRADE approach, a recommendation is adopted when it receives a simple majority — defined as 50% plus one of all eligible voting panel members (those with no conflicts of interest).

Key Recommendations: The 15 Clinical Questions

The table below summarizes all 15 clinical questions addressed in this guideline article, along with the strength of each recommendation and the overall certainty of the supporting evidence.

Imaging and Diagnosis (Questions 1, 2, and 12)

Question 1: Which imaging test is best for staging?

For staging GEP-NETs, the panel recommends that [68Ga]Ga-DOTA-peptides PET-CT should be considered the primary imaging option, rather than the older [111In]In-pentetreotide scintigraphy (commonly known as Octreoscan). This recommendation was rated strong in favor with moderate certainty of evidence.

What does this mean for patients? PET-CT using gallium-68-labeled DOTA-peptides is a modern, more sensitive imaging technique that can detect smaller or more numerous tumor deposits than the traditional Octreoscan. It provides better information for staging and treatment planning.

Question 2: Should patients with intermediate or high-grade tumors receive two PET scans?

For patients with G2-G3 GEP-NETs, the panel considered whether performing both a [68Ga]Ga-DOTA-peptides PET-CT and an [18F]F-FDG-PET-CT provides added value compared with the DOTA-peptide PET-CT alone. The recommendation was conditional in favor with low certainty: dual PET-CT could be taken into account in selected cases.

The FDG-PET scan measures glucose metabolism and can identify more aggressive areas within a tumor. This approach helps doctors understand the tumor’s biological behavior more completely, but it is not necessary for every patient.

Question 12: What is the best way to image liver metastases?

In patients with GEP-NETs and liver metastases, the panel suggests that abdominal MRI with biliary excretion could be preferred over standard MRI or CT scan with contrast. This was rated conditional in favor with low certainty. The biliary-excretion contrast agent may provide better detection and characterization of liver lesions, which is crucial for surgical planning.

Treatment After Surgery (Question 3)

After a patient with a non-functioning GEP-NET has undergone radical (complete) surgery to remove the primary tumor, should they receive adjuvant treatment with somatostatin analogs (SSA)?

The panel’s answer is no: adjuvant SSA should not be recommended. This recommendation was rated conditional against and was based on expert opinion, meaning there was insufficient high-quality evidence to support routine use of SSA after surgery. Patients who have had complete resection should instead be followed with regular monitoring. This avoids unnecessary treatment and potential side effects when there is no evidence of remaining disease.

First-Line Treatment for Advanced Tumors (Question 4)

For patients with non-functioning, advanced (locally advanced not resectable or metastatic) GEP-NET that is not rapidly progressive, has a low Ki-67 (a marker of cell proliferation; lower means slower-growing), and is SSTR-2-positive (meaning the tumor cells have receptors that somatostatin analogs can bind to), the panel made a strong recommendation in favor of using somatostatin analogs (SSA) as the primary option instead of follow-up without any therapy. The certainty of evidence was moderate.

In plain terms: if your tumor is slow-growing and has the right receptor profile, starting SSA treatment (rather than waiting and watching) is strongly supported by the evidence. SSAs help control tumor growth and can keep the disease stable for long periods.

PRRT for Progressive Disease (Question 5)

When a patient with advanced, SSTR-2-positive GEP-NET has progressed despite SSA treatment, what is the next step?

The panel issued a strong recommendation in favor of [177Lu]Lu-oxodotreotide — a form of peptide receptor radionuclide therapy (PRRT). The certainty of evidence was low.

PRRT works by attaching a radioactive isotope (lutetium-177) to a peptide that binds to somatostatin receptors on tumor cells, delivering targeted radiation directly to the cancer. This recommendation means that for patients whose disease is progressing on SSA, PRRT is a preferred subsequent treatment option.

Chemotherapy for Poorly Differentiated Tumors (Questions 6–8)

Neuroendocrine carcinomas (NECs) are the poorly differentiated, aggressive form of GEP-NENs. They grow quickly and require chemotherapy. The guideline addresses three chemotherapy scenarios for these patients.

Question 6: First-line chemotherapy for GEP-NEC

The panel recommends that cisplatin or carboplatin combined with etoposide should be proposed as first-line systemic chemotherapy for patients with advanced GEP-NEC. This was rated conditional in favor, with very low certainty of evidence. This platinum-based doublet has long been the standard of care for these aggressive tumors, though the evidence base is limited.

Question 7: A temozolomide-based alternative for certain Ki-67 ranges

For patients with GEP-NEC and a Ki-67 between 20% and 55% (a somewhat intermediate range, though still classified as NEC), the panel suggested that temozolomide-based chemotherapy could be preferred to cisplatin/carboplatin + etoposide as first-line treatment. This was rated conditional in favor with very low certainty.

Temozolomide is an oral chemotherapy drug that is generally easier to tolerate than platinum-based regimens. For certain patients whose tumors fall in this Ki-67 window, it may offer a reasonable alternative with less toxicity — though the evidence supporting this choice remains weak.

Question 8: Second-line treatment after progression

For patients with advanced GEP-NEC who progress after first-line treatment with cisplatin/carboplatin + etoposide, the panel considered whether second-line treatment with temozolomide, irinotecan, oxaliplatin, or fluoropyrimidine should be preferred over best supportive care alone. The recommendation was conditional in favor, with very low certainty of evidence.

This means that although the evidence is weak, offering one of these chemotherapy options to patients who have progressed on first-line treatment is considered reasonable, rather than switching exclusively to comfort-focused care.

Chemotherapy for Pancreatic NETs (Question 9)

For patients with advanced, progressive G1-G2 pancreatic neuroendocrine tumors (Pan-NETs), the panel considered whether temozolomide-based chemotherapy should be preferred over other chemotherapy options such as oxaliplatin or irinotecan.

The recommendation was conditional in favor of temozolomide-based chemotherapy, with very low certainty of evidence. This suggests that temozolomide may be a good choice for treating progressive pancreatic NETs, but the evidence is not robust enough to make a stronger statement. The choice between chemotherapy agents should be individualized based on the patient’s specific situation.

Surgery and Locoregional Treatments (Questions 10, 11, and 13)

Question 10: Surgery for borderline resectable primary tumors with liver metastases

In patients with non-functioning GEP-NEN whose primary tumor is borderline resectable and who have concomitant liver metastases where more than 90% of the liver disease is expected to be resected, the panel suggested that a surgical approach could be preferred over a non-surgical approach. This was rated conditional in favor with very low certainty.

This is a highly selected group of patients. The key condition — that more than 90% of liver disease can be removed — means surgery is only considered when the metastatic burden in the liver is largely removable. Patients who meet this criterion may benefit from aggressive surgical management.

Question 11: Vascular interventional locoregional treatments

For patients with non-functioning GEP-NEN, the panel considered whether vascular interventional locoregional treatments (such as hepatic arterial embolization or chemoembolization, which cut off or deliver treatment directly to the blood supply of liver tumors) should be preferred over other therapies. The recommendation was conditional in favor with low certainty of evidence.

These treatments are typically used for patients with liver-dominant disease who are not candidates for surgery. The panel’s conditional endorsement reflects that these approaches can be useful, but patient selection is important.

Question 13: Liver transplantation

The guideline also addressed whether liver transplantation should be considered in patients with GEP-NETs with concomitant liver metastases. The full text of this recommendation was not available in the published article excerpt, but its inclusion in the guideline reflects the ongoing interest in transplantation as a potential option for carefully selected patients with liver-only or liver-dominant metastatic disease.

Clinical Implications: What This Means for Patients

These guidelines provide a clear roadmap for doctors treating patients with advanced non-functioning GEP-NENs. Several messages stand out:

• Modern imaging matters. Ga-68 DOTA-peptide PET-CT is now the preferred staging tool over Octreoscan. In selected intermediate/high-grade cases, adding FDG-PET provides valuable information about tumor aggressiveness.
• Don’t overtreat after complete surgery. Adjuvant SSA after radical resection is not recommended. Monitoring is the standard approach.
• Start SSA early in advanced slow-growing NETs. Rather than watchful waiting, strong evidence supports initiating SSA in patients with advanced, non-functioning, SSTR-2-positive, low Ki-67 tumors.
• PRRT is a key second-line option. For patients who progress on SSA, lutetium-177 oxodotreotide (PRRT) is strongly recommended.
• Chemotherapy choices depend on tumor type and Ki-67. Platinum-based regimens remain the backbone for NECs, but temozolomide-based approaches may be appropriate for certain Ki-67 ranges and for pancreatic NETs.
• Surgery and liver-directed therapies have a role. In highly selected patients (e.g., >90% of liver disease resectable), surgery can be preferred. Liver-directed interventional treatments are also reasonable options.

Perhaps the most important takeaway: GEP-NENs are complex, and treatment must be individualized. No single recommendation fits every patient. The panel emphasizes that multidisciplinary management by experienced teams remains essential to achieve the best outcomes.

Limitations of the Guidelines

It is important for patients to understand that this guideline — like all medical guidelines — has limitations:

• Low certainty of evidence for many recommendations. Of the 15 recommendations, only two (Questions 1 and 4) were supported by moderate certainty evidence. Six recommendations were based on very low certainty, meaning the true effect could be substantially different from what the evidence suggests.
• One recommendation relied on expert opinion. The recommendation against adjuvant SSA (Question 3) was not based on direct clinical trial evidence but on expert consensus.
• Rare disease challenges. Because GEP-NENs are uncommon, conducting large, high-quality randomized controlled trials is difficult. Many treatment decisions are supported by smaller, non-randomized studies.
• Only 15 of 56 questions were presented. This publication focuses on non-functioning advanced GEP-NENs; other aspects of NEN management are covered in the full guideline.
• Rapidly evolving field. New treatments and data are continually emerging. Recommendations may change as new evidence becomes available.
• Context-specific recommendations. These guidelines were developed for the Italian healthcare context, though they draw on international evidence. Availability of specific treatments may vary by country.

Recommendations for Patients

If you or a loved one has been diagnosed with a GEP-NEN, here are several practical points based on these guidelines:

1. Seek a specialized, multidisciplinary center. The guidelines strongly recommend that GEP-NEN patients be treated by experienced teams. Look for centers with dedicated neuroendocrine tumor programs (often designated as ENETS Centers of Excellence).
2. Ask about modern imaging. If staging is being done, ask whether [68Ga]Ga-DOTA-peptides PET-CT is available. It is now the preferred imaging tool over Octreoscan for staging.
3. Discuss Ki-67 and SSTR status. These biomarkers guide treatment selection. Know your tumor’s Ki-67 index (proliferation rate) and somatostatin receptor status, as they directly influence whether SSA, PRRT, or chemotherapy is recommended.
4. Understand the rationale for SSA therapy. If your tumor is slow-growing and SSTR-positive, SSA is the first-line standard. It can stabilize disease for extended periods with relatively mild side effects.
5. If you progress on SSA, ask about PRRT. Lutetium-177 oxodotreotide is strongly recommended for patients who progress on SSA. It delivers targeted radiation to tumor cells and can be highly effective.
6. Don’t expect chemotherapy if you have a low-grade NET. Chemotherapy is mainly reserved for poorly differentiated NECs or for progressive pancreatic NETs where other options have been exhausted. Temozolomide-based regimens are emerging as preferred options in select situations.
7. Surgical evaluation is important. Even with metastatic disease, surgery may be an option if a high percentage of liver disease can be removed. Always have your case reviewed by a surgical team experienced in NENs.
8. Participate in shared decision-making. Several recommendations in this guideline are “conditional,” meaning the right choice depends on individual circumstances. Discuss the benefits, risks, and uncertainties of each option with your care team.

Remember that guidelines are not rigid rules — they are tools to support decision-making. Your doctors will adapt these recommendations to your specific situation, preferences, and overall health.

Frequently Asked Questions

What is the difference between well-differentiated and poorly differentiated GEP-NENs?

Well-differentiated tumors, called neuroendocrine tumors or NETs, tend to grow slowly and are generally less aggressive. Poorly differentiated neoplasms, called neuroendocrine carcinomas or NECs, grow quickly and are much more aggressive. This difference is based on how similar the cells look to normal cells under a microscope.

What imaging test is now preferred for staging GEP-NETs?

The guidelines strongly recommend using a [68Ga]Ga-DOTA-peptides PET-CT scan instead of the older Octreoscan for staging. This modern PET-CT is more sensitive and can detect smaller or more numerous tumor deposits, providing better information for staging and treatment planning. The recommendation is based on moderate certainty evidence.

Should I receive somatostatin analog therapy after complete surgery?

No. The panel recommends against adjuvant somatostatin analog (SSA) treatment after radical surgery for non-functioning GEP-NET. This recommendation is based on expert opinion because there is insufficient high-quality evidence to support routine use. After complete resection, regular monitoring is the standard approach.

What is the first-line treatment for advanced slow-growing non-functioning GEP-NET?

For patients with advanced, non-functioning, not rapidly progressive, low Ki-67, SSTR-2-positive GEP-NET, the panel strongly recommends starting somatostatin analogs (SSA) as the primary option rather than follow-up without therapy. This is supported by moderate certainty evidence. SSAs help control tumor growth and can keep the disease stable.

What treatment is recommended if my tumor progresses on SSA?

If your advanced SSTR-2-positive GEP-NET progresses despite SSA treatment, the guidelines strongly recommend peptide receptor radionuclide therapy (PRRT) with lutetium-177 oxodotreotide. PRRT delivers targeted radiation directly to tumor cells. The recommendation is strong in favor, though the certainty of evidence is low.

Is chemotherapy used for low-grade NETs?

Chemotherapy is mainly reserved for poorly differentiated NECs or for progressive pancreatic NETs where other options have been exhausted. For GEP-NEC, first-line chemotherapy is cisplatin or carboplatin plus etoposide. Temozolomide-based regimens may be preferred for certain Ki-67 ranges and for pancreatic NETs, but evidence is weak.

When can surgery be considered for metastatic GEP-NEN?

Surgery could be preferred in patients with a borderline resectable primary tumor and liver metastases when more than 90% of liver disease is expected to be resected. The recommendation is conditional and based on very low certainty evidence. It applies only to this highly selected group, and multidisciplinary review is essential.

Can a second opinion change the treatment plan for advanced GEP-NEN?

For advanced GEP-NEN, many guideline recommendations are conditional rather than strong, and most are based on low or very low certainty evidence. This means the right choice depends on individual tumor grade, Ki-67 index, somatostatin receptor status, extent of disease, and patient health. Different experienced specialists may reasonably weigh the benefits and risks differently, especially for choices like surgery, liver-directed therapies, or temozolomide-based chemotherapy. A second opinion can help confirm that your treatment plan reflects the latest evidence and your specific situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article Title: Clinical practice guidelines for the management of non-functioning advanced GEP-NENs: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology (AIOM) in collaboration with the Italian Association for Neuroendocrine Tumors (ITANET).

License: CC BY-NC-ND (open access)

Authors: Spada F, Gelsomino F, Rinzivillo M, Cinquini M, Fittipaldo VA, Tralongo A, Moschetti I, Albertelli M, Ambrosini V, Amoroso V, Antonuzzo L, Badalamenti G, Bajetta E, Baldari S, Barberis M, Berruti A, Bertani E, Bonomo G, Bodei L, Buzzoni R, Brizzi MP, Campana D, Capurso G, Casadei R, Castellano M, Cingarlini S, Cives M, Colao AM, Coppa J, Cremonini N, Davì MV, De Angelis CG, de Braud F, De Robertis R, Faggiano A, Falconi M, Fassan M, Ferolla P, Ferone D, Filice A, Fiore F, Funicelli L, Granata V, Giuffrida D, Grana CM, Grimaldi F, Ibrahim T, La Salvia A, Laghi A, Luppi G, Maccauro M, Marconcini R, Massironi S, Mazzaferro V, Merola E, Milione M, Modica R, Ortolani S, Papotti MG, Partelli S, Pelosi G, Pusceddu S, Ramundo V, Ravizza D, Razzore P, Reimondo G, Ricci C, Rindi G, Rizzo FM, Rossi RE, Tafuto S, Tiberio GAM, Versari A, Vigorito R, Zatelli MC, Di Maio M, Perrone F, Cinieri S, Panzuto F, Fazio N.

Corresponding Authors: Dr. Nicola Fazio (European Institute of Oncology, IEO, IRCCS, Milan, Italy; nicola.fazio@ieo.it) and Dr. Francesco Panzuto (Sant’Andrea University Hospital, Sapienza University of Rome, Rome, Italy; francesco.panzuto@uniroma1.it)

Journal: ESMO Open, Volume 10, Issue 11, 2025

DOI: https://doi.org/10.1016/j.esmoop.2025.105878

Publisher: Published by Elsevier Ltd on behalf of European Society for Medical Oncology. Open access article under the CC BY-NC-ND license.

Note: This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and does not replace professional medical advice. Always consult your healthcare team about your specific condition and treatment options.