Consensus Guidelines for the Management of Patients with Neuroendocrine Tumours (NETs)

1. Overview

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms arising from the diffuse neuroendocrine system. Their incidence has risen over the past two decades, largely due to improved imaging and heightened clinical awareness. The clinical behaviour of NETs ranges from indolent, welldifferentiated lesions to highly aggressive poorlydifferentiated carcinomas. Consequently, management requires a nuanced, evidencebased approach that integrates tumor biology, stage, functional status, and patient comorbidities.

The present consensus guideline, developed by an international panel of oncologists, surgeons, radiologists, pathologists, and endocrinologists, synthesises current evidence (LevelIIII) and expert opinion to provide practical recommendations for clinicians caring for adults with NETs.

2. Diagnosis and Staging

2.1 Clinical Presentation

Patients may present with:

• Incidental radiologic finding.
• Hormonerelated syndromes (e.g., flushing, diarrhea, hypoglycaemia).
• Masseffect symptoms (obstructive, pain).

2.2 Biochemical Workup

Baseline laboratory assessment should include:

• ChromograninA (CgA) elevated in 7080% of NETs.
• 5Hydroxyindoleacetic acid (5HIAA) for serotoninproducing tumours.
• Specific hormone panels when a functional syndrome is suspected (e.g., insulin, gastrin, glucagon).

2.3 Imaging

Imaging strategy depends on tumour grade and localisation:

• Crosssectional Imaging: Multiphasic contrastenhanced CT or MRI of the abdomen and pelvis for localisation and staging.
• Functional Imaging:
  • 68GaDOTATATE PET/CT for somatostatinreceptor positive lesions (preferred).
  • 18FFDG PET/CT for highgrade (G3) NETs or poorly differentiated neuroendocrine carcinomas.

2.4 Histopathology

All biopsies should be reviewed by an experienced pathologist. Key reporting elements:

• World Health Organization (WHO) grade (G1, G2, G3) based on Ki67 index and mitotic count.
• Differentiation (well vs. poorlydifferentiated).
• Immunohistochemistry: synaptophysin, chromogranin, somatostatinreceptor expression.

2.5 Staging System

The American Joint Committee on Cancer (AJCC) 8th edition staging system is recommended for pancreatic, gastrointestinal, and bronchial NETs. Staging should be documented using TNM descriptors and tumour grade.

3. Treatment Strategies

Treatment algorithms differ according to tumour grade, stage, functional status, and resectability. The following recommendations address each scenario.

3.1 CurativeIntent Surgery

Resection is the only potentially curative modality for localized disease.

• For G1G2 NETs <10cm without major vascular involvement, consider primary tumour resection with +/- regional lymphadenectomy.
• In functional tumours, surgery also ameliorates hormonal syndrome.
• For metastatic disease limited to the liver, cytoreductive surgery or hepaticdirected therapies (RFA, embolisation) are recommended when >70% of tumour burden can be removed.

3.2 Somatostatin Analogue Therapy

Firstline medical therapy for most advanced welldifferentiated NETs.

3.3 Targeted Therapies

• Everolimus: mTOR inhibitor; indicated for progressive, nonfunctional NETs of pancreas, gut, and lung after SSA failure (RADIANT3/4). GradeIII.
• Sunitinib: Tyrosinekinase inhibitor; approved for progressive pancreatic NETs after SSA (PhaseIII).

3.4 PeptideReceptor Radionuclide Therapy (PRRT)

68GaDOTATATE PETpositive, somatostatinreceptorpositive NETs benefit from 177LuDOTATATE.

• Indicated after progression on SSAs or in patients unsuitable for surgery.
• NETTER1 trial demonstrated a median PFS of 28.4months vs. 8.4months with highdose octreotide (LevelI).

3.5 Chemotherapy

Reserved for highgrade (G3) NETs and poorly differentiated neuroendocrine carcinomas.

• CAPTEM (capecitabine+temozolomide) is preferred for G2G3 pancreatic NETs.
• Platinumetoposide regimen for poorly differentiated NECs.

3.6 LiverDirected Therapies

For dominant hepatic disease:

• Transientorifice embolisation (TAE) or drugeluting embolisation (TACE) for unresectable liver metastases.
• Radioembolisation (Y90) for tumors refractory to TAE/TACE.

3.7 Management of Hormonal Syndromes

In addition to SSAs, consider:

• Interferon for refractory carcinoid syndrome.
• Telotristat ethyl for serotoninrelated diarrhea, adjunct to SSA.
• Specific agents (e.g., diazoxide, octreotide infusion) for insulinoma.

4. Surveillance and Followup

Longterm monitoring is essential due to the indolent nature of many NETs.

Any new symptoms should prompt immediate reassessment irrespective of schedule.

5. Multidisciplinary Care

Optimal outcomes are achieved through coordinated care within a NETspecialised centre. The core team includes:

• Medical oncologist with NET expertise.
• Endocrine surgeon or hepatobiliary surgeon.
• Radiologist experienced in functional imaging.
• Pathologist familiar with NET grading.
• Interventional radiologist for hepatic therapies.
• Endocrinologist for hormonal syndrome management.
• Nurse navigator and dietitian for supportive care.

Regular tumour board meetings should review each case, update treatment plans, and incorporate patient preferences.

6. Key Takehome Messages

• Accurate grading (Ki67) and staging are the foundation of all management decisions.
• Somatostatin analogues are firstline for most advanced welldifferentiated NETs.
• PRRT with 177LuDOTATATE provides durable disease control when SSAresponsive disease progresses.
• Surgery remains the only curative option; consider cytoreduction for liverdominant metastases.
• Tailored surveillance intervals balance early detection of progression with patient burden.
• Multidisciplinary teams improve survival, quality of life, and access to emerging therapies.