The management of Neuroendocrine Tumors (NETs) has been organized in reference centers since over 10 years, enabling accurate diagnosis, customized management, and development of clinical research programs leading to approval of targeted therapies.
Rare cancer of the neuroendocrine system
Neuroendocrine neoplasms (NENs) are rare malignancies, but their incidence and prevalence is increasing. Given these patients’ often long survival, the prevalence of NENs is now known to be significantly higher than gastric, pancreatic, esophageal or hepatobiliary adenocarcinomas.
The management of NENs in Europe has been organized in reference centres for almost 15 years, enabling accurate diagnosis, customized management, and development of translational and clinical research programs or clinical trials leading to approval of several therapies. NENs can arise from any organ of the body but most commonly in the small bowel, pancreas and lung.
Diagnosis
The biological behaviour of NENs varies widely and is influenced by tumour grade based on Ki67 proliferation index staining on pathology slides of tumour specimens. Division is made between well differentiated neuroendocrine tumours (NET) Grade 1 Ki67: <3% of tumour cells; Grade 2, Ki67:3-20%; and grade 3, Ki67: >20% and poorly differentiated neuroendocrine carcinomas (NECs) with Ki67: >20%. Additionally, stage (involving local and distant metastatic spread and local tumour expansion) and primary site of origin also affect the biological behaviour and, therefore, choice of management of patients with NENs.
Recommendations
In the care for NEN, an expert multidisciplinary meeting to guide management decisions remains paramount.
The most sensitive imaging modality is based on the 68Gallium, 64Cupper Somatostatin Analog PET imaging in combination with CT and MRI. In localized pancreatic disease endoscopic ultrasound may play an important role.
Localized NENs with only local spread may undergo surgical resection. However, treatment options for metastatic NEN are broad and encompass therapies for control of hormonal hypersecretion, surgery, liver directed therapies and systemic therapies including radionuclide therapy.
Surgery remains the only treatment option which may lead to cure. While this should be considered for all patients, surgery may be difficult and patients should be referred to high-volume centres in order to evaluate the best approach and to avoid complications related to surgery such as short bowel syndrome in small intestinal NETs.
Somatostatin analogs are the first line therapy for hormonal syndrome control, and the recently approved tryptophan hydroxylase inhibitor telotristate ethyl can be used in serotonin induced diarrhoea in small intestinal NET patient’s refractory to somatostatin analog treatment. The anti-tumour therapies have advanced with the randomised studies in the last decades. Somatostatin analogs are usually first line therapy for tumour control in well differentiated (G1-2) NETs. Molecular targeted agents e.g. everolimus or sunitinib are often used as second line for slowly progressive pancreatic NETs. Everolimus has also been licensed for use in intestinal NET and bronchial NETs. However, the greatest advance in the last decades has been Peptide Receptor Radionuclide Therapy (PRRT) with 177Lutetium DOTATATE or DOTATOC. Based on recent publications in the medical literature, this treatment is moving up in the current treatment algorithms. Expression of somatostatin receptors is a prerequisite for this approach which is also known as theranostics. Chemotherapy for large volume or more rapidly progressive NET especially in the pancreas includes capecitabine temozolomide-based regimen, and for poorly differentiated NEC platinum-based regimens are often used as first-line treatment.
Novel treatment options must be explored, especially in the high-grade cohort. While prognostic factors are well-defined in the literature, new biomarkers and predictors of treatment response are greatly needed and will be expanded in the future by the molecular profiling of these tumours. Imaging options and modalities are still being improved and expanded, leading to improved staging of tumours. Finally, the frequently seen long patient survival and multiple sequential therapies with potential adverse effects, places strong emphasis on the importance of quality of life and survivorship in this patient population. This must certainly remain to be prioritized in the future and highlights the crucial role patient support and advocacy groups have in the holistic management of these patients.
Access to reference centres
Improving the access to reference centres for patients with NENs is therefore essential since these patients often have multiple therapeutic options which have to be prioritized in the multidisciplinary team discussions. These recommendations form the cornerstone for further discussion with the NEN patient with regard to their personal treatment algorithm and their personal wishes and expectations.As a result, long life expectancy is the main aim of this approach when treated according to clinical practice guidelines which are regularly updated.
Access toall the current diagnostic tools and therapeutic modalities is important to optimize care and ensure the longest possible survival and quality of life for patients with neuroendocrine tumours.
Guidelines and clinical decision support tools
