Identifying and assessing progression in neuroendocrine tumors
Understand how to identify progression of neuroendocrine tumors, including the signs and symptoms of progression, how to assess progression, and relevant monitoring requirements
Progression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) significantly impacts both patient survival and quality of life. Despite their slow growth, GEP-NETs can advance even with treatment, potentially leading to death.1 2 3 Both incidence and prevalence of metastatic GEP-NETs are rising due to the diagnosis of early-stage disease and subsequent stage migration.4
Recognizing progression of neuroendocrine tumors
Recognizing disease progression is crucial for helping to improve disease management, as it may provide an opportunity to refine treatment approaches.
In clinical practice, there are various factors that can be considered when deciding the optimal timing for therapeutic adjustments5a 6a:
Tumor burden assessment
Evaluation of drug-related toxicity
Monitoring and assessing cancer-related symptoms
Clinical judgment of the healthcare provider
Symptoms of neuroendocrine tumor progression
Evaluating symptoms can indicate disease progression, prompting the need for further diagnostic tests.7a
Potential symptoms of tumor progression include8a 9a:
Carcinoid syndrome (CS)
CS often arises in functional GEP-NET patients with liver metastases. It results from the release and interaction of hormones and vasoactive substances like serotonin, prostaglandins, and histamine.
Carcinoid crisis (CC)
CC is a more critical condition that can occur in those with CS—triggered, for example, by general anesthesia in surgery. It is an episode of circulatory collapse, caused by an acute surge of hormone release. Somatostatin analogues (SSAs) such as octreotide can prevent CC when administered as presurgical prophylaxis and, if necessary, during surgery.
Carcinoid heart disease (CHD)
Advanced NET patients with severe CS may develop CHD, a rare cardiac complication. CHD is characterized by fibrosis of the right-side heart valves, ultimately leading to heart failure.
Symptoms from other causes
Patients may also experience symptoms due to increased tumor burden or secretion of bioactive substances from functional tumors.8b
Symptoms due to functional carcinoid tumors usually include8c 9b:
Symptoms due to increased tumor burden usually include7b:
Recognizing progression | Monitoring recommendations | Assessing progression | Monitoring recommendations |
Assessing progression of neuroendocrine tumors
The assessment of disease progression in individuals with GEP-NETs uses various radiological techniques such as computed tomography (CT) scans, magnetic resonance imaging (MRI) scans, somatostatin receptor (SSTR) imaging, and positron emission tomography (PET)/CT imaging.5b Additionally, the evaluation of biomarkers may offer another valuable insight used to evaluate and monitor disease progression.
CgA serves as a universal marker for GEP-NETs, regardless of functional status. Most malignant neuroendocrine cells continue to secrete CgA
Elevated serum CgA levels are indicative of tumor burden and have been linked to disease progression
Limitations include low sensitivity, variations within and between patients, and the potential for false positive results due to multiple reasons, including medications, medical conditions, and diet
5-HIAA, a urinary metabolite of serotonin, is a marker of functional NETs
The role of 5-HIAA in monitoring presents challenges as it may not be consistently reliable as a prognostic marker
Radiological evaluation provides an objective measurement of the size of the tumor and may detect new lesions. The assessment of tumor burden frequently requires multiple imaging modalities as well as clinical assessment.6b 7c
CT
CT scans are widely available and provide high diagnostic accuracy for NETs. They excel in detecting liver, lung, and brain metastases. However, they may not be as sensitive as MRI for identifying liver metastases. Contrast-enhanced ultrasound (CEUS) is valuable for characterizing liver lesions that remain unclear on CT/MRI.
MRI scans
MRI scans outperform CT scans when detecting liver metastases. Their high contrast helps to measure lesion size without contrast agents. They are preferred for initial staging and preoperative workup, particularly pancreatic examinations. Diffusion-weighted MRI aids in lesion detection. Endoscopic ultrasound (EUS) is the preferred method for diagnosing small pancreatic NETs with high sensitivity and specificity.
SSTR imaging
SSTR imaging assesses SSTR expression in GEP-NETs, aiding in identifying primary sites and determining the extent of certain metastases. It complements CT and MRI by excelling in evaluating bones and mediastinum for specific metastatic lesions.
PET/CT imaging
PET/CT imaging by 68Gallium-DOTATE-SSA PET/CT offers high sensitivity for visualizing various NET lesions. It should be part of tumor staging, preoperative imaging, and restaging. Fluorodeoxyglucose (FDG) imaging is useful for higher-grade 2 NETs, which typically exhibit higher glucose metabolism and less SSTR expression than low-grade NETs.
Biomarkers provide an indication of disease progression.
Chromogranin A (CgA) as a GEP-NET marker8d 10a:
5-hydroxyindoleacetic acid (5-HIAA) as a functional NET marker10b:
Recognizing progression | Monitoring recommendations | Monitoring recommendations | Monitoring recommendations |
Monitoring recommendations for neuroendocrine tumors
The European Neuroendocrine Tumor Society (ENETS) and the European Society for Medical Oncology (ESMO) both recommend regular follow-ups for individuals with NETs. Monitoring should involve clinical symptom monitoring, biochemical parameters, and conventional and SSTR imaging studies to track tumor growth. The frequency and specific tests depend on the tumor characteristics and treatment.6c 8e
Identifying disease progression is essential to help improve patient outcomes, as it may offer an opportunity to modify treatment strategies and ultimately leading to the potential improvement in quality of life for the patient.11
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5-HIAA, 5-hydroxyindoleacetic acid
CgA, chromogranin A
CC, carcinoid crisis
CEUS, contrast-enhanced ultrasound
CHD, carcinoid heart disease
CS, carcinoid syndrome
CT, computed tomography
ENETS, European Neuroendocrine Tumor Society
ESMO, European Society for Medical Oncology
EUS, endoscopic ultrasound
FDG, flourodeoxyglucose
68Ga-DOTATE-SSA, 68Gallium labeled somatostatin analogues
GEP-NETs, gastroenteropancreatic neuroendocrine tumors
MRI, magnetic resonance imaging
NET, neuroendocrine tumor
PET, positron emission tomography
RLT, radioligand therapy
SSA, somatostatin analogue
SSTR, somatostatin receptor
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