Understand how to identify progression of neuroendocrine tumors, including the signs and symptoms of progression, how to assess progression, and relevant monitoring requirements
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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 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
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.
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:
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:
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-hydroxyindoleacetic acid (5-HIAA) as a functional NET marker10b:
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
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
1 Rinke A, Wittenberg M, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): results of long-term survival. Neuroendocrinology. 2017;104(1):26-32. doi:10.1159/000443612
2 Strosberg J, Wolin E, Chasen B; the NETTER-1 Study Group. Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-dotatate in the phase III NETTER-1 trial. J Clin Oncol. 2018;36(25):2578-2584. doi:10.1200/JCO2018.78.5865
3 Khan S, Krenning EP, van Essen M, Kam BL, Teunissen JJ, Kwekkeboom DJ. Quality of life in 265 patients with gastroentereopancreatic or bronchial neuroendocrine tumors treated with [177Lu-DOTA3,Tyr3]Octreotate. J Nucl Med. 2011;52(9):1361-1368. doi:10.2967/jnumed.111.087932
4 Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335-1342. doi:10.1001/jamaoncol.2017.0589
5a 5b Merino-Casabiel X, Aller J, Arbizu J, et al. Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors. Clin Transl Oncol. 2018;20(12):1522-1528. doi:10.1007/s12094-018-1881-9
6a 6b 6c Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860. doi:10.1016/j.annonc.2020.03.304
7a 7b 7c de Mestier L, Dromain C, d'Assignies G, et al. Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art. Endocr Relat Cancer. 2014;21(3):R105-R120. doi:10.1530/ERC-13-0365
8a 8b 8c 8d 8e Pape UF, Perren A, Niederle B, et al. ENETS Consensus Guidelines for the management of patients with neuroendocrine neoplasms from the jejuno-ileum and the appendix including goblet cell carcinomas. Neuroendocrinology. 2012;95(2):135-156. doi:10.1159/000335629
9a 9b Grozinsky-Glasberg S, Grossman AB, Gross DJ. Carcinoid heart disease: from pathophysiology to treatment—'something in the way it moves'. Neuroendocrinology. 2015;101(4):263-273. doi:10.1159/000381930
10a 10b Kocha W, Maroun J, Kennecke H, et al. Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumors: a revised statement from a Canadian National Expert Group. Curr Oncol. 2010;17(3):49-64. doi:10.3747/co.v17i3.484
11 Lutathera (lutetium Lu 177 dotatate). Summary of product characteristics. Advanced Accelerator Applications Ibérica, S.L.U. Accessed July 19, 2024. https://www.ema.europa.eu/en/documents/product-information/lutathera-epar-product-information_en.pdf
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