Standard management of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs) is surgical resection. However, identifying the primary tumor and burden of disease can be problematic, leading to challenges in surgical planning, optimal chemotherapy selection, and surveillance. Since the Food and Drug Administration approved gallium 68 dotatate (Ga-68) positron emission tomography (PET) on June 1, 2016, clinical management of GEP-NETs has rapidly evolved, and this new imaging modality has opened the field to new surveillance schema, as well as targeted interventions, such as lutetium 177 dotatate (Lutathera).
GEP-NETs are rare tumors of the pancreas and the tubular gastrointestinal (GI) tract (stomach, duodenum, small bowel, pancreas, appendix, colon, and rectum). These tumors can secrete bioactive substances (functional tumors), leading to constellations of clinical syndromes. Overall, incidence of GEP-NETs increased from approximately one per 100,000 persons in 1973, to seven per 100,000 in 2012.1 In 2017, the World Health Organization (WHO) recategorized neuroendocrine neoplasms into low proliferative index neuroendocrine tumors and high proliferative index neuroendocrine carcinomas deemphasizing anatomic location.2 Proliferative indices are determined by Ki-67 levels (a nuclear protein associated with cellular division) with a high-grade (G3) tumor defined as more than 20 percent staining positive (see Table 1). While some anatomic locations can be associated with improved outcomes, high Ki-67 percentages found in poorly differentiated and undifferentiated neuroendocrine carcinomas can predict worse overall survival.3
Table 1. WHO classification 2017 for gastroenteropancreatic neoplasms
Well-differentiated GEP-NETs typically overexpress somatostatin receptors, specifically somatostatin receptor subtype 2. In both functional and nonfunctional GEP-NETs, somatostatin analogs (such as octreotide, lanreotide, and pasireotide) can inhibit tumor growth and improve progression-free survival as demonstrated in the PROMID (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) and CLARINET (Placebo-Controlled Study of Lanreotide Antiproliferative Response in Patients with Enteropancreatic Neuroendocrine Tumors) trials.4-6
Progress to date
Taking advantage of somatostatin receptor overexpression, GEP-NETs can be localized using somatostatin receptor-targeted imaging modalities.7 Imaging of somatostatin receptors in a tumor was first described in 1984 and more specifically for NETs in 1993.7,8 Gamma radiation-based octreotide scan, which has been in use for more than 20 years, uses an indium 111 isotope with known poor image quality, has a high radiation dose requirement, and requires prolonged scintigraphy for imaging (typically more than one day). Radiolabeled meta-iodobenzylguanidine (MIBG) with iodide 123 or 131 also has been used for neuroendocrine cancers but similarly struggles with spatial resolution.
Ga-68 PET combined with computed tomography (CT) or magnetic resonance imaging substantially improves spatial differentiation and detection of NETs with sensitivity ranging from 80 percent to 100 percent and specificity ranging from 82 percent to 90 percent. The patient experience is much better than in previous studies because imaging takes two hours rather than two days. Ga-68 imaging has a significantly improved detection rate for primary tumor compared with octreotide scan. Importantly, studies have demonstrated that Ga-68 imaging provides additional information resulting in change in clinical management for more than 70 percent of patients.3 Improved GEP-NET imaging can assist with locating the primary tumor, preoperative planning, quantification of disease burden, and surveillance monitoring. For example, in a 51-year-old man who presented with shock from upper GI bleeding from presumed peptic ulcer disease, gastroduodenal artery coils placed by interventional radiology obscured visualization of a duodenal NET on CT but was readily visible on Ga-68 PET/CT (see Figure 1).
Figure 1. Coronal Ga-68 vs. Coronal CT imaging
Reflecting improvements in image quality, guidelines by the National Comprehensive Cancer Network and the North American Neuroendocrine Tumor Society have now recommended Ga-68 imaging over somatostatin receptor scintigraphy (octreotide scan) for the detection and surveillance of GEP-NETs.9-11
While Ga-68 PET has become the standard imaging study for evaluation of GEP-NETs, multiple studies are ongoing to define its optimal role in clinical practice. Retrospective studies have suggested that Ga-68 imaging altered diagnosis and management in up to one-third of NET patients and 50 percent of those referred for surgical resection. Most changes in surgical management were found in small bowel NETs (6/7) and consisted of additional lesions that precluded curative therapy in four patients. In 77 patients with known metastatic disease, additional sites of metastases were seen in 37 and consisted of distant lymph nodes (18), bone (15), and liver (9). Occult primary tumors were seen in 3/13 (28 percent) of patients who presented with M1 (metastatic spread) disease.12
Based on a recent review of clinicaltrials.gov, 51 studies are evaluating Ga-68 PET with 23 recruiting participants, 7 closed to enrollment, and 12 sponsored by the National Institutes of Health. We eagerly look forward to the results of these studies, particularly as a means of clearly identifying which patients would benefit most from liver-directed therapy, cytotoxic systemic chemotherapy, or other novel targeted treatment options, including Lutathera. In the Neuroendocrine Tumor Therapy (NETTER-1) phase 3 trial, the peptide receptor radionucleotide therapy Lutathera resulted in an improved 20-month progression-free survival of 65.2 percent over the 10.8 percent demonstrated in the octreotide long-acting repeatable group.13 Additionally, targeted molecules for imaging and treatment for non-somatostatin expressing GEP-NETs are still lacking and critically needed in these patients with a traditionally more aggressive disease.
- 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.
- Lloyd R, Osamura R, Klöppelm G, Rosai J, eds. WHO Classification of Tumours of Endocrine Organs, 4th edition. World Health Organization, Geneva; 2017.
- Wang R, Zheng-Pywell R, Chen HA, Bibb JA, Chen H, Rose JB. Management of gastrointestinal neuroendocrine tumors. Clin Med Insights Endocrinol Diabetes. October 24, 2019 [Epub ahead of print].
- Caplin ME, Pavel M, Cwikła JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(3):224-233.
- 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.
- Rinke A, Müller H-H, 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: A report from the PROMID study group. J Clin Oncol. 2009;27(28):4656-4663.
- Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: The Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716-731.
- Reubi JC, Landolt AM. High density of somatostatin receptors in pituitary tumors from acromegalic patients. J Clin Endocrinol Metab. 1984;59(6):1148-1151.
- Shah MH, Burns J, Zuccarino-Catania G. Neuroendocrine and adrenal tumors. NCCN Guidelines Version 1.2019. Available at: www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. June 2019. Accessed March 3, 2020.
- Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46(6):707-714.
- Howe JR, Merchant NB, Conrad C, et al. The North American Neuroendocrine Tumor Society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Vol 49. 2020. Available at: https://nanets.net/images/guidelines/NANETS_2020_Surgical_Management_of_PNETS.pdf. Accessed June 8, 2020.
- Crown A, Rocha FG, Raghu P, et al. Impact of initial imaging with gallium-68 dotatate PET/CT on diagnosis and management of patients with neuroendocrine tumors. J Surg Oncol. 2020;121(3):480-485.
- Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177 Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135.