Neuroendocrine tumors (NETs) are comprised of biologically diverse neoplasms. The presence of systemic symptoms is dependent on NET location and differentiation. New treatment modalities have become available, offering patients improved symptom management and survival. Advanced practice RNs (APRNs) provide direct care to and coordination of treatment for patients with NETs, including treatment of somatostatin receptor–positive disease with lutetium Lu 177 dotatate (Lutathera®) peptide receptor radionuclide therapy.
AT A GLANCE
- NETs are complex and may cause a variety of symptoms, such as those associated with carcinoid syndrome.
- APRNs are key members of the interprofessional team and are involved in the diagnosis, treatment, and coordination of care of patients with NETs.
- Somatostatin receptor–positive NETs may be treated with targeted treatments containing radioactive isotopes, such as lutetium Lu 177 dotatate.
Neuroendocrine tumors (NETs) are biologically diverse tumors comprised of neoplastic neuroendocrine cells. The function of normal neuroendocrine cells in the gastrointestinal tract is to secrete metabolically active substances, including hormones and additional substances that aid in digestion and other physiologic functions (Christopoulos & Papavassiliou, 2005). The secretory activity of neuroendocrine cells is stimulated by physiologic processes, including the hormone somatostatin (Bosquet et al., 2019; Mittra, 2018). NETs produce a range of symptoms dependent on tumor size and location, spread of disease, and amount of hormone hypersecretion from the tumor(s). In early stages, surgery with curative intent is considered. Once the disease has metastasized beyond the primary organ, goals of care become managing symptoms and controlling the spread of disease.
Advanced practice RNs (APRNs) are essential to the provision of care to and the management of symptoms of patients diagnosed with NETs. New targeted treatments using peptide receptor radionuclide therapy (PRRT) show promise in terms of response and improved quality of life (Mittra, 2018). PRRT uses radionuclides, either yttrium-90 or lutetium-177, which vary in their physical properties. PRRT using lutetium-177 allows for longer half-life, and this radionuclide emits y-rays that persist on imaging for several days, allowing verification of dosing targets. This article refers to PRRT using lutetium-177.
Incidence of Neuroendocrine Carcinomas
The incidence of NETs has increased in the United States. In 1993, the overall incidence of NETs was 1 per 100,000, whereas in 2012, the incidence had risen to 6.98 per 100,000 (Dasari et al., 2017). This heightened rate of incidence can be attributed to advances in radiographic imaging and increased incidental findings in emergent and urgent care settings (Dasari et al., 2017; Sackstein et al., 2018). Gastrointestinal NETs comprise almost half of all newly diagnosed primary NETs (Sackstein et al., 2018). Almost one-fourth of all patients newly diagnosed with NETs present with metastatic disease (Oronsky et al., 2017).
Classification and Diagnosis
Historically, NETs were organized into three classifications: (a) foregut tumors arising from the respiratory system, thymus, stomach, duodenum, and pancreas; (b) midgut tumors arising from the small intestine, appendix, and right colon; and (c) hindgut tumors arising from the transverse colon, sigmoid, and rectum (Kaltsas et al., 2004; Williams & Sandler, 1963). This classification method organized tumors by symptoms, treatments, and prognosis (Kaltsas et al., 2004). Classification and grading systems have been revised to include histopathology analyses, such as Ki-67 proliferation index and mitotic count. The terminology of NET versus neuroendocrine carcinoma has been poorly defined. Although consensus is not absolute, the term neuroendocrine carcinoma refers to poorly differentiated tumors with high Ki-67 scores (Sorbye et al., 2018).
Imaging techniques, such as gallium(Ga)-68 dotatate scans, exploit the presence of somatostatin receptors on neuroendocrine cells (Sampathirao & Basu, 2017). This technology uses the somatostatin-like molecule octreotide as a carrier for the isotope 68Ga to detect sites of disease (see Figure 1). Similarly, lutetium Lu 177 dotatate and other types of PRRTs use octreotide-bound radioisotopes for treatment.
Similar to imaging techniques depending on somatostatin receptors to define utility, functional versus nonfunctional NETs are defined by excessive metabolic functioning. Metabolically active substances consisting of neurotransmitters and hormones, such as histamine, serotonin, and dopamine, can be produced and secreted in excess by NETs (Tzontcheva, 2010). Disproportionate production of these substances distinguishes NETs as functional (secreting) or as nonfunctional (nonsecreting). Carcinoid syndrome is the clinical syndrome associated with functional NETs. Symptoms associated with the syndrome may include abdominal pain, diarrhea, flushing, bowel obstruction, and carcinoid heart disease (Raphael et al., 2017).
PRRT became standard of care in Europe in the 1990s but did not gain U.S. Food and Drug Administration approval in the United States until January 26, 2018 (Hennrich & Kopka, 2019). Until the approval of PRRT, systemic treatment consisted of somatostatin receptor analogs, chemotherapy, and molecular targeted therapy. The somatostatin receptor analogs octreotide and lanreotide control carcinoid symptoms and may also control tumor growth (Öberg, 2017). Chemotherapy regimens are standard with metastatic, recurrent, and symptomatic disease. Regimens vary, with drug selection based on available evidence and tumor characteristics, such as differentiation and hypersecretion (Dasari et al., 2017; Kaltsas et al., 2004; Öberg, 2017). Everolimus is an example of a molecularly targeted treatment that may be used alone or in combination with somatostatin receptor analogs (Öberg, 2017).
P.A., a 42-year-old woman, initially presented in 2015 with abdominal pain and jaundice. Needle biopsy of a pancreatic mass demonstrated an intermediate (grade 2) pancreatic neuroendocrine carcinoma. The advanced tumor was inoperable, and P.A. received palliative biliary stent placement to relieve obstructive jaundice. She then received four cycles of chemotherapy to slow disease progression. Unfortunately, P.A. experienced significant toxicities from chemotherapy, including a 65-pound weight loss and the onset of carcinoid syndrome consisting of flushing and diarrhea.
Octreotide therapy was initiated in 2016 but was discontinued following the first dose because of the onset of anasarca (extreme generalized edema). An APRN worked diligently to reduce P.A.’s swelling and carcinoid symptoms by titrating diuretics and antidiarrheals. Care was focused on symptom management and coordination with the interprofessional oncology team, including social workers and dietitians. P.A. continued to follow up with the APRN, with imaging ordered every four to six months. A follow-up scan in 2017 demonstrated three new hepatic sites that were concerning for metastases. P.A. enrolled in a clinical trial protocol and experienced decreased adenopathy. Her disease was stable for about one year until it progressed. Standard-of-care combination chemotherapy regimens including everolimus, capecitabine, and temozolomide, with and without short-acting octreotide injections, were prescribed as P.A. continued to have disease progression and symptom distress.
In 2019, P.A. obtained insurance approval for initiation of lutetium Lu 177 dotatate (Lutathera®) PRRT. She received the first dose in January 2019 and completed all four doses by October 2019. She tolerated the lutetium Lu 177 dotatate PRRT fairly well, with overall disease stability to date. P.A. experienced improved pain control and reduced fatigue within four to five months of her first dose, which has remained consistent. She has not experienced any new symptoms since completing her last dose and maintains improved quality of life. P.A. continues to receive computed tomography scans every three months for active surveillance.
Lutetium Lu 177 Dotatate Peptide Receptor Radionuclide Therapy
Patients with refractory disease and those with disease progression after standard treatments may be prescribed lutetium Lu 177 dotatate PRRT, which was approved by the U.S. Food and Drug Administration in 2018. This radiopharmaceutical consists of octreotide peptide linked with the beta-emitting isotope 177Lutetium. Therapy is administered as an IV infusion given every eight weeks for a total of four doses. The half-life of the isotope is 6.7 days (Advanced Accelerator Applications, 2018).
Patients must meet various criteria, including parameters for renal, hepatic, and bone marrow function prior to receiving lutetium Lu 177 dotatate PRRT (see Table 1). Lutetium Lu 177 dotatate PRRT is typically administered in an observation or inpatient unit as a 23-hour admission and requires coordination of patient, personnel, and work processes (see Figure 2). Precautions are necessary to reduce potential radiation exposure. A dedicated bathroom, lined with absorbent pads surrounding the toilet and on the bathroom floor to contain radioactive urine and reduce contamination, is recommended; the room does not need to be lead lined (Mittra, 2018). Incontinent patients may require extended admission and additional precautions. Patients and families must be educated about urine precautions and hygiene recommendations, including avoiding contact with children, pregnant women, and crowds for about three days after treatment (Advanced Accelerator Applications, 2018; Mittra, 2018).
Standard antiemetics and infusion of an amino acid solution for renal protection should be given prior to administration of the radionuclide compound. Administration of amino acids prevents potential dose-limiting renal toxicities of radiolabeled compounds. Initial formulations of amino acid infusions triggered acute nausea and vomiting, but subsequent formulations are more tolerable (Rolleman et al., 2003).
In general, patients experience minimal immediate side effects from lutetium Lu 177 dotatate PRRT. In a review of medical records at the University of Kentucky, Chacko et al. (2019) found that about 38%, or 11 of 29 patients, who had received at least one dose of PRRT developed thrombocytopenia or pancytopenia. In addition, bone marrow suppression may occur immediately following lutetium Lu 177 dotatate PRRT (Bergsma et al., 2018). Long-term or late adverse effects may preclude additional PRRT dosing. The potential for long-term toxicities includes the development of hematologic malignancies and persistent cytopenias. Among 274 patients receiving lutetium Lu 177 dotatate PRRT in a study by Bergsma et al. (2018), the relative risk for developing a hematopoietic neoplasm was 2.7.
Advanced Practice in the Neuroendocrine Clinic
The complex management of NETs with palliation of symptoms, the requirement of advanced imaging technologies, and the use of emerging therapies create opportunities for dedicated providers who specialize in neuroendocrine carcinomas. Treatment with PRRT, such as lutetium Lu 177 dotatate PRRT, requires a high level of coordination. APRNs are involved in every stage of protocol development and the delivery of therapy, as well as post-therapy patient monitoring and symptom management. Coordination is necessary in an interprofessional sense but also between APRNs and nurses who provide direct care (e.g., administration; monitoring of patients for postinfusion complications, such as hormone crisis) (Mittra, 2018).
The complexity of oncology care has increased the need for knowledgeable advanced practice providers in offering collaborative patient care, which includes patient coordination, screening, education, and management to improve patient satisfaction, outcomes, and quality of care (Bruinooge et al., 2018). Dedicated neuroendocrine advanced practice providers focus on the coordination of patients receiving PRRT. This process begins with screening existing and referred patients prior to the initial appointment and ordering diagnostics to determine baseline functional status and that patients meet criteria for treatment. Providers must streamline coordination of care with radiology, radiation oncology and nuclear medicine, and insurance providers to potentially reduce time to treatment with PRRT, which may reduce waiting lists for treatment. Initial and follow-up appointments are opportunities for optimal patient education, continued symptom management, and increased postprocedure access to care.
Lutetium Lu 177 dotatate PRRT offers a new additional treatment option and an opportunity for APRNs to enhance the quality of care for patients diagnosed with NETs. APRNs are in a position to provide coordination of care through direct patient care, screening, insurance peer review, and collaboration with other providers to obtain necessary imaging, appointments, and follow-up after patients receive lutetium Lu 177 dotatate PRRT.
About the Author(s)
Adria Myers, MSN, DNPc, APRN, AOCNP®, is an oncology nurse practitioner, and Holly Renea Chitwood, MSN, APRN, FNP-C, AGACNP-BC, is an advanced practice provider II, both at the University of Kentucky in Lexington. The authors take full responsibility for this content and did not receive honoraria or disclose any relevant financial relationships. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Oncology Nursing Society. Myers can be reached at email@example.com, with copy to CJONEditor@ons.org.
Advanced Accelerator Applications. (2018). Lutathera® (lutetium Lu 177 dotatate) [Package insert]. http://bit.ly/39ZXQtd
Bergsma, H., van Lom, K., Raaijmakers, M.H.G.P., Konijnenberg, M., Kam, B.L.B.L.R., Teunissen, J.J.M., . . . Kwekkeboom, D.J. (2018). Persistent hematologic dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE: Incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors. Journal of Nuclear Medicine, 59(3), 452–458.
Bosquet, C., Castaño, J.P., Csaba, Z., Culler, M., Dournaud, P., Epelbaum, J., Feniuk, W., . . . Wester, H.-J. (2019). Somatostatin receptors (version 2019.4) in the IUPHAR/BPS guide to pharmacology database. IUPHAR/BPS Guide to Pharmacology CITE, 2019(4). https://doi.org/10.2218/gtopdb/F61/2019.4
Bruinooge, S.S., Pickard, T.A., Vogel, W., Hanley, A., Schenkel, C., Garrett-Mayer, E., . . . Williams, S.F. (2018). Understanding the role of advanced practice providers in oncology in the United States. Journal of Oncology Practice, 14(9), e518–e532. https://doi.org/10.1200/JOP.18.00181
Chacko, C.A., Chauhan, A., El Khouli, R., & Anthony, L. (2019). Lutetium 177-DOTATATE therapy in progressive metastatic well-differentiated G1/G2 neuroendocrine tumors: Review of the University of Kentucky’s post-FDA approval PRRT program. https://bit.ly/2xdS20J
Christopoulos, C., & Papavassiliou, E. (2005). Gastric neuroendocrine tumors: Biology and management. Annals of Gastroenterology, 18(2), 127–140.
Dasari, A., Shen, C., Halperin, D., Zhao, B., Zhou, S., Xu, Y., . . . Yao, J.C. (2017). Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology, 3(10), 1335–1342.
Hennrich, U., & Kopka, K. (2019). Lutathera®: The first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals, 12(3), 114.
Kaltsas, G.A., Besser, G.M., & Grossman, A.B. (2004). The diagnosis and medical management of advanced neuroendocrine tumors. Endocrine Reviews, 25(3), 458–511.
Mittra, E.S. (2018). Neuroendocrine tumor therapy: 177Lu-DOTATATE. American Journal of Roentgenology, 211, 278–285. https://doi.org/10.2214/AJR.18.19953
Öberg, K. (2017). Medical therapy of gastrointestinal neuroendocrine tumors. Visceral Medicine, 33(5), 352–356.
Oronsky, B., Ma, P.C., Morgensztern, D., & Carter, C.A. (2017). Nothing but NET: A review of neuroendocrine tumors and carcinomas. Neoplasia, 19(12), 991–1002.
Raphael, M.J., Chan, D.L., Law, C., & Singh, S. (2017). Principles of diagnosis and management of neuroendocrine tumours. Canadian Medical Association Journal, 189(10), E398–E404. https://doi.org/10.1503/cmaj.160771
Rolleman, E.J., Valkema, R., de Jong, M., Kooij, P., & Krenning, E.P. (2003). Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. European Journal of Nuclear Medicine and Molecular Imaging, 30(1), 9–15.
Sackstein, P.E., O’Neil, D.S., Neugut, A.I., Chabot, J., & Fojo, T. (2018). Epidemiologic trends in the neuroendocrine tumors: An examination of incidence rates and survival of specific patient subgroups over the past 20 years. Seminars in Oncology, 45(4), 249–258.
Sampathirao, N., & Basu, S. (2017). MIB-1 index-stratified assessment of dual-tracer PET/CT with 68Ga-DOTATATE and 18F-FDG and multimodality anatomic imaging in metastatic neuroendocrine tumors of unknown primary in a PRRT workup setting. Journal of Nuclear Medicine Technology, 45(1), 34–41.
Sorbye, H., Baudin, E., & Perren, A. (2018). The problem of high-grade gastroenteropancreatic neuroendocrine neoplasms: Well-differentiated neuroendocrine tumors, neuroendocrine carcinomas, and beyond. Endocrinology and Metabolism Clinics of North America, 47(3), 683–698.
Tzontcheva, A. (2010). Neuroendocrine tumors: Laboratory diagnosis. Journal of Medical Biochemistry, 29(4), 254–264. https://doi.org/10.2478/v10011-010-0028-5
Williams, E.D., & Sandler, M. (1963). The classification of carcinoid tumours. Lancet, 281(7275), 238–239.