NEUROENDOCRINE TUMORS
Neuroendocrine tumors are a heterogeneous group of tumors that originate from the neuroendocrine cells in the diffuse neuroendocrine system anywhere in the body but more commonly in the gastrointestinal tract and the respiratory system. Approximately 61 percent of all neuroendocrine tumors originate from gastrointestinal system or pancreas and are referred to as gastroenteropancreatic neuroendocrine tumors. Lung neuroendocrine tumors may also be referred to as pulmonary neuroendocrine tumors, pulmonary carcinoids, or bronchopulmonary neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors may further be characterized as functional or nonfunctional based on whether they secrete hormones that result in clinical symptoms particularly serotonin, which results in “carcinoid syndrome” that is characterized by flushing and diarrhea.
Neuroendocrine tumors are classified as orphan diseases by the Food and Drug Administration (FDA). Based on an analysis of Surveillance, Epidemiology, and End Results Program registry data from 1973 to 2012 (Dasari A, 2017), the overall incidence of neuroendocrine tumors has been reported to be in the range of 6.98 per 100,000 people per year.
DIAGNOSIS
Neuroendocrine tumors are not easy to diagnose because of the rarity of the condition. Symptoms are often nonspecific or mimic other disorders such as irritable bowel syndrome (in the case of gastroenteropancreatic neuroendocrine tumors) or asthma (in the case of a lung neuroendocrine tumors) resulting in an average diagnosis delay of 5 to 7 years after symptom onset (Frilling A, 2012). In many cases, diagnosis is incidental to imaging for other unrelated cause. Most gastroenteropancreatic neuroendocrine tumors express somatostatin receptors that can be imaged using a radiolabeled form of the somatostatin analogue octreotide (e.g., 111In pentetreotide).
TREATMENT APPROACH
There is a general lack of prospective data to guide the treatment of neuroendocrine tumors. Gastroenteropancreatic neuroendocrine tumors are chemotherapy-responsive neoplasms, and platinum-based chemotherapy represents the backbone of treatment for both early and advanced-stage tumors (Sorbye H, 2014). Surgery alone or followed by chemotherapy along with treatment of hormone-related symptoms may be the initial approach for localized disease. For asymptomatic individuals with slow progression, observation with routine surveillance imaging is an option. The prognosis for individuals with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors is highly variable. Based on retrospective analyses of large databases, the prognosis for individuals with metastatic gastroenteropancreatic neuroendocrine tumors is variable. The median overall survival (from diagnosis) for individuals with metastatic pancreatic neuroendocrine tumors has been reported to range from 2 to 5.8 years (Yao JC, 2008; Strosberg J, 2009), while the median overall survival for small bowel neuroendocrine tumors has been reported as 7.9 years (Ter-Minassian M, 2013).
PHARMACOLOGICAL TREATMENT
First-Line Treatment Options
Somatostatin Analogues (Octreotide and Lanreotide)
Somatostatin is a peptide that binds to somatostatin receptors that are expressed in a majority of carcinoid tumors and inhibits the secretion of a broad range of hormones. Somatostatin analogues (e.g., octreotide, lanreotide) were initially developed to manage the hormonal symptoms related to neuroendocrine tumors, they were found to exert antiproliferative activity, and clinical studies have demonstrated prolonged progression-free survival (PFS) in individuals with neuroendocrine tumors treated with somatostatin analogues (Rinke A, 2009; Caplin ME, 2015). However, the role of somatostatin analogues in individuals with nonfunctioning neuroendocrine tumors is unclear (Ramage JK, 2012).
Commercially available long-acting release forms of octreotide and lanreotide (e.g., Sandostatin LAR, Somatuline Depot), which are administered intramuscularly on a monthly basis, have largely eliminated the need for daily self-injection of short-acting subcutaneous formulations (A-berg K, 2015; O'Toole D, 2000).
Second-Line Treatment Options
Currently, there are no data to support a specific sequence of therapies and only streptozocin, everolimus, and sunitinib are FDA approved for the treatment of pancreatic neuroendocrine tumors.
Mechanistic Target of Rapamycin Inhibitors
The mechanistic target of rapamycin is an enzyme that regulates cell metabolism and proliferation in response to environmental stimuli. It is upregulated in a variety of malignancies in response to stimulation by growth factors and cytokines. Whole-exome genomic analysis has shown that approximately 15 percent of pancreatic neuroendocrine tumors are associated with somatic variants in genes associated with the mechanistic target of rapamycin pathway (Strosberg J, 2013). Everolimus, an oral mechanistic target of rapamycin inhibitor, has been shown to significantly prolonged PFS vs placebo in individuals with pancreatic neuroendocrine tumors (RADIANT-3 trial) (Yao JC, 2011), and lung and gastrointestinal neuroendocrine tumors nonfunctional (RADIANT-4 trial) (Yao JC, 2016). Note that everolimus is approved by FDA for adults with progressive neuroendocrine tumors of pancreatic origin and adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin that are unresectable, locally advanced or metastatic. The RADIANT-2 trial individuals with progressive advanced neuroendocrine tumors associated with carcinoid syndrome failed to show a statistically significant improvement in the primary end point of PFS (Pavel ME, 2011).
Tyrosine Kinase Receptor Inhibitors
Neuroendocrine tumors frequently overexpress the vascular endothelial growth factor and receptor. Sunitinib, is a multi-targeted tyrosine kinase inhibitor that targets multiple signaling pathways and growth factors and receptors including vascular endothelial growth factor and receptor 1, 2, and 3 (Strosberg J, 2013). It has been shown that daily sunitinib at a dose of 37.5 mg improves PFS, overall survival, and the overall response rate as compared with placebo among individuals with advanced pancreatic neuroendocrine tumors (Raymond E, 2011). Note that sunitinib is FDA approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in individuals with unresectable locally advanced or metastatic disease.
Chemotherapy
Response to chemotherapy for advanced neuroendocrine tumors of the gastrointestinal tract and lung is highly variable and, at best, modest. Tumor response rates are generally low and no PFS benefit has been clearly demonstrated. Therefore, the careful selection of individuals is critical to maximize the chance of response and avoid unnecessary toxicity. In advanced neuroendocrine tumors, platinum-based regimens are generally used. They include cisplatin and etoposide (most widely used), carboplatin and etoposide, 5-fluorouracil, capecitabine, dacarbazine, oxaliplatin, streptozocin, and temozolomide (Garcia-Carbonero R, 2016).
Lutetium 177 Dotatate
Lutetium 177 dotatate is a radiolabeled-somatostatin analogue that binds to somatostatin receptor expressing cells, including malignant somatostatin receptor-positive tumors. It is then internalized and beta particle emission from lutetium 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive and neighboring cells.
Lutathera (Lutetium Lu 177 dotatate) [Advanced Accelerator Applications (AAA), New York, NY] received FDA approval on January 26, 2018. Lutathera is approved for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors, in adults. Lutathera is the first available FDA-approved Peptide Receptor Radionuclide Therapy (PRRT), a form of treatment comprising of a targeting molecule that carries a radioactive component. Currently, there are no other radiolabeled somatostatin analog conjugates that are FDA approved specifically for use in PRRT.
FDA approval for Lutathera was based on the results from two studies, NETTER 1 (Strosberg J, 2017; U.S. Food and Drug Administration, 2018) and ERASMUS (Kwekkeboom DJ, 2008; Brabander T, 2017; U.S. Food and Drug Administration, 2018).
NETTER 1 was an open-label randomized, controlled trial (RCT) that compared treatment with Lutathera to octreotide in individuals with inoperable, progressive somatostatin receptor-positive midgut carcinoid tumors. Eligibility included a Ki-67 index 20 percent or less, confirmed presence of somatostatin receptors on all lesions (octreoscan uptake greater than or equal to that of the normal liver), Karnofsky Performance Status score of 60 or more, creatinine clearance of 50 mL/min or more, no prior treatment with Peptide Receptor Radionuclide Therapy (PRRT), and no prior external radiation therapy to more than 25 percent of the bone marrow. Randomization was stratified by octreoscan tumor uptake score (grade 2, 3 or 4) and the length of time that individuals had been on the most recent constant dose of octreotide prior to randomization (less than or equal to 6 months or > 6 months). The primary outcome was progression free survival (PFS). A total of 229 individuals were randomized to either Lutathera (7.4 GBq [200 mCi]) for four infusions every 8 weeks concurrently with 30 mg of long-acting octreotide (n = 116) or 60 mg of high-dose octreotide alone (n = 113). At the data-cutoff date for the primary analysis, PFS at 20 months was 65.2 percent (95 percent confidence interval [CI], 50.0 to 76.8) in the Lutathera group and 10.8 percent (95 percent CI, 3.5 to 23.0) in the control group. The response rate was 18 percent in the Lutathera group versus 3 percent in the control group (p<0.001). In the planned interim analysis of overall survival (OS), 14 deaths occurred in the Lutathera group and 26 in the control group ([hazard ratio: 0.40] p=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1 percent, 2 percent, and 9 percent, respectively, of individuals in the Lutathera group as compared with no individuals in the control group, with no evidence of renal toxic effects during the observed time frame. Adverse events (AEs) that were considered by the investigator to be related to trial treatment occurred in 129 individuals: 95 individuals (86 percent) in the Lutathera group and 34 individuals (31 percent) in the control group. The most common AEs among individuals in the Lutathera group were nausea (65 individuals [59 percent]) and vomiting (52 individuals [47 percent]). Other common AEs in the Lutathera group included fatigue or asthenia, abdominal pain, and diarrhea.
The ERASMUS study was a retrospective, case series that included 1214 individuals with bronchial and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) who received Lutathera, 610 of whom were treated with a cumulative dose of at least 100 mCi (3.7 GBq) for safety analysis. Another subgroup of 443 Dutch individuals were treated with a cumulative dose of at least 600 mCi (22.2 GBq). The objective response rate (ORR) of the total group of individuals was 39 percent. Stable disease (SD) was reached in 43 percent of individuals. PFS and OS for all neuroendocrine tumor individuals were 29 months [95 percent confidence interval (CI), 26–33 months] and 63 months (95 percent CI, 55–72 months). Long-term toxicity included acute leukemia in four individuals (0.7 percent) and myelodysplastic syndrome in nine individuals (1.5 percent). No therapy-related long-term renal or hepatic failure occurred.