Bronchial Neuroendocrine Tumors Research Articles

Ectopic acromegaly due to bronchial neuroendocrine tumors: the first description in Russia of three clinical cases

Acromegaly is a neuroendocrine disorder caused by excessive production of growth hormone (GH). In the majority of cases the cause of acromegaly is a pituitary tumor producing GH. Cases of ectopic acromegaly are much rarer. Ectopic acromegaly occurs in cases of tumors which produce growth hormone-releasing hormone (GHRH) or extrapituitary tumors which produce GH. The main sources of excessive GHRH production are neuroendocrine tumors (NETs) of the lung or pancreas. Treatment of ectopic acromegaly consists of surgical removal of the source of GHRH hyperproduction and in cases where surgery is not an option, somatostatin analogues, pegvisomant, chemotherapy, immunotherapy or radiation therapy are used.In this article three cases of ectopic acromegaly due to GHRH-producing lung NETs are presented, each of them being notable for a number of features. In the first two cases, clinical symptoms were mild, besides in the second case ectopic acromegaly was accompanied by primary hyperparathyroidism. In the third case ectopic acromegaly was accompanied by pituitary macroadenoma, and after surgical removal of the lung NET remission of acromegaly was not achieved. In all three cases, lung NETs were detected incidentally on radiologic chest screening for other conditions.

SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022).

Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.

Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review

We have performed a systematic review to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Studies identified in PubMed from inception to 13 May 2021 must have assessed [177Lu]Lu-DOTA-TATE as a single agent and reported outcome data for the specific NET types of interest. Two independent reviewers performed the screening and data extraction, resulting in 16 publications: PPGL (n = 7), bronchial NETs (n = 6; one also included NETs of unknown origin), and MTC (n = 3). Overall, [177Lu]Lu-DOTA-TATE offers encouraging antitumor activity (overall tumor response rates and disease control rates) across NET types. Safety was favorable with most adverse events mild to moderate in severity, transient, and consistent with those seen in patients with gastroenteropancreatic (GEP)-NETs. [177Lu]Lu-DOTA-TATE has been used effectively in clinical practice to treat NETs of non-GEP origin.

The occurrence and associated risk factors of brain metastases in well differentiated grade 1 and 2 bronchial neuroendocrine tumours: A single centre retrospective analysis of 280 patients

Typical and atypical bronchial carcinoid account for around 2% of all neuroendocrine neoplasms of pulmonary origin. Fewer than 5% of patients with these cancers are thought to develop brain metastases, and hence routine intracranial imaging is not currently included in staging investigations. In this study, retrospective case note analysis was performed on 280 patients diagnosed with either typical carcinoid (TC) or atypical carcinoid (AC) at a large, single-site cancer centre. None of the 219 patients with TC developed brain metastases during the course of their disease, whereas seven of the 61 AC (11.5%) were found to have intracranial spread, four of which were present at the point of diagnosis. A Cox proportional hazard model showed that a Ki-67 expression ≥18%, patient age ≥65 years and disease stage at diagnosis were all independently and significantly associated with the development of brain metastases in AC. This study has found new evidence that the incidence of brain metastases in AC is significantly higher than previously thought. Of all the variables reviewed, Ki-67 expression was most strongly associated with the development of intracranial disease in AC and could be readily translated into clinical practice. Predictive factors such as age, disease stage and Ki-67 expression could be used to identify patients at particularly increased risk of brain metastases, who would benefit from early intracranial imaging. This could allow for earlier detection and treatment of metastases, with the potential to improve clinical outcomes and patient quality of life.

Multifocal bronchial neuroendocrine tumor (bNET): A new clinical entity.

9135 Background: Bronchial carcinoid (BC) is often categorized into multifocal (MBC) or solitary (SBC). MBC, excluding tumorlet and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, is considered a relatively uncommon subgroup of BC, with much of the MBC literature stemming from case reports/small series. Our study analyzes MBC among a large cohort of 569 patients with BC and argues for change to the current clinical understanding of MBC. We suggest using the term bronchial neuroendocrine tumor (bNET) to more accurately represent its cells of origin and move away from “carcinoid” (historically meaning “carcinoma-like”) and the outdated associated connotation that carcinoids all have a similar, benign clinical and biological behavior. Methods: Using the Mayo Clinic Epidemiology and Genetics of Lung Cancer Database with Institutional Review Board approval, we retrospectively reviewed 569 patients with bNET (204 males, 365 females) presenting to Mayo Clinic Rochester between 1/1997-12/2012. We used univariate and multivariate Cox regression analyses to evaluate factors affecting overall survival. Results: 80 patients (of 569, 14.1%) were diagnosed with multifocal (MbNET) and 489 with solitary (SbNET). Two-sided Fisher’s exact tests found that older age, female gender, never having smoked cigarettes, and tumorlets were associated with MbNET diagnosis. Family lung cancer history, histopathologic grading (pathology: typical vs. atypical), Ki67, and presence of syndromes (carcinoid, Cushing, and MEN1 syndromes) were similar between MbNET and SbNET groups. Most MbNET cases were stage III-IV at the time of diagnosis, while the majority of SbNET cases were stage I. 5-year OS (83%) and 5-year PFS (75%) of MbNET patients were higher than those of their SbNET counterparts (74% and 68%, respectively). Metastasis status was an independent prognostic factor of poor OS in SbNET (P<0.001) but not in MbNET (P=0.71)(Table). Conclusions: Clinical, radiologic, and histopathologic characteristics and prognostic factors differed between SbNET and MbNET. MbNET arose as a new entity often with advanced stage disease, but good prognosis, which does not follow the NSCLC TNM staging system as in the 2009 NCCN guidelines (used during this study) or the updated 2021 NCCN guidelines which continue to stage lung carcinoid similarly to NSCLC. It may be beneficial to consider multifocal lung carcinoid instead as multifocal bNET, a new clinical entity, warranting a novel staging approach that more accurately reflects prognosis.[Table: see text]

P55-7 Bronchial neuroendocrine tumor causing acromegaly – a rare occurrence

P55-7 Bronchial neuroendocrine tumor causing acromegaly – a rare occurrence

Abstract 2939: Activation of NRF2 signaling accelerates development of small cell lung cancer in mice

Abstract Activating mutations in NRF2 frequently occur in human lung cancers, especially the E79Q mutation. However, how the activating mutation contributes to lung tumor development is not well understood. We used a new genetically engineered mouse model (GEMM), LSL-Nrf2E79Q/+ with Cre-inducible expression of this mutation within the endogenous Nrf2 locus, to understand its contribution to lung tumor development. We compared tumor development in p53fl/fl;p16fl/fl;LSL-Nrf2+/+ (WT) versus p53fl/fl;p16fl/fl;Nrf2E79Q/+ (Het) mice after intranasal instillation of Adenoviral Cre. While we did not observe a significant difference in lung adenocarcinoma (LUAC) between the Het and WT mice, the Het mice showed significantly higher frequencies of bronchial neuroendocrine tumors that resembled small cell lung carcinomas (SCLC) compared to WT. Additionally, the latency of SCLC lesions was lower in Het mice compared to WT. Surprisingly, LUACs in both groups were negative for NRF2 by IHC labeling despite recombination of the mutant Nrf2 allele. While all lesions in the WT and Het mice displayed positive ASCL1 and CGRp (NE markers) IHC labeling, only the SCLCs in Het mice expressed NRF2. This is the first study showing activation of Nrf2E79Q mutation drives development of small cell lung carcinomas. Interestingly, our data also suggest that the E79Q NRF2 activating mutation may inhibit the progression of LUAD. Citation Format: Samera Hamad, Stephanie Montgomery, Brittany Bowman, Ryan Murphy, Scott Randell, Trudy Oliver, D. Neil Hayes, M. Ben Major, Bernard Weissman. Activation of NRF2 signaling accelerates development of small cell lung cancer in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2939.

Dual PET Imaging in Bronchial Neuroendocrine Neoplasms: The NETPET Score as a Prognostic Biomarker.

PET scans using 18F-FDG and somatostatin receptor imaging agents are both used in imaging of neuroendocrine neoplasms (NENs). We have suggested the "NETPET score," using uptake of both PET tracers, as a prognostic biomarker in NENs. The name NETPET score was suggested previously to capture the score's intent to summarize information from dual PET imaging in neuroendocrine tumors. We previously demonstrated the effectiveness of the NETPET score in gastroenteropancreatic NENs (GEPNENs). Its prognostic relevance in bronchial NENs remains undetermined. Methods: This is a retrospective multicenter study (2011-2018) assessing patients who had advanced bronchial NEN and who underwent both 18F-FDG and 68Ga-DOTATATE PET within 60 d of each other. The NETPET score was assigned by experienced nuclear medicine physicians and compared with other clinical data such as World Health Organization grade. The primary outcome was overall survival; NETPET score and other prognostic variables were analyzed using univariate and multivariate analyses by the Cox proportional-hazards model. Results: Thirty-eight patients were included for review. The NETPET score and histology were significantly correlated with overall survival in univariate analyses (P = 0.003, P = 0.01). On multivariate analysis, only the NETPET score remained significant (P = 0.03). The NETPET score was significantly associated with histologic grade (P = 0.006, χ2 test). Conclusion: The NETPET score is a prognostic biomarker in bronchial NENs as well as GEPNENs. Although it needs to be validated in prospective studies, it holds significant promise as a biomarker for a wide range of NENs.

Phase I Study of Lysine-Specific Demethylase 1 Inhibitor, CC-90011, in Patients with Advanced Solid Tumors and Relapsed/Refractory Non-Hodgkin Lymphoma

Lysine-specific demethylase 1 (LSD1) is implicated in multiple tumor types, and its expression in cancer stem cells is associated with chemoresistance. CC-90011 is a potent, selective, and reversible oral LSD1 inhibitor. We examined CC-90011 in advanced solid tumors and relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). CC-90011-ST-001 (NCT02875223; 2015-005243-13) is a phase I, multicenter, first-in-human dose-escalation study. Nine dose levels of CC-90011 (1.25-120 mg) given once per week were explored. Primary objectives were to determine safety, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to evaluate preliminary efficacy and pharmacokinetics. Fifty patients were enrolled, 49 with solid tumors (27 neuroendocrine tumors/carcinomas) and 1 with R/R NHL. Median age was 61 years (range, 22-75). Patients received a median of three (range, 1-9) prior anticancer regimens. The RP2D was 60 mg once per week; the nontolerated dose (NTD) and MTD were 120 mg once per week and 80 mg once per week, respectively. Grade 3/4 treatment-related toxicities were thrombocytopenia (20%; an on-target effect unassociated with clinically significant bleeding), neutropenia (8%; in the context of thrombocytopenia at the highest doses), and fatigue (2%). The patient with R/R NHL had a complete response, currently ongoing in cycle 34, and 8 patients with neuroendocrine tumors/carcinomas had stable disease ≥6 months, including bronchial neuroendocrine tumors, kidney tumor, and paraganglioma. CC-90011 is well tolerated, with the RP2D established as 60 mg once per week. The MTD and NTD were determined to be 80 mg once per week and 120 mg once per week, respectively. Further evaluation of CC-90011 is warranted.

Clinical Heterogeneity of Ectopic ACTH Syndrome: A Long-Term Follow-Up Study

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a heterogeneous condition caused by neuroendocrine neoplasms (NENs) located in the lungs, thymus, or pancreas. Our purpose was to evaluate the long-term outcome of these patients. Retrospective study at a referral center. The charts of 164 patients with Cushing syndrome, followed at our center from 1993 to 2019, were analyzed. EAS was found in 16 patients (9.75%, 9 women, mean age 36.01 years) who had been followed for a median of 72 months. The source of EAS was a NEN in 10 patients (8 bronchial and 2 thymic carcinoid tumors) and a mixed corticomedullary tumor, consisting of a pheochromocytoma and an adrenocortical carcinoma in 1 patient. In 2 of the 6 patients initially considered to have occult EAS, the source of the ACTH excess became apparent after adrenalectomy, whereas in the remaining 4 (25%) patients, it has remained occult. Of the 11 patients in whom resection of the NEN was attempted, 10 patients achieved an early remission (91%), but 4 (25%) of these patients had a recurrence during follow-up (biochemically and clinically silent in 2 patients). Three patients died (18.75%): the young woman with the mixed corticomedullary tumor, a man with a thymic NEN that evolved into a neuroendocrine (NE) carcinoma after 11 years of follow-up, and a woman with a bronchial NEN. The course of EAS varies according to tumor type and grade. Some patients have a protracted course, whereas others may evolve into neuroendocrine carcinomas. ACTH = adrenocorticotropic hormone; CS = Cushing syndrome; CT = computed tomography; CV = coefficient of variation; EAS = ectopic ACTH syndrome; IQR = interquartile range; NEN = neuroendocrine neoplasm; SCCL = small cell carcinoma of the lung; TSS = transsphenoidal surgery; UFC = urinary free cortisol.

Efficacy and tolerability of peptide receptor radionuclide therapy (PRRT) in advanced metastatic bronchial neuroendocrine tumours (NETs)

IntroductionPeptide receptor radionuclide therapy (PRRT) has been proven to be effective in gastro-entero-pancreatic neuroendocrine tumours (NETs) using 90Yttrium (90Y)- or 177Lutetium (177Lu)-based somatostatin peptides, with 177Lu-DOTATATE recently licensed. There is less published evidence of PRRT in metastatic bronchial NETs. ObjectiveThe aim of this study was to evaluate the efficacy, safety and toxicity of PRRT in patients with bronchial NETs, to expand the evidence base in this rare type of tumour. Materials and methodsThis was a retrospective analysis of all patients with moderate to well-differentiated typical or atypical bronchial NETs treated at the Royal Free Hospital Nuclear Medicine Department with at least two cycles of 90Y-DOTA−OCTREOTATE and/or 177Lu-DOTA−OCTREOTATE between 2009 and 2020. Response rates, progression free survival (PFS), overall survival and toxicity were evaluated. Factors associated with treatment response were evaluated. ResultsOf the 25 patients with bronchial NETs treated with PRRT in our department between 2009–2020, 7 (28 %) had 90Y-DOTATATE and 18 (72 %) had 177Lu-DOTATATE. 44 % of patients had PRRT as third, fourth of fifth line treatment. 72 % of patients had liver metastases and 76 % skeletal metastases at baseline. Median progression-free survival (PFS) was 17 months (177Lu-DOTATATE = 18 months; 90Y-DOTATATE = 12 months) and the median overall survival was 42 months. High proliferation rate (ki-67 > 20) and low somatostatin receptor (SSR) uptake (score of 2) were associated with shorter PFS. ConclusionPRRT appears to be a safe treatment in somatostatin receptor positive bronchial NETs, even in patients who have been heavily pre-treated. The efficacy of PRRT is comparable with if not favourable to other systemic therapeutic options.

Syndromes de prédisposition aux tumeurs neuroendocrines gastro-entéro-pancréatiques et thoraciques

About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.

The antidiarrheal efficacy of a proprietary amino acid mixture (enterade) in neuroendocrine tumor (NET) patients: Updated data.

614 Background: Diarrhea is a common quality of life limiting symptom seen in neuroendocrine tumor patient. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. In this study we summarize our single center experience with enterade. Methods: Medical records of all the NET patients treated with enterade for symptomatic diarrhea were retrospectively reviewed after appropriate IRB approval. Patients were treated at Markey cancer center between May 2017-June 2019. Results: Total 98 patients were offered enterade. enterade was instructed to be taken as one 8 Oz bottle BID for 1 week. Antidiarrheal efficacy data was available on 49 patients at the time of abstract submission. 37 (75%) patients had GEPNETs, 8 had bronchial NETs, 1 gynecological NET and 3 patients had unknown primary. 28 (57%) patients had history of prior bowel resection either for primary neuroendocrine tumor resection or debulking. 28 (57%) patients were on somatostatin analog at the time of initiation of enterade. 42 (85%) out of 49 patients reported subjective improvement in diarrheal symptoms. 27 (64%) out of these 42 responders reported at least 50 percent reduction in diarrhea frequency. Conclusions: 85% (42/49) neuroendocrine tumor patients reported improvement in diarrhea with enterade. 64% (27/42) reported more than 50% reduction in diarrhea frequency. A prospective Phase II study of enterade in neuroendocrine tumor patients with quality of life limiting diarrhea is currently being conducted (NCT03722511).

High Metabolic Tumour Volume on 18-Fluorodeoxyglucose Positron Emission Tomography Predicts Poor Survival from Neuroendocrine Neoplasms

Introduction: 18-Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) avidity in neuroendocrine neoplasms (NENs) has been associated with higher-grade disease. ¹⁸F-FDG avidity and high SUV_max have been demonstrated to predict poor outcome. Quantitative metrics of ¹⁸F-FDG PET, specifically metabolic tumour volume (MTV) and total lesion glycolysis (TLG), have been shown to be prognostic factors in other malignancies, but these have not been investigated to date in NENs. Methods: Patients with NEN undergoing ¹⁸F-FDG at Royal North Shore Hospital from 2012 to 2018 were included. Images were analysed with automated segmentation (SUV cut-off of 4) followed by contour verification by a nuclear medicine physician and manual segmentation where required. Variables collected included patient age, histological grade, MTV, TLG, and SUV_max/SUV_mean. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Univariate (UV) and multivariate (MV) analyses were performed for OS and PFS for MTV and TLG separately. For UV analysis, the median MTV and TLG were used to dichotomise the cohort. MTV/TLG for NENs of different histological grade were compared using ANOVA. Results: One hundred and ninety patients were included (median age 63.5, 49% female). Primary site: 42% small bowel, 32% pancreas, 15% other gastrointestinal, 6% lung, 6% other. Grade for gastroenteropancreatic NENs and bronchial NEN: G1/typical carcinoid 37%, G2/atypical carcinoid 40%, G3/large-cell/small-cell neuroendocrine carcinoma 16%, unknown 8%. Median MTV was 4.83 mL (range 0–3,161 mL) and median TLG was 29.22. Patients with high MTV had worse median OS compared to those with low MTV (29.7 months vs. not reached, HR 4.1, 95% CI 2.25–7.49, p < 0.00001). Considered as a continuous variable, MTV predicted for poorer OS on UV (p < 0.00001) and MV (p = 0.003) analyses. Whilst histological grade was significant on both UV and MV, SUV_max was significant on UV (p < 0.00001) but not MV (p = 0.76). Tumours of higher grade had higher MTV (mean MTV – G1: 39.6 mL, G2: 107 mL, G3: 337 mL; p = 0.0001 by ANOVA). Conclusions: Quantitative analysis of ¹⁸F-FDG PET in NEN is feasible. High MTV/TLG are predictors of poor prognosis in NEN. Further analyses are underway to investigate a larger cohort of NEN patients.

Follow-Up Recommendations after Curative Resection of Well-Differentiated Neuroendocrine Tumours: Review of Current Evidence and Clinical Practice

The incidence of neuroendocrine neoplasms (NENs) is increasing, especially for patients with early stages and grade 1 tumours. Current evidence also shows increased prevalence, probably reflecting earlier stage diagnosis and improvement of treatment options. Definition of adequate postsurgical follow-up for NENs is a current challenge. There are limited guidelines, and heterogeneity in adherence to those available is notable. Unfortunately, the population of patients at greatest risk of recurrence has not been defined clearly. Some studies support that for patients with pancreatic neuroendocrine tumours (PanNETs), factors such as primary tumour (T), stage, grade (Ki-67), tumour size, and lymph node metastases (N) are of relevance. For bronchial neuroendocrine tumours (LungNETs) and small intestinal neuroendocrine tumours (siNETs), similar factors have been identified. This review summarises the evidence supporting the rationale behind follow-up after curative resection in well-differentiated PanNETs, siNETs, and LungNETS. Published evidence informing relapse rate, disease-free survival, and relapse patterns are discussed, together with an overview of current guidelines informing postsurgical investigations and duration of follow-up.

1383PD - Phase I study of CC-90011 in patients with advanced solid tumours (STs) and relapsed/refractory non-hodgkin lymphoma (R/R NHL)

1383PD - Phase I study of CC-90011 in patients with advanced solid tumours (STs) and relapsed/refractory non-hodgkin lymphoma (R/R NHL)

7O - Phase I study of CC-90011 in patients with advanced solid tumors and relapsed/refractory non-Hodgkin lymphoma (R/R NHL)

Background: CC-90011 is a potent, selective, reversible oral inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-proliferative activity against cancer cells in vitro and in patient-derived xenograft models. Methods: CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of September 4, 2018, 50 pts were enrolled. All had advanced solid tumors except 1 pt with R/R NHL; 26 pts had neuroendocrine neoplasms (NENs). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The non-tolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. The median age was 61 y (range, 22–75), 52% were male, and pts had received a median of 3 (range, 1–4) prior systemic anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (16%) and neutropenia (8%; occurring in the context of thrombocytopenia at the highest doses). Serious AEs occurred in 40% of pts; 6% were treatment-related. Peak plasma concentrations occurred 2-4 h post-dose and average terminal half-life was ∼60 h; exposure was dose proportional. PD analysis showed decreased CgA and MMD in response to CC-90011, correlating with clinical benefit. One pt achieved a complete response (CR) and 22 had stable disease (SD). Prolonged SD ≥ 4 months occurred in 7 pts, 5 with bronchial NEN and 2 with prostate NEN. Conclusions: CC-90011 is well-tolerated with promising antitumor activity in solid tumors and R/R NHL, including a CR and prolonged SD in pts with NENs. PD and PK data showed sufficient target engagement. Taken together, the preliminary clinical data provides the rationale for dose expansion of CC-90011 in pts with NENs. Editorial acknowledgement: Editorial assistance was provided by Johna Van Stelten, Ph.D., of BioConnections LLC, funded by Celgene Corp. Clinical trial identification: NCT02875223 and EUDRACT 2015-005243-13. Legal entity responsible for the study: Celgene Corp. Funding: Celgene Corp. Disclosure: A. Hollebecque: Honoraria: Merck Serono; Consultant or advisor: Gritstone Oncology; Travel funding: Amgen. J.S. de Bono: Advisor: AstraZeneca, Genentech, Pfizer, Merck Sharp & Dohme, Bayer, Merck Serono, Janssen, Astellas, Seattle Genetics; Research funds: AZ, Sanofi, Genentech, GSK, Daiichi Sankyo, Taiho Oncology, Merck Serono, Merck Sharp & Dohme, Sierra Oncology; Speaker bureau: AZ. R. Plummer: Honoraria: Novartis, BristolMyers Squibb; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents: with Clovis Oncology; Travel funding: Merck Sharp & Dohme, Bristol Myers Squibb. S. Mora: Travel funding: Celgene; Employment and equity ownership: Celgene. E. Filvaroff: Employee: Celgene; Stock or equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents/royalties: Celgene and Genentech. M. Lamba: Employee, equity ownership, research funding: Pfizer, Celgene; Patents/royalties: Pfizer. Z. Nikolova: Employee, equity ownership, travel funding: Celgene. All other authors have declared no conflicts of interest.

Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review.

The worldwide incidence of neuroendocrine tumors (NETs) has been increasing. They are a very diverse group of tumors which are commonly found in the gastrointestinal and bronchopulmonary tracts. These tumors usually express somatostatin receptors. Therefore, somatostatin analogs are used for symptom relief as well as treatment. Of the many therapeutic options available, peptide receptor radionuclide therapy (PRRT) has been shown to be very promising. In January 2018, the Food Drug and Authority (FDA) approved 177Lu-Dotatate for use in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutetium is a lower energy beta-emitting radionuclide. The therapeutic use of lutetium-177 (177Lu) has shown better results in advanced gastroenteropancreatic and bronchial neuroendocrine tumors when compared with other therapies available. Adverse effects associated with this therapy include myelotoxicity and nephrotoxicity as the radiopeptides are reabsorbed and accumulate in the renal interstitium. Everolimus is a good and safe option in patients pretreated with 177Lu-Dotatate. Lutetium, in combination with somatostatin analogs, has proven efficacy to treat gastroenteropancreatic neuroendocrine tumors in candidates with somatostatin receptor-positive advanced tumors and normal renal function. This therapy has great potential as it decreases tumor size, improves symptoms, and improves quality of life.

SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2018)

NENs are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise across all sites, stages and grades. Although improved diagnostic techniques have led to earlier detection and stage migration, the improved prognosis documented over time for advanced gastrointestinal and pancreatic neuroendocrine tumors also reflect improvements in therapy. The aim of this guideline is to update practical recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification and therapeutic options are briefly discussed, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, and treatment algorithms are provided.

The antidiarrheal efficacy of a proprietary amino acid mixture in neuroendocrine tumor (NET) patients.

218 Background: Gastroenteropancreatic neuroendocrine tumor (GEPNET) incidence has risen 6-fold over past 3 decades. North American Neuroendocrine Tumor Society estimates that over 100,000 GEPNET patients are currently living in the United States. One of the common quality of life limiting symptom seen in GEPNET patient is diarrhea. Diarrhea in these patients could be due to excessive serotonin production, secondary to post-operative short gut syndrome, steatorrhea from somatostatin analogs, bile acid colitis or intestinal bacterial overgrowth. A novel amino acid based oral rehydration solution (enterade) is currently being evaluated in a Phase II clinical trial for antidiarrheal effects in post bone marrow transplant patients (NCT02919670). We conducted a pilot study of enterade in neuroendocrine tumor (NET's) patients with quality of life limiting diarrhea. Methods: Medical records of all the NET patients given enterade to alleviate symptomatic diarrhea were evaluated. Patients were treated at Markey Cancer Center between May 2017-June 2018. Results: Total 69 NETs patients were treated with enterade. Enterade was administered as 8 Oz bottle BID for 1 a week. Antidiarrheal efficacy data was available on 41 patients at the time of abstract submission. 15 patients had small bowel NETs, 5 had bronchial NETs, 1 had colorectal NETs, 3 had NETs of unknown primary, 3 had gastric NETS, 3 had pancreatic NETs and one had high grade neuroendocrine carcinoma of the prostate. Data regarding primary site was unavailable in 10/41 patients. 21 patients had history of prior bowel resection either for primary neuroendocrine tumor resection or debulking. 25 patients were on somatostatin analogs at the time of initiation of enterade. 31 out of 41 patients reported some reduction in diarrhea frequency. 21 out of these 41 patients reported at least a 50% reduction in diarrhea frequency. Conclusions: 75.6% (31/41) neuroendocrine tumor patients reported improvement in diarrhea frequency with enterade. 51.2% (21/41) reported more than 50% reduction in diarrhea frequency. A prospective Phase II study of enterade in neuroendocrine tumor patients with quality of life limiting diarrhea is currently planned.