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Background: High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs., Patients and Methods: We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX., Results: A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities., Conclusions: mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to somatostatin receptors and are used for palliation of hormonal syndromes and control of tumor growth. The long-acting SSAs octreotide long-acting release and lanreotide are commonly used in the first-line metastatic setting because of their tolerable side effect profile. Radiolabeled SSAs are used both for imaging and for treatment of NETs. 177 Lu-DOTATATE is a β-emitting radiolabeled SSA that has been proven to significantly improve progression-free survival among patients with progressive midgut NETs and is approved for treatment of metastatic gastroenteropancreatic NETs. A key question in management of patients with gastroenteropancreatic and lung NETs is the sequencing of 177 Lu-DOTATATE in relation to other systemic treatments (such as everolimus) or liver-directed therapies. This question is particularly complicated given the heterogeneity of NETs and the near absence of randomized trials comparing active treatment options. This state-of-the-art review examines the evidence supporting use of somatostatin-receptor-targeted treatments within the larger landscape of NET therapy and offers insights regarding optimal patient selection, assessment of benefit versus risk, and treatment sequencing., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Somatostatin receptor (SSTR) expression in metastatic lung neuroendocrine tumors (NETs) has not been well characterized using PET imaging. Understanding the degree and uniformity of SSTR expression is important to establish the role of SSTR-targeted treatments in lung NETs. Methods: A retrospective institutional review of patients with metastatic lung NETs who underwent DOTATATE PET imaging from March 2017 to February 2023 was performed. Results: In total, 48 patients with metastatic lung NETs who underwent 68 Ga- or 64 Cu-DOTATATE PET imaging were identified. Four had completely negative SSTR expression, and 10 had very weak expression (less than in a normal liver). Among the remaining 34 patients, 21 had uniformly positive DOTATATE PET scans, and 13 had heterogeneous expression. Only 44% had uniformly positive receptor expression, identifying them as candidates for peptide receptor radionuclide therapy. Conclusion: Most metastatic lung NETs lack uniform SSTR expression and are thus suboptimal candidates for SSTR-targeted therapy. SSTR imaging in lung NETs should be evaluated carefully for uniformity of expression., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Targeted radionuclide therapy plays an increasingly important role in managing endocrine-related tumors and significantly advances the therapeutic landscape for patients with these diseases. With increasing FDA-approved therapies and advances in the field, come an increased knowledge of the potential for long-term toxicities associated with these therapies and the field must develop new strategies to increase potency and efficacy while individualizing the selection of patients to those most likely to respond to treatment. Novel agents and modalities of therapy are also being explored. This review will discuss the current landscape and describe the avenues for growth in the field currently being explored., Competing Interests: GE-H: Novartis, Bayer, Boston Scientific, Terumo Consult; JH-J: HRA Pharma Consult. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Al-Toubah, Strosberg, Hallanger-Johnson and El-Haddad.)

Ectopic Cushing's syndrome (CS) occurs rarely in patients with pancreatic neuroendocrine neoplasms. Early recognition of symptoms is critical given the high morbidity and mortality associated with CS. A database of pancreatic neuroendocrine neoplasms (NENs) seen at the Moffitt Cancer Center between 1/2008 and 4/2022 was reviewed and cases of ectopic CS were identified. Information was extracted on tumor characteristics, clinical signs and symptoms, therapies, and outcomes. Thirteen cases were identified, ranging in age from 16 to 65 years at the initial time of diagnosis (median 42). Twelve of 13 patients had metastatic tumors at presentation. All were well-differentiated at diagnosis although two were described as transformed to poorly differentiated on rebiopsy. A total of 4 patients also experienced Zollinger-Ellison syndrome. Three patients underwent bilateral adrenalectomy to manage uncontrolled CS. Median overall survival of was 56 months from the time of initial cancer diagnosis but only 18 months from diagnosis of CS. Our study showed that ectopic CS is a highly morbid condition when occurring in pancreatic NENs and is associated with aggressive disease. Bilateral adrenalectomy can be considered for syndrome control. To our knowledge, this is the largest institutional case-series of ACTH-secreting metastatic pancreatic NEN., (© 2023 British Society for Neuroendocrinology.)

Background: Nearly 30% of neuroendocrine tumors (NETs) have evidence of immunohistochemical (IHC) expression of estrogen (ER) and/or progesterone (PR) receptors. Therefore, targeting ER/PR may offer an effective NET-directed treatment to select patients., Methods: We conducted a multicenter Simon two-stage single-arm phase II trial of tamoxifen in patients with metastatic, progressive NETs. Eligible patients had positive IHC expression of ER and/or PR ⩾ 1%. Prior therapy with somatostatin analogs was required for progressing/functioning cases. Main exclusion criterion was aggressive disease requiring cytotoxic therapy. The primary end point was disease control rate (DCR) at week 24 by Response Evaluation Criteria in Solid Tumors version 1.1. We planned to enroll 23 patients in the first stage, to reach a DCR at week 24 of 70% ( versus 50%); if ⩾12 patients reached the primary end point, a total of 37 would be included., Results: From February 2019 to February 2022, 23 out of 59 patients were eligible and enrolled: 15 (65%) were females; the most common sites were pancreas (11; 48%) and small bowel (6; 26%). In all, 13 patients (56.5%) had G2 NETs. At a median follow-up of 27 months, 13 patients (56.5%) had stable disease at week 24 and median progression-free survival (PFS) was 7.9 months [interquartile range (IQR): 3.7-12.1]. The best response was stable disease in 13 patients, with most patients experiencing minor tumor growth. Median PFS times were not significantly different according to ER/PR < or ⩾30% ( p  = 0.49) or ER versus PR expression ( p  = 0.19). One patient experienced grade 2 constipation., Conclusion: Tamoxifen for ER-/PR-positive NETs patients is safe but offers modest antitumor effects., Trial Registry Name: Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET)., Url: https://clinicaltrials.gov/ct2/show/NCT03870399?term=03870399&draw=2&rank=1., Registration Number: NCT03870399., Competing Interests: MJB: none; JS: Honoraria from Ipsen and Tersera; TAT: none; LD: none; MDD: honoraria from Novartis and Ipsen; CAM: none; VHFJ: none; TCF: none; RGT: none; RPR: honoraria from Novartis and Ipsen., (© The Author(s), 2023.)

Competing Interests: We declare no competing interests.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

The capecitabine/temozolomide regimen has significant activity in pancreatic NETs; however, data are limited in NETs of the small bowel (midgut). A retrospective study of all patients with metastatic midgut NETs seen at Moffitt Cancer Center between January 2008 and June 2019 treated with CAPTEM was conducted. 32 patients with proven or suspected well-differentiated primary small bowel NETs (excluding duodenum) were identified. 6 patients were found to have a radiographic response (19%), 5 of whom had high-grade disease. Only one patient among 23 with low/intermediate-grade disease responded (4%), whereas the response rate for patients with high-grade disease was 56%. Among patients with low/intermediate-grade disease, 44% discontinued due to poor tolerability. The CAPTEM regimen appears to have an activity in patients with high-grade small bowel NETs and is largely inactive in patients with low/intermediate-grade tumors.

Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer., Competing Interests: Cathy EngConsulting or Advisory Role: Bayer Schering Pharma, Foundation Medicine, Array BioPharma, Natera Emerson Y. ChenOther Relationship: Horizon CME, Taiho Pharmaceutical Mark LewisConsulting or Advisory Role: Boehringer IngelheimOther Relationship: Medscape Jonathan StrosbergConsulting or Advisory Role: NovartisSpeakers' Bureau: Ipsen, LexiconResearch Funding: Novartis Ramya ThotaConsulting or Advisory Role: Array BioPharmaResearch Funding: Abbvie, Bristol-Myers Squibb Paul ObersteinConsulting or Advisory Role: Merck, BTG, Tyme, IpsenResearch Funding: Merck, Roche/GenentechTravel, Accommodations, Expenses: Merck Gary BuchschacherResearch Funding: Roche/Genentech, AstraZeneca, MerckTravel, Accommodations, Expenses: Roche/Genentech, AstraZeneca Sandip PatelConsulting or Advisory Role: Bristol-Myers Squibb, AstraZeneca/MedImmune, Nektar, Compugen, IlluminaSpeakers' Bureau: Merck, Boehringer IngelheimResearch Funding: Bristol-Myers Squibb, Pfizer, Roche/Genentech, Amgen, AstraZeneca/MedImmune, Fate Therapeutics, Merck Davendra SohalConsulting or Advisory Role: Perthera, Ability PharmaSpeakers' Bureau: IncyteResearch Funding: Celgene, Genentech, Bristol-Myers Squibb, Rafael Pharmaceuticals, Apexigen, Amgen Philip PhilipHonoraria: Celgene, Bayer, Ipsen, Merck, AstraZeneca, TriSalus Life Sciences, Blueprint Medicines, Syncore, Array BioPharmaConsulting or Advisory Role: Celgene, Ipsen, Merck, TriSalus Life Sciences, Daiichi Sankyo, Syncore, Taiho PharmaceuticalSpeakers' Bureau: Celgene, Bayer, Ipsen, Novartis, IncyteResearch Funding: Bayer, Incyte, Karyopharm Therapeutics, Merck, Taiho Pharmaceutical, Momenta Pharmaceuticals, Novartis, Plexxikon, Immunomedics, Regeneron, Genentech, Tyme, Caris Life Sciences, ASLAN Pharmaceuticals, QED Therapeutics, Halozyme, Boston Biomedical, Advanced Accelerator Applications, Lilly, Merus, QED Therapeutics, Incyte, Caris Life SciencesTravel, Accommodations, Expenses: Rafael Pharmaceuticals, Celgene, AbbVie Arvind DasariConsulting or Advisory Role: Ipsen, Novartis, Voluntis, LexiconResearch Funding: Novartis, Eisai, Hutchison MediPharma, Merck, Guardant Health, Ipsen Hagan KenneckeHonoraria: IpsenResearch Funding: Taiho Pharmaceutical Stacey SteinConsulting or Advisory Role: Genentech/Roche, Eisai, QED Therapeutics, ExelixisNo other potential conflicts of interest were reported.

The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.

Background: The capecitabine/temozolomide (CAPTEM) regimen has significant activity in advanced neuroendocrine tumors (NETs). Questions exist regarding activity in pancreatic versus nonpancreatic NETs, risk of opportunistic infections, long-term myelotoxicity, and safety of prolonged treatment duration. Analysis of large patient cohorts is needed for the evaluation of rare toxicities and assessment of risk factors., Methods: We conducted a retrospective study of all patients with advanced NETs seen at Moffitt Cancer Center between January 2008 and June 2019 who received treatment with CAPTEM., Results: A total of 462 patients were eligible. The objective radiographic response rate was 46%, and the disease control rate was 81%. Median progression-free survival (PFS) was 18 months (95% CI, 14.0-21.9 months) and median overall survival was 51 months (95% CI, 42.8-59.2 months): 62 months in well-differentiated NETs versus 14 months in poorly differentiated neuroendocrine carcinomas (P<.0001). Patients with primary pancreatic tumors had the highest partial response rates and longest median PFS. Incidences of grade 4 thrombocytopenia and neutropenia were 7% and 3%, respectively, and substantially higher in women than men (P=.02 and P=.004, respectively). Only 1 case (0.2%) of suspected Pneumocystis pneumonia (PCP) was observed in a patient receiving corticosteroids. Three patients developed myelodysplastic disease, all of whom had received prior peptide receptor radiotherapy (PRRT). There were no acute treatment-related deaths; 1 patient died 2 months after a thrombocytopenic bleed., Conclusions: The CAPTEM regimen is exceptionally safe. Efficacy is particularly robust in well-differentiated pancreatic NETs. Severe myelotoxicity is rare; the risk of grade 4 cytopenias is significantly increased in women, and therefore sex-based dosing should be considered. There were no cases of myelodysplastic syndromes, except among patients who had received PRRT, a known risk factor. The risk of PCP is negligible.

Background: Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited., Materials and Methods: To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014-2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints., Results: A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6-173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6-16.2) and 11.9 months (95% CI, 8.6-14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2-16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1-4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8-86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2-10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea., Conclusion: SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%., Implications for Practice: The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population., (© 2020 AlphaMed Press.)

Objectives: Positively charged amino acids (AA) such as arginine/lysine are coinfused with radiolabeled somatostatin analogs to reduce rates of nephrotoxicity. In the phase 3 NETTER-1 trial, commercial AA formulations were used in association with 177Lu-DOTA-0-Tyr3-Octreotate (DOTATATE). These formulations were also used in an early-access program (EAP) before regulatory approval of 177Lu-DOTATATE. Our program transitioned to compounded l-arginine 2.5%/l-lysine 2.5% in 0.9% NaCl after commercial approval of 177Lu-DOTATATE. We sought to compare rates of nausea/vomiting with arginine/lysine versus commercial parenteral AA formulations., Methods: Rates of nausea/vomiting of all 20 EAP patients who received commercial AAs (15% Clinisol) were compared with the first 29 patients to receive 177Lu-DOTATATE after commercial approval and coinfused with arginine/lysine. Other parameters reviewed included infusion rates, need for PRN nausea medications, and other toxicities., Results: Seventeen percent of patients who received compounded arginine/lysine experienced nausea, compared with 100% of patients in the EAP group (P < 0.0001). Infusion-related reactions occurred in 3% of the arginine/lysine cohort versus 35% in the EAP group. Infusion durations were substantially shorter in the arginine/lysine cohort (reduced by 61%)., Conclusions: Coinfusions of arginine/lysine with radiolabeled somatostatin analogs result in substantially lower rates of nausea/vomiting compared with commercial AA formulations designed for parenteral nutrition., Competing Interests: S.B. is on the speaker's bureau of Merck & Co Pharmaceuticals and on the advisory board of Eisai and Array Biopharma. J.St. has consulted for Novartis and is on the speaker's bureau of Ipsen and Lexicon. G.E.-H. is on the advisory board for Actinium Pharmaceuticals, Inc. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.

Opinion Statement: DIPNECH is caused by an idiopathic proliferation of pulmonary neuroendocrine cells which can lead to bronchiolitis and multifocal lung neuroendocrine tumors. Patients often present with chronic cough and dyspnea. Larger NETs may develop malignant potential. Somatostatin analogs can palliate chronic symptoms, particularly cough. Surgical resection can be considered for relatively large (e.g. >1 cm), progressive tumors.

Background: 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has activity in pancreatic neuroendocrine tumors (pNETs), but its use is limited, partly because of toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine plus temozolomide (cap/tem) among other treatments., Materials and Methods: This was a retrospective study of all patients with well-differentiated metastatic pNETs, treated at an academic cancer center between January 2008 and June 2019, who received FOLFOX and had received cap/tem in the past. The primary endpoint was objective response rate., Results: Thirty-one patients met eligibility criteria. Twenty-five received FOLFOX, and six received FOLFOX with bevacizumab. Patients were heavily pretreated, having received a median of three prior lines of systemic therapy prior to FOLFOX (range, 1-8). Three (9.7%) patients had grade [G]1 tumors, 16 (51.6%) had G2, and 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%) patients. Fourteen (45.2%) exhibited a best response of partial radiographic response per RECIST 1.1 criteria, 15 (48.4%) stable disease, and 2 (6.4%) progressive disease; overall response rate was 45.2% and disease control rate was 93.5%. Median progression-free survival was 6 months (95% confidence interval [CI], 5.0-7.0), and median overall survival was 16 months from onset of study treatment (95% CI, 11.3-20.7) and 67 months from date of diagnosis (95% CI, 49.8-84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen., Conclusion: FOLFOX is active in aggressive, heavily pretreated pNETs that have progressed on prior cap/tem chemotherapy; response durations are relatively short., Implications for Practice: FOLFOX chemotherapy has robust activity in patients with rapidly progressive, heavily pretreated pancreatic neuroendocrine tumors (NETs), a setting in which few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs., (© 2020 AlphaMed Press.)

177 Lu-Dotatate treatment is indicated for progressive, well-differentiated, small bowel neuroendocrine tumours) NETs. These tumours often metastasise to mesenteric lymph nodes and produce a desmoplastic reaction, consisting of tumour cells interspersed with fibrotic tissue. We hypothesised that, in patients treated with 177 Lu-Dotatate, mesenteric tumours would remain stable even as liver tumour size changes were observed. We retrospectively reviewed the records of all patients treated with 177 Lu-Dotatate between April 2018 and December 2019. Among patients with desmoplastic mesenteric tumours and liver metastases, we evaluated changes in tumour size of mesenteric and liver lesions based on pre- and post-treatment anatomic scans. As a result of the infrequency of objective radiographic response, any reported changes in tumour size were considered significant. Twenty-one patients met the inclusion criteria: nine had evidence of shrinkage of liver lesion(s), one had mild progression of liver lesions, seven had stable hepatic disease and four had a mixed hepatic response. Two of the patients with hepatic tumour shrinkage met the criteria for a partial response via RECIST 1.1 (https://recist.eortc.org). Desmoplastic mesenteric lesions remained unchanged in size, regardless of the changes detected in liver lesions. In conclusion, 177 Lu-Dotatate does not impact desmoplastic mesenteric tumours which are typically associated with midgut NETs. Patients whose disease is predominantly confined to desmoplastic mesenteric lesions are unlikely to respond radiographically to peptide receptor radionuclide therapy. Moreover, the inclusion of desmoplastic mesenteric lesions as target lesions in RECIST measurements tends to increase rates of disease stability vs response or progression., (© 2021 British Society for Neuroendocrinology.)

Background: Secretory tumor markers traditionally measured in patients with neuroendocrine tumors (NET) are lacking sensitivity and specificity, and consequently they are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population of metastatic well-differentiated NETs of gastroenteropancreatic and lung origin and to evaluate NETest specificity in a mixed population of metastatic non-NET gastrointestinal (GI) malignancies and healthy individuals., Design and Methods: Forty-nine patients with metastatic NETs, 21 patients with other metastatic GI cancers, and 26 healthy individuals were enrolled in the study. Samples were sent in a blinded fashion to a central laboratory, and an NETest value of 0-13% was considered normal., Results: Using 13% as the upper limit of normal, the sensitivity of the NETest was 98% (95% CI 89-100%). The overall specificity was 66% (95% CI 51-79%), with 16 false-positive results. Specificity was 81% (95% CI 62-92%) among 26 healthy individuals and 48% (95% CI 26-70%) among patients with other GI malignancies. Using an updated normal range of 0-20%, sensitivity was unchanged, but specificity improved to 100% among healthy participants and to 67% among patients with other cancers., Conclusions: The sensitivity of the NETest is exceptionally high (>95%) in a population of metastatic, well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20% but relatively low when evaluating patients with other GI malignancies., (© 2020 S. Karger AG, Basel.)

Although radiation-induced mesenteritis or peritonitis can potentially exacerbate the risk of bowel obstruction, there are no data in the literature on the incidence of intestinal obstruction related to peptide receptor radionuclide therapy. Methods: The records of all patients treated with 177 Lu-DOTATATE at Moffitt Cancer Center between April 2018 and October 2019 were evaluated. The number of patients who developed bowel obstruction within 3 mo of a 177 Lu-DOTATATE treatment was divided by the total number of patients with preexisting peritoneal or mesenteric disease. Management strategies and outcomes were evaluated. Results: Of a total of 159 patients treated, 81 had baseline mesenteric or peritoneal disease, among whom 5 (6%) experienced at least 1 episode of bowel obstruction within 3 mo of treatment. Two of the patients underwent surgical exploration during obstruction describing a "frozen abdomen." All 5 responded at least temporarily to high-dose corticosteroid treatment and regained bowel function, but 2 patients eventually succumbed to progressive peritoneal disease. Conclusion: Peptide receptor radionuclide therapy can lead to bowel obstruction in patients with mesenteric or peritoneal disease, likely by inducing inflammation. Corticosteroids can potentially play a role in treatment and prophylaxis., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are a heterogeneous family of neoplasms. Well-differentiated tumors are often slow growing and characterized by low tumor mutational burden. Poorly differentiated NECs are aggressive, with an increased mutational burden and higher propensity to express PD-L1. While the therapeutic landscape for neuroendocrine neoplasms (NENs) has evolved substantially over the past decade, immunotherapy has been unexplored in NENs until recently. Checkpoint inhibitors such as anti-PD-1 and anti-CTLA-4 agents, bi-specific tumor-targeting antibodies, and chimeric antigen receptor (CAR) T-cell therapy are examples of treatments that have demonstrated efficacy in other cancers and have recently been investigated in NENs. This review examines the immune landscape of NENs in detail, summarizes recent clinical study results, and discusses potential future directions for immunotherapy., Competing Interests: Conflicts of Interest: J Strosberg: Consult (Novartis); Speakers bureau (Ipsen and Lexicon). The other authors have no conflicts of interest to declare., (2020 Translational Gastroenterology and Hepatology. All rights reserved.)

Opinion Statement: Neuroendocrine tumors (NETs) can occur in a wide variety of organs and display a spectrum of pathologic behavior. Accurate and effective imaging is paramount to the diagnosis, staging, therapy, and surveillance of patients with NET. There have been continuous advancements in the imaging of NET which includes anatomic and functional techniques.

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. The objective of this study was to assess changes in symptoms and pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment., Methods: Patients with clinical and/or pathologic diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the H. Lee Moffitt Cancer Center and Research Institute, Hadassah-Hebrew University Medical Center, and Mayo Clinic Cancer Center. Their charts were reviewed to assess changes in symptoms and PFTs., Results: Forty-two patients were identified who had either chronic cough or dyspnea because of proven or suspected DIPNECH and who had received treatment with an SSA. Thirty-three patients experienced symptomatic improvement. Additionally, 14 of 15 patients in whom PFTs were checked were noted to have an improvement in FEV 1 after treatment., Conclusions: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs., Methods: Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint., Results: Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related., Conclusions: Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered., Clinical Trial Registration Number: NCT02939651 (10/20/2016).

Purpose of Review: Neuroendocrine tumors are heterogeneous neoplasms with variable prognoses and clinical behaviors. The majority of well differentiated NETs express somatostatin receptors. Identification of these receptors has contributed to advancements in molecular and targeted radiotherapies., Recent Findings: Molecular scans provide important diagnostic, staging, and prognostic data. Somatostatin-receptor imaging aids in selection of patients who are eligible for somatostatin-receptor-targeting therapies. Peptide receptor radionuclide therapy has recently demonstrated robust efficacy in a phase III study of progressive midgut NETs. Current studies are investigating novel receptor agonists and antagonists, new classes of radioactive isotopes, and radiosensitizing combination treatments., Summary: The sophistication of molecular imaging is improving and its importance is increasing as a diagnostic, predictive, and prognostic tool. Theranostics, the coupling of molecular imaging with receptor-targeted therapy, represents a novel approach to cancer treatment.

Background: Ibrutinib is an orally administered inhibitor of Bruton's tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited within neuroendocrine neoplasms (NENs) where they stimulate angiogenesis and tumor growth. Ibrutinib inhibits mast cell degranulation and has been associated with regression of tumors in a mouse insulinoma model., Methods: A prospective, phase II trial evaluated patients with advanced gastrointestinal (GI)/lung NENs and pancreatic NENs (pNENs) who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560 mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. The primary endpoint was objective response rate., Results: Twenty patients were enrolled on protocol from November 2015 to December 2017 (15 advanced GI/lung NENs and 5 pNENs). No patient reached an objective response. Median PFS was 3.0 months. A total of 44 drug-related adverse events (AEs) were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs, and 1 patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment., Conclusions: Ibrutinib does not show significant evidence of activity in well-differentiated gastroenteropancreatic and lung NENs., (© 2019 S. Karger AG, Basel.)

Background: Patients with advanced lung neuroendocrine neoplasms (NENs) have few treatment options. Capecitabine and temozolomide have recently showed significant activity in patients with pancreatic neuroendocrine tumors (NETs), but data in lung NETs are limited., Methods: We retrospectively reviewed the records of patients treated at a large referral center to identify patients seen between January 2008 and September 2018 with metastatic lung NENs who received treatment with capecitabine and temozolomide (CAPTEM). Patients with small cell lung cancer were excluded. The primary endpoint was overall response rate per RECIST 1.1. Secondary endpoints included progression-free survival, overall survival, and toxicity., Results: Twenty patients were identified who received treatment with capecitabine and temozolomide. Fourteen (70%) had typical lung NETs, five had (25%) atypical carcinoids, and one (5%) had disease defined as a large-cell neuroendocrine carcinoma. Nineteen patients were evaluable for response. Six (30%) patients exhibited a best response of partial response per RECIST 1.1 criteria, 11 (55%) stable disease, and 2 (10%) progressive disease; objective response rate was 30%, and disease control rate was 85%. Eleven patients eventually progressed, only six of whom exhibited progression per RECIST 1.1 criteria. Median progression-free survival was 13 months (95% confidence interval [CI], 4.4-21.6 months). Median overall survival was 68 months (95% CI, 35.3-100.7 months). Toxicity profile was mild with mainly grade 1, expected toxicities. Six patients required dose reduction because of toxicity., Conclusion: The CAPTEM regimen is associated with a high response rate and a relatively tolerable toxicity profile in lung NENs. This regimen warrants further exploration in a prospective clinical trial., Implications for Practice: Patients with advanced lung neuroendocrine neoplasms have very few systemic treatment options. The capecitabine and temozolomide regimen has previously shown significant activity in patients with pancreatic neuroendocrine tumors (NETs) but has not been explored in metastatic lung NETs. This study showed that this regimen is associated with a high response rate (30%) and a relatively tolerable toxicity profile in this population., (© AlphaMed Press 2019.)

Introduction : 177 Lutetium-[DOTA°,Tyr 3 ]octreotate ( 177 Lu-DOTATATE) is a type of peptide receptor radionuclide therapy that garnered FDA approval in January 2018 for the treatment of somatostatin receptor-positive gastroenteropancreatic (GEP) neuroendocrine tumor (NET) patients. The therapy approval was based on findings from the randomized international phase III NETTER-1 trial as well as outcome data from a large European registry. The mechanism of the drug stems directly from its structure: a somatostatin analog (octreotate) selectively binding to somatostatin receptor expressing cells and being internalized, along with a chelated beta-emitting isotope 177 Lu. Areas Covered : Herein we describe the pharmacology, clinical efficacy and adverse event data from prospective and retrospective studies with 177 Lu-DOTATATE. We discuss the role of 177 Lu-DOTATATE within the current treatment landscape for GEP NET patients. Expert Opinion : 177 Lu-DOTATATE represents a unique addition to the treatment armamentarium for GEP NETs because of its potential to elicit tumor cytoreduction, which is rare among other existing treatment options, and prolonged disease control. Where 177 Lu-DOTATATE fits into the treatment sequence for GEP NET patients remains an area of active investigation.

New systemic treatments have improved the therapeutic landscape for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While drugs such as everolimus, sunitinib, temozolomide, and 177Lutetium-dotatate are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE), or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy, and sparing them toxicities of a new systemic treatment. We identified 69 patients with metastatic GEP-NETs who underwent a local treatment for focal progression in the setting of widespread metastases. 26% underwent resection, 27% RFA, 23% external beam radiation, and 23% selective HAE. With a median follow-up of 25 months, 42 (61%) patients subsequently progressed to the point of requiring additional intervention (12 locoregional, 30 systemic) for disease control. Median time to new systemic treatment was 32 months (95% CI, 16.5 - 47.5 months). Median time to any additional intervention was 19 months (95% CI, 8.7 - 25.3 months). Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.

Peptide receptor radionuclide therapy is a form of systemic radiotherapy shown to be effective in treating neuroendocrine tumors expressing somatostatin receptors. The NETTER-1 trial was the first randomized phase III clinical trial evaluating a radiolabeled somatostatin analog, and demonstrated significant improvement in progression-free survival among patients with midgut neuroendocrine tumors treated with 177 Lu-DOTATATE versus high-dose octreotide. This article discusses the evolution of peptide receptor radionuclide therapy, side effects, and potential future treatment approaches., (Copyright © 2018 Elsevier Inc. All rights reserved.)