Efficacy and Toxicity Analysis of mFOLFIRINOX in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

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.

Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor.

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.

Phase 2 study of copanlisib in combination with gemcitabine and cisplatin in advanced biliary tract cancers.

BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis despite treatment with first-line gemcitabine and cisplatin. In BTC, PI3K/AKT pathway activation has been shown to increase resistance to chemotherapy, which may be overcome with PI3K inhibition. This phase 2 study evaluated the safety and efficacy of copanlisib, a PI3K inhibitor, with gemcitabine and cisplatin in advanced BTCs. The role of PTEN expression in outcomes was also explored. METHODS: Patients with advanced/unresectable BTC received gemcitabine, cisplatin, and copanlisib as their first-line treatment. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were the response rate (RR), median overall survival (OS)/PFS, and safety profile. An assessment of PTEN expression by immunohistochemistry was also performed along with molecular profiling. RESULTS: Twenty-four patients received at least 1 dose of the study drug. The PFS rate at 6 months was 51%; the median OS was 13.7 months (95% CI, 6.8-18.0 months), and the median PFS was 6.2 months (95% CI, 2.9-10.1 months). Nineteen patients were evaluable for RR: 6 patients achieved a partial response (31.6%), and 11 (57.9%) had stable disease. The most common grade 3/4 adverse events were a decreased neutrophil count (45.83%), anemia (25%), increased lipase (25%), and hypertension (20.8%). Twenty patients had tissue evaluable for the PTEN status. The PFS for low (n = 9) and high PTEN expression (n = 11) was 8.5 and 4.6 months, respectively (P = .19). The median OS for low and high PTEN expression groups was 17.9 and 7.0 months, respectively (P = .19). CONCLUSIONS: The addition of copanlisib to gemcitabine and cisplatin does not improve PFS at 6 months. However, future studies using PTEN as a potential biomarker should be considered. LAY SUMMARY: The addition of copanlisib, a PI3K inhibitor, to standard chemotherapy for advanced biliary tract cancers was assessed for efficacy and safety. Twenty-four patients with advanced biliary tract cancer received treatment in this study. There was no difference in survival with the addition of copanlisib in comparison with standard chemotherapy. Copanlisib may be more effective and increase survival in patients with low PTEN expression levels. Further studies are needed to confirm this. No unexpected adverse events occurred.

Efficacy of FOLFOX in Patients with Aggressive Pancreatic Neuroendocrine Tumors After Prior Capecitabine/Temozolomide.

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.

Somatostatin Analogs for Pancreatic Neuroendocrine Tumors: Any Benefit When Ki-67 Is ≥10%?

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.

Sensitivity and Specificity of the NETest: A Validation Study.

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.

Efficacy and Toxicity Analysis of Capecitabine and Temozolomide in Neuroendocrine Neoplasms.

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.

An Update on the Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH).

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.

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials.

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).

Capecitabine and Temozolomide in Advanced Lung Neuroendocrine Neoplasms.

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.

A Phase II Study of Ibrutinib in Advanced Neuroendocrine Neoplasms.

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.

Anatomic and Functional Imaging of Neuroendocrine Tumors.

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.

Sequencing of Somatostatin-Receptor-Based Therapies in Neuroendocrine Tumor Patients.

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. 177Lu-DOTATATE is a ß-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 177Lu-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.

ACTH-secreting pancreatic neuroendocrine neoplasms: A case-series.

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.

Targeted radionuclide therapy in endocrine-related cancers: advances in the last decade.

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.

Somatostatin Receptor Expression in Lung Neuroendocrine Tumors: An Analysis of DOTATATE PET Scans.

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 68Ga- or 64Cu-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.

HORMONET: a phase II trial of tamoxifen for estrogen/progesterone receptor-positive neuroendocrine tumors.

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.

Efficacy of Capecitabine and Temozolomide in Small Bowel (Midgut) Neuroendocrine Tumors.

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.

Chemotherapy in Neuroendocrine Tumors.

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.