Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors

Introduction. Capecitabine-temozolomide (CAPTEM) has significant activity in patients (pts) with metastatic low grade pancreatic neuroendocrine tumors (NETs). However, there is limited data regarding its activity in pts with metastatic well-differentiated intermediate and high grade pancreatic and nonpancreatic NETs. The objective of this study was to assess the functional imaging response, survival, and tolerability of CAPTEM in this population.Methods. A retrospective audit of pts with metastatic well-differentiated intermediate (WHO grade 2) or high grade (WHO grade 3) NETs treated at Peter MacCallum Cancer Centre between March 2013 and March 2017. Pts received capecitabine 750 mg/m2orally twice daily (bd) from days1 to 14 and temozolomide 100 mg/m2bd from days 10 to 14 every 28 days. Data regarding functional imaging response, progression-free and overall survival, and toxicities was collected.Results. Thirty-two pts received a median of 6 cycles (range: 2-16) of CAPTEM for grade 2 (n=21, 66%) or grade 3 (n=11, 34%), Ki67 <55% (n= 7, 21.9%) or Ki67 ≥55% (n= 4, 12.5 %) NET. Primary site included gastroenteropancreatic (n= 17, 53%), lung (n= 12, 37.5%), and unknown origin (n = 3, 9.4%). Twenty-two percent received CAPTEM as first-line therapy. After a median of 31 months of follow-up, the two-year overall survival (OS) was 42%, with a median OS of 24 months. There was a trend towards improved median progression-free survival (PFS) in pts with low grade 3 (Ki67<55%) versus high grade 3 (Ki67 ≥55%) NETs (15 vs 4 months, p= 0.11). Ten (31.3%) experienced grade 3/4 toxicity, with nausea (15.6%), thrombocytopaenia (12.5%), and fatigue (9.4%) the most common toxicities reported.Conclusion. CAPTEM has significant activity in patients with metastatic grades 2 and 3 NETs with manageable toxicity. The PFS benefit observed in the grade 3 subgroup with Ki67<55% warrants further evaluation in a larger randomized trial.

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FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

Neuroendocrinology ◽

10.1159/000514339 ◽

2021 ◽

Author(s):

Jane E. Rogers ◽

Michael Lam ◽

Daniel M. Halperin ◽

Cecile G. Dagohoy ◽

James C. Yao ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Cox Regression ◽

Progression Free Survival ◽

Pancreatic Neuroendocrine Tumors ◽

Free Survival ◽

Prior Therapy ◽

Well Differentiated ◽

Grade 3 ◽

Line Of Therapy

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.

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Prognostic transcriptome classes of duodenopancreatic neuroendocrine tumors

Endocrine Related Cancer ◽

10.1530/erc-21-0051 ◽

2021 ◽

Author(s):

Marc Diedisheim ◽

Solène Dermine ◽

Anne Jouinot ◽

Amandine Septier ◽

Sébastien Gaujoux ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Beta Cell ◽

Tumor Biology ◽

Disease Free Survival ◽

Tumor Grade ◽

Pancreatic Alpha Cell ◽

Liver Gene ◽

Well Differentiated ◽

Grade 3 ◽

Definition Of

Duodenopancreatic neuroendocrine tumors (DPNETs) aggressiveness is heterogeneous. Tumor grade and extension are commonly used for prognostic determination. Yet, grade classes are empirically defined, with regular up-dates changing the definition of classes. Genomic screening may provide more objective classes, and reflect tumor biology. The aim of this study was to provide a transcriptome classification of DPNETs. We included 66 DPNETs, covering the entire clinical spectrum of the disease in terms of secretion, grade, and stage. Three distinct molecular groups were identified, associated with distinct outcome (log-rank p<0.01): (i) better-outcome DPNETs with pancreatic beta-cell signature. This group was mainly composed of well-differentiated, grade 1 insulinomas; (ii) poor-outcome DPNETs with pancreatic alpha-cell and hepatic signature. This group included all neuroendocrine carcinomas and grade 3 DPNETs, but also some grade 1 and grade 2 DPNETs; and (iii) intermediate-outcome DPNETs with pancreatic exocrine and progenitor signature. This group included grade 1 and grade 2 DPNETs, with some insulinomas. Fibrinogen gene FGA expression was one of the top most expressed liver gene. FGA expression was associated with disease-free survival (HR=1.13, p=0.005), and could be validated on two independent cohorts. This original pathophysiologic insight provides new prognostic classification perspectives.

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Well differentiated grade 3 pancreatic neuroendocrine tumors compared with related neoplasms: A morphologic study

Cancer Cytopathology ◽

10.1002/cncy.21982 ◽

2018 ◽

Vol 126 (5) ◽

pp. 326-335 ◽

Cited By ~ 6

Author(s):

Carlie S. Sigel ◽

Vitor Werneck Krauss Silva ◽

Michelle D. Reid ◽

David Chhieng ◽

Olca Basturk ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Pancreatic Neuroendocrine Tumors ◽

Morphologic Study ◽

Well Differentiated ◽

Grade 3

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A phase II study of temozolomide and bevacizumab in patients with advanced neuroendocrine tumors

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4044 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4044-4044 ◽

Cited By ~ 31

Author(s):

M. H. Kulke ◽

K. Stuart ◽

C. C. Earle ◽

P. Bhargava ◽

J. W. Clark ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Phase Ii ◽

Phase Ii Study ◽

Response Table ◽

Pancreatic Net ◽

Prospective Phase ◽

Vegf Pathway ◽

Well Differentiated ◽

Grade 3 ◽

Ecog Ps

4044 Background: Inhibitors of the VEGF pathway have been shown to have activity in neuroendocrine tumors (NETs). Temozolomide (TMZ), an oral analog of dacarbazine is also active in this setting. We performed a prospective, phase II study to assess the safety and efficacy of TMZ, administered in combination with bevacizuamb, in patients (pts) with advanced NETs. Methods: Pts received TMZ, 150 mg/m2/day po for 7 days every other week, and bevacizumab, 5 mg/kg IV every other week. Due to anticipated lymphopenia, pts received prophylaxis with trimethoprim/sulfamethoxazole (1 DS tablet q MWF) and acyclovir (400 mg po TID). Pts were followed for toxicity, response, and survival. Results: Enrolled patients (n=34) had the following characteristics: M:F = 19:15; median age 61 (range 37–75); ECOG PS 0/1/2 = 12/20/2; carcinoid/pancreatic NET = 16/18. Prior treatments included chemoembolization (n=7) chemotherapy (n=12); and octreotide (n=17); pts on octreotide remained on octreotide at stable doses for the duration of the study. Pts had either well-differentiated tumors (n=27) or moderately/poorly-differentiated NETs (n=7); pts with small cell carcinoma were not eligible for the study. Pts have received treatment for a median of 22 weeks. Grade 3–4 toxicities included: lymphopenia (n=21, 62%), leukopenia (n=2, 6%), thrombocytopenia (n=7, 21%), neutropenia (n=2, 6%), hyponatremia (n=1, 3%), vomiting (n=3, 9%), nausea (n=2, 6%), dehydration (n=1, 3%), fatigue (n=2, 6%), constipation (n=1, 3%), and hypertension (n=1, 3%). 20 pts had elevated CGA levels (>36.4 ng/ml) at baseline; 0/9 (0%) carcinoid and 4/11 (36%) pancreatic NET experienced CGA decreases of >50% from baseline on two consecutive assessments. 29 pts are currently evaluable for radiologic response ( Table ). Conclusions: The combination of TMZ and bevacizumab can be safely administered and shows promising activity in pts with advanced pancreatic NETs. Additional studies with this combination are warranted. [Table: see text] [Table: see text]

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Gastroenteropancreatic Well‐Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement

The Oncologist ◽

10.1634/theoncologist.2015-0476 ◽

2016 ◽

Vol 21 (10) ◽

pp. 1191-1199 ◽

Cited By ~ 60

Author(s):

Romain Coriat ◽

Thomas Walter ◽

Benoît Terris ◽

Anne Couvelard ◽

Philippe Ruszniewski

Keyword(s):

Neuroendocrine Tumors ◽

Position Statement ◽

Well Differentiated ◽

Grade 3

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The Spectrum of Neuroendocrine Tumors: Histologic Classification, Unique Features and Areas of Overlap

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.92 ◽

2015 ◽

pp. 92-103 ◽

Cited By ~ 22

Author(s):

David S. Klimstra ◽

Himisha Beltran ◽

Rogerio Lilenbaum ◽

Emily Bergsland

Keyword(s):

Neuroendocrine Tumors ◽

Prostate Gland ◽

Neuroendocrine Differentiation ◽

Large Cell ◽

Genetic Alterations ◽

Neuroendocrine Cells ◽

Neuroendocrine Neoplasms ◽

Platinum Based Chemotherapy ◽

Well Differentiated ◽

Grade 3

Neuroendocrine neoplasms are diverse in terms of sites of origin, functional status, and degrees of aggressiveness. This review will introduce some of the common features of neuroendocrine neoplasms and will explore the differences in pathology, classification, biology, and clinical management between tumors of different anatomic sites, specifically, the lung, pancreas, and prostate. Despite sharing neuroendocrine differentiation and histologic evidence of the neuroendocrine phenotype in most organs, well-differentiated neuroendocrine tumors (WD-NETs) and poorly differentiated neuroendocrine carcinomas (PD-NECs) are two very different families of neoplasms. WD-NETs (grade 1 and 2) are relatively indolent (with a natural history that can evolve over many years or decades), closely resemble non-neoplastic neuroendocrine cells, and demonstrate production of neurosecretory proteins, such as chromogranin A. They arise in the lungs and throughout the gastrointestinal tract and pancreas, but WD-NETs of the prostate gland are uncommon. Surgical resection is the mainstay of therapy, but treatment of unresectable disease depends on the site of origin. In contrast, PD-NECs (grade 3, small cell or large cell) of all sites often demonstrate alterations in P53 and Rb, exhibit an aggressive clinical course, and are treated with platinum-based chemotherapy. Only WD-NETs arise in patients with inherited neuroendocrine neoplasia syndromes (e.g., multiple endocrine neoplasia type 1), and some common genetic alterations are site-specific (e.g., TMPRSS2-ERG gene rearrangement in PD-NECs arising in the prostate gland). Advances in our understanding of the molecular basis of NETs should lead to new diagnostic and therapeutic strategies and is an area of active investigation.

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Phase II study of ibrutinib in advanced carcinoid and pancreatic neuroendocrine tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.434 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 434-434

Author(s):

Taymeyah E. Al-Toubah ◽

Tiffany Valone ◽

Michael J. Schell ◽

Jonathan R. Strosberg

Keyword(s):

Neuroendocrine Tumors ◽

Phase Ii ◽

Objective Response ◽

Prior Therapy ◽

Progression Of Disease ◽

Prospective Phase ◽

Well Differentiated ◽

Grade 3 ◽

Unacceptable Toxicity ◽

Clinical Trial Information

434 Background: Ibrutinib is an orally administered, inhibitor of Bruton’s tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited with neuroendocrine tumors (NETs) where they remodel the stroma and stimulate angiogenesis, driving macroscopic tumor expansion. Ibrutinib inhibits mast cell degranulation, and has been associated with regression of a mouse insulinoma model. Methods: A prospective, phase II trial evaluated patients with advanced GI/lung NETs and pNETs who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. Primary endpoint was objective response rate. Results: 20 patients were enrolled on protocol from November 2015 – December 2017 (15 carcinoid and five pNETs). No patients experienced objective response. Median PFS was 3.1 months. A total of 43 drug related AEs were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs and one 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 when compared to other agents (e.g. Everolimus) in well-differentiated gastroenteropancreatic and lung NETs. Clinical trial information: 02575300.

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Gastroenteropancreatic neuroendocrine tumors: clinicopathological evaluation at Shifa International Hospital, Islamabad. A single centre experience

Journal of the Pakistan Medical Association ◽

10.47391/jpma.835 ◽

2020 ◽

pp. 1-14

Author(s):

Nadira Mamoon ◽

Hania Naveed ◽

Mariam Abid ◽

Humaira Nasir ◽

Imran Nazir Ahmad ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Neuroendocrine Tumors ◽

Neuroendocrine Carcinoma ◽

World Health ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Single Centre Experience ◽

Who 2010 Classification ◽

Well Differentiated ◽

Grade 3 ◽

Health Organization

Abstract Objective: Clinicopathological features of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have rarely been studied in the Pakistani population. We investigated the clinical characteristics of these tumors according to the updated World Health Organization (WHO) 2010 classification. Methods: The data of Shifa International Hospital, Islamabad was retrospectively analysed for pathologically confirmed GEP-NETs from January 2013 to March 2018. Results: One hundred and eighteen patients (mean age, 52.2 years; male, 55.1%) were identified. 83.1% of the patients were symptomatic including5.1% functional tumors. Pancreas (28%) was the most frequent primary site noted. The most common histologic type was well differentiated neuroendocrine tumor (WDNET) in 81.4% followed by neuroendocrine carcinoma (NEC) in 16.1%. 45.8% cases of WDNET were grade 1, 27.1% were grade 2, and 8.5% were grade 3.15.3% had distant metastasis at the time of diagnosis with liver (77.7%) as the most common metastatic site. Synaptophysin positivity was seen in 96.8% of grade 1 & grade 2 WDNET, 100% of grade 3 WDNET and 92.3% of NEC and chromogranin was positive in 94.2% of grade 1 &grade 2 WDNET, 83.3% of grade 3 WDNET and 45.4% of NEC. Conclusion: GEP-NETs showed a wide clinicopathological spectrum. Pancreas is the most site of involvement by the GEP-NET however grade 3 WDNET had a predilection for the colon. Small cell carcinomas were commonly observed in esophagus. Keywords: Gastroenteropancreatic neuroendocrine tumor, well differentiated neuroendocrine tumor, neuroendocrine carcinoma. Continuous...

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Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up

Acta Endocrinologica ◽

10.1530/eje-15-0917 ◽

2016 ◽

Vol 174 (3) ◽

pp. 335-341 ◽

Cited By ~ 16

Author(s):

Cécile Nozières ◽

Laurence Chardon ◽

Bernard Goichot ◽

Françoise Borson-Chazot ◽

Valérie Hervieu ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Poor Prognosis ◽

Carcinoid Syndrome ◽

Medullary Thyroid Cancer ◽

High Grade ◽

Poor Differentiation ◽

Histological Characteristics ◽

Grade 3 ◽

Pancreatic Origin

ObjectivesInappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up.MethodsAll patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied.ResultsTwenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100 ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100 ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses.ConclusionSerum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies.

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