Treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3)

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.

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Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3)

Cancers ◽

10.3390/cancers13081936 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1936

Author(s):

Leonidas Apostolidis ◽

Arianna Dal Buono ◽

Elettra Merola ◽

Henning Jann ◽

Dirk Jäger ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Progression Free Survival ◽

First Line ◽

Treatment Protocols ◽

First Line Therapy ◽

Line Therapy ◽

Multicenter Analysis ◽

Net G3 ◽

Well Differentiated ◽

Grade 3

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months; p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.

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1169P First-line fluoropyrimidine and oxaliplatin chemotherapy in gastro-entero-pancreatic grade 3 well-differentiated neuroendocrine tumours (NET G3)

Annals of Oncology ◽

10.1016/j.annonc.2020.08.1382 ◽

2020 ◽

Vol 31 ◽

pp. S776

Author(s):

G. Lamberti ◽

S. Pusceddu ◽

T. Ibrahim ◽

A. Bongiovanni ◽

R. Berardi ◽

...

Keyword(s):

Neuroendocrine Tumours ◽

First Line ◽

Net G3 ◽

Well Differentiated ◽

Grade 3

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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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