scholarly journals Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms

2015 ◽  
Vol 22 (4) ◽  
pp. 657-664 ◽  
Author(s):  
M Heetfeld ◽  
C N Chougnet ◽  
I H Olsen ◽  
A Rinke ◽  
I Borbath ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Free Survival ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Platinum Based Chemotherapy ◽  
Net G3 ◽  
Well Differentiated ◽  
Third Line ◽  
Line Chemotherapy

Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21–89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC;P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18–28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3;P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

scholarly journals HIGH-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE NEOPLASMS. MODERN CLASSIFICATION, DIAGNOSTICS AND TREATMENT

2018 ◽  
Vol 8 (3) ◽  
pp. 13-20
Author(s):  
A. A. Kolomeytseva ◽  
V. A. Gorbunova ◽  
N. F. Orel ◽  
G. S. Emelianova ◽  
A. M. Ivanov ◽  
...  
Keyword(s):  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
First Line Therapy ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Platinum Based Chemotherapy ◽  
Poorly Differentiated ◽  
Net G3 ◽  
Well Differentiated ◽  
Health Organization

Poorly differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare malignancies, most of which are characterized by aggressiveness, a tendency to rapid metastasis and an unfavorable prognosis even when localized. In 2017 World Health Organization (WHO) updated classification of GEP NENs and recognized the category of well-differentiated pancreatic NET G3, associated with Ki‑67 index usually over 20%. The upper level of Ki‑67 is not defined. Usually it is 55%. Highgrade poorly differentiated pancreatic NENs are defined as pancreatic neuroendocrine carcinomas (panNECs). Although the NET G3 category is recognized for pancreatic neuroendocrine neoplasms only, many specialists consider it reasonable to apply this term to all well-differentiated GEP NETs with Ki‑67 index in the 20 to 55 percent range. Clinical behavior and therapeutic approaches for advanced GEP NECs and NETs G3 are different. Standard palliative chemotherapy for GEP NECs consists of cisplatin or carboplatin combined with etoposide. The second-line regimens include irinotecan-, oxaliplatin, fluoropyrimidine- and temozolomide-based regimens. Temozolomide-based chemotherapy regimens, as well as targeted therapy are more preferable as first line therapy for patients with NETs G3. The platinum-based chemotherapy regimens are considered at the time of disease progression. Further clinical studies with the inclusion of much more patients will determine the optimal treatment strategy for this category of patients.

scholarly journals PRRT in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

2020 ◽  
Vol 27 (3) ◽  
pp. R67-R77 ◽  
Author(s):  
Halfdan Sorbye ◽  
Grace Kong ◽  
Simona Grozinsky-Glasberg
Keyword(s):  
Residual Disease ◽  
Somatostatin Receptor ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Receptor Imaging ◽  
High Grade ◽  
Ki 67 ◽  
Free Survival ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Net G3

Peptide receptor radionuclide therapy (PRRT) is an established treatment for grade 1 and 2 gastroenteropancreatic neuroendocrine tumors with an increased uptake on somatostatin receptor imaging (SRI). Patients with metastatic high-grade (WHO G3) gastroenteropancreatic neuroendocrine neoplasms (NET G3 and NEC) represent a heterogeneous subgroup with poor prognosis and standard platinum-etoposide chemotherapy have limited therapeutic benefit. However, there is promising emerging evidence supporting the effectiveness of PRRT in SRI-positive G3 disease. A review search for studies reporting on PRRT in gastroenteropancreatic neuroendocrine neoplasms G3 was performed: four studies with more than ten cases were found. PRRT was mainly given as second- or third-line treatment in patients with progressive disease. Most patients had a pancreatic primary, 50% had well-differentiated tumors, and most had a Ki-67 <55%. Three studies showed similar results with promising response rates (31–41%) and disease control rates (69–78%). Progression-free survival (11–16 months) and survival (22–46 months) were best concerning patients with a Ki-67 <55%. Progression-free survival was 19 months in NET G3, 11 months for lowNEC (Ki-67 ≤55%) and 4 months for highNEC (Ki-67 >55%). PRRT should be considered for patients with increased uptake on SRI, both in gastroenteropancreatic NET G3 cases and as well as in NEC cases with a Ki-67 21–55%. PRRT for NEC with a Ki-67 >55% is less defined, but could be considered in highly selected cases after response to initial chemotherapy where all residual disease have high uptake on SRI. Dual tracer using 18F-FDG PET/CT and SRI provides important information for patient selection for PRRT in this heterogeneous complex high-grade disease.

Clinical and Biomarker Evaluations of Sunitinib in Patients with Grade 3 Digestive Neuroendocrine Neoplasms

2018 ◽  
Vol 107 (1) ◽  
pp. 24-31 ◽  
Author(s):  
Anna Pellat ◽  
Chantal Dreyer ◽  
Camille Couffignal ◽  
Thomas Walter ◽  
Catherine Lombard-Bohas ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Lower Response ◽  
Potential Biomarker ◽  
Pancreatic Neuroendocrine Tumours ◽  
Net G3 ◽  
Well Differentiated ◽  
Grade 3

Background/Aims: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumours (PanNET) where sunitinib was shown to prolong progression-free survival, leading to nationwide approval. However, clinical experience in patients with grade 3 gastroenteropancreatic neuroendocrine neoplasms (GEPNEN-G3) remains limited. This prospective phase II trial evaluated potential predictive biomarkers of sunitinib activity in patients with advanced GEPNEN-G3. Methods: Sunitinib was given at a dose of 37.5 mg/day as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAE v4. Pharmacokinetics of sunitinib and its main active metabolite SU12662 were evaluated. All tumour samples were reviewed histologically for tumour differentiation. PDGFRβ, carbonic anhydrase 9, Ki-67, VEGFR2, and p-AKT were quantified using immunohistochemistry and their expression correlated with response by RECIST1.1. Results: Thirty-one patients were included and 26 had available histological tissue. Six and 20 patients presented well-differentiated tumours (NET-G3) and neuroendocrine carcinoma (NEC), respectively. Eighteen patients responded to sunitinib (4 experienced partial responses and 14 tumour stabilization). A high p-AKT expression correlated with lower response to sunitinib (OR 0.94, 95% CI 0.89–0.99, p = 0.04). Safety and PK exposure to sunitinib and SU12662 in these patients were consistent with that reported in PanNET. Conclusion: Sunitinib showed evidence of activity in patients with GEPNEN-G3 with expected toxicity profile. In the NET-G3 and NEC groups, 4/6 and 11/20 patients were responders, respectively. High p-AKT expression predicted a lower response to sunitinib. Our study allowed the identification of a potential biomarker of resistance/sensitivity to sunitinib in aggressive GEPNEN-G3.

scholarly journals Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study

2019 ◽  
Vol 37 (28) ◽  
pp. 2571-2580 ◽  
Author(s):  
Alberto Carmona-Bayonas ◽  
Paula Jiménez-Fonseca ◽  
Ángela Lamarca ◽  
Jorge Barriuso ◽  
Ángel Castaño ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Failure Time ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Accelerated Failure Time Model ◽  
Endocrine Tumors ◽  
First Line ◽  
Ki 67 ◽  
Free Survival ◽  
Well Differentiated

PURPOSE Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

Effectiveness of peptide receptor radionuclide therapy for neuroendocrine neoplasms: A multi-institutional registry study with prospective follow-up.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4033-4033
Author(s):  
Dieter Hörsch ◽  
Keyword(s):  
Small Bowel ◽  
Radionuclide Therapy ◽  
Peptide Receptor Radionuclide Therapy ◽  
Progression Free Survival ◽  
Unknown Primary ◽  
Neuroendocrine Neoplasms ◽  
Registry Study ◽  
Free Survival ◽  
Peptide Receptor ◽  
Well Differentiated

4033 Background: Peptide receptor radionuclide therapy targets somatostatin receptors expressed on well differentiated neuroendocrine neoplasms. Retrospective monocentric studies indicate that peptide receptor radionuclide therapy is an effective treatment for patients with neuroendocrine neoplasms. Methods: We initiated a multi-institutional, prospective and board reviewed registry study for patients treated with peptide receptor radionuclide therapy. 450 patients were included and followed for a mean of 24.4 months. Patients were treated with Lutetium-177 (54%), Yttrium-90 (17%) or both radionuclides (29%). Primary neuroendocrine neoplasms were derived of pancreas (38%), small bowel 30%), unknown primary (19%), lung (4%) and colorectum (3,5%). Most neuroendocrine neoplasms were well differentiated with a proliferation rate below 20% in 54% and were pretreated by 1 or more therapies in 73%. Results: Overall survival of all patients from the beginning of therapy was 59 months in median. Median survival depended on radionuclides used (Yttrium-90: 38 months; Lutetium-177: not reached; both: 58 months), proliferation rate (G1: median not reached; G2: 58 months; G3: 33 months; unknown: 55 months) and origin of primary tumors (pancreas: 53 months; small bowel: not reached; unknown primary: 47 months; lung: 38 months) but not upon number of previous therapies. Median progression-free survival measured from last cycle of therapy accounted to 41 months for all patients. Progression-free survival of pancreatic neuroendocrine neoplasms was 39 months in median. Similar results were obtained for neuroendocrine neoplasms of unknown primary with a median of 38 months whereas neuroendocrine neoplasm of small bowel were progression-free for a median of 51 months. Side effects like G3-G4 nephrotoxicity or hematological function were observed in 0.2% and 2% of patients. Conclusions: Peptide receptor radionuclide therapy is effective for patients with G1-G2 neuroendocrine tumors irrespective of previous therapies with a survival advantage of several years compared to other therapies and only minor side effects.

scholarly journals Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms

2019 ◽  
Vol 8 (6) ◽  
pp. 641-653 ◽  
Author(s):  
Kosmas Daskalakis ◽  
Marina Tsoli ◽  
Anna Angelousi ◽  
Evanthia Kassi ◽  
Krystallenia I Alexandraki ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Clinicopathological Characteristics ◽  
Neuroendocrine Neoplasms ◽  
Second Line ◽  
First Line ◽  
Free Survival ◽  
Predictors Of Response ◽  
Well Differentiated ◽  
Tumour Activity ◽  
Additive Toxicity

Comparisons between everolimus and sunitinib regarding their efficacy and safety in neuroendocrine neoplasms (NENs) are scarce. We retrospectively analysed the clinicopathological characteristics and outcomes in 92 patients with well-differentiated (WD) NEN of different origin (57 pancreatic NENs (PanNENs)), treated with molecular targeted therapy (MTT) with everolimus or sunitinib, first- (73:19) or second-line (sequential; 12:22) for progressive disease. Disease control rates (DCR: partial response or stable disease) at first-line were higher in all patients treated with everolimus than sunitinib (64/73 vs 12/19, P = 0.012). In PanNENs, DCR at first-line everolimus was 36/42 versus 9/15 with sunitinib (P = 0.062). Progression-free survival (PFS) at first-line everolimus was longer than sunitinib (31 months (95% CI: 23.1–38.9) vs 9 months (95% CI: 0–18.5); log-rank P < 0.0001) in the whole cohort and the subset of PanNENs (log-rank P < 0.0001). Median PFS at second-line MTT was 12 months with everolimus (95% CI: 4.1–19.9) vs 13 months with sunitinib (95% CI: 9.3–16.7; log-rank P = 0.951). Treatment with sunitinib (HR: 3.47; 95% CI: 1.5–8.3; P value: 0.005), KI67 >20% (HR: 6.38; 95% CI: 1.3–31.3; P = 0.022) and prior chemotherapy (HR: 2.71; 95% CI: 1.2–6.3; P = 0.021) were negative predictors for PFS at first line in multivariable and also confirmed at multi-state modelling analyses. Side effect (SE) analysis indicated events of serious toxicities (Grades 3 and 4: n = 13/85 for everolimus and n = 4/41 for sunitinib). Discontinuation rate due to SEs was 20/85 for everolimus versus 4/41 for sunitinib (P = 0.065). No additive toxicity of second-line MTT was confirmed. Based on these findings, and until reliable predictors of response become available, everolimus may be preferable to sunitinib when initiating MTT in progressive NENs.

Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors

2012 ◽  
Vol 43 (4) ◽  
pp. 489-495 ◽  
Author(s):  
Deepti Dhall ◽  
Richard Mertens ◽  
Catherine Bresee ◽  
Rugvedita Parakh ◽  
Hanlin L. Wang ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Progression Free Survival ◽  
Proliferative Index ◽  
Ki 67 ◽  
Free Survival ◽  
Well Differentiated

scholarly journals Amrubicin Monotherapy for Patients with Platinum-Refractory Gastroenteropancreatic Neuroendocrine Carcinoma

2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Takayuki Ando ◽  
Ayumu Hosokawa ◽  
Hiroki Yoshita ◽  
Akira Ueda ◽  
Shinya Kajiura ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
First Line ◽  
Ki 67 ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Platinum Refractory ◽  
Grade 3

Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC.Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively.Results. Eight males and two females (median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n=7, 70%), cisplatin plus etoposide (n=2, 20%), and carboplatin plus etoposide (n=1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Furthermore, NEC with response for amrubicin had characteristics with a high Ki-67 index and receipt of prior chemotherapy with cisplatin and irinotecan. Grade 3-4 neutropenia and anemia were observed in four and five patients, respectively.Conclusion. Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC.

scholarly journals PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 3

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243900
Author(s):  
Abir Salwa Ali ◽  
Seppo W. Langer ◽  
Birgitte Federspiel ◽  
Geir Olav Hjortland ◽  
Henning Grønbæk ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Clinical Parameters ◽  
Future Possibility ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Platinum Based Chemotherapy ◽  
Grade 3 ◽  
Immune Checkpoint Proteins

Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.

scholarly journals Efficacy and toxicity profile of maintenance pemetrexed in patients with stage IV adenocarcinoma lung in Indian population

2016 ◽  
Vol 05 (04) ◽  
pp. 196-203 ◽  
Author(s):  
Goyal Pankaj ◽  
Batra Ullas ◽  
Dinesh Chandra Doval ◽  
Jain Parveen ◽  
Upadhyay Kumar Amitabh ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Stage Iv ◽  
Progression Free Survival ◽  
North India ◽  
Toxicity Profile ◽  
First Line ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Line Chemotherapy ◽  
Grade Iii

Abstract Context: Lung cancer has been the most common cancer in the world for several decades. Pemetrexed is recommended as an option for the maintenance treatment in metastatic adenocarcinoma lung, if disease has not progressed immediately following platinum-based chemotherapy. Aims: To study efficacy and toxicity profile of pemetrexed as a maintenance chemotherapeutic agent in patients with stage IV adenocarcinoma lung, not progressing after first line chemotherapy. Settings and Design: This was an observational, prospective. We enrolled patients with stage IV adenocarcinoma lung who has not progressed on first line chemotherapy, from September 2013 to August 2014 at a tertiary care cancer institute in North India. Materials and Methods: In all, 108 patients with stage IV adenocarcinoma lung were started on induction pemetrexed/platinum chemotherapy. 60 patients with no disease progression & ECOG PS 0-2 were started on Pemetrexed maintenance. Progression free survival (PFS) and toxicity profile were recorded. Results: The mean number of maintenance cycles was 8.3 (range 2-28). 13 (21.6%) patients took >10 maintenance cycles. Pemetrexed maintenance therapy resulted in progression free survival (PFS) of 5.4 months. PFS on pemetrexed was consistent for all patient subgroups, including induction response: complete/partial responders (n-31) and stable disease (n-29). 14 patients had grade III/IV adverse events with anemia being the most common in 3/60 patients (5%). 3 patients (5%) developed renal dysfunction out of which 1 was grade III. Conclusions: Pemetrexed continuation maintenance chemotherapy is active and well tolerated. Pemetrexed maintenance should be considered in patients with advanced adenocarcinoma lung patients who have not progressed on completion of induction chemotherapy.

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