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 Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 643
Author(s):  
Caroline Lacombe ◽  
Ophélie De Rycke ◽  
Anne Couvelard ◽  
Anthony Turpin ◽  
Aurélie Cazes ◽  
...  
Keyword(s):  
Objective Response ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Quantitative Score ◽  
Well Differentiated ◽  
Grade 3 ◽  
Additional Value ◽  
Platinum Chemotherapy

Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p < 0.001). The ORR was significantly higher in NEN presenting with Rbinap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb < 150 optimally identified responders (AUC = 0.657, p < 0.001). The ORR was 67% in Rb < 150 (vs. 25%, p = 0.005). On multivariate analysis, only Rb < 150 was independently associated with ORR (OR 4.16, 95% CI 1.11–15.53, p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.

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

Cancers ◽  
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.

Clinical and biomarker evaluations of sunitinib in patients (pts) with advanced well-differentiated grade 3 (G3) and poorly differentiated neuroendocrine neoplasms (PD-NEN).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 274-274 ◽  
Author(s):  
Chantal Dreyer ◽  
Anne Couvelard ◽  
Thomas Walter ◽  
Catherine Lombard Bohas ◽  
Patricia Niccoli ◽  
...  
Keyword(s):  
Previous Treatment ◽  
Progression Free Survival ◽  
Roc Curves ◽  
Threshold Value ◽  
Neuroendocrine Neoplasms ◽  
Tumor Biomarkers ◽  
Prospective Phase ◽  
Carbonic Anhydrase 9 ◽  
Well Differentiated ◽  
Grade 3

274 Background: Angiogenesis is extensively developed in well-differentiated pancreatic neuroendocrine tumors (PNET) where sunitinib was showed to prolong progression-free survival leading to FDA and EMA approval. However, clinical experience in pts with well-differentiated G3 & PD-NEN remains limited. Methods: This prospective phase II trial evaluate potential biomarkers correlating with sunitinib activity in pts with advanced well differentiated G3 or PD-NEN. Sunitinib was given at the dose of 37.5 mg/d as a continuous daily dosing until progression or unacceptable toxicity. Evaluation of activity was based on RECIST1.1. Safety was evaluated according to NCI-CTCAEv4. Pharmacokinetics (PK) of sunitinib and SU12662 (main active metabolite) were evaluated. Tumor biomarkers (PDGFR-b, VEGFR2, Carbonic Anhydrase 9, Ki67 and p-AKT) were evaluated in tumor tissues, quantified in tumor cells and stroma (vessels, fibroblasts) using immunohistochemistry and correlated with response by RECIST. Results: Among 31 pts (M/F: 18/13, median age 61), 13 pancreatic, 5 gastric, 5 rectal, 4 colonic, and 4 other G3 & PD-NEN were entered. 27 pts had previous treatment with chemotherapy (mainly platinum/VP16). Among 26 pts evaluable for safety and activity, 7 pts (23%, 95%CI: 6.9%-39.3%), including 3 pts classified as well-differentiated G3 neoplasms) experienced partial responses and tumor stabilizations (clinical benefit). Safety and PK exposure to sunitinib and SU12662 in those pts was consistent with that experienced in PNET. Among the above evaluated tumor biomarkers, only Ki67 correlated with sunitinib activity. The median Ki67 was 20% and 77.5% in pts with CB versus non-responders (p=.002), respectively. ROC curves showed correlations between lower Ki67 in tumors and sunitinib activity (OR:0.9; IC95%:0.831-0.9, p=.039). With a threshold value of Ki67 of 47%, sensitivity and specificity were 80%, the predictive positive value was 67% and the negative predictive value was 86%. Conclusions: In pts with well-differentiated G3 & PD-NEN, sunitinib showed evidence of activity that was more pronounced in pts with Ki67<47%. Clinical trial information: NCT01215578.

scholarly journals Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1677
Author(s):  
Anna Pellat ◽  
Romain Coriat
Keyword(s):  
Digestive Tract ◽  
Neuroendocrine Tumors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Small Sample ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G−3 represents about one third of NEN G−3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G−3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G−2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G−3.

scholarly journals Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2448
Author(s):  
Anna Pellat ◽  
Anne Ségolène Cottereau ◽  
Lola-Jade Palmieri ◽  
Philippe Soyer ◽  
Ugo Marchese ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Functional Imaging ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Tumor Site ◽  
Ki 67 ◽  
Future Directions ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

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.

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

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

scholarly journals FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors

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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