Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms

2021 ◽  
Author(s):  
James C Yao ◽  
Jonathan Strosberg ◽  
Nicola Fazio ◽  
Marianne E Pavel ◽  
Emily Bergsland ◽  
...  
Keyword(s):  
Adverse Events ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Neuroendocrine Neoplasms ◽  
Cd8 Cells ◽  
Programmed Death ◽  
Independent Review ◽  
Programmed Death Protein 1 ◽  
Poorly Differentiated ◽  
Well Differentiated

Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) monoclonal antibody, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly-differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% confidence interval [CI]: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5% and 0%, respectively, and the 12-month overall survival was 73.5% and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort is encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.

scholarly journals Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1247
Author(s):  
Tiziana Feola ◽  
Roberta Centello ◽  
Franz Sesti ◽  
Giulia Puliani ◽  
Monica Verrico ◽  
...  
Keyword(s):  
Systematic Review ◽  
Peptide Receptor Radionuclide Therapy ◽  
Progression Free Survival ◽  
Large Cell ◽  
Clinicopathological Characteristics ◽  
Proliferation Index ◽  
Cochrane Library ◽  
Neuroendocrine Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated

Background: Highly proliferative (G3) neuroendocrine neoplasms are divided into well differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), based on the morphological appearance. This systematic review aims to evaluate the clinicopathological features and the treatment response of the NEC subgroup with a Ki67 labeling index (LI) < 55%. Methods: A literature search was performed using MEDLINE, Cochrane Library, and Scopus between December 2019 and April 2020, last update in October 2020. We included studies reporting data on the clinicopathological characteristics, survival, and/or therapy efficacy of patients with NECs, in which the Ki67 LI was specified. Results: 8 papers were included, on a total of 268 NEC affected patients. NECs with a Ki67 LI < 55% have been reported in patients of both sexes, mainly of sixth decade, pancreatic origin, and large-cell morphology. The prevalent treatment choice was chemotherapy, followed by surgery and, in only one study, peptide receptor radionuclide therapy. The subgroup of patients with NEC with a Ki67 LI < 55% showed longer overall survival and progression free survival and higher response rates than the subgroup of patients with a tumor with higher Ki67 LI (≥55%). Conclusions: NECs are heterogeneous tumors. The subgroup with a Ki67 LI < 55% has a better prognosis and should be treated and monitored differently from NECs with a Ki67 LI ≥ 55%.

scholarly journals Outcomes after high-dose radiation in the management of neuroendocrine neoplasms

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252574
Author(s):  
Katherine S. Chen ◽  
Courtney Lawhn-Heath ◽  
Spencer Behr ◽  
Roxanna Juarez ◽  
Julia Whitman ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Progression Free Survival ◽  
Disease Status ◽  
Oncologic Outcomes ◽  
Neuroendocrine Neoplasms ◽  
High Dose ◽  
Free Survival ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Dose Radiation

Background Neuroendocrine neoplasms (NENs) comprise a rare and heterogenous group of cancers, for which the role of radiation therapy continues to evolve. The purpose of this study is to analyze oncologic outcomes after the use of high-dose radiation in management of NENs at a tertiary hospital. Materials and methods We performed a retrospective review of patients who received high-dose radiation with intent to cure or provide durable local control (defined as biologically effective dose (BED) ≥40, α/β = 10) for a localized or metastatic NEN from 2006 to 2019. Evaluation of disease status after radiation was performed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria when possible. Patients were grouped by differentiation (well-differentiated (WD) or poorly-differentiated (PD)) and stage (localized/locally advanced disease (L) or metastatic (M)) in analysis of probabilities of progression after radiation. Results 45 patients completed a radiation course with BED ≥40 for a NEN (median BED 72). With a median follow-up of 24 months after radiation, the 2-year actuarial rates of local relapse-free survival, new metastasis-free survival, progression-free survival, and overall survival after radiation were 98%, 45%, 41%, and 69%, respectively. 25 patients (56%) developed new metastases after completion of radiation, including 33% (n = 3) of patients with WD-L disease, 44% (n = 8) of WD-M, 77% (n = 10) of PD-L, and 80% (n = 4) of PD-M, with progressively shorter median times to progression (26, 9, 8, and 3 months, respectively; p = 0.093). Of the 25 patients evaluable by RECIST, 68% (n = 17) achieved either a complete or partial best response in the irradiated lesion. Conclusions These data suggest that focal, high-dose radiation has a role in the management of selected patients with NENs. Local failure is rare in patients with both well-differentiated and poorly-differentiated disease, although the predominant pattern of failure remains development of new metastases.

scholarly journals INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas

2020 ◽  
Vol 153 (6) ◽  
pp. 811-820 ◽  
Author(s):  
Kelsey E McHugh ◽  
Sanjay Mukhopadhyay ◽  
Erika E Doxtader ◽  
Christopher Lanigan ◽  
Daniela S Allende
Keyword(s):  
Goblet Cell ◽  
Neuroendocrine Differentiation ◽  
Neuroendocrine Neoplasms ◽  
Specific Marker ◽  
Low Grade ◽  
Ki 67 ◽  
Neuroendocrine Markers ◽  
Primary Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated

Abstract Objectives INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms. Methods Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67. Results INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively). Conclusions INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific.

First-Line Irinotecan Combined with 5-Fluorouracil and Leucovorin for High-Grade Metastatic Gastrointestinal Neuroendocrine Carcinoma

2013 ◽  
Vol 99 (1) ◽  
pp. 57-60 ◽  
Author(s):  
Zedong Du ◽  
Yi Wang ◽  
Yi Zhou ◽  
Feng Wen ◽  
Qiu Li
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Neuroendocrine Neoplasms ◽  
High Grade ◽  
First Line ◽  
Laboratory Findings ◽  
Poorly Differentiated ◽  
Prospective Trials ◽  
Line Setting

Aim and background High-grade gastrointestinal neuroendocrine neoplasms, ie, poorly differentiated neuroendocrine carcinomas, with no effective therapeutic approaches, have a high ability to metastasize. Methods A review of the hospital information system was performed. Patients with histologically proven gastrointestinal neuroendocrine carcinoma who were treated with irinotecan combined with 5-fluorouracil and leucovorin in a first-line setting were eligible for analysis. We extracted information on age, sex, disease stage, laboratory findings, radiological findings, pathological findings, chemotherapy, effectiveness and adverse events of therapy, and outcomes. Results Eleven patients were included in the study. Partial response was observed in 7 patients. Median progression-free survival and overall survival were 6.5 (95% CI, 5.1–7.9) and 13.0 (95% CI, 9.8–16.2) months, respectively. No treatment-related deaths occurred. Conclusions The results demonstrated that irinotecan combined with 5-fluorouracil and leucovorin is an active regimen with acceptable toxicity for patients with metastatic high-grade gastointestinal neuroendocrine carcinoma that merits further investigation in prospective trials.

Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms

2011 ◽  
Vol 18 (S1) ◽  
pp. S1-S16 ◽  
Author(s):  
Günter Klöppel
Keyword(s):  
Gastrointestinal Tract ◽  
Neuroendocrine Tumours ◽  
Neuroendocrine Tumour ◽  
Tnm Stage ◽  
Neuroendocrine Neoplasms ◽  
Gastroenteropancreatic Neuroendocrine Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Neuroendocrine Carcinomas

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are composed of cells with a neuroendocrine phenotype. The old and the new WHO classifications distinguish between well-differentiated and poorly differentiated neoplasms. All well-differentiated neoplasms, regardless of whether they behave benignly or develop metastases, will be called neuroendocrine tumours (NETs), and graded G1 (Ki67 <2%) or G2 (Ki67 2–20%). All poorly differentiated neoplasms will be termed neuroendocrine carcinomas (NECs) and graded G3 (Ki67 >20%). To stratify the GEP-NETs and GEP-NECs regarding their prognosis, they are now further classified according to TNM-stage systems that were recently proposed by the European Neuroendocrine Tumour Society (ENETS) and the AJCC/UICC. In the light of these criteria the pathology and biology of the various NETs and NECs of the gastrointestinal tract (including the oesophagus) and the pancreas are reviewed.

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 The efficacy and adverse events of anlotinib plus PD-1 inhibitor for metastatic solid tumors

2021 ◽  
Author(s):  
Hao Lin ◽  
Tao Liu ◽  
Xinli Zhou ◽  
Xiaohua Liang
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitors ◽  
Response Rate ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Kaplan Meier ◽  
Hemorrhagic Events ◽  
Tumor Immune Microenvironment

Abstract Background Several antiangiogenic tyrosine kinase inhibitors (TKIs) have the potential to modulate the tumor immune microenvironment and improve immunotherapy effect Of these, anlotinib has demonstrated antitumor efficacy in clinical trials. However, its role in immune regulation and the potential synergistic antitumor effect of its combination with PD-1 inhibitor remain unclear. This study investigated the efficacy and adverse events (AEs) of the combination of anlotinib and PD-1 inhibitor for solid tumors in real-world settings. Methods This retrospective study included patients with metastatic solid tumors treated with anlotinib plus PD-1 inhibitor at Huashan hospital, Fudan University between October 1, 2018 and August 31, 2020. The objective response rate was assessed using the response evaluation criteria in solid tumors v1.1. Descriptive statistics were performed using the Kaplan–Meier method, and any AEs were noted. Results Partial response was achieved in 13 patients, and 8 patients showed stable disease, representing a response rate of 43.3% and a disease control rate of 70%. The median progression-free survival was 3.8 months. Although AEs were observed in 50% of patients, most of them were Grades 1–2 and well tolerated. The most common AEs were thrombocytopenia (16%), thromboembolic or hemorrhagic events (16%), and rash (13%). Conclusions Anlotinib plus PD-1 inhibitor is an alternative salvage treatment choice in metastatic solid tumors with Favorable efficacy and tolerable toxicities.

scholarly journals Kidney injury associated with antitumor therapy: focus on the adverse events of modern immuno-oncological drugs

2021 ◽  
Vol 93 (6) ◽  
pp. 649-660
Author(s):  
Elena S. Kamyshova ◽  
Irina N. Bobkova ◽  
Marina I. Sekacheva
Keyword(s):  
Adverse Events ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Inhibitory Effect ◽  
Immune System Activation ◽  
Programmed Death ◽  
Programmed Death Protein 1 ◽  
System Activation ◽  
New Generation

Immune checkpoint inhibitors (ICIs), including cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death protein 1 (PD-1) or its ligand (PD-L1), are a new generation of immuno-oncological drugs that to date have demonstrated efficacy in a number of malignancies. The mechanism of ICT inhibitors action consist in the potentiation of the immune response by eliminating the tumor cells inhibitory effect on the T-lymphocytes activation. However, excessive immune system activation can cause the development of a special class of immune-related adverse events (irAEs) involved a wide variety of organs and systems, including the kidneys. Despite the fact that immuno-mediated kidney injury caused by ICI therapy develops quite rarely, it can be serious and determine the patient's prognosis, which necessitates early diagnosis and timely start of treatment. In this regard, awareness of the manifestations of ICI-associated renal irAEs is particularly relevant not only for oncologists and for nephrologists, but for doctors of other specialties. In this review, we elucidated the main variants of immuno-mediated kidney injury caused by ICI therapy, discussed possible predictors and mechanisms of their development, and considers the general principles of diagnosis and management of patients according to the severity of irAEs.

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.

scholarly journals Tumor Macroscopic Morphology Is an Important Prognostic Factor in Predicting Chemotherapeutic Efficacy and Clinical Outcomes of Patients With Colorectal Neuroendocrine Neoplasms, One Multicenter Retrospective Cohort Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhijie Wang ◽  
Ke An ◽  
Rui Li ◽  
Qian Liu
Keyword(s):  
Prognostic Factor ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Tnm Stage ◽  
Stage Ii ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Dismal Prognosis ◽  
Poorly Differentiated

Background and AimsLocally advanced and metastatic colorectal neuroendocrine neoplasm (NEN) is a rare disease with a dismal prognosis. We aimed to explore the value of the macroscopic morphology of NENs in the management of TNM stage II-IV colorectal NENs, which has not been fully elucidated in previous reports.MethodsWe retrospectively enrolled 125 eligible patients with TNM stage II-IV colorectal NENs who were diagnosed between 2000 and 2020 from three Chinese hospitals. All were categorized into either protruding or ulcerative NEN groups through endoscopic evaluation of their macroscopic morphology. Clinicopathological data were collected and compared between the two groups. Survival analysis was performed to assess the survival outcomes between the two groups.ResultsA total of 77 and 48 patients had protruding and ulcerative NENs, respectively. Patients with ulcerative NENs had a larger median tumor size (P&lt;0.001) and higher median Ki-67 index (P&lt;0.001), and a larger proportion of these patients had grade G3 disease (P=0.001) and poorly differentiated neoplasms (P=0.001), as well as higher frequencies of T3 and T4 tumors (P=0.006) than patients with protruding NENs. In addition, patients with ulcerative NENs showed a much lower response to first-line chemotherapy [50% (95% CI: 27.3% - 72.7%) versus 20% (95% CI: 3.1% - 36.9%), P=0.03] and a worse 3-year progression-free survival (PFS) rate [19.7% (95% CI: 7.2% - 32.2%) versus 49.5% (95% CI: 37.5% - 61.5%), P=0.001] and 3-year overall survival (OS) rate [30.7% (95% CI: 15.6% - 45.8%) versus 76.9% (95% CI: 66.5% - 87.3%), P&lt;0.001] than those with protruding NENs. The multivariate analysis results indicated that the macroscopic shape of NENs was an independent prognostic factor affecting both PFS (HR = 1.760, 95% CI: 1.024 – 3.026, P = 0.04) and OS (HR = 2.280, 95% CI: 1.123 – 4.628, P = 0.02).ConclusionsUlcerative NENs were more malignant and chemotherapy resistant than protruding NENs. Tumor macroscopic morphology is a valuable prognostic factor for stage II-IV colorectal NENs.

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