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      Chemotherapy in Resected Neuroendocrine Carcinomas of the Digestive Tract: A National Study from the French Group of Endocrine Tumours

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          Abstract

          Background: Neuroendocrine carcinomas (NECs) of the digestive tract are rare and aggressive tumours. In localised disease the treatment is surgery. Based on expert consensus, international guidelines recommend the administration of adjuvant chemotherapy combining etoposide and platinum derivatives, justified by the high risk of metastatic relapse. However, no clinical study has proven the benefit of neoadjuvant or adjuvant chemotherapy. Objectives: We aimed to evaluate the effect of neoadjuvant +/– adjuvant and adjuvant therapy in this indication. Methods: We performed a retrospective observational French study to evaluate overall survival (OS) and disease-free survival (DFS), prognostic factors for survival, and chemotherapy toxicity. Results: Seventy-three patients had surgical resection of a localised digestive NEC between January 1, 2000 and December 31, 2016. The majority of patients presented colorectal (35%) tumours and the median Ki-67 value was 70%. Forty-three patients received chemotherapy, either perioperative (neoadjuvant +/– adjuvant) or adjuvant. The median OS and DFS for the whole population was 24 and 9 months, respectively. The median OS and DFS for patients receiving chemotherapy was 62 and 13 months, respectively. Positive postoperative node status and Ki-67 ≥80% had a negative prognostic impact on OS and DFS. Administration of chemotherapy had a positive prognostic impact on OS and DFS. Sixteen grade 3/4 toxicities were reported without toxic death. Conclusions: Our results suggest a positive effect on survival of chemotherapy in resected digestive NECs, but further studies are needed to confirm these results.

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          Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

          As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.
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            ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas

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              The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms.

              The 2010 World Health Organization (WHO) classification recommends that pancreatic neuroendocrine tumors (PanNETs) be graded on the basis of the mitotic rate and Ki67 index, with grade 2 (G2) PanNETs defined as having a mitotic rate of 2 to 20 mitotic figures/10 high-power fields or a Ki67 index of 3% to 20%. Grade 3 (G3) pancreatic neuroendocrine carcinoma (NEC) is defined as having >20 mitotic figures/10 high-power fields or a Ki67 index of >20%. However, some PanNETs show discordance between the mitotic rate and Ki67 index, usually having a Ki67 index in the G3 range but a mitotic rate suggesting G2, prompting us to examine the clinical significance of the Ki67 index in a large series of clinically well-characterized mitotic G2 PanNETs. Mitotic G2 well differentiated PanNETs, surgically resected at our institutions were reviewed. Of those, 19 cases had a Ki67>20% and were selected as the study group of grade-discordant (mitotic count G2/Ki67 index G3) PanNETs. For comparison, 53 grade-concordant (both mitotic count and Ki67 index G2) PanNETs matched for presenting stage with the discordant group as well as 43 morphologically poorly differentiated (either small cell or large cell type) pancreatic NECs were also included. The percentage of Ki67-positive neoplastic cells was quantified by manual counting of at least 500 cells on printed photographic images of "hot spots." The mean Ki67 index for grade-concordant and grade-discordant PanNETs and poorly differentiated NECs were 8.1% (range, 3% to 20%), 40% (range, 24% to 80%), and 70% (range, 40% to 98%), respectively. Overall, patients with grade-discordant PanNETs had significantly longer survival time compared with the patients with poorly differentiated NEC (median survival of 54.1 vs. 11 mo and 5 y survival of 29.1% vs. 16.1%; P=0.002). In addition, the survival time of the patients with grade-discordant PanNETs was shorter than that of the patients with grade-concordant PanNETs (median survival of 67.8 mo and 5 y survival of 62.4%); however, the difference was not statistically significant (P=0.2). Our data support the notion that the mitotic rate and Ki67 index-based grades of PanNETs can be discordant, and when the Ki67 index indicates G3, the clinical outcome is slightly worse. More importantly, we demonstrate that well differentiated PanNETs that are G3 by Ki67 are significantly less aggressive than bona fide poorly differentiated NECs, suggesting that the current WHO G3 category is heterogenous, contains 2 distinct neoplasms, and can be further separated into well differentiated PanNET with an elevated proliferation rate and poorly differentiated NEC.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2020
                April 2020
                21 August 2019
                : 110
                : 5
                : 404-412
                Affiliations
                [_a] aDepartment of Medical Oncology, Saint-Antoine Hospital, Paris, France
                [_b] bSorbonne University, Paris, France
                [_c] cDepartment of Medical Oncology, Edouard Herriot Hospital, Lyon, France
                [_d] dDepartment of Pathology, Pitié-Salpêtrière Hospital, Paris, France
                [_e] eDepartment of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
                [_f] fDepartment of Gastroenterology and Pancreatology, Beaujon Hospital, Clichy, France
                [_g] gDepartment of Endocrinology, CHU Lille, Lille, France
                [_h] hDepartment of Gastroenterology, CHU Rennes, Rennes 1 University, Rennes, France
                [_i] iGastroenterology and Digestive Oncology, Cochin Hospital, Paris, France
                [_j] jDepartment of Digestive Oncology, Beaujon Hospital, Clichy, France
                [_k] kGastroenterology and Digestive Oncology, Pitié-Salpêtrière Hospital, Paris, France
                [_l] lDepartment of Pathology, Bichat Hospital and University Paris Diderot, Paris, France
                [_m] mDepartment of Pathology, Saint-Antoine Hospital, Paris, France
                [_n] nDepartment of Endocrinology, Institut Gustave Roussy, Villejuif, France
                Author notes
                *Dr. Anna Pellat, MD, Department of Medical Oncology, Saint-Antoine Hospital, 184 rue du Faubourg Saint-Antoine, FR–75012 Paris (France), E-Mail anna.pellat@aphp.fr
                Article
                502825 Neuroendocrinology 2020;110:404–412
                10.1159/000502825
                31430756
                e90fcf81-f64d-41e8-a55a-ae514bd865a6
                © 2019 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 19 March 2019
                : 19 August 2019
                Page count
                Figures: 3, Tables: 3, Pages: 9
                Categories
                Research Article

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Neuroendocrine carcinomas,Ki-67 index,Chemotherapy

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