Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2021; 27(10): 976-989
Published online Mar 14, 2021. doi: 10.3748/wjg.v27.i10.976
Advanced small-bowel well-differentiated neuroendocrine tumours: An international survey of practice on 3rd-line treatment
Angela Lamarca, Mauro Cives, Louis de Mestier, Joakim Crona, Francesca Spada, Kjell Öberg, Marianne Pavel, Teresa Alonso-Gordoa
Angela Lamarca, Department of Medical Oncology, European Neuroendocrine Tumor Society Centre of Excellence, The Christie NHS Foundation Trust, University of Manchester, Manchester M20 4BX, United Kingdom
Mauro Cives, Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari 70121, Italy
Louis de Mestier, Department of Gastroenterology and Pancreatology, European Neuroendocrine Tumor Society Center of Excellence, Paris-Diderot University, Clichy 75006, France
Joakim Crona, Department of Medical Sciences, Uppsala University, Uppsala SE-751 85, Sweden
Francesca Spada, Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan 20141, Italy
Kjell Öberg, Department of Endocrine Oncology, Uppsala University Hospital, Uppsala SE-751 85, Sweden
Marianne Pavel, Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen 91054, Germany
Teresa Alonso-Gordoa, Medical Oncology Department, The Ramón y Cajal Health Research Institute, Alcalá University, University Hospital Ramon y Cajal, Madrid 28034, Spain
Author contributions: Lamarca A and Alonso-Gordoa T designed the survey, which was also reviewed and approved by all authors; Lamarca A analysed the data and prepared first draft of manuscript. All authors reviewed the manuscript and approved final version.
Institutional review board statement: This was an online survey and participation was anonymous and voluntary, the Institutional review board statement is not applicable to our study.
Informed consent statement: This was an online survey and participation was anonymous and voluntary, the Informed consent statement is not applicable to our study.
Conflict-of-interest statement: Dr Angela Lamarca received travel and educational support from Ipsen, Pfizer, Bayer, AAA, SirtEx, Novartis, Mylan and Delcath; speaker honoraria from Merck, Pfizer, Ipsen, Incyte and AAA; advisory honoraria from EISAI, Nutricia Ipsen, QED and Roche. Dr. Mauro Cives received travel support from Ipsen, Novartis, Pfizer and AAA; speaker honoraria from Ipsen, Novartis and AAA; advisory honoraria from AAA. Dr. Joakim Crona received educational honoraria from Novartis.
STROBE statement: The authors have read the STROBE statement, and the manuscript was prepared and revised according to the STROBE statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Angela Lamarca, MD, MSc, PhD, Department of Medical Oncology, European Neuroendocrine Tumor Society Centre of Excellence, The Christie NHS Foundation Trust, University of Manchester, Wilmslow Road, Manchester M20 4BX, United Kingdom. angela.lamarca@nhs.net
Received: November 23, 2020
Peer-review started: November 23, 2020
First decision: January 7, 2021
Revised: January 12, 2021
Accepted: February 26, 2021
Article in press: February 26, 2021
Published online: March 14, 2021
Abstract
BACKGROUND

Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence.

AIM

To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey.

METHODS

Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored.

RESULTS

Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4).

CONCLUSION

Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.

Keywords: Neuroendocrine tumour, Small bowel, Survey, Third-line, Advanced, Practice

Core Tip: Our survey delineates a possible treatment algorithm in patients with advanced small bowel neuroendocrine tumour (SBNET). While somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT) and everolimus are usually considered preferred first, second and third-line options respectively, chemotherapy is generally used when all other available treatments have failed. Locoregional therapies appear particularly useful when facing patients with functioning tumours, but their use is mainly limited to after at least two prior lines of treatment. We were also able to identify relevant unanswered questions in the field of advanced SBNET treatment, mainly in regards to the role of maintenance SSA after PRRT for non-functioning tumours. Multiple factors were identified as relevant at time of decision making; among them, Ki-67, rate of progression, tumour functionality and tumour burden may have a key role in helping physicians tailoring the treatment. Based on this, we would encourage for treatment decisions to be made within a multidisciplinary setting.