Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Stefano Partelli¹, John K Ramage², Sara Massironi³, Alessandro Zerbi⁴, Hong Beom Kim⁵, Patricia Niccoli⁶, Francesco Panzuto⁷, Luca Landoni⁸, Ales Tomazic⁹, Toni Ibrahim¹⁰, Gregory Kaltsas¹¹, Emilio Bertani¹², Alain Sauvanet¹³, Eva Segelov¹⁴, Martyn Caplin¹⁵, Jorgelina Coppa¹⁶, Thomas Armstrong¹⁷, Martin O Weickert¹⁸, Giovanni Butturini¹⁹, Stefan Staettner²⁰, Florian Boesch²¹, Mauro Cives²², Carol Anne Moulton^{23

24}, Jin He²⁵, Andreas Selberherr²⁶, Orit Twito²⁷, Antonio Castaldi²⁸, Claudio Giovanni De Angelis²⁹, Sebastien Gaujoux³⁰, Hussein Almeamar³¹, Andrea Frilling³², Emanuel Vigia³³, Colin Wilson³⁴, Francesca Muffatti¹, Raj Srirajaskanthan², Pietro Invernizzi³, Andrea Lania⁴, Wooil Kwon⁵, Jacques Ewald⁶, Maria Rinzivillo⁷, Chiara Nessi⁸, Lojze M Smid⁹, Andrea Gardini³⁵, Marina Tsoli¹¹, Edgardo E Picardi¹², Olivia Hentic¹³, Daniel Croagh¹⁴, Christos Toumpanakis¹⁵, Davide Citterio¹⁶, Emma Ramsey¹⁷, Barbara Mosterman¹⁸, Paolo Regi¹⁹, Silvia Gasteiger³⁶, Roberta E Rossi³⁷, Valeria Smiroldo⁴, Jin-Young Jang⁵, Massimo Falconi¹

Affiliations

¹ Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
² Kings Health Partners NET Center, Kings College Hospital London, London, United Kingdom.
³ Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
⁴ Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.
⁵ Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
⁶ Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.
⁷ Digestive Disease Unit, ENETS Center of Excellence, Sant' Andrea University Hospital, Rome, Italy.
⁸ Department of Surgery, Pancreas Institute, Verona ENETS Center of Excellence, University and Hospital Trust of Verona, Verona, Italy.
⁹ Department of Abdominal Surgery and Gastroenterology and Hepatology, Faculty of Medicine, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.
¹⁰ Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
¹¹ First Department of Propaedeutic and Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
¹² Division of Gastrointestinal Surgery, European Institute of Oncology, Milan, Italy.
¹³ Department of HPB Surgery and Liver Transplantation and Pancreatology, Beaujon Hospital, University Paris 7 Denis Diderot, Assistance publique-Hôpitaux de Paris, 100, Boulevard du Général-Leclerc, Clichy, France.
¹⁴ Department of Oncology and Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, Australia.
¹⁵ Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom.
¹⁶ Gastrointestinal and Hepato-Pancreatic Surgery and Liver Transplantation Unit, Fondazione, IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute) and Università degli Studi di Milano, Milan, Italy.
¹⁷ Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Southampton, United Kingdom.
¹⁸ The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.
¹⁹ Department of Surgery, Pederzoli Hospital, Peschiera del Garda, Italy.
²⁰ Department of General, Visceral and Vascular Surgery, Salzkammergutklinikum Vöcklabruck, Vöcklabruck, Austria.
²¹ Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany.
²² Section of Medical Oncology, Department of Biomedical Sciences and Clinical Oncology (DIMO), University of Bari 'Aldo Moro', Bari, Italy.
²³ Division of General Surgery, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MA, United States.
²⁶ Section Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University, Vienna, Austria.
²⁷ Sackler Faculty of Medicine, Endocrine Institute, Meir Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
²⁸ Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
²⁹ Gastroenterology Unit, Department of Medical Sciences, City of Health and Science Hospital, Turin, Italy.
³⁰ Department of Digestive, Hepatobiliary and Endocrine Surgery, Paris Descartes University, Cochin Hospital, Paris, France.
³¹ National NET Centre and ENETS Centre of Excellence, St Vincent's University Hospital, Dublin, Ireland.
³² Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
³³ Centro Hepatobiliopancreático, Hospital Curry Cabral, Nova Univerditu of Lisbon, Lisbon, Portugal.
³⁴ HPB Surgical Unit, Newcastle upon Tyne Teaching Hospitals Foundation Trust, Newcastle upon Tyne, United Kingdom.
³⁵ General and Oncologic Surgery Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
³⁶ Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.
³⁷ Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy.

PMID: 33425946
PMCID: PMC7785972
DOI: 10.3389/fmed.2020.598438

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Stefano Partelli et al. Front Med (Lausanne). 2020.

. 2020 Dec 23:7:598438.

doi: 10.3389/fmed.2020.598438. eCollection 2020.

Authors

Affiliations

¹ Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
² Kings Health Partners NET Center, Kings College Hospital London, London, United Kingdom.
³ Division of Gastroenterology, Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
⁴ Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.
⁵ Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
⁶ Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.
⁷ Digestive Disease Unit, ENETS Center of Excellence, Sant' Andrea University Hospital, Rome, Italy.
⁸ Department of Surgery, Pancreas Institute, Verona ENETS Center of Excellence, University and Hospital Trust of Verona, Verona, Italy.
⁹ Department of Abdominal Surgery and Gastroenterology and Hepatology, Faculty of Medicine, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.
¹⁰ Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
¹¹ First Department of Propaedeutic and Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece.
¹² Division of Gastrointestinal Surgery, European Institute of Oncology, Milan, Italy.
¹³ Department of HPB Surgery and Liver Transplantation and Pancreatology, Beaujon Hospital, University Paris 7 Denis Diderot, Assistance publique-Hôpitaux de Paris, 100, Boulevard du Général-Leclerc, Clichy, France.
¹⁴ Department of Oncology and Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, Australia.
¹⁵ Centre for Gastroenterology, Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom.
¹⁶ Gastrointestinal and Hepato-Pancreatic Surgery and Liver Transplantation Unit, Fondazione, IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute) and Università degli Studi di Milano, Milan, Italy.
¹⁷ Department of Hepatobiliary Surgery, Wessex NET Group ENETS Centre of Excellence, University Hospital Southampton, Southampton, United Kingdom.
¹⁸ The ARDEN NET Centre, European Neuroendocrine Tumour Society (ENETS) Centre of Excellence (CoE), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, United Kingdom.
¹⁹ Department of Surgery, Pederzoli Hospital, Peschiera del Garda, Italy.
²⁰ Department of General, Visceral and Vascular Surgery, Salzkammergutklinikum Vöcklabruck, Vöcklabruck, Austria.
²¹ Department of General, Visceral and Transplantation Surgery, University Hospital, LMU Munich, Munich, Germany.
²² Section of Medical Oncology, Department of Biomedical Sciences and Clinical Oncology (DIMO), University of Bari 'Aldo Moro', Bari, Italy.
²³ Division of General Surgery, University of Toronto, Toronto, ON, Canada.
²⁴ Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada.
²⁵ Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, MA, United States.
²⁶ Section Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University, Vienna, Austria.
²⁷ Sackler Faculty of Medicine, Endocrine Institute, Meir Medical Center, Tel-Aviv University, Tel-Aviv, Israel.
²⁸ Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
²⁹ Gastroenterology Unit, Department of Medical Sciences, City of Health and Science Hospital, Turin, Italy.
³⁰ Department of Digestive, Hepatobiliary and Endocrine Surgery, Paris Descartes University, Cochin Hospital, Paris, France.
³¹ National NET Centre and ENETS Centre of Excellence, St Vincent's University Hospital, Dublin, Ireland.
³² Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
³³ Centro Hepatobiliopancreático, Hospital Curry Cabral, Nova Univerditu of Lisbon, Lisbon, Portugal.
³⁴ HPB Surgical Unit, Newcastle upon Tyne Teaching Hospitals Foundation Trust, Newcastle upon Tyne, United Kingdom.
³⁵ General and Oncologic Surgery Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
³⁶ Department of Visceral, Transplantation and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria.
³⁷ Department of Pathophysiology and Transplantation, University of Milan, Milano, Italy.

PMID: 33425946
PMCID: PMC7785972
DOI: 10.3389/fmed.2020.598438

Abstract

Introduction: The optimal treatment for small, asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms (NF-PanNEN) is still controversial. European Neuroendocrine Tumor Society (ENETS) guidelines recommend a watchful strategy for asymptomatic NF-PanNEN <2 cm of diameter. Several retrospective series demonstrated that a non-operative management is safe and feasible, but no prospective studies are available. Aim of the ASPEN study is to evaluate the optimal management of asymptomatic NF-PanNEN ≤2 cm comparing active surveillance and surgery. Methods: ASPEN is a prospective international observational multicentric cohort study supported by ENETS. The study is registered in ClinicalTrials.gov with the identification code NCT03084770. Based on the incidence of NF-PanNEN the number of expected patients to be enrolled in the ASPEN study is 1,000 during the study period (2017-2022). Primary endpoint is disease/progression-free survival, defined as the time from study enrolment to the first evidence of progression (active surveillance group) or recurrence of disease (surgery group) or death from disease. Inclusion criteria are: age >18 years, the presence of asymptomatic sporadic NF-PanNEN ≤2 cm proven by a positive fine-needle aspiration (FNA) or by the presence of a measurable nodule on high-quality imaging techniques that is positive at ⁶⁸Gallium DOTATOC-PET scan. Conclusion: The ASPEN study is designed to investigate if an active surveillance of asymptomatic NF-PanNEN ≤2 cm is safe as compared to surgical approach.

Keywords: ASPEN study; NF-PanNEN_2 cm; follow-up; management; small nonfunctioning pancreatic neuroendocrine neoplasm; surgery; surveillance.

Copyright © 2020 Partelli, Ramage, Massironi, Zerbi, Kim, Niccoli, Panzuto, Landoni, Tomazic, Ibrahim, Kaltsas, Bertani, Sauvanet, Segelov, Caplin, Coppa, Armstrong, Weickert, Butturini, Staettner, Boesch, Cives, Moulton, He, Selberherr, Twito, Castaldi, De Angelis, Gaujoux, Almeamar, Frilling, Vigia, Wilson, Muffatti, Srirajaskanthan, Invernizzi, Lania, Kwon, Ewald, Rinzivillo, Nessi, Smid, Gardini, Tsoli, Picardi, Hentic, Croagh, Toumpanakis, Citterio, Ramsey, Mosterman, Regi, Gasteiger, Rossi, Smiroldo, Jang and Falconi.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GL declared a shared affiliation, though no other collaboration, with one of the authors MC to the handling Editor.

Figures

**Figure 1**
Diagnostic work up at inclusion.

**Figure 2**
Suggested scheme of active surveillance for sporadic asymptomatic NF-PanNEN ≤2 cm.

**Figure 3**
Suggested scheme after surgical resection for sporadic asymptomatic NF-PanNEN ≤2 cm.

See this image and copyright information in PMC

References

1. Klimstra DS, Kloppell G, La Rosa SRG. editor. The 2019 WHO classification of tumors of the digestive system. In: 5th International Agency for Research on Cancer. Lyon: (2019) p. 16.
1. Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. (2016) 103:153–71. 10.1159/000443171 - DOI - PMC - PubMed
1. Jilesen APJ, Van Eijck CHJ, Busch ORC, Van Gulik TM, Gouma DJ, Van Dijkum EJMN. Postoperative outcomes of enucleation and standard resections in patients with a pancreatic neuroendocrine tumor. World J Surg. (2016) 40:715–28. 10.1016/j.hpb.2016.01.283 - DOI - PMC - PubMed
1. Hashim YM, Trinkaus KM, Linehan DC, Strasberg SS, Fields RC, Cao D, et al. . Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. (2014) 259:197–203. 10.1097/SLA.0000000000000348 - DOI - PMC - PubMed
1. Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol. (2013) 20:2815–21. 10.1245/s10434-013-3005-7 - DOI - PubMed

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Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Affiliations

Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Associated data

LinkOut - more resources

Full Text Sources

Medical