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

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.

Frequency, Progression, and Current Management: Report of 16 New Cases of Nonfunctional Pancreatic Neuroendocrine Tumors in Tuberous Sclerosis Complex and Comparison With Previous Reports

“…Surgical resection is indicated in cases of large tumors, rapidly growing or poorly differentiated Grade 3 PNEC (14). For welldifferentiated, Grade 1 and 2 nonfunctional PNETs <2 cm and growing <0.5 cm during 6-12 month time frame conservative management is recommended with follow up imaging (CT or MRI); however, prospective studies are needed to further define surgical intervention, as early removal of this lesions may be associated with better long term outcomes (24,28). The 5-year progression free survival for incidentally diagnosed nonfunctional PNETs is 86%, compared to 59% in symptomatic functional tumors (26).…”

The Increasing Incidence of Neuroendocrine Neoplasms Worldwide: Current Knowledge and Open Issues

“…The most typical example is represented by pancreatic NENs. Considering that, in the most recent decade, we observed a dramatic increase in the diagnosis of small, incidentally discovered, nonfunctioning pancreatic NENs [3,5], and a clear relationship between the tumor diameter and the risk of malignancy and recurrence has been reported [18], ENET guidelines started to recommend a "wait and see" approach for small asymptomatic non-functioning pancreatic NENs [12], and a European trial is currently ongoing [19]. Furthermore, endoscopic ablative technologies may also be utilized in patients with pancreatic NENs not suitable for surgery or who refused the surgical approach.…”

Multimodal Management of Grade 1 and 2 Pancreatic Neuroendocrine Tumors

“…Several series and a review published by Partelli S et al in 2017 [ 19 ] suggested that patients with incidental tumors less than 2 cm in diameter experienced a limited risk of tumor recurrence and were all alive at 5 years. The European Neuroendocrine Tumor Society (ENETS) guidelines then proposed a “watch and wait” policy in asymptomatic patients with sporadic < 2 cm low-grade (G1) p-NETs [ 20 ]. Histopathological confirmation is mandatory in this situation [ 21 ], but no consensus has emerged regarding the follow-up protocol.…”