Recurrence in Resected Gastroenteropancreatic Neuroendocrine Tumors

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are widely heterogeneous malignant abnormalities.¹ Their natural history is poorly described, with little understanding of recurrence patterns. Surveillance for resected GEP-NETs may include clinical review, laboratory tests, and numerous medical and nuclear imaging modalities. These modalities can increase patient anxiety, may be associated with potential harm (eg, exposure to ionizing radiation), and have not been shown to improve outcomes. Current guidelines vary widely in recommendations, reflecting the lack of data.^2,3 Information on the natural history and recurrence of the disease may improve patient-centered follow-up of this population. We hypothesized that GEP-NETs may recur over a longer time course compared with other gastrointestinal malignant abnormalities.

A cohort study consisting of patients with a first resected GEP-NET between 1994 and 2012 was conducted in Ontario, Canada, at the Institute for Clinical Evaluative Sciences (ICES). Administrative databases were linked using unique encoded patient identifiers to obtain information on demographics, histological diagnoses, curative operation codes, use of imaging, recurrence, and death. Patients were grouped by primary site into small intestinal NETs (SI-NETs), pancreatic NETs (pNETs), or NETs of other sites. Recurrence was defined as a composite of International Classification of Disease codes for metastatic disease or repeated surgery more than 6 months after the initial NET diagnosis date. Overall survival (OS) was estimated with the Kaplan-Meier method; and the cumulative probability of recurrence was estimated using the cumulative incidence function (CIF), accounting for death as a competing risk.⁴ Use of imaging tests was presented descriptively. Statistical analyses were performed with SAS statistical software (version 9.4; SAS Institute, Inc). This study was approved by the institutional review board at Sunnybrook Health Sciences Centre, which granted a waiver of consent owing to the deidentification of data used.

Of the 936 patients included in the analysis, the median age at diagnosis was 60 years (interquartile range, 48-70 years), 480 (51.3%) were women. Median follow-up was 46.8 months. The predominant tumor site was small intestine (43 [46.6%]), and pancreatic NETs accounted for 187 (20.0%). The OS was 92.2% at 3 years, 85.4% at 5 years, and 68.1% at 10 years among all patients (Table), with significant difference across the sites of origin (log-rank P = .04). The cumulative incidence of recurrence was 23.3% at 3 years, 33.5% at 5 years, and 48.5% at 10 years, with recurrence occurring earliest among patients with pancreatic NETs (Gray's test for equality of CIF P < .001) (Table) (Figure).

This is the largest known series examining outcomes of patients with fully resected GEP-NETs. Disease recurrence occurs much later than most other gastrointestinal tract cancers, and patients with pNETs recur earlier than those with SI-NETs. The observed patterns of imaging are incongruent with the observed timeframe of recurrence, particularly in the first 3 years where only one-third of cancers recur. These data are limited by the lack of detailed pathologic data, particularly Ki-67 index and lymph node status.

Future research should focus on the cost-effectiveness of surveillance and its impact on patient outcomes. These data can inform guidelines for surveillance in this population that accounts for the natural history of this disease.

Corresponding Author: Simron Singh, MD, MPH, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Rd, Toronto, ON M4N3M5, Canada (simron.singh@sunnybrook.ca).

Accepted for Publication: December 26, 2017.

Published Online: March 15, 2018. doi:10.1001/jamaoncol.2018.0024

Author Contributions: Dr Singh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Singh, Moody, Fischer, Segelov.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Singh, Chan, Moody, Segelov.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Singh, Moody, Austin, Liu.

Obtained funding: Singh, Segelov.

Administrative, technical, or material support: Singh, Chan, Moody.

Study supervision: Singh, Moody, Segelov.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by the Commonwealth Neuroendocrine Tumour Collaboration (CommNETs). It was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Dr Austin is supported by a Career Investigator Award from the Heart & Stroke Foundation (Ontario office).

Role of the Funder/Sponsor: The Commonwealth Neuroendocrine Tumour Collaboration, ICES, and MOHLTC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions, and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. Parts of this material are based on data and information provided by Cancer Care Ontario (CCO). The opinions, results, view, and conclusions reported in this article are those of the authors and do not necessarily reflect those of CCO. No endorsement by CCO is intended or should be inferred.