Abstract
This cohort study examines recurrence outcomes in patients with fully resected gastroenteropancreatic neuroendocrine tumors.
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are widely heterogeneous malignant abnormalities. 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. 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.
Methods
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. 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.
Results
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).
Table. Overall Survival and Cumulative Incidence of Recurrence Among 936 Patients With Resected Gastroenteropancreatic Neuroendocrine Tumors.
| Time, y | Overall Survival, % (95% CI) | Cumulative Incidence of Recurrence, % (95% CI) | ||||
|---|---|---|---|---|---|---|
| All NETs | Small Intestinal NETs | Pancreatic NETs | All NETs | Small Intestinal NETs | Pancreatic NETs | |
| 3 | 92.2 (90.3-93.8) | 93.7 (91.0-95.7) | 95.6 (91.4-97.8) | 23.3 (20.6-26.1) | 22.8 (18.9-26.9) | 26.5 (20.6-33.1) |
| 5 | 85.4 (82.8-87.6) | 86.5 (82.7-89.6) | 88.9 (82.9-92.9) | 33.5 (30.4-36.9) | 33.8 (29.4-39.0) | 39.6 (32.0-47.1) |
| 10 | 68.1 (64.1-71.7) | 66.9 (60.8-72.3) | 74.2 (64.9-81.4) | 48.5 (44.4-52.4) | 52.9 (46.7-58.7) | 57.0 (47.4-65.6) |
| 15 | 54.6 (49.2-59.7) | 49.1 (40.8-56.9) | 68.1 (55.7-77.8) | 58.3 (53.3-63.0) | 62.0 (54.6-68.6) | 69.4 (60.0-78.9) |
Abbreviation: NETs, neuroendocrine tumors.
Figure. Cumulative Incidence of Recurrence in NETs by Primary Site.
The number of imaging tests declined over time since neuroendocrine tumor (NET) diagnosis, from 1.04 investigations per 100 patient-days in months 1 to 3 to 0.29 in months 25 to 36, and 0.18 in months 109 to 120.
Discussion
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.
References
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