Epidemiologic Trends of and Factors Associated With Overall Survival for Patients With Gastroenteropancreatic Neuroendocrine Tumors in the United States

Abstract

Importance: Although the incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have been thought to have increased during the past decades, updated epidemiologic and survival data are lacking.

Objectives: To conduct an epidemiologic and survival analysis of the largest cohort of patients with GEP-NETs using the latest data and to establish a novel nomogram to predict the survival probability of individual patients with GEP-NETs.

Design, setting, and participants: In this cohort study, 43 751 patients with GEP-NETs diagnosed from January 1, 1975, to December 31, 2015, were identified from the Surveillance, Epidemiology, and End Results Program. Associated data were used for epidemiologic and survival analysis, as well as the establishment and validation of a nomogram to predict the survival probability of individual patients with GEP-NETs. The study cutoff date was December 31, 2018. Statistical analysis was performed from February 1 to April 30, 2020.

Main outcomes and measures: Incidence, factors associated with overall survival, and a nomogram model for patients with GEP-NETs.

Results: A total of 43 751 patients received a diagnosis of GEP-NETs from 1975 to 2015 (22 398 women [51.2%], 31 976 White patients [73.1%], 7097 Black patients [16.2%], 3207 Asian and Pacific Islander patients [7.3%], 270 American Indian and Alaska Native patients [0.6%], and 4546 patients of unknown race [10.4%]; mean [SD] age at diagnosis, 58 [15] years). The age-adjusted incidence rate of GEP-NETs increased 6.4-fold from 1975 to 2015 (annual percentage change [APC], 4.98; 95% CI, 4.75-5.20; P < .001). Furthermore, among site groups, the incidence of GEP-NETs in the rectum increased most significantly (APC, 6.43; 95% CI, 5.65-7.23; P < .001). As for stage and grade, the incidence increased the most in localized GEP-NETs (APC, 6.53; 95% CI, 6.08-6.97; P < .001) and G1 GEP-NETs (APC, 18.93; 95% CI, 17.44-20.43; P < .001). During the study period, the mean age at diagnosis for localized disease increased by 9.0 years (95% CI, 3.3-14.7 years; P = .002), which remained unchanged for regional and distant cases. On multivariable analyses, age, sex, marital status, and tumor size, grade, stage, and site were significantly associated with overall survival for patients with GEP-NETs (eg, patients with distant vs localized disease: hazard ratio, 10.32; 95% CI, 8.56-12.43; G4 vs G1 GEP-NET: hazard ratio, 6.37; 95% CI, 5.39-7.53). Furthermore, a nomogram comprising age, size, grade, stage, and site was established to predict the 3-year and 5-year survival probability, with the concordance indexes of 0.893 (95% CI, 0.883-0.903) for the internal validations and 0.880 (95% CI, 0.866-0.894) for the external validations. The receiver operating characteristic curve demonstrated that the nomogram exhibited better discrimination power than TNM classification (area under the curve for 3-year overall survival, 0.908 vs 0.795; for 5-year overall survival, 0.893 vs 0.791).

Conclusions and relevance: In this study, the incidence and prevalence of GEP-NETs have continued to increase over 40 years, especially among patients with rectal GEP-NETs. In addition, this study suggests that a nomogram with 5 prognostic parameters may accurately quantify the risk of death among patients with GEP-NETs, indicating that it has satisfactory clinical practicality.

Figure 1.. Incidence of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) Over Time by Sex and Race

A, Annual age-adjusted incidence of all GEP-NETs by year (1975-2015). The incidence is presented as the number of tumors per 100 000 population (with 95% CIs presented as whiskers) age-adjusted for the 2000 US standard population. B, Time-trend analyses of the incidence of GEP-NETs by sex (1975-2015). C, The incidence of GEP-NETs by race (1975-2015), including expanded racial categories (1992-2015). AI/AN indicates American Indian and Alaska Native; AP, Asian and Pacific Islander; and SEER, Surveillance, Epidemiology, and End Results Program.

Figure 2.. Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) Incidence Trends by Sex, Race, and Age at Diagnosis, Surveillance, Epidemiology, and End Results Program 9 (1975-1991) and 13 (1992-2015)

Figure 3.. Incidence and Limited Duration Prevalence of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) Over Time by Site, Disease Stage, and Grade

Figure 4.. Multivariable Regression Analysis for Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

HR indicates hazard ratio.

Figure 5.. Nomogram to Predict the 3-Year and 5-Year Survival Probabilities of Patients With Gastroenteropancreatic Neuroendocrine Tumors and the Calibration of the Nomogram Using the Training and Validation Sets

A, Points for age, tumor size, tumor grade, disease stage, and primary tumor site are obtained by drawing a line upward from the corresponding values to the “Points” line. The sum of the points of these 5 factors is located on the “Total points” line, and a line projected down to the bottom scales determines the probabilities of 3-year and 5-year overall survival (OS). B, Calibration plots of the nomogram for 3-year and 5-year survival probabilities in the training set. C, Calibration plots of the nomogram for 3-year and 5-year survival probabilities in the validation set. The gray line represents the ideal nomogram, and the orange line represents the observed nomogram. The predicted probability of OS by the nomogram is projected onto the x-axis, and the actual OS is projected onto the y-axis. Error bars indicate 95% CIs.