Volume 121, Issue 4 p. 589-597
Original Article
Free Access

Exploring the rising incidence of neuroendocrine tumors: A population-based analysis of epidemiology, metastatic presentation, and outcomes

Julie Hallet MD

Corresponding Author

Julie Hallet MD

Division of General Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Division of General Surgery, University of Toronto, Toronto, Ontario, Canada

Corresponding author: Julie Hallet, MD, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Suite T2-063, Toronto, Ontario M4N 3M5, Canada; Fax: (416) 480-6002; [email protected]Search for more papers by this author
Calvin How Lim Law MD, MPH

Calvin How Lim Law MD, MPH

Division of General Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Division of General Surgery, University of Toronto, Toronto, Ontario, Canada

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Moises Cukier MD

Moises Cukier MD

Division of General Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Division of General Surgery, University of Toronto, Toronto, Ontario, Canada

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Refik Saskin MSc

Refik Saskin MSc

Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada

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Ning Liu MSc

Ning Liu MSc

Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada

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Simron Singh MD, MPH

Simron Singh MD, MPH

Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Department of Medicine, University of Toronto, Toronto, Ontario, Canada

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First published: 13 October 2014
Citations: 573

Part of this work was presented as a poster presentation at the 2012 Gastrointestinal Symposium and at the 2014 Annual Meeting of the American Society of Clinical Oncology and as a podium presentation at the 2014 Canadian Surgery Forum.

Abstract

BACKGROUND

An increased incidence of neuroendocrine tumors (NETs) has been reported worldwide, but the reasons underlying this rise have not been identified. By assessing patterns of metastatic presentation, this study sought to examine the epidemiologic characteristics of NETs and the contribution of early-stage detection to the rising incidence.

METHODS

A population-based retrospective cohort study was conducted with prospectively maintained databases linked at the Institute for Clinical Evaluative Sciences. Adult patients with a NET diagnosis from 1994 to 2009 in Ontario, Canada were included. The main outcomes included the overall and site-specific incidence, proportion of metastatic disease, overall survival (OS), and recurrence-free survival (RFS).

RESULTS

Five thousand six hundred nineteen NET cases were identified. The incidence of NETs increased from 2.48 to 5.86 per 100,000 per year. Metastases were found in 20.8% at presentation and in another 38% after the initial diagnosis. The proportion of metastases at presentation decreased from 1994 to 2009 (from 29% to 13%). Therefore, although the incidence of all NETs increased, the overall incidence of metastases did not change (0.63-0.69 per 100,000 per year). The 10-year OS rate was 46.5%, and the RFS rate was 64.6%. In addition to the primary tumor site, independent predictors of worse OS included an advanced age (P < .0001), male sex (P < .0001), a low socioeconomic status (P < .0001), and rural living (P = 0.049).

CONCLUSIONS

The incidence of NETs has markedly increased over the course of 15 years. This is the first study to provide evidence suggesting that the increase in the incidence of NETs may be due to increased detection. In addition to tumor characteristics, low income and rural residency portend worse survival for patients with NETs. Cancer 2015;121:589–597. © 2014 American Cancer Society.

INTRODUCTION

Neuroendocrine tumors (NETs) are a group of rare cancers accounting for 0.46% of gastrointestinal and bronchopulmonary malignancies.1-4 They are a heterogeneous group of malignancies most commonly found in the gastrointestinal system, but they can also originate in other areas, including the pancreas, lungs, ovaries, thyroid, pituitary, and adrenal glands.1, 4, 5 They exhibit a wide range of clinical behaviors due to the secretion of hormones, most often serotonin, which creates nonspecific but debilitating systemic symptoms such as diarrhea, bronchospasm, flushing, and cardiac valve disease.2

Despite their identification more than a century ago, NETs remain a poorly understood disease. Because of their rarity, tumor heterogeneity, nonspecific presentation symptoms, and unique indolent biology as well as a lack of awareness, patients with NETs can suffer delays in diagnosis of up to 7 years.1, 6, 7 As a result, they often present at an advanced stage when a cure is no longer possible.1, 7 In such metastatic presentations, the combination of slow progression and hormonal production may produce debilitating symptoms with a potentially significant impact that leads to deteriorating quality of life as well as health care resource consumption. Recently, international collaborations have resulted in promising randomized controlled trials that revealed significant benefits of somatostatin analog and targeted biologic therapies, which offer NET patients improved progression-free survival.8, 9 However, much remains to be learned about these malignancies to improve survival, which has been stagnating for the past 3 decades.1-3 A better understanding of NETs becomes even more important and relevant as they are now more prevalent than esophageal, gastric, pancreatic, or hepatobiliary cancers, perhaps due to their indolent behavior.1 Previous epidemiological assessments of NETs have reported a rise in their incidence over the past decades.1, 10, 11 Although hypotheses of overdetection or changes in tumor biology have been formulated to explain this observation,12 no data currently exist to support either.

This study used a population-based approach to examine the epidemiologic characteristics of NETs and to determine whether the changes in their incidence are related to early detection as demonstrated by patterns of metastatic presentation. This richly detailed population data set could provide the first ever data and evidence that could help us to understand why there has been this observed rise in the incidence of NETs. We hypothesized that the incidence of NETs rising over the study period with a concomitant decrease in metastatic presentation would bring light to the role of increased detection in this phenomenon.

MATERIALS AND METHODS

The study was approved by the research ethics board of Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada).

Design

A retrospective, population-based cohort study was conducted with data linked from prospectively maintained administrative databases stored at the Institute for Clinical Evaluative Sciences (ICES) in Toronto, Ontario.13

Study Population

This population-based study was conducted with all patients with a valid Ontario Health Insurance Plan (OHIP) number from 1994 to 2009. During the study period, the population in Ontario grew from 8,054,030 in 1994 to 10,004,048 in 2009. Under the Canada Health Act, the Ontario population benefits from universally accessible and funded health care through OHIP.14 All residents of Ontario are eligible for OHIP after they have resided in the province for 3 months.

Data Sources

Three administrative population-based data sets were linked at ICES. The Ontario Cancer Registry (OCR) is a registry of all Ontario residents diagnosed with cancer since 1964, and it receives hospital discharge records, pathology reports, death certificates, and reports from regional cancer centers in the province of Ontario.15 All medical reports containing a cancer diagnosis are legally subjected to a mandatory report to the OCR. The reliability of data contained in the OCR has been previously ascertained.16-18 Diagnoses are classified according to International Classification of Diseases, Ninth Revision (ICD-9), or International Classification of Diseases, Tenth Revision (ICD-10), for the primary disease site and according to International Classification of Diseases for Oncology (ICD-O) for morphology.19, 20 The Registered Persons Database (RPDB) collects data on all individuals eligible for OHIP. It contains demographic information, including age, sex, postal code, socioeconomic status, and date of death. Each individual is identified at ICES by a unique numeric encrypted identifier that can be used to link these data sources.

Cohort

Adults (>18 years old) with a diagnosis of NET in the OCR were identified with ICD-O codes. Carcinoid tumors of uncertain malignant potential, enterochromaffin cell carcinoid, enterochromaffin-like cell tumors, goblet cell carcinoid, tubular carcinoid, neuroendocrine carcinoma, atypical carcinoid, islet cell tumors, insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma, enteroglucagonoma, and mixed islet cell and exocrine adenocarcinoma (ICD-O: 8240, 8241, 8242, 8243, 8245, 8246, 8249, 8150, 8152, 8153, 8154, 8155, 8156, and 8157) were included. Small cell and large cell lung carcinoma, pheochromocytoma, paraganglioma, extra-adrenal paraganglioma, medullary thyroid carcinoma, and Merckel cell carcinoma (ICD-O: 8002, 8040, 8041, 8042, 8043, 8045, 8013, 8247, 8700, 8680, 8693, and 8510) were excluded because they represent biologically different diseases.

Demographic Characteristics

Age and sex were obtained from the RPDB. Socioeconomic status was assessed through income quintiles based on the median income of a patient's postal code of residence.21 The following primary NET sites were described: stomach, small intestine (including duodenum), large intestine (including appendix), rectum, pancreas, bronchus and lungs (ICD-9: 151, 152, 153, 15, 157, and 162), and others (other ICD-9 codes). Rare NET sites (eg, biliary, prostate, breast, head, and neck) were included under the other category because a small number of cases were anticipated. Metastatic disease was captured with ICD-9 and ICD-10 codes (ICD-9: 196, 197, 198, 199, and 209; ICD-10: C77, 78, and 79) and was characterized as at presentation (metastasis code during the same episode as the first NET diagnosis) or after initial diagnosis (metastasis code after the episode of the first NET diagnosis).

Outcome Measures

The incidence of NETs—overall and by the primary NET site—was determined for the defined adult Ontario population for each year from 1994 to 2009. The date of diagnosis was obtained from the OCR. The prevalence of metastatic disease was determined for the whole cohort and by the primary NET site. The 3-, 5-, and 10-year overall survival (OS) rates were computed with the date of death according to the RPDB as of March 31, 2010. Patients with a diagnosis of non-NET cancer within 60 days of their NET diagnosis were excluded from that survival measure. Recurrence-free survival (RFS), defined as the occurrence of metastatic disease after the initial diagnosis, was examined. The end of follow-up was defined as the date of death, the date of last contact, or 10 years after the diagnosis as of March 31, 2010.

Statistical Analysis

Statistical analyses were performed with SAS 9.2 (SAS Institute, Inc, Cary, NC). Demographic characteristics of the study cohort were reported as means and standard deviations for continuous variables and as proportions and absolute counts for categorical variables. The chi-square statistic was used to compare proportions between sex and primary tumor location groups. The incidence was computed with the defined adult Ontario population as the denominator and was reported as the incidence per 100,000 per year with the incident case count for that year. OS and RFS were estimated with Kaplan-Meier analyses, and comparisons were performed with a log-rank test. Predictors of 10-year OS and RFS were determined through Cox regression analyses and were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Statistical significance was set at P < .05.

RESULTS

During the study period, 5619 NET cases were identified in Ontario. The baseline characteristics are presented in Table 1. The mean age at diagnosis was 60.9 years, and 49.5% of the patients were male.

Table 1. Demographics and Distribution of NETs Among Adult Patients in Ontario by Primary Tumor Site, 1994-2009
All NETs Stomach Small Intestine Pancreas Large Intestine Rectum Bronchus, Lung Other NETs
Distribution, n (%) 5619 (100) 282 (5.0) 1015 (18.2) 531 (9.4) 727 (12.9) 690 (12.3) 1403 (25.0) 971 (17.3)
Age at NET diagnosis, mean ± SD 60.9 ± 14.5 63.9 ± 13.6 63.8 ± 13.2 56.7 ± 13.3 58.8 ± 15.9 56.7 ± 12.8 61.3 ± 14.6 63.1 ± 14.9
Male sex, n (%) 2784 (49.5) 131 (46.5) 558 (55.0) 303 (57.1) 377 (51.9) 351 (50.9) 591 (42.1) 473 (48.7)
Income quintile, na (%)
1 (lowest) 1072 (19.1) 58 (20.6) 202 (19.9) 92 (17.3) 137 (18.8) 116 (16.8) 281 (20.0) 186 (19.2)
2 1081 (19.2) 53 (18.8) 183 (18.0) 101 (19.0) 136 (18.7) 121 (17.5) 282 (20.1) 205 (21.1)
3 1123 (20.0) 62 (22.0) 197 (19.4) 105 (19.8) 148 (20.4) 137 (19.9) 280 (20.0) 194 (20.0)
4 1135 (20.2) 52 (18.4) 212 (20.9) 100 (18.8) 137 (18.8) 167 (24.2) 276 (19.7) 191 (19.7)
5 (highest) 1192 (21.2) 56 (19.9) 219 (21.6) 133 (25.0) 166 (22.8) 148 (21.4) 280 (20.0) 190 (19.6)
  • Abbreviations: NET, neuroendocrine tumor; SD, standard deviation.
  • a Accounting for missing data.

Incidence

From 1994 to 2009, the incidence increased from 2.48 (95% CI, 2.13-2.83) to 5.86 cases (95% CI, 5.40-6.35) per 100,000 per year; this represented a 2.36-fold increase. The incidence of NETs increased steadily among all age groups but varied according to the primary site of NETs. During the study period, the incidence of all cancers in Ontario went from 541.38 to 611.42 per 100,000 per year (or a 1.13-fold increase; Fig. 1A). There was a progressive increase in incidence in almost all primary NET site groups (Table 2). Similar increases in incidence were observed between sexes, age groups, and income quintiles (Fig. 1B-D).

Details are in the caption following the image

Incidence of neuroendocrine tumors (NETs) in the adult population in Ontario, 1994-2009: (A) the incidence of NETs versus the incidence of all other cancers, (B) the incidence of NETs by sex, (C) the incidence of NETs by age group (in years), and (D) the incidence of NETs by income quintile.

Table 2. Incidence of NETs per 100,000 per Year in the Adult Population in Ontario by Sex and Primary Tumor Site, 1994-2009
Year All NETs Stomach Small Intestine Pancreas Large Intestine Rectum Bronchus, Lungs Other NETs All Cancers
All Male Female
1994 2.46 (198) 2.6 (102) 2.32 (96) 0.07 (6) 0.42 (34) 0.1 (8) 0.37 (30) 0.22 (18) 0.83 (67) 0.43 (35) 541.38 (43,603)
1995 2.35 (192) 2.5 (99) 2.22 (93) 0.11 (9) 0.4 (33) 0.29 (24) 0.27 (22) 0.04 (3) 0.72 (59) 0.52 (42) 532.24 (43,404)
1996 2.84 (234) 3.02 (121) 2.66 (113) 0.07 (6) 0.53 (44) 0.32 (26) 0.35 (29) 0.27 (22) 0.70 (58) 0.59 (49) 542.67 (44,783)
1997 2.89 (242) 2.55 (104) 3.21 (138) 0.18 (15) 0.44 (37) 0.27 (23) 0.37 (31) 0.19 (16) 0.92 (77) 0.51 (43) 557.68 (46,694)
1998 3.29 (279) 3.44 (142) 3.14 (137) 0.12 (10) 0.58 (49) 0.24 (20) 0.42 (36) 0.24 (20) 1.05 (89) 0.65 (55) 567.92 (48,190)
1999 3.03 (261) 2.91 (122) 3.15 (139) 0.07 (6) 0.49 (42) 0.26 (22) 0.33 (28) 0.19 (16) 1.03 (89) 0.67 (58) 578.73 (49,817)
2000 3.44 (301) 4.02 (172) 2.87 (129) 0.13 (11) 0.68 (60) 0.35 (31) 0.3 (26) 0.43 (38) 0.90 (79) 0.64 (56) 586.86 (51,421)
2001 3.46 (309) 3.98 (174) 2.95 (135) 0.16 (14) 0.57 (51) 0.34 (30) 0.55 (49) 0.3 (27) 0.91 (81) 0.64 (57) 594.19 (53,141)
2002 3.23 (295) 3.14 (140) 3.32 (155) 0.14 (13) 0.55 (50) 0.38 (35) 0.49 (45) 0.39 (36) 0.78 (71) 0.49 (45) 587.88 (53,642)
2003 3.50 (325) 3.6 (163) 3.41 (162) 0.26 (24) 0.7 (65) 0.31 (29) 0.45 (42) 0.37 (34) 0.83 (77) 0.58 (54) 584.81 (54,264)
2004 4.12 (389) 4.15 (191) 4.1 (198) 0.24 (23) 0.84 (79) 0.31 (29) 0.55 (52) 0.49 (46) 1.07 (101) 0.63 (59) 601.56 (56,737)
2005 4.34 (415) 4.73 (221) 3.96 (194) 0.21 (20) 0.87 (83) 0.36 (34) 0.54 (52) 0.62 (59) 1.07 (102) 0.68 (65) 608.98 (58,296)
2006 4.92 (478) 4.77 (226) 5.07 (252) 0.31 (30) 0.93 (90) 0.44 (43) 0.69 (66) 0.64 (62) 1.07 (104) 0.85 (83) 615.83 (59,813)
2007 5.17 (509) 5.12 (246) 5.21 (263) 0.32 (32) 0.89 (88) 0.58 (57) 0.75 (74) 0.89 (88) 0.96 (95) 0.76 (75) 629.19 (61,991)
2008 5.96 (596) 5.76 (281) 6.15 (315) 0.34 (34) 1.07 (107) 0.59 (59) 0.75 (75) 1.087 (107) 1.24 (124) 0.90 (90) 615.54 (61,579)
2009 5.86 (596) 5.64 (280) 6.07 (316) 0.29 (29) 1.01 (103) 0.6 (61) 0.69 (70) 0.96 (98) 1.28 (130) 1.03 (105) 611.42 (62,174)
Absolute difference 3.40 (398) 3.04 (178) 3.75 (220) 0.22 (23) 0.59 (69) 0.5 (53) 0.32 (40) 0.74 (80) 0.45 (63) 0.60 (70) 70.04 (18,571)
% of change 138 117 162 314 140 119 86 336 542 139 13
  • Abbreviation: NET, neuroendocrine tumor.
  • Data are presented as incidences (with absolute counts in parentheses) except for the last row.

Tumor Characteristics and Metastatic Disease

Overall, the most frequent primary NET sites were bronchopulmonary sites (25.0%) and the small intestine (18.1%). The proportion of patients presenting with metastatic disease in the cohort during the study period is depicted in Figure 2A. Overall, 20.8% of the patients with NETs (n = 1166) presented with metastatic disease at the time of diagnosis, and an additional 38.0% (n = 2133) presented with metastases during follow-up. The proportion of patients presenting with metastatic disease at the time of diagnosis decreased from 29% (n = 51/177) in 1994 to 13% (n = 70/545) in 2009. As a result of the increased incidence of all NETs and the decreased proportion of metastatic presentation, the incidence of metastatic NETs at presentation remained stable (Fig. 2B,C).

Details are in the caption following the image

Patterns of metastases in neuroendocrine tumors (NETs) in the adult population in Ontario by the primary tumor site, 1994-2009: (A) the distribution of metastatic NETs over the course of the disease according to the primary tumor site, (B) the proportion of metastases at presentation for NETs, and (C) the incidence of NETs metastatic at presentation versus the incidence of all NETs.

OS and RFS

The median follow-up was 3.8 years. The 3-, 5-, and 10-year OS rates for patients with NETs were 68.3%, 61.0%, and 46.5%, respectively (Table 3). OS differed significantly according to the primary tumor site (P < .0001; Table 3) as well as sex, age group, and income quintile (P < .0001; Fig. 3). A metastatic status was associated with worse survival, with 10-year OS rates of 68.2% for nonmetastatic disease, 17.5% for metastases at presentation, and 18.7% for metastases after the initial diagnosis (P < .0001). Independent predictors of 10-year mortality included age (HR, 1.04; P < .0001), male sex (HR, 1.3; P < .0001), socioeconomic status (lowest income quintile: HR, 1.25; P = .001), rural living (HR, 1.13; P = .049), and NET primary tumor sites (Table 4).

Table 3. Overall Survival for Patients With NETs Among the Adult Population in Ontario, 1994-2009
Overall Survival (%)
1 Year 3 Years 5 Years 10 Years
All patients 80.8 68.3 61.0 46.5
Sex
Female 83.3 71.8 65.2 50.6
Male 78.0 64.7 56.6 42.3
Age at NET diagnosis
19-50 y 92.0 83.6 78.9 69.7
51-60 y 84.2 73.0 67.1 53.6
61-70 y 79.8 67.2 59.6 43.1
≥71 y 67.5 50.2 39.3 20.4
Income quintile
1 (lowest) 77.1 62.5 55.7 40.3
2 80.3 67.6 59.6 45.9
3 81.6 70.0 62.2 49.9
4 81.2 70.5 63.8 46.8
5 (highest) 82.7 70.3 63.2 48.9
Primary NET site
Stomach 82.1 76.2 67.4 49.7
Small intestine 90.7 81.7 73.4 51.2
Pancreas 78.0 60.7 48.8 30.2
Large intestine 82.2 70.7 64.3 48.3
Rectum 95.3 89.2 87.2 84.0
Bronchus, lung 77.0 64.9 59.7 49.7
Others 66.8 46.8 36.7 23.1
  • Abbreviation: NET, neuroendocrine tumor.
Details are in the caption following the image

Overall survival for adult patients with neuroendocrine tumors (NETs) in Ontario with an adjustment for the age at diagnosis, 1994-2009: (A) overall survival for all patients with NETs, (B) overall survival for patients with NETs by sex, (C) overall survival for patients with NETs by age group, and (D) overall survival for patients with NETs by income quintile.

Table 4. Predictors of 10-Year Overall and Recurrence-Free Survival for Patients With NETs Among the Adult Population in Ontario, 1994-2009
Variable 10-Year Mortality Recurrence at the End of Follow-Up
Hazard Ratio (95% Confidence Interval) P Hazard Ratio (95% Confidence Interval) P
Male sex 1.30 (1.19-1.41) <.0001 1.11 (0.99-1.24) .07
Age 1.04 (1.038-1.045) <.0001 1.01 (1.003-1.011) .0003
Income quintilea
1 (lowest) 1.25 (1.09-1.43) .001 0.92 (0.77-1.10) .39
2 1.09 (0.95-1.25) .22 1.01 (0.85-1.20) .92
3 0.98 (0.86-1.13) .80 0.94 (0.79-1.12) .50
4 1.09 (0.95-1.25) .23 0.97 (0.82-1.15) .73
Rural livingb 1.13 (1.00-1.27) .049 1.03 (0.87-1.21) .74
Primary NET sitec
Stomach 0.82 (0.65-1.03) .08 0.66 (0.47-0.93) .02
Pancreas 1.40 (1.20-1.63) <.0001 2.23 (1.86-2.69) <.0001
Small intestine 0.59 (0.51-0.68) <.0001 1.08 (0.9-1.30) .41
Large intestine 0.94 (0.81-1.09) .42 1.09 (0.89-1.33) .42
Rectum 0.34 (0.27-0.44) <.0001 0.36 (0.27-0.49) <.0001
Other NETs 1.59 (1.41-1.79) <.0001 1.75 (1.48-2.06) <.0001
  • Abbreviation: NET, neuroendocrine tumor.
  • a The reference is the fifth income quintile (highest).
  • b Living in a community with <10,000 people.
  • c The reference is a bronchus and lung site.

The 3-, 5-, and 10-year RFS rates were 75.0%, 71.0%, and 64.6%, respectively (Table 5 and Fig. 4). In addition to the primary tumor site, advancing age was associated with higher recurrence rates (P = .0003; Table 4).

Table 5. Recurrence-Free Survival for Patients With NETs Among the Adult Population in Ontario, 1994-2009
Recurrence-Free Survival (%)
1 Year 3 Years 5 Years 10 Years
All patients 81.4 75.0 71.0 64.6
Sex
Female 81.6 76.5 73.0 67.5
Male 81.2 73.5 69.0 61.6
Age at NET diagnosis
19-50 y 86.0 80.4 76.5 69.8
51-60 y 77.8 70.0 66.5 61.1
61-70 y 81.3 74.4 70.6 63.1
≥71 y 80.0 74.6 69.6 63.9
Income quintile
1 (lowest) 82.8 76.6 72.6 64.3
2 80.3 73.0 69.1 64.0
3 82.1 75.4 71.2 65.6
4 81.3 76.0 71.8 64.6
5 (highest) 80.6 74.5 70.8 64.4
Primary NET site
Stomach 88.6 84.7 82.1 77.0
Small intestine 80.9 76.0 72.9 64.5
Pancreas 71.6 56.5 46.4 37.1
Large intestine 80.4 76.3 73.1 67.9
Rectum 93.5 91.5 90.3 88.8
Bronchus, lung 83.0 77.5 74.8 69.4
Others 74.5 63.7 55.7 45.9
  • Abbreviation: NET, neuroendocrine tumor.
Details are in the caption following the image

Recurrence-free survival for adult patients with neuroendocrine tumors in Ontario, 1994-2009.

DISCUSSION

This study represents one of the largest and most detailed cohort analyses of the epidemiology and outcomes of NETs performed for this unique malignancy. Over a 15-year period, the incidence of NETs increased almost 2.5-fold and reached 5.86 per 100,000 per year in 2009. Overall, 1 in 5 patients initially presented with metastatic disease. Interestingly, this figure decreased by close to 50% from 1994 to 2009 (from 29% to 13%) while the overall incidence of NETs was rising. In addition to the primary tumor site and metastatic status, advancing age, male sex, low socioeconomic status, and rural area living were also associated with worse survival.

The epidemiology of NETs has been examined in previous national and regional registries, with the largest ones using SEER and Norway National Cancer Registry data.1, 3, 10 Although the increase in the incidence of NETs appears consistent among studies,1, 11, 22 the magnitude of the change that we are reporting (from 2.46 to 5.86 cases per 100,000 per year) was observed only in the latest SEER analysis (from 1.09 to 5.25 cases per year per 100,000).1 In Europe and Asia, the incidence appears significantly lower and ranges from 1.1 to 3.24 cases per 100,000 per year.10, 22-25 This may be due to older data and differences in data registration, but it could also reveal variability in environmental factors and tumorigenesis. Health care resource utilization leading to differences in the frequency of diagnosis is also likely to play a role in explaining regional and national differences in the incidence of NETs.

Improvements in diagnostic imaging, particularly computed tomography and gastrointestinal endoscopy, leading to the incidental identification of asymptomatic NETs have been suggested to explain the incidence change.12 In addition, an increased detection rate could suggest the identification of earlier stage lesions and thereby lead to the diagnosis of perhaps less aggressive tumors that may not have been revealed otherwise. No study has formally looked at the use of diagnostic modalities with respect to diagnoses of NETs. Directly exploring this increased detection hypothesis, we observed a decrease in the proportion of NETs presenting with metastases while the overall incidence was rising. Thus, the increased incidence of all NETs was accompanied by a stable incidence of advanced NETs. For the first time, the current study examined the rate of metastatic disease at presentation with respect to the overall incidence of NETs to better understand the relationship between the reported increase in NETs and earlier detection. The decrease in metastatic presentation in the midst of a rising incidence of all NETs suggests that earlier detection of NETs is taking place. These results shed light on the observations made by previous epidemiology analyses around the world.1, 10, 23-25

Whether this is due to more frequent use of diagnostic modalities or alterations in pathological disease definition is yet to be defined. Moreover, the identification of socioeconomic outcome disparities outlines the possible implication of access to care and health care delivery variability in patterns of diagnosis and changes in incidence. Indeed, NET patients often lack a clear pathway in their cancer journey, and this is characterized by difficulties in obtaining a diagnosis.26 These observations warrant further investigation of health care delivery to improve outcomes for patients with NETs through a chance at an timely diagnosis for all NET patients. Indeed, improvements in diagnostic processes and access to a timely diagnosis have previously been identified as priorities in NET research.6

Identified predictors of OS and RFS offer insight into variables to examine in future studies to better understand the behavior of NETs, achieve a timely diagnosis, and improve management. Worse OS was associated not only with nonmodifiable variables such as male sex and advanced age but also with low socioeconomic status and rural residency. As previously mentioned, these differences may be underlined by variations in access to care in populations having lower incomes or living in rural areas further away from major cancer centers.27 Rural and urban patients may also have different environmental exposures and risk factors, although this has not been examined to date.

Despite the inherent challenges associated with population-based studies, this examination provides a long-term detailed and robust appraisal of NETs. It is acknowledged that this study has limitations, the most important being the identification of NETs through ICD-O codes, which are complex and not ideally suited for the identification of a heterogeneous disease whose definition may have changed over time. This study also relies on pathology diagnoses, which could have led to an underestimation of the actual incidence, an issue for all previous studies as well. We have chosen to use metastases as a surrogate for advanced disease rather than TNM staging. Indeed, NETs currently lack a unified specific staging system beyond the World Health Organization grade classification. This decision relies on the unique biology of NETs and previous observations of metastatic status as the most significant prognostic factor (as opposed to nodal disease).1 We acknowledge that regional nodal disease is also relevant in NETs, but with respect to symptoms rather than survival.28 Finally, our OS analysis defined the last follow-up and, therefore, censoring as the date of death, March 31, 2010, or the date of last contact with the health care system. We acknowledge that this later censoring criterion does not account for patients who may have moved to another jurisdiction and are still alive: this decision was made to obtain a conservative estimate of survival rather than an overestimation.

However, this study provides a uniquely detailed assessment of the NET landscape to improve our understanding of the disease and guide future research efforts and awareness initiatives. It distinguishes itself from previous work by providing an exploration of the underlying mechanism of the increased NET incidence through an analysis of patterns of metastatic presentation over time. It also offers a detailed description of patterns and predictors of recurrence in a large cohort of patients with NETs.

In conclusion, the incidence of NETs has markedly increased over a 15-year period, and this has been paralleled by a decreased proportion with metastatic presentation. This points toward increased detection as a possible explanation for the significant rise in incidence. Beyond the primary tumor site and metastatic disease, the socioeconomic factors of income and rural residence are significantly associated with NET outcomes.

In an effort to raise awareness, promote timely diagnoses, and improve the management of NETs, particular attention should be paid to factors associated with worse outcomes, especially low socioeconomic status and rural residency. This highlights the need for examinations of health care delivery patterns in the diagnosis and management of NETs. We believe that the findings of this unique study will help to further increase our understanding of the incidence of NETs and shape future processes of care strategies for the management of patients with NETs.

FUNDING SUPPORT

This study was funded by an unrestricted grant from the Ontario Institute for Cancer Research.

CONFLICT OF INTEREST DISCLOSURES

Simron Singh reports grants, personal fees, and nonfinancial support from Novartis and personal fees from Pfizer outside the submitted work.