Background: Although patients with neuroendocrine tumors (NETs) are known to have prolonged overall survival, the contribution of cancer-specific and noncancer deaths is undefined. This study examined cancer-specific and noncancer death after NET diagnosis. Methods: We conducted a population-based retrospective cohort study of adult patients with NETs from 2001 through 2015. Using competing risks methods, we estimated the cumulative incidence of cancer-specific and noncancer death and stratified by primary NET site and metastatic status. Subdistribution hazard models examined prognostic factors. Results: Among 8,607 included patients, median follow-up was 42 months (interquartile range, 17–82). Risk of cancer-specific death was higher than that of noncancer death, at 27.3% (95% CI, 26.3%–28.4%) and 5.6% (95% CI, 5.1%–6.1%), respectively, at 5 years. Cancer-specific deaths largely exceeded noncancer deaths in synchronous and metachronous metastatic NETs. Patterns varied by primary tumor site, with highest risks of cancer-specific death in bronchopulmonary and pancreatic NETs. For nonmetastatic gastric, small intestine, colonic, and rectal NETs, the risk of noncancer death exceeded that of cancer-specific deaths. Advancing age, higher material deprivation, and metastases were independently associated with higher hazards, and female sex and high comorbidity burden with lower hazards of cancer-specific death. Conclusions: Among all NETs, the risk of dying of cancer was higher than that of dying of other causes. Heterogeneity exists by primary NET site. Some patients with nonmetastatic NETs are more likely to die of noncancer causes than of cancer causes. This information is important for counseling, decision-making, and design of future trials. Cancer-specific mortality should be included in outcomes when assessing treatment strategies.
Submitted May 6, 2020; final revision received September 9, 2020; accepted for publication October 7, 2020. Published online June 4, 2021.
Previous presentation: Part of this work was presented as a poster presentation at the 2020 ASCO Virtual Scientific Program; May 29–31, 2020. Abstract 4605.
Author contributions:Study concept and design: Hallet, Law. Data abstraction: Hallet, Law, Mahar, Zuk, Zhao, Chan, Coburn. Data analysis and interpretation: All authors. Manuscript preparation: All authors. Critical revision: All authors.
Disclosures: Dr. Hallet and Dr. Law have reported receiving speaking honoraria from Ipsen Biopharmaceuticals Canada and Novartis Oncology, and travel support from the Baxter Corporation. Dr. Singh has reported receiving speaking honoraria from Ipsen Biopharmaceuticals Canada and Novartis Oncology, and research grants from Novartis Oncology and EMD Serono. Dr. Myrehaug has reported being the Principal Investigator on the NETTER-2 trial sponsored by AAA/Novartis. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). This work was supported by the NANETS New Clinical Investigator Scholarship and an operating grant from the Canadian Institute of Health Research (FRN #47301).
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 information compiled and provided by CIHI. However, the analyses, conclusions, opinions, and statements expressed herein are those of the author, 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 paper are those of the authors and do not necessarily reflect those of CCO. No endorsement by CCO is intended or should be inferred.
Correspondence: Julie Hallet, MD, MSc, Department of Surgery, Odette Cancer Centre – Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, T2-102, Toronto, Ontario M4N 3M5, Canada. Email: email@example.com
YaoJC, HassanM, PhanA, One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063–3072.1856589410.1200/JCO.2007.15.4377)| false
HalletJ, CukierM, SaskinR, LiuN. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015;121:589–597.2531276510.1002/cncr.29099)| false
DasariA, ShenC, HalperinD, Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:1335–1338.10.1001/jamaoncol.2017.058928448665)| false
YaoJC, FazioN, SinghS,
Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet2016;387:968–977.
YaoJC, FazioN, SinghS, Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387:968–977.10.1016/S0140-6736(15)00817-X26703889)| false
PowersBD, RothermelLD, FlemingJB,
A survival analysis of patients with localized, asymptomatic pancreatic neuroendocrine tumors: no surgical survival benefit when examining appropriately selected outcomes.J Gastrointest Surg2020;24:2773–2779
BenchimolEI, SmeethL, GuttmannA, The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLOS Med 2015;12:e1001885.2644080310.1371/journal.pmed.1001885)| false
IronZ, ZagorskiBM, SykoraK. Living and Dying in Ontario: An Opportunity for Improved Health Information. ICES Investigative Report. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences (ICES); 2008.
IronZ, ZagorskiBM, SykoraK. Living and Dying in Ontario: An Opportunity for Improved Health Information. ICES Investigative Report. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences (ICES); 2008.)| false
RoblesSC, MarrettLD, ClarkeEA, An application of capture-recapture methods to the estimation of completeness of cancer registration. J Clin Epidemiol 1988;41:495–501.10.1016/0895-4356(88)90052-23367181)| false
HalletJ, LawCHL, SaskinR, LiuN. Rural-urban disparities in incidence and outcomes of neuroendocrine tumors: a population-based analysis of 6271 cases. Cancer 2015;121:2214–2221.2582366710.1002/cncr.29338)| false
BrennerDR, TammemägiMC, BullSB,
Using cancer registry data: agreement in cause-of-death data between the Ontario Cancer Registry and a longitudinal study of breast cancer patients. Chronic Dis Can2009;30:16–19.
BrennerDR, TammemägiMC, BullSB, Using cancer registry data: agreement in cause-of-death data between the Ontario Cancer Registry and a longitudinal study of breast cancer patients. Chronic Dis Can 2009;30:16–19.)| false
KriegerN. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health 1992;82:703–710.10.2105/AJPH.82.5.7031566949)| false
ReidRJ, RoosNP, MacWilliamL,
Assessing population health care need using a claims-based ACG morbidity measure: a validation analysis in the Province of Manitoba. Health Serv Res2002;37:1345–1364.
ReidRJ, RoosNP, MacWilliamL, Assessing population health care need using a claims-based ACG morbidity measure: a validation analysis in the Province of Manitoba. Health Serv Res 2002;37:1345–1364.10.1111/1475-6773.01029)| false
WissingMD, GreenwaldZR, FrancoEL. Improving the reporting of cancer-specific mortality and survival in research using cancer registry data. Cancer Epidemiol 2019;59:232–235.10.1016/j.canep.2019.02.004)| false
ShenC, DasariA, ChuY,
Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors. Ann Oncol2017;28:1582–1589.
ShenC, DasariA, ChuY, Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors. Ann Oncol 2017;28:1582–1589.2844410510.1093/annonc/mdx164)| false
CitterioD, PuscedduS, FacciorussoA,
Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur J Surg Oncol2017;43:380–387.
BoothCM, LiG, Zhang-SalomonsJ, MackillopWJ. The impact of socioeconomic status on stage of cancer at diagnosis and survival: a population-based study in Ontario, Canada. Cancer 2010;116:4160–4167.2068101210.1002/cncr.25427)| false