Risk of Cancer-Specific Death for Patients Diagnosed With Neuroendocrine Tumors: A Population-Based Analysis

Authors: Julie Hallet MD, MSc1,2,3,4, Calvin Law MD, MPH1,2,4, Simron Singh MD, MPH1,2,3,4, Alyson Mahar PhD5, Sten Myrehaug MD1,2,4, Victoria Zuk MSc4, Haoyu Zhao MPH3, Wing Chan MPH3, Angela Assal MD, MSc1,2, and Natalie Coburn MD, MPH1,2,3,4
View More View Less
  • 1 Faculty of Medicine, University of Toronto, Toronto, Ontario;
  • | 2 Susan Leslie Clinic for Neuroendocrine Tumors–Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario;
  • | 3 ICES, Toronto, Ontario;
  • | 4 Cancer Program–Clinical Evaluative Sciences, Sunnybrook Research Institute, Toronto, Ontario; and
  • | 5 Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Restricted access

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: julie.hallet@sunnybrook.ca

Supplementary Materials

    • Supplemental Materials (PDF 136 KB)
  • 1.

    National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts. Accessed August 21, 2019. Available at: https://seer.cancer.gov/statfacts/

    • Search Google Scholar
    • Export Citation
  • 2.

    Kunz PL . Understanding neuroendocrine tumors: a NET gain. JAMA Oncol 2017;3:13431344.

  • 3.

    Yao JC , Hassan M , Phan A , et al. 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;26:30633072.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Hallet J , Cukier M , Saskin R , Liu N . Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015;121:589597.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Dasari A , Shen C , Halperin D , et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 2017;3:13351338.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Yao JC , Fazio N , Singh S , et al. 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;387:968977.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Singh S , Moody L , Chan DL , et al. Follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. JAMA Oncol 2018;4:15971604.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Halperin DM , Shen C , Dasari A , et al. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol 2017;18:525534.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Pavel M , Gross DJ , Benavent M , et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer 2018;25:309322.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Hemingway H , Croft P , Perel P , et al. Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes. BMJ 2013;346:e5595.

  • 11.

    Ye H , Xu HL , Shen Q , et al. Palliative resection of primary tumor in metastatic nonfunctioning pancreatic neuroendocrine tumors. J Surg Res 2019;243:578587.

  • 12.

    Fraenkel M , Kim MK , Faggiano A , Valk GD . Epidemiology of gastroenteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol 2012;26:691703.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Powers BD , Rothermel LD , Fleming JB , et al. A survival analysis of patients with localized, asymptomatic pancreatic neuroendocrine tumors: no surgical survival benefit when examining appropriately selected outcomes. J Gastrointest Surg 2020;24:27732779

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Li Z , Du S , Feng W , et al. Competing risks and cause-specific mortality in patients with pancreatic neuroendocrine tumors. Eur J Gastroenterol Hepatol 2019;31:749755.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    He CB , Zhang Y , Cai ZY , et al. The impact of surgery in metastatic pancreatic neuroendocrine tumors: a competing risk analysis. Endocr Connect 2019;8:239251.

  • 16.

    Benchimol EI , Smeeth L , Guttmann A , et al. The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLOS Med 2015;12:e1001885.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Iron Z , Zagorski BM , Sykora K . Living and Dying in Ontario: An Opportunity for Improved Health Information. ICES Investigative Report. Toronto, Ontario, Canada: Institute for Clinical Evaluative Sciences (ICES); 2008.

    • Search Google Scholar
    • Export Citation
  • 18.

    Clarke EA , Marrett LD , Kreiger N . Cancer registration in Ontario: a computer approach. IARC Sci Publ 1991;(95):246257.

  • 19.

    Robles SC , Marrett LD , Clarke EA , et al. An application of capture-recapture methods to the estimation of completeness of cancer registration. J Clin Epidemiol 1988;41:495501.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Government of Canada. Canada Health Act. Accessed August 21, 2019. Available at: https://www.canada.ca/en/health-canada/services/health-care-system/canada-health-care-system-medicare/canada-health-act.html

  • 21.

    Hallet J , Law CHL , Saskin R , Liu N . Rural-urban disparities in incidence and outcomes of neuroendocrine tumors: a population-based analysis of 6271 cases. Cancer 2015;121:22142221.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Brenner DR , Tammemägi MC , Bull SB , et al. 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;30:1619.

    • Search Google Scholar
    • Export Citation
  • 23.

    Afifi AM , Saad AM , Al-Husseini MJ , et al. Causes of death after breast cancer diagnosis: a US population-based analysis. Cancer 2020;126:15591567.

  • 24.

    Karlj B . Measuring “rurality” for purposes of health-care planning: an empirical measure for Ontario. Ont Med Rev 2009;33:52.

  • 25.

    Krieger N . Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health 1992;82:703710.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Matheson FI , Dunn JR , Smith KLW , et al. Development of the Canadian Marginalization Index: a new tool for the study of inequality. Can J Pub Health 2012;103:S1216.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Reid RJ , Roos NP , MacWilliam L , et al. Assessing population health care need using a claims-based ACG morbidity measure: a validation analysis in the Province of Manitoba. Health Serv Res 2002;37:13451364.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Reid RJ , MacWilliam L , Verhulst L , et al. Performance of the ACG case-mix system in two Canadian provinces. Med Care 2001;39:8699.

  • 29.

    Weiner JP , Starfield BH , Steinwachs DM , et al. Development and application of a population-oriented measure of ambulatory care case-mix. Med Care 1991;29:452472.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Austin PC , Lee DS , Fine JP . Introduction to the analysis of survival data in the presence of competing risks. Circulation 2016;133:601609.

  • 31.

    Austin PC , Fine JP . Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med 2017;36:43914400.

  • 32.

    Hallet J , Coburn NG , Singh S , et al. Access to care and outcomes for neuroendocrine tumours: does socioeconomic status matter? Curr Oncol 2018;25:e356364.

  • 33.

    Wissing MD , Greenwald ZR , Franco EL . Improving the reporting of cancer-specific mortality and survival in research using cancer registry data. Cancer Epidemiol 2019;59:232235.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Shen C , Dasari A , Chu Y , et al. Clinical, pathological, and demographic factors associated with development of recurrences after surgical resection in elderly patients with neuroendocrine tumors. Ann Oncol 2017;28:15821589.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Putter H , Fiocco M , Geskus RB . Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007;26:23892430.

  • 36.

    Citterio D , Pusceddu S , Facciorusso A , et al. Primary tumour resection may improve survival in functional well-differentiated neuroendocrine tumours metastatic to the liver. Eur J Surg Oncol 2017;43:380387.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Daskalakis K , Karakatsanis A , Stålberg P , et al. Clinical signs of fibrosis in small intestinal neuroendocrine tumours. Br J Surg 2016;104:6975.

  • 38.

    Townsley CA , Selby R , Siu LL . Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol 2005;23:31123124.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Hurria A , Dale W , Mooney M , et al. Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol 2014;32:25872594.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Booth CM , Li G , Zhang-Salomons J , Mackillop WJ . The impact of socioeconomic status on stage of cancer at diagnosis and survival: a population-based study in Ontario, Canada. Cancer 2010;116:41604167.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Woods LM , Rachet B , Coleman MP . Origins of socio-economic inequalities in cancer survival: a review. Ann Oncol 2006;17:519.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1014 1014 978
PDF Downloads 556 556 534
EPUB Downloads 0 0 0