Symptom Burden at the End of Life for Neuroendocrine Tumors: An Analysis of 2579 Prospectively Collected Patient-Reported Outcomes



Given a slow course of disease, end-of-life issues are understudied in neuroendocrine tumors (NETs). To date, there are no data regarding symptoms at the end of life. This study examined symptom trajectories and factors associated with high symptom burden in NETs at the end of life.


We conducted a retrospective cohort study of NET patients diagnosed from 2004 to 2015 and who died between 2007 and 2016, in Ontario, Canada. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to administrative healthcare datasets. Moderate-to-severe symptom scores (≥ 4 out of 10) in the 6 months before death were analyzed, with multivariable modified Poisson regression identifying factors associated with moderate-to-severe symptoms scores.


Among 677 NET decedents, 2579 symptom assessments were recorded. Overall, moderate-to-severe scores were most common for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%), with these proportions increasing as death approached. For symptoms of lack of appetite, drowsiness, and shortness of breath, the increase was steepest in the 8 weeks before death. On multivariable analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months before death and for patients with shorter survival (< 6 months). Women had higher risks of anxiety, nausea, and pain.


A high prevalence of moderate-to-severe symptoms was observed for NETs at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptoms, this information is important to improve patient-centred and personalized supportive care for NETs at the end of life.

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  1. 1.

    Hallet J, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer. 2015;121:589–97.

    Article  PubMed  Google Scholar 

  2. 2.

    Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–42.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Singh S, Granberg D, Wolin E, Warner R, Sissons M, Kolarova T, et al. Patient-reported burden of a neuroendocrine tumor (NET) diagnosis: results from the first global survey of patients with NETs. J Glob Oncol. 2017;3:43–53.

    Article  PubMed  Google Scholar 

  4. 4.

    Feinberg Y, Law C, Singh S, Wright FC. Patient experiences of having a neuroendocrine tumour: a qualitative study. Eur J Oncol Nurs. 2013;17:541–5.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol. 2009;9:61–72.

    Article  CAS  Google Scholar 

  6. 6.

    Martini C, Gamper E-M, Wintner L, Nilica B, Sperner-Unterweger B, Holzner B, et al. Systematic review reveals lack of quality in reporting health-related quality of life in patients with gastroenteropancreatic neuroendocrine tumours. Health Qual Life Outcomes. 2016;14:1–18.

    Article  Google Scholar 

  7. 7.

    Beaumont JL, Cella D, Phan AT, Choi S, Liu Z, Yao JC. Comparison of health-related quality of life in patients with neuroendocrine tumors with quality of life in the general US population. Pancreas. 2012;41:461–6.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Haugland T, Vatn MH, Veenstra M, Wahl AK, Natvig GK. Health related quality of life in patients with neuroendocrine tumors compared with the general Norwegian population. Qual Life Res. 2009;18:719–26.

    Article  PubMed  Google Scholar 

  9. 9.

    Chau I, Casciano R, Willet J, Wang X, Yao JC. Quality of life, resource utilisation and health economics assessment in advanced neuroendocrine tumours: a systematic review. Eur J Cancer Care. 2013;22:714–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Jiménez-Fonseca P, Carmona-Bayonas A, Martín-Pérez E, Crespo G, Serrano R, Llanos M, et al. Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. Cancer Metastasis Rev. 2015;34:381–400.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Hallet J, Coburn NG, Singh S, Beyfuss KA, Koujanian S, Liu N, et al. Access to care and outcomes for neuroendocrine tumors: does socio-economic status matter? Curr Oncol. 2018;25(5):e356–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Pavel M, Gross DJ, Benavent M, Perros P, Srirajaskanthan R, Warner RRP, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer. 2018;25(3):309–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Anthony L, Ervin C, Lapuerta P, Kulke MH, Kunz P, Bergsland E, et al. Understanding the patient experience with carcinoid syndrome: exit interviews from a randomized, placebo-controlled study of telotristat ethyl. Clin Ther. 2017;39:2158–68.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Meng Y, McCarthy G, Berthon A, Dinet J. Patient-reported health state utilities in metastatic gastroenteropancreatic neuroendocrine tumours—an analysis based on the CLARINET study. Health Qual Life Outcomes. 2017;15:1–9.

    Article  Google Scholar 

  15. 15.

    Caplin M, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–33.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Rinke A, Müller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–63.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Lorenz K, Lynn J, Dy S, Hughes R, Mularski RA, Shugarman LR, et al. Cancer care quality measures: symptoms and end-of-life care. Evid Rep Technol Assess (Full Rep). 2006;(137):1–77.

    Google Scholar 

  18. 18.

    Benchimol EI, Smeeth L, Guttmann A, Harron K, Moher D, Petersen I, et al. The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement. PLoS Med. 2015;12:e1001885–22.

    Article  Google Scholar 

  19. 19.

    Iron K, Zagorski BM, Sykora K, Manuel DG: Living and dying in Ontario: an opportunity for improved health information. Toronto: ICES Investigative Report; 2008.

    Google Scholar 

  20. 20.

    Bubis LD, Davis L, Mahar A, Barbera L, Li Q, Moody L, et al. Symptom burden in the first year after cancer diagnosis: an analysis of patient-reported outcomes. J Clin Oncol. 2018;36:1103–11.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Barbera L, Seow H, Howell D, Sutradhar R, Earle C, Liu Y, et al. Symptom burden and performance status in a population-based cohort of ambulatory cancer patients. Cancer. 2010;116:5767–76.

    Article  PubMed  Google Scholar 

  22. 22.

    Government of Canada, Health Canada: Canada Health Act – Health Care System – Health Canada.

  23. 23.

    Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K. The Edmonton Symptom Assessment System (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care. 1991;7:6–9.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Nekolaichuk C, Watanabe S, Beaumont C. The Edmonton Symptom Assessment System: a 15-year retrospective review of validation studies (1991–2006). Palliat Med. 2008;22:111–22.

    Article  PubMed  Google Scholar 

  25. 25.

    Oldenmenger WH, de Raaf PJ, de Klerk C, van der Rijt CCD. Cut points on 0-10 numeric rating scales for symptoms included in the Edmonton Symptom Assessment Scale in cancer patients: a systematic review. J Pain Symptom Manag. 2013;45:1083–93.

    Article  PubMed  Google Scholar 

  26. 26.

    Selby D, Gardiner K, Do R, Myers J. A single set of numerical cutpoints to define moderate and severe symptoms for the Edmonton Symptom Assessment System. J Pain Symptom Manag. 2010;39:241–9.

    Article  PubMed  Google Scholar 

  27. 27.

    Du Plessis V, Beshiri R, Bollman R. Definitions of “rural”. Rural Small Town Canada Anal Bull. 2013;3:1–43.

    Google Scholar 

  28. 28.

    Alter DA, Naylor CD, Austin P, Tu JV. Effects of socioeconomic status on access to invasive cardiac procedures and on mortality after acute myocardial infarction. N Engl J Med. 1999;341:1359–67.

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Reid RJ, Roos NP, MacWilliam L, Frohlich N, Black C. Assessing population health care need using a claims-based ACG morbidity measure: a validation analysis in the Province of Manitoba. Health Serv Res. 2002;37:1345–64.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Reid RJ, MacWilliam L, Verhulst L, Roos N, Atkinson M. Performance of the ACG case-mix system in two Canadian provinces. Med Care. 2001;39:86–99.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Lipsitz SR, Kim K, Zhao L. Analysis of repeated categorical data using generalized estimating equations. Stat Med. 1994;13:1149–63.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Lorenz KA, Lynn J, Dy SM, Shugarman LR, Wilkinson A, Mularski RA, et al. Evidence for improving palliative care at the end of life: a systematic review. Ann Intern Med. 2008;148:147–59.

    Article  PubMed  Google Scholar 

  33. 33.

    Breitbart W, Rosenfeld B, Pessin H, Kaim M, Funesti-Esch J, Galietta M, et al. Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. JAMA. 2000;284:2907–11.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    Mystakidou K, Parpa E, Katsouda E, Galanos A, Vlahos L. Pain and desire for hastened death in terminally ill cancer patients. Cancer Nurs. 2005;28:318–24.

    Article  PubMed  Google Scholar 

  35. 35.

    Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD. Current status of gastrointestinal carcinoids. Gastroenterology. 2005;128:1717–51.

    Article  PubMed  Google Scholar 

  36. 36.

    Langton JM, Blanch B, Drew AK, Haas M, Ingham JM, Pearson S-A. Retrospective studies of end-of-life resource utilization and costs in cancer care using health administrative data: a systematic review. Palliat Med. 2014;28:1167–96.

    Article  PubMed  Google Scholar 

  37. 37.

    Cheung WY, Le LW, Gagliese L, Zimmermann C. Age and gender differences in symptom intensity and symptom clusters among patients with metastatic cancer. Support Care Cancer. 2011;19:417–23.

    Article  PubMed  Google Scholar 

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This study was supported by an unrestricted grant to the Sunnybrook Foundation by the NANETS Clinical Investigator Scholarship, Ipsen Biopharmaceuticals Canada, and the Sherif and Mary-Lou Hanna Chair in Surgical Oncology. The funding source had no role in the design, conduct, or interpretation of this study. This study was also supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by the 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 also based on data and information provided by 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.

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Correspondence to Julie Hallet MD, MSc.

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Hallet, J., Davis, L.E., Mahar, A.L. et al. Symptom Burden at the End of Life for Neuroendocrine Tumors: An Analysis of 2579 Prospectively Collected Patient-Reported Outcomes. Ann Surg Oncol 26, 2711–2721 (2019).

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