Immunotherapy pp 165-182 | Cite as

Symptoms as Patient-Reported Outcomes in Cancer Patients Undergoing Immunotherapies

  • Tito R. MendozaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 995)


Cancer therapies are toxic. Newer oncological treatments such as immunotherapy produce unconventional adverse events that are collectively referred to as immune-related adverse events (irAEs). These irAEs are clinician-rated and typically reported via tabulation of adverse events from the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). However, the symptomatic effects of treatment and the severity of disease are best reported by the patient themselves. Although many pivotal trials for immunotherapeutic agents include health-related quality-of-life measures, symptom-focused assessments are more proximal to the effects of treatment and disease burden. This chapter discusses how best to measure symptoms, describes the desirable properties of a psychometrically valid symptom assessment tool, reviews available symptom assessment tools, provides methods to assist in the interpretation of PRO data, elucidates the feasibility and benefit of incorporating PRO in several cancer cohorts, describes the current use of PROs in immunotherapy, and identifies areas where further research are needed to enhance the use of PROs in cancer patients undergoing immunotherapy.


Patient-reported outcomes Symptoms Immunotherapy Cancer 


Conflicts of Interest

The author reports no conflict of interest in this work.


  1. 1.
    Patient-Reported Outcomes Measurement Information System. Welcome to PROMIS. Available from: Accessed 26 June 2018.
  2. 2.
    US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Center for Devices and Radiological Health. Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims. Available from: Accessed 26 June 2018.
  3. 3.
    Basch E, Reeve BB, Mitchell SA, Clauser SB, Minasian LM, Dueck AC, et al. Development of the National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J Natl Cancer Inst. 2014;106(9). pii: dju244.Google Scholar
  4. 4.
    de Haes JC. Quality of life: conceptual and theoretical considerations. In: Watson M, Greer S, Thomas C, editors. Psychosocial oncology. Oxford: Pergamon Press; 1988. p. 61–70.Google Scholar
  5. 5.
    Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I Conceptual framework and item selection. Med Care. 1992;30(6):473–83.CrossRefGoogle Scholar
  6. 6.
    Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy Scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570–9.CrossRefGoogle Scholar
  7. 7.
    Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365–76.CrossRefGoogle Scholar
  8. 8.
    Cleeland CS. Symptom burden: multiple symptoms and their impact as patient-reported outcomes. J Natl Cancer Inst Monogr. 2007;(37):16–21.Google Scholar
  9. 9.
    Crocker LM, Algina J. Introduction to classical and modern test theory. Pacific Grove: Wadsworth Publishing; 2006.Google Scholar
  10. 10.
    Litwin MS. How to measure survey reliability and validity, vol. 7: The survey kit. Thousand Oaks: Sage; 1995.CrossRefGoogle Scholar
  11. 11.
    Nunnally JC, Bernstein IH. Psychometric theory, vol. 3. New York: McGraw-Hill; 1994. McGraw-Hill Series in PsychologyGoogle Scholar
  12. 12.
    American Educational Research Association, American Psychological Association, National Council on Measurement in Education, Joint Committee on Standards for Educational and Psychological Testing. Standards for educational and psychological testing. 2nd ed. Washington, DC: American Educational Research Association; 1999.Google Scholar
  13. 13.
    Turner RR, Quittner AL, Parasuraman BM, Kallich JD, Cleeland CS. Patient-reported outcomes: instrument development and selection issues. Value Health. 2007;10(s2):S86–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Willis GB, Reeve BB, Barofsky I, Invited Paper C. The use of cognitive interviewing techniques in quality of life and patient-reported outcomes assessment. In: Lipscomb J, Gotay CC, Snyder C, editors. Outcomes assessment in cancer: measures, methods and applications. Cambridge: Cambridge University Press; 2004. p. 610–22.CrossRefGoogle Scholar
  15. 15.
    Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain. 2005;113(1–2):9–19.CrossRefGoogle Scholar
  16. 16.
    Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singap. 1994;23(2):129–38.PubMedGoogle Scholar
  17. 17.
    Cleeland CS. Measurement of pain by subjective report. In: Chapman CR, Loeser JD, editors. Issues in pain measurement, vol. 12: Advances in pain research and therapy. New York: Raven Press; 1989. p. 391–403.Google Scholar
  18. 18.
    Dworkin RH, Turk DC, Revicki DA, et al. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain. 2009;144(1–2):35–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 1999;85(5):1186–96.PubMedCrossRefGoogle Scholar
  20. 20.
    Lai JS, Crane PK, Cella D. Factor analysis techniques for assessing sufficient unidimensionality of cancer related fatigue. Qual Life Res. 2006;15(7):1179–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Okuyama T, Akechi T, Kugaya A, et al. Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients. J Pain Symptom Manage. 2000;19(1):5–14.PubMedCrossRefGoogle Scholar
  22. 22.
    Hann DM, Jacobsen PB, Azzarello LM, et al. Measurement of fatigue in cancer patients: development and validation of the Fatigue Symptom Inventory. Qual Life Res. 1998;7(4):301–10.PubMedCrossRefGoogle Scholar
  23. 23.
    Cella D. The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol. 1997;34(3 Suppl 2):13–9.PubMedGoogle Scholar
  24. 24.
    Lee KA, Hicks G, Nino-Murcia G. Validity and reliability of a scale to assess fatigue. Psychiatry Res. 1991;36(3):291–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Smets EM, Garssen B, Bonke B, de Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res. 1995;39(3):315–25.PubMedCrossRefGoogle Scholar
  26. 26.
    Piper BF, Dibble SL, Dodd MJ, Weiss MC, Slaughter RE, Paul SM. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum. 1998;25(4):677–84.PubMedGoogle Scholar
  27. 27.
    Schwartz AL. The Schwartz Cancer Fatigue Scale: testing reliability and validity. Oncol Nurs Forum. 1998;25(4):711–7.PubMedGoogle Scholar
  28. 28.
    Dueck AC, Mendoza TR, Mitchell SA, Reeve BB, Castro KM, Rogak LJ, et al. Validity and reliability of the US National Cancer Institute’s Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 2015;1(8):1051–9.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Basch E, Pugh SL, Dueck AC, Mitchell SA, Berk L, Fogh S, et al. Feasibility of patient reporting of symptomatic adverse events via the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial. Int J Radiat Oncol Biol Phys. 2017;98(2):409–18.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Cleeland CS, Mendoza TR, Wang XS, et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000;89(7):1634–46.CrossRefGoogle Scholar
  31. 31.
    de Haes JC, van Knippenberg FC, Neijt JP. Measuring psychological and physical distress in cancer patients: structure and application of the Rotterdam Symptom Checklist. Br J Cancer. 1990;62(6):1034–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    McCorkle R, Young K. Development of a symptom distress scale. Cancer Nurs. 1978;1(5):373-378.CrossRefGoogle Scholar
  33. 33.
    Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer. 1994;30A(9):1326–36.PubMedCrossRefGoogle Scholar
  34. 34.
    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(2):6–9.PubMedGoogle Scholar
  35. 35.
    Hoekstra J, Bindels PJ, van Duijn NP, Schadé E. The symptom monitor. A diary for monitoring physical symptoms for cancer patients in palliative care: feasibility, reliability and compliance. J Pain Symptom Manage. 2004;27(1):24–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol. 2008;61(2):102–9.CrossRefGoogle Scholar
  37. 37.
    Guyatt GH, Osoba D, Wu AW, Wyrwich KW, Norman GR. Methods to explain the clinical significance of health status measures. Mayo Clin Proc. 2002;77(4):371–83.PubMedCrossRefGoogle Scholar
  38. 38.
    Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care. 2003;41(5):582–92.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Sloan JA, Dueck A. Issues for statisticians in conducting analyses and translating results for quality of life end points in clinical trials. J Biopharm Stat. 2004;14(1):73–96.PubMedCrossRefGoogle Scholar
  40. 40.
    Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale: Lawrence Earlbaum; 1988.Google Scholar
  41. 41.
    Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol. 1999;52(9):861–73.CrossRefGoogle Scholar
  42. 42.
    Guyatt G, Walter S, Norman G. Measuring change over time: assessing the usefulness of evaluative instruments. J Chronic Dis. 1987;40(2):171–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain. 1995;61(2):277–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Zelman DC, Gore M, Dukes E, Tai KS, Brandenburg N. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manag. 2005;29(4):401–10.CrossRefGoogle Scholar
  45. 45.
    Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 2004;20(5):309–18.PubMedCrossRefGoogle Scholar
  46. 46.
    Cleeland CS, Portenoy RK, Rue M, et al. Does an oral analgesic protocol improve pain control for patients with cancer? An intergroup study coordinated by the Eastern Cooperative Oncology Group. Ann Oncol. 2005;16(6):972–80.PubMedCrossRefGoogle Scholar
  47. 47.
    Wong GY, Schroeder DR, Carns PE, et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. JAMA. 2004;291(9):1092–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang XS, Shi Q, Yue J, Chen TY, Xu T, Komaki R, et al. Predictive value of patient-reported outcomes on radiation pneumonitis related normal lung uptake of FDG on PET in patients with non-small cell lung cancer treated with concurrent chemoradiation [abstract 3015]. International Society for Quality of Life Research 23rd annual conference; Copenhagen, Denmark; Oct 19-22, 2016. Qual Life Res. 2016;25(Suppl 1):157–8.Google Scholar
  49. 49.
    Wang XS, Shi Q, Lu C, Basch EM, Johnson VE, Mendoza TR, et al. Prognostic value of symptom burden for overall survival in patients receiving chemotherapy for advanced nonsmall cell lung cancer. Cancer. 2010;116(1):137–45.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Barney BJ, Wang XS, Lu C, Liao Z, Johnson VE, Cleeland CS, et al. Prognostic value of patient-reported symptom interference in patients with late-stage lung cancer. Qual Life Res. 2013;22(8):2143–50. PMCID: PMC3724766.PubMedCrossRefGoogle Scholar
  51. 51.
    Williams LA, Giralt SA, Wang XS, Mobley GM, Mendoza TR, Cohen MZ, et al., editors. Measuring the symptom burden of allogeneic hematopoietic stem cell transplantation in patients with and without acute graft-versus-host disease [abstract 49]. Biol Blood Marrow Transplant. 2009;15(Suppl 2):20–1.Google Scholar
  52. 52.
    Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood. 2004;104(12):3501–6.PubMedCrossRefGoogle Scholar
  53. 53.
    Williams LA, Garcia Gonzalez AG, Ault P, Mendoza TR, Sailors ML, Williams JL, Huang F, Nazha A, Kantarjian HM, Cleeland CS, Cortes JE. Measuring the symptom burden associated with the treatment of chronic myeloid leukemia. Blood. 2013;122(5):641–7.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Rosenthal DI, Mendoza TR, Fuller CD, Hutcheson KA, Wang XS, Hanna EY, et al. Patterns of symptom burden during radiotherapy or concurrent chemoradiotherapy for head and neck cancer: a prospective analysis using The University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module. Cancer. 2014;120(13):1975–84.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Long GV, Atkinson V, Ascierto PA, Robert C, Hassel JC, Rutkowski P, et al. Effect of nivolumab on health-related quality of life in patients with treatment-naive advanced melanoma: results from the phase III CheckMate 066 study. Ann Oncol. 2016;27:1940–6.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Schadendorf D, Dummer R, Hauschild A, Robert C, Hamid O, Daud A, et al. Health-related quality of life in the randomised KEYNOTE-002 study of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory melanoma. Eur J Cancer. 2016;67:46–54.PubMedCrossRefGoogle Scholar
  57. 57.
    Bordoni R, Ciardiello F, von Pawel J, Cortinovis D, Karagiannis T, Ballinger M, Sandler A, Yu W, He P, Matheny C, Felizzi F, Rittmeyer A. Patient-reported outcomes in OAK: a phase III study of Atezolizumab versus Docetaxel in advanced non-small-cell lung cancer. Clin Lung Cancer. 2018. pii: S1525-7304(18)30131-1.
  58. 58.
    Basch E, Iasonos A, McDonough T, Barz A, Culkin A, Kris MG, et al. Patient versus clinician symptom reporting using the National Cancer Institute common terminology criteria for adverse events: results of a questionnaire-based study. Lancet Oncol. 2006;7:903–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Hong DS, Hui D, Bruera E, Janku F, Naing A, Falchook GS, Piha-Paul S, Wheler JJ, Fu SQ, Tsimberidou AM, Stecher M, Mohanty P, Simard J, Kurzrock R. MABp1, a first-in-class true human antibody targeting interleukin-1 alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study. Lancet Oncol. 2014;15:656–66.PubMedCrossRefGoogle Scholar
  60. 60.
    George GC, Iwuanyanwu EC, Anderson KO, Yusuf A, Zinner RG, Piha-Paul SA, et al. Sleep quality and its association with fatigue, symptom burden, and mood in patients with advanced cancer in a clinic for early-phase oncology clinical trials. Cancer. 2016;122:3401–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Mendoza TR, George G, Williams L, Shi Q, Naing A, Hong DS, et al, editors. Feasibility and added value of multiple baseline symptom assessments in early-phase clinical trials [abstract]. Presented at the International Society for Quality of Life Research (ISOQOL) 24th annual conference, Philadelphia; 2017.Google Scholar

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Symptom ResearchThe University of Texas MD Anderson Cancer CenterHoustonUSA

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