Quality of Life Research

, Volume 21, Issue 5, pp 765–775 | Cite as

Evaluating health-related quality-of-life therapeutic effectiveness in a clinical trial with extensive nonignorable missing data and heterogeneous response: results from a phase III randomized trial of gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer

  • Carol M. MoinpourEmail author
  • Gary W. Donaldson
  • Astra M. Liepa
  • Allen S. Melemed
  • Joyce O’Shaughnessy
  • Kathy S. Albain



This manuscript presents health-related quality of life (HRQL) results from a phase III trial of gemcitabine-paclitaxel (GT) versus paclitaxel (T) in metastatic breast cancer patients.


Patients completed the Rotterdam Symptom Checklist (RSCL) and Brief Pain Inventory (BPI) at baseline and at the end of each cycle. Sensitivity analyses for six longitudinal pattern mixture models (PMMs) assessed potential bias due to informative dropout. Cumulative probability plots with 50% confidence intervals indicated the proportion of patients whose HRQL was likely to improve, decline, or stay the same.


Sensitivity analyses addressing nonignorable missing RSCL data included 351 patients. The mean RSCL global HRQL score for GT was significantly and consistently better than that for T (all PMMs P < 0.040). The slope estimate of 1.5 points (100-point scale) per cycle from one PMM translated to a clinically significant 9-point improvement over six cycles with GT versus T. For GT, ~25% of patients were more likely than not to have improved HRQL, whereas that proportion for T was ~5%. PMMs showed no consistent treatment arm differences for BPI or other RSCL outcomes.


Adding gemcitabine to paclitaxel for the treatment of metastatic breast cancer is more likely to improve global HRQL over time compared to monotherapy treatment.


Gemcitabine Paclitaxel Quality of life Phase III study Breast cancer Missing data 



Brief Pain Inventory




Health-related quality of life


Missing not at random


Pattern mixture models


Rotterdam Symptom Checklist





The authors gratefully acknowledge the participation of the patients in this trial who completed questionnaires, the study personnel at participating institutions, and the investigators who enrolled patients on the trial. The authors also acknowledge Mary Dugan Wood, Lorinda Simms, Yun Ding, Pete Fairfield, Mark Blitzer, and Linda Massey for their assistance in preparing this manuscript. This research was funded by Eli Lilly and Company.


  1. 1.
    Bishop, J. F., Dewar, J., Toner, G. C., et al. (1999). Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. Journal of Clinical Oncology, 17(8), 2355–2364.PubMedGoogle Scholar
  2. 2.
    Jones, S. E., Erban, J., Overmoyer, B., et al. (2005). Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of Clinical Oncology, 23(24), 5542–5551.PubMedCrossRefGoogle Scholar
  3. 3.
    Hakamies-Blomqvist, L., Luoma, M., Sjöström, J., et al. (2000). Quality of life in patients with metastatic breast cancer receiving either docetaxel or sequential methotrexate and 5-fluorouracil. A multicentre randomised phase III trial by the Scandinavian breast group. European Journal of Cancer, 36(11), 1411–1417.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Shaughnessy, J., Miles, D., Vukelja, S., et al. (2002). Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. Journal of Clinical Oncology, 20(12), 2812–2823.PubMedCrossRefGoogle Scholar
  5. 5.
    Sledge, G. W., Neuberg, D., Bernardo, P., et al. (2003). Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). Journal of Clinical Oncology, 21(4), 588–592.PubMedCrossRefGoogle Scholar
  6. 6.
    Winer, E. P., Berry, D. A., Woolf, S., et al. (2004). Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and leukemia group B trial 9342. Journal of Clinical Oncology, 22(11), 2061–2068.PubMedCrossRefGoogle Scholar
  7. 7.
    Bernhard, J., Gusset, H., & Hürny, C. (1998). Practical issues in quality of life assessment in multicentre trials conducted by the Swiss group for clinical cancer research. Statistics in Medicine, 17(5/6/7), 633–639.PubMedCrossRefGoogle Scholar
  8. 8.
    Moinpour, C. M., Sawyers, T. J., McKnight, B., et al. (2000). Challenges posed by non-random missing quality of life data in an advanced-stage colorectal cancer clinical trial. Psycho-Oncology, 9(4), 340–354.PubMedCrossRefGoogle Scholar
  9. 9.
    Fairclough, D. L. (2010). Design and analysis of quality of life studies in clinical trials, 2nd ed. Interdisciplinary statistics. Boca Raton, FL: Chapman & Hall/CRC.CrossRefGoogle Scholar
  10. 10.
    Fayers, P. M., & Machin, D. (2000). Quality of life: Assessment, analysis, and interpretation. Chichester, United Kingdom: John Wiley & Sons Ltd.Google Scholar
  11. 11.
    Pauler, D. K., McCoy, S., & Moinpour, C. (2003). Pattern mixture models for longitudinal quality of life studies in advanced stage disease. Statistics in Medicine, 22(5), 795–809.PubMedCrossRefGoogle Scholar
  12. 12.
    Donaldson, G. W., & Moinpour, C. M. (2005). Learning to live with missing quality-of-life data in advanced-stage disease trials. Journal of Clinical Oncology, 23(30), 7380–7384.PubMedCrossRefGoogle Scholar
  13. 13.
    Nabholtz, J. M., Senn, H. J., Bezwoda, W. R., et al. (1999). Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. Journal of Clinical Oncology, 17(5), 1413–1424.PubMedGoogle Scholar
  14. 14.
    Kramer, J. A., Curran, D., Piccart, M., et al. (2000). Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. European Journal of Cancer, 36(12), 1488–1497.PubMedCrossRefGoogle Scholar
  15. 15.
    Nabholtz, J. M., Falkson, C., Campos, D., et al. (2003). Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. Journal of Clinical Oncology, 21(6), 968–975.PubMedCrossRefGoogle Scholar
  16. 16.
    O’Shaughnessy, J., Nag, S., & Calderillo-Ruiz, G., et al. (2003). Gemcitabine plus paclitaxel (GT) versus paclitaxel (T) as first-line treatment for anthracycline pre-treated metastatic breast cancer (MBC): Interim results of a global phase III study. Proceedings of the American Society of Clinical Oncology, 22(7s), 25.Google Scholar
  17. 17.
    Albain, K., Nag, S., & Calderillo-Ruiz, G., et al. (2004). Global phase III study of gemcitabine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): First report of overall survival. Journal of Clinical Oncology, 22(14s), 510.Google Scholar
  18. 18.
    Moinpour, C. M., Wu, J., & Donaldson, G. W., et al. (2004). Gemcitabine plus paclitaxel versus paclitaxel as first-line treatment for anthracycline pre-treated metastatic breast cancer: Quality-of-life and pain palliation results from the global phase III study. Journal of Clinical Oncology, 22(14s), 621.Google Scholar
  19. 19.
    Albain, K. S., Nag, S. M., Calderillo-Ruiz, G., et al. (2008). Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. Journal of Clinical Oncology, 26(24), 3950–3957.PubMedCrossRefGoogle Scholar
  20. 20.
    Hogan, J. W., & Laird, N. M. (1997). Mixture models for the joint distribution of repeated measures and event times. Statistics in Medicine, 16(3), 239–257.PubMedCrossRefGoogle Scholar
  21. 21.
    Hogan, J. W., & Laird, N. M. (1997). Model-based approaches to analysing incomplete longitudinal and failure time data. Statistics in Medicine, 16(3), 259–273.PubMedCrossRefGoogle Scholar
  22. 22.
    Nabholtz, J. M., Gelmon, K., Bontenbal, M., et al. (1996). Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. Journal of Clinical Oncology, 14(6), 1858–1867.PubMedGoogle Scholar
  23. 23.
    de Haes, J. C., van Knippenberg, F. C., & Neijt, J. P. (1990). Measuring psychological and physical distress in cancer patients: Structure and application of the Rotterdam symptom checklist. British Journal of Cancer, 62(6), 1034–1038.PubMedCrossRefGoogle Scholar
  24. 24.
    de Haes, J. C. J. M., Olschewski, M., Fayers, P., et al. (1996). Measuring the quality of life of cancer patients with the Rotterdam symptom checklist (RSCL). A Manual. Groningen, the Netherlands: Northern Centre for Healthcare Research, University of Groningen.Google Scholar
  25. 25.
    Cleeland, C. S., & Ryan, K. M. (1994). Pain assessment: Global use of the brief pain inventory. Annals of the Academy of Medicine, Singapore, 23(2), 129–138.PubMedGoogle Scholar
  26. 26.
    Hopwood, P., Howell, A., & Maguire, P. (1991). Screening for psychiatric morbidity in patients with advanced breast cancer: Validation of two self-report questionnaires. British Journal of Cancer, 64(2), 353–356.PubMedCrossRefGoogle Scholar
  27. 27.
    Ramirez, A. J., Towlson, K. E., Leaning, M. S., et al. (1998). Do patients with advanced breast cancer benefit from chemotherapy? British Journal of Cancer, 78(11), 1488–1494.PubMedCrossRefGoogle Scholar
  28. 28.
    Richards, M. A., Hopwood, P., Ramirez, A. J., et al. (1992). Doxorubicin in advanced breast cancer: Influence of schedule on response, survival and quality of life. European Journal of Cancer, 28(6–7), 1023–1028.CrossRefGoogle Scholar
  29. 29.
    Cleeland, C. S., Gonin, R., Hatfield, A. K., et al. (1994). Pain and its treatment in outpatients with metastatic cancer. New England Journal of Medicine, 330(9), 592–596.PubMedCrossRefGoogle Scholar
  30. 30.
    Twycross, R., Harcourt, J., & Bergl, S. (1996). A survey of pain in patients with advanced cancer. Journal of Pain and Symptom Management, 12(5), 273–282.PubMedCrossRefGoogle Scholar
  31. 31.
    Collins, C., Eary, J. F., Donaldson, G., et al. (1993). Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: A phase I/II trial. Journal of Nuclear Medicine, 34(11), 1839–1844.PubMedGoogle Scholar
  32. 32.
    Donaldson, G. W. (1989). The determining role of theory in measurement practice. In C. R. Chapman & J. D. Loeser (Eds.), Advances in pain research and therapy: Issues in pain measurement (Vol. 12, pp. 17–35). New York, NY: Raven Press.Google Scholar
  33. 33.
    Little, R. J. A. (1993). Pattern-mixture models for multivariate incomplete data. Journal of the American Statistical Association, 88(421), 125–134.CrossRefGoogle Scholar
  34. 34.
    Little, R. J. A. (1994). A class of pattern-mixture models for multivariate incomplete data. Biometrika, 81(3), 471–483.CrossRefGoogle Scholar
  35. 35.
    Hedeker, D., & Gibbons, R. D. (1997). Application of random-effects pattern-mixture models for missing data in longitudinal studies. Psychological Methods, 2(1), 64–78.CrossRefGoogle Scholar
  36. 36.
    Lin, H., McCulloch, C. E., & Rosenheck, R. A. (2004). Latent pattern mixture models for informative intermittent missing data in longitudinal studies. Biometrics, 60(2), 295–305.PubMedCrossRefGoogle Scholar
  37. 37.
    Cleveland, W. S. (1985). The elements of graphing data. Monterey, CA: Wadsworth.Google Scholar
  38. 38.
    Donaldson, G. (2008). Patient-reported outcomes and the mandate of measurement. Quality of Life Research, 17(10), 1303–1313.PubMedCrossRefGoogle Scholar
  39. 39.
    Donaldson, G. W., & Moinpour, C. M. (2002). Individual differences in quality of life treatment response. Medical Care, 40(6), III39–III53.Google Scholar
  40. 40.
    Littell, R. C., Milliken, G. A., Stroup, W. W., et al. (1996). SAS system for mixed models. Cary, NC: SAS Institute.Google Scholar
  41. 41.
    Moinpour, C. M., Donaldson, G. W., & Liepa, A. M., et al. (2007). Cumulative probability plots: A visual summary of patient benefit due to therapy. 2007 International Society for Quality of Life Research meeting abstracts []. The QLR Journal, A-9, Abstract #1583.
  42. 42.
    US Department of Health and Human Services, Food and Drug Administration. (Dec 2009). Guidance for industry. Patient-reported outcome measures: use in medical product development to support labeling claims.
  43. 43.
    Cohen, J. (1988). Statistical power analysis for behavioral sciences (2nd ed.). Hillsdale, NJ: Lawrence Erlbaum and Associates.Google Scholar
  44. 44.
    Osoba, D., Rodrigues, G., Myles, J., et al. (1998). Interpreting the significance of changes in health-related quality-of-life scores. Journal of Clinical Oncology, 16(1), 139–144.PubMedGoogle Scholar
  45. 45.
    Geels, P., Eisenhauer, E., Bezjak, A., et al. (2000). Palliative effect of chemotherapy: Objective tumor response is associated with symptom improvement in patients with metastatic breast cancer. Journal of Clinical Oncology, 18(12), 2395–2405.PubMedGoogle Scholar
  46. 46.
    Hopwood, P., Watkins, J., Ellis, P., et al. (2008). Clinical interpretation of quality-of-life outcomes: An investigation of data from the randomized trial of gemcitabine plus paclitaxel compared with paclitaxel alone for advanced breast cancer. The Breast Journal, 14(3), 228–235.PubMedCrossRefGoogle Scholar
  47. 47.
    Goodwin, P. J., Black, J. T., Bordeleau, L. J., et al. (2003). Health-related quality-of-life measurement in randomized clinical trials in breast cancer–taking stock. The Journal of the National Cancer Institute, 95(4), 263–281.CrossRefGoogle Scholar
  48. 48.
    Bottomley, A., & Therasse, P. (2002). Quality of life in patients undergoing systemic therapy for advanced breast cancer. The lancet Oncology, 3(10), 620–628.PubMedCrossRefGoogle Scholar
  49. 49.
    Bernhard, J., Cella, D. F., Coates, A. S., Fallowfield, L., Ganz, P. A., Moinpour, C. M., et al. (1998). Missing quality of life data in cancer clinical trials: Serious problems and challenges. Statistics in Medicine, 17(5–7), 517–532.PubMedCrossRefGoogle Scholar
  50. 50.
    Bernhard, J., & Gelber, R. D. [Guest Editors] (1998). Workshop on missing data in quality of life research in cancer clinical trials: Practical and methodological issues. Statistics in Medicine, 17(5–7), 511–796.Google Scholar
  51. 51.
    Singer, J. D., & Willett, J. B. (2003). Applied longitudinal data analysis: Modeling change and event occurrence. New York: Oxford University Press.Google Scholar
  52. 52.
    Little, R. J. A. (1995). Modeling the drop-out mechanism in repeated-measures studies. Journal of the American Statistical Association, 90(431), 1112–1121.Google Scholar
  53. 53.
    Rubin, D. B. (1976). Inference and missing data. Biometrika, 63(3), 581–592.CrossRefGoogle Scholar
  54. 54.
    Laird, N. M., & Ware, J. H. (1982). Random-effects models for longitudinal data. Biometrics, 38(4), 963–974.PubMedCrossRefGoogle Scholar
  55. 55.
    Troxel, A. B., Fairclough, D. L., Curran, D., & Hahn, E. A. (1998). Statistical analysis of quality of life with missing data in cancer clinical trials. Statistics in Medicine, 17(5–7), 653–666.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Carol M. Moinpour
    • 1
    Email author
  • Gary W. Donaldson
    • 1
    • 2
  • Astra M. Liepa
    • 3
  • Allen S. Melemed
    • 3
  • Joyce O’Shaughnessy
    • 4
  • Kathy S. Albain
    • 5
  1. 1.Fred Hutchinson Cancer Research Center/M3-C102SeattleUSA
  2. 2.University of UtahSalt Lake CityUSA
  3. 3.Eli Lilly and CompanyIndianapolisUSA
  4. 4.Baylor-Sammons Cancer CenterDallasUSA
  5. 5.Loyola University Chicago Medical CenterMaywoodUSA

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