Breast Cancer Research and Treatment

, Volume 139, Issue 2, pp 607–616 | Cite as

Cognitive function in older women with breast cancer treated with standard chemotherapy and capecitabine on Cancer and Leukemia Group B 49907

  • Rachel A. FreedmanEmail author
  • Brandelyn Pitcher
  • Nancy L. Keating
  • Karla V. Ballman
  • Jeanne Mandelblatt
  • Alice B. Kornblith
  • Gretchen G. Kimmick
  • Arti Hurria
  • Eric P. Winer
  • Clifford A. Hudis
  • Harvey Jay Cohen
  • Hyman B. Muss
  • for the Alliance for Clinical Trials in Oncology
Brief Report


Cognitive changes in older women receiving chemotherapy are poorly understood. We examined self-reported cognitive function for older women who received adjuvant chemotherapy on Cancer and Leukemia Group B (CALGB) 49907. CALGB 49907 randomized 633 women aged ≥65 with stage I–III breast cancer to standard adjuvant chemotherapy (cyclophosphamide–methotrexate–5-fluorouracil or doxorubicin–cyclophosphamide) versus capecitabine. We examined self-reported cognitive function in 297 women (CALGB 361002) who enrolled on the quality of life substudy and had no gross impairment on cognitive screening. Women were evaluated using an 18-item instrument at six time points (baseline through 24 months). At each time point for each patient, we calculated a cognitive function score (CFS) defined as the mean response of items 1–18 and defined impairment as a score >1.5 standard deviations above the overall average baseline score. Differences in scores by patient characteristics were evaluated using a Kruskal–Wallis test. A linear mixed-effects model was used to assess CFSs by treatment over time. Among 297 women, the median age was 71.5 (range 65–85) and 73 % had performance status of 0. Baseline depression and fatigue were reported in 6 and 14 % of patients, respectively. The average CFS at baseline was 2.08 (corresponding to “normal ability”), and baseline cognitive function did not differ by treatment regimen (p = 0.350). Over 24 months, women reported minimal changes at each time point and insignificant differences by treatment arm were observed. In a healthy group of older women, chemotherapy was not associated with longitudinal changes in self-reported cognitive function.


Cognitive function  Older women  Breast cancer  Age 



We thank all of the breast cancer patients who shared their experiences while participating in this study. We also thank Dr. Andrew Saykin for his guidance in using his cognitive function measure and Jacqueline Lafky for her administrative and logistical support. We acknowledge support from Celgene provided through the Cancer and Leukemia Group B Foundation Young Investigator Award [RF]. This research was also supported in part by the National Cancer Institute at the National Institutes of Health [Grant # U10 CA 84131, CA 127617, CA096940, and CA129769 to JSM] and by the National Institute on Aging at the National Institutes of Health [Grant #CA85850 to HM]. The research for CALGB 49907 was also supported, in part, by the National Cancer Institute at the National Institutes of Health [Grant # CA31946 to the Cancer and Leukemia Group B (Monica Bernagnoli, MD, Chairman) and Grant # CA33601 to the CALGB Statistical Center (Stephen George, PhD)].


The content of this manuscript is solely the responsibility of the authors and does not represent the official views of the National Cancer Institute at the National Institutes of Health or the Cancer and Leukemia Group B. Cancer and Leukemia Group B is presently part of the Alliance for Clinical Trials in Oncology. The sponsors had no role in the design, methods, subject recruitment, data collection, analysis, or preparation of this manuscript.

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Surveillance Epidemiology and End Results Cancer Statistics Review 1975–2006. Accessed 20 Dec 2009
  2. 2.
    Muss HB, Woolf S, Berry D, Cirrincione C, Weiss RB, Budman D, Wood WC, Henderson IC, Hudis C, Winer E et al (2005) Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293(9):1073–1081PubMedCrossRefGoogle Scholar
  3. 3.
    Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Goodwin JS (2006) Use and outcomes of adjuvant chemotherapy in older women with breast cancer. J Clin Oncol 24(18):2750–2756PubMedCrossRefGoogle Scholar
  4. 4. Accessed 2 Aug 2013
  5. 5.
  6. 6.
    Hutchinson AD, Hosking JR, Kichenadasse G, Mattiske JK, Wilson C (2012) Objective and subjective cognitive impairment following chemotherapy for cancer: a systematic review. Cancer Treat Rev 38(7):926–934Google Scholar
  7. 7.
    Vardy J, Rourke S, Tannock IF (2007) Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research. J Clin Oncol 25(17):2455–2463PubMedCrossRefGoogle Scholar
  8. 8.
    Vardy J, Tannock I (2007) Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol 63(3):183–202PubMedCrossRefGoogle Scholar
  9. 9.
    Fan HG, Houede-Tchen N, Yi QL, Chemerynsky I, Downie FP, Sabate K, Tannock IF (2005) Fatigue, menopausal symptoms, and cognitive function in women after adjuvant chemotherapy for breast cancer: 1- and 2-year follow-up of a prospective controlled study. J Clin Oncol 23(31):8025–8032PubMedCrossRefGoogle Scholar
  10. 10.
    van Dam FS, Schagen SB, Muller MJ, Boogerd W, vd Wall E, Droogleever Fortuyn ME, Rodenhuis S (1998) Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 90(3):210–218PubMedCrossRefGoogle Scholar
  11. 11.
    Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA (2004) The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 100(11):2292–2299PubMedCrossRefGoogle Scholar
  12. 12.
    Brezden CB, Phillips KA, Abdolell M, Bunston T, Tannock IF (2000) Cognitive function in breast cancer patients receiving adjuvant chemotherapy. J Clin Oncol 18(14):2695–2701PubMedGoogle Scholar
  13. 13.
    Tchen N, Juffs HG, Downie FP, Yi QL, Hu H, Chemerynsky I, Clemons M, Crump M, Goss PE, Warr D et al (2003) Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer. J Clin Oncol 21(22):4175–4183PubMedCrossRefGoogle Scholar
  14. 14.
    Schagen SB, Muller MJ, Boogerd W, Rosenbrand RM, van Rhijn D, Rodenhuis S, van Dam FS (2002) Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients. Ann Oncol 13(9):1387–1397PubMedCrossRefGoogle Scholar
  15. 15.
    Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE (2003) Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc 9(7):967–982PubMedCrossRefGoogle Scholar
  16. 16.
    McAllister TW, Ahles TA, Saykin AJ, Ferguson RJ, McDonald BC, Lewis LD, Flashman LA, Rhodes CH (2004) Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments. Curr Psychiatry Rep 6(5):364–371PubMedCrossRefGoogle Scholar
  17. 17.
    Ahles TA, Saykin AJ, Noll WW, Furstenberg CT, Guerin S, Cole B, Mott LA (2003) The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 12(6):612–619PubMedCrossRefGoogle Scholar
  18. 18.
    Ganz PA, Bower JE, Kwan L, Castellon SA, Silverman DH, Geist C, Breen EC, Irwin MR, Cole SW (2012) Does tumor necrosis factor-alpha (TNF-alpha) play a role in post-chemotherapy cerebral dysfunction? Brain Behav Immun suppl:S99–108Google Scholar
  19. 19.
    Cimprich B, Hayes DF, Askren MK, Jung MS, Berman MG, Ossher L, Therrien B, Reuter-Lorenz PA, Zhang M, Peltier S et al (2012) Neurocognitive impact in adjuvant chemotherapy for breast cancer linked to fatigue: a prospective MRI study. San Antonio Breast Cancer Symposium; Presented as oral abstract on December 7, 2012. Abstract #S6-3Google Scholar
  20. 20.
    Ahles TA, Saykin AJ, McDonald BC, Li Y, Furstenberg CT, Hanscom BS, Mulrooney TJ, Schwartz GN, Kaufman PA (2010) Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol 28(29):4434–4440PubMedCrossRefGoogle Scholar
  21. 21.
    Hurria A, Rosen C, Hudis C, Zuckerman E, Panageas KS, Lachs MS, Witmer M, van Gorp WG, Fornier M, D’Andrea G et al (2006) Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: a pilot prospective longitudinal study. J Am Geriatr Soc 54(6):925–931PubMedCrossRefGoogle Scholar
  22. 22.
    Hurria A, Goldfarb S, Rosen C, Holland J, Zuckerman E, Lachs MS, Witmer M, van Gorp WG, Fornier M, D’Andrea G et al (2006) Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient’s perspective. Breast Cancer Res Treat 98(3):343–348PubMedCrossRefGoogle Scholar
  23. 23.
    Downie FP, Mar Fan HG, Houede-Tchen N, Yi Q, Tannock IF (2006) Cognitive function, fatigue, and menopausal symptoms in breast cancer patients receiving adjuvant chemotherapy: evaluation with patient interview after formal assessment. Psychooncology 15(10):921–930PubMedCrossRefGoogle Scholar
  24. 24.
    Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER et al (2002) Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 20(2):485–493PubMedCrossRefGoogle Scholar
  25. 25.
    Schagen SB, van Dam FS, Muller MJ, Boogerd W, Lindeboom J, Bruning PF (1999) Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 85(3):640–650PubMedCrossRefGoogle Scholar
  26. 26.
    Phillips KA, Bernhard J (2003) Adjuvant breast cancer treatment and cognitive function: current knowledge and research directions. J Natl Cancer Inst 95(3):190–197PubMedCrossRefGoogle Scholar
  27. 27.
    Pullens MJ, De Vries J, Roukema JA (2010) Subjective cognitive dysfunction in breast cancer patients: a systematic review. Psychooncology 19(11):1127–1138PubMedCrossRefGoogle Scholar
  28. 28.
    Shaffer VA, Merkle EC, Fagerlin A, Griggs JJ, Langa KM, Iwashyna TJ (2012) Chemotherapy was not associated with cognitive decline in older adults with breast and colorectal cancer: findings from a prospective cohort study. Med Care 50(10):849–855Google Scholar
  29. 29.
    Yamada TH, Denburg NL, Beglinger LJ, Schultz SK (2010) Neuropsychological outcomes of older breast cancer survivors: cognitive features ten or more years after chemotherapy. J Neuropsychiatry Clin Neurosci 22(1):48–54PubMedCrossRefGoogle Scholar
  30. 30.
    Du XL, Xia R, Hardy D (2010) Relationship between chemotherapy use and cognitive impairments in older women with breast cancer: findings from a large population-based cohort. Am J Clin Oncol 33(6):533–543PubMedCrossRefGoogle Scholar
  31. 31.
    Jim HS, Phillips KM, Chait S, Faul LA, Popa MA, Lee YH, Hussin MG, Jacobsen PB, Small BJ (2012) Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 30(29):3578–3587PubMedCrossRefGoogle Scholar
  32. 32.
    Phillips KM, Jim HS, Small BJ, Laronga C, Andrykowski MA, Jacobsen PB (2012) Cognitive functioning after cancer treatment: a 3-year longitudinal comparison of breast cancer survivors treated with chemotherapy or radiation and noncancer controls. Cancer 118(7):1925–1932PubMedCrossRefGoogle Scholar
  33. 33.
    Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP et al (2009) Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360(20):2055–2065PubMedCrossRefGoogle Scholar
  34. 34.
    Kornblith AB, Lan L, Archer L, Partridge A, Kimmick G, Hudis C, Winer E, Casey R, Bennett S, Cohen HJ et al (2011) Quality of life of older patients with early-stage breast cancer receiving adjuvant chemotherapy: a companion study to cancer and leukemia group B 49907. J Clin Oncol 29(8):1022–1028PubMedCrossRefGoogle Scholar
  35. 35.
    Katzman R, Brown T, Fuld P, Peck A, Schechter R, Schimmel H (1983) Validation of a short orientation-memory-concentration test of cognitive impairment. Am J Psychiatry 140(6):734–739PubMedGoogle Scholar
  36. 36.
    Souder E, Saykin AJ, Alavi A (1995) Multi-modal assessment in Alzheimer’s disease. ADL in relation to PET, MRI and neuropsychology. J Gerontol Nurs 21(9):7–13PubMedGoogle Scholar
  37. 37.
    Saykin AJ, Janssen RS, Sprehn GC, Kaplan JE, Spira TJ, O’Connor B (1991) Longitudinal evaluation of neuropsychological function in homosexual men with HIV infection: 18-month follow-up. J Neuropsychiatry Clin Neurosci 3(3):286–298PubMedGoogle Scholar
  38. 38.
    George LK, Fillenbaum GG (1985) OARS methodology. A decade of experience in geriatric assessment. J Am Geriatr Soc 33(9):607–615PubMedGoogle Scholar
  39. 39.
    Fillenbaum GG, Smyer MA (1981) The development, validity, and reliability of the OARS multidimensional functional assessment questionnaire. J Gerontol 36(4):428–434PubMedCrossRefGoogle Scholar
  40. 40.
    Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC et al (1993) 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 85(5):365–376PubMedCrossRefGoogle Scholar
  41. 41.
    Sprangers MA, Cull A, Bjordal K, Groenvold M, Aaronson NK (1993) The European Organization for Research and Treatment of Cancer. Approach to quality of life assessment: guidelines for developing questionnaire modules. EORTC Study Group on Quality of Life. Qual Life Res 2(4):287–295PubMedCrossRefGoogle Scholar
  42. 42.
    Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67(6):361–370PubMedCrossRefGoogle Scholar
  43. 43.
    Cimprich B, Reuter-Lorenz P, Nelson J, Clark PM, Therrien B, Normolle D, Berman MG, Hayes DF, Noll DC, Peltier S et al (2010) Prechemotherapy alterations in brain function in women with breast cancer. J Clin Exp Neuropsychol 32(3):324–331PubMedCrossRefGoogle Scholar
  44. 44.
    Cimprich B, So H, Ronis DL, Trask C (2005) Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer. Psychooncology 14(1):70–78PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rachel A. Freedman
    • 1
    Email author
  • Brandelyn Pitcher
    • 2
  • Nancy L. Keating
    • 3
    • 4
  • Karla V. Ballman
    • 5
  • Jeanne Mandelblatt
    • 6
  • Alice B. Kornblith
    • 1
  • Gretchen G. Kimmick
    • 7
  • Arti Hurria
    • 8
    • 12
  • Eric P. Winer
    • 1
  • Clifford A. Hudis
    • 9
  • Harvey Jay Cohen
    • 10
  • Hyman B. Muss
    • 11
  • for the Alliance for Clinical Trials in Oncology
  1. 1.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Alliance Statistics and Data CenterDuke UniversityDurhamUSA
  3. 3.Department of Health Care PolicyHarvard Medical SchoolBostonUSA
  4. 4.Division of General Internal MedicineBrigham and Women’s HospitalBostonUSA
  5. 5.Alliance Statistics and Data CenterMayo ClinicRochesterUSA
  6. 6.Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  7. 7.Duke Medical OncologyDurhamUSA
  8. 8.Department of Medical Oncology & Therapeutics ResearchCity of HopeDuarteUSA
  9. 9.Department of Medical OncologyMemorial Sloan KetteringNew YorkUSA
  10. 10.Center for the Study of AgingDuke Medical OncologyDurhamUSA
  11. 11.Department of Medicine and Lineberger Comprehensive Cancer CenterUniversity of North CarolinaChapel HillUSA
  12. 12.Department of Population SciencesCity of HopeDuarteUSA

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