Advertisement

Breast Cancer Research and Treatment

, Volume 107, Issue 2, pp 167–180 | Cite as

Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy

  • David Cella
  • Lesley J. Fallowfield
Review

Abstract

In postmenopausal women with hormone receptor-positive early-stage breast cancer, the use of aromatase inhibitors (AIs) to suppress estrogen is associated with improved clinical outcomes compared with tamoxifen therapy. Women receiving such endocrine therapy may experience treatment-related side effects that negatively affect health-related quality of life (QoL) and adherence to therapy. In published clinical trials and in clinical practice, adverse events (AEs) constitute the main reason for nonadherence to endocrine treatment. Serious AEs are sometimes resolved by switching to a different agent, whereas other side effects can often be managed to allow patients to remain on therapy without sacrificing QoL. Across all adjuvant endocrine trials, regardless of the treatment received, vasomotor symptoms such as hot flashes are the most common side effects. Other frequently reported side effects, such as vaginal discharge, vaginal dryness, dyspareunia, and arthralgia, vary in prevalence between tamoxifen and AIs. Here we provide an overview of reported AEs of adjuvant endocrine therapy, focusing on those that are amenable to pharmacologic or nonpharmacologic management without treatment discontinuation. Also highlighted are specific management strategies that may improve patient QoL and thereby optimize adherence to therapy, which in turn might improve patient outcomes.

Keywords

Breast cancer Endocrine therapy Adverse events Aromatase Tamoxifen Quality of life Adherence 

References

  1. 1.
    ATAC Trialists’ Group (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early stage breast cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) randomised trial. Lancet 359:2131–2139CrossRefGoogle Scholar
  2. 2.
    Howell A, Cuzick J, Baum M et al (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62PubMedCrossRefGoogle Scholar
  3. 3.
    Thürlimann B, Keshaviah A, Coates AS et al, for the Breast International Group (BIG) 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757Google Scholar
  4. 4.
    Coombes RC, Hall E, Gibson LJ et al, for the Intergroup Exemestane Study (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092Google Scholar
  5. 5.
    Jakesz R, Jonat W, Gnant M et al, on behalf of the ABCSG and the GABG (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455–462Google Scholar
  6. 6.
    Boccardo F, Rubagotti A, Puntoni M et al (2005) Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole trial. J Clin Oncol 23:5138–5147PubMedCrossRefGoogle Scholar
  7. 7.
    Goss PE, Ingle JN, Martino S et al (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271PubMedGoogle Scholar
  8. 8.
    Jakesz R, Samonigg H, Greil R et al (2005) Extended adjuvant treatment with anastrozole: results from the Austrian Breast and Colorectal Cancer Study Group Trial 6a (ABCSG-6a). J Clin Oncol 23:526 (abstract)Google Scholar
  9. 9.
    Winer EP, Hudis C, Burstein HJ et al (2005) American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 23:619–629PubMedCrossRefGoogle Scholar
  10. 10.
    National Comprehensive Cancer Network (2005) Breast cancer: clinical practice guidelines in oncology – v.2.2005. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. Cited 14 June 2005
  11. 11.
    Whelan TJ, Pritchard KI (2006) Managing patients on endocrine therapy: focus on quality-of-life issues. Clin Cancer Res 12:1056s–1060sPubMedCrossRefGoogle Scholar
  12. 12.
    Partridge AH (2006) Non-adherence to endocrine therapy for breast cancer. Ann Oncol 17:183–184PubMedCrossRefGoogle Scholar
  13. 13.
    Partridge AH, Wang PS, Winer EP et al (2003) Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602–606PubMedCrossRefGoogle Scholar
  14. 14.
    Fallowfield L, Atkins L, Catt S et al (2006) Patients’ preference for administration of endocrine treatments by injection or tablets: results from a study of women with breast cancer. Ann Oncol 17:205–210PubMedCrossRefGoogle Scholar
  15. 15.
    Atkins L, Fallowfield L (2006) Intentional and non-intentional non-adherence to medication amongst breast cancer patients. Eur J Cancer 42:2271–2276PubMedCrossRefGoogle Scholar
  16. 16.
    Lash TL, Fox MP, Westrup JL et al (2006) Adherence to tamoxifen over the five-year course. Breast Cancer Res Treat 99:215–220PubMedCrossRefGoogle Scholar
  17. 17.
    Grunfeld EA, Hunter MS, Sikka P et al (2005) Adherence beliefs among breast cancer patients taking tamoxifen. Patient Educ Couns 59:97–102PubMedCrossRefGoogle Scholar
  18. 18.
    Wasan KM, Goss PE, Pritchard PH et al (2005) The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 16:707–715PubMedCrossRefGoogle Scholar
  19. 19.
    Sloan JA, Frost MH, Berzon R et al (2006) The clinical significance of quality of life assessments in oncology: a summary for clinicians. Support Care Cancer 14:988–998PubMedCrossRefGoogle Scholar
  20. 20.
    Fallowfield L, Cella D, Cuzick J et al (2004) Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant breast cancer trial. J Clin Oncol 22:4261–4271PubMedCrossRefGoogle Scholar
  21. 21.
    Cella D, Fallowfield L, on behalf of the ATAC Trialists’ Group (2005) Five-year quality of life (QOL) follow-up of adjuvant endocrine therapy for postmenopausal women in the arimidex (A), tamoxifen (T), alone or in combination (ATAC) trial. J Clin Oncol 23:577 (abstract)Google Scholar
  22. 22.
    Cella D, Fallowfield L, Barker P et al (2006) Quality of life of postmenopausal women in the ATAC (“Arimidex”, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer. Breast Cancer Res Treat 100:273–284PubMedCrossRefGoogle Scholar
  23. 23.
    Massacesi C, Zepponi L, Rocchi MB et al (2006) Tamoxifen-related endocrine symptoms in early breast cancer patients are relieved when it is switched to anastrozole. J Clin Oncol 24:10597 (abstract)Google Scholar
  24. 24.
    Fallowfield LJ, Bliss JM, Porter LS et al (2006) Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 24:910–917PubMedCrossRefGoogle Scholar
  25. 25.
    Whelan TJ, Goss PE, Ingle JN et al (2005) Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931–6940PubMedCrossRefGoogle Scholar
  26. 26.
    Fellowes D, Fallowfield LJ, Saunders CM et al (2001) Tolerability of hormone therapies for breast cancer: how informative are documented symptom profiles in medical notes for ‘well-tolerated’ treatments?. Breast Cancer Res Treat 66:73–81PubMedCrossRefGoogle Scholar
  27. 27.
    Coombes C, Bliss J, Hall E et al (2003) Under-reporting of symptoms in patients with early breast cancer (EBC) who have received tamoxifen treatment for 2–3 years. Proc Am Soc Clin Oncol 22:13 (abstract 48)Google Scholar
  28. 28.
    Fallowfield L, Cella D, on behalf of the ATAC Trialists’ Group (2002) Assessing the quality of life (QOL) of postmenopausal women randomized into the ATAC (‘arimidex’, tamoxifen, alone or in combination) adjuvant breast cancer trial. Poster presented at: American Society of Clinical Oncology 38th Annual Meeting; May 18–21, 2002; Orlando, FLGoogle Scholar
  29. 29.
    Buzdar A, Howell A, Cuzick J et al (2006) Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 7:633–643PubMedCrossRefGoogle Scholar
  30. 30.
    Morales L, Neven P, Paridaens R (2005) Choosing between an aromatase inhibitor and tamoxifen in the adjuvant setting. Curr Opin Oncol 17:559–565PubMedCrossRefGoogle Scholar
  31. 31.
    Powles TJ, Hickish T, Kanis JA et al (1996) Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78–84PubMedGoogle Scholar
  32. 32.
    Viale PH (2005) Aromatase inhibitor agents in breast cancer: evolving practices in hormonal therapy treatment. Oncol Nurs Forum 32:343–353PubMedCrossRefGoogle Scholar
  33. 33.
    Taylor M, Rastelli A, Civitelli R et al (2004) Incidence of 25-OH vitamin D deficiency in patients with a history of breast cancer who have musculoskeletal symptomatology. Abstract presented at the 27th Annual San Antonio Breast Cancer Symposium; December 8–11, 2004; San Antonio, TXGoogle Scholar
  34. 34.
    Thompson JN, Napoli N, Civitelli R et al (2006) Effects of dietary calcium vs. calcium supplements on estrogen metabolism and bone density. Osteoporos Int 17:S205 (abstract P696MO)Google Scholar
  35. 35.
    Rosen LS, Gordon DH, Dugan W Jr et al (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100:36–43PubMedCrossRefGoogle Scholar
  36. 36.
    Brufsky A (2006) Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: A Z-FAST update. Semin Oncol 33:S13–S17PubMedCrossRefGoogle Scholar
  37. 37.
    Anastrozole bisphosphonate study in postmenopausal women with hormone-receptor-positive early breast cancer. Available at: http://www.clinicaltrials.gov/ct/show/NCT00082277. Cited 10 October 2006
  38. 38.
    McClung MR (2006) Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies. Curr Osteoporos Rep 4:28–33PubMedCrossRefGoogle Scholar
  39. 39.
    Hamdy NAT (2005) Osteoprotegerin as a potential therapy for osteoporosis. Curr Osteoporos Rep 3:121–125PubMedCrossRefGoogle Scholar
  40. 40.
    Harrington L, Schneider JI (2006) Atraumatic joint and limb pain in the elderly. Emerg Med Clin N Am 24:389–412CrossRefGoogle Scholar
  41. 41.
    Sarzi-Puttini P, Atzeni F, Capsoni F et al (2005) Drug-induced lupus erythematosus. Autoimmunity 38:507–518PubMedCrossRefGoogle Scholar
  42. 42.
    Abu-Khalaf MM, Windsor S, Ebisu K et al (2005) Five-year update of an expanded phase II study of dose-dense and -intense doxorubicin, paclitaxel and cyclophosphamide (ATC) in high-risk breast cancer. Oncology 69:372–383PubMedCrossRefGoogle Scholar
  43. 43.
    Formenti SC, Volm M, Skinner KA et al (2003) Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial. J Clin Oncol 21:864–870PubMedCrossRefGoogle Scholar
  44. 44.
    Donnellan PP, Douglas SL, Cameron DA et al (2001) Aromatase inhibitors and arthralgia. J Clin Oncol 19:2767PubMedGoogle Scholar
  45. 45.
    McCloskey E (2006) Effects of third-generation aromatase inhibitors on bone. Eur J Cancer 42:1044–1051PubMedCrossRefGoogle Scholar
  46. 46.
    Felson DT, Cummings SR (2005) Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 52:2594–2598PubMedCrossRefGoogle Scholar
  47. 47.
    Plourde P, Locker G, Hoctin-Boes G et al (2005) Arthralgia in postmenopausal breast cancer patients on adjuvant endocrine therapy: a risk-benefit analysis. Poster presented at: 7th Annual Lynn Sage Breast Cancer Symposium; October 6–9 2005; Chicago, IllinoisGoogle Scholar
  48. 48.
    Mom CH, Buijs C, Willemse PHB et al (2006) Hot flushes in breast cancer patients. Crit Rev Oncol Hematol 57:63–77PubMedGoogle Scholar
  49. 49.
    Holmberg L, Anderson H, for the HABITS Steering, Data Monitoring Committees (2004) HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped. Lancet 363:453–455Google Scholar
  50. 50.
    Bertelli G, Venturini M, Del Mastro L et al (2002) Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol 13:883–888PubMedCrossRefGoogle Scholar
  51. 51.
    Barton DL, Loprinzi C, Atherton PJ et al (2006) Dehydroepiandrosterone for the treatment of hot flashes: a pilot study. Support Canc Ther 3:91–97Google Scholar
  52. 52.
    Loprinzi CL, Sloan JA, Perez EA et al (2002) Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol 20:1578–1583PubMedCrossRefGoogle Scholar
  53. 53.
    Stearns V, Isaacs C, Rowland J et al (2000) A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol 11:17–22PubMedCrossRefGoogle Scholar
  54. 54.
    Stearns V, Beebe KL, Iyengar M et al (2003) Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 289:2827–2834PubMedCrossRefGoogle Scholar
  55. 55.
    Loprinzi CL, Kugler JW, Sloan JA et al (2000) Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356:2059–2063PubMedCrossRefGoogle Scholar
  56. 56.
    Barton DL, Loprinzi CL, Novotny P et al (2003) Pilot evaluation of citalopram for the relief of hot flashes. J Support Oncol 1:47–51PubMedGoogle Scholar
  57. 57.
    Loprinzi CL, Levitt R, Barton D et al (2006) Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol 24:1409–1414PubMedCrossRefGoogle Scholar
  58. 58.
    Jin Y, Desta Z, Stearns V et al (2005) CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 97:30–39PubMedCrossRefGoogle Scholar
  59. 59.
    Stearns V, Johnson MD, Rae JM et al (2003) Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst 95:1758–1764PubMedGoogle Scholar
  60. 60.
    Pandya KJ, Morrow GR, Roscoe JA et al (2005) Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 366:818–824PubMedCrossRefGoogle Scholar
  61. 61.
    Filshie J, Bolton T, Browne D et al (2005) Acupuncture and self acupuncture for long term treatment of vasomotor symptoms in cancer patients—audit and treatment algorithm. Acupunct Med 23:171–180PubMedCrossRefGoogle Scholar
  62. 62.
    Goss PE, Ingle JN, Martino S et al (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802PubMedCrossRefGoogle Scholar
  63. 63.
    Schover LR (2005) Sexuality and fertility after cancer. Hematology (Am Soc Hematol Educ Program) 1:523–527Google Scholar
  64. 64.
    Kendall A, Dowsett M, Folkerd E et al (2006) Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 17:584–587PubMedCrossRefGoogle Scholar
  65. 65.
    Mok K, Mireskandari S, Juraskova I et al (2006) OVER (Olive oil Vaginal Exercises and Replens) Come. Psycho-Oncology 15:S332 (abstract 778)Google Scholar
  66. 66.
    Shifren JL, Braunstein GD, Simon JA et al (2000) Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 343:682–688PubMedCrossRefGoogle Scholar
  67. 67.
    Goldstat R, Briganti E, Tran J et al (2003) Transdermal testosterone therapy improves well-being, mood, and sexual function in premenopausal women. Menopause 10:390–398PubMedCrossRefGoogle Scholar
  68. 68.
    Mathias C, Cardeal MC, Ponde de SE et al (2006) An open-label, fixed-dose study of bupropion effect on sexual function scores in women treated for breast cancer. Ann Oncol 17:1792–1796PubMedCrossRefGoogle Scholar
  69. 69.
    Gregorian RS, Golden KA, Bahce A et al (2002) Antidepressant-induced sexual dysfunction. Ann Pharmacother 36:1577–1589PubMedCrossRefGoogle Scholar
  70. 70.
    Jansen CE, Miaskowski C, Dodd M et al (2005) Chemotherapy-induced cognitive impairment in women with breast cancer: a critique of the literature. Oncol Nurs Forum 32:329–342PubMedCrossRefGoogle Scholar
  71. 71.
    Jenkins V, Shilling V, Deutsch G et al (2006) A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer. Br J Cancer 94:828–834PubMedCrossRefGoogle Scholar
  72. 72.
    van Dam FS, Schagen SB, Muller MJ et al (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 90:210–218PubMedCrossRefGoogle Scholar
  73. 73.
    Castellon SA, Ganz PA, Bower JE et al (2004) Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 26:955–969PubMedCrossRefGoogle Scholar
  74. 74.
    Ahles TA, Saykin AJ (2002) Breast cancer chemotherapy-related cognitive dysfunction. Clin Breast Cancer 3(Suppl 3):S84–S90PubMedGoogle Scholar
  75. 75.
    Jenkins V, Shilling V, Fallowfield L et al (2004) Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psycho-Oncology 13:61–66PubMedCrossRefGoogle Scholar
  76. 76.
    Eberling JL, Wu C, Tong-Turnbeaugh R et al (2004) Estrogen- and tamoxifen-associated effects on brain structure and function. NeuroImage 21:364–371PubMedCrossRefGoogle Scholar
  77. 77.
    Ernst T, Chang L, Cooray D et al (2002) The effects of tamoxifen and estrogen on brain metabolism in elderly women. J Natl Cancer Inst 94:592–597PubMedGoogle Scholar
  78. 78.
    Ganz PA, Castellon SA, Silverman DH (2002) Estrogen, tamoxifen, and the brain. J Natl Cancer Inst 94:547–549PubMedGoogle Scholar
  79. 79.
    Cimprich B, So H, Ronis DL et al (2005) Pre-treatment factors related to cognitive functioning in women newly diagnosed with breast cancer. Psycho-Oncology 14:70–78PubMedCrossRefGoogle Scholar
  80. 80.
    Howell A, Cuzick J (2005) Vascular effects of aromatase inhibitors: data from clinical trials. J Steroid Biochem Mol Biol 95:143–149PubMedCrossRefGoogle Scholar
  81. 81.
    Cella D (2006) Quality of life and clinical decisions in chemotherapy-induced anemia. Oncology (Williston Park) 20:25–28Google Scholar
  82. 82.
    Leyland-Jones B, O’Shaughnessy JA (2003) Erythropoietin as a critical component of breast cancer therapy: survival, synergistic, and cognitive applications. Semin Oncol 30:174–184PubMedCrossRefGoogle Scholar
  83. 83.
    O’Shaughnessy JA, Vukelja SJ, Holmes FA et al (2005) Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. Clin Breast Cancer 5:439–446PubMedGoogle Scholar
  84. 84.
    Finelli PF, Carley MD (2000) Cerebral venous thrombosis associated with epoetin alfa therapy. Arch Neurol 57:260–262PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Center on Outcomes, Research and EducationNorthwestern University Feinberg School of MedicineEvanstonUSA
  2. 2.Cancer Research UK Psychosocial Oncology GroupBrighton & Sussex Medical SchoolFalmerUK

Personalised recommendations