Metabolic Effects of Hormone Deprivation Therapy: Weighing the Evidence

Publication
Article
OncologyONCOLOGY Vol 24 No 9
Volume 24
Issue 9

Adjuvant hormonal deprivation therapy is often administered long-term to patients with hormone receptor–positive cancers for primary prevention of breast cancer and secondary prevention of a recurrence.[1,2] This treatment modality is of particular importance to the elderly for two reasons: 1) the incidence of hormone-sensitive cancers (eg, prostate cancer and breast cancer) increases with age,[3] and 2) the systemic treatment regimens for elderly patients with hormone-responsive cancers are often limited to long-term hormonal deprivation therapy (HDT), most commonly androgen deprivation therapy for prostate cancer and aromatase inhibitor therapy for breast cancer, with chemotherapy often omitted.[2,4]

Adjuvant hormonal deprivation therapy is often administered long-term to patients with hormone receptor–positive cancers for primary prevention of breast cancer and secondary prevention of a recurrence.[1,2] This treatment modality is of particular importance to the elderly for two reasons: 1) the incidence of hormone-sensitive cancers (eg, prostate cancer and breast cancer) increases with age,[3] and 2) the systemic treatment regimens for elderly patients with hormone-responsive cancers are often limited to long-term hormonal deprivation therapy (HDT), most commonly androgen deprivation therapy for prostate cancer and aromatase inhibitor therapy for breast cancer, with chemotherapy often omitted.[2,4]

However, HDT is not a harmless intervention. Some of its adverse effects may be more immediate and reversible (eg, decreased quality of life, vasomotor instability, musculoskeletal discomfort, loss of libido, impotence, fatigue, anemia),[5,6] while others may be irreversible and may not become clinically apparent until years later. The best recognized long-term effect of HDT is the loss of bone mass, which predisposes to fractures and for which there are established clinical recommendations for surveillance, prevention, and treatment.[7] However, there is also an emerging recognition, as described in the article by Redig and Munshi, that HDT can induce subtle but significant metabolic changes that can increase cardiovascular risk.[8]

The association between HDT and cardiovascular morbidity/mortality and diabetes mellitus is strongest for androgen deprivation therapy, which may shorten life-expectancy; this association has prompted a science advisory by the American Heart Association and American Cancer Society.[9] Treatment of postmenopausal breast cancer with aromatase inhibitor therapy decreases endogenous, circulating estradiol by about 98%,[10] which may accelerate the onset of heart disease (this is particularly true of upfront therapy rather than therapy that follows 2 to 3 years of tamoxifen).[11,12] However, the relationship between aromatase inhibitor therapy and cardiovascular disease[13-18] has, to date, been less compelling than that for androgen deprivation therapy. The weak relationship may be attributed to the following: 1) the large trials were powered for breast cancer–related outcomes and not for cardiovascular morbidity/mortality; 2) pooling of data is difficult due to the varying definitions and methods that were used to identify and report cardiovascular events; 3) the use of tamoxifen, which is cardioprotective, as the comparison agent; and 4) the limitation of follow-up to no more than 100 months (about 8 years), which may be too short to detect slowly developing cardiovascular disease. Indeed, concern about the long-term safety of aromatase inhibitors requires further follow-up.[19] The need for such follow-up is now even more important because clinical trials such as NSABP B-42 are currently investigating the use of extended aromatase inhibitor adjuvant therapy for up to 10 years.

Paralleling these observations on the possible adverse metabolic effects of HDT, evidence is growing that patients with cancer may be overdiagnosed and overtreated. A recent review has calculated that, assuming the entire disease reservoir is detected, patients with prostate cancer aged 60 years and over have a probability of 87% to 94% of being overdiagnosed (ie, having a condition diagnosed that would otherwise not go on to cause symptoms or death), while patients with breast cancer aged 40 to 70 years have a probability of overdiagnosis of 43% to 90%.[20,21] One recent paper reported that adjuvant radiation therapy may not provide any survival benefit for patients with newly diagnosed breast cancer who are 70 years of age or over and who have undergone lumpectomy and received 5 years of tamoxifen therapy.[22] In addition, it has been suggested that androgen deprivation therapy may not provide any survival benefit in the majority of elderly men with localized prostate cancer compared with a conservative approach.[23]

Thus, the prescription of long-term adjuvant HDT may not always result in a positive benefit/risk ratio with regard to quality of life and life expectancy. It is therefore of great importance that we gain better insight into the wide spectrum of noncancerous effects associated with HDT and the predisposing, baseline characteristics of the patients for whom it is prescribed. The article by Redig and Munshi has framed the issue nicely. Physicians should be aware of the potential long-term effects of HDT, and future clinical trials should carefully analyze and quantify the cardiovascular, lipid, and metabolic consequences of anti-cancer therapy. The ability to better determine which adjuvant hormonal deprivation therapy modality-if any-will provide the optimal benefit/risk ratio will facilitate the much anticipated higher level of individualized prescribing of hormonal deprivation therapy.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Carlson RW, Allred DC, Anderson BO, et al: Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 7:122-192, 2009.

2. Mohler J, Bahnson RR, Boston B, et al: NCCN clinical practice guidelines in oncology: Prostate cancer. J Natl Compr Canc Netw 8:162-200, 2010.

3. Jemal A, Siegel R, Xu J, Ward E: Cancer Statistics, 2010. CA Cancer J Clin 2010 Jul 7. [Epub ahead of print]

4. Naeim A, Wong FL, Pal SK, Hurria A: Oncologists’ recommendations for adjuvant therapy in hormone receptor-positive breast cancer patients of varying age and health status. Clin Breast Cancer 10:136-143, 2010.

5. Saylor PJ, Keating NL, Smith MR: Prostate cancer survivorship: prevention and treatment of the adverse effects of androgen deprivation therapy. J Gen Intern Med 24(Suppl 2):S389-S394, 2009.

6. Files JA, Ko MG, Pruthi S: Managing aromatase inhibitors in breast cancer survivors: Not just for oncologists. Mayo Clin Proc 85:560-566; quiz 566, 2010.

7. Gralow JR, Biermann JS, Farooki A, et al: NCCN Task Force Report: Bone health in cancer care. J Natl Compr Canc Netw 7(Suppl 3):S1-S32; quiz S33-S35, 2009.

8. Alberti KGMM, Eckel RH, Grundy SM, et al: Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640-1645, 2009.

9. Levine GN, D’Amico AV, Berger P, et al: Androgen-deprivation therapy in prostate cancer and cardiovascular risk: A science advisory from the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 60:194-201, 2010.

10. Smith IE, Dowsett M: Aromatase inhibitors in breast cancer. N Engl J Med 348:2431-2442, 2003.

11. Mercuro G, Deidda M, Piras A, et al: Gender determinants of cardiovascular risk factors and diseases. J Cardiovasc Med (Hagerstown) 11:207-220, 2010.

12. Bairey Merz CN, Mark S, Boyan BD, et al: Proceedings from the scientific symposium: Sex differences in cardiovascular disease and implications for therapies. J Womens Health (Larchmt) 19:1059-1072, 2010.

13. Abdulhaq H, Geyer C: Safety of adjuvant endocrine therapy in postmenopausal women with breast cancer. Am J Clin Oncol 31:595-605, 2008.

14. Ewer MS, Gluck S: A woman’s heart: The impact of adjuvant endocrine therapy on cardiovascular health. Cancer 115:1813-1826, 2009.

15. Gandhi S, Verma S: Aromatase inhibitors and cardiac toxicity: Getting to the heart of the matter. Breast Cancer Res Treat 106:1-9, 2007.

16. Lewis S: Do endocrine treatments for breast cancer have a negative impact on lipid profiles and cardiovascular risk in postmenopausal women? Am Heart J 153:182-188, 2007.

17. Cuppone F, Bria E, Verma S, et al: Do adjuvant aromatase inhibitors increase the cardiovascular risk in postmenopausal women with early breast cancer? Meta-analysis of randomized trials. Cancer 112:260-267, 2008.

18. Perez EA: Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer. Ann Oncol 18(Suppl 8):viii26-viii35, 2007.

19. Seruga B, Tannock IF: Up-front use of aromatase inhibitors as adjuvant therapy for breast cancer: The emperor has no clothes. J Clin Oncol 27:840-842, 2009.

20. Welch HG, Black WC: Overdiagnosis in cancer. J Natl Cancer Inst 102:605-613, 2010.

21. Esserman L, Thompson I: Solving the overdiagnosis dilemma. J Natl Cancer Inst 102:582-583, 2010.

22. Hughes KS, Cirrincione C, Berry DA, et al: Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer. J Clin Oncol 28(Suppl; abstr 507):15s, 2010.

23. Lu-Yao GL, Albertsen PC, Moore DF, et al: Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA 300:173-181, 2008.

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