Metabolic Effects of Hormone Deprivation Therapy: Weighing the Evidence

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

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