Management of Hot Flushes Due to Endocrine Therapy for Prostate Carcinoma

Quality of life of patients undergoing androgen deprivation isan issue that has received limited attention in the past but iscurrently being actively evaluated in clinical trials. This issuebecomes more important as patients with longer life expectancyand no metastatic disease are treated for longer durations.

The type and extent of potential long-term androgen deprivation-relatedside effects, such as osteoporosis and effects on muscle mass,heart, and lipids, are not clear. However, the association ofimpotence and hot flashes with the two leading modalities of androgendeprivation--bilateral orchiectomy and luteinizing hormone-re-leasing hormone (LHRH) agonists--is better documented. These sideeffects seem to be the most bothersome from the patient's perspective.While not a serious adverse effect, hot flashes, when severe,are annoying and interfere with quality of life, although theyrarely warrant discontinuation of therapy.

Dr. Smith provides a fair assessment of hot flashes and theirmanagement in patients undergoing androgen deprivation. The causeof vasomotor hot flashes is not entirely clear, but Dr. Smithdiscusses potential physiologic mechanisms.

Therapy of hot flashes is not always necessary and is dictatedby the severity of symptoms. As outlined in the article, varioustherapeutic interventions, both hormonal and nonhormonal, areavailable. However, therapy must be individualized, weighing therisks vs benefits of such treatment.

Hormonal Treatments

Of the available remedies, hormonal agents, such as estrogens,lowdose megestrol acetate, and cyproterone acetate, are reportedto be the most effective. Estrogens are associated with cardiovascularadverse effects, gynecomastia, and breast tenderness, however,and cyproterone acetate is not commercially available in thiscountry. Low-dose megestrol acetate could be offered as an effectivetreatment of hot flashes, although the possible effects of long-term,low-dose therapy with this agent on the course of prostate cancerand other biologic systems are unknown.[1]

In general, nonhormonal agents are not very effective.[1] In hormonallytreated breast cancer patients, the palliation of hot flasheshas not been limited to prescribed medications but also includesagents that might be viewed as "natural" remedies, suchas vitamin E, ginseng, and garlic tablets. Anecdotally, thesesubstances seem to afford some symptomatic relief in certain hormonallytreated prostate cancer patients.

Intermittent Androgen Deprivation?

Recent interest in improving the efficacy of hormone therapy whileenhancing quality of life has led to the clinical investigationof intermittent androgen deprivation. This involves, on average,8 to 10 months of treatment with an LHRH agonist plus an antiandrogento ensure a sustained suppression of prostate-specific antigen(PSA) to a nadir below the normal range, followed by an off-therapyperiod. The off-therapy period will last as long as the PSA doesnot rise above an arbitrarily determined level of 10 to 20 ng/mL.The cycle is then repeated.

Preclinical data suggest a therapeutic advantage of intermittentandrogen deprivation over continuous therapy. The potential forfull recovery from medical castration makes this approach feasible,as is suggested by the preliminary clinical data.[2] Serum testosteronereturns to the normal range within 8 weeks on average.[2] Thisgenerally results in an improvement in patients' sense of well-beingin addition to a marked reduction in or elimination of hot flashes.

The efficacy of intermittent androgen suppression relative tothe continuous approach is currently being investigated in patientswith newly diagnosed metastatic prostate cancer in a phase IIIrandomized intergroup trial (INT-0162 ). The intermittent approachis a very promising alternative to continuous androgen deprivation,particularly when long-term therapy is entertained, as it appearsto minimize such side effects as hot flashes. However, patientsmust be counseled about its investigational nature.

References:

1. Loprinzi CL, Michalak JC, Quella SK, et al: Megestrol acetatefor the prevention of hot flashes. N Engl J Med 331:347-352, 1994.

2. Goldenberg SL, Bruchovsky N, Gleave ME, et al: Intermittentandrogen suppression in the treatment of prostate cancer: A preliminaryreport. Urology 45:839-845, 1995.