More effective treatments needed to manage hot flashes in men with prostate cancer

Hot flashes are a very disturbing adverse effect of some treatments for breast cancer, but they also can affect men who undergo androgen deprivation treatment for prostate cancer.

Hot flashes — which affect up to 80% of men treated with ADT — manifest themselves by episodes of vasodilation, sweating and a sudden feeling of warmth. They can range in frequency from a few times per month to several times a day. Many men report hot flashes to be the most distressing adverse effect of prostate cancer treatment.

Vasomotor flushing is thought to be the result of dysregulation in the thermoregulatory center in the hypothalamus. These fluctuations, due to the sharp fall in testosterone levels, are mediated via the norepinephrine and serotonin neurotransmitters. This results in changes in the temperature set-point, which leads to periodic sweating and vasodilation as a way to lower body temperature.

Lisa Lohr

Agents from several pharmacologic classes have been proposed as treatments to reduce the severity and/or frequency of hot flashes. In many trials, there is a placebo response of about 20% to 30%. This may represent a natural improvement in symptoms with time or a true placebo response.

Hormonal treatments

Agents such as cyproterone, medroxyprogesterone, megestrol and estrogen have been proposed as treatments for hot flashes in men with prostate cancer.

Cyproterone has demonstrated the ability to relieve hot flashes, but concerns that it may interfere with prostate cancer treatment has limited its use. It is not available in the United States. Medroxyprogesterone has shown some positive effects, but use is somewhat limited by adverse effects.

Megestrol also has shown a dramatic effect in reducing hot flashes, but it appeared that patients’ PSA levels dropped when megestrol was discontinued, raising the concern that it might be interfering with the cancer treatment. Diethylstilbestrol has been shown to ameliorate hot flashes, but adverse effects include gynecomastia, as well as cardiovascular and thromboembolic complications.

Other agents

Several other agents have been evaluated as potential treatments:

Clonidine, a centrally acting alpha-agonist, has shown some activity in women but failed to show any advantage over placebo in men with prostate cancer.
Gabapentin, a GABA analogue, is useful for treating vasomotor symptoms in women, although the specific mechanism of action is not understood.

Gabapentin was evaluated in a randomized, placebo-controlled trial that included 214 men treated with ADT for prostate cancer. Researchers randomly assigned patients to one of four treatment groups: gabapentin 300 mg daily, gabapentin 300 mg twice daily, gabapentin 300 mg three times daily or placebo.

In the short-term randomized phase, the 300-mg, once-daily dose of gabapentin was no more effective than placebo for reduction of hot flash frequency and severity. Patients who received two or three doses of gabapentin each day demonstrated a much greater reduction in hot flash score.

In the continuation phase, in which the patients could titrate their gabapentin dose, most patients gravitated to a gabapentin dose of 300 mg twice daily. Gabapentin was well tolerated and may be an attractive choice to reduce hot flash burden.

Two classes of depression/anxiety medications, the selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs,) have shown some activity in reducing hot flashes in women. It is thought that these agents reduce hot flashes by modifying central nervous system dopaminergic activity.

Venlafaxine is a SSRI agent and has been investigated in a couple of studies in men receiving ADT for prostate cancer.

In one study, Irani and colleagues randomly assigned 311 men to one of three treatments: venlafaxine 75 mg daily, medroxyprogesterone acetate 20 mg daily or cyproterone acetate 100 mg daily. All treatments significantly reduced the mean hot flash scores, but researchers observed a greater reduction in scores in the cyproterone and medroxyprogesterone groups. All three treatments were fairly well tolerated, but more adverse effects were attributed to cyproterone than venlafaxine or medroxyprogesterone.

In another study, Vitolins and colleagues randomly assigned men to one of four treatment groups: venlafaxine 75 mg daily, soy protein (20 g daily), the combination of soy protein and venlafaxine, or placebo. Hot flash scores declined significantly in all four groups. Men treated with venlafaxine had perhaps a quicker reduction in hot flash score, but researchers observed no statistical difference in hot flash score between any of the groups by the end of the 12-week study period.

Acupuncture

Acupuncture has shown some efficacy in reducing hot flashes. This is thought to be mediated through effects on beta-endorphin and the stabilization of the thermoregulatory center.

A meta-analysis by Frisk and colleagues examined studies of acupuncture treatments for hot flashes in men with prostate cancer and women with breast cancer. Results showed acupuncture treatments lasting from 5 to 12 weeks led to an average 43% reduction in hot flashes. The benefit was long-lasting, as the duration of response was at least 3 months after the end of acupuncture treatments. These effects are comparable to other non-hormonal treatments for hot flashes, with very few adverse effects.

Conclusion

Hot flashes resulting from ADT can be an extremely bothersome adverse effect in men with prostate cancer.

Agents such as medroxyprogesterone, gabapentin, venlafaxine and acupuncture have shown some benefit in relieving hot flashes. However, treatments with more activity and fewer adverse effects are needed.

— Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist and oncology medication therapy management provider at the University of Minnesota Physicians Cancer Care at Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. She may be reached at the University of Minnesota Physicians Cancer Care at Fairview, 424 Harvard St. SE (MMC 114), Minneapolis, MN 55455.

Disclosure: Lohr reports no relevant financial disclosures.

References

Frisk JW. Support Care Cancer. 2014;22:1409-1415.
Irani J. Lancet Oncol. 2010;11:147-154.
Loprinzi CL. Ann Oncol. 2009;20:542-549.
Moraska AR. J Support Oncol. 2010;8:128-132.
Vitolins MZ. J Clin Oncol. 2013;31:4092-4098.