How Do I Treat…?

Practical perspectives on cancer treatment by thought leaders, explaining how they would approach the treatment of a patient in their area of expertise.

Tuesday, October 4, 2011

ONLINE FIRST: CHARLES LOPRINZI: How Do I Treat Hot Flashes in Cancer Survivors?

Over the past two decades, we have become much better in understanding and treating cancer-related and treatment-related side effects. Leaders in the field of supportive care oncology have worked tirelessly to improve the quality of life of our patients with cancer by designing and conducting good clinical trials. Dr. Charles Loprinzi, a pioneer in this area of research, discusses his approach to the management of “hot flashes,” a common symptom among peri-menopausal women in general and among certain groups of cancer survivors.

--Ramaswamy Govindan, MD

OT Clinical Advisory Editor for Oncology 


BY Charles Loprinzi, MD


While hot flashes are common in women without a history of breast cancer, they are even more common in those who do have such a history. In part, this is because breast cancer survivors are given a variety of treatments that inhibit normal female hormonal function, including chemotherapy, ovarian ablation, or other anti-estrogen treatments such as tamoxifen or aromatase inhibitors. In addition, these patients are usually denied estrogen therapy, because of fears regarding breast cancer issues. 

In addition to hot flashes being quite bothersome during daytime hours, they, frequently, are more troublesome at night, due to night sweats with resultant sleep interruption. 


A number of non-hormonal agents decrease hot flashes, to a moderate degree.  Amongst the best studied class of drugs are serotonin plus/minus norepinephrine reuptake inhibitors, which have been studied in multiple double-blinded, placebo-controlled trials.  The most effective of these drugs are venlafaxine, desvenlafaxine, citalopram, and paroxetine. 


Cross study comparisons suggest that they equivalently diminish hot flashes, each appearing to be more effective than two other similar antidepressants, fluoxetine and sertraline.  Given the relatively equivalent efficacy of these four drugs, toxicity issues are important.  Citalopram appears to be one of the better tolerated of these effective antidepressants. 


Gabapentin and pregabalin, agents initially developed as anticonvulsants, appear to have efficacy similar to the above noted antidepressants.  Despite similar efficacy and the relatively similar degrees of toxicities between gabapentin/pregabalin and these antidepressants, my practice is to use newer antidepressants first.  This is largely based on randomized data from Bordeleau et al, whereby a comparison of venlafaxine with gabapentin led to patients preferring venlafaxine over gabapentin, by a 2:1 margin. 


Despite this preference, there were some patients who appeared to get better benefit and less toxicity from gabapentin, compared with what they experienced with venlafaxine. 


Given this, my practice has been to try a newer antidepressant first and then go with a gaba analog, if the newer antidepressant did not work well or quit working.  If this doesn’t work, there are anecdotal observations that support that switching to a different antidepressant will help hot flashes, when the first one does not.


Clonidine is another non-hormonal option that has been demonstrated to decrease hot flashes more than does a placebo.  My bias, however, is that it has a little less efficacy and a little more toxicity than the other agents discussed above. 


When non-hormonal agents do not appear to be effective, I, then, consider using a progesterone analog -- that being either a low oral dose of megestrol acetate (20-40 mg/day) or an intramuscular injection of medroxyprogesterone acetate (400-500 mg as a one-time dose), with my preference being the latter. 


While this dose of intramuscular medroxyprogesterone acetate might sound high to some, it is considerably lower than the doses that were commonly given to treat metastatic breast cancer, in the not-too-distant past.  With regards to reducing hot flashes, these drugs are more effective than are non-hormonal agents, as they decrease hot flashes to a similar degree as to what is seen with estrogen therapy. 


A single dose of intramuscular medroxyprogesterone acetate, associated with a half life of about six weeks, reduces hot flashes by about 80%, at 6 weeks.  While some patients do not require more than one dose, other patients desire a repeat dose, months following the first dose.


Prior to using these progesterone analog agents, I always discuss with my patients that their safety, with regard to breast cancer issues, has not been definitively determined.  While there is literature that suggests that progesterone analogs might be detrimental, regarding breast cancer, there is a similar amount of data supporting that they are safe, when used without concomitant estrogen. 


This is said, acknowledging that the combination of medroxyprogesterone acetate and estrogen does increase the incidence of breast cancer, as has been illustrated in Women’s Health Initiative trials.  This safety contention is supported by data that suggest that testosterone might protect against estrogen-caused breast cancer and that medroxyprogesterone acetate might prevent this testosterone-caused protective effect.


Thus, medroxyprogesterone acetate might be safe when given alone, but detrimental when given with estrogen.


On another note, there are good pilot data and smaller randomized trials supporting that hypnosis and/or paced respirations/yoga can decrease hot flashes, to a moderate degree.  However, these therapies have not yet been well-enough defined and/or studied to put them into mainstream clinical practice. 


Additionally there is pilot information, from three different sources, suggesting that stellate ganglion blocks can decrease hot flashes, moderately. 


On the other hand, despite considerable study, most of the randomized trials have not supported the use of soy products and/or acupuncture as effective treatments for hot flashes. 


Considerable data support that the treatments, which decrease hot flashes in breast cancer survivors, work equally well in women who do not have breast cancer.  Likewise, the treatments seem to work equally well whether or not patients are on tamoxifen.  Having said this, CYP 2D6 inhibitors (such as paroxetine) should be avoided in women on tamoxifen. 


Considerably more study has been performed in women with hot flashes, when compared with men with androgen-deprivation associated hot flashes.  Nonetheless, a randomized trial did demonstrate that gabapentin seems to work as well in men as it does in women. 


Likewise, medroxyprogesterone acetate and megestrol acetate work in men, as well as they do in women.  Pilot data suggest that newer antidepressants work for androgen-deprivation hot flashes, although good randomized, placebo-controlled trials have not yet been published regarding newer antidepressants for the treatment of hot flashes in men.


In total, the treatment of men with hot flashes is largely informed by treatments that appear to be effective in women, in a similar manner that the treatment of breast cancer in men is largely defined from data generated in women.




Charles Loprinzi, MD, is Regis Professor of Breast Cancer Research in the Division of Medical Oncology of the Mayo Clinic