Hi. My name is Dr Michelle Melisko and I’m a medical oncologist at the University of California San Francisco. I am here today to talk about the management of vaginal dryness and urogenital atrophy in patients with breast cancer.
I’ve had a long interest in symptom management issues related to estrogen deprivation in patients with breast cancer. I have had a personal interest in trying to help women be able to continue to enjoy having a sexual relationship, or even managing urogenital symptoms like frequent urination. This has resulted in a number of clinical trials.
Dating back to the early 2000s in the treatment of breast cancer, many, many oncologists were very frightened of using any form of vaginal estrogens for the treatment of vaginal dryness and urogenital atrophy. The initial studies that looked at dealing with this problem tended to use non-estrogenic products, including vaginal moisturizers, such as RepHresh, Replens, or HYALO GYN. These were somewhat beneficial.
I always tend to tell my patients that, as they age, women are very, very focused on buying expensive cosmetic products to put on their face, but they don’t necessarily pay attention to needing to moisturize other areas of their body as much.
Certainly, the first step in management of urogenital atrophy is often the use of topical over-the-counter products. Some other suppositories and different moisturizers, at various price points, can be very, very beneficial.
People have wondered whether the use of vaginal estrogens would be safe, dating back to around the year 2006 when there was a study done in a very, very small number of patients with breast cancer using the vaginal estradiol tablet at a dose of 10 micrograms. In that study, it was seen that there was an increase in systemic estrogen that led to a significant concern about the use of vaginal estrogens.
However, that initial study with the vaginal estrogen tablet was using 25 micrograms, and that dose has subsequently been discontinued, and now the products on the market are 4 and 10 microgram tablets. Since that time, there have been several studies looking at the lower dose of the 10-microgram estrogen tablet, and have seen very little increase in systemic absorption, making it a more acceptable option for patients with breast cancer.
There have also been studies looking at topical testosterone, including various versions of creams and patches. In several of these studies, it did actually show improvements in sexual functioning without rises in estradiol or testosterone levels. However, these studies were dating back to the early 2000s, 2011, and 2014. The collection of the estrogen levels were not quite as rigid as in some of the other studies.
We at UCSF did a study looking at and comparing a compounded testosterone cream to the vaginal estrogen ring, Estring. We actually found no sustained elevations of estradiol with the use of the Estring. However, with the testosterone cream, we did see some elevations, and that largely had to do with a quite high dose of vaginal testosterone that was being used. All of these agents — the Vagifem insert, the Estring, and the testosterone cream — do seem to have both subjective and objective benefits in terms of improving vaginal dryness.
Even with these small studies showing no significant elevation in serum estrogen levels with the Estring or the Vagifem tablets, there were still medical oncologists who were very wary of using vaginal estrogens. It wasn’t until there were a number of large epidemiologic studies that looked at patients who’d been dispensed vaginal estrogens, and those with a history of breast cancer.
There are now at least three or four studies that have shown that the use of vaginal estrogens, ironically, was associated not even with a worse outcome, but in fact overall mortality improvement in patients using these products.
Now, obviously these aren’t randomized trials. These are epidemiologic studies that probably do have some selection bias that women who are interested in using these products may be healthier, may be more interested, obviously interested in having an active sex life. There may be biases that would explain why women do better when they are using these products.
There was concern about one Danish study. That was, again, a retrospective analysis from a national prescription registry that showed, like the other studies, that there was improvement in mortality in women using vaginal estrogens. But they did see a slight increase in the relative risk of recurrence in the subset of women receiving adjuvant aromatase inhibitors.
Now, there were a number of issues around this study, but I think it is important for oncologists prescribing these medications to be aware in case a patient comes back to them and actually mentions that they read somewhere that the use of vaginal estrogens could increase recurrence because this was just one of three or four epidemiology studies and the others have not shown this finding.
Other than the vaginal estrogens, another product that was studied was DHEA (dehydroepiandrosterone), which was studied in a randomized, very well designed clinical trial by the NCCTG (North Central Cancer Treatment Group). Interestingly, the DHEA was tested at two different doses and there was no improvement in vaginal dryness or dyspareunia. However, women on the higher dose did report significantly better sexual health. That’s quite interesting because we usually tell patients that, in order to improve their sex life, the first thing we need to do is to get rid of the vaginal dryness and pain.
One of the bigger challenges though, for patients, even once we can take care of the atrophy and the dryness, is that some women still suffer from a low sexual desire, and this remains quite a challenge for us. There have been a number of studies looking at the antidepressant bupropion. One small study did show an improvement in sexual functioning. However, this study was not replicated and it was a nonrandomized trial. Again, there’s always this placebo effect of patients wanting to be hopeful that something will be helping them.
There are very little data on the use of agents like Viagra in patients with breast cancer. In fact, it suggests that these agents may not be very beneficial for women, in the data that do exist.
However, the last drug that we are somewhat excited about that is actually approved for premenopausal women with hypoactive sexual desire disorder is a drug called flibanserin, or the brand name Addyi. This is an interesting agent because it acts centrally to reduce serotonin, so it may have the opposite effect where serotonin reuptake inhibitors may suppress sexual function, this drug actually acts to increase serotonin.
Unfortunately, there are limited data in patients with breast cancer, but there has been a small study conducted by the group at Memorial Sloan Kettering showing some benefit in patients with breast cancer, and we are hoping that a larger study will be done that can show some benefit for this agent.
One of the challenges with this agent is that it needs to be taken every night, whether a patient is sexually active or not, and it can be associated with some side effects such as dizziness and sleepiness. There’s also a contraindication to taking it with alcohol.
Therefore, we still have a great need in this space to come up with better drugs that have fewer side effects. Looking ahead, this is an area of significant research. There are certainly behavioral aspects of the sexual response that are not as well understood for women, and I surely hope that we’ll continue to make progress in this area.
Once again, many women who are already taking a number of medications for their breast cancer are not interested in taking another medication to deal with a side effect. Some women are interested in looking at other options that might be nonpharmacologic to manage their vaginal dryness, and that has led to an explosion of interest in vaginal laser therapy for the treatment of urogenital atrophy.
There are, sad to say, very few randomized clinical trials that include patients with breast cancer to show any substantial benefit. There are a number of trials in women who are postmenopausal without a history of breast cancer, and one small study, looking at a microablative CO2 laser therapy called the MonaLisa Touch. This did actually show an improvement in sexual quality of life, but this was a relatively small study of 67 patients and certainly does need to be repeated.
Once again, the NCCTG and other cooperative groups are trying to get a study off the ground looking at this in a more systematic way. However, at this moment, most of the use of lasers are being supported and promoted by community practice gynecologists, and it is for cash payment only. There’s no insurance coverage. I do not discourage my patients from trying this, although I do explain to them that there is very little supportive data for this product, and in fact, very little control of the safety of this procedure, which does lead me to have some concern.
I look forward to having new interventions and new treatments with fewer side effects. Thank you for listening to this topic.
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