This week, the American College of Obstetricians and Gynecologists (ACOG) endorsed the use of vaginal estrogen in breast cancer survivors to treat urogenital symptoms, if more conservative therapies have failed. Vaginal estrogen contains a black box warning, which tends to deter cancer survivors from its use, though the North American Menopause Society (NAMS) .
Given this multi-faceted issue, we contacted both breast cancer experts and OB/GYNs via email to ask:
When do you feel it is appropriate for breast cancer survivors to use vaginal estrogen?
Do the risks outweigh the benefits?
Do you think the black box warning for vaginal estrogen needs to be changed -- why or why not?
The participants this week are:
, surgeon with the Saul and Joy Brandman Breast Center and assistant professor of surgery at Cedars-Sinai in Los Angeles
, professor and chair, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus in Aurora
, assistant professor, medicine (Medical Oncology) at the Yale Cancer Center in New Haven, Conn.
, an OB/GYN at Farmington Hills Obstetrics and Gynecology, a part of Beaumont Health System, in Farmington Hills, Mich.
, an OB/GYN at Spectrum Health in Grand Rapids, Mich.
, clinical director, breast medical oncology and associate member, Comprehensive Breast Program at Moffitt Cancer Center in Tampa
Limited Research
Chung: The effects of hormone replacement in breast cancer survivors are not well studied in the medical literature, but the large randomized trial by the Women's Health Initiative provided solid scientific evidence that the combination of oral estrogen and progesterone caused an increased risk of breast cancer associated with the duration of hormone exposure. Because of the findings of the WHI study, there is hesitation in recommending hormone replacement therapy in breast cancer survivors, especially in patients who have had hormone-responsive tumors. Interestingly, estrogen alone without progesterone did not cause an increased risk of breast cancer in the WHI trial.
Santoro: The safety profile of this tiny amount of estrogen has never been tested in a large scale clinical trial, like the Women's Health initiative -- yet that is the only comparator that's out there. The FDA does not embrace this use of estrogen and also considers the only other FDA approved medication to treat vaginal atrophy symptoms, ospemifene, to be relatively contraindicated in the case of breast cancer. Yet -- there is no alternative. So what's a physician to do? It's not appropriate for a physician to turn his or her back on a patient's suffering and tell her there's nothing that can be done. Virtually every medication interaction involves a risk to benefit calculation. That's what doctors are trained to provide.
Nonhormonal Treatments First
Mougalian: Breast cancer treatment can have a number of effects related to decreased estrogen levels. For women with troublesome vaginal dryness, pain with sexual intercourse, or frequent urinary tract infections, I always start with nonhormonal approaches, such as vaginal moisturizers and lubricants, but for patients who do not respond to these interventions, I do think topical estrogen may be considered.
Horowitz: Due to the endocrine treatment of breast cancer, drugs such as tamoxifen and aromatase inhibitors, many women experience vaginal pain due to lack of estrogen. Nonhormonal treatments should be tried first. Moisturizers such as Replens can be used 1-3 times a week and lubricants, e.g., coconut oil, sesame oil, can be used safely during sexual activity. If this fails, then it is reasonable to use hormonal, low dose vaginal estrogen if certain criteria are met. First of all, there should always be a consultation with the patient's oncologist. There should also be a low risk of recurrence, no use of aromatase inhibitors and failed nonhormonal treatment -- as well as a discussion with the patient that there are no well-designed studies that evaluate this issue.
Bitner: Regarding the use of vaginal estrogen in breast cancer survivors, the effect on sexuality can be profound in that the loss of estrogen can cause pain with sex and affect a woman's ability to have satisfying sexual events and increases her likelihood to avoid sex and feel less like herself. After a physical exam and explaining why she is having her symptoms, I first offer nonhormonal treatments with lubricants and moisturizers. However, if these are not effective, I have a discussion about the risks ad benefits for the individual woman, and often recommend the use of low dose vaginal estrogen which is very effective in a short time. Many women feel they get their life back. The systemic absorption of vaginal estrogen is very low, below post menopause levels of estrogen and therefore we feel, while waiting for more research, that there is a low risk of increasing cancer recurrence.
Black Box Warning Necessary
Minton: Breast cancer survivors may consider the use of vaginal estrogens when they have debilitating symptoms impacting their quality of life and routine use of vaginal moisturizers is not alleviating the symptoms. Vagifem is recommended in low dose and used only intermittently twice weekly to limit the estrogen dosage to the blood stream. The black box warnings are meant to educate women about the potential risks of estrogen so that they can make informed decisions about usage.
Chung: Although vaginal estrogen is considered to be local therapy, systemic absorption of the drug can still potentially occurs. For these reasons, I feel that it is appropriate only for its use in breast cancer survivors in whom there is no other alternative to manage symptoms such as vaginal dryness, which can contribute to dyspareunia and bladder infections. I think it is still appropriate to exercise caution in the use of any form of hormone replacement therapy in women who have had breast cancer, since there is not enough medical literature to support its safety in this setting.
Mougalian: After a detailed discussion about the risk and benefits, including the theoretical risk of cancer recurrence, many patients decide that an improvement in quality of life is worth a theoretical increased risk of recurrence. Because a meaningful discussion between a woman and her oncologist is critical to informed decision-making in this regard, I think that the black box warning should remain in place.
Warning May Not Be Necessary
Bitner: The black box warning should be removed. I agree with everything presented to the FDA recently in order to get this removed. The risk factors of systemic and vaginal estrogen should not be compared and the warning causes undue concern on the level of the patient. I feel very comfortable prescribing the vaginal estrogen and feel comfortable the patient is understanding of the risks and benefits but then she gets home and reads the (inaccurate) warning on the label, and wonders if I know what I am doing and wonders why I misled her. She then does not use a well-established and safe therapy for a condition severely affecting the quality of her life.
Horowitz: Although the black box warnings on vaginal estrogen preparations are the same as systemic estrogen preparations, there is a difference in the levels of estrogen in the patient's system. Women who take low dosage vaginal estrogen have similar systemic estrogen levels as those who do not take estrogen. Initially, systemic levels will rise but as the vaginal tissue improves there is less systemic absorption. I feel it is a mistake to use the same label warnings on vaginal estrogen that is used on systemic estrogen. Ultimately, it is up to our patients to make the right decision for themselves.
Santoro: Do I think the black box warning on vaginal estrogen needs to be revised? You bet I do! I have personally petitioned for a change. The doses we are using to treat vaginal symptoms are about 1/10 the doses of hormone used in the Women's Health Initiative clinical trial. No progesterone/progestin is needed. This alters the risk/benefit equation but the reduced risk is difficult to measure without doing an enormous study, and that's unlikely to happen. Meanwhile, this becomes taxing clinically, because my patients get denials from their pharmacy for the medications, I have to write letters back and forth, and it becomes very frustrating.