Breast cancer specialists from one of the UK's leading cancer centers cautioned doctors of the risks in prescribing vaginal estrogen to breast cancer patients being treated with three new aromatase inhibiting drugs: anastrozole, letrozole and exemestane.
Their concerns follow findings from the first study to examine the impact of vaginal estrogen in women receiving aromatase inhibitors (AIs) for breast cancer, published in the journal Annals of Oncology, by a team from the Royal Marsden NHS Foundation Trust in London.
AIs work by inhibiting the enzyme aromatase, which promotes the conversion of androgens to estrogens in postmenopausal women. Breast cancer feeds off estrogen, so reducing the circulating levels of the hormone as much as possible lessens the chance of the cancer recurring. The new AIs reduce circulating estradiol by over 97%.
Around a fifth of patients on adjuvant AIs suffer from atrophic vaginitis – a distressing skin condition of the genitals caused by lack of estrogen. Many ask if they can use topical estrogen to alleviate the symptoms as conventional HRT is not recommended.
Senior author Professor Ian Smith, Head of the Breast Unit at the Royal Marsden, said: "Using this vaginal form of estrogen which, we found, increases systemic estradiol levels, will counteract AI treatment. With long term use, women may be risking the chance that their cancer may return, although this is probably not an issue if estrogen rises for only one to two months."
Using a sensitive radioimmunoassay that they developed to quantify even extremely low levels, the researchers measured serum estradiol in six women on adjuvant AI therapy who had actively asked to use the vaginal estradiol tablet Vagifem for severe symptoms of atrophic vaginitis. They also monitored a seventh patient with metastatic breast cancer who was using Premarin estradiol cream. Measurements were taken at baseline, then at 2, 4, 7-10 weeks and over 12 weeks from starting Vagifem.
Lead Researcher Dr. Anne Kendall, Clinical Research Fellow at the Academic Department of Biochemistry at the Royal Marsden, said: "Our results showed a significant rise in serum estradiol levels two weeks after starting Vagifem in six of the seven women (five of those on Vagifem and the one on Premarin). Typically, they fell after one month, but with a return to pre-Vagifem levels in only two women after seven and 12 weeks respectively. Two women who continued using Vagifem showed further increases between weeks seven and 10."
Kendall said that in the UK and the USA there was currently uncertainty among cancer specialists and other doctors, including gynecologists, about the safety of preparations such as Vagifem for women receiving AIs, yet they are widely used. Some doctors do measure serum estradiol, but most assays are not sensitive enough to detect changes in the low levels seen in women on AIs.
Although Vagifem is supposed to be used for a maximum of three months at a time, recurrence of symptoms often means repeat courses are prescribed. The manufacturers' patient information sheet does state that Vagifem should not be used in women with a history of breast cancer, but it also states that although there are reports of increased risk of breast cancer in women on HRT, Vagifem is not expected to pose an increased risk.
According to Smith: "Although the study is small, the magnitude of the effect in such a high proportion of the women strongly indicates it would be reproduced in a larger study population. It is particularly important that doctors are aware of the new findings, as increasing uptake of AI therapy means that it is likely that around 15,000 new women a year in the UK would be receiving AIs, a total of 100,000 at any one time."
The women in the study had been warned at the outset that they would be recommended to stop using the topical preparation at an early stage if there were concerns. One patient continued to use a low dose with regular monitoring. One elected to stop AI treatment and continue with Vagifem because of her poor quality of life. The others have stopped.
According to Kendall: "Our results raise concerns over the appropriateness of the combination of AI treatment and Vagifem, since the efficacy of aromatase inhibition depends on near total suppression of estrogenic stimulation. The third generation AIs that inhibit aromatase by over 97% are more effective in controlling breast cancer than earlier agents, which achieved only 90%; this suggests that even a small increase in systemic estrogen may be detrimental."
She added: "Our view is that the combination of AIs and Vagifem is contraindicated, apart from exceptional circumstances where regular monitoring of plasma estradiol with specialist assays is available. Other non-hormonal vaginal moisturizing gels or creams should be used in most cases." She said it was impossible to generalize about all vaginal estrogens. However, given that a similar effect was seen with Premarin cream, caution was needed with all topical estrogens.
Smith concluded: "It is important that women discuss this with their doctor. Some complications related to atrophic vaginitis, such as recurrent urinary tract infection, may need treatment to be completed before stopping Vagifem. One option in those cases would be to switch from AIs to tamoxifen, which appears not to allow as much estrogen to enter the system."
SOURCES:
Annals of Oncology, online edition, January 25, 2006
European Society for Medical Oncology (http://www.esmo.org)
