Topics still taboo

Vaginal health of breast cancer survivors.

Dr. Dana SAWAN and Pr Barbara HERSANT.

1. Henri Mondor Thoracic Surgery, Henri Mondor University Hospitals, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France.

2. Department of maxillofacial, plastic and reconstructive surgery. Hôpitaux Universitaires Henri Mondor, 51 Avenue Marechal de Lattre de Tassigny, 94010 Créteil, France.

Dana Sawan: dana.s.sawan@gmail.com

Barbara Hersant: Barbara.hersant@gmail.com

Summary

Most breast cancers are hormone-sensitive or hormone-dependent to estrogen. The therapeutic strategy is therefore to wean the body off estrogen, which leads to an early menopause in patients who are often still young and genitally active. Menopause is accompanied by a series of general and local symptoms.

In the urogenital sphere, these are summarized in a so-called genitourinary menopausal syndrome (vaginal dryness, atrophy, dyspareunia, dysuria, etc.). The treatment of this syndrome gives pride of place to estrogens. However, estrogen carries a risk of recurrence in patients with a history of breast cancer. It is therefore imperative to find alternatives to hormonal treatment. This work proposes to do without these means.

Keywords: genitourinary syndrome of menopause - breast cancer - hormone therapy - alternatives - sexual life.

Introduction

Breast cancer is the most common cancer and the leading cause of cancer death in women. 

¾ of breast cancers express estrogen receptors, including the Estrogen Receptor alpha (ERα)1-4Tumors that do not express estrogen receptors often express epidermal growth factor receptor (EGFR).  The latter has been correlated with larger tumors and metastatic forms5.

The hormonal sensitivity and dependence of breast cancers makes hormone therapy one of the main means of treatment for these cancers.  It consists of weaning them off the estrogenic supply that sustains their growth, either by suppressing endogenous production (chemotherapy or irradiation of the ovaries) or by systemically administering an anti-estrogenic substance.

Advances in breast cancer detection technology now allow tumors to be detected at an earlier stage than before and, given that adjuvant chemotherapy is associated with ovarian failure 6an increasing proportion of breast cancer survivors are becoming postmenopausal at an earlier age after cancer treatment7In addition, estrogen levels gradually decrease as menopause approaches, which can lead to disabling genital and urinary symptoms in these women8.

Hormone replacement therapy (HRT) is known for its effectiveness and recommended for the control of menopausal symptoms such as hot flashes, sleep disorders, sexual dysfunction or vaginal atrophy and even the prevention of osteoporosis and cardiovascular disease9,10. In general, systemic estrogen therapy is recommended for women with systemic symptoms, while local estrogen therapy is recommended for those with vulvovaginal atrophy (VVA) or genitourinary syndrome of menopause (GUM)11However, this HS is risky in breast cancer survivors. Indeed, it has been shown that current and former HS users have a higher risk of developing breast cancer because estrogen plays a central role in the development of breast cancer12.

For example, women who have received primary treatment for early breast cancer may have a recurrence of the disease after HS13.    Therefore, clinicians should consider the goals of systemic endocrine therapy and the safety of this treatment modality in healthy women and those with a history of breast cancer11. Given the safety concerns regarding the use of HS in women with a history of breast cancer, this paper examines alternatives to estrogen replacement therapy that may help address specific survivorship issues, such as MGS, in this group of women.

Alternatives to hormone replacement therapy

Several alternatives to the use of hormone replacement therapy have been proposed for women previously diagnosed with breast cancer. 

1. Medical means

1.1. Autologous platelet-rich plasma and hyaluronic acid (Cellular Matrix)

A multicenter, randomized, controlled, open-label study of 144 women found that vaginal gel with hyaluronic acid was effective in improving vaginal dryness in postmenopausal women14.

A recent Phase 2 clinical study suggested that intraperitoneal administration of a combination of autologous platelet-rich plasma and hyaluronic acid appeared to improve MUMS in women previously diagnosed with breast cancer15. The researchers reported a significant increase in the volume of vaginal secretions after the start of treatment.

The participants' sexual quality of life was also significantly improved, as evidenced by a decrease in female sexual distress score one, three and six months after treatment with autologous platelet-rich plasma and hyaluronic acid15. See the video: youtube.com/watch > CellularMatrix INTIMACY

The patient's own platelet-rich plasma combined with hyaluronic acid for skin and mucosa regeneration.

TREATMENT OF GENITOURINARY MENOPAUSAL SYNDROME (GMS):

- New vascularization stimulated by the release of vascular endothelial growth factor (VEGF).
- Increased elasticity thanks to a new synthesis of collagen and elastin.
- Overall reduction of pain and discomfort.
GSM: A set of symptoms and signs associated with a decrease in estrogen.
- Genital symptoms: - Dryness - Burning - Irritation.
- Sexual symptoms: - Lack of lubrication - Discomfort/pain - Altered function
- Urinary symptoms: - Urgency - Dysuria - Recurrent urinary infections.
The cellular matrix is also evaluated for lichen sclerosus, bartholinitis, caesarean scars, episiotomy scars and stretch mark treatments.

1.2. Vaginal laser therapy

Laser therapy has recently been proposed as a viable treatment for MGS. The use of vaginal carbon dioxide for menopausal symptoms is somewhat new and very few studies have explored its efficacy just 12 weeks after therapy16-1. A single-arm pilot study showed that vaginal carbon dioxide laser improved stroke symptoms and sexual function16. In addition, a systematic review including six non-randomized studies suggested that vaginal carbon dioxide laser may improve vaginal health in women diagnosed with breast cancer19.

The CO2 laser used to reshape the vaginal epithelium activates heat shock proteins which in turn activate growth factors that increase vascularization, collagen, extracellular matrix production and vaginal mucosal thickness20. Recently, the VeLVET was conducted to compare the safety and efficacy of laser therapy with vaginal estrogen after six months of follow-up21. The investigators found that women in the laser-treated group and the vaginal estrogen group had comparable improvements in GSM symptoms and sexual function after six months of follow-up.

Approximately 70 to 80 % of women in both groups reported being satisfied or very satisfied with their treatment option.  No serious adverse events were reported by participants.

The erbium:YAG laser has also been satisfactorily tested in MGS, showing greater long-term efficacy than estriol22.

1.3. Intravaginal use of estrogen gels or creams

The use of estrogen gels and creams provides significant relief in patients with EMSM. The main concern is the safety of this treatment, as the systemic passage of estrogen is through the vaginal mucosa. Several studies suggest the safety of this treatment23,24Indeed, systemic estrogen levels remain very low and the risk of cancer recurrence is not significantly elevated for estriol doses of 0.25 mg and estradiol doses between 12.5 and 25 µg. The aspects that put off some patients are the "messy" nature of the administration, the unhygienic reusable applicator and the approximate dosage because there is often no dosing device, which is problematic in our population25Administration is usually daily for the first two weeks, then twice weekly for the maintenance period.

Intravaginal estradiol 4µg eggs are also safely used in breast cancer survivors25They offer the advantage of precise dosage and easier application. On the same principle, there are vaginal rings which release estradiol at a rate of 7.5µg per day and can remain in place for 90 days25This local hormone therapy should be used only when non-hormonal methods do not work, and if possible for a limited period.  Long-term use can be made in patients on tamoxifen or raloxifene22,26,27. These block the possible estrogenic effect in case of significant systemic passage. Hormone therapy should be avoided in any patient with unlabeled vaginal bleeding.  Similarly, bleeding that occurs during intravaginal hormone therapy should be investigated seriously (imaging, endometrial biopsy).

1.4. Specific estrogen receptor modulators (SERMs)

These molecules are non-steroidal agents that exert a plethora of estrogen agonist or antagonist effects on the target organs. Only ospemifene is currently used in the management of MGS (60 mg/day), particularly in the treatment of moderate to severe dyspareunia.  It improves the maturation of the vaginal mucosa and acidifies the pH25.

Tamoxifen has various effects on the vagina and can cause dyspareunia, increased white discharge or vaginal dryness28.

Raloxifene and bazedoxifene do not have a direct effect on the vagina.

However, in combination with equine estrogens (20/0.45 mg daily), they significantly improved the signs and symptoms of MGS without causing endometrial hyperplasia29.

1.5. Vaginal dehydroepiandrosterone (DHEA)

DHEA is a pro-hormone in the biosynthesis of testosterone and estradiol. Trials have shown its effectiveness on the symptoms of MGS (dyspareunia, vaginal maturation index, pH). DHEA is believed to exert its vaginal effects through in situ conversion to testosterone and estradiol. Serum levels are not elevated because these products are locally inactivated30. IIt is therefore a safer alternative to local estrogens in breast cancer survivors.  Moreover, since aromatase does not exist in the endometrium, DHEA has no proliferative effect on it31.

2. Non-medical means

2.1 Education

Women need to be educated about the changes that occur due to estrogen decline. Many patients are unaware of these changes and therefore cannot seek appropriate medical help. They need to be aware that the symptoms and signs of MGS will not spontaneously resolve and be aware of the various treatment options available to them25. 

2.2 Lubricants and vaginal humidifiers

They offer an immediate solution to the problem of pain during intromission that is the result of vaginal dryness. Lubricants are used at the time of sexual intercourse while humidifiers are used at a distance32.  There are water-based and silicone-based lubricants. The former do not stain and are better tolerated than the latter.  However, the effectiveness of lubricants depends on their osmolarity. Osmolarity above 1200 mOsm/kg is associated with irritation, contact dermatitis and cytotoxicity32.

Humidifiers increase the hydration of the vaginal mucosa by adhering to it, imitating vaginal secretions. They also contain additives that lower the pH and affect osmolarity32.

2.3. Use of vibrators and vaginal dilators

They help maintain sexual function by stretching vaginal and vulvar tissue. In fact, they stimulate these tissues and increase blood flow, whether or not the patients have a sexual partner25. Women with vaginismus can use these devices for conscious relaxation to facilitate the resumption of penetrative sexual activity33.

2.4. Pelvic floor rehabilitation

Physiotherapy should ideally be guided by a professional who specializes in pelvic pathology. It is indicated for women who have pelvic muscle hypertonia caused by painful sexual activity secondary to MUMS34.

2.5 Topical Lidocaine

Aqueous lidocaine at 4% applied in the vulvar vestibule a few minutes before intercourse significantly reduces the pain of penetration. It can be used as an adjunct to other measures (lubricants, humidifiers, rehabilitation)35.

Conclusion

Genitourinary syndrome of menopause is a consequence of breast cancer treatment that deprives the body of its estrogen supply.

It poses a management problem because all modalities including estrogens must be either ruled out or carefully weighed on the risk/benefit balance.

However, There are multiple alternatives that allow most patients to find the right formula for them.

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