Clinical trial NCT03238053: Laser Treatment of Genito-urinary Syndrome in Women
Official title: Laser Treatment of Genito-urinary Syndrome in Women With Breast and Endometrial Cancer and Menopausal Women
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: NA
Conditions: Laser-Induced Scar
Breast Cancer
Endometrial Cancer
Menopause
Vaginal Atrophy
Bladder, Overactive
Keywords: laser treatment, randomized trial, menopause, vaginitis, urge
Lead sponsor: Herning Hospital
Sponsor class: OTHER
First posted: 2017-08-03
Enrollment: 0
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Four Groups of women randomized for thre months to either laser og sham treatment
Primary purpose: SUPPORTIVE_CARE

Brief summary: Women with genitourinary syndrome of menopause, overactive bladder, with breast or endometrial cancer are randomized to either laser treatment og sham treatment for 3 months. The randomization is stratified for estrogen treatment. The effect is evaluated by questionnaire, histology and microbiology swaps

Detailed description: Genitourinary syndrome of menopause (GSM) is characterized by symptoms such as vaginal dryness, dyspareunia, irritation, urinary incontinence, overactive bladder , and urinary tract infections. GSM replaces the previous term vulvovaginal atrophy as agreed upon by a joint terminology conference sponsored by the North American Menopause Society and the International Society for the Study of Women's Sexual Health. GSM is a new terminology more accurate than the terms of VVA/atrophic vaginitis, because it describes the clinical signs and symptoms of the vulva, vagina and lower urinary system. In contrast, VVA/atrophic vaginitis describes the appearance of the vulvovaginal structures only. The GSM has a prevalence of more or less 50%, depending on country of origin, with a negative impact on sexuality, quality of life and well-being.

The aging process is genetically determined and environmentally modulated. Estrogen deficiency occurring after menopause causes a series of modifications in many different areas of the female body, including the pelvic floor. Menopause can, therefore, lead to functional genital or urinary symptoms impacting women's quality of life. It is debatable to which extent modifications and symptoms occurring after menopause are related to estrogen deficiency or to the aging process per se. Vulvovaginal atrophy (VVA) involves histological, morphological, microbiological, and clinical changes. These include alteration in collagens, decreased quantity of elastic fibers, reduced vascularization, thinning and flattening of the vaginal epithelium, and production of glycogen, an essential factor for the growth of vaginal lactobacilli. As a consequence, the vaginal canal becomes shorter and narrower, and the vaginal epithelium becomes paler and more likely to develop petechiae. Further, a decrease in Lactobacillus species and a rise of vaginal pH values over 4.5 are observed, resulting in the loss of the local vaginal defense mechanisms against bacterial pathogens, which may predispose to local inflammation and/or infections.

Women with VVA commonly complain of vaginal dryness, burning, irritation or itching, and dyspareunia. Local estrogens represent the first-line therapy for VVA. However, women's compliance with and preference for this treatment are poor; alternatives and palliative solutions, such as moisturizing or lubricant local creams or gels, are commonly proposed. In recent years, fractional CO 2 laser has become a popular, efficient, precise, and safe system, particularly for dermatologists and plastic surgeons. CO 2 laser has many applications, including treatment of skin lesions (ie, seborrheic keratosis, syringomas, and xanthelasmas around the eye), warts, and toenail diseases, as well as anti-aging function.

Various therapeutic strategies, hormonal or not, oral or local, have been proposed for the improvement of the vaginal microecosystem of postmenopausal women (e.g. estrogens, probiotics, combination of vaginal estrogens with live Lactobacillus). Hormonal therapy (oral or local) has been associated with a healthier vaginal microecosystem by repopulating the Lactobacillus species to a premenopausal status and by reducing the pH of vaginal fluid.

In women treated for estrogen dependent cancer i.e. endometrial and breast cancer women and practioners are reluctant to use estrogens and favor non-hormonal treatment modalities. The effect of these on the histological, microbiological and clinical symptoms is poorly understood and lack randomized trials to evaluate effect. Several proof of concept and feasibility studies have shown clinical effects of laser as potential treatment but little is known if it can stand alone or if supplementation with estrogens may benefit the clinical symptoms and vulvovaginal environment further. Thus, the ideal management for the achievement of the optimal benefit - risk balance is still under investigation. The choice of treatment is often guided by clinical experience and patient preference.

In postmenopausal women, the disturbance of Lactobacillary flora was correlated with the presence of Gardnerella vaginalis, Trichomonas vaginalis, enterococci, group B streptococci, and Escherichia coli. Available data indicate that pre-existing vaginal colonization with pathogenic enterobacteria is essential for the appearance and recurrence of urinary tract infections (UTIs). Indeed, postmenopausal women are prone to UTIs with an incidence of about 8% per year and a 4% likelihood of recurrence, while symptomatic bacteriuria was estimated in up to 15% of women. The general population of lactobacilli, as assessed in the routine practice, provides indirect information regarding the estrogenic status. To our knowledge there is currently no evidence regarding the potential impact that the intravaginal laser therapy may have on the vaginal microenvironment in women with symptoms of GSM.

Laser treatment improves significantly the VVA symptoms, sexual function and quality of life of postmenopausal women, as well as the vaginal health index. Other studies found restored thickness of the squamous stratified epithelium of the vaginal mucosa with a significant storage of glycogen in the epithelial cells and remodelling the vaginal connective tissue with the production of new collagen and ground substance molecules.

Breast cancer is the most common cancer in women in Denmark, annually ca. 4600 women are diagnosed with the disease, of whom 30% are under the age of 55. Most patients undergo breast conserving surgery followed by adjuvant therapy. Adjuvant therapy varies according to stage of disease, but radiotherapy is often added, as well as chemotherapy. If the cancer is hormonally responsive, long term antihormonal treatment is also given, such as the selective estrogen receptor modulator (SERM) tamoxifen for pre-menopausal women, that works as a inhibitor of estrogen in breast tissue, but as an estrogen in other tissues such as the endometrium. Post-menopausal women with hormone responsive breast cancer are treated with aromatase inhibitors for five years. Most side effects associated with tamoxifen (TAM) and aromatase inhibitors (AIs) are related to estrogen deprivation, and the symptoms are similar to those experienced during natural menopause. It has been reported that up to 50-75% of breast cancer survivors experience one or more genitourinary symptoms and puts the sexual life of women under stress. Postmenopausal women may have many common age-related symptoms but also have the above mentioned iatrogenic factors entering their lives to aggravate the symptom complex.

The aim of the current study was to assess the effect of laser laser therapy with and without local estrogens. The study groups consist of 1) postmenopausal women and 2 ) women treated for breast cancer. The laser treatment was given randomized to these women. The effects were evaluated in the histopathology of the vagina, the vaginal microenvironment, and health related questionnaires.

Eligibility criteria: Inclusion Criteria:

* menopause i.e. age more than 50 years and absence of menstruation for twelve months
* breast cancer
* endometrial cancer
* symptoms of vaginal dryness
* dyspareunia rated as moderate or severe most bothersome symptoms

Exclusion Criteria:

* use of vaginal moisturizers, lubricants or any other local preparation within the thirty days prior to inclusion
* acute or recurrent urinary tract infections
* active genital infections i.e. herpes genitalis, candida
* previous reconstructive pelvic surgery
* pelvis organ prolapse stage 2
* any serious disease or chronic condition that could interfere with study compliance except from breast and endometrial cancer
* psychiatric disorders precluding informed consent

Primary outcomes:
measure: Visual analogue score on vaginal symptoms
timeFrame: three months
Secondary outcomes:
measure: histopathology
timeFrame: three months
measure: microbiology
timeFrame: three months
Other outcomes:
Locations:
city: Herning
country: Denmark
facility: Gynecology Dept. Herning Hospital
Study officials:
affiliation: Randers Regional Hospital
name: Sine Jakobsen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Herning Hopsital
name: Finn F Lauszus
role: STUDY_CHAIR
References:
citation: Salvatore S, Nappi RE, Parma M, Chionna R, Lagona F, Zerbinati N, Ferrero S, Origoni M, Candiani M, Leone Roberti Maggiore U. Sexual function after fractional microablative CO(2) laser in women with vulvovaginal atrophy. Climacteric. 2015 Apr;18(2):219-25. doi: 10.3109/13697137.2014.975197. Epub 2014 Dec 16.
citation: Salvatore S, Leone Roberti Maggiore U, Athanasiou S, Origoni M, Candiani M, Calligaro A, Zerbinati N. Histological study on the effects of microablative fractional CO2 laser on atrophic vaginal tissue: an ex vivo study. Menopause. 2015 Aug;22(8):845-9. doi: 10.1097/GME.0000000000000401.
citation: Athanasiou S, Pitsouni E, Antonopoulou S, Zacharakis D, Salvatore S, Falagas ME, Grigoriadis T. The effect of microablative fractional CO2 laser on vaginal flora of postmenopausal women. Climacteric. 2016 Oct;19(5):512-8. doi: 10.1080/13697137.2016.1212006. Epub 2016 Aug 24.