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Vaginal laser therapy versus hyaluronic acid suppositories for women with symptoms of urogenital atrophy after treatment for breast cancer: A randomized controlled trial

Open AccessPublished:September 08, 2022DOI:https://doi.org/10.1016/j.maturitas.2022.08.013

      Highlights

      • Both intravaginal laser therapy and hyaluronic acid suppositories are effective treatment options for women after breast cancer suffering from symptoms of urogenital atrophy.
      • Intravaginal laser therapy and hyaluronic acid suppositories significantly improved subjective and objective symptoms of urogenital atrophy in this study.
      • There was no difference in symptoms of urogenital atrophy between the treatment groups (intravaginal laser therapy and hyaluronic acid suppositories) at the end of the study period.

      Abstract

      Background

      Urogenital atrophy affects >50 % of women after breast cancer (BC) and there is reluctance to use local estrogen for this group. Hormone-free therapies like intravaginal laser therapy and hyaluronic acid suppositories have been shown to produce symptom relief in women with BC and urogenital atrophy, but have not been tested against each other. The aim of this study was to compare these nonhormonal modalities in women with urogenital atrophy after BC in a randomized fashion.

      Study design

      We randomly assigned 43 women (aged 49–58 years, mean age 54 years) with urogenital atrophy and a history of BC to receive intravaginal laser therapy (2 courses within 1 month) or hyaluronic acid suppositories (3 times/week continuously for three months). The primary endpoint was score on the Vaginal Health Index after 3 months. Secondary endpoints were subjective bother on a numeric rating scale for all urogenital atrophy domains, quality of life, sexual health and pelvic organ prolapse symptoms using validated questionnaires.

      Results

      Of the 43 women who participated, 22 were randomized to intravaginal laser therapy, and 21 to vaginal suppositories. At 3 months score on the Vaginal Health Index had improved significantly in both groups (p = 0.001), without a significant difference between treatment groups (p = 0.232). Significant improvement was also seen in both groups for subjective bother of urogenital atrophy, quality of life and sexual health, without significant differences between laser or hyaluronic acid therapy.

      Conclusions

      Both intravaginal laser therapy and hyaluronic acid suppositories are effective treatment options for women after BC suffering from urogenital atrophy. No difference was found between treatment regimens.

      Keywords

      1. Introduction

      Common concerns during menopause include vaginal dryness, burning, discharge, itching, sexual discomfort or pain and/or urinary symptoms of urgency and dysuria and occur in up to 50 % in postmenopausal women [
      • Parish S.J.
      • Nappi R.E.
      • Krychman M.L.
      • et al.
      Impact of vulvovaginal health on postmenopausal women: a review of surveys on symptoms of vulvovaginal atrophy.
      ]. These symptoms are associated with estrogen deficiency related tissue changes of the vulva, vagina and lower urinary tract [
      • Portman D.J.
      • Gass M.L.
      Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's sexual health and the North American Menopause Society.
      ]. In clinical trials, dyspareunia and vaginal dryness are the most bothersome symptoms reported [
      • Ettinger B.
      • Hait H.
      • Reape K.Z.
      • Shu H.
      Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach.
      ].
      Especially in women after breast cancer (BC) treatment like chemotherapy or antihormonal therapy symptoms are even worse and the above listed symptoms occur in up to 75 % [
      • Trinkaus M.
      • Chin S.
      • Wolfman W.
      • Simmons C.
      • Clemons M.
      Should urogenital atrophy in breast cancer survivors be treated with topical estrogens?.
      ]. Due to the radical decrease of circulating estrogen biologic and clinical changes in the urogenital tissues, such as decrease of elastin, thinning of the epithelium, reduced vaginal blood flow, diminished lubrication, and decreased flexibility and elasticity further aggravate clinical bother. Estrogen therapy is the most effective treatment for urogenital atrophy, however many providers and patients are reluctant to use estrogen in this setting [
      • Sousa M.S.
      • Peate M.
      • Jarvis S.
      • Hickey M.
      • Friedlander M.
      A clinical guide to the management of genitourinary symptoms in breast cancer survivors on endocrine therapy.
      ]. Urogenital atrophy symptoms will not resolve without treatment but will deteriorate over time; hence, a sufficient treatment is necessary to avoid negative impact on a woman's quality of life (QoL).
      Nonhormonal treatment options for urogenital atrophy include vaginal lubricants or hormone free suppositories and laser therapy. Hyaluronic acid was effective to treat dryness, dyspareunia and urinary incontinence [
      • Jokar A.
      • Davari T.
      • Asadi N.
      • Ahmadi F.
      • Foruhari S.
      Comparison of the hyaluronic acid vaginal cream and conjugated estrogen used in treatment of vaginal atrophy of menopause women: a randomized controlled clinical trial.
      ,
      • Advani P.
      • Brewster A.M.
      • Baum G.P.
      • Schover L.R.
      A pilot randomized trial to prevent sexual dysfunction in postmenopausal breast cancer survivors starting adjuvant aromatase inhibitor therapy.
      ]. Hyaluronic acid is a natural substance that occurs in human tissue, which exhibits water-binding properties and thus regulates the moisture content of the tissue. The erbium-doped yttrium-aluminum-garnet (Er:YAG) laser is based on photothermic treatment of connective tissue by affecting collagen remodeling resulting in tightening of the supportive tissue [
      • Hantash B.M.
      • Ubeid A.A.
      • Chang H.
      • Kafi R.
      • Renton B.
      Bipolar fractional radiofrequency treatment induces neoelastogenesis and neocollagenesis.
      ,
      • Lapii G.A.
      • Yakovleva A.Y.
      • Neimark A.I.
      Structural reorganization of the vaginal mucosa in stress urinary incontinence under conditions of er:YAG laser treatment.
      ,
      • Pitsouni E.
      • Grigoriadis T.
      • Tsiveleka A.
      • Zacharakis D.
      • Salvatore S.
      • Athanasiou S.
      Microablative fractional CO2-laser therapy and the genitourinary syndrome of menopause: an observational study.
      ]. Pilot studies of intravaginal microablative or non-ablative laser therapies with Erbium-YAG or CO2 lasers have demonstrated significant clinical improvement of urogenital atrophy and stress urinary incontinence [
      • Gambacciani M.
      • Levancini M.
      • Cervigni M.
      Vaginal erbium laser: the second-generation thermotherapy for the genitourinary syndrome of menopause.
      ,
      • Vizintin Z.
      • Lukac M.
      • Kazic M.
      • Tettamanti M.
      Erbium laser in gynecology.
      ]. Recent systematic reviews indicate that vaginal laser might be able to improve bothersome symptoms of urogenital atrophy [
      • Mension E.
      • Alonso I.
      • Tortajada M.
      • et al.
      Vaginal laser therapy for genitourinary syndrome of menopause - systematic review.
      ] while it seems that in BC survivors the efficacy is even less [
      • Knight C.
      • Logan V.
      • Fenlon D.
      A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors.
      ]. Others have investigated hyaluronic acid-based liquid preparation for vaginal use [
      • Jokar A.
      • Davari T.
      • Asadi N.
      • Ahmadi F.
      • Foruhari S.
      Comparison of the hyaluronic acid vaginal cream and conjugated estrogen used in treatment of vaginal atrophy of menopause women: a randomized controlled clinical trial.
      ,
      • Origoni M.
      • Cimmino C.
      • Carminati G.
      • et al.
      Postmenopausal vulvovaginal atrophy (VVA) is positively improved by topical hyaluronic acid application. A prospective, observational study.
      ].
      The aim of this study was to compare intravaginal laser therapy with local hyaluronic acid in women with urogenital atrophy and a history of BC in a randomized fashion. (ClinicalTrials.gov number, NCT03816735).

      2. Materials and methods

      This is a single center, randomized controlled trial of patients with urogenital atrophy after BC.
      Patients were recruited from follow-up BC clinics at our institution. Women with a history of BC and completed locoregional therapy were screened for urogenital atrophy and invited to participate in the study. Eligible patients had to report at least one of the following symptoms: vaginal dryness, burning or irritation; lack of lubrication during sexual intercourse/ sexual discomfort or pain; symptoms of urgency and dysuria; recurrent urinary tract infection. Exclusion criteria were current or past genitourinary malignancy, abnormal PAP smear, current genitourinary tract infection, abnormal uterine bleeding or the use of photosensitive medication.
      After study inclusion patients underwent a gynecological examination, including completion of the Vaginal Health Index (VHI) to assess degree of atrophy and mucosal appearance. Both before treatment and 3 months later patients had a structured interview and filled out the below mentioned validated questionnaires.
      Patients were randomly allocated to either intravaginal laser therapy or hyaluronic acid treatment using an online randomizer tool (www.randomizer.at). Laser treatments were performed with the Erbium:Yag Laser Juliet, MCL31 Dermablate (Asclepion Laser Technology GmbH, Jena, Germany). Before the procedure, the vagina was inspected and dried with a swab. The vaginal probe was inserted and laser parameters were set to Cold mode (Fluence 20 J/cm2). The probe was rotated and retracted using the graduated scale on the probe, resulting in a circular irradiation of the entire vaginal wall. The procedure was repeated using the Warm mode (Fluence 6 J/cm2). Laser application and parameters were used according to the manufacturer's recommendations. Patients were treated with 2 laser applications (at baseline and again 1 month later); a follow-up visit was performed 3 months after the initial treatment.
      Patients randomized to the suppository group received Cikatridina vaginal suppositories (provided by the company Angelini). These suppositories include natural plant extracts from aloe vera, marigold, tiger grass and tea tree that are meant to support the wound-healing effect of hyaluronic acid and have an anti-inflammatory effect. The suppositories had to be applied vaginally daily during the first 10 days, and then every third day during the entire study period. Patients were asked to complete a diary to document days of suppository use. After study completion at 3 months, women were offered two laser treatments in case they were not satisfied with the suppository treatment.
      The primary outcome parameter was the VHI score to evaluate the appearance of the vaginal mucosa (elasticity, pH, vaginal discharge, mucosal integrity and moisture) on a scale from 1 to 5 each [
      • Bachmann G.
      • Notelovitz M.
      • Kelly S.
      • et al.
      Long-term nonhormonal treatment of vaginal dryness.
      ] with a low score indicating vaginal atrophy.
      Secondary outcome parameters were subjective bother of urogenital atrophy and degree of discomfort or pain during laser therapy using a numeric rating scale (NRS) ranging from 0 to 10 with 0 indicating no bother at all and 10 the highest bother possible. Further parameters were the Patient Global Impression of Improvement (PGI-I) [
      • Srikrishna S.
      • Robinson D.
      • Cardozo L.
      Validation of the patient global impression of improvement (PGI-I) for urogenital prolapse.
      ] and Patient Global Impression of Severity (PGI-S) [
      • Tincello D.G.
      • Owen R.K.
      • Slack M.C.
      • Abrams K.R.
      Validation of the patient global impression scales for use in detrusor overactivity: secondary analysis of the RELAX study.
      ].
      Quality of life (QoL) was determined by the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (EORTC-QLQ-BR45) with higher values indicating better QoL [
      • Winters Z.E.
      • Afzal M.
      • Rutherford C.
      • et al.
      International validation of the European Organisation for Research and Treatment of Cancer QLQ-BRECON23 quality-of-life questionnaire for women undergoing breast reconstruction.
      ]. Sexual health was determined with the female sexual health questionnaire with lower scores indicating better sexual health/less sexual health problems (EORTC SHQ C22) [
      • Oberguggenberger A.
      • Nagele E.
      • Inwald E.C.
      Phase 1 to 3 of the cross-cultural development of an EORTC questionnaire for the assessment of sexual health in cancer patients: the EORTC SHQ-22.
      ]. Pelvic floor symptoms were determined using the validated Australian pelvic floor questionnaire [
      • Baessler K.
      • Kempkensteffen C.
      Validation of a comprehensive pelvic floor questionnaire for the hospital, private practice and research.
      ] (translated and validated for German known as the “Deutscher Beckenboden- Fragebogen” [
      • Baessler K.
      • Kempkensteffen C.
      Validierung eines umfassenden Beckenboden-Fragebogens für Klinik, Praxis und Forschung.
      ]) also with lower scores being associated with less pelvic floor symptom bother. No clinical assessment in regard to pelvic floor muscle strength or incontinence was performed. However, self-report questionnaires have become a standard measure to assess treatment outcomes view. Treatment satisfaction was evaluated with the Zuf-8 questionnaire with higher scores being associated with high treatment satisfaction [
      • Schmidt J.
      • Lamprecht F.
      • Wittmann W.W.
      Satisfaction with inpatient management. Development of a questionnaire and initial validity studies.
      ].
      Adverse events included side effects of the vaginal treatment like vaginal burns, or allergic reactions to the suppositories. Serious adverse events were defined as any problems being fatal or life-threatening, leading to permanent damage, or rendering in-hospital treatment and had to be reported within 72 h after identification.

      2.1 Sample size calculation

      Gambacciani et al. (2015) found an increase of the VHI score from 10.6 ± 3.6 to 19.8 ± 1.3 in women treated with an Erbium:Yag Laser and from 11.2 ± 2.8 to 15.3 ± 1.5 in women treated with estriol gel after 12 weeks. Assuming comparable VHI/urogenital atrophy scores in our study, the sample size calculation based on a baseline score of 11 for both groups and an increase to a urogenital atrophy score of 19 and 15 in the laser therapy and vaginal hyaluronic acid therapy, respectively. A sample size of 20 patients in each group was needed to detect this different changes (interaction: α = 0.05, 1-β = 0.90) using a univariate two-group repeated measures analysis of variance. Theses sample size calculation is based on a common standard deviation of 4 and a correlation of measurements of ρij = 0.4. Assuming a dropout rate of approximately 10 % 22 patients in each group have to be included in this study, resulting in a total of 44 patients to be included.

      2.2 Statistical analysis

      Descriptive statistics are presented as median and interquartile range (IQR) for continuous variables and as counts and percentages for categorical variables. Questionnaire scales were calculated according to the questionnaire manuals and treated as continuous variables. Since responses to the many single item domains of the EORTC QLQ-BR45 only varied between two or three response categories the calculation of mean or median was not meaningful. Therefore the results for these single item domains are given as frequencies.
      Changes within groups were analyzed using Wilcoxon signed-rank test and McNemar test, Differences between laser and suppositories were analyzed using Mann Whitney U Test, Chi-square Test or Fisher's exact Test. The level of significance is set to 5 %. SPSS 26.0.0.0 was used for data analysis.
      The protocol was approved by the local ethics committee and the Austrian Federal Office for Safety in Health Care. All women gave written informed consent.

      3. Results

      50 women with urogenital atrophy after BC were screened and six had to be excluded for cervical dysplasia or untreated vulvar dermatosis; one was excluded after randomization because she was included even though untreated vulvar dermatosis was present. Hence, a total of 43 women were enrolled from January 2019 to December 2020. Table 1 shows baseline demographic and clinical characteristics for each group; no significant differences were seen between the two groups. Women with a history of BC were aged between 49 and 58 years with a mean BMI of 23. Two thirds of women had not had intravaginal treatments, and one third had used intravaginal treatments with various non-hormonal products in the past. Study participants were asked to cease any intravaginal treatment except the allocated study medication at time of study inclusion. Lubricants for sexual intercourse were allowed throughout the study. 22 women were randomized to the laser therapy group, 21 to the vaginal suppositories group, respectively.
      Table 1Demographic data of patients (n = 43).
      Laser (n = 22)Hyaluronic acid (n = 21)Total (n = 43)p- value
      Age (years)54 (48–58)56 (49–58)54 (49–58)0.798
      BMI (kg/m2)23.4 (21.2–26.1)23.2 (22.4–25.3)23.3 (21.6–26.0)0.930
      Parity [Median (Range)]2 (0–3)1 (0–2)2 (0–3)0.462
      Hormonal status:0.864
       Premenopausal4 (19.0 %)5 (22.7 %)9 (20.9 %)
       Postmenopausal17 (81.0 %)17 (77.3 %)34 (79.1 %)
      Smoker:0.488
       No21 (100.0 %)19 (95.0 %)40 (97.6 %)
       Yes0 (0.0 %)1 (5.0 %)1 (2.4 %)
      Current AH therapy0.086
       AI13 (61.9 %)12 (57.1 %)25 (59.5 %)
       Tamoxifen1 (4.8 %)6 (28.6 %)7 (16.7 %)
       None7 (33.3 %)3 (14.3 %)10 (23.8 %)
      Preceding vaginal therapy0.123
       No16 (76.2 %)12 (57.1 %)28 (66.7 %)
       Yes5 (23.8 %)9 (42.9 %)14 (33.3 %)
      Data are given as median and interquartile range (IQR) for continuous variables; and as counts and percentages for categorical variables. HA, hyaluronic acid; AH, antihormonal therapy; AI, aromatase inhibitor.

      3.1 Primary outcome

      At baseline the mean VHI was 9 (8–13) in the laser groups vs. 13 (10–16) in the suppository group (p = 0.031), indicating vaginal atrophy in all study participants. The VHI improved significantly in both groups (p = 0.001) with no differences between treatment groups (p = 0.232).

      3.2 Secondary outcomes

      At baseline, vaginal dryness and dyspareunia were the most bothersome subjective urogenital atrophy symptoms affecting >80 % of women (Table 2). At 3 months, most subjective urogenital atrophy symptoms improved significantly without any significant difference between treatment type. Before the study, subjective vaginal atrophy was reported by 91 % and 86 % of women both in the laser and suppository group with a non-significant reduction to 73 % (p = 0.219) and 67 % (p = 0.289) at three months. The bother of vaginal atrophy on a NRS from 0 to 10 improved from 7 (3–8) to 3 (0–7) points in the laser group (p < 0.001) and from 4 (0–8) to 2 (0–4) in the suppository group (p = 0.002) in line with a significantly improved VHI scores in both groups.
      Table 2Reported GSM symptoms at baseline and 3 months follow-up.
      Laser (n = 22)HA (n = 21)Laser vs HA at 3 Months
      BaselineFollow-upp-valueBaselineFollow-upp-valuep-value
      Vaginal dryness20 (90.9 %)16 (72.7 %)0.21918 (85.7 %)14 (66.7 %)0.2890.747
       Bother on NRS7 (3–8)3 (0–7)<0.0014 (0–8)2 (0–4)0.0020.411
      Dyspareunia19 (86.4 %)15 (68.2 %)16 (76.2 %)13 (61.9 %)0.907
       Dyspareunia *17/1714/170.24814/1713/171.000
       Not sexually active3 (13.6 %)4 (18.2 %)1.0002 (9.5 %)4 (19.0 %)0.5000.942
       Bother on NRS9 (8–10)7 (1–9)0.0027 (5–10)5 (0–8)<0.0010.216
      OAB dry7 (31.8 %)3 (13.6 %)0.1259 (42.9 %)8 (38.1 %)1.0000.088
      OAB wet3 (13.6 %)0n.a.2 (9.5 %)2 (9.5 %)1.0000.233
       Bother on NRS0 (0–6)0 (0–0)0.0160 (0–4)0 (0–3)0.0210.261
      Recurrent UTIs4 (18.2 %)4 (18.2 %)1.0005 (23.8 %)1 (4.8 %)0.1250.345
       Bother on NRS0 (0–0)0 (0–0)0.0630 (0–0)0 (0–0)0.0630.206
      SUI6 (27.3 %)6 (27.3 %)1.0008 (38.1 %)8 (38.1 %)1.0000.526
       Bother on NRS0 (0–4)0 (0–4)0.0310 (0–3)0 (0–2)0.0630.309
      Data are presented as median (interquartile range, IQR). NRS, numeric rating scale; ranging from 0 to 10, OAB, overactive bladder; UTI, urinary tract infection; SUI, stress urinary incontinence. HA, hyaluronic acid; Dyspareunia * included only women who were sexually active at both timepoints.
      88 % of study participants were sexually active at time of randomization with 32/35 (91 %) of women suffering from dyspareunia. While 100 % of sexually active women had dyspareunia before laser therapy only 80 % experienced dyspareunia after treatment. The related bother decreased from 9 (8–10) to 7 (5–10) (p = 0.002). While in the suppository group dyspareunia rate did not significantly decrease, the mean bother scores decreased from 7 (5–10) to 5 (0–8) (p < 0.001).
      Most women reported symptoms of urinary incontinence according to the pelvic floor questionnaire; 12 % had overactive bladder (OAB) without urinary incontinence (OAB dry), 37 % overactive bladder with urinary incontinence (OAB wet) and 32 % stress urinary incontinence (SUI) with low bother scores for all types of urinary incontinence. No treatment arm was able to completely resolve subjective urinary incontinence symptoms, however, in both groups the bother of OAB symptoms decreased significantly [laser group: 0 (0–6) to 0 (0–0), p = 0.016; suppository group: 0 (0–4) to 0 (0–3), p = 0.021], respectively. In regards to SUI, the bother decreased only significantly (p = 0.031) in the laser group [laser group: 0 (0–4) to 0 (0–0), p = 0.031; suppository group: 0 (0–3) to 0 (0–2), p = 0.063].
      PGI-S improvement was seen in the laser group while there was no significant change in the suppository group [laser group: 3 (2–3) to 2 (1–3), p = 0.003; suppository group: 2 (1–3) to 2 (1–2), p = 0.101]. The median PGI-I at 3 months was 3 in both groups (slightly better); the interquartile range was between 2 and 4 (better to no change) without a significant differences between groups (p = 0.897).
      Treatment satisfaction in general was high in both groups with 20.5 (20.0–22.0) (laser group) and 20 (19–21) out of 32 points (supp. group) on the ZUF scale.
      11/ 21 (ca 52 %) of women from the suppository group opted for a laser therapy after 3 months due to ongoing urogenital atrophy symptoms. We recommended suppository use after unsuccessful laser therapy, however, we do not have the data on the percentage of women who opted for ongoing suppository treatment in the laser group.
      The results from the questionnaires mirror subjective and objective findings in regard to treatment success.
      The EORTC QLQ-BR45 questionnaire showed significant improvement in several QoL domains like systemic therapy side effects, endocrine therapy symptoms skin, mucosis symptoms and sexual domains like sexual enjoyment, and endocrine sexual symptoms after laser therapy while the “sexual functioning domain” worsened. After suppository treatment, there were less pronounced differences with only QoL domains like systemic therapy side effects and endocrine sexual symptoms improving significantly (Table 3).
      Table 3Quality of Life (EORTC-QLQ-BR45 questionnaire).
      LaserHALaser vs HA
      Baseline (median)Follow-up

      (median)
      p-valueBaseline

      (median)
      Follow-up

      (median)
      p- valuep- value
      Body image75.075.00.75275.075.00.3800.536
      (33 0.3–100.0)(66.7–91.7)(41.7–91.7)(58.3–91.7)
      Future perspective33.366.70.07150.066.70.7630.806
      (33.3–66.7)(33.3–66.7)(33.3–66.7)(16.7–100.0)
      Sexual functioning16.733.30.00433.333.30.1500.677
      (8.3–33.3)(0.0–50.0)(16.7–33.3)(16.7–50.0)
      Sexual enjoyment100.033.30.02383.350.00.1600.897
      (33.3–100.0)(33.3–100.0)(50.0–100.0)(16.7–100.0)
      Breast satisfaction100.0100.00.739100.0100.00.3190.528
      (83.3–100.0)(83.3–100.0)(66.7–100.0)(50.0–100.0)
      Systemic therapy side-effects28.621.40.03423.821.40.0240.244
      (19.0–38.1)(14.3–38.1)(14.3–33.3)(11.9–23.8)
      Upset by hair loss33.333.31.00016.733.31.0001.000
      (0.0–66.7)(33.3–66.7)(0.0–50.0)(33.3–66.7)
      Arm symptoms27.822.20.74222.211.10.1100.639
      (0.0–44.4)(0.0–33.3)(5.6–33.3)(0.0–33.3)
      Breast symptoms33.316.70.49625.016.70.8870.822
      (8.3–44.4)(8.3–33.3)(8.3–33.3)(16.7–29.2)
      Endocrine therapy symptoms48.340.00.03333.328.30.5700.845
      (22.2–63.0)(25.9–43.3)(20.0–50.0)(16.7–54.4)
      Skin mucosis symptoms36.122.20.00516.713.90.4540.191
      (22.2–44.4)(11.1–33.3)(0.0–33.3)(0.0–27.8)
      Endocrine sexual symptoms83.350.0<0.00183.337.5<0.0010.362
      (66.7–100.0)(33.3–66.7)(66.7–91.7)(9.7–66.7)
      Data are given as medians and IQR. HA, hyaluronic acid.
      According to the EORTC SHQ-C22 only the multi-item domain sexual pain decreased significantly in the laser group from 62.5 (45.8–66.7) to 33.3 (25.0–50.0; p = 0.001) while it did not quite reach significance in the suppository group [58.3 (33.3–66.7) to 54.2 (8.3–66.7); p = 0.055]. The second multi-item domain sexual satisfaction did not improve significant throughout the study (Laser: p = 0.051, suppository group: p = 0.082). The remaining single-item domains did not reveal any significant changes after treatment and between treatment groups. Study participants had high scores in all subdomains indicating poor sexual health; hence data are shown in frequencies (Table 4).
      Table 4Sexual Health (EORTC SHQ C22 questionnaire).
      LaserHALaser vs HA
      Baseline

      (median)
      Follow-up

      (median)
      p-valueBaseline

      (median)
      Follow-up

      (median)
      p-valuep-value
      Sexual satisfaction23,4

      (14,1-31,3)
      28,13

      (15,6-39,3)
      0.05131,3

      (13,6-37,5)
      31,7

      (23,4-45,3)
      0.0820.388
      Sexual pain62,5

      (45,8-66,7)
      33,3

      (25,0-50,0)
      0.00158,3

      (33,3-66,7)
      54,2

      (8,3-66,7)
      0.0550.390
      Importance of sexual activityNot at all2 (11 %)2 (10 %)0.2280 (0 %)0 (0 %)0.149
      A little2 (11 %)5 (24 %)0 (0 %)1 (5 %)
      Quite a bit6 (32 %)8 (38 %)14 (74 %)11 (55 %)
      Very much9 (47 %)6 (29 %)5 (26 %)8 (40 %)
      Decreased libidoNot at all0 (0 %)1 (5 %)2 (11 %)1 (5 %)0.3920.742
      A little0 (0 %)4(20 %)1 (5 %)2 (11 %)
      Quite a bit4 (21 %)7(35 %)2 (11 %)5 (26 %)
      Very much15 (79 %)8 (40 %)14 (74 %)11 (58 %)
      Worry incontinenceNot at all10 (53 %)13 (72 %)13 (65 %)13 (65 %)0.3110.330
      A little5 (26 %)5 (28 %)3 (15 %)4 (20 %)
      Quite a bit2 (11 %)0 (0 %)4 (20 %)3 (15 %)
      Very much2 (11 %)0 (0 %)0 (0 %)0 (0 %)
      FatigueNot at all2 (12 %)3 (17 %)0.4065 (25 %)7 (35 %)0.1560.283
      A little7 (41 %)3 (17 %)2 (10 %)6 (30 %)
      Quite a bit4 (24 %)7 (39 %)7 (35 %)5 (25 %)
      Very much4 (24 %)5 (28 %)6 (30 %)2 (10 %)
      Treatment effect on sexual activityNot at all1 (6 %)7 (41 %)0.1970 (0 %)7 (39 %)0.929
      A little1 (6 %)2 (12 %)1 (8 %)4 (22 %)
      Quite a bit3 (19 %)3 (18 %)3 (23 %)3 (17 %)
      Very much11 (69 %)5 (29 %)9 (69 %)4 (22 %)
      Communication with professionalsNot at all4 (27 %)4 (22 %)0.0924 (24 %)6 (33 %)0.6690.283
      A little6 (40 %)2 (11 %)7 (41 %)5 (28 %)
      Quite a bit4 (27 %)8 (44 %)5 (29 %)3 (17 %)
      Very much1 (7 %)4 (22 %)1 (6 %)4 (22 %)
      Insecurity with partnerNot at all2 (13 %)4 (21 %)0.5026 (33 %)6 (32 %)0.1760.845
      A little3 (19 %)6 (32 %)4 (22 %)4 (21 %)
      Quite a bit6 (38 %)6 (32 %)7 (39 %)5 (26 %)
      Very much5 (31 %)3 (16 %)1 (6 %)4 (21 %)
      Vaginal drynessNot at all0 (0 %)3 (16 %)1 (6 %)6 (35 %)0.0750.633
      A little0 (0 %)2 (11 %)1 (6 %)2 (12 %)
      Quite a bit4 (25 %)7 (37 %)4 (25 %)5 (29 %)
      Very much12 (75 %)7 (37 %)10 (63 %)4 (24 %)
      Treatment effect on body imageNot at all5 (31 %)7 (37 %)0.2875 (31 %)9 (47 %)0.2210.929
      A little4 (25 %)6 (32 %)5 (31 %)5 (26 %)
      Quite a bit1 (6 %)2 (11 %)4 (25 %)1 (5 %)
      Very much6 (38 %)4 (21 %)2 (13 %)4 (21 %)
      Data are given as medians and IQR. HA Hyaluronic acid.
      Pelvic floor symptoms were assessed with the Australian Pelvic Floor Questionnaire. The overall score improved significantly in both groups (laser: 6.7 (4.7–9.0) to 5.4 (3.2–7.5); p = 0.008 and suppository group: 7.1 (6.2–9.3) to 5.9 (4.9–7.8); p = 0.029). However, similar to the remaining results, treatment groups were comparable at follow up (p = 0.650). As expected from the subjective bother score, the incontinence domain showed a significant improvement in the laser group [1.0 (0.4–2.1) to 1.0 (0.2–1.8); p = 0.017] but not in the suppository group [1.4 (0.7–2.1) to 1.1 (0.7–2.7); p = 0.826]. Conversely, the sexual health domain improved significantly in the suppository group [4.2 (3.3–4.8) to 3.3 (2.5–4.2); p = 0.007] but did not reach significance in the laser group [3.8 (3.3–4.2) to 3.3 (2.3–3.8); p = 0.054] (Table 5).
      Table 5POP symptoms (Pelvic organ prolapse questionnaire).
      LaserHALaser vs. HA
      Baseline

      (median)
      Follow-upp-valueBaselineFollow-upp-valuep-value
      Bladder function0,9810.0171,371,110.8260,306
      (0,44-2,14)(0,24-1,78)(0,69-2,11)(0,71 -2,67)
      Bowel function1,080,910.0101,150,910.0690,722
      (0,61-2,22)(0,30-1,67)(0,61-2,03)(0,61 -1,94)
      Prolapse000.070000.5000,139
      (0,00-1,50)(0,00-0,83)(0,00−0,00)(0,00-0,00)
      Sexual function3,753,330.0544,173,330.0070,895
      (3,33-4,17)(2,29-3,78)(3,33-4,79)(2,50-4,17)
      Total6,725,350.0087,115,870.0290,65
      (4,66-8,99)(3,24-7,47)(6,16-9,29)(4,88-7,75)
      Data are given as medians and IQR. HA, Hyaluronic acid.

      4. Discussion

      Our study shows a significant improvement of any urogenital atrophy related symptoms both after treatment with intravaginal laser and hyaluronic acid suppository therapy with no difference between treatment groups.
      Vaginal dryness and dyspareunia were found to be the most bothersome symptoms, which is in accordance with a recent systematic review [
      • Knight C.
      • Logan V.
      • Fenlon D.
      A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors.
      ]. Each of our vaginal therapies has shown similar effects in previous studies on its own [
      • Gambacciani M.
      • Levancini M.
      Vaginal erbium laser as second-generation thermotherapy for the genitourinary syndrome of menopause: a pilot study in breast cancer survivors.
      ,
      • Mension E.
      • Alonso I.
      • Castelo-Branco C.
      Genitourinary syndrome of menopause: current treatment options in breast cancer survivors - systematic review.
      ]. We found significant improvements of presence and bother of these urogenital atrophy symptoms after three months of treatment. However, women still experienced bothersome problems after study completion, i.e. 50 % of women from the suppository group opted for a succeeding laser therapy due to ongoing urogenital atrophy problems. This is in line with recent systematic reviews; with vaginal laser therapy showing limited efficacy for the treatment of urogenital atrophy compared to placebo treatment [
      • Mension E.
      • Alonso I.
      • Tortajada M.
      • et al.
      Vaginal laser therapy for genitourinary syndrome of menopause - systematic review.
      ,
      • Knight C.
      • Logan V.
      • Fenlon D.
      A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors.
      ,
      • Li F.
      • Picard-Fortin V.
      • Maheux-Lacroix S.
      • et al.
      The efficacy of vaginal laser and other energy-based treatments on genital symptoms in postmenopausal women: a systematic review and meta-analysis.
      ,
      • Pitsouni E.
      • Grigoriadis T.
      • Falagas M.E.
      • Salvatore S.
      • Athanasiou S.
      Laser therapy for the genitourinary syndrome of menopause. A systematic review and meta-analysis.
      ].
      There is a long list of factors that negatively impact on a woman's QoL after BC [
      • Mokhatri-Hesari P.
      • Montazeri A.
      Health-related quality of life in breast cancer patients: review of reviews from 2008 to 2018.
      ]. Sexual health is definitely an important aspect in women's QoL with and without BC. QoL according to the EORTC QLQ-BR45 questionnaire did not markedly improve after therapy, however, in the sexual domain women showed significant improvement after laser therapy. This is in line with our findings of the EORTC SHQ-C22 questionnaire where it seemed that laser therapy was superior in terms of sexual health, however, the study was not powered to answer this question.
      Women with primary subjective SUI showed large variety in symptom improvement after vaginal laser therapy [
      • Gambacciani M.
      • Palacios S.
      Laser therapy for the restoration of vaginal function.
      ]. In our study laser therapy significantly reduced the subjective bother of SUI suggesting that laser therapy might be favorable in women with urogenital atrophy and coexisting urinary incontinence. In case of OAB any treatment of urogenital atrophy seems to improve symptoms according to the pelvic floor questionnaire. In any case, several pelvic floor symptoms improve after treatment of existing urogenital atrophy; however, the study was not powered nor was there any clinical examination performed in regard to urinary incontinence to allow final conclusions.
      Several gynecological and similar societies have recommended vaginal laser therapy for urogenital atrophy only in the course of clinical studies due to unknown side effects [
      • Knight C.
      • Logan V.
      • Fenlon D.
      A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors.
      ,
      • Shobeiri S.A.
      • Kerkhof M.H.
      • Minassian V.A.
      • Bazi T.
      IUGA committee opinion: laser-based vaginal devices for treatment of stress urinary incontinence, genitourinary syndrome of menopause, and vaginal laxity.
      ,
      • Preti M.
      • Vieira-Baptista P.
      • Digesu G.A.
      • et al.
      The clinical role of LASER for vulvar and vaginal treatments in gynecology and female urology: an ICS/ISSVD best practice consensus document.
      ]. No adverse effects have been reported in the course of this study similar to previous results. While there are almost no contraindications for the therapy with hyaluronic acid suppositories there are some that apply for laser therapy which needs to be taken into account when counselling patients.
      Laser therapy treatment efficacy might be dependent on treatment regime. Sparse data are available on existing protocols [
      • Knight C.
      • Logan V.
      • Fenlon D.
      A systematic review of laser therapy for vulvovaginal atrophy/genitourinary syndrome of menopause in breast cancer survivors.
      ]. Treatment success might improve after optimizing treatment protocols. In our study we only performed two laser treatments to avoid loss to follow-up or side effects in women with a history of BC. Further studies will be needed focusing on treatment regimens.
      Salvatore et al. published one of the first papers to treat urogenital atrophy with a CO2 laser with significant improvement after 12 weeks [
      • Salvatore S.
      • Nappi R.E.
      • Zerbinati N.
      • et al.
      A 12-week treatment with fractional CO2 laser for vulvovaginal atrophy: a pilot study.
      ]. The CO2 laser has also been investigated in the treatment of urogenital atrophy in women with BC and similar to our data showed significant improvement of symptoms [
      • Quick A.M.
      • Zvinovski F.
      • Hudson C.
      • et al.
      Patient-reported sexual function of breast cancer survivors with genitourinary syndrome of menopause after fractional CO2 laser therapy.
      ]. In our study, we opted for an Erbium:Yag Laser with a microablative mode instead of a CO2 laser due to the recent FDA warning about certain vaginal ablative laser therapy.
      Similar to urinary incontinence it might be necessary to analyse the minimal important difference for women with urogenital atrophy to determine whether a treatment was successful or just statistically meaningful. Further research will be needed in this regard.
      Strengths of this study were the randomized controlled design, and the comprehensive assessment of urogenital atrophy symptoms in various ways including subjective and objective outcome measurements with validated questionnaires being used.
      A limitation of our trial is the relatively short follow-up. Long-term follow up was not evaluated through this study, since many women opted for laser therapy after they were allocated to suppository therapy in the first line and were not completely satisfied. Previous studies have suggested that recurrent treatment sessions may be necessary to maintain treatment effect in patients with urogenital atrophy, however, in our study only two laser treatments were available. Further studies will be needed to evaluate long-term results. Since the study was not designed to evaluate cross over therapy after 3 months and there was no funding to offer suppository treatment after initial laser therapy this could not be offered to our women. A slight bias might be present since the VHI score at time of randomization differed between treatment groups, however, we are unable to explain this finding since randomization was performed via an online tool without the possibility to influence randomization results. Since both treatment types are different, blinded randomization was not possible. Furthermore, it would have been difficult to design “placebo”-suppositories for the purpose of this study not to bias our results.

      5. Conclusion

      In conclusion, both intravaginal laser and suppository treatment appear safe and efficient for treatment of urogenital atrophy short-term in women with a history of BC. Long- term efficacy and safety need to be assessed.

      Contributors

      Daniela Gold contributed to study design, clinical duties, paper writing.
      Laura Nicolay contributed to clinical duties.
      Alexander Avian contributed to statistical analysis.
      Elfriede Greimel contributed to study design, proofreading.
      Marija Balic contributed to clinical duties, proofreading.
      Gunda Pristauz-Telsnigg contributed to clinical duties, proofreading.
      Karl Tamussino contributed to study design, proofreading.
      Gerda Trutnovsky contributed to study design, clinical duties, proof reading.

      Funding

      Angelini sponsored the suppositories, Asclepion provided the laser device.

      Ethical approval

      The protocol was approved by the local ethics committee and the Austrian Federal Office for Safety in Health Care (30-225 ex 17/18). All women gave written informed consent.

      Provenance and peer review

      This article was not commissioned and was externally peer reviewed.

      Research data (data sharing and collaboration)

      There are no linked research data sets for this paper. Data will be made available on request.

      Declaration of competing interest

      The authors declare that they have no competing interest.

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