Laser and radiofrequency for treating genitourinary syndrome of menopause in breast cancer survivors: a systematic review and meta-analysis protocol

Abstract

Introduction

Breast cancer survivors (BCSs) experience more severe symptoms of genitourinary syndrome of menopause (GSM) than healthy postmenopausal women. As hormonal therapy with oestrogen should be avoided in BCSs, finding an effective and safe therapy to address vaginal symptoms and sexual dysfunction is urgently needed. Physical methods may be promising alternatives for the specificities of this group of women. This review aims to evaluate the efficacy and safety of physical methods (laser and radiofrequency) for treating GSM in BCSs.

Methods and analysis

The PubMed, Embase, Web of Science, SciELO, LILACS, Scopus, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases will be searched. A search strategy was developed to retrieve clinical trials that evaluate the efficacy and safety of any physical method (laser or radiofrequency) used for GSM in BCSs. No date or language restrictions will be imposed. Two authors will independently select studies by title, abstract and full text to meet the inclusion criteria. Data will be extracted, and the risk of bias will be evaluated using the Cochrane risk-of-bias tool (RoB 2). Review Manager 5.4.1 will be used for data synthesis. The Grading of Recommendations, Assessment, Development and Evaluation will be used to assess the strength of the evidence.

Ethics and dissemination

This study reviews the published data; thus, obtaining ethical approval is unnecessary. The findings of this systematic review will be published in a peer-reviewed journal.

PROSPERO registration number

CRD42023387680.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Hormonal therapy is contraindicated for breast cancer survivors.

• Physical energy can be an option for urogenital atrophy.

• We intend to evaluate the use of physical energy in breast cancer survivors.

• We will strictly follow the Cochrane recommendations.

• We recognise the risk of obtaining a limited number of studies with small sample sizes.

Introduction

Description of the condition

Women’s life expectation is increasing, and most will experience symptoms of genitourinary syndrome of menopause (GSM).¹ One of the most distressing symptoms reported by women is vulvovaginal atrophy (VVA); up to 70% of breast cancer survivors (BCSs) experience at least one genitourinary symptom due to physiological changes in menopause or adverse effects of oncological treatments (chemotherapy, tamoxifen, aromatase inhibitors and ovarian suppression),^{2 3} used to worsen the basal hypoestrogenic state. GSM is a common and underreported condition that results from decreased circulating oestrogen levels in the genital tissue.⁴

Hypoestrogenism leads to the thinning and drying of the vaginal epithelium, a decrease in the number of collagen and elastin fibres, lower vascularisation of the subepithelium, reduced elasticity of the vaginal walls and changes in vaginal pH and commensal flora. All of these modifications lead to functional and sexual changes, including vaginal dryness, dyspareunia, burning and irritation, vulvovaginal pruritus, dysuria and an increased frequency of genitourinary infections. Vaginal changes can lead to chronic symptoms that worsen over time and are unlikely to resolve without treatment.⁵ They have been reported to be a major factor in the impairment of quality of life in patients with breast cancer.^6–8

Topical oestrogen is the most effective treatment for GSM symptoms.⁹ However, concerns about systemic absorption limit their use, and clinicians are often hesitant to prescribe them for BCSs.¹⁰ Non-hormonal therapies, such as lubricants and vaginal moisturisers, are the first-line therapies for BCSs. However, these therapies provide temporary relief, do not reverse urogenital ageing and do not improve vaginal epithelial characteristics.^{11 12}

Safe and effective non-hormonal treatments are needed to improve the long-term health of women with breast cancer. Intravaginal energy-based methods (laser and radiofrequency) have recently been proposed as non-pharmacological therapeutical options for managing GSM.

Description of the intervention

New energy-based devices have been the most widely investigated: non-ablative erbium:YAG (Er:YAG laser), fractional microablative CO2 laser and radiofrequency. Its main action is based on thermal effects, resulting in morphological changes in the collagen fibres in the vaginal epithelial tissue.

The CO2 laser works by vaporising tissue columns through the interaction between a specific CO2 pulsed laser and the vaginal area,¹³ and the Er:YAG laser has a smooth mode with sequential bursts of erbium pulses without damaging the mucosa.¹⁴ The most popular type of radiofrequency is transcutaneous temperature-controlled radiofrequency, which uses a high-frequency alternating current, resulting in the denaturation of collagen, promoting the contraction of its fibres, activating fibroblasts and leading to neocollagenesis and subsequent remodelling of the tissue.^{15 16}

How the intervention may work

They differ in their characteristics and mechanisms of action. However, the fundamental effect is assumed to be a vaginal remodelling pathway involving neocollagenesis and neoangiogenesis, stimulating tissue restructuring and reversing urogenital ageing.^17–19

The current data suggest promising positive results in improving vaginal health, GSM symptoms (dryness and dyspareunia) and sexual function in postmenopausal women and BCSs, with equivalent efficacy and no significant adverse events.^{20 21} However, few systematic reviews have evaluated all physical energy methods for GSM in BCSs, with insufficient evidence and no data on radiofrequency.^{8 22 23}

Why it is important to conduct this review

The use of physical energy in clinical practice requires further discussion. Therefore, a systematic review that aims to evaluate and improve the decision-making of all available physical energy interventions for GSM in BCSs and define indications for the use of physical methods through evidence-based medicine will bring many benefits to BCSs where the use of traditional hormone replacement is contraindicated.

Objectives

This systematic review and meta-analysis aims to evaluate the efficacy and safety of physical methods (laser and radiofrequency) for treating GSM in BCSs.

Methods and analysis

Design and registration

This systematic review protocol followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Protocols.²⁴ The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO CRD42023387680).

Eligibility criteria

Inclusion criteria

Randomised and quasi-randomised clinical trials that investigate both the efficacy and safety of any intravaginal physical energy (laser and radiofrequency) in non-metastatic BCSs, irrespective of age, who are still sexually active or willing to resume sexual activity with one or more GSM symptoms, will be included.

Exclusion criteria

Studies involving women with recurrent or metastatic cancer, prior reconstructive pelvic surgery involving a mesh for prolapse and active genital infections (diagnosed by Gram staining and multiplex PCR) and studies that do not assess the outcomes will be excluded. Observational studies, case reports, review articles, reports and case series will also be excluded.

Patient, intervention, comparison, outcome and type of study strategy

• Population/participants: BCSs.

• Intervention: intravaginal physical energy (laser or radiofrequency).

• Comparator/control: no treatment, placebo, sham and/or other treatment.

• Outcomes: improvements in vaginal atrophy (dryness, dyspareunia, itching and burning), sexual dysfunction, urinary symptoms (incontinence, urgency and frequency) and vaginal health.

• Type of study: randomised or quasi-randomised clinical trials.

Types of outcome measures

Primary outcome

The primary outcome evaluated will be the improvement of GSM:

• Vaginal atrophy (dryness, dyspareunia, itching and burning) will be assessed by the Visual Analogue Scale (VAS).²⁵

• Sexual dysfunction will be assessed by the Female Sexual Function Index (FSFI).²⁶

• Frequency, urgency, nocturia and leakage will be assessed by the International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB) and Urinary Distress Inventory-6 (UDI-6).²⁷

• Urinary incontinence will be assessed by the International Consultation on Incontinence Questionnaire–Short Form (ICIQ-UI SF) and International Consultation on Incontinence Questionnaires (ICIQ-UIF).²⁸

Secondary outcomes

• Vaginal health will be evaluated using the Vaginal Health Index (VHI) (epithelial integrity, vaginal elasticity, moisture, fluid volume and vaginal pH).²⁹

• Vaginal Maturation Index (VMI) (epithelial maturation, maturation value).³⁰

• Vaginal microbiota (Nugent criteria).³¹

• Quality of life.³²

• Side effects.

Patient and public involvement

Patients and/or the public were not be directly involved in this systematic review, as all relevant metrics will be sourced from original published studies.

Search strategy

A comprehensive search of the PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register of Controlled Trials, CINAHL and clinical trial databases (www.trialscentral.org, www.controlled-trials.com and ClinicalTrials.gov) will be conducted without language or data restrictions. All electronic databases will be searched in January 2024, and we plan to complete our study in January 2025. A combination of Medical Subject Headings terms, text words and keywords will be used to search the database. The search strategy used for PubMed is shown in table 1 (online supplemental table 1).

Table 1.

PubMed search strategy

	MeSH terms and keywords
1	Breast Neoplasm
2	Breast Cancer
3	Female cancer
4	Cancer Survivors
5	Menopause
6	Postmenopause
7	OR / 1–6
8	Laser Therapy
9	Lasers
10	Erbium YAG Laser
11	Lasers, CO2
12	Laser, Carbon Dioxide
13	Radiofrequency Therapy
14	Radiofrequency therapies
15	Therapy, Radiofrequency
16	Radio-Frequency therapy
17	Energy based devices
18	OR / 8–17
19	Genitourinary syndrome of menopause
20	Atrophic vaginitis
21	Atrophy
22	Dyspareunia
23	Sexual health
24	Sexual Disfunctions, Physiological
25	Dysuria
26	Quality of Life
27	OR / 18–26
28	7 AND 18 AND 27

Other sources

Eligible studies may also be selected from the reference lists of the retrieved articles. The scope of the computerised literature search may be widened based on the reference lists of the retrieved articles.

Data collection and analysis

Selection of studies

After standardised database searches, the studies will be imputed into Rayyan software. Duplicates will be removed. The initial selection of titles and abstracts will be performed independently by three authors (ACAS, NS and KSM), and disagreements will be resolved by the fourth author (AKG). The PRISMA flow diagram (figure 1) will show the selection process.

Figure 1.

PRISMA flow diagram for the search of eligible studies.

Data extraction and management

Three authors (ACAS, NS and KSM) will independently extract the study characteristics (author, country, type of study, follow-up, mean age, sample size, type of intravaginal physical energy and outcomes). Disagreements regarding the study acceptability were resolved through discussions among the authors.

Addressing missing data

In the event of missing data from selected studies, the authors of the article in question will be contacted via email. If it is impossible to retrieve the missing information, the data will be imputed or deleted, which will be covered in the discussion.

Data synthesis

The authors will use Review Manager Software V.5.4.1 to enter the data. Effect sizes will be expressed as risk ratios, ORs or prevalence ratios (for dichotomous data) and weighted (or standardised) mean differences (for continuous data), and their 95% CI will be calculated. In the case of heterogeneity (I² ≥ 50%), a random-effects model will combine the studies to calculate the OR and 95% CI. The χ² test will be used to evaluate the study outcomes (significance level of p < 0.1). Heterogeneity will be evaluated according to the Cochrane Handbook criteria using the I² statistic. If the I² value is <50%, heterogeneity will be considered low, and a fixed-effects model will be used in the analysis. Otherwise, heterogeneity will be considered high if the I² value is ≥50%; a random-effects model will be used. It is essential to note that this evaluation will be executed if the achievement of the meta-analysis is appropriate. Forest plots will be constructed to show study-specific and pooled risk ratio/OR estimates. Egger’s test, Duval and Tweedie’s trim-and-fill method and forest plots will be used to plot the data.

Risk of bias assessment

Two authors will independently (NS and ACAS) assess the risk of bias using the Cochrane risk-of-bias tool (RoB 2). The RoB 2 tool is structured into domains through which bias might be introduced into the result; the domains evaluated included randomisation process, deviations from intended interventions, missing outcome data, measurement of the outcome, selection of the reported results and overall.^{33 34}

Egger’s funnel plot will assess publication bias, which will be assessed as a judgement (high, low or unclear) if at least ten studies are included in the meta-analysis.

Assessing certainty in the findings

The Grading of Recommendations, Assessment, Development and Evaluation will be used to classify the strength of the evidence obtained by the meta-analysis for each outcome. The quality of evidence will be assessed based on the risk of bias, indirect bias, inconsistency, inaccuracy and publication bias.³⁵

Discussion

According to international guidelines, non-hormonal therapies (moisturising or lubricants) are the first-line treatment for mild-to-moderate VVA in BCSs.¹¹ They are less effective than hormonal therapies, often promote temporary symptom relief and require frequent reapplication. Notably, they do not induce changes in the local epithelium or reverse urogenital ageing.^{36 37}

Intravaginal physical energy has been proposed as a non-pharmacological therapeutical alternative for the management of GSM. Several studies have evaluated the effectiveness and safety of laser and radiofrequency therapy in postmenopausal women with GSM.³⁸ However, most of them exclude women with breast cancer. Studies on BCSs have a low or very low quality of evidence, with little data on intravaginal radiofrequency therapy,²² although in 2018, the Food and Drug Administration (FDA) published a statement regarding the use of vaginal devices for ‘vaginal rejuvenation, vaginal cosmetic procedures or symptoms of menopause, urinary incontinence or sexual function’.³⁹

In response to the FDA warning, a panel of experts pointed out that all devices should be accredited by the regulatory agencies, and only professionals with appropriate skills and who know the precise indications should be allowed to use them. They describe that similar medical and surgical techniques can be associated with adverse effects. Moreover, they agree that long-term safety and efficacy studies are needed before energy-based treatment can be recommended as a standard therapy.⁴⁰

A recent systematic review showed similar improvements in GSM symptoms with vaginal laser therapy versus vaginal oestrogen treatment in terms of the VAS, VHI, VMI and FSFI scores.^{21 41 42} However, a survey of health professionals caring for BCSs revealed that only 3% of respondents recommended vaginal lasers for treating GSM. The major concerns and barriers to recommendation were cost, efficacy, safety, availability and lack of knowledge that vaginal laser is an option.^{43 44}

We anticipate limitations in this review in the form that most of the studies are performed in the non-breast cancer population and the high heterogeneity of studies investigating the effects and safety of physical methods. Most are single-centre and not blinded, with short-term follow-up.

To date, there is no consensus regarding the treatment of moderate/severe GSM in BCSs. More alternatives for treatment in this group are urgently needed because hormonal therapy is contraindicated, and their symptoms are more intensive with oncological treatments. Robust evidence is warranted to be introduced into clinical practice and improve quality of life and sexual function. We aim to overcome this by placing vast evidence to support different physical methods to treat GSM in BCSs in this systematic review and meta-analysis.

Ethics and dissemination

This study is a systematic review with a possible meta-analysis, which will use data from previously conducted studies; therefore, it does not require ethical approval. The outcome of this research will be submitted for publication in a peer-reviewed journal.

Ethics statements

Patient consent for publication

Not applicable.