Erbium laser in the management of the genitourinary syndrome in patients after radical therapy for uterine cancer

Connective tissue has a wide variety of functions including protecting, general and local adaptogenic, regenerative, and morphogenetic. Collagen is the main component of connective tissue, making up about one-third of the total protein content of the human body.

The literature describes 28 types of collagen, but over 90% of the collagen in the human body are type I, II, III, IV and V, which form fibrils that assemble into fibers [1, 2].

The vaginal wall is 3-4 mm thick and does not contain any glands and sensitive nerve endings. The muscular sheath of the vagina is formed mainly by longitudinal bundles of smooth muscle fibers, outward from which is the adventitia - a sheath of dense connective tissue with a high content of elastic fibers, type I and III collagen fibers; it contains the extensive venous plexus, nerve cells and bundles of nerve fibers. The basement membrane is about 1 micron thick and consists of two plates: clear (lamina lucida) consisting of amorphous substance, and dark (lamina densa) with an amorphous matrix consisting of loose connective tissue (type IV collagen), providing mechanical strength. A stratified squamous epithelium (SSE) consists of squamous epithelial cells arranged in 4 layers upon a basal membrane; it is 150 - 200 microns thick reaching up to 2 mm in some areas. The vagina is innervated by the sympathetic and parasympathetic nervous system. There are two types of thermoreceptors sensitive to cold (Krause’s cones), lying at a depth of about 0.17 mm, and heat (Ruffini corpuscles), located at a depth of about 0.3 mm from the surface of the epithelium, as well as bare endings of afferent nerve fibers. The vulvar epithelium contains thermoreceptors, free nerve endings and encapsulated sensory nerve endings (Vater-Pacini corpuscle and Meissner’s corpuscle) [3-8]. The structure of the vaginal wall and SSE, as well as the vulvar epithelium and the depth of the thermal receptors, must be considered during the clinical implementation of the modern treatment modalities based on selective photothermolysis.

Lasers are now widely used in several fields of medicine, including gynecology, which makes the question of the interaction of laser radiation with biological tissue, in particular, connective tissue, relevant. The current literature provides sufficient coverage of the research evidence regarding the effect of laser radiation on the remodeling of collagen molecules [9, 10].

The main physical parameters of the laser, determining the impact on a particular biological target, are wavelength, energy flux density and the time of exposure. Biological tissues are heterogeneous and are intensively scattering media. Only absorption of laser energy has a therapeutically significant effect on tissue. The absorption spectrum of water - the main chromophore of biological tissue - lies in the mid- and far-infrared wavelength range. Erbium laser has a wavelength of 2.90 μm (middle infrared range), is maximally absorbed by water, which determines its effect on biological tissue without coagulation and ablation and providing an extensive but a very shallow penetration depth [11, 12].

These facts suggest the need for further studies aimed at investigating the effects of laser energy on the structure of collagen, vaginal SSE and valvular epithelium, both in reproductive and perimenopausal age. It is necessary to confirm the effectiveness and safety of this treatment modality, clarify the indications for its use and parameters of the procedures, and determine the treatment effect durability.

Management of genitourinary disorders in patients undergoing treatment for gynecologic cancers is particularly relevant, since some cases hormonal therapy is contraindicated, or patients are reluctant to use hormones, while surgery is highly undesirable due to pronounced scarring after primary treatment.

This study aimed to investigate the effectiveness of erbium laser in the management of the genitourinary menopausal syndrome in gynecologic oncology patients.

Material and methods

The study comprised 17 patients with stage I uterine cancer, who underwent a combination therapy (hysterectomy with bilateral salpingo-oophorectomy + radiation therapy) 5 and more years ago and achieved a stable remission of the disease. All patients received clinical follow-up oncology care at the place of residence with regular outpatient examinations. The diagnoses at the time of enrollment in the study included I-II grade pelvic organ prolapse, mixed urinary incontinence (overactive bladder with stress incontinence), stress urinary incontinence (SUI), vulvovaginal atrophy (VVA). The mean age of the patients was 63.5 (5.9 years. The study was conducted at the Department of Gynecology of the N.I. Pirogov CCH №1 (Moscow). Before treatment, all patients underwent a standard clinical examination (gynecological examination, vaginal swab test of vaginal secretions for vaginal flora, cytology for atypical cells, pelvic ultrasound examination, and cough test). Patients and their relatives were informed in simple terms about the laser radiation mechanism of the action and the stages of the procedures. To measure symptoms of genital prolapse and urinary incontinence, the study participants completed the PFDI-20 (Pelvic Floor Disorders Distress Inventory) questionnaire, which has three scales: pelvic organ prolapse symptoms (POPDI - Pelvic Organ Prolapse Distress Inventory - 6), colorectal-anal symptoms (CRAD - Colorectal Anal Distress Inventory - 8), and symptoms of urinary incontinence (UDI - Urinary Distress Inventory - 6). VVA was measured using VSQ (The Vulvovaginal Symptom Questionnaire), consisting of 21 questions that can be answered “yes” or “no”. Also, changes in the vaginal health index (VHI) were assessed over time. Vaginal wall trophism was examined using color Doppler mapping, and real-time sonoelastography with Toshiba Aplio 500 Ultrasound System was used to assess the tissue density. Statistical analysis was performed using the Statistica 10 software package.

All patients were treated with three applications of laser radiation on the vaginal walls, vaginal vestibule and vulva (mean energy density flux was 10 J/cm2): IntimaLase procedure (gradual exposure of the vaginal walls from the inside to the outside with up to four consecutive SMOOTH pulses for each section) and the IncontiLase procedure (application of laser energy with up to four consecutive SMOOTH pulses to the vaginal walls to each section, for the next stage - after replacing the adapter with two or three pulses at each point, perform treatment of vaginal vestibule and periurethral area). After the procedures, all patients immediately returned to their normal everyday activities.

In our study, YAG laser treatment was used as monotherapy without topical estriol treatment and anesthesia. With thinned vaginal epithelium in perimenopause, lack of glycogen in SSE cells, atrophic changes in the SSE of the vagina, vaginal vestibule and vulva, the target tissue loses the chromophore (water) and becomes more sensitive. Irritation of thermoreceptors is perceived by the patient as a painful sensation of varying intensity, and therefore each specific case requires selecting exposure parameters (reduction of the energy flux density to the required level J/cm2). So, 76% of patients (n = 13) reported painful sensations during laser energy application in the vaginal vestibule and vulva. In those cases, the parameters of the energy flow during the first procedure were reduced to 6-8 J/cm2, which does not reduce the effectiveness of therapy, contrary to the protocol of the procedures and the opinion of other researchers [13-16]. Subsequently, during the second and third procedures, in almost all patients (n = 15, 88%) the energy flux density was 10 J/cm2. No treatment-related complications were observed.

Results

Responses to PFDI-20 questionnaire suggested that the patients’ complaints were mainly associated with the symptoms of urinary incontinence (UDI-6 subscale): frequency, dripping of urine, and stress urinary incontinence. Baseline median score was 87 [67; 105]; after one-month follow-up after the 3rd procedure, the score decreased to a median of 21 [17; 30], indicating a regression or disappearance of the symptoms of genitourinary disorders after three sessions of exposure to laser radiation (Fig. 1).

Responses to UDI-6 subscale (Fig. 2) showed a decrease in all symptoms of dysuria, especially in the rates and the severity of stress urinary incontinence (SUI) and frequency by more than 50%. Nocturia (waking at night one or more times for voiding) before and after treatment was reported by 95% (n = 16) and 35% (n = 6) of patients, respectively.

Vulvovaginal symptom questionnaire (VSQ) was used to assess subjective symptoms of VVA (Fig. 3). The questionnaire has a maximum score of 20. In women who do not report current sexual activity, (“No to question 17), the final 4 questions are omitted. Mean scores in the study group at baseline and one month after the 3rd procedure were 10.9 ± 2.3 and 4.5 ± 2.0, respectively. There was a decrease both in the frequency and intensity of VVA manifestations, in particular, such as dryness, itching and burning sensation in the vagina and the vaginal vestibule by more than 50% compared with baseline (Wilcoxon t-test, p < 0.05).

VHI was used to evaluate vaginal elasticity, fluid volume, pH, epithelial integrity, and moisture on a scale of 1 to 5. The scores were distributed as follows: 25-21 - healthy vaginal epithelium, 20-16 - mild atrophy, 15 and less - moderate and significant atrophic changes in the vaginal epithelium. VHI score from 21 to 25, characterizing the healthy state of the vaginal epithelium, was observed in 12% (n = 2) of patients before treatment. At one month follow-up after the 3rd procedure, VHI ranged from 21 to 25 points in 76% (n = 13) patients, in the remaining 24% (n = 4) scores ranged from 16 to 20, which suggests normalizing pH, reducing dryness, and improving the moisture (table).

Vaginal wall elasticity (or stiffness) was measured using real-time sonoelastography, which allows determination of vaginal wall hardness using an endo-vaginal probe with a central frequency of 6.0 MHz. Changes in the frequency of the echo signal were registered while applying pressure on the vaginal wall with the vaginal probe. On the color elastogram, dense and soft tissues are depicted as purple-blue and red-yellow, respectively. The predominance of red-yellow color indicates a loss of tissue elasticity. In 70% of patients (n = 12), post-treatment sonoelastography findings showed an increase in the elasticity of the vaginal wall (the predominance of blue color on the color scale) compared with baseline values (p <0.05), which indirectly indicates the initiation of neocollagenogenesis. According to the findings of post-treatment tissue trophism assessment, 56% (n = 10) of patients showed an increase in the number of visualized vaginal wall vessels (p <0.05), which confirms the initiation of neoangiogenesis.

Discussion

Though similar studies may be found in the current literature, the relevance of the topic and the need for further research is not in doubt.

Our study, which included postmenopausal patients, showed a positive result regarding the symptoms of urinary incontinence (more than 50% reduction in the incidence and severity of SUI manifestations). A prospective cohort study conducted in 2016 by Lapii G.A. et al. included 85 patients suffering from SUI. The treatment was carried out with Er: YAG laser with a wavelength of 2940 nm (XS Dynamis, Fotona, Slovenia). The authors concluded that a ≥30% decrease in ICIQ-UI score could be predicted based on age (less than 47.5 years), body mass index (≤ 23.3), perineometer exposure time at the initial stage (≥ 3.51 seconds) and ICIQ-UI score ​​before the intervention (≤10) [17].

According to the findings of sonoelastography and color Doppler mapping, after the treatment completion, 70% and 56% of patients were found to have an improvement in turgor and trophism of the vaginal wall, respectively. In a 2017 study, the authors used IncontiLase technology to treat SUI. Before treatment, vaginal biopsy specimens showed degenerative and atrophic changes in SSE, disorganization of fibrillar structures, the extracellular matrix, and microcirculation disturbances. After exposure to a Er:YAG laser, the authors also identified signs of neocollagenogenesis and elastogenesis, foci of neoangiogenesis, a decrease in epithelial degeneration and atrophy and an increase in the fibroblast population, as well as an increase in the capillary mass density and thickness of the epithelial layer by 61.1 and 64.5%, respectively, [ 18].

Another study (Neimark AI et al., 2018) included 98 patients aged 37–63 years who were treated with an Er: YAG laser (Fotona, Slovenia) using the SMOOTH regimen for SUI and 0-2 grade genital prolapse. After the procedures, there were no deterioration and side effects, as in our study. Analysis of the PFIQ-7 and PISQ-12 questionnaires, as well as uroflowmetry, showed highly positive results. According to the Doppler flowmetry, there was an improvement in microvascular blood flow, which was comparable with our data. The vaginal wall biopsy after laser exposure demonstrated neoangiogenesis phenomena [19].

Our findings can also be compared to other clinical study results. The authors randomized 114 premenopausal SUI patients into two equal groups. In group 1 group, treatment was performed by the IncontiLase protocol (Er: YAG laser), while in group 2 (placebo), treatment was carried out without applying laser energy. Three months after treatment, patients in group 1 had significantly better scores on ICIQ-UI SF, PISQ-12, and FSFI questionnaires, as well as perineometry data (assessment of the pelvic floor muscle function) than in the control group [20]. In our study, patients after radical therapy for stage I uterine cancer also showed a significant positive effect of laser energy exposure on SUI manifestations according to the questionnaire responses.

However, despite a plethora of research, there are also conflicting opinions regarding the effects of laser radiation on the state of mature collagen. The mechanical properties of procollagen are much worse, and the half-life of mature collagen is so great that a substantial modification of the structure of the molecule under quasi-physiological conditions cannot occur for several days or weeks after the laser procedure. The long-term positive effect was not observed in any of the well-known clinical studies. During procedures, collagen synthesis is stimulated not by physiological neocollagenogenesis, but as a result of pathological fibrosis, which is a direct effect of fractional methods of rejuvenation [21].

On July 30, 2018, the FDA issued a warning to alert health care providers, who use of energy-based devices to perform vaginal “rejuvenation,” cosmetic vaginal procedures, or non-surgical vaginal procedures to treat symptoms related to menopause, urinary incontinence, or sexual function, as well as patients considering this type of treatment. Energy-based devices (commonly radiofrequency or laser) have received FDA clearance for general gynecologic indications. “Vaginal rejuvenation” is an inaccurate term used to describe non-surgical procedures for treating vaginal symptoms and/or conditions (relaxed vaginal syndrome, vaginal atrophy, dyspareunia, urinary disorders, sexual dysfunction). Health providers were advised to remember that the safety and effectiveness of energy-based devices for treatment of these conditions has not been established, and it is necessary to discuss the benefits and risks of all available treatment options for vaginal symptoms with their patients [22].

The study by Bezmenko A.A., Koval A.A. (2015) evaluated the effectiveness of SUI treatment in patients of reproductive age using two sessions of an Er: YAG laser with a 28-day interval. Magnetic resonance imaging data, PDGFR-α, VEGF, and Ki-67 expressions as markers of proliferation, were in line with the results of urodynamic studies, explaining the mechanism of storage improvement after treatment with erbium laser, namely the increase in vaginal wall thickness, the formation of new collagen and improved tissue trophism. The improvement of the quality of life also was identified when analyzing data from various questionnaires [23].

Conclusion

Our findings suggest that erbium laser is effective for the treatment of genitourinary syndrome and could be recommended as monotherapy in patients after radical therapy for stage I uterine cancer and have stress and mixed urinary incontinence and VVA. However, the positive effect is short-term and requires repeated treatment courses. Given a considerable lack of research addressing application of selective photothermolysis and its influence on the reparative processes of the vaginal and vulvar epithelium, it is necessary to adjust the power parameters (energy flux density) taking into account individual patient factors (severity of atrophy, individual sensitivity, pain threshold), which does not contradict protocol of procedures for laser exposure and does not reduce the therapeutic value of the method, but eliminates the risk of possible complications.

Management of genitourinary disorders in patients with a history of cancer treatment is particularly relevant since the choice of treatment modalities is limited. Our findings suggest that laser energy can be an option in selected patients in complete remission after consultation with a gynecologic oncologist.