Sexual and Vaginal Health in Breast Cancer Women Receiving Aromatase Inhibitors Before and After CO2 Laser Therapy: A Randomized, Double-blind, Sham-controlled Trial - LIGHT Study
Phase: NA
Conditions: Breast Cancer, Genitourinary Syndrome of Menopause
Sponsor: Hospital Clinic of Barcelona

 
TITLE OF STUDY:  
Sexual and vaginal health in breast cancer women receiving aromatase inhibitors before and after 
CO2 laser therapy: a randomized, double-blind, sham-controlled trial. 
 
NCT number: Not yet assigned 
 
Document date: 24th August 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
GLOSSARY: 
 
BCS: Breast cancer survivors 
AI: Aromatase inhibitors 
GSM: Genitourinary syndrome of menopause 
PLISSIT Model: Permission, Limited information, Specific suggestions, intensive therapy 
FSFI: Female sexual function index 
VAS: Visual analogue scale 
S-BIS: Spanish- Body image scale 
SF-12: Short form-12 healthy survey 
AEs: Adverse events 
SAEs: Serious adverse events 
 
 
 
SUMMARY (max 300 words):  
 
Please summarise the background, aims, methods and expected impact in simple terms 
 
Background: Vulvovaginal health, directly linked to sexual health, is a key factor for female pleasure. 
BCS receiving AI are likely to present severe GSM and sexual complaints. Innovative options, as 
vaginal laser therapy, are emerging to treat GSM and sexual dysfunctions. Nowadays, data in BCS is 
scarce, moreover, few studies included patients receiving AI [16]. Different meta-analysis [17-23] 
found GSM [24, 25] and sexual function [9, 10] may improve significantly at short-term, however, 
the body of evidence is of low quality. Therefore, before recommendation of laser therapy for sexual 
complaints in BCS with GSM, there are unmet needs to be solved: efficacy and safety at long-term, 
biases related to patients’ expectations and a detailed assessment of the complex underpinnings of 
sexuality. 
Aims: To evaluate sexual and vaginal health in BCS receiving AI with GSM, before and after CO2 
laser therapy compared to a sham-controlled group. 
Methods: Prospective, randomized, double-blind controlled study with two parallel study arms: 1) 
Fractional CO2 laser therapy (5monthly sessions). 2) Sham laser therapy (5monthly sessions). After 
end-treatment, patients are followed up at 1 month and 6 months. BCS treated or undergoing AI with 
GSM and sexual function impairment, will be suitable. All patients will maintain first-line non-
hormonal treatment and sexual assessment (PLISSIT Model) according with usual care. The primary 
outcome is improvement in sexual function (FSFI total score). As secondary outcomes: resumption 
sexual activity, sexual activity frequency, dyspareunia (VAS), female sexual dysfunction, sexual 
dimensions (FSFI), body image (S-BIS), quality of life (SF-12), vaginal pH acidification, maturation 
index and Vaginal Health Index of Gloria Backmann, adverse events, satisfaction (Likert scale) and 
adherence to treatment. 
Expected impact: Emergent, non-invasive, laser therapy has significant benefit for BCS with AI, 
improving subjective and objective sexual and vaginal health outcomes and adding value to the usual 
care multidisciplinary approach.  
 
 
 
BACKGROUND (max 500 words):  

Sexuality is a central aspect of being human throughout life encompasses sex, gender identities and 
roles, sexual orientation, eroticism, pleasure, intimacy and reproduction [1]. Most of these aspects 
may be affected in breast cancer survivors (BCS). In a recent meta-analysis [2, 3] focused on sexual 
function through Female Sexual Function Index (FSFI) among BCS, female sexual dysfunction 
prevalence was 73,4% (95 % CI 64–82.8 %, I2 = 96.8 %) and mean FSFI 19.28 (95 % CI 17.39–
21.16, I2 = 97.6 %). Several modifiable risk factors for sexual dysfunction in BCS may be optimum 
targets for intervention: amelioration of vaginal discomfort and urinary incontinence, the benefits of 
breast conserving surgery on body image or the evaluation of relationship quality [4, 5] Due to the 
multifaceted nature of the factors affecting sexuality in BCS, most authors [3-10] encouraged the 
need for comprehensive assessment and for a multidisciplinary approach. 
 
BC diagnosis and/or its treatments (surgery, chemoradiotherapy, hormonal therapy) may altered 
sexual health. Vulvovaginal health, directly linked to sexual health, is a key factor for female pleasure. 
Genitourinary syndrome of menopause (GSM) is caused by decline in estrogen at menopause, which 
may also appear or worsen after systemic cancer treatments as aromatase inhibitors (AI). GSM is 
associated with sexual symptoms (lack of lubrication, discomfort or pain, impaired function), genital 
symptoms (dryness, burning, irritation) and urinary symptoms (urgency, dysuria, recurrent urinary 
tract infections). BCS receiving AI are one of the groups most likely to present severe GSM and 
sexual complaints [11]. A cross-sectional study [12] on 129 BCS during the first 2 years of adjuvant 
AI therapy, found 3 out of 4 women were distressed about their sexual problems. Only 52% of women 
had been sexually active when endocrine therapy began, but 79% of that group developed new sexual 
problems.  
 
The first line of treatment for GSM is non-hormonal therapy (regular sexual activity, moisturizers-
lubricants, pelvic-floor relaxation techniques, dilators) although in many women these options will 
not adequately control symptoms. Hormonal therapies must be used with caution in women with 
estrogen-dependent cancers [13-15]. So, alternative options are emerging for this subset of patients, 
such as vaginal laser therapy. Different studies [16-18] provided short-term data on non-cancer 
patients that showed laser therapy was feasible, safe and improved objective and subjective GSM. 
Data regarding sexuality derived from secondary endpoints and suggested that laser therapy may 
improve sexual function, mainly decreasing sexual pain [16, 18].  To date, data on laser therapy in 
BCS is scarce, moreover, few studies included patients receiving ongoing AI [19]. The CO2 laser 
was the most frequently used device. Different reviews and meta-analysis [20-26] found GSM [27, 
28] and sexual function [9, 10] may improve significantly at short-term, however, the body of 
evidence is of low quality. Therefore, before recommendation for the use of laser therapy for sexual 
complaints in BCS with GSM, there are unmet needs to be solved as efficacy and safety at long-term, 
biases related to patients’ expectations of therapy and a detailed assessment of the complex 
underpinnings of sexuality. 
 
 
 
AIMS (max 200 words):  
 
To answer the unmet needs previously mentioned, the aim of the current study is to verify the 
outcomes of sexual and vaginal health in breast cancer women receiving AI, who were experiencing 
symptoms of GSM, before and after CO2 laser therapy compared to a sham-controlled group. 
 
Specifically, we will compare the following subjective and objective measurements of sexual and 
vaginal health: 
 
MAIN GOAL: Report an improvement in sexuality:  
- Primary outcome: sexual function (FSFI total score) 

- Secondary sexual outcomes: resumption sexual activity (sexually active vs non-sexually active), 
sexual activity frequency (nº sexual activity/week), dyspareunia (VAS), female sexual dysfunction 
(VAS sexual life distress), sexual dimensions: desire, arousal, lubrication, orgasm, satisfaction and 
pain (FSFI) and body image (S-BIS) 
 
OTHER OBJECTIVES: Report an improvement on GSM symptoms (efficacy) and quality of life, 
feasibility and safety of laser therapy in BCS: 
- Secondary non-sexual outcomes: quality of life (SF-12). Verify an acidification of the vaginal pH, 
an improvement in the maturation index and an improvement in the Gloria Backmann Index: Vaginal 
Health Index. To evaluate toxicity associated with vaginal laser therapy in this population (AEs and 
SAEs). To determine how many women with the defined patient eligibility will complete all 
treatments. 
 
 
 
METHODS (max 500 words): 
 
DESIGN: Prospective, randomized, double-blind controlled study with two parallel study arms: 
ARM I: Patients undergo fractional CO2 laser therapy at 5 times points 30 days apart. ARM II: 
Patients undergo sham laser therapy at 5 time points 30 days apart. After completion of the treatment, 
patients are followed up at 1 month and 6 months. 
 
RANDOMIZATION PROCESS: A randomization list will be generated in multiple blocks of 2 and 
1: 1 ratio with STATA version 15.1 or higher. 
  
STUDY SUBJECTS: Patients treated or undergoing AI for BC in the Breast Cancer Unit of the 
Hospital Clínic and who present symptoms related to GSM that condition their sexual function and 
quality of life, despite receiving first-line non-hormonal treatment: regular sexual activity (such as 
mutual and self-touch masturbation, manual or vibrator stimulation, oral sex, sexual intercourse, 
massage and other forms of physical intimacy), moisturizers, lubricants, pelvic-floor relaxation 
techniques and/or dilators. Inclusion and exclusion criteria are summarized in Table 1. 
 
STUDY GROUPS: All patients will receive instructions to maintain first-line non-hormonal 
treatment, as well as sexual assessment using the PLISSIT Model according with usual care in our 
hospital.  
The study group will be treated with a vaginal fractionated CO2 laser protocol (The SMARTXIDE 
TOUCH (Deka) equipment with an autoclavable vaginal probe following the manufacturer's protocol 
(Annex 9).  
The control group will receive treatment with a sham-CO2 laser using a double-blinded protocol.  
 
STUDY STRUCTURE (See Annex 1). 
 
SAMPLE CALCULATION 
Considering FSFI score as the main variable of the study, we performed a calculation of the 
hypothesis contrast study sample with the comparison of two independent means. Accepting an alpha 
risk of 0.05 and a beta risk of less than 0.1 in a bilateral contrast, 44 subjects in the first group and 44 
in the second. The common standard deviation is assumed to be 1. A follow-up loss rate of 15% has 
been estimated. 
 
STATISTIC ANALYSIS 
Descriptive statistics will be used according to standard calculation methods.  

The comparison between the two treatments at the end of the study will be evaluated through the 
change with the baseline using a mixed repeated measures model (MMRM) adjusted for the baseline 
value and including the treatment and the time in the model. 
The variables of repetitive evaluation over time are analyzed according to the following strategy: (a) 
continuous variables with a repeated measures mixed longitudinal model (MMRM); (b) binary or 
non-normal variables with marginal models (Generalized Estimating Equation: GEE). Other 
variables will be studied as follows: Fisher's exact test for categorical variables, Student's t test for 
continuous variables between 2 groups. Non-parametric methods for independent data (Mann-
Whitney U for 2 groups or Kruskall-Wallis test for more than 2 groups) will be used if necessary. 
The level of statistical significance will be 5% bilateral. The main analysis will be by Intention to 
Treat (ITT). 
 
 
 
REFERENCES: 
 
1. World Health Organization. Defining sexual health. Report of a technical consultation on sexual 
health 28-31, January 2002, Geneva. Geneva: World Health Organization, 2006. 
2. MI Maiorino, P Chiodini, G Bellastella, D Giugliano, K Exposito. Sexual dysfunction in women 
with cancer: a systematic review with meta-analysis of studies using the Female Sexual Function 
Index. Endocrine (2016) 54:329–3413.  
3. Jing L, Zhang C, Li W,  Jin F, Wang A. Incidence and severity of sexual dysfunction among women 
with breast cancer: a meta-analysis based on female sexual function index. Supportive Care in Cancer 
(2019) 27:1171–1180. 
4. Greendale G, Petersen L, Zibecchi L, Ganz P. Factors related to sexual function in postmenopausal 
women with a history of breast cancer. Menopause. Vol. 8, No. 2, pp. 111–119 
5. Boquiren VM, Esplen MJ, Wong J, Toner B, Warner E, Malik N. Sexual functioning in breast 
cancer survivors experiencing body image disturbance. Psychooncology. 2016;25(1):66-76.  
6. Fatehi S, Maasoumi R, Atashsokhan G, Hamidzadeh A, Janbabaei G, Mirrezaie SM. The effects 
of psychosexual counseling on sexual quality of life and function in Iranian breast cancer survivors: 
a randomized controlled trial. Breast Cancer Res Treat. 2019;175(1):171-179.  
7. Faghani S, Ghaffari F. Effects of Sexual Rehabilitation Using the PLISSIT Model on Quality of 
Sexual Life and Sexual Functioning in Post-Mastectomy Breast Cancer Survivors. Asian Pac J 
Cancer Prev. 2016;17(11):4845-4851. Published 2016 Nov 1.  
8. Advani P, Brewster AM, Baum GP, Schover LR. A pilot randomized trial to prevent sexual 
dysfunction in postmenopausal breast cancer survivors starting adjuvant aromatase inhibitor 
therapy. J Cancer Surviv. 2017;11(4):477-485.  
9. Athanasiou S, Pitsouni E, Douskos A, Salvatore S, Loutradis D, Grigoriadis T. Intravaginal energy-
based devices and sexual health of female cancer survivors: a systematic review and meta-
analysis. Lasers Med Sci. 2020;35(1):1-11.  
10. Jha S, Wyld L, Krishnaswamy PH. The Impact of Vaginal Laser Treatment for Genitourinary 
Syndrome of Menopause in Breast Cancer Survivors: A Systematic Review and Meta-analysis. Clin 
Breast Cancer. 2019;19(4):e556-e562.  
11. Baumgart J, Nilsson K, Evers AS, Kallak TK, Poromaa IS. Sexual dysfunction in women on 
adjuvant endocrine therapy after breast cancer. Menopause. 2013;20(2):162-168.  
12. Schover LR, Baum GP, Fuson LA, Brewster A, Melhem-Bertrandt A (2014) Sexual problems 
during the first 2 years of adjuvant treatment with aromatase inhibitors. J Sex Med 11(12):3102–
3111. 
13. Crean-Tate KK, Faubion SS, Pederson HJ, Vencill JA, Batur P. Management of genitourinary 
syndrome of menopause in female cancer patients: a focus on vaginal hormonal therapy. Am J Obstet 
Gynecol. 2020;222(2):103-113.  

14. Oyarzun MFG,Castelo-Branco C. Local hormone therapy for genitourinary syndrome of 
menopause in breast cancer patients: is it safe? Gynecol Endocrinol. 2017;33(6):418-420. 
15. Sánchez-Borrego R, Mendoza N, Beltrán E, Comino R, Allué J, Castelo-Branco C et al. Position 
of the Spanish Menopause Society regarding the management of menopausal symptoms in breast 
cancer patients. Maturitas. 2013 Jul;75(3):294-300. 
16.Salvatore S, Pitsouni E, Del Deo F, Parma M, Athanasiou S, Candiani M. Sexual Function in 
Women Suffering From Genitourinary Syndrome of Menopause Treated With Fractionated 
CO2 Laser. Sex Med Rev. 2017;5(4):486-494.  
17. Pitsouni E, Grigoriadis T, Falagas ME, Salvatore S, Athanasiou S. Laser therapy for the 
genitourinary syndrome of menopause. A systematic review and meta-analysis. Maturitas. 
2017;103:78-88.  
18. Romero-Otero J, Lauterbach R, Aversa A, et al. Laser-Based Devices for Female Genitourinary 
Indications: Position Statements From the European Society for Sexual Medicine (ESSM). J Sex 
Med. 2020;17(5):841-848.  
19. Quick AM, Zvinovski F, Hudson C, et al. Fractional CO2 laser therapy for genitourinary 
syndrome of menopause for breast cancer survivors. Support Care Cancer. 2020;28(8):3669-3677.  
20. Pagano T, De Rosa P, Vallone R, et al. Fractional microablative CO2 laser in breast cancer 
survivors affected by iatrogenic vulvovaginal atrophy after failure of nonestrogenic local treatments:  
retrospective study [published correction appears in Menopause. 2018 Oct;25(10):1169]. Menopause. 
2018;25(6):657-662.  
21. Pagano T, De Rosa P, Vallone R, et al. Fractional microablative CO2 laser for vulvovaginal 
atrophy in women treated with chemotherapy and/or hormonal therapy for breast cancer: a 
retrospective study. Menopause. 2016;23(10):1108-1113.  
22. Pieralli A, Fallani MG, Becorpi A, et al. Fractional CO2 laser for vulvovaginal atrophy (VVA) 
dyspareunia relief in breast cancer survivors. Arch Gynecol Obstet. 2016;294(4):841-846.  
23. Pearson A, Booker A, Tio M, Marx G. Vaginal CO2 laser for the treatment of vulvovaginal 
atrophy in women with breast cancer: LAAVA pilot study. Breast Cancer Res Treat. 
2019;178(1):135-140.  
24. Mothes AR, Runnebaum M, Runnebaum IB. Ablative dual-phase Erbium:YAG laser treatment 
of atrophy-related vaginal symptoms in post-menopausal breast cancer survivors omitting hormonal 
treatment. J Cancer Res Clin Oncol. 2018;144(5):955-960.  
25. Gambacciani M, Levancini M. Vaginal erbium laser as second-generation thermotherapy for the 
genitourinary syndrome of menopause: a pilot study in breast cancer survivors. Menopause. 
2017;24(3):316-319.  
26. Gittens P, Mullen G. The effects of fractional microablative CO2 laser therapy on sexual function 
in postmenopausal women and women with a history of breast cancer treated with endocrine 
therapy. J Cosmet Laser Ther. 2019;21(3):127-131.  
27. Tranoulis A, Georgiou D, Michala L. Laser treatment for the management of genitourinary 
syndrome of menopause after breast cancer. Hope or hype?. Int Urogynecol J. 2019;30(11):1879-
1886.  
28. Knight C, Logan V, Fenlon D. A systematic review of laser therapy for vulvovaginal 
atrophy/genitourinary syndrome of menopause in breast cancer survivors. Ecancermedicalscience. 
2019;13:988. Published 2019 Dec 12.  
 
 
IMPACT (max 300 words): 
What would be the impact of the project on sexual medicine field when it is successfully completed? 
Please explain how your project fits to the specific call 
 
The BCS receiving AI are at higher risk of developing GSM symptoms. Sexual issues are common, 
either secondary to painful sex or as a direct effect of estrogen deprivation in the brain. However, 

addressing sexual health issues in BCS still meets several barriers from both, patient and health care 
professionals. GSM symptoms do not put survival at risk, however, have a significant impact in the 
quality of life [26].  
 
The first-line treatment for GSM symptoms should be non-hormonal therapies according clinical 
guidelines, although frequently it will be insufficient to alleviate symptoms. Hormonal therapies are 
not currently recommended and must be used with caution in BCS [13-15]. So, energy-based 
treatments have emerged as a promising option in this subgroup of patients. However, the body of 
evidence is lacking to make decisive recommendations [18], specially to treat sexual complaints. 
There is an urgent need to carry out RCT with larger sample size, long-term follow-up and blinded 
control group for answer various unmet needs in this field: short/mid and long-term safety issues and 
efficacy, treatment modalities (type of laser) and protocols (laser parameters, sessions numbers, 
repetitions). 
 
This project aims to demonstrate that emergent, non-invasive, non-anesthetic laser therapy has 
significant benefit for BCS with AI, measured in a prospective, randomized, double-blind controlled 
trial using validated tools for subjective and objective sexual and vaginal health outcomes and quality 
of life.  
 
Moreover, sexual health is a state of physical, emotional, mental and social well-being in relation to 
sexuality which requires the possibility of having pleasurable and safe sexual experiences [1]. So, 
both arms of study groups will benefit from multidisciplinary approach including non-hormonal 
therapies (regular sexual activity, moisturizers, lubricants, pelvic floor relaxation techniques and/or 
dilators) and sexual assessment using the PLISSIT Model according with usual care in our hospital 
and with international recommendations [7, 8, 18]. 
 
 
ETHICAL AND REGULATORY PERMISSIONS:  
Please explain the ethical and regulatory permissions already obtained or to be obtained for (if 
applicable): 
1) Animal research 
2) Human tissue 
3) Research with human participants 
If the permissions have not been obtained already, please give timelines of when they are expected to 
be obtained and how obtaining such permissions will affect the overall project timelines. 
 
 
This study will be conducted according to the Helsinki Declaration and to Good Practice Guidelines. 
Approval from Ethics Committee of Hospital Clínic de Barcelona has been recently applied (August 
2020) and the study will be registered on ClinicalTrials.gov. As we are on holiday time in Spain 
(August) and also due to the current COVID-19 situation in Barcelona, a delay in the usual approval 
rhythm of our ethical committee is expected. However, we hope to obtained such a permission on 
October 2020, which will not affect the overall project timelines.  
 
All eligible women will be informed about the study by briefing the participants on the study 
objectives and taking into account their willingness to participate (telematic visit). After an interval 
of at least 48h the patient will have a second visit (presential) and if she wants to participate the signed 
informed consent form will be checked. Both in- and exclusion criteria will be reviewed and if found 
suitable, the patient will be randomized. Both the patient information letter and informed consent 
form are attached as a separate document. Patients can leave the study at any time for any reason if 
they wish to do so without any consequences. The investigator can decide to withdraw a subject from 

the study for urgent medical reasons. Patients who withdrew their informed consent will not be 
replaced. We will replace patients that are randomized by mistake, for example because of technical 
errors with online randomization. Patients withdrawn from the intervention but not from informed 
consent will be followed up. 
 
None of the subjects will receive any (financial) compensation for participating in this trial. However, 
to minimize dropouts and build patient loyalty, we will offer them at the end of the study an additional 
laser treatment session, and those in the placebo group will be offered the 5 treatment sessions. 
 
 
 
 
BUDGET: 
Please give a detailed and itemized budget, see T&C for eligible and ineligible costs 
Execution Expenses 
A) Personnel costs  
 
A postgraduate research student (Dr. Mension) will be hired 15h/week during 18months in order to 
perform task described in the Workplan. In addition, will be in charge of: 
- Transcription of data to database. 
- Management and coordination of patient appointments, as well as evaluation and resolution of 
problems derived from the study. 
- Evaluation of results. 
- Writing of manuscript. 
 
 
B) Acquisition of materials and contracting of services 
 
PH meter paper roll 5m x 2 IU x 10 = € 20 
Maturation index (provided by Hospital Clinic de Barcelona): 12€ x 264 (88 patients throughout the 
study in 3 timepoints) = 3168€ 
Kit Silicone vaginal dilator (ref 69-4805-05-3) 44 units x 34,95 € (50% patients of the study) = 
1537,8€ 
Vaginal vibrator (ref. 729232) x 88 units x € 8.95 =787,6€ 
Vaginal lubricant tube 100 mL x 616 IU x € 3,5 (for 88 patients throughout the study) = 2156€ 
Moisturizer hyaluronic acid-based ovules (Cerviron®) provided free of charge by Interpharm (for 88 
patients throughout the study) = 0€ 
CO2 laser equipment: The SMARTXIDE TOUCH provided free of charge by DEKA = 0€ 
Tablet: 
Smartphone and phone line (18 months - study phone contact): 
 
C) Travel Expenses 
Dissemination of the results of the study of national / international conferences 1500€ 
 
 
COST CATEGORY 
COST 
1. Personnel 
20.830,6 € 
2. Consumables and services 
7669,4 € 
3. Travel expenses 
1.500 € 
TOTAL  
30.000 

 
 
 
 
 
 
SCHEDULE: 
 
 
0-1 
2-3 4 
5 
6 
7 
8 
9 
10 
11-14 15 16 17 18 
Database design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruitment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analysis results  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Manuscript edition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATTACHMENTS: 
Please attach: 
CV of the PI including list of all peer reviewed publications 
Copies of ethics and regulatory permissions 
Any figures or tables 
 
 
 

Table 1: inclusion and exclusion criteria 
 
Inclusion Criteria 
 
BC treated with aromatase inhibitors ± GnRH analogues (aGnRH) 
 
Menopause (natural or induced) and signs / symptoms of GSM; Vaginal pH ≥5 
 
Negative Human Papillomavirus (HPV) cytology and / or determination 
 
Intention or willingness to have sex 
 
Signed informed consent 
Exclusion criteria 
 
Vaginal hormonal treatment in the last 6 months 
 
Vaginal moisturizers and / or lubricants during the 30 days prior to study treatment 
 
Laser treatment, radiofrequency, hyaluronic acid, lipofilling in the vagina during the last 
2 years 
 
Ospemifene treatment 
 
Being affected for: active infection of the genital tract; intraepithelial neoplasm of cervix, 
vagina, or vulva; have or have been treated for genital cancer; Genital prolapse stage ≥II. 
 
 
 

 
 
ANNEXED: 
 
Annex 1: STUDY STRUCTURE (Table 2):  
A) Screening/Recruitment telematic visit (T-2): to select elegible patients and to deliver information 
sheet and explanation of the project. 
B) Screening/Recruitment presential visit (T-1): to perform physical examination and sexual 
assessment, to confirm elegibility and to sign informed consent. 
C) Baseline presential Visit (T0): to fill in baseline questionnaires and to assess sexuality using 
PLISSIT Model according usual care in our hospital. 
D) Treatment visits: T1 (session 1), T2 (session 2), T3 (session 3), T4 (session 4), T5 (session 5): to 
perform the intervention according previous description. 
E) Follow-up visits: T6 (1 month after session 5), T12 (7 months after session 5): to perform physical 
examination and fill in questionnaires at short and mid-term. Out of timeline project, a visit T24 (13 
months after session 5) is planned as usual care practice in our hospital to assess outcomes at long-
term follow-up (also approved by our Ethical Committee). 
 
Table 2. Study structure 
Endpoint 
Instrument 
T-2 
T-1 
T0 
T1-T5 
T6 
T12 
Inclusion/exclusion 
criteria 
Checklist database 
X 
 
 
 
 
 
Trial information 
Delivery Written and verbal 
information 
Signature Informed consent 
X 
 
 
X 
 
 
 
 
Baseline 
characteristics 
General Anamnesis 
BC Anamnesis 
Sexual Anamnesis 
Socio-demographic data 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Physical 
examination 
Gynaecological examination 
VHI of Gloria Bachmann *1 
Vaginal pH *2 
Maturation index *3  
(vaginal cytology)  
Liquid cytology 
(reflex HPV determination) 
Pelvic floor muscle function 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
X 
GSM symptoms 
 
VAS dispareunia *4 
VAS dryness *4 
VAS burning *4 
ICIQ-IU-SF + CACV 
 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Sexual symptoms 
FSFI total score *5 
VAS sexual life distress *4 
 
 
X 
X 
 
X 
X 
X 
X 
Body image 
S-BIS *6 
 
 
X 
 
X 
X 
Generic quality of 
life 
SF-12 *7 
 
 
X 
 
X 
X 
Intervention 
Laser vs sham 
 
 
 
X 
 
 
Adherence to 
treatment 
Adherence diary 
 
 
 
X 
 
 
Adverse events 
Database/ AEs form 
 
 
 
X 
X 
X 
Treatment 
satisfaction 
Likert scale 
 
 
 
 
X 
X 
 
*1Evaluation of the Vaginal Health Index of Gloria Bachmann: An exploration of the lower genital 
tract 
will 
be 
carried 
out 
and 
the 
degree 
of 
AVV 
will 
be 
assessed 
through 

(https://www.maturitas.org/article/0378-5122(95)00956-6 / pdf). This index subjectively assesses the 
vagina's staticity, the amount of discharge, the integrity of the epithelium and humidity, along with 
pH as the only objective criterion. A score of ≤ 15 indicates AVV. It is the Index most used in 
publications reporting improvement of AVV with the use of lasers. 
 
*2Vaginal vaginal pH: Using a pH test strip, colorimetric analysis of the pH of the vaginal discharge 
is performed. 
 
*3Maturative Index: Using vaginal cytology, the percentage of parabasal, intermediate and superficial 
cells is calculated, allowing us to calculate the epithelial thickness indirectly. 
 
*4 Visual Analog Scale (VAS): Evaluates 3 symptoms of AVV: dyspareunia, dryness and burning. 
Score from 0 to 10 (unbearable symptom). Symptoms are considered moderate from ≥ 4. 
 
*5 Female Sexual Function Index (FSFI): Generic sexual questionnaire validated for cancer survivors. 
We used the 19-item self-reported Spanish validated questionnaire to assess 6 sexual dimensions 
(desire, arousal, lubrication, orgasm, satisfaction and pain) and the global sexual function. Score 
ranges from 1,6 to 36, with the higher score indicating a better sexual 
Function. Function. A cut-off value of ≤ 26.55 indicates risk of sexual dysfunction, however, it could 
inflate female sexual dysfunction rates in those women whose sexual activity frequency is lower than 
once a month or in non-sexually active women. (https://scielo.conicyt.cl/pdf/rchog/v69n2/art06.pdf) 
 
*6 Body Image Scale-Spanish version (S-BIS): Assesses 10 domains of body image in 10 questions 
and is applicable in patients with any type of cancer and different therapeutic regimens. The total 
score ranges from 0 to 30. The higher the score, the greater the concern regarding body image. 
(https://www.ncbi.nlm.nih.gov/pubmed/25135839). 
 
*7 Quality of life Short Form 12 (SF-12): It consists of 12 items from the 8 dimensions of the SF-36 
Physical Function (2), Social Function (1), Physical Role (2), Emotional Role (2), Mental health (2), 
Vitality 
(1), 
Body 
pain 
(1), 
General 
Health 
(1). 
(http://www.ser.es/wp-
content/uploads/2015/03/SF12_CUESTIONARIO.pdf) 
 
 

Annex 2: Vaginal Health Index of Gloria Bachmann 
 
 
 
 
 

Annex 3: VAS 
 
 
 
 
 

Annex 4: FSFI 
 
 
 

 
 

 
 

 
 

 
 
 

Annex 5: S-BIS 
 
 
 

 
 
 

Annex 6: SF-12 
 
 
Annex 7: Adherence diary 
 

  
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
SUNDAY 
WEEK 
M 
  
L 
  
M 
  
L 
  
M 
  
L 
  
M 
  
L 
  
M 
  
L 
  
M 
  
L 
  
M 
  
L 
  
1 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
2 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
5 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
6 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
7 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
9 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
11 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
12 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
13 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
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19 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
20 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
S 
Mark with an "X" in the corresponding box if you have completed the treatment as 
indicated by your health care professional: M (moisturizer) and/or L (lubricant).  
S If you used some other therapies as D (dilator) or V (vibrator), please fill in.  
 
 

Annex 8: Laser protocol 
 
The laser parameters will be as follows: 
(1) Power: 30 W. 
(2) Dwell time: 1000 ls. 
(3) Spacing: 1000 lm. 
(4) Depth: SmartStak parameter from 1 to 3 depending on 
the treatment status. 
(5) D-pulse mode. 
(6) At the introitus the power will be reduced to 24 W. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex 9: AEs form 
 
Adverse Event 
 
Has the patient experienced any Adverse Event between this 
visit and the previous visit? 
O Yes   O No  
 
If “Yes”, please fill in the Adverse Event 
Page for each Adverse Event. 

 
(Serious) Adverse Events 
Patient Identification Number1: |__|__|__|__|__| 
                                                                                  Date of birth (dd mm yyyy: |__|__|__|__|__|_  |__|__| 
 
 
ADVERSE EVENTS*  
 
Description  
(diagnosis (if known) or 
sign/symptoms) 
Start date 
Severity 
 
Relation to 
study device  
Action study treatment 
 
Other action taken 
 
End date (if applicable)  
……………………
……. 
……………………
……. 
……………………
……. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start 
|__|__| - |__|__|__| - |__|__|__|__|   |__|__|:|__|__| 
 d  d   -  m m m   -  y   y   y   y     h  h  :  m m 
 
O mild 
O moderate 
O severe 
 
O Definitely not 
Device-related 
O Remotely 
Device-related 
O Possibly 
Device-related 
O Probably 
Device-related 
O Definitely 
Device-related 
O unassessable 
 
O none 
O temporary stop 
O permanent stop 
O modification, specify : 
     ……………………………… 
     ……………………………… 
O unknown  
O not applicable6 
O none 
O comedication: please fill out comedication page 
O (prolongation of) hospitalisation  
O other, specify: 
     ………………………………………………… 
     ………………………………………………… 
O unknown  
O not applicable 
End 
|__|__| - |__|__|__| - |__|__|__|__|   |__|__|:|__|__| 
d  d   -  m m m   -  y   y   y   y      h  h  :  m m 
OR   
O if ongoing  

 
Outcome 
Serious Adverse Event?               (check one or more of the boxes below) 
O  recovered/resolved 
O not recovered/resolved 
      If stabilized, specify date:  |__|__|-|__|__|__|-
|__|__|__|__| 
                                                  d  d   - m  m  m -  y   y   y   y 
O recovering/resolving 
O recovered/resolved with sequelae 
O fatal,  date of death:  |__|__|-|__|__|__|-|__|__|__|__| 
                                         d  d   - m  m  m  -  y   y   y   y 
O unknown 
O Yes, specify: 
………………
………………
………………
……… 
O No 
□ results in death 
□ life threatening 
□ (prolonged) hospitalisation 
□ persistent or significant disability/ incapacity 
□ congenital anomaly/ birth defect 
□ other medically important serious event: 
       …………………………………………………………….. 
*: The study period during which adverse events must be reported is normally defined as the period from the time of signed informed consent to the end of the study treatment follow-up. 
#: Any event meeting the definition of “serious” requires notification.

 
 
28 
Annex 10: Likert scale 
 
 
 
 
 

 
 
29 
 
Annex 11: ICIQ-IU-SF 
 

 
 
30 
Annex 12: CACV 
 
 
 

 
 
31