A Phase II Prospective, Randomized, Double-Blind, Placebo-Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor-Positive Postmenopausal Women with Early Stage Breast Cancer in Treatment with Aromatase Inhibitor in the Adjuvant Setting

Pedro Sánchez-Rovira, Angelica Lindén Hirschberg, Miguel Gil-Gil, Begoña Bermejo-De Las Heras, Concepción Nieto-Magro, Pedro Sánchez-Rovira, Angelica Lindén Hirschberg, Miguel Gil-Gil, Begoña Bermejo-De Las Heras, Concepción Nieto-Magro

Abstract

Lessons learned: The levels of circulating follicle-stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12-week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor-positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies.

Background: Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients' quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear.

Methods: Postmenopausal women with hormone receptor-positive early breast cancer receiving NSAI and moderate-to-severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12.

Results: Sixty-one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit-of-quantitation in almost all samples.

Conclusion: Ultralow-dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens.

Trial registration: ClinicalTrials.gov NCT02413008.

© 2020 ITF Research Pharma S.L.U. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

Figures

Figure 1
Figure 1
Box‐plot of the FSH and LH values determined at each of the indicated visits in the active and placebo groups (intention‐to‐treat population). (A): FSH levels. (B): LH levels. Abbreviations: FSH, follicle‐stimulating hormone; LH, luteinizing hormone.
Figure 2
Figure 2
Flow diagram of the patients included in the study.

References

    1. Sousa MS, Peate M, Jarvis S et al. A clinical guide to the management of genitourinary symptoms in breast cancer survivors on endocrine therapy. Ther Adv Med Oncol 2017;9:269–285.
    1. Biglia N, Bounous VE, Sgro LG et al. Genitourinary syndrome of menopause in breast cancer survivors: Are we facing new and safe hopes? Clin Breast Cancer 2015;15:413–420.
    1. Hickey M, Saunders C, Partridge A et al. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann Oncol 2008;19:1669–1680.
    1. Melisko ME, Goldman M, Rugo HS. Amelioration of sexual adverse effects in the early breast cancer patient. J Cancer Surviv 2010;4:247–255.
    1. Buhling KJ, Eydeler U, Borregaard S et al Systemic bioavailability of estriol following single and repeated vaginal administration of 0.03 mg estriol containing pessaries. Arzneimittelforschung 2012;62:378–383.
    1. Heimer G, Englund D. Estriol: Absorption after long‐term vaginal treatment and gastrointestinal absorption as influenced by a meal. Acta Obstet Gynecol Scand 1984;63:563–567.
    1. Karch FE, Lasagna L. Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther 1977;21:247–254.
    1. Pfeiler G, Glatz C, Königsberg R et al. Vaginal estriol to overcome side‐effects of aromatase inhibitors in breast cancer patients. Climacteric 2011;14:339–344.
    1. Arslan AA, Gu Y, Zeleniuch‐Jacquotte A et al. Reproducibility of serum pituitary hormones in women. Cancer Epidemiol Biomarkers Prev 2008;17:1880–1883.
    1. Katzenellenbogen BS. Biology and receptor interactions of estriol and estriol derivatives in vitro and in vivo. J Steroid Biochem 1984;20:1033–1037.
    1. Mas M. Tratamiento de la atrofia urogenital mediante administración intravaginal de estrógenos a bajas dosis, con especial referencia al estriol. Bases fisiológicas y farmacológicas. Prog Obs Ginecol 2011;54(suppl 2):1–21.
    1. Delgado JL, Estevez J, Radicioni M et al. Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra‐low‐dose estriol in postmenopausal women. Climacteric 2016;19:172–180.
    1. Cano A, Estévez J, Usandizaga R et al. The therapeutic effect of a new ultra low concentration estriol gel formulation (0.005% estriol vaginal gel) on symptoms and signs of postmenopausal vaginal atrophy: Results from a pivotal phase III study. Menopause 2012;19:1130–1139.
    1. Donders G, Neven P, Moegele M et al. Ultra‐low‐dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor®) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: Pharmacokinetic, safety, and efficacy phase I clinical study. Breast Cancer Res Treat 2014;145:371–379.
    1. Knobf MT. The influence of endocrine effects of adjuvant therapy on quality of life outcomes in younger breast cancer survivors. The Oncologist 2006;11:96–110.
    1. Diller M, Schüler S, Buchholz S et al. Effects of estriol on growth, gene expression and estrogen response element activation in human breast cancer cell lines. Maturitas 2014;77:336–343.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する