Estrogen vs Moisturizer for Vaginal Dryness in Breast Cancer Patients

(REVIVE Trial)

Overseen By Polly Niravath, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Polly A. Niravath, MD

Must be taking: Adjuvant AI therapy

Must not be taking: Exogenous estrogen

Disqualifiers: Current vaginal infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 10

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if breast cancer patients on anti-estrogen treatment can relieve vaginal dryness using either vaginal estrogen or a moisturizer called Replens. It compares two treatments: ESTRING, a form of vaginal estrogen, and Replens, a non-estrogen moisturizer. Post-menopausal women with stage I-III estrogen-receptor-positive breast cancer who experience vaginal dryness or discomfort while on anti-estrogen therapy might be suitable for this study. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important findings.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must not use any additional estrogen during the study. You can continue using non-estrogen lubricants.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that Estring, a vaginal ring releasing a small amount of estrogen, is generally safe for individuals who have had breast cancer. It alleviates symptoms like vaginal dryness. Research suggests it does not significantly increase the risk of breast cancer recurrence. However, experts recommend further studies to fully understand its safety, especially for those with hormone-sensitive cancers.

Replens, a non-hormonal vaginal moisturizer, is considered safe and approved by health authorities. It addresses vaginal dryness without hormones, making it a suitable option for breast cancer survivors concerned about hormone use.

Both treatments are usually well-tolerated, but individual experiences may vary. Consulting a healthcare professional before starting any new treatment is advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for vaginal dryness that often rely on traditional moisturizers or systemic hormone therapy, ESTRING is unique because it delivers estrogen directly to the vaginal tissues through a flexible ring inserted into the vagina. This localized delivery method can provide targeted relief while minimizing systemic hormone exposure, which is particularly beneficial for breast cancer patients who need to be cautious about hormone levels. Researchers are excited about ESTRING because it offers a novel way to provide relief from vaginal dryness with potentially fewer systemic effects, making it a promising option for those who cannot use standard systemic hormone therapies.

What evidence suggests that this trial's treatments could be effective for vaginal dryness in breast cancer patients?

In this trial, participants will receive either Estring or Replens to address vaginal dryness. Research has shown that vaginal estrogen treatments like Estring effectively treat vaginal atrophy, a condition where the vaginal walls become thin and inflamed, and relieve dryness. This treatment is often considered the best option and does not seem to increase the risk of breast cancer recurrence in survivors. Conversely, studies have found that Replens, a non-hormonal moisturizer, significantly reduces vaginal dryness in breast cancer patients. Both treatments are beneficial but work differently. Estring delivers estrogen directly, while Replens adds moisture without hormones. ^{2 3 4 6 7}

Who Is on the Research Team?

Polly Niravath, MD

Principal Investigator

Houston Methodist Cancer Center

Are You a Good Fit for This Trial?

This trial is for post-menopausal women aged 18 or older with stage I-III ER+ breast cancer, currently on adjuvant AI therapy, and suffering from vaginal dryness or related symptoms since starting the therapy. Participants must not use additional estrogen during the study and should have no current vaginal infections.

Inclusion Criteria

I have been diagnosed with early-stage, estrogen-receptor positive breast cancer.

I am post-menopausal based on age, surgery, or hormone levels.

I agree not to use any estrogen products for five years.

Exclusion Criteria

I have a current vaginal infection.

I have not used any estrogen products in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either vaginal estrogen or Replens for the treatment of atrophic vaginitis

6 months

Visits at baseline, 4 weeks, 12 weeks, and 24 weeks

Follow-up

Participants are monitored for compliance with aromatase inhibitor therapy and changes in serum estrogen levels

4.5 years

Every 6 months

Long-term follow-up

Evaluation of breast cancer recurrence and vaginal dryness by vaginal pH

5 years

What Are the Treatments Tested in This Trial?

Interventions

• ESTRING
• Replens

Trial Overview The REVIVE study compares two treatments for vaginal dryness in breast cancer patients on anti-estrogen treatment: a vaginal estrogen product called ESTRING and a non-hormonal moisturizer known as Replens.

How Is the Trial Designed?

Group I: Estring Experimental Treatment 1 Intervention

ESTRING

Group II: REPLENS Active Control 1 Intervention

Replens

ESTRING is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Estring for:

• Moderate to severe symptoms of vulvar and vaginal atrophy due to menopause

Approved in European Union as Estradiol Vaginal Ring for:

• Vaginal dryness, itching, and burning caused by low estrogen levels or menopause

Approved in Canada as Estring for:

• Moderate to severe symptoms of vulvar and vaginal atrophy due to menopause

Who Is Running the Clinical Trial?

Polly A. Niravath, MD

Lead Sponsor

Trials

2

Recruited

80+

Published Research Related to This Trial

In a pilot study involving 28 female breast cancer patients, a 12-week treatment with a water-based cellulose gel significantly reduced the severity of vulvovaginal atrophy (VVA) symptoms, with the most bothersome symptom scores decreasing from an average of 2.71 to 1.33.

The gel was found to be safe, with 39% of participants reporting adverse events, and it is recommended as a suitable nonhormonal treatment option for VVA symptoms in breast cancer patients undergoing aromatase-inhibitor therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Open, Uncontrolled Pilot Study on 12-Week Use of VagiVital for Treatment of Vulvovaginal Atrophy in Breast Cancer Patients Undergoing Adjuvant Aromatase-Inhibitor Therapy. Jonasson, AF., Åstrom, M.[2022]

The study involved 61 women with hormone receptor-positive early breast cancer, showing that the ultra-low dose 0.005% estriol vaginal gel significantly improved symptoms of vulvovaginal atrophy, including vaginal dryness and overall symptom scores after 12 weeks of treatment.

The treatment was safe, with minimal changes in hormone levels, indicating that it can be a suitable option for women with breast cancer experiencing vulvovaginal symptoms while on nonsteroidal aromatase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial. Hirschberg, AL., Sánchez-Rovira, P., Presa-Lorite, J., et al.[2022]

TX-004HR, a low-dose vaginal estradiol softgel capsule, significantly improved symptoms of vulvar and vaginal atrophy in postmenopausal women, including vaginal dryness and dyspareunia, based on results from phase 2 and phase 3 studies.

The safety profile of TX-004HR was comparable to placebo, with negligible systemic absorption of estradiol, indicating it may be a safe treatment option that does not increase systemic estradiol levels above postmenopausal ranges.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A vaginal estradiol softgel capsule, TX-004HR, has negligible to very low systemic absorption of estradiol: Efficacy and pharmacokinetic data review. Simon, JA., Archer, DF., Constantine, GD., et al.[2018]

In a 12-week study involving 30 women, a nonhormonal bioadhesive vaginal moisturizer was found to be a safe and effective alternative to local estrogen therapy for treating vaginal dryness.

Both treatments significantly improved vaginal moisture, fluid volume, and elasticity, restoring the vaginal pH to premenopausal levels, indicating their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative study: Replens versus local estrogen in menopausal women. Nachtigall, LE.[2022]

Up to 50% of postmenopausal women experience vulvovaginal atrophy-related symptoms, negatively affecting their quality of life, and many avoid standard topical vaginal estrogen due to safety concerns, especially breast cancer survivors.

Vaginal moisturizers may offer similar efficacy to topical vaginal estrogen and should be considered as a safe alternative for women seeking non-hormonal treatments, while lubricants provide temporary relief but lack long-term benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-hormonal topical treatment of vulvovaginal atrophy: an up-to-date overview. Sinha, A., Ewies, AA.[2018]

Both low-dose vaginal estrogen treatments (estriol cream and estradiol tablets) significantly improved symptoms of urogenital atrophy in postmenopausal breast cancer survivors over 12 weeks, with effects measured by subjective and objective assessments.

The non-hormonal vaginal moisturizer provided only a temporary improvement in symptoms, highlighting that while both estrogen treatments are effective, the moisturizer's benefits do not last beyond the initial weeks of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-dose vaginal estrogens or vaginal moisturizer in breast cancer survivors with urogenital atrophy: a preliminary study. Biglia, N., Peano, E., Sgandurra, P., et al.[2016]

In a clinical trial involving 45 breast cancer survivors, both the nonhormonal lubricant Replens and a placebo significantly reduced vaginal dryness and dyspareunia, with Replens showing a 60% improvement in dyspareunia scores (P = .05).

The beneficial effects of Replens were mostly observed within the first two weeks of treatment, indicating that it can provide quick relief for symptoms related to estrogen depletion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized double-blind study to evaluate the efficacy of a polycarbophil-based vaginal moisturizer in women with breast cancer. Loprinzi, CL., Abu-Ghazaleh, S., Sloan, JA., et al.[2022]

Estriol (E3) can stimulate the growth of estrogen receptor-positive breast cancer cells, similar to estradiol (E2), at concentrations as low as 10(-10)M, indicating that it has a potent estrogenic effect.

The study suggests that breast cancer survivors should be cautious when using E3 for vulvovaginal atrophy, as it can activate genes associated with cell proliferation and growth in breast cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of estriol on growth, gene expression and estrogen response element activation in human breast cancer cell lines. Diller, M., Schüler, S., Buchholz, S., et al.[2021]

Citations

1. ajog.org ajog.org/article/S0002-9378(24)01126-8/fulltext

Vaginal estrogen use in breast cancer survivors The use of vaginal estrogen in patients with a history of breast cancer does not appear to be associated with an increased risk of breast cancer recurrence.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3862044/

Vaginal Estrogen Therapy for Patients with Breast Cancer The most effective treatment for vaginal atrophy comprises the use of a topically applied estrogen therapy.

3. acog.org acog.org/clinical/clinical-guidance/clinical-consensus/articles/2021/12/treatment-of-urogenital-symptoms-in-individuals-with-a-history-of-estrogen-dependent-breast-cancer

Treatment of Urogenital Symptoms in Individuals With a ... This document has been updated to review the safety and efficacy of newer hormonal treatment options as well as nonhormonal modalities.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT00984399

Study Details | NCT00984399 | Serum Estradiol Levels In ... The purpose of this study is to see if Vagifem® 10mcg is safe for women who have had breast cancer. Vagifem is an estrogen product. It is a tiny tablet that is ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12254641/

Vaginal health in breast cancer survivors: a practical clinical ... Data demonstrate that polycarbophil-based non-hormonal moisturizers are superior to lubricants in temporarily mitigating vaginal dryness and ...

6. estring.com estring.com/vaginal-atrophy-relief

Vaginal Atrophy Relief |ESTRING® (estradiol vaginal ring) Estring is a soft, flexible ring used after menopause that continuously releases an estrogen over 3 months to treat menopausal changes in and around the vagina.

7. mayoclinic.org mayoclinic.org/drugs-supplements/estradiol-vaginal-route/description/drg-20075648

Estradiol (vaginal route) - Side effects & dosage Estradiol vaginal gel, insert, and ring are used to treat changes in and around the vagina (such as vaginal dryness, itching, and burning) ...