Breast Cancer, Gynecologic Cancer
Conditions
Keywords
depression, anxiety disorder, cognitive/functional effects, sexual dysfunction, cancer survivor, breast cancer, cervical cancer, fallopian tube cancer, uterine sarcoma, vaginal cancer, vulvar cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian sarcoma, ovarian stromal cancer, primary peritoneal cavity cancer, endometrial cancer
Brief summary
RATIONALE: Dehydroepiandrosterone (DHEA) may help relieve vaginal symptoms in female cancer survivors. PURPOSE: This randomized phase III trial studies DHEA to see how well it works compared to placebo in treating postmenopausal cancer survivors with vaginal symptoms.
Detailed description
Primary Goal: * To determine the effectiveness of two doses of daily vaginal prasterone (dehydroepiandrosterone \[DHEA\]) versus placebo for alleviation of the most bothersome vaginal symptom (vaginal dryness or dyspareunia) over 12 weeks. Exploratory Goals: * To evaluate any toxicities arising from DHEA in this patient population. (Exploratory) * To evaluate the impact of vaginal DHEA on negative sexual thoughts, sexual function and urologic symptoms. (Exploratory) * To explore the role of psychologic (mood, stress), physical (demographics and treatment variables) and situational factors (partner variables and fatigue) as predictors of vaginal dryness and performance outcomes at baseline and at various endpoints throughout the study. (Exploratory) * To explore the characteristics of vaginal atrophy and the relationship between vaginal atrophy and quality-of-life questionnaire responses and exposure to hormonal therapy (tamoxifen, exemestane, anastrozole, or letrozole). (Exploratory) * To examine the effects of the use of open-label vaginal DHEA gel over 8 weeks in women completing the placebo gel arm of the randomized trial. (Exploratory) Correlative Research Goals: * To evaluate the impact of vaginal DHEA on maturation index and pH (select institutions). * To evaluate the impact of vaginal DHEA on sex steroid concentrations (estradiol, free testosterone, estrone, and DHEA-S) and markers of bone turnover (osteocalcin and bone alkaline phosphatase). (Correlative) * As part of ongoing research for NCCTG Cancer Control studies, we are banking blood products for future studies. (Correlative) OUTLINE: This is a multicenter study. Patients are stratified according to current tamoxifen therapy (yes vs no), concurrent aromatase inhibitor use (anastrozole/letrozole vs exemestane vs none), hysterectomy (yes vs no), and cigarette smoking (current vs past vs never). Patients are randomized to 1 of 3 treatment arms, patients receive low dose vaginal DHEA, high dose vaginal DHEA or vaginal placebo gel. Participants may complete the Profile of Mood States (POMS), the Perceived Stress Scale (PSS), the Fatigue: Vitality subscale of the SF-36, the Vaginal Symptom Quality Questionnaire, the DHEA Side Effect Questionnaire, the Female Sexual Function Index (FSFI), the Sexually Related Intrusive Thoughts - ITS, Impact of Treatment Scale, the Urogenital Atrophy Questionnaire, and the Subject Global Impression of Change at baseline and periodically during study.
Interventions
DRUGprasterone
Applied vaginally
OTHERplacebo
Applied vaginally
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Postmenopausal women with a history of breast or gynecologic cancer (currently no evidence of disease). Note: Postmenopausal status will be determined by the following criteria: 1. 12 months without a period or bilateral oophorectomy or complete chemical ovarian suppression for the past 12 months with continued suppression planned throughout the course of the study 2. menopausal status will be determined by an FSH and an estradiol value in the postmenopausal range (generally FSH \> 40IU/L and estradiol \< 10 pg/ml, depending on laboratory) if: * 9 months without a period or * post hysterectomy with at least one ovary remaining and less than 55 years old. Note: if age 55 or older with these criteria, then menopausal status does not need to be determined by labs 3. Significant vaginal complaints. Note: Defined as persistent vaginal dryness and/or pain with intercourse (dyspareunia) of sufficient severity to make a patient desire therapeutic intervention. 4. Eligibility questionnaire response must be moderate or worse levels of severity on one of the two symptoms, either dryness or dyspareunia. The protocol contains more information. 5. Vaginal symptoms must have been present ≥ 2 months prior to randomization. 6. Life expectancy \> 12 months. 7. Ability to complete questionnaires by themselves or with assistance. 8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1. 9. The patient must provide informed written consent. 10. Willing to return to the enrolling institution for follow-up. 11. Willing to provide blood samples for correlative research purposes.
Exclusion criteria
1. Initiation or discontinuation of tamoxifen or aromatase inhibitors ≤ 2 months prior to randomization or plans to initiate or discontinue any of these medications during the 12-week study. 2. Current diagnosis of an active vaginal infection, if symptoms of vaginal infection, this must be ruled out (ie, foul discharge, fever). 3. Concurrent chemotherapy (long term adjuvant herceptin, lapatanib, and/or bevacizumab is allowed. 4. Planned use of any vaginal preparations during the study period (including any over the counter or herbal preparations). Note: Water-based lubricants (such as KY jelly) are allowed during sexual intercourse. 5. Use of any daily non-hormonal vaginal preparations ≤ 1 week prior to study entry. Exception: Daily water-based lubricants for sexual intercourse. Note: Patients who stop agent may be enrolled after one week. 6. Current (≤ 4 weeks prior to randomization), or planned during the study period, use of any estrogen product or any kind of hormonal vaginal product including bioidentical hormones, estriol or any androgen product. 7. Use of pharmacologic soy or phytoestrogen preparations (Dietary intake of soy - ie milk is acceptable). 8. On a placebo controlled trial for endocrine therapy. 9. Prior or concurrent pelvic radiation therapy. 10. Prior radical pelvic surgery, specifically vaginectomy or pelvic exenteration (TAH/BSO) is allowed). 11. Diagnosis of any of the following conditions within the past five years: 1. Essential vulvodynia 2. Vulvar vestibulitis 3. Bartholin cyst/abscess 4. History of Bartholin gland surgery 5. Lichen sclerosis 6. Lichen planus of the vulvovaginal region 7. Desquamative vaginitis 12. History or current diagnosis of any of the following conditions: 1. Vulvar or vaginal dysplasia 2. Vaginal prolapse 13. Women of childbearing potential, premenopausal women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alleviation of the Most Bothersome Vaginal Symptom (Vaginal Dryness or Dyspareunia) Over 12 Weeks | At baseline and 12 weeks | The primary outcome is severity of the most bothersome vaginal symptom: dryness or dyspareunia. The Vaginal Symptom Measure (VSM) was used to evaluate the severity of vaginal dryness and dyspareunia. The VSM uses a 5- point ordinal response scale; 1=none, 2=mild, 3=moderate, 4=severe and 5=very severe to measure the severity associated with vaginal dryness and/or dyspareunia. For each patient, the change in severity was calculated by subtracting the baseline from the week 12 reported score. Therefore, the full range of scores ranges from -4 (greatest decrease in severity) to 4 (greatest increase in severity). A negative score indicates a decrease in severity from baseline, zero indicates no reported affect and positive scores indicate a more severe report at week 12. The primary assessment method will be a comparison of the averages of the changes over time in the severity items for the most bothersome symptom from baseline to 12 weeks (as indicated at baseline). |
Countries
United States
Participant flow
Pre-assignment details
A total of 464 patients were accrued to this trial. Nineteen patients withdrew consent prior to randomization and were not included in the analysis of this study. Two additional patients were unable to classify the primary symptom and were not randomized to the trial and were not included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Low Dose DHEA Participants apply a low dose (3.25 mg) of vaginal prasterone (dehydroepiandrosterone \[DHEA\]) gel once daily (QD), at bed time, for 12 weeks. Treatment continues until unacceptable adverse events or patient refusal to continue participation on the study. | 147 |
| Arm II High Dose DHEA Participants apply a high dose (6.5 mg) of vaginal DHEA gel QD, at bed time, for 12 weeks. Treatment continues until unacceptable adverse events or patient refusal to continue participation on the study. | 149 |
| Arm III Placebo Participants apply a vaginal placebo gel QD, at bed time, for 12 weeks. \>
\> There is an Optional Continuation Phase (for placebo arm only): Participants apply a high dose of vaginal DHEA gel QD, at bed time, for 12 weeks. Treatment continues until unacceptable adverse events or patient refusal to continue participation on the study. | 147 |
| Total | 443 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Raondomized Treatment | Adverse Event | 13 | 17 | 14 |
| Raondomized Treatment | Alternative Treatment | 0 | 0 | 1 |
| Raondomized Treatment | Unkown | 1 | 2 | 1 |
| Raondomized Treatment | Withdrawal by Subject | 10 | 16 | 13 |
Baseline characteristics
| Characteristic | Arm I Low Dose DHEA | Arm II High Dose DHEA | Arm III Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 6.7 | 57.3 years STANDARD_DEVIATION 8.2 | 58 years STANDARD_DEVIATION 7.3 | 57.3 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment United States | 147 participants | 149 participants | 147 participants | 443 participants |
| Sex: Female, Male Female | 147 Participants | 149 Participants | 147 Participants | 443 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 91 / 147 | 105 / 148 | 93 / 147 | 28 / 94 |
| serious Total, serious adverse events | 3 / 147 | 7 / 148 | 4 / 147 | 0 / 94 |
Outcome results
Primary
Alleviation of the Most Bothersome Vaginal Symptom (Vaginal Dryness or Dyspareunia) Over 12 Weeks
The primary outcome is severity of the most bothersome vaginal symptom: dryness or dyspareunia. The Vaginal Symptom Measure (VSM) was used to evaluate the severity of vaginal dryness and dyspareunia. The VSM uses a 5- point ordinal response scale; 1=none, 2=mild, 3=moderate, 4=severe and 5=very severe to measure the severity associated with vaginal dryness and/or dyspareunia. For each patient, the change in severity was calculated by subtracting the baseline from the week 12 reported score. Therefore, the full range of scores ranges from -4 (greatest decrease in severity) to 4 (greatest increase in severity). A negative score indicates a decrease in severity from baseline, zero indicates no reported affect and positive scores indicate a more severe report at week 12. The primary assessment method will be a comparison of the averages of the changes over time in the severity items for the most bothersome symptom from baseline to 12 weeks (as indicated at baseline).
Time frame: At baseline and 12 weeks
Population: All patients that started treatment and completed their week 12 evaluation are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I Low Dose DHEA | Alleviation of the Most Bothersome Vaginal Symptom (Vaginal Dryness or Dyspareunia) Over 12 Weeks | -2 change in units on a scale |
| Arm II High Dose DHEA | Alleviation of the Most Bothersome Vaginal Symptom (Vaginal Dryness or Dyspareunia) Over 12 Weeks | -2 change in units on a scale |
| Arm III Placebo | Alleviation of the Most Bothersome Vaginal Symptom (Vaginal Dryness or Dyspareunia) Over 12 Weeks | -1 change in units on a scale |
p-value: 0.08Wilcoxon (Mann-Whitney)
p-value: 0.48Wilcoxon (Mann-Whitney)