Vulvovaginal dryness and symptoms including discomfort and dyspareunia are common complaints of breast cancer survivors.1 Urogenital tract atrophy is a manifestation of estrogen deprivation in breast cancer patients who have received chemotherapy or endocrine therapy.2 This may induce various symptoms of the vulvovaginal area including vaginal dryness, burning sense, itching, dyspareunia, and abnormal discharge. Although estrogen replacement could resolve urogenital symptoms, it is contraindicated in breast cancer patients. Even the local administration of estradiol (E2) tablets could affect serum hormonal levels.3 Thus, alternative remedies have been developed to alleviate these problems.4 However, these alternative therapies with a moisturizer or a lubricant have not remarkably relieved the symptoms.
Vaginal atrophy caused by either natural or iatrogenic menopause is a universal condition characterized by decreased vaginal secretions, thinned vaginal tissue, and elevated vaginal pH. Estrogen influences the vaginal epithelium on glycogen content, and glycogen maintains lactobacilli in the vagina. Lactobacillus-dominant flora protects women from vaginitis and urogenital tract infections through maintenance of vaginal pH in the range of 3.6–4.5.5 Therefore, deprivation of glycogen-rich cells due to a low estrogen level inhibits lactic acid production and increases vaginal pH.6,7 Elevated vaginal pH higher than 4.5 is associated with vaginitis, which causes several vaginal symptoms.5,8 Thus, it seems that maintaining a low pH in the vagina could potentially reduce the incidence of troublesome symptoms and infection of the vulvovagina.
We hypothesize that vaginal pH-balanced gel may be useful in the regulation of vaginal health by lowering vaginal pH as well as in the lubrication of the vagina itself. The gel contains lactic acid to maintain the vaginal pH at about 4.0 (package insert from Han Kook Pharmed Co, Ltd, Seoul, Korea). Based on this, the present randomized, prospective trial aimed to assess the efficacy of vaginal pH-balanced gel containing lactic acid for the control of vaginal atrophy in breast cancer survivors after cancer treatment.
PATIENTS AND METHODS
Participants were recruited at Seoul National University Hospital between November 2007 and November 2008 after ethical approval from the Institutional Review Board. Written informed consent was obtained from all participants. The trial was performed in accordance with the Declaration of Helsinki and with the principles of good clinical practice. Eligible participants were those who were at least 18 years old, had a history of primary breast cancers managed with chemotherapy or hormonal therapy, experienced menopause for a period of at least 12 months before the study, and had vulvovaginal dryness with pain scored over 5.0 on the visual analog scale (VAS). The exclusion criteria were as follows: 1) natural menopause antecedent to the diagnosis of breast cancer; 2) presence of severe medical disease or complication; 3) presence of other malignancies including cervical, ovarian, and uterine cancers; 4) an operative history of hysterectomy or oophorectomy; 5) current use of medication for urogynecologic problems; 6) unexplained vaginal bleeding; and 7) previous use of systemic or local sex hormones within 6 months of the study.
Participants were randomly assigned to either the pH-balanced gel group or the placebo group. The same-sized vaginal gel tubes with or without lactic acid (pH 4.0 and pH 7.2, respectively) were packaged identically by the manufacturer and labeled with sequential numbers according to the randomization code. Random assignment was made from a confidential list of permuted blocks of four by a third party before the study. Participants received 2 mL of gel with a provided vaginal applicator each time. The vaginal gel was inserted three times per week at bedtime for 12 weeks.
The sample size was calculated to provide sufficient power to test the main study outcome. In a previous report studying Replens and deinoestrol cream in vaginal atrophy, vaginal moisturizer Replens was considered effective for vaginal dryness with 16% improvement.9 Thus, we proposed improving the atrophic vaginal symptoms over 16% (α error=0.05, β error=0.20). We calculated that 49 patients had to be included in each group after considering a dropout rate of 20%. Targeted sample size was calculated using PASS 8.
At the beginning of the study, each participant had her history taken and underwent a pelvic examination and pelvic ultrasonography. Vulvovaginal symptoms were measured according to the VAS for vulvovaginal dryness with pain and dyspareunia. The VAS was rated from 0 to 10.0 on the 10-cm bar (Appendix 1, available online at http://links.lww.com/AOG/A233) by the participant. After 12 weeks of treatment, the participants were assessed in terms of changes in their symptoms.
Vaginal health index was evaluated with regard to moisture, fluid volume, elasticity, epithelial integrity, and pH according to the methods of Robert Wood Johnson Medical School.10 Vaginal pH was assessed with a pH indicator strip. Vaginal smear was performed from the lateral vaginal wall, and vaginal maturation index was scored under a light microscope by a single pathologist. Vaginal maturation index was calculated with a sum of percentages of superficial cells, intermediate cells, and parabasal cells that were assigned point values of 1.0, 0.6, and 0.2, respectively.11
Hormonal therapy, including tamoxifen, could induce side effects such as endometrial thickening and ovarian cyst formation. Although the study gel does not contain hormonal components, adverse effects including endometrial thickening and ovarian cyst formation were measured.
The primary end point for this trial was the change of VAS from baseline during treatment for vaginal symptoms. Secondary end points included the change of vaginal health and vaginal maturation indexes. The Student t test and x2 test were used to compare variables in two groups. The paired t test was used to analyze outcome changes of the primary and secondary end points prior and subsequent to the treatment between pH-balanced gel and placebo. Differences were considered significant at P<.05. SPSS 12.0 was used for statistical analysis.
One hundred eighty-seven women were screened for this trial, of whom 89 did not meet eligibility criteria or refused to participate. In total, 98 participants were randomly assigned to the pH-balanced gel (n=44) or placebo group (n=42) between November 2007 and November 2008 and were followed until April 2009. The flow of participants is presented in the Consolidated Standards of Reporting Trials diagram in Figure 1. About 12% of the participants were lost to follow-up (n=12); five and seven participants had been allocated to the pH-balanced gel and placebo groups, respectively. Among them, three and two women complained of vaginal irritation, two and two women did not complete the application schedule, and 0 and three women refused further treatment because of inconvenience in the pH-balanced gel and placebo groups, respectively. All adverse events were considered to be mild in severity and self-limited. The characteristics of all participants are described in Table 1. The mean age of the participants in the pH-balanced gel group was 45.86 years (range, 34–53 years), and that of the placebo group was 44.98 years (range, 37–53 years). All individuals had been treated with surgery and adjuvant therapy including chemotherapy or hormonal therapy or both. Before the trial, all of the participants who measured follicle-stimulating hormone and E2 showed high follicle-stimulating hormone (more than 20 international units/L) and low E2 (less than 15 pg/mL) levels.
The overall results of the trial are summarized in Table 2. The analysis of the primary outcome factor, the VAS for vulvovaginal dryness with pain and dyspareunia, revealed that vaginal pH-balanced gel had a significant effect during the 12 weeks of therapy (P=.001 and .040, respectively; Fig. 2). With regard to dyspareunia, 35 participants (71.4%) in the pH-balanced gel group and 31 participants (63.3%) in the control group were analyzed for the evaluation of dyspareunia in the two groups, respectively, because the other women were not sexually active at that time. Vaginal pH-balanced gel was also effective according to the vaginal health index (P=.002). Vaginal pH was decreased more in the pH-balanced gel group (P<.001). Vaginal maturity index was increased in both groups and changed significantly in the pH-balanced gel group (P<.001).
Complications were observed in 50 cases (Table 3). Some participants complained of multiple complications, so we counted all complications. Adverse effects were reported in 19 participants (38.8%) treated with vaginal pH-balanced gel compared with 16 participants (32.7%) in the placebo group. Vulvovaginal irritation and a burning sense were the most common symptoms, and these were more prevalent in the pH-balanced gel group than in the placebo group. However, according to the severity criteria defined as limitation of daily life activities, all adverse events were considered to be mild or moderate in severity, occurred with the highest frequency during the first 4 weeks of therapy, and were self-limited. For checking adverse effects on the genital tract, endometrial thickness and ovarian cyst formation were measured by ultrasonography. No significant difference was observed between the two groups (Table 3). Although 11 participants had an endometrium thickened more than 0.5 cm, endometrial biopsy revealed no abnormal pathology in the patients showing endometrium thickened more than 1.0 cm (one in the pH-balanced gel group and two in the placebo group). Ovarian cyst formation larger than 3.0 cm was found in eight women. However, all of the cysts were smaller than 6.0 cm and appeared to be simple cysts; thus, we did not perform surgical intervention.
Therefore, the pH-balanced vaginal gel is effective for breast cancer survivors who complain of atrophic vaginitis after chemotherapy, endocrine therapy, or both.
Breast cancer is one of the most common malignancies in women, with more than a million new cases worldwide annually.12 Nevertheless, the survival rate of breast cancer patients is high; thus, many breast cancer survivors suffer either from the disease itself or from side effects attributable to treatments. The main adjuvant treatment modalities, including chemotherapy and hormonal therapy, can cause either temporary or permanent menopause. In contrast to hot flushes, vaginal atrophy is the most long-lasting symptom of menopause.7,13 Large cohort studies have depicted a 27–55% prevalence of vaginal atrophy in menopausal women.14,15 Clinical conditions and symptoms related to vaginal atrophy caused by a low estrogen condition are not life-threatening but can worsen the quality of life by affecting comfort and causing libido problems.16 Breast cancer survivors rarely visited the clinic for the symptoms of vaginal atrophy in the past. However, many women now want to improve their quality of life, including sexual satisfaction, and they consult their doctor about these problems.
Although intravaginal estrogen formulations have been developed to avoid systemic exposure to estrogens, previous studies have clearly demonstrated that such preparations intended for exclusive local estrogen action lead to relatively high serum estrogen levels, thus raising an issue related to an increased risk of breast cancer and possibly also uterine cancer.17,18 Thus, estrogen agents are greatly limited in their use in breast cancer survivors.
Nonhormonal treatments are often first-line options in symptomatic women with vaginal atrophy in breast cancer survivors. In clinical trials, vaginal moisturizers, including water-based lubricants and polycarbophil lubricants, have been reported to modify maturation index and increase lubrication, and have shown a similar efficacy in vaginal symptoms, including itching, irritation, and dyspareunia, compared with local hormonal therapy.9,19
The present study confirmed that vaginal pH-balanced gel was significantly more efficient than placebo in decreasing vaginal pH and increasing the mean maturation value, and relieving the symptoms of vaginal atrophy in breast cancer survivors with a favorable compliance rate. Improvement in the symptoms was also found by the patients using the placebo gel, suggesting a remarkable effect of simple lubricant. However, women using the pH-balanced gel consistently showed a higher symptom-free rate. A low vaginal pH is considered the primary mechanism in controlling the vaginal microflora. Several studies have reported that lowering vaginal pH can improve vaginal health and sometimes bacterial vaginitis.20,21 Boric acid suppository is one of the proven agents to be effective in chronic vulvovaginal candidiasis and bacterial vaginitis.22,23 Although more than 30% adverse rates have been reported, there were no severe adverse effects in the current study and all of these effects were self-limited after a month. This suggests that vaginal pH-balanced gel can be a well-tolerated and effective regimen for breast cancer survivors who complain of atrophic vaginitis after chemotherapy or endocrine therapy.
A possible criticism of this study is that long-term follow-up observations were limited. Further studies should be conducted with longer follow-up periods to confirm our results. Previous studies with breast cancer survivors have mainly focused on improving hot flushes. The present study is one of the few trials measuring potential benefits of vaginal pH-balanced gel in breast cancer survivors. Although our study did not perform long-term application of the gel, it can provide reassuring data on the efficacy and safety of vaginal pH-balanced gel. In conclusion, the results of the present study suggest that vaginal pH-balanced gel can alleviate vulvovaginal symptoms in breast cancer survivors who have experienced menopause after cancer treatment.
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