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Try out PMC Labs and tell us what you think. Learn More. Hot flashes HFs negatively affect quality of life among perimenopausal and postmenopausal women. This study investigated the efficacy of oxybutynin vs placebo in decreasing HFs.

The primary endpoint was the intrapatient change from baseline in weekly HF score between each oxybutynin dose and placebo using a repeated-measures mixed model. Secondary endpoints included changes in weekly HF frequency, HF-related daily interference scale questionnaires, and self-reported symptoms.

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We enrolled women. Baseline characteristics were well balanced. Mean SD age was 57 8. Patients on both oxybutynin arms reported more side effects than patients on placebo, particularly dry mouth, difficulty urinating, and abdominal pain. Most side effects were grade 1 or 2.

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There were no differences in study discontinuation because of adverse effects. Oxybutynin is an effective and Hot women in Wichita Kansas s c well-tolerated treatment option for women with HFs. Breast cancer survivors are at higher risk for long-term and more severe HFs as a consequence of chemotherapy-induced menopause, ovarian function suppression, and the use of tamoxifen or aromatase inhibitors 3.

Development of HFs can be associated with premature discontinuation of adjuvant endocrine therapy and lead to worse breast cancer outcomes 4—6. The most established treatment for HFs is estrogen-based therapy 7 ; however, it is usually avoided in women with a history of, or at increased risk for, breast cancer.

Several randomized trials have identified non estrogen medications that are effective for HFs treatment, such as serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors 8—21and anticonvulsants 1022— Moreover, some antidepressants inhibit CYP2D6, which has been associated with decreased tamoxifen efficacy 28although data on this are mixed Therefore, additional nonestrogen treatment options for women with breast cancer and HFs are needed.

Although the pathophysiology of HFs is not fully understood, multiple neurotransmitters have been implicated, including norepinephrine, serotonin, and acetylcholine 30— Oxybutynin is an anticholinergic drug approved by the US Food and Drug Administration for treatment of overactive bladder symptoms. Decreased sweating is a common side effect of oxybutynin, which has led to its successful use in the treatment of generalized hyperhidrosis Anecdotal and retrospective data suggest that oxybutynin could also be effective in the treatment of refractory HFs Unfortunately, this dose was associated with excess toxicity and treatment discontinuation because of side effects.

The present trial evaluated the hypothesis that oxybutynin, at lower doses of 2. In this randomized, double-blind, placebo-controlled clinical trial, we recruited premenopausal and postmenopausal women with HFs from 10 centers in the United States, all members of the Academic and Community Cancer Research United Network. Patients with or without a history of breast cancer were eligible, as long as they did not have evidence of active disease. Additional inclusion criteria were: Eastern Cooperative Oncology Group performance status of 0—1 and the ability of the participant to provide informed written consent and to complete study questionnaires.

Patients were excluded if they were receiving cytotoxic chemotherapy, estrogen, progestogens, androgens, or potent anticholinergics. Human epidermal growth factor receptor 2 HER2 —directed therapy was allowed. Additional exclusion criteria were prior use of oxybutynin during the period in which the patient experienced HFspregnancy, breastfeeding, or contraindications to the use of oxybutynin.

Written informed consent was obtained from each participant, and the study protocol was reviewed and approved by the appropriate local institutional review boards of each study center. Women were randomly ased to receive either 2. Web-based randomization was used, using the Pocock and Simon dynamic allocation procedure All patients started at a dose of 2.

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HFs were measured by a prospective, self-reported HF diary Secondary endpoints included change from baseline of HF frequency; change from baseline of daily HF interference between oxybutynin and placebo, as measured by the HFRDIS 39summarized by descriptive statistics, and then compared using Wilcoxon rank sum tests or two sample t-tests; and adverse effects, evaluated using the National Cancer Institute Common Terminology for Adverse Events CTCAE version 4.

The HFRDIS and adverse effects were rated on a 0- to point scale, where 0 is as bad as it can be and 10 is as good as it can be. Sample-size calculations were based on a time-averaged repeated-measures model, comparing oxybutynin to placebo. Model assumptions include a moderate correlation of 0.

The time-averaged intrapatient changes in HF activity from baseline during the treatment period were compared between treatment and placebo arms using a repeated-measures mixed model of weekly HF scores and frequency. Patient baseline characteristics, including age, concurrent use of tamoxifen or aromatase inhibitor, and baseline HF duration and frequency, were used as covariates in the model.

Sensitivity analyses, using 10 different methods of imputing missing values, were conducted to provide evidence that missing data did not unduly influence the of the study. Because the two treatment arms represented different doses of the same drug, a fixed sequence of up to two hypotheses tests was performed, rather than two simultaneous tests, as would generally be done for studies in which the primary analysis involves two independent hypotheses.

This is based on the belief that the treatment effect of oxybutynin, if one existed, would change monotonically with respect to dose. To control the overall type-I error for the primary analysis, a gatekeeping procedure, a method recommended by the Food and Drug Administration and the National Cancer Institute for adjusting for multiple testing 40was employed.

In particular, a time-averaged longitudinal model to test the higher-dose oxybutynin arm vs placebo was first used at the level 0. Plans to test the lower-dose oxybutynin arm vs placebo was to be carried out only if the higher-dose arm—vs-placebo test was statistically ificant, again at the level 0. An intention-to-treat analysis ITT was also performed to for missing data.

Both oxybutynin doses were compared against placebo using the Fisher exact test. Additionally, a logistic regression model was used, adjusting for age, concomitant tamoxifen or aromatase inhibitor use, baseline HF duration, and baseline of HFs per day. This study was registered in Clinicaltrials. In total, women were accrued between February 23,and March 5, Mean SD patient age was 57 8. Baseline characteristics were well balanced and are detailed in Table 1.

Patients on each of the oxybutynin arms, compared with those on placebo, achieved greater reductions in both HF score and HF frequency Figure 2 and Table 2. Mean hot flash HF score percentage of baseline. s under each week of treatment represent the of evaluable patients at each week. The only interference measures not improved by Oxy5 were concentration and sexuality. Similarly, most interference measures were statistically ificantly improved with Oxy2. To evaluate whether study could have been influenced by the missing data on 37 patients, an ITT analysis including data for all randomly ased patients was conducted.

Thirteen patients Similarly, 10 patients These differences remained after adjusting for baseline factors using a logistic regression model. Oxybutynin was well tolerated at both doses. Diarrhea was reported less frequently with Oxy2. Self-reported changes in baseline symptoms after the initiation of oxybutynin, which are probably a better measure of toxicity than are obtained with CTCAE criteria, are provided in Table 4 and Figure 3. Mean change from baseline in select adverse events.

A Mean change from baseline in abdominal pain, B Mean change from baseline in dry mouth, C Mean change from Hot women in Wichita Kansas s c in constipation, D Mean change from baseline in difficulty urinating, and E Mean change from baseline in diarrhea. There were no statistically ificant differences in reasons for study discontinuation between the oxybutynin arms and placebo. The from this study support the prestudy hypothesis that oxybutynin would improve HF frequency and severity. The positive effect of treatment with oxybutynin on several HF interference measures and QoL supports that the magnitude of the effect was clinically meaningful.

The degree of HF improvement with oxybutynin compares favorably with other agents that have been evaluated in prospective trials 89182741—43with greater reduction in HF than has been observed with antidepressants and gabapentinoids, and similar to what has been reported with progesterone analogues. The toxicity profile seen in the present trial contrasts Hot women in Wichita Kansas s c the toxicity profile seen in the study by Simon et al.

Though some of the self-reported adverse effects Table 4 were slightly worse on the Oxy2. The magnitude of the effect on HF on the trial by Simon et al. As such, this trial demonstrated that oxybutynin provided short-term relief and that its short-term use was safe. Furthermore, there are no data to suggest that therapeutic efficacy on HF diminishes over time. However, long-term safety may be a different issue. Anticholinergic drugs can be associated with acute mentation changes, delirium, electroencephalogram changes, and other negative cognitive effects 45— There are also reports linking anticholinergic drugs and dementia 52although causality has not been established.

The link with negative cognitive effects has been mostly reported in the elderly and in those with preexisting neurologic conditions. However, there are no good data to support or disprove that similar effects may occur in healthy younger women. The present trial did not conduct formal cognitive or psychometric testing.

Patients in the Oxy2. Patients and clinicians need to be aware of these concerns, particularly because cognitive impairment may be a problem among breast cancer survivors. A possible advantage of oxybutynin for HF management over most antidepressants is the lack of interference with CYP2D6. This enzyme is important in the metabolic activation of tamoxifen, and it has been shown that concurrent use of CYP2D6 inhibitors le to decreased plasma concentrations of endoxifen the most potent tamoxifen metabolite.

Whether this effect can affect the anticancer efficacy of this agent continues to be a matter of debate, with different studies showing mixed 2953— However, given this potential, patients and physicians may have concerns about using potent CYP2D6 inhibitors for HF treatment in women taking tamoxifen. Thus, oxybutynin may be an attractive choice for this patient population.

Although this study included only women, in a recent letter to the editor 57Smith et al. After discontinuation of oxybutynin because of insomnia, dry mouth, and restless legs, HFs recurred but improved again within hours of restarting it, at a dose of 2. Further prospective evaluation of oxybutynin in men with androgen deprivation—related HFs is planned.

Strengths of this study are the inclusion of breast cancer patients on active antiestrogen therapy, the use of standardized HF metric tools and questionnaires, and its prospective, randomized de. Despite these limitations, this study supports the short-term use of oxybutynin in patients with HFs refractory to other agents. The funder had no role in the de of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

The authors declare the following potential conflicts of interest: RALF reports nonfinancial support from Immunomedics, outside the submitted work. KJR reports stock ownership of Merck and Pfizer, outside the submitted work. The authors wish to acknowledge Mr Jason Ellis for reviewing the manuscript for style.

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National Center for Biotechnology InformationU. Published online Oct Author information Article notes Copyright and information Disclaimer. Correspondence to: Roberto A. Published by Oxford University Press. For commercial re-use, please contact journals. This article has been cited by other articles in PMC. Abstract Background Hot flashes HFs negatively affect quality of life among perimenopausal and postmenopausal women.

Conclusion Oxybutynin is an effective and relatively well-tolerated treatment option for women with HFs. Patients and Methods Participants In this randomized, double-blind, placebo-controlled clinical trial, we recruited premenopausal and postmenopausal women with HFs from 10 centers in the United States, all members of the Academic and Community Cancer Research United Network. Random Asment and Masking Women were randomly ased to receive either 2. Statistical Analysis Sample-size calculations were based on a time-averaged repeated-measures model, comparing oxybutynin to placebo.

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Table 1. Open in a separate window. Figure 1. Consolidated Standards of Reporting Trials diagram. Table 2. Reductions in hot flash HF score and frequency from baseline to week 6.

Hot women in Wichita Kansas s c

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Oxybutynin vs Placebo for Hot Flashes in Women With or Without Breast Cancer: A Randomized, Double-Blind Clinical Trial (ACCRU SC)