OXYBUTYNIN, AN ANTICHOLINERGIC drug approved for the treatment of overactive bladder, reduced the frequency and intensity of hot flashes in women who were suffering frequent hot flashes, including breast cancer survivors who were receiving tamoxifen or aromatase inhibitors. These results of the randomized, double-blind, placebo-controlled ACCRU study SC-1603 were presented at the 2018 San Antonio Breast Cancer Symposium.¹

Roberto A. Leon-Ferre, MD

“Hot flashes are a common and often persistent problem for up to 75% of midlife women as well as for breast cancer survivors. Hot flashes have a negative impact on quality of life, affecting spheres of life that include work, sleep relationships, sexuality, social, and leisure activities,” explained lead author Roberto A. Leon-Ferre, MD, senior associate oncologist at the Mayo Clinic, Rochester, Minnesota.

“Women with breast cancer are at higher risk for longer-term and more severe hot flashes due to chemotherapy-induced menopause and treatment with antiestrogens,” he continued. “In patients with breast cancer, hot flashes can interfere with adjuvant therapy compliance. Women with breast cancer cannot take hormone replacement therapy, which is currently the most effective treatment for hot flashes, so alternatives are needed,” Dr. Leon-Ferre told the audience.

Randomized trials suggest that antidepressants have efficacy in managing this side effect, but these drugs can interfere with the metabolism of tamoxifen. In addition, patients may be reluctant to take antidepressants without a diagnosis of depression, due to the stigma associated with having a mood disorder, he explained. Some oncologists recommend the antidepressant venlafaxine for patients who have both depression and hot flashes.

There are limited data on nonpharmacologic approaches to managing hot flashes such as lifestyle and behavioral modifications as well as herbal supplements.

Study Rationale and Details

OXYBUTYNIN IS AVAILABLE in oral or transdermal formulations and is approved for an overactive bladder at a dose of 5 to 20 mg/d. Patients with an overactive bladder who were taking oxybutynin noticed a decrease in sweating, providing a rationale for studying the drug in people with hot flashes.

Two prior studies in postmenopausal women who had refractory hot flashes reported decreases in symptoms when receiving full-dose oxybutynin. The toxicity data suggested that lower doses may be used, Dr. Leon-Ferre explained.

The study enrolled 150 women with frequent hot flashes (≥ 28 per week for at least 30 days and severe enough to warrant treatment), including breast cancer survivors receiving tamoxifen or aromatase inhibitors, who comprised 65% of the study population. Patients were randomly assigned 1:1:1 to receive oxybutynin at 2.5 mg/d twice daily, oxybutynin at 5 mg/d twice daily (both doses at the lower end of the dosing spectrum), or placebo; they were treated for 6 weeks. Concurrent potential anticholinergic medications were not allowed.

“Almost all quality-of-life measures improved on oxybutynin at 5 mg/d [twice daily], including mood, life enjoyment, sleep, social activities, and relationships.”

— Roberto A. Leon-Ferre, MD

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Hot flashes were measured by weekly questionnaires and a hot flash diary. The primary endpoint was the intrapatient change in weekly hot flash score (calculated by severity and frequency), changes in the Hot Flash Related Daily Interference Scale, and changes in self-reported symptoms. “Each patient was evaluated against herself,” Dr. Leon-Ferre noted.

Patients were stratified by age, concurrent use of tamoxifen or an aromatase inhibitor, and the baseline duration and frequency of hot flashes. At baseline, demographics and hot flash characteristics were well balanced between the three treatment arms.

Key Findings

AT THE END of the 6-week study, evaluable patients included 40 in the low-dose oxybutynin arm, 35 in the higher-dose oxybutynin arm, and 38 in the placebo arm. The mean hot flash score, based on the frequency and severity of each hot flash, showed a mean change of –16.9 points in the oxybutynin 5-mg (twice daily) group vs –5.7 in the placebo group; the mean change in the oxybutynin 2.5-mg (twice daily) group was –10.6. Patients who received the higher oxybutynin dose experienced an average of 7.5 fewer hot flashes per day, compared with 4.8 fewer flashes in the lower-dose group and 2.6 fewer flashes in the placebo group.

Overall, patients who received placebo had a 27% reduction in hot flashes, compared with an 86% reduction in patients treated with higher-dose oxybutynin (P < .01) and about a 70% reduction in patients treated with lower-dose oxybutynin (P < .01 for both doses vs placebo). “The study was not designed to compare the two oxybutynin arms; each arm was compared with the placebo,” he said.

Similar results were observed in mean hot flash frequency, quality-of-life metrics, and changes in Hot Flash Related Daily Interference Scale compared with placebo. “The higher dose had a larger effect on these measures. Almost all quality-of-life measures improved on oxybutynin at 5 mg [twice daily], including mood, life enjoyment, sleep, social activities, and relationships. On the lower dose, improvements were seen in all of these measures except for mood and life enjoyment.

Side effects of the 6-week course of treatment with both doses of oxybutynin were as expected with an anticholinergic agent. They included dry mouth, abdominal pain, and slightly worsened ability to urinate. Dr. Leon-Ferre said that most of these side effects were mild. With the higher dose of oxybutynin, additional side effects were dry eyes, episodes of confusion, diarrhea, and headaches.

Comparison With Other Agents

AT THE MAYO CLINIC, 13 different placebo-controlled phase III trials with similar designs have been performed to evaluate the effect of nonestrogenic medications on hot flashes. Across all placebo arms, a 20% to 25% reduction in mean hot flash score was observed. Agents such as venlafaxine and pregabalin had a 60% reduction, and citalopram had about a 55% reduction.

“The most robust reduction in hot flash score was in the oxybutynin trial,” Dr. Leon-Ferre noted. He added that prior to this study, venlafaxine was the drug of choice for most patients with cancer, especially for those taking tamoxifen. “This study makes us at Mayo more keen on using oxybutynin for managing hot flashes,” he told listeners.

“I would not use oxybutynin in an older patient with comorbidities and polypharmacy, but it is a good option for younger patients with no comorbidities.”

— Roberto A. Leon-Ferre, MD

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“In a patient with both depression and hot flashes, venlafaxine is a good choice. I would not use oxybutynin in an older patient with comorbidities and polypharmacy, but it is a good option for younger patients with no comorbidities. I would start on the lower dose and ramp up the dose if necessary,” Dr. Leon-Ferre advised.

Dr. Leon-Ferre offered one note of caution: “This is a short-term study. Oxybutynin and other anticholinergics have been reported to potentially affect cognition over the longer term, but this was not evaluated in our study.” ■

DISCLOSURE: The study was supported by a grant from the Breast Cancer Research Foundation. Dr. Leon-Ferre has received travel support from Immunomedics (not relevant to this presentation).

REFERENCE

1. Leon-Ferre RA, Novotny P, Faubion SS, et al: A randomized, double-blind, placebo-controlled trial of oxybutynin for hot flashes: ACCRU study SC-1603. 2018 San Antonio Breast Cancer Symposium. Abstract GS6-02. Presented December 7, 2018.