Oxybutynin use as a hot flash reducer in breast cancer survivors in the use of tamoxifen: a pilot randomized clinical trial
DOI:
https://doi.org/10.29289/2594539420240021Keywords:
oxybutynin, breast cancer, tamoxifen, hot flashesAbstract
Breast cancer is a heterogeneous disease in which genetic and environmental factors are involved. The most prevalent types are those expressing hormone receptors, consisting of 60% to 70% of all cases in developed countries. Therefore, the most common type of therapeutic approach is hormone therapy. Estrogen blockers, such as tamoxifen, and aromatase inhibitors, such as anastrozole, are the most prescribed medicines for these types of cancer. The purpose of this article was to assess the effects of once-daily oxybutynin 5 mg on frequency and severity of hot flashes in women with breast cancer using tamoxifen. Methods: A two-month double-blind, placebo-controlled, pilot randomized clinical trial in women with breast cancer using tamoxifen that were experiencing hot flashes. These women were treated daily with oxybutynin 5 mg (n=11) or a placebo (n=12). The co-primary outcome was to reduce, from baseline to month two, the frequency and severity of hot flashes symptoms. Results: Reductions in both frequency and severity of hot flashes were observed in women who received oxybutynin 5 mg/day compared to placebo, even though it was not statistically significant. Adverse effects reported by the oxybutynin arm were tachycardia and decrease in appetite (9.1%), and in the placebo arm were headaches (8.3%), xerostomia (16.6%), diarrhea (8.3%), and dry skin (8.3%). Conclusions: oxybutynin is a safe nonhormonal therapy for hot flashes in women with breast cancer using tamoxifen.
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References
1. Barzaman K, Karami J, Zarei Z, Hosseinzadeh A, Kazemi MH, Moradi-Kalbolandi S, et al. Breast cancer: biology, biomarkers, and treatments. Int Immunopharmacol. 2020;84:106535. https://doi.org/10.1016/j.intimp.2020.106535
2. Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275-81. https://doi.org/10.1200/JCO.2007.14.4147
3. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig. 2011;121(7):2750-67. https://doi.org/10.1172/JCI45014
4. Chen X, Xu D, Li X, Zhang J, Xu W, Hou J, et al. Latest overview of the cyclin-dependent kinases 4/6 inhibitors in breast cancer: the past, the present and the future. J Cancer. 2019;10(26):6608-17. https://doi.org/10.7150/jca.33079
5. Reinert T, Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304-20. https://doi.org/10.1177/1758834015608993
6. Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer. 2008;44(1):30-8. https://doi.org/10.1016/j.eca.2007.11.002
7. Jordan VC, Obiorah I, Fan P, Kim HR, Ariazi E, Cunliffe H, et al. The St. Gallen prize lecture 2011: evolution of long-term adjuvant anti-hormone therapy: consequences and opportunities. Breast. 2011;20(3):S1-S11. https://doi.org/10.1016/S0960-9776(11)70287-9
8. Early breast cancer trialistis’ collaborative group (EBCTCG), Davies C, Godwin J, Gray R, Clarke M, Cutter D, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level metanalysis of randomised trials. Lancet. 2011;378(9793):771-84. https://doi.org/10.1016/S0140-6736(11)60993-8
9. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Long-term effect of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of estrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-16. https://doi.org/10.1016/S0140-6736(12)61963-1
10. Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008;108(3):421-6. https://doi.org/10.1007/s10549-007-9612-x
11. Ayres LR, Baldoni AO, Borges APS, Pereira LRL. Adherence and discontinuation of oral hormonal therapy in patients with hormone receptor positive breast cancer. Int J Clin Pharm. 2014;36(1):45-54. https://doi.org/10.1007/s11096-013-9833-5
12. Lorizio W, Wu AHB, Beattie MS, Rugo H, Tchu S, Kerlikowske K, et al. Clinical and biomarker predictors of side effects from tamoxifen. Breast Cancer Res Treat. 2012;132(3):1107-18. https://doi.org/10.1007/s10549-011-1893-4
13. Goetz MP, Rae JM, Suman VJ, Safgren SL, Ames MM, Wisscher DW, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005;23(36):9312-8. https://doi.org/10.1200/JCO.2005.03.3266
14. Cuzick J, Sestak I, Cella D, Fallowfield L; ATAC Trialists’ Group. Treatment-emergent endocrine symptoms and the risk of breast cancer recurrence: a retrospective analysis of the ATAC trial. Lancet Oncol. 2008;9(12):1143-1148. https://doi.org/10.1016/S1470-2045(08)70259-6
15. Baxter SD, Teft WA, Choi Y-H, Winquist E, Kim RB. Tamoxifen-associated hot flash severity is inversely correlated with endoxifen concentration and CYP3A4*22. Breast Cancer Res Treat. 2014;145(2):419-28. https://doi.org/10.1007/s10549-014-2963-1
16. Nawrocki S, Cha J. The etiology, diagnosis, and management of hyperhidrosis: a comprehensive review: therapeutic options. J Am Acad Dermatol. 2019;81(3):669-80. https://doi.org/10.1016/j.jaad.2018.11.066
17. Sexton T, Younus J, Perera F, Kligman L, Lock M. Oxybutynin for refractory hot flashes in cancer patients. Menopause. 2007;14(3):505-9. https://doi.org/10.1097/01.gme.0000243574.01441.3e
18. Leon-Ferre RA, Novotny PJ, Wolfe EG, Faubion SS, Ruddy KJ, Flora D, et al. Oxybutynin vs placebo for hot flashes in women with or without breast cancer: a randomized, double-blind clinical trial (ACCRU SC-1603). JNCI Cancer Spectr. 2019;4(1):pkz088. https://doi.org/10.1093/jncics/pkz088
19. Yarker YE, Goa KL, Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetics properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6(3):243-62. https://doi.org/10.2165/00002512-199506030-00007
20. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103-15.
21. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-717. https://doi.org/10.1016/S0140-6736(05)66544-0
22. Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al. Long-term results of tamoxifen prophylaxis for breast cancer –96 – month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst. 2007;99(4):272-82. https://doi.org/10.1093/jnci/djk049
23. Lim YC, Desta Z, Flockhart DA, Skaar TC. Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifen. Cancer Chemother Pharmacol. 2005;55(5):471-8. https://doi.org/10.1007/s00280-004-0926-7
24. Mortimer JE, Flatt SW, Parker BA, Gold EB, Wasserman L, Natarajan L, et al. Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat. 2008;108(3):421-6. https://doi.org/10.1007/s10549-007-9612-x
25. Freedman RR, Blacker CM. Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril. 2002;77(3):487-90. https://doi.org/10.1016/s0015-0282(01)03009-6
26. Stearns V, Ullmer L, López JF, Smith Y, Isaacs C, Hayes DF. Hot flushes. Lancet. 2002;360(9348):1851-61. https://doi.org/10.1016/s0140-6736(02)11774-0
27. Forma E, Urbańska K, Bryś M. Menopause hot flashes and molecular mechanisms modulated by food-derived nutrients. Nutrients 2024;16(5):655-70. https://doi.org//10.3390/nu16050655
28. Kronenberg F. Hot flashes: epidemiology and physiology. Ann NY Acad Sci. 1990;592(1):52-86. https://doi.org/10.1111/j.1749-6632.1990.tb30316.x
29. Patel B, Dhillo WS. Menopause review: emerging treatments for menopausal symptoms. Best Pract Res Clin Obstet Gynaecol. 2022;81:134-44. https://doi.org/10.1016/j.bpobgyn.2021.10.010
30. Yelland S, Steenson S, Creedon A, Stanner S. The role of diet in managing menopausal symptoms: a narrative review. Nutr Bull. 2023;48(1):43-65. https://doi.org/10.1111/nbu.12607
31. Casper RF, Yen SS. Neuroendocrinology of menopausal flushes: an hypothesis of flush mechanism. Clin Endocrinol. 1985;22(3):293-312. https://doi.org10.1111/j.1365-2265.1985.tb03243.x
32. Sexton T, Younus J, Perera F, Kligman L, Lock M. Oxybutynin for refractory hot flashes in cancer patients. Menopause. 2007;14(3):505-9. https://doi.org/10.1097/01.gme.0000243574.01441.3e
33. Yarker YE, Goa KL, Fitton A. Oxybutynin. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging. 1995;6(3):243-62. https://doi.org/10.2165/00002512-199506030-00007
34. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology. 2000;55(5A):33-46. https://doi.org/10.1016/s0090-4295(99)00492-6
35. Simon JA, Gaines T, LaGuardia KD; Extended-Release Oxybutynin Therapy for VMS Study Group. Extended-release oxybutynin therapy for vasomotor symptoms in women: a randomized clinical trial. Menopause. 2016;23(11):1214-21. https://doi.org/10.1097/GME.0000000000000773
36. Sanchez-Spitman A, Dezentjé V, Swen J, Moes DJAR, Böhringer S, Batman E, et al. Tamoxifen pharmacogenetics and metabolism: results from the prospective CYPTAM study. J Clin Oncol. 2019;37(8):636-46. https://doi.org/10.1200/JCO.18.00307
37. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37. https://doi.org/10.2174/1389200023338017
38. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee K-H, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97(1):30-39. https://doi.org/10.1093/jnci/dji005
39. Goetz MP, Sangkuhl K, Guchelaar H-K, Schwab M, Province M, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther. 2018;103(5):770-7. https://doi.org/10.1002/cpt.1007
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Copyright (c) 2025 Beatriz Ferreira Maraccini, Micaela Gomes de Oliveira, Leandra Ernst Kerche, Suelen Umbelino da Silva, Rafael da Silva Sá

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