Breast Cancer Research and Treatment

, Volume 106, Issue 3, pp 389–397 | Cite as

A phase II trial of Afimoxifene (4-hydroxytamoxifen gel) for cyclical mastalgia in premenopausal women

  • Robert Mansel
  • Amit Goyal
  • Elisabeth Le Nestour
  • Valérie Masini-Etévé
  • Katharine O’Connell
  • Afimoxifene (4-OHT) Breast Pain Research Group
Clinical Trial

Abstract

Background

Many women experience symptoms of cyclical mastalgia, such as breast pain, tenderness, and nodularity. Tamoxifen and other drugs have been used to alleviate cyclical mastalgia symptoms; however, their use is associated with potentially serious side effects. The current study compared the safety and efficacy of two doses of a topical gel containing 4-hydroxytamoxifen (Afimoxifene, formerly known as 4-OHT) with placebo gel for the treatment of moderate to severe cyclical mastalgia.

Methods

Premenopausal women aged at least 18 years experiencing moderate to severe symptoms were randomized to receive placebo, 2 mg, or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles. The primary efficacy parameter was change in mean pain intensity as measured by the Visual Analog Scale (VAS) for the seven worst pain score days within a cycle from baseline to the fourth cycle.

Results

After 4 cycles of treatment, statistically significant improvements relative to placebo were measured in mean VAS score in the 4-mg Afimoxifene group (−12.71 mm [95% confidence interval, −0.96 to −24.47; P = 0.034]). Patient global assessment of pain, physician’s assessment of pain, tenderness on palpation, and nodularity following 4 cycles of treatment were significantly more likely to show improvements in the 4-mg group, compared with placebo (P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]). Overall, Afimoxifene was well tolerated with few adverse events and no drug-related SAE occurred in any group.

There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene.

Conclusion

After 4 months of treatment, daily topical breast application of Afimoxifene resulted in statistically significant improvements in signs and symptoms of cyclical mastalgia across patient- and physician-rated scales with excellent tolerability and safety.

Keywords

4-Hydroxytamoxifen Afimoxifene Mastalgia Cyclical mastalgia Breast tenderness Breast pain 

Notes

Acknowledgments

Conflict of Interest: R Mansel had full access to all the data in the study and had final responsibility for the decision to submit for publication; A Goyal and K O’Connell have no conflict of interest; E Le Nestour and Valérie Masini-Etévé are full-time employees of Besins International.

References

  1. 1.
    Ader DN, Browne MW (1997) Prevalence and impact of cyclic mastalgia in a United States clinic-based sample. Am J Obstet Gynecol 177(1):126–132PubMedCrossRefGoogle Scholar
  2. 2.
    Ader DN, South-Paul J, Adera T, Deuster PA. (2001) Cyclical mastalgia: prevalence and associated health and behavioral factors. J Psychosom Obstet Gynaecol 22(2):71–76PubMedGoogle Scholar
  3. 3.
    Goodwin PJ, Miller A, Del Giudice ME, Ritchie K (1997) Breast health and associated premenstrual symptoms in women with severe cyclic mastopathy. Am J Obstet Gynecol 176(5):998–1005PubMedCrossRefGoogle Scholar
  4. 4.
    Woods NF, Most A, Dery GK (1982) Prevalence of perimenstrual symptoms. Am J Public Health 72(11):1257–1264PubMedGoogle Scholar
  5. 5.
    Boyle CA, Berkowitz GS, Kelsey JL (1987) Epidemiology of premenstrual symptoms. Am J Public Health 77(3):349–350PubMedGoogle Scholar
  6. 6.
    Preece PE, Mansel RE, Bolton PM, Hughes LM, Baum M, Gravelle IH (1976) Clinical syndromes of mastalgia. Lancet 2(7987):670–673PubMedCrossRefGoogle Scholar
  7. 7.
    Ader DN, Shriver CD (1997) Cyclical mastalgia: prevalence and impact in an outpatient breast clinic sample. J Am Coll Surg 185(5):482–486Google Scholar
  8. 8.
    Deschamps M, Band PR, Coldman AJ, Hislop TG, Longley DJ (1996) Clinical determinants of mammographic dysplasia patterns. Cancer Detect Prev 20(6):610–619PubMedGoogle Scholar
  9. 9.
    Khanna AK, Tapodar J, Misra MK (1997) Spectrum of benign breast disorders in a university hospital. J Indian Med Assoc 95(1):5–8PubMedGoogle Scholar
  10. 10.
    Leinster SJ, Whitehouse GH, Walsh PV (1987) Cyclical mastalgia: clinical and mammographic observations in a screened population. Br J Surg 74(3):220–222PubMedCrossRefGoogle Scholar
  11. 11.
    Khan SA, Apkarian AV (2002) The characteristics of cyclical and non-cyclical mastalgia: a prospective study using a modified McGill Pain Questionnaire. Breast Cancer Res Treat 75(2):147–157PubMedCrossRefGoogle Scholar
  12. 12.
    Mansel RE, Wisbey JR, Hughes LE (1982) Controlled trial of the antigonadotropin danazol in painful nodular benign breast disease. Lancet 1(8278):928–930PubMedCrossRefGoogle Scholar
  13. 13.
    Mansel RE, Dogliotti L (1990) European multicentre trial of bromocriptine in cyclical mastalgia. Lancet 335(8683):190–193PubMedCrossRefGoogle Scholar
  14. 14.
    Fentiman IS, Caleffi M, Brame K, Chaudary MA, Hayward JL (1986) Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1(8476):287–288PubMedCrossRefGoogle Scholar
  15. 15.
    Fentiman IS, Caleffi M, Hamed H, Chaudary MA (1988) Dosage and duration of tamoxifen treatment for mastalgia: a controlled trial. Br J Surg 75(9):845–846PubMedCrossRefGoogle Scholar
  16. 16.
    Jordan VC, Collins MM, Rowsby L, Prestwich G (1977) A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol 75(2):305–316PubMedCrossRefGoogle Scholar
  17. 17.
    Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S et al (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138(3):863–870PubMedCrossRefGoogle Scholar
  18. 18.
    Malet C, Gompel A, Spritzer P, Bricout N, Yaneva H, Mowszowicz I et al (1988) Tamoxifen and hydroxytamoxifen isomers versus estradiol effects on normal human breast cells in culture. Cancer Res 48(24 Pt 1):7193–7199PubMedGoogle Scholar
  19. 19.
    Katzenellenbogen BS, Norman MJ, Eckert RL, Peltz SW, Mangel WF (1984) Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res 44(1):112–119PubMedGoogle Scholar
  20. 20.
    Rouanet P, Linares-Cruz G, Dravet F, Poujol S, Gourgou S, Simony-Lafontaine J et al (2005) Neoadjuvant percutaneous 4-hydroxytamoxifen decreases breast tumoral cell proliferation: a prospective controlled randomized study comparing three doses of 4 OHT gel to oral tamoxifen. J Clin Oncol 23(13):2980–2987PubMedCrossRefGoogle Scholar
  21. 21.
    Colak T, Ipek T, Kanik A, Ogetman Z, Aydin S (2003) Efficacy of topical nonsteroidal anti-inflammatory drugs in mastalgia treatment. J Am Coll Surg 196:525–530PubMedCrossRefGoogle Scholar
  22. 22.
    Irving AD, Morrison SL (1998) Effectiveness of topical non-steroidal anti-inflammatory drugs in the management of breast pain. J R Coll Surg Edinb 43(3):158–159PubMedGoogle Scholar
  23. 23.
    Price DD, McGrath PA, Rafii A, Buckingham B (1983) The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 17(1):45–56PubMedCrossRefGoogle Scholar
  24. 24.
    Messinis IE, Lolis D (1988) Treatment of premenstrual mastalgia with tamoxifen. Acta Obstet Gynecol Scand 67(4):307–309PubMedGoogle Scholar
  25. 25.
    Kontostolis E, Stefanidis K, Navrozoglou I, Lolis D (1997) Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol 11(6):393–397PubMedCrossRefGoogle Scholar
  26. 26.
    Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL et al (2002) Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 20(19):4040–4049PubMedCrossRefGoogle Scholar
  27. 27.
    Hammack JE, Mailliard JA, Loprinzi CL, Rospond RM, O’Fallon JR, Wilwerding MB et al (1996) Transdermal fentanyl in the management of cancer pain in ambulatory patients: an open-label pilot study. J Pain Symptom Manage 12(4):234–240PubMedCrossRefGoogle Scholar
  28. 28.
    Mansel RE, Goyal A, Preece P et al (2004) European randomized, multicenter study of goserelin (Zoladex) in the management of mastalgia. Am J Obstet Gynecol 191:1942–1949PubMedCrossRefGoogle Scholar
  29. 29.
    Goyal A, Mansel RE (2005) on behalf of the Efamast Study Group. A Randomized multicenter study of gamolenic acid (Efamast) with and without antioxidant vitamins and minerals in the management of mastalgia. Breast J 11:41–47PubMedCrossRefGoogle Scholar
  30. 30.
    Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM et al (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90(18):1371–1388PubMedCrossRefGoogle Scholar
  31. 31.
    Gallicchio L, Lord G, Tkaczuk K, Danton M, Lewis LM, Lim CK et al (2004) Association of tamoxifen (TAM) and TAM metabolite concentrations with self-reported side effects of TAM in women with breast cancer. Breast Cancer Res Treat 85(1):89–97PubMedCrossRefGoogle Scholar
  32. 32.
    MacCallum J, Cummings J, Dixon JM, Miller WR (2000) Concentrations of tamoxifen and its major metabolites in hormone responsive and resistant breast tumours. Br J Cancer 82(10):1629–1635PubMedCrossRefGoogle Scholar
  33. 33.
    Mourits MJ, De Vries EG, Willemse PH, Ten Hoor KA, Hollema H, Van der Zee AG (2001) Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol 97(5 Pt 2):855–866PubMedCrossRefGoogle Scholar
  34. 34.
    Chalas E, Costantino JP, Wickerham DL, Wolmark N, Lewis GC, Bergman C et al (2005) Benign gynecologic conditions among participants in the Breast Cancer Prevention Trial. Am J Obstet Gynecol 192(4):1230–1237PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Robert Mansel
    • 1
  • Amit Goyal
    • 1
  • Elisabeth Le Nestour
    • 2
  • Valérie Masini-Etévé
    • 2
  • Katharine O’Connell
    • 3
  • Afimoxifene (4-OHT) Breast Pain Research Group
  1. 1.Department of Surgery, Wales College of MedicineCardiff UniversityCardiffUK
  2. 2.Besins InternationalParisFrance
  3. 3.Columbia University Medical CenterNew YorkUSA

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