Breast Cancer Research and Treatment

, Volume 73, Issue 2, pp 161–175

Phase III Randomized Trial of Droloxifene and Tamoxifen As First-Line Endocrine Treatment of ER/PgR-Positive Advanced Breast Cancer

  • A. Buzdar
  • D. Hayes
  • A. El-Khoudary
  • S. Yan
  • P. Lønning
  • M. Lichinitser
  • R. Gopal
  • G. Falkson
  • K. Pritchard
  • A. Lipton
  • K. Wolter
  • A. Lee
  • K. Fly
  • R. Chew
  • M. Alderdice
  • K. Burke
  • P. Eisenberg
Conference Report

Abstract

Purpose:This trial was designed to demonstrate equivalence between droloxifene 40 mg/d and tamoxifen 20 mg/d as first-line treatment in pre- and post-menopausal women with ER+ and/or PgR+ advanced breast cancer based on time to disease progression and tumor response.

Materials and methods:One thousand three hundred fifty four women with measurable disease, previously untreated by hormonal or chemotherapy for advanced or recurrent breast cancer, were enrolled by 179 institutions in 35 countries. Patients were stratified at baseline for menopausal status. Patients receiving adjuvant hormonal therapy within 1 year were excluded. All patients gave written informed consent, were randomized to 40 mg droloxifene or 20 mg tamoxifen daily as single-agent therapy and underwent tumor assessment every 3 months. A central committee reviewed digitized images for all cases of tumor progression or objective response.

Results:The hazard ratio (droloxifene/tamoxifen) for the primary endpoint, time to disease progression, was 1.287 favoring tamoxifen (95% C.I.: 1.114–1.487; p  <  .001). The objective response rate (CR + PR) was 22.4% for droloxifene and 28.6% for tamoxifen (p = .02). Tamoxifen was superior to droloxifene overall, among both pre- and postmenopausal patients and among patients ≤65 years; there was no difference among women ≥65 years. The hazard ratio for all-cause mortality was 0.871 (95% C.I.: 0.672–1.129; p = .29), favoring droloxifene but not statistically significant.

Conclusions:Droloxifene was significantly less effective than tamoxifen overall and particularly among women under 65 years. Tamoxifen and droloxifene were both less effective in pre-menopausal women with receptor-positive disease compared to post-menopausal women. Further clinical development of droloxifene was stopped.

advanced breast cancer droloxifene positive hormone receptors randomized trial tamoxifen 

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References

  1. 1.
    Haarstad H, Lønning PE, Gundersen S, Wist E, Raabe N, Kvinnsland S: Influence of droloxifene on metastatic breast cancer as first-line endocrine treatment. Acta Oncol 37: 365–368, 1998Google Scholar
  2. 2.
    Buzdar AU, Kau S, Hortobagyi GN, Theriault R, Booser D, Valero V, Ibrahim N, Smith T, Asmar L, Frye D, Manuel N, Kau S, McNeese M: Phase I trial of droloxifene in patients with metastatic breast cancer. Cancer Chemother Pharmacol 33: 313–316, 1994Google Scholar
  3. 3.
    Rauschning W, Pritchard KI: Droloxifene, a new antiestrogen: its role in metastatic breast cancer. Breast Cancer Res Treat 31: 83–94, 1994Google Scholar
  4. 4.
    Chevallier B, Spielmann M, Marty M, Serin D, Parillart P, Tubiana, Mignot L, Pujade L, Krams, Mertens H: [Treatment of advanced breast cancer in postmenopausal women with droloxifene: results of a double-blind phase II trial for dose determination]. Bull Cancer (Paris) 80: 624–628, 1993 (French)Google Scholar
  5. 5.
    Bruning PF: Droloxifene, a new antiestrogen in postmenopausal advanced breast cancer: preliminary results of a double-blind dose-finding phase II trial. Eur J Cancer 28A: 1404–1407, 1992Google Scholar
  6. 6.
    Deschenes L: Droloxifene, a new antiestrogen, in advanced breast cancer. A double-blind dose-finding study. The Droloxifene 002 International Study Group. Am J Clin Onc 14: S52–55, 1991Google Scholar
  7. 7.
    Abe O: Japanese early phase II study of droloxifene in the treatment of advanced breast cancer. Preliminary dose-finding study. Am J Clin Onc 14: S40–45, 1991Google Scholar
  8. 8.
    Bellmunt J, Sole L: European early phase II dose-finding study of droloxifene in advanced breast cancer. Am J Clin Onc 14: S36–39, 1991Google Scholar
  9. 9.
    Hassmann M, Rattel B, Löser R: Preclinical data for droloxifene. Cancer Lett 84: 101–116, 1994Google Scholar
  10. 10.
    Data on file: Pfizer Global Research and Development, New London, CT USAGoogle Scholar
  11. 11.
    Haarstad H, Gundersen S, Wist E, Raabe N, Meela O, Kvinnsland S: Droloxifene – a new anti-estrogen. A phase II study in advanced breast cancer. Acta Oncol 31: 425–428, 1992Google Scholar
  12. 12.
    Hayward JL, Carbone PP, Heuson JC, Kumaoka S, Segaloff A, Rubens R: Assessment of response to therapy in advanced breast cancer. Eur J Cancer 13: 89–94, 1977Google Scholar
  13. 13.
    Lien EA, Solheim E, Ueland PM: Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res 51: 4837–4844, 1991Google Scholar
  14. 14.
    Helle SI, Anker GB, Tally M, Hall K, Lonning P: Influence of droloxifene on plasma levels of insulin-like growth factor (IGF)-I, pro-IGF IIE, insulin-like growth factor binding protein (IGFBP)-1 and IGFBP-3 in breast cancer patients. J Steroid Biochem Mol Biol 57: 167–171, 1996Google Scholar
  15. 15.
    Geisler J, Haarstad H, Gunderson S, Rabbe N, Kvinnsland S, Lonning P: Influence of treatment with the anti-estrogen 3-hydroxytamoxifen (droloxifene) on plasma sex hormone levels in postmenopausal patients with breast cancer. J Endocrin 146: 359–363, 1995Google Scholar
  16. 16.
    Lønning PE, Hall K, Aakvaag A, Lien E: Influence of tamoxifen on plasma levels of insulin-like growth factor I and insulin-like growth factor bonding protein in breast cancer patients. Cancer Res 52: 4719–4723, 1992Google Scholar
  17. 17.
    Geisler J, Ekse D, Hösch S, Lonning P: Influence of droloxifene 40mg daily on plasma gonadotropins, sex hormone bonding globulin and estrogen levels in postmenopausal breast cancer patients. J Steroid Biochem Mol Biol 55: 193–195, 1995Google Scholar
  18. 18.
    Lønning PE, Johannessen DC, Lien EA, Ekse D, Fotsis T, Adlercreutz H: Influence of tamoxifen on sex hormones, gonadotropins and sex hormone binding globulin in postmenopausal breast cancer patients. J Steroid Biochem Mol Biol 52: 491–496, 1995Google Scholar
  19. 19.
    Houston SJ, Plunkett TA, Barnes DM, Smith P, Rubens R, Miles D: Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79: 1220–1226, 1999Google Scholar
  20. 20.
    Leitzel K, Teramoto Y, Konrad K, Chinchilli V, Volas G, Grossberg H, Harvey H, Demers L, Lipton A: Elevated serum c-erbB-2 antigen levels and decreased response to hormone therapy of breast cancer. J Clin Oncol 13: 1129–1135, 1995Google Scholar
  21. 21.
    Yamauchi H, O'Neill A, Gelman R, Carney W, Tenny D, Hosch S, Hayes D: Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein. J Clin Oncol 15: 2518–2525, 1997Google Scholar
  22. 22.
    Jennison C, Turnbull B: Interim analyses: the repeated confidence interval approach. J R Stat Soc Ser B 51: 305–361, 1989Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • A. Buzdar
    • 1
  • D. Hayes
    • 2
  • A. El-Khoudary
    • 3
  • S. Yan
    • 4
  • P. Lønning
    • 5
  • M. Lichinitser
    • 6
  • R. Gopal
    • 7
  • G. Falkson
    • 8
  • K. Pritchard
    • 9
  • A. Lipton
    • 10
  • K. Wolter
    • 11
  • A. Lee
    • 11
  • K. Fly
    • 11
  • R. Chew
    • 11
  • M. Alderdice
    • 11
  • K. Burke
    • 12
  • P. Eisenberg
    • 13
    • 14
  1. 1.M.D. Anderson Cancer CenterThe University of TexasHouston
  2. 2.Georgetown University Medical CenterWashington, DCUSA
  3. 3.National Cancer InstituteCairo University, CairoEgypt
  4. 4.Cancer Hospital of the Chinese Academy of Medical ScienceBeijingChina
  5. 5.Haukeland SykehusBergenNorway
  6. 6.Cancer Research CenterMoscowRussia
  7. 7.Tata Memorial HospitalBombayIndia
  8. 8.University of Pretoria and Pretoria Academic HospitalsPretoriaSouth Africa
  9. 9.Toronto-Sunnybrook Regional Cancer CenterTorontoCanada
  10. 10.M. S. Hershey Medical CenterHershey
  11. 11.Pfizer Central ResearchGrotonUSA
  12. 12.Klinge Pharma GmbHMunichGermany
  13. 13.Sutter/CHS Cancer Research GroupGreenbraeUSA
  14. 14.For the Droloxifene 301 Study GroupGreenbraeUSA

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