A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol

Ruth E Langley, Howard G Kynaston, Abdulla A Alhasso, Trinh Duong, Edgar M Paez, Gordana Jovic, Christopher D Scrase, Andrew Robertson, Fay Cafferty, Andrew Welland, Robin Carpenter, Lesley Honeyfield, Richard L Abel, Michael Stone, Mahesh K B Parmar, Paul D Abel, Ruth E Langley, Howard G Kynaston, Abdulla A Alhasso, Trinh Duong, Edgar M Paez, Gordana Jovic, Christopher D Scrase, Andrew Robertson, Fay Cafferty, Andrew Welland, Robin Carpenter, Lesley Honeyfield, Richard L Abel, Michael Stone, Mahesh K B Parmar, Paul D Abel

Abstract

Background: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa.

Objective: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP).

Design, setting, and participants: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr.

Interventions: LHRHa as per local practice, OP (FemSeven 100μg/24h patches).

Outcome measurements and statistical analysis: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance.

Results and limitations: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001).

Conclusions: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial.

Patient summary: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial.

Trial registration: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Keywords: Androgen-deprivation therapy; Bone mineral density; Prostate cancer; Transdermal oestradiol.

Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
PATCH trial schema. The allocation ratio was 1:2 for luteinising hormone-releasing hormone agonists (LHRHa) to oestradiol patches during the first stage of the trial (before February 21, 2011) to optimise the experience of the patches and 1:1 thereafter. Patients in the bone mineral density study were enrolled from seven of the participating sites between August 2006 and September 2012. PFS = progression-free survival.
Fig. 2
Fig. 2
Flowchart of patients included in the analysis of change in lumbar spine bone mineral density at 1 yr from baseline (primary outcome measure). BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; LHRHa = luteinising hormone-releasing hormone agonists; LS = lumbar spine; OP = oestradiol patches. * The allocation ratio was 1:2 for LHRHa to OP before February 21, 2011, and 1:1 thereafter. $ The patch dose regimen was increased in August 2007 . + These patients contributed to at least one of the analyses on BMD change. ^ The main analysis of the primary outcome was restricted to patients with at least two evaluable LS vertebrae within L1–4 on both the baseline and 1-yr scans.
Fig. 3
Fig. 3
Mean percentage change (95% confidence interval) in bone mineral density at 1 and 2 yr from baseline by treatment arms. (a) All patients; (b) patients still on allocated treatment only (ie, patients who were still on allocated treatment at the time of the scan with no additional anticancer therapy, with those on oestradiol patch with oestradiol values

References

    1. Bourke L., Kirkbride P., Hooper R., Rosario A.J., Chico T.J., Rosario D.J. Endocrine therapy in prostate cancer: time for reappraisal of risks, benefits and cost-effectiveness? Br J Cancer. 2013;108:9–13.
    1. Longcope C., Kato T., Horton R. Conversion of blood androgens to estrogens in normal adult men and women. J Clin Invest. 1969;48:2191–2201.
    1. Diamond T.H., Higano C.S., Smith M.R., Guise T.A., Singer F.R. Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies. Cancer. 2004;100:892–899.
    1. Morote J., Orsola A., Abascal J.M. Bone mineral density changes in patients with prostate cancer during the first 2 years of androgen suppression. J Urol. 2006;175:1679–1683. discussion 1683.
    1. Smith M.R., McGovern F.J., Zietman A.L. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med. 2001;345:948–955.
    1. Nguyen P.L., Alibhai S.M., Basaria S. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol. 2015;67:825–836.
    1. Berruti A., Dogliotti L., Terrone C. Changes in bone mineral density, lean body mass and fat content as measured by dual energy x-ray absorptiometry in patients with prostate cancer without apparent bone metastases given androgen deprivation therapy. J Urol. 2002;167:2361–2367. discussion 2367.
    1. Smith M.R., Eastham J., Gleason D.M., Shasha D., Tchekmedyian S., Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003;169:2008–2012.
    1. Shahinian V.B., Kuo Y.F., Freeman J.L., Goodwin J.S. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med. 2005;352:154–164.
    1. Shao Y.H., Moore D.F., Shih W., Lin Y., Jang T.L., Lu-Yao G.L. Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications. BJU Int. 2013;111:745–752.
    1. Turo R., Smolski M., Esler R. Diethylstilboestrol for the treatment of prostate cancer: past, present and future. Scand J Urol. 2014;48:4–14.
    1. Byar D.P. Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer. 1973;32:1126–1130.
    1. von Schoultz B., Carlstrom K., Collste L. Estrogen therapy and liver function--metabolic effects of oral and parenteral administration. Prostate. 1989;14:389–395.
    1. Henriksson P., Blomback M., Eriksson A., Stege R., Carlstrom K. Effect of parenteral oestrogen on the coagulation system in patients with prostatic carcinoma. Br J Urol. 1990;65:282–285.
    1. Langley R.E., Cafferty F.H., Alhasso A.A. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09) Lancet Oncol. 2013;14:306–316.
    1. Langley R.E., Godsland I.F., Kynaston H. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer. BJU Int. 2008;102:442–445.
    1. Smith M.R., Egerdie B., Hernandez Toriz N. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745–755.
    1. Vickers A.J. The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study. BMC Med Res Methodol. 2001;1:6.
    1. Chang C.H., Tsai C.S., Jim Y.F., Wu H.C., Lin C.C., Kao A. Lumbar bone mineral density in prostate cancer patients with bone metastases. Endocr Res. 2003;29:177–182.
    1. Doren M., Samsioe G. Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995. Hum Reprod Update. 2000;6:419–426.
    1. Ockrim J.L., Lalani E.N., Banks L.M. Transdermal estradiol improves bone density when used as single agent therapy for prostate cancer. J Urol. 2004;172:2203–2207.
    1. Hedlund P.O., Damber J.E., Hagerman I. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5. Scand J Urol Nephrol. 2008;42:220–229.
    1. Small R.E. Uses and limitations of bone mineral density measurements in the management of osteoporosis. MedGenMed. 2005;7:3.
    1. Finkelstein J.S., Lee H., Burnett-Bowie S.A. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med. 2013;369:1011–1022.
    1. Phillips I., Shah S., Duong T., Abel P., Langley R.E. Androgen deprivation therapy and the re-emergence of parenteral oestrogen in prostate cancer. Oncol Haematol Rev. 2014;10:42–47.
    1. Falahati-Nini A., Riggs B.L., Atkinson E.J., O’Fallon W.M., Eastell R., Khosla S. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest. 2000;106:1553–1560.
    1. Krassas G.E., Papadopoulou P. Oestrogen action on bone cells. J Musculoskelet Neuronal Interact. 2001;2:143–151.
    1. Lee C.E., Leslie W.D., Czaykowski P., Gingerich J., Geirnaert M., Lau Y.K. A comprehensive bone-health management approach for men with prostate cancer receiving androgen deprivation therapy. Curr Oncol. 2011;18:e163–e172.
    1. Serpa Neto A., Tobias-Machado M., Esteves M.A. Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2012;15:36–44.
    1. Bolland M.J., Leung W., Tai V. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580.
    1. Reid I.R., Bolland M.J., Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014;383:146–155.
    1. Tai V., Leung W., Grey A., Reid I.R., Bolland M.J. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ. 2015;351:h4183.
    1. Smith M.R., Halabi S., Ryan C.J. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (Alliance) J Clin Oncol. 2014;32:1143–1150.
    1. Fizazi K., Carducci M., Smith M. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813–822.
    1. James N.D., Sydes M.R., Clarke N.W. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387:1163–1177.
    1. Smith M.R., Saad F., Coleman R. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39–46.
    1. Hedlund P.O., Henriksson P. Parenteral estrogen versus total androgen ablation in the treatment of advanced prostate carcinoma: effects on overall survival and cardiovascular mortality. The Scandinavian Prostatic Cancer Group (SPCG)-5 trial study. Urology. 2000;55:328–333.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する