Prostate CancerTamoxifen as Prophylaxis for Prevention of Gynaecomastia and Breast Pain Associated with Bicalutamide 150 mg Monotherapy in Patients with Prostate Cancer: A Randomised, Placebo-Controlled, Dose–Response Study
Introduction
Bicalutamide (CASODEX™) is the most widely studied nonsteroidal antiandrogen for prostate cancer monotherapy and has tolerability advantages compared with the other drugs in its class [1], [2], [3], [4]. Gynaecomastia and breast pain are well-recognised and common pharmacologic side-effects of all nonsteroidal antiandrogens [1]. Although generally mild to moderate in severity, these breast events may lead to treatment withdrawal, thereby compromising cancer control.
Gynaecomastia is caused by an imbalance between the effects of oestrogens and androgens on receptors in the breast, leading to breast enlargement [5], [6]. Various treatment options for nonsteroidal antiandrogen-induced gynaecomastia and breast pain have been investigated, including surgery, radiotherapy, and hormonal therapies [7], [8], [9], [10]. Tamoxifen has been shown to be an effective prophylactic therapy in several studies [9], [11], [12], [13], but the optimal dose has not yet been established. The impact of tamoxifen on prostate cancer control is also unknown; however, coadministration of tamoxifen appears to have no significant influence on plasma concentrations of bicalutamide [9], [14] or prostate-specific antigen (PSA) response [9], [11], [12], [13] in patients with prostate cancer and does not interfere with the inhibitory effects of bicalutamide on prostate cancer cells in vitro [15].
This dose–response study explored the relationship between the prophylactic dose of tamoxifen and the incidence of gynaecomastia and breast pain in patients receiving bicalutamide 150 mg/d for localised or locally advanced prostate cancer. The extent of bicalutamide-induced PSA inhibition was monitored as a measure of tumour control.
Section snippets
Patients
Eligible patients had T1–T4, any N, M0 histologically confirmed prostate cancer requiring immediate hormonal therapy. Patients may have received primary therapy of curative intent (≥6 mo previously for nonsurgical therapies). Other inclusion criteria were a life expectancy of >3 yr and a baseline PSA level of ≥4 ng/ml (to ensure detectable changes in PSA inhibition).
Exclusion criteria included pre-existing gynaecomastia or breast pain, previous hormonal therapy for prostate cancer (except
Patient population
A total of 282 patients with a mean age of 75 yr (range: 47–94 yr) were recruited (Fig. 1). Patient demographics, disease characteristics, and prior treatment were reasonably well-balanced across the six treatment groups (Table 1). A total of 278 patients received at least one assessment following randomisation and formed the ITT population for analysis of incidence of breast events; 277 patients formed the ITT population for analysis of PSA inhibition.
Breast events
Increasing doses of tamoxifen were
Discussion
In this study, coadministration of tamoxifen and bicalutamide decreased the incidence of breast events in a dose-dependent manner; all doses of tamoxifen >1 mg were significantly superior to placebo (p ≤ 0.0002) after 6 mo of treatment, an effect that remained significant at 12 mo. Similar dose responses were noted for the separate incidences of gynaecomastia and breast pain, intensity of breast pain, and objective calliper measurement of the degree of gynaecomastia. In all analyses, tamoxifen 20
Acknowledgements
We thank Dr. Chris Rapier from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. We would also like to thank the following principal investigators for their substantial contributions to the study:
Canada: A. Aprikian (McGill Urology Associates, Montreal, PQ); J. Barkin (The Male Health Centres, North York, ON); M. Carmel (CHUS-Hospital Fleur, Sherbrooke, PQ); R. Casey (The Male Health Centres, Oakville, ON); D. Eiley (Ultra-Med, Pointe-Claire, PQ); N.
References (22)
- et al.
Antiandrogens in the treatment of prostate cancer
Eur Urol
(2007) - et al.
Gynecomastia in patients with prostate cancer: a review of treatment options
Urology
(2000) - et al.
A systematic approach to the surgical treatment of gynaecomastia
Br J Plast Surg
(2003) The safety and tolerability of low-dose irradiation for the management of gynaecomastia caused by antiandrogen monotherapy
Lancet Oncol
(2003)- et al.
Management of gynaecomastia in patients with prostate cancer: a systematic review
Lancet Oncol
(2005) - et al.
Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial
Lancet Oncol
(2005) - et al.
Once weekly tamoxifen in the prevention of gynaecomastia and breast pain secondary to bicalutamide therapy
J Urol
(2004) - et al.
Risks and benefits of hormonal manipulation as monotherapy or adjuvant treatment in localised prostate cancer
Eur Urol
(2005) - et al.
Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy
J Urol
(2005) - et al.
Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer
Eur Urol
(2005)