Elsevier

European Urology

Volume 52, Issue 1, July 2007, Pages 106-115
European Urology

Prostate Cancer
Tamoxifen 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

https://doi.org/10.1016/j.eururo.2007.01.031Get rights and content

Abstract

Objective

To define the optimum tamoxifen dose for reducing bicalutamide (CASODEX™) 150 mg monotherapy-induced breast events (ie, gynaecomastia or breast pain or both) without compromising disease control.

Methods

This was a double-blind, parallel-group, multicentre trial in which 282 patients with prostate cancer were randomised to receive bicalutamide 150 mg/d plus either daily tamoxifen (1, 2.5, 5, 10, or 20 mg) or placebo for 12 mo, followed by 12 mo of treatment with bicalutamide only. Primary end points were incidence of breast events and prostate-specific antigen (PSA) inhibition and were analysed at 6 mo (the primary analysis) and also at 12 and 24 mo.

Results

At 6 and 12 mo, tamoxifen decreased the incidence of breast events in a dose-dependent manner, with breast events observed in 86.2%, 60.0%, 55.3%, 23.5%, and 8.8% of patients receiving tamoxifen 1, 2.5, 5, 10, and 20 mg, respectively, compared with 96.7% of patients receiving placebo at 6 mo. At 24 mo (ie, after 12 mo of bicalutamide monotherapy), a high incidence of breast events was seen in all groups. There was no evidence of a negative effect on PSA inhibition at any assessment. Other nonbreast adverse effects were similar across groups, except for an increase in hot flushes with tamoxifen doses ≥5 mg.

Conclusion

These findings suggest that prophylactic tamoxifen 20 mg/d is an effective dose for reduction of bicalutamide-induced breast events and does not appear to affect disease control based on PSA suppression.

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.

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