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Meta-Analysis
. 2025 Jul;48(7):1659-1668.
doi: 10.1007/s40618-025-02583-8. Epub 2025 Apr 17.

Prevention of bicalutamide-induced breast events in patients with prostate cancer: a meta-analysis of randomized controlled trials

Luca Spagnolo  1 , Daniele Tienforti  2   3   4 , Carolina Moretto  1 , Camilla Tonni  1 , Vittoria Donatelli  5 , Alessandro Ferranti  1 , Gennaro Puocci  1 , Claudio Capuano  1 , Arcangelo Barbonetti  1
Affiliations
Meta-Analysis

Prevention of bicalutamide-induced breast events in patients with prostate cancer: a meta-analysis of randomized controlled trials

Luca Spagnolo et al. J Endocrinol Invest. 2025 Jul.

Abstract

Purpose: This study aimed to quantitatively assess the effectiveness of tamoxifen, anastrozole, and radiotherapy in preventing bicalutamide-induced breast events-specifically gynecomastia and breast pain-in patients with prostate cancer.

Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted according to PRISMA-P guidelines. A comprehensive search was performed in PubMed, Scopus, and Web of Science for English-language studies without temporal restrictions. Studies were included if they involved prostate cancer patients treated with bicalutamide receiving preventive interventions (tamoxifen, anastrozole, or radiotherapy) compared to bicalutamide alone (or bicalutamide plus placebo/sham). Data extraction focused on the incidence of gynecomastia and breast pain, and study quality was assessed using the Jadad scale. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using fixed- or random-effects models, and heterogeneity was evaluated with the I² statistic. Publication bias was explored via funnel plots and the trim-and-fill method.

Results: Nine RCTs met the inclusion criteria. Tamoxifen significantly reduced the risk of breast events by 82% (RR: 0.18, 95% CI: 0.08-0.38 for gynecomastia and RR: 0.18, 95% CI: 0.07-0.43 for breast pain). Radiotherapy reduced gynecomastia risk by 52% (RR: 0.48, 95% CI: 0.38-0.59) and breast pain by 34% (RR: 0.66, 95% CI: 0.48-0.90). Anastrozole did not show significant benefit.

Conclusion: Tamoxifen appears to be the most effective strategy for preventing bicalutamide-induced breast events, with radiotherapy serving as a viable alternative, and anastrozole offering no benefit. Further large-scale, high-quality studies are needed to confirm these findings and refine preventive treatment recommendations.

Keywords: Aromatase; Bicalutamide; Gynecomastia; Radiotherapy; Tamoxifen; Testosterone.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare they have no financial interests. Marco Giorgio Baroni and Arcangelo Barbonetti are members of the Editorial Board of the J Endocrinol Invest.

Figures

Fig. 1
Fig. 1
Flow diagram showing an overview of the study selection process
Fig. 2
Fig. 2
(A) Forest plot and (B) funnel plot depicting the effect of tamoxifen in preventing bicalutamide-induced gynecomastia. In panel A, the diamond represents the overall estimate (with the width indicating the 95% CI), and the boxes represent the weight of individual studies in the pooled result. In panel B, the trim-and-fill test identifies two putative missing studies (white circles) on the right side of the distribution
Fig. 3
Fig. 3
(A) Forest plot and (B) funnel plot depicting the effect of tamoxifen in preventing bicalutamide-induced breast pain. In panel A, the diamond represents the overall estimate (with the width indicating the 95% CI), and the boxes represent the weight of individual studies in the pooled result. In panel B, the trim-and-fill test identifies two putative missing studies (white circles) on the right side of the distribution
Fig. 4
Fig. 4
(A) Forest plot and (B) funnel plot depicting the effect of radiotherapy in preventing bicalutamide-induced gynecomastia. The diamond represents the overall estimate (with the width indicating the 95% CI), and the boxes represent the weight of individual studies in the pooled result. In panel B, the trim-and-fill test identifies one putative missing study (white circle) on the right side of the distribution
Fig. 5
Fig. 5
(A) Forest plot and (B) funnel plot depicting the effect of radiotherapy in preventing bicalutamide-induced breast pain. In panel A, the diamond represents the overall estimate (with the width indicating the 95% CI), and the boxes represent the weight of individual studies in the pooled result. In panel B, the trim-and-fill test identifies one putative missing study (white circle) on the right side of the distribution
See this image and copyright information in PMC

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