Elsevier

European Urology

Volume 47, Issue 5, May 2005, Pages 587-592
European Urology

Efficacy and Tolerability of Radiotherapy as Treatment for Bicalutamide-induced Gynaecomastia and Breast Pain in Prostate Cancer

https://doi.org/10.1016/j.eururo.2004.12.003Get rights and content

Abstract

Objective:

To assess the efficacy and tolerability of localised radiotherapy for the treatment of bicalutamide (‘Casodex’1)-induced gynaecomastia and/or breast pain.

Methods:

This open-label, non-comparative, multicentre study included 51 patients receiving bicalutamide 150 mg for the treatment of non-metastatic prostate cancer (T1b–T4, Nx, M0). Patients who developed symptomatic gynaecomastia and/or breast pain received two 6-Gy fractions of external-beam radiation to the breasts and were then assessed at two 3-monthly follow-up visits.

Results:

37/51 (72.5%) patients experienced gynaecomastia and 41/51 (80.4%) experienced breast pain, typically within the first 6 months. Twenty seven and 38 patients, respectively, went on to receive breast irradiation. Following radiotherapy, gynaecomastia improved or resolved in 7/27 (25.9%) and 2/27 (7.4%) cases, respectively, and breast pain improved or resolved in 12/38 (31.6%) and 3/38 (7.9%) cases, respectively. No change was observed in 7 patients (25.9%) with gynaecomastia and 12 patients (31.6%) with breast pain, while 9 patients (33.3%) and 8 patients (21.1%), respectively, worsened. Radiotherapy-related adverse events, reported by 18/41 (43.9%) patients, were generally mild and short lived (median duration approximately 5 weeks).

Conclusions:

Therapeutic radiotherapy, using two fractions of 6 Gy external-beam radiation to the male breast, improves the intensity of bicalutamide-induced gynaecomastia and/or breast pain in approximately one-third of patients. Adverse events were often mild and short lived.

Introduction

In patients with locally advanced disease, bicalutamide (‘Casodex’) 150 mg is increasingly being used to reduce the risk of disease progression. This non-steroidal antiandrogen has fewer adverse events compared with other androgen deprivation strategies, such as surgical or medical castration, offering significant benefits in terms of physical capacity, maintenance of sexual interest and function, and preservation of bone mineral density [1], [2]. Results from the bicalutamide Early Prostate Cancer (EPC) programme show that, at 5.4 years’ median follow-up, bicalutamide 150 mg significantly improved objective progression-free survival in patients with locally advanced disease (T3–4, M0, any N or any T, M0, N+) [3]. Gynaecomastia and breast pain are frequent adverse events of non-steroidal antiandrogens, arising from an increase in the effective oestrogen:androgen ratio in the breast, due to the hypergonadotrophic effects of the drugs [4]. In its early stages, gynaecomastia is often associated with breast pain and tenderness due to the benign proliferation of the glandular tissue. After approximately 1 year, progressive fibrosis and hyalinisation of the stroma may occur, a condition that is frequently irreversible [5].

In the EPC programme, the incidences of gynaecomastia and breast pain were 68.3% and 73.6%, respectively, with symptoms developing in ≥80% of cases within the first 6–9 months of bicalutamide 150 mg therapy [3], [6]. Although these adverse events were mild to moderate in >90% of cases, at a median 5.4 years’ follow-up, 16.7% of patients had withdrawn from the programme due to gynaecomastia and/or breast pain, with the risk of compromising their treatment outcome [3].

For some patients there is a need for effective treatment strategies for antiandrogen-induced gynaecomastia and breast pain in prostate cancer. Radiation, surgery and medical therapy are commonly used to alleviate or prevent the development of gynaecomastia and breast pain of other aetiologies [4], [5]. Controlled trials have demonstrated the efficacy of prophylactic breast irradiation and tamoxifen for bicalutamide-induced gynaecomastia and breast pain [7], [8], [9], [10]. Other studies evaluating the effects of irradiation on the treatment of gynaecomastia and breast pain induced by other endocrine therapies have focused primarily on the prophylactic approach [11], [12], [13], [14]. Only a few small studies, with various dosage regimes, have previously evaluated the effect of therapeutic irradiation [15], [16], [17]. The latest study, published in 1988, reported that 3/11 patients (27%) with diethylstilbestrol-induced gynaecomastia had a significant decrease in their breast size whilst all 11 patients had satisfactory pain relief following irradiation [16]. As not all patients receiving bicalutamide 150 mg treatment develop gynaecomastia or breast pain, and given that for many of those who do these adverse events are mild to moderate [3], one approach could be to wait until the onset of symptoms before initiating treatment.

This paper presents the findings of an exploratory study of therapeutic local radiotherapy administered as two equal fractions of 6 Gy external-beam irradiation on consecutive days, as a potential management option for bicalutamide-induced gynaecomastia and breast pain. The study was non-comparative, as the aim was to evaluate a new procedure for the treatment of recognised adverse events.

Section snippets

Patient selection

The study consisted of adult men with non-metastatic adenocarcinoma of the prostate gland (T1b–4, Nx, M0) suitable for bicalutamide 150 mg monotherapy. Patients were permitted to have received prior therapy of curative intent for prostate cancer.

Patients with liver disease (bilirubin > 2.0 mg/dl; aspartate aminotransferase [AST] or alanine aminotransferase [ALT] > 2 times the upper limit of normal), pre-existing gynaecomastia/breast pain and those receiving concurrent drug therapy that could cause

Patients

Fifty-one Caucasian patients aged 50–82 (mean 71.1) years were enrolled in this exploratory study. Prostate-specific antigen levels at study entry ranged from 0.1–144.6 ng/ml; levels at 3 and 12 months were 0.1–81 ng/ml (median 1.4) and 0.1–4.7 ng/ml (median 0.48), respectively.

Two patients completed the study without exhibiting any symptoms, whereas 49 patients developed gynaecomastia and/or breast pain within 12 months of study entry, of which 41 received localised radiotherapy for these adverse

Discussion

This study was designed to aid the management of gynaecomastia and breast pain following antiandrogen monotherapy in prostate cancer patients. The benefit of therapeutic irradiation, rather than prophylactic treatment, was to avoid treating patients who had not developed gynaecomastia and breast pain. The trial assessed the efficacy of two doses of 6 Gy external-beam radiation administered to the breast on consecutive days after symptom onset, and was designed to reflect clinical practice. As

Acknowledgement

This study was sponsored by AstraZeneca.

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1

‘Casodex’ is a trademark of the AstraZeneca group of companies.

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