Elsevier

The Lancet Oncology

Volume 6, Issue 5, May 2005, Pages 295-300
The Lancet Oncology

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Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial

https://doi.org/10.1016/S1470-2045(05)70103-0Get rights and content

Summary

Background

Gynaecomastia and breast pain are frequent adverse events with bicalutamide monotherapy, and might cause some patients to withdraw from treatment. We aimed to compare tamoxifen with radiotherapy for prevention and treatment of gynaecomastia, breast pain, or both during bicalutamide monotherapy for prostate cancer.

Methods

51 patients were randomly assigned to 150 mg bicalutamide per day, 50 patients to 150 mg bicalutamide per day and to 10 mg tamoxifen per day for 24 weeks, and 50 patients to 150 mg bicalutamide per day and radiotherapy (one 12-Gy fraction on the day of starting bicalutamide). 35 of the 51 patients allocated bicalutamide alone developed gynaecomastia or breast pain and were subsequently randomly allocated to tamoxifen (n=17) or radiotherapy (n=18) soon after symptoms started (median 180 days, range 160–195). Gynaecomastia and breast pain were assessed once a month. Severity of gynaecomastia was scored on the basis of the largest diameter. Breast pain was scored as none, mild, moderate, or severe. The primary outcome was frequency of gynaecomastia or breast pain; secondary outcomes were safety and tolerability, relapse-free survival, as assessed by concentration of prostate specific antigen, and quality of life. Analyses were by intention to treat.

Results

35 of 51 patients assigned bicalutamide alone developed gynaecomastia, compared with four of 50 assigned bicalutamide and tamoxifen (odds ratio [OR] 0·1 [95% CI 0·08–0·12], p=0·0009), and with 17 of 50 assigned bicalutamide and radiotherapy (0·51 [0·47–0·54], p=0·008). Breast pain was seen in 29 of 51 patients allocated bicalutamide alone, compared with three allocated bicalutamide and tamoxifen (0·1 [0·07–0·11], p=0·009), and with 15 allocated bicalutamide and radiotherapy (0·43 [0·40–0·45], p=0·02) In 35 patients assigned bicalutamide alone who subsequently developed gynaecomastia, breast pain, or both, tamoxifen significantly reduced the frequency of gynaecomastia (0·2 [0·18–0·22], p=0·02).

Interpretation

Antioestrogen treatment with tamoxifen could help patients with prostate cancer to tolerate the hypergonadotropic effects of bicalutamide monotherapy.

Published online April 14, 2005 DOI 10.1016/S1470-2045(05)-70103-0

Introduction

The progression of prostate cancer is a continuum through four main stages of localised, locally advanced, metastatic, and hormone-refractory disease.1 Treatment options with curative intent for early stages include radical prostatectomy and radiotherapy, and many men who receive early treatment have an excellent outcome. However, many men have disease recurrence,2 measured by an increased concentration of prostate specific antigen (PSA), which is generally considered to be the earliest evidence of persistent or recurrent disease after primary treatment with curative intent.3

Bicalutamide is a potent, well tolerated non-steroidal antiandrogen. In previously untreated patients with non-metastatic prostate cancer, 150 mg bicalutamide was equal to castration in terms of survival after a median follow-up of 6·3 years, and had benefit with regard to sexual interest and physical capacity.4 Two smaller European comparisons of 150 mg bicalutamide with complete androgen blockade confirmed these findings.5, 6

The benefit of adding 150 mg bicalutamide per day to standard care for patients with early prostate cancer is being investigated in the bicalutamide early prostate cancer (EPC) programme, which consists of three multicentre trials of 8113 patients worldwide with localised or locally advanced prostate cancer. At a median follow-up of 5·4 years, analyses have shown a clinical benefit for bicalutamide in patients with locally advanced disease. The EPC programme is continuing, and data for the effect of bicalutamide on mortality are awaited. Moreover, follow-up data will clarify further the role of bicalutamide in this setting.7 To date, monotherapy with 150 mg bicalutamide has not been approved by the US Food and Drug Administration, but has been licensed in some European countries as adjuvant treatment for early prostate cancer.

Gynaecomastia, with or without breast pain, is a frequent adverse event of treatment with non-steroidal antiandrogens, and arises from an increase in the ratio of effective oestrogen to androgen in the breast as a result of hypergonadotropic effects of the drugs.8 In the EPC programme, 2747 (68%) of 4022 patients developed gynaecomastia and 2960 (74%) developed breast pain, and symptoms developed mostly in the first 6–9 months of bicalutamide treatment. Although these events were mostly mild and moderate, 671 (17%) patients have been withdrawn from the programme because of gynaecomastia, breast pain, or both.7

Because early withdrawal from treatment with 150 mg bicalutamide might compromise outcome, effective management strategies for gynaecomastia and breast pain are needed. Controlled trials have shown the efficacy of prophylactic antioestrogen treatment and prophylactic breast irradiation for gynaecomastia and breast pain caused by bicalutamide monotherapy.8, 9

We aimed to compare the efficacy of tamoxifen with that of electron-beam radiotherapy for the prevention and treatment of gynaecomastia and breast pain caused by monotherapy with 150 mg bicalutamide for prostate cancer.

Section snippets

Patients

We did a randomised trial in five Italian Centres between January, 2002, and February, 2004. The study consisted of men who had histologically confirmed prostate cancer, no distant metastases (ie, T1–T4, any N, and M0), and no evidence of current gynaecomastia or breast pain. All patients had had primary treatment with curative intent (ie, radical prostatectomy or radiotherapy). All 151 patients enrolled had breast examinations, laboratory and eligibility assessments, and completed

Results

151 patients were randomised and included in analyses (figure 1). Table 1 shows baseline characteristics. Median follow-up was 25 months (range 12–35 months). Figure 2 shows the frequency of grade 3–4 gynaecomastia and moderate-severe breast pain after 6 months. 35 of 51 patients assigned bicalutamide alone developed gynaecomastia, compared with four of 50 assigned bicalutamide and tamoxifen (odds ratio [OR] 0·1 [95% CI 0·08–0·12], p=0·0009), and with 17 of 50 assigned bicalutamide and

Discussion

We have shown that antioestrogen treatment with tamoxifen was more effective than was radiotherapy in preventing the development of bicalutamide-induced gynaecomastia and breast pain in patients with prostate cancer. Moreover, we found that tamoxifen combined with bicalutamide did not increase adverse events and did not compromise quality of life and PSA relapse-free survival compared with bicalutamide alone. To our knowledge, no randomised comparisons of radiotherapy and hormone treatment for

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