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and Prostatic (2005) 8, 75–83 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan Prevention and management of -induced and pain: randomized endocrinologic and clinical studies with and

D Saltzstein1*, P Sieber2, T Morris3 & J Gallo4 1Urology San Antonio Research PA, Pasteur Medical Plaza, San Antonio, Texas, USA; 2Urological Associates of Lancaster, Lancaster, Pennsylvania, USA; 3AstraZeneca, Macclesfield, Cheshire, UK; and 4AstraZeneca, Wilmington, Deleware, USA

A randomized, double-blind, placebo-controlled multicenter trial involving 107 men receiving bicalutamide (‘Casodex’) 150 mg/day therapy following radical therapy for assessed tamoxifen (‘Nolvadex’) 20 mg/day and anastrozole (‘Arimidex’) 1 mg/day for the prophylaxis and treatment of gynecomastia/. Tamoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically. Serum levels increased with tamoxifen relative to placebo but prostate-specific antigen levels declined in all treatment groups. Further studies are needed to define the optimum tamoxifen dose and to assess any impact on cancer control. The use of tamoxifen in this setting remains to be investigated. Prostate Cancer and Prostatic Diseases (2005) 8, 75–83. doi:10.1038/sj.pcan.4500782 Published online 1 February 2005

Keywords: tamoxifen; anastrozole; bicalutamide; gynecomastia; breast pain

Introduction and after administration, in- creased availability of testosterone leads to increased The nonsteroidal antiandrogen bicalutamide (‘Casodex’) is and hence an increase in circulating being evaluated in the ongoing bicalutamide Early Prostate levels.4 Additionally, the action of estrogen in the breast is Cancer (EPC) program as immediate monotherapy or as an unopposed due to the blockade of the adjuvant to radical therapy, and has been found to provide by the nonsteroidal antiandrogen. Although bicalutamide- benefits in patients with locally advanced prostate cancer.1 induced gynecomastia and breast pain are rarely severe,1 Gynecomastia and breast pain are the main side effects of evidence from the EPC program suggests that the bicalutamide monotherapy,1,2 as predicted from the phar- condition may be more troublesome to men who receive macologic profile of nonsteroidal (Figure 1). bicalutamide as an adjuvant to radical therapy (radical Gynecomastia is caused by an increase in estrogenic prostatectomy or radiotherapy) for early than those activity relative to androgenic activity at the breast tissue3 treated with immediate monotherapy.1,2 Thus, for patients with early disease to benefit fully from bicaluta- mide 150 mg, management options (both prophylactic and *Correspondence: D Saltzstein, Urology San Antonio Research PA, therapeutic) are needed for bicalutamide-induced gyneco- Pasteur Medical Plaza, 7909 Fredericksburg Drive, Suite 115, mastia and breast pain. San Antonio, TX 78229, USA. Three forms of therapy have been used to prevent or E-mail: [email protected] alleviate gynecomastia and/or breast pain of other ‘Arimidex’, ‘Casodex’, and ‘Nolvadex’ are trademarks of the etiologies: low-dose irradiation, , and hormonal AstraZeneca group of companies. 3 Received 23 July 2004; revised 1 November 2004; accepted 8 therapies. A recent randomized study has demonstrated December 2004; published online 1 February 2005 that a single dose of prophylactic irradiation (10 Gy) is Management of bicalutamide-induced gynecomastia D Saltzstein et al 76 HypothalamusLHRH Pituitary and tamoxifen or anastrozole in the pilot study. There- fore, we were able to proceed to the . Here we LH Bicalutamide ACTH report the design, methodology and findings of the FSH Negative clinical trial, as well as summarizing the hormonal feedback changes seen in the pilot study. Testes Adrenal glands

Breast − tissue Methods + Bicalutamide Testosterone + DHT Pilot study Aromatization Healthy elderly male volunteers (n ¼ 14) were random- Figure 1 Rationale for the clinical trial showing where the nonsteroidal antiandrogen bicalutamide acts on the hypothalamic–pituitary–gonadal ized 1:1 to either bicalutamide 150 mg once daily for hormonal pathways in males (adapted with kind permission3). In untreated 6 weeks plus anastrozole 1 mg once daily for the final 2 men, there is a balance between the stimulatory effects of estrogens ( þ ) weeks, or bicalutamide 150 mg once daily plus tamoxifen and the inhibitory effects of (À) at the breast. Under 20 mg once daily for 6 weeks. (testosterone, nonsteroidal antiandrogen treatment, the action of androgens at the breast , (LH), sex is blocked, while estrogenic activity rises due to increased aromatization of hormone binding globulin (SHBG), , follicle- circulating testosterone caused by the inhibition of the mechanism, thus the stimulatory effects of estrogens predominate. stimulating hormone (FSH) and ) serum levels block the activity of estrogens at the breast, while were assessed periodically during the dosing period and inhibitors will inhibit the conversion of testosterone to estrogen by at a follow-up visit at 84–90 days. aromatase. Both types of hormonal therapy therefore decrease estrogenic activity at the breast. Clinical trial

Patients Eligible patients had histologically confirmed localized or locally advanced (T1–4, M0, any N) prostate effective in reducing the incidence of gynecomastia in cancer, had undergone radical therapy (radical prosta- 5 bicalutamide-treated patients. Similar results were tectomy, radiotherapy) and were noncastrate. Absence of reported from a recent Scandinavian study in which metastatic disease was confirmed by bone scan within 69% of patients received prophyalctic irradiation for 30 weeks of randomization. All patients had a life gynecomastia induced by the nonsteroidal antiandrogen expectancy of at least 1 y. Patients were excluded from 6 . Hormonal therapies that reduce estrogen the trial if they had gynecomastia X2 cm in diameter activity at the breast (Figure 1), such as the aromatase or breast discomfort, had previously received hormonal inhibitors, which block the peripheral aromatization of therapy (except neoadjuvant hormonal therapy X6 circulating androgens to estrogens, and the antiestro- months previously), or were currently receiving or had gens, which are antagonists at the estrogen receptors, received in the past 6 months any known to should also reduce the tendency for gynecomastia to cause gynecomastia. Further exclusion criteria were occur in the presence of androgen blockade. Aromatase evidence of abuse, abnormal function tests, inhibitors and antiestrogens have both been used to treat elevated estradiol levels, or decreased age-adjusted established gynecomastia of other etiologies, with some testosterone levels. All eligible patients gave written 7–12 or good . informed consent before trial entry. Based on the above rationale, a clinical trial assessing the efficacy and of the tamoxifen (‘Nolvadex’) 20 mg and the anastro- Trial design This was a randomized, three-arm, double- zole (‘Arimidex’) 1 mg both as prophylaxis and treatment blind, placebo-controlled trial conducted at nine centers for gynecomastia and breast pain in non-castrate patients in the USA. The trial was designed and monitored in receiving bicalutamide 150 mg after radical therapy accordance with the ethical principles of Good Clinical for early prostate cancer was planned. Prior to initiating Practice and in accordance with the Declaration of the clinical trial, a pilot study was undertaken to assess Helsinki. The protocol was approved by the Institutional the effects of bicalutamide 150 mg plus tamoxifen 20 mg Review Board at each participating center. Randomiza- and bicalutamide 150 mg plus anastrozole 1 mg on tion was performed centrally according to a schedule free testosterone concentrations in healthy elderly men. prepared for each center. Patient numbers were allocated This pilot study was carried out as published in a strict sequential order and were not reused in the data13,14 suggested that, by influencing the negative event of patient withdrawal. Eligible patients were feedback effects of estradiol on the hypothalamic– randomized 1 : 1 : 1 to receive tamoxifen 20 mg, anastro- pituitary-axis, the addition of aromatase inhibitors and zole 1 mg, or placebo in addition to bicalutamide 150 mg antiestrogens to bicalutamide 150 mg therapy could for 3 months. All study were taken orally once increase serum testosterone to levels above those daily and treatment commenced within 3 days of induced by bicalutamide 150 mg alone. These higher randomization. After the 3-month prophylactic phase serum testosterone levels might potentially have reduced of the trial, patients received bicalutamide 150 mg alone the bicalutamide-mediated androgen-receptor blockade for 9 months. However, any patient who developed and, consequently, the antitumor activity of bicaluta- gynecomastia and/or breast pain during this period was mide. However, there was no evidence of such a re-treated with tamoxifen 20 mg or anastrozole 1 mg for a pharmacodynamic interaction between bicalutamide maximum duration of 3 months. Patients in the

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al tamoxifen and anastrozole groups received their original Results 77 randomized therapy, while those in the placebo group received tamoxifen 20 mg. With the exception of ran- Pilot study domized therapy, no other treatment for prostate cancer, including experimental therapy, was permitted during The changes in serum levels of sex in the 14 the trial. Patients were also not permitted to receive any healthy volunteers (aged 66–76 y) who received bicalu- concurrent medication known to cause gynecomastia or tamide 150 mg plus either anastrozole 1 mg (n ¼ 7) or any alternative therapies. tamoxifen 20 mg (n ¼ 7) are summarized in Tables 1 and Physical examinations for the presence of gyneco- 2, respectively. None of the volunteers reported gyneco- mastia were performed at screening, on initiation of mastia during the study; three reported breast tender- randomized therapy, and every 3 months thereafter. ness, which resolved spontaneously in each case. Only Patients also completed a questionnaire, recording the one serious adverse event () was occurrence of gynecomastia and breast pain at these time reported; there were no unexpected tolerability findings. points. For both methods of assessment, the criterion for a response to randomized therapy was the complete absence of gynecomastia and/or breast pain. Blood Clinical trial samples were taken at each visit and sent to a central laboratory for the determination of serum prostate- Patient demography and exposure to randomized therapy spectific antigen (PSA), testosterone, estradiol, LH, A total of 107 male patients aged 49–81 y were enrolled FSH, and SHBG levels. Plasma levels of the bicalutamide into the trial and randomized to tamoxifen 20 mg R- at 3 and 6 months were measured by a (n ¼ 35), anastrozole 1 mg (n ¼ 36), or placebo (n ¼ 36) in central laboratory using enantioselective high-pressure addition to bicalutamide 150 mg (Figure 2). The majority liquid chromatography and ultraviolet detection. of patients had T2–3 disease (92.5%) at diagnosis and Details of adverse events occurring during the trial were node-negative (93.5%). Mean PSA levels at study were elicited by open questioning. Adverse events were entry were 1.49 ng/ml. The three treatment groups were categorized using the FDA Coding Symbols for The- well balanced with respect to baseline demographics and saurus of Adverse Reaction Terms. Liver biochemistry tumor characteristics (Table 3). Three patients had (bilirubin, alanine aminotransferase (ALT), aspartate protocol violations, one in the tamoxifen group (use of aminotransferase (AST)) was assessed at baseline and medication known to cause gynecomastia within the 6 at each 3-monthly visit. months prior to study entry) and two in the anastrozole group (prior hormonal therapy, one patient; hormonal level outside the normal range, one patient). None of these protocol violations were considered likely to affect Statistical methods the trial results and these patients were therefore included in the statistical analyses. The primary end point of the clinical trial was the All but one patient (in the tamoxifen group) received development of gynecomastia and/or breast pain (as- randomized therapy (Figure 2). Of the 106 patients who sessed by both physical examination and questionnaire) commenced randomized therapy, six patients (17.7%) in at 3 months. Previously published data indicated that the tamoxifen group, seven (19.4%) in the anastrozole 70% of patients in the bicalutamide 150 mg plus placebo group, and 4 (11.1%) in the placebo group were group could be expected to develop gynecomastia and/ subsequently withdrawn from therapy (Figure 2). All or breast pain.15 The clinical trial was designed to have but three withdrawals were due to the occurrence of an 80% power (5% two-sided significance) to detect a 35% adverse event or concurrent illness. The other reasons for reduction in the incidence of gynecomastia and breast study withdrawal were withdrawal of consent (n ¼ 2) pain in the tamoxifen and anastrozole groups relative to and loss to follow-up (n ¼ 1). Six patients (5.6%) with- the placebo group. Secondary end points included the drew during the 3-month prophylactic phase of the time to onset and the time to resolution of gynecomastia study, three (2.8%) during the observation phase while and breast pain (assessed by both physical examination receiving bicalutamide 150 mg only and eight (7.5%) and questionnaire) following re-treatment. Other sec- during re-treatment (Figure 2). ondary endpoints were the changes in serum levels of PSA, testosterone, estradiol, LH, FSH, and SHBG at 3 months relative to baseline (trial entry). Only patients Efficacy of randomized therapy as prophylaxis All who received randomized therapy were included in the patients who received randomized therapy were in- efficacy and safety analyses. cluded in the analysis of gynecomastia and breast pain at Data on the incidence of gynecomastia and breast pain 3 months, with the exception of one patient in the were analyzed using the Cochran–Mantel–Haenszel test tamoxifen group who withdrew prematurely due to an and the results adjusted for the potentially confounding adverse event (asthenia) and was lost to follow-up. At center effect. Odds ratios and their 95% confidence 3 months, the incidence of gynecomastia and/or breast intervals (CI) were also generated. The time-to-onset pain assessed by physical examination was identical to endpoint was analyzed using a Cox’s proportional that obtained by questionnaire in each treatment group hazards model with the results again adjusted for the (tamoxifen 11.8%, anastrozole 63.9%, placebo 69.4%; potentially confounding center effect. A statistical ana- Figure 3). In the tamoxifen group, only three patients lysis of the time-to-resolution end point was not done, (8.8%) developed breast pain and one more patient due to the smaller sample size used in the re-treatment (2.9%) developed both gynecomastia and breast pain phase of the trial. (Figure 3). The difference between the tamoxifen group

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 78 Table 1 Changes in serum levels of sex hormones in healthy volunteers (n ¼ 7) receiving bicalutamide 150 mg (from days 1 to 42) plus anastrozole 1 mg (from days 29 to 42) in the pilot study Time (days)

1 29 36 43 84–90 (follow-up)

Free testosterone Geometric mean (CV) (nmol/l) 0.048 (30.415) 0.076 (26.219) 0.075 (45.199) 0.074 (46.883) 0.049 (36.081) % change from baseline — +58 +56 +54 +2

Total testosterone Mean (s.d.) (nmol/l) 16.12 (4.75) 21.74 (6.31) 24.51 (7.95) 25.52 (7.77) 20.68 (5.77) % change from baseline — +35 +52 +58 +28

Dihydrotestosterone Mean (s.d.) (pg/ml) 818.9 (267.3) 1082.3 (619.0) 1110.3 (548.7) 1188.9 (589.4) 656.1 (439.1) % change from baseline — +32 +36 +45 À20

Luteinizing hormone Mean (s.d.) (IU/l) 6.17 (7.37) 11.11 (10.79) 14.97 (12.29) 17.31 (16.98) 7.37 (10.47) % change from baseline — +80 +143 +181 +19

Sex hormone binding globulin Mean (s.d.) (pmol/ml) 0.071 (0.016) 0.058 (0.016) 0.057 (0.014) 0.060 (0.022) 0.064 (0.017) % change from baseline — À19 À20 À15 À10

Prolactin Mean (s.d.) (IU/l) 6.27 (3.64) 9.73 (3.71) 9.19 (3.60) 8.74 (3.31) 6.14 (1.96) % change from baseline — +55 +47 +40 À2

Follicle-stimulating hormone Mean (s.d.) (IU/l) 15.66 (29.72) 14.01 (25.91) 16.33 (27.2) 17.03 (28.0) 15.41 (28.02) % change from baseline — À10 +4 +9 À2

Estradiol Mean (s.d.) (pmol/l) 76.71 (6.07) 108.71 (26.95) 70.29 (16.46) 67.86 (14.54) 97.71 (15.12) % change from baseline — +42 À8 À12 +27

CV, coefficient of variation; s.d., standard deviation.

and the placebo group with respect to the development pain in the tamoxifen, anastrozole, and placebo groups of gynecomastia and/or breast pain was statistically was 26 (76.5%), 32 (88.8%), and 32 (88.8%), respectively significant (Po0.0001). However, the difference between (Figure 2). Resolution of gynecomastia and breast pain the anastrozole group and the placebo group was not occurred in 65.4% of patients in the tamoxifen group, significant (P ¼ 0.749). Patients in the tamoxifen group 71.8% of patients in the placebo group (who received were 3.22 times less likely (relative risk estimate, 95% CI tamoxifen) and 18.8% of patients in the anastrozole 1.28, 7.69) to develop gynecomastia and/or breast pain group. The median time to resolution in the tamoxifen during the 3 months after randomization than those in group was 106 days as assessed by physical examination the placebo group. Patients in the anastrozole group and 102 days as assessed by questionnaire; correspond- were 1.14 times less likely (relative risk estimate, 95% CI ing times to resolution in the placebo group were 108 and 0.91, 1.43) to develop the condition within 3 months of 91 days, respectively. randomization than those in the placebo group. The median time to onset of gynecomastia and/or PSA and hormonal end points The mean absolute and breast pain was significantly longer in the tamoxifen percentage changes in serum PSA and sex hormone group than in the placebo group (P ¼ 0.001 and 0.003 as levels at 3 months are presented in Table 4. Mean serum assessed by physical examination and questionnaire, PSA levels declined in each of the three treatment respectively) (Figure 4). groups. The mean percentage change in serum PSA Interpretation of the results at 6, 9, and 12 months after level was greater in the placebo group (–30.1%) than in randomization is confounded by the re-treatment of the tamoxifen and anastrozole groups (–24.4 and –16.7%, some patients with tamoxifen 20 mg or anastrozole 1 mg respectively). Mean serum testosterone levels increased (Figure 2) for gynecomastia/breast pain developing by 162.8% in the tamoxifen group, 124.3% in the before these timepoints, and these results are therefore anastrozole group, and 63.7% in the placebo group. not presented. Mean percentage changes in serum estradiol, LH, and FSH levels were also greater in the tamoxifen and anastrozole groups than in the placebo group. Serum Efficacy of randomized therapy as treatment The number SHBG levels increased across all three groups, with the of patients actively re-treated for gynecomastia/breast greatest percentage increase seen in the tamoxifen group.

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 79 Table 2 Changes in serum levels of sex hormones in healthy volunteers (n ¼ 7) receiving bicalutamide 150 mg plus tamoxifen 20 mg (both from days 1 to 42) in the pilot study Time (days)

1 8 22 43 84–90 (follow-up)

Free testosterone Geometric mean (CV) (nmol/l) 0.045 (11.970) 0.059 (18.628) 0.077 (34.582) 0.063 (34.303) 0.056 (22.686) % change from baseline — 31 71 40 24

Total testosterone Mean (s.d.) (nmol/l) 14.82 (2.11) 21.38 (3.90) 22.92 (4.42) 22.50 (5.19) 24.19 (6.49) % change from baseline — 44 55 52 63

Dihydrotestosterone Mean (s.d.) (pg/ml) 666.3 (177.2) 830.7 (169.8) 973.4 (207.5) 785.7 (224.3) 875.6 (308.7) % change from baseline — 25 46 18 31

Luteinizing hormone Mean (s.d.) (IU/l) 3.34 (1.61) 8.21 (3.38) 12.56 (6.84) 13.34 (8.04) 6.56 (2.52) % change from baseline — 146 276 299 96

Sex hormone binding globulin Mean (s.d.) (pmol/ml) 0.083 (0.011) 0.093 (0.020) 0.083 (0.017) 0.067 (0.016) 0.068 (0.019) % change from baseline — 12 0 À20 À18

Prolactin Mean (s.d.) (IU/l) 5.04 (2.30) 5.63 (2.84) 4.80 (3.46) 5.53 (3.11) 6.11 (2.86) % change from baseline — 12 À51021

Follicle-stimulating hormone Mean (s.d.) (IU/l) 5.87 (4.23) 8.71 (6.2) 8.34 (6.63) 9.33 (7.38) 7.04 (5.23) % change from baseline — 48 42 59 20

Estradiol Mean (s.d.) (pmol/l) 95.71 (24.30) 105.00 (25.36) 133.57 (26.39) 131.57 (40.32) 135.29 (34.45) % change from baseline — 10 40 37 41

CV, coefficient of variation; s.d., standard deviation.

107 patients randomized

35 patients randomized to 36 patients randomized to 36 patients randomized to tamoxifen 20 mg plus anastrozole 1 mg plus placebo plus bicalutamide bicalutamide 150 mg bicalutamide 150 mg 150 mg - 1 patient did not receive randomized therapy

34 patients received 36 patients received 36 patients received randomized therapy randomized therapy randomized therapy - 2 patients withdrew due to AEs - 3 patients withdrew due to AEs - 1 patient withdrew due to AE

32 patients entered the 33 patients entered the 35 patients entered the observation phase observation phase observation phase - 1 patient withdrew informed - 1 patient withdrew informed consent consent - 1 patient withdrew due to AEs

26 patients had symptoms 32 patients had symptoms 32 patients had symptoms and were re-treated with and were re-treated with and were re-treated with tamoxifen 20 mg anastrozole 1 mg tamoxifen 20 mg - 2 patients withdrew due to AEs - 3 patients withdrew due to AEs - 1 patient lost to follow-up - 2 patients withdrew due to AEs

Figure 2 Flow diagram of clinical trial patients.

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 80 Table 3 Baseline demographic and tumor characteristics of patients in the clinical trial Tamoxifen 20 mg plus Anastrozole 1 mg plus Placebo plus bicalutamide bicalutamide 150 mg bicalutamide 150 mg 150 mg (n ¼ 36) (n ¼ 35) (n ¼ 36)

Mean age (range) (y) 64.6 (52–79) 64.4 (49–75) 67.1 (49–81) Mean weight (range) (kg) 82.4 (70.5–110.5) 86.7 (62.7–102.7) 82.7 (52.7–118.6) Mean height (range) (cm) 176.8 (160.0–194.0) 177.5 (147.3–191.0) 176.0 (160.0–186.7) Race n (%) Caucasian 27 (77.1) 33 (91.7) 33 (91.7) Other 8 (22.9) 3 (8.4) 3 (8.4)

Tumor stage, n (%) T1 1 (2.9) 1 (2.8) 2 (5.6) T2 19 (54.4) 24 (66.6) 21 (58.3) T3 15 (42.9) 9 (25.0) 11 (30.6) T4 0 (0) 2 (5.6) 2 (5.6)

Lymph node status, n (%) N0 34 (97.1) 34 (94.4) 32 (88.9) N Â 1 (2.9) 2 (5.6) 1 (2.8) N+ 0 (0) 0 (0) 3 (8.3)

Mean prostate-specific antigen 2.05 1.06 1.38 (ng/ml)

Gynecomastia Physical examination Breast pain Questionnaire Gynecomastia plus breast pain 170 P < 0.0001 Bicalutamide 150 mg + tamoxifen 20 mg 170 80 P = 0.749

Bicalutamide 150 mg 85 ∗∗ 60 + anastrozole 1 mg 85

73 40 Bicalutamide 150 mg + placebo 76 Patients (%) 20 0 50 100 150 200 Days PE Q PE Q PE Q ∗∗ 0 p ≤ 0.003 bicalutamide 150 mg + tamoxifen 20 mg Bicalutamide 150 mg Bicalutamide 150 mg Bicalutamide 150 mg vs bicalutamide 150 mg + placebo plus tamoxifen 20 mg plus anastrozole 1 mg plus placebo (n=34) (n=36) (n=36) Figure 4 Median time (as estimated by Kaplan–Meier analysis) to onset of gynecomastia/breast pain in the clinical trial as assessed by physical PE, physical examination; Q, questionnaire examination and questionnaire. Figure 3 Incidence of gynecomastia and/or breast pain in the clinical trial as assessed by physical examination (PE) and questionnaire (Q) at 3 months after randomization. these were less frequent in the tamoxifen group than in the anastrozole or placebo groups. No other significant safety issues were identified. The geometric mean plasma level of Three serious events (adenoma, aortic stenosis, urinary R-bicalutamide in the trial population (n ¼ 95) at 3 tract disorder) were reported during the trial, one event months was 16.4 mg/ml (range 2.4–44.6), and the means in each treatment group. The demographic characteris- and ranges were similar across all three treatment tics of these patients were similar to those of the rest of groups. The geometric mean plasma level of R-bicalu- the trial population. However, none of these events were tamide at 6 months (n ¼ 86) was 16.9 mg/ml (range considered related to trial therapy or led to withdrawal 1.3–47.6) and, again, the means and ranges were similar of trial therapy. There were no deaths during the trial. across all treatment groups. Fourteen patients (13.2%) withdrew from trial therapy (tamoxifen, five patients; anastrozole, six patients; placebo, three patients; Figure 2) as a result of a total of Safety All patients experienced at least one adverse 23 adverse events, which included gynecomastia in two event during the trial. Details of adverse events withdrawals and breast pain in five. One patient (0.9%) occurring in X5% of patients in any treatment group, was withdrawn due to moderate rises in serum AST regardless of causality, are shown in Table 5. The most and ALT levels, which later resolved after treatment common events were gynecomastia and breast pain, but withdrawal.

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 81 Table 4 Summary of changes in prostate-specific antigen and hormone levels at 3 months after randomization in the clinical trial Tamoxifen 20 mg plus Anastrozole 1 mg plus bicalutamide 150 mg bicalutamide 150 mg

Prostate-specific antigen (ng/ml) Mean absolute change (s.d.) À1.67 (5.22) À0.59 (1.98) Mean % change À24.4 À16.7

Testosterone (nmol/l) Mean absolute change (s.d.) 20.53 (12.86) 16.20 (7.26) Mean % change 162.8 124.3

Estradiol, pmol/l Mean absolute change (s.d.) 213.78 (281.84) 34.41 (39.64) Mean % change 314.7 54.6

Luteinizing hormone (IU/l) Mean absolute change (s.d.) 11.22 (7.54) 7.10 (4.01) Mean % change 257.8 182.1

Follicle-stimulating hormone (IU/l) Mean absolute change (s.d.) 5.13 (5.60) 0.82 (13.95) Mean % change 40.9 72.8

Sex hormone binding globulin (lmol/l) Mean absolute change (s.d.) 0.03 (0.03) 0.01 (0.01) Mean % change 48.5 17.7 s.d., standard deviation.

Discussion The optimal dose of tamoxifen, either as prophylaxis or treatment for gynecomastia/breast pain (of any Prophylactic and treatment options for the gynecomastia etiology) has not been established. Doses ranging from and breast pain associated with nonsteroidal antiandro- 10 to 40 mg/day have been used with good effect.3 gen monotherapy would enable patients with early As most studies of tamoxifen for gynecomastia have prostate cancer to derive maximal benefit from their been relatively small, uncontrolled, and with variable treatment. Hormonal therapies that reduce estrogenic response criteria, no conclusions can be drawn relating activity in the breast tissue are one potential manage- to the dose-response relationship of tamoxifen in this ment option. Here, we have explored the efficacy, setting. In the current study, a dose of 20 mg/day (that tolerability, and safety of the antiestrogen, tamoxifen, licensed for early ) was chosen and, using and the aromatase inhibitor, anastrozole, as both the complete absence of gynecomastia and/or breast prophylaxis and treatment for gynecomastia and breast pain as the criterion of response, achieved an approx- pain in noncastrate patients receiving bicalutamide imate response rate of two-thirds in both the prophylac- 150 mg/day for early prostate cancer. Although the use tic and re-treatment phases of the clinical trial. Given that of these hormonal agents in combination with bicaluta- other trials have reported that a dose of 10 mg/day mide might be expected to induce a rise in serum reduces gynecomastia and/or alleviates breast pain,8,11 testosterone levels above that seen with bicalutamide there is clearly a case for evaluating lower doses in alone,13,14 the initial pilot study showed no evidence of patients receiving bicalutamide 150 mg. any such pharmacodynamic interaction in healthy In contrast to tamoxifen, anastrozole 1 mg/day ex- elderly men. The clinical trial was therefore able to proceed. hibited only minimal efficacy in both the prophylactic At 3 months, the incidence of gynecomastia and/or and re-treatment phases of the trial. This is the first study breast pain as assessed by physical examination or in which a third-generation, selective, aromatase inhi- questionnaire was lower in the tamoxifen 20 mg group bitor has been evaluated for the management of than in the anastrozole 1 mg or placebo groups (11.8 vs gynecomastia. The literature on the use of the first- 63.9 and 69.4%, respectively). Although, as expected generation compound, , in the management based on the pharmacologic mechanisms involved, the of gynecomastia is sparse and the results are incon- benefits of prophylactic tamoxifen 20 mg did not persist clusive.3,7 The reasons for the disappointing efficacy of once therapy was discontinued. Re-treatment with the more selective compound anastrozole, which was tamoxifen 20 mg was effective, with approximately given at the dosage used in its licensed indications two-thirds of patients experiencing complete resolution (1 mg/day), in patients receiving nonsteroidal antiandro- of bicalutamide-induced gynecomastia/breast pain with- gens are unclear. in 3 months. Patients initially randomized to placebo in As expected, serum testosterone, estradiol, LH, and the prophylactic stage of the trial also responded FSH levels increased during nonsteroidal antiandrogen similarly to tamoxifen treatment. The latter finding is therapy, both in the pilot study and the clinical trial. In in accordance with the results of previous studies on the the clinical trial, the increase in serum testosterone levels therapeutic use of antiestrogens in established gyneco- was greater in the tamoxifen and anastrozole groups mastia/breast pain of other etiologies.8–12 than in the placebo group, despite the absence of any

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 82 Table 5 Adverse events occurring in X5% of patients in any treatment group (regardless of causality) in the clinical trial % patients

Tamoxifen 20 mg plus Anastrozole 1 mg plus Placebo plus bicalutamide bicalutamide 150 mg bicalutamide 150 mg 150 mg (n ¼ 36) (n ¼ 35) (n ¼ 36)

Breast pain 82.4 94.4 94.4 Gynecomastia 50.0 63.9 66.7 17.6 8.3 13.9 Vasodilation 14.7 8.3 5.6 11.8 5.6 19.4 Accidental injury 8.8 0 2.8 Asthenia 8.8 11.1 13.9 Back pain 8.8 8.3 0.0 Dizziness 8.8 2.8 2.8 Sinusitis 8.8 2.8 0.0 5.9 8.3 0.0 Decreased 5.9 2.8 2.8 5.9 2.8 0.0 Dyspnea 5.9 0.0 0.0 Gastritis 5.9 0.0 0.0 5.9 2.8 8.3 Pain 5.9 5.6 5.6 Pelvic pain 5.9 0.0 0.0 Periodontal abscess 5.9 0.0 2.8 Pruritus 5.9 2.8 2.8 Somnolence 5.9 5.6 0.0 Urinary frequency 5.9 0.0 0.0 5.9 2.8 0.0 Urinary tract disorder 5.9 5.6 2.8 Urinary urgency 5.9 0.0 0.0 Vomiting 5.9 0.0 0.0 Abdominal pain 2.9 5.6 0.0 Paresthesia 2.9 2.8 5.6 Urinary tract infection 2.9 5.6 0.0 Dry 0.0 0.0 5.6 Hypercholesterolemia 0.0 0.0 8.3 Hypertension 0.0 0.0 5.6 Increased cough 0.0 8.3 0.0 Peripheral 0.0 2.8 5.6 Urticaria 0.0 0.0 5.6

pharmacodynamic interaction in either treatment group Again, contrary to the pilot study, serum SHBG levels in the pilot study. The reasons for the difference between increased in all three groups in the clinical trial, most the pilot study and the clinical trial are not clear. The notably in the tamoxifen group. Serum SHBG levels tend concentrations of free and total testosterone and dihy- to increase with age, thereby reducing free testosterone drotestosterone observed before and after the addition of levels, which may result in .16 How- anastrozole or tamoxifen to bicalutamide in the healthy ever, given that the observed percentage increase in total elderly men in the pilot study were similar to those testosterone levels following tamoxifen therapy was reported previously with bicalutamide 150 mg mono- several-fold higher than the increase in serum SHBG therapy in prostate cancer patients.4 However, the levels, a clinically relevant impact on sexual function is increases in mean serum LH levels in both treatment unlikely in this trial. This is supported by our adverse groups in the pilot study were greater than previously event data which show no evidence of increased sexual reported with bicalutamide alone.4 dysfunction in these patients, with fewer than 5% of men Although serum testosterone levels in the tamoxifen in all treatment groups reporting either loss of libido or group were higher than those in the placebo group erectile difficulties. Future clinical studies of tamoxifen in during the prophylactic phase of the clinical trial, we did bicalutamide 150-mg-treated patients should provide not observe any adverse impact of combination therapy confirmation that the combination has no adverse on cancer control as assessed by PSA levels. However, implications for sexual interest and function. the baseline serum PSA levels in our patients were low No other significant safety issues were identified and we are therefore unable to rule out any long-term during the clinical trial and there was no evidence of a implications of tamoxifen 20 mg in combination with pharmacokinetic interaction between bicalutamide and bicalutamide 150 mg on patient outcome. The use of either tamoxifen or anastrozole, although further studies tamoxifen in the management of bicalutamide-induced are needed to fully assess this issue. Although the mean gynecomastia and breast pain should therefore remain R-bicalutamide levels in our patients were slightly lower investigational until long-term trials have excluded an than reported in an earlier bicalutamide 150 mg mono- impact on prostate cancer control. therapy study (approximately 17 vs 22 mg/ml),17 they are

Prostate Cancer and Prostatic Diseases Management of bicalutamide-induced gynecomastia D Saltzstein et al 83 consistent with the findings of other recent studies 3 McLeod DG, Iversen P. Gynecomastia in patients with prostate (unpublished data). cancer: a review of treatment options. Urology 2000; 56: 713–720. 4 Verhelst J et al. Endocrine profiles during administration of the new non-steroidal anti-androgen Casodex in prostate cancer. Conclusion Clin Endocrinol (Oxf) 1994; 41: 525–530. 5 Tyrrell CJ et al. Prophylactic breast irradiation with a single dose The incidence of gynecomastia and breast pain was of electron beam radiotherapy (10 Gy) significantly reduces the significantly reduced by tamoxifen 20 mg/day initiated incidence of bicalutamide-induced gynecomastia. Int J Radiat at the same time as bicalutamide 150 mg monotherapy or Oncol Phys Biol 2004; 60: 476–483. following the development of bicalutamide-related 6 Widmark A et al. Does prophylactic breast irradiation prevent breast changes. However, further studies are needed to antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3. Urology determine the optimum dose of tamoxifen for both 2003; 61: 145–151. prophylaxis and treatment, and to assess any impact on 7 Braunstein GD. Aromatase and gynecomastia. Endocr Relat prostate cancer control. Anastrozole 1 mg/day does not Cancer 1999; 6: 315–324. appear to be a viable management option for bicaluta- 8 Parker LN, Gray DR, Lai MK, Levin ER. Treatment of mide-induced gynecomastia and breast pain. gynecomastia with tamoxifen: a double-blind crossover study. 1986; 35: 705–708. 9 Alagaratnam TT. Idiopathic gynecomastia treated with tamo- xifen: a preliminary report. Clin Ther 1987; 9: 483–487. Acknowledgements 10 McDermott MT, Hofeldt FD, Kidd GS. Tamoxifen therapy for painful idiopathic gynecomastia. South Med J 1990; 83: We gratefully acknowledge the contribution to the trial of 1283–1285. the following investigators: A Cantwell (Atlantic Uro- 11 Staiman VR, Lowe FC. Tamoxifen for flutamide/- logical Associates, Daytona Beach, FL, USA); J Ross induced gynecomastia. Urology 1997; 50: 929–933. (Mississippi Center for Clinical Research, Jackson, MI, 12 Serels S, Melman A. Tamoxifen as treatment for gynecomastia USA); RJ Ross (Hattiesburg Clinic, Hattiesburg, MS, and mastodynia resulting from hormonal deprivation. JUrol USA); K Tomera (Alaska Clinical Research Center, 1998; 59: 1309. Anchorage, Alaska); N Nemoy (Cedars-Sinai Medical 13 Goss PE, Tye LM. Anastrozole: a new selective nonsteroidal Center, Los Angeles, CA, USA); D Keiller (4033 3rd aromatase inhibitor. Oncology (Huntingt) 1997; 11: 1697–1703. Avenue, San Diego, CA); and PM Knapp (Urology of 14 Krause W, Holland-Moritz H, Schramm P. Treatment of Indiana; Indianapolis, IN, USA). idiopathic oligozoospermia with tamoxifen—a randomized controlled study. Int J Androl 1992; 15: 14–18. 15 Soloway MS et al. Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial References evaluating safety, efficacy and long-term endocrine effects of monotherapy. JUrol1995; 154: 2110–2114. 1 Wirth MP et al. Bicalutamide 150 mg in addition to standard care 16 Ahn HS, Park CM, Lee SW. The clinical relevance of sex in patients with localized or locally advanced prostate cancer: hormone levels and sexual activity in the ageing male. BJU Int results from the second analysis of the early prostate cancer 2002; 89: 526–530. program at median followup of 5.4 years. JUrol2004; 172: 17 Tyrrell CJ et al. Casodext 10-200 mg daily, used as mono- 1865–1870. therapy for the treatment of patients with advanced prostate 2IversenP et al. Bicalutamide monotherapy compared with cancer. An overview of the efficacy, tolerability and pharmaco- in patients with nonmetastatic locally advanced prostate kinetics from three Phase II dose-ranging studies. Eur Urol 1998; 33: cancer: 6.3 years of followup. JUrol2000; 164: 1579–1582. 39–53.

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