Table 2.

Characteristics of prospective randomized controlled trials evaluating the role of drug therapy for ADT-related gynecomastia and/or breast pain

Publication/author	Patients (N)	Trial design	Study period	Interventions and results	Side effects and/or QoL
Fradet et al. [8]	282	Randomized, placebo controlled	11/2002–06/2003	Patients were randomized to different prophylactic doses of TMX (1, 2.5, 5, 10, or 20 mg/day) or placebo given for 12 months. Increasing doses of TMX decreased incidence of breast events (gynecomastia and/or breast pain) in a dose-dependent manner at the 3‑, 6‑ and 12-month assessments, where breast events were presented in 96.7% or 98.3% after placebo and in 8.8% or 20.6% of patients after 20 mg TMX. At 24 months (i.e., after 12 months of bicalutamide monotherapy), a high incidence of breast events (>90%) was seen in all groups	Dizziness and hot flushes increased by TMX
Bedognetti et al. [9]	80	Randomized, noninferiority	12/2003–2/2006	Patients were randomized to prophylactic daily TMX 20 mg or daily TMX 20 mg for 8 weeks and weekly TMX 20 mg thereafter. After a preplanned interims analysis gynecomastia developed in 31.7% of patients in the daily group and in 74.4% of patients in the weekly group (p < 0.0001), and it was more severe in patients who switched to weekly tamoxifen (p = 0.001). Mastalgia occurred in 12.2 and 46.1% of patients, respectively (p = 0.001)	No difference in treatment-related toxicity
Saltzstein [10]	107	Randomized, placebo controlled	n.a.	Patients were randomized to 3 months of prophylactic daily TMX 20 mg or daily anastrozole 1 mg or placebo. After 3 months bicalutamide was continued for another 9 months. Patients who developed gynecomastia and/or breast pain during this period underwent TMX or anastrozole for 3 months. The incidence of gynecomastia and/or breast pain was 11.8% for TMX, 63.9% for anastrozole and 69.4% for placebo (p < 0.0001). Resolution of gynecomastia and breast pain for therapeutically treated patients occurred in 65.4% in the TMX group, 71.8% of patients in the placebo group (who received TMX) and 18.8% of patients in the anastrozole group	Dizziness increased by TMX
Boccardo [11]	114	Randomized, placebo controlled	12/2000–12/2002	Patients were randomized to 48 weeks of prophylactic daily TMX 20 mg or daily anastrozole 1 mg or placebo. Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-TMX group, and 51% of patients in the bicalutamide-anastrozole group (p = 0.001); breast pain developed in 39%, 6% and 27% of patients, respectively (p = 0.006)	Treatment was well tolerated and the incidence of toxicity was higher in the anastrozole arm (69.5% of patients) as compared to placebo (37.5%) or TMX (35.1%)
Serretta [12]	176	Randomized controlled	06/2005–06/2007	Patients were randomized to 1 year daily 20 mg TMX within 1 month from the onset of gynecomastia and/or breast pain (Arm A, therapeutic treatment) or 1 year prophylactic daily 10 mg TMX (Arm B). In Arm A gynecomastia and/or breast pain increased with time with a rate of 39.8%, 57.8%, 69.9% and 78.3% at 3, 6, 9, and 12 months after initiation of bicalutamide. After therapy with TMX gynecomastia and/or breast pain persisted in 27.7% of cases. In arm B, the prevalence of gynecomastia and/or breast pain was 35% after 12 months of therapy. The difference in gynecomastia and/or breast pain between the 2 arms was statistically significant (p = 0.0001). The differences in prevalence of gynecomastia and breast pain between the 2 arms both favored TMX prophylaxis (p = 0.0001 and p = 0.001, respectively)	No significant difference between the trial arms

ADT androgen deprivation therapy, TMX Tamoxifen, QoL quality of life