Radiation Oncology/Supportive care/Gynecomastia

Gynecomastia Overview Frequent side effect of androgen deprivation therapy for prostate cancer, particularly with androgen receptor blockers such as Casodex. In the EPC Programme, 68% of patients developed gynecomastia and 74% developed breast pain Increases in testosterone levels are also accompanied by increases in 17-beta estradiol due to aromatization of androgens in extragonadal tissues Estrogens induce benign proliferation of male breast glandular tissue Proliferation phase can last up to ~1 year, and is often associated with breast tenderness and pain. Long-term, irreversible fibrosis develops Prophylactic RT can be effective Typically single electron beam, sharp dose-gradient (6-12 MeV depending on patient size) Multiple fractionation regimens (15/1, 12/1, 10/1, 12/2, 12/3) have been used Prophylactic hormonal therapies have also shown efficacy Tamoxifen shows dose-dependent response, with 20 mg QD showing best outcome Anastrozole was not shown to be efficacious An Italian randomized trial showed better efficacy of tamoxifen compared directly with RT. Side effects were minimal in both arms Surgery (subcutaneous mastectomy) is typically reserved for advanced cases that don't respond to initial management RT vs. Hormonal agents Italy (2002-2004) -- observation vs. tamoxifen vs RT Randomized, 3 arms. 5 centers. 151 patients with prostate cancer, any TN, M0, no gynecomastia/breast pain. Arm 1) bicalutamide 150 mg alone vs. Arm 2) bicalutamide 150 mg + tamoxifen 10 mg x24 weeks vs. Arm 3) bicalutamide 150 mg + RT 12/1. RT given as electrons to 5cm diameter of tissue around each nipple, 6-12 MeV to deliver 90% between skin and chest wall. In observation patients who developed gynecomastia (35/50), subsequently randomized to TAM or RT 2005 PMID 15863377 -- "Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial." (Perdona S, Lancet Oncol. 2005 May;6(5):295-300.) Outcome: Gynecomastia observation 69% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain observation 57% vs. TAM 6% (SS) vs. RT 30% (SS). In observation patients randomized secondarily, gynecomastia TAM 12% vs. RT 56% (SS) Toxicity: both TAM and RT well tolerated Conclusion: Antiestrogen treatment with TAM appears superior to RT Italy (2002-2004) -- observation vs. tamoxifen vs RT Randomized. 102 patients, treated with RP for localized or locally advanced PCA. Treated with adjuvant bicalutamide and Arm 1) observation vs. Arm 2) tamoxifen 10 mg vs. Arm 3) RT. Arm 1 failures subsequently randomized to TAM vs. RT 2005 PMID 16280763 -- "Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy." (DiLorenzo G, J Urol. 2005 Dec;174(6):2197-203.) Outcome: Gynecomastia observation 67% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain 58% vs. 7% vs. 30% Toxicity: No difference in QoL between TAM and RT Conclusion: Gynecomastia and breast pain induced by bicalutamide after RP can be prevented. Tamoxifen more effective than RT RT European (1999-2001) -- RT 10/1 vs. sham Randomized. 106 patients, prostate cancer (T1b-T4NxM0), Casodex 150 mg/d x1 year. Arm 1) RT 10/1 electrons vs. Arm 2) sham RT. 2004 PMID 15380582 -- "Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia." (Tyrrell CJ, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):476-83.) Outcome: Gynecomastia RT 52% vs. sham 85% (SS), fewer were >5 cm (11% vs. 50%) and fewer were moderate/severe (21% vs 48%). Breast pain 83% vs. 91% (NS) Conclusion: Prophylactic breast RT is effective and well tolerated for prevention of gynecomastia Hormonal therapies Canada/EU -- Tamoxifen (dose escalation) vs observation Randomized. 282 patients, prostate cancer, treated with biclutamide 150 mg x2 years. Arm 1) Tamoxifen (1 mg, 2.5 mg, 5 mg, 10 mg, or 20 mg) vs. Arm 2) placebo x12 months 2007 PMID 17270340 -- "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study." (Fradet Y, Eur Urol. 2007 Jul;52(1):106-14. Epub 2007 Jan 16.) Outcome: 1-year breast events TAM 86% - 60% - 55% - 23% - 9% vs. observation 97%; TAM response was dose-dependent. At 2-year (after 1 year of casodex monotherapy), all groups comparable breast events Toxicity: Hot flashes if TAM >= 5 mg. No impact on PSA control Conclusion: Prophylactic TAM 20 mg/d is an effective dose Italy (2000-2002) -- observation vs. tamoxifen vs. anastrozole Randomized. 114 patients with localized, locally advanced, or recurrent prostate cancer. Treated with bicalutamide 150 mg. Arm 1) placebo vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x 48 weeks 2005 PMID 15681525 -- "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer." (Boccardo F, J Clin Oncol. 2005 Feb 1;23(4):808-15.) Outcome: Gynecomastia observation 73% vs TAM 10% vs. anastrozole 51% (SS). Breast pain 39% vs. 6% vs. 27% (SS). Toxicity: No difference in PSA response. Adverse events 37% vs. 35% vs. 69% (SS). No difference in sexual function Conclusion: Tamoxifen was effective, no significant benefit for anastrozole US Multi-institutional -- placebo vs. tamoxifen vs. anastrozole Randomized, 3 arms. 107 patients with prostate cancer, T1-4 any NM0 (T2-3 in 92%), on bicalutamide 150 mg/d. Arm 1) observation vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x3 months. Excluded if gynecomastia >2cm or breast discomfort 2005 PMID 15685254 -- "Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole." (Saltzstein D, Prostate Cancer Prostatic Dis. 2005;8(1):75-83.) Outcome: 3-month gynecomastia TAM 12% (SS) vs. anastrozole 64% (NS) vs. placebo 69% Toxicity: PSA decreased in all groups Conclusion: Incidence of gynecomastia reduced by tamoxifen; anastrozole 1mg/d not a viable option