Radiation Oncology/Supportive care/Gynecomastia

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Gynecomastia


Overview[edit]

  • 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[edit]

  • 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[edit]

  • 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[edit]

  • 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