Radiation Oncology/Prostate/Hormones/Drugs

Classes of Androgen Suppressive Agents

• (Bilateral orchiectomy)
• Estrogens
  • Diethyl stilbestrol (DES)
  • Estramustine - derivative of estradiol with nitrogen mustard, an alkylating agent with estrogen-induced specificity
• Progestins
  • Medroxyprogesterone acetate (Provera)
  • Megestrol acetate (Megace) - synthetic progestin, able to lower testosterone and LH/FSH, and block binding of testosterone and dihydrotestosterone to androgen receptor
• Adrenal enzyme inhibitors
  • Ketoconazole (works in the testis and adrenal glands) - weak antiandrogen, can reduce levels of androgens produced in testicles and adrenal glands
  • Aminoglutethimide (first generation aromatase inhibitor)
• 5-Alpha reductase inhibitors - prevent conversion of testosterone into dihydrotestosterone (DHT)
  • Finasteride (Proscar, Propecia) - inhibits only type II
  • Dutasteride (Avodart) - inhibits both type I and II
  • FCE 28260 (Experimental)
• Gonadotropin-releasing hormone inhibition (Injectable)
  • Gonadotropin-releasing hormone agonists
    • Leuprolide acetate (Lupron)
    • Goserelin acetate (Zoladex)
  • Gonadotropin-releasing hormone antagonists
    • Abarelix (Plenaxis)- withdrawn
    • Cetrorelix (Cetrotide)
    • Degarelix (Firmagon)
    • Ganirelix (Antagon)
• Non-steroidal anti-androgens (Oral) - androgen receptor blockers
  • Flutamide (Eulexin) - 250 mg TID
  • Nilutamide (Nilandron)
  • Bicalutamide (Casodex) - 50 mg QD - appears to have least side effects
• Steroid anti-androgens - androgen receptor blockers
  • Cyproterone acetate (Androcur) - also has weak progestational and glucocorticoid activity
• Abiraterone:
  • Medication used in Castration Resistant Prostate Ca
  • Increase OS 4m
  • Inhibits biosynthesis of testosterione
    • By inhibiting CYP17
      • A hydroxylase enzyme
      • Produced in
        • testis
        • tumor
        • adrenal
      • Action
        • Pregnolonone --> hydroxy-pregnolone
        • Hydroxy-P --> DHEA
    • Side effects:
      • HTN
      • Hypokalemia
      • Fluid retention
    • Required reduced dose in patients with liver disease

Physiology Overview

• GnRH is released by hypothalamus in a pulsatile fashion, and acts on pituitary gland
• Anterior pituitary releases LH and FSH. LH acts on testes to produce testosterone
• Testosterone is metabolized to DHT by 5-alpha reductase
• DHT (and to much smaller extent testosterone) stimulate prostate cancer cells

Side-effects Overview

• Hot flashes, effect on libido, muscle wasting, mood/personality changes, bone loss, gynecomastia (due to significantly increased levels of LH -> estrogen)