Early Versus Delayed Hormonal Therapy Versus Total Androgen Blockade Nicholas Hegarty Hypothalamus Pituitary Axis Mode of Action Options Surgical Castration Oestrogens Anti-androgens LHRH analogues LHRH agonists Hormonal treatments For: Hormonal treatments palliate cancer- related symptoms, prolong time to clinical progression and ?influence survival Against: Side effects - acute and chronic Expense Early Versus Late VA studies – Mellinger J Urol 1964 No difference between early and late – Byar Cancer 1973 Subset may benefit MRC trial - 937 asymptomatic M0 & M1 – BJU 1997 & 2002 less complications, reduced cancer specific mortality, particularly in the M0 and younger men In Specific Disease Subsets Post RRP – Messing NEJM 1999 Node positive men post radical prostatectomy Post Radiotherapy – Pilepich J Clin Oncol 1997 – Bolla NEJM 1997 In combination with radiotherapy Disadvantages Prolonged treatment often required Cumulative side effects Influence on tumour biology? Total Androgen Blockade Synonyms : TAB, CAB, MAB Rationale – blocking testicular and adrenal androgens Huggins 1945 adrenalectomy following orchiectomy Support for MAB: ED Crawford, NEJM 1989 – 603 men D2 prostate cancer 300 Leuprolide + Placebo, 303 Leuprolide + Flutamide longer progression free survival, increased median survival LJ Denis, Urology 1993 Goserelin + flutamide versus orchiectomy – improved survival RA Janknegt, J Urol Orchiectomy ± nilutamide increased time to progression and median survival Against: Prostate Cancer Trialists’ Collaborative Group. Lancet 1995 No difference in time to progression or overall survival in 5710 patients from 22 trials. Do selected patients benefit? (good risk patients with good performance status and minimal disease) Steroidal versus non-steroidal antiandrogens Addition of Anti-androgen Early – prevention of flare Median time to progression LHRH analogue = 18 to 24 months Further PSA response possible with addition of antiandrogen Flutamide Withdrawal Syndrome Decrease in PSA in 15-40% of patients on maximal androgen blockade Kelly & Scher J Urol 1993 ? Related to androgen receptor mutation Also occurs with biclutamide & nilutamide ? Advantage to secondary anti-androgen therapy Scher J Clin Oncol 1997 Intermittent Androgen Suppression Strategy – PSA nadir / Pre-treatment level Rationale – less expense, less acute and chronic side effects, return of potency. Unknown effects on tumour biology and survival Anti Androgen Monotherapy CAPRI trial: Over 8000 men USA, Europe, Scandinavia 1995- 1998 April 2003 Second analysis of data (542 deaths): No difference in overall survival Reduced risk of clinical progression Survival trend in favour in locally advanced Survival benefit for placebo in localised disease Next review of data 2005/2006 Bone Mineral Density Osteopenia/osteoporosis Effects of various endocrine treatments Concern in prolonged treatment groups Role of bisphosphonates For Discussion Does delaying treatment reduce a patient’s likelihood of responding to treatment? How does PSA influence treatment decisions? Do you alter treatment in the androgen- independent state?