Early Versus Delayed Hormonal Therapy Versus Total Androgen Blockade

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Early Versus Delayed Hormonal Therapy Versus Total Androgen Blockade Powered By Docstoc
					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?

				
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