Clinical Practice Guidelines for the management of locally advanced ...

production of androgens which drive cancer growth. There have been twelve small- to medium-sized
randomised clinical studies assessing a variety of second-line hormone manipulations. Although the
studies are numerous, the amount of meaningful data is limited. This is due to the small size of many
of the studies introducing a significant risk of a bias, differing primary hormone therapies and
manipulations. Interventions included institution of non-steroidal anti-androgens if not already being
taken 2 ; comparisons of anti-androgens with low-dose corticosteroids 3, 4 and oestrogens 5, 6 ;
comparisons of megesterol acetate with oestrogens 7 and corticosteroids 8 ; high-dose oestrogens 9 ;
medroxyprogesterone acetate 10 ; and adrenal androgen suppression with agents like ketoconazole (with
hydrocortisone). 11
No second-line hormone manipulation has clearly been shown in a randomised controlled trial (RCT)
to lead to an improvement in overall survival. It is unknown whether this is because this strategy is
not effective in enough people to affect the overall survival of the population or because of the paucity
of well-powered trials to answer this question. It is well demonstrated that a minority of patients will
have some evidence of prolonged (greater than 12 months) disease control as evidenced by reduction
in symptoms and/or PSA declines and rarely, changes in radiographic evidence of disease. 5, 11 For
patients who had previously undergone castration only, there was no significant difference between
the response rates for anti-androgens and prednisone or diethylstilbestrol. 3-5 For patients who had had
failed combined androgen deprivation, there were significant clinical and/or biochemical
improvements with changing the anti-androgen 2 and, when anti-androgens were withdrawn, with
ketoconazole and hydrocortisone. 11 There are no RCTs comparing ketoconazole with other secondline
hormone therapies.
There are no RCTs examining the effects of androgen withdrawal. Case series have shown that for a
subgroup of patients who have progressed on combined androgen deprivation, withdrawal of the antiandrogen
can cause a decline in PSA levels. 11-13 In one of the larger and more recent series 11% of
patients who stopped anti-androgen (flutamide, bicalutamide or nilutamide) therapy had a PSA
decrease > 50% which lasted a median of 5.9 months. 11
The lack of clear-cut data guiding therapy for this patient population is problematic because most
patients with metastatic prostate cancer progress on androgen deprivation and any response from
altering hormonal therapy regimens is short-lived for most patients with our current agents. As such,
findings from studies in this setting are relevant to a large patient population. Guidance and
availability of agents to treat this patient population is a significant clinical need, as once progression
is demonstrated, the patients have a relatively short life expectancy. All of the agents listed above
have a manageable side-effect profile and would favour trialling a hormone manipulation, especially
in patients with no or minimal symptoms. This approach will not inappropriately defer the institution
of chemotherapy, which will be used when a patient has progressed, and the manoeuvre possibly
results in significantly delaying the use of chemotherapy in a minority of patients.
The agents that can be employed as second-line hormone manipulations are generally available in
Australia and have a mild side-effect profile which makes it feasible to trial these in most patients.
The one caveat is ketoconazole, which, when used in high doses (400mg tds) can cause some
significant adverse events. 11 This can be minimised by close monitoring of liver function tests and
starting with 200mg tds with replacement doses of hydrocortisone and escalate as tolerated. Antiandrogens
and low-dose corticosteroids are available on the PBS for metastatic prostate cancer.
Ketoconazole however is not available and costs approximately $150 per month unless it is on a
hospital formulary for this indication. Only one RCT examined quality of life outcomes using a
validated instrument, the EORTC-C30 instrument. In that study overall quality of life scores, pain
scores and gastrointestinal symptom scores were significantly better with prednisone as compared
with flutamide over 24 weeks. 3
To help put the prior data in the context of current drug availability, one has to consider the following.
With the emergence of chemotherapy and/or stage migration and/or improved supportive cancer care,
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