Is any one hormone therapy (androgen ablation) superior to another when given in the first line setting in terms of survival in metastatic disease?
Once a patient’s cancer has started to grow again or recur with a castrate level of testosterone, he enters another stage, called castrate-resistant prostate cancer. However, despite the fact the cancer is growing with a castrate level of testosterone (e.g. less 50ng/dL), there are some cancers that respond to further hormone manipulations. This has been attributed to a number of mechanisms including (i) upregulation of the androgen receptor and low circulating levels of androgen and (ii) intratumoralproduction 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; comparisons of anti-androgens with low-dose corticosteroids and oestrogens comparisons of megesterol acetate with oestrogens and corticosteroids; high-dose oestrogens; medroxyprogesterone acetate; and adrenal androgen suppression with agents like ketoconazole (with hydrocortisone).
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. For patients who had previously undergone castration only, there was no significant difference between the response rates for anti-androgens and prednisone or diethylstilbestrol. For patients who had had failed combined androgen deprivation, there were significant clinical and/or biochemical improvements with changing the anti-androgen and, when anti-androgens were withdrawn, with ketoconazole and hydrocortisone. 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. 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. 
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.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 compare with flutamide over 24 weeks.
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, the median overall survival for patients with castrate-resistant prostate cancer is now 18 months from the start of chemotherapy. It is of note that the median overall survival is detailed to be about 12 months from institution of second-line hormone manipulation in the studies listed. These studies were done prior to the demonstrated benefit of docetaxel for patients with castrate-resistant prostate cancer. Specifically, prior studies have shown mitoxantrone plus prednisone was associated with a better palliative response than the prednisone (low-dose corticosteroid) alone. It is also of note that in the pivotal docetaxel plus prednisone versus mitoxantrone plus prednisone studies, patients had a median of four previous hormone manipulations, indicating common use of hormone manipulations prior to trialling chemotherapy. It is of relevance to point out the ‘clock’ for the median overall survival of about 18.5 months for docetaxel and 16.4 months for mitoxantrone started from when the chemotherapy was given (ie after the hormone manipulations). It is also worth noting that more recently, agents which (i) block the formation of testosterone from cholesterol by inhibiting an enzyme known as 17-hydroxylase/17,20 lyase (abiraterone), and (ii) are more potent antagonists of the androgen receptor, have been shown to cause disease regression as single agents in the postchemotherapy setting. These agents are being assessed in patients with castrate-resistant disease (for example the NCT00638690 or COU-AA-301 trial of abiraterone acetate). These are well-powered studies and will provide important information about the utility of second-line hormone manipulations in patients with castrate disease.
Evidence summary and recommendations
| Data from large randomised studies are limited.
No second-line hormone manipulation in an RCT has been clearly shown to lead to an improvement in overall survival. A minority of patients have prolonged disease control with further hormone manipulations such as an anti-androgen or adrenal androgen suppression with ketoconazole and hydrocortisone In one RCT, overall quality of life scores, pain scores and gastrointestinal symptom scores were significantly better with prednisone compared with flutamide.
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When assessing the data in total and in the context of the role of docetaxel (active chemotherapy), are recommendation of a course of action can be made for patients with evidence of progression on androgen deprivation.
There is a sequence of actions that should be followed when a patient is shown to have progressive cancer on androgen deprivation therapy.
First, confirm that the patient has a castrate level of testosterone if on an LHRH agonist therapy. If the patient is also on a nonsteroidal anti-androgen, this agent could be withdrawn and observed for the possibility of an anti-androgen withdrawal phenomenon.
It is reasonable to trial further hormone manipulations if the patient is asymptomatic or minimally symptomatic prior to use of chemotherapy (e.g. docetaxel).
Bisphosphonates, radiotherapy and chemotherapy will need to be integrated at some time into overall treatment regimens at this stage of the disease.
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