EFFECTIVENESS OF CYPROTERONE ACETATE IN ACHIEVING CASTRATION AND PREVENTING LUTEINIZING HORMONE RELEASING HORMONE ANALOGUE INDUCED TESTOSTERONE SURGE IN PATIENTS WITH PROSTATE CANCER

Standard treatment for advanced prostate cancer is the elimination of testicular androgen production (testosterone) by pharmacological or surgical means. Commonly used antigonadotrophic pharmacological agents to achieve the elimination of testicular androgen (chemical castration) are luteinizing hormone releasing hormone analogues (LHRHAs) such as leuprolide acetate. However, the initial effect of LHRHA is stimulatory to the pituitary-gonadal axis.1 As a result, between 4% and 80% (mean 11%) of patients experience symptoms of disease flare.2 This phenomenon of disease flare is usually preceded by a increase in serum testosterone and prostate specific antigen (PSA).1 Most commonly the disease flare clinically manifests as increased bone pain or worsening of voiding symptoms. The most serious complications are spinal cord compression or obstructive uropathy.1

Cyproterone acetate (CPA) is a steroidal antiandrogen that has dual action as a peripheral testosterone receptor blocker and as a central agent on the hypothalamus to decrease overall serum testosterone to castrate levels.3,4 Hence, it can be regarded as the only antihormone therapy that causes complete androgen blockade as monotherapy and it is used as monotherapy in the treatment of advanced prostate cancer at some centers.5-7 However, CPA is more commonly given prior to the first dose of LHRHA to blunt the induced testosterone surge believed to be responsible for disease flare.8 There is limited literature on how rapidly and to what extent CPA monotherapy decreases serum testosterone, and how effectively the LHRHA induced testosterone surge and disease flare is blocked.1,9,10

Since the recent publication of the European Organisation for the Research and Treatment of Cancer trial comparing flutamide with CPA as monotherapy in prostate cancer demonstrated no significant differences in efficacy between the 2 treatments, renewed interest in CPA and its role in treating prostate cancer has emerged.7 To our knowledge this study represents the first analysis monitoring the efficacy of CPA monotherapy for achieving castrate testosterone prior to administering LHRHA in the PSA era. Specifically PSA and luteinizing hormone were examined, as was the effectiveness of CPA for preventing testosterone flare after 2 weeks of priming prior to administering an LHRHA.

A total of 21 patients with previously untreated prostate cancer presenting to the urology outpatients clinic were recruited prospectively during the 12-month period of March 2003 to March 2004. All patients had locally advanced (TNM stage T3 or 4) or metastatic prostate adenocarcinoma. The decision to start hormone treatment was made on clinical grounds after having discussed the potential benefits and side effects of such treatment with the patient. All patients were given an ethics committee approved information booklet and they provided written consent. No patients refused to enter the study. Six patients were excluded based on prior hormonal therapy, neurological impairment due to spinal cord compression, renal impairment, abnormal liver function tests, life expectancy less than 3 months and the inability to provide informed consent.

The treatment schedule consisted of a 28-day course of oral CPA at a dose of 100 mg 3 times daily and the LHRHA leuprolide acetate as a 30 mg depot injection on study day 14. Serum PSA, luteinizing hormone and testosterone were tested on days 0, 14, 16, 18, 21, 28 and 56 using the solid phase Immulite® 2000 chemiluminescence immunosassay. Additionally, serum testosterone was also tested on days 2 and 7.

Data were analyzed using the StatCrunch 3.0 computer package (Integrated Analytics, Lafayette, Louisiana) to create 95% CIs (p <0.05) when assessing data. A total of 15 patients were considered a sufficient population based on statistical modeling and previous studies.1,9,10

A total of 15 patients were enrolled in the trial. Mean patient age at entry was 74 years (range 64 to 85). In this study castrate serum testosterone was considered to be 50 ng/dl (1.7 nmol/l) or less (range 285 to 807 ng/dl or 9.9 to 28.0 nmol/l) in healthy males with normal PSA less than 4.0 μg/l and normal luteinizing hormone between 1.4 and 7.7 U/l.

Considering serum testosterone, near castrate levels of a mean ± 95% CI or 83.38 ± 17.87 ng/dl were achieved on day 7 (fig. 1). There was a further decrease to 73.49 ± 17.58 ng/dl by day 14 but it was not significant (p >0.44). There was a significant testosterone increase after LHRHA administration on day 14 to 160.23 ± 36.60 ng/dl on day 16. This was statistically significant (p <0.01).

Fig. 1. Increase in serum testosterone after introduction of LHRHA on day 14 despite 2 days of preceding CPA. CPA monotherapy resulted in slow decrease in serum testosterone to near castrate levels (1.9 ng/mol) by day 14.

Serum luteinizing hormone mirrored testosterone (fig. 2). Luteinizing hormone increased from 4.93 ± 0.61 to 15.4 ± 6.12 nmol/l after LHRHA administration. There was a steady decrease to 1.67 ± 0.8 nmol/l by day 28.

Fig. 2. Serum luteinizing hormone levels mirrored testosterone with increase after LHRHA administration on day 14.

Serum PSA demonstrated a fairly consistent decrease from 199.25 ± 6.12 μg/l at day 0 to 43.77 ± 33.08 μg/l by day 56 (fig. 3). There was no flare in PSA mirroring testosterone after LHRHA administration. Furthermore, no patients experienced symptoms consistent with clinical flare.

Fig. 3. Serum PSA did not increase during testosterone and luteinizing hormone surge after LHRHA administration on day 14. It continued stepwise decrease until end of study period.

The use of LHRHA for prostate cancer has been well documented in the last 20 years.11,12 However, the risk of disease flare with LHRA monotherapy is also well documented13 and Labrie et al are credited with proposing the combination of an antiandrogen with an LHRA for prostate cancer.14

CPA is commonly given prior to commencing LHRHA to prevent disease flare but to our knowledge the optimal timing of such a dose is unknown. Only small studies exist in which CPA has been used to prevent disease flare, given concurrently or up to 4 weeks prior to LHRHA and often in combination with diethylstilbestrol.1,9,10,15,16 Furthermore, not all parameters such as serum testosterone, luteinizing hormone and PSA were tested during the study periods. Only 3 studies measured serum testosterone1,9,10 and only 1 measured luteinizing hormone,1 while none have measured serum PSA. No studies have shown the results of 2 weeks of CPA administration prior to LHRHA therapy. The historical period of 4 weeks of pretreatment with agents to prevent disease flare evolved because of the use of diethylstilbestrol in early studies.16 The time frame of the administration of CPA alone prior to LHRHA was later modified to 1 week1,9 with 1 day considered too short to be effective in other studies.9,10 The chosen period of 1 week of CPA pretreatment prior to LHRHA administration was supported by studies demonstrating near castrate levels of testosterone when CPA was used in combination with diethylstilbestrol.17

The optimal dose of CPA to prevent disease flare is not known with regimens of 100 mg 3 times daily, 100 mg twice daily and 50 mg 3 times daily having been studied.1,9,15 We chose 100 mg 3 times daily because this is the dose routinely used in monotherapy studies to suppress testosterone to castrate levels.7,9 Our treatment period of 2 weeks of CPA after LHRA administration is a commonly used regimen with 1 to 4 weeks also appropriate.2 Our study demonstrates that CPA decreases serum testosterone slowly and achieves near castrate levels at day 7 with a further small decrease by day 14 (not significant). This would suggest that only 1 week of CPA is necessary to achieve near castrate levels and 2 or more weeks may not be necessary, as is practiced at some centers.1,9

A surge in serum luteinizing hormone LH and testosterone upon the introduction of LHRHA was not completely prevented by 2 weeks of priming with CPA. In a previous study Boccon-Gibbod et al noted in 10 patients that 1 week of priming with CPA prevented an increase in serum testosterone above pretreatment levels.9 This was validated in our larger series. Importantly even with the increase in serum testosterone there was no significant increase in serum PSA. This may reflect the protective antiandrogen effect of CPA on peripheral receptors. An alternative consideration is that the increase in serum testosterone was not sufficient to produce a clinical flare effect in our patient group. Other agents such as oral diethylstilbestrol and flutamide have been previously compared with cyproterone acetate and they have similar results in preventing disease flare but with lower toxicity.7,18

Surgical orchiectomy results in earlier castrate levels with almost all patients having castrate levels (less than 50 ng/dl or 1.7nmol/l) within 24 hours. This is well described in the literature with castrate levels of testosterone normally achieved in 3 to 12 hours (mean 8.6).19,20 Therefore, surgical castration may be a better alternative in patients needing rapid onset of treatment for prostate cancer.

To our knowledge this study represents the first prospective documentation of the effect of CPA monotherapy on serum testosterone, luteinizing hormone and PSA. Briefly, 2 weeks of priming with cyproterone acetate does not eliminate the surge in serum testosterone (testosterone flare) when LHRHA is administered. However, this increase in serum testosterone does not exceed pretreatment levels. Furthermore, 2 weeks of CPA may not offer a benefit over 1 week in lowering serum testosterone. This study confirms that there is no increase in serum PSA when LHRHA is administered after priming with CPA. CPA is not as effective or as rapid as surgical orchiectomy for decreasing serum testosterone even if given for 2 weeks as monotherapy. Finally, clinicians need not give CPA for more than 2 weeks prior to LHRHA administration to have the desired effect on testosterone suppression and in many patients 1 week may be sufficient.