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Home , Bicalutamide, Cimetidine, Cyproterone, Flutamide, Goserelin, Steroidal antiandrogen

Cancer and Prostatic (2005) 8, 91–94 & 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00 www.nature.com/pcan vs in preventing flare with LHRH analogue therapy for —a pilot study

M Sugiono1, MH Winkler1*, AA Okeke1, M Benney1 & DA Gillatt1 1Bristol Urological Institute, Southmead Hospital, UK

Objective: To evaluate the of bicalutamide vs in preventing PSA flare (as a surrogate for tumour flare) for patients requiring luteinizing -releasing hormone (LHRH) analogue therapy for prostate cancer. Patients and Methods: In this pilot study, 40 men were randomized 1 : 1 to bicalutamide 50 mg o.d. or cyproterone acetate 100 mg t.i.d. 5 days prior to acetate and continued for 21 days thereafter. PSA, (LH), follicle-stimulating hormone (FSH) and were obtained before treatment and on days 6, 8, 10, 16, 21 and 28. Primary end point was PSA. Hormone profile and clinical features including urinary symptoms and bone were secondary end points. Results: Both groups were equally matched apart from serum and ALP. The speed and magnitude of the percentage change in median PSA from baseline was increased for the CPA group but there was no statistically significant difference in the two groups. Although those receiving bicalutamide all showed a testosterone peak, this remained within the normal range. No difference in the frequency of drug-specific adverse events was found. None of the patients died or developed cord compression during the study period. Conclusion: Bicalutamide is able to suppress the initial PSA surge as effectively as cyproterone acetate albeit slightly delayed. A statement whether bicalutamide is equally good at preventing clinical flare cannot be made and should be assessed in an appropriately powered study. Prostate Cancer and Prostatic Diseases (2005) 8, 91–94. doi:10.1038/sj.pcan.4500784 Published online 15 February 2005

Keywords: tumour flare; bicalutamide; cyproterone acetate

Introduction with a better profile that is effective in treating prostate cancer and is also used by Despite a stage migration towards localized , some clinicians to suppress flare. many patients still present with locally advanced or We conducted a prospective randomized pilot study to metastatic prostate cancer.1 The first-line treatment in assess whether bicalutamide is as effective as cyproter- this group is deprivation therapy, usually with one acetate in preventing biochemical and clinical flare. a luteinizing hormone-releasing hormone Efficacy was assessed on the ability of bicalutamide to (LHRHa). However, the initial surge in luteinizing suppress PSA levels following administration of LHRHa. hormone (LH) and hence testosterone prior to down- Prevention of worsening bone-pain, LUTS, adverse regulation can cause disease flare in patients. Cypro- events, serum LH and testosterone levels were secondary terone acetate is the antiandrogen most often used to end points. prevent flare. Bicalutamide is a newer

*Correspondence: M Winkler, 42A Hornsey Rise, London N19 3SQ, UK. Patients and methods E-mail: [email protected] Received 24 September 2004; revised 6 December 2004; accepted 6 In this pilot study, 40 patients from a single centre were December 2004; published online 15 February 2005 randomized to receive either bicalutamide 50 mg o.d. or Bicalutamide vs cyproterone acetate in preventing PSA M Sugiono et al

92 cyproterone acetate 100 mg t.i.d. 5 days prior to LHRHa the two groups. The Mann–Whitney U-test was used for therapy (a subcutaneous of goserelin acetate statistical comparison of median PSA changes. 3.6 mg). Both groups continued antiandrogen treatment Changes in serum testosterone and LH levels were for 21 days thereafter. Randomization was balanced by expressed as the median values on each evaluation day blocks of 4 and stratified by a computer-generated and compared between the groups using the Mann– random-number table. Whitney U-test. Eligible patients had histologically confirmed adeno- The scores were expressed as the number of carcinoma of the prostate stages T1c-T4, NX-N1, M0-M1 men with an increase or decrease of more than 10 mm on (TNM staging; UICC 2003). An isotope bone scan had the VAP score when compared to the value before been performed within 3 months of commencing LHRHa injection. treatment and all had a baseline PSA at least twice the The frequency of adverse events was compared using age specific upper limit of normal and a serum the w2 test. P-values less than 0.05 were considered testosterone level 45 nmol/l. Exclusion criteria were significant. previous hormonal therapy for prostate cancer, other neoplastic lesion (apart from nonmelanomatous skin cancer), metastases of the , renal (creatinineX2 Â normal) or (AST and Results X ALT 3 Â normal) insufficiency, treatment with coumar- In all, 20 patients were randomized to each arm. None of in , , or ketoco- the patients died during the study period. One patient on nazole, hypophysectomy, adrenalectomy, use of any cyproterone acetate was withdrawn at the third visit due experimental drug within the last 3 months prior to the to new onset of dyspnoea and was subsequently study, to any of the study drugs, alcohol admitted to hospital with a diagnosis of chest . dependence, use of recreational drugs and inability to All patients were followed up for a total of 27 days. comply with the study protocol. All patients were The summary statistics of the two groups is shown in counselled before the study and gave written informed Table 1. All parameters were equally distributed between consent. The protocol was approved by the hospital the two groups apart from the serum creatinine and ALP. ethics committee. Although more patients in the CPA group had Following randomization, patients and investigators this was not statistically significant (Table 1). were aware of which drugs were being used. At each visit, a full history and examination was undertaken including the IPSS and assesment of bone pain using a PSA and hormone profile 100 mm visual analogue pain (VAP) score. Serum levels of PSA, LH and testosterone were The median PSA before treatment was lower in the determined throughout the study on days 1 (visit1), 6, bicalutamide group, although this was not statistically 8, 10, 16, 21 and 27 (final visit). In addition, blood significant. The magnitude and speed of the percentage samples for renal and were measured. of median PSA change was increased for the CPA group Safety assessments included targeted questioning and but there was no statistically significant difference examination for potential adverse events as defined by between the groups, with no patient experiencing a rise the good clinical practice (GCP) guidelines. One inves- in PSA between visits (Table 2 and Figure 1). tigator assessed the relationship between treatment and Changes in the LH level in the two groups were adverse events. mirrored by the median testosterone levels (Figure 2, Group equivalence prior to treatment was assessed by results for LH not shown). In the bicalutamide group, the w2 or Fisher’s exact test for binary and categorical testosterone levels peaked on day 8 before falling variables and by the Mann–Whitney U-test for nonpara- steadily to reach castrate levels by day 27 (Figure 2). In metric variables. those on cyproterone acetate, there was an initial As the PSA values had a wide range of distribution, decrease in both hormone levels before a slight testoster- changes were graphically expressed as the percentage one bounce on day 8 followed by a similar continuous change of the median value between consecutive visits in decline (Figure 2).

Table 1 Summary statistics for the two groups Characteristic Bicalutamide (n ¼ 20) Cyproterone acetate (n ¼ 20) P-value

Median age 75 75 0.78 Median IPSS 15 16.5 0.45 Skeletal metastases (M1b) 7 10 0.59 Median PSA before treatment (ng/ml) 66.4 96.1 0.54 Median LH (IU/l) 5.1 5.4 0.68 Median FSH (IU/l) 5.3 7.0 0.33 Median testosterone (nmol/l) 11.1 11.8 0.97 Median ALP (IU/l) 67.5 112 0.013 Median ALT (IU/l) 20.9 20.5 0.79 Median haemoglobin (g/dl) 14.9 13.4 0.12 Median creatinine (mmol/l) 114 103 0.007

Prostate Cancer and Prostatic Diseases Bicalutamide vs cyproterone acetate in preventing PSA M Sugiono et al 93 Table 2 Median changes in serum PSA during study period, acetate developed acute 16 days after expressed as percentage of the pretreatment levels LHRHa was started. Days after Bicalutamide Cyproterone acetate P-value In all, 12 patients on bicalutamide and 11 on start of (% decrease (% decrease cyproterone acetate experienced improvements in their therapy in PSA) in PSA) IPSS between their first and last visits. The mean IPSS was 15.1 and 13.6 before treatment and 10.1 and 8.8 at the 6 À16.8 À37.7 0.25 final visit in the bicalutamide and cyproterone acetate 8 À22 À46.7 0.33 group, respectively. 10 À31.6 À56.1 0.42 16 À41.8 À64.2 0.95 21 À47.2 À70.45 0.93 27 À54 À87.5 0.97 Adverse events In total, three patients in the bicalutamide group experienced nonspecific adverse events compared to 11 % change in Median PSA on cyproterone acetate (Po0.001). None of the patients 0 developed drug-specific adverse events such as renal or liver impairment based on biochemical parameters. Two -20 patients in the cyproterone acetate group had serious nonspecific adverse events; one had worsening LUTS -40 culminating in acute urinary retention which required -60 admission and another had dyspnoea and chest infection as previously mentioned. -80 % decrease in PSA -100 0 6 8 10 16 21 27 Discussion Days after therapy Goserelin + Bicalutamide Disease flare during initial LHRHa therapy can occur in 2 Goserelin + CPA 4–33% of patients and may have a negative impact on quality of life. In this pilot study, we found that Figure 1 Trend of median PSA reduction as percentage of pretreatment bicalutamide 50 mg o.d. was as effective as cyproterone values (CPA ¼ cyproterone acetate). acetate 100 mg t.i.d. in preventing a PSA surge (bio- chemical flare) as well as worsening symptoms (clinical flare), although a statement about the latter cannot be Changes in plasma level of testosterone made safely from this study. Only an appropriately (Normal range: 10.0-30.0 nmol/litre) powered study will answer this question. 25 There has been no previous report on the role of bicalutamide specifically for the prevention of flare. In 20 the context of combined androgen blockade (CAB) with an LHRHa, bicalutamide 50 mg od has been compared to 15 250 mg tds.3 In the first report of the latter study, there was a similar incidence of flare4 between the 10 2 groups. Pharmacokinetic studies have also shown that bicalu- 5 tamide 50 mg od is at least equivalent to flutamide 5

Testosterone (nmol / l) 250 mg tds in terms of affinity and . 0 The efficacy of flutamide in preventing flare has in 0 6 8 10 16 21 27 turn been shown in several studies, although most of 6–8 Days after therapy these were conducted in the context of CAB. Its use is limited by gastrointestinal toxicity, haemolytic anaemia Median testosterone - and visual disturbance. Goserelin + Bicalutamide Cyproterone acetate is a that acts on the pituitary as well as peripherally, and is Median testosterone - thereby able to directly suppress LH production.9 Side Goserelin + CPA effects include direct hepatic toxicity, which may be fatal, Figure 2 Median levels of testosterone during treatment. increased risk of thromboembolism, sickle cell anaemia, and inhibition of . Bicalutamide is a newer nonsteroidal antiandrogen Bone pain and IPSS that is more peripherally selective. It has a good profile with demonstrated efficacy in various There was no significant difference among the two stages of prostate cancer.10 treatment groups in terms of the number of men with or In our study, there was no statistical difference in the without pain prior to treatment. One patient in each percentage of median PSA decline in the two treatment group complained of worsening bone pain. arms. However, four patients on bicalutamide and three Similarly, one patient in each treatment arm had a patients on CPA showed a slight PSA rise in the first worsening of their IPSS. One patient on cyproterone week following LHRHa therapy; none of the patients

Prostate Cancer and Prostatic Diseases Bicalutamide vs cyproterone acetate in preventing PSA M Sugiono et al 94 experienced a sign of clinical flare. The magnitude and Acknowledgements speed of PSA decline was increased for the CPA group. As expected, those on CPA showed an immediate This study was supported by an educational grant from decline in LH and testosterone levels. A small unex- Astra . We thank the urology outpatients staff of pected testosterone bounce was observed on day 8. In the Southmead Hospital, Bristol, UK for their contribution in bicalutamide group, there was an initial rise in LH and organizing the additional clinics. testosterone that peaked on day 8, caused by the selective blocking of peripheral androgen receptors.11 The sub- sequent testosterone decline is solely ascribed to the LHRHa therapy. Nevertheless, in both arms, the median References testosterone remained within the normal range (Figure 2). None of the patients developed cord compression 1 Miller DC et al. Prostate carcinoma presentation, diagnosis and during the study period. staging: an update from the National Cancer Database. Cancer 2003; 98: 1169–1178. There were significantly more patients experiencing 2 Mahler C. Is disease flare a problem? Cancer 1993; 72: 3799–3802. nonspecific adverse events in the CPA group, most of 3 Schellhammer PF et al. Clinical benefits of bicalutamide whom had dyspnoea and which did not require compared with flutamide in combined androgen blockade for any intervention. The one patient who developed acute patients with advanced prostatic carcinoma: final report of a retention underwent TURP. There were no drug-specific double-blind, randomized, multicenter trial. Urology 1997; 50: adverse effects in either group. Although nonspecific and 330–336. drug-specific adverse effects can be difficult to disen- 4 Schellhammer PF et al. A controlled trial of bicalutamide versus tangle. This is particularly true for symptoms such as flutamide, each in combination with luteinizing hormone- dyspnoea which could theoretically be caused by fluid releasing hormone analogue therapy in patients with advanced prostate cancer. Urology 1995; 45: 745–752. retention secondary to the -like character- 5 Blackledge G. Casodex—mechanisms of action and opportu- istics of CPA. nities for usage. Cancer 1993; 72: 3830–3833. The results indicate that bicalutamide 50 mg is able to 6 Crawford ED et al. A controlled trial of leuprolide with and prevent biochemical (PSA) flare as effectively as cypro- without flutamide in prostatic carcinoma. N Eng J Med 1989; 321: terone acetate 100 mg t.i.d., possibly with fewer adverse 419–424. effects. Although statistically insignificant, the speed and 7 Keuppens F et al. Zoladex and flutamide versus bilateral magnitude of PSA suppression was better for the CPA . A randomized phase III EORTC 30853 study. group. If one assumes that PSA is a surrogate for tumour Cancer 1990; 66: 1045–1057. flare12 one may deduct from these results that bicaluta- 8 Labrie F, Dupont A, Belanger A, Lachance R. Flutamide mide also suppresses clinical tumour flare. However, this eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. J relationship is by no means well investigated. It therefore Urol 1987; 138: 804–806. remains to be seen whether bicalutamide provides a 9 Schroder FH. Cyproterone acetate— and useful and well-tolerated alternative in preventing flare clinical effectiveness in prostate cancer treatment. Cancer 1993; during initial treatment with LHRHa. 72: 3810–3815. On the basis of our results an appropriately powered 10 Schellhammer PF. An evaluation of bicalutamide in the treat- study to assess the efficacy of bicalutamide vs cyproter- ment of prostate cancer. Expert Opin Pharmacol 2002; 3: 1313– one acetate for the prevention of tumour flare is possible. 1328. We do not believe the addition of a treatment arm with 11 Verhelst J et al. Endocrine profiles during administration of the no antiandrogen for flare cover is ethically acceptable new non-steroidal anti-androgen Casodex in prostate cancer. Clin Endocrinol 1994; 41: 525–530. because even minimal metastatic burden at the wrong 12 Tomera K et al. The -releasing hormone antagonist sites can sometimes lead to disastrous consequences. depot versus luteinizing hormone releasing hormone However, only the inclusion of a treatment arm with no leuprolide or goserelin: initial results of endocrinologi- flare cover would answer the questions about the clinical cal and biochemical in patients with prostate cancer. J relevance of testosterone flare. Urol 2001; 165: 1585–1589.

Prostate Cancer and Prostatic Diseases