A Re-Assessment of the Role of Combined Androgen Blockade For

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Mini review COMBINED THERAPY FOR ADVANCED PROSTATE CANCER L. KLOTZ et al.

Combined androgen blockade is a A re-assessment of the role of controversial topic, which has arguments both for and against. It combined androgen blockade for is revisited by the authors of this advanced prostate cancer mini-review, with a full discussion on the benefits and cautions with L. KLOTZ, P. SCHELLHAMMER* and K. CARROLL† this approach. A wide range of Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, Canada, *Eastern other issues is also addressed in this Virginia Medical School, Norfolk, Virginia, USA, and †AstraZeneca, Macclesfield, UK Accepted for publication 2 February 2004 section: bilateral testicular cancer, male-factor infertility, and buccal mucosa urethroplasty. All of these are of interest to general KEYWORDS glands continue to produce the androgens, urologists, as well as to those with androsterone and dehydroepiandrosterone. a more specific area of interest. combined androgen blockade, bicalutamide, These are converted to testosterone in antiandrogen, prostate cancer, advanced, the peripheral tissues and in the prostate castration gland (Fig. 1). After castration minimal amounts of testosterone may persist, derived from the adrenal and residual testicular secretion. INTRODUCTION It is well established that antiandrogens act The addition of an antiandrogen to surgical or through competition with the testosterone medical castration, termed combined therapy, metabolite dihydrotestosterone and other was first described in 1979. Twenty-five years androgens for binding sites on the androgen later, much debate still surrounds the benefits receptors in the prostate cell nucleus. Their of combined therapy compared with blockade of the androgen receptor activation castration alone. Here we address the by nonsteroidal growth factors, cytokines, question ‘Does combined therapy have a role and other nonligand dependent activators in the current treatment of metastatic is less well recognized [2]. This latter prostate cancer?’. We review pertinent study mechanism is important in the androgen- data, particularly that relating to the depleted environment and implies that nonsteroidal antiandrogen bicalutamide and the antiandrogens should be considered present an analysis combining historical trial more accurately as ‘androgen receptor data that provides an estimate of the benefit antagonists’. The combination of medical of combined therapy using bicalutamide or surgical castration plus an antiandrogen compared with castration alone. blocks the action of androgens produced by both the testes and adrenal glands. Androgen-dependent genes responsible for prostate cell function and division are THE RATIONALE FOR COMBINED THERAPY activated by the androgen receptor (Fig. 2). Therefore, inhibiting receptor activation The testes produce most of the serum (either by androgen or ligand independent testosterone and the adrenal glands produce activators) by antiandrogens promotes the remaining androgens [1]. After castration apoptosis and inhibits prostate cancer (whether surgical or medical), the adrenal growth.

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WHICH ANTIANDROGEN FOR IGF-1 FIG. 1. COMBINATION THERAPY? KGF The rationale for combination EGF therapy consisting of castration Hypothalamus STEROIDAL OR NONSTEROIDAL IL-6 Feedback plus an antiandrogen. ACTH, ANTIANDROGENS FOR LHRH CRH control adrenocorticotropic hormone; COMBINATION THERAPY? ACTH CRH, corticotropin-releasing LH hormone; EGF, epidermal growth Both steroidal antiandrogens, e.g. cyproterone Adrenal Adrenal androgens factor; IGF-1, insulin-like growth acetate (CPA) and chlormadinone acetate, and Pituitary gland glands factor-1; IL-6, interleukin-6; KGF, the nonsteroidal antiandrogens bicalutamide, keratinocyte growth factor; T, ﬂutamide and nilutamide, have been Leydig T Peripheral cells testosterone. investigated in clinical trials as part of cells of testes combined therapy for advanced prostate Adipose muscle Circulation cancer. A survival disadvantage for combined T therapy with the steroidal antiandrogen CPA compared with castration alone has been demonstrated in a subset analysis of data from the Prostate Cancer Trialists’ Collaborative Group (PCTCG) meta-analysis Zn Zn FIG. 2. [3] (discussed in more detail later). Functional regions of the N terminusDNA Hinge C terminus androgen receptor. AF, activation WHICH NONSTEROIDAL ANTIANDROGEN FOR function; Zn, zinc. COMBINED THERAPY? AF1 domain AF1 domain

The properties of the three nonsteroidal antiandrogens differ in several important Transcription Ligand respects. One such property is their blockade regulation binding DNA binding of nonandrogenic activation of androgen receptors. These factors include cytokines, e.g. interleukin-6, growth factors such as Nuclear localization IGF and epidermal growth factor, and signal transduction factors such as protein kinase A. These factors are capable of activating was 2.4–4 times greater in LNCaP-abl cells independent progression. Other key normal androgen receptors. In the presence of than in LNCaP cells. For bicalutamide, the differences between the nonsteroidal androgen-receptor mutations the androgen induction of reporter gene activity was antiandrogens are their androgen receptor receptor may become ‘promiscuous’ and lower than that seen with flutamide. The binding affinities and potencies, clinical be activated by a much wider variety of stimulatory effects of bicalutamide on efficacies and tolerability profiles. ligands, cytokines and other molecules. androgen receptor activity were 2–2.5-times The nonsteroidal antiandrogens differ in greater in LNCaP-abl cells than in LNCaP In vitro studies show that the binding affinity the degree to which they block androgen cells. of bicalutamide for the human and rat independent activation [4]. Flutamide has prostate androgen receptor is 2–4 times been shown to activate cells with specific There are differential effects of the greater than that of flutamide and twice that single-point mutations of promiscuous nonsteroidal antiandrogens in their of nilutamide. Moreover, bicalutamide androgen receptors identified from patients interaction with androgen receptor co- showed greater potency than flutamide in with androgen insensitivity syndrome [4]. suppressors and co-activators. For example, reducing intact rat ventral prostate and Similarly, nilutamide caused transcription bicalutamide has been shown to activate the seminal vesicle weights [7]. of a mutant androgen receptor extracted nuclear androgen receptor co-suppressor N- from a human metastatic cancer and with CoR and inhibit the co-activator SRC-1. Both In a randomized, double-blind direct a point mutation in the same codon as the these effects would result in inhibition of comparison trial in 813 men with metastatic mutation in the androgen-independent cell cell growth signals by activated androgen prostate cancer [8] there was a trend to line LNCaP, while bicalutamide maintained receptors. However, the effect of flutamide in improved overall survival with bicalutamide antagonistic action [2]. However, in a this system is much more muted [6]. plus an LHRH agonist than with flutamide novel cell subline, LNCaP-abl, which has plus an LHRH agonist (median survival 180 vs a hypersensitive proliferative response to These studies emphasize the important 148 weeks), although the difference did not androgen, bicalutamide showed agonistic biological differences between the achieve statitical significance (hazard ratio, effects on androgen-receptor transactivation nonsteroidal antiandrogens in the androgen- HR, 0.87; 95% CI 0.72–1.05; P = 0.15). This is activity and was unable to block androgen depleted environment and suggest that the only trial comparing two nonsteroidal effects [5]. Flutamide also exerted stimulatory bicalutamide may be superior to flutamide antiandrogens as components of combined effects on androgen receptor activity that and nilutamide in delaying androgen- therapy.

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FIG. 3. Overall survival data as HRs for combined therapy compared with castration alone from published signiﬁcantly reduces the power to detect meta-analyses. Figure reproduced with permission from [4]. Derived from information in [3]; †Relative risks differences in any analysis/study with a using data from [3]; CPA, cyproterone acetate; FLUT, ﬂutamide; NILUT, nilutamide; NSAA, nonsteroidal relatively short follow-up. antiandrogen; NSAA(LH), relative risks (log HR) from P values; NSAA(PH), relative risks (proportional hazards) from discrete proportional hazards model. COMBINED THERAPY VS CASTRATION ALONE: META-ANALYSES 1.5 2P >0.01 0.02 0.04 <0.001 0.041 0.05 >0.01 0.004 0.005 <0.001 0.038 In an attempt to better understand this large worse

therapy volume of trial data there have been several

Combination meta-analyses [3,12,13]. The beneﬁts and 1.0 limitations of the various meta-analyses of HR (95% CI) studies comparing combined therapy with better

therapy castration alone were reviewed previously

Combination [14]. The most complete assessment of 0.5 Overall FLUT CPA NSAA(PH) NSAA FLUT evidence is the meta-analysis published in N 8215 4803 1661 1978 5015 4128 2000 by the PCTCG, which assessed data from Reference [3] [3] [3] [15] [16] [18] 27 trials (including a total of 8275 patients) NILUT NILUT + FLUT* NSAA† NSAA(LH) NILUT and incorporated individual patient data [3]. N 1751 6554 3732 2357 1191 Reference [3] [3] [3] [15] [17] The PCTCG meta-analysis found an overall trend for improved overall survival in patients The nonsteroidal antiandrogens also have advantage of combined therapy over treated with combined therapy compared different tolerability profiles. Flutamide is castration alone for treating metastatic with castration alone, although this was not associated with diarrhoea [9,10] and liver prostate cancer. There were significant statistically significant (HR 0.958; SEM 0.026; toxicity [10]. High rates of visual disturbances improvements in progression-free (median P = 0.11, two-sided) (Fig. 3); the survival and alcohol intolerance have been reported 16.5 vs 13.9 months; P = 0.039) and overall differences were not apparent before 2 with nilutamide [10]. Bicalutamide is better (median 35.6 vs 28.3 months; P = 0.035) years of follow-up. When steroidal and tolerated [1,10]. In the trial by Schellhammer survival with leuprolide plus flutamide nonsteroidal antiandrogens were et al. [8] the incidence of diarrhoea was compared with leuprolide plus placebo. disaggregated, combined therapy with the statistically significantly lower with nonsteroidal antiandrogens flutamide and bicalutamide plus an LHRH agonist than with The largest randomized trial of combined nilutamide was associated with a statistically flutamide plus an LHRH agonist (12% vs 26%; therapy vs. monotherapy conducted to date significant 8% decrease in the risk of death P < 0.001). In that study, haematuria was the studied bilateral orchidectomy plus either over castration alone (95% CI 3–13; only adverse event to occur significantly more flutamide or placebo in 1387 patients with P = 0.005, two-sided); this translated into a frequently with bicalutamide plus agonist metastatic prostate cancer [9]. There was a 2.9% absolute improvement in 5-year survival than with flutamide plus agonist (12% vs 6%; trend for improved survival (a survival benefit (Fig. 3) [14]. However, combined therapy with P = 0.007); in most cases this was mild to of ª10%) with combined therapy over the steroidal antiandrogen CPA was moderate, unrelated to treatment (96%), and castration alone, but this was not statistically associated with a statistically significant 13% did not lead to treatment withdrawal. Overall, significant (HR for risk of death with increase in the risk of death compared with the incidence of withdrawal from therapy due flutamide vs placebo, 0.91, 90% CI 0.81–1.01; castration alone (95% CI 0–27; P = 0.04, two- to an adverse event was lower with P = 0.14). The trial was powered to detect the sided), and this equated to a 2.8% reduction bicalutamide plus agonist (10%) than with 25% difference that had been observed in the in 5-year survival. flutamide plus agonist (16%). study by Crawford et al. [11]. At progression, the treatment arm was unblinded and In the PCTCG meta-analysis [3] the results patients who had been on placebo could then appeared to be independent of patient age, CLINICAL EVIDENCE FOR THE receive open-label flutamide; therefore, the disease stage or whether surgical or medical EFFECTIVENESS OF COMBINED THERAPY trial actually compared initial with delayed castration was used. Although the results of combined therapy. the trials differed, such variation could be Evidence for the effectiveness of combined expected by chance (the test of treatment- therapy compared with castration alone To date, over 31 randomized, long-term by-trial interaction was not significant, comes from individual trials, meta-analyses of (treatment for > 1 year) trials in >8000 men P > 0.1). trial results and, in the case of combined with advanced prostate cancer have therapy using bicalutamide, from the latest investigated the effectiveness and tolerability BICALUTAMIDE COMBINED THERAPY VS analysis of historical trial data. of combined therapy, with variable results [3]. CASTRATION ALONE: ANALYSIS USING Differences between therapies are unlikely to HISTORICAL DATA INDIVIDUAL TRIALS be detected during the early follow-up, as most deaths within 1–1.5 years from As bicalutamide was not available when most Crawford et al. [11] reported the first large diagnosis of advanced cancer are likely to combined vs monotherapy studies were controlled trial (603 men) to show an be from causes other than cancer. This conducted, no data on this agent were

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available for inclusion in the meta-analysis FIG. 4. discussed above. There is no direct Schellhammer et al [8]: HRs and 95% CI for overall bicalutamide plus castration comparison of combined therapy using versus flutamide plus castration survival for bicalutamide plus bicalutamide 50 mg with castration alone. A castration vs flutamide plus double-blind randomized trial is currently castration, flutamide plus PCTCG meta-analysis [3]: ongoing in Japan of bicalutamide 80 mg (the flutamide plus castration castration vs castration alone, registered dose in Japan) combined with an versus castration alone and for bicalutamide plus LHRH agonist vs an agonist plus placebo in castration vs castration alone. 205 men with advanced prostate cancer. New analysis: Preliminary data at a median follow-up of bicalutamide plus castration versus castration alone 15 months indicate that combined therapy with bicalutamide has significant benefits 0.6 0.7 0.8 0.9 1.0 1.1 over LHRH agonist monotherapy; there was HR (plus 95% CI) an improvement in PSA normalization rate (79.4% vs 38.6%; P < 0.001); reduction of the risk of treatment failure (median time to capecitabine with 5-fluorouracil plus metastatic disease) upon which the size of the failure 22.1 vs 15.6 months; P = 0.038) and leucovorin and a meta-analysis of trials effect of bicalutamide relative to flutamide progression (median time not reached; comparing 5-fluorouracil plus leucovorin to would differ, and that patients in the trials P = 0.015); and improvement in quality of life 5-fluorouracil alone. Fisher et al. [17] included in the PCTCG meta-analysis [3] (P < 0.001). There were too few events to described a similar application to estimate the were managed similarly to those in the assess overall survival [15]. effect of clopidogrel relative to placebo in comparative trial of bicalutamide and patients with myocardial infarction, flutamide [8]. The main limitation of As described earlier, bicalutamide was ischaemic stroke or symptomatic peripheral combining data across studies is that it is compared in a large trial with another arterial disease. Results from an active- impossible to completely verify the above nonsteroidal antiandrogen, flutamide, in the controlled trial comparing clopidogrel with assumptions. However, the statistical combined therapy setting (HR 0.87; 95% CI aspirin were used with data from 40 trials of consistency of the effect of flutamide in the 0.72–1.05) [8]. At the time this trial was aspirin vs placebo to obtain an estimate of the PCTCG analysis [3] provides some reassurance designed a direct comparison of combined effect of clopidogrel vs placebo. of the validity of the assumptions. therapy using bicalutamide with castration alone was considered unethical, as combined Using these methods the HR for combined THE FUTURE OF COMBINED THERAPY therapy was considered standard care and therapy using bicalutamide vs castration superior to monotherapy. To understand the alone is estimated by multiplying the HR for CLINICAL AND COST IMPLICATIONS role of bicalutamide in combined therapy we bicalutamide combined therapy vs flutamide used data from the Schellhammer trial [8] in combined therapy with the HR for flutamide When considering therapeutic options the conjunction with the PCTCG meta-analysis combined therapy vs castration alone (i.e. clinician and patient must consider many data [3] for flutamide plus castration vs 0.87 ¥ 0.92 = 0.80, see Appendix). factors. These include the patient’s disease castration alone (HR 0.92, 95% CI 0.86–0.98) status, benefits of therapy, treatment side- to calculate an estimate of the likely benefit of On applying this analysis the balance of effects, quality-of-life issues and cost. bicalutamide combined therapy vs castration evidence suggests that there is a high Individual trial and meta-analysis data alone (Fig. 4). probability (98.5%) that bicalutamide as part suggest that there is a modest improvement of combined therapy provides a survival in overall survival with combined therapy Conventional wisdom dictates that data from advantage over castration alone. The HR is using nonsteroidal antiandrogens over different trials should not be directly 0.80, indicating a 20% reduction in the risk of castration alone in advanced disease, compared. In fact , a methodologically death, with a 95% CI of 0.66–0.98, indicating although these do not appear until after validated technique has evolved to integrate that this benefit could range from an absolute 2 years. An overall survival benefit, although the results of trials which share a common benefit of 2% to 34% (Fig. 4). These CIs are modest, in the aged population where there is arm (in this case, flutamide as MAB) but differ calculated from the combined SEM, which was a high competing risk of death from other in the alternate arm. Typically, this is larger than the SEM from either [8] or the causes is noteworthy. The analysis reported employed where a placebo arm may no longer PCTCG meta-analysis [3], and reflects a here using historical data estimates the be feasible or ethical. Stringent criteria greater uncertainty when combining results benefit of bicalutamide combination therapy regarding comparability of the patient (see Appendix). The key assumptions made as a 20% reduction in the risk of death (HR populations must be met. The PCTCG trials when estimating the effect of bicalutamide 0.8; 95% CI 0.66–0.98) over castration alone. and the Schellhammer trial, both of which are that the effect of flutamide in the trials in enrolled D2 patients from the pre-PSA era, the PCTCG meta-analysis [3] was of a similar Compared with other cancer interventions the appear to meet these criteria. Rothmann et al. magnitude to that in the study population of cost of combined therapy in advanced [16] applied the method to estimate the effect Schellhammer et al. [8]. This would require prostate cancer is reasonable [18]. Using of capecitabine relative to 5-fluorouracil there to be no important prognostic factors Canadian drug costs and assuming a alone for metastatic colorectal cancer, by which were represented differently between 4–7-month survival benefit with combined combining the results from a trial comparing the study populations (such as the extent of therapy in advanced prostate cancer, the

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estimated cost of combined therapy with therapy into context with previously reported 5 Culig Z, Hoffmann J, Erdel M et al. bicalutamide per month of survival benefit is meta-analyses. An estimate of the benefit of Switch from antagonist to agonist of the calculated as Can$437-$1107 [18]. The combined therapy with bicalutamide suggests androgen receptor bicalutamide is estimates of cost per month of survival there is a high probability (estimated to be associated with prostate tumour gained are higher with other cancer therapies 98.5%) that bicalutamide 50 mg combined progression in a new model system. Br J [18]. For example, when vinorelbine is therapy provides a survival advantage over Cancer 1999; 81: 242–51 added to cisplatinum for nonsmall-cell castration alone. The HR for survival in this 6 Hu X, Lazar MA. Transcriptional lung cancer (median 2-month survival analysis was 0.80, indicating a 20% reduction repression by nuclear hormone receptors. benefit) the cost is calculated as Can$1241 in the risk of death with combined therapy Trends Endocrinol Metab 2000; 11: 6–10 per month of survival gained. For metastatic using bicalutamide over castration alone 7 Kolvenbag GJCM, Furr BJA, Blackledge colorectal cancer, irinotecan added to 5- (with 95% CI indicating that the absolute GRP. Receptor affinity and potency of fluorouracil and leucovorin provides a 2–3- survival benefit of 2–34%). When using non-steroidal antiandrogens: translation month survival benefit and the cost is combined therapy other properties of the of preclinical findings into clinical activity. calculated to be Can$11 214 per month of nonsteroidal antiandrogens should also be Prostate Cancer PD 1998; 1: 307–14 survival gained. considered, i.e. tolerability, binding affinity 8 Schellhammer PF, Sharifi R, Block NL and the ability to block androgen- et al. Clinical benefits of bicalutamide independent activation of the androgen compared with flutamide in combined RESEARCH NEEDS receptor in the androgen-depleted androgen blockade for patients with environment. advanced prostatic carcinoma: final Trial data suggest that patients with minimal results of a multicentre, double-blind, metastatic disease may have the greatest ACKNOWLEDGEMENTS randomized trial. Br J Urol 1997; 80: 278 benefits from combined therapy. It may also 9 Eisenberger MA, Blumenstein BA, be possible to use molecular markers, e.g. Laurence Klotz and Paul Schellhammer are Crawford ED et al. Bilateral orchiectomy androgen-receptor gene amplification in members of the Combination Therapy with or without flutamide for metastatic tumours, to identify patients who would Advisory Group and group meetings are prostate cancer. New Engl J Med 1998; derive the greatest benefit from combined supported by AstraZeneca Pharmaceuticals. 339: 1036–42 therapy. Further research is warranted to 10 McLeod DG. Tolerability of nonsteroidal identify subsets of patients who would CONFLICT OF INTEREST antiandrogens in the treatment of benefit most from combined therapy. advanced prostate cancer. Oncologist L. Klotz is a study investigator for AstraZeneca 1997; 2: 18–27 The timing of nonsteroidal antiandrogen and a paid member of the advisory board. 11 Crawford ED, Eisenberger MA, McLeod administration in combined therapy is an P. Schellhammer is a study investigator for DG et al. A controlled trial of leuprolide important consideration. Can the benefit of AstraZeneca. K. Carroll is an employee of with and without flutamide in prostatic combined therapy be obtained by initiating AstraZeneca. carcinoma. New Engl J Med 1989; 321: antiandrogens at the time of progression? To 419–24 date, no trial comparing early vs delayed 12 Agency for Health Care Policy and combined therapy has been conducted. PSA REFERENCES Research. Relative effectiveness and responses to antiandrogens given at the time cost-effectiveness of methods of of biochemical progression occur in about 1 Schellhammer PF. An evaluation of androgen suppression in the treatment half of patients, but these responses are bicalutamide in the treatment of prostate for advanced prostatic cancer. Available generally of short duration (median cancer. Expert Opin Pharmacother 2002; at: http://www.ahcpr.gov/clinic/tp/ 3 months) [19]. A reasonable inference from 3: 1313–28 prostp.htm Accessed 27 January 2004 these data is that this is not likely to translate 2 Kuil CW, Berrevoets CA, Mulder E. 13 Samson DJ, Seidenfeld J, Schmitt B et into an equivalent survival benefit. Ligand-induced conformational al. Systematic review and meta-analysis alterations of the androgen receptor of monotherapy compared with analyzed by limited trypsinization. Studies combined androgen blockade for patients CONCLUSIONS on the mechanism of antiandrogen with advanced prostate carcinoma. action. J Biol Chem 1995; 270: 27569– Cancer 2002; 95: 361–76 The use of combined therapy in prostate 76 14 Klotz L. Combined androgen blockade in cancer management remains controversial. 3 Prostate Cancer Trialists’ Collaborative prostate cancer: meta-analyses and Such therapy with nonsteroidal Group. Maximum androgen blockade in associated issues. BJU Int 2001; 87: 806– antiandrogens offers a modest survival advanced prostate cancer: an overview of 13 benefit compared with castration alone, the randomised trials. Lancet 2000; 355: 15 Akaza H, Arai Y, Usami M et al. which must be balanced against the 1491–8 Bicalutamide 80 mg in combination with potential for an increase in side-effects 4 Gottlieb B, Vasiliou DM, Lumbroso R, a luteinizing hormone-releasing hormone and a consequent adverse effect on the Beitel LK, Pinsky L, Trifiro MA. Analysis agonist (LHRHa) versus LHRHa patient’s quality of life. In this review we have of exon 1 mutations in the androgen monotherapy as first-line treatment for placed the data from the trial comparing receptor gene. Hum Mutat 1999; 14: advanced prostate cancer. In Program and bicalutamide and flutamide in combined 527–39 Abstracts of the 39th Annual Meeting of

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the American Society of Clinical Oncology. therapy for prostate cancer after therapy compared with castration alone. The Chicago, Ill. May 31–June 3, 2003: androgen ablation fails. J Urol 2003; 169: formula for calculating the combined SEM,

Abstract 1695 1742–4 where X1 represents the Schellhammer data

16 Rothmann M, Li N, Chen G, Chi GY, [8] and X2 the PCTCG data [3]: Temple R, Tsou HH. Design and analysis Correspondence: L. Klotz, Division of Urology, 2 2 of non-inferiority mortality trials in Sunnybrook and Women’s College Health SEM(X1 + X2) = ÷(SEM(X1) + SEM(X2) ) oncology. Stat Med 2003; 22: 239–64 Sciences Centre, 2075 Bayview Avenue, SEM = ÷(0.09592 + 0.034552) 17 Fisher LD, Gent M, Buller HR. Active Toronto, Ontario, M4N 3M5, Canada. = 0.1019 control trials: how would a new agent e-mail: [email protected] compare with placebo? A method Calculation of 95% CI: illustrated with clopidogrel, aspirin and Abbreviations: CPA, cyproterone acetate; placebo. Am Heart J 2001; 141: 26–32 PCTCG, Prostate Cancer Trialists’ Collaborative 95% CI = mean ± 1.96 SEM 18 Aprikian AG, Fleshner N, Langleben A, Group; HR, hazard ratio. Mean HR = 0.80 = 0.87 ¥ 0.92 Hames J. An oncology perspective on the 95% CI log scale = -0.223 ± 1.96 (0.1019) beneﬁts and cost of combined androgen = -0.42, – 0.02 blockade in advanced prostate cancer. APPENDIX Can J Urol 2003; 10: 1986–94 Exponentiate to original scale: 19 Kassouf W, Tanguay S, Aprikian AG. Combination of uncertainty in estimates of Nilutamide as second line hormone the likely beneﬁt of bicalutamide combined 95% CI = 0.66, 0.98