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Blackwell Science, LtdOxford, UKBJUBJU International1464-4096BJU InternationalJune 2004939 COMBINED THERAPY FOR ADVANCED PROSTATE CANCERL. 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†
Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, Canada, *Eastern
this approach. A wide range of
Virginia Medical School, Norfolk, Virginia, USA, and †AstraZeneca, Macclesfield, UK other issues is also addressed in this
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, androsterone and dehydroepiandrosterone. urologists, as well as to those with
combined androgen blockade, bicalutamide, a more specific area of interest.
antiandrogen, prostate cancer, advanced, the peripheral tissues and in the prostate 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 blockade of the androgen receptor activation by nonsteroidal growth factors, cytokines, question ‘Does combined therapy have a role and other nonligand dependent activators is less well recognized [2]. This latter prostate cancer?’. We review pertinent study nonsteroidal antiandrogen bicalutamide and present an analysis combining historical trial data that provides an estimate of the benefit antagonists’. The combination of medical or surgical castration plus an antiandrogen 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 (either by androgen or ligand independent testosterone and the adrenal glands produce the remaining androgens [1]. After castration (whether surgical or medical), the adrenal 2 0 0 4 B J U I N T E R N A T I O N A L | 9 3 , 11 7 7 – 11 8 2 | doi:10.1111/j.1464-410X.2004.04803.x WHICH ANTIANDROGEN FOR
COMBINATION THERAPY?
Both steroidal antiandrogens, e.g. cyproterone factor; IGF-1, insulin-like growth acetate (CPA) and chlormadinone acetate, and factor-1; IL-6, interleukin-6; KGF, the nonsteroidal antiandrogens bicalutamide, investigated in clinical trials as part of cancer. A survival disadvantage for combined 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 [3] (discussed in more detail later).
Functional regions of the androgen receptor. AF, activation The properties of the three nonsteroidal antiandrogens differ in several important respects. One such property is their blockade of nonandrogenic activation of androgen receptors. These factors include cytokines, e.g. interleukin-6, growth factors such as 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 normal androgen receptors. In the presence of than in LNCaP cells. For bicalutamide, the androgen-receptor mutations the androgen antiandrogens are their androgen receptor receptor may become ‘promiscuous’ and lower than that seen with flutamide. The binding affinities and potencies, clinical efficacies and tolerability profiles.
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 independent activation [4]. Flutamide has prostate androgen receptor is 2–4 times been shown to activate cells with specific greater than that of flutamide and twice that androgen receptors identified from patients 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 nuclear androgen receptor co-suppressor N- CoR and inhibit the co-activator SRC-1. Both 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 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 148 weeks), although the difference did not 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 the only trial comparing two nonsteroidal effects [5]. Flutamide also exerted stimulatory bicalutamide may be superior to flutamide effects on androgen receptor activity that 2 0 0 4 B J U I N T E R N A T I O N A L C O M B I N E D T H E R A P Y F O R A D V A N C E D P R O S T A T E C A N C E R 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 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 In an attempt to better understand this large volume of trial data there have been several meta-analyses [3,12,13]. The benefits and limitations of the various meta-analyses of castration alone were reviewed previously evidence is the meta-analysis published in 2000 by the PCTCG, which assessed data from 27 trials (including a total of 8275 patients) and incorporated individual patient data [3].
The PCTCG meta-analysis found an overall trend for improved overall survival in patients The nonsteroidal antiandrogens also have different tolerability profiles. Flutamide is castration alone for treating metastatic with castration alone, although this was not associated with diarrhoea [9,10] and liver 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 with nilutamide [10]. Bicalutamide is better (median 35.6 vs 28.3 months; P = 0.035) tolerated [1,10]. In the trial by Schellhammer et al. [8] the incidence of diarrhoea was compared with leuprolide plus placebo.
disaggregated, combined therapy with the 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 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 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, 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- 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 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 the trials differed, such variation could be Evidence for the effectiveness of combined expected by chance (the test of treatment- by-trial interaction was not significant, comes from individual trials, meta-analyses of (treatment for > 1 year) trials in >8000 men trial results and, in the case of combined therapy using bicalutamide, from the latest investigated the effectiveness and tolerability of combined therapy, with variable results [3]. Differences between therapies are unlikely to 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 2 0 0 4 B J U I N T E R N A T I O N A L available for inclusion in the meta-analysis bicalutamide 50 mg with castration alone. A double-blind randomized trial is currently ongoing in Japan of bicalutamide 80 mg (the registered dose in Japan) combined with an LHRH agonist vs an agonist plus placebo in 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 over LHRH agonist monotherapy; there was an improvement in PSA normalization rate (79.4% vs 38.6%; P < 0.001); reduction of the risk of treatment failure (median time to 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 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] (P < 0.001). There were too few events to described a similar application to estimate the effect of clopidogrel relative to placebo in ischaemic stroke or symptomatic peripheral combining data across studies is that it is arterial disease. Results from an active- impossible to completely verify the above nonsteroidal antiandrogen, flutamide, in the controlled trial comparing clopidogrel with 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 therapy using bicalutamide with castration alone was considered unethical, as 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 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 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 probability (98.5%) that bicalutamide as part suggest that there is a modest improvement in overall survival with combined therapy Conventional wisdom dictates that data from advantage over castration alone. The HR is 0.80, indicating a 20% reduction in the risk of 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 here using historical data estimates the be feasible or ethical. Stringent criteria greater uncertainty when combining results benefit of bicalutamide combination therapy (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 [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 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 2 0 0 4 B J U I N T E R N A T I O N A L C O M B I N E D T H E R A P Y F O R A D V A N C E D P R O S T A T E C A N C E R therapy into context with previously reported 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 combined therapy with bicalutamide suggests there is a high probability (estimated to be gained are higher with other cancer therapies progression in a new model system. Br J therapy provides a survival advantage over Cancer 1999; 81: 242–51
castration alone. The HR for survival in this Hu X, Lazar MA. Transcriptional
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 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 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
considered, i.e. tolerability, binding affinity Schellhammer PF, Sharifi R, Block NL
et al. Clinical benefits of bicalutamide RESEARCH NEEDS
Trial data suggest that patients with minimal metastatic disease may have the greatest ACKNOWLEDGEMENTS
randomized trial. Br J Urol 1997; 80: 278
benefits from combined therapy. It may also Eisenberger MA, Blumenstein BA,
be possible to use molecular markers, e.g. Laurence Klotz and Paul Schellhammer are Crawford ED et al. Bilateral orchiectomy
with or without flutamide for metastatic prostate cancer. New Engl J Med 1998; derive the greatest benefit from combined supported by AstraZeneca Pharmaceuticals.
339: 1036–42
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CONFLICT OF INTEREST
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