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BMC Cancer Mar 2013There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
There is currently no consensus regarding the optimal timing for androgen suppression therapy in patients with prostate cancer that have undergone local therapy with curative intent but are proven to have node-positive disease without signs of distant metastases at the time of local therapy. The objective of this systematic review was to determine the benefits and harms of early (at the time of local therapy) versus deferred (at the time of clinical disease progression) androgen suppression therapy for patients with node-positive prostate cancer after local therapy.
METHODS
The protocol was registered prospectively (CRD42011001221; http://www.crd.york.ac.uk/PROSPERO). We searched the MEDLINE, EMBASE, and CENTRAL databases, as well as reference lists, the abstracts of three major conferences, and three trial registers, to identify randomized controlled trials (search update 04/08/2012). Two authors independently screened the identified articles, assessed trial quality, and extracted data.
RESULTS
Four studies including 398 patients were identified for inclusion. Early androgen suppression therapy lead to a significant decrease in overall mortality (HR 0.62, 95% CI 0.46-0.84), cancer-specific mortality (HR 0.34, 95% CI 0.18-0.64), and clinical progression at 3 or 9 years (RR 0.29, 95% CI 0.16-0.52 at 3 years and RR 0.49, 95% CI 0.36-0.67 at 9 years). One study showed an increase of adverse effects with early androgen suppression therapy. All trials had substantial methodological limitations.
CONCLUSIONS
The data available suggest an improvement in survival and delayed disease progression but increased adverse events for patients with node-positive prostate cancer after local therapy treated with early androgen suppression therapy versus deferred androgen suppression therapy. However, quality of data is low. Randomized controlled trials with blinding of outcome assessment, planned to determine the timing of androgen suppression therapy in node-positive prostate cancer using modern diagnostic imaging modalities, biochemical testing, and standardized follow-up schedules should be conducted to confirm these findings.
Topics: Adult; Aged; Aged, 80 and over; Androgen Antagonists; Antineoplastic Agents, Hormonal; Disease Progression; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Grading; Prostatic Neoplasms
PubMed: 23510155
DOI: 10.1186/1471-2407-13-131 -
BMC Cancer Feb 2012Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the preferred treatment for this condition. More recent evidence from randomised trials has demonstrated clinical benefit with the combined use of androgen suppression in such cases. The aim of this meta-analysis is to compare the combination of distinct hormone therapy modalities versus radiotherapy alone for overall survival, disease-free survival and toxicity.
METHODS
Databases (MEDLINE, EMBASE, LILACS, Cochrane databases and ClinicalTrials.gov) were scanned for randomised clinical trials involving radiotherapy with or without androgen suppression in local prostate cancer. The search strategy included articles published until October 2011. The studies were examined and the data of interest were plotted for meta-analysis. Survival outcomes were reported as a hazard ratio with corresponding 95% confidence intervals.
RESULTS
Data from ten trials published from 1988 to 2011 were included, comprising 6555 patients. There was a statistically significant advantage to the use of androgen suppression, in terms of both overall survival and disease free survival, when compared to radiotherapy alone. The use of long-term goserelin (up to three years) was the strategy providing the higher magnitude of clinical benefit. In contrast to goserelin, there were no trials evaluating the use of other luteinizing hormone-releasing hormone (LHRH) analogues as monotherapy. Complete hormonal blockade was not shown to be superior to goserelin monotherapy.
CONCLUSIONS
Based on the findings of this systematic review, the evidence supports the use of androgen suppression with goserelin monotherapy as the standard treatment for patients with prostate cancer treated with radiotherapy, which are at high risk of recurrence or metastases.
Topics: Adenocarcinoma; Androgen Antagonists; Antineoplastic Agents, Hormonal; Combined Modality Therapy; Humans; Male; Prostatic Neoplasms; Survival Analysis
PubMed: 22299707
DOI: 10.1186/1471-2407-12-54 -
Cancer Jun 2009Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer. Although ADT is effective at suppressing prostate-specific antigen (PSA),... (Review)
Review
Androgen-deprivation therapy (ADT) is a common treatment for men with prostate cancer. Although ADT is effective at suppressing prostate-specific antigen (PSA), stabilizing disease, alleviating symptoms in advanced disease, and potentially prolonging survival, it is not without serious side effects. However, to the authors' knowledge, there is lack of a systematic review of its major adverse effects to date. The authors of this report systematically reviewed and quantitatively assessed the literature on skeletal and cardiac side effects associated with ADT in men with prostate cancer. The PubMed database was searched for relevant published articles from 1966 to May 2008, and 683 articles were reviewed systematically from an original 20 different Medical Subject Heading search combinations. The focus of the review was on bone-related and cardiovascular-related outcomes. When appropriate, results were pooled from articles on specific adverse outcomes, summary risk estimates were calculated, and tests of heterogeneity were performed. Fourteen articles were identified that met inclusion criteria from the original 683 studies. Men who underwent ADT for prostate cancer had a significantly increased risk of overall fracture of 23% (summary relative risk, 1.23; 95% confidence interval [95% CI], 1.10-1.38) compared with men who had prostate cancer but who did not undergo ADT. Furthermore, men who underwent ADT had a 17% increase in cardiovascular-related mortality compared with men who did not undergo with ADT (summary hazards ratio, 1.17; 95% CI, 1.07-1.29). Significant elevations in the risk of diabetes also were observed from 2 large studies. ADT was associated with an increased risk of skeletal fracture, incident diabetes, and cardiovascular-related mortality, although the absolute risk of these events was low. Preventive measures against these adverse effects and careful assessment of patient's baseline health status should be considered.
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Fractures, Bone; Humans; Male; Osteoporosis; Prostatic Neoplasms; Quality of Life; Risk Assessment; Treatment Outcome
PubMed: 19399748
DOI: 10.1002/cncr.24283 -
The Cochrane Database of Systematic... Oct 2007After lung cancer, prostate cancer is the most common cause of death among males. The aim of treatment is to prevent disease-related morbidity and mortality while... (Comparative Study)
Comparative Study Meta-Analysis Review
BACKGROUND
After lung cancer, prostate cancer is the most common cause of death among males. The aim of treatment is to prevent disease-related morbidity and mortality while minimizing intervention-related adverse events. Androgen suppression therapy (AST) to reduce circulating serum testosterone and disease progression is considered a mainstay of treatment for men with advanced prostate cancer. It has been increasingly utilized for early stage disease despite a lack of evidence of effectiveness.
OBJECTIVES
Evaluate the effectiveness and safety of intermittent androgen suppression (IAS) compared to continuous androgen suppression for treating prostatic cancer.
SEARCH STRATEGY
The following databases were searched to identify randomised or quasi-randomised, controlled trials comparing intermittent and continuous androgen suppression in the treatment of any stage of prostate cancer: the Cochrane Central Register of Controlled Trials; EMBASE and LILACS.
SELECTION CRITERIA
Studies were included if they were randomised or quasi-randomized, and compare the effects of IAS versus CAS.
DATA COLLECTION AND ANALYSIS
Two reviewers selected relevant trials, assessed methodological quality and extracted data.
MAIN RESULTS
Five randomized studies involving 1382 patients were included in this review. All the included studies involved advanced (T3 or T4) prostate cancer, had relatively small populations, and were of short duration. Few events were reported and did not assess disease-specific survival or metastatic disease. Only one study (N = 77) evaluated biochemical outcomes. A subgroup analysis found no significant differences in biochemical progression (defined by the authors as PSA >/= 10 ng/mL) between IAS and CAS for Gleason scores 4 - 6, 7, and 8 - 10. For patients with a Gleason score > 6, reduction in biochemical progression favoured the IAS group (RR 0.10, 95% CI 0.01 to 0.67, P = 0.02). Studies primarily reported on adverse events. One trial (N = 43) found no difference in adverse effects (gastrointestinal, gynecomastia and asthenia) between IAS ( two events) and CAS (five events), with the exception of impotence, which was significantly lower in the IAS group (RR 0.72, 95% CI 0.56 to 0.92, P = 0.008).
AUTHORS' CONCLUSIONS
Data from RCTs comparing IAS to CAS are limited by small sample size and short duration. There are no data for the relative effectiveness of IAS versus CAS for overall survival, prostate cancer-specific survival, or disease progression. Limited information suggests IAS may have slightly reduced adverse events. Overall, IAS was also as effective as CAS for potency, but was superior during the interval of cycles (96%).
Topics: Androgen Antagonists; Drug Administration Schedule; Humans; Male; Neoplasm Staging; Orchiectomy; Prostate-Specific Antigen; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 17943832
DOI: 10.1002/14651858.CD005009.pub2 -
The Cochrane Database of Systematic... Jul 2007Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women.
OBJECTIVES
To determine the effectiveness and tolerability of Danazol when used for heavy menstrual bleeding in women of reproductive years.
SEARCH STRATEGY
We searched the Menstrual Disorders and Subfertility Group's Specialised Register (April 2007). We also searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2007), MEDLINE (1966 to April 2007), EMBASE (1980 to April 2007, CINAHL (1982 to April 2007). Attempts were also made to identify trials from citation lists of included trials and relevant review articles.
SELECTION CRITERIA
Randomised controlled trials of Danazol versus placebo, any other medical (non-surgical) therapy or Danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded.
DATA COLLECTION AND ANALYSIS
Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format.
MAIN RESULTS
Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with Danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7 to 28.2) and progestogens (OR 4.05, 95% CI 1.6 to10.2). Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8 to -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3 to -4.8). There were no randomised trials comparing Danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system.
AUTHORS' CONCLUSIONS
Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments. The use of Danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. The small number of trials, and the small sample sizes of the included trials limit the recommendations for clinical care. Further studies are unlikely in the future and this review will not be updated unless further studies are identified.
Topics: Danazol; Estrogen Antagonists; Female; Humans; Menorrhagia; Randomized Controlled Trials as Topic
PubMed: 17636649
DOI: 10.1002/14651858.CD001017.pub2 -
The Cochrane Database of Systematic... 2002Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an... (Review)
Review
BACKGROUND
Heavy menstrual bleeding (HMB) is an important cause of ill health in pre menopausal women. Medical therapy, with the avoidance of possibly unnecessary surgery is an attractive treatment option, but there is considerable variation in practice and uncertainty about the most effective therapy. Danazol is a synthetic steroid with anti-oestrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses oestrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women.
OBJECTIVES
To determine the effectiveness and tolerability of danazol when used for heavy menstrual bleeding in women of reproductive years.
SEARCH STRATEGY
All studies which might describe randomised controlled trials of danazol for the treatment of heavy menstrual bleeding were obtained by electronic searches of MEDLINE, EMBASE, Current Contents, CINAHL, National Research Register and the Menstrual Disorders and Subfertility Group's Specialist Register of controlled trials (on 6 November 2001). Attempts were also made to identify trials from citation lists of included trials and relevant review articles. In most cases the first author of each included trial was contacted for unpublished additional information.
SELECTION CRITERIA
Randomised controlled trials of danazol versus placebo, any other medical (non-surgical) therapy or danazol in different dosages for heavy menstrual bleeding in women of reproductive age with regular HMB measured either subjectively or objectively. Trials that included women with post menopausal bleeding, intermenstrual bleeding and pathological causes of heavy menstrual bleeding were excluded.
DATA COLLECTION AND ANALYSIS
Nine RCTs, with 353 women, were identified that fulfilled the inclusion criteria for this review. Quality assessment and data extraction were performed independently by two reviewers. The main outcomes were menstrual blood loss, the number of women experiencing adverse effects, weight gain, withdrawals due to adverse effects and dysmenorrhoea. If data could not be extracted in a form suitable for meta-analysis, they were presented in a descriptive format.
MAIN RESULTS
Most data were not in a form suitable for meta analysis, and the results are based on a small number of trials, all of which are under-powered. Danazol appears to be more effective than placebo, progestogens, NSAIDs and the OCP at reducing MBL, but confidence intervals were wide. Treatment with danazol caused more adverse events than NSAIDs (OR 7.0; 95% CI 1.7, 28.2) and progestogens (OR 4.05, 95% CI 1.6, 10.2), but this did not appear to affect adherence to treatment. Danazol was shown to significantly lower the duration of menses when compared with NSAIDs (WMD -1.0; 95% CI -1.8, -0.3) and a progesterone releasing IUD (WMD -6.0; 95% CI -7.3, -4.8). There were no randomised trials comparing danazol with tranexamic acid or the levonorgestrel-releasing intrauterine system.
REVIEWER'S CONCLUSIONS
Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments, though it is uncertain whether it is acceptable to women. The use of danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. Overall no strong recommendations can be made due to the small number of trials, and the small sample sizes of the included trials.
Topics: Danazol; Estrogen Antagonists; Female; Humans; Menorrhagia; Randomized Controlled Trials as Topic
PubMed: 12076401
DOI: 10.1002/14651858.CD001017 -
Evidence Report/technology Assessment... May 1999With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic... (Review)
Review
OBJECTIVES
With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic review of the evidence from randomized controlled trials on the relative effectiveness of alternative strategies for androgen suppression as treatment of advanced prostate cancer. Three key issues are addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone-releasing hormone [LHRH] agonists, and antiandrogens), (2) the effectiveness of combined androgen blockade compared to monotherapy, and (3) the effectiveness of immediate androgen suppression compared to androgen suppression deferred until clinical progression. Outcomes of interest are overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life. Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3), and (2) cost-effectiveness analysis.
SEARCH STRATEGY
The MEDLINE, CANCERLIT, and EMBASE databases were searched from 1966 to March 1998, and Current Contents to August 24, 1998, for the terms: leuprolide (Lupron); goserelin (Zoladex); buserelin (Suprefact); flutamide (Eulexin); nilutamide (Anandron, Nilandron); bicalutamide (Casodex); cyproterone acetate (Androcur); diethylstilbestrol (DES); and orchiectomy (castration, orchidectomy). The search was then limited to human studies indexed under the MeSH term "prostatic neoplasms" and by the UK Cochrane Center search strategy for randomized controlled trials. Total yield was 1,477 references.
SELECTION CRITERIA
We Reports of efficacy outcomes were limited to randomized controlled trials. Phase II studies that reported on withdrawals from therapy and all studies reporting on quality of life were also included.
DATA COLLECTION AND ANALYSIS
The systematic review used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis combined data on overall survival using a random effects model. The cost-effectiveness analysis used a decision analysis model of advanced prostate cancer with health states and transitions derived from the literature and estimates of effectiveness derived from the meta-analysis. The cost-effectiveness analysis is conducted from a societal perspective, consistent with the guidelines of the U.S. Public Health Service Panel on Cost-Effectiveness in Health and Medicine.
MAIN RESULTS
Survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy. The available LHRH agonists are equally effective, and no LHRH agonist is superior to the other when adverse effects are considered. Survival may be somewhat lower with use of a nonsteroidal antiandrogen. There is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy. Meta-analysis of the limited data available shows a statistically significant difference in survival at 5 years that favors combined androgen blockade. However, the magnitude of this difference is of questionable clinical significance. For the subgroup of patients with good prognosis, there is no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade. No evidence is yet available from randomized controlled trials of androgen suppression initiated at prostate-specific antigen (PSA) rise after definitive therapy for clinically localized disease. For patients who are newly diagnosed with locally advanced or asymptomatic metastatic disease, the evidence is insufficient to determine whether primary androgen suppression initiated at diagnosis improves outcomes. (ABSTRACT TRUNCATED)
Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Cost-Benefit Analysis; Evidence-Based Medicine; Gonadotropin-Releasing Hormone; Goserelin; Humans; Leuprolide; Male; Orchiectomy; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 11098244
DOI: No ID Found -
The Cochrane Database of Systematic... 2000Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is... (Review)
Review
BACKGROUND
Oligo-astheno-teratospermia (sperm of low concentration, reduced motility and increased abnormal morphology) of unknown cause is common and the need for treatment is felt by patients and doctors alike. As a result, a variety of empirical, non-specific treatments have been used in an attempt to improve semen characteristics and fertility. Androgens have been suggested as a treatment because its binding proteins maintain a maintain a high intratesticular level testosterone essential for spermatogenesis and because the epididymis and seminal vesicles affect the seminal constitution and sperm motility and are also androgen-dependent. However exogenous testosterone was found to exert negative feedback on the pituitary-gonadal axis and thereby to suppress FSH and LH secretion. Spermatogenesis was thus adversely affected. Nevertheless androgens are used for the treatment of male infertility either for a putative direct "stimulatory" or "rebound" therapy. The stimulatory androgens used are mesterolone and testosterone undecanoate which, it is postulated, in a form and dosage that does not influence pituitary gonadotrophin secretion, either have a direct stimulatory effect on spermatogenesis or influence sperm transport and maturation though an effect on the epididymis, ductus deferens and seminal vesicles. Other androgens have been used to produce a rebound effect. These androgens are administered to suppress gonadotrophin secretion and spermatogenesis. After androgen therapy is discontinued there is a surge of FSH and LH and spermatogenesis is recommenced. Because of their different proposed mechanisms of action, stimulatory and rebound androgen therapy are analysed separately in the comparisons. This review considers the available evidence of the effect of androgens for idiopathic oligo and/or asthenospermia.
OBJECTIVES
The objective of this review was to assess the effect of androgen treatment of men among couples where failure to conceive has been attributed to idiopathic oligo- and/or asthenospermia.
SEARCH STRATEGY
The Cochrane Subfertility Review Group specialised register of controlled trials was searched".
SELECTION CRITERIA
Randomised trials of mesterolone or testosterone undecanoate versus placebo or no treatment (stimulatory therapy), or testosterone enanthate or testosterone undecanoate versus placebo or no treatment (rebound therapy) in couples where subfertility is attributed to male factor.
DATA COLLECTION AND ANALYSIS
Eligibility and trial quality were assessed.
MAIN RESULTS
Eleven trials involving 930 patients were included. For stimulatory therapy, androgens had little effect on endocrinal outcomes and sperm parameters. The rate of pregnancy after androgens with stimulatory effect compared to no treatment or placebo was also similar (odds ratio 1.10, 95% confidence interval 0.75 to 1.61). In rebound therapy, no difference was found in sperm parameters. The pregnancy rate after androgens with rebound effect also showed no difference compared to no treatment or placebo (odds ratio 1.60, 95% confidence interval 0.42 to 6.16). Adverse effects such as headaches and exanthema were reported.
REVIEWER'S CONCLUSIONS
There is not enough evidence to evaluate the use of androgens for male subfertility. [This abstract has been prepared centrally.]
Topics: Androgens; Humans; Infertility, Male; Male; Mesterolone; Oligospermia; Testosterone
PubMed: 10796496
DOI: 10.1002/14651858.CD000150