Intermittent Androgen Deprivation for Prostate Cancer
Intermittent Androgen Deprivation for Prostate Cancer
This study has no protocol. Methods are reported according to the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
We included all randomised studies comparing IAD with CAD in patients diagnosed with any stage of prostate cancer. For inclusion in the quantitative synthesis, studies were required to compare the efficacy of IAD and CAD by assessing OS, disease-specific survival and/or progression to castrate-resistant disease. Two authors (DB and JC) independently performed the search and screened the studies. The primary outcome measure was OS; secondary outcomes comprised disease-specific survival, progression-free survival, mortality unrelated to prostate cancer, QOL and toxicity outcomes.
The following databases were interrogated during April 2013 for randomised controlled trials fulfilling the above criteria: Medline (1950–present); EMBASE (1966–present); Current Contents (1998–present); Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews; Cumulative Index to Nursing and Allied Health Literature (CINAHL); and ASCO conference abstracts. The search strategy was designed to maximise sensitivity, and used the following terms: 'prostatic neoplasms' OR ' prostat* cancer.mp' OR ' prostat* carcinoma.mp' OR 'metast* prostat*.mp'; 'hormone therapy.mp' OR 'intermittent androgen.mp' OR 'exp androgen antagonists' OR 'hormone blockade.mp' OR 'androgen deprivation.mp' OR 'continuous androgen.mp' OR ' hormone deprivation.mp' OR 'LHRH.mp' OR 'luteinising hormone-releasing hormone.mp' OR ' flutamide' OR 'bicalutamide' OR 'cyproterone' OR 'buserelin' OR 'goserelin' OR ' leupro*' OR 'triptorelin' OR 'nilutamide'; 'randomized controlled trial.pt' OR 'controlled clinical trial.pt' OR 'randomized.ab' OR 'placebo.ab' OR 'clinical trials as topic/' OR 'randomly.ab' OR 'trial.ti'. The prostate cancer, hormone and RCT search terms were combined with a Boolean 'AND' term. Searches were restricted to English language publications. Reference lists of identified studies were then checked for additional pertinent source material.
The risk of bias summary is included in Supplementary 1. Only one of the included studies provided information regarding random sequence generation for patient randomisation, and no studies reported allocation concealment or blinding of participants and personnel. No study reported blinding of outcome assessor, though in four studies the measured outcomes (OS, PSA progression) were objective and unlikely to be affected by unblinded assessment. Three studies were deemed at risk of attrition bias as they did not report losses to follow-up. All other included studies had acceptable losses to follow-up, and five studies reported intention-to-treat analysis. There were no studies at high risk of selective reporting bias.
Studies were assessed for bias using the Cochrane Collaboration tool, and the results presented as a risk of bias summary (Supplementary 1). The domains assessed were random sequence generation, allocation concealment, allocation and outcome blinding, withdrawals and loss to follow-up, and use of intention-to-treat analysis.
(Enlarge Image)
Supplement 1.
Risk of bias summary.
-High risk of bias.
+ Low risk of bias.
? Unclear risk of bias.
Two authors (DB and JC) independently extracted data relating to study characteristics and study quality using standardised electronic data abstraction forms. Specifically, we recorded details of sample size, how randomisation to either treatment arm was performed (random sequence generation and allocation concealment); blinding (of participants and outcome assessors); withdrawals, completeness of follow-up, use of intention-to-treat analysis; included stages of prostate cancer (non-metastatic, locally advanced, recurrent or metastatic); number of patients in each treatment arm; mean age and baseline PSA of participants; hormone treatment regimen (CAD and IAD arms); PSA cutoffs for treatment; definitions of progression; primary and secondary end points and outcomes.
We extracted the hazard ratio (HR) and their 95% confidence interval (CI) for time-to-event outcomes including OS, prostate cancer-specific survival and progression-free survival comparing IAD with CAD. Where no HR was provided in published data, it was estimated from Kaplan–Meier survival curves using previously described methods. HRs were synthesised using the generic inverse variance method and a fixed effect model using RevMan5.1 analysis software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Statistical heterogeneity was assessed using the I statistic. Pre-specified subgroup analysis for OS was conducted on patients with and without metastatic disease. The HR for mortality unrelated to prostate cancer could not be calculated due to insufficient published data, so a risk ratio was calculated instead using event numbers provided by individual studies.
Materials and Methods
Study Protocol and Registration
This study has no protocol. Methods are reported according to the Preferred Reporting for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Study Selection Criteria
We included all randomised studies comparing IAD with CAD in patients diagnosed with any stage of prostate cancer. For inclusion in the quantitative synthesis, studies were required to compare the efficacy of IAD and CAD by assessing OS, disease-specific survival and/or progression to castrate-resistant disease. Two authors (DB and JC) independently performed the search and screened the studies. The primary outcome measure was OS; secondary outcomes comprised disease-specific survival, progression-free survival, mortality unrelated to prostate cancer, QOL and toxicity outcomes.
Search Strategy for Systematic Review
The following databases were interrogated during April 2013 for randomised controlled trials fulfilling the above criteria: Medline (1950–present); EMBASE (1966–present); Current Contents (1998–present); Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews; Cumulative Index to Nursing and Allied Health Literature (CINAHL); and ASCO conference abstracts. The search strategy was designed to maximise sensitivity, and used the following terms: 'prostatic neoplasms' OR ' prostat* cancer.mp' OR ' prostat* carcinoma.mp' OR 'metast* prostat*.mp'; 'hormone therapy.mp' OR 'intermittent androgen.mp' OR 'exp androgen antagonists' OR 'hormone blockade.mp' OR 'androgen deprivation.mp' OR 'continuous androgen.mp' OR ' hormone deprivation.mp' OR 'LHRH.mp' OR 'luteinising hormone-releasing hormone.mp' OR ' flutamide' OR 'bicalutamide' OR 'cyproterone' OR 'buserelin' OR 'goserelin' OR ' leupro*' OR 'triptorelin' OR 'nilutamide'; 'randomized controlled trial.pt' OR 'controlled clinical trial.pt' OR 'randomized.ab' OR 'placebo.ab' OR 'clinical trials as topic/' OR 'randomly.ab' OR 'trial.ti'. The prostate cancer, hormone and RCT search terms were combined with a Boolean 'AND' term. Searches were restricted to English language publications. Reference lists of identified studies were then checked for additional pertinent source material.
Bias Risk
The risk of bias summary is included in Supplementary 1. Only one of the included studies provided information regarding random sequence generation for patient randomisation, and no studies reported allocation concealment or blinding of participants and personnel. No study reported blinding of outcome assessor, though in four studies the measured outcomes (OS, PSA progression) were objective and unlikely to be affected by unblinded assessment. Three studies were deemed at risk of attrition bias as they did not report losses to follow-up. All other included studies had acceptable losses to follow-up, and five studies reported intention-to-treat analysis. There were no studies at high risk of selective reporting bias.
Risk of Bias in Individual Studies
Studies were assessed for bias using the Cochrane Collaboration tool, and the results presented as a risk of bias summary (Supplementary 1). The domains assessed were random sequence generation, allocation concealment, allocation and outcome blinding, withdrawals and loss to follow-up, and use of intention-to-treat analysis.
(Enlarge Image)
Supplement 1.
Risk of bias summary.
-High risk of bias.
+ Low risk of bias.
? Unclear risk of bias.
Data Collection
Two authors (DB and JC) independently extracted data relating to study characteristics and study quality using standardised electronic data abstraction forms. Specifically, we recorded details of sample size, how randomisation to either treatment arm was performed (random sequence generation and allocation concealment); blinding (of participants and outcome assessors); withdrawals, completeness of follow-up, use of intention-to-treat analysis; included stages of prostate cancer (non-metastatic, locally advanced, recurrent or metastatic); number of patients in each treatment arm; mean age and baseline PSA of participants; hormone treatment regimen (CAD and IAD arms); PSA cutoffs for treatment; definitions of progression; primary and secondary end points and outcomes.
Statistical Analysis
We extracted the hazard ratio (HR) and their 95% confidence interval (CI) for time-to-event outcomes including OS, prostate cancer-specific survival and progression-free survival comparing IAD with CAD. Where no HR was provided in published data, it was estimated from Kaplan–Meier survival curves using previously described methods. HRs were synthesised using the generic inverse variance method and a fixed effect model using RevMan5.1 analysis software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Statistical heterogeneity was assessed using the I statistic. Pre-specified subgroup analysis for OS was conducted on patients with and without metastatic disease. The HR for mortality unrelated to prostate cancer could not be calculated due to insufficient published data, so a risk ratio was calculated instead using event numbers provided by individual studies.
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