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Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens |
Caubet J F, Tosteson T D, Dong E W, Naylon E M, Whiting G W, Ernstoff M S, Ross S D |
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Authors' objectives To assess the effect of maximum androgen blockade (MABs) using non-steroidal antiandrogens (NSAAs) on survival in patients with advanced prostate cancer.
Searching MEDLINE and Cancerlit were searched through 1996, and Current Contents for 1994 and 1995. Additional studies were identified by examining the bibliographies of relevant articles and reviews, and through contact with investigators. The search strategy was given. Studies reported in any language were included.
Study selection Study designs of evaluations included in the reviewRandomised clinical trials. Only studies published as full articles and reporting survival data were included. The median length of follow-up ranged from 6 to 35 months.
Specific interventions included in the reviewMAB using NSAAs plus either luteinising hormone-releasing hormone (LHRH) or orchiectomy, versus treatment with LHRH or orchiectomy alone. The NSAAs included in the review were nilutamide (Anandron; 300 mg daily) and flutamide (Eulexin; 250 mg, three times a day); none of the studies used bicalutamide (Casodex). The LHRH agonists were goserelin (Zoladex), leuprolide (Lupron), and buserelin (Centorelix).
Participants included in the reviewPatients with advanced prostate cancer, stage C, D1 and D2 tumours. The mean ages of the patients were between 70 and 75 years. Hormonal pre-treatment was an exclusion criterion.
Outcomes assessed in the reviewThe main outcome was survival data. In addition, progression-free survival and tumour response were assessed.
How were decisions on the relevance of primary studies made?Two independent reviewers, who were blinded to the source and treatment identifiers, selected the papers for the review.
Assessment of study quality The studies were assessed using the quality scoring system of Chalmers et al. (see Other Publications of Related Interest). However, comparisons of NSAA plus LHRH with orchiectomy were not rated for blinding because the treatment could not be blinded. The selected studies were blinded as to the source, authors and treatment groups. Judgements were made independently by at least two reviewers, and any differences were resolved in consensus conferences.
Data extraction The selected studies were blinded as to the source, authors and treatment groups. Data extraction forms were used. The data were extracted independently by at least two reviewers, and any differences were resolved in consensus conferences. Data from the extraction forms were entered into a database and quality checked. The number of patients analysed was extracted from the studies.
Methods of synthesis How were the studies combined?Life tables were used in a meta-analysis using a random-effects model. Data for the life tables were often estimated from the information provided in the individual studies. The approximate median survival times were calculated by two different methods. For the analysis of tumour response, the pooled odds ratios were calculated using a random-effects model.
How were differences between studies investigated?Separate analyses were conducted for patients with stage D2 tumors and for studies using blinded randomisation procedures. The results were calculated and compared for the studies with the highest, median and lowest quality scores.
Results of the review Thirteen studies with a total 3,427 patients were included in the review. Nine studies were included in the meta-analysis for survival (number of patients not stated), and 12 in the analysis for complete and partial tumour responses (2,922 patients).
The relative risk for overall survival (3 to 4 years) was 0.78 (95% confidence interval, CI: 0.67, 0.90, P<0.001) or 0.84 (95% CI: 0.76, 0.93, P<0.001), depending on which method was used. There was an increase in time to progression (relative risk 0.74, 95% CI: 0.63, 0.86, P<0.001), and also an increase for objective tumour responses for MAB using NSAAs, compared with castration alone (odds ratio 0.65, 95% CI: 0.51, 0.81, P=0.00022).
The pooled survival curves imply a difference in overall survival of 7.3 months; 7.6 months for studies including only patients with stage D2 disease, and 7.3 months for studies using blinded randomisation procedures.
Authors' conclusions This meta-analysis supported a beneficial effect for MAB using NSAAs compared with castration alone. The sensitivity analyses suggested that the design of future trials should carefully address issues of patient characterisation, randomisation blinding (concealed treatment allocation), and other study quality issues.
CRD commentary The inclusion and exclusion criteria were well described, and the methodology, validity assessment and synthesis were generally clear. The search strategy had shortcomings. In a systematic review involving drugs, it is usually advisable to also search EMBASE. The inclusion of data only from studies published as full articles and reporting survival data could result in a retrieval or selection bias for overall survival, and especially for tumour response outcomes.
The examination of the homogeneity of the included studies could have been more thorough. The differentiation between the 13 full articles obtained and the 9 providing sufficient data for further analysis, was indistinct.
The authors' conclusions follow from the results presented. The authors also discuss the need for further research.
Implications of the review for practice and research The review indicated that MAB may be beneficial, but there is a need for further well-designed randomised trials.
Funding Zeneca Pharmaceuticals Inc.
Bibliographic details Caubet J F, Tosteson T D, Dong E W, Naylon E M, Whiting G W, Ernstoff M S, Ross S D. Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens. Urology 1997; 49(1): 71-78 Other publications of related interest Chalmers TC, Smith H, Blackburn B, Silverman B, Schroeder B, Reitman D, et al. A method for assessing the quality of a randomized control trial. Control Clin Trials 1981;2:31-49.
Indexing Status Subject indexing assigned by NLM MeSH Androgen Antagonists /therapeutic use; Disease-Free Survival; Humans; Male; Prostatic Neoplasms /drug therapy /mortality; Randomized Controlled Trials as Topic; Survival Rate AccessionNumber 11997000177 Date bibliographic record published 31/10/1999 Date abstract record published 31/10/1999 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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