eprintid: 1472425 rev_number: 47 eprint_status: archive userid: 608 dir: disk0/01/47/24/25 datestamp: 2016-01-26 11:29:13 lastmod: 2021-12-13 02:10:04 status_changed: 2016-01-26 11:29:13 type: article metadata_visibility: show creators_name: Vale, CL creators_name: Burdett, S creators_name: Rydzewska, LH creators_name: Albiges, L creators_name: Clarke, NW creators_name: Fisher, D creators_name: Fizazi, K creators_name: Gravis, G creators_name: James, ND creators_name: Mason, MD creators_name: Parmar, MK creators_name: Sweeney, CJ creators_name: Sydes, MR creators_name: Tombal, B creators_name: Tierney, JF title: Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data ispublished: pub divisions: UCL divisions: B02 divisions: D65 divisions: J38 note: © Vale et al. Open Access article distributed under the terms of CC-BY. abstract: BACKGROUND: Results from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel). FINDINGS: We identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68-0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5-14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58-0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12-19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69-1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61-0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5-10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79-0·98]; p=0·025), which translates to 5% (1-8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83-1·07]; p=0·323), which translates to an absolute improvement in survival of 2% (-3 to 7). Of 17 trials of bisphosphonates for men with M0 disease, survival results from four trials (4079 [66%] of 6220 men) showed no evidence of benefit from the addition of bisphosphonates (1·03 [0·89-1·18]; p=0·724) or zoledronic acid (0·98 [0·82-1·16]; p=0·782). Failure-free survival definitions were too inconsistent for formal meta-analyses for the bisphosphonate trials. INTERPRETATION: The addition of docetaxel to standard of care should be considered standard care for men with M1 hormone-sensitive prostate cancer who are starting treatment for the first time. More evidence on the effects of docetaxel on survival is needed in the M0 disease setting. No evidence exists to suggest that zoledronic acid improves survival in men with M1 or M0 disease, and any potential benefit is probably small. FUNDING: Medical Research Council UK. date: 2016-02-01 official_url: http://dx.doi.org/10.1016/S1470-2045(15)00489-1 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: JOURNAL ARTICLE verified: verified_manual elements_id: 1070335 doi: 10.1016/S1470-2045(15)00489-1 pii: S1470-2045(15)00489-1 lyricists_name: Burdett, Sarah lyricists_name: Fisher, David lyricists_name: Parmar, Mahesh lyricists_name: Rydzewska, Larysa lyricists_name: Sydes, Matthew lyricists_name: Tierney, Jayne lyricists_name: Vale, Claire lyricists_id: SBURD20 lyricists_id: DFISH32 lyricists_id: MKBPA56 lyricists_id: LHMTR57 lyricists_id: MRSYD21 lyricists_id: JFTIE32 lyricists_id: CVALE61 actors_name: Burdett, Sarah actors_id: SBURD20 actors_role: owner full_text_status: public publication: The Lancet Oncology volume: 17 number: 2 pagerange: 243-256 issn: 1474-5488 citation: Vale, CL; Burdett, S; Rydzewska, LH; Albiges, L; Clarke, NW; Fisher, D; Fizazi, K; ... Tierney, JF; + view all <#> Vale, CL; Burdett, S; Rydzewska, LH; Albiges, L; Clarke, NW; Fisher, D; Fizazi, K; Gravis, G; James, ND; Mason, MD; Parmar, MK; Sweeney, CJ; Sydes, MR; Tombal, B; Tierney, JF; - view fewer <#> (2016) Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. The Lancet Oncology , 17 (2) pp. 243-256. 10.1016/S1470-2045(15)00489-1 <https://doi.org/10.1016/S1470-2045%2815%2900489-1>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1472425/1/PIIS1470204515004891.pdf