Journal of the National Cancer Institute Advance Access published online on December 9, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn414
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© The Author 2008. Published by Oxford University Press.
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Multiple-Treatments Meta-analysis of Chemotherapy and Targeted Therapies in Advanced Breast Cancer
Affiliations of authors: Clinical Trials and Evidence-Based Medicine Unit, Department of Hygiene and Epidemiology (DM, NPP, GS, JPAI) and Department of Medical Oncology (DM, NP), University of Ioannina School of Medicine, Ioannina, Greece; Department of Medical Oncology, Lamia Polyclinic, Lamia, Greece (DM); Biomedical Research Institute, Foundation for Research and Technology—Hellas, Ioannina, Greece (JPAI); Institute for Clinical Research and Health Policy Studies, Department of Medicine, Tufts Medical Center, Tufts University School of Medicine, Boston, MA (JPAI)
Correspondence to: John P. A. Ioannidis, MD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).
Background: Many systemic nonhormonal regimens have been evaluated across several hundreds of randomized trials in advanced breast cancer. We aimed to quantify the relative merits of these regimens in prolonging survival.
Methods: We performed a systematic review of all trials that compared different regimens involving chemotherapy and/or targeted therapy in advanced breast cancer (1973–2007). Regimens were categorized a priori into different treatment types. We performed multiple-treatments meta-analysis and calculated hazard ratios for each treatment category relative to monotherapy with old agents (ie, regimens not including anthracyclines, anthracenediones, vinorelbine, gemcitabine, capecitabine, taxanes, marimastat, thalidomide, trastuzumab, lapatinib, or bevacizumab).
Results: We identified 370 eligible randomized trials (54 189 patients), of which 172 (31 552 patients) compared different types of treatment. Survival data from 148 comparisons pertaining to 128 of the 172 trials (26 031 patients, 22 different types of treatment) were available for inclusion in the multiple-treatments meta-analysis. Compared with single-agent chemotherapy with old nonanthracycline drugs, anthracycline regimens achieved 22%–33% relative risk reductions in mortality (ie, hazard ratio [HR] for standard-dose anthracycline-based combination: 0.67, 95% credibility interval [CrI] 0.57–0.78). Several newer regimens achieved further benefits (eg, HR [95% CrI] 0.67 [0.55–0.81] for single-drug taxane, 0.64 [0.53–0.78] for combination of anthracyclines with taxane, 0.49 [0.37–0.67] for taxane-based combination with capecitabine or gemcitabine), and similar benefits were seen with several regimens including molecular targeted treatments. Most regimens had very similar efficacy profiles (<5% difference in HR) as first- and subsequent-line therapies.
Conclusions: Stepwise improvements in efficacy of chemotherapy and targeted treatments cumulatively have achieved major improvements in the survival of patients with advanced breast cancer. Many options that can be used in first and subsequent lines of therapy have comparable efficacy profiles.
| Context and Caveats Prior knowledge Although many nonhormonal regimens for advanced breast cancer have been evaluated across hundreds of randomized clinical trials, the relative merits of these regimens were not known with precision. Study design Multiple-treatments meta-analysis of survival data based upon direct and indirect comparisons to estimate hazard ratios for different chemotherapy regimens as first- and subsequent-line treatments relative to older nonanthracycline single-agent therapy. Contribution This study quantified the survival gains of 21 different classes of therapy relative to older single-agent therapy. Implications Whether used in first or subsequent lines of therapy, many classes of modern breast cancer therapy, including anthracyclines, taxanes, novel non-taxane agents, and molecular targeted therapies used in the context of single-agent or combination therapy, produce gains in absolute survival over older single agents. Limitations A comprehensive understanding of the effectiveness of newer molecular targeted therapies will require additional trial information. The extent of intertrial variability and its effect on the results of the meta-analysis cannot be known with certainty. From the Editors
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Manuscript received March 24, 2008; revised August 20, 2008; accepted October 16, 2008.
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J Natl Cancer Inst 2008 100: 1741.
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