title: Radiotherapy effects on early breast cancer survival in observational and randomized studies: a systematic analysis of advantages, disadvantages and differences between the two study types.
abstract: OBJECTIVE
  Treatment-outcome associations often differ substantially between observational studies (OSs) and randomized controlled trials (RCTs). We investigate causes, focusing on radiotherapy (RT) effects in early breast cancer treatment, to better understand each study type's merits.
  
  
  METHODS
  We systematically analyzed three potential causes, by comparing data from a large OS with results from two previously published meta-analyses of RCTs: differences in patient populations combined with heterogeneous treatment effects, non-random treatment decisions in OSs, and differences in therapy administration.
  
  
  RESULTS
  RT-survival associations were considerably stronger in our OS than in the RCTs, e.g., a hazard rate for overall survival after breast-conserving therapy of 0.57 in the OS vs 0.90 in the RCTs. The first proposed reason has limited relevance: patient populations differed considerably, but effect heterogeneity between patient groups was limited. The second reason does explain part of the difference: in the OS treatment decisions (being nonrandomized) and prospects differed with patient characteristics. Notably, patients with early recurrences or mortality are generally excluded from RCTs. Their inclusion in OSs leads to stronger treatment-outcome associations.
  
  
  CONCLUSIONS
  RCTs and OSs each have their own merits. While RCTs have their undisputed benefits, results from OSs that indicate that RT effects in early breast cancer are even stronger than those reported in RCTs should not be ignored.
authors.affiliation: University Medical Centre, Institute for Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Jochem
authors.initials: J
authors.lastname: König
authors.affiliation: University Medical Centre, Institute for Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg-University of Mainz, Mainz, Germany. vanewijk@uni-mainz.de.|Faculty of Economics, Johannes Gutenberg-University of Mainz, Jakob Welder-Weg 4, 55128, Mainz, Germany. vanewijk@uni-mainz.de.
authors.forename: Reyn
authors.initials: R
authors.lastname: van Ewijk
authors.affiliation: Institute of Medical Statistics, Informatics and Epidemiology, University Hospital, Cologne, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kuhr
authors.affiliation: Department of Radiation Oncology, University Medical Centre, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidberger
authors.affiliation: Department of Gynecology and Obstetrics, University of Würzburg, Würzburg, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Wöckel
authors.affiliation: Department of Obstetrics and Gynaecology, University of Ulm Medical School, Ulm, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.affiliation: University Medical Centre, Institute for Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Blettner
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000453:epidemiology / Q000401:mortality* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D015897:Comorbidity; D005260:Female; D006801:Humans; D016015:Logistic Models; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic
keywords: Breast cancer; Observational studies; Radiotherapy; Randomized controlled trials