title: Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and meta-analysis of 762,468 patients.
abstract: OBJECTIVE
  Radiotherapy for breast cancer both decreases loco-regional recurrence rates and improves overall survival. However, radiotherapy has also been associated with increased second cancer risk at exposed sites. In this meta-analysis, we estimated the risk of second non-breast cancers after radiotherapy for breast cancer.
  
  
  METHODS
  The databases Medline/Pubmed, Cochrane, Embase and Cinahl were systematically searched, for cohort studies on second cancer after radiotherapy for breast cancer, from inception to August 1st 2013. Included studies were to report the relative risk (RR) of second cancers comparing irradiated female breast cancer patients to unirradiated patients. Primary endpoints were all second non-breast-cancers and second cancers of the lung, esophagus, thyroid and second sarcomas. RRs were pooled using random-effects meta-analysis.
  
  
  RESULTS
  Thirteen studies comprising 762,468 breast cancer patients were included in the meta-analysis. Five or more years after breast cancer diagnosis radiotherapy was significantly associated with an increased risk of second non-breast cancer RR 1.12 (95% confidence interval [CI] 1.06-1.19), second cancer of the lung RR 1.39 (95% CI 1.28-1.51), esophagus RR 1.53 (95% CI 1.01-2.31) and second sarcomas RR 2.53 (95% CI 1.74-3.70). The risk increased over time, and was highest 15 or more years after breast cancer diagnosis, for second lung RR 1.66 (95% CI 1.36-2.01) and second esophagus cancer RR 2.17 (95% CI 1.11-4.25). There was no significant association between radiotherapy and second thyroid cancer.
  
  
  CONCLUSIONS
  Radiotherapy for breast cancer is significantly associated with increased risks of second non-breast cancer, overall and in organs adjacent to the previous treatment fields. Despite a relative small absolute risk, the growing number of long-time survivors after breast cancer warrants the need for normal tissue sparing radiotherapy techniques.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. Electronic address: grantzau@oncology.dk.
authors.forename: Trine
authors.initials: T
authors.lastname: Grantzau
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000532:radiotherapy*; D015331:Cohort Studies; D004938:Esophageal Neoplasms / Q000209:etiology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000532:radiotherapy*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology*; D016609:Neoplasms, Second Primary / Q000209:etiology*; D012307:Risk Factors