title: Systematic Review of the Side Effects Associated With Anti-HER2-Targeted Therapies Used in the Treatment of Breast Cancer, on Behalf of the EORTC Quality of Life Group.
abstract: Targeted therapies (TTs), notably trastuzumab, have improved outcomes for breast cancer characterised by overexpression of human epidermal growth factor receptors including HER2. Compared with chemotherapy treatments, TTs are more specific in their targets and are delivered over longer periods of time, thus presenting different side-effect profiles. The objective of this paper is to systematically review and describe the side effects associated with TTs used in the adjuvant and metastatic settings for HER2+ breast cancer.
  
  
  
  The MEDLINE, EMBASE, CINAHL, Web of Science and Cochrane Library databases were searched from January 2007 to March 2015 to identify clinical trials and prospective studies reporting toxicities associated with TTs (mainly trastuzumab and lapatinib) used without other therapies in the treatment of HER2-positive breast cancer. Two independent reviewers selected papers based on their titles and abstracts. All papers selected by either reviewer were included. A third reviewer extracted and tabulated the relevant data using a data extraction form.
  
  
  
  We identified 5478 papers, of which 299 were reviewed and 18 trials identified involving 6980 patients. A total of 66 side effects were identified, including 46 "patient-based" symptoms and 20 "medically defined" outcomes. Side effects were more common for patients treated with therapies other than trastuzumab or with dual-HER2 regimens and for patients with metastatic disease. Diarrhoea and skin rash were the most prevalent symptoms, experienced by 29 % and 22 % of patients overall, respectively. There were 119 (2 %) cardiac events reported, and these were not exclusive to trastuzumab-treated patients. The majority of side effects (n = 52) were experienced by 1 % or less of patients and were predominantly of grade 1/2 toxicity.
  
  
  
  This systematic review provides a detailed analysis of side effects of HER2+ therapies in a large number of patients included in trials, enabling an accurate estimate of prevalence and a complete understanding of the patients' experience. This will help clinicians and patients in treatment planning.
authors.affiliation: Cancer Sciences, University of Southampton, Southampton, SO16 6YD, UK. S.C.Sodergren@soton.ac.uk.
authors.forename: Samantha C
authors.initials: SC
authors.lastname: Sodergren
authors.affiliation: Cancer Sciences, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Ellen
authors.initials: E
authors.lastname: Copson
authors.affiliation: Cancer Sciences, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Alice
authors.initials: A
authors.lastname: White
authors.affiliation: Health Outcomes Research Unit, Gimema, Italian Group for Adult Hematologic Diseases (GIMEMA), Rome, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Efficace
authors.affiliation: Department of Medical Psychology, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Sprangers
authors.affiliation: Swansea Centre for Health Economics, Swansea University, Swansea, SA2 8PP, UK.
authors.forename: Deborah
authors.initials: D
authors.lastname: Fitzsimmons
authors.affiliation: European Organisation for Research and Treatment of Cancer Quality of Life Department, 1200, Brussels, Belgium.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bottomley
authors.affiliation: Cancer Sciences, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Johnson
mesh_terms: D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D011788:Quality of Life / Q000523:psychology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases