title: Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis.
abstract: BACKGROUND
  Aromatase inhibitors are associated with consistent improvements in disease-free survival but not in overall survival. We conducted a literature-based meta-analysis of randomized trials to examine whether the relative toxicity of aromatase inhibitors compared with tamoxifen may explain this finding.
  
  
  METHODS
  We conducted a systematic review to identify randomized controlled trials that compared aromatase inhibitors and tamoxifen as primary adjuvant endocrine therapy in postmenopausal women by searching MEDLINE, EMBASE, and databases of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm associated with one adverse event were computed for prespecified serious adverse events including cardiovascular disease, cerebrovascular disease, bone fractures, thromboembolic events, endometrial carcinoma and other second cancers not including new breast cancer. All statistical tests were two-sided.
  
  
  RESULTS
  Seven trials enrolling 30,023 patients met the inclusion criteria. Longer duration of aromatase inhibitor use was associated with increased odds of developing cardiovascular disease (OR = 1.26, 95% CI = 1.10 to 1.43, P < .001; number needed to harm = 132) and bone fractures (OR = 1.47, 95% CI = 1.34 to 1.61, P < .001; number needed to harm = 46), but a decreased odds of venous thrombosis (OR = 0.55, 95% CI = 0.46 to 0.64, P < .001; number needed to harm = 79) and endometrial carcinoma (OR = 0.34, 95% CI = 0.22 to 0.53, P < .001; number needed to harm = 258). Five years of aromatase inhibitors was associated with a non-statistically significant increased odds of death without recurrence compared with 5 years of tamoxifen alone or tamoxifen for 2-3 years followed by an aromatase inhibitor for 2-3 years (OR = 1.11, 95% CI = 0.98 to 1.26, P = .09).
  
  
  CONCLUSIONS
  The cumulative toxicity of aromatase inhibitors when used as up-front treatment may explain the lack of overall survival benefit despite improvements in disease-free survival. Switching from tamoxifen to aromatase inhibitors reduces this toxicity and is likely the best balance between efficacy and toxicity.
authors: Division of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave, Toronto, ON M5G 2M9, Canada. eitan.amir@uhn.on.ca
authors: Eitan
authors: E
authors: Amir
authors: Bostjan
authors: B
authors: Seruga
authors: Saroj
authors: S
authors: Niraula
authors: Lindsay
authors: L
authors: Carlsson
authors: Alberto
authors: A
authors: Ocaña
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D002318:Cardiovascular Diseases / Q000139:chemically induced; D002561:Cerebrovascular Disorders / Q000139:chemically induced; D017024:Chemotherapy, Adjuvant; D015986:Confounding Factors, Epidemiologic; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000139:chemically induced; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000139:chemically induced; D016017:Odds Ratio; D017698:Postmenopause; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects*; D013923:Thromboembolism / Q000139:chemically induced; D020246:Venous Thrombosis / Q000139:chemically induced
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D013629:Tamoxifen