title: Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials.
abstract: BACKGROUND
  Dose-dense chemotherapy has become a mainstay regimen in the adjuvant setting for women with high-risk breast cancer. We performed a systematic review and meta-analysis of the existing data from randomized controlled trials regarding the efficacy and toxicity of the dose-dense chemotherapy approach in nonmetastatic breast cancer.
  
  
  METHODS
  Randomized controlled trials that compared a dose-dense chemotherapy protocol with a standard chemotherapy schedule in the neoadjuvant or adjuvant setting in adult women older than 18 years with breast cancer were identified by searching The Cochrane Cancer Network register of trials, The Cochrane Library, and LILACS and MEDLINE databases (from January 1966 to January 2010). Hazard ratios (HRs) of death and recurrence and relative risks of adverse events were estimated and pooled. All statistical tests were two-sided.
  
  
  RESULTS
  Ten trials met the inclusion criteria and were classified into two categories based on trial methodology. Three trials enrolling 3337 patients compared dose-dense chemotherapy with a conventional chemotherapy schedule (similar agents). Patients who received dose-dense chemotherapy had better overall survival (HR of death = 0.84, 95% confidence interval [CI] = 0.72 to 0.98, P = .03) and better disease-free survival (HR of recurrence or death = 0.83, 95% CI = 0.73 to 0.94, P = .005) than those on the conventional schedule. No benefit was observed in patients with hormone receptor-positive tumors. Seven trials enrolling 8652 patients compared dose-dense chemotherapy with regimens that use standard intervals but with different agents and/or dosages in the treatment arms. Similar results were obtained for these trials with respect to overall survival (HR of death = 0.85, 95% CI = 0.75 to 0.96, P = .01) and disease-free survival (HR of recurrence or death = 0.81, 95% CI = 0.73 to 0.88, P < .001). The rate of nonhematological adverse events was higher in the dose-dense chemotherapy arms than in the conventional chemotherapy arms.
  
  
  CONCLUSIONS
  Dose-dense chemotherapy results in better overall and disease-free survival, particularly in women with hormone receptor-negative breast cancer. However, additional data from randomized controlled trials are needed before dose-dense chemotherapy can be considered as the standard of care.
authors.affiliation: Institute of Oncology, Davidoff Center, Rabin Medical Center, Petah Tikva, Israel.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonilla
authors.forename: Irit
authors.initials: I
authors.lastname: Ben-Aharon
authors.forename: Liat
authors.initials: L
authors.lastname: Vidal
authors.forename: Anat
authors.initials: A
authors.lastname: Gafter-Gvili
authors.forename: Leonard
authors.initials: L
authors.lastname: Leibovici
authors.forename: Salomon M
authors.initials: SM
authors.lastname: Stemmer
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015233:Models, Statistical; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D012107:Research Design; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone