title: Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.
abstract: OBJECTIVE
  To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen.
  
  
  METHODS
  The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication.
  
  
  RESULTS
  MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole.
  
  
  CONCLUSIONS
  Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.
authors.affiliation: Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA. mannb@cder.fda.gov
authors.forename: Bhupinder S
authors.initials: BS
authors.lastname: Mann
authors.forename: John R
authors.initials: JR
authors.lastname: Johnson
authors.forename: Roswitha
authors.initials: R
authors.lastname: Kelly
authors.forename: Rajeshwari
authors.initials: R
authors.lastname: Sridhara
authors.forename: Grant
authors.initials: G
authors.lastname: Williams
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D015519:Bone Density / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004244:Dizziness / Q000139:chemically induced; D004311:Double-Blind Method; D017277:Drug Approval; D005260:Female; D005500:Follow-Up Studies; D006261:Headache / Q000139:chemically induced; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009367:Neoplasm Staging; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use*; D017698:Postmenopause / Q000187:drug effects* / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D012871:Skin Diseases / Q000139:chemically induced; D013629:Tamoxifen / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole