Combination therapy, as compared with anastrozole alone, resulted in a significant improvement in the secondary end point of overall survival by more than 6 months (hazard ratio for death with combination therapy, 0.81). This finding suggests that the combination therapy is more effective than is the sequential use of anastrozole and fulvestrant. Although a substantial proportion of patients in the anastrozole-alone group (41%) who had disease with a good prognosis crossed over to fulvestrant (albeit low-dose fulvestrant), the overall survival for the combined cohort of patients who received anastrozole alone or anastrozole followed by fulvestrant remained inferior to the overall survival for patients who received the combination therapy. It is unclear whether the former group would have fared better if patients who crossed over to fulvestrant had received high-dose fulvestrant.10,12,13 The indirect data that speak to this point are inconsistent. On
the one hand, high-dose fulvestrant was superior to anastrozole as first-line hormonal therapy in a phase 2 trial.13 On the other hand, in the Comparison of Faslodex in Recurrent or Metastatic
Breast Cancer (CONFIRM) trial, high-dose fulvestrant, as compared with low-dose fulvestrant, as second-line endocrine treatment was associated with a nonsignificant median survival benefit
of only 2 months.10