Search

Postmenopausal women with hormone receptor-positive advanced breast cancer are candidates for endocrine therapy. As the disease will eventually progress in most patients, it is important to investigate agents with novel modes of action to reduce the likelihood of treatment cross-resistance. Fulvestrant is an estrogen receptor antagonist with no known agonist effects that has been shown to be as effective as anastrozole following failure on tamoxifen, at the approved dose of 250 mg/mo. However, pharmacokinetic modelling and evidence of clinical efficacy in early trials, together with the favorable tolerability profile of fulvestrant 250 mg, led to suggestions that increasing the fulvestrant dose would lead to an improved benefit-risk profile. This review describes the rationale behind the development of a 500 mg/mo higher dose of fulvestrant and details relevant clinical trials, including the pivotal phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study. CONFIRM demonstrated a significant improvement in progression-free survival for fulvestrant 500 mg versus 250 mg in postmenopausal patients who had progressed on previous endocrine therapy. Here, we present and discuss a pooled safety analysis of CONFIRM and three further clinical studies demonstrating fulvestrant 500 mg to be well-tolerated with no evidence of dose-related adverse events. Overall, these data indicate an improved benefit-risk profile for fulvestrant 500 mg versus 250 mg following failure on prior endocrine therapy, and suggest that fulvestrant 500 mg may be considered in future as initial endocrine treatment for advanced breast cancer., (Copyright © 2011. Published by Elsevier Inc.)

Purpose: Fulvestrant is at least as effective as anastrozole in the treatment of postmenopausal women with advanced breast cancer whose disease has previously progressed or recurred on antiestrogen therapy. Pharmacokinetic data have shown that, at the approved dose (250 mg/month), it takes approximately 3-6 months for fulvestrant to reach steady-state levels. Theoretically, a more rapid attainment of steady state might reduce the number of early progressions. A pharmacokinetic model simulating plasma concentrations expected to be achieved with a fulvestrant loading dose (LD) regimen suggested that steady state might be achieved earlier with the LD. The aim of this study was to characterize the pharmacokinetics of the fulvestrant LD regimen. This pharmacokinetic substudy was conducted within a phase III trial, EFECT (Evaluation of Fulvestrant versus Exemestane Clinical Trial), comparing fulvestrant with exemestane in postmenopausal women with hormone-sensitive advanced breast cancer whose disease had progressed or recurred following nonsteroidal aromatase inhibitor treatment., Patients and Methods: Patients received fulvestrant intramuscularly using a LD regimen of 500 mg on day 0, 250 mg on days 14 and 28, and then 250 mg each month thereafter. Blood samples were collected throughout the first month and on day 28 of each subsequent month. Plasma fulvestrant concentrations were determined by highperformance liquid chromatography-mass spectrometry, and pharmacokinetic parameters were estimated with nonlinear mixed-effects modeling., Results: Thirty-seven patients receiving fulvestrant were enrolled into the pharmacokinetic substudy, and 269 fulvestrant plasma concentrations were recorded. Maximum fulvestrant concentration (19.7 ng/mL) was observed at an average of 12 days within the first month and maintained at 12-15 ng/mL throughout the remainder of the dosing period., Conclusion: Steady-state plasma levels were attained within the first month of treatment with fulvestrant LD, in line with the predictions of the pharmacokinetic model.

Background: The objective of this study was to review the need for radiotherapy or not in patients with occult primary breast cancer presenting with axillary metastases treated with breast conservation usually with no surgery to the breast., Methods: From 1975 to 2001, 58 patients were treated with axillary lymphadenopathy from a cryptic primary breast carcinoma. After clinical and radiological assessment, 29 patients retained a diagnosis of occult primary breast carcinoma. Clinical and pathological data were collected retrospectively on the 29 patients and survival was calculated from the date of initial diagnosis using the Kaplan-Meier method. The median follow-up was 44 months., Results: Median age at diagnosis was 57 years (range 28-81 years). Sixteen patients had radiotherapy to the ipsilateral breast. Eleven patients received no local therapy to the ipsilateral breast and two patients had quadrantectomies which were negative for malignancy. Locoregional relapse occurred in 12.5% of patients who had received radiotherapy and 69% of those who had not received any radiotherapy (P=0.02). Fifty-seven per cent of patients having a local relapse were salvaged with further surgery. The eventual breast conservation rate was 93%. Patients who received radiotherapy to the breast had significantly improved relapse-free survival (HR=0.31; P=0.04) and local relapse-free survival (HR=0.09; P=0.004). There were no significant differences in overall survival between those patients who had breast irradiation and those who did not (HR 0.91; 95% CI 0.18-4.5)., Conclusion: Occult primary carcinoma with axillary metastases can be treated successfully with breast preservation but radiotherapy to the breast is necessary to minimize the risk of locoregional recurrence.