Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial.

CONTEXT: Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available. OBJECTIVE: To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy. DESIGN, SETTING, AND PATIENTS: The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients-Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data. INTERVENTIONS: Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy. MAIN OUTCOME MEASURE: Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy). RESULTS: The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of -17% (95% confidence interval, -26% to -7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001). CONCLUSION: The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00311636.

Role of fulvestrant in the treatment of postmenopausal metastatic breast cancer patients.

INTRODUCTION: Endocrine therapy is considered the cornerstone treatment for postmenopausal women with hormone-receptor positive metastatic breast cancer. Fulvestrant is a selective estrogen receptor down-regulator (SERD) with demonstrated activity and efficacy in the treatment of these patients. AREAS COVERED: The present manuscript aims to review the mechanism of action of fulvestrant, the clinical efficacy data with the use of different dosages and schedules, and finally its role in association with other medications. Expert commentary: Fulvestrant is an active compound with an excellent safety profile for the treatment of women with hormone receptor-positive metastatic breast cancer, The combination of fulvestrant with targeted agents showed increased efficacy and is expected to become a new standard treatment. Results of two clinical trials (i.e. the FALCON and FEVEX trials) are awaited to better clarify the place of fulvestrant in the armamentarium of the available therapies for the treatment of hormone receptor-positive metastatic breast cancer.

Phase II open-label study of bevacizumab combined with neoadjuvant anthracycline and taxane therapy for locally advanced breast cancer.

BACKGROUND: Neoadjuvant anthracycline- and taxane-based chemotherapy is frequently administered in breast cancer. Pathological complete response (pCR) rates vary according to clinical disease stage and biology of breast cancer. The critical role of angiogenesis in the progression of breast cancer, together with significantly improved efficacy when bevacizumab is combined with chemotherapy in the metastatic setting, provides a strong rationale for evaluating the integration of bevacizumab into neoadjuvant chemotherapy regimens. METHODS: A single-arm, multicentre, phase II, open-label study evaluated four 3-weekly cycles of FEC (5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)) followed by 12 cycles of weekly paclitaxel (80 mg/m(2)) in combination with bevacizumab 10 mg/kg every 2 weeks as neoadjuvant therapy for HER2-negative stage III locally advanced or inflammatory breast carcinoma. The primary endpoint was pCR rate. RESULTS: Planned treatment was completed in 49 of the 56 enrolled patients. In the intent-to-treat population, the pCR rate was 21% and the clinical response rate was 59%. Breast-conserving surgery was achieved in 34% of patients. In the subgroup of 15 patients with triple-negative disease, the pCR rate was 47%. Grade 3 adverse events in ≥5% of patients were neutropenia, leucopenia, asthenia, and rash. One case each of hypertensive retinopathy and post-operative wound complication, both after treatment completion, were considered probably related to bevacizumab. There were no treatment-related deaths and no cardiac function abnormalities. CONCLUSIONS: This study indicates that FEC followed by weekly paclitaxel with bevacizumab is an active neoadjuvant regimen for locally advanced breast cancer, with no major safety concerns. CLINICAL TRIAL REGISTRATION: NCT00559845.