First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. Neoadjuvant chemotherapy in operable breast cancer. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. A phase III randomized study on the sequencing of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Combination chemotherapy for advanced breast cancer: two regimens containing adriamycin. High-dose chemotherapy for breast cancer: the French PEGASE experience.
First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice.
                Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point.
                Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9).
                The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials. Aromatase inhibitors (AIs) are accepted as adjuvant therapy for postmenopausal women (PMW) with hormone-responsive early breast cancer (EBC) with superior efficacy to tamoxifen. However, increased bone loss is associated with AIs.
                PMW with EBC receiving letrozole (2.5 mg/day for 5 years) were randomly assigned to immediate zoledronic acid (ZOL; 4 mg every 6 months) or delayed ZOL (initiated only for fracture or high risk thereof).
                Patients (N = 1065) had a median age of 58 years; 54% had received prior adjuvant chemotherapy. At 36 months, mean change in L2-L4 bone mineral density (BMD) was +4.39% for immediate versus -4.9% for delayed ZOL (P < 0.0001). Between-group differences were 5.27% at 12 months, 7.94% at 24 months, and 9.29% at 36 months (P < 0.0001 for all). At 36 months, the immediate-ZOL group had a significant 41% relative risk reduction for disease-free survival (DFS) events (P = 0.0314). Adverse events are consistent with the known safety profiles of the study drugs.
                At 36 months, immediate ZOL was more effective in preserving BMD during letrozole therapy. Immediate versus delayed ZOL led to significantly improved DFS. Benefits are observed in the context of a favorable, well-established safety profile for letrozole and ZOL. The question of whether platinum-based adjuvant chemotherapy can improve outcomes in patients with early-stage epithelial ovarian cancer is an important one. We carried out a multicenter, open randomized trial to determine whether adjuvant chemotherapy would improve overall survival and prolong recurrence-free survival in women with early-stage epithelial ovarian cancer.
                Between August 1991 and January 2000, 477 patients in 84 centers in five countries were randomly assigned to receive either adjuvant chemotherapy immediately following surgery (n = 241) or no adjuvant chemotherapy until clinically indicated (n = 236). Kaplan-Meier curves of overall survival and recurrence-free survival were compared using the Mantel-Cox version of the log-rank test. All statistical tests were two-sided.
                Women who received adjuvant chemotherapy had better overall survival than women who did not (hazard ratio [HR] of 0.66, 95% confidence interval [CI] = 0.45 to 0.97; P =.03). These results translate into 5-year survival figures of 70% for women who did not receive adjuvant chemotherapy and 79% for women who did receive adjuvant chemotherapy, a difference of 9% (95% CI = 1% to 15%). Adjuvant chemotherapy also improved recurrence-free survival (HR = 0.65; 95% CI = 0.46 to 0.91; P =.01). These results translate into 5-year recurrence-free survival figures of 62% for women who did not receive adjuvant chemotherapy and 73% for women who did receive adjuvant chemotherapy, a difference of 11% (95% CI = 3% to 18%).
                These results suggest that platinum-based adjuvant chemotherapy improves survival and delays recurrence in patients with early-stage ovarian cancer. Primary chemotherapy in localised breast cancer may prevent tumour spread during surgical treatment and reduce proliferation of micrometastases. A randomised clinical trial, in 196 premenopausal and postmenopausal patients with operable (T2-3, N0-1b) breast cancer, was started in November 1983 at the Institut Curie to compare neoadjuvant and adjuvant regimens of chemotherapy with radiotherapy with or without surgery. The patients have been followed up for 35-70 months (median 54). A neoadjuvant group received two monthly cycles of intravenous doxorubicin/cyclophosphamide/5-fluorouracil before locoregional therapy and four cycles subsequently. Six monthly cycles following locoregional therapy were administered to the adjuvant group. Because of inclusion of postmenopausal and/or node-negative patients, compliance was less than optimal in 39 patients who were analysed separately according to actual dose received. Tumour response, evaluated after two cycles of neoadjuvant chemotherapy, was significantly associated with dose (P = 0.003). Survival showed a slight non-significant advantage for the neoadjuvant group. Survival plotted by actual dose was also similar. Neoadjuvant chemotherapy was safe and at least as effective as the adjuvant regimen. Patients have been accrued to a subsequent larger trial of chemotherapy as first-line treatment. To determine whether patients with high-risk metastatic breast cancer draw benefit from combination chemotherapy as first-line treatment.
                A total of 260 women with measurable metastatic breast cancer fulfilling high-risk criteria, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either mitoxantrone 12 mg/m(2) or the combination of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) every 3 weeks. Treatment was continued until complete remission plus two cycles, or until disease progression. In the case of partial remission or stable disease, treatment was stopped after 12 cycles. Second-line treatment was vindesine, mitomycin and prednisolone. Gain from treatment was estimated using a modified Brunner's score composed of time to progression, patients' rating of the treatment benefit, alopecia, vomiting and performance status.
                After recruitment from 1992 to 1997 and observation from 1997 to 1999, the final evaluation showed that single-agent treatment with mitoxantrone does not differ significantly from combination treatment with FEC in terms of response, objective remission rate, remission duration, time to response, time to best response, time to progression or overall survival. There was, however, a significant difference in gain from treatment using a modified Brunner's score favoring the single-agent treatment arm. There was no evidence that any subgroup would fare better with combination treatment.
                No significant difference was detected between the treatment with mitoxantrone as a single agent and the combination of low-dose FEC in terms of response or survival; therefore, the imperative of the necessity of first-line combination chemotherapy for patients with high-risk metastatic breast cancer may be questioned. Since toxicity and quality of life score favored the single-agent mitoxantrone treatment arm, this treatment may be offered to patients preferring quality of life to a potential small prolongation of survival. To compare two different timings of radiation treatment in patients with breast cancer who underwent conservative surgery and were candidates to receive adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy.
                A total of 206 patients who had quadrantectomy and axillary dissection for breast cancer and were planned to receive adjuvant CMF chemotherapy were randomized to concurrent or sequential radiotherapy. Radiotherapy was delivered only to the whole breast through tangential fields to a dose of 50 Gy in 20 fractions over 4 weeks, followed by an electron boost of 10-15 Gy in 4-6 fractions to the tumor bed.
                No differences in 5-year breast recurrence-free, metastasis-free, disease-free, and overall survival were observed in the two treatment groups. All patients completed the planned radiotherapy. No evidence of an increased risk of toxicity was observed between the two arms. No difference in radiotherapy and in the chemotherapy dose intensity was observed in the two groups.
                In patients with negative surgical margins receiving adjuvant chemotherapy, radiotherapy can be delayed to up to 7 months. Concurrent administration of CMF chemotherapy and radiotherapy is safe and might be reserved for patients at high risk of local recurrence, such as those with positive surgical margins or larger tumor diameters. A randomized phase III trial in high-risk breast cancer patients was conducted, to further explore the impact of dose-density in the adjuvant treatment for breast cancer. The safety analysis is presented.
                From October 2000 until June 2005, 1121 node-positive patients were randomized to sequential dose-dense epirubicin 110 mg/m(2) and paclitaxel (Taxol, Bristol Myers-Squibb, Princeton, New Jersey, USA) 250 mg/m(2) (group A), or concurrent epirubicin 83 mg/m(2) and paclitaxel 187 mg/m(2) (group B), both followed by three cycles of 'intensified' combination chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF). Granulocyte colony-stimulating factor was given prophylactically with the dose-dense treatments.
                Median dose intensity of epirubicin and paclitaxel was double in group A, as designed, with significantly less cycles administered at full dose (P < 0.001). Median cumulative dose of all drugs and total treatment duration, however, were identical between groups. Severe taxane-related toxic effects were more frequent in group A, while severe thrombocytopenia was low and present only in group A. There were no differences in the rates of other hematological toxic effects, including febrile neutropenia. The rates of secondary malignancies were low.
                Both regimens as used in the present study are well tolerated and safe. The rates of severe taxane-related toxic effects and thrombocytopenia, although low overall, are significantly increased with the dose-dense sequential regimen. Forty-eight women with advanced metastatic carcinoma of the breast were treated with one of two combination chemotherapy regimens: 1) adriamycin and cyclophosphamide or 2) adriamycin, cyclophosphamide, methotrexate and 5-fluorouracil. The response rate in the two-drug treatment group was 50% and in the four-drug treatment group, 55%. The median duration of response was ten months in both treatment groups. Dramatic responses were seen in patients with visceral metastases. Patients who responded to chemotherapy had a significantly longer survival than nonresponders (p less than 0.01). The long interval between adriamycin doses (six weeks) in the four drug regimen did not adversely effect the response rate--an important finding in view of the dose-related cardiac toxicity of this agent. Early studies of high-dose chemotherapy (HDC) for breast cancer were limited by small numbers and the lack of adequate control groups. The French PEGASE Group was founded to perform larger and properly randomized comparative studies of this approach.
                The program was created to determine the effects of intensive chemotherapy for breast cancer. The seven PEGASE protocols addressed HDC as adjuvant therapy (01 and 06) and as treatment for inflammatory nonmetastatic disease (02, 05, and 07) and metastatic disease (03 and 04). Two of these protocols are ongoing.
                The PEGASE 01 adjuvant therapy trial showed that 3-year disease-free survival was significantly better in the HDC arm but overall survival was unchanged. The ongoing phase III 06 trial is studying a higher dosage regimen. The HDC trials for metastatic and inflammatory nonmetastatic disease are encouraging.
                Many clinicians no longer subscribe to the concept of HDC for breast cancer. Overall outcomes from management of poor-risk breast cancer remain poor, however, and it is possible that some selected subgroups of patients may benefit from such an approach.
This meta-analysis of studies supports the use of taxane containing adjuvant chemotherapy regimens with improvement of overall survival and disease-free survival for women with operable early breast cancer. The review did not identify a subgroup of patients where taxane containing treatment may have been more or less effective. Dosage and scheduling of the taxane drug is not clearly defined and we await results of the next generation of studies to determine the optimal use of taxanes in early breast cancer.