Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BACKGROUND: In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study. PATIENTS AND METHODS: Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations. RESULTS: The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%). CONCLUSIONS: Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education. TRIAL REGISTRATION NUMBER: NCT00863655.

Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: The Zoladex Early Breast Cancer Research Association Study.

PURPOSE: Current adjuvant therapies have improved survival for premenopausal patients with breast cancer but may have short-term toxic effects and long-term effects associated with premature menopause. PATIENTS AND METHODS: The Zoladex Early Breast Cancer Research Association study assessed the efficacy and tolerability of goserelin (3.6 mg every 28 days for 2 years; n = 817) versus cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (six 28-day cycles; n = 823) for adjuvant treatment in premenopausal patients with node-positive breast cancer. RESULTS: Analysis was performed when 684 events had been achieved, and the median follow-up was 6 years. A significant interaction between treatment and estrogen receptor (ER) status was found (P =.0016). In ER-positive patients (approximately 74%), goserelin was equivalent to CMF for disease-free survival (DFS) (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.84 to 1.20). In ER-negative patients, goserelin was inferior to CMF for DFS (HR, 1.76; 95% CI, 1.27 to 2.44). Amenorrhea occurred in more than 95% of goserelin patients by 6 months versus 58.6% of CMF patients. Menses returned in most goserelin patients after therapy stopped, whereas amenorrhea was generally permanent in CMF patients (22.6% v 76.9% amenorrheic at 3 years). Chemotherapy-related side effects such as nausea/vomiting, alopecia, and infection were higher with CMF than with goserelin during CMF treatment. Side effects related to estrogen suppression were initially higher with goserelin, but when goserelin treatment stopped, reduced to a level below that observed in the CMF group. CONCLUSION: Goserelin offers an effective, well-tolerated alternative to CMF in premenopausal patients with ER-positive and node-positive early breast cancer.

[Taxane-based palliative chemotherapy for metastatic breast cancer: matched pair analysis to compare the efficacy and safety of docetaxel and paclitaxel]. / Die palliative Behandlung des metastasierten Mammakarzinoms mit Taxanen: Ein Wirkungsvergleich zwischen Docetaxel und Paclitaxel mittels Matched-Pair-Analyse.

OBJECTIVE: A retrospective comparison of the efficacy and toxicity of docetaxel and paclitaxel in the treatment of metastatic breast cancer (MBC) was conducted based on our institution's experience since 1992. METHODS: Two groups of 43 patients who received a similar chemotherapy regimen containing either docetaxel or paclitaxel were matched for the number of prior treatments. RESULTS: Toxicity was mild in both groups. Tumour growth control, defined as either objective response or stable disease for at least 6 months, was obtained in a significantly higher proportion of patients treated with docetaxel compared with paclitaxel (67 % vs. 44 %, p = 0.001). Moreover, fewer patients progressed during treatment with docetaxel (28 % vs. 53 %, p < 0.001). At a median follow-up of 17 months there was no significant difference between the groups in median progression-free survival (7 vs. 5 months, p = 0.123) or median overall survival (OS) (12 vs. 11 months, p = 0.211). According to the method of Kaplan and Meier estimated OS rates at 1 year (74 % vs. 62 %) and 2 years (50 % vs. 26 %), however, were in favour of docetaxel. In a multivariate analysis only a positive hormone receptor status was significantly associated with improved OS. CONCLUSION: These results suggest that docetaxel may be superior to paclitaxel in the treatment of MBC.

Tandem high-dose chemotherapy in high-risk primary breast cancer: a multivariate analysis and a matched-pair comparison with standard-dose chemotherapy.

Stem cell-supported high-dose chemotherapy (HDCT) is currently being evaluated in patients with high-risk primary breast cancer (HRPBC), as defined by extensive axillary lymph node involvement. Conclusive results from randomized studies with sufficient patient numbers and follow-up are pending. We retrospectively analyzed 144 HRPBC patients enrolled in a single-arm trial of tandem HDCT at the University of Heidelberg to evaluate the prognostic value of nodal ratio, HER2/neu status, and cytokeratin-positive bone marrow cells and to compare the outcomes of these patients with those of a conventionally treated control group of 91 patients matched by nodal ratio, tumor size, combined hormone-receptor status, and HER2/neu status. The tandem HDCT regimen consisted of 2 cycles of induction chemotherapy followed by 2 cycles of blood stem cell-supported high-dose ifosfamide, 12 g/m2; carboplatin, 900 mg/M2; and epirubicin, 180 mg/m2. Conventionally treated patients received a regimen containing anthracycline without taxanes (52 patients) or CMF (cyclophosphamide, methotrexate, and 5-flurouracil; 39 patients). With a median follow-up of 3.8 years, disease-free, distant disease-free, and overall survival rates were 62%, 65%, and 84%, respectively. In univariate analysis, besides the hormone receptor status (P = .007), HER2/neu overexpression was the strongest predictor of earlier death (P = .017). In multivariate analysis, a nodal ratio of > or =0.8 was found to be the only independent predictor of relapse (relative risk [RR] = 2.09; 95% confidence interval [CI], 1.21-3.60; P = .008) and only the absence of hormone receptors was associated with earlier death (RR = 3.59; 95% CI, 1.45-8.86; P = .006). Despite a trend toward later distant relapse after HDCT compared with standard-dose chemotherapy with a median follow-up of 3 years (P = .059), thus far, matched-pair analysis has not demonstrated significantly better survival rates after HDCT in all matched patients (P = .786) or in the subgroups of anthracycline-treated patients and patients with and without overexpression of HER2/neu. So far, the follow-up time has been too short to draw definite conclusions; however, patients with a nodal ratio of > or =0.8, receptor-negative tumors, or HER2/neu overexpression are at high risk for relapse and death, irrespective of the kind of adjuvant chemotherapy.

Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin.

Heparin-induced thrombocytopenia type II is a serious, immune-mediated complication of heparin therapy. Due to its low cross-reactivity with heparin-associated antibodies (10-20%), danaparoid has successfully been administered in these patients. In recent studies, r-hirudin as a potent and specific thrombin inhibitor, was demonstrated to be a safe and effective anticoagulant. We report a pregnant woman with systemic lupus erythematosus and recurrent venous thromboembolism who suffered from heparin-induced thrombocytopenia type II while treated with dalteparin sodium. Positive cross-reactivities with danaparoid were found. Anticoagulation with 15 mg subcutaneous r-hirudin was performed twice daily from the 25th week of pregnancy until delivery. No thromboembolism or bleeding or fetal toxicity of r-hirudin was detected. Recombinant hirudin is a potent and specific thrombin inhibitor that can be used as a safe and effective anticoagulant in pregnancy.