RESUMEN
This multicenter, open-label, randomized phase II trial compared the efficacy and tolerability of weekly ixabepilone versus the standard 3 weekly dosing regimen. Patients with human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC) were randomly assigned to receive either ixabepilone 16 mg/m(2) as a 1-h intravenous (IV) infusion weekly on days 1, 8, and 15 of a 28-day cycle (1 week off therapy; n = 85), or 40 mg/m(2) as a 3-h IV infusion on day 1 of a 21-day cycle (n = 91), until disease progression or unacceptable toxicity. Randomization was stratified by (i) measurable versus nonmeasurable (evaluable) disease, (ii) ≤two versus >two prior chemotherapy regimens for MBC, and (iii) hormone receptor (HR)-positive versus HR-negative breast cancer. The primary endpoint was rate of progression-free survival (PFS) at 6 months. Of 176 randomized patients, 171 were treated. The 6-month PFS rate was significantly higher in patients treated with ixabepilone every 3 weeks (42.7, 95 % confidence interval [CI] 31.5-53.5) compared with those who received ixabepilone weekly (28.6, 95 % CI 18.9-38.9; log-rank P = 0.03). Every-3-week dosing significantly prolonged median PFS versus weekly dosing (5.3 vs. 2.9 months; log-rank P = 0.05). The every-3-week regimen was associated with higher rates of grade 3/4 toxicities, particularly neutropenia (38.2 vs. 6.1 %) and a higher rate of patient withdrawal due to adverse events. These results suggest that every-3-week ixabepilone is more effective than weekly treatment in MBC, albeit with more toxicity.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Epotilonas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Esquema de Medicación , Epotilonas/efectos adversos , Epotilonas/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Neutropenia/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Resultado del TratamientoRESUMEN
Neuropilin-1 (NRP-1), a co-receptor for VEGF165, is overexpressed in various prostate cancer cell lines and in advanced prostate tumors. However, distribution of the NRP-1 in prostate tumors has not yet been evaluated. Using immunohistochemical analysis, we evaluated 21 archival prostate tumors and 5 benign glands for the expression of NRP-1. In addition, we utilized a quantitative RT-PCR method to examine mRNA expression in 9 additional prostate tumors obtained from radical prostatectomy specimens and compared this expression to the adjacent normal tissue. The RT-PCR analyses demonstrated overexpression of NRP-1 mRNA in malignant tissue samples by 10.0-fold as compared to adjacent normal tissue. By immunohistochemistry, NRP-1 protein was undetected or minimally detected in the epithelial tumor cells. However, NRP-1 immuno-reaction was detected in the surrounding tumor stroma. Variable immuno-reaction for NRP-1 was also seen in the adjacent normal tumor stroma and the stroma of the benign prostate samples. These observations suggest that neuropilin-1 is expressed in the prostatic stromal cells, not epithelial tumor cells, and this expression is significantly increased in the malignant phenotype.