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Abstract : Weekly Neoadjuvant Ixabepilone on Surgical Feasibility and Clinical Outcomes in Locally Advanced High-Risk Prostate Cancer: A Phase II Clinical Trial
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Abstract: Background:Men diagnosed with locally advanced high-risk prostate cancer have up to a 40% risk of biochemical recurrence after prostatectomy. The authors performed a phase II trial of neoadjuvant weekly ixabepilone prior to radical prostatectomy. Methods:Enrollment criteria included patients with high-risk prostate cancer defined by D’Amico criteria or high-volume Gleason 4+3 with a palpable nodule. Patients received ixabepilone 20 mg/m2/week or 16 mg/m2/week for 3 weeks every 28 days for 4 cycles followed by surgery 2-8 weeks later. Results:Sixteen patients were enrolled with a mean age of 56.5 years (range 43-70). PSA values decreased by a mean of 47% in 14/16 men with patients receiving a mean of 8.25 weeks of treatment (range 2-12). Nine men experienced an adverse event requiring dose modification or premature cessation of chemotherapy. Pathologic staging in 9 patients showed T3a, 5 with T3b, and 1 with T2c disease; 8 had R1 disease and 2 demonstrated nodal involvement. Mean operative time, blood loss, and hospital stay were 189 minutes, 184 mL, and 1.5 days, respectively. At median follow-up of 32 months (range 15-45), 4 patients experienced biochemical recurrence. Conclusions: Neoadjuvant weekly ixabepilone had a good PSA response and no increased surgical morbidity; however, a higher dose is associated with significant persistent neuropathy. There were no complete pathologic responses, but biochemical recurrence rate is low. Further assessment of time to treatment failure will require continued, planned follow-up to evaluate the long-term potential clinical benefit of this study. Keywords: Ixabepilone, prostate cancer, neoadjuvant chemotherapy, taxanes, epothilone.Download Full Article |
Abstract : Effects of Nodal Status and Extent of Surgery on Survival in Triple Negative Breast Cancer
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Abstract: Background: Triple Negative Breast Cancer (TNBC) is one of the most aggressive but least understood subtypes of breast cancer. The roles of nodal status and type of surgery while essential in determining the outcomes of patients with TNBC remain controversial and require more examination. Materials and Methods: Clinical and pathological data were retrieved from 1990 until 2001 by retrospective chart review for patients with breast cancer at the American University of Beirut Medical Center. Out of 1455 patients, 524 had complete histological data, of which 138 (26.3%) were diagnosed with TNBC. Median follow up time of patients with TNBC was 3.34 years (Range 0.55 - 10 years). We used the Kaplan-Meier and Cox proportional hazard models to evaluate prognostic effects and estimate hazard ratios (HR). Results: For the 138 patients with TNBC, median age at presentation was 50.91 years (Range 26 - 81). One-year, 5 and 10-year survivals for node-negative patients (N0) were respectively 98.3 %, 91.1% and 74.5 %, compared to 98.5%, 70.3 % and 42.2% for node-positive patients (N1-N3). Numerical nodal staging did not significantly correlate with survival. On multivariate analysis, higher stage (H.R 3.01) and Breast-Conserving Therapy (BCT) had a significant effect on the survival of TNBC patients (H.R 0.195) Conclusion: Lymph node-positivity predicted poorer survival in patients with TNBC. However, within the group of patients with positive LN, the number of positive lymph nodes did not alter survival nor did the tumor size. BCT including radiation therapy had a better effect on survival when compared to mastectomy. Keywords: Triple negative breast cancer, nodal status, breast conservative therapy, modified radical mastectomy, survival.Download Full Article |
Abstract : Is the Neoadjuvant Docetaxel, Cisplatin and 5-Fluorouracil Regimen Superior to Classic Cisplatin and 5-Fluorouracil for Locoregionally Advanced Nasopharyngeal Carcinoma?
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Abstract: Objectives: We retrospectively compared the toxicity and efficacy of two neoadjuvant chemotherapy regimens (docetaxel+cisplatin+5-fluorouracil vs. cisplatin+5-fluorouracil) followed by chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma. Patients and Materials: We analysed 135 patients with stage III and IVA-B nasopharyngeal carcinoma. Forty-four patients were treated with docetaxel+cisplatin+5-fluorouracil and chemoradiotherapy (TPF group), and 91 were treated with cisplatin+5-fluorouracil and chemoradiotherapy (PF group). Chemoradiotherapy was administered with weekly cisplatin. Radical radiotherapy with total doses of 70–74Gy was administered using a conventional technique, over 7 weeks in 2.0Gy/fraction; boost doses of 6–10Gy were administered in 55.6% patients (n=75) with locally advanced cancer. Results: The median follow-up was 46.5 months (range, 9.8–62.8 months), and the follow-up rate was 95%. The TPF group had better 5-year estimated progression-free survival (77.0% vs. 73.5%; P = 0.510) and overall survival than the PF group (80.7% vs. 77.9%, P = 0.446); however, there was no statistically significant difference between the groups. Toxicities in the two groups were similar; grade 3/4 oral mucositis was more common in the TPF group (27.3%) than in the PF group (15.3%) during chemoradiotherapy. Conclusions: The neoadjuvant docetaxel+cisplatin+5-fluorouracil chemotherapy led to satisfactory long-term survival and slight improvement in progression-free survival and overall survival as compared with the classic cisplatin+5-fluorouracil regimen; toxicity was tolerable. However, prospective trials are needed to prove whether docetaxel+cisplatin+5-fluorouracil is a substitute for cisplatin+5-fluorouracil. Keywords: Nasopharyngeal carcinoma, induction-concurrent chemotherapy, docetaxel, cisplatin, 5-fluorouracil.Download Full Article |
Abstract : Vemurafenib (PLX4032, Zelboraf®), a BRAF Inhibitor, Modulates ABCB1-, ABCG2-, and ABCC10-Mediated Multidrug Resistance
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Abstract: In this study, we examined the in vitro effects of vemurafenib, a specific inhibitor of V600E mutated BRAF enzyme, on the response of cells overexpressing the ATP binding cassette (ABC) efflux transporters ABCG2, ABCB1, ABCC1 and ABCC10. Vemurafenib, at 5 µM and 20 µM, produced a significant concentration-dependent increase in the cytotoxicity of paclitaxel in cells overexpressing ABCB1 and ABCC10 and mitoxantrone in cells overexpressing ABCG2. Vemurafenib also significantly enhanced the accumulation of paclitaxel in cell lines overexpressing ABCB1 and ABCC10. Vemurafenib significantly increased the intracellular accumulation of mitoxantrone in cells overexpressing ABCG2. In contrast, vemurafenib did not significantly alter the sensitivity of ABCC1 overexpressing HEK/ABCC1 cells to vincristine. Finally, as determined by Western blotting, vemurafenib (20 µM) did not significantly alter the expression of the proteins for ABCG2, ABCC10 or ABCB1. Thus, vemurafenib most likely reverses multidrug resistance by altering the transport function of these aforementioned ABC transporters, as opposed to affecting the expression of ABC proteins. The docking analysis of vemurafenib with the ABCB1 homology model also suggested that vemurafenib binds to the ABCB1 and ABCG2 drug binding site. These findings suggest that combination of specific inhibitors like vemurafenib with chemotherapeutic drugs may be used to overcome multidrug resistance in cells that overexpress ABCB1, ABCC10 and/or ABCG2 transporters. Keywords: Vemurafenib, ABCC10, ABCG2, MDR.Download Full Article |
