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  • Chemotherapy  (2)
  • METHYLATION  (2)
  • 1
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; Germany ; TOXICITY ; FOLLOW-UP ; imaging ; GENE ; TISSUE ; PATIENT ; CONTRAST ; TRIAL ; PROMOTER ; AGE ; EFFICACY ; inactivation ; ORGANIZATION ; METHYLATION ; MULTIFORME ; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ; PHASE-II ; ONCOLOGY ; ADULT ; METHYLTRANSFERASE ; GLIOMA ; overall survival ; SCIENCE ; MGMT ; methods ; PLUS ; temozolomide ; PROMOTER METHYLATION ; GLIOBLASTOMA ; indomethacin ; MGMT GENE ; EORTC ; BENEFIT ; Follow up
    Abstract: Purpose: To evaluate the toxicity and efficacy of chemoradiotherapy with temozolomide (TMZ) administered in an intensified 1-week on/1-week off schedule plus indomethacin in patients with newly diagnosed glioblastoma. Patients and Methods: A total of 41 adult patients (median Karnofsky performance status, 90%; median age, 56 years) were treated with preirradiation TMZ at 150 mg/m(2) (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m(2)), maintenance TMZ starting at 150 mg/m(2) using a 1-week on/1-week off schedule, plus maintenance indomethacin (25 mg twice daily). Results: The median follow-up interval was 21.7 months. Grade 4 hematologic toxicity was observed in 15 patients (36.6%). Treatment-related nonhematologic Grade 4-5 toxicity was reported for 2 patients (4.9%). The median progression-free survival was 7.6 months (95% confidence interval, 6.2-10.4). The 1-year survival rate was 73.2% (95% confidence interval, 56.8-84.2%). The presence of O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was associated with significantly superior progression-free survival. Conclusion: The dose-dense regimen of TMZ administered in a 1-week on/1-week off schedule resulted in acceptable nonhematologic toxicity. Compared with data from the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981-22981/CE.3, patients with an unmethylated MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding the median progression-free survival and overall survival. In contrast, data are promising for patients with a methylated MGMT promoter. (C) 2010 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 19836157
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  • 2
    Keywords: radiotherapy ; SURVIVAL ; tumor ; evaluation ; Germany ; TOXICITY ; COMMON ; DIAGNOSIS ; GENE ; TISSUE ; TUMORS ; TIME ; PATIENT ; DNA ; INFECTION ; treatment ; PROGRESSION ; PROMOTER ; EFFICACY ; chemotherapy ; INFECTIONS ; RECURRENT ; METHYLATION ; GLIOMAS ; DNA methyltransferase ; LACKING ; PHASE-II ; ONCOLOGY ; ADULT ; METHYLTRANSFERASE ; GLIOMA ; MALIGNANT GLIOMA ; GRADE ; GENE PROMOTER ; MGMT ; TUMOR TISSUE ; methods ; EVENTS ; temozolomide ; GLIOBLASTOMA-MULTIFORME ; CRITERIA ; USA ; PROMOTER METHYLATION ; O-6-methylguanine ; survival rate ; GLIOBLASTOMA ; PROGRESSION-FREE SURVIVAL ; REGIMEN ; evidence ; MGMT GENE ; O-6-methylguanine-DNA-methyltransferase
    Abstract: Purpose Evaluation of toxicity and efficacy of an alternating weekly regimen of temozolomide administered 1 week on and 1 week off in patients with recurrent glioma. Patients and Methods Ninety adult patients with recurrent gliomas accrued in one center received chemotherapy with temozolomide at 150 mg/ m(2)/ d ( days 1 through 7 and 15 through 21 every 4 weeks) with individual dose adjustments according to hematologic toxicity. Results A total of 906 treatment weeks were delivered. Grade 4 hematotoxicity according to the Common Terminology Criteria for Adverse Events ( CTCAE; version 3.0) was observed in 24 treatment weeks ( 2.6%). CTCAE grade 4 lymphopenia eventually developed in 11 patients ( 12%). There were neither cumulative lymphopenias nor opportunistic infections. The progression-free survival ( PFS) rate at 6 months for glioblastoma patients was 43.8%. The median PFS in these patients was 24 weeks ( 95% Cl, 17 to 26 weeks), the median survival time from diagnosis of progression was 38 weeks ( 95% Cl, 30 to 46 weeks), and the 1-year survival rate from progression was 23%. O-6-methylguanine DNA methyltransferase ( MGMT) gene promoter methylation in the tumor tissue was not associated with longer PFS ( log-rank P = .37). Conclusion These data imply that the alternating weekly schedule is feasible, safe, and effective and clearly warrants investigation in randomized studies. Compared with more protracted low-dose temozolomide schedules, the 1-week-on/ 1-week-off schedule may be less toxic. We provide preliminary evidence that this dose-dense schedule is also active in patients with tumors lacking MGMT gene promoter methylation
    Type of Publication: Journal article published
    PubMed ID: 17664483
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  • 3
    ISSN: 1432-0533
    Keywords: Key words Glioma ; Multidrug resistance ; Chemotherapy ; Endothelial ; Blood brain barrier
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Human malignant gliomas are commonly resistant to chemotherapy. Here, we examined the role of the multidrug resistance (mdr) mechanism in the chemoresistance of these tumors, using a twofold approach: (i) by assessing a possible mdr phenotype before and after chronic drug exposure of glioma cells in vitro, and (ii) by assessing the modulation of expression of the mdr-associated P-glycoprotein (Pgp) using radiotherapy and serial cycles of chemotherapy in human glioblastoma patients in vivo. T98G, and to a lesser degree, LN-229 human malignant glioma cells exhibit a constitutive mdr phenotype as determined by the modulation of dye transport and by the augmentation of chemosensitivity by the mdr antagonist, verapamil. Thus, coexposure to verapamil enhances the cytotoxicity of vincristine, doxorubicin and VM26 in T98G cells and that of vincristine in LN-229 cells. Chronic exposure of the cells to low concentrations of vincristine and doxorubicin, but not VM26, topotecan or BCNU, moderately enhances the mdr-like phenotype, as assessed by drug expulsion assays. However, chronic exposure to increasing drug concentrations does not significantly alter the sensitivity to the respective drugs. These data are consistent with a constitutive, but not drug-inducible, mdr-like drug resistance in glioma cells in vitro. Immunocytochemical analysis of human malignant gliomas in vivo reveals that Pgp expression is more abundant in endothelial cells within the gliomas, than in the glioma cells proper. Importantly, Pgp expression is unaltered by radiochemotherapy, assessed by comparative immunocytochemistry of glioma specimens obtained serially before and after radiochemotherapy. We conclude that (i) glioma cells exhibit constitutive mdr-like drug resistance that is not significantly altered by chronic drug exposure in vitro; (ii) endothelial cells may play an important role in Pgp-mediated drug resistance of gliomas in vivo; (iii) radiotherapy and repeated chemotherapy cycles do not modulate Pgp expression in human malignant gliomas in vivo; (iv) there is preliminary evidence for a non-Pgp, verapamil-sensitive drug transport activity in glioma cells.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-1459
    Keywords: Key words Oligodendroglioma ; Oligoastrocytoma ; PCV ; Chemotherapy ; Brain tumor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Oligodendroglial tumors have been identified as a subgroup of glial neoplasms with a distinctly better response to chemotherapy and overall survival than purely astrocytic gliomas. Here we report our experience with adjuvant postirradiation and preirradiation chemotherapy using procarbazine, lomustine, and vincristine (PCV) in 27 patients with WHO grade II or III oligodendroglioma or oligoastrocytoma. The efficacy of chemotherapy was assessed according to the Macdonald response criteria (complete response, CR; partial response, PR; stable disease, SD; progressive disease, PD) and progression-free survival intervals by computed tomography or magnetic resonance imaging. First, we confirm that PCV salvage therapy for patients progressing after radiotherapy is highly effective (n = 11, 1 CR, 5 PR, 5 SD; median progression-free survival has not yet been reached, but is longer than 18 months). Second, 3 patients who received radiotherapy plus PCV as first-line therapy achieved CR and 2 achieved SD, and all 5 are progression-free with a median follow-up of 12 months. Third, given these encouraging results, 11 patients received postoperative preirradiation PCV chemotherapy and were given radiotherapy only upon progression. Preirradiation PCV chemotherapy was also effective (2 CR, 3 PR, 6 SD; median progression-free survival has not been yet reached, but is longer than 14 months). Patients with anaplastic oligoastrocytomas were as likely to respond to PCV chemotherapy, as were patients with anaplastic oligodendroglioma. Three patients who had previously responded to PCV were successfully treated with a second course of PCV upon recurrence. PCV chemotherapy was also effective in patients with leptomeningeal spread of oligodendrogliomas. A randomized prospective trial is required to compare the effectiveness and neurotoxicity of first-line PCV chemotherapy followed by radiotherapy to the traditional reverse sequence.
    Type of Medium: Electronic Resource
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