Showing papers by "Michael D. Prados published in 2002"

Genetic aberrations defined by comparative genomic hybridization distinguish long-term from typical survivors of glioblastoma.

Abstract: Glioblastoma (GBM) remains a highly lethal neoplasm, refractory to current therapies The molecular genetic aberrations most closely related to clinical aggressiveness in GBM have been difficult to identify, perhaps due in part to the short survival range observed in cohorts of GBM patients To address this, we characterized 39 tumors from rare patients (2-5% of all GBM cases) who experienced long-term survival (>3 years) using comparative genomic hybridization as a genome-wide screen We then compared the frequency and type of aberrations with those in tumors from 24 typical or short-term survivors [STSs (<15 years)] Losses of 9p and 10 and simple gains of chromosome 7 showed at least trends toward increased frequency in the STS group Additional aberrations, including loss of 6q and gains of 19q and 20q, were significantly more frequent in the STS group The presence of 19q loss was exclusive to the long-term survivor (LTS) group Multivariate analyses indicated that 6q loss, 10q loss, and 19q gain were associated with short-term survival (all P < 001) The combination of any two of these three aberrations was seen in 16 of 24 STSs but only 1 of 39 LTSs This comparison of rare LTSs with STSs (typical GBM survivors) identified 6q loss, 10q loss, and 19q gain, particularly when two or more of these were present, as most closely associated with aggressive clinical behavior in GBM Loss of 19q may be a marker of long-term survival

Aberrant p53, mdm2, and proliferation differ in glioblastomas from long-term compared with typical survivors.

Abstract: Purpose : Glioblastoma multiforme (GBM) is a highly lethal neoplasm with a median survival of ∼1 year. Only 2–5% of patients originally diagnosed with GBM will survive ≥ 3 years. Whether tumors from these long-term survivors (LTSs) exhibit molecular genetic differences compared with typical GBM survivors is not known. Experimental design : Tumors from 41 patients initially diagnosed with GBM and having survival ≥ 3 years (LTS) was compared with 48 GBMs from short-term survivors (STSs, survival ≤ 1.5 years) for p53 aberrations (expression/mutation), epidermal growth factor receptor overexpression, mdm2 overexpression, and proliferation index. Results : Nuclear p53 expression was significantly more frequent in the LTS group. However, no difference in the rate of p53 mutation was evident. Overexpression of epidermal growth factor receptor was slightly more frequent in the STS patients, but this is not statistically different. mdm2 overexpression was significantly more frequent in the STSs, and this group had a significantly higher median proliferation index. Conclusion : Long-term GBM survivors were more likely to have p53-overexpressing tumors, although a difference in p53 mutation rate could not be detected. They were less likely to exhibit mdm2 overexpression and had a lower proliferation rate compared with typical GBM survivors.

A phase II study of temozolomide in patients with newly diagnosed supratentorial malignant glioma before radiation therapy

Abstract: Temozolomide is a novel second-generation oral alkylating agent with demonstrated efficacy and safety in patients with recurrent glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). A multicenter phase II trial was conducted to determine the efficacy and safety of temozolomide before radiotherapy in patients with newly diagnosed GBM and AA. Fifty-seven patients (51 adult, 6 pediatric) with newly diagnosed supratentorial GBM or AA were treated with temozolomide (200 mg/m ( 2 ) per day for 5 consecutive days every 28 days) for a maximum of 4 cycles. All patients were then treated with external beam radiotherapy. Twenty-two patients (39%) achieved objective response, including 6 (11%) with complete response (CR) and 16 (28%) with partial response (PR). Additionally, 18 (32%) patients had stable disease (SD). Of 21 patients (18 adult, 3 pediatric) with AA, 2 (10%) achieved CR, 5 (24%) achieved PR, and 8 (38%) had SD. Among adult patients with AA, the median progression-free and overall survival rates were 7.6 and 23.5 months, respectively. Among 36 patients (33 adult, 3 pediatric) with GBM, 4 (11%) had CR, 11 (31%) had PR, and 10 (28%) had SD. The median progression-free and overall survival rates among adult patients with GBM were 3.9 and 13.2 months, respectively. Temozolomide was safe and well tolerated in adult and pediatric patients. Grades 3 and 4 adverse events were reported in 16 (28%) and 7 (12%) patients, respectively. Temozolomide was safe and effective in treating newly diagnosed GBM and AA before radiotherapy. This pre-irradiation treatment approach appears promising, but will require additional evaluation in comparative studies.

Phase II study of high central dose Gamma Knife radiosurgery and marimastat in patients with recurrent malignant glioma.

Abstract: Purpose: To assess the outcome of high central dose Gamma Knife radiosurgery plus marimastat in patients with recurrent malignant glioma. Methods and Materials: Twenty-six patients with recurrent malignant glioma were enrolled in a prospective Phase II study between November 1996 and January 1999. The radiosurgery dose was prescribed at the 25–30% isodose surface to increase the dose substantially within the tumor's presumably hypoxic core. Marimastat was administered after radiosurgery to restrict regional tumor progression. Survival was compared with that of historical patients treated at our institution with standard radiosurgery. Results: The median times to progression after radiosurgery for Grade 3 and 4 patients was 31 and 15 weeks, respectively. The corresponding median survival time after radiosurgery was 68 and 38 weeks. The median survival time after radiosurgery in the historical patients was 59 and 44 weeks. Conclusion: The dual strategies of using high central dose radiosurgery to overcome tumor hypoxia together with marimastat to inhibit local tumor invasion may offer a small survival advantage for recurrent Grade 3 tumors; they do not offer an advantage for recurrent Grade 4 tumors.

A phase II trial of thymidine and carboplatin for recurrent malignant glioma: a North American Brain Tumor Consortium Study.

Abstract: This phase II study in recurrent high-grade glioma evaluated the response rate, toxicities, and time to treatment failure of high-dose carboplatin modulated by a 24-h infusion of thymidine (75 g/m(2)). The trial was based on preclinical data and a prior phase I study ( J. Clin. Oncol. 17, 2922-2931, 1999); a phase II recurrent high-grade glioma study was initiated in July of 1998. Thymidine was given over 24 h; carboplatin was given over 20 min at hour 20 of the thymidine infusion. The starting dose of carboplatin had a value of 7 for the area under the curve (AUC), with allowance for dose escalation of 1 AUC unit per cycle if grade 2 toxicity was observed. Treatment cycles were repeated every 4 weeks. Accrual as of September 1999 was 45 patients [4 were unevaluable]: 76% with glioblastoma multiforme (GBM), 20% with anaplastic oligodendroglioma, 2% with mixed type, and 2% with anaplastic astrocytoma. Most patients had prior chemotherapy (78%). As observed in the earlier phase I study (in which carboplatin pharmacokinetics were unaltered by thymidine or antiseizure medications), thymidine was myeloprotective, resulting in a minimal need for dose reduction for patients having a >2 grade toxicity (in only 4% of the courses of treatment). Of 101 total courses, the number of courses (at the AUCs) was 3 (5), 4 (6), 58 (7), 20 (8), 11 (9), and 5 (10). Grade 3 nonhematologic toxicities included headache (4%), altered consciousness (3%), fatigue (1%), and nausea (3%). Responses included 2 partial (1 oligodendroglioma, 1 GBM; 5%); 3 minor (1 anaplastic astrocytoma, 2 GBM; 7.3%); 6 stable disease (14.6%); and 30 progressive disease (73.2%). For GBM patients, median survival was 23 weeks (with a 95% confidence interval of 20 to 50 weeks), and progression-free survival was 8 weeks (with a 95% confidence interval of 7-16 weeks). These results in GBM were comparable to other phase II GBM trials and thus do not represent a therapeutic advance in the treatment of GBM. Taken collectively, however, results are consistent with continued investigation of thymidine in combination with chemotherapeutic agents for high-grade glioma and other malignant diseases. The significant myeloprotection afforded by thymidine may have particular relevance to polychemotherapeutic regimens.