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Temporal relationship of post-operative radiotherapy with temozolomide and oncologic outcome for glioblastoma.

ABSTRACT: To determine the impact of delay between surgery and radiotherapy on overall survival (OS) in temozolomide treatmented patients with the incorporation of O6-methylguanine-DNA methyltransferase (MGMT). From 2000 to 2012, 345 consecutive glioblastoma patients were treated with surgery, radiotherapy, and temozolomide at our institution. A Cox-regression model was constructed using significant univariate parameters, known prognostic factors including MGMT, and the interval from surgery to radiotherapy (? 2, 2-5, and ? 6 weeks). Survival rates were calculated by Kaplan-Meier methods. Cox-regression was utilized to calculate adjusted hazard ratios (HR). The median survival for the entire cohort was 12.2 months. The 1 year actuarial OS was 43.1 %, 53.3 %, and 64.3 % (p = 0.11), for intervals from surgery to radiotherapy of ? 2, 2-5, and ? 6 weeks, respectively. Patients radiated within 2 weeks post-surgery were more likely to have older age (p = 0.03), treated with 2D techniques (p < 0.001) and dose <36 Gy (p < 0.001), undergo a biopsy only (p < 0.001), KPS of <70 (p < 0.001), severe pre-radiotherapy neurologic symptoms (p = 0.04), and bilateral disease (p = 0.02). Multivariate analysis including MGMT status demonstrated a significant detriment in delaying radiotherapy (? 2 weeks as reference); 3-5 weeks (HR 2.80 [0.72-10.89], p = 0.14), and >6 weeks (HR 3.76 [1.01-14.57], p = 0.05). We report the first analysis on the survival impact of delaying post-operative radiotherapy for temozolomide treated glioblastoma patients with MGMT information. Our data does not support the OS benefit previously seen in delayed RT when correcting for important covariates. We demonstrate a survival detriment with delaying RT post-surgery greater than 6 weeks on multivariate analysis.

SUBMITTER: Spratt DE

PROVIDER: S-EPMC6683285 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Temporal relationship of post-operative radiotherapy with temozolomide and oncologic outcome for glioblastoma.

Spratt Daniel E DE Folkert Michael M Zumsteg Zachary S ZS Chan Timothy A TA Beal Kathryn K Gutin Philip H PH Pentsova Elena E Yamada Yoshiya Y

Journal of neuro-oncology 20131105 2

To determine the impact of delay between surgery and radiotherapy on overall survival (OS) in temozolomide treatmented patients with the incorporation of O6-methylguanine-DNA methyltransferase (MGMT). From 2000 to 2012, 345 consecutive glioblastoma patients were treated with surgery, radiotherapy, and temozolomide at our institution. A Cox-regression model was constructed using significant univariate parameters, known prognostic factors including MGMT, and the interval from surgery to radiothera ...[more]

PMID: 24190580

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Project description:The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens.From 2003 to 2016, 104 patients ??70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria.Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT?+?TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT?+?TMZ (P?=?0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P?=?0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P?=?0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P?=?0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P?<?0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor.These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

Project description:PurposeBevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Experimental designPatients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.ResultsForty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.ConclusionsThis aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma.

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Temporal relationship of post-operative radiotherapy with temozolomide and oncologic outcome for glioblastoma.

Publications

Temporal relationship of post-operative radiotherapy with temozolomide and oncologic outcome for glioblastoma.

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