Molecular-Based Recursive Partitioning Analysis Model for Glioblastoma in the Temozolomide Era: A Correlative Analysis Based on NRG Oncology RTOG 0525.
ABSTRACT: Importance:There is a need for a more refined, molecularly based classification model for glioblastoma (GBM) in the temozolomide era. Objective:To refine the existing clinically based recursive partitioning analysis (RPA) model by incorporating molecular variables. Design, Setting, and Participants:NRG Oncology RTOG 0525 specimens (n?=?452) were analyzed for protein biomarkers representing key pathways in GBM by a quantitative molecular microscopy-based approach with semiquantitative immunohistochemical validation. Prognostic significance of each protein was examined by single-marker and multimarker Cox regression analyses. To reclassify the prognostic risk groups, significant protein biomarkers on single-marker analysis were incorporated into an RPA model consisting of the same clinical variables (age, Karnofsky Performance Status, extent of resection, and neurologic function) as the existing RTOG RPA. The new RPA model (NRG-GBM-RPA) was confirmed using traditional immunohistochemistry in an independent data set (n?=?176). Main Outcomes and Measures:Overall survival (OS). Results:In 452 specimens, MGMT (hazard ratio [HR], 1.81; 95% CI, 1.37-2.39; P?
Project description:<h4>Background</h4>Glioblastoma (GBM) is the most common primary malignant brain tumor. Nomograms are often used for individualized estimation of prognosis. This study aimed to build and independently validate a nomogram to estimate individualized survival probabilities for patients with newly diagnosed GBM, using data from 2 independent NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials.<h4>Methods</h4>This analysis included information on 799 (RTOG 0525) and 555 (RTOG 0825) eligible and randomized patients with newly diagnosed GBM and contained the following variables: age at diagnosis, race, gender, Karnofsky performance status (KPS), extent of resection, O6-methylguanine-DNA methyltransferase (MGMT) methylation status, and survival (in months). Survival was assessed using Cox proportional hazards regression, random survival forests, and recursive partitioning analysis, with adjustment for known prognostic factors. The models were developed using the 0525 data and were independently validated using the 0825 data. Models were internally validated using 10-fold cross-validation, and individually predicted 6-, 12-, and 24-month survival probabilities were generated to measure the predictive accuracy and calibration against the actual survival status.<h4>Results</h4>A final nomogram was built using the Cox proportional hazards model. Factors that increased the probability of shorter survival included greater age at diagnosis, male gender, lower KPS, not having total resection, and unmethylated MGMT status.<h4>Conclusions</h4>A nomogram that assesses individualized survival probabilities (6-, 12-, and 24-mo) for patients with newly diagnosed GBM could be useful to health care providers for counseling patients regarding treatment decisions and optimizing therapeutic approaches. Free software for implementing this nomogram is provided: http://cancer4.case.edu/rCalculator/rCalculator.html.
Project description:Importance:The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported. Objective:To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes. Design, Setting, and Participants:Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses. Main Outcomes and Measures:Progression-free survival (PFS) and overall survival (OS). Results:Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P?<?.001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P?<?.001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P?=?.045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P?=?.02). Conclusions and Relevance:In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status. Trial Registration:ClinicalTrials.gov Identifier: NCT00114140.
Project description:Background:We previously reported the unexpected finding of significantly improved survival for newly diagnosed glioblastoma in patients when radiation therapy (RT) was initiated later (>4 wk post-op) compared with earlier (≤2 wk post-op). In that analysis, data were analyzed from 2855 patients from 16 NRG Oncology/Radiotherapy Oncology Group (RTOG) trials conducted prior to the era of concurrent temozolomide (TMZ) with RT. We now report on 1395 newly diagnosed glioblastomas from 2 studies, treated with RT and concurrent TMZ followed by adjuvant TMZ. Our hypothesis was that concurrent TMZ has a synergistic/radiosensitizing mechanism, making RT timing less significant. Methods:Data from patients treated with TMZ-based chemoradiation from NRG Oncology/RTOG 0525 and 0825 were analyzed. An analysis comparable to our prior study was performed to determine whether there was still an impact on survival by delaying RT. Overall survival (OS) was investigated using the Kaplan-Meier method and Cox proportional hazards model. Early progression (during time of diagnosis to 30 days after RT completion) was analyzed using the chi-square test. Results:Given the small number of patients who started RT early following surgery, comparisons were made between >4 and ≤4 weeks delay of radiation from time of operation. There was no statistically significant difference in OS (hazard ratio = 0.93; P = 0.29; 95% CI: 0.80-1.07) after adjusting for known prognostic factors (recursive partitioning analysis and O6-methylguanine-DNA methyltransferase methylation status). Similarly, the rate of early progression did not differ significantly (P = 0.63). Conclusions:We did not observe a significant prognostic influence of delaying radiation when given concurrently with TMZ for newly diagnosed glioblastoma. The effects of early (1-3 wk post-op) or late (>5 wk) initiation of radiation tested in our prior study could not be replicated.
Project description:BACKGROUND:There are controversial results concerning the prognostic implication of TERT promoter mutation in glioma patients concerning MGMT status. In this meta-analysis, we investigated whether there are any interactions of these two genetic markers on the overall survival (OS) of glioma patients. METHODS:Electronic databases including PubMed and Web of Science were searched for relevant studies. Hazard ratio (HR) and its 95% confidence interval (CI) for OS adjusted for selected covariates were calculated from the individual patient data (IPD), Kaplan-Meier curve (KMC), or directly obtained from the included studies. RESULTS:A total of nine studies comprising 2819 glioma patients were included for meta-analysis. Our results showed that TERT promoter mutation was associated with a superior outcome in MGMT-methylated gliomas (HR?=?0.73; 95% CI?=?0.55-0.98; p-value?=?0.04), whereas this mutation was associated with poorer survival in gliomas without MGMT methylation (HR?=?1.86; 95% CI?=?1.54-2.26; p-value <?0.001). TERT-mutated glioblastoma (GBM) patients with MGMT methylation benefited from temozolomide (TMZ) treatment (HR?=?0.33; 95% CI?=?0.23-0.47; p-value <?0.001). MGMT methylation was not related with any improvement in OS in TERT-wild type GBMs (HR?=?0.80; 95% CI?=?0.56-1.15; p-value?=?0.23). CONCLUSIONS:The prognostic value of TERT promoter mutation may be modulated by MGMT methylation status. Not all MGMT-methylated GBM patients may benefit from TMZ; it is possible that only TERT-mutated GBM with MGMT methylation, in particular, may respond.
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:Valproic acid (VA) is an antiepileptic drug (AED) and histone deacetylase (HDAC) inhibitor taken by patients with glioblastoma (GB) to manage seizures, and it can modulate the biologic effects of radiation therapy (RT). We investigated whether VA use during RT for GB was associated with overall survival (OS).Medical records of 544 adults with GB were retrospectively reviewed. Analyses were performed to determine the association of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) class, seizure history, and concurrent temozolomide (TMZ) and AED use during RT with OS.Seizures before the end of RT were noted in 217 (40%) patients, and 403 (74%) were taking an AED during RT; 29 (7%) were taking VA. Median OS in patients taking VA was 16.9 months (vs 13.6 months taking another AED, P=.16). Among patients taking an AED during RT, OS was associated with VA (P=.047; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.27-1.07), and RTOG RPA class (P<.0001; HR, 1.49; 95% CI, 1.37-1.61). Of the 5 most common AEDs, only VA was associated with OS. Median OS of patients receiving VA and TMZ during RT was 23.9 months (vs 15.2 months for patients taking another AED, P=.26). When the analysis was restricted to patients who received concurrent TMZ, VA use was marginally associated with OS (P=.057; HR, 0.54; 95% CI, -0.09 to 1.17), independently of RTOG RPA class and seizure history.VA use during RT for GB was associated with improved OS, independently of RTOG RPA, seizure history, and concurrent TMZ use. Further studies of treatment that combines HDAC inhibitors and RT are warranted.
Project description:Background and objective:Promoter status of O6-methylguanine-DNA methyltransferase (MGMT) has been widely established as a clinically relevant factor in glioblastoma (GBM) patients. However, in addition to varied therapy schedule, the prognosis of GBM patients is also affected by variations of age, race, primary or recurrent tumor. This study comprehensively investigated the association between MGMT promoter status and prognosis in overall GBM patients and in different GBM subtype including new diagnosed patients, recurrent patients and elderly patients. Methods:A comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients. Results:Totally, 66 studies including 7,886 patients met the inclusion criteria. Overall GBM patients with a methylated status of MGMT receiving temozolomide (TMZ)-containing treatment had better overall survival (OS) and progression-free survival (PFS) [OS: hazard ratio (HR)?=?0.46, 95% confidence interval (CI): 0.41-0.52, p?<?0.001, Bon?=?0.017; PFS: HR?=?0.48, 95% CI 0.40-0.57, p?<?0.001, Bon?=?0.014], but no significant advantage on OS or PFS in GBM patients with TMZ-free treatment was observed (OS: HR?=?0.97, 95% CI 0.91-1.03, p?=?0.08, Bon?=?1; PFS: HR?=?0.76, 95% CI 0.57-1.02, p?=?0.068, Bon?=?0.748). These different impacts of MGMT status on OS were similar in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM. Among patients receiving TMZ-free treatment, survival benefit in Asian patients was not observed anymore after Bonferroni correction (Asian OS: HR?=?0.78, 95% CI 0.64-0.95, p?=?0.02, Bon?=?0.24, I2?=?0%; PFS: HR?=?0.69, 95% CI 0.50-0.94, p?=?0.02, Bon?=?0.24). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment. Conclusion:The meta-analysis highlights the universal predictive value of MGMT methylation in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM patients. For elderly methylated GBM patients, TMZ alone therapy might be a more suitable option than radiotherapy alone therapy. Future clinical trials should be designed in order to optimize therapeutics in different GBM subpopulation.
Project description:Abstract BACKGROUND Depatuxizumab-mafodotin is an EGFR-directed monoclonal antibody that targets activated EGFR (wild type or EGFRvIII) conjugated to a microtubule inhibitor. EGFRamp correlated with recurrent GBM response in a phase I trial (M12-356, NCT01800695), thus becoming a centrally determined inclusion criterion in an ensuing phase II/III randomized study for newly diagnosed disease now accruing (RTOG 3508, M13-813, NCT02573324). Centrally detected EGFRvIII mutation and MGMT promoter methylation are also stratification factors in RTOG 3508 to balance randomization for biomarkers of potential predictive or prognostic significance. Allowing use of locally determined molecular profiling may reduce accrual barriers by avoiding added time of tissue shipping and repeat central testing. However, discordant results between local and central tests could confound interpretation of clinical trial results. Therefore, we compared local vs. central biomarker results among patients screened for M12-356 or RTOG 3508 at Columbia University Medical Center (CUMC). METHODS We retrospectively tabulated local and central EGFRamp, EGFRvIII, and MGMT results. EGFRamp was analyzed by FISH/CISH and EGFRvIII and MGMT by PCR, although the assays for each differed slightly between laboratories. RESULTS 109 GBMs were molecularly profiled from 73 patients who underwent 1–4 resection(s) and screened for M12-356 (n=44) or RTOG 3508 (n=29) at CUMC. EGFRamp, EGFRvIII, and MGMT promoter methylation each was observed in 54, 36, and 27% of tumors tested locally vs. 68, 33, and 43% centrally, respectively. Concordance between laboratories was observed 88%, 86%, and 61%. CONCLUSIONS EGFRamp and EGFRvIII results were mainly concordant (over 85%) between local and central laboratories. EGFRamp frequency was higher centrally, likely biased by investigators who preferentially sent cases known to harbor EGFRamp locally for central testing. Of concern, MGMT results were discordant in 39%. Allowing local MGMT testing for stratification could unacceptably imbalance randomization if confirmed in a larger dataset.
Project description:O6-methylguanine-DNA methyltransferase (MGMT) is an independent predictor of therapeutic response and potential prognosis in patients with glioblastoma multiforme (GBM). However, its significance of clinical prognosis in different continents still needs to be explored.To explore the effects of MGMT promoter methylation on both progression-free survival (PFS) and overall survival (OS) among GBM patients from different continents, a systematic review of published studies was conducted.A total of 5103 patients from 53 studies were involved in the systematic review and the total percentage of MGMT promoter methylation was 45.53%. Of these studies, 16 studies performed univariate analyses and 17 performed multivariate analyses of MGMT promoter methylation on PFS. The pooled hazard ratio (HR) estimated for PFS was 0.55 (95% CI 0.50, 0.60) by univariate analysis and 0.43 (95% CI 0.38, 0.48) by multivariate analysis. The effect of MGMT promoter methylation on OS was explored in 30 studies by univariate analysis and in 30 studies by multivariate analysis. The combined HR was 0.48 (95% CI 0.44, 0.52) and 0.42 (95% CI 0.38, 0.45), respectively.In each subgroup divided by areas, the prognostic significance still remained highly significant. The proportion of methylation in each group was in inverse proportion to the corresponding HR in the univariate and multivariate analyses of PFS. However, from the perspective of OS, compared with data from Europe and the US, higher methylation rates in Asia did not bring better returns.
Project description:The prognostic value of the status of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation measured by pyrosequencing assay (PSQ) among glioblastoma (GBM) patients was examined in meta-analysis.Eligible studies that reported the association between the status of MGMT promoter methylation by PSQ and prognostic value of GBM patients from three electronic databases, like PubMed, EMBASE, and Cochrane library were involved in meta-analysis. Using Stata 11.0, the summarized hazard ratios (HRs) for overall survival (OS) and the progression-free survival (PFS) with 95 % confidence interval (CI) were calculated.Eleven studies were included to evaluate the relationship between the status of MGMT promoter methylation and GBM patients' survival. Overall, regardless of the cut-off value of methylation status of MGMT promoter by PSQ, methylated-positive patients were evidently associated with an improved HRs for OS (HRs?=?0.50, 95 % CI?=?0.35-0.66). For summary, progression-free survival (PFS) from four studies, the prognostic effect was also found (HRs?=?0.56, 95 % CI?=?0.32-0.80).Methylation positivity of MGMT promoter by PSQ was related to an increased survival in GBM patients. Thus, the status of MGMT promoter methylation by PSQ might be used to be a prognostic biomarker, and GBM patients might have a vested interest in clinical application of standardized PSQ.