Showing papers by "Roger Stupp published in 2008"

Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity

Abstract: Resistance to alkylating agents via direct DNA repair by O(6)-methylguanine methyltransferase (MGMT) remains a significant barrier to the successful treatment of patients with malignant glioma. The relative expression of MGMT in the tumor may determine response to alkylating agents, and epigenetic silencing of the MGMT gene by promoter methylation plays an important role in regulating MGMT expression in gliomas. MGMT promoter methylation is correlated with improved progression-free and overall survival in patients treated with alkylating agents. Strategies to overcome MGMT-mediated chemoresistance are being actively investigated. These include treatment with nontoxic pseudosubstrate inhibitors of MGMT, such as O(6)-benzylguanine, or RNA interference-mediated gene silencing of MGMT. However, systemic application of MGMT inhibitors is limited by an increase in hematologic toxicity. Another strategy is to deplete MGMT activity in tumor tissue using a dose-dense temozolomide schedule. These alternative schedules are well tolerated; however, it remains unclear whether they are more effective than the standard dosing regimen or whether they effectively deplete MGMT activity in tumor tissue. Of note, not all patients with glioblastoma having MGMT promoter methylation respond to alkylating agents, and even those who respond will inevitably experience relapse. Herein we review the data supporting MGMT as a major mechanism of chemotherapy resistance in malignant gliomas and describe ongoing studies that are testing resistance-modulating strategies.

Stem Cell–Related “Self-Renewal” Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma

Abstract: Purpose Glioblastomas are notorious for resistance to therapy, which has been attributed to DNA-repair proficiency, a multitude of deregulated molecular pathways, and, more recently, to the particu...

Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3

Abstract: Summary Background A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy in the treatment of patients with newly diagnosed glioblastoma significantly improved survival. We aimed to undertake an exploratory subanalysis of the EORTC and NCIC data to confirm or identify new prognostic factors for survival in adult patients with glioblastoma, derive nomograms that predict an individual patient's prognosis, and suggest stratification factors for future trials. Methods Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase ( MGMT ) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care. Findings Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT , better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator. Interpretation MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.

Phase II Study of Imatinib in Patients With Recurrent Gliomas of Various Histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study

Abstract: Purpose To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. Patients and Methods This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. Results A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor–A or –B were found.

Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker.

Abstract: Silencing of O6-methylguanine-DNA methyltransferase (MGMT) protein expression because of MGMT gene promoter hypermethylation is considered to be associated with postoperative chemoradiotherapy benefits in glioblastoma multiforme (GBM) patients. The objective of this study was to clarify the usability of MGMT immunohistochemistry (IHC) as a clinical biomarker. We immunostained a tissue microarray containing biopsy samples of 164 GBM patients from the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada (EORTC/NCIC) trial 26981/22981 using two commercial anti-MGMT antibodies (clones MT3.1 and MT23.2). Immunostaining results were semiquantitatively evaluated by four observers from three neuropathological laboratories using a predefined algorithm. We analyzed (i) inter- and intraobserver agreement on MGMT expression (kappa statistics); (ii) correlation of MGMT expression with MGMT promoter methylation status (kappa statistics); and (iii) correlation of MGMT expression with patient outcome (log-rank test). Interobserver agreement on MGMT expression varied from slight to almost perfect, whereas intraobserver agreement ranged from substantial to almost perfect. MGMT expression showed poor to moderate correlation with MGMT promoter methylation status. We found no significant association of MGMT expression with patient outcome. In our hands, observer variability as well as lack of association with the MGMT promoter methylation status and patient survival impeded the use of anti-MGMT immunohistochemistry as a clinical biomarker for routine diagnostic purposes.

Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme

Abstract: Background: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent αvβ3 and αvβ5 integrin inhibitor. Objective: To summarize the preclinical and clinical experience with cilengitide for GBM. Methods: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. Results/conclusions: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.

Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments

Abstract: Despite advances in diagnosis and treatment made over the past two decades, high-grade gliomas are still incurable neoplasms. Moreover, after failing adjuvant therapy, few active treatments are available. In this setting, novel agents, such as new chemotherapy compounds and anticancer agents against specific molecular targets, have therefore been investigated. Epidermal growth factor receptor (EGFR) is an intriguing target in high-grade gliomas because it is frequently overexpressed due to amplification of the EGFR gene. Gefitinib and erlotinib act as ATP mimetic agents, binding to the cytoplasmic ATP pocket domain and blocking receptor phosphorylations and, thereby, EGFR-mediated activation of downstream pathways. These drugs have been evaluated in several clinical trials treating recurrent high-grade gliomas with contrasting results. Retrospective correlative analyses generated a plethora of putative predictive factors of activity of EGFR tyrosine kinase inhibitors. The first generations of studies on EGFR inhibitors have not found significant activity of these agents in high-grade gliomas. Furthermore, no clear molecular or clinical predictors have been identified. As with other targeted agents, prospective trials using specific criteria and standardized methods to evaluate tissue biomarkers are required to find predictors of EGFR inhibitors activity in high-grade glioma patients.

A novel tool to analyze MRI recurrence patterns in glioblastoma

Abstract: At least 10% of glioblastoma relapses occur at distant and even contralateral locations. This disseminated growth limits surgical intervention and contributes to neurological morbidity. Preclinical data pointed toward a role for temozolomide (TMZ) in reducing radiotherapy-induced glioma cell invasiveness. Our objective was to develop and validate a new analysis tool of MRI data to examine the clinical recurrence pattern of glioblastomas. MRIcro software was used to map the location and extent of initial preoperative and recurrent tumors on MRI of 63 patients in the European Organisation for Research and Treatment of Cancer (EORTC) 26981/22981/National Cancer Institute of Canada (NCIC) CE.3 study into the same stereotaxic space. This allowed us to examine changes of site and distance between the initial and the recurrent tumor on the group level. Thirty of the 63 patients were treated using radiotherapy, while the other patients completed a radiotherapy-plus-TMZ treatment. Baseline characteristics (median age, KPS) and outcome data (progression-free survival, overall survival) of the patients included in this analysis resemble those of the general study cohort. The patient groups did not differ in the promoter methylation status of methyl guanine methyltransferase (MGMT). Overall frequency of distant recurrences was 20%. Analysis of recurrence patterns revealed no difference between the groups in the size of the recurrent tumor or in the differential effect on the distance of the recurrences from the preoperative tumor location. The data show the feasibility of groupwise recurrence pattern analysis. An effect of TMZ treatment on the recurrence pattern in the EORTC 26981/22981/NCIC CE.3 study could not be demonstrated.

Tenascin‐W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients

Abstract: Tenascins are extracellular matrix proteins present during the development of organisms as well as in pathological conditions. Tenascin-W, the fourth and last member of the tenascin family remains the least well-characterized one. Our study aimed to evaluate the potential significance of tenascin-W as cancer biomarker by monitoring its presence in the serum of colorectal and breast cancer patients and its expression in colorectal tumor tissues. To measure serum tenascin-W levels, a sensitive sandwich-ELISA was established. Mean tenascin-W concentration in sera of patients with nonmetastatic colorectal cancer at time of diagnosis was highly increased compared to that of healthy volunteers. A similar tendency was observed for tenascin-C in the same patient cohort. However, the increase was much more striking for tenascin-W. We also detected elevated tenascin-W levels in sera of breast cancer patients. Furthermore, we could show a prominent expression of tenascin-W in extracts from colorectal tumor tissues by immunoblot analysis, whereas tenascin-W was not detectable in the corresponding normal colon mucosa. To confirm the western blot results, we performed immunohistochemistry of frozen sections of the same patients as well as of an additional, independently chosen collection of colorectal cancer tissues. In all cases, similarly to tenascin-C, tenascin-W was detected in the tumor stroma. Our results reveal a clear association between elevated levels of tenascin-W and the presence of cancer. These results warrant further studies to evaluate the potential value of serum and tissue tenascin-W levels as diagnostic, prognostic or monitoring biomarker in colorectal, breast and possibly other solid cancers.

Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study

Abstract: BACKGROUND. The study aimed to compare the cost-effectiveness of concomitant and adjuvant temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma multiforme versus initial radiotherapy alone from a public health care perspective. METHODS. The economic evaluation was performed alongside a randomized, multicenter, phase 3 trial. The primary endpoint of the trial was overall survival. Costs included all direct medical costs. Economic data were collected prospectively for a subgroup of 219 patients (38%). Unit costs for drugs, procedures, laboratory and imaging, radiotherapy, and hospital costs per day were collected from the official national reimbursement lists based on 2004. For the cost-effectiveness analysis, survival was expressed as 2.5 years restricted mean estimates. The incremental cost-effectiveness ratio (ICER) was constructed. Confidence intervals for the ICER were calculated using the Fieller method and bootstrapping. RESULTS. The difference in 2.5 years restricted mean survival between the treatment arms was 0.25 life-years and the ICER was €37,361 per life-year gained with a 95% confidence interval (CI) ranging from €19,544 to €123,616. The area between the survival curves of the treatment arms suggests an increase of the overall survival gain for a longer follow-up. An extrapolation of the overall survival per treatment arm and imputation of costs for the extrapolated survival showed a substantial reduction in ICER. CONCLUSIONS. The ICER of €37,361 per life-year gained is a conservative estimate. We concluded that despite the high TMZ acquisition costs, the costs per life-year gained are comparable to accepted first-line treatment with chemotherapy in patients with cancer.

Valproic acid related idiosyncratic drug induced hepatotoxicity in a glioblastoma patient treated with temozolomide

Abstract: Glioblastoma patients undergoing treatment with surgery followed by radiation and temozolomide chemotherapy often develop a state of immunosuppression and are at risk for opportunistic infections and reactivation of hepatitis and herpes viruses. We report the case of a 48-year-old glioblastoma patient who developed acute cholestatic hepatitis with hepatic failure during adjuvant treatment with temozolomide and the integrin inhibitor cilengitide. A viral hepatitis was excluded and valproic acid treatment was stopped. Upon normalisation of the liver tests, temozolomide treatment was resumed without perturbation of the liver tests. Valproic acid related idiosyncratic drug induced hepatotoxicity should be considered as a differential diagnosis in glioblastoma patients undergoing adjuvant therapy.

Management of malignant glioma--quo vadis?

Abstract: dence that the outcomes measured in the setting of clinical trials can indeed be reproduced in real life. Similarly, the side effects of this treatment regimen remain mild to moderate. Yaman et al. report improved progression free survival and overall survival for their glioblastoma population compared to those published in the phase III trial, even though cross-trial comparisons have to be cautioned, as well as comparisons between a phase III trial and a single-arm retrospective review [4]. The authors speculate about reasons for improved outcome, notably prolonged administration of TMZ for more than 6 cycles in two thirds of the patients while unfortunately ignoring established clinical prognostic factors and omitting to analyze molecular markers [9, 10]. For instance, the patient population reported here is almost 10 years younger than in the pivotal TMZ trials. In this study almost 95% of the patients had debulking surgery (compared to 80% in other reports) and the percentage of patients requiring steroids for symptom control was also much lower. No effort was made to analyze MGMT, the strongest variable of outcome in previous reports. Nevertheless, the authors raise a number of important questions: The role of intensified TMZ administration schedules will be answered soon by the ongoing RTOG0525/EORTC 26052–22053 Intergroup trial. The accrual goal of over 1,100 patients will be reached in June 2008. In this protocol patients are stratified by MGMT promoter methylation status, and then randomized after the end of TMZ/RT to either standard dose (daily × 5/28 days) maintenance therapy versus dosedense (21/28 days). It will also allow confirming the predictive value of MGMT status within a prospective trial. Controversy remains about the optimal duration of TMZ treatment. In the randomized EORTC/NCIC (European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada) landmark phase III trial [4], and in the preceding phase II trial [3], temozolomide was administered for a total of maximum 6 adjuvant (maintenance) cycles After years of disappointment and nihilism, treatment of glioblastoma has emerged as a worthwhile and rewarding endeavor. This does not mean patients suffering from malignant primary brain tumors are all of a sudden cured or carry an excellent prognosis. However, persistent research, rational development of new agents, systematic clinical investigation and multimodality treatments have led to tangible improvements in outcome and quality of life of patients, better understanding of the disease(s) and renewed interest in further investigation. Temozolomide (TMZ) has emerged from mastering of chemistry and rational drug design as a modestly active agent against recurrent glioma (reviewed in [1]). Subsequent academic investigation developed alternative administration schedules, notably prolonged continuous TMZ exposure allowing for higher dose intensity and potentially increased efficacy by exhausting the endogenous methyl-guanine methyl-transferase (MGMT) reservoir [2]. As first line treatment of glioblastoma, concomitant administration of TMZ and radiotherapy followed by up to 6 cycles of maintenance TMZ (TMZ/RT → TMZ) have led to prolonged survival as repeatedly shown in phase II and phase III clinical trials [3–5]. Importantly, correlative science has demonstrated that MGMT gene promoter methylation status is an important predictive marker for outcome [6, 7]. In this issue of ONKOLOGIE, Yaman and colleagues report on their experience of treating patients with glioblastoma and anaplastic astrocytoma with the current standard of care of TMZ/RT followed by TMZ as a first line of treatment [8]. They retrospectively analyzed the outcome of 64 patients with glioblastoma or anaplastic astrocytoma treated between 2005 and 2007. They define the eligibility criteria, although they do not provide assurance that all patients diagnosed during that time were evaluated, and data are presented clearly. Their publication confirms the wide applicability of the established treatment in the setting of routine practice and thus provides evi-

Phase II trial of the epothilone analog sagopilone (ZK219477; ZK EPO) in patients with recurrent glioblastoma: Initial report of the EORTC study 26061

Abstract: 2015 Background: Sagopilone is a fully synthetic analog of epothilone B. It inhibits microtubule depolarization and induces cell cycle arrest. Not a substrate for ABCB1, good penetration into normal brain is expected. In orthotopically implanted brain tumor models it has demonstrated antitumor activity. This early clinical trial aims at evaluating the efficacy of sagopilone in recurrent glioblastoma, the success rate as a composite of response or progression-free survival at 6 months [PFS-6] is the primary endpoint. Methods: Pts with measurable first recurrence or progressive disease after ≥ 3 mo from the end of radiochemotherapy were eligible, if WHO performance status [PS] ≤ 2, no significant co-morbidity and adequate hematological, liver and renal function tests. Sagopilone (16mg/m²) was administered as 3 h infusion every 3 wks. Response was assessed every 2 cycles (6 wks). Fleming's one stage design was selected assuming: P0, unacceptable success rate=8%; P1, target success rate=23%; if ≥ 5 successes ...

The EORTC QLQ-BN20 questionnaire for assessing the health-related quality of life (HRQoL) in brain cancer patients: A phase IV validation study on behalf of the EORTC QLG, BCG, ROG, NCIC-CTG

Abstract: 2041 Background: While new brain cancer therapies may help extend survival, both the disease and its treatment can have substantial impact on HRQoL. In this analysis we evaluated the psychometric properties of the EORTC QLQ-BN20, a brain cancer specific HRQoL questionnaire. Methods: Data were derived from two completed phase III EORTC / NCIC clinical trials including 891 brain cancer patients from 119 centers in 15 countries. Experimental treatments were surgery followed by radiotherapy and adjuvant PCV chemotherapy for highly anaplastic oligodendroglioma; and surgery followed by concomitant radiotherapy plus temozolomide (TMZ) chemotherapy and adjuvant TMZ chemotherapy for glioblastoma multiforme. Standard treatment consisted of surgery and postoperative radiotherapy alone. HRQoL assessments were performed before randomization, 1 month after ending radiation, and every 3 months after the start of chemotherapy. The BN20 scoring transforms 20 questions into 11 scales to assess neurological deficits (visual...

Malignant Glioma: Chemotherapy Perspective

Abstract: Despite optimal surgery and adjuvant radiotherapy, malignant gliomas almost always recur. One cause of failure is explained by the diffusely infiltrating pattern of growth displayed by most gliomas, with malignant cells disseminated far beyond the initial bulky tumor. Although most relapses occur at or near the initial site of tumor, either along the resection margin or at the edge of the radiation field, distant recurrences or seeding of the cerebrospinal fluid (CSF) occurs in long-surviving patients. Malignant gliomas are not a localized disease but instead affect the whole brain and may display wide dissemination even at early stages. Thus, therapeutic strategies aiming only at bulky local disease are doomed to fail. The successful treatments of the future will need to eradicate microscopic disease in many sites within the brain and do so without neurotoxic effects. Here, we summarize progress in the medical treatment of malignant glioma.