Showing papers by "Roger Stupp published in 2011"
TL;DR: This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications, and aims to provide a guide for clinicians confronted with gliobeastoma patients in their everyday practice.
Abstract: Glioblastoma is the most common malignant primary brain tumor in adults. Its often rapid clinical course, with many medical and psychosocial challenges, requires a multidisciplinary management. Modern multimodality treatment and care improve patients' life expectancy and quality of life. This review covers major aspects of care of glioblastoma patients with a focus on the management of common symptoms and complications. We aim to provide a guide for clinicians confronted with glioblastoma patients in their everyday practice.
425 citations
TL;DR: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy, and future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.
Abstract: Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981–22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24–0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53–0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49–0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.
263 citations
European Organisation for Research and Treatment of Cancer1, University of Sydney2, University of Toronto3, University of North Carolina at Chapel Hill4, University of British Columbia5, Medical University of Graz6, Otto-von-Guericke University Magdeburg7, University of Texas Health Science Center at Houston8, University of Regensburg9, University of Freiburg10, University Hospital of Lausanne11
TL;DR: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trials.
138 citations
TL;DR: This study confirmed the prognostic significance of MGMT methylation in GBM and demonstrated the feasibility of tumor tissue collection, molecular stratification and collection of patient outcomes in a large transatlantic intergroup trial and established this as a viable clinical trial paradigm.
Abstract: 2006 Background: Radiotherapy with concomitant and adjuvant TMZ (TMZ/RT→TMZ) is the standard of care for newly diagnosed GBM. MGMT methylation status may be an important determinant of treatment response. Compared with the standard adjuvant TMZ, dd TMZ results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial determined if intensified TMZ improves survival (OS) or progression free survival (PFS). Methods: This phase III trial was conducted by the RTOG, EORTC and NCCTG. Neurologically stable patients with adequate tissue for prospective MGMT analysis were randomized to Arm 1: standard TMZ (150-200 mg/m2 x 5 d) or Arm 2: dd TMZ (75-100 mg/m2 x 21 d) q 4 wks for 6-12 cycles. Symptom, QOL and neurocognitive testing was performed in a subset of patients. The primary endpoint was OS. Secondary analyses evaluated impact of MGMT status. Eligibility criteria included age > 18 yrs, KPS ≥ 60, and tissue block with > 1cm2 tumor. Results: A total of 833 patients were randomize...
119 citations
TL;DR: Evidence is provided that WIF1 has tumor suppressing properties that may render glioblastomas sensitive to inhibitors of Wnt signaling, potentially by diverting the tumor cells into a senescence-like state.
Abstract: Gene expression-based prediction of genomic copy number aberrations in the chromosomal region 12q13 to 12q15 that is flanked by MDM2 and CDK4 identified Wnt inhibitory factor 1 (WIF1) as a candidate tumor suppressor gene in glioblastoma. WIF1 encodes a secreted Wnt antagonist and was strongly downregulated in most glioblastomas as compared with normal brain, implying deregulation of Wnt signaling, which is associated with cancer. WIF1 silencing was mediated by deletion (7/69, 10%) or epigenetic silencing by promoter hypermethylation (29/110, 26%). Co-amplification of MDM2 and CDK4 that is present in 10% of glioblastomas was associated in most cases with deletion of the whole genomic region enclosed, including the WIF1 locus. This interesting pathogenetic constellation targets the RB and p53 tumor suppressor pathways in tandem, while simultaneously activating oncogenic Wnt signaling.
96 citations
TL;DR: Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology, and is currently under evaluation in a pivotal, randomized Phase III study for newly diagnosed GBM.
Abstract: Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανβ3 and ανβ5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.
92 citations
TL;DR: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele, raising the question of the clinically relevant cutoff of MGMT methylation therapy.
Abstract: Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase ( MGMT ) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity. Results: In glioblastoma, MGMT -methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception ( MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity. Conclusions: In MGMT -methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255–66. ©2010 AACR .
80 citations
TL;DR: Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration, and no evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected.
38 citations
TL;DR: The results show that cancer cells can program proangiogenic activity in CD11b(+) myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner and impact breast cancer biology, detection, and treatment.
Abstract: Tumor-mobilized bone marrow-derived CD11b(+) myeloid cells promote tumor angiogenesis, but how and when these cells acquire proangiogenic properties is not fully elucidated. Here, we show that CD11b(+) myelomonocytic cells develop proangiogenic properties during their differentiation from CD34(+) hematopoietic progenitors and that placenta growth factor (PlGF) is critical in promoting this education. Cultures of human CD34(+) progenitors supplemented with conditioned medium from breast cancer cell lines or PlGF, but not from nontumorigenic breast epithelial lines, generate CD11b(+) cells capable of inducing endothelial cell sprouting in vitro and angiogenesis in vivo. An anti-Flt-1 mAb or soluble Flt-1 abolished the generation of proangiogenic activity during differentiation from progenitor cells. Moreover, inhibition of metalloproteinase activity, but not VEGF, during the endothelial sprouting assay blocked sprouting induced by these proangiogenic CD11b(+) myelomonocytes. In a mouse model of breast cancer, circulating CD11b(+) cells were proangiogenic in the sprouting assays. Silencing of PlGF in tumor cells prevented the generation of proangiogenic activity in circulating CD11b(+) cells, inhibited tumor blood flow, and slowed tumor growth. Peripheral blood of breast cancer patients at diagnosis, but not of healthy individuals, contained elevated levels of PlGF and circulating proangiogenic CD11b(+) myelomonocytes. Taken together, our results show that cancer cells can program proangiogenic activity in CD11b(+) myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner. These findings impact breast cancer biology, detection, and treatment.
35 citations
TL;DR: Preclinical and clinical data on integrin inhibition in malignant gliomas, including cilengitide, which appeared to prolong progression-free and overall survival in patients with newly diagnosed glioblastomas and methylation of the promoter of the O⁶ methylguanine methyltransferase (MGMT) gene, are reviewed.
Abstract: The tumor environment is critical for tumor maintenance and progression. Integrins are a large family of cell surface receptors mediating the interaction of tumor cells with their microenvironment and play important roles in glioma biology, including migration, invasion, angiogenesis and tumor stem cell anchorage. Here, we review preclinical and clinical data on integrin inhibition in malignant gliomas. Various pharmacological approaches to the modulation of integrin signaling have been explored including antibodies and peptide- based agents. Cilengitide, a cyclic RGD-mimetic peptide of αvβ3 and αvβ5 integrins is in advanced clinical development in glioblastoma. Cilengitide had only limited activity as a single agent in glioblastoma, but, when added to standard radiochemotherapy, appeared to prolong progression-free and overall survival in patients with newly diagnosed glioblastomas and methylation of the promoter of the O6 methylguanine methyltransferase (MGMT) gene. MGMT gene promoter methylation in turn predicts benefit from alkylating chemotherapy. A phase III randomized clinical trial in conjunction with standard radiochemotherapy in newly diagnosed glioblastoma patients with MGMT gene promoter methylation has recently completed accrual (EORTC 26071-22072). A companion trial explores a dose-escalated regimen of cilengitide added to radiotherapy plus temozolomide in patients without MGMT gene promoter methylation. Promising results in these trials would probably result in a broader interest in integrins as targets for glioma therapy and hopefully the development of a broader panel of anti-integrin agents.
34 citations
TL;DR: New molecular subgroups will help tailor treatment and further develop new targeted therapies in adult medulloblastomas patients and should be complemented with new molecular prognostic markers.
Abstract: PURPOSE OF REVIEW Medulloblastomas are very rare in adults. Usual treatment consists of craniospinal radiation with or without chemotherapy. Current efforts focus on a better understanding of tumour biology, stratifying patients into risk groups and adapting treatment accordingly. This review discusses clinical and new molecular risk factors that will help to optimize treatment in adult medulloblastoma patients. RECENT FINDINGS The clinical risk stratification should be complemented with new molecular prognostic markers. Gene-expression profiling has permitted identification of four to six molecular medulloblastoma subgroups. The WNT subgroup shows overexpression of genes of the WNT/wingless signalling pathway with frequent mutations of the CNNTB1 gene, loss of chromosome 6 and accumulation of nuclear β-catenin, and is most often seen in children with medulloblastomas of classical histology. This variant has a good prognosis. Activation of the sonic hedgehog pathway with frequent mutations of the PTCH and SUFU genes, loss of 9q, and positivity for GLI1 and SFRP1 is more frequent in children less than 3 years old and in adults, commonly associated with desmoplastic histology. Other subgroups are not so well defined and have overlapping characteristics, but MYC/MYCN amplification, 17q gain and, large cell/anaplastic histology are factors of poor prognosis. SUMMARY New molecular subgroups will help tailor treatment and further develop new targeted therapies. Prospective and ideally randomized trials should be performed in adults, including risk stratification by molecular markers, to identify optimal treatment for each risk group.
TL;DR: In this article, the authors developed a resolutely therapeutic approach for grade-II glioblastoma multiforme (GBM) grade II gliomas, where the objective is to avoid malignant transformation as long as possible while preserving the quality of life.
Abstract: A better understanding of the natural history of World Health Organization (WHO) grade-II gliomas (ie the regular progression, the infiltration along white matter tracts and especially the risk of anaplastic transformation, which are function- or life-threatening), associated with reduced treatment risks, has modified the standard "no-treatment" approach in a resolutely therapeutic approach. From now on, the aim is to work towards the elaboration of real therapeutic strategies adapted to each patient, ie to determine the sequence and timing for each treatment (first or even second surgical excision, first or even second line of chemotherapy, radiotherapy) according to tumour progression (assessed using routine MRI examinations), according to the clinical and neuropsychological status as well as to the individual brain anatomic and functional organization (assessed with mapping techniques). The objective is to avoid malignant transformation as long as possible while preserving the quality of life, since this tumour mostly occurs in young patients having a family life and a regular social and professional activity.
TL;DR: Changes in total and subset lymphocyte counts were time- and in some cases dose-related and reflected common IL2 effects, and effects on immune function were consistent with those of IL2.
Abstract: 2556 Background: EMD 273066 (humanized KS‐interleukin‐2 [huKS-IL2]) is an immunocytokine consisting of a humanized antibody specific for EpCAM fused at its Fc end to two molecules of interleukin‐2 ...
21 Sep 2011
TL;DR: The objective is to avoid malignant transformation as long as possible while preserving the quality of life, since this tumour mostly occurs in young patients having a family life and a regular social and professional activity.
Abstract: A better understanding of the natural history of World Health Organization (WHO) grade-II gliomas (ie the regular progression, the infiltration along white matter tracts and especially the risk of anaplastic transformation, which are function- or life-threatening), associated with reduced treatment risks, has modified the standard "no-treatment" approach in a resolutely therapeutic approach. From now on, the aim is to work towards the elaboration of real therapeutic strategies adapted to each patient, ie to determine the sequence and timing for each treatment (first or even second surgical excision, first or even second line of chemotherapy, radiotherapy) according to tumour progression (assessed using routine MRI examinations), according to the clinical and neuropsychological status as well as to the individual brain anatomic and functional organization (assessed with mapping techniques). The objective is to avoid malignant transformation as long as possible while preserving the quality of life, since this tumour mostly occurs in young patients having a family life and a regular social and professional activity.